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Sample records for genotype-dependent tumor regression

  1. Blockade of Notch Signaling in Tumor-Bearing Mice May Lead to Tumor Regression, Progression, or Metastasis, Depending on Tumor Cell Types

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    Xing-Bin Hu

    2009-01-01

    Full Text Available It has been reported that blocking Notch signaling in tumor-bearing mice results in abortive angiogenesis and tumor regression. However, given that Notch signaling influences numerous cellular processes in vivo, a comprehensive evaluation of the effect of Notch inactivation on tumor growth would be favorable. In this study, we inoculated four cancer cell lines in mice with the conditional inactivation of recombination signal-binding protein-Jκ (RBP-J, which mediates signaling from all four mammalian Notch receptors. We found that whereas three tumors including hepatocarcinoma, lung cancer, and osteogenic sarcoma grew slower in the RBP-J-deficient mice, at least a melanoma, B16, grew significantly faster in the RBP-J-deficient mice than in the controls, suggesting that the RBP-J-deficient hosts could provide permissive cues for tumor growth. All these tumors showed increased microvessels and up-regulated hypoxia-inducible factor 1α, suggesting that whereas defective angiogenesis resulted in hypoxia, different tumors might grow differentially in the RBP-J-deleted mice. Similarly, increased infiltration of Gr1+/Mac1+ cells were noticed in tumors grown in the RBP-J-inactivated mice. Moreover, we found that when inoculated in the RBP-J knockout hosts, the H22 hepatoma cells had a high frequency of metastasis and lethality, suggesting that at least for H22, deficiency of environmental Notch signaling favored tumor metastasis. Our findings suggested that the general blockade of Notch signaling in tumor-bearing mice could lead to defective angiogenesis in tumors, but depending on tumor cell types, general inhibition of Notch signaling might result in tumor regression, progression, or metastasis.

  2. Tumor regression patterns in retinoblastoma

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    Zafar, S.N.; Siddique, S.N.; Zaheer, N.

    2016-01-01

    To observe the types of tumor regression after treatment, and identify the common pattern of regression in our patients. Study Design: Descriptive study. Place and Duration of Study: Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from October 2011 to October 2014. Methodology: Children with unilateral and bilateral retinoblastoma were included in the study. Patients were referred to Pakistan Institute of Medical Sciences, Islamabad, for chemotherapy. After every cycle of chemotherapy, dilated funds examination under anesthesia was performed to record response of the treatment. Regression patterns were recorded on RetCam II. Results: Seventy-four tumors were included in the study. Out of 74 tumors, 3 were ICRB group A tumors, 43 were ICRB group B tumors, 14 tumors belonged to ICRB group C, and remaining 14 were ICRB group D tumors. Type IV regression was seen in 39.1% (n=29) tumors, type II in 29.7% (n=22), type III in 25.6% (n=19), and type I in 5.4% (n=4). All group A tumors (100%) showed type IV regression. Seventeen (39.5%) group B tumors showed type IV regression. In group C, 5 tumors (35.7%) showed type II regression and 5 tumors (35.7%) showed type IV regression. In group D, 6 tumors (42.9%) regressed to type II non-calcified remnants. Conclusion: The response and success of the focal and systemic treatment, as judged by the appearance of different patterns of tumor regression, varies with the ICRB grouping of the tumor. (author)

  3. Transcriptional profiling provides insights into metronomic cyclophosphamide-activated, innate immune-dependent regression of brain tumor xenografts

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    Doloff, Joshua C; Waxman, David J

    2015-01-01

    Cyclophosphamide treatment on a six-day repeating metronomic schedule induces a dramatic, innate immune cell-dependent regression of implanted gliomas. However, little is known about the underlying mechanisms whereby metronomic cyclophosphamide induces innate immune cell mobilization and recruitment, or about the role of DNA damage and cell stress response pathways in eliciting the immune responses linked to tumor regression. Untreated and metronomic cyclophosphamide-treated human U251 glioblastoma xenografts were analyzed on human microarrays at two treatment time points to identify responsive tumor cell-specific factors and their upstream regulators. Mouse microarray analysis across two glioma models (human U251, rat 9L) was used to identify host factors and gene networks that contribute to the observed immune and tumor regression responses. Metronomic cyclophosphamide increased expression of tumor cell-derived DNA damage, cell stress, and cell death genes, which may facilitate innate immune activation. Increased expression of many host (mouse) immune networks was also seen in both tumor models, including complement components, toll-like receptors, interferons, and cytolysis pathways. Key upstream regulators activated by metronomic cyclophosphamide include members of the interferon, toll-like receptor, inflammatory response, and PPAR signaling pathways, whose activation may contribute to anti-tumor immunity. Many upstream regulators inhibited by metronomic cyclophosphamide, including hypoxia-inducible factors and MAP kinases, have glioma-promoting activity; their inhibition may contribute to the therapeutic effectiveness of the six-day repeating metronomic cyclophosphamide schedule. Large numbers of responsive cytokines, chemokines and immune regulatory genes linked to innate immune cell recruitment and tumor regression were identified, as were several immunosuppressive factors that may contribute to the observed escape of some tumors from metronomic CPA

  4. Analysis of animal experiments of radiation dependent tumor regression in relation to different parameters

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    Heinzel, F.; Mueller-Duysing, W.; Blattman, H.; Bacesa, L.; Rao, K.R.; Mindek, G.

    In order to be able to test the therapeutic value of the pions in comparison with conventional X-rays, analyses of animal experiments with induced tumors, transplantation tumors, and comparative cellular kinetic studies of tissue cultures will be performed. So that differences in radiation effect and a possible superiority of the pion therapy be objectively acknowledged, the reaction systems to be tested must be as homogenous as possible. For this purpose, the dependence of the radiation related regression on various parameters such as sex, age of hosts, environmental factors radiation conditions (intensity, fractionation, and so on), tumor size, and so on, must be investigated on sterile animals in a sterile environment. The experiments should be conducted under conditions as close as possible to clinical ones. For comparison, the reaction of normal tissue (in vitro and in vivo) and of malignant cells in short-time tissue cultures will be analysed. Cellular kinetics, alteration of chromosomes and metabolic activity of the cells will be studied

  5. Risk of new tumors in von Hippel-Lindau patients depends on age and genotype

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Budtz-Jørgensen, Esben; Bisgaard, Søs Marie Luise

    2016-01-01

    PURPOSE: The von Hippel-Lindau (vHL) phenotype is variable, which complicates genetic counseling and surveillance. We describe how the rate of new tumor development varies through the lifetimes of vHL patients and how it is influenced by age and genotype. METHODS: In a national cohort study, we i...... 02 April 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.44....

  6. Longitudinal Studies of Angiogenesis in Hormone-Dependent Shionogi Tumors

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    Trevor P. Wade

    2007-07-01

    Full Text Available Vessel size imaging was used to assess changes in the average vessel size of Shionogi tumors throughout the tumor growth cycle. Changes in R2 and R2* relaxivities caused by the injection of a superparamagnetic contrast agent (ferumoxtran-10 were measured using a 2.35-T animal magnetic resonance imaging system, and average vessel size index (VSI was calculated for each stage of tumor progression: growth, regression, and relapse. Statistical analysis using Spearman rank correlation test showed no dependence between vessel size and tumor volume at any stage of the tumor growth cycle. Paired Student's t test was used to assess the statistical significance of the differences in average vessel size for the three stages of the tumor growth cycle. The average VSI for regressing tumors (15.1 ± 6.6 wm was significantly lower than that for growing tumors (35.2 ± 25.5 μm; P < .01. Relapsing tumors also had an average VSI (45.4 ± 41.8 μm higher than that of regressing tumors, although the difference was not statistically significant (P = .067. This study shows that VSI imaging is a viable method for the noninvasive monitoring of angiogenesis during the progression of a Shionogi tumor from androgen dependence to androgen independence.

  7. Do clinical data and human papilloma virus genotype influence spontaneous regression in grade I cervical intraepithelial neoplasia?

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    Cortés-Alaguero, Caterina; González-Mirasol, Esteban; Morales-Roselló, José; Poblet-Martinez, Enrique

    2017-03-15

    To determine whether medical history, clinical examination and human papilloma virus (HPV) genotype influence spontaneous regression in cervical intraepithelial neoplasia grade I (CIN-I). We retrospectively evaluated 232 women who were histologically diagnosed as have CIN-I by means of Kaplan-Meier curves, the pattern of spontaneous regression according to the medical history, clinical examination, and HPV genotype. Spontaneous regression occurred in most patients and was influenced by the presence of multiple HPV genotypes but not by the HPV genotype itself. In addition, regression frequency was diminished when more than 50% of the cervix surface was affected or when an abnormal cytology was present at the beginning of follow-up. The frequency of regression in CIN-I is high, making long-term follow-up and conservative management advisable. Data from clinical examination and HPV genotyping might help to anticipate which lesions will regress.

  8. Filter Paper-based Nucleic Acid Storage in High-throughput Solid Tumor Genotyping.

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    Stachler, Matthew; Jia, Yonghui; Sharaf, Nematullah; Wade, Jacqueline; Longtine, Janina; Garcia, Elizabeth; Sholl, Lynette M

    2015-01-01

    Molecular testing of tumors from formalin-fixed paraffin-embedded (FFPE) tissue blocks is central to clinical practice; however, it requires histology support and increases test turnaround time. Prospective fresh frozen tissue collection requires special handling, additional storage space, and may not be feasible for small specimens. Filter paper-based collection of tumor DNA reduces the need for histology support, requires little storage space, and preserves high-quality nucleic acid. We investigated the performance of tumor smears on filter paper in solid tumor genotyping, as compared with paired FFPE samples. Whatman FTA Micro Card (FTA preps) smears were prepared from 21 fresh tumor samples. A corresponding cytology smear was used to assess tumor cellularity and necrosis. DNA was isolated from FTA preps and FFPE core samples using automated methods and quantified using SYBR green dsDNA detection. Samples were genotyped for 471 mutations on a mass spectrophotometry-based platform (Sequenom). DNA concentrations from FTA preps and FFPE correlated for untreated carcinomas but not for mesenchymal tumors (Spearman σ=0.39 and σ=-0.1, respectively). Average DNA concentrations were lower from FTA preps as compared with FFPE, but DNA quality was higher with less fragmentation. Seventy-six percent of FTA preps and 86% of FFPE samples generated adequate DNA for genotyping. FTA preps tended to perform poorly for collection of DNA from pretreated carcinomas and mesenchymal neoplasms. Of the 16 paired DNA samples that were genotyped, 15 (94%) gave entirely concordant results. Filter paper-based sample preservation is a feasible alternative to FFPE for use in automated, high-throughput genotyping of carcinomas.

  9. Regression of uveal malignant melanomas following cobalt-60 plaque. Correlates between acoustic spectrum analysis and tumor regression

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    Coleman, D.J.; Lizzi, F.L.; Silverman, R.H.; Ellsworth, R.M.; Haik, B.G.; Abramson, D.H.; Smith, M.E.; Rondeau, M.J.

    1985-01-01

    Parameters derived from computer analysis of digital radio-frequency (rf) ultrasound scan data of untreated uveal malignant melanomas were examined for correlations with tumor regression following cobalt-60 plaque. Parameters included tumor height, normalized power spectrum and acoustic tissue type (ATT). Acoustic tissue type was based upon discriminant analysis of tumor power spectra, with spectra of tumors of known pathology serving as a model. Results showed ATT to be correlated with tumor regression during the first 18 months following treatment. Tumors with ATT associated with spindle cell malignant melanoma showed over twice the percentage reduction in height as those with ATT associated with mixed/epithelioid melanomas. Pre-treatment height was only weakly correlated with regression. Additionally, significant spectral changes were observed following treatment. Ultrasonic spectrum analysis thus provides a noninvasive tool for classification, prediction and monitoring of tumor response to cobalt-60 plaque

  10. Apoptosis in the transplanted canine transmissible venereal tumor during growth and regression phases Apoptose no tumor venéreo transmissível canino durante as fases de crescimento e regressão

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    F.G.A. Santos

    2008-06-01

    Full Text Available Twelve male, mongrel, adult dogs were subcutaneously transplanted with cells originated from two canine transmissible venereal tumors (TVT. The aim was to demonstrate and to quantify the occurrence of apoptosis in the TVT regression. After six months of transplantation, a tumor sample was obtained from each dog, being six dogs with TVT in the growing phase and six in the regression phase as verified by daily measurements. Samples were processed for histological and ultrastructural purposes as well as for DNA extraction. Sections of 4µm were stained by HE, Shorr, methyl green pyronine, Van Gieson, TUNEL reaction and immunostained for P53. The Shorr stained sections went through morphometry that demonstrated an increase of the apoptotic cells per field in the regressive tumors. It was also confirmed by transmission electron microscopy, which showed cells with typical morphology of apoptosis and by the TUNEL reaction that detected in situ the 3'OH nick end labeling mainly in the regressive tumors. The regressive TVTs also showed an intensified immunostaining for P53 besides a more intense genomic DNA fragmentation detected by the agarose gel electrophoresis. In conclusion, apoptosis has an important role in the regression of the experimental TVT in a way that is P53-dependent.Doze cães, adultos, machos e sem raça definida foram transplantados subcutaneamente, na região hipogástrica, com células originadas de dois tumores venéreos transmissíveis caninos (TVT. O objetivo do estudo foi demonstrar e quantificar a ocorrência de apoptose na regressão do TVT. Após seis meses, foi obtido um tumor de cada animal, totalizando seis em crescimento e seis em regressão. Fragmentos dos tumores foram processados para avaliação histológica, ultra-estrutural e também para extração de DNA. Cortes de 4µm foram corados em HE, Shorr, verde de metila pironina e Van Gieson e alguns foram submetidos à reação do TUNEL e à imunoistoquímica para P53

  11. TumorBoost: Normalization of allele-specific tumor copy numbers from a single pair of tumor-normal genotyping microarrays

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    Neuvial Pierre

    2010-05-01

    Full Text Available Abstract Background High-throughput genotyping microarrays assess both total DNA copy number and allelic composition, which makes them a tool of choice for copy number studies in cancer, including total copy number and loss of heterozygosity (LOH analyses. Even after state of the art preprocessing methods, allelic signal estimates from genotyping arrays still suffer from systematic effects that make them difficult to use effectively for such downstream analyses. Results We propose a method, TumorBoost, for normalizing allelic estimates of one tumor sample based on estimates from a single matched normal. The method applies to any paired tumor-normal estimates from any microarray-based technology, combined with any preprocessing method. We demonstrate that it increases the signal-to-noise ratio of allelic signals, making it significantly easier to detect allelic imbalances. Conclusions TumorBoost increases the power to detect somatic copy-number events (including copy-neutral LOH in the tumor from allelic signals of Affymetrix or Illumina origin. We also conclude that high-precision allelic estimates can be obtained from a single pair of tumor-normal hybridizations, if TumorBoost is combined with single-array preprocessing methods such as (allele-specific CRMA v2 for Affymetrix or BeadStudio's (proprietary XY-normalization method for Illumina. A bounded-memory implementation is available in the open-source and cross-platform R package aroma.cn, which is part of the Aroma Project (http://www.aroma-project.org/.

  12. Shigella mediated depletion of macrophages in a murine breast cancer model is associated with tumor regression.

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    Katharina Galmbacher

    Full Text Available A tumor promoting role of macrophages has been described for a transgenic murine breast cancer model. In this model tumor-associated macrophages (TAMs represent a major component of the leukocytic infiltrate and are associated with tumor progression. Shigella flexneri is a bacterial pathogen known to specificly induce apotosis in macrophages. To evaluate whether Shigella-induced removal of macrophages may be sufficient for achieving tumor regression we have developed an attenuated strain of S. flexneri (M90TDeltaaroA and infected tumor bearing mice. Two mouse models were employed, xenotransplantation of a murine breast cancer cell line and spontanous breast cancer development in MMTV-HER2 transgenic mice. Quantitative analysis of bacterial tumor targeting demonstrated that attenuated, invasive Shigella flexneri primarily infected TAMs after systemic administration. A single i.v. injection of invasive M90TDeltaaroA resulted in caspase-1 dependent apoptosis of TAMs followed by a 74% reduction in tumors of transgenic MMTV-HER-2 mice 7 days post infection. TAM depletion was sustained and associated with complete tumor regression.These data support TAMs as useful targets for antitumor therapy and highlight attenuated bacterial pathogens as potential tools.

  13. Establishment of regression dependences. Linear and nonlinear dependences

    International Nuclear Information System (INIS)

    Onishchenko, A.M.

    1994-01-01

    The main problems of determination of linear and 19 types of nonlinear regression dependences are completely discussed. It is taken into consideration that total dispersions are the sum of measurement dispersions and parameter variation dispersions themselves. Approaches to all dispersions determination are described. It is shown that the least square fit gives inconsistent estimation for industrial objects and processes. The correction methods by taking into account comparable measurement errors for both variable give an opportunity to obtain consistent estimation for the regression equation parameters. The condition of the correction technique application expediency is given. The technique for determination of nonlinear regression dependences taking into account the dependence form and comparable errors of both variables is described. 6 refs., 1 tab

  14. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site.

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    Antonescu, Cristina R; Viale, Agnes; Sarran, Lisa; Tschernyavsky, Sylvia J; Gonen, Mithat; Segal, Neil H; Maki, Robert G; Socci, Nicholas D; DeMatteo, Ronald P; Besmer, Peter

    2004-05-15

    Gastrointestinal stromal tumors (GISTs) are specific KIT expressing and KIT-signaling driven mesenchymal tumors of the human digestive tract, many of which have KIT-activating mutations. Previous studies have found a relatively homogeneous gene expression profile in GIST, as compared with other histological types of sarcomas. Transcriptional heterogeneity within clinically or molecularly defined subsets of GISTs has not been previously reported. We tested the hypothesis that the gene expression profile in GISTs might be related to KIT genotype and possibly to other clinicopathological factors. An HG-U133A Affymetrix chip (22,000 genes) platform was used to determine the variability of gene expression in 28 KIT-expressing GIST samples from 24 patients. A control group of six intra-abdominal leiomyosarcomas was also included for comparison. Statistical analyses (t tests) were performed to identify discriminatory gene lists among various GIST subgroups. The levels of expression of various GIST subsets were also linked to a modified version of the growth factor/KIT signaling pathway to analyze differences at various steps in signal transduction. Genes involved in KIT signaling were differentially expressed among wild-type and mutant GISTs. High gene expression of potential drug targets, such as VEGF, MCSF, and BCL2 in the wild-type group, and Mesothelin in exon 9 GISTs were found. There was a striking difference in gene expression between stomach and small bowel GISTs. This finding was validated in four separate tumors, two gastric and two intestinal, from a patient with familial GIST with a germ-line KIT W557R substitution. GISTs have heterogeneous gene expression depending on KIT genotype and tumor location, which is seen at both the genomic level and the KIT signaling pathway in particular. These findings may explain their variable clinical behavior and response to therapy.

  15. HMGB1 mediates endogenous TLR2 activation and brain tumor regression.

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    James F Curtin

    2009-01-01

    Full Text Available Glioblastoma multiforme (GBM is the most aggressive primary brain tumor that carries a 5-y survival rate of 5%. Attempts at eliciting a clinically relevant anti-GBM immune response in brain tumor patients have met with limited success, which is due to brain immune privilege, tumor immune evasion, and a paucity of dendritic cells (DCs within the central nervous system. Herein we uncovered a novel pathway for the activation of an effective anti-GBM immune response mediated by high-mobility-group box 1 (HMGB1, an alarmin protein released from dying tumor cells, which acts as an endogenous ligand for Toll-like receptor 2 (TLR2 signaling on bone marrow-derived GBM-infiltrating DCs.Using a combined immunotherapy/conditional cytotoxic approach that utilizes adenoviral vectors (Ad expressing Fms-like tyrosine kinase 3 ligand (Flt3L and thymidine kinase (TK delivered into the tumor mass, we demonstrated that CD4(+ and CD8(+ T cells were required for tumor regression and immunological memory. Increased numbers of bone marrow-derived, tumor-infiltrating myeloid DCs (mDCs were observed in response to the therapy. Infiltration of mDCs into the GBM, clonal expansion of antitumor T cells, and induction of an effective anti-GBM immune response were TLR2 dependent. We then proceeded to identify the endogenous ligand responsible for TLR2 signaling on tumor-infiltrating mDCs. We demonstrated that HMGB1 was released from dying tumor cells, in response to Ad-TK (+ gancyclovir [GCV] treatment. Increased levels of HMGB1 were also detected in the serum of tumor-bearing Ad-Flt3L/Ad-TK (+GCV-treated mice. Specific activation of TLR2 signaling was induced by supernatants from Ad-TK (+GCV-treated GBM cells; this activation was blocked by glycyrrhizin (a specific HMGB1 inhibitor or with antibodies to HMGB1. HMGB1 was also released from melanoma, small cell lung carcinoma, and glioma cells treated with radiation or temozolomide. Administration of either glycyrrhizin or anti

  16. Regression analysis using dependent Polya trees.

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    Schörgendorfer, Angela; Branscum, Adam J

    2013-11-30

    Many commonly used models for linear regression analysis force overly simplistic shape and scale constraints on the residual structure of data. We propose a semiparametric Bayesian model for regression analysis that produces data-driven inference by using a new type of dependent Polya tree prior to model arbitrary residual distributions that are allowed to evolve across increasing levels of an ordinal covariate (e.g., time, in repeated measurement studies). By modeling residual distributions at consecutive covariate levels or time points using separate, but dependent Polya tree priors, distributional information is pooled while allowing for broad pliability to accommodate many types of changing residual distributions. We can use the proposed dependent residual structure in a wide range of regression settings, including fixed-effects and mixed-effects linear and nonlinear models for cross-sectional, prospective, and repeated measurement data. A simulation study illustrates the flexibility of our novel semiparametric regression model to accurately capture evolving residual distributions. In an application to immune development data on immunoglobulin G antibodies in children, our new model outperforms several contemporary semiparametric regression models based on a predictive model selection criterion. Copyright © 2013 John Wiley & Sons, Ltd.

  17. Context-dependent effects of genome-wide association study genotypes and macroenvironment on time to biochemical (prostate specific antigen) failure after prostatectomy.

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    Rebbeck, Timothy R; Weber, Anita L; Walker, Amy H; Stefflova, Klara; Tran, Teo V; Spangler, Elaine; Chang, Bao-Li; Zeigler-Johnson, Charnita M

    2010-09-01

    Disparities in cancer defined by race, age, or gender are well established. However, demographic metrics are surrogates for the complex contributions of genotypes, exposures, health care, socioeconomic and sociocultural environment, and many other factors. Macroenvironmental factors represent novel surrogates for exposures, lifestyle, and other factors that are difficult to measure but might influence cancer outcomes. We applied a "multilevel molecular epidemiology" approach using a prospective cohort of 444 White prostate cancer cases who underwent prostatectomy and were followed until biochemical failure (BF) or censoring without BF. We applied Cox regression models to test for joint effects of 86 genome-wide association study-identified genotypes and macroenvironment contextual effects after geocoding all cases to their residential census tracts. All analyses were adjusted for age at diagnosis and tumor aggressiveness. Residents living in census tracts with a high proportion of older single heads of household, high rates of vacant housing, or high unemployment had shorter time until BF postsurgery after adjustment for patient age and tumor aggressiveness. After correction for multiple testing, genotypes alone did not predict time to BF, but interactions predicting time to BF were observed for MSMB (rs10993994) and percentage of older single heads of households (P = 0.0004), and for HNF1B/TCF2 (rs4430796) and census tract per capita income (P = 0.0002). The context-specific macroenvironmental effects of genotype might improve the ability to identify groups that might experience poor prostate cancer outcomes. Risk estimation and clinical translation of genotype information might require an understanding of both individual- and macroenvironment-level context. (c) 2010 AACR.

  18. Predicting respiratory tumor motion with multi-dimensional adaptive filters and support vector regression

    International Nuclear Information System (INIS)

    Riaz, Nadeem; Wiersma, Rodney; Mao Weihua; Xing Lei; Shanker, Piyush; Gudmundsson, Olafur; Widrow, Bernard

    2009-01-01

    Intra-fraction tumor tracking methods can improve radiation delivery during radiotherapy sessions. Image acquisition for tumor tracking and subsequent adjustment of the treatment beam with gating or beam tracking introduces time latency and necessitates predicting the future position of the tumor. This study evaluates the use of multi-dimensional linear adaptive filters and support vector regression to predict the motion of lung tumors tracked at 30 Hz. We expand on the prior work of other groups who have looked at adaptive filters by using a general framework of a multiple-input single-output (MISO) adaptive system that uses multiple correlated signals to predict the motion of a tumor. We compare the performance of these two novel methods to conventional methods like linear regression and single-input, single-output adaptive filters. At 400 ms latency the average root-mean-square-errors (RMSEs) for the 14 treatment sessions studied using no prediction, linear regression, single-output adaptive filter, MISO and support vector regression are 2.58, 1.60, 1.58, 1.71 and 1.26 mm, respectively. At 1 s, the RMSEs are 4.40, 2.61, 3.34, 2.66 and 1.93 mm, respectively. We find that support vector regression most accurately predicts the future tumor position of the methods studied and can provide a RMSE of less than 2 mm at 1 s latency. Also, a multi-dimensional adaptive filter framework provides improved performance over single-dimension adaptive filters. Work is underway to combine these two frameworks to improve performance.

  19. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors.

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    Deng, Liufu; Liang, Hua; Xu, Meng; Yang, Xuanming; Burnette, Byron; Arina, Ainhoa; Li, Xiao-Dong; Mauceri, Helena; Beckett, Michael; Darga, Thomas; Huang, Xiaona; Gajewski, Thomas F; Chen, Zhijian J; Fu, Yang-Xin; Weichselbaum, Ralph R

    2014-11-20

    Ionizing radiation-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response, but several pathways control I IFN induction. Here, we demonstrate that adaptor protein STING, but not MyD88, is required for type I IFN-dependent antitumor effects of radiation. In dendritic cells (DCs), STING was required for IFN-? induction in response to irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) mediated sensing of irradiated-tumor cells in DCs. Moreover, STING was essential for radiation-induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-? treatment rescued the cross-priming by cGAS or STING-deficient DCs. Accordingly, activation of STING by a second messenger cGAMP administration enhanced antitumor immunity induced by radiation. Thus radiation-mediated antitumor immunity in immunogenic tumors requires a functional cytosolic DNA-sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxycitrate, lipoic acid and capsaicin.

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    Schwartz, Laurent; Guais, Adeline; Israël, Maurice; Junod, Bernard; Steyaert, Jean-Marc; Crespi, Elisabetta; Baronzio, Gianfranco; Abolhassani, Mohammad

    2013-04-01

    Cellular metabolic alterations are now well described as implicated in cancer and some strategies are currently developed to target these different pathways. In previous papers, we demonstrated that a combination of molecules (namely alpha-lipoic acid and hydroxycitrate, i.e. Metabloc™) targeting the cancer metabolism markedly decreased tumor cell growth in mice. In this work, we demonstrate that the addition of capsaicin further delays tumor growth in mice in a dose dependant manner. This is true for the three animal model tested: lung (LLC) cancer, bladder cancer (MBT-2) and melanoma B16F10. There was no apparent side effect of this ternary combination. The addition of a fourth drug (octreotide) is even more effective resulting in tumor regression in mice bearing LLC cancer. These four compounds are all known to target the cellular metabolism not its DNA. The efficacy, the apparent lack of toxicity, the long clinical track records of these medications in human medicine, all points toward the need for a clinical trial. The dramatic efficacy of treatment suggests that cancer may simply be a disease of dysregulated cellular metabolism.

  1. Context-Dependent Effects of Genome-Wide Association Study Genotypes and Macro-Environmental Factors on Time to Biochemical (PSA) Failure after Prostatectomy

    Science.gov (United States)

    Rebbeck, Timothy R.; Weber, Anita L.; Walker, Amy H.; Stefflova, Klara; Tran, Teo V.; Spangler, Elaine; Chang, Bao-Li; Zeigler-Johnson, Charnita M.

    2010-01-01

    Background Disparities in cancer defined by race, age, or gender are well established. However, demographic metrics are surrogates for the complex contributions of genotypes, exposures, health care, socioeconomic and sociocultural environment, and many other factors. Macro-environmental factors represent novel surrogates for exposures, lifestyle and other factors that are difficult to measure but may influence cancer outcomes. Methods We applied a “multilevel molecular epidemiology” approach using a prospective cohort of 444 White prostate cancer cases who underwent prostatectomy and were followed until biochemical failure (BF) or censoring without BF. We applied Cox regression models to test for joint effects of 86 genome-wide association study-identified genotypes and macro-environmental contextual effects after geocoding all cases to their residential census tracts. All analyses were adjusted for age at diagnosis and tumor aggressiveness. Results Residents living in macroenvironments with a high proportion of older single heads of household, high rates of vacant housing, or high unemployment had shorter time until BF post-surgery after adjustment for patient age and tumor aggressiveness. After correction for multiple testing, genotypes alone did not predict time to BF, but interactions predicting time to BF were observed for MSMB (rs10993994) and percent of older single head of households (p=0.0004), and for HNF1B/TCF2 (rs4430796) and macroenvironment per capita income (p=0.0002). Conclusions Context-specific macro-environmental effects of genotype may improve the ability to identify groups that may experience poor prostate cancer outcomes. Impact Risk estimation and clinical translation of genotype information may require an understanding of both individual-level and macroenvironmental context. PMID:20826827

  2. Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer.

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    Vanderlaan, Paul A; Yamaguchi, Norihiro; Folch, Erik; Boucher, David H; Kent, Michael S; Gangadharan, Sidharta P; Majid, Adnan; Goldstein, Michael A; Huberman, Mark S; Kocher, Olivier N; Costa, Daniel B

    2014-04-01

    Identification of some somatic molecular alterations in non-small-cell lung cancer (NSCLC) has become evidence-based practice. The success and failure rate of using commercially available tumor genotyping techniques in routine day-to-day NSCLC pathology samples is not well described. We sought to evaluate the success and failure rate of EGFR mutation, KRAS mutation, and ALK FISH in a cohort of lung cancers subjected to routine clinical tumor genotype. Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 381 patient-tumor samples. From these 381 patients with lung cancer, the mean age was 65 years, 61.2% were women, 75.9% were white, 27.8% were never smokers, 73.8% had advanced NSCLC and 86.1% had adenocarcinoma histology. The tumor tissue was obtained from surgical specimens in 48.8%, core needle biopsies in 17.9%, and as cell blocks from aspirates or fluid in 33.3% of cases. Anatomic sites for tissue collection included lung (49.3%), lymph nodes (22.3%), pleura (11.8%), bone (6.0%), brain (6.0%), among others. The overall success rate for EGFR mutation analysis was 94.2%, for KRAS mutation 91.6% and for ALK FISH 91.6%. The highest failure rates were observed when the tissue was obtained from image-guided percutaneous transthoracic core-needle biopsies (31.8%, 27.3%, and 35.3% for EGFR, KRAS, and ALK tests, respectively) and bone specimens (23.1%, 15.4%, and 23.1%, respectively). In specimens obtained from bone, the failure rates were significantly higher for biopsies than resection specimens (40% vs. 0%, p=0.024 for EGFR) and for decalcified compared to non-decalcified samples (60% vs. 5.5%, p=0.021 for EGFR). Tumor genotype techniques are feasible in most samples, outside small image-guided percutaneous transthoracic core-needle biopsies and bone samples from core biopsies with decalcification, and therefore expansion of routine tumor genotype into the care of patients with NSCLC may not require special

  3. Histological Regression of Giant Cell Tumor of Bone Following RANK Ligand Inhibition

    Directory of Open Access Journals (Sweden)

    Martin F. Dietrich MD, PhD

    2014-11-01

    Full Text Available Lung metastases are a rare complication of giant cell tumors of bone. We herein describe an interesting case of histological regression and size reduction of lung metastases originating from a primary giant cell tumor of bone in response to the RANK ligand inhibitor denosumab.

  4. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Directory of Open Access Journals (Sweden)

    Nibedita Chattopadhyay

    Full Text Available In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

  5. KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

    Science.gov (United States)

    Chattopadhyay, Nibedita; Berger, Allison J; Koenig, Erik; Bannerman, Bret; Garnsey, James; Bernard, Hugues; Hales, Paul; Maldonado Lopez, Angel; Yang, Yu; Donelan, Jill; Jordan, Kristen; Tirrell, Stephen; Stringer, Bradley; Xia, Cindy; Hather, Greg; Galvin, Katherine; Manfredi, Mark; Rhodes, Nelson; Amidon, Ben

    2015-01-01

    In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

  6. CYP2D6 genotype dependent oxycodone metabolism in postoperative patients.

    Science.gov (United States)

    Stamer, Ulrike M; Zhang, Lan; Book, Malte; Lehmann, Lutz E; Stuber, Frank; Musshoff, Frank

    2013-01-01

    The impact of polymorphic cytochrome P450 CYP2D6 enzyme on oxycodone's metabolism and clinical efficacy is currently being discussed. However, there are only spare data from postoperative settings. The hypothesis of this study is that genotype dependent CYP2D6 activity influences plasma concentrations of oxycodone and its metabolites and impacts analgesic consumption. Patients received oxycodone 0.05 mg/kg before emerging from anesthesia and patient-controlled analgesia (PCA) for the subsequent 48 postoperative hours. Blood samples were drawn at 30, 90 and 180 minutes after the initial oxycodone dose. Plasma concentrations of oxycodone and its metabolites oxymorphone, noroxycodone and noroxymorphone were analyzed by liquid chromatography-mass spectrometry with electrospray ionization. CYP2D6 genotyping was performed and 121 patients were allocated to the following genotype groups: PM (poor metabolizer: no functionally active CYP2D6 allele), HZ/IM (heterozygous subjects, intermediate metabolizers with decreased CYP2D6 activity), EM (extensive metabolizers, normal CYP2D6 activity) and UM (ultrarapid metabolizers, increased CYP2D6 activity). Primary endpoint was the genotype dependent metabolite ratio of plasma concentrations oxymorphone/oxycodone. Secondary endpoint was the genotype dependent analgesic consumption with calculation of equianalgesic doses compared to the standard non-CYP dependent opioid piritramide. Metabolism differed between CYP2D6 genotypes. Mean (95%-CI) oxymophone/oxycodone ratios were 0.10 (0.02/0.19), 0.13 (0.11/0.16), 0.18 (0.16/0.20) and 0.28 (0.07/0.49) in PM, HZ/IM, EM and UM, respectively (p = 0.005). Oxycodone consumption up to the 12(th) hour was highest in PM (p = 0.005), resulting in lowest equianalgesic doses of piritramide versus oxycodone for PM (1.6 (1.4/1.8); EM and UM 2.2 (2.1/2.3); p<0.001). Pain scores did not differ between genotypes. In this postoperative setting, the number of functionally active CYP2D6 alleles had an impact

  7. CYP2D6 genotype dependent oxycodone metabolism in postoperative patients.

    Directory of Open Access Journals (Sweden)

    Ulrike M Stamer

    Full Text Available BACKGROUND: The impact of polymorphic cytochrome P450 CYP2D6 enzyme on oxycodone's metabolism and clinical efficacy is currently being discussed. However, there are only spare data from postoperative settings. The hypothesis of this study is that genotype dependent CYP2D6 activity influences plasma concentrations of oxycodone and its metabolites and impacts analgesic consumption. METHODS: Patients received oxycodone 0.05 mg/kg before emerging from anesthesia and patient-controlled analgesia (PCA for the subsequent 48 postoperative hours. Blood samples were drawn at 30, 90 and 180 minutes after the initial oxycodone dose. Plasma concentrations of oxycodone and its metabolites oxymorphone, noroxycodone and noroxymorphone were analyzed by liquid chromatography-mass spectrometry with electrospray ionization. CYP2D6 genotyping was performed and 121 patients were allocated to the following genotype groups: PM (poor metabolizer: no functionally active CYP2D6 allele, HZ/IM (heterozygous subjects, intermediate metabolizers with decreased CYP2D6 activity, EM (extensive metabolizers, normal CYP2D6 activity and UM (ultrarapid metabolizers, increased CYP2D6 activity. Primary endpoint was the genotype dependent metabolite ratio of plasma concentrations oxymorphone/oxycodone. Secondary endpoint was the genotype dependent analgesic consumption with calculation of equianalgesic doses compared to the standard non-CYP dependent opioid piritramide. RESULTS: Metabolism differed between CYP2D6 genotypes. Mean (95%-CI oxymophone/oxycodone ratios were 0.10 (0.02/0.19, 0.13 (0.11/0.16, 0.18 (0.16/0.20 and 0.28 (0.07/0.49 in PM, HZ/IM, EM and UM, respectively (p = 0.005. Oxycodone consumption up to the 12(th hour was highest in PM (p = 0.005, resulting in lowest equianalgesic doses of piritramide versus oxycodone for PM (1.6 (1.4/1.8; EM and UM 2.2 (2.1/2.3; p<0.001. Pain scores did not differ between genotypes. CONCLUSIONS: In this postoperative setting, the number of

  8. Prognostic value of tumor regression evaluated after first course of radiotherapy for anal canal cancer

    International Nuclear Information System (INIS)

    Chapet, Olivier; Gerard, Jean-Pierre; Riche, Benjamin; Alessio, Annunziato; Mornex, Francoise; Romestaing, Pascale

    2005-01-01

    Purpose: To evaluate whether the tumor response after an initial course of irradiation predicts for colostomy-free survival and overall survival in patients with anal canal cancer. Methods and Materials: Between 1980 and 1998, 252 patients were treated by pelvic external-beam radiotherapy (EBRT) followed by a brachytherapy boost in 218 or EBRT in 34. EBRT was combined with chemotherapy in 168 patients. An evaluation of tumor regression, before the boost, was available for 221 patients. They were divided into four groups according to the tumor response: 80% but 80% vs. ≤80%. The group with a T3-T4 lesion and tumor regression ≤80% had the poorest overall (52.8% ± 12.3%), disease-free (19.9% ± 9.9%), and colostomy-free survival (24.8% ± 11.2%) rates. Conclusion: The amount of tumor regression before EBRT or brachytherapy boost is a strong prognostic factor of disease control without colostomy. When regression is ≤80% in patients with an initial T3-T4 lesion, the use of conservative RT should be carefully evaluated because of the very poor disease-free and colostomy-free survival

  9. Cloning and Characterizing Genes Involved in Monoterpene Induced Mammary Tumor Regression.

    Science.gov (United States)

    1996-10-01

    AD GRANT NUMBER DAMDI7-94-J-4041 TITLE: Cloning and Characterizing Genes Involved in Monoterpene Induced Mammary Tumor Regression PRINCIPAL...October 1996 Annual (1 Sep 95 - 31 Aug 96) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Cloning and Characterizing Genes Involved in Monoterpene Induced... Monoterpene -induced/repressed genes were identified in regressing rat mammary carcinomas treated with dietary limonene using a newly developed method

  10. Methylated DNA for monitoring tumor growth and regression

    DEFF Research Database (Denmark)

    Kristiansen, Søren; Nielsen, Dorte; Söletormos, Georg

    2014-01-01

    Abstract A wide range of protein cancer biomarkers is currently recommended in international guidelines for monitoring the growth and regression of solid tumors. However, a number of these markers are also present in low concentrations in blood obtained from healthy individuals and from patients...... of gene promoters. Because tumor cells naturally secrete DNA and upon cell death leak DNA, modified methylated DNA can be detected in blood, urine, sputum and other body fluids. At present international guidelines do not include recommendations for monitoring modified methylated DNA. The low level...... of evidence can partly be explained by incomplete collection of serial blood samples, by analytical challenges, and by lack of knowledge of how monitoring studies should be designed and how serial marker data obtained from individual patients should be interpreted. Here, we review the clinical validity...

  11. Detection of high GS risk group prostate tumors by diffusion tensor imaging and logistic regression modelling.

    Science.gov (United States)

    Ertas, Gokhan

    2018-07-01

    To assess the value of joint evaluation of diffusion tensor imaging (DTI) measures by using logistic regression modelling to detect high GS risk group prostate tumors. Fifty tumors imaged using DTI on a 3 T MRI device were analyzed. Regions of interests focusing on the center of tumor foci and noncancerous tissue on the maps of mean diffusivity (MD) and fractional anisotropy (FA) were used to extract the minimum, the maximum and the mean measures. Measure ratio was computed by dividing tumor measure by noncancerous tissue measure. Logistic regression models were fitted for all possible pair combinations of the measures using 5-fold cross validation. Systematic differences are present for all MD measures and also for all FA measures in distinguishing the high risk tumors [GS ≥ 7(4 + 3)] from the low risk tumors [GS ≤ 7(3 + 4)] (P Logistic regression modelling provides a favorable solution for the joint evaluations easily adoptable in clinical practice. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Reducing false-positive incidental findings with ensemble genotyping and logistic regression based variant filtering methods.

    Science.gov (United States)

    Hwang, Kyu-Baek; Lee, In-Hee; Park, Jin-Ho; Hambuch, Tina; Choe, Yongjoon; Kim, MinHyeok; Lee, Kyungjoon; Song, Taemin; Neu, Matthew B; Gupta, Neha; Kohane, Isaac S; Green, Robert C; Kong, Sek Won

    2014-08-01

    As whole genome sequencing (WGS) uncovers variants associated with rare and common diseases, an immediate challenge is to minimize false-positive findings due to sequencing and variant calling errors. False positives can be reduced by combining results from orthogonal sequencing methods, but costly. Here, we present variant filtering approaches using logistic regression (LR) and ensemble genotyping to minimize false positives without sacrificing sensitivity. We evaluated the methods using paired WGS datasets of an extended family prepared using two sequencing platforms and a validated set of variants in NA12878. Using LR or ensemble genotyping based filtering, false-negative rates were significantly reduced by 1.1- to 17.8-fold at the same levels of false discovery rates (5.4% for heterozygous and 4.5% for homozygous single nucleotide variants (SNVs); 30.0% for heterozygous and 18.7% for homozygous insertions; 25.2% for heterozygous and 16.6% for homozygous deletions) compared to the filtering based on genotype quality scores. Moreover, ensemble genotyping excluded > 98% (105,080 of 107,167) of false positives while retaining > 95% (897 of 937) of true positives in de novo mutation (DNM) discovery in NA12878, and performed better than a consensus method using two sequencing platforms. Our proposed methods were effective in prioritizing phenotype-associated variants, and an ensemble genotyping would be essential to minimize false-positive DNM candidates. © 2014 WILEY PERIODICALS, INC.

  13. Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression

    Directory of Open Access Journals (Sweden)

    Chong-Sheng Chen

    2014-01-01

    Full Text Available Metronomic chemotherapy using cyclophosphamide (CPA is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25% reduction in CPA dose. Moreover, an ~20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses.

  14. SU-F-J-64: Comparison of Dosimetric Robustness Between Proton Therapy and IMRT Plans Following Tumor Regression for Locally Advanced Non-Small Cell Lung Cancer (NSCLC)

    Energy Technology Data Exchange (ETDEWEB)

    Teng, C; Ainsley, C; Teo, B; Burgdorf, B; Berman, A; Levin, W; Xiao, Y; Lin, L; Simone, C; Solberg, T [University of Pennsylvania, Philadelphia, PA (United States); Janssens, G [IBA, Louvain-la-Neuve (Belgium)

    2016-06-15

    Purpose: In the light of tumor regression and normal tissue changes, dose distributions can deviate undesirably from what was planned. As a consequence, replanning is sometimes necessary during treatment to ensure continued tumor coverage or to avoid overdosing organs at risk (OARs). Proton plans are generally thought to be less robust than photon plans because of the proton beam’s higher sensitivity to changes in tissue composition, suggesting also a higher likely replanning rate due to tumor regression. The purpose of this study is to compare dosimetric deviations between forward-calculated double scattering (DS) proton plans with IMRT plans upon tumor regression, and assesses their impact on clinical replanning decisions. Methods: Ten consecutive locally advanced NSCLC patients whose tumors shrank > 50% in volume and who received four or more CT scans during radiotherapy were analyzed. All the patients received proton radiotherapy (6660 cGy, 180 cGy/fx). Dosimetric robustness during therapy was characterized by changes in the planning objective metrics as well as by point-by-point root-mean-squared differences for the entire PTV, ITV, and OARs (heart, cord, esophagus, brachial plexus and lungs) DVHs. Results: Sixty-four pairs of DVHs were reviewed by three clinicians, who requested a replanning rate of 16.7% and 18.6% for DS and IMRT plans, respectively, with a high agreement between providers. Robustness of clinical indicators was found to depend on the beam orientation and dose level on the DVH curve. Proton dose increased most in OARs distal to the PTV along the beam path, but these changes were primarily in the mid to low dose levels. In contrast, the variation in IMRT plans occurred primarily in the high dose region. Conclusion: Robustness of clinical indicators depends where on the DVH curves comparisons are made. Similar replanning rates were observed for DS and IMRT plans upon large tumor regression.

  15. Logistic regression models for polymorphic and antagonistic pleiotropic gene action on human aging and longevity

    DEFF Research Database (Denmark)

    Tan, Qihua; Bathum, L; Christiansen, L

    2003-01-01

    In this paper, we apply logistic regression models to measure genetic association with human survival for highly polymorphic and pleiotropic genes. By modelling genotype frequency as a function of age, we introduce a logistic regression model with polytomous responses to handle the polymorphic...... situation. Genotype and allele-based parameterization can be used to investigate the modes of gene action and to reduce the number of parameters, so that the power is increased while the amount of multiple testing minimized. A binomial logistic regression model with fractional polynomials is used to capture...... the age-dependent or antagonistic pleiotropic effects. The models are applied to HFE genotype data to assess the effects on human longevity by different alleles and to detect if an age-dependent effect exists. Application has shown that these methods can serve as useful tools in searching for important...

  16. UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients

    International Nuclear Information System (INIS)

    Sparks, Rachel; Yuan, Xiaopu; Lin, Ming Gang; McVarish, Lynda; Aiello, Erin J; McTiernan, Anne; Ulrich, Cornelia M; Bigler, Jeannette; Tworoger, Shelley S; Yasui, Yutaka; Rajan, Kumar B; Porter, Peggy; Stanczyk, Frank Z; Ballard-Barbash, Rachel

    2004-01-01

    UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes are involved in removing sex hormones from circulation. Polymorphic variation in five UGT and SULT genes – UGT1A1 ((TA) 6 /(TA) 7 ), UGT2B4 (Asp 458 Glu), UGT2B7 (His 268 Tyr), UGT2B15 (Asp 85 Tyr), and SULT1A1 (Arg 213 His) – may be associated with circulating sex hormone concentrations, or the risk of an estrogen receptor-negative (ER - ) or progesterone receptor-negative (PR - ) tumor. Logistic regression analysis was used to estimate the odds ratios of an ER - or PR - tumor associated with polymorphisms in the genes listed above for 163 breast cancer patients from a population-based cohort study of women in western Washington. Adjusted geometric mean estradiol, estrone, and testosterone concentrations were calculated within each UGT and SULT genotype for a subpopulation of postmenopausal breast cancer patients not on hormone therapy 2–3 years after diagnosis (n = 89). The variant allele of UGT1A1 was associated with reduced risk of an ER - tumor (P for trend = 0.03), and variants of UGT2B15 and SULT1A1 were associated with non-statistically significant risk reductions. There was some indication that plasma estradiol and testosterone concentrations varied by UGT2B15 and SULT1A1 genotypes; women with the UGT2B15 Asp/Tyr and Tyr/Tyr genotypes had higher concentrations of estradiol than women with the Asp/Asp genotype (P = 0.004). Compared with women with the SULT1A1 Arg/Arg and Arg/His genotypes, women with the His/His genotype had elevated concentrations of testosterone (P = 0.003). The risk of ER - breast cancer tumors may vary by UGT or SULT genotype. Further, plasma estradiol and testosterone concentrations in breast cancer patients may differ depending on some UGT and SULT genotypes

  17. Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFN gamma Signaling

    DEFF Research Database (Denmark)

    Donia, Marco; Harbst, Katja; van Buuren, Marit

    2017-01-01

    Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed ...

  18. Correlation between tumor regression grade and rectal volume in neoadjuvant concurrent chemoradiotherapy for rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hong Seok; Choi, Doo Ho; Park, Hee Chul; Park, Won; Yu, Jeong Il; Chung, Kwang Zoo [Dept. of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2016-09-15

    To determine whether large rectal volume on planning computed tomography (CT) results in lower tumor regression grade (TRG) after neoadjuvant concurrent chemoradiotherapy (CCRT) in rectal cancer patients. We reviewed medical records of 113 patients treated with surgery following neoadjuvant CCRT for rectal cancer between January and December 2012. Rectal volume was contoured on axial images in which gross tumor volume was included. Average axial rectal area (ARA) was defined as rectal volume divided by longitudinal tumor length. The impact of rectal volume and ARA on TRG was assessed. Average rectal volume and ARA were 11.3 mL and 2.9 cm². After completion of neoadjuvant CCRT in 113 patients, pathologic results revealed total regression (TRG 4) in 28 patients (25%), good regression (TRG 3) in 25 patients (22%), moderate regression (TRG 2) in 34 patients (30%), minor regression (TRG 1) in 24 patients (21%), and no regression (TRG0) in 2 patients (2%). No difference of rectal volume and ARA was found between each TRG groups. Linear correlation existed between rectal volume and TRG (p = 0.036) but not between ARA and TRG (p = 0.058). Rectal volume on planning CT has no significance on TRG in patients receiving neoadjuvant CCRT for rectal cancer. These results indicate that maintaining minimal rectal volume before each treatment may not be necessary.

  19. Correlation between tumor regression grade and rectal volume in neoadjuvant concurrent chemoradiotherapy for rectal cancer

    International Nuclear Information System (INIS)

    Lee, Hong Seok; Choi, Doo Ho; Park, Hee Chul; Park, Won; Yu, Jeong Il; Chung, Kwang Zoo

    2016-01-01

    To determine whether large rectal volume on planning computed tomography (CT) results in lower tumor regression grade (TRG) after neoadjuvant concurrent chemoradiotherapy (CCRT) in rectal cancer patients. We reviewed medical records of 113 patients treated with surgery following neoadjuvant CCRT for rectal cancer between January and December 2012. Rectal volume was contoured on axial images in which gross tumor volume was included. Average axial rectal area (ARA) was defined as rectal volume divided by longitudinal tumor length. The impact of rectal volume and ARA on TRG was assessed. Average rectal volume and ARA were 11.3 mL and 2.9 cm². After completion of neoadjuvant CCRT in 113 patients, pathologic results revealed total regression (TRG 4) in 28 patients (25%), good regression (TRG 3) in 25 patients (22%), moderate regression (TRG 2) in 34 patients (30%), minor regression (TRG 1) in 24 patients (21%), and no regression (TRG0) in 2 patients (2%). No difference of rectal volume and ARA was found between each TRG groups. Linear correlation existed between rectal volume and TRG (p = 0.036) but not between ARA and TRG (p = 0.058). Rectal volume on planning CT has no significance on TRG in patients receiving neoadjuvant CCRT for rectal cancer. These results indicate that maintaining minimal rectal volume before each treatment may not be necessary

  20. Zero-inflated beta regression model for leaf citrus canker incidence in orange genotypes grafted onto different rootstocks

    Directory of Open Access Journals (Sweden)

    Oilson Alberto Gonzatto Junior

    2017-06-01

    Full Text Available Data with excess zeros are frequently found in practice, and the recommended analysis is to use models that adequately address the counting of zero observations. In this study, the Zero Inflated Beta Regression Model (BeZI was used on experimental data to describe the mean incidence of leaf citrus canker in orange groves under the influence of genotype and rootstocks of origin. Based on the model, it was possible to quantify the odds that a null observation to mean incidence comes from a particular plant according to genotype and rootstock, and estimate its expected value according to this combination. Laranja Caipira rootstock proved to be the most resistant to leaf citrus canker as well as Limão Cravo proved to be the most fragile. The Ipiguá IAC, Arapongas, EEL and Olímpia genotypes have statistically equivalent chances.

  1. Estimation of lung tumor position from multiple anatomical features on 4D-CT using multiple regression analysis.

    Science.gov (United States)

    Ono, Tomohiro; Nakamura, Mitsuhiro; Hirose, Yoshinori; Kitsuda, Kenji; Ono, Yuka; Ishigaki, Takashi; Hiraoka, Masahiro

    2017-09-01

    To estimate the lung tumor position from multiple anatomical features on four-dimensional computed tomography (4D-CT) data sets using single regression analysis (SRA) and multiple regression analysis (MRA) approach and evaluate an impact of the approach on internal target volume (ITV) for stereotactic body radiotherapy (SBRT) of the lung. Eleven consecutive lung cancer patients (12 cases) underwent 4D-CT scanning. The three-dimensional (3D) lung tumor motion exceeded 5 mm. The 3D tumor position and anatomical features, including lung volume, diaphragm, abdominal wall, and chest wall positions, were measured on 4D-CT images. The tumor position was estimated by SRA using each anatomical feature and MRA using all anatomical features. The difference between the actual and estimated tumor positions was defined as the root-mean-square error (RMSE). A standard partial regression coefficient for the MRA was evaluated. The 3D lung tumor position showed a high correlation with the lung volume (R = 0.92 ± 0.10). Additionally, ITVs derived from SRA and MRA approaches were compared with ITV derived from contouring gross tumor volumes on all 10 phases of the 4D-CT (conventional ITV). The RMSE of the SRA was within 3.7 mm in all directions. Also, the RMSE of the MRA was within 1.6 mm in all directions. The standard partial regression coefficient for the lung volume was the largest and had the most influence on the estimated tumor position. Compared with conventional ITV, average percentage decrease of ITV were 31.9% and 38.3% using SRA and MRA approaches, respectively. The estimation accuracy of lung tumor position was improved by the MRA approach, which provided smaller ITV than conventional ITV. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

  2. Genotype x diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis

    DEFF Research Database (Denmark)

    Gordon, Ryan R; Hunter, Kent W; Merrill, Michele La

    2008-01-01

    either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL × diet interaction effects. Here we describe......High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F2 mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F2 mice...... effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer...

  3. A case of parotid tumor showing remarkable regression following hyperthermo-chemo-radiotherapy

    International Nuclear Information System (INIS)

    Fujimura, Takashi; Yonemura, Yutaka; Kamata, Toru

    1987-01-01

    A 72-year-old woman developed adenocarcinoma of the left parotid gland. Because of the excessive size of her tumor and the fact that she suffered from severe liver dysfunction, she was treated by hyperthermo-chemo-radiotherapy (HCR therapy). After ten sessions of radiofrequency hyperthermia with HEH 500 (13.56 MHz radiofrequency wave), 50-Gy irradiation from a linac and administration of 33.0 g of tegafur in suppository form, the tumor mass showed remarkable regression decreasing in size by as much as 84 % on computed tomography. Histologically, the tumor which was resected under local anesthesia, showed almost total necrosis. The multidisciplinary HCR therapy was well tolerated and effective as a therapy for cancer in this case. (author)

  4. Genotype modulates testosterone-dependent activity and reactivity in male mice.

    Science.gov (United States)

    Broida, J; Svare, B

    1983-03-01

    Adult castration significantly reduced the homecage locomotor activity of both inbred C57BL/6J and DBA/2J and outbred Rockland-Swiss (R-S) male mice. Castrated C57BL animals exhibited greater reductions in this behavior than did the other genotypes. Locomotor activity in a novel environment (reactivity) was also reduced by castration but only for inbred males. In both test situations, postcastration reductions in ambulation were prevented by implants of testosterone (T)-containing Silastic capsules. Thus, testicular hormones promote activity and reactivity in the male mouse in a genotype-dependent fashion.

  5. Wilms tumors: genotypes and phenotypes

    NARCIS (Netherlands)

    H. Segers (Heidi)

    2013-01-01

    textabstractWilms tumor, or nephroblastoma, represents about 90% of all pediatric renal tumors and about 7% of all pediatric malignancies. Most Wilms tumors are unilateral, although in 5-10 % of the patients both kidneys are infected. Wilms tumor typically occurs between the age of 2 and 4 years,

  6. Hapten-Induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Dan A. Erkes

    2014-01-01

    Full Text Available Haptens are small molecule irritants that bind to proteins and elicit an immune response. Haptens have been commonly used to study allergic contact dermatitis (ACD using animal contact hypersensitivity (CHS models. However, extensive research into contact hypersensitivity has offered a confusing and intriguing mechanism of allergic reactions occurring in the skin. The abilities of haptens to induce such reactions have been frequently utilized to study the mechanisms of inflammatory bowel disease (IBD to induce autoimmune-like responses such as autoimmune hemolytic anemia and to elicit viral wart and tumor regression. Hapten-induced tumor regression has been studied since the mid-1900s and relies on four major concepts: (1 ex vivo haptenation, (2 in situ haptenation, (3 epifocal hapten application, and (4 antigen-hapten conjugate injection. Each of these approaches elicits unique responses in mice and humans. The present review attempts to provide a critical appraisal of the hapten-mediated tumor treatments and offers insights for future development of the field.

  7. Genotype x environment interaction for grain yield of wheat genotypes tested under water stress conditions

    International Nuclear Information System (INIS)

    Sail, M.A.; Dahot, M.U.; Mangrio, S.M.; Memon, S.

    2007-01-01

    Effect of water stress on grain yield in different wheat genotypes was studied under field conditions at various locations. Grain yield is a complex polygenic trait influenced by genotype, environment and genotype x environment (GxE) interaction. To understand the stability among genotypes for grain yield, twenty-one wheat genotypes developed Through hybridization and radiation-induced mutations at Nuclear Institute of Agriculture (NIA) TandoJam were evaluated with four local check varieties (Sarsabz, Thori, Margalla-99 and Chakwal-86) in multi-environmental trails (MET/sub s/). The experiments were conducted over 5 different water stress environments in Sindh. Data on grain yield were recorded from each site and statistically analyzed. Combined analysis of variance for all the environments indicated that the genotype, environment and genotype x environment (GxE) interaction were highly significant (P greater then 0.01) for grain yield. Genotypes differed in their response to various locations. The overall highest site mean yield (4031 kg/ha) recorded at Moro and the lowest (2326 kg/ha) at Thatta. Six genotypes produced significantly (P=0.01) the highest grain yield overall the environments. Stability analysis was applied to estimate stability parameters viz., regression coefficient (b), standard error of regression coefficient and variance due to deviation from regression (S/sub 2/d) genotypes 10/8, BWS-78 produced the highest mean yield over all the environments with low regression coefficient (b=0.68, 0.67 and 0.63 respectively and higher S/sup 2/ d value, showing specific adaptation to poor (un favorable) environments. Genotype 8/7 produced overall higher grain yield (3647 kg/ha) and ranked as third high yielding genotype had regression value close to unity (b=0.9) and low S/sup d/ value, indicating more stability and wide adaptation over the all environments. The knowledge of the presence and magnitude of genotype x environment (GE) interaction is important to

  8. Tumor regression achieved by encapsulating a moderately soluble drug into a polymeric thermogel

    Science.gov (United States)

    Ci, Tianyuan; Chen, Liang; Yu, Lin; Ding, Jiandong

    2014-07-01

    For cancer chemotherapy, a tumor regression without any surgical resection and severe side effects is greatly preferred to merely slowing down the growth of tumors. Here, we report a formulation composed of irinotecan (IRN) and poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA). IRN is a clinically used antitumor drug with active and inactive chemical forms in equilibrium, and the major form at physiological conditions is inactive but still has side effects. The aqueous solution of the PLGA-PEG-PLGA is a sol at room temperature and physically gels at body temperature, forming a thermogel. We successfully mixed this moderately soluble drug into the amphiphilic copolymer aqueous solution for the first time. The mixture was subcutaneously injected into nude mice with xenografted SW620 human colon tumors. Excellent in vivo antitumor efficacy was observed in the group that received the IRN-loaded thermogel. The tumor was significantly regressed after being treated with the IRN/thermogel, and the side effects (blood toxicity and body weight decrease) were very mild. These results might be attributed to the ideal sustained release profile and period of release of the drug from the thermogel and to the significant enhancement of the fraction of the active form of the drug by the thermogel.

  9. Canine transmissible venereal tumor and seminoma: a cytohistopathology and chemotherapy study of tumors in the growth phase and during regression after chemotherapy.

    Science.gov (United States)

    Javanbakht, J; Pedram, B; Taheriyan, M R; Khadivar, F; Hosseini, S H; Abdi, F S; Hosseini, E; Moloudizargari, M; Aghajanshakeri, S H; Javaherypour, S; Shafiee, R; Emrani Bidi, R

    2014-06-01

    In this study, 12 dogs affected by canine transmissible venereal tumor (CTVT) and testicular seminoma tumor were studied retrospectively. The cytological sample was smeared onto a glass slide and either air-dried for May-Grünwald-stain, and masses were surgically removed. The tumors were grossly examined, and sections of 4-μm thick were obtained from each sample and stained with H&E. For chemotherapy, vincristine sulfate was administered weekly as an infusion over 3 min via the cephalic vein at a dose of 0.025 mg/kg after diluting with physiological saline to a total amount of 10 ml. If no remission was observed after 8 weeks, chemotherapy was continued with weekly doxorubicin infusion at a dose of 1 mg/kg. All the tumor samples were divided into four cytohistopathologic groups, namely: multilobular (six cases), papillary (two cases), pedunculated (two cases), and tubular (two cases of seminoma). The most frequently represented tumor type was multilobular (6/10, 60 %) followed by pedunculated (2/10, 20 %), papillary (2/10, 20 %), and tubular (two cases of seminoma, 100 %). Cytological smears from eight tumors in regression after chemotherapy were poorly cellular, and many cells were fragmented. In two progressive tumors, there was an average of 1,406 ± 972 CTVT 200 cells/μl or 96.71 % of total cells counted. Thus, tumor cells represented 96.71 % of total cells within the biopsy specimens and the leukocytes 4.29 % (leukocyte, tumor cell ratio=0.062 ± 0.031). In eight regressive tumors, there was an average of 1,245 ± 1,032 CTVT 200 cells/μl or 97.31 % of total cells counted. Thus, tumor cells represented 97.31 % of total cells and leukocytes 2.69 % (leukocyte, tumor cell ratio=0.071 ± 0.174). Our data suggested that combination treatment with vincristine and doxorubicin in the future could be an excellent therapeutic alternative for the treatment of TVT for probably reducing the resistance to vincristine, and also, treatment success could easily be followed

  10. Comprehensive modulation of tumor progression and regression with periodic fasting and refeeding circles via boosting IGFBP-3 loops and NK responses.

    Science.gov (United States)

    Chen, Xiancheng; Lin, Xiaojuan; Li, Meng

    2012-10-01

    Progressive tumor-bearing patients deserve to benefit from more realistic approaches. Here, a study revealed the impact of modified periodic fasting and refeeding regimen on tumor progression or regression with little or no loss of food intake and body weight. Human A549 lung, HepG-2 liver, and SKOV-3 ovary progressive tumor-bearing mice were established and subjected to 4 wk of periodic fasting/refeeding cycles (PFRC), including periodic 1-d fasting/6-d refeeding weekly (protocol 1) and periodic 2-d fasting/5-d refeeding weekly (P2DF/5DR, protocol 2), with ad libitum (AL)-fed hosts as controls. Afterwards, PFRC groups exhibited tumor growth arrest with some tendency towards regression; especially, complete regression of progressive tumors and metastases comprised between 43.75 and 56.25% of tumor-challenged hosts in P2DF/5DR group (P fasting/6-d refeeding weekly groups survived a 4-month study period vs. only 31.25-37.5% in AL control group. Immunological assays and Luminex microarray revealed that tumor growth remission is mainly via natural killer cell (NK) reactivity and cross-regulation of IGF-binding protein-3, IGF/IGF-receptor, and megakaryocyte growth and development factor autocrine and paracrine loops. In vivo cellular and humoral assays indicated that tumor-regressive induction by PFRC protocols could be partly terminated by NK cell and IGF-binding protein-3 blockade or replenishment of IGF-I/-II and megakaryocyte growth and development factor. These findings offer a better understanding of comprehensive modulation of periodic fasting/refeeding strategy on the balance between tumor progression and regression.

  11. SU-E-J-137: Incorporating Tumor Regression Into Robust Plan Optimization for Head and Neck Radiotherapy

    International Nuclear Information System (INIS)

    Zhang, P; Hu, J; Tyagi, N; Mageras, G; Lee, N; Hunt, M

    2014-01-01

    Purpose: To develop a robust planning paradigm which incorporates a tumor regression model into the optimization process to ensure tumor coverage in head and neck radiotherapy. Methods: Simulation and weekly MR images were acquired for a group of head and neck patients to characterize tumor regression during radiotherapy. For each patient, the tumor and parotid glands were segmented on the MR images and the weekly changes were formulated with an affine transformation, where morphological shrinkage and positional changes are modeled by a scaling factor, and centroid shifts, respectively. The tumor and parotid contours were also transferred to the planning CT via rigid registration. To perform the robust planning, weekly predicted PTV and parotid structures were created by transforming the corresponding simulation structures according to the weekly affine transformation matrix averaged over patients other than him/herself. Next, robust PTV and parotid structures were generated as the union of the simulation and weekly prediction contours. In the subsequent robust optimization process, attainment of the clinical dose objectives was required for the robust PTV and parotids, as well as other organs at risk (OAR). The resulting robust plans were evaluated by looking at the weekly and total accumulated dose to the actual weekly PTV and parotid structures. The robust plan was compared with the original plan based on the planning CT to determine its potential clinical benefit. Results: For four patients, the average weekly change to tumor volume and position was −4% and 1.2 mm laterally-posteriorly. Due to these temporal changes, the robust plans resulted in an accumulated PTV D95 that was, on average, 2.7 Gy higher than the plan created from the planning CT. OAR doses were similar. Conclusion: Integration of a tumor regression model into target delineation and plan robust optimization is feasible and may yield improved tumor coverage. Part of this research is supported

  12. Pitfalls in the assessment of radioresponse as determined by tumor regression. Consideration based on the location and histologic constitution of tumors

    Energy Technology Data Exchange (ETDEWEB)

    Ohara, Kiyoshi; Shimizu, Wakako; Itai, Yuji [Tsukuba Univ., Ibaraki (Japan). Inst. of Clinical Medicine

    2000-05-01

    To prove the following hypotheses regarding tumor shrinkage after radiotherapy. Tumors located on an outer tissue surface, e.g. esophageal tumors shrink faster than parenchymal tumors, e.g. lymph-node metastasis, because two clearance mechanisms, exfoliation and absorption, can operate in the former type of tumors whereas only absorption can function in the latter. Tumors which are being controlled do not necessarily respond completely, because tumors are constituted not only of tumor cells but also stromal tissues that are difficult to be absorbed. Long-term shrinkage patterns of a parenchymal tumor were determined by using 18 curatively irradiated hepatomas. Preoperatively irradiated thymomas (10) and lymph-node metastases (37) from head and neck cancers were examined histopathologically. Twenty-one esophageal cancers were used for intra-patient response comparison between the primary disease and the lymph-node metastases. Shrinkage patterns were generally biphasic: rapid exponential regression followed by a plateau phase. Histologically, thymomas generally consisted of predominant fibrous tissues and few remaining tumor cells. Radioresponse did not predict the presence of remaining cancer cells in the lymph nodes. Esophageal-cancer radiorespone was always higher for the primary disease than the lymph-node metastases. The location and histologic constitution of tumors must be taken into account in predicting radiocurability using radioresponse. (author)

  13. Use of Sequenom sample ID Plus® SNP genotyping in identification of FFPE tumor samples.

    Directory of Open Access Journals (Sweden)

    Jessica K Miller

    Full Text Available Short tandem repeat (STR analysis, such as the AmpFlSTR® Identifiler® Plus kit, is a standard, PCR-based human genotyping method used in the field of forensics. Misidentification of cell line and tissue DNA can be costly if not detected early; therefore it is necessary to have quality control measures such as STR profiling in place. A major issue in large-scale research studies involving archival formalin-fixed paraffin embedded (FFPE tissues is that varying levels of DNA degradation can result in failure to correctly identify samples using STR genotyping. PCR amplification of STRs of several hundred base pairs is not always possible when DNA is degraded. The Sample ID Plus® panel from Sequenom allows for human DNA identification and authentication using SNP genotyping. In comparison to lengthy STR amplicons, this multiplexing PCR assay requires amplification of only 76-139 base pairs, and utilizes 47 SNPs to discriminate between individual samples. In this study, we evaluated both STR and SNP genotyping methods of sample identification, with a focus on paired FFPE tumor/normal DNA samples intended for next-generation sequencing (NGS. The ability to successfully validate the identity of FFPE samples can enable cost savings by reducing rework.

  14. Adaptabilidade e estabilidade via regressão não paramétrica em genótipos de café Adaptability and stability based on nonparametric regression in coffee genotypes

    Directory of Open Access Journals (Sweden)

    Moysés Nascimento

    2010-01-01

    Full Text Available O objetivo deste trabalho foi avaliar uma metodologia de análise de adaptabilidade e estabilidade fenotípica de genótipos de café baseada em regressão não paramétrica. A técnica utilizada difere das demais, pois reduz a influência na estimação do parâmetro de adaptabilidade de algum ponto extremo, ocasionado pela presença de genótipos com respostas demasiadamente diferenciadas a determinado ambiente. Foram utilizados dados provenientes de um experimento sobre produtividade média de grãos de 40 genótipos de café (Coffea canephora, com delineamento em blocos ao acaso, com seis repetições. Os genótipos foram avaliados em cinco anos (1996, 1998, 1999, 2000 e 2001, em dois locais (Sooretama e Marilândia, ES no total de dez ambientes. A metodologia proposta demonstrou ser adequada e eficiente, pois extingue os efeitos impróprios induzidos pela presença de pontos extremos e evita a recomendação incorreta de genótipos quanto à adaptabilidade.The objective of this work was to evaluate a methodology of phenotypic adaptability and stability analyses of coffee genotypes based on nonparametric regression. The technique used differs from other techniques because it reduces the influence of extreme points resulting from the presence of genotypes whose answers to a certain environment are too different on the estimation of the adaptability parameter. Data from an experiment studying the average yield of 40 coffee (Coffea canephora genotypes in a randomized block design with six replicates were used to evaluate the method. The genotypes were evaluated along five years (1996, 1998, 1999, 2000 and 2001 in two locations (Sooretama and Marilândia, ES, Brazil, in a total of ten environments. The methodology proposed proved adequate and efficient, since it eliminates the disproportionate effects induced by the presence of extreme points and avoids misleading recommendations of genotypes in terms of adaptability.

  15. Regression of conjunctival tumor during dietary treatment of celiac disease

    Directory of Open Access Journals (Sweden)

    Tuncer Samuray

    2010-01-01

    Full Text Available A 3-year-old girl presented with a hemorrhagic conjunctival lesion in the right eye. The medical history revealed premature cessation of breast feeding, intolerance to the ingestion of baby foods, anorexia, and abdominal distention. Prior to her referral, endoscopic small intestinal biopsy had been carried out under general anesthesia with a possible diagnosis of Celiac Disease (CD. Her parents did not want their child to undergo general anesthesia for the second time for the excisional biopsy. We decided to follow the patient until all systemic investigations were concluded. In evaluation, the case was diagnosed with CD and the conjunctival tumor showed complete regression during gluten-free dietary treatment. The clinical fleshy appearance of the lesion with spider-like vascular extensions and subconjunctival hemorrhagic spots, possible association with an acquired immune system dysfunction due to CD, and spontaneous regression by a gluten-free diet led us to make a presumed diagnosis of conjunctival Kaposi sarcoma.

  16. Osteoradionecrosis in Head-and-Neck Cancer Has a Distinct Genotype-Dependent Cause

    Energy Technology Data Exchange (ETDEWEB)

    Lyons, Andrew J., E-mail: Andrew.Lyons@gstt.nhs.uk [Head and Neck Unit, Guy' s and St. Thomas' Hospital NHS Foundation Trust, London (United Kingdom); West, Catharine M. [University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester (United Kingdom); Risk, Janet M. [Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool (United Kingdom); Slevin, Nick J.; Chan, Clara [Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester (United Kingdom); Crichton, Siobhan [Division of Health and Social Care Research, King' s College, London (United Kingdom); Rinck, Gabrielle; Howell, Dawn [Laboratory 21, Cambridge (United Kingdom); Shaw, Richard J. [Liverpool CR-UK Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool (United Kingdom)

    2012-03-15

    Purpose: We performed a case-control study to establish whether the development of osteoradionecrosis (ORN) was related to a variant allele substituting T for C at -509 of the transforming growth factor-{beta}1 gene (TGF-{beta}1). Patients and Methods: A total of 140 patients, 39 with and 101 without ORN, who underwent radiotherapy for head-and-neck cancer with a minimum of 2 years follow-up, were studied. None of the patients had clinical evidence of recurrence at this time. DNA extracted from blood was genotyped for the -509 C-T variant allele of the TGF-{beta}1 gene. Results: There were no significant differences in patient, cancer treatment, or tumor characteristics between the two groups. Of the 39 patients who developed ORN, 9 were homozygous for the common CC allele, 19 were heterozygous, and 11 were homozygous for the rare TT genotype. Of the 101 patients without ORN, the distribution was 56 (CC), 33 (CT), and 12 (TT). The difference in distribution was significant, giving an increased risk of ORN of 5.7 (95% CI, 1.7-19.2) for homozygote TT patients (p = 0.001) and 3.6 (95% CI, 1.3-10.0) for heterozygotes (p = 0.004) when compared with patients with the CC genotype. Postradiotherapy dentoalveolar surgery preceding the development of ORN was associated with the CC genotype (p = 0.02). Conclusions: Our findings support the postulate that the development of ORN is related to the presence of the T variant allele at -509 within the TGF-{beta}1 gene.

  17. Osteoradionecrosis in Head-and-Neck Cancer Has a Distinct Genotype-Dependent Cause

    International Nuclear Information System (INIS)

    Lyons, Andrew J.; West, Catharine M.; Risk, Janet M.; Slevin, Nick J.; Chan, Clara; Crichton, Siobhan; Rinck, Gabrielle; Howell, Dawn; Shaw, Richard J.

    2012-01-01

    Purpose: We performed a case-control study to establish whether the development of osteoradionecrosis (ORN) was related to a variant allele substituting T for C at -509 of the transforming growth factor-β1 gene (TGF-β1). Patients and Methods: A total of 140 patients, 39 with and 101 without ORN, who underwent radiotherapy for head-and-neck cancer with a minimum of 2 years follow-up, were studied. None of the patients had clinical evidence of recurrence at this time. DNA extracted from blood was genotyped for the -509 C-T variant allele of the TGF-β1 gene. Results: There were no significant differences in patient, cancer treatment, or tumor characteristics between the two groups. Of the 39 patients who developed ORN, 9 were homozygous for the common CC allele, 19 were heterozygous, and 11 were homozygous for the rare TT genotype. Of the 101 patients without ORN, the distribution was 56 (CC), 33 (CT), and 12 (TT). The difference in distribution was significant, giving an increased risk of ORN of 5.7 (95% CI, 1.7–19.2) for homozygote TT patients (p = 0.001) and 3.6 (95% CI, 1.3–10.0) for heterozygotes (p = 0.004) when compared with patients with the CC genotype. Postradiotherapy dentoalveolar surgery preceding the development of ORN was associated with the CC genotype (p = 0.02). Conclusions: Our findings support the postulate that the development of ORN is related to the presence of the T variant allele at -509 within the TGF-β1 gene.

  18. Frequency of polymorphisms and protein expression of cyclin-dependent kinase inhibitor 1A (CDKN1A in central nervous system tumors

    Directory of Open Access Journals (Sweden)

    Mev Dominguez Valentin

    Full Text Available CONTEXT AND OBJECTIVE: Genetic investigation of central nervous system (CNS tumors provides valuable information about the genes regulating proliferation, differentiation, angiogenesis, migration and apoptosis in the CNS. The aim of our study was to determine the prevalence of genetic polymorphisms (codon 31 and 3' untranslated region, 3'UTR and protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A gene in patients with and without CNS tumors. DESIGN AND SETTING: Analytical cross-sectional study with a control group, at the Molecular Biology Laboratory, Pediatric Oncology Department, Hospital das Clínicas de Ribeirão Preto. METHODS: 41 patients with CNS tumors and a control group of 161 subjects without cancer and paires for sex, age and ethnicity were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP. Protein analysis was performed on 36 patients with CNS tumors, using the Western Blotting technique. RESULTS: The frequencies of the heterozygote (Ser/Arg and polymorphic homozygote (Arg/Arg genotypes of codon 31 in the control subjects were 28.0% and 1.2%, respectively. However, the 3'UTR site presented frequencies of 24.2% (C/T and 0.6% (T/T. These frequencies were not statistically different (P > 0.05 from those seen in the patients with CNS tumors (19.4% and 0.0%, codon 31; 15.8% and 2.6%, 3'UTR site. Regarding the protein expression in ependymomas, 66.67% did not express the protein CDKN1A. The results for medulloblastomas and astrocytomas were similar: neither of them expressed the protein (57.14% and 61.54%, respectively. CONCLUSION: No significant differences in protein expression patterns or polymorphisms of CDKN1A in relation to the three types of CNS tumors were observed among Brazilian subjects.

  19. Esophageal Stenosis Associated With Tumor Regression in Radiotherapy for Esophageal Cancer: Frequency and Prediction

    Energy Technology Data Exchange (ETDEWEB)

    Atsumi, Kazushige [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Shioyama, Yoshiyuki, E-mail: shioyama@radiol.med.kyushu-u.ac.jp [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Arimura, Hidetaka [Department of Health Sciences, Kyushu University, Fukuoka (Japan); Terashima, Kotaro [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Matsuki, Takaomi [Department of Health Sciences, Kyushu University, Fukuoka (Japan); Ohga, Saiji; Yoshitake, Tadamasa; Nonoshita, Takeshi; Tsurumaru, Daisuke; Ohnishi, Kayoko; Asai, Kaori; Matsumoto, Keiji [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Nakamura, Katsumasa [Department of Radiology, Kyushu University Hospital at Beppu, Oita (Japan); Honda, Hiroshi [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan)

    2012-04-01

    Purpose: To determine clinical factors for predicting the frequency and severity of esophageal stenosis associated with tumor regression in radiotherapy for esophageal cancer. Methods and Materials: The study group consisted of 109 patients with esophageal cancer of T1-4 and Stage I-III who were treated with definitive radiotherapy and achieved a complete response of their primary lesion at Kyushu University Hospital between January 1998 and December 2007. Esophageal stenosis was evaluated using esophagographic images within 3 months after completion of radiotherapy. We investigated the correlation between esophageal stenosis after radiotherapy and each of the clinical factors with regard to tumors and therapy. For validation of the correlative factors for esophageal stenosis, an artificial neural network was used to predict the esophageal stenotic ratio. Results: Esophageal stenosis tended to be more severe and more frequent in T3-4 cases than in T1-2 cases. Esophageal stenosis in cases with full circumference involvement tended to be more severe and more frequent than that in cases without full circumference involvement. Increases in wall thickness tended to be associated with increases in esophageal stenosis severity and frequency. In the multivariate analysis, T stage, extent of involved circumference, and wall thickness of the tumor region were significantly correlated to esophageal stenosis (p = 0.031, p < 0.0001, and p = 0.0011, respectively). The esophageal stenotic ratio predicted by the artificial neural network, which learned these three factors, was significantly correlated to the actual observed stenotic ratio, with a correlation coefficient of 0.864 (p < 0.001). Conclusion: Our study suggested that T stage, extent of involved circumference, and esophageal wall thickness of the tumor region were useful to predict the frequency and severity of esophageal stenosis associated with tumor regression in radiotherapy for esophageal cancer.

  20. Dose-dependent response of Trichoderma harzianum in improving drought tolerance in rice genotypes.

    Science.gov (United States)

    Pandey, Veena; Ansari, Mohammad W; Tula, Suresh; Yadav, Sandep; Sahoo, Ranjan K; Shukla, Nandini; Bains, Gurdeep; Badal, Shail; Chandra, Subhash; Gaur, A K; Kumar, Atul; Shukla, Alok; Kumar, J; Tuteja, Narendra

    2016-05-01

    This study demonstrates a dose-dependent response of Trichoderma harzianum Th-56 in improving drought tolerance in rice by modulating proline, SOD, lipid peroxidation product and DHN / AQU transcript level, and the growth attributes. In the present study, the effect of colonization of different doses of T. harzianum Th-56 strain in rice genotypes were evaluated under drought stress. The rice genotypes treated with increasing dose of T. harzianum strain Th-56 showed better drought tolerance as compared with untreated control plant. There was significant change in malondialdehyde, proline, higher superoxide dismutase level, plant height, total dry matter, relative chlorophyll content, leaf rolling, leaf tip burn, and the number of scorched/senesced leaves in T. harzianum Th-56 treated rice genotypes under drought stress. This was corroborated with altered expression of aquaporin and dehydrin genes in T. harzianum Th-56 treated rice genotypes. The present findings suggest that a dose of 30 g/L was the most effective in improving drought tolerance in rice, and its potential exploitation will contribute to the advancement of rice genotypes to sustain crop productivity under drought stress. Interaction studies of T. harzianum with three aromatic rice genotypes suggested that PSD-17 was highly benefitted from T. harzianum colonization under drought stress.

  1. Genotype-phenotype associations in obesity dependent on definition of the obesity phenotype.

    Science.gov (United States)

    Kring, Sofia Inez Iqbal; Larsen, Lesli Hingstrup; Holst, Claus; Toubro, Søren; Hansen, Torben; Astrup, Arne; Pedersen, Oluf; Sørensen, Thorkild I A

    2008-01-01

    In previous studies of associations of variants in the genes UCP2, UCP3, PPARG2, CART, GRL, MC4R, MKKS, SHP, GHRL, and MCHR1 with obesity, we have used a case-control approach with cases defined by a threshold for BMI. In the present study, we assess the association of seven abdominal, peripheral, and overall obesity phenotypes, which were analyzed quantitatively, and thirteen candidate gene polymorphisms in these ten genes in the same cohort. Obese Caucasian men (n = 234, BMI >or= 31.0 kg/m(2)) and a randomly sampled non-obese group (n = 323), originally identified at the draft board examinations, were re-examined at median ages of 47.0 or 49.0 years by anthropometry and DEXA scanning. Obesity phenotypes included BMI, fat body mass index, waist circumference, waist for given BMI, intra-abdominal adipose tissue, hip circumference and lower body fat mass (%). Using logistic regression models, we estimated the odds for defined genotypes (dominant or recessive genetic transmission) in relation to z-scores of the phenotypes. The minor (rare) allele for SHP 512G>C (rs6659176) was associated with increased hip circumference. The minor allele for UCP2 Ins45bp was associated with increased BMI, increased abdominal obesity, and increased hip circumference. The minor allele for UCP2 -866G>A (rs6593669) was associated with borderline increased fat body mass index. The minor allele for MCHR1 100213G>A (rs133072) was associated with reduced abdominal obesity. None of the other genotype-phenotype combinations showed appreciable associations. If replicated in independent studies with focus on the specific phenotypes, our explorative studies suggest significant associations between some candidate gene polymorphisms and distinct obesity phenotypes, predicting beneficial and detrimental effects, depending on compartments for body fat accumulation. Copyright 2008 S. Karger AG, Basel.

  2. Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise G; Nielsen, Jens N; Lindebjerg, Jan

    2007-01-01

    ) followed by total mesorectal excision eight weeks after treatment. Pathologic response was evaluated according to the tumor regression grade system. RESULTS: Thirty percent (18/60) of patients presented with complete pathologic response. Patients with thymidylate synthase genotype 2/2 had a significantly...

  3. A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression

    Directory of Open Access Journals (Sweden)

    Green HN

    2014-11-01

    Full Text Available Hadiyah N Green,1,2 Stephanie D Crockett,3 Dmitry V Martyshkin,1 Karan P Singh,2,4 William E Grizzle,2,5 Eben L Rosenthal,2,6 Sergey B Mirov11Department of Physics, Center for Optical Sensors and Spectroscopies, 2Comprehensive Cancer Center, 3Department of Pediatrics, Division of Neonatology, 4Department of Medicine, Division of Preventive Medicine, Biostatistics and Bioinformatics Shared Facility, 5Department of Pathology, 6Department of Surgery, Division of Otolaryngology, Head and Neck Surgery, The University of Alabama at Birmingham, Birmingham, AL, USAPurpose: Nanoparticle (NP-enabled near infrared (NIR photothermal therapy has realized limited success in in vivo studies as a potential localized cancer therapy. This is primarily due to a lack of successful methods that can prevent NP uptake by the reticuloendothelial system, especially the liver and kidney, and deliver sufficient quantities of intravenously injected NPs to the tumor site. Histological evaluation of photothermal therapy-induced tumor regression is also neglected in the current literature. This report demonstrates and histologically evaluates the in vivo potential of NIR photothermal therapy by circumventing the challenges of intravenous NP delivery and tumor targeting found in other photothermal therapy studies.Methods: Subcutaneous Cal 27 squamous cell carcinoma xenografts received photothermal nanotherapy treatments, radial injections of polyethylene glycol (PEG-ylated gold nanorods and one NIR 785 nm laser irradiation for 10 minutes at 9.5 W/cm2. Tumor response was measured for 10–15 days, gross changes in tumor size were evaluated, and the remaining tumors or scar tissues were excised and histologically analyzed.Results: The single treatment of intratumoral nanorod injections followed by a 10 minute NIR laser treatment also known as photothermal nanotherapy, resulted in ~100% tumor regression in ~90% of treated tumors, which was statistically significant in a

  4. Neem leaf glycoprotein prophylaxis transduces immune dependent stop signal for tumor angiogenic switch within tumor microenvironment.

    Directory of Open Access Journals (Sweden)

    Saptak Banerjee

    Full Text Available We have reported that prophylactic as well as therapeutic administration of neem leaf glycoprotein (NLGP induces significant restriction of solid tumor growth in mice. Here, we investigate whether the effect of such pretreatment (25µg/mice; weekly, 4 times benefits regulation of tumor angiogenesis, an obligate factor for tumor progression. We show that NLGP pretreatment results in vascular normalization in melanoma and carcinoma bearing mice along with downregulation of CD31, VEGF and VEGFR2. NLGP pretreatment facilitates profound infiltration of CD8+ T cells within tumor parenchyma, which subsequently regulates VEGF-VEGFR2 signaling in CD31+ vascular endothelial cells to prevent aberrant neovascularization. Pericyte stabilization, VEGF dependent inhibition of VEC proliferation and subsequent vascular normalization are also experienced. Studies in immune compromised mice confirmed that these vascular and intratumoral changes in angiogenic profile are dependent upon active adoptive immunity particularly those mediated by CD8+ T cells. Accumulated evidences suggest that NLGP regulated immunomodulation is active in tumor growth restriction and normalization of tumor angiogenesis as well, thereby, signifying its clinical translation.

  5. Asymptotics of Multivariate Regression with Consecutively Added Dependent Varibles

    NARCIS (Netherlands)

    Raats, V.M.; van der Genugten, B.B.; Moors, J.J.A.

    2004-01-01

    We consider multivariate regression where new dependent variables are consecutively added during the experiment (or in time).So, viewed at the end of the experiment, the number of observations decreases with each added variable. The explanatory variables are observed throughout.In a previous paper

  6. Logistic regression analysis of risk factors for postoperative recurrence of spinal tumors and analysis of prognostic factors.

    Science.gov (United States)

    Zhang, Shanyong; Yang, Lili; Peng, Chuangang; Wu, Minfei

    2018-02-01

    The aim of the present study was to investigate the risk factors for postoperative recurrence of spinal tumors by logistic regression analysis and analysis of prognostic factors. In total, 77 male and 48 female patients with spinal tumor were selected in our hospital from January, 2010 to December, 2015 and divided into the benign (n=76) and malignant groups (n=49). All the patients underwent microsurgical resection of spinal tumors and were reviewed regularly 3 months after operation. The McCormick grading system was used to evaluate the postoperative spinal cord function. Data were subjected to statistical analysis. Of the 125 cases, 63 cases showed improvement after operation, 50 cases were stable, and deterioration was found in 12 cases. The improvement rate of patients with cervical spine tumor, which reached 56.3%, was the highest. Fifty-two cases of sensory disturbance, 34 cases of pain, 30 cases of inability to exercise, 26 cases of ataxia, and 12 cases of sphincter disorders were found after operation. Seventy-two cases (57.6%) underwent total resection, 18 cases (14.4%) received subtotal resection, 23 cases (18.4%) received partial resection, and 12 cases (9.6%) were only treated with biopsy/decompression. Postoperative recurrence was found in 57 cases (45.6%). The mean recurrence time of patients in the malignant group was 27.49±6.09 months, and the mean recurrence time of patients in the benign group was 40.62±4.34. The results were significantly different (Pregression analysis of total resection-related factors showed that total resection should be the preferred treatment for patients with benign tumors, thoracic and lumbosacral tumors, and lower McCormick grade, as well as patients without syringomyelia and intramedullary tumors. Logistic regression analysis of recurrence-related factors revealed that the recurrence rate was relatively higher in patients with malignant, cervical, thoracic and lumbosacral, intramedullary tumors, and higher Mc

  7. State-Dependent Impulsive Control Strategies for a Tumor-Immune Model

    Directory of Open Access Journals (Sweden)

    Kwang Su Kim

    2016-01-01

    Full Text Available Controlling the number of tumor cells leads us to expect more efficient strategies for treatment of tumor. Towards this goal, a tumor-immune model with state-dependent impulsive treatments is established. This model may give an efficient treatment schedule to control tumor’s abnormal growth. By using the Poincaré map and analogue of Poincaré criterion, some conditions for the existence and stability of a positive order-1 periodic solution of this model are obtained. Moreover, we carry out numerical simulations to illustrate the feasibility of our main results and compare fixed-time impulsive treatment effects with state-dependent impulsive treatment effects. The results of our simulations say that, in determining optimal treatment timing, the model with state-dependent impulsive control is more efficient than that with fixed-time impulsive control.

  8. Translating Response During Therapy into Ultimate Treatment Outcome: A Personalized 4-Dimensional MRI Tumor Volumetric Regression Approach in Cervical Cancer

    International Nuclear Information System (INIS)

    Mayr, Nina A.; Wang, Jian Z.; Lo, Simon S.; Zhang Dongqing; Grecula, John C.; Lu Lanchun; Montebello, Joseph F.; Fowler, Jeffrey M.; Yuh, William T.C.

    2010-01-01

    Purpose: To assess individual volumetric tumor regression pattern in cervical cancer during therapy using serial four-dimensional MRI and to define the regression parameters' prognostic value validated with local control and survival correlation. Methods and Materials: One hundred and fifteen patients with Stage IB 2 -IVA cervical cancer treated with radiation therapy (RT) underwent serial MRI before (MRI 1) and during RT, at 2-2.5 weeks (MRI 2, at 20-25 Gy), and at 4-5 weeks (MRI 3, at 40-50 Gy). Eighty patients had a fourth MRI 1-2 months post-RT. Mean follow-up was 5.3 years. Tumor volume was measured by MRI-based three-dimensional volumetry, and plotted as dose(time)/volume regression curves. Volume regression parameters were correlated with local control, disease-specific, and overall survival. Results: Residual tumor volume, slope, and area under the regression curve correlated significantly with local control and survival. Residual volumes ≥20% at 40-50 Gy were independently associated with inferior 5-year local control (53% vs. 97%, p <0.001) and disease-specific survival rates (50% vs. 72%, p = 0.009) than smaller volumes. Patients with post-RT residual volumes ≥10% had 0% local control and 17% disease-specific survival, compared with 91% and 72% for <10% volume (p <0.001). Conclusion: Using more accurate four-dimensional volumetric regression analysis, tumor response can now be directly translated into individual patients' outcome for clinical application. Our results define two temporal thresholds critically influencing local control and survival. In patients with ≥20% residual volume at 40-50 Gy and ≥10% post-RT, the risk for local failure and death are so high that aggressive intervention may be warranted.

  9. Molecular Genetic Changes Associated With Colorectal Carcinogenesis Are Not Prognostic for Tumor Regression Following Preoperative Chemoradiation of Rectal Carcinoma

    International Nuclear Information System (INIS)

    Zauber, N. Peter; Marotta, Steven P.; Berman, Errol; Grann, Alison; Rao, Maithili; Komati, Naga; Ribiero, Kezia; Bishop, D. Timothy

    2009-01-01

    Purpose: Preoperative chemotherapy and radiation has become the standard of care for many patients with rectal cancer. The therapy may have toxicity and delays definitive surgery. It would therefore be desirable to identify those cancers that will not regress with preoperative therapy. We assessed a series of rectal cancers for the molecular changes of loss of heterozygosity of the APC and DCC genes, K-ras mutations, and microsatellite instability, changes that have clearly been associated with rectal carcinogenesis. Methods and Materials: Diagnostic colonoscopic biopsies from 53 patients who received preoperative chemotherapy and radiation were assayed using polymerase chain reaction techniques followed by single-stranded conformation polymorphism and DNA sequencing. Regression of the primary tumor was evaluated using the surgically removed specimen. Results: Twenty-three lesions (45%) were found to have a high degree of regression. None of the molecular changes were useful as indicators of regression. Conclusions: Recognized molecular changes critical for rectal carcinogenesis including APC and DCC loss of heterozygosity, K-ras mutations, and microsatellite instability are not useful as indicators of tumor regression following chemoradiation for rectal carcinoma.

  10. Serial megavoltage CT imaging during external beam radiotherapy for non-small-cell lung cancer: Observations on tumor regression during treatment

    International Nuclear Information System (INIS)

    Kupelian, Patrick A.; Ramsey, Chester; Meeks, Sanford L.; Willoughby, Twyla R.; Forbes, Alan; Wagner, Thomas H.; Langen, Katja M.

    2005-01-01

    Purpose: The ability to obtain soft-tissue imaging in the treatment room, such as with megavoltage CT imaging, enables the observation of tumor regression during a course of external beam radiation therapy. In this current study, we report on the most extensive study looking at the rate of regression of non-small-cell lung cancers during a course of external beam radiotherapy by analyzing serial megavoltage CT images obtained on 10 patients. Methods and Materials: The analysis is performed on 10 patients treated with the Helical Tomotherapy Hi*Art device. All 10 patients had non-small-cell lung cancer. A total of 274 megavoltage CT sets were obtained on the 10 patients (average, 27 scans per patient; range, 9-35). All patients had at least a scan at beginning and at the end of treatment. The frequency of scanning was determined by the treating physician. The treatment was subsequently delivered with the Tomotherapy Hi*Art system. The gross tumor volumes (GTVs) were later contoured on each megavoltage CT scan, and tumor volumes were calculated. Although some patients were treated to draining nodal areas in addition to the primary tumor, only the primary GTVs were tracked. Response to treatment was quantified by the relative decrease in tumor volume over time, i.e., elapsed days from the first day of therapy. The individual GTVs ranged from 5.9 to 737.2 cc in volume at the start of treatment. In 6 of the 10 patients, dose recalculations were also performed to document potential variations in delivered doses within the tumors. The megavoltage CT scans were used, and the planned treatment was recalculated on the daily images. The hypothesis was that dose deposited in the target would increase throughout the course of radiotherapy because of tumor shrinkage and subsequent decreasing attenuation. Specifically, the dose received by 95% of the GTV (D 95 ) was monitored over time for each of the 6 patients treated at M.D. Anderson Cancer Center Orlando. Results: Regression

  11. Overview of Radiosensitivity of Human Tumor Cells to Low-Dose-Rate Irradiation

    International Nuclear Information System (INIS)

    Williams, Jerry R.; Zhang Yonggang; Zhou Haoming; Gridley, Daila S.; Koch, Cameron J.; Slater, James M.; Little, John B.

    2008-01-01

    Purpose: We compared clonogenic survival in 27 human tumor cell lines that vary in genotype after low-dose-rate (LDR) or high-dose rate (HDR) irradiation. We measured susceptibility to LDR-induced redistribution in the cell cycle in eight of these cell lines. Methods and Materials: We measured clonogenic survival after up to 96 hours of LDR (0.25 Gy/h) irradiation. We compared these with clonogenic survival after HDR irradiation (50 Gy/h). Using flow cytometry, we measured LDR-induced redistribution as a function of time during LDR irradiation in eight of these cell lines. Results: Coefficients that describe clonogenic survival after both LDR and HDR irradiation segregate into four radiosensitivity groups that associate with cell genotype: mutant (mut)ATM, wild-type TP53, mutTP53, and an unidentified gene in radioresistant glioma cells. The LDR and HDR radiosensitivity correlates at lower doses (∼2 Gy HDR, ∼6 Gy LDR), but not at higher doses (HDR > 4 Gy; LDR > 6 Gy). The rate of LDR-induced loss of clonogenic survival changes at approximately 24 hours; wild-type TP53 cells become more resistant and mutTP53 cells become more sensitive. Redistribution induced by LDR irradiation also changes at approximately 24 hours. Conclusions: Radiosensitivity of human tumor cells to both LDR and HDR irradiation is genotype dependent. Analysis of coefficients that describe cellular radiosensitivity segregates 27 cell lines into four statistically distinct groups, each associating with specific genotypes. Changes in cellular radiosensitivity and redistribution in the cell cycle are strongly time dependent. Our data establish a genotype-dependent time-dependent model that predicts clonogenic survival, explains the inverse dose-rate effect, and suggests possible clinical applications

  12. Plasmin-driven fibrinolysis facilitates skin tumor growth in a gender-dependent manner

    DEFF Research Database (Denmark)

    Hald, Andreas; Eickhardt, Hanne; Maerkedahl, Rasmus Baadsgaard

    2012-01-01

    deficiency was due to thrombosis and lost patency of the tumor vasculature, resulting in tumor necrosis. The connection between plasmin-dependent fibrinolysis, vascular patency, and tumor growth was further substantiated as the effect of plasminogen deficiency on tumor growth could be reverted...

  13. Time-dependent transcriptional response of GOT1 human small intestine neuroendocrine tumor after 177Lu[Lu]-octreotate therapy.

    Science.gov (United States)

    Spetz, Johan; Rudqvist, Nils; Langen, Britta; Parris, Toshima Z; Dalmo, Johanna; Schüler, Emil; Wängberg, Bo; Nilsson, Ola; Helou, Khalil; Forssell-Aronsson, Eva

    2018-05-01

    Patients with neuroendocrine tumors expressing somatostatin receptors are often treated with 177 Lu[Lu]-octreotate. Despite being highly effective in animal models, 177 Lu[Lu]-octreotate-based therapies in the clinical setting can be optimized further. The aims of the study were to identify and elucidate possible optimization venues for 177 Lu[Lu]-octreotate tumor therapy by characterizing transcriptional responses in the GOT1 small intestine neuroendocrine tumor model in nude mice. GOT1-bearing female BALB/c nude mice were intravenously injected with 15 MBq 177 Lu[Lu]-octreotate (non-curative amount) or mock-treated with saline solution. Animals were killed 1, 3, 7 or 41 d after injection. Total RNA was extracted from the tumor samples and profiled using Illumina microarray expression analysis. Differentially expressed genes were identified (treated vs. control) and pathway analysis was performed. Distribution of differentially expressed transcripts indicated a time-dependent treatment response in GOT1 tumors after 177 Lu[Lu]-octreotate administration. Regulation of CDKN1A, BCAT1 and PAM at 1 d after injection was compatible with growth arrest as the initial response to treatment. Upregulation of APOE and BAX at 3 d, and ADORA2A, BNIP3, BNIP3L and HSPB1 at 41 d after injection suggests first activation and then inhibition of the intrinsic apoptotic pathway during tumor regression and regrowth, respectively. Transcriptional analysis showed radiation-induced apoptosis as an early response after 177 Lu[Lu]-octreotate administration, followed by pro-survival transcriptional changes in the tumor during the regrowth phase. Time-dependent changes in cell cycle and apoptosis-related processes suggest different time points after radionuclide therapy when tumor cells may be more susceptible to additional treatment, highlighting the importance of timing when administering multiple therapeutic agents. Copyright © 2018 The Authors. Published by Elsevier Inc. All

  14. Role of Immunomodulators in Tumor Regression in Mice Exposed to Fractionated Low Dose of Gamma Radiation

    International Nuclear Information System (INIS)

    Rokaya Elsayed Maaroaf Elsayed

    2015-01-01

    Immunotherapy is one of the most promising approaches of cancer treatment. The present study was designed to examine the role of irradiated tumor cell lysate vaccine, IFNα-2b and low dose of gamma irradiation as immunomodulators either alone or combined in tumor regression. Ehrlich ascite carcinoma (EAC) cells and 9 groups of female mice were used. Mice were immunized intramuscularly by tumor cell lysate vaccine one time/week for 3 weeks in the right thigh of mice. After two weeks from last immunization, all mice were challenged with normal viable EAC cells at count of 2.5 ×10 6 /mouse in the opposite left thigh for Ehrlich carcinoma (EC) production. Mice were subcutaneously injected with 10.000 units of IFNα-2b 3 times/week for 4 weeks and others were exposed to fractionated dose of γ- radiation (0.5 Gy/day x 4, day after day). Tumor size, serum tumor markers (TNF-α and CEA), tumor DNA fragmentation and Caspase-3 were evaluated. Oxidative stress (MDA and NO) markers and antioxidants (GSH, GPX and SOD) were determined in spleen and tumor tissues. Histopathological examinations, apoptosis and necrosis in spleen and tumor tissues were also examined. The results revealed significant inhibition in tumor size throughout the observation period either for treatments with vaccine or IFNα-2b either alone or combined with γ-irradiation. DNA fragmentation and Caspase-3 enzyme activities were significantly elevated in immunized mice as compared with EC group along with diminished tumor size while, tumor markers were significantly decreased. MDA and NO were significantly increased in tumor tissue.while, tumor GSH content, GPX and SOD activities were significantly decreased. Combined treatments of female mice bearing EC with IFN-α-2b, tumor cell lysate vaccine and low dose of γ-radiation cause a highly significant decrease in serum TNF-α and CEA levels, increase in Cas-3 activity, no DNA fragmentation, significant increase in MDA, decrease in SOD activity and decreased

  15. Time-dependent cell disintegration kinetics in lung tumors after irradiation

    International Nuclear Information System (INIS)

    Chvetsov, Alexei V; Palta, Jatinder J; Nagata, Yasushi

    2008-01-01

    We study the time-dependent disintegration kinetics of tumor cells that did not survive radiotherapy treatment. To evaluate the cell disintegration rate after irradiation, we studied the volume changes of solitary lung tumors after stereotactic radiotherapy. The analysis is performed using two approximations: (1) tumor volume is a linear function of the total cell number in the tumor and (2) the cell disintegration rate is governed by the exponential decay with constant risk, which is defined by the initial cell number and a half-life T 1/2 . The half-life T 1/2 is determined using the least-squares fit to the clinical data on lung tumor size variation with time after stereotactic radiotherapy. We show that the tumor volume variation after stereotactic radiotherapy of solitary lung tumors can be approximated by an exponential function. A small constant component in the volume variation does not change with time; however, this component may be the residual irregular density due to radiation fibrosis and was, therefore, subtracted from the total volume variation in our computations. Using computerized fitting of the exponent function to the clinical data for selected patients, we have determined that the average half-life T 1/2 of cell disintegration is 28.2 days for squamous cell carcinoma and 72.4 days for adenocarcinoma. This model is needed for simulating the tumor volume variation during radiotherapy, which may be important for time-dependent treatment planning of proton therapy that is sensitive to density variations

  16. Cryospectrophotometric determination of tumor intravascular oxyhemoglobin saturations: dependence on vascular geometry and tumor growth.

    Science.gov (United States)

    Fenton, B M; Rofstad, E K; Degner, F L; Sutherland, R M

    1988-12-21

    To delineate the complex relationships between overall tumor oxygenation and vascular configuration, intravascular oxyhemoglobin (HbO2) saturation distributions were measured with cryospectrophotometric techniques. Four factors related to vascular morphometry and tumor growth were evaluated: a) vessel diameter, b) distance of vessel from the tumor surface, c) tumor volume, and d) vascular density. To measure intertumor heterogeneity, two murine sarcomas (RIF-1 and KHT) and two human ovarian carcinoma xenografts (OWI and MLS) were utilized. In contrast to skeletal muscle, a preponderance of very low HbO2 saturations was observed for both large and small tumors of all lines. Saturations up to about 90% were also generally present, however, even in very large tumors. Variations in vascular configuration were predominantly tumor-line dependent rather than due to inherent characteristics of the host vasculature, and widely disparate HbO2 distributions were found for alternate lines implanted in identical host mice. Although peripheral saturations remained fairly constant with tumor growth, HbO2 values were markedly lower for vessels nearer the tumor center and further decreased with increasing tumor volume. HbO2 saturations did not change substantially with increasing vascular density (except for KHT tumors), although density did decrease with increasing distance from tumor surface. Combined effects of vessel diameter, tumor volume, and vessel location on HbO2 saturations were complex and varied markedly with both tumor line and vessel class. For specific classes, HbO2 distributions correlated closely with radiobiological hypoxic fractions, i.e., for tumor lines in which hypoxic fraction increased substantially with tumor volume, corresponding HbO2 values decreased, while for lines in which hypoxic fraction remained constant, HbO2 values also were unchanged. Although these trends may also be a function of differing oxygen consumption rates between tumor lines

  17. Genotype dependent callus induction and shoot regeneration in ...

    African Journals Online (AJOL)

    This study aims to observe the effect of genotype, hormone and culture conditions on sunflower (Helianthus annuus L.) callus induction and indirect plant regeneration. Calli were obtained from hypocotyl and cotyledon explants of five different sunflower genotypes; Trakya 80, Trakya 129, Trakya 259, Trakya 2098 and ...

  18. Time-dependent cell disintegration kinetics in lung tumors after irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Chvetsov, Alexei V; Palta, Jatinder J [Department of Radiation Oncology, University of Florida, Gainesville, FL (United States); Nagata, Yasushi [Department of Therapeutic Radiology and Oncology, Kyoto University, Kyoto (Japan)], E-mail: chvetsov@ufl.edu

    2008-05-07

    We study the time-dependent disintegration kinetics of tumor cells that did not survive radiotherapy treatment. To evaluate the cell disintegration rate after irradiation, we studied the volume changes of solitary lung tumors after stereotactic radiotherapy. The analysis is performed using two approximations: (1) tumor volume is a linear function of the total cell number in the tumor and (2) the cell disintegration rate is governed by the exponential decay with constant risk, which is defined by the initial cell number and a half-life T{sub 1/2}. The half-life T{sub 1/2} is determined using the least-squares fit to the clinical data on lung tumor size variation with time after stereotactic radiotherapy. We show that the tumor volume variation after stereotactic radiotherapy of solitary lung tumors can be approximated by an exponential function. A small constant component in the volume variation does not change with time; however, this component may be the residual irregular density due to radiation fibrosis and was, therefore, subtracted from the total volume variation in our computations. Using computerized fitting of the exponent function to the clinical data for selected patients, we have determined that the average half-life T{sub 1/2} of cell disintegration is 28.2 days for squamous cell carcinoma and 72.4 days for adenocarcinoma. This model is needed for simulating the tumor volume variation during radiotherapy, which may be important for time-dependent treatment planning of proton therapy that is sensitive to density variations.

  19. Characterization of sonographically indeterminate ovarian tumors with MR imaging. A logistic regression analysis

    International Nuclear Information System (INIS)

    Yamashita, Y.; Hatanaka, Y.; Torashima, M.; Takahashi, M.; Miyazaki, K.; Okamura, H.

    1997-01-01

    Purpose: The goal of this study was to maximize the discrimination between benign and malignant masses in patients with sonographically indeterminate ovarian lesions by means of unenhanced and contrast-enhanced MR imaging, and to develop a computer-assisted diagnosis system. Material and Methods: Findings in precontrast and Gd-DTPA contrast-enhanced MR images of 104 patients with 115 sonographically indeterminate ovarian masses were analyzed, and the results were correlated with histopathological findings. Of 115 lesions, 65 were benign (23 cystadenomas, 13 complex cysts, 11 teratomas, 6 fibrothecomas, 12 others) and 50 were malignant (32 ovarian carcinomas, 7 metastatic tumors of the ovary, 4 carcinomas of the fallopian tubes, 7 others). A logistic regression analysis was performed to discriminate between benign and malignant lesions, and a model of a computer-assisted diagnosis was developed. This model was prospectively tested in 75 cases of ovarian tumors found at other institutions. Results: From the univariate analysis, the following parameters were selected as significant for predicting malignancy (p≤0.05): A solid or cystic mass with a large solid component or wall thickness greater than 3 mm; complex internal architecture; ascites; and bilaterality. Based on these parameters, a model of a computer-assisted diagnosis system was developed with the logistic regression analysis. To distinguish benign from malignant lesions, the maximum cut-off point was obtained between 0.47 and 0.51. In a prospective application of this model, 87% of the lesions were accurately identified as benign or malignant. (orig.)

  20. NetRaVE: constructing dependency networks using sparse linear regression

    DEFF Research Database (Denmark)

    Phatak, A.; Kiiveri, H.; Clemmensen, Line Katrine Harder

    2010-01-01

    NetRaVE is a small suite of R functions for generating dependency networks using sparse regression methods. Such networks provide an alternative to interpreting 'top n lists' of genes arising out of an analysis of microarray data, and they provide a means of organizing and visualizing the resulting...

  1. Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients

    DEFF Research Database (Denmark)

    Ahern, Thomas P; Hertz, Daniel L; Damkier, Per

    2017-01-01

    -infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association...... genotyped DNA from tumor-infiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the CYP2D6 locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor...

  2. T cell receptor (TCR-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFβ signaling mediate superior tumor regression in an animal model of adoptive cell therapy

    Directory of Open Access Journals (Sweden)

    Quatromoni Jon G

    2012-06-01

    Full Text Available Abstract Tumor antigen-reactive T cells must enter into an immunosuppressive tumor microenvironment, continue to produce cytokine and deliver apoptotic death signals to affect tumor regression. Many tumors produce transforming growth factor beta (TGFβ, which inhibits T cell activation, proliferation and cytotoxicity. In a murine model of adoptive cell therapy, we demonstrate that transgenic Pmel-1 CD8 T cells, rendered insensitive to TGFβ by transduction with a TGFβ dominant negative receptor II (DN, were more effective in mediating regression of established B16 melanoma. Smaller numbers of DN Pmel-1 T cells effectively mediated tumor regression and retained the ability to produce interferon-γ in the tumor microenvironment. These results support efforts to incorporate this DN receptor in clinical trials of adoptive cell therapy for cancer.

  3. Locoregional control of non-small cell lung cancer in relation to automated early assessment of tumor regression on cone beam computed tomography

    DEFF Research Database (Denmark)

    Brink, Carsten; Bernchou, Uffe; Bertelsen, Anders

    2014-01-01

    was estimated on the basis of the first one third and two thirds of the scans. The concordance between estimated and actual relative volume at the end of radiation therapy was quantified by Pearson's correlation coefficient. On the basis of the estimated relative volume, the patients were stratified into 2...... for other clinical characteristics. RESULTS: Automatic measurement of the tumor regression from standard CBCT images was feasible. Pearson's correlation coefficient between manual and automatic measurement was 0.86 in a sample of 9 patients. Most patients experienced tumor volume regression, and this could...

  4. On coding genotypes for genetic markers with multiple alleles in genetic association study of quantitative traits

    Directory of Open Access Journals (Sweden)

    Wang Tao

    2011-09-01

    Full Text Available Abstract Background In genetic association study of quantitative traits using F∞ models, how to code the marker genotypes and interpret the model parameters appropriately is important for constructing hypothesis tests and making statistical inferences. Currently, the coding of marker genotypes in building F∞ models has mainly focused on the biallelic case. A thorough work on the coding of marker genotypes and interpretation of model parameters for F∞ models is needed especially for genetic markers with multiple alleles. Results In this study, we will formulate F∞ genetic models under various regression model frameworks and introduce three genotype coding schemes for genetic markers with multiple alleles. Starting from an allele-based modeling strategy, we first describe a regression framework to model the expected genotypic values at given markers. Then, as extension from the biallelic case, we introduce three coding schemes for constructing fully parameterized one-locus F∞ models and discuss the relationships between the model parameters and the expected genotypic values. Next, under a simplified modeling framework for the expected genotypic values, we consider several reduced one-locus F∞ models from the three coding schemes on the estimability and interpretation of their model parameters. Finally, we explore some extensions of the one-locus F∞ models to two loci. Several fully parameterized as well as reduced two-locus F∞ models are addressed. Conclusions The genotype coding schemes provide different ways to construct F∞ models for association testing of multi-allele genetic markers with quantitative traits. Which coding scheme should be applied depends on how convenient it can provide the statistical inferences on the parameters of our research interests. Based on these F∞ models, the standard regression model fitting tools can be used to estimate and test for various genetic effects through statistical contrasts with the

  5. Modified Regression Correlation Coefficient for Poisson Regression Model

    Science.gov (United States)

    Kaengthong, Nattacha; Domthong, Uthumporn

    2017-09-01

    This study gives attention to indicators in predictive power of the Generalized Linear Model (GLM) which are widely used; however, often having some restrictions. We are interested in regression correlation coefficient for a Poisson regression model. This is a measure of predictive power, and defined by the relationship between the dependent variable (Y) and the expected value of the dependent variable given the independent variables [E(Y|X)] for the Poisson regression model. The dependent variable is distributed as Poisson. The purpose of this research was modifying regression correlation coefficient for Poisson regression model. We also compare the proposed modified regression correlation coefficient with the traditional regression correlation coefficient in the case of two or more independent variables, and having multicollinearity in independent variables. The result shows that the proposed regression correlation coefficient is better than the traditional regression correlation coefficient based on Bias and the Root Mean Square Error (RMSE).

  6. VEGF-dependent mechanism of anti-angiogenic action of diamond nanoparticles in Glioblastoma Multiforme tumor

    DEFF Research Database (Denmark)

    Grodzik, M.; Sawosz, E.; Wierzbicki, M.

    2012-01-01

    Malignant gliomas are highly lethal cancers dependent on angiogenesis. The concept of treating tumors by inhibiting tumor angiogenesis was first articulated almost 30 years ago. Inhibition of tumor angiogenesis suppresses both tumor growth and metastasis. We determined the inhibition effect of di...

  7. PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice.

    Science.gov (United States)

    Langut, Yael; Talhami, Alaa; Mamidi, Samarasimhareddy; Shir, Alexei; Zigler, Maya; Joubran, Salim; Sagalov, Anna; Flashner-Abramson, Efrat; Edinger, Nufar; Klein, Shoshana; Levitzki, Alexander

    2017-12-26

    There is an urgent need for an effective treatment for metastatic prostate cancer (PC). Prostate tumors invariably overexpress prostate surface membrane antigen (PSMA). We designed a nonviral vector, PEI-PEG-DUPA (PPD), comprising polyethylenimine-polyethyleneglycol (PEI-PEG) tethered to the PSMA ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid (DUPA), to treat PC. The purpose of PEI is to bind polyinosinic/polycytosinic acid (polyIC) and allow endosomal release, while DUPA targets PC cells. PolyIC activates multiple pathways that lead to tumor cell death and to the activation of bystander effects that harness the immune system against the tumor, attacking nontargeted neighboring tumor cells and reducing the probability of acquired resistance and disease recurrence. Targeting polyIC directly to tumor cells avoids the toxicity associated with systemic delivery. PPD selectively delivered polyIC into PSMA-overexpressing PC cells, inducing apoptosis, cytokine secretion, and the recruitment of human peripheral blood mononuclear cells (PBMCs). PSMA-overexpressing tumors in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with partially reconstituted immune systems were significantly shrunken following PPD/polyIC treatment, in all cases. Half of the tumors showed complete regression. PPD/polyIC invokes antitumor immunity, but unlike many immunotherapies does not need to be personalized for each patient. The potent antitumor effects of PPD/polyIC should spur its development for clinical use.

  8. Methods for identifying SNP interactions: a review on variations of Logic Regression, Random Forest and Bayesian logistic regression.

    Science.gov (United States)

    Chen, Carla Chia-Ming; Schwender, Holger; Keith, Jonathan; Nunkesser, Robin; Mengersen, Kerrie; Macrossan, Paula

    2011-01-01

    Due to advancements in computational ability, enhanced technology and a reduction in the price of genotyping, more data are being generated for understanding genetic associations with diseases and disorders. However, with the availability of large data sets comes the inherent challenges of new methods of statistical analysis and modeling. Considering a complex phenotype may be the effect of a combination of multiple loci, various statistical methods have been developed for identifying genetic epistasis effects. Among these methods, logic regression (LR) is an intriguing approach incorporating tree-like structures. Various methods have built on the original LR to improve different aspects of the model. In this study, we review four variations of LR, namely Logic Feature Selection, Monte Carlo Logic Regression, Genetic Programming for Association Studies, and Modified Logic Regression-Gene Expression Programming, and investigate the performance of each method using simulated and real genotype data. We contrast these with another tree-like approach, namely Random Forests, and a Bayesian logistic regression with stochastic search variable selection.

  9. Comprehensive genotyping for 18 blood group systems using a multiplex ligation-dependent probe amplification assay shows a high degree of accuracy

    NARCIS (Netherlands)

    Haer-Wigman, Lonneke; Ji, Yanli; Lodén, Martin; de Haas, Masja; van der Schoot, C. Ellen; Veldhuisen, Barbera

    2013-01-01

    In recent years genotyping methods have been implemented in blood banks as alternative to comprehensive serologic typing. We evaluated a newly developed assay for convenient and comprehensive genotyping of blood group alleles based on multiplex ligation-dependent probe amplification (MLPA)

  10. Predictive factors of esophageal stenosis associated with tumor regression in radiation therapy for locally advanced esophageal cancer

    International Nuclear Information System (INIS)

    Atsumi, Kazushige; Shioyama, Yoshiyuki; Nakamura, Katsumasa

    2010-01-01

    The purpose of this retrospective study was to clarify the predictive factors correlated with esophageal stenosis within three months after radiation therapy for locally advanced esophageal cancer. We enrolled 47 patients with advanced esophageal cancer with T2-4 and stage II-III who were treated with definitive radiation therapy and achieving complete response of primary lesion at Kyushu University Hospital between January 1998 and December 2005. Esophagography was performed for all patients before treatment and within three months after completion of the radiation therapy, the esophageal stenotic ratio was evaluated. The stenotic ratio was used to define four levels of stenosis: stenosis level 1, stenotic ratio of 0-25%; 2, 25-50%; 3, 50-75%; 4, 75-100%. We then estimated the correlation between the esophageal stenosis level after radiation therapy and each of numerous factors. The numbers and total percentages of patients at each stenosis level were as follows: level 1: n=14 (30%); level 2: 8 (17%); level 3: 14 (30%); and level 4: 11 (23%). Esophageal stenosis in the case of full circumference involvement tended to be more severe and more frequent. Increases in wall thickness tended to be associated with increases in esophageal stenosis severity and frequency. The extent of involved circumference and wall thickness of tumor region were significantly correlated with esophageal stenosis associated with tumor regression in radiation therapy (p=0.0006, p=0.005). For predicting the possibility of esophageal stenosis with tumor regression within three months in radiation therapy, the extent of involved circumference and esophageal wall thickness of the tumor region may be useful. (author)

  11. Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

    DEFF Research Database (Denmark)

    Schmidt, Marjanka K; Hogervorst, Frans; van Hien, Richard R

    2016-01-01

    PURPOSE: CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor...... subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. PATIENTS AND METHODS: CHEK2*1100delC genotyping was mostly done by a custom Taqman assay....... Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. RESULTS: Proportions...

  12. A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Paul Savage

    2017-10-01

    Full Text Available Summary: Therapies targeting epidermal growth factor receptor (EGFR have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC patient-derived xenografts (PDXs, we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR. Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster. Sorted EGFRhi subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFRhi cells gave rise to EGFRhi and EGFRlo cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFRhi subpopulations were identified in independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity. This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention. : Savage et al. demonstrate that sensitivity to EGFR inhibitor, gefitinib, in triple-negative breast cancer is paradoxically associated with EGFR heterogeneity. Using single-cell RNA sequencing in conjunction with functional assays, they identify TNBC tumors in which EGFR expression identifies cells with tumor-initiating capacity whose proliferative expansion is sensitive to EGFR inhibition. Keywords: breast cancer, tumor heterogeneity, patient-derived xenograft, single-cell RNA sequencing, EGFR inhibition, therapeutic response, tumor-initiating cell, cell hierarchy, BRCA1 mutation

  13. [Characteristics of polyamine biosynthesis regulation and tumor growth rate in hormone-dependant grafted breast tumors of mice and rats].

    Science.gov (United States)

    Orlovskiĭ, A A

    2007-01-01

    Effect of the inhibitors of polyamines biosynthesis on completely or partially hormone-dependant breast tumors (mouse Ca755 carcinoma and Walker W-256 carcinosarcoma) is essentially special: in contrary to hormone-dependant tumors, this effect may be not only breaking but stimulating as well. Change-over from one to another mode of reaction is conditioned, most probable, by hormonal status, which is determined by one or another estral cycle phase. Biochemical mechanisms of this change-over are closely connected with polyamines metabolism, namely the degree of polyamines (especially spermine) interconvertion and physiological reactivity level of the system controlling expression of ornithin-decarboxilase. At that, the first of these pathways is predominant for completely hormone-dependant Ca755 and the second one -for partially hormone-dependant W-256.

  14. Genotype dependant callogenic and morphogenic response of lycopersicon esculentum hybrids

    International Nuclear Information System (INIS)

    Jatoi, S.A.; Sajid, G.M.; Ahmad, S.; Anwar, R.; Munir, M.

    2002-01-01

    Leaf explants from field grown F1 hybrids of Lycopersicon esculentum, namely Bornia and Royesta were cultured on MS media containing 5 x 5 diallelic combinations of IAA and Kin at 0, 4, 8, 12 and 16 micro M/l each. Callogenesis, root and shoot regeneration potential of these hybrids were compared on these hormonal regimes. Royesta exhibited better callogenesis response (85%) than Bornia (72%). However, callogenesis on a given hormonal regime was genotype dependant. Root and shoot regeneration was better in case of Bornia than in Royesta. Hybrid Bornia produced shoots much more frequently (6-14%) on many diverse hormonal regimes than Royesta which produced shoots only rarely (5%) on a single hormonal regime. (author)

  15. A note on modeling of tumor regression for estimation of radiobiological parameters

    International Nuclear Information System (INIS)

    Zhong, Hualiang; Chetty, Indrin

    2014-01-01

    Purpose: Accurate calculation of radiobiological parameters is crucial to predicting radiation treatment response. Modeling differences may have a significant impact on derived parameters. In this study, the authors have integrated two existing models with kinetic differential equations to formulate a new tumor regression model for estimation of radiobiological parameters for individual patients. Methods: A system of differential equations that characterizes the birth-and-death process of tumor cells in radiation treatment was analytically solved. The solution of this system was used to construct an iterative model (Z-model). The model consists of three parameters: tumor doubling time T d , half-life of dead cells T r , and cell survival fraction SF D under dose D. The Jacobian determinant of this model was proposed as a constraint to optimize the three parameters for six head and neck cancer patients. The derived parameters were compared with those generated from the two existing models: Chvetsov's model (C-model) and Lim's model (L-model). The C-model and L-model were optimized with the parameter T d fixed. Results: With the Jacobian-constrained Z-model, the mean of the optimized cell survival fractions is 0.43 ± 0.08, and the half-life of dead cells averaged over the six patients is 17.5 ± 3.2 days. The parameters T r and SF D optimized with the Z-model differ by 1.2% and 20.3% from those optimized with the T d -fixed C-model, and by 32.1% and 112.3% from those optimized with the T d -fixed L-model, respectively. Conclusions: The Z-model was analytically constructed from the differential equations of cell populations that describe changes in the number of different tumor cells during the course of radiation treatment. The Jacobian constraints were proposed to optimize the three radiobiological parameters. The generated model and its optimization method may help develop high-quality treatment regimens for individual patients

  16. Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in a murine melanoma model

    DEFF Research Database (Denmark)

    Sørensen, Maria Rathmann; Holst, Peter J; Steffensen, Maria Abildgaard

    2010-01-01

    that the delay in tumor growth can be converted to complete regression and long-term survival in 30-40% of the mice by a booster vaccination plus combinational treatment with agonistic anti-CD40 monoclonal antibodies (mAb) and anti-CTLA-4 mAb. Regarding the mechanism underlying the improved clinical effect......, analysis of the tumor-specific response revealed a significantly prolonged tumor-specific CD8 T cell response in spleens of the mice receiving the combinational treatment compared with mice receiving either treatment individually. Matching this, CD8 T cell depletion completely prevented tumor control...

  17. Comparative characteristics of immune answers indicators depending on the replicative activity and genotype of hepatitis c virus

    Directory of Open Access Journals (Sweden)

    Олеся Василівна Гололобова

    2015-08-01

    Full Text Available Aim. To analyze the character of changes and disorders of immune system with the help of complex study of indicators of cellular and humor section of immunity, cytokine status in patients with HCV-infection taking into account the replicative activity, genotype of virus and to formulate the possible causes of chronization.Methods. There were examined 155 patients with HCV-infection. An acute hepatitis C AHC was fixed in 23,9 %, chronic hepatitis C (CHC– in 76,1 %, 18–70 years old. Among examined patients with AHC and CHC prevailed men (67,6 and 72 % respectively. Diagnosis was set on the base of clinic and amnestic, epidemiologic, laboratory and instrumental data. Epidemiologic verification of diagnosis was realized by detection the specific serologic markers of HC (anti-HCV (sum, anti-HCV IgM and Ig G, anti-HCV core and anti-HCV NS-3, NS-4, NS-5 in blood serum using ELISA method. Molecular and genetic studies that included definition of replicative activity of HCV evaluated on the base of detection of RNA HCV in blood serum using the qualitative PCR method were carried out in 126 patients (31 with AHC and 95 with CHC. At the same time RNA of HCV was detected in peripheral blood in all (31 patients with AHC and in 74 (77,89 % patients with CHC. Using the method of restriction analysis we carried out the genetic typing of HCV in 90 patients with AHC and 60 with CHC. We carried out the comparative characteristics of the content of immunologic indicators in 45 (75 % patients with CHC with positive and 15 (25 % patients with negative results of PCR-study (polymerase chain reaction of HCV RNA in blood. For detection of regularities of changes of immune status depending on virus genotype there was carried out the comparative assessment of the content of immunologic indicators in patients with AHC and CHC with the most widespread genotypes of HVC– 1b and 3a. Immunologic studies included the definitions of the main subpopulations of lymphocytes

  18. Occurrence of mammary tumors in beagls given radium-226

    International Nuclear Information System (INIS)

    Bruenger, F.W.; Lloyd, R.D.; Miller, S.C.; Taylor, G.N.; Angus, W.; Huth, D.A.

    1994-01-01

    A total of 128 primary mammary tumors (66 of them malignant) occurred in 35 female beagles injected with 226 Ra at eight dose levels ranging from 0.2 to 440 kBq/kg body mass as young adults, while a total of 156 mammary tumors (57 of them malignant) were seen in 46 female control beagles not given any radioactivity. Sixty-three of 65 control dogs and 59 of 61 dogs given 226 Ra survived the minimum age for diagnosis of mammary tumors of 3.75 years. Based on the observed age-dependent tumor incidence rates in the controls and on the corresponding number of dog-years at risk, the total number of observed malignant tumors in the radium group was statistically greater than the number of expected malignant tumors (66 observed vs 34 expected, P < 0.005). There was no such difference for the benign tumors. Cox regression analysis indicated no increased risk for the first tumor occurrence in irradiated dogs. Cox regression analysis of the multivariate risk sets showed no significantly increased risk for the occurrence of benign tumors but a statistically higher risk of 1.66 with a confidence interval of 1.15-2.40 for the occurrence of malignant tumors. The increased risk was dependent on dose, but a dependence on the frequency of previous occurrence of mammary tumors could not be confirmed. Censoring ovariectomized dogs at time of surgery decreased the relative risks slightly but did not alter the significance. Exposure to diagnostic X rays with cumulative exposures below 0.2 Gy had no effect on tumor formation. It is unknown whether the increased risk for malignant mammary tumors was due to some initial deposition of radium in sensitive tissue, a possible irradiation of fatty mammary tissue from transient radon → polonium deposition, or a general effect of the overall radium deposition on the immune system of the dogs that lowered their resistance to formation of mammary tumors. 27 refs., 5 figs., 4 tabs

  19. Role of Erbin in ErbB2-dependent breast tumor growth

    Science.gov (United States)

    Tao, Yanmei; Shen, Chengyong; Luo, Shiwen; Traoré, Wilfried; Marchetto, Sylvie; Santoni, Marie-Josée; Xu, Linlin; Wu, Biao; Shi, Chao; Mei, Jinghong; Bates, Ryan; Liu, Xihui; Zhao, Kai; Xiong, Wen-Cheng; Borg, Jean-Paul; Mei, Lin

    2014-01-01

    ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression. PMID:25288731

  20. Indirect macrophage responses to ionizing radiation: implications for genotype-dependent bystander signaling.

    Science.gov (United States)

    Coates, Philip J; Rundle, Jana K; Lorimore, Sally A; Wright, Eric G

    2008-01-15

    In addition to the directly mutagenic effects of energy deposition in DNA, ionizing radiation is associated with a variety of untargeted and delayed effects that result in ongoing bone marrow damage. Delayed effects are genotype dependent with CBA/Ca mice, but not C57BL/6 mice, susceptible to the induction of damage and also radiation-induced acute myeloid leukemia. Because macrophages are a potential source of ongoing damaging signals, we have determined their gene expression profiles and we show that bone marrow-derived macrophages show widely different intrinsic expression patterns. The profiles classify macrophages derived from CBA/Ca mice as M1-like (pro-inflammatory) and those from C57BL/6 mice as M2-like (anti-inflammatory); measurements of NOS2 and arginase activity in normal bone marrow macrophages confirm these findings. After irradiation in vivo, but not in vitro, C57BL/6 macrophages show a reduction in NOS2 and an increase in arginase activities, indicating a further M2 response, whereas CBA/Ca macrophages retain an M1 phenotype. Activation of specific signal transducer and activator of transcription signaling pathways in irradiated hemopoietic tissues supports these observations. The data indicate that macrophage activation is not a direct effect of radiation but a tissue response, secondary to the initial radiation exposure, and have important implications for understanding genotype-dependent responses and the mechanisms of the hemotoxic and leukemogenic consequences of radiation exposure.

  1. The in vivo mechanism of action of CD20 monoclonal antibodies depends on local tumor burden

    Science.gov (United States)

    Boross, Peter; Jansen, J.H. Marco; de Haij, Simone; Beurskens, Frank J.; van der Poel, Cees E.; Bevaart, Lisette; Nederend, Maaike; Golay, Josée; van de Winkel, Jan G.J.; Parren, Paul W.H.I.; Leusen, Jeanette H.W.

    2011-01-01

    Background CD20 monoclonal antibodies are widely used in clinical practice. Antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and direct cell death have been suggested to be important effector functions for CD20 antibodies. However, their specific contributions to the in vivo mechanism of action of CD20 immunotherapy have not been well defined. Design and Methods Here we studied the in vivo mechanism of action of type I (rituximab and ofatumumab) and type II (HuMab-11B8) CD20 antibodies in a peritoneal, syngeneic, mouse model with EL4-CD20 cells using low and high tumor burden. Results Interestingly, we observed striking differences in the in vivo mechanism of action of CD20 antibodies dependent on tumor load. In conditions of low tumor burden, complement was sufficient for tumor killing both for type I and type II CD20 antibodies. In contrast, in conditions of high tumor burden, activating FcγR (specifically FcγRIII), active complement and complement receptor 3 were all essential for tumor killing. Our data suggest that complement-enhanced antibody-dependent cellular cytotoxicity may critically affect tumor killing by CD20 antibodies in vivo. The type II CD20 antibody 11B8, which is a poor inducer of complement activation, was ineffective against high tumor burden. Conclusions Tumor burden affects the in vivo mechanism of action of CD20 antibodies. Low tumor load can be eliminated by complement alone, whereas elimination of high tumor load requires multiple effector mechanisms. PMID:21880632

  2. Effect of genotyped cows in the reference population on the genomic evaluation of Holstein cattle.

    Science.gov (United States)

    Uemoto, Y; Osawa, T; Saburi, J

    2017-03-01

    This study evaluated the dependence of reliability and prediction bias on the prediction method, the contribution of including animals (bulls or cows), and the genetic relatedness, when including genotyped cows in the progeny-tested bull reference population. We performed genomic evaluation using a Japanese Holstein population, and assessed the accuracy of genomic enhanced breeding value (GEBV) for three production traits and 13 linear conformation traits. A total of 4564 animals for production traits and 4172 animals for conformation traits were genotyped using Illumina BovineSNP50 array. Single- and multi-step methods were compared for predicting GEBV in genotyped bull-only and genotyped bull-cow reference populations. No large differences in realized reliability and regression coefficient were found between the two reference populations; however, a slight difference was found between the two methods for production traits. The accuracy of GEBV determined by single-step method increased slightly when genotyped cows were included in the bull reference population, but decreased slightly by multi-step method. A validation study was used to evaluate the accuracy of GEBV when 800 additional genotyped bulls (POPbull) or cows (POPcow) were included in the base reference population composed of 2000 genotyped bulls. The realized reliabilities of POPbull were higher than those of POPcow for all traits. For the gain of realized reliability over the base reference population, the average ratios of POPbull gain to POPcow gain for production traits and conformation traits were 2.6 and 7.2, respectively, and the ratios depended on heritabilities of the traits. For regression coefficient, no large differences were found between the results for POPbull and POPcow. Another validation study was performed to investigate the effect of genetic relatedness between cows and bulls in the reference and test populations. The effect of genetic relationship among bulls in the reference

  3. Tumor regression induced by intratumor therapy with a disabled infectious single cycle (DISC) herpes simplex virus (HSV) vector, DISC/HSV/murine granulocyte-macrophage colony-stimulating factor, correlates with antigen-specific adaptive immunity.

    Science.gov (United States)

    Ali, Selman A; Lynam, June; McLean, Cornelia S; Entwisle, Claire; Loudon, Peter; Rojas, José M; McArdle, Stephanie E B; Li, Geng; Mian, Shahid; Rees, Robert C

    2002-04-01

    Direct intratumor injection of a disabled infectious single cycle HSV-2 virus encoding the murine GM-CSF gene (DISC/mGM-CSF) into established murine colon carcinoma CT26 tumors induced a significant delay in tumor growth and complete tumor regression in up to 70% of animals. Pre-existing immunity to HSV did not reduce the therapeutic efficacy of DISC/mGM-CSF, and, when administered in combination with syngeneic dendritic cells, further decreased tumor growth and increased the incidence of complete tumor regression. Direct intratumor injection of DISC/mGM-CSF also inhibited the growth of CT26 tumor cells implanted on the contralateral flank or seeded into the lungs following i.v. injection of tumor cells (experimental lung metastasis). Proliferation of splenocytes in response to Con A was impaired in progressor and tumor-bearer, but not regressor, mice. A potent tumor-specific CTL response was generated from splenocytes of all mice with regressing, but not progressing tumors following in vitro peptide stimulation; this response was specific for the gp70 AH-1 peptide SPSYVYHQF and correlated with IFN-gamma, but not IL-4 cytokine production. Depletion of CD8(+) T cells from regressor splenocytes before in vitro stimulation with the relevant peptide abolished their cytolytic activity, while depletion of CD4(+) T cells only partially inhibited CTL generation. Tumor regression induced by DISC/mGM-CSF virus immunotherapy provides a unique model for evaluating the immune mechanism(s) involved in tumor rejection, upon which tumor immunotherapy regimes may be based.

  4. Dose-Dependent Effects of Statins for Patients with Aneurysmal Subarachnoid Hemorrhage: Meta-Regression Analysis.

    Science.gov (United States)

    To, Minh-Son; Prakash, Shivesh; Poonnoose, Santosh I; Bihari, Shailesh

    2018-05-01

    The study uses meta-regression analysis to quantify the dose-dependent effects of statin pharmacotherapy on vasospasm, delayed ischemic neurologic deficits (DIND), and mortality in aneurysmal subarachnoid hemorrhage. Prospective, retrospective observational studies, and randomized controlled trials (RCTs) were retrieved by a systematic database search. Summary estimates were expressed as absolute risk (AR) for a given statin dose or control (placebo). Meta-regression using inverse variance weighting and robust variance estimation was performed to assess the effect of statin dose on transformed AR in a random effects model. Dose-dependence of predicted AR with 95% confidence interval (CI) was recovered by using Miller's Freeman-Tukey inverse. The database search and study selection criteria yielded 18 studies (2594 patients) for analysis. These included 12 RCTs, 4 retrospective observational studies, and 2 prospective observational studies. Twelve studies investigated simvastatin, whereas the remaining studies investigated atorvastatin, pravastatin, or pitavastatin, with simvastatin-equivalent doses ranging from 20 to 80 mg. Meta-regression revealed dose-dependent reductions in Freeman-Tukey-transformed AR of vasospasm (slope coefficient -0.00404, 95% CI -0.00720 to -0.00087; P = 0.0321), DIND (slope coefficient -0.00316, 95% CI -0.00586 to -0.00047; P = 0.0392), and mortality (slope coefficient -0.00345, 95% CI -0.00623 to -0.00067; P = 0.0352). The present meta-regression provides weak evidence for dose-dependent reductions in vasospasm, DIND and mortality associated with acute statin use after aneurysmal subarachnoid hemorrhage. However, the analysis was limited by substantial heterogeneity among individual studies. Greater dosing strategies are a potential consideration for future RCTs. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. HPV prevalence and genotypes in different histological subtypes of cervical adenocarcinoma, a worldwide analysis of 760 cases.

    Science.gov (United States)

    Pirog, Edyta C; Lloveras, Belen; Molijn, Anco; Tous, Sara; Guimerà, Núria; Alejo, Maria; Clavero, Omar; Klaustermeier, Joellen; Jenkins, David; Quint, Wim Gv; Xavier Bosch, Francesc; Alemany, Laia; de Sanjosé, Silvia

    2014-12-01

    The goal of our study was to provide comprehensive data on the worldwide human papillomavirus (HPV) genotype distribution in patients with invasive cervical adenocarcinoma in correlation with histologic tumor subtypes, geographical location, patients' age, and duration of sample storage. Paraffin-embedded samples of 760 cervical adenocarcinoma cases were collected worldwide. A three-level pathology review of cases was performed to obtain consensus histologic diagnoses and 682 cases were determined to be eligible for further analysis. HPV DNA detection and genotyping was performed using SPF-10/DEIA/LiPA(25) system (version 1). Classic cervical adenocarcinoma accounted for 83.1% of cases, while rare histological variants accounted for a few percent of cases individually. HPV positivity varied significantly between the different histologic tumor subtypes. Classic cervical adenocarcinoma showed high HPV positivity (71.8%), while other adenocarcinoma types had significantly lower HPV prevalence (endometrioid 27.3%, serous 25%, clear cell 20%, not otherwise specified 13.9%, and minimal deviation 8.3%). In all, 91.8% of HPV-positive tumors showed the presence of a single viral type and in 7% of cases multiple viral types were detected. Three HPV genotypes, HPV 16, 18, and 45, dominated in all adenocarcinomas and together accounted for 94.1% of HPV-positive tumors. HPV16 was the most common and found in 50.9% of HPV-positive cases, followed by HPV18 (31.6%) and HPV45 (11.6%). HPV prevalence varied depending on geographical region, patient age, and sample storage time. Tumors from older patients and tumor samples with longer storage time showed lower HPV prevalence. Our results indicate that HPV vaccines may prevent up to 82.5% (HPV16/18) and up to 95.3% (9-valent vaccine) of HPV-positive cervical adenocarcinomas, mostly the classic type. HPV testing and vaccination will not provide full coverage for a very small subset of classical adenocarcinomas and most of the rare

  6. Condition-dependence, genotype-by-environment interactions and the lek paradox.

    Science.gov (United States)

    Kokko, Hanna; Heubel, Katja

    2008-09-01

    The lek paradox states that maintaining genetic variation necessary for 'indirect benefit' models of female choice is difficult, and two interrelated solutions have been proposed. 'Genic capture' assumes condition-dependence of sexual traits, while genotype-by-environment interactions (GEIs) offer an additional way to maintain diversity. However, condition-dependence, particularly with GEIs, implies that environmental variation can blur the relationship between male displays and offspring fitness. These issues have been treated separately in the past. Here we combine them in a population genetic model, and show that predictions change not only in magnitude but also in direction when the timing of dispersal between environments relative to the life cycle is changed. GEIs can dramatically improve the evolution of costly female preferences, but also hamper it if much dispersal occurs between the life history stage where condition is determined and mating. This situation also arises if selection or mutation rates are too high. In general, our results highlight that when evaluating any mechanism promoted as a potential resolution of the lek paradox, it is not sufficient to focus on its effects on genetic variation. It also has to be assessed to what extent the proposed mechanism blurs the association between male attractiveness and offspring fitness; the net balance of these two effects can be positive or negative, and often strongly context-dependent.

  7. CHRNA3 genotype, nicotine dependence, lung function and disease in the general population

    DEFF Research Database (Denmark)

    Kaur-Knudsen, Diljit; Nordestgaard, Børge G; Bojesen, Stig E

    2012-01-01

    The CHRNA3 rs1051730 polymorphism has been associated to chronic obstructive pulmonary disease (COPD), lung cancer and nicotine dependence in case-control studies with high smoking exposure; however, its influence on lung function and COPD severity in the general population is largely unknown. We...... genotyped 57,657 adult individuals from the Copenhagen General Population Study, of whom 34,592 were ever-smokers. Information on spirometry, hospital admissions, smoking behaviour and use of nicotinic replacement therapy was recorded. In homozygous (11%), heterozygous (44%) and noncarrier (45%) ever...

  8. Effects of acute dopamine precusor depletion on immediate reward selection bias and working memory depend on catechol-O-methyltransferase genotype.

    Science.gov (United States)

    Kelm, Mary Katherine; Boettiger, Charlotte A

    2013-12-01

    Little agreement exists as to acute dopamine (DA) manipulation effects on intertemporal choice in humans. We previously found that catechol-O-methyltransferase (COMT) Val158Met genotype predicts individual differences in immediate reward selection bias among adults. Moreover, we and others have shown that the relationship between COMT genotype and immediate reward bias is inverted in adolescents. No previous pharmacology studies testing DA manipulation effects on intertemporal choice have accounted for COMT genotype, and many have included participants in the adolescent age range (18-21 years) as adults. Moreover, many studies have included female participants without strict cycle phase control, although recent evidence demonstrates that cyclic estradiol elevations interact with COMT genotype to affect DA-dependent cognition. These factors may have interacted with DA manipulations in past studies, potentially occluding detection of effects. Therefore, we predicted that, among healthy male adults (ages 22-40 years), frontal DA tone, as indexed by COMT genotype, would interact with acute changes in DA signaling to affect intertemporal choice. In a double-blind, placebo-controlled design, we decreased central DA via administration of an amino acid beverage deficient in the DA precursors, phenylalanine and tyrosine, and tested effects on immediate reward bias in a delay-discounting (DD) task and working memory (WM) in an n-back task. We found no main effect of beverage on DD or WM performance but did find significant beverage*genotype effects. These results suggest that the effect of DA manipulations on DD depends on individual differences in frontal DA tone, which may have impeded some past efforts to characterize DA's role in immediate reward bias in humans.

  9. Preclinical experiments for analysis of tumor regression due to negative pions

    International Nuclear Information System (INIS)

    Blattmann, H.; Cabeza, L.; Fritz-Niggli, H.

    To test the potential therapeutic value of negative pions in comparison with conventional x-rays, cobalt-60 γ rays, and high energy electrons and photons (Betatron), experimental analyses with induced tumors (transplant tumors) after irradiation are to be performed in vivo and in vitro (tumor cell suspensions, cell cultures, spontaneous tumors, carcinoma in ascites form); in addition to tumors primarily of mice, human cell tumors will be used; studies will also be made of cell kinetics with various cell types (normal cells, transformed (malignant) cells, beam-resistant, beam-sensitive types) using cell cultures from Chinese hamsters. An attempt will be made to compare slow- and fast-growing tumors. In a second phase, human tumors in conditioned animals will be tested in situ or as cell cultures. Skin, small intestine, regenerating liver and kidney, together with cell cultures, will serve as normal reaction systems

  10. PET measurements of hyperthermia-induced suppression of protein synthesis in tumors in relation to effects on tumor growth

    International Nuclear Information System (INIS)

    Daemen, B.J.; Elsinga, P.H.; Mooibroek, J.; Paans, A.M.; Wieringa, A.R.; Konings, A.W.; Vaalburg, W.

    1991-01-01

    Hyperthermia-induced metabolic changes in tumor tissue have been monitored by PET. Uptake of L-[1-11C]tyrosine in rhabdomyosarcoma tissue of Wag/Rij rats was dose-dependently reduced after local hyperthermia treatment at 42, 45, or 47 degrees C. Tumor blood flow, as measured by PET with 13NH3, appeared to be unchanged. The L-[1-11C]tyrosine uptake data were compared to uptake data of L-[1-14C]tyrosine and with data on the incorporation of L-[1-14C]tyrosine into tumor proteins. After intravenous injection, the 14C data were obtained from dissected tumor tissue. Heat-induced inhibition of the incorporation of L-[1-14C]tyrosine into tumor proteins tallied with the L-[1-11C]tyrosine uptake data. Heat-induced inhibition of amino acid uptake in the tumor correlated well with regression of tumor growth. It is concluded that PET using L-[1-11C]tyrosine is eligible for monitoring the effect of hyperthermia on tumor growth

  11. Using the classical linear regression model in analysis of the dependences of conveyor belt life

    Directory of Open Access Journals (Sweden)

    Miriam Andrejiová

    2013-12-01

    Full Text Available The paper deals with the classical linear regression model of the dependence of conveyor belt life on some selected parameters: thickness of paint layer, width and length of the belt, conveyor speed and quantity of transported material. The first part of the article is about regression model design, point and interval estimation of parameters, verification of statistical significance of the model, and about the parameters of the proposed regression model. The second part of the article deals with identification of influential and extreme values that can have an impact on estimation of regression model parameters. The third part focuses on assumptions of the classical regression model, i.e. on verification of independence assumptions, normality and homoscedasticity of residuals.

  12. Ordinary least square regression, orthogonal regression, geometric mean regression and their applications in aerosol science

    International Nuclear Information System (INIS)

    Leng Ling; Zhang Tianyi; Kleinman, Lawrence; Zhu Wei

    2007-01-01

    Regression analysis, especially the ordinary least squares method which assumes that errors are confined to the dependent variable, has seen a fair share of its applications in aerosol science. The ordinary least squares approach, however, could be problematic due to the fact that atmospheric data often does not lend itself to calling one variable independent and the other dependent. Errors often exist for both measurements. In this work, we examine two regression approaches available to accommodate this situation. They are orthogonal regression and geometric mean regression. Comparisons are made theoretically as well as numerically through an aerosol study examining whether the ratio of organic aerosol to CO would change with age

  13. Primary tumor regression speed after radiotherapy and its prognostic significance in nasopharyngeal carcinoma: a retrospective study

    International Nuclear Information System (INIS)

    Zhang, Ning; Liu, Dong-Sheng; Chen, Yong; Liang, Shao-Bo; Deng, Yan-Ming; Lu, Rui-Liang; Chen, Hai-Yang; Zhao, Hai; Lv, Zhi-Qian; Liang, Shao-Qiang; Yang, Lin

    2014-01-01

    To observe the primary tumor (PT) regression speed after radiotherapy (RT) in nasopharyngeal carcinoma (NPC) and evaluate its prognostic significance. One hundred and eighty-eight consecutive newly diagnosed NPC patients were reviewed retrospectively. All patients underwent magnetic resonance imaging and fiberscope examination of the nasopharynx before RT, during RT when the accumulated dose was 46–50 Gy, at the end of RT, and 3–4 months after RT. Of 188 patients, 40.4% had complete response of PT (CRPT), 44.7% had partial response of PT (PRPT), and 14.9% had stable disease of PT (SDPT) at the end of RT. The 5-year overall survival (OS) rates for patients with CRPT, PRPT, and SDPT at the end of RT were 84.0%, 70.7%, and 44.3%, respectively (P < 0.001, hazard ratio [HR] = 2.177, 95% confidence interval [CI] = 1.480-3.202). The 5-year failure-free survival (FFS) and distant metastasis-free survival (DMFS) rates also differed significantly (87.8% vs. 74.3% vs. 52.7%, P = 0.001, HR = 2.148, 95% CI, 1.384-3.333; 91.7% vs. 84.7% vs. 66.1%, P = 0.004, HR = 2.252, 95% CI = 1.296-3.912). The 5-year local relapse–free survival (LRFS) rates were not significantly different (95.8% vs. 86.0% vs. 81.8%, P = 0.137, HR = 1.975, 95% CI, 0.976-3.995). By multivariate analyses, the PT regression speed at the end of RT was the only independent prognostic factor of OS, FFS, and DMFS (P < 0.001, P = 0.001, and P = 0.004, respectively). The 5-year FFS rates for patients with CRPT during RT and CRPT only at the end of RT were 80.2% and 97.1%, respectively (P = 0.033). For patients with persistent PT at the end of RT, the 5-year LRFS rates of patients without and with boost irradiation were 87.1% and 84.6%, respectively (P = 0.812). PT regression speed at the end of RT was an independent prognostic factor of OS, FFS, and DMFS in NPC patients. Immediate strengthening treatment may be provided to patients with poor tumor regression at the end of RT

  14. Cell culture-adaptive mutations of NS5A affect replication of hepatitis C virus differentially depending on the viral genotypes.

    Science.gov (United States)

    Chung, Aeri; Jin, Bora; Han, Kwang-Hyub; Ahn, Sang Hoon; Kim, Seungtaek

    2017-01-01

    Most of HCV RNAs require cell culture-adaptive mutations for efficient replication in cell culture and a number of such mutations have been described including a well-known S2204I substitution mutation in NS5A protein. In contrast, the replication of genotype 2a JFH1 RNA in cell culture does not require any cell culture-adaptive mutation. Rather, the presence of S2204I mutation impaired the JFH1 RNA replication. In this study, we examined the effect of reversions and substitutions of NS5A cell culture-adaptive mutations on virus replication in different genotypic backgrounds after either placing genotype 1a NS5A in the genotype 2a JFH1 or vice versa. The results from this investigation suggest that the S2204I mutation affects HCV RNA replication differentially depending on the viral genotypes but that the effect was not simply explained by the genotypic background. Perhaps, the effect of the S2204I mutation on HCV replication reflects both intra- and intergenic interactions of NS5A protein. J. Med. Virol. 89:146-152, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Improved Regression Analysis of Temperature-Dependent Strain-Gage Balance Calibration Data

    Science.gov (United States)

    Ulbrich, N.

    2015-01-01

    An improved approach is discussed that may be used to directly include first and second order temperature effects in the load prediction algorithm of a wind tunnel strain-gage balance. The improved approach was designed for the Iterative Method that fits strain-gage outputs as a function of calibration loads and uses a load iteration scheme during the wind tunnel test to predict loads from measured gage outputs. The improved approach assumes that the strain-gage balance is at a constant uniform temperature when it is calibrated and used. First, the method introduces a new independent variable for the regression analysis of the balance calibration data. The new variable is designed as the difference between the uniform temperature of the balance and a global reference temperature. This reference temperature should be the primary calibration temperature of the balance so that, if needed, a tare load iteration can be performed. Then, two temperature{dependent terms are included in the regression models of the gage outputs. They are the temperature difference itself and the square of the temperature difference. Simulated temperature{dependent data obtained from Triumph Aerospace's 2013 calibration of NASA's ARC-30K five component semi{span balance is used to illustrate the application of the improved approach.

  16. HFE genotype affects exosome phenotype in cancer.

    Science.gov (United States)

    Mrowczynski, Oliver D; Madhankumar, A B; Slagle-Webb, Becky; Lee, Sang Y; Zacharia, Brad E; Connor, James R

    2017-08-01

    Neuroblastoma is the third most common childhood cancer, and timely diagnosis and sensitive therapeutic monitoring remain major challenges. Tumor progression and recurrence is common with little understanding of mechanisms. A major recent focus in cancer biology is the impact of exosomes on metastatic behavior and the tumor microenvironment. Exosomes have been demonstrated to contribute to the oncogenic effect on the surrounding tumor environment and also mediate resistance to therapy. The effect of genotype on exosomal phenotype has not yet been explored. We interrogated exosomes from human neuroblastoma cells that express wild-type or mutant forms of the HFE gene. HFE, one of the most common autosomal recessive polymorphisms in the Caucasian population, originally associated with hemochromatosis, has also been associated with increased tumor burden, therapeutic resistance boost, and negative impact on patient survival. Herein, we demonstrate that changes in genotype cause major differences in the molecular and functional properties of exosomes; specifically, HFE mutant derived exosomes have increased expression of proteins relating to invasion, angiogenesis, and cancer therapeutic resistance. HFE mutant derived exosomes were also shown to transfer this cargo to recipient cells and cause an increased oncogenic functionality in those recipient cells. Copyright © 2017. Published by Elsevier B.V.

  17. YKL-40/c-Met expression in rectal cancer biopsies predicts tumor regression following neoadjuvant chemoradiotherapy: a multi-institutional study.

    Science.gov (United States)

    Senetta, Rebecca; Duregon, Eleonora; Sonetto, Cristina; Spadi, Rossella; Mistrangelo, Massimiliano; Racca, Patrizia; Chiusa, Luigi; Munoz, Fernando H; Ricardi, Umberto; Arezzo, Alberto; Cassenti, Adele; Castellano, Isabella; Papotti, Mauro; Morino, Mario; Risio, Mauro; Cassoni, Paola

    2015-01-01

    Neoadjuvant chemo-radiotherapy (CRT) followed by surgical resection is the standard treatment for locally advanced rectal cancer, although complete tumor pathological regression is achieved in only up to 30% of cases. A clinicopathological and molecular predictive stratification of patients with advanced rectal cancer is still lacking. Here, c-Met and YKL-40 have been studied as putative predictors of CRT response in rectal cancer, due to their reported involvement in chemoradioresistance in various solid tumors. A multicentric study was designed to assess the role of c-Met and YKL-40 expression in predicting chemoradioresistance and to correlate clinical and pathological features with CRT response. Immunohistochemistry and fluorescent in situ hybridization for c-Met were performed on 81 rectal cancer biopsies from patients with locally advanced rectal adenocarcinoma. All patients underwent standard (50.4 gy in 28 fractions + concurrent capecitabine 825 mg/m2) neoadjuvant CRT or the XELOXART protocol. CRT response was documented on surgical resection specimens and recorded as tumor regression grade (TRG) according to the Mandard criteria. A significant correlation between c-Met and YKL-40 expression was observed (R = 0.43). The expressions of c-Met and YKL-40 were both significantly associated with a lack of complete response (86% and 87% of c-Met and YKL-40 positive cases, prectal cancer. Targeted therapy protocols could take advantage of prior evaluations of c-MET and YKL-40 expression levels to increase therapeutic efficacy.

  18. DLEC1 Expression Is Modulated by Epigenetic Modifications in Hepatocelluar Carcinoma Cells: Role of HBx Genotypes

    International Nuclear Information System (INIS)

    Niu, Dandan; Feng, Huixing; Chen, Wei Ning

    2010-01-01

    Deleted in Lung and Esophageal Cancer 1 (DLEC1) is a functional tumor suppressor gene (TSG). It has been found to be silenced in a variety of human cancers including hepatocellular carcinoma (HCC). The silencing of DLEC1 can be modulated by epigenetic modifications, such as DNA hypermethylation and histone hypoacetylation. In the case of HCC, hepatitis B virus X protein (HBx) has been implicated in methylation of target promoters resulting in the down-regulation of tumor suppressor genes, which in turn contributes to the development of HCC. In the present study, we first established a cell system in which epigenetic modifications can be modulated using inhibitors of either DNA methylation or histone deacetylation. The cell system was used to reveal that the expression of DLEC1 was upregulated by HBx in a genotype-dependent manner. In particular, HBx genotype A was found to decrease DNA methylation of the DLEC1 promoter. Our results have provided new insights on the impact of HBx in HCC development by epigenetic modifications

  19. [Correlation coefficient-based classification method of hydrological dependence variability: With auto-regression model as example].

    Science.gov (United States)

    Zhao, Yu Xi; Xie, Ping; Sang, Yan Fang; Wu, Zi Yi

    2018-04-01

    Hydrological process evaluation is temporal dependent. Hydrological time series including dependence components do not meet the data consistency assumption for hydrological computation. Both of those factors cause great difficulty for water researches. Given the existence of hydrological dependence variability, we proposed a correlationcoefficient-based method for significance evaluation of hydrological dependence based on auto-regression model. By calculating the correlation coefficient between the original series and its dependence component and selecting reasonable thresholds of correlation coefficient, this method divided significance degree of dependence into no variability, weak variability, mid variability, strong variability, and drastic variability. By deducing the relationship between correlation coefficient and auto-correlation coefficient in each order of series, we found that the correlation coefficient was mainly determined by the magnitude of auto-correlation coefficient from the 1 order to p order, which clarified the theoretical basis of this method. With the first-order and second-order auto-regression models as examples, the reasonability of the deduced formula was verified through Monte-Carlo experiments to classify the relationship between correlation coefficient and auto-correlation coefficient. This method was used to analyze three observed hydrological time series. The results indicated the coexistence of stochastic and dependence characteristics in hydrological process.

  20. Early life stress predicts negative urgency through brooding, depending on 5-HTTLPR genotype: A pilot study with 6-month follow-up examining suicide ideation.

    Science.gov (United States)

    Valderrama, Jorge; Miranda, Regina

    2017-12-01

    The present study examined the interaction between early life stress and 5-HTT genotypes in predicting two risk factors for suicidal behavior - the brooding subtype of rumination and impulsivity, in the form of negative urgency - over time. Furthermore, we examined early life stress, brooding, and impulsivity as predictors of suicidal ideation over time. Participants with and without a history of early life stress were genotyped for the 5-HTTLPR polymorphism and completed assessments assessing brooding and negative urgency at baseline and 6-month follow up. Early life emotional abuse was associated with negative urgency at follow-up. We found an indirect effect of early life emotional abuse on negative urgency through brooding among individuals with 5-HTT low expressing genotypes but not among individuals with 5-HTT high expressing genotypes. Further, a logistic regression analysis revealed that negative urgency was associated with higher odds (O.R. = 16.2) of reporting suicide ideation (versus no ideation) at follow-up. Our findings suggest that brooding and negative urgency may result from the interaction between early life emotional abuse and 5-HTT low expressing genotypes. Further research is necessary to understand how early life stress interacts with 5-HTT genotypes to confer risk for suicidal behavior through psychological mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Genetic ecotoxicology IV: survival and DNA strand breakage is dependent on genotype in radionuclide-exposed mosquitofish

    Energy Technology Data Exchange (ETDEWEB)

    Theodorakis, C.W. [Texas A and M University, Department of Wildlife and Fisheries Sciences, College Station, TX 77843-2258 (United States); Elbl, T. [University of Pennsylvania, Department of Cell and Molecular Biology, Philadelphia, PA 19102 (United States); Shugart, L.R. [L.R. Shugart and Associates, Oak Ridge, TN 37831 (United States)

    1999-05-01

    Western mosquitofish (Gambusia affinis) were caged in situ in a radioactively-contaminated pond in order to determine if survival and amount of DNA strand breakage were dependent on genotype. Genotypes of fish were determined using the randomly amplified polymorphic (RAPD) technique, and DNA strand breakage was determined using agarose gel electrophoresis. This study is a continuation of research undertaken at the Oak Ridge National Laboratory, which examined the effects of radionuclide contamination on the population genetic structure of mosquitofish. The previous research found 17 RAPD markers that were present at a higher frequency in contaminated than in reference populations ('contaminant-indicative bands'), and fish from contaminated sites which possessed these markers had higher fecundity and fewer strand breaks than fish which did not. One of the contaminated populations (Pond 3513) was colonized from one of the reference populations (Crystal Springs) in 1977. In the present study, fish were obtained from Crystal Springs and an additional reference site, and caged in Pond 3513. The percent survival and amount of DNA strand breakage were then determined for fish with and without the contaminant-indicative markers. When Crystal Springs fish were caged in Pond 3513, it was found that the genotypic distribution of the survivors was more similar to the native Pond 3513 population than to the Crystal Springs population. Furthermore, for nine of the contaminant-indicative markers, the percent survival was greater for fish which possessed these markers than for fish which did not. For five of these markers, fish which possessed them had higher DNA integrity (fewer strand breaks) than fish which did not. These data indicate that probability of survival and degree of DNA strand breakage in radionuclide-exposed mosquitofish are dependent on RAPD genotype, and are consistent with the hypothesis that the contaminant-indicative RAPD bands are markers of loci

  2. Regression Analysis for Multivariate Dependent Count Data Using Convolved Gaussian Processes

    OpenAIRE

    Sofro, A'yunin; Shi, Jian Qing; Cao, Chunzheng

    2017-01-01

    Research on Poisson regression analysis for dependent data has been developed rapidly in the last decade. One of difficult problems in a multivariate case is how to construct a cross-correlation structure and at the meantime make sure that the covariance matrix is positive definite. To address the issue, we propose to use convolved Gaussian process (CGP) in this paper. The approach provides a semi-parametric model and offers a natural framework for modeling common mean structure and covarianc...

  3. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor.

    Science.gov (United States)

    Zhao, Yangbing; Moon, Edmund; Carpenito, Carmine; Paulos, Chrystal M; Liu, Xiaojun; Brennan, Andrea L; Chew, Anne; Carroll, Richard G; Scholler, John; Levine, Bruce L; Albelda, Steven M; June, Carl H

    2010-11-15

    Redirecting T lymphocyte antigen specificity by gene transfer can provide large numbers of tumor-reactive T lymphocytes for adoptive immunotherapy. However, safety concerns associated with viral vector production have limited clinical application of T cells expressing chimeric antigen receptors (CAR). T lymphocytes can be gene modified by RNA electroporation without integration-associated safety concerns. To establish a safe platform for adoptive immunotherapy, we first optimized the vector backbone for RNA in vitro transcription to achieve high-level transgene expression. CAR expression and function of RNA-electroporated T cells could be detected up to a week after electroporation. Multiple injections of RNA CAR-electroporated T cells mediated regression of large vascularized flank mesothelioma tumors in NOD/scid/γc(-/-) mice. Dramatic tumor reduction also occurred when the preexisting intraperitoneal human-derived tumors, which had been growing in vivo for >50 days, were treated by multiple injections of autologous human T cells electroporated with anti-mesothelin CAR mRNA. This is the first report using matched patient tumor and lymphocytes showing that autologous T cells from cancer patients can be engineered to provide an effective therapy for a disseminated tumor in a robust preclinical model. Multiple injections of RNA-engineered T cells are a novel approach for adoptive cell transfer, providing flexible platform for the treatment of cancer that may complement the use of retroviral and lentiviral engineered T cells. This approach may increase the therapeutic index of T cells engineered to express powerful activation domains without the associated safety concerns of integrating viral vectors. Copyright © 2010 AACR.

  4. Polymorphisms in tumor necrosis factor genes and susceptibility to visceral leishmaniasis in Moroccan children

    Directory of Open Access Journals (Sweden)

    Rajaa Ejghal

    2015-05-01

    Full Text Available Objective: To examine whether polymorphic alleles at these two loci are involved in the susceptibility to visceral leishmaniasis (VL in Moroccan children. Methods: We have genotyped polymorphisms by PCR-restricted fragment length polymorphisms in 102 patients with VL, 92 asymptomatic carriers [positive skin test delayedtype hypersensitivity (DTH+] and 40 healthy controls (negative skin test delayed-type hypersensitivity, with no history of Leishmania infection. Results: Regression analysis showed no significant association between polymorphisms of tumor necrosis factors-ααwhen comparing VL and DTH + group (P > 0.05. The associations were detected between VL and negative skin test delayed-type hypersensitivity for the heterozygote genotype (P = 0.021, the recessive model: 1/2 + 2/2 (P = 0.044 and the minor allele 2 (P = 0.019. The resistance to VL was found to be under the recessive model 1/2 + 2/2 of tumor necrosis factors-β, when comparing VL and DTH + group (odds ratios: 0.558, 95%; confidence interval: 0.316-0.987; P = 0.044. Conclusions: These results must be regarded to preliminary but suggestive that further study with larger populations is worthwhile.

  5. Cytokine Gene Polymorphisms in Egyptian Cases with Brain Tumors

    International Nuclear Information System (INIS)

    Badr El-Din, N.K.; Abdel-Hady, E.K.; Salem, F.K.; Settin, A.; ALI, N.

    2009-01-01

    Background: Cytokines are proposed to play important roles in brain tumor biology as well as neuro degeneration or impaired neuronal function. Objectives: This work aimed to check the association of polymorphisms of cytokine genes in Egyptian cases with brain tumors. Methods: This work included 45 cases affected by brain tumors diagnosed as 24 benign and 21 malignant. Their median age was 45 years, and they were 20 males and 25 females. These cases were taken randomly from the Neurosurgery Department of Mansoura University Hospital, Egypt. Case genotypes were compared to 98 healthy unrelated controls from the same locality. DNA was amplified using PCR utilizing sequence specific primers (SSP) for detection of polymorphisms related to TNF-a-308 (G/A), IL-10-1082 (G/A), IL-6-174 (G/C) and IL-1Ra (VNTR) genes. Results: Cases affected with benign brain tumors showed a significant higher frequency of IL-10-1082 A/A [odds ratio (OR=8.0), p<0.001] and IL-6-174 C/C (OR=6.3, p=0.002) homozygous genotypes as compared to controls. Malignant cases, on the other hand, showed significantly higher frequency of IL-6-174 C/C (OR =4.8, p=0.002) homozygous genotype and TNF-a-308 A/A (OR=4.9, p<0.001) homozygous genotype when compared to controls. In the meantime, all cases showed no significant difference regarding the distribution of IL-1Ra VNTR genotype polymorphism compared to controls. Conclusions: Cytokine gene polymorphisms showed a pattern of association with brain tumors which may have potential impact on family counseling and disease management.

  6. Defining a Cancer Dependency Map.

    Science.gov (United States)

    Tsherniak, Aviad; Vazquez, Francisca; Montgomery, Phil G; Weir, Barbara A; Kryukov, Gregory; Cowley, Glenn S; Gill, Stanley; Harrington, William F; Pantel, Sasha; Krill-Burger, John M; Meyers, Robin M; Ali, Levi; Goodale, Amy; Lee, Yenarae; Jiang, Guozhi; Hsiao, Jessica; Gerath, William F J; Howell, Sara; Merkel, Erin; Ghandi, Mahmoud; Garraway, Levi A; Root, David E; Golub, Todd R; Boehm, Jesse S; Hahn, William C

    2017-07-27

    Most human epithelial tumors harbor numerous alterations, making it difficult to predict which genes are required for tumor survival. To systematically identify cancer dependencies, we analyzed 501 genome-scale loss-of-function screens performed in diverse human cancer cell lines. We developed DEMETER, an analytical framework that segregates on- from off-target effects of RNAi. 769 genes were differentially required in subsets of these cell lines at a threshold of six SDs from the mean. We found predictive models for 426 dependencies (55%) by nonlinear regression modeling considering 66,646 molecular features. Many dependencies fall into a limited number of classes, and unexpectedly, in 82% of models, the top biomarkers were expression based. We demonstrated the basis behind one such predictive model linking hypermethylation of the UBB ubiquitin gene to a dependency on UBC. Together, these observations provide a foundation for a cancer dependency map that facilitates the prioritization of therapeutic targets. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Novel applications of multitask learning and multiple output regression to multiple genetic trait prediction.

    Science.gov (United States)

    He, Dan; Kuhn, David; Parida, Laxmi

    2016-06-15

    Given a set of biallelic molecular markers, such as SNPs, with genotype values encoded numerically on a collection of plant, animal or human samples, the goal of genetic trait prediction is to predict the quantitative trait values by simultaneously modeling all marker effects. Genetic trait prediction is usually represented as linear regression models. In many cases, for the same set of samples and markers, multiple traits are observed. Some of these traits might be correlated with each other. Therefore, modeling all the multiple traits together may improve the prediction accuracy. In this work, we view the multitrait prediction problem from a machine learning angle: as either a multitask learning problem or a multiple output regression problem, depending on whether different traits share the same genotype matrix or not. We then adapted multitask learning algorithms and multiple output regression algorithms to solve the multitrait prediction problem. We proposed a few strategies to improve the least square error of the prediction from these algorithms. Our experiments show that modeling multiple traits together could improve the prediction accuracy for correlated traits. The programs we used are either public or directly from the referred authors, such as MALSAR (http://www.public.asu.edu/~jye02/Software/MALSAR/) package. The Avocado data set has not been published yet and is available upon request. dhe@us.ibm.com. © The Author 2016. Published by Oxford University Press.

  8. Effectiveness of Stability Indices for Bread Wheat Genotypes Selection to Water Deficit Tolerant

    Directory of Open Access Journals (Sweden)

    A Naderi

    2013-12-01

    Full Text Available In countries such as Iran which will be faced water deficit as the main challenge in the future and the food production is going to be dependent to water recourses, wheat water-deficit tolerant and adapted genotypes release is one of the most important strategies under such a condition. In order to study the adaptation and terminal water deficit stress tolerance, fifteen bread wheat lines and Chamran cultivar as the check were evaluated. This research was carried out at Ahvaz, Dezfool, Zabol and Darab, south warm region research stations, in 2007-08 and 2008-09, in two separated experiments (1-well-watered and 2- terminal water deficit stress, using complete randomized block design with three replications. Data were analyzed and genotypes response was evaluated based on tolerance indices. Results showed that the difference among stations, years, genotypes and double and triple effects of source variations were significant at 1% probability level. Mean grain yield was 4300 Kg/ha in first year, while grain yield increased significantly in second year and reached to 5692 Kg/ha. Mean grain yield were 5840 and 4591Kg/ha under well-watered and terminal water deficit stress conditions, respectively. Correlation coefficients among STI, GMP ،MP and K1STI were significant. Correlation coefficient between slop of linear regression of grain yield in response to drought stress intensity and grain yield under terminal water deficit stress was positively and, with K2STI, TOL and SSI was negatively significant. Grain yield index, (YIR the proportion of grain yield of each genotype to grand mean of grain yield of all genotypes was the most important components to define grain yield in stepwise regression under both experiment conditions. According to the results of this research and based on tolerance indices, lines No. 2, 14 and 15 were selected as the high potential- terminal water deficit stress tolerant genotypes.

  9. Genotype-Dependent Interaction of Lentil Lines with Ascochyta lentis

    Directory of Open Access Journals (Sweden)

    Ehsan Sari

    2017-05-01

    Full Text Available Ascochyta blight of lentil is a prevalent disease in many lentil producing regions and can cause major yield and grain quality losses. The most environmentally acceptable and economically profitable method of control is to develop varieties with high levels of durable resistance. Genetic studies to date suggest that ascochyta blight resistance genes (R-gene in lentil lines CDC Robin, ILL 7537, 964a-46, and ILL 1704 are non-allelic. To understand how different R-genes manifest resistance in these genotypes and an accession of Lens ervoides, L-01-827A, with high level of resistance to ascochyta blight, cellular and molecular defense responses were compared after inoculation with the causal pathogen Ascochyta lentis. Pathogenicity testing of the resistant lines to A. lentis inoculation revealed significantly lower disease severity on CDC Robin and ILL 7537 compared to ILL 1704 and 964a-46, and no symptoms of disease were observed on L-01-827A. Histological examinations indicated that cell death triggered by the pathogen might be disrupted as a mechanism of resistance in CDC Robin. In contrast, limiting colonization of epidermal cells by A. lentis is a suggested mechanism of resistance in 964a-46. A time-series comparison of the expressions of hallmark genes in salicylic acid (SA and jasmonic acid (JA signal transduction pathways between CDC Robin and 964a-46 was conducted. These partially resistant genotypes differed in the timing and the magnitude of SA and JA signaling pathway activation. The SA signaling pathway was only triggered in 964a-46, whereas the JA pathway was triggered in both partially resistant genotypes CDC Robin and 964a-46. The expression of JA-associated genes was lower in 964a-46 than CDC Robin. These observations corroborate the existence of diverse ascochyta blight resistance mechanisms in lentil genotypes carrying different R-genes.

  10. [Regression and therapy-resistance of primary liver tumors and liver metastases after regional chemotherapy and local tumor ablation].

    Science.gov (United States)

    Fischer, H-P

    2005-05-01

    High dosage regional chemotherapy, chemoembolization and other methods of regional treatment are commonly used to treat unresectable primary liver malignancies and liver metastases. In liver malignancies of childhood neoadjuvant chemotherapy is successfully combined with surgical treatment. Chemotherapy and local tumor ablation lead to characteristic histomorphologic changes: Complete destruction of the tumor tissue and its vascular bed is followed by encapsulated necroses. After selective eradication of the tumor cells under preservation of the fibrovasular bed the tumor is replaced by hypocellular edematous and fibrotic tissue. If completely damaged tumor tissue is absorbed quickly, the tumor area is replaced by regenerating liver tissue. Obliterating fibrohyalinosis of tumor vessels, and perivascular edema or necrosis indicate tissue damage along the vascular bed. Degenerative pleomorphism of tumor cells, steatosis, hydropic swelling and Malloryhyalin in HCC can represent cytologic findings of cytotoxic cellular damage. Macroscopic type of HCC influences significantly the response to treatment. Multinodular HCC often contain viable tumor nodules close to destroyed nodules after treatment. Encapsulated uninodular tumors undergo complete necrosis much easier. Large size and a tumor capsule limitate the effect of percutaneous injection of ethanol into HCC. In carcinomas with an infiltrating border, especially in metastases of adenocarcinomas and hepatic cholangiocarcinoma cytostatic treatment damages the tumor tissue mainly in the periphery. Nevertheless the infiltrating rim, portal veins, lymphatic spaces and bile ducts as well as the angle between liver capsule, tumor nodule and bordering parenchyma are the main refugees of viable tumor tissue even after high dosage regional chemotherapy. This local resistance is caused by special local conditions of vascularization and perfusion. These residues are the source of local tumor progression and distant metastases

  11. EGFR overexpressing cells and tumors are dependent on autophagy for growth and survival

    International Nuclear Information System (INIS)

    Jutten, Barry; Keulers, Tom G.; Schaaf, Marco B.E.; Savelkouls, Kim; Theys, Jan; Span, Paul N.; Vooijs, Marc A.; Bussink, Johan; Rouschop, Kasper M.A.

    2013-01-01

    Background and purpose: The epidermal growth factor receptor (EGFR) is overexpressed, amplified or mutated in various human epithelial tumors, and is associated with tumor aggressiveness and therapy resistance. Autophagy activation provides a survival advantage for cells in the tumor microenvironment. In the current study, we assessed the potential of autophagy inhibition (using chloroquine (CQ)) in treatment of EGFR expressing tumors. Material and methods: Quantitative PCR, immunohistochemistry, clonogenic survival, proliferation assays and in vivo tumor growth were used to assess this potential. Results: We show that EGFR overexpressing xenografts are sensitive to CQ treatment and are sensitized to irradiation by autophagy inhibition. In HNSSC xenografts, a correlation between EGFR and expression of the autophagy marker LC3b is observed, suggesting a role for autophagy in EGFR expressing tumors. This observation was substantiated in cell lines, showing high EGFR expressing cells to be more sensitive to CQ addition as reflected by decreased proliferation and survival. Surprisingly high EGFR expressing cells display a lower autophagic flux. Conclusions: The EGFR high expressing cells and tumors investigated in this study are highly dependent on autophagy for growth and survival. Inhibition of autophagy may therefore provide a novel treatment opportunity for EGFR overexpressing tumors

  12. YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression

    Directory of Open Access Journals (Sweden)

    Julien Fitamant

    2015-03-01

    Full Text Available Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC. Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach.

  13. Multiplex ligation-dependent probe amplification (MLPA) assay for blood group genotyping, copy number quantification, and analysis of RH variants

    NARCIS (Netherlands)

    Veldhuisen, Barbera; van der Schoot, C. E.; de Haas, Masja

    2015-01-01

    The blood group multiplex ligation-dependent probe amplification (MLPA) is a comprehensive assay, developed for genotyping the majority of clinically relevant blood group antigens in both patients and donors. The MLPA is an easy method to apply and only requires a thermal cycler and capillary

  14. Análise de fatores e regressão bissegmentada em estudos de estratificação ambiental e adaptabilidade em milho Factor analysis and bissegmented regression for studies about environmental stratification and maize adaptability

    Directory of Open Access Journals (Sweden)

    Deoclécio Domingos Garbuglio

    2007-02-01

    Full Text Available O objetivo deste trabalho foi verificar possíveis divergências entre os resultados obtidos nas avaliações da adaptabilidade de 27 genótipos de milho (Zea mays L., e na estratificação de 22 ambientes no Estado do Paraná, por meio de técnicas baseadas na análise de fatores e regressão bissegmentada. As estratificações ambientais foram feitas por meio do método tradicional e por análise de fatores, aliada ao porcentual da porção simples da interação GxA (PS%. As análises de adaptabilidade foram realizadas por meio de regressão bissegmentada e análise de fatores. Pela análise de regressão bissegmentada, os genótipos estudados apresentaram alta performance produtiva; no entanto, não foi constatado o genótipo considerado como ideal. A adaptabilidade dos genótipos, analisada por meio de plotagens gráficas, apresentou respostas diferenciadas quando comparada à regressão bissegmentada. A análise de fatores mostrou-se eficiente nos processos de estratificação ambiental e adaptabilidade dos genótipos de milho.The objective of this work was to verify possible divergences among results obtained on adaptability evaluations of 27 maize genotypes (Zea mays L., and on stratification of 22 environments on Paraná State, Brazil, through techniques of factor analysis and bissegmented regression. The environmental stratifications were made through the traditional methodology and by factor analysis, allied to the percentage of the simple portion of GxE interaction (PS%. Adaptability analyses were carried out through bissegmented regression and factor analysis. By the analysis of bissegmented regression, studied genotypes had presented high productive performance; however, it was not evidenced the genotype considered as ideal. The adaptability of the genotypes, analyzed through graphs, presented different answers when compared to bissegmented regression. Factor analysis was efficient in the processes of environment stratification and

  15. Advanced statistics: linear regression, part II: multiple linear regression.

    Science.gov (United States)

    Marill, Keith A

    2004-01-01

    The applications of simple linear regression in medical research are limited, because in most situations, there are multiple relevant predictor variables. Univariate statistical techniques such as simple linear regression use a single predictor variable, and they often may be mathematically correct but clinically misleading. Multiple linear regression is a mathematical technique used to model the relationship between multiple independent predictor variables and a single dependent outcome variable. It is used in medical research to model observational data, as well as in diagnostic and therapeutic studies in which the outcome is dependent on more than one factor. Although the technique generally is limited to data that can be expressed with a linear function, it benefits from a well-developed mathematical framework that yields unique solutions and exact confidence intervals for regression coefficients. Building on Part I of this series, this article acquaints the reader with some of the important concepts in multiple regression analysis. These include multicollinearity, interaction effects, and an expansion of the discussion of inference testing, leverage, and variable transformations to multivariate models. Examples from the first article in this series are expanded on using a primarily graphic, rather than mathematical, approach. The importance of the relationships among the predictor variables and the dependence of the multivariate model coefficients on the choice of these variables are stressed. Finally, concepts in regression model building are discussed.

  16. Poor Prognosis Associated With Human Papillomavirus α7 Genotypes in Cervical Carcinoma Cannot Be Explained by Intrinsic Radiosensitivity

    International Nuclear Information System (INIS)

    Hall, John S.; Iype, Rohan; Armenoult, Lucile S.C.; Taylor, Janet; Miller, Crispin J.; Davidson, Susan; Sanjose, Silvia de; Bosch, Xavier; Stern, Peter L.; West, Catharine M.L.

    2013-01-01

    Purpose: To investigate the relationship between human papillomavirus (HPV) genotype and outcome after radiation therapy and intrinsic radiosensitivity. Methods and Materials: HPV genotyping was performed on cervix biopsies by polymerase chain reaction using SPF-10 broad-spectrum primers, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse hybridization line probe assay (LiPA 25 ) (version 1) (n=202). PapilloCheck and quantitative reverse transcription-polymerase chain reaction were used to genotype cervix cancer cell lines (n=16). Local progression-free survival after radiation therapy alone was assessed using log-rank and Cox proportionate hazard analyses. Intrinsic radiosensitivity was measured as surviving fraction at 2 Gy (SF2) using clonogenic assays. Results: Of the 202 tumors, 107 (53.0%) were positive for HPV16, 29 (14.4%) for HPV18, 9 (4.5%) for HPV45, 23 (11.4%) for other HPV genotypes, and 22 (10.9%) were negative; 11 (5.5%) contained multiple genotypes, and 1 tumor was HPV X (0.5%). In 148 patients with outcome data, those with HPVα9-positive tumors had better local progression-free survival compared with α7 patients in univariate (P<.004) and multivariate (hazard ratio 1.54, 95% confidence interval 1.11-1.76, P=.021) analyses. There was no difference in the median SF2 of α9 and α7 cervical tumors (n=63). In the cell lines, 9 were α7 and 4 α9 positive and 3 negative. There was no difference in SF2 between α9 and α7 cell lines (n=14). Conclusion: The reduced radioresponsiveness of α7 cervical tumors is not related to intrinsic radiosensitivity

  17. Poor Prognosis Associated With Human Papillomavirus α7 Genotypes in Cervical Carcinoma Cannot Be Explained by Intrinsic Radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Hall, John S.; Iype, Rohan; Armenoult, Lucile S.C. [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom); Taylor, Janet [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom); Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester (United Kingdom); Miller, Crispin J. [Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester (United Kingdom); Davidson, Susan [Christie National Health Service Foundation Trust, Manchester (United Kingdom); Sanjose, Silvia de; Bosch, Xavier [Cancer Epidemiology Research Program, Catalan Institute of Oncology, L' Hospitalet de Llobregat (Spain); Stern, Peter L. [Immunology Group, Paterson Institute for Cancer Research, Manchester (United Kingdom); West, Catharine M.L., E-mail: Catharine.West@manchester.ac.uk [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom)

    2013-04-01

    Purpose: To investigate the relationship between human papillomavirus (HPV) genotype and outcome after radiation therapy and intrinsic radiosensitivity. Methods and Materials: HPV genotyping was performed on cervix biopsies by polymerase chain reaction using SPF-10 broad-spectrum primers, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse hybridization line probe assay (LiPA{sub 25}) (version 1) (n=202). PapilloCheck and quantitative reverse transcription-polymerase chain reaction were used to genotype cervix cancer cell lines (n=16). Local progression-free survival after radiation therapy alone was assessed using log-rank and Cox proportionate hazard analyses. Intrinsic radiosensitivity was measured as surviving fraction at 2 Gy (SF2) using clonogenic assays. Results: Of the 202 tumors, 107 (53.0%) were positive for HPV16, 29 (14.4%) for HPV18, 9 (4.5%) for HPV45, 23 (11.4%) for other HPV genotypes, and 22 (10.9%) were negative; 11 (5.5%) contained multiple genotypes, and 1 tumor was HPV X (0.5%). In 148 patients with outcome data, those with HPVα9-positive tumors had better local progression-free survival compared with α7 patients in univariate (P<.004) and multivariate (hazard ratio 1.54, 95% confidence interval 1.11-1.76, P=.021) analyses. There was no difference in the median SF2 of α9 and α7 cervical tumors (n=63). In the cell lines, 9 were α7 and 4 α9 positive and 3 negative. There was no difference in SF2 between α9 and α7 cell lines (n=14). Conclusion: The reduced radioresponsiveness of α7 cervical tumors is not related to intrinsic radiosensitivity.

  18. Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome.

    Science.gov (United States)

    Wang, Linan; Ma, Ning; Okamoto, Sachiko; Amaishi, Yasunori; Sato, Eiichi; Seo, Naohiro; Mineno, Junichi; Takesako, Kazutoh; Kato, Takuma; Shiku, Hiroshi

    2016-01-01

    Carcinoembryonic antigen (CEA) is a cell surface antigen highly expressed in various cancer cell types and in healthy tissues. It has the potential to be a target for chimeric antigen receptor (CAR)-modified T-cell therapy; however, the safety of this approach in terms of on-target/off-tumor effects needs to be determined. To address this issue in a clinically relevant model, we used a mouse model in which the T cells expressing CEA-specific CAR were transferred into tumor-bearing CEA-transgenic (Tg) mice that physiologically expressed CEA as a self-antigen. The adoptive transfer in conjunction with lymphodepleting and myeloablative preconditioning mediated significant tumor regression but caused weight loss in CEA-Tg, but not in wild-type mice. The weight loss was not associated with overt inflammation in the CEA-expressing gastrointestinal tract but was associated with malnutrition, reflected in elevated systemic levels of cytokines linked to anorexia, which could be controlled by the administration of an anti-IL-6 receptor monoclonal antibody without compromising efficacy. The apparent relationship between lymphodepleting and myeloablative preconditioning, efficacy, and off-tumor toxicity of CAR-T cells would necessitate the development of CEA-specific CAR-T cells with improved signaling domains that require less stringent preconditioning for their efficacy. Taken together, these results suggest that CEA-specific CAR-based adoptive T-cell therapy may be effective for patients with CEA + solid tumors. Distinguishing the fine line between therapeutic efficacy and off-tumor toxicity would involve further modifications of CAR-T cells and preconditioning regimens.

  19. Developmental plasticity: re-conceiving the genotype.

    Science.gov (United States)

    Sultan, Sonia E

    2017-10-06

    In recent decades, the phenotype of an organism (i.e. its traits and behaviour) has been studied as the outcome of a developmental 'programme' coded in its genotype. This deterministic view is implicit in the Modern Synthesis approach to adaptive evolution as a sorting process among genetic variants. Studies of developmental pathways have revealed that genotypes are in fact differently expressed depending on environmental conditions. Accordingly, the genotype can be understood as a repertoire of potential developmental outcomes or norm of reaction. Reconceiving the genotype as an environmental response repertoire rather than a fixed developmental programme leads to three critical evolutionary insights. First, plastic responses to specific conditions often comprise functionally appropriate trait adjustments, resulting in an individual-level, developmental mode of adaptive variation. Second, because genotypes are differently expressed depending on the environment, the genetic diversity available to natural selection is itself environmentally contingent. Finally, environmental influences on development can extend across multiple generations via cytoplasmic and epigenetic factors transmitted to progeny individuals, altering their responses to their own, immediate environmental conditions and, in some cases, leading to inherited but non-genetic adaptations. Together, these insights suggest a more nuanced understanding of the genotype and its evolutionary role, as well as a shift in research focus to investigating the complex developmental interactions among genotypes, environments and previous environments.

  20. Hepatitis C viral load, genotype 3 and interleukin-28B CC genotype predict mortality in HIV and hepatitis C-coinfected individuals

    DEFF Research Database (Denmark)

    Clausen, Louise Nygaard; Astvad, Karen; Ladelund, Steen

    2012-01-01

    OBJECTIVE: We hypothesized that hepatitis C virus (HCV) load and genotype may influence all-cause mortality in HIV-HCV-coinfected individuals. DESIGN AND METHODS: Observational prospective cohort study. Mortality rates were compared in a time-updated multivariate Poisson regression analysis....... RESULTS: We included 264 consecutive HIV-HCV-coinfected individuals. During 1143 person years at risk (PYR) 118 individuals died [overall mortality rate 10 (95% confidence interval; 8, 12)/100 PYR]. In multivariate analysis, a 1 log increase in HCV viral load was associated with a 30% higher mortality......) CC genotype was associated with 54% higher mortality risk [aMRR: 1.54 (0.89, 3.82] compared to TT genotype. CONCLUSION: High-HCV viral load, HCV genotype 3 and IL28B genotype CC had a significant influence on the risk of all-cause mortality among individuals coinfected with HIV-1. This may have...

  1. Anti-tumor effects of nitrosylcobalamin against spontaneous tumors in dogs.

    Science.gov (United States)

    Bauer, Joseph A; Frye, Gerald; Bahr, Anne; Gieg, Jennifer; Brofman, Peter

    2010-10-01

    Given the limited options available to treat canine cancers, the use of companion animals for evaluating new drugs may identify better therapies for veterinary and human oncology. The anti-tumor effects of nitrosylcobalamin (NO-Cbl), an apoptosis-inducing, vitamin B12-based carrier of nitric oxide (NO), was evaluated in four dogs with spontaneous cancer. (1) A 13 year-old female spayed Giant Schnauzer with inoperable thyroid carcinoma and hypercalcemia. (2) A 6 year-old male neutered Golden Retriever with a malignant peripheral nerve sheath tumor (MPNST). (3) A ten yr-old neutered male Bichon Frise with apocrine gland anal sac adenocarcinoma (AGACA). (4) A 7 year-old female spayed Labrador mix with spinal meningioma following partial surgical resection. Tumor regression was measured by physical exam and verified using ultrasound (case 1) and MRI (case 2-4). Serum chemistries and hematologic parameters were monitored throughout the studies. (1) The Giant Schnauzer demonstrated a 77% reduction in tumor volume after ten weeks of daily NO-Cbl treatment. (2) The Golden Retriever demonstrated a 53% reduction in tumor volume after 15 months of daily NO-Cbl therapy. (3) The Bichon Frise demonstrated a 43% regression of the primary tumor and a 90% regression of an iliac lymph node measured by MRI after 15 months of treatment. After 61 months, the dog currently has stable disease, normal liver enzymes, CBC analysis, and no evidence of toxicity. (4) The Labrador demonstrated complete regression of the residual tumor after 6 months of treatment. We have shown previously that NO-Cbl is endocytosed by malignant cells, resulting in intra-tumoral NO release. In this study, we have shown that daily long-term use of NO-Cbl induced responses in all dogs without any signs of toxicity. The use of NO-Cbl capitalizes on the tumor-specific properties of the vitamin B12 receptor and represents a promising anti-cancer therapy.

  2. Characterization of vegetative and grain filling periods of winter wheat by stepwise regression procedure. II. Grain filling period

    Directory of Open Access Journals (Sweden)

    Pržulj Novo

    2011-01-01

    Full Text Available In wheat, rate and duration of dry matter accumulation and remobilization depend on genotype and growing conditions. The objective of this study was to determine the most appropriate polynomial regression of stepwise regression procedure for describing grain filling period in three winter wheat cultivars. The stepwise regression procedure showed that grain filling is a complex biological process and that it is difficult to offer a simple and appropriate polynomial equation that fits the pattern of changes in dry matter accumulation during the grain filling period, i.e., from anthesis to maximum grain weight, in winter wheat. If grain filling is to be represented with a high power polynomial, quartic and quintic equations showed to be most appropriate. In spite of certain disadvantages, a cubic equation of stepwise regression could be used for describing the pattern of winter wheat grain filling.

  3. Do sex reversal procedures differentially affect agonistic behaviors and sex steroid levels depending on the sexual genotype in Nile tilapia?

    Science.gov (United States)

    Gennotte, Vincent; Akonkwa, Balagizi; Mélard, Charles; Denoël, Mathieu; Cornil, Charlotte A; Rougeot, Carole

    2017-04-01

    In Nile tilapia Oreochromis niloticus, phenotypic males and females with different sexual genotypes (XX, XY, YY) have particular behavioral and physiological traits. Compared to natural XX females and XY males, XY and YY females and XX males expressed higher level of aggressiveness that could be related to higher levels of 17β-estradiol and 11-ketotestosterone, respectively. Our results suggest that the presence of a Y chromosome increases aggressiveness in females. However, since the same relationship between aggressiveness and the Y chromosome is not observed in males, we can hypothesize that the differences in aggressiveness are not directly dependent on the genotype but on the sex reversal procedures applied on young fry during their sexual differentiation to produce these breeders. These hormonal treatments could have permanently modified the development of the brain and consequently influenced the behavior of adults independently of their genotype. In both hypotheses (genotype or sex reversal influence), the causes of behavioral modifications have to be searched in an early modification of the brain sexual differentiation. © 2017 Wiley Periodicals, Inc.

  4. Retrospective feasibility study of simultaneous integrated boost in cervical cancer using Tomotherapy: the impact of organ motion and tumor regression.

    Science.gov (United States)

    Herrera, Fernanda G; Callaway, Sharon; Delikgoz-Soykut, Ela; Coskun, Mehtap; Porta, Laetitia; Meuwly, Jean-Yves; Soares-Rodrigues, Joao; Heym, Leonie; Moeckli, Raphael; Ozsahin, Mahmut

    2013-01-03

    Whole pelvis intensity modulated radiotherapy (IMRT) is increasingly being used to treat cervical cancer aiming to reduce side effects. Encouraged by this, some groups have proposed the use of simultaneous integrated boost (SIB) to target the tumor, either to get a higher tumoricidal effect or to replace brachytherapy. Nevertheless, physiological organ movement and rapid tumor regression throughout treatment might substantially reduce any benefit of this approach. To evaluate the clinical target volume - simultaneous integrated boost (CTV-SIB) regression and motion during chemo-radiotherapy (CRT) for cervical cancer, and to monitor treatment progress dosimetrically and volumetrically to ensure treatment goals are met. Ten patients treated with standard doses of CRT and brachytherapy were retrospectively re-planned using a helical Tomotherapy - SIB technique for the hypothetical scenario of this feasibility study. Target and organs at risk (OAR) were contoured on deformable fused planning-computed tomography and megavoltage computed tomography images. The CTV-SIB volume regression was determined. The center of mass (CM) was used to evaluate the degree of motion. The Dice's similarity coefficient (DSC) was used to assess the spatial overlap of CTV-SIBs between scans. A cumulative dose-volume histogram modeled estimated delivered doses. The CTV-SIB relative reduction was between 31 and 70%. The mean maximum CM change was 12.5, 9, and 3 mm in the superior-inferior, antero-posterior, and right-left dimensions, respectively. The CTV-SIB-DSC approached 1 in the first week of treatment, indicating almost perfect overlap. CTV-SIB-DSC regressed linearly during therapy, and by the end of treatment was 0.5, indicating 50% discordance. Two patients received less than 95% of the prescribed dose. Much higher doses to the OAR were observed. A multiple regression analysis showed a significant interaction between CTV-SIB reduction and OAR dose increase. The CTV-SIB had important

  5. Retrospective feasibility study of simultaneous integrated boost in cervical cancer using tomotherapy: the impact of organ motion and tumor regression

    International Nuclear Information System (INIS)

    Herrera, Fernanda G; Ozsahin, Mahmut; Callaway, Sharon; Delikgoz-Soykut, Ela; Coskun, Mehtap; Porta, Laetitia; Meuwly, Jean-Yves; Soares-Rodrigues, Joao; Heym, Leonie; Moeckli, Raphael

    2013-01-01

    Whole pelvis intensity modulated radiotherapy (IMRT) is increasingly being used to treat cervical cancer aiming to reduce side effects. Encouraged by this, some groups have proposed the use of simultaneous integrated boost (SIB) to target the tumor, either to get a higher tumoricidal effect or to replace brachytherapy. Nevertheless, physiological organ movement and rapid tumor regression throughout treatment might substantially reduce any benefit of this approach. To evaluate the clinical target volume - simultaneous integrated boost (CTV-SIB) regression and motion during chemo-radiotherapy (CRT) for cervical cancer, and to monitor treatment progress dosimetrically and volumetrically to ensure treatment goals are met. Ten patients treated with standard doses of CRT and brachytherapy were retrospectively re-planned using a helical Tomotherapy - SIB technique for the hypothetical scenario of this feasibility study. Target and organs at risk (OAR) were contoured on deformable fused planning-computed tomography and megavoltage computed tomography images. The CTV-SIB volume regression was determined. The center of mass (CM) was used to evaluate the degree of motion. The Dice’s similarity coefficient (DSC) was used to assess the spatial overlap of CTV-SIBs between scans. A cumulative dose-volume histogram modeled estimated delivered doses. The CTV-SIB relative reduction was between 31 and 70%. The mean maximum CM change was 12.5, 9, and 3 mm in the superior-inferior, antero-posterior, and right-left dimensions, respectively. The CTV-SIB-DSC approached 1 in the first week of treatment, indicating almost perfect overlap. CTV-SIB-DSC regressed linearly during therapy, and by the end of treatment was 0.5, indicating 50% discordance. Two patients received less than 95% of the prescribed dose. Much higher doses to the OAR were observed. A multiple regression analysis showed a significant interaction between CTV-SIB reduction and OAR dose increase. The CTV-SIB had important

  6. Retrospective feasibility study of simultaneous integrated boost in cervical cancer using tomotherapy: the impact of organ motion and tumor regression

    Directory of Open Access Journals (Sweden)

    Herrera Fernanda G

    2013-01-01

    Full Text Available Abstract Background Whole pelvis intensity modulated radiotherapy (IMRT is increasingly being used to treat cervical cancer aiming to reduce side effects. Encouraged by this, some groups have proposed the use of simultaneous integrated boost (SIB to target the tumor, either to get a higher tumoricidal effect or to replace brachytherapy. Nevertheless, physiological organ movement and rapid tumor regression throughout treatment might substantially reduce any benefit of this approach. Purpose To evaluate the clinical target volume - simultaneous integrated boost (CTV-SIB regression and motion during chemo-radiotherapy (CRT for cervical cancer, and to monitor treatment progress dosimetrically and volumetrically to ensure treatment goals are met. Methods and materials Ten patients treated with standard doses of CRT and brachytherapy were retrospectively re-planned using a helical Tomotherapy - SIB technique for the hypothetical scenario of this feasibility study. Target and organs at risk (OAR were contoured on deformable fused planning-computed tomography and megavoltage computed tomography images. The CTV-SIB volume regression was determined. The center of mass (CM was used to evaluate the degree of motion. The Dice’s similarity coefficient (DSC was used to assess the spatial overlap of CTV-SIBs between scans. A cumulative dose-volume histogram modeled estimated delivered doses. Results The CTV-SIB relative reduction was between 31 and 70%. The mean maximum CM change was 12.5, 9, and 3 mm in the superior-inferior, antero-posterior, and right-left dimensions, respectively. The CTV-SIB-DSC approached 1 in the first week of treatment, indicating almost perfect overlap. CTV-SIB-DSC regressed linearly during therapy, and by the end of treatment was 0.5, indicating 50% discordance. Two patients received less than 95% of the prescribed dose. Much higher doses to the OAR were observed. A multiple regression analysis showed a significant interaction

  7. Therapeutic Implications from Sensitivity Analysis of Tumor Angiogenesis Models

    Science.gov (United States)

    Poleszczuk, Jan; Hahnfeldt, Philip; Enderling, Heiko

    2015-01-01

    Anti-angiogenic cancer treatments induce tumor starvation and regression by targeting the tumor vasculature that delivers oxygen and nutrients. Mathematical models prove valuable tools to study the proof-of-concept, efficacy and underlying mechanisms of such treatment approaches. The effects of parameter value uncertainties for two models of tumor development under angiogenic signaling and anti-angiogenic treatment are studied. Data fitting is performed to compare predictions of both models and to obtain nominal parameter values for sensitivity analysis. Sensitivity analysis reveals that the success of different cancer treatments depends on tumor size and tumor intrinsic parameters. In particular, we show that tumors with ample vascular support can be successfully targeted with conventional cytotoxic treatments. On the other hand, tumors with curtailed vascular support are not limited by their growth rate and therefore interruption of neovascularization emerges as the most promising treatment target. PMID:25785600

  8. Limited role of murine ATM in oncogene-induced senescence and p53-dependent tumor suppression.

    Directory of Open Access Journals (Sweden)

    Alejo Efeyan

    Full Text Available Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, in turn, results in ATM/p53-dependent cellular senescence. Here, we have tested this model in a variety of murine experimental systems. Overexpression of oncogenic Ras in murine fibroblasts efficiently induced senescence but this occurred in the absence of detectable DNA damage signaling, thus suggesting a fundamental difference between human and murine cells. Moreover, lung adenomas initiated by endogenous levels of oncogenic K-Ras presented abundant senescent cells, but undetectable DNA damage signaling. Accordingly, K-Ras-driven adenomas were also senescent in Atm-null mice, and the tumorigenic progression of these lesions was only modestly accelerated by Atm-deficiency. Finally, we have examined chemically-induced fibrosarcomas, which possess a persistently activated DNA damage response and are highly sensitive to the activity of p53. We found that the absence of Atm favored genomic instability in the resulting tumors, but did not affect the persistent DNA damage response and did not impair p53-dependent tumor suppression. All together, we conclude that oncogene-induced senescence in mice may occur in the absence of a detectable DNA damage response. Regarding murine Atm, our data suggest that it plays a minor role in oncogene-induced senescence or in p53-dependent tumor suppression, being its tumor suppressive activity probably limited to the maintenance of genomic stability.

  9. Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokines

    Directory of Open Access Journals (Sweden)

    Fox Bernard A

    2007-11-01

    -deficient (PKO effector T cells induced macrophages to secrete nitric oxide (NO, providing an additional effector mechanism for T cell-mediated tumor regression. Conclusion These data suggest two possible sources for chemokine secretion that stimulates macrophage recruitment to the site of tumor metastases. Both appear to be initiated by T cell recognition of specific antigen, but one is dependent on the tumor cells to produce the chemokines that recruit macrophages.

  10. Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors

    International Nuclear Information System (INIS)

    Nakata, Toru; Shimizu, Hiromichi; Nagata, Sayaka; Ito, Go; Fujii, Satoru; Suzuki, Kohei; Kawamoto, Ami; Ishibashi, Fumiaki; Kuno, Reiko; Anzai, Sho; Murano, Tatsuro; Mizutani, Tomohiro; Oshima, Shigeru; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Hozumi, Katsuto; Watanabe, Mamoru; Okamoto, Ryuichi

    2017-01-01

    Ligand-dependent activation of Notch signaling is required to maintain the stem-cell niche of normal intestinal epithelium. However, the precise role of Notch signaling in the maintenance of the intestinal tumor stem cell niche and the importance of the RBPJ-independent non-canonical pathway in intestinal tumors remains unknown. Here we show that Notch signaling was activated in LGR5 +ve cells of APC-deficient mice intestinal tumors. Accordingly, Notch ligands, including Jag1, Dll1, and Dll4, were expressed in these tumors. In vitro studies using tumor-derived organoids confirmed the intrinsic Notch activity-dependent growth of tumor cells. Surprisingly, the targeted deletion of Jag1 but not RBPJ in LGR5 +ve tumor-initiating cells resulted in the silencing of Hes1 expression, disruption of the tumor stem cell niche, and dramatic reduction in the proliferation activity of APC-deficient intestinal tumors in vivo. Thus, our results highlight the importance of ligand-dependent non-canonical Notch signaling in the proliferation and maintenance of the tumor stem cell niche in APC-deficient intestinal adenomas. - Highlights: • Notch signaling is activated in LGR5 +ve cells of APC-deficient intestinal tumors. • Lack of Jag1 but not RBPJ disrupts stem cell niche formation in those tumors. • Lack of Jag1 reduces the proliferation activity of APC-deficient intestinal tumors.

  11. Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence

    Science.gov (United States)

    Irwin, Michael R.; Olmstead, Richard; Valladares, Edwin M.; Breen, Elizabeth Crabb; Ehlers, Cindy L.

    2009-01-01

    Background In alcohol dependence, markers of inflammation are associated with increases in rapid eye movement (REM) sleep, which is thought to be a prognostic indicator of alcohol relapse. This study was undertaken to test whether blockade of biologically active tumor necrosis factor-α (TNF-α) normalizes REM sleep in alcohol-dependent adults. Methods In a randomized, placebo-controlled, double-blind, crossover trial, 18 abstinent alcohol-dependent male adults received a single dose of etanercept (25 mg) versus placebo in a counterbalanced order. Polysomnographic sleep was measured at baseline and for 3 nights after the acute dose of etanercept or placebo. Results Compared with placebo, administration of etanercept produced significant decreases in the amount and percentage of REM sleep. Decreases in REM sleep were robust and approached low levels typically found in age-comparable control subjects. Individual differences in biologically active drug as indexed by circulating levels of soluble tumor necrosis factor receptor II negatively correlated with the percentage of REM sleep. Conclusions Pharmacologic neutralization of TNF-α activity is associated with significant reductions in REM sleep in abstinent alcohol-dependent patients. These data suggest that circulating levels of TNF-α may have a physiologic role in the regulation of REM sleep in humans. PMID:19185287

  12. Uncovering state-dependent relationships in shallow lakes using Bayesian latent variable regression.

    Science.gov (United States)

    Vitense, Kelsey; Hanson, Mark A; Herwig, Brian R; Zimmer, Kyle D; Fieberg, John

    2018-03-01

    Ecosystems sometimes undergo dramatic shifts between contrasting regimes. Shallow lakes, for instance, can transition between two alternative stable states: a clear state dominated by submerged aquatic vegetation and a turbid state dominated by phytoplankton. Theoretical models suggest that critical nutrient thresholds differentiate three lake types: highly resilient clear lakes, lakes that may switch between clear and turbid states following perturbations, and highly resilient turbid lakes. For effective and efficient management of shallow lakes and other systems, managers need tools to identify critical thresholds and state-dependent relationships between driving variables and key system features. Using shallow lakes as a model system for which alternative stable states have been demonstrated, we developed an integrated framework using Bayesian latent variable regression (BLR) to classify lake states, identify critical total phosphorus (TP) thresholds, and estimate steady state relationships between TP and chlorophyll a (chl a) using cross-sectional data. We evaluated the method using data simulated from a stochastic differential equation model and compared its performance to k-means clustering with regression (KMR). We also applied the framework to data comprising 130 shallow lakes. For simulated data sets, BLR had high state classification rates (median/mean accuracy >97%) and accurately estimated TP thresholds and state-dependent TP-chl a relationships. Classification and estimation improved with increasing sample size and decreasing noise levels. Compared to KMR, BLR had higher classification rates and better approximated the TP-chl a steady state relationships and TP thresholds. We fit the BLR model to three different years of empirical shallow lake data, and managers can use the estimated bifurcation diagrams to prioritize lakes for management according to their proximity to thresholds and chance of successful rehabilitation. Our model improves upon

  13. Genotype distribution and treatment response among incarcerated drug-dependent patients with chronic hepatitis C infection.

    Directory of Open Access Journals (Sweden)

    Chun-Han Cheng

    Full Text Available The prevalence of hepatitis C virus (HCV infection is disproportionately high among prisoners, especially among those who are drug-dependent. However, current screening and treatment recommendations are inconsistent for this population, and appropriate care is not reliably provided. To address these problems, the present study aimed to identify unique characteristics and clinical manifestations of incarcerated patients with HCV infection. We included incarcerated patients who received treatment with pegylated-interferon combined with ribavirin at Mackay Memorial Hospital in Taitung and were serving sentences at either the Taiyuan Skill Training Institute or the Yanwan Training Institute. HCV genotypes 1 (41.4%, 3 (25.9%, and 6 (24.1% were the most prevalent in the incarcerated patients. During the study period, we analyzed treatment response among 58 incarcerated patients and compared obtained results with treatment response among 52 patients who were living in the community. Higher sustained virological response rate was observed among patients with incarceration and HCV genotype other than 1. The odds ratios (corresponding 95% confidence intervals for incarceration and genotype 1 were 2.75 (1.06-7.11 and 0.37 (0.14-0.99, respectively. Better treatment compliance among incarcerated patients might partially explain these results. The results of this study suggest that treatment of prisoners with HCV infection is feasible and effective. More appropriate and timely methods are needed to prevent HCV transmission among injection drug users inside prisons.

  14. Contribution of Matrix Metalloproteinase-7 Genotypes to the Risk of Non-solid Tumor, Childhood Leukemia.

    Science.gov (United States)

    Pei, Jen-Sheng; Chou, An-Kuo; Hsu, Pei-Chen; Tsai, Chia-Wen; Chang, Wen-Shin; Wu, Meng-Feng; Wu, Ming-Hsien; Hsia, Te-Chun; Cheng, Shun-Ping; Bau, DA-Tian

    2017-12-01

    The matrix metalloproteinases (MMPs) are important in inflammation and carcinogenesis, and the genotypic role of MMP7 has never been examined in leukemia to date. Therefore, in this study we aimed to evaluate the contribution of the genotypic variants in the promoter region of MMP7 (A-181G and C-153T) to childhood acute lymphoblastic leukemia (ALL) risk in Taiwan. In this case-control study, 266 patients with childhood ALL and 266 non-cancer controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism methodology. The distribution of AA, AG and GG for MMP7 promoter A-181G genotype was 83.5, 12.0 and 4.5% in the childhood ALL group and 89.8%, 9.4 and 0.8% in the non-cancer control group, respectively (p for trend=0.0134), significantly differentially distributed between childhood ALL and control groups. The comparisons in allelic frequency distribution also support the findings that G appears to be the risky allele in childhood ALL. In genotype and gender interaction analysis, it was found that boys carrying the MMP7 A-181G GG and AG+GG genotypes had 9.05- and 2.45-fold odds ratios (ORs) (p=0.0135 and 0.0142, respectively) for childhood ALL compared to those carrying wild-type AA genotype. But these differences were not found in girls. Analysis of genotype interaction with age of onset age showed those aged less than 3.5 years at onset carrying the GG or AG+GG genotypes also had elevated ORs of 8.79- and 2.04-fold (p=0.0150 and 0.0413, respectively) for childhood ALL, but there was no such difference for those having an age at onset of 3.5 years or more. Our results indicate that the MMP7 A-181G genotype interacts with age and gender and may serve as an early and predictive biomarker for childhood ALL. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  15. Fibroblast growth factor receptor mediates fibroblast-dependent growth in EMMPRIN-depleted head and neck cancer tumor cells.

    Science.gov (United States)

    Liu, Zhiyong; Hartman, Yolanda E; Warram, Jason M; Knowles, Joseph A; Sweeny, Larissa; Zhou, Tong; Rosenthal, Eben L

    2011-08-01

    Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma-mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer, there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here, we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were cocultured with fibroblasts or inoculated with fibroblasts into severe combined immunodeficient mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Coculture experiments showed fibroblast-dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN-silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN-silenced cells compared with control vector-transfected cells, whereas inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast coculture, suggesting the importance of FGFR2 signaling in fibroblast-mediated tumor growth. Analysis of xenografted tumors revealed that EMMPRIN-silenced tumors had a larger stromal compartment compared with control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast-independent tumor growth.

  16. Fibroblast growth factor receptor mediates fibroblast-dependent growth in EMMPRIN depleted head and neck cancer tumor cells

    Science.gov (United States)

    Liu, Zhiyong; Hartman, Yolanda E.; Warram, Jason M.; Knowles, Joseph A.; Sweeny, Larrisa; Zhou, Tong; Rosenthal, Eben L.

    2011-01-01

    Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were co-cultured with fibroblasts or inoculated with fibroblasts into SCID mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Co-culture experiments demonstrated fibroblast-dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN silenced cells compared to control vector transfected cells, while inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast co-culture, suggesting the importance of FGFR2 signaling in fibroblast mediated tumor growth. Analysis of xenografted tumors revealed EMMPRIN silenced tumors had a larger stromal compartment compared to control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast independent tumor growth. PMID:21665938

  17. Assessment of genotype x environment interaction on yield and ...

    African Journals Online (AJOL)

    Days to heading, plant height, number of spikes per square meter, number of kernels per spike, spike weight, 1000 kernel weight and grain yield of the genotypes were evaluated in each location. The regression coefficient (bi) of Finlay and Wilkinson (1963) and mean square of deviation from regression (S2d) of Eberhart ...

  18. Can Linear Regression Modeling Help Clinicians in the Interpretation of Genotypic Resistance Data? An Application to Derive a Lopinavir-Score

    DEFF Research Database (Denmark)

    Cozzi-Lepri, Alessandro; Prosperi, Mattia C F; Kjær, Jesper

    2011-01-01

    explored the potential of linear regression to construct a simple predictive model for lopinavir/r-based TCE. Although, the performance of our proposed score was similar to that of already existing IS, previously unrecognized lopinavir/r-associated mutations were identified. The analysis illustrates......BACKGROUND: The question of whether a score for a specific antiretroviral (e.g. lopinavir/r in this analysis) that improves prediction of viral load response given by existing expert-based interpretation systems (IS) could be derived from analyzing the correlation between genotypic data......). Our analysis identified mutations V82A, I54V, K20I and I62V, which were associated with reduced viral response and mutations I15V and V91S which determined lopinavir/r hypersensitivity. All models performed equally well (ASE on test ranging between 1.1 and 1.3, p¿=¿0.34). CONCLUSIONS: We fully...

  19. Dependence of FDG uptake on tumor microenvironment

    International Nuclear Information System (INIS)

    Pugachev, Andrei; Ruan, Shutian; Carlin, Sean; Larson, Steven M.; Campa, Jose; Ling, C. Clifton; Humm, John L.

    2005-01-01

    Purpose: To investigate the factors affecting the 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake in tumors at a microscopic level, by correlating it with tumor hypoxia, cellular proliferation, and blood perfusion. Methods and Materials: Nude mice bearing Dunning prostate tumors (R3327-AT) were injected with 18 F-FDG and pimonidazole, bromodeoxyuridine, and, 1 min before sacrifice, with Hoechst 33342. Selected tumor sections were imaged by phosphor plate autoradiography, while adjacent sections were used to obtain the images of the spatial distribution of Hoechst 33342, pimonidazole, and bromodeoxyuridine. The images were co-registered and analyzed on a pixel-by-pixel basis. Results: Statistical analysis of the data obtained from these tumors demonstrated that 18 F-FDG uptake was positively correlated with pimonidazole staining intensity in each data set studied. Correlation of FDG uptake with bromodeoxyuridine staining intensity was always negative. In addition, FDG uptake was always negatively correlated with the staining intensity of Hoechst 33342. Conclusions: For the Dunning prostate tumors studied, FDG uptake was always positively correlated with hypoxia and negatively correlated with both cellular proliferation and blood flow. Therefore, for the tumor model studied, higher FDG uptake is indicative of tumor hypoxia, but neither blood flow nor cellular proliferation

  20. Tumor regression following intravenous administration of lactoferrin- and lactoferricin-bearing dendriplexes.

    Science.gov (United States)

    Lim, Li Ying; Koh, Pei Yin; Somani, Sukrut; Al Robaian, Majed; Karim, Reatul; Yean, Yi Lyn; Mitchell, Jennifer; Tate, Rothwelle J; Edrada-Ebel, RuAngelie; Blatchford, David R; Mullin, Margaret; Dufès, Christine

    2015-08-01

    The possibility of using gene therapy for the treatment of cancer is limited by the lack of safe, intravenously administered delivery systems able to selectively deliver therapeutic genes to tumors. In this study, we investigated if the conjugation of the polypropylenimine dendrimer to lactoferrin and lactoferricin, whose receptors are overexpressed on cancer cells, could result in a selective gene delivery to tumors and a subsequently enhanced therapeutic efficacy. The conjugation of lactoferrin and lactoferricin to the dendrimer significantly increased the gene expression in the tumor while decreasing the non-specific gene expression in the liver. Consequently, the intravenous administration of the targeted dendriplexes encoding TNFα led to the complete suppression of 60% of A431 tumors and up to 50% of B16-F10 tumors over one month. The treatment was well tolerated by the animals. These results suggest that these novel lactoferrin- and lactoferricin-bearing dendrimers are promising gene delivery systems for cancer therapy. Specific targeting of cancer cells should enhance the delivery of chemotherapeutic agents. This is especially true for gene delivery. In this article, the authors utilized a dendrimer-based system and conjugated this with lactoferrin and lactoferricin to deliver anti-tumor genes. The positive findings in animal studies should provide the basis for further clinical studies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Facile synthesis of soybean phospholipid-encapsulated MoS2 nanosheets for efficient in vitro and in vivo photothermal regression of breast tumor

    Directory of Open Access Journals (Sweden)

    Li X

    2016-04-01

    Full Text Available Xiang Li,1 Yun Gong,2,3 Xiaoqian Zhou,1 Hui Jin,1 Huanhuan Yan,1 Shige Wang,2 Jun Liu11Department of Breast-Thyroid Surgery, Shanghai General Hospital of Nanjing Medical University, Shanghai, People’s Republic of China; 2College of Science, University of Shanghai for Science and Technology, 3Shanghai Publishing and Printing College, Shanghai, People’s Republic of ChinaAbstract: Two-dimensional MoS2 nanosheet has been extensively explored as a photothermal agent for tumor regression; however, its surface modification remains a great challenge. Herein, as an alternative to surface polyethylene glycol modification (PEGylation, a facile approach based on “thin-film” strategy has been proposed for the first time to produce soybean phospholipid-encapsulated MoS2 (SP-MoS2 nanosheets. By simply vacuum-treating MoS2 nanosheets/soybean phospholipid/chloroform dispersion in a rotary evaporator, SP-MoS2 nanosheet was successfully constructed. Owing to the steric hindrance of polymer chains, the surface-coated soybean phospholipid endowed MoS2 nanosheets with excellent colloidal stability. Without showing detectable in vitro and in vivo hemolysis, coagulation, and cyto-/histotoxicity, the constructed SP-MoS2 nanosheets showed good photothermal conversion performance and photothermal stability. SP-MoS2 nanosheet was shown to be a promising platform for in vitro and in vivo breast tumor photothermal therapy. The produced SP-MoS2 nanosheets featured low cost, simple fabrication, and good in vivo hemo-/histocompatibility and hold promising potential for future clinical tumor therapy.Keywords: soybean phospholipid, MoS2 nanosheets, in vivo, photothermal regression, breast tumor

  2. B16 melanoma tumor growth is delayed in mice in an age-dependent manner

    Directory of Open Access Journals (Sweden)

    Christina Pettan-Brewer

    2012-08-01

    Full Text Available A major risk factor for cancer is increasing age, which suggests that syngeneic tumor implants in old mice would grow more rapidly. However, various reports have suggested that old mice are not as permissive to implanted tumor cells as young mice. In order to determine and characterize the age-related response to B16 melanoma, we implanted 5×105 tumor cells into 8, 16, 24, and 32-month-old male C57BL/6 (B6 and C57BL/6×BALB/c F1 (CB6 F1 mice subcutaneously in the inguinal and axillary spaces, or intradermally in the lateral flank. Results showed decreased tumor volume with increasing age, which varied according to mouse genetic background and the implanted site. The B6 strain showed robust tumor growth at 8 months of age at the inguinal implantation site, with an average tumor volume of 1341.25 mm3. The 16, 24, and 32-month age groups showed a decrease in tumor growth with tumor volumes of 563.69, 481.02, and 264.55 mm3, respectively (p≤0.001. The axillary implantation site was less permissive in 8-month-old B6 mice with an average tumor volume of 761.52 mm3. The 24- and 32-month age groups showed a similar decrease in tumor growth with tumor volumes of 440 and 178.19 mm3, respectively (p≤0.01. The CB6F1 strain was not as tumor permissive at 8 months of age as B6 mice with average tumor volumes of 446.96 and 426.91 mm3 for the inguinal and axillary sites, respectively. There was a decrease in tumor growth at 24 months of age at both inguinal and axillary sites with an average tumor volume of 271.02 and 249.12 mm3, respectively (p≤0.05. The strain dependence was not apparent in 8-month-old mice injected intradermally with B16 melanoma cells, with average tumor volumes of 736.82 and 842.85 mm3 for B6 and CB6 F1, respectively. However, a strain difference was seen in 32-month-old B6 mice with an average decrease in tumor volume of 250.83 mm3 (p≤0.01. In contrast, tumor growth significantly decreased earlier in CB6 F1 mice with average

  3. Diltiazem enhances tumor blood flow: MRI study in a murine tumor

    International Nuclear Information System (INIS)

    Muruganandham, M.; Kasiviswanathan, A.; Jagannathan, N.R.; Raghunathan, P.; Jain, P.C.; Jain, V.

    1999-01-01

    Purpose: Diltiazem, a calcium-channel blocker, is known to differentially influence the radiation responses of normal and murine tumor tissues. To elucidate the underlying mechanisms, the effects of diltiazem on the radiation response of Ehrlich ascites tumor (EAT) in mice have been investigated, and the hemodynamic changes induced by diltiazem in tumor and normal muscle have been studied using magnetic resonance imaging (MRI) techniques. Methods and Materials: Ehrlich ascites tumors were grown subcutaneously in Swiss albino strain A mice. Dynamic gadodiamide and blood oxygen level dependent (BOLD) contrast enhanced 1 H MR imaging studies of EAT and normal muscle were performed after administration of diltiazem in mice using a 4.7 Tesla MR scanner. Tumor radiotherapy experiments (total dose = 10 Gy, 0.4-0.5 Gy/min, single fraction) were carried out with 30 min preadministration of diltiazem (27.5 or 55 mg/kg i.p.) to EAT-bearing mice using a teletherapy machine. Results: The diltiazem+ radiation treated group showed significant tumor regression (in congruent with 65% of the animals) and enhanced animal survival. MR-gadodiamide contrast kinetics revealed a higher magnitude of signal enhancement in diltiazem treated groups as compared to the controls. The observed changes in the magnitude of kinetic parameters were the same for both tumor and normal muscle. BOLD-MR images at 30 min after diltiazem administration showed a 25% and 8% (average) intensity enhancement from their basal values in tumor and normal muscle regions, respectively. The control group showed no significant changes. Conclusion: The present studies demonstrate the radiosensitization potential of diltiazem in the mice EAT model. The enhanced radiation response observed with diltiazem correlates with the diltiazem-induced increase in tumor blood flow (TBF) and tumor oxygenation. The present results also demonstrate the applications of BOLD-MR measurements in investigating the alterations in tumor

  4. Autophagy-dependent secretion: contribution to tumor progression

    Directory of Open Access Journals (Sweden)

    Tom Keulers

    2016-11-01

    Full Text Available Autophagy is best known as a lysosomal degradation and recycling pathway to maintain cellular homeostasis. During autophagy, cytoplasmic content is recognized and packed in autophagic vacuoles, or autophagosomes, and targeted for degradation. However, during the last years, it has become evident that the role of autophagy is not restricted to degradation alone but also mediates unconventional forms of secretion. Furthermore, cells with defects in autophagy apparently are able to reroute their cargo, like mitochondria, to the extracellular environment; effects that contribute to an array of pathologies. In this review we discuss the current knowledge of the physiological roles of autophagy-dependent secretion, i.e. the effect on inflammation and insulin/ hormone secretion. Finally, we focus on the effects of autophagy-dependent secretion on the tumour microenvironment and tumour progression. The autophagy mediated secreted factors may stimulate cellular proliferation via auto- and paracrine signaling. The autophagy mediated release of immune modulating proteins change the immunosuppresive tumor microenvironment and may promote an invasive phenotype. These effects may be either direct or indirect through facilitating formation of the mobilized vesicle, aid in anterograde trafficking or alterations in homeostasis and/or autonomous cell signaling.

  5. Desmanthus GENOTYPES

    Directory of Open Access Journals (Sweden)

    JOSÉ HENRIQUE DE ALBUQUERQUE RANGEL

    2015-01-01

    Full Text Available Desmanthus is a genus of forage legumes with potential to improve pastures and livestock produc-tion on clay soils of dry tropical and subtropical regions such as the existing in Brazil and Australia. Despite this patterns of natural or enforced after-ripening of Desmanthus seeds have not been well established. Four year old seed banks of nine Desmanthus genotypes at James Cook University were accessed for their patterns of seed softe-ning in response to a range of temperatures. Persistent seed banks were found to exist under all of the studied ge-notypes. The largest seeds banks were found in the genotypes CPI 78373 and CPI 78382 and the smallest in the genotypes CPI’s 37143, 67643, and 83563. An increase in the percentage of softened seeds was correlated with higher temperatures, in two patterns of response: in some accessions seeds were not significantly affected by tempe-ratures below 80º C; and in others, seeds become soft when temperature rose to as little as 60 ºC. At 80 °C the heat started to depress germination. High seed production of Desmanthus associated with dependence of seeds on eleva-ted temperatures to softening can be a very important strategy for plants to survive in dry tropical regions.

  6. Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization

    DEFF Research Database (Denmark)

    Scheel, Troels Kasper Høyer; Gottwein, Judith Margarete; Jensen, Tina Birk

    2008-01-01

    in serial passages. Sequence analysis of recovered viruses and subsequent reverse genetic studies revealed a vital dependence on one or two NS2 mutations, depending on the 4a/2a junction. Infectivity of ED43/JFH1 viruses was CD81 dependent. The genotype 4 cell culture systems permit functional analyses...... as well as drug and vaccine research on an increasingly important genotype in the Middle East, Africa, and Europe. We also developed genotype 1a intergenotypic recombinants from H77C with vital mutations in NS3. Using H77C/JFH1 and ED43/JFH1 viruses, we demonstrated high homologous neutralizing antibody...... titers in 1a and 4a patient sera, respectively. Furthermore, availability of JFH1 viruses with envelope proteins of the six major HCV genotypes permitted cross-neutralization studies; 1a and 4a serum cross-neutralized 1a, 4a, 5a, and 6a but not 2a and 3a viruses. Thus, the JFH1 intergenotypic...

  7. Evidence for Gender-Dependent Genotype by Environment Interaction in Adult Depression.

    Science.gov (United States)

    Molenaar, Dylan; Middeldorp, Christel M; Willemsen, Gonneke; Ligthart, Lannie; Nivard, Michel G; Boomsma, Dorret I

    2015-10-14

    Depression in adults is heritable with about 40 % of the phenotypic variance due to additive genetic effects and the remaining phenotypic variance due to unique (unshared) environmental effects. Common environmental effects shared by family members are rarely found in adults. One possible explanation for this finding is that there is an interaction between genes and the environment which may mask effects of the common environment. To test this hypothesis, we investigated genotype by environment interaction in a large sample of female and male adult twins aged 18-70 years. The anxious depression subscale of the Adult Self Report from the Achenbach System of Empirically Based Assessment (Achenbach and Rescorla in Manual for the ASEBA adult: forms and profiles, 2003) was completed by 13,022 twins who participate in longitudinal studies of the Netherlands Twin Register. In a single group analysis, we found genotype by unique environment interaction, but no genotype by common environment interaction. However, when conditioning on gender, we observed genotype by common environment interaction in men, with larger common environmental variance in men who are genetically less at risk to develop depression. Although the effect size of the interaction is characterized by large uncertainty, the results show that there is at least some variance due to the common environment in adult depression in men.

  8. Flunarizine Prevents Hepatitis C Virus Membrane Fusion in a Genotype-dependent Manner by Targeting the Potential Fusion Peptide within E1

    Science.gov (United States)

    Perin, Paula M.; Haid, Sibylle; Brown, Richard J. P.; Doerrbecker, Juliane; Schulze, Kai; Zeilinger, Carsten; von Schaewen, Markus; Heller, Brigitte; Vercauteren, Koen; Luxenburger, Eva; Baktash, Yasmine M.; Vondran, Florian W. R.; Speerstra, Sietkse; Awadh, Abdullah; Mukhtarov, Furkat; Schang, Luis M; Kirschning, Andreas; Müller, Rolf; Guzman, Carlos A.; Kaderali, Lars; Randall, Glenn; Meuleman, Philip; Ploss, Alexander; Pietschmann, Thomas

    2015-01-01

    To explore mechanisms of hepatitis C virus (HCV) replication we screened a compound library including licensed drugs. Flunarizine, a diphenylmethylpiperazine used to treat migraine, inhibited HCV cell entry in vitro and in vivo in a genotype-dependent fashion. Analysis of mosaic viruses between susceptible and resistant strains revealed that E1 and E2 glycoproteins confer susceptibility to flunarizine. Time of addition experiments and single particle tracking of HCV demonstrated that flunarizine specifically prevents membrane fusion. Related phenothiazines and pimozide also inhibited HCV infection and preferentially targeted HCV genotype 2 viruses. However, phenothiazines and pimozide exhibited improved genotype coverage including the difficult to treat genotype 3. Flunarizine-resistant HCV carried mutations within the alleged fusion peptide and displayed cross-resistance to these compounds, indicating that these drugs have a common mode of action. Conclusion: These observations reveal novel details about HCV membrane fusion. Moreover, flunarizine and related compounds represent first-in-class HCV fusion inhibitors that merit consideration for repurposing as cost-effective component of HCV combination therapies. PMID:26248546

  9. Assessment of diagnostic value of tumor markers for colorectal neoplasm by logistic regression and ROC curve

    International Nuclear Information System (INIS)

    Ping, G.

    2007-01-01

    Full text: Objective: To assess the diagnostic value of CEA CA199 and CA50 for colorectal neoplasm by logistic regression and ROC curve. Methods: The subjects include 75 patients of colorectal cancer, 35 patients of benign intestinal disease and 49 health controls. CEA CA199 and CA50 are measured by CLIA ECLIA and IRMA respectively. The area under the curve (AUC) of CEA CA 199 CA50 and logistic regression results are compared. [Result] In the cancer-benign group, the AUC of CA50 is larger than the AUC of CA199 Compared with the AUC of combination of CEA CA199 and CA50 (0.604),the AUC of combination of CEA and CA50 (0.875) is larger and it is also larger than any other AUC of CEA CA199 or CA50 alone. In the cancerhealth group, the AUC of combination of CEA CA199 and CA50 is larger than any other AUC of CEA CA199 or CA50 alone. No matter in the cancer-benign group or cancerhealth group. The AUC of CEA is larger than the AUC of CA199 or CA50. Conclusion: CEA is useful in the diagnosis of colorectal cancer. In the process of differential diagnosis, the combination of CEA and CA50 can give more information, while the combination of three tumor markers does not perform well. Furthermore, as a statistical method, logistic regression can improve the diagnostic sensitivity and specificity. (author)

  10. Online Support Vector Regression with Varying Parameters for Time-Dependent Data

    International Nuclear Information System (INIS)

    Omitaomu, Olufemi A.; Jeong, Myong K.; Badiru, Adedeji B.

    2011-01-01

    Support vector regression (SVR) is a machine learning technique that continues to receive interest in several domains including manufacturing, engineering, and medicine. In order to extend its application to problems in which datasets arrive constantly and in which batch processing of the datasets is infeasible or expensive, an accurate online support vector regression (AOSVR) technique was proposed. The AOSVR technique efficiently updates a trained SVR function whenever a sample is added to or removed from the training set without retraining the entire training data. However, the AOSVR technique assumes that the new samples and the training samples are of the same characteristics; hence, the same value of SVR parameters is used for training and prediction. This assumption is not applicable to data samples that are inherently noisy and non-stationary such as sensor data. As a result, we propose Accurate On-line Support Vector Regression with Varying Parameters (AOSVR-VP) that uses varying SVR parameters rather than fixed SVR parameters, and hence accounts for the variability that may exist in the samples. To accomplish this objective, we also propose a generalized weight function to automatically update the weights of SVR parameters in on-line monitoring applications. The proposed function allows for lower and upper bounds for SVR parameters. We tested our proposed approach and compared results with the conventional AOSVR approach using two benchmark time series data and sensor data from nuclear power plant. The results show that using varying SVR parameters is more applicable to time dependent data.

  11. Different patterns in the prognostic value of age for bladder cancer-specific survival depending on tumor stages.

    Science.gov (United States)

    Feng, Huan; Zhang, Wei; Li, Jiajun; Lu, Xiaozhe

    2015-01-01

    To compare the pathological features and long-term survival of bladder cancer (BCa) in young patients with elderly counterparts. Using the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) population-based data, we identified 93115 patients with non-metastatic bladder cancer diagnosed between 1988 and 2003. Patients were categorized into young (50 years and under) and elderly groups (over 50 years of age). The overall and five-year bladder cancer specific survival (BCSS) data were obtained using Kaplan-Meier plots. Multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors. There were significant differences between the two groups in primary site, pathologic grading, histologic type, AJCC stage (pstage patients. The study findings show different patterns in the prognostic value of age for determining BCSS, depending on the tumor stages. Compared with elderly patients, young patients with bladder cancer surgery appear to have unique characteristics and a higher overall and cancer specific survival rate.

  12. The study of correlation between HBV genotype and the response to transcatheter arterial chemoembolization therapy in hepatocellular carcinoma patients

    International Nuclear Information System (INIS)

    Huang Keyao; Yang Weizhu; Jiang Na; Zheng Qubing

    2004-01-01

    Objective: To evaluate the influence of hepatitis B virus(HBV) genotype on response to transcatheter arterial embolization therapy in patients with HBV-related HCC. Methods: Transcatheter arterial chemoem-bolization therapy was conducted in patients with HBV-related HCC and response to embolization therapy were observed according to the tumor necrosis rate, the HCC recurrence rate, the cumulative incidence of survival rate and the change of AFP. The HBV genotype was determined by sequencing directly the polymerase chain reaction products of the HBV S gene. The response of HCC to embolization therapy was compared between patients who were infected with different genotypic HBV. Results: The tumor necrosis rate of genotype C patients was similar to that of genotype B patients (P=0.099). The HCC recurrence rate of genotype B was lower than that of genotype C patients (P=0.036). The cumulative incidence of survival rates of 2 and 3 years were significantly higher in the genotype B patients (P=0.036 and P=0.013). There was no difference between the two genotypes, patients in the change of AFP (P>0.05). Conclusions: HBV genotype B patients seem to have a better response to embolization therapy as compared to genotype C patients. Determination of HBV genotype may be useful in predicting the outcomes of TACE therapy in HBV-related HCC. (authors)

  13. Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses

    Science.gov (United States)

    Sundaresan, Tilak K.; Sequist, Lecia V.; Heymach, John V.; Riely, Gregory J.; Jänne, Pasi A.; Koch, Walter H.; Sullivan, James P.; Fox, Douglas B.; Maher, Robert; Muzikansky, Alona; Webb, Andrew; Tran, Hai T.; Giri, Uma; Fleisher, Martin; Yu, Helena A.; Wei, Wen; Johnson, Bruce E.; Barber, Thomas A.; Walsh, John R.; Engelman, Jeffrey A.; Stott, Shannon L.; Kapur, Ravi; Maheswaran, Shyamala; Toner, Mehmet

    2015-01-01

    Purpose The T790M gatekeeper mutation in the Epidermal Growth Factor Receptor (EGFR) is acquired by some EGFR-mutant non-small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKIs). As third generation EGFR TKIs that overcome T790M-associated resistance become available, noninvasive approaches to T790M detection will become critical to guide management. Experimental Design As part of a multi-institutional Stand-Up-To-Cancer collaboration, we performed an exploratory analysis of 40 patients with EGFR-mutant tumors progressing on EGFR TKI therapy. We compared the T790M genotype from tumor biopsies with analysis of simultaneously collected circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Results T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples and 32 (80%) ctDNA samples. The resistance-associated mutation was detected in 47–50% of patients using each of the genotyping assays, with concordance among them ranging from 57–74%. While CTC- and ctDNA-based genotyping were each unsuccessful in 20–30% of cases, the two assays together enabled genotyping in all patients with an available blood sample, and they identified the T790M mutation in 14 (35%) patients in whom the concurrent biopsy was negative or indeterminate. Conclusion Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations. The use of complementary approaches may provide the most complete assessment of each patient’s cancer, which should be validated in predicting response to T790M-targeted inhibitors. PMID:26446944

  14. A simple bias correction in linear regression for quantitative trait association under two-tail extreme selection.

    Science.gov (United States)

    Kwan, Johnny S H; Kung, Annie W C; Sham, Pak C

    2011-09-01

    Selective genotyping can increase power in quantitative trait association. One example of selective genotyping is two-tail extreme selection, but simple linear regression analysis gives a biased genetic effect estimate. Here, we present a simple correction for the bias.

  15. Detection of epistatic effects with logic regression and a classical linear regression model.

    Science.gov (United States)

    Malina, Magdalena; Ickstadt, Katja; Schwender, Holger; Posch, Martin; Bogdan, Małgorzata

    2014-02-01

    To locate multiple interacting quantitative trait loci (QTL) influencing a trait of interest within experimental populations, usually methods as the Cockerham's model are applied. Within this framework, interactions are understood as the part of the joined effect of several genes which cannot be explained as the sum of their additive effects. However, if a change in the phenotype (as disease) is caused by Boolean combinations of genotypes of several QTLs, this Cockerham's approach is often not capable to identify them properly. To detect such interactions more efficiently, we propose a logic regression framework. Even though with the logic regression approach a larger number of models has to be considered (requiring more stringent multiple testing correction) the efficient representation of higher order logic interactions in logic regression models leads to a significant increase of power to detect such interactions as compared to a Cockerham's approach. The increase in power is demonstrated analytically for a simple two-way interaction model and illustrated in more complex settings with simulation study and real data analysis.

  16. Can linear regression modeling help clinicians in the interpretation of genotypic resistance data? An application to derive a lopinavir-score.

    Science.gov (United States)

    Cozzi-Lepri, Alessandro; Prosperi, Mattia C F; Kjær, Jesper; Dunn, David; Paredes, Roger; Sabin, Caroline A; Lundgren, Jens D; Phillips, Andrew N; Pillay, Deenan

    2011-01-01

    The question of whether a score for a specific antiretroviral (e.g. lopinavir/r in this analysis) that improves prediction of viral load response given by existing expert-based interpretation systems (IS) could be derived from analyzing the correlation between genotypic data and virological response using statistical methods remains largely unanswered. We used the data of the patients from the UK Collaborative HIV Cohort (UK CHIC) Study for whom genotypic data were stored in the UK HIV Drug Resistance Database (UK HDRD) to construct a training/validation dataset of treatment change episodes (TCE). We used the average square error (ASE) on a 10-fold cross-validation and on a test dataset (the EuroSIDA TCE database) to compare the performance of a newly derived lopinavir/r score with that of the 3 most widely used expert-based interpretation rules (ANRS, HIVDB and Rega). Our analysis identified mutations V82A, I54V, K20I and I62V, which were associated with reduced viral response and mutations I15V and V91S which determined lopinavir/r hypersensitivity. All models performed equally well (ASE on test ranging between 1.1 and 1.3, p = 0.34). We fully explored the potential of linear regression to construct a simple predictive model for lopinavir/r-based TCE. Although, the performance of our proposed score was similar to that of already existing IS, previously unrecognized lopinavir/r-associated mutations were identified. The analysis illustrates an approach of validation of expert-based IS that could be used in the future for other antiretrovirals and in other settings outside HIV research.

  17. Advanced statistics: linear regression, part I: simple linear regression.

    Science.gov (United States)

    Marill, Keith A

    2004-01-01

    Simple linear regression is a mathematical technique used to model the relationship between a single independent predictor variable and a single dependent outcome variable. In this, the first of a two-part series exploring concepts in linear regression analysis, the four fundamental assumptions and the mechanics of simple linear regression are reviewed. The most common technique used to derive the regression line, the method of least squares, is described. The reader will be acquainted with other important concepts in simple linear regression, including: variable transformations, dummy variables, relationship to inference testing, and leverage. Simplified clinical examples with small datasets and graphic models are used to illustrate the points. This will provide a foundation for the second article in this series: a discussion of multiple linear regression, in which there are multiple predictor variables.

  18. Regression analysis of mixed panel count data with dependent terminal events.

    Science.gov (United States)

    Yu, Guanglei; Zhu, Liang; Li, Yang; Sun, Jianguo; Robison, Leslie L

    2017-05-10

    Event history studies are commonly conducted in many fields, and a great deal of literature has been established for the analysis of the two types of data commonly arising from these studies: recurrent event data and panel count data. The former arises if all study subjects are followed continuously, while the latter means that each study subject is observed only at discrete time points. In reality, a third type of data, a mixture of the two types of the data earlier, may occur and furthermore, as with the first two types of the data, there may exist a dependent terminal event, which may preclude the occurrences of recurrent events of interest. This paper discusses regression analysis of mixed recurrent event and panel count data in the presence of a terminal event and an estimating equation-based approach is proposed for estimation of regression parameters of interest. In addition, the asymptotic properties of the proposed estimator are established, and a simulation study conducted to assess the finite-sample performance of the proposed method suggests that it works well in practical situations. Finally, the methodology is applied to a childhood cancer study that motivated this study. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  19. Radiation regression patterns after cobalt plaque insertion for retinoblastoma

    International Nuclear Information System (INIS)

    Buys, R.J.; Abramson, D.H.; Ellsworth, R.M.; Haik, B.

    1983-01-01

    An analysis of 31 eyes of 30 patients who had been treated with cobalt plaques for retinoblastoma disclosed that a type I radiation regression pattern developed in 15 patients; type II, in one patient, and type III, in five patients. Nine patients had a regression pattern characterized by complete destruction of the tumor, the surrounding choroid, and all of the vessels in the area into which the plaque was inserted. This resulting white scar, corresponding to the sclerae only, was classified as a type IV radiation regression pattern. There was no evidence of tumor recurrence in patients with type IV regression patterns, with an average follow-up of 6.5 years, after receiving cobalt plaque therapy. Twenty-nine of these 30 patients had been unsuccessfully treated with at least one other modality (ie, light coagulation, cryotherapy, external beam radiation, or chemotherapy)

  20. Radiation regression patterns after cobalt plaque insertion for retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Buys, R.J.; Abramson, D.H.; Ellsworth, R.M.; Haik, B.

    1983-08-01

    An analysis of 31 eyes of 30 patients who had been treated with cobalt plaques for retinoblastoma disclosed that a type I radiation regression pattern developed in 15 patients; type II, in one patient, and type III, in five patients. Nine patients had a regression pattern characterized by complete destruction of the tumor, the surrounding choroid, and all of the vessels in the area into which the plaque was inserted. This resulting white scar, corresponding to the sclerae only, was classified as a type IV radiation regression pattern. There was no evidence of tumor recurrence in patients with type IV regression patterns, with an average follow-up of 6.5 years, after receiving cobalt plaque therapy. Twenty-nine of these 30 patients had been unsuccessfully treated with at least one other modality (ie, light coagulation, cryotherapy, external beam radiation, or chemotherapy).

  1. Malignancy risk prediction for primary jejunum-ileal tumors

    Directory of Open Access Journals (Sweden)

    MARQUES Ruy Garcia

    2000-01-01

    Full Text Available This work is aimed at identifying factors associated with primary jejunum-ileal tumors malignancy, defining a prediction model with sensitivity, specificity and accuracy to distinguish malign from benign neoplasms. These tumors are rare, have highly unspecific presentation and, frequently, are diagnosed late. We reviewed the charts of 42 patients with primary jejunum-ileal tumors treated in the Department of General Surgery of Rio de Janeiro State University Hospital, Rio de Janeiro, RJ, Brazil, from 1969 to 1998. We performed bivariate analyses, based on chi² test, searching associations between tumors malignancy and demographic and clinical variables. Then logistic regression was employed to consider the independent effect of variables previously identified on malignancy risk. The malign tumors included 11 adenocarcinomas, 7 leiomyosarcomas, 5 carcinoids and 4 lymphomas; the benign tumors included 10 leiomyomas, 2 hamartomas, and single cases of adenoma, multiple neurilemoma and choristoma. The bivariate analyses indicated the association between malignancy and palpable abdominal mass (P = 0.003, period from signs and symptoms onset to diagnosis (P = 0.016, anemia (P = 0.020, anorexia (P = 0.003, abdominal pain (P = 0.031, weight loss (P = 0.001, nausea and vomit (P = 0.094, and intestinal obstruction (P = 0.066; no association with patients demographic characteristics were found. In the final logistic regression model, weight loss, anemia and intestinal obstruction were statistically associated with the dependent variable of interest. Based only on three variables -- weight loss, anemia and intestinal obstruction -- the model defined was able to predict primary jejunum-ileal tumors malignancy with sensitivity of 85.2%, specificity of 80.0%, and accuracy of 83.3%.

  2. Significant association between ERCC2 and MTHR polymorphisms and breast cancer susceptibility in Moroccan population: genotype and haplotype analysis in a case-control study.

    Science.gov (United States)

    Hardi, Hanaa; Melki, Rahma; Boughaleb, Zouhour; El Harroudi, Tijani; Aissaoui, Souria; Boukhatem, Noureddine

    2018-03-15

    Genetic determinants of breast cancer (BC) remained largely unknown in the majority of Moroccan patients. The purpose of this study was to explore the association of ERCC2 and MTHFR polymorphisms with genetic susceptibility to breast cancer in Moroccan population. We genotyped ERCC2 polymorphisms (rs1799793 (G934A) and rs13181 (A2251C)) and MTHFR polymorphisms (rs1801133 (C677T) and rs1801131 (A1298C)) using TaqMan SNP Genotyping Assays. Genotypes were compared in 151 BC cases and 156 population-matched controls. Allelic, genotypic and haplotype associations with the risk and clinicopathological features of BC were assessed using logistic regression analyses. ERCC2-rs1799793-AA genotype was associated with high risk of BC compared to wild type genotype (recessive model: OR: 2.90, 95% CI: 1.34-6.26, p = 0.0069) even after Bonferroni correction (p < 0,0125). MTHFR rs1801133-TT genotype was associated with increased risk of BC (recessive model, OR: 2.49, 95% CI: 1.17-5.29, p = 0.017) but the association turned insignificant after Bonferroni correction. For the rest of SNPs, no statistical associations to BC risk were detected. Significant association with clinical features was detected for MTHFR-rs1801133-TC genotype with early age at diagnosis and familial BC. Following Bonferroni correction, only association with familial BC remained significant. MTHFR-rs1801131-CC genotype was associated with sporadic BC. ERCC2-rs1799793-AA genotype correlated with ER+ and PR+ breast cancer. ERCC2-rs13181-CA genotype was significantly associated large tumors (T ≥ 3) in BC patients. None of these associations passed Bonferroni correction. Haplotype analysis showed that ERCC2 A-C haplotype was significantly associated with increased BC risk (OR: 3.71, 95% CI: 1.7-8.12, p = 0.0002 and p = 0.0008 before and after Bonferroni correction, respectively) and positive expression of ER and PR in BC patients. ERCC2 G-C haplotype was correlated with PR negative and

  3. Application of single-step genomic best linear unbiased prediction with a multiple-lactation random regression test-day model for Japanese Holsteins.

    Science.gov (United States)

    Baba, Toshimi; Gotoh, Yusaku; Yamaguchi, Satoshi; Nakagawa, Satoshi; Abe, Hayato; Masuda, Yutaka; Kawahara, Takayoshi

    2017-08-01

    This study aimed to evaluate a validation reliability of single-step genomic best linear unbiased prediction (ssGBLUP) with a multiple-lactation random regression test-day model and investigate an effect of adding genotyped cows on the reliability. Two data sets for test-day records from the first three lactations were used: full data from February 1975 to December 2015 (60 850 534 records from 2 853 810 cows) and reduced data cut off in 2011 (53 091 066 records from 2 502 307 cows). We used marker genotypes of 4480 bulls and 608 cows. Genomic enhanced breeding values (GEBV) of 305-day milk yield in all the lactations were estimated for at least 535 young bulls using two marker data sets: bull genotypes only and both bulls and cows genotypes. The realized reliability (R 2 ) from linear regression analysis was used as an indicator of validation reliability. Using only genotyped bulls, R 2 was ranged from 0.41 to 0.46 and it was always higher than parent averages. The very similar R 2 were observed when genotyped cows were added. An application of ssGBLUP to a multiple-lactation random regression model is feasible and adding a limited number of genotyped cows has no significant effect on reliability of GEBV for genotyped bulls. © 2016 Japanese Society of Animal Science.

  4. Risk of Recurrence in Operated Parasagittal Meningiomas: A Logistic Binary Regression Model.

    Science.gov (United States)

    Escribano Mesa, José Alberto; Alonso Morillejo, Enrique; Parrón Carreño, Tesifón; Huete Allut, Antonio; Narro Donate, José María; Méndez Román, Paddy; Contreras Jiménez, Ascensión; Pedrero García, Francisco; Masegosa González, José

    2018-02-01

    Parasagittal meningiomas arise from the arachnoid cells of the angle formed between the superior sagittal sinus (SSS) and the brain convexity. In this retrospective study, we focused on factors that predict early recurrence and recurrence times. We reviewed 125 patients with parasagittal meningiomas operated from 1985 to 2014. We studied the following variables: age, sex, location, laterality, histology, surgeons, invasion of the SSS, Simpson removal grade, follow-up time, angiography, embolization, radiotherapy, recurrence and recurrence time, reoperation, neurologic deficit, degree of dependency, and patient status at the end of follow-up. Patients ranged in age from 26 to 81 years (mean 57.86 years; median 60 years). There were 44 men (35.2%) and 81 women (64.8%). There were 57 patients with neurologic deficits (45.2%). The most common presenting symptom was motor deficit. World Health Organization grade I tumors were identified in 104 patients (84.6%), and the majority were the meningothelial type. Recurrence was detected in 34 cases. Time of recurrence was 9 to 336 months (mean: 84.4 months; median: 79.5 months). Male sex was identified as an independent risk for recurrence with relative risk 2.7 (95% confidence interval 1.21-6.15), P = 0.014. Kaplan-Meier curves for recurrence had statistically significant differences depending on sex, age, histologic type, and World Health Organization histologic grade. A binary logistic regression was made with the Hosmer-Lemeshow test with P > 0.05; sex, tumor size, and histologic type were used in this model. Male sex is an independent risk factor for recurrence that, associated with other factors such tumor size and histologic type, explains 74.5% of all cases in a binary regression model. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Regression and local control rates after radiotherapy for jugulotympanic paragangliomas: Systematic review and meta-analysis

    International Nuclear Information System (INIS)

    Hulsteijn, Leonie T. van; Corssmit, Eleonora P.M.; Coremans, Ida E.M.; Smit, Johannes W.A.; Jansen, Jeroen C.; Dekkers, Olaf M.

    2013-01-01

    The primary treatment goal of radiotherapy for paragangliomas of the head and neck region (HNPGLs) is local control of the tumor, i.e. stabilization of tumor volume. Interestingly, regression of tumor volume has also been reported. Up to the present, no meta-analysis has been performed giving an overview of regression rates after radiotherapy in HNPGLs. The main objective was to perform a systematic review and meta-analysis to assess regression of tumor volume in HNPGL-patients after radiotherapy. A second outcome was local tumor control. Design of the study is systematic review and meta-analysis. PubMed, EMBASE, Web of Science, COCHRANE and Academic Search Premier and references of key articles were searched in March 2012 to identify potentially relevant studies. Considering the indolent course of HNPGLs, only studies with ⩾12 months follow-up were eligible. Main outcomes were the pooled proportions of regression and local control after radiotherapy as initial, combined (i.e. directly post-operatively or post-embolization) or salvage treatment (i.e. after initial treatment has failed) for HNPGLs. A meta-analysis was performed with an exact likelihood approach using a logistic regression with a random effect at the study level. Pooled proportions with 95% confidence intervals (CI) were reported. Fifteen studies were included, concerning a total of 283 jugulotympanic HNPGLs in 276 patients. Pooled regression proportions for initial, combined and salvage treatment were respectively 21%, 33% and 52% in radiosurgery studies and 4%, 0% and 64% in external beam radiotherapy studies. Pooled local control proportions for radiotherapy as initial, combined and salvage treatment ranged from 79% to 100%. Radiotherapy for jugulotympanic paragangliomas results in excellent local tumor control and therefore is a valuable treatment for these types of tumors. The effects of radiotherapy on regression of tumor volume remain ambiguous, although the data suggest that regression can

  6. Gleditsia Saponin C Induces A549 Cell Apoptosis via Caspase-Dependent Cascade and Suppresses Tumor Growth on Xenografts Tumor Animal Model

    Directory of Open Access Journals (Sweden)

    Ye Cheng

    2018-01-01

    Full Text Available Saponins are natural compounds and possess the most promising anti-cancer function. Here, a saponin gleditsia saponin C (GSC, extracted from gleditsiae fructus abnormalis, could induce apoptosis of lung tumor cell line A549 via caspase dependent cascade and this effect could be prevented by the caspase inhibitors. In addition, GSC induced cell death companied with an increase ratio of Bax:Bcl-2 and inhibition of ERK and Akt signaling pathways. Meanwhile, GSC suppressed TNFα inducing NF-κB activation and increased the susceptibility of lung cancer cell to TNFα induced apoptosis. Furthermore, on mouse xenograft model, GSC significantly suppressed tumor growth and induced cancer cell apoptosis, which validated the anti-tumor effect of GSC. Based on these results, GSC might be a promising drug candidate of anti-lung cancer for its potential clinical applications.

  7. A simple bias correction in linear regression for quantitative trait association under two-tail extreme selection

    OpenAIRE

    Kwan, Johnny S. H.; Kung, Annie W. C.; Sham, Pak C.

    2011-01-01

    Selective genotyping can increase power in quantitative trait association. One example of selective genotyping is two-tail extreme selection, but simple linear regression analysis gives a biased genetic effect estimate. Here, we present a simple correction for the bias. © The Author(s) 2011.

  8. Evaluation of Sugar Beet (Beta vulgaris L. Genotypes for Their Trait Associations under Saline Conditions

    Directory of Open Access Journals (Sweden)

    B Bashiri

    2015-08-01

    Full Text Available To evaluate sugar-beet genotypes for their trait associations, two separate RCBD experiments with three replications were conducted both under non-saline (normal and saline conditions at the Agricultural Research of Miandoab. Analysis of variance of the data collected showed that there were significant differences among genotypes for all traits studied under non-saline condition. But, differences of genotypes under saline condition were significant only for root yield, root potassium content, sugar extraction coefficient, impure and pure (white sugar yields. Salinity stress, in this study, reduced root potassium content, root yield, sugar extraction coefficient, impure and pure (white sugar yields. Mean comparisons of genotypes indicated that root yield of all genotypes, under non-saline condition, were higher than those of under saline one. As whole, genotypes number 1 and 2 produced higher root yields, impure and pure sugar yields respectively, under both saline and non-saline conditions. Based on the results obtained it was revealed that regression coefficients for the traits under study were significant. Step-wise regression and path coefficient analyses also indicated that traits like root yield, pure sugar and root nitrogen contents highly affected white sugar yield under non-saline conditions.

  9. [Correlation analysis of G870A CCND1 gene polymorphism with digestive system tumors].

    Science.gov (United States)

    Yang, Shu-Min; Shi, Ya-Lin

    2016-11-20

    To study the correlation of G870A CCND1 gene polymorphism and digestive system tumors. From August 2010 to August 2014, 164 digestive system cancer patients (including 82 patients with gastric cancer and 82 with colorectal cancer) and 82 healthy subjects (control group) were examined with PCR-restriction fragment length polymorphism (PCR-RFLP). The distribution of CCND1 gene G870A frequency in the 3 groups and its association with tumor staging and grading were analyzed. The frequencies of the GG, GA and AA genotypes in G870A CCND1 gene loci in patients with gastric cancer and colorectal cancer differed significantly from those in the control group (Pdigestive system tumors (Pdigestive system cancer risk than the GG genotype (Pdigestive system tumors. The allele A is associated with an increased risk of digestive system tumors and correlated with the tumor differentiation and staging of the tumor.

  10. The tumor necrosis factor alpha - 308G>A polymorphism is associated with dementia in the oldest-old

    DEFF Research Database (Denmark)

    Bruunsgaard, Helle; Benfield, Thomas L; Andersen-Ranberg, Karen

    2004-01-01

    OBJECTIVES: To test the hypothesis that the tumor necrosis factor (TNF) -308 G>A promoter gene polymorphism is a risk factor in age-related dementia and longevity. DESIGN: A cross-sectional and a longitudinal study. SETTING: A population-based sample of Danish centenarians. PARTICIPANTS: One...... was investigated (Fischer exact test). Furthermore, whether the TNF -308 G>A polymorphism was associated with the prevalence of dementia (logistic regression analysis), the plasma level of TNF-alpha (analysis of variance), and mortality in the following 5 years (Cox regression analysis) within the cohort...... higher plasma levels of TNF-alpha, but the significance was questionable due to a low number of subjects with this genotype. CONCLUSION: It is possible that the TNF -308 A allele is maintained during aging because subjects who are heterozygous for this polymorphism possess the optimal inflammatory...

  11. Genotype-dependent participation of coat color gene loci in the behavioral traits of laboratory mice.

    Science.gov (United States)

    Yamamuro, Yutaka; Shiraishi, Aya

    2011-10-01

    To evaluate if loci responsible for coat color phenotypes contribute to behavioral characteristics, we specified novel gene loci associated with social exploratory behavior and examined the effects of the frequency of each allele at distinct loci on behavioral expression. We used the F2 generation, which arose from the mating of F1 mice obtained by interbreeding DBA/2 and ICR mice. Phenotypic analysis indicated that the agouti and albino loci affect behavioral traits. A genotype-based analysis revealed that novel exploratory activity was suppressed in a manner dependent on the frequency of the dominant wild-type allele at the agouti, but not albino, locus. The allele-dependent suppression was restricted to colored mice and was not seen in albino mice. The present results suggest that the agouti locus contributes to a particular behavioral trait in the presence of a wild-type allele at the albino locus, which encodes a structural gene for tyrosinase. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Analysis of HBV genotype distribution and its association with liver cirrhosis in Xinjiang Uygur Autonomous Region, China

    Directory of Open Access Journals (Sweden)

    WANG Xiaozhong

    2014-12-01

    Full Text Available ObjectiveTo investigate the distribution of hepatitis B virus (HBV genotypes among patients in Xinjiang Uygur Autonomous Region, China, and to explore its association with liver cirrhosis. MethodsHBV genotypes of 1018 hepatitis B patients were determined by PCR analysis. The relationship of HBV genotype with clinical outcomes and relevant chronic liver diseases was assessed by contingency chi-square test, Kruskal-Wallis test, and multivariate unconditional logistic regression analysis. ResultsAmong the 828 patients whose HBV genotyping was completed in this study, type C was the major genotype and the percentage was 54.11% (448/828, 25.15% (200/828 had type B, and 16.18% (134/828 had type D. Among the 116 patients with liver cirrhosis, 20.84% had type C, which was significantly more frequent than other genotypes (P<0.00. The multivariate unconditional logistic regression model identified several risk factors for liver cirrhosis, including duration of hepatitis B≥10 years, C genotype, high HBV DNA viral load, and impaired liver function characterized by abnormal alanine aminotransferase test. Among all these factors, genotype C had the highest relevance to liver cirrhosis (OR=2819. ConclusionThe leading genotype of HBV in Xinjiang Uygur Autonomous Region is type C, followed by type B and type D. Genotype C is an independent risk factor for HBV-related liver cirrhosis.

  13. Immunotherapy with neuraminidase-treated tumor cells after radiotherapy

    International Nuclear Information System (INIS)

    Song, C.W.; Levitt, S.H.

    1975-01-01

    The effect of active immunotherapy with Vibrio cholerae neuraminidase-treated syngeneic tumor cells (VCN-cells) following radiotherapy has been studied with 3-methylcholanthrene-induced fibrosarcoma, M-79, transplanted to the thigh of C3H/HeJ mice. When the tumors reached 4 to 8 mm in diameter, various treatments were started. X-irradiation with 2000 rad in a single dose induced a complete regression of 24 out of 103 tumors (23.3 percent). The inoculation of 1 x 10 6 of VCN-cells to the tumor-bearing animals, every other day for a total of three doses, caused a complete regression of 6 out of 57 tumors (10.5 percent). Treatments of animals with the immunotherapy starting 1 day after X-irradiation of tumors with 2000 rad resulted in a complete regression of 22 out of 58 tumors (37.9 percent). The median survival time of animals that received combined radiotherapy and immunotherapy was longer than that observed after either treatment alone

  14. Multiattribute Response of Maize Genotypes Tested in Different Coastal Regions of Brazil

    Directory of Open Access Journals (Sweden)

    Lúcio Borges de Araújo

    2011-01-01

    Full Text Available This work applies the three mode principal components analysis to analyze simultaneously the multiple attributes; to fit of models with additive main effects and multiplicative interaction effects (AMMI models and the regressions models on sites (SREG models; to evaluate, respectively, the multivariate response of the genotype × environment interaction and the mean response of 36 genotypes of corn tested in 4 locations in Brazil. The results were presented by joint plots to identify the best genotypes for their adaptability and performance in the set of attributes.

  15. Neonatal umbilical inflammatory myofibroblastic tumor

    African Journals Online (AJOL)

    antenatal scan. The preferred treatment option is resection of the tumor. Spontaneous regression has been described. Ann Pediatr Surg 13:160–162 c 2017 Annals of Pediatric. Surgery. ... Keywords: inflammatory myofibroblastic tumor, neonatal tumor, surgical resection ... Other anatomical regions were the brain, the.

  16. Liposome accumulation in irradiated tumors display important tumor and dose dependent differences

    DEFF Research Database (Denmark)

    Hansen, Anders Elias; Fliedner, Frederikke Petrine; Henriksen, Jonas Rosager

    2018-01-01

    Radiation therapy may affect several important parameters in the tumor microenvironment and thereby influence the accumulation of liposomes by the enhanced permeability and retention (EPR)-effect. Here we investigate the effect of single dose radiation therapy on liposome tumor accumulation by PET...

  17. Quantile Regression Methods

    DEFF Research Database (Denmark)

    Fitzenberger, Bernd; Wilke, Ralf Andreas

    2015-01-01

    if the mean regression model does not. We provide a short informal introduction into the principle of quantile regression which includes an illustrative application from empirical labor market research. This is followed by briefly sketching the underlying statistical model for linear quantile regression based......Quantile regression is emerging as a popular statistical approach, which complements the estimation of conditional mean models. While the latter only focuses on one aspect of the conditional distribution of the dependent variable, the mean, quantile regression provides more detailed insights...... by modeling conditional quantiles. Quantile regression can therefore detect whether the partial effect of a regressor on the conditional quantiles is the same for all quantiles or differs across quantiles. Quantile regression can provide evidence for a statistical relationship between two variables even...

  18. Tumor-specific CD4+ T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells.

    Science.gov (United States)

    Akhmetzyanova, Ilseyar; Zelinskyy, Gennadiy; Schimmer, Simone; Brandau, Sven; Altenhoff, Petra; Sparwasser, Tim; Dittmer, Ulf

    2013-02-01

    The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.

  19. Purging of the neuroblastoma stem cell compartment and tumor regression on exposure to hypoxia or cytotoxic treatment.

    Science.gov (United States)

    Marzi, Ilaria; D'Amico, Massimo; Biagiotti, Tiziana; Giunti, Serena; Carbone, Maria Vittoria; Fredducci, David; Wanke, Enzo; Olivotto, Massimo

    2007-03-15

    We worked out an experimental protocol able to purge the stem cell compartment of the SH-SY5Y neuroblastoma clone. This protocol was based on the prolonged treatment of the wild-type cell population with either hypoxia or the antiblastic etoposide. Cell fate was monitored by immunocytochemical and electrophysiologic (patch-clamp) techniques. Both treatments produced the progressive disappearance of neuronal type (N) cells (which constitute the bulk of the tumor), leaving space for a special category of epithelial-like substrate-adherent cells (S(0)). The latter represent a minimal cell component of the untreated population and are endowed with immunocytochemical markers (p75, c-kit, and CD133) and the electrophysiologic "nude" profile, typical of the neural crest stem cells. S(0) cells displayed a highly clonogenic potency and a substantial plasticity, generating both the N component and an alternative subpopulation terminally committed to the fibromuscular lineage. Unlike the N component, this lineage was highly insensitive to the apoptotic activity of hypoxia and etoposide and developed only when the neuronal option was abolished. Under these conditions, the fibromuscular progeny of S(0) expanded and progressed up to the exhaustion of the staminal compartment and to the extinction of the tumor. When combined, hypoxia and etoposide cooperated in abolishing the N cell generation and promoting the conversion of the tumor described. This synergy might mirror a natural condition in the ischemic areas occurring in cancer. These results have relevant implications for the understanding of the documented tendency of neuroblastomas to regress from a malignant to a benign phenotype, either spontaneously or on antiblastic treatment.

  20. Vector regression introduced

    Directory of Open Access Journals (Sweden)

    Mok Tik

    2014-06-01

    Full Text Available This study formulates regression of vector data that will enable statistical analysis of various geodetic phenomena such as, polar motion, ocean currents, typhoon/hurricane tracking, crustal deformations, and precursory earthquake signals. The observed vector variable of an event (dependent vector variable is expressed as a function of a number of hypothesized phenomena realized also as vector variables (independent vector variables and/or scalar variables that are likely to impact the dependent vector variable. The proposed representation has the unique property of solving the coefficients of independent vector variables (explanatory variables also as vectors, hence it supersedes multivariate multiple regression models, in which the unknown coefficients are scalar quantities. For the solution, complex numbers are used to rep- resent vector information, and the method of least squares is deployed to estimate the vector model parameters after transforming the complex vector regression model into a real vector regression model through isomorphism. Various operational statistics for testing the predictive significance of the estimated vector parameter coefficients are also derived. A simple numerical example demonstrates the use of the proposed vector regression analysis in modeling typhoon paths.

  1. Human papillomavirus genotypes distribution in 175 invasive cervical cancer cases from Brazil

    International Nuclear Information System (INIS)

    Oliveira, Cristina Mendes de; Fregnani, José Humberto Tavares Guerreiro; Carvalho, Jesus Paula; Longatto-Filho, Adhemar; Levi, José Eduardo

    2013-01-01

    Invasive cervical cancer is the second most common malignant tumor affecting Brazilian women. Knowledge on Human Papillomavirus (HPV) genotypes in invasive cervical cancer cases is crucial to guide the introduction and further evaluate the impact of new preventive strategies based on HPV. We aimed to provide updated comprehensive data about the HPV types’ distribution in patients with invasive cervical cancer. Fresh tumor tissue samples of histologically confirmed invasive cervical cancer were collected from 175 women attending two cancer reference hospitals from São Paulo State: ICESP and Hospital de Câncer de Barretos. HPV detection and genotyping were performed by the Linear Array HPV Genotyping Test (Roche Molecular Diagnostics, Pleasanton,USA). 170 out of 172 valid samples (99%) were HPV DNA positive. The most frequent types were HPV16 (77.6%), HPV18 (12.3%), HPV31 (8.8%), HPV33 (7.1%) and HPV35 (5.9%). Most infections (75%) were caused by individual HPV types. Women with adenocarcinoma were not younger than those with squamous cell carcinoma, as well, as women infected with HPV33 were older than those infected by other HPV types. Some differences between results obtained in the two hospitals were observed: higher overall prevalence of HPV16, absence of single infection by HPV31 and HPV45 was verified in HC-Barretos in comparison to ICESP patients. To our knowledge, this is one of the largest studies made with fresh tumor tissues of invasive cervical cancer cases in Brazil. This study depicted a distinct HPV genotype distribution between two centers that may reflect the local epidemiology of HPV transmission among these populations. Due to the impact of these findings on cervical cancer preventive strategies, extension of this investigation to routine screening populations is warranted

  2. Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

    Science.gov (United States)

    Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

    2012-01-01

    The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

  3. Random regression models to account for the effect of genotype by environment interaction due to heat stress on the milk yield of Holstein cows under tropical conditions.

    Science.gov (United States)

    Santana, Mário L; Bignardi, Annaiza Braga; Pereira, Rodrigo Junqueira; Menéndez-Buxadera, Alberto; El Faro, Lenira

    2016-02-01

    The present study had the following objectives: to compare random regression models (RRM) considering the time-dependent (days in milk, DIM) and/or temperature × humidity-dependent (THI) covariate for genetic evaluation; to identify the effect of genotype by environment interaction (G×E) due to heat stress on milk yield; and to quantify the loss of milk yield due to heat stress across lactation of cows under tropical conditions. A total of 937,771 test-day records from 3603 first lactations of Brazilian Holstein cows obtained between 2007 and 2013 were analyzed. An important reduction in milk yield due to heat stress was observed for THI values above 66 (-0.23 kg/day/THI). Three phases of milk yield loss were identified during lactation, the most damaging one at the end of lactation (-0.27 kg/day/THI). Using the most complex RRM, the additive genetic variance could be altered simultaneously as a function of both DIM and THI values. This model could be recommended for the genetic evaluation taking into account the effect of G×E. The response to selection in the comfort zone (THI ≤ 66) is expected to be higher than that obtained in the heat stress zone (THI > 66) of the animals. The genetic correlations between milk yield in the comfort and heat stress zones were less than unity at opposite extremes of the environmental gradient. Thus, the best animals for milk yield in the comfort zone are not necessarily the best in the zone of heat stress and, therefore, G×E due to heat stress should not be neglected in the genetic evaluation.

  4. Influence of hepatitis C virus and IL28B genotypes on liver stiffness.

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    Lene Fogt Lundbo

    Full Text Available Liver fibrosis has been associated with hepatitis C virus (HCV genotype and genetic variation near the interleukin 28B (IL28B gene, but the relative contribution is unknown. We aimed to investigate the relation between HCV genotypes, IL28B and development of liver stiffness.This cross-sectional study consists of 369 patients with chronic hepatitis C (CHC. Liver stiffness was evaluated using transient elastograhy (TE. Factors associated with development of liver fibrosis were identified by logistic regression analysis.We identified 369 patients with CHC. 235 were male, 297 Caucasians, and 223 had been exposed to HCV through intravenous drug use. The overall median TE value was 7.4 kPa (interquartile range (IQR 5.7-12.1. HCV replication was enhanced in patients carrying the IL28B CC genotype compared to TT and TC (5.8 vs. 5.4 log10 IU/mL, p = 0.03. Patients infected with HCV genotype 3 had significantly higher TE values (8.2 kPa; IQR, 5.9-14.5 compared to genotype 1 (6.9 kPa; IQR, 5.4-10.9 and 2 (6.7 kPa; IQR, 4.9-8.8 (p = 0.02. Within patients with genotype 3, IL28B CC genotype had the highest TE values (p = 0.04. However, in multivariate logistic regression, using various cut-off values for fibrosis and cirrhosis, only increasing age (odds ratio (OR 1.09 (95% confidence interval (CI, 1.05-1.14 per year increment, ALT (OR 1.01 (95% CI, 1.002-1.011, per unit increment and HCV genotype 3 compared to genotype 1 (OR 2.40 (95% CI, 1.19-4.81, were consistently associated with cirrhosis (TE>17.1 kPa.Age, ALT and infection with HCV genotype 3 were associated with cirrhosis assessed by TE. However, IL28B genotype was not an independent predictor of fibrosis in our study.

  5. Physiological responses to glyphosate are dependent on Eucalyptus urograndis genotype

    Science.gov (United States)

    Two experiments were conducted to evaluate the response of Eucalyptus urograndis genotypes (C219 and GG100) to glyphosate in growth chambers. As glyphosate dose increased (18 up to 720 g ae ha-1), CO2 assimilation rate, transpiration rate, and stomatal conductance decreased fastest and strongest in ...

  6. High diversity of vacA and cagA Helicobacter pylori genotypes in patients with and without gastric cancer.

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    Yolanda López-Vidal

    Full Text Available BACKGROUND: Helicobacter pylori is associated with chronic gastritis, peptic ulcers, and gastric cancer. The aim of this study was to assess the topographical distribution of H. pylori in the stomach as well as the vacA and cagA genotypes in patients with and without gastric cancer. METHODOLOGY/PRINCIPAL FINDINGS: Three gastric biopsies, from predetermined regions, were evaluated in 16 patients with gastric cancer and 14 patients with dyspeptic symptoms. From cancer patients, additional biopsy specimens were obtained from tumor centers and margins; among these samples, the presence of H. pylori vacA and cagA genotypes was evaluated. Positive H. pylori was 38% and 26% in biopsies obtained from the gastric cancer and non-cancer groups, respectively (p = 0.008, and 36% in tumor sites. In cancer patients, we found a preferential distribution of H. pylori in the fundus and corpus, whereas, in the non-cancer group, the distribution was uniform (p = 0.003. A majority of the biopsies were simultaneously cagA gene-positive and -negative. The fundus and corpus demonstrated a higher positivity rate for the cagA gene in the non-cancer group (p = 0.036. A mixture of cagA gene sizes was also significantly more frequent in this group (p = 0.003. Ninety-two percent of all the subjects showed more than one vacA gene genotype; s1b and m1 vacA genotypes were predominantly found in the gastric cancer group. The highest vacA-genotype signal-sequence diversity was found in the corpus and 5 cm from tumor margins. CONCLUSION/SIGNIFICANCE: High H. pylori colonization diversity, along with the cagA gene, was found predominantly in the fundus and corpus of patients with gastric cancer. The genotype diversity observed across systematic whole-organ and tumor sampling was remarkable. We find that there is insufficient evidence to support the association of one isolate with a specific disease, due to the multistrain nature of H. pylori infection shown in this work.

  7. Staphylococcal Entertotoxins of the Enterotoxin Gene Cluster (egcSEs Induce Nitrous Oxide- and Cytokine Dependent Tumor Cell Apoptosis in a Broad Panel of Human Tumor Cells

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    David eTerman

    2013-08-01

    Full Text Available The egcSEs comprise five genetically linked staphylococcal enterotoxins, SEG, SEI, SElM, SElN and SElO and two pseudotoxins which constitute an operon present in up to 80% of Staphylococcus aureus isolates. A preparation containing theses proteins was recently used to treat advanced lung cancer with pleural effusion. We investigated the hypothesis that egcSEs induce nitrous oxide (NO and associated cytokine production and that these agents may be involved in tumoricidal effects against a broad panel of clinically relevant human tumor cells. Preliminary studies showed that egcSEs and SEA activated T cells (range: 11-25% in a concentration dependent manner. Peripheral blood mononuclear cells (PBMCs stimulated with equimolar quantities of egcSEs expressed NO synthase and generated robust levels of nitrite (range: 200-250 µM, a breakdown product of NO; this reaction was inhibited by NG-monomethyl-L-arginine (L-NMMA (0.3 mM, an NO synthase antagonist. Cell free supernatants (CSFs of all egcSE-stimulated PBMCs were also equally effective in inducing concentration dependent tumor cell apoptosis in a broad panel of human tumor cells. The latter effect was due in part to the generation of NO and TNF-α since it was significantly abolished by L-NMMA, anti-TNF-α antibodies respectively and a combination thereof. A hierarchy of tumor cell sensitivity to these CFSs was as follows: lung carcinoma>osteogenic sarcoma>melanoma>breast carcinoma>neuroblastoma. Notably, SEG induced robust activation of NO/TNFα-dependent tumor cell apoptosis comparable to the other egcSEs and SEA despite TNF-α and IFN-γ levels that were 2 and 8 fold lower respectively than the other egcSEs and SEA. Thus, egcSEs produced by S. aureus induce NO synthase and the increased NO formation together with TNF-α appear to contribute to egcSE-mediated apoptosis against a broad panel of human tumor cells.

  8. Regression Patterns of Iris Melanoma after Palladium-103 (103Pd) Plaque Brachytherapy.

    Science.gov (United States)

    Chaugule, Sonal S; Finger, Paul T

    2017-07-01

    To evaluate the patterns of regression of iris melanoma after treatment with palladium-103 ( 103 Pd) plaque brachytherapy. Retrospective, nonrandomized, interventional case series. Fifty patients with primary malignant melanoma of the iris. Palladium-103 plaque brachytherapy. Changes in tumor size, pigmentation, and vascularity; incidence of iris neovascularization; and radiation-related complications. The mean age in the case series was 61.2±14.9 years. The mean tumor thickness was 1.4±0.6 mm. According to the American Joint Committee on Cancer, eighth edition, staging criteria for iris melanoma, 21 tumors (42%) were T1a, 5 tumors (10%) were T1b, and 24 tumors (48%) were T2a. The tumor was melanotic in 37 cases (74%) and amelanotic in 13 cases (26%); of these, 13 tumors (26%) showed variable pigmentation. After brachytherapy, mean tumor thickness decreased to 0.9±0.2 mm. Pigmentation increased in 32 tumors (64%), decreased in 11 tumors (22%), and was unchanged in 6 tumors (12%). For intrinsic vascularity (n = 19), 12 tumors (63%) showed decrease and 7 tumors (37%) showed complete resolution. Appearance of ectropion uveae showed diminution in 15 tumors (43%); newly present corectopia was observed in 6 patients (12%). On high-frequency ultrasound imaging, of the 42 tumors (84%) with low to moderate internal reflectivity, 30 tumors (60%) showed an increase in internal reflectivity on regression. Iris stromal atrophy was noted in 26 patients (52%), progression or new-onset cataract was noted in 22 patients (44%), neovascular glaucoma was noted in 1 patient (2%), and there were no cases of corneal opacity. There was no clinical evidence (0%) of radiation-induced retinopathy, maculopathy, or optic neuropathy. Mean follow-up in this series was 5.2 years (range, 0.5-17 years). The most common findings related to iris melanoma regression after 103 Pd plaque brachytherapy included decreased intrinsic tumor vascularity, increased tumor pigmentation, and decreased tumor

  9. Two-temperature LATE-PCR endpoint genotyping

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    Reis Arthur H

    2006-12-01

    Full Text Available Abstract Background In conventional PCR, total amplicon yield becomes independent of starting template number as amplification reaches plateau and varies significantly among replicate reactions. This paper describes a strategy for reconfiguring PCR so that the signal intensity of a single fluorescent detection probe after PCR thermal cycling reflects genomic composition. The resulting method corrects for product yield variations among replicate amplification reactions, permits resolution of homozygous and heterozygous genotypes based on endpoint fluorescence signal intensities, and readily identifies imbalanced allele ratios equivalent to those arising from gene/chromosomal duplications. Furthermore, the use of only a single colored probe for genotyping enhances the multiplex detection capacity of the assay. Results Two-Temperature LATE-PCR endpoint genotyping combines Linear-After-The-Exponential (LATE-PCR (an advanced form of asymmetric PCR that efficiently generates single-stranded DNA and mismatch-tolerant probes capable of detecting allele-specific targets at high temperature and total single-stranded amplicons at a lower temperature in the same reaction. The method is demonstrated here for genotyping single-nucleotide alleles of the human HEXA gene responsible for Tay-Sachs disease and for genotyping SNP alleles near the human p53 tumor suppressor gene. In each case, the final probe signals were normalized against total single-stranded DNA generated in the same reaction. Normalization reduces the coefficient of variation among replicates from 17.22% to as little as 2.78% and permits endpoint genotyping with >99.7% accuracy. These assays are robust because they are consistent over a wide range of input DNA concentrations and give the same results regardless of how many cycles of linear amplification have elapsed. The method is also sufficiently powerful to distinguish between samples with a 1:1 ratio of two alleles from samples comprised of

  10. Analysis of extreme drinking in patients with alcohol dependence using Pareto regression.

    Science.gov (United States)

    Das, Sourish; Harel, Ofer; Dey, Dipak K; Covault, Jonathan; Kranzler, Henry R

    2010-05-20

    We developed a novel Pareto regression model with an unknown shape parameter to analyze extreme drinking in patients with Alcohol Dependence (AD). We used the generalized linear model (GLM) framework and the log-link to include the covariate information through the scale parameter of the generalized Pareto distribution. We proposed a Bayesian method based on Ridge prior and Zellner's g-prior for the regression coefficients. Simulation study indicated that the proposed Bayesian method performs better than the existing likelihood-based inference for the Pareto regression.We examined two issues of importance in the study of AD. First, we tested whether a single nucleotide polymorphism within GABRA2 gene, which encodes a subunit of the GABA(A) receptor, and that has been associated with AD, influences 'extreme' alcohol intake and second, the efficacy of three psychotherapies for alcoholism in treating extreme drinking behavior. We found an association between extreme drinking behavior and GABRA2. We also found that, at baseline, men with a high-risk GABRA2 allele had a significantly higher probability of extreme drinking than men with no high-risk allele. However, men with a high-risk allele responded to the therapy better than those with two copies of the low-risk allele. Women with high-risk alleles also responded to the therapy better than those with two copies of the low-risk allele, while women who received the cognitive behavioral therapy had better outcomes than those receiving either of the other two therapies. Among men, motivational enhancement therapy was the best for the treatment of the extreme drinking behavior. Copyright 2010 John Wiley & Sons, Ltd.

  11. High quality copy number and genotype data from FFPE samples using Molecular Inversion Probe (MIP) microarrays

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    Wang, Yuker; Carlton, Victoria E.H.; Karlin-Neumann, George; Sapolsky, Ronald; Zhang, Li; Moorhead, Martin; Wang, Zhigang C.; Richardson, Andrea L.; Warren, Robert; Walther, Axel; Bondy, Melissa; Sahin, Aysegul; Krahe, Ralf; Tuna, Musaffe; Thompson, Patricia A.; Spellman, Paul T.; Gray, Joe W.; Mills, Gordon B.; Faham, Malek

    2009-02-24

    A major challenge facing DNA copy number (CN) studies of tumors is that most banked samples with extensive clinical follow-up information are Formalin-Fixed Paraffin Embedded (FFPE). DNA from FFPE samples generally underperforms or suffers high failure rates compared to fresh frozen samples because of DNA degradation and cross-linking during FFPE fixation and processing. As FFPE protocols may vary widely between labs and samples may be stored for decades at room temperature, an ideal FFPE CN technology should work on diverse sample sets. Molecular Inversion Probe (MIP) technology has been applied successfully to obtain high quality CN and genotype data from cell line and frozen tumor DNA. Since the MIP probes require only a small ({approx}40 bp) target binding site, we reasoned they may be well suited to assess degraded FFPE DNA. We assessed CN with a MIP panel of 50,000 markers in 93 FFPE tumor samples from 7 diverse collections. For 38 FFPE samples from three collections we were also able to asses CN in matched fresh frozen tumor tissue. Using an input of 37 ng genomic DNA, we generated high quality CN data with MIP technology in 88% of FFPE samples from seven diverse collections. When matched fresh frozen tissue was available, the performance of FFPE DNA was comparable to that of DNA obtained from matched frozen tumor (genotype concordance averaged 99.9%), with only a modest loss in performance in FFPE. MIP technology can be used to generate high quality CN and genotype data in FFPE as well as fresh frozen samples.

  12. A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas.

    Science.gov (United States)

    Infante, Jeffrey R; Cassier, Philippe A; Gerecitano, John F; Witteveen, Petronella O; Chugh, Rashmi; Ribrag, Vincent; Chakraborty, Abhijit; Matano, Alessandro; Dobson, Jason R; Crystal, Adam S; Parasuraman, Sudha; Shapiro, Geoffrey I

    2016-12-01

    Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb + ). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb + advanced solid tumors or lymphomas. Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle. Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months. Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I-III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696-705. ©2016 AACR. ©2016 American Association for Cancer Research.

  13. Dihydromyricetin promotes hepatocellular carcinoma regression via a p53 activation-dependent mechanism

    Science.gov (United States)

    Zhang, Qingyu; Liu, Jie; Liu, Bin; Xia, Juan; Chen, Nianping; Chen, Xiaofeng; Cao, Yi; Zhang, Chen; Lu, Caijie; Li, Mingyi; Zhu, Runzhi

    2014-04-01

    The development of antitumor chemotherapy drugs remains a key goal for oncologists, and natural products provide a vast resource for anti-cancer drug discovery. In the current study, we found that the flavonoid dihydromyricetin (DHM) exhibited antitumor activity against liver cancer cells, including primary cells obtained from hepatocellular carcinoma (HCC) patients. In contrast, DHM was not cytotoxic to immortalized normal liver cells. Furthermore, DHM treatment resulted in the growth inhibition and remission of xenotransplanted tumors in nude mice. Our results further demonstrated that this antitumor activity was caused by the activation of the p53-dependent apoptosis pathway via p53 phosphorylation at serine (15Ser). Moreover, our results showed that DHM plays a dual role in the induction of cell death when administered in combination with cisplatin, a common clinical drug that kills primary hepatoma cells but not normal liver cells.

  14. KChIP2 genotype dependence of transient outward current (Ito) properties in cardiomyocytes isolated from male and female mice.

    Science.gov (United States)

    Waldschmidt, Lara; Junkereit, Vera; Bähring, Robert

    2017-01-01

    The transient outward current (Ito) in cardiomyocytes is largely mediated by Kv4 channels associated with Kv Channel Interacting Protein 2 (KChIP2). A knockout model has documented the critical role of KChIP2 in Ito expression. The present study was conducted to characterize in both sexes the dependence of Ito properties, including current magnitude, inactivation kinetics, recovery from inactivation and voltage dependence of inactivation, on the number of functional KChIP2 alleles. For this purpose we performed whole-cell patch-clamp experiments on isolated left ventricular cardiomyocytes from male and female mice which had different KChIP2 genotypes; i.e., wild-type (KChIP2+/+), heterozygous knockout (KChIP2+/-) or complete knockout of KChIP2 (KChIP2-/-). We found in both sexes a KChIP2 gene dosage effect (i.e., a proportionality between number of alleles and phenotype) on Ito magnitude, however, concerning other Ito properties, KChIP2+/- resembled KChIP2+/+. Only in the total absence of KChIP2 (KChIP2-/-) we observed a slowing of Ito kinetics, a slowing of recovery from inactivation and a negative shift of a portion of the voltage dependence of inactivation. In a minor fraction of KChIP2-/- myocytes Ito was completely lost. The distinct KChIP2 genotype dependences of Ito magnitude and inactivation kinetics, respectively, seen in cardiomyocytes were reproduced with two-electrode voltage-clamp experiments on Xenopus oocytes expressing Kv4.2 and different amounts of KChIP2. Our results corroborate the critical role of KChIP2 in controlling Ito properties. They demonstrate that the Kv4.2/KChIP2 interaction in cardiomyocytes is highly dynamic, with a clear KChIP2 gene dosage effect on Kv4 channel surface expression but not on inactivation gating.

  15. Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.

    Science.gov (United States)

    Dolman, M Emmy M; Poon, Evon; Ebus, Marli E; den Hartog, Ilona J M; van Noesel, Carel J M; Jamin, Yann; Hallsworth, Albert; Robinson, Simon P; Petrie, Kevin; Sparidans, Rolf W; Kok, Robbert J; Versteeg, Rogier; Caron, Huib N; Chesler, Louis; Molenaar, Jan J

    2015-11-15

    MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519. Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma. AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug. This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. ©2015 American Association for Cancer Research.

  16. Multiple centroid method to evaluate the adaptability of alfalfa genotypes

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    Moysés Nascimento

    2015-02-01

    Full Text Available This study aimed to evaluate the efficiency of multiple centroids to study the adaptability of alfalfa genotypes (Medicago sativa L.. In this method, the genotypes are compared with ideotypes defined by the bissegmented regression model, according to the researcher's interest. Thus, genotype classification is carried out as determined by the objective of the researcher and the proposed recommendation strategy. Despite the great potential of the method, it needs to be evaluated under the biological context (with real data. In this context, we used data on the evaluation of dry matter production of 92 alfalfa cultivars, with 20 cuttings, from an experiment in randomized blocks with two repetitions carried out from November 2004 to June 2006. The multiple centroid method proved efficient for classifying alfalfa genotypes. Moreover, it showed no unambiguous indications and provided that ideotypes were defined according to the researcher's interest, facilitating data interpretation.

  17. T3SS-dependent differential modulations of the jasmonic acid pathway in susceptible and resistant genotypes of Malus spp. challenged with Erwinia amylovora.

    Science.gov (United States)

    Dugé De Bernonville, Thomas; Gaucher, Matthieu; Flors, Victor; Gaillard, Sylvain; Paulin, Jean-Pierre; Dat, James F; Brisset, Marie-Noëlle

    2012-06-01

    Fire blight is a bacterial disease of Maloideae caused by Erwinia amylovora (Ea). This necrogenic enterobacterium uses a type III secretion system (T3SS) to inject type III effectors into the plant cells to cause disease on its susceptible hosts, including economically important crops like apple and pear. The expressions of marker genes of the salicylic acid (SA) and jasmonic acid (JA) defense regulation pathways were monitored by RT-qPCR in leaves of two apple genotypes, one susceptible and one resistant, challenged with a wild type strain, a T3SS-deficient strain or water. The transcriptional data taken together with hormone level measurements indicated that the SA pathway was similarly induced in both apple genotypes during infection by Ea. On the contrary, the data clearly showed a strong T3SS-dependent down-regulation of the JA pathway in leaves of the susceptible genotype but not in those of the resistant one. Accordingly, methyl-jasmonate treated susceptible plants displayed an increased resistance to Ea. Bacterial mutant analysis indicated that JA manipulation by Ea mainly relies on the type III effector DspA/E. Taken together, our data suggest that the T3SS-dependent down-regulation of the JA pathway is a critical step in the infection process of Malus spp. by Ea. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells.

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    Pawan Kaler

    2010-07-01

    Full Text Available We recently reported that colon tumor cells stimulate macrophages to release IL-1beta, which in turn inactivates GSK3beta and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells.Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1beta by neutralizing IL-1beta antibody, or silencing of IL-1beta in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1beta was sufficient to inhibit TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (Delta psi and activation of caspases were prevented by macrophages or by recombinant IL-1beta. Pharmacological inhibition of IL-1beta release from macrophages by vitamin D(3, a potent chemopreventive agent for colorectal cancer, restored the ability of TRAIL to induce apoptosis of tumor cells cultured with macrophages. Macrophages and IL-1beta failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnIkappaB, dnAKT or dnTCF4, confirming that they oppose TRAIL-induced cell death through induction of Wnt signaling in tumor cells. We showed that macrophages and IL-1beta stabilized Snail in tumor cells in an NF-kappaB/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1beta, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL.We have identified a positive feedback loop between tumor cells and macrophages that propagates the growth and promotes the survival of colon cancer cells: tumor cells stimulate macrophages to secrete IL-1beta, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL. Vitamin D(3 halts this amplifying loop by interfering with the release of IL-1beta from macrophages. Accordingly, vitamin D(3 sensitizes tumor cells to TRAIL

  19. N-end rule pathway inhibition assists colon tumor regression via necroptosis

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    Pritha Agarwalla

    2016-01-01

    Full Text Available Recent study has shown that N-end rule pathway, an ubiquitin dependent proteolytic system, counteracts cell death by degrading many antisurvival protein fragments like BCLxL, BRCA1, RIPK1, etc. Inhibition of the N-end rule pathway can lead to metabolic stabilization of proapoptotic protein fragments like RIPK1, thereby sensitizing cells to programmed cell death. Receptor interacting serine-threonine protein kinase-1 (RIPK1 is one of the upstream regulators of programmed necrosis known as necroptosis. Necroptosis is particularly gaining attention of cancer biologists as it provides an alternate therapeutic modality to kill cancer cells, which often evolve multiple strategies to circumvent growth inhibition by apoptosis. Utilizing the over expression of biotin receptor in cancer cells, herein, we report that coadministration of synthetic hetero-bivalent N-end rule inhibitor RFC11 and anticancer drug shikonin solubilized in a stable biotin receptor-targeted liposome exhibited significant synergistic antitumor effect in both subcutaneous and orthotopic mouse colon tumor model through induction of necroptosis with distinctive upregulation of RIPK1. Besides developing a newly targeted formulation for necroptosis induction, this report is the first in vivo evidence demonstrating that potent inhibition of N-end rule pathway can enhance therapeutic efficacy of conventional chemotherapeutics.

  20. Radiation therapy of brain tumor

    International Nuclear Information System (INIS)

    Sung, K. J.; Lee, D. H.; Park, C. Y.

    1980-01-01

    One hundred and six cases of brain tumors were treated at the Yonsei Cancer Center from January 1972 to August 1978 by Co-60 teletherapy unit. We analyses their clinical findings, histopathological findings, treatment and results. In those cases which computerized tomography had been used before and after radiation therapy, changes in tumor size and the presence of edema or necrosis following treatment was evaluated. 1. Among 106 cases, 90 cases were primary brain tumors and 16 cases were metastatic brain tumors. Pituitary tumors (38), glioma (34) and pinealoma (10) composed of most of primary brain tumors. 2. Post treatment follow-up was possible in 38 cases more than 1 years. Four among 11 cases of giloma expired and survivors had considerable neurological symptoms except 2 cases. Sixty five percent (12/20) of pituitary tumors showed improvement of visual symptoms and all cases (7) of pinealoma which post treatment follow-up was possible, showed remarkable good response. 3. Findings of CT scan after radiation treatment were compatible with results of clinical findings and post treatment follow-up. It showed complete regression of tumor mass in one case of pinealoma and medulloblastoma. One case of pituitary tumor showed almost complete regression of tumor mass. It also showed large residual lesion in cases of glioblastoma multiforme and cystic astrocytoma.

  1. ON REGRESSION REPRESENTATIONS OF STOCHASTIC-PROCESSES

    NARCIS (Netherlands)

    RUSCHENDORF, L; DEVALK, [No Value

    We construct a.s. nonlinear regression representations of general stochastic processes (X(n))n is-an-element-of N. As a consequence we obtain in particular special regression representations of Markov chains and of certain m-dependent sequences. For m-dependent sequences we obtain a constructive

  2. Irradiation-Dependent Effects on Tumor Perfusion and Endogenous and Exogenous Hypoxia Markers in an A549 Xenograft Model

    International Nuclear Information System (INIS)

    Fokas, Emmanouil; Haenze, Joerg; Kamlah, Florentine; Eul, Bastian G.; Lang, Nico; Keil, Boris; Heverhagen, Johannes T.; Engenhart-Cabillic, Rita; An Hanxiang; Rose, Frank

    2010-01-01

    Purpose: Hypoxia is a major determinant of tumor radiosensitivity, and microenvironmental changes in response to ionizing radiation (IR) are often heterogenous. We analyzed IR-dependent changes in hypoxia and perfusion in A549 human lung adenocarcinoma xenografts. Materials and Methods: Immunohistological analysis of two exogenously added chemical hypoxic markers, pimonidazole and CCI-103F, and of the endogenous marker Glut-1 was performed time dependently after IR. Tumor vessels and apoptosis were analyzed using CD31 and caspase-3 antibodies. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and fluorescent beads (Hoechst 33342) were used to monitor vascular perfusion. Results: CCI-103F signals measuring the fraction of hypoxic areas after IR were significantly decreased by approximately 50% when compared with pimonidazole signals, representing the fraction of hypoxic areas from the same tumors before IR. Interestingly, Glut-1 signals were significantly decreased at early time point (6.5 h) after IR returning to the initial levels at 30.5 h. Vascular density showed no difference between irradiated and control groups, whereas apoptosis was significantly induced at 10.5 h post-IR. DCE-MRI indicated increased perfusion 1 h post-IR. Conclusions: The discrepancy between the hypoxic fractions of CCI-103F and Glut-1 forces us to consider the possibility that both markers reflect different metabolic alterations of tumor microenvironment. The reliability of endogenous markers such as Glut-1 to measure reoxygenation in irradiated tumors needs further consideration. Monitoring tumor microvascular response to IR by DCE-MRI and measuring tumor volume alterations should be encouraged.

  3. Endocrine tumors other than thyroid tumors

    International Nuclear Information System (INIS)

    Takeichi, Norio; Dohi, Kiyohiko

    1992-01-01

    This paper discusses the tendency for the occurrence of tumors in the endocrine glands, other than the thyroid gland, in A-bomb survivors using both autopsy and clinical data. ABCC-RERF sample data using 4136 autopsy cases (1961-1977) revealed parathyroid tumors in 13 A-bomb survivors, including 3 with the associated hyperparathyroidism, with the suggestion of dose-dependent increase in the occurrence of tumors. Based on clinical data from Hiroshima University, 7 (46.7%) of 15 parathyroid tumors cases were A-bomb survivors. Data (1974-1987) from the Tumor Registry Committee (TRC) in Hiroshima Prefecture revealed that a relative risk of parathyroid tumors was 5.6 times higher in the entire group of A-bomb survivors and 16.2 times higher in the group of heavily exposed A-bomb survivors, suggesting the dose-dependent increase in their occurrence. Adrenal tumors were detected in 47 of 123 cases from the TRC data, and 15 (31.5%) of these 47 were A-bomb survivors. Particularly, 11 cases of adrenal tumors associated with Cushing syndrome included 6 A-bomb survivors (54.5%). The incidence of multiple endocrine gonadial tumors (MEGT) tended to be higher with increasing exposure doses; and the 1-9 rad group, the 10-99 rad group, and the 100 or more rad group had a risk of developing MEGT of 4.1, 5.7, and 7.1, respectively, relative to both the not-in the city group and the 0 rad group. These findings suggested that there is a correlation between A-bomb radiation and the occurrence of parathyroid tumors (including hyperparathyroidism), adrenal tumors associated with Cushing syndrome and MEGT (especially, the combined thyroid and ovarian tumors and the combined thyroid and parathyroid tumors). (N.K.)

  4. IDH Mutations: Genotype-Phenotype Correlation and Prognostic Impact

    Directory of Open Access Journals (Sweden)

    Xiao-Wei Wang

    2014-01-01

    Full Text Available IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1R132H, IDH1nonR132H, and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1nonR132H in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated—which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.

  5. The influence of 5-HTTLPR genotype on the association between the plasma concentration and therapeutic effect of paroxetine in patients with major depressive disorder.

    Directory of Open Access Journals (Sweden)

    Tetsu Tomita

    Full Text Available The efficacy of treatment with selective serotonin reuptake inhibitors in patients with major depressive disorder (MDD can differ depending on the patient's serotonin transporter-linked polymorphic region (5-HTTLPR genotype, and the effects of varying plasma concentrations of drugs can also vary. We investigated the association between the paroxetine plasma concentration and clinical response in patients with different 5-HTTLPR genotypes.Fifty-one patients were enrolled in this study. The Montgomery-Asberg Depression Rating Scale (MADRS was used to evaluate patients at 0, 1, 2, 4, and 6 weeks. The patients' paroxetine plasma concentrations at week 6 were measured using high-performance liquid chromatography. Additionally, their 5-HTTLPR polymorphisms (alleles S and L were analyzed using a polymerase chain reaction with specific primers. We divided the participants into two groups based on their L haplotype: the SS group and the SL and LL group. We performed single and multiple regression analyses to investigate the associations between MADRS improvement and paroxetine plasma concentrations or other covariates for each group.There were no significant differences between the two groups with regard to demographic or clinical data. In the SS group, the paroxetine plasma concentration was significantly negatively correlated with improvement in MADRS at week 6. In the SL and LL group, the paroxetine plasma concentration was significantly positively correlated with improvement in MADRS at week 6 according to the results of the single regression analysis; however, it was not significantly correlated with improvement in MADRS at week 6 according to the results of the multiple regression analysis.Among patients with MDD who do not respond to paroxetine, a lower plasma concentration or a lower oral dose of paroxetine might be more effective in those with the SS genotype, and a higher plasma concentration might be more effective in those with the SL or LL

  6. Stromal-dependent tumor promotion by MIF family members.

    Science.gov (United States)

    Mitchell, Robert A; Yaddanapudi, Kavitha

    2014-12-01

    Solid tumors are composed of a heterogeneous population of cells that interact with each other and with soluble and insoluble factors that, when combined, strongly influence the relative proliferation, differentiation, motility, matrix remodeling, metabolism and microvessel density of malignant lesions. One family of soluble factors that is becoming increasingly associated with pro-tumoral phenotypes within tumor microenvironments is that of the migration inhibitory factor family which includes its namesake, MIF, and its only known family member, D-dopachrome tautomerase (D-DT). This review seeks to highlight our current understanding of the relative contributions of a variety of immune and non-immune tumor stromal cell populations and, within those contexts, will summarize the literature associated with MIF and/or D-DT. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Design of radiation dose tumor response assays

    International Nuclear Information System (INIS)

    Suit, H.D.; Hwang, T.; Hsieh, C.; Thames, H.

    1985-01-01

    The efficient utilization of animals in a radiation dose response assay for tumor control requires a definition of the goal, e.g., TCD50 or slope. A series of computer modelled ''experiments'' have been performed for each of a number of allocations of dose levels (DL) and number of animals/DL. The authors stipulated that the assumed TCD50 was .85 of true value; assumed slope was correct. They stipulated a binominal distribution of observed tumor control results at each dose level. A pilot assay used 6 tumors at 7 DL (from TCD1-TCD97). The second assay used 30 tumors assigned to 2,3,5 or 9 DL and to selected tumor control probabilities (TCP derived from the pilot run. Results from 100 test runs were combined with the pilot run for each of the combination of DL and TCP values. Logit regression lines were fitted through these ''data'' and the 95% CL around the TCD50 and the TCD37 values and the variances of the slopes were computed. These experiments were repeated using the method suggested by Porter (1980). Results show that a different strategy is needed depending upon the goal, viz. TCD50 or TCD37 vs slope. The differences between the two approaches are discussed

  8. Influence of methylenetetrahydrofolate reductase genotype, exercise and other risk factors on endothelial function in healthy individuals.

    Science.gov (United States)

    Pullin, Catherine H; Wilson, John F; Ashfield-Watt, Pauline A L; Clark, Zoë E; Whiting, Jenny M; Lewis, Malcolm J; McDowell, Ian F W

    2002-01-01

    Cardiovascular disease has a multifactorial aetiology that is influenced by both genetic and environmental factors. Endothelial dysfunction is a key event in the pathogenesis of vascular disease that occurs before structural vascular changes or clinical symptoms are evident. Conventional risk factors, for example hypertension and diabetes mellitus, are associated with endothelial dysfunction, but the influence of other putative risk factors is not clear. The methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a common polymorphism that induces hyperhomocysteinaemia, has been proposed as being a genetic risk factor for cardiovascular disease. A total of 126 healthy adults recruited by MTHFR C677T genotype (42 of each genotype, i.e. CC, CT and TT) underwent assessment of endothelial function. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) was measured using high-resolution ultrasonic vessel "wall-tracking". Using multiple regression analysis, MTHFR genotype and 21 other subject and subject-lifestyle variables were investigated as potential predictors of endothelial function. FMD was influenced positively by frequency of aerobic exercise and by hormone replacement therapy, and negatively by increases in systolic blood pressure. MTHFR C677T genotype and the associated variation in plasma homocysteine levels did not influence FMD. Additionally, other factors, including plasma cholesterol and self-supplementation with either antioxidant vitamins or cod liver oil, showed no significant relationship with FMD, although these findings are compromised by the narrow range studied for cholesterol and the small number of subjects taking supplements. These observations have implications for risk factor management in the primary prevention of cardiovascular disease in healthy individuals.

  9. Effects of using phenotypic means and genotypic values in GGE biplot analyses on genotype by environment studies on tropical maize (Zea mays).

    Science.gov (United States)

    Granato, I S C; Fritsche-Neto, R; Resende, M D V; Silva, F F

    2016-10-05

    The objective of this study was to examine the effects of the type and intensity of nutritional stress, and of the statistical treatment of the data, on the genotype x environment (G x E) interaction for tropical maize (Zea mays). For this purpose, 39 hybrid combinations were evaluated under low- and high-nitrogen and -phosphorus availability. The plants were harvested at the V6 stage, and the shoot dry mass was estimated. The variance components and genetic values were assessed using the restricted maximum likelihood/best linear unbiased prediction method, and subsequently analyzed using the GGE biplot method. We observed differences in the performances of the hybrids depending on both the type and intensity of nutritional stress. The results of relationship between environments depended on whether genotypic values or phenotypic means were used. The selection of tropical maize genotypes against nutritional stress should be performed for each nutrient availability level within each type of nutritional stress. The use of phenotypic means for this purpose provides greater reliability than do genotypic values for the analysis of the G x E interaction using GGE biplot.

  10. Tumor Volume Reduction Rate Measured by Magnetic Resonance Volumetry Correlated With Pathologic Tumor Response of Preoperative Chemoradiotherapy for Rectal Cancer

    International Nuclear Information System (INIS)

    Yeo, Seung-Gu; Kim, Dae Yong; Kim, Tae Hyun; Jung, Kyung Hae; Hong, Yong Sang; Chang, Hee Jin; Park, Ji Won; Lim, Seok-Byung; Choi, Hyo Seong; Jeong, Seung-Yong

    2010-01-01

    Purpose: To determine whether the tumor volume reduction rate (TVRR) measured using three-dimensional region-of-interest magnetic resonance volumetry correlates with the pathologic tumor response after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. Methods and Materials: The study included 405 patients with locally advanced rectal cancer (cT3-T4) who had undergone preoperative CRT and radical proctectomy. The tumor volume was measured using three-dimensional region-of-interest magnetic resonance volumetry before and after CRT but before surgery. We analyzed the correlation between the TVRR and the pathologic tumor response in terms of downstaging and tumor regression grade (TRG). Downstaging was defined as ypStage 0-I (ypT0-T2N0M0), and the TRG proposed by Dworak et al. was used. Results: The mean TVRR was 65.0% ± 22.3%. Downstaging and complete regression occurred in 167 (41.2%) and 58 (14.3%) patients, respectively. The TVRRs according to ypT classification (ypT0-T2 vs. ypT3-T4), ypN classification (ypN0 vs. ypN1-N2), downstaging (ypStage 0-I vs. ypStage II-III), good regression (TRG 3-4 vs. TRG 1-2), and complete regression (TRG 4 vs. TRG 1-3) were all significantly different (p 80%), the rates of ypT0-T2, ypN0, downstaging, and good regression were all significantly greater for patients with a TVRR of ≥60%, as was the complete regression rate for patients with a TVRR >80% (p <.05). Conclusion: The TVRR measured using three-dimensional region-of-interest magnetic resonance volumetry correlated significantly with the pathologic tumor response in terms of downstaging and TRG after preoperative CRT for locally advanced rectal cancer.

  11. The AA genotype of the regulatory BCL2 promoter polymorphism ( 938C>A) is associated with a favorable outcome in lymph node negative invasive breast cancer patients.

    Science.gov (United States)

    Bachmann, Hagen S; Otterbach, Friedrich; Callies, Rainer; Nückel, Holger; Bau, Maja; Schmid, Kurt W; Siffert, Winfried; Kimmig, Rainer

    2007-10-01

    Expression of the antiapoptotic and antiproliferative protein Bcl-2 has been repeatedly shown to be associated with better clinical outcome in breast cancer. We recently showed a novel regulatory (-938C>A) single-nucleotide polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generating significantly different BCL2 promoter activities. Paraffin-embedded neoplastic and nonneoplastic tissues from 274 patients (161 still alive after a follow-up period of at least 80 months) with primary unilateral invasive breast carcinoma were investigated. Bcl-2 expression of tumor cells was shown by immunohistochemistry; nonneoplastic tissues were used for genotyping. Both the Bcl-2 expression and the (-938C>A) genotypes were correlated with the patients' survival. Kaplan-Meier curves revealed a significant association of the AA genotype with increased survival (P = 0.030) in lymph node-negative breast cancer patients, whereas no genotype effect could be observed in lymph node-positive cases. Ten-year survival rates were 88.6% for the AA genotype, 78.4% for the AC genotype, and 65.8% for the CC genotype. Multivariable Cox regression identified the BCL2 (-938CC) genotype as an independent prognostic factor for cancer-related death in lymph node-negative breast carcinoma patients (hazard ratio, 3.59; P = 0.032). Immunohistochemical Bcl-2 expression was significantly associated with the clinical outcome of lymph node-positive but not of lymph node-negative breast cancer patients. In lymph node-negative cases, the (-938C>A) SNP was both significantly related with the immunohistochemically determined level of Bcl-2 expression (P = 0.044) and the survival of patients with Bcl-2-expressing carcinomas (P = 0.006). These results suggest the (-938C>A) polymorphism as a survival prognosticator as well as indicator of a high-risk group within patients with lymph node-negative breast cancer.

  12. RHD genotype and zygosity analysis in the Chinese Southern Han D plus , D- and D variant donors using the multiplex ligation-dependent probe amplification assay

    NARCIS (Netherlands)

    Ji, Y. L.; Luo, H.; Wen, J. Z.; Haer-Wigman, L.; Veldhuisen, B.; Wei, L.; Wang, Z.; Ligthart, P.; Lodén-van Straaten, M.; Fu, Y. S.; van der Schoot, C. E.; Luo, G. P.

    2017-01-01

    Background and ObjectivesSeveral comprehensive genotyping platforms for determining red blood cell (RBC) antigens have been established and validated for use in the Caucasian and Black populations, but not for the Chinese. The multiplex ligation-dependent probe amplification (MLPA) assay was

  13. ENVIRONMENTAL AND SOCIO-ECONOMIC ASPECT OF GROWING MISCANTHUS GENOTYPES

    Directory of Open Access Journals (Sweden)

    Marián KOTRLA

    2013-01-01

    Full Text Available Deliberate cultivation of plants for energy biomass is becoming increasingly important. Biomass should significantly contribute to increase the share of renewable energy in the European Union. On the research locality of Slovak University of Agriculture in Nitra localized in the village Kolíňany (Slovak Republic is implemented basic research focused on the growth and production of the two genotypes energy grass Miscanthus. Research is carried out since 2010. In the third year after planting (the year 2012 were confirmed biomass production depending on the genotype of 35.45 and 36.67 t ha-1. Based on the analysis of growth and production performance of Miscanthus genotypes can be evaluated the high environmental and socio-economic aspects of growing energy crops, depending on the specific agro-ecological conditions.

  14. TU-AB-202-07: A Novel Method for Registration of Mid-Treatment PET/CT Images Under Conditions of Tumor Regression for Patients with Locally Advanced Lung Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Sharifi, Hoda [Department of Radiation Oncology, Henry Ford Health System, Detroit, MI (United States); Department of Physics, Oakland University, Rochester, MI (United States); Zhang, Hong; Jin, Jian-Yyue; Kong, Feng-Ming [Department of Radiation Oncology, GRU Cancer Center, Augusta GA (United States); Chetty, Indrin J [Department of Radiation Oncology, Henry Ford Health System, Detroit, MI (United States); Zhong, Hualiang

    2016-06-15

    Purpose: In PET-guided adaptive radiotherapy (RT), changes in the metabolic activity at individual voxels cannot be derived until the duringtreatment CT images are appropriately registered to pre-treatment CT images. However, deformable image registration (DIR) usually does not preserve tumor volume. This may induce errors when comparing to the target. The aim of this study was to develop a DIR-integrated mechanical modeling technique to track radiation-induced metabolic changes on PET images. Methods: Three patients with non-small cell lung cancer (NSCLC) were treated with adaptive radiotherapy under RTOG 1106. Two PET/CT image sets were acquired 2 weeks before RT and 18 fractions after the start of treatment. DIR was performed to register the during-RT CT to the pre-RT CT using a B-spline algorithm and the resultant displacements in the region of tumor were remodeled using a hybrid finite element method (FEM). Gross tumor volume (GTV) was delineated on the during-RT PET/CT image sets and deformed using the 3D deformation vector fields generated by the CT-based registrations. Metabolic tumor volume (MTV) was calculated using the pre- and during–RT image set. The quality of the PET mapping was evaluated based on the constancy of the mapped MTV and landmark comparison. Results: The B-spline-based registrations changed MTVs by 7.3%, 4.6% and −5.9% for the 3 patients and the correspondent changes for the hybrid FEM method −2.9%, 1% and 6.3%, respectively. Landmark comparisons were used to evaluate the Rigid, B-Spline, and hybrid FEM registrations with the mean errors of 10.1 ± 1.6 mm, 4.4 ± 0.4 mm, and 3.6 ± 0.4 mm for three patients. The hybrid FEM method outperforms the B-Spline-only registration for patients with tumor regression Conclusion: The hybrid FEM modeling technique improves the B-Spline registrations in tumor regions. This technique may help compare metabolic activities between two PET/CT images with regressing tumors. The author gratefully

  15. Gender dependent association between perinatal morbidity and estrogen receptor-alpha Pvull polymorphism.

    Science.gov (United States)

    Derzbach, László; Treszl, András; Balogh, Adám; Vásárhelyi, Barna; Tulassay, Tivadar; Rigó J, János

    2005-01-01

    Assuming the importance of estrogen in perinatal physiology, we tested the association of an estrogen receptor-alpha (ER-alpha) gene Pvull pP polymorphism with perinatal morbidity in premature infants. The ER-alpha Pp genotype was determined in 69 low-birth weight (LBW) boys and 72 LBW girls, 86 term boys and 81 term girls. The association between risk factors, genotype, gender and perinatal morbidity was tested with binary logistic regression analysis. Boys carrying "p" allele were at lower risk for necrotizing enterocolitis (OR [95% Cl]: 0.24 [0.07-0.83]) and patent ductus arteriosus (OR [95% Cl]: 0.24 [0.05-0.97]). The carrier state of the "p" allele was associated with a 34-h shorter period of oxygen supplementation on average (P=0.0018). Boys with pp genotype were at greater risk for intraventricular hemorrhage (OR [95% Cl]: 4.39 [1.15-16.82]). No association between ER-alpha Pvull polymorphism and morbidity was present in girls. Since homozygocity for any Pvull alleles (i.e. having PP or pp genotype) increases the risk for at least one of the most common perinatal complications, it is likely that the heterozygous carrier state of Pvull genotypes has a protective effect, which is gender-dependent.

  16. Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort.

    Science.gov (United States)

    Vengalil, Seena; Preethish-Kumar, Veeramani; Polavarapu, Kiran; Mahadevappa, Manjunath; Sekar, Deepha; Purushottam, Meera; Thomas, Priya Treesa; Nashi, Saraswathi; Nalini, Atchayaram

    2017-01-01

    Studies of cases of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) confirmed by multiplex ligation-dependent probe amplification (MLPA) have determined the clinical characteristics, genotype, and relations between the reading frame and phenotype for different countries. This is the first such study from India. A retrospective genotype-phenotype analysis of 317 MLPA-confirmed patients with DMD or BMD who visited the neuromuscular clinic of a quaternary referral center in southern India. The 317 patients comprised 279 cases of DMD (88%), 32 of BMD (10.1%), and 6 of intermediate phenotype (1.9%). Deletions accounted for 91.8% of cases, with duplications causing the remaining 8.2%. There were 254 cases of DMD (91%) with deletions and 25 (9%) due to duplications, and 31 cases (96.8%) of BMD with deletions and 1 (3.2%) due to duplication. All six cases of intermediate type were due to deletions. The most-common mutation was a single-exon deletion. Deletions of six or fewer exons constituted 68.8% of cases. The deletion of exon 50 was the most common. The reading-frame rule held in 90% of DMD and 94% of BMD cases. A tendency toward a lower IQ and earlier wheelchair dependence was observed with distal exon deletions, though a significant correlation was not found. The reading-frame rule held in 90% to 94% of children, which is consistent with reports from other parts of the world. However, testing by MLPA is a limitation, and advanced sequencing methods including analysis of the structure of mutant dystrophin is needed for more-accurate assessments of the genotype-phenotype correlation.

  17. Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors

    Directory of Open Access Journals (Sweden)

    Xiaonan Zhang

    2015-11-01

    Full Text Available The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an “Achilles heel” for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations.

  18. Does the Magnitude of the Link between Unemployment and Crime Depend on the Crime Level? A Quantile Regression Approach

    Directory of Open Access Journals (Sweden)

    Horst Entorf

    2015-07-01

    Full Text Available Two alternative hypotheses – referred to as opportunity- and stigma-based behavior – suggest that the magnitude of the link between unemployment and crime also depends on preexisting local crime levels. In order to analyze conjectured nonlinearities between both variables, we use quantile regressions applied to German district panel data. While both conventional OLS and quantile regressions confirm the positive link between unemployment and crime for property crimes, results for assault differ with respect to the method of estimation. Whereas conventional mean regressions do not show any significant effect (which would confirm the usual result found for violent crimes in the literature, quantile regression reveals that size and importance of the relationship are conditional on the crime rate. The partial effect is significantly positive for moderately low and median quantiles of local assault rates.

  19. In-vivo luminescence model for the study of tumor regression and regrowth following combination regimens with differentiation-promoting agents and photodynamic therapy

    Science.gov (United States)

    Rollakanti, K.; Anand, S.; Maytin, E. V.

    2013-03-01

    Photodynamic therapy with aminolevulinic acid can be modified by pretreatment regimens with drugs such as 5- Fluorouracil (5-FU) or Vitamin D (calcitriol) that enhance accumulation of protoporphyrin IX (PpIX) within tumor tissue which presumably will enhance the therapeutic response to light. However, histological approaches for monitoring therapeutic responses are poorly suited for studying long term survival because large numbers of mice need to be sacrificed. To address this limitation, a non-invasive model to monitor tumor regression and regrowth has been established. Breast cancer cells, stably transfected with firefly luciferase (MDA-Luc cell line), are implanted orthotopically in nude mice (0.25 - 1 x 106 cells/site), and monitored 0-60 min after s.c. injection of luciferin, with Xenogen in-vivo imaging system. Luminescence is detectable at day 1 post-implantation. Tumors are suitable for experimentation on day 6, when daily injections of pretreatment agents (5-FU, 300 mg/kg; calcitriol, 1 μg/kg) begin. On day 9, ALA (75 mg/kg i.p.) is given for 4 hr, followed by illumination (633 nm, 100 J/cm2). Tumor luminescence post- PDT is monitored daily and compared with caliper measurements. Pretreatments (5-FU, calcitriol) by themselves do not inhibit luciferase expression, and all tumors grow at a similar rate during the pretreatment period. Results from in vivo survival experiments can be correlated to survival responses of MDA-Luc cells grown in monolayer cultures +/- PDT and +/- pretreatments, and additional mechanistic information (e.g. Ki67 and E-cadherin expression) obtained. In summary, this noninvasive model will permit testing of the therapeutic survival advantages of various pretreatments during cPDT.

  20. BCL2 genotypes and prostate cancer survival

    Energy Technology Data Exchange (ETDEWEB)

    Renner, Wilfried [Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz (Austria); Langsenlehner, Uwe [GKK Outpatient Department, Division of Internal Medicine, Graz (Austria); Krenn-Pilko, Sabine; Langsenlehner, Tanja [Medical University of Graz, Department of Therapeutic Radiology and Oncology, Graz (Austria); Eder, Petra [University Hospital Wuerzburg, Department of Internal Medicine I, Wuerzburg (Germany)

    2017-06-15

    The antiapoptotic B-cell lymphoma 2 (BCL2) gene is a key player in cancer development and progression. A functional single-nucleotide polymorphism (c.-938C>A, rs2279115) in the inhibitory P2 BCL2 gene promoter has been associated with clinical outcomes in various types of cancer. Aim of the present study was to analyze the role of BCL2-938C>A genotypes in prostate cancer mortality. The association between BCL2-938C>A (rs2279115) genotypes and prostate cancer outcome was studied within the prospective PROCAGENE study comprising 702 prostate cancer patients. During a median follow-up time of 92 months, 120 (17.1%) patients died. A univariate Cox regression model showed a significant association of the CC genotype with reduced cancer-specific survival (CSS; hazard ratio, HR, 2.13, 95% confidence interval, CI, 1.10-4.12; p = 0.024) and overall survival (OS; HR 2.34, 95% CI 1.58-3.47; p < 0.001). In a multivariate Cox regression model including age at diagnosis, risk group, and androgen deprivation therapy, the CC genotype remained a significant predictor of poor CSS (HR 2.05, 95% CI 1.05-3.99; p = 0.034) and OS (HR 2.25, 95% CI 1.51-3.36; p < 0.001). This study provides evidence that the homozygous BCL2-938 CC genotype is associated with OS and C in prostate cancer patients. (orig.) [German] Das antiapoptotische Gen B cell lymphoma 2 (BCL2) spielt eine Schluesselrolle in der Entstehung und Progression von Krebserkrankungen. Ein funktioneller Einzelnukleotid-Polymorphismus (c.-938C>A, rs2279115) im inhibitorischen P2-BCL2-Promotor wurde mit dem klinischen Outcome verschiedener Krebserkrankungen verknuepft. Ziel der vorliegenden Studie war die Untersuchung der Rolle von BCL2-938C>A-Genotypen fuer die Mortalitaet bei Patienten mit Prostatakarzinom. Der Zusammenhang zwischen BCL2-938C>A-Genotypen (rs2279115) und dem Outcome bei Prostatakrebs wurde in der prospektiven PROCAGENE-Studie, die 702 Patienten mit Prostatakarzinom umfasste, untersucht. Waehrend der medianen

  1. MMP-8 genotypes influence the inflammatory response in human endotoxemia.

    Science.gov (United States)

    Rella, Judith M; Jilma, Bernd; Fabry, Astrid; Kaynar, A Murat; Mayr, Florian B

    2014-04-01

    Clinical studies have reported associations between MMP-8 genotypes and clinical outcomes without exploring underlying mechanisms. This study aims to understand the influence of the rs1940475 SNP on downstream chemokine and cytokine response in human endotoxemia. Rs1940475 was genotyped in 44 healthy Caucasian males, who were challenged with an intravenous bolus of 2 ng/kg lipopolysaccharide (LPS). Plasma levels of tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1α were measured at baseline and 2, 4, 6, and 24 h after LPS infusion with high-sensitivity enzyme immunoassays. Peak TNF levels at 2 h after LPS infusion were significantly higher in subjects with AA genotype compared to subjects with AG or GG genotypes (185 pg/mL [IQR, 154-234] vs. 94 pg/mL [IQR, 65-125] vs. 107 pg/mL [IQR, 80-241], respectively; p = 0.03 between groups). Peak IL-6 levels were trend-wise higher in subjects with AA genotype compared to those with AG or GG genotypes (566 pg/mL [IQR, 294-644] vs. 278 pg/mL [IQR, 184-539] and 329 pg/mL [IQR, 240-492], respectively; p = 0.15 between groups). In contrast, peak MIP-1α at 2 h was highest in GG genotype carriers compared to those with AG or AA genotypes (602 pg/mL [IQR, 449-727] vs. 389 pg/mL [IQR, 375-490] and 510 pg/mL [425-813], respectively; p < 0.03 between groups). AA genotype carriers had highest peak TNF and IL-6 levels after LPS challenge, whereas peak MIP-1α levels were highest in GG carriers. This indicates that the rs1940475 SNP modifies the host response to inflammatory stimuli, which may in part explain previously shown associations with clinical outcomes.

  2. Analysis of the ACTN3 heterozygous genotype suggests that α-actinin-3 controls sarcomeric composition and muscle function in a dose-dependent fashion.

    Science.gov (United States)

    Hogarth, Marshall W; Garton, Fleur C; Houweling, Peter J; Tukiainen, Taru; Lek, Monkol; Macarthur, Daniel G; Seto, Jane T; Quinlan, Kate G R; Yang, Nan; Head, Stewart I; North, Kathryn N

    2016-03-01

    A common null polymorphism (R577X) in ACTN3 causes α-actinin-3 deficiency in ∼ 18% of the global population. There is no associated disease phenotype, but α-actinin-3 deficiency is detrimental to sprint and power performance in both elite athletes and the general population. However, despite considerable investigation to date, the functional consequences of heterozygosity for ACTN3 are unclear. A subset of studies have shown an intermediate phenotype in 577RX individuals, suggesting dose-dependency of α-actinin-3, while others have shown no difference between 577RR and RX genotypes. Here, we investigate the effects of α-actinin-3 expression level by comparing the muscle phenotypes of Actn3(+/-) (HET) mice to Actn3(+/+) [wild-type (WT)] and Actn3(-/-) [knockout (KO)] littermates. We show reduction in α-actinin-3 mRNA and protein in HET muscle compared with WT, which is associated with dose-dependent up-regulation of α-actinin-2, z-band alternatively spliced PDZ-motif and myotilin at the Z-line, and an incremental shift towards oxidative metabolism. While there is no difference in force generation, HET mice have an intermediate endurance capacity compared with WT and KO. The R577X polymorphism is associated with changes in ACTN3 expression consistent with an additive model in the human genotype-tissue expression cohort, but does not influence any other muscle transcripts, including ACTN2. Overall, ACTN3 influences sarcomeric composition in a dose-dependent fashion in mouse skeletal muscle, which translates directly to function. Variance in fibre type between biopsies likely masks this phenomenon in human skeletal muscle, but we suggest that an additive model is the most appropriate for use in testing ACTN3 genotype associations. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Experimentally testing the dependence of momentum transport on second derivatives using Gaussian process regression

    Science.gov (United States)

    Chilenski, M. A.; Greenwald, M. J.; Hubbard, A. E.; Hughes, J. W.; Lee, J. P.; Marzouk, Y. M.; Rice, J. E.; White, A. E.

    2017-12-01

    It remains an open question to explain the dramatic change in intrinsic rotation induced by slight changes in electron density (White et al 2013 Phys. Plasmas 20 056106). One proposed explanation is that momentum transport is sensitive to the second derivatives of the temperature and density profiles (Lee et al 2015 Plasma Phys. Control. Fusion 57 125006), but it is widely considered to be impossible to measure these higher derivatives. In this paper, we show that it is possible to estimate second derivatives of electron density and temperature using a nonparametric regression technique known as Gaussian process regression. This technique avoids over-constraining the fit by not assuming an explicit functional form for the fitted curve. The uncertainties, obtained rigorously using Markov chain Monte Carlo sampling, are small enough that it is reasonable to explore hypotheses which depend on second derivatives. It is found that the differences in the second derivatives of n{e} and T{e} between the peaked and hollow rotation cases are rather small, suggesting that changes in the second derivatives are not likely to explain the experimental results.

  4. Characterization and Selection of Phosphorus Deficiency Tolerant Rice Genotypes in Sri Lanka

    Directory of Open Access Journals (Sweden)

    Y.C. Aluwihare

    2016-07-01

    Full Text Available Phosphorus (P deficiency in soil is a major constrain for rice production. An important set of rice genotypes (landraces, old improved and new improved varieties were screened for P deficiency tolerance in two major cropping seasons of Sri Lanka, in 2012. The Ultisol soil, which was collected from a plot cultivated with rice without fertilizer application for past 40 years (P0 at the Rice Research and Development Institute (RRDI, Bathalagoda, Sri Lanka, was used as the potting medium for greenhouse trials. Two field trials were conducted in the same plots at RRDI. Both P0 and P30 (30 mg/kg P2O5 conditions were used in the two greenhouse trials. At the early vegetative (three weeks after transplanting, late vegetative (six weeks after transplanting and flowering stages, plant height and number of tillers per plant were recorded. At the flowering stage, shoots were harvested and shoot dry weight, shoot P concentration, shoot P uptake and P utilization efficiency were measured. All data were statistically analyzed using analysis of variance, regression and cluster procedures. The measured parameters were significantly different between P0 and P30 conditions (P < 0.05. Higher shoot dry weight was reported by the rice genotypes H4 and Marss under P0 conditions. The regression analysis between shoot dry weight and P utilization efficiency revealed that the studied rice genotypes could be categorized to three P deficiency tolerance classes. A total of 13 genotypes could be considered as highly tolerant and 4 genotypes as sensitive for P deficiency. These results could be used to select parental genotypes for breeding and genetic studies and also to select interesting varieties or landraces for organic rice production.

  5. Regression Association Analysis of Yield-Related Traits with RAPD Molecular Markers in Pistachio (Pistacia vera L.

    Directory of Open Access Journals (Sweden)

    Saeid Mirzaei

    2017-10-01

    molecular date (as independent variable and morphological data (as dependent variable was performed using multiple regression analysis to identify informative markers associated with the yield related traits. Multiple regression analysis was conducted using stepwise method of linear regression analysis option of SPSS. Student t-test was performed to assess significance difference between mean trait estimates of genotypes where specific markers were present and absent. Markers shown significant regression values were considered to be associated with the trait under consideration. Results and Discussion: Finally 11 primers were polymorphic and a total of 56 pieces (loci were amplified that among these, 36 segments (64.29% showed polymorphism with an average of 5.09% per primers and the rate of this polymorphism ranged from at least 25% for AJ05 primer up to 87.5% for OPAD02 primer. Polymorphic information content ranged from 0.095 (AJ05 and OPAD14 to 0.39 (OPC05, with an average of 0.23. Stepwise regression analysis between molecular data and traits was performed to identify informative markers associated with yield component traits. Nineteen RAPD fragments were found associated with six yield related traits. Some of RAPD markers were associated with more than one trait in multiple regression analysis that may be due to pleiotropic effect of the linked quantitative trait locus on different traits. However, to better understand these relationships, preparation of segregating population and linkage mapping is necessary. Also, these results could be useful in marker-assisted breeding programs when no other genetic information is available. Conclusion: This investigation on molecular markers associated with yield traits in Pistachio has provided clues for identification of the genotypes with higher yield value. In breeding programs selection of quality material is often a time-consuming process, and thus marker-assisted selection could be of great useful in identification of

  6. Differential survival of mosquitofish exposed to radionuclides is dependent on RAPD genotype

    International Nuclear Information System (INIS)

    Theodorakis, C.W.; Shugart, L.R.

    1995-01-01

    In previous studies, it was found that certain RAPD (Randomly Amplified Polymorphic DNA) markers were present at higher frequencies in radionuclide-contaminated mosquitofish (Gambusia affinis) populations than in reference populations. These markers will be referred to as contaminant specific markers. In the present study, fish with and without these markers were collected from non-contaminated populations and exposed in situ to radionuclides by caging them in one of the contaminated sites. Forty fish were exposed for 1--6 weeks, after which the survivors were collected and DNA was extracted for genotypic analysis. In one experiment, the frequencies of contaminant specific markers in the survivors were compared to the frequencies of these markers in the native contaminated and uncontaminated (the source of the caged fish) populations. It was found that the genotypic distributions were more similar to the native contaminated population. In another experiment, samples of caudal fin tissue were collected for DNA extraction before and after placing fish in the cages, in order to compare survival rates of different genotypes. It was found that fish with the contaminant indicative bands had higher percent survival than the other fish. Experiments are underway or are being planned in order to determine the molecular identity of these bands and the ecological significance of altered band frequencies in hopes of developing population-level biomarkers of contaminant exposure and ecological affects

  7. Loss of ERβ expression as a common step in estrogen-dependent tumor progression

    Science.gov (United States)

    Bardin, Allison; Boulle, Nathalie; Lazennec, Gwendal; Vignon, Françoise; Pujol, Pascal

    2004-01-01

    The characterization of estrogen receptor beta (ERβ) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues and the mitogenic effects of estrogen in these tissues (e.g. breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERβ expression in cancer as compared to benign tumors or normal tissues, whereas ERα expression persists. The loss of ERβ expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERα target genes by ERβ, or ERβ specific gene induction could indicate that ERβ has a differential effect on proliferation as compared to ERα. ERβ may exert a protective effect and thus constitute a new target for hormone therapy, e.g. via ligand specific activation. The potential distinct roles of ERα and ERβ expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review. PMID:15369453

  8. Demonstration of non-Gaussian restricted diffusion in tumor cells using diffusion-time dependent diffusion weighted MR contrast

    Directory of Open Access Journals (Sweden)

    Tuva Roaldsdatter Hope

    2016-08-01

    Full Text Available The diffusion weighted imaging (DWI technique enables quantification of water mobility for probing microstructural properties of biological tissue, and has become an effective tool for collecting information about the underlying pathology of cancerous tissue. Measurements using multiple b-values have indicated a bi-exponential signal attenuation, ascribed to fast (high ADC and slow (low ADC diffusion components. In this empirical study, we investigate the properties of the diffusion time (∆ - dependent components of the diffusion-weighted (DW signal in a constant b-value experiment. A Xenograft GBM mouse was imaged using ∆ = 11 ms, 20 ms, 40 ms, 60 ms and b=500-4000 s/mm2 in intervals of 500s/mm2. Data was corrected for EPI distortions and the ∆-dependence on the DW signal was measured within three regions of interest (intermediate- and high-density tumor regions and normal appearing brain tissue regions (NAB. In this empirical study we verify the assumption that the slow decaying component of the DW-signal is non-Gaussian and dependent on ∆, consistent with restricted diffusion of the intracellular space. As the DW-signal as a function of ∆ is specific to restricted diffusion, manipulating ∆ at constant b-value (cb provides a complementary and direct approach for separating the restricted from the hindered diffusion component. Our results show that only tumor tissue signal of our data demonstrate ∆-dependence, based on a bi-exponential model with a restricted diffusion component, we successfully estimated the restricted ADC, signal volume fraction and cell size within each tumor ROI.

  9. Induction of apoptosis by Fe(salenCl through caspase-dependent pathway specifically in tumor cells

    Directory of Open Access Journals (Sweden)

    Nitika Pradhan

    2017-10-01

    Full Text Available Iron-based compounds possess the capability of inducing cell death due to their reactivity with oxidant molecules, but their specificity towards cancer cells and the mechanism of action are hitherto less investigated. A Fe(salenCl derivative has been synthesized that remains active in monomer form. The efficacy of this compound as an anti-tumor agent has been investigated in mouse and human leukemia cell lines. Fe(salenCl induces cell death specifically in tumor cells and not in primary cells. Mouse and human T-cell leukemia cell lines, EL4 and Jurkat cells are found to be susceptible to Fe(salenCl and undergo apoptosis, but normal mouse spleen cells and human peripheral blood mononuclear cells (PBMC remain largely unaffected by Fe(salenCl. Fe(salenCl treated tumor cells show significantly higher expression level of cytochrome c that might have triggered the cascade of reactions leading to apoptosis in cancer cells. A significant loss of mitochondrial membrane potential upon Fe(salenCl treatment suggests that Fe(salenCl induces apoptosis by disrupting mitochondrial membrane potential and homeostasis, leading to cytotoxity. We also established that apoptosis in the Fe(salenCl-treated tumor cells is mediated through caspase-dependent pathway. This is the first report demonstrating that Fe(salenCl can specifically target the tumor cells, leaving the primary cells least affected, indicating an excellent potential for this compound to emerge as a next-generation anti-tumor drug.

  10. Induction of apoptosis by Fe(salen)Cl through caspase-dependent pathway specifically in tumor cells.

    Science.gov (United States)

    Pradhan, Nitika; Pratheek, B M; Garai, Antara; Kumar, Ashutosh; Meena, Vikram S; Ghosh, Shyamasree; Singh, Sujay; Kumari, Shikha; Chandrashekar, T K; Goswami, Chandan; Chattopadhyay, Subhasis; Kar, Sanjib; Maiti, Prasanta K

    2014-10-01

    Iron-based compounds possess the capability of inducing cell death due to their reactivity with oxidant molecules, but their specificity towards cancer cells and the mechanism of action are hitherto less investigated. A Fe(salen)Cl derivative has been synthesized that remains active in monomer form. The efficacy of this compound as an anti-tumor agent has been investigated in mouse and human leukemia cell lines. Fe(salen)Cl induces cell death specifically in tumor cells and not in primary cells. Mouse and human T-cell leukemia cell lines, EL4 and Jurkat cells are found to be susceptible to Fe(salen)Cl and undergo apoptosis, but normal mouse spleen cells and human peripheral blood mononuclear cells (PBMC) remain largely unaffected by Fe(salen)Cl. Fe(salen)Cl treated tumor cells show significantly higher expression level of cytochrome c that might have triggered the cascade of reactions leading to apoptosis in cancer cells. A significant loss of mitochondrial membrane potential upon Fe(salen)Cl treatment suggests that Fe(salen)Cl induces apoptosis by disrupting mitochondrial membrane potential and homeostasis, leading to cytotoxity. We also established that apoptosis in the Fe(salen)Cl-treated tumor cells is mediated through caspase-dependent pathway. This is the first report demonstrating that Fe(salen)Cl can specifically target the tumor cells, leaving the primary cells least affected, indicating an excellent potential for this compound to emerge as a next-generation anti-tumor drug. © 2014 International Federation for Cell Biology.

  11. Identifying the most promising genotypes in lentil for cultivation in a wide range of environments of Pakistan using various yield stability measures

    International Nuclear Information System (INIS)

    Ali, A.; Zahid, M.A.

    2012-01-01

    The present study was aimed to identify the most promising high yielding lentil genotype for a wide range of environments of Pakistan using 8 stability measures. The experiment consisted of 12 lentil genotypes grown at 11 locations falling in different agro-ecological zones of Pakistan for 2 years during 2006/07 and 2007/08 under national uniform yield testing. The General Linear Model (GLM) of MINITAB (version 15) was used for two-way analysis of variance for lentil yield data to examine the total variation into genotypes, environments and genotype x environment interaction. The percent variation of 2 major contributors, environment and GxE interaction, was permissible to perform stability analysis to evaluate stable genotypes across the environments. The genotype x environment interaction means were used for eight stability measures (genotype mean, genotype variance, coefficient of variation, ecovalence, interaction variance, regression slope, deviation mean square, coefficient of determination). The stability measures depicted that the genotype NARC-06-1 with high mean yield (1140 kg/ha -1/), regression slope (1.09) close to unity and less statistics of remaining stability measures except high value of R/sup 2/ for yield proved to be the best within the pool of studied genotypes. The results clearly suggest that the genotype NARC-06-1 may prove to be a widely adapted high yielding stable variety for a broad spectrum of environments of Pakistan. (author)

  12. Distribution of genotypes C825T polymorphism G-protein β3-subunit gene in patients with hypertension depending on body mass index

    Directory of Open Access Journals (Sweden)

    Prystupa L.N.

    2015-09-01

    Full Text Available The aim of the study was to investigate the frequency of genotypes of C825T polymorphism G-protein β3-subunit gene (GNB3 in patients with arterial hypertension (AH, depending on body mass index (BMI. The study involved 155 patients with verified diagnosis of AH (study group and 50 healthy individuals (control group. The patients of the main group were divided into 3 groups according to BMI: I - 35 patients with normal body weight, II - 38 patients with overweight, III - 82 patients with obesity. We used general clinical, anthropometric, instrumental, molecular-genetic and statistical methods. Probability of differences in the frequency of alleles and genotypes was determined using χ² criteria. Pairwise comparison of groups was made using nonparametric Mann-Whitney test. The difference was considered statistically significant at p <0,05. Investigation of the distribution of genotypes C825T polymorphism GNB3 in patients with AH according to BMI showed statistically significant increase in the frequency of genotypes C / T and T / T and T allele in patients with overweight and obesity as compared with patients with normal body weight (χ² = 26 8; p <0.001. The risk of weight increase in AH patients with T allele carriers is 2,2 times higher than in C allele carriers. Association of C825T polymorphism of GNB3 with a tendency to obesity and overweight in patients with AH was proved.

  13. CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.

    Science.gov (United States)

    Zhou, You; Shan, Song; Li, Zhi-Bin; Xin, Li-Jun; Pan, De-Si; Yang, Qian-Jiao; Liu, Ying-Ping; Yue, Xu-Peng; Liu, Xiao-Rong; Gao, Ji-Zhou; Zhang, Jin-Wen; Ning, Zhi-Qiang; Lu, Xian-Ping

    2017-03-01

    Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC 50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R + cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  14. Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism.

    LENUS (Irish Health Repository)

    Wang, Jiang Huai

    2012-02-03

    Beta(1) integrins play a crucial role in supporting tumor cell attachment to and invasion into the extracellular matrix. Endotoxin\\/LPS introduced by surgery has been shown to enhance tumor metastasis in a murine model. Here we show the direct effect of LPS on tumor cell adhesion and invasion in extracellular matrix proteins through a beta(1) integrin-dependent pathway. The human colorectal tumor cell lines SW480 and SW620 constitutively expressed high levels of the beta(1) subunit, whereas various low levels of alpha(1), alpha(2), alpha(4), and alpha(6) expression were detected. SW480 and SW620 did not express membrane-bound CD14; however, LPS in the presence of soluble CD14 (sCD14) significantly up-regulated beta(1) integrin expression; enhanced tumor cell attachment to fibronectin, collagen I, and laminin; and strongly promoted tumor cell invasion through the Matrigel. Anti-beta(1) blocking mAbs (4B4 and 6S6) abrogated LPS- plus sCD14-induced tumor cell adhesion and invasion. Furthermore, LPS, when combined with sCD14, resulted in NF-kappaB activation in both SW480 and SW620 cells. Inhibition of the NF-kappaB pathway significantly attenuated LPS-induced up-regulation of beta(1) integrin expression and prevented tumor cell adhesion and invasion. These results provide direct evidence that although SW480 and SW620 cells do not express membrane-bound CD14, LPS in the presence of sCD14 can activate NF-kappaB, up-regulate beta(1) integrin expression, and subsequently promote tumor cell adhesion and invasion. Moreover, LPS-induced tumor cell attachment to and invasion through extracellular matrix proteins is beta(1) subunit-dependent.

  15. Genomic breeding value estimation using nonparametric additive regression models

    Directory of Open Access Journals (Sweden)

    Solberg Trygve

    2009-01-01

    Full Text Available Abstract Genomic selection refers to the use of genomewide dense markers for breeding value estimation and subsequently for selection. The main challenge of genomic breeding value estimation is the estimation of many effects from a limited number of observations. Bayesian methods have been proposed to successfully cope with these challenges. As an alternative class of models, non- and semiparametric models were recently introduced. The present study investigated the ability of nonparametric additive regression models to predict genomic breeding values. The genotypes were modelled for each marker or pair of flanking markers (i.e. the predictors separately. The nonparametric functions for the predictors were estimated simultaneously using additive model theory, applying a binomial kernel. The optimal degree of smoothing was determined by bootstrapping. A mutation-drift-balance simulation was carried out. The breeding values of the last generation (genotyped was predicted using data from the next last generation (genotyped and phenotyped. The results show moderate to high accuracies of the predicted breeding values. A determination of predictor specific degree of smoothing increased the accuracy.

  16. A preliminary study of murine walker-256 tumor hypoxia detected by blood oxygen level dependent-MR

    International Nuclear Information System (INIS)

    Zhang Shengjian; Mao Jian; Wu Bin; Peng Weijun

    2013-01-01

    Objective: To establish Walker-256 transplantation tumor model in SD Rats. To study of R_2"* signal changes on murine Walker-256 tumor after inhaling Carbogen by blood oxygen level dependent (BOLD)-MR, and to explore the feasibility of BOLD-MRI on detecting tumor hypoxia. Methods: Walker-256 tumor cell implanted subcutaneously in right lower abdomen of 95 female SD rats. MR was performed on the tumor-forming rats when the maximum diameter of tumor reached 1-3 cm, using a 3.0 T MR scanner equipped with a 3 inch animal surface coil. BOLD-MRI was done by using a multiecho SPGR sequence during inhaling air and at 10 minute after inhaling Carbogen, respectively. All images were transferred to GE ADW 4.3 workstation, then a baseline R_2"* (R_2"* a) and R_2"* (R_2"* b) after inhaling Carbogen of tumor was calculated using R_2 Star analysis software and ΔR_2"* was calculated through ΔR_2"* = R_2"* b -R_2"* a", meanwhile the volume of tumor were calculated as well. The difference of R_2"* signal pre and post-inhaling of Carbogen was compared with a paired t test, Pearson correlation was calculated between R_2"* a, ΔR_2"* and the volume of tumor, respectively. The correlation between ΔR_2"* and R_2"* a was also assessed by Pearson correlation. Results: Sixty-eight of ninety-five female SD rats formed the tumor (71.6%). The volume of tumor was from 352 to 13 173 mm"3. Mean ΔR_2"* decreased significantly (-2.26 ± 3.90) s"-"1 from (41.18 ± 22.29) s"-"1 during breathing air to (38.91 ± 21.35) s"-"1 10 min after inhaling Carbogen (t = 4.01, P 0.05). Conclusions: BOLD-MRI can detect the R_2"* signal change of murine Walker-256 tumor pre-and post-inhaling of Carbogen. The R_2"* signal showed significant decrease after inhaling Carbogen, however, the individual variation was remarkable. (authors)

  17. Haemoglobin genotype of children with severe malaria seen at the ...

    African Journals Online (AJOL)

    Prof Ezechukwu

    2011-10-23

    Oct 23, 2011 ... malaria seen in University of Benin. Teaching Hospital (UBTH), Benin. City. Patients and methods: ... gested to play crucial role in the defense of host against malaria infection and reduce susceptibility to severe .... Binary logistic regression model using Hb genotype status (abnormal Hb versus HbAA) as the ...

  18. Doping test results dependent on genotype of uridine diphospho-glucuronosyl transferase 2B17, the major enzyme for testosterone glucuronidation.

    Science.gov (United States)

    Schulze, Jenny Jakobsson; Lundmark, Jonas; Garle, Mats; Skilving, Ilona; Ekström, Lena; Rane, Anders

    2008-07-01

    Testosterone abuse is conventionally assessed by the urinary testosterone/epitestosterone (T/E) ratio, levels above 4.0 being considered suspicious. The large variation in testosterone glucuronide (TG) excretion and its strong association with a deletion polymorphism in the uridine diphospho-glucuronosyl transferase (UGT) 2B17 gene challenge the accuracy of the T/E ratio test. Our objective was to investigate whether genotype-based cutoff values will improve the sensitivity and specificity of the test. This was an open three-armed comparative study. A total of 55 healthy male volunteers with either two, one, or no allele [insertion/insertion, insertion/deletion, or deletion/deletion (del/del)] of the UGT2B17 gene was included in the study. A single im dose of 500 mg testosterone enanthate was administered. Urinary excretion of TG after dose and the T/E ratio during 15 d were calculated. The degree and rate of increase in the TG excretion rate were highly dependent on the UGT2B17 genotype with a 20-fold higher average maximum increase in the insertion/insertion group compared with the del/del group. Of the del/del subjects, 40% never reached the T/E ratio of 4.0 on any of the 15 d after the dose. When differentiated cutoff levels for the del/del (1.0) and the other genotypes (6.0) were applied, the sensitivity increased substantially for the del/del group, and false positives in the other genotypes were eliminated. Consideration of the genetic variation in disposition of androgens will improve the sensitivity and specificity of the testosterone doping test. This is of interest not only for combating androgen doping in sports, but also for detecting and preventing androgen abuse in society.

  19. Amino acid digestibility of different rye genotypes in caecectomised laying hens.

    Science.gov (United States)

    Zuber, Tobias; Miedaner, Thomas; Rosenfelder, Pia; Rodehutscord, Markus

    2016-12-01

    This study investigated the variability of amino acid (AA) digestibility of rye grains in laying hens. Relationships between AA digestibility and physical properties (thousand seed weight, test weight, falling number, and extract viscoelasticity), chemical composition (proximate nutrients, non-starch polysaccharides, AA, minerals, and inositol phosphates), gross energy concentration, and in vitro solubility of nitrogen (N) of the grains were also examined. Twenty rye genotypes were grown under standardised agronomic and environmental conditions as part of a collaborative research project known as "GrainUp". Each genotype was added to a basal diet at 500 g/kg at the expense of maize starch to produce 20 rye diets. The experimental design comprised four Latin Squares (6 × 6) distributed over two runs, resulting in 12 experimental periods. Caecectomised laying hens (LSL-Classic) were individually kept in metabolism cages. Excreta were collected quantitatively for 4 d, and AA digestibility of the rye genotypes was determined using a regression approach. The digestibility of AA was generally low but varied significantly among the 20 rye genotypes, especially for Lys (digestibility range 35-59%), Met (57-75%), Thr (34-54%), and Trp (36-71%). Nevertheless, physical and chemical characteristics as well as the in vitro solubility of N correlated in only a few cases with AA digestibility. Multiple linear regression was used to calculate equations to predict AA digestibility based on the analysed characteristics. However, their explanatory power, as judged by the adjusted R(2), was not sufficiently precise for practical application (below 0.6 for most AA). In conclusion, the AA digestibility of rye grain is generally low and varies significantly between crop genotypes. Equations based on its physical and chemical characteristics are not sufficiently precise to be useful for feed formulation.

  20. Selective anti-tumor activity of the novel fluoropyrimidine polymer F10 towards G48a orthotopic GBM tumors.

    Science.gov (United States)

    Gmeiner, William H; Lema-Tome, Carla; Gibo, Denise; Jennings-Gee, Jamie; Milligan, Carol; Debinski, Waldemar

    2014-02-01

    F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.

  1. Assessment of adaptability and stability of grain yield in bread wheat genotypes under different sowing times in Punjab

    International Nuclear Information System (INIS)

    Anwar, J.; Hussain, M.; Ali, M.A.; Subhani, G.M.; Munir, M.

    2011-01-01

    Twenty advanced lines/genotypes of wheat including two check varieties were sown under two different sowing times through out the Punjab province at 18 different locations with diverse environments to study their stability and adaptability. Normal sowing was done in second week of November 2007 while the delayed sowing was completed during second week of December 2007 during crop season 2007-08. The pooled analysis of variance showed significant differences among environments and genotypes for grain yield demonstrating the presence of considerable variations (p<0.01) among genotypes as well as diversity of growing environments at various locations for both normal and late sown wheat crops. The highest average grain yield was obtained at Jalandar Seed Farm, Arifwala and Pak. German Farm, Multan for normal and delayed sown crops, respectively. Most of the locations emerged as high yielding in normal sowing compared to late sown crop. Dendrograms of 18 locations based on the average yield of 20 wheat genotypes grown under normal and late sown crop revealed two main clusters. Under both normal and late sowing, none of the varieties exceeded the check Seher-2006, however, the check was followed by the advanced lines V-04022 and V-05066 for normal sown crop and Shafaq-2006, V-05066 and V-04022 under delayed sowing. All the genotypes revealed decline in grain yield for late sown wheat crop. The analysis of stability based on mean grain yield, regression coefficient and deviation from regression advocated that the cultivars V-05066 and V-03BT007 were most stable and adapted to diverse environmental conditions of Punjab. These cultivars revealed unit regression and non-significant deviations from regression. The check variety Seher-2006 produced maximum yield for both sowing times that suggested its consistent and stable performance across the environments. (author)

  2. Impact of secondary hyperparathyroidism on ventricular mass regression after aortic valve replacement for aortic stenosis in hemodialysis-dependent patients.

    Science.gov (United States)

    Takami, Yoshiyuki; Tajima, Kazuyoshi

    2015-07-01

    In hemodialysis (HD)-dependent patients, secondary hyperparathyroidism induces cardiac hypertrophy. This study investigated whether parathyroid hormone (PTH) levels affect the degree of left ventricular (LV) mass regression in HD patients after aortic valve replacement (AVR) for aortic stenosis (AS). We retrospectively obtained preoperative and 2-year postoperative echocardiography and intact PTH measurements in 88 HD patients who underwent AVR, with bioprostheses (n = 35, 40%) and mechanical valves (n = 53, 60%) of effective orifice area >0.80 cm2/m2, between January 1997 and December 2010. The LV mass decreased significantly from 308 ± 88 to 217 ± 68 g at follow-up of 28 ± 4 months after AVR (p regression at follow-up was inversely related to preoperative PTH values (R = 0.44, p = 0.001). The LV mass regression at follow-up was significantly smaller in the patients (n = 47) with PTH ≥100 pg/mL than in those (n = 41) with PTH regression at 2-year follow-up (β = 0.23, r2 = 0.24, p = 0.02). In conclusion, the HD patients with high levels of PTH presented with less LV mass regression after AVR for AS without patient-prosthesis mismatch. Secondary hyperparathyroidism may impair regression of cardiac hypertrophy after AVR in HD patients with AS.

  3. Genetic variability, partial regression, Co-heritability studies and their implication in selection of high yielding potato gen

    International Nuclear Information System (INIS)

    Iqbal, Z.M.; Khan, S.A.

    2003-01-01

    Partial regression coefficient, genotypic and phenotypic variabilities, heritability co-heritability and genetic advance were studied in 15 Potato varieties of exotic and local origin. Both genotypic and phenotypic coefficients of variations were high for scab and rhizoctonia incidence percentage. Significant partial regression coefficient for emergence percentage indicated its relative importance in tuber yield. High heritability (broadsense) estimates coupled with high genetic advance for plant height, number of stems per plant and scab percentage revealed substantial contribution of additive genetic variance in the expression of these traits. Hence, the selection based on these characters could play a significant role in their improvement the dominance and epistatic variance was more important for character expression of yield ha/sup -1/, emergence and rhizoctonia percentage. This phenomenon is mainly due to the accumulative effects of low heritability and low to moderate genetic advance. The high co-heritability coupled with negative genotypic and phenotypic covariance revealed that selection of varieties having low scab and rhizoctonia percentage resulted in more potato yield. (author)

  4. HPMA copolymer-bound doxorubicin induces immunogenic tumor cell death.

    Science.gov (United States)

    Sirova, M; Kabesova, M; Kovar, L; Etrych, T; Strohalm, J; Ulbrich, K; Rihova, B

    2013-01-01

    Treatment of murine EL4 T cell lymphoma with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates of doxorubicin (Dox) leads to complete tumor regression and to the development of therapy-dependent longlasting cancer resistance. This phenomenon occurs with two types of Dox conjugates tested, despite differences in the covalent linkage of Dox to the polymer carrier. Such a cancer resistance cannot fully express in conventional treatment with free Dox, due to substantial immunotoxicity of the treatment, which was not observed in the polymer conjugates. In this study, calreticulin (CRT) translocation and high mobility group box-1 protein (HMGB1) release was observed in EL4 cells treated with a conjugate releasing Dox by a pH-dependent manner. As a result, the treated tumor cells were engulfed by dendritic cells (DC) in vitro, and induced their expression of CD80, CD86, and MHC II maturation markers. Conjugates with Dox bound via an amide bond only increased translocation of HSPs to the membrane, which led to an elevated phagocytosis but was not sufficient to induce increase of the maturation markers on DCs in vitro. Both types of conjugates induced engulfment of the target tumor cells in vivo, that was more intense than that seen with free Dox. It means that the induction of anti-tumor immunity documented upon treatment of EL4 lymphoma with HPMA-bound Dox conjugates does not rely solely on CRT-mediated cell death, but involves multiple mechanisms.

  5. Improving accuracy of genomic prediction in Brangus cattle by adding animals with imputed low-density SNP genotypes.

    Science.gov (United States)

    Lopes, F B; Wu, X-L; Li, H; Xu, J; Perkins, T; Genho, J; Ferretti, R; Tait, R G; Bauck, S; Rosa, G J M

    2018-02-01

    Reliable genomic prediction of breeding values for quantitative traits requires the availability of sufficient number of animals with genotypes and phenotypes in the training set. As of 31 October 2016, there were 3,797 Brangus animals with genotypes and phenotypes. These Brangus animals were genotyped using different commercial SNP chips. Of them, the largest group consisted of 1,535 animals genotyped by the GGP-LDV4 SNP chip. The remaining 2,262 genotypes were imputed to the SNP content of the GGP-LDV4 chip, so that the number of animals available for training the genomic prediction models was more than doubled. The present study showed that the pooling of animals with both original or imputed 40K SNP genotypes substantially increased genomic prediction accuracies on the ten traits. By supplementing imputed genotypes, the relative gains in genomic prediction accuracies on estimated breeding values (EBV) were from 12.60% to 31.27%, and the relative gain in genomic prediction accuracies on de-regressed EBV was slightly small (i.e. 0.87%-18.75%). The present study also compared the performance of five genomic prediction models and two cross-validation methods. The five genomic models predicted EBV and de-regressed EBV of the ten traits similarly well. Of the two cross-validation methods, leave-one-out cross-validation maximized the number of animals at the stage of training for genomic prediction. Genomic prediction accuracy (GPA) on the ten quantitative traits was validated in 1,106 newly genotyped Brangus animals based on the SNP effects estimated in the previous set of 3,797 Brangus animals, and they were slightly lower than GPA in the original data. The present study was the first to leverage currently available genotype and phenotype resources in order to harness genomic prediction in Brangus beef cattle. © 2018 Blackwell Verlag GmbH.

  6. Improving drug accumulation and photothermal efficacy in tumor depending on size of ICG loaded lipid-polymer nanoparticles.

    Science.gov (United States)

    Zhao, Pengfei; Zheng, Mingbin; Yue, Caixia; Luo, Zhenyu; Gong, Ping; Gao, Guanhui; Sheng, Zonghai; Zheng, Cuifang; Cai, Lintao

    2014-07-01

    A key challenge to strengthen anti-tumor efficacy is to improve drug accumulation in tumors through size control. To explore the biodistribution and tumor accumulation of nanoparticles, we developed indocyanine green (ICG) loaded poly (lactic-co-glycolic acid) (PLGA) -lecithin-polyethylene glycol (PEG) core-shell nanoparticles (INPs) with 39 nm, 68 nm and 116 nm via single-step nanoprecipitation. These INPs exhibited good monodispersity, excellent fluorescence and size stability, and enhanced temperature response after laser irradiation. Through cell uptake and photothermal efficiency in vitro, we demonstrated that 39 nm INPs were more easily be absorbed by pancreatic carcinoma tumor cells (BxPC-3) and showed better photothermal damage than that of 68 nm and 116 nm size of INPs. Simultaneously, the fluorescence of INPs offered a real-time imaging monitor for subcellular locating and in vivo metabolic distribution. Near-infrared imaging in vivo and photothermal therapy illustrated that 68 nm INPs showed the strongest efficiency to suppress tumor growth due to abundant accumulation in BxPC-3 xenograft tumor model. The findings revealed that a nontoxic, size-dependent, theranostic INPs model was built for in vivo cancer imaging and photothermal therapy without adverse effect. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. [High-throughput genotyping multiplex ligation-dependent probe amplification for assisting diagnosis in a case of anti-Di(a)-induced severe hemolytic disease of the newborn].

    Science.gov (United States)

    Ji, Yanli; Mo, Chunyan; Wei, Ling; Zhou, Xiuzhen; Zhang, Runqing; Zhao, Yang; Luo, Hong; Wang, Zhen; Luo, Guangping

    2012-02-01

    To report a rare case of hemolytic disease of the newborn (HDN) with kernicterus caused by anti-Di(a) diagnosed using high-throughput genotyping multiplex ligation-dependent probe amplification (MLPA). Conventional serological methods were used to detect the antibodies related with HDN. The genotypes of more than 40 red blood cell antigens for the newborn and her parents were obtained using the high-throughput MLPA assay. The antibody titers were tested using a standard serological method. The unknown antibody against the low-frequency antigens was predicted based on the primary serological tests. The genotyping results for more than 40 red blood cell antigens of the newborn and her parents showed incompatible antigens of MNS and Diego blood group system, indicating the existence of anti-N or anti-Di(a). Further serological tests confirmed anti-Di(a) existence in the plasma of the newborn and her mother. The titer of anti-Di(a) in the mother's plasma was 1:32. Severe HDN including kernicterus can result from anti-Di(a). High-throughput genotyping MLPA assay can help type some rare antigens in complicated cases. The reagent red cell panels including Di(a)-positive cells are necessary in routine antibody screening test in Chinese population.

  8. Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

    Science.gov (United States)

    Yano, Shuya; Takehara, Kiyoto; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi; Hoffman, Robert M.

    2017-01-01

    ABSTRACT We previously demonstrated that quiescent cancer cells in a tumor are resistant to conventional chemotherapy as visualized with a fluorescence ubiquitination cell cycle indicator (FUCCI). We also showed that proliferating cancer cells exist in a tumor only near nascent vessels or on the tumor surface as visualized with FUCCI and green fluorescent protein (GFP)-expressing tumor vessels. In the present study, we show the relationship between cell-cycle phase and chemotherapy-induced tumor angiogenesis using in vivo FUCCI real-time imaging of the cell cycle and nestin-driven GFP to detect nascent blood vessels. We observed that chemotherapy-treated tumors, consisting of mostly of quiescent cancer cells after treatment, had much more and deeper tumor vessels than untreated tumors. These newly-vascularized cancer cells regrew rapidly after chemotherapy. In contrast, formerly quiescent cancer cells decoyed to S/G2 phase by a telomerase-dependent adenovirus did not induce tumor angiogenesis. The present results further demonstrate the importance of the cancer-cell position in the cell cycle in order that chemotherapy be effective and not have the opposite effect of stimulating tumor angiogenesis and progression. PMID:27715464

  9. Implication of p53-dependent cellular senescence related gene, TARSH in tumor suppression

    International Nuclear Information System (INIS)

    Wakoh, Takeshi; Uekawa, Natsuko; Terauchi, Kunihiko; Sugimoto, Masataka; Ishigami, Akihito; Shimada, Jun-ichi; Maruyama, Mitsuo

    2009-01-01

    A novel target of NESH-SH3 (TARSH) was identified as a cellular senescence related gene in mouse embryonic fibroblasts (MEFs) replicative senescence, the expression of which has been suppressed in primary clinical lung cancer specimens. However, the molecular mechanism underlying the regulation of TARSH involved in pulmonary tumorigenesis remains unclear. Here we demonstrate that the reduction of TARSH gene expression by short hairpin RNA (shRNA) system robustly inhibited the MEFs proliferation with increase in senescence-associated β-galactosidase (SA-β-gal) activity. Using p53 -/- MEFs, we further suggest that this growth arrest by loss of TARSH is evoked by p53-dependent p21 Cip1 accumulation. Moreover, we also reveal that TARSH reduction induces multicentrosome in MEFs, which is linked in chromosome instability and tumor development. These results suggest that TARSH plays an important role in proliferation of replicative senescence and may serve as a trigger of tumor development.

  10. Antitumor effectiveness of different amounts of electrical charge in Ehrlich and fibrosarcoma Sa-37 tumors

    International Nuclear Information System (INIS)

    Ciria, HC; Quevedo, MS; Cabrales, LB; Bruzón, RP; Salas, MF; Pena, OG; González, TR; López, DS; Flores, JM

    2004-01-01

    In vivo studies were conducted to quantify the effectiveness of low-level direct electric current for different amounts of electrical charge and the survival rate in fibrosarcoma Sa-37 and Ehrlich tumors, also the effect of direct electric in Ehrlich tumor was evaluate through the measurements of tumor volume and the peritumoral and tumoral findings. BALB/c male mice, 7–8 week old and 20–22 g weight were used. Ehrlich and fibrosarcoma Sa-37 cell lines, growing in BALB/c mice. Solid and subcutaneous Ehrlich and fibrosarcoma Sa-37 tumors, located dorsolaterally in animals, were initiated by the inoculation of 5 × 10 6 and 1 × 10 5 viable tumor cells, respectively. For each type of tumor four groups (one control group and three treated groups) consisting of 10 mice randomly divided were formed. When the tumors reached approximately 0.5 cm 3 , four platinum electrodes were inserted into their bases. The electric charge delivered to the tumors was varied in the range of 5.5 to 110 C/cm 3 for a constant time of 45 minutes. An additional experiment was performed in BALB/c male mice bearing Ehrlich tumor to examine from a histolological point of view the effects of direct electric current. A control group and a treated group with 77 C/cm 3 (27.0 C in 0.35 cm 3 ) and 10 mA for 45 min were formed. In this experiment when the tumor volumes reached 0.35 cm 3 , two anodes and two cathodes were inserted into the base perpendicular to the tumor long axis. Significant tumor growth delay and survival rate were achieved after electrotherapy and both were dependent on direct electric current intensity, being more marked in fibrosarcoma Sa-37 tumor. Complete regressions for fibrosarcoma Sa-37 and Ehrlich tumors were observed for electrical charges of 80 and 92 C/cm 3 , respectively. Histopathological and peritumoral findings in Ehrlich tumor revealed in the treated group marked tumor necrosis, vascular congestion, peritumoral neutrophil infiltration, an acute inflammatory

  11. Direct visualization of electroporation-assisted in vivo gene delivery to tumors using intravital microscopy – spatial and time dependent distribution

    International Nuclear Information System (INIS)

    Cemazar, Maja; Wilson, Ian; Dachs, Gabi U; Tozer, Gillian M; Sersa, Gregor

    2004-01-01

    Electroporation is currently receiving much attention as a way to increase drug and DNA delivery. Recent studies demonstrated the feasibility of electrogene therapy using a range of therapeutic genes for the treatment of experimental tumors. However, the transfection efficiency of electroporation-assisted DNA delivery is still low compared to viral methods and there is a clear need to optimize this approach. In order to optimize treatment, knowledge about spatial and time dependency of gene expression following delivery is of utmost importance in order to improve gene delivery. Intravital microscopy of tumors growing in dorsal skin fold window chambers is a useful method for monitoring gene transfection, since it allows non-invasive dynamic monitoring of gene expression in tumors in a live animal. Intravital microscopy was used to monitor real time spatial distribution of the green fluorescent protein (GFP) and time dependence of transfection efficiency in syngeneic P22 rat tumor model. DNA alone, liposome-DNA complexes and electroporation-assisted DNA delivery using two different sets of electric pulse parameters were compared. Electroporation-assisted DNA delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz was superior to other methods and resulted in 22% increase in fluorescence intensity in the tumors up to 6 days post-transfection, compared to the non-transfected area in granulation tissue. Functional GFP was detected within 5 h after transfection. Cells expressing GFP were detected throughout the tumor, but not in the surrounding tissue that was not exposed to electric pulses. Intravital microscopy was demonstrated to be a suitable method for monitoring time and spatial distribution of gene expression in experimental tumors and provided evidence that electroporation-assisted gene delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz is an effective method, resulting in early onset and homogenous distribution of gene expression in the syngeneic P22 rat tumor model

  12. Skeletal metastases of carcinomas of prostate in dependence on tumor size and tumor differentiation

    International Nuclear Information System (INIS)

    Krause, U.

    1981-01-01

    153 patients with carcinoma of the prostate underwent holebody skeletal scintiscanning. It resulted that the tendency to the development of skeletal metastases increases with increasing dedifferentiation of the tumor. Also the tumor size correlated with the metastase identification. The tumor dedifferentiation also increased with the tumor size. The findings proved that the early diagnosis of a carcinoma of the prostate is a necessary prerequisite, because a radical total removal can only be curative when any metastases are absent. The comparative evaluation of the diagnostic methods proved the superiority of the nuclear medical examination. In 68% of the cases the roentgenologic examination led to correctly positive results. This investigation showed with 98% a high diagnostic specificity and therefore it should be applied in addition to scintiscanning in order to obtain supplementary information. The alkaline and the acid phosphatase offering an almost identical informative value resulted to be not useful for establishing an early diagnosis of skeletal metastases. It was found that the determination of the blood sedimentation rate and of the lactate dehydrogenase do also not render possible the early diagnosis of skeletal metastases. (orig./MG) [de

  13. BOX-COX REGRESSION METHOD IN TIME SCALING

    Directory of Open Access Journals (Sweden)

    ATİLLA GÖKTAŞ

    2013-06-01

    Full Text Available Box-Cox regression method with λj, for j = 1, 2, ..., k, power transformation can be used when dependent variable and error term of the linear regression model do not satisfy the continuity and normality assumptions. The situation obtaining the smallest mean square error  when optimum power λj, transformation for j = 1, 2, ..., k, of Y has been discussed. Box-Cox regression method is especially appropriate to adjust existence skewness or heteroscedasticity of error terms for a nonlinear functional relationship between dependent and explanatory variables. In this study, the advantage and disadvantage use of Box-Cox regression method have been discussed in differentiation and differantial analysis of time scale concept.

  14. Gene Expression in Uterine Leiomyoma from Tumors Likely to Be Growing (from Black Women over 35) and Tumors Likely to Be Non-Growing (from White Women over 35)

    Science.gov (United States)

    Davis, Barbara J.; Risinger, John I.; Chandramouli, Gadisetti V. R.; Bushel, Pierre R.; Baird, Donna Day; Peddada, Shyamal D.

    2013-01-01

    The study of uterine leiomyomata (fibroids) provides a unique opportunity to investigate the physiological and molecular determinants of hormone dependent tumor growth and spontaneous tumor regression. We conducted a longitudinal clinical study of premenopausal women with leiomyoma that showed significantly different growth rates between white and black women depending on their age. Growth rates for leiomyoma were on average much higher from older black women than for older white women, and we now report gene expression pattern differences in tumors from these two groups of study participants. Total RNA from 52 leiomyoma and 8 myometrial samples were analyzed using Affymetrix Gene Chip expression arrays. Gene expression data was first compared between all leiomyoma and normal myometrium and then between leiomyoma from older black women (age 35 or older) and from older white women. Genes that were found significant in pairwise comparisons were further analyzed for canonical pathways, networks and biological functions using the Ingenuity Pathway Analysis (IPA) software. Whereas our comparison of leiomyoma to myometrium produced a very large list of genes highly similar to numerous previous studies, distinct sets of genes and signaling pathways were identified in comparisons of older black and white women whose tumors were likely to be growing and non-growing, respectively. Key among these were genes associated with regulation of apoptosis. To our knowledge, this is the first study to compare two groups of tumors that are likely to have different growth rates in order to reveal molecular signals likely to be influential in tumor growth. PMID:23785396

  15. Logistic regression applied to natural hazards: rare event logistic regression with replications

    OpenAIRE

    Guns, M.; Vanacker, Veerle

    2012-01-01

    Statistical analysis of natural hazards needs particular attention, as most of these phenomena are rare events. This study shows that the ordinary rare event logistic regression, as it is now commonly used in geomorphologic studies, does not always lead to a robust detection of controlling factors, as the results can be strongly sample-dependent. In this paper, we introduce some concepts of Monte Carlo simulations in rare event logistic regression. This technique, so-called rare event logisti...

  16. Spikelet sterility in rice genotypes affected by temperature at microsporogenesis

    Directory of Open Access Journals (Sweden)

    Natalia M. de Souza

    Full Text Available ABSTRACT This study evaluated the effect of temperatures during the phase of microsporogenesis on spikelet sterility of paddy rice and identified genotypes tolerant to low temperatures at this growth stage. The inbreds SC681, SC491, and SC676 and the cultivars Epagri 109 and SCS116 Satoru were assessed. The genotypes were submitted for three days in a growth chamber to five temperatures at microsporogenesis: 9, 12, 15, 18, and 21 oC. For each tested temperature, a control was kept in the greenhouse under environmental conditions. After harvest, full and empty spikelets were counted and weighed and the percentage of spikelet sterility was determined. Data were evaluated by variance analysis using the F test. Averages were compared by Tukey’s test and regression analysis. The highest spikelet sterilities were observed when the genotypes were exposed to the temperatures of 9 and 12 oC. Genotype spikelet sterility was similar to that of the control at 21 ºC. The inbred SC 676 presented higher tolerance to lower temperatures is therefore potentially suited to generate a cultivar with adequate agronomic performance in rice growing areas prone to cold conditions at microsporogenesis.

  17. bayesQR: A Bayesian Approach to Quantile Regression

    Directory of Open Access Journals (Sweden)

    Dries F. Benoit

    2017-01-01

    Full Text Available After its introduction by Koenker and Basset (1978, quantile regression has become an important and popular tool to investigate the conditional response distribution in regression. The R package bayesQR contains a number of routines to estimate quantile regression parameters using a Bayesian approach based on the asymmetric Laplace distribution. The package contains functions for the typical quantile regression with continuous dependent variable, but also supports quantile regression for binary dependent variables. For both types of dependent variables, an approach to variable selection using the adaptive lasso approach is provided. For the binary quantile regression model, the package also contains a routine that calculates the fitted probabilities for each vector of predictors. In addition, functions for summarizing the results, creating traceplots, posterior histograms and drawing quantile plots are included. This paper starts with a brief overview of the theoretical background of the models used in the bayesQR package. The main part of this paper discusses the computational problems that arise in the implementation of the procedure and illustrates the usefulness of the package through selected examples.

  18. Tumor-Derived G-CSF Facilitates Neoplastic Growth through a Granulocytic Myeloid-Derived Suppressor Cell-Dependent Mechanism

    Science.gov (United States)

    Waight, Jeremy D.; Hu, Qiang; Miller, Austin; Liu, Song; Abrams, Scott I.

    2011-01-01

    Myeloid-derived suppressor cells (MDSC) are induced under diverse pathologic conditions, including neoplasia, and suppress innate and adaptive immunity. While the mechanisms by which MDSC mediate immunosuppression are well-characterized, details on how they develop remain less understood. This is complicated further by the fact that MDSC comprise multiple myeloid cell types, namely monocytes and granulocytes, reflecting diverse stages of differentiation and the proportion of these subpopulations vary among different neoplastic models. Thus, it is thought that the type and quantities of inflammatory mediators generated during neoplasia dictate the composition of the resultant MDSC response. Although much interest has been devoted to monocytic MDSC biology, a fundamental gap remains in our understanding of the derivation of granulocytic MDSC. In settings of heightened granulocytic MDSC responses, we hypothesized that inappropriate production of G-CSF is a key initiator of granulocytic MDSC accumulation. We observed abundant amounts of G-CSF in vivo, which correlated with robust granulocytic MDSC responses in multiple tumor models. Using G-CSF loss- and gain-of-function approaches, we demonstrated for the first time that: 1) abrogating G-CSF production significantly diminished granulocytic MDSC accumulation and tumor growth; 2) ectopically over-expressing G-CSF in G-CSF-negative tumors significantly augmented granulocytic MDSC accumulation and tumor growth; and 3) treatment of naïve healthy mice with recombinant G-CSF protein elicited granulocytic-like MDSC remarkably similar to those induced under tumor-bearing conditions. Collectively, we demonstrated that tumor-derived G-CSF enhances tumor growth through granulocytic MDSC-dependent mechanisms. These findings provide us with novel insights into MDSC subset development and potentially new biomarkers or targets for cancer therapy. PMID:22110722

  19. Semiparametric Allelic Tests for Mapping Multiple Phenotypes: Binomial Regression and Mahalanobis Distance.

    Science.gov (United States)

    Majumdar, Arunabha; Witte, John S; Ghosh, Saurabh

    2015-12-01

    Binary phenotypes commonly arise due to multiple underlying quantitative precursors and genetic variants may impact multiple traits in a pleiotropic manner. Hence, simultaneously analyzing such correlated traits may be more powerful than analyzing individual traits. Various genotype-level methods, e.g., MultiPhen (O'Reilly et al. []), have been developed to identify genetic factors underlying a multivariate phenotype. For univariate phenotypes, the usefulness and applicability of allele-level tests have been investigated. The test of allele frequency difference among cases and controls is commonly used for mapping case-control association. However, allelic methods for multivariate association mapping have not been studied much. In this article, we explore two allelic tests of multivariate association: one using a Binomial regression model based on inverted regression of genotype on phenotype (Binomial regression-based Association of Multivariate Phenotypes [BAMP]), and the other employing the Mahalanobis distance between two sample means of the multivariate phenotype vector for two alleles at a single-nucleotide polymorphism (Distance-based Association of Multivariate Phenotypes [DAMP]). These methods can incorporate both discrete and continuous phenotypes. Some theoretical properties for BAMP are studied. Using simulations, the power of the methods for detecting multivariate association is compared with the genotype-level test MultiPhen's. The allelic tests yield marginally higher power than MultiPhen for multivariate phenotypes. For one/two binary traits under recessive mode of inheritance, allelic tests are found to be substantially more powerful. All three tests are applied to two different real data and the results offer some support for the simulation study. We propose a hybrid approach for testing multivariate association that implements MultiPhen when Hardy-Weinberg Equilibrium (HWE) is violated and BAMP otherwise, because the allelic approaches assume HWE

  20. Exploiting tumor shrinkage through temporal optimization of radiotherapy

    International Nuclear Information System (INIS)

    Unkelbach, Jan; Craft, David; Hong, Theodore; Papp, Dávid; Wolfgang, John; Bortfeld, Thomas; Ramakrishnan, Jagdish; Salari, Ehsan

    2014-01-01

    In multi-stage radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated mostly by radiobiological considerations, but also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. The paper considers the optimal design of multi-stage treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cell repopulation. The design of multi-stage radiotherapy is formulated as a mathematical optimization problem in which the total dose to the normal tissue is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one-third of the dose should be delivered in the first stage. The projected benefit of multi-stage treatments in terms of normal tissue sparing depends on model assumptions. However, the model predicts large dose reductions by more than a factor of 2 for plausible model parameters. The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at multi-stage radiotherapy for selected disease sites where substantial tumor regression translates into reduced target volumes. (paper)

  1. DD Genotype of ACE I/D Polymorphism Might Confer Protection against Dental Caries in Polish Children.

    Science.gov (United States)

    Olszowski, Tomasz; Adler, Grażyna; Janiszewska-Olszowska, Joanna; Safranow, Krzysztof; Chlubek, Dariusz

    2015-01-01

    The aim of the study was to examine the frequencies of the genotypes and alleles of ACE insertion/deletion (I/D) polymorphism and their association with dental caries in a sample of Polish children. The study subjects were 120 children with dental caries experience (cases) and 41 caries-free individuals (controls). The genotyping was performed using polymerase chain reaction. The genotype distributions of ACE I/D polymorphism were not statistically different between carious and control children. However, we found a borderline overrepresentation of the II + ID genotypes versus the DD genotype in the carious compared to the control group (69.2% and 51.2%, respectively, p = 0.057). Logistic regression analysis adjusted for age and sex revealed that I allele carriage was a significant predictor of dental caries susceptibility (OR = 2.14, 95% CI = 1.02-4.49, p = 0.041). In conclusion, the DD genotype of ACE I/D polymorphism might be protective against dental caries in Polish children. © 2015 S. Karger AG, Basel.

  2. Antitumor action of 3-bromopyruvate implicates reorganized tumor growth regulatory components of tumor milieu, cell cycle arrest and induction of mitochondria-dependent tumor cell death.

    Science.gov (United States)

    Yadav, Saveg; Kujur, Praveen Kumar; Pandey, Shrish Kumar; Goel, Yugal; Maurya, Babu Nandan; Verma, Ashish; Kumar, Ajay; Singh, Rana Pratap; Singh, Sukh Mahendra

    2018-01-15

    Evidences demonstrate that metabolic inhibitor 3-bromopyruvate (3-BP) exerts a potent antitumor action against a wide range of malignancies. However, the effect of 3-BP on progression of the tumors of thymic origin remains unexplored. Although, constituents of tumor microenvironment (TME) plays a pivotal role in regulation of tumor progression, it remains unclear if 3-BP can alter the composition of the crucial tumor growth regulatory components of the external surrounding of tumor cells. Thus, the present investigation attempts to understand the effect of 3-BP administration to a host bearing a progressively growing tumor of thymic origin on tumor growth regulatory soluble, cellular and biophysical components of tumor milieu vis-à-vis understanding its association with tumor progression, accompanying cell cycle events and mode of cell death. Further, the expression of cell survival regulatory molecules and hemodynamic characteristics of the tumor milieu were analysed to decipher mechanisms underlying the antitumor action of 3-BP. Administration of 3-BP to tumor-bearing hosts retarded tumor progression accompanied by induction of tumor cell death, cell cycle arrest, declined metabolism, inhibited mitochondrial membrane potential, elevated release of cytochrome c and altered hemodynamics. Moreover, 3-BP reconstituted the external milieu, in concurrence with deregulated glucose and pH homeostasis and increased tumor infiltration by NK cells, macrophages, and T lymphocytes. Further, 3-BP administration altered the expression of key regulatory molecules involved in glucose uptake, intracellular pH and tumor cell survival. The outcomes of this study will help in optimizing the therapeutic application of 3-BP by targeting crucial tumor growth regulatory components of tumor milieu. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Determination of processing and nutritional quality attributes of potato genotypes in Pakistan

    International Nuclear Information System (INIS)

    Abbas, G.; Hafiz, I.A.; Hussain, A.

    2011-01-01

    The acceptability of potatoes for processing as french fries is largely dependent on the quality of the end products. Processing industry is totally dependent on the quality parameters of tuber to satisfy the increasing demand of customers. Thirty two potato genotypes for processing and yield quality traits were assessed for screening. Significant differences in all the quality parameters and various characteristics were found, while the genotypes; 394021-120, 9625, Kiran, NARC 2002-1, NARC 1-2006/1 and VR 90-217 gave the highest results regarding yield and quality of potato tubers except kiran, which has a high yield but low quality characters. The tuber sizes an d weight was also significantly different among genotypes except weight of big size tubers. Variations existed among genotypes in tuber characteristics (skin color, tuber shape, eye depth, flesh color and general appearance). The results regarding correlation studies indicated that french fry color exhibited negative correlation with reducing sugar (r = -0.7046), total sugars (r = -0.6659) and positive correlation with dry matter (r = 0.5013).This screening is helpful to the ongoing efforts to select the best genotype for the emerging processing industry of Pakistan. (author)

  4. Tumor residual pós-quimioterapia neoadjuvante para câncer de mama: impacto sobre o tratamento cirúrgico conservador Residual tumor after neoadjuvant chemotherapy for breast cancer: impact on conservative surgical treatment

    Directory of Open Access Journals (Sweden)

    Edison Mantovani Barbosa

    1999-05-01

    Full Text Available Objetivo: analisar as alterações histopatológicas provocadas pela ação da quimioterapia neoadjuvante (fluoracil, epirrubicina e ciclofosfamida; FEC -- 4 ciclos na área tumoral, no tecido mamário adjacente e nos linfonodos homolaterais, em peças cirúrgicas obtidas de pacientes portadoras de carcinomas primários da mama. Método: estudo histológico detalhado de 30 peças cirúrgicas obtidas por mastectomia radical (Patey de pacientes portadoras de carcinomas primários da mama, previamente submetidas a esse tipo de terapêutica sistêmica. Resultados: observamos regressão tumoral, de grau variável, em todas as peças analisadas. Esta regressão ocorreu de forma irregular, restando inúmeros focos refratários na área ocupada pelo tumor primário. Observamos focos celulares resistentes independentes do tumor primário no tecido mamário. Detalhamos outros achados histopatológicos decorrentes da ação quimioterápica nos tecidos tumoral e mamário, como calcificações e fibrose, e nos linfonodos axilares homolaterais. Conclusão: concluímos que a ação da quimioterapia neoadjuvante não é uniforme, restando focos tumorais refratários, tanto na área do tumor inicial, quanto à distância. A regressão do tumor independe da resposta de regressão dos linfonodos axilares metastáticos. A utilização da cirurgia conservadora pós-quimioterapia neoadjuvante (FEC deve ser evitada.Purpose: analysis of histopathologic alterations caused by neoadjuvant chemotherapy (fluorouracil, epirubicine, cyclophosphamide; FEC - 4 cycles at the tumor site, adjacent mammary tissue and homolateral lymph nodes, as observed in sections of patients with primary breast carcinomas. Method: histological studies performed on 30 surgical sections obtained from radical mastectomy (Patey of patients with primary breast carcinomas, who underwent prior neoadjuvant systemic therapy. Results: all sections showed tumor regression with variable intensity. This

  5. Merkel Cell Carcinoma with Spontaneous Regression: A Case Report and Immunohistochemical Study

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    Hitoshi Terui

    2016-02-01

    Full Text Available Merkel cell carcinoma (MCC is an aggressive neuroendocrine carcinoma that only rarely regresses spontaneously. Since little is known about the immunological mechanisms involved in the spontaneous regression of MCC, we describe a case of MCC with spontaneous regression and employed immunohistochemical staining for cytotoxic and immunosuppressive molecules to investigate possible mechanisms involved in the spontaneous regression of MCC. Interestingly, compared to conventional MCC, tumor-infiltrating lymphocytes in MCC with spontaneous regression contained higher numbers of CD8+ cells and granulysin-bearing cells and lower numbers of CD206+ cells. Our present study suggests one of the possible reasons for the spontaneous regression of MCC.

  6. Therapeutically targeting cyclin D1 in primary tumors arising from loss of Ini1

    Science.gov (United States)

    Smith, Melissa E.; Cimica, Velasco; Chinni, Srinivasa; Jana, Suman; Koba, Wade; Yang, Zhixia; Fine, Eugene; Zagzag, David; Montagna, Cristina; Kalpana, Ganjam V.

    2011-01-01

    Rhabdoid tumors (RTs) are rare, highly aggressive pediatric malignancies with poor prognosis and with no standard or effective treatment strategies. RTs are characterized by biallelic inactivation of the INI1 tumor suppressor gene. INI1 directly represses CCND1 and activates cyclin-dependent kinase (cdk) inhibitors p16Ink4a and p21CIP. RTs are exquisitely dependent on cyclin D1 for genesis and survival. To facilitate translation of unique therapeutic strategies, we have used genetically engineered, Ini1+/− mice for therapeutic testing. We found that PET can be used to noninvasively and accurately detect primary tumors in Ini1+/− mice. In a PET-guided longitudinal study, we found that treating Ini1+/− mice bearing primary tumors with the pan-cdk inhibitor flavopiridol resulted in complete and stable regression of some tumors. Other tumors showed resistance to flavopiridol, and one of the resistant tumors overexpressed cyclin D1, more than flavopiridol-sensitive cells. The concentration of flavopiridol used was not sufficient to down-modulate the high level of cyclin D1 and failed to induce cell death in the resistant cells. Furthermore, FISH and PCR analyses indicated that there is aneuploidy and increased CCND1 copy number in resistant cells. These studies indicate that resistance to flavopiridol may be correlated to elevated cyclin D1 levels. Our studies also indicate that Ini1+/− mice are valuable tools for testing unique therapeutic strategies and for understanding mechanisms of drug resistance in tumors that arise owing to loss of Ini1, which is essential for developing effective treatment strategies against these aggressive tumors. PMID:21173237

  7. The microbiome modulates the tumor macroenvironment.

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    Erdman, Susan E; Poutahidis, Theofilos

    2014-01-01

    Earlier investigations of the tumor microenvironment unveiled systemic networks presenting novel therapeutic opportunities. It has been recently shown that gut microbes modulate whole host immune and neuroendocrine factors impacting the fate of distant preneoplastic lesions toward malignancy or regression. These findings establish a new paradigm of holobiont therapeutic engineering in emerging tumor macroenvironments.

  8. Active specific immunotherapy using the immune reaction of a low-dose irradiated tumor tissue

    International Nuclear Information System (INIS)

    Ogawa, Y.; Imanaka, K.; Ashida, C.; Takashima, H.; Imajo, Y.; Kimura, S.

    1983-01-01

    Active specific immunotherapy using the immune reaction of a low-dose irradiated tumor tissue was studied on the transplanted MM46 tumor of female C3H/He mice after radiotherapy. MM46 tumor cells were inoculated into the right hind paws of mice. On the 5th day, irradiation with the dose irradiated tumor tissue (2000 rad on the fifth day), were injected into the left hind paws of the tumor-bearing mice. Effectiveness of this active specific immunotherapy against tumor was evaluated by the regression of tumor and survival rate of mice. Tumor was markedly regressed and survival rate was significantly increased by the active specific immunitherapy

  9. Non-Invasive Radiofrequency Field Treatment of 4T1 Breast Tumors Induces T-cell Dependent Inflammatory Response.

    Science.gov (United States)

    Newton, Jared M; Flores-Arredondo, Jose H; Suki, Sarah; Ware, Matthew J; Krzykawska-Serda, Martyna; Agha, Mahdi; Law, Justin J; Sikora, Andrew G; Curley, Steven A; Corr, Stuart J

    2018-02-22

    Previous work using non-invasive radiofrequency field treatment (RFT) in cancer has demonstrated its therapeutic potential as it can increase intratumoral blood perfusion, localization of intravenously delivered drugs, and promote a hyperthermic intratumoral state. Despite the well-known immunologic benefits that febrile hyperthermia can induce, an investigation of how RFT could modulate the intra-tumoral immune microenvironment had not been studied. Thus, using an established 4T1 breast cancer model in immune competent mice, we demonstrate that RFT induces a transient, localized, and T-cell dependent intratumoral inflammatory response. More specifically we show that multi- and singlet-dose RFT promote an increase in tumor volume in immune competent Balb/c mice, which does not occur in athymic nude models. Further leukocyte subset analysis at 24, 48, and 120 hours after a single RFT show a rapid increase in tumoral trafficking of CD4+ and CD8+ T-cells 24 hours post-treatment. Additional serum cytokine analysis reveals an increase in numerous pro-inflammatory cytokines and chemokines associated with enhanced T-cell trafficking. Overall, these data demonstrate that non-invasive RFT could be an effective immunomodulatory strategy in solid tumors, especially for enhancing the tumoral trafficking of lymphocytes, which is currently a major hindrance of numerous cancer immunotherapeutic strategies.

  10. Histoimmunogenetics Markup Language 1.0: Reporting next generation sequencing-based HLA and KIR genotyping.

    Science.gov (United States)

    Milius, Robert P; Heuer, Michael; Valiga, Daniel; Doroschak, Kathryn J; Kennedy, Caleb J; Bolon, Yung-Tsi; Schneider, Joel; Pollack, Jane; Kim, Hwa Ran; Cereb, Nezih; Hollenbach, Jill A; Mack, Steven J; Maiers, Martin

    2015-12-01

    We present an electronic format for exchanging data for HLA and KIR genotyping with extensions for next-generation sequencing (NGS). This format addresses NGS data exchange by refining the Histoimmunogenetics Markup Language (HML) to conform to the proposed Minimum Information for Reporting Immunogenomic NGS Genotyping (MIRING) reporting guidelines (miring.immunogenomics.org). Our refinements of HML include two major additions. First, NGS is supported by new XML structures to capture additional NGS data and metadata required to produce a genotyping result, including analysis-dependent (dynamic) and method-dependent (static) components. A full genotype, consensus sequence, and the surrounding metadata are included directly, while the raw sequence reads and platform documentation are externally referenced. Second, genotype ambiguity is fully represented by integrating Genotype List Strings, which use a hierarchical set of delimiters to represent allele and genotype ambiguity in a complete and accurate fashion. HML also continues to enable the transmission of legacy methods (e.g. site-specific oligonucleotide, sequence-specific priming, and Sequence Based Typing (SBT)), adding features such as allowing multiple group-specific sequencing primers, and fully leveraging techniques that combine multiple methods to obtain a single result, such as SBT integrated with NGS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Variability of traits quinoa introduced genotypes (Chenopodium quinoa Willd.

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    Dražić Slobodan

    2013-01-01

    Full Text Available We analyzed variability and influence of investigated factors on grain yield of quinoa during three year period (2009, 2010, 2011. The experiment was conducted at two locations (Nova Pazova and Surduk, using two introduced genotypes of quinoa: KVL 37 and KVL 52. We detected that location and genotype had important impact. Grain yield varied according to years of study (1224 kg/ha to 1671 kg/ha. Results of regression and correlation analysis indicate on variation of the impact of plant height and number of plants per meter on the grain yield. Correlation coefficients were generally low and didn't show as significant. This indicates that these studies included small number of properties that can affect grain yield. In further work with this introduced species, more properties should be included.

  12. Parental smoking and risk of childhood brain tumors by functional polymorphisms in polycyclic aromatic hydrocarbon metabolism genes.

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    Jessica L Barrington-Trimis

    Full Text Available BACKGROUND: A recent meta-analysis suggested an association between exposure to paternal smoking during pregnancy and childhood brain tumor risk, but no studies have evaluated whether this association differs by polymorphisms in genes that metabolize tobacco-smoke chemicals. METHODS: We assessed 9 functional polymorphisms in 6 genes that affect the metabolism of polycyclic aromatic hydrocarbons (PAH to evaluate potential interactions with parental smoking during pregnancy in a population-based case-control study of childhood brain tumors. Cases (N = 202 were ≤10 years old, diagnosed from 1984-1991 and identified in three Surveillance, Epidemiology, and End Results (SEER registries in the western U.S. Controls in the same regions (N = 286 were frequency matched by age, sex, and study center. DNA for genotyping was obtained from archived newborn dried blood spots. RESULTS: We found positive interaction odds ratios (ORs for both maternal and paternal smoking during pregnancy, EPHX1 H139R, and childhood brain tumors (P(interaction = 0.02; 0.10, such that children with the high-risk (greater PAH activation genotype were at a higher risk of brain tumors relative to children with the low-risk genotype when exposed to tobacco smoke during pregnancy. A dose-response pattern for paternal smoking was observed among children with the EPHX1 H139R high-risk genotype only (OR(no exposure = 1.0; OR(≤3 hours/day = 1.32, 95% CI: 0.52-3.34; OR(>3 hours/day = 3.18, 95% CI: 0.92-11.0; P(trend = 0.07. CONCLUSION: Parental smoking during pregnancy may be a risk factor for childhood brain tumors among genetically susceptible children who more rapidly activate PAH in tobacco smoke.

  13. Metastatic Breast Cancer With ESR1 Mutation: Clinical Management Considerations From the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital.

    Science.gov (United States)

    Bardia, Aditya; Iafrate, John A; Sundaresan, Tilak; Younger, Jerry; Nardi, Valentina

    2016-09-01

    : The last decade in oncology has witnessed impressive response rates with targeted therapies, largely because of collaborative efforts at understanding tumor biology and careful patient selection based on molecular fingerprinting of the tumor. Consequently, there has been a push toward routine molecular genotyping of tumors, and large precision medicine-based clinical trials have been launched to match therapy to the molecular alteration seen in a tumor. However, selecting the "right drug" for an individual patient in clinic is a complex decision-making process, including analytical interpretation of the report, consideration of the importance of the molecular alteration in driving growth of the tumor, tumor heterogeneity, the availability of a matched targeted therapy, efficacy and toxicity considerations of the targeted therapy (compared with standard therapy), and reimbursement issues. In this article, we review the key considerations involved in clinical decision making while reviewing a molecular genotyping report. We present the case of a 67-year-old postmenopausal female with metastatic estrogen receptor-positive (ER+) breast cancer, whose tumor progressed on multiple endocrine therapies. Molecular genotyping of the metastatic lesion revealed the presence of an ESR1 mutation (encoding p.Tyr537Asn), which was absent in the primary tumor. The same ESR1 mutation was also detected in circulating tumor DNA (ctDNA) extracted from her blood. The general approach for interpretation of genotyping results, the clinical significance of the specific mutation in the particular cancer, potential strategies to target the pathway, and implications for clinical practice are reviewed in this article. ER+ breast tumors are known to undergo genomic evolution during treatment with the acquisition of new mutations that confer resistance to treatment.ESR1 mutations in the ligand-binding domain of ER can lead to a ligand-independent, constitutively active form of ER and mediate

  14. Selector genes display tumor cooperation and inhibition in Drosophila epithelium in a developmental context-dependent manner

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    Ram Prakash Gupta

    2017-11-01

    Full Text Available During animal development, selector genes determine identities of body segments and those of individual organs. Selector genes are also misexpressed in cancers, although their contributions to tumor progression per se remain poorly understood. Using a model of cooperative tumorigenesis, we show that gain of selector genes results in tumor cooperation, but in only select developmental domains of the wing, haltere and eye-antennal imaginal discs of Drosophila larva. Thus, the field selector, Eyeless (Ey, and the segment selector, Ultrabithorax (Ubx, readily cooperate to bring about neoplastic transformation of cells displaying somatic loss of the tumor suppressor, Lgl, but in only those developmental domains that express the homeo-box protein, Homothorax (Hth, and/or the Zinc-finger protein, Teashirt (Tsh. In non-Hth/Tsh-expressing domains of these imaginal discs, however, gain of Ey in lgl− somatic clones induces neoplastic transformation in the distal wing disc and haltere, but not in the eye imaginal disc. Likewise, gain of Ubx in lgl− somatic clones induces transformation in the eye imaginal disc but not in its endogenous domain, namely, the haltere imaginal disc. Our results reveal that selector genes could behave as tumor drivers or inhibitors depending on the tissue contexts of their gains.

  15. Direct visualization of electroporation-assisted in vivo gene delivery to tumors using intravital microscopy – spatial and time dependent distribution

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    Dachs Gabi U

    2004-11-01

    Full Text Available Abstract Background Electroporation is currently receiving much attention as a way to increase drug and DNA delivery. Recent studies demonstrated the feasibility of electrogene therapy using a range of therapeutic genes for the treatment of experimental tumors. However, the transfection efficiency of electroporation-assisted DNA delivery is still low compared to viral methods and there is a clear need to optimize this approach. In order to optimize treatment, knowledge about spatial and time dependency of gene expression following delivery is of utmost importance in order to improve gene delivery. Intravital microscopy of tumors growing in dorsal skin fold window chambers is a useful method for monitoring gene transfection, since it allows non-invasive dynamic monitoring of gene expression in tumors in a live animal. Methods Intravital microscopy was used to monitor real time spatial distribution of the green fluorescent protein (GFP and time dependence of transfection efficiency in syngeneic P22 rat tumor model. DNA alone, liposome-DNA complexes and electroporation-assisted DNA delivery using two different sets of electric pulse parameters were compared. Results Electroporation-assisted DNA delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz was superior to other methods and resulted in 22% increase in fluorescence intensity in the tumors up to 6 days post-transfection, compared to the non-transfected area in granulation tissue. Functional GFP was detected within 5 h after transfection. Cells expressing GFP were detected throughout the tumor, but not in the surrounding tissue that was not exposed to electric pulses. Conclusions Intravital microscopy was demonstrated to be a suitable method for monitoring time and spatial distribution of gene expression in experimental tumors and provided evidence that electroporation-assisted gene delivery using 8 pulses, 600 V/cm, 5 ms, 1 Hz is an effective method, resulting in early onset and homogenous

  16. Logistic regression applied to natural hazards: rare event logistic regression with replications

    Science.gov (United States)

    Guns, M.; Vanacker, V.

    2012-06-01

    Statistical analysis of natural hazards needs particular attention, as most of these phenomena are rare events. This study shows that the ordinary rare event logistic regression, as it is now commonly used in geomorphologic studies, does not always lead to a robust detection of controlling factors, as the results can be strongly sample-dependent. In this paper, we introduce some concepts of Monte Carlo simulations in rare event logistic regression. This technique, so-called rare event logistic regression with replications, combines the strength of probabilistic and statistical methods, and allows overcoming some of the limitations of previous developments through robust variable selection. This technique was here developed for the analyses of landslide controlling factors, but the concept is widely applicable for statistical analyses of natural hazards.

  17. Influence of maternal and own genotype at tanning dependence-related SNPs on sun exposure in childhood.

    Science.gov (United States)

    Khouja, Jasmine; Lewis, Sarah J; Bonilla, Carolina

    2018-04-12

    Research suggests there may be a genetic influence on the likelihood of becoming tanning dependent (TD). The way in which mothers regulate their children's sun exposure may be affected by being TD. We investigated the associations between single nucleotide polymorphisms (SNPs) related to being TD and early sun exposure. Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used. Associations between 17 TD related SNPs in children and their mothers and 10 sun exposure variables in children (assessed via questionnaire at age 8) were analyzed in logistic and ordinal logistic regressions. Analyses were adjusted for principal components of population structure and age (at time of questionnaire response). Models with additional adjustment for maternal or offspring genotypes were also tested. Secondary analyses included adjustment for sex and skin pigmentation. Among ALSPAC children, the rs29132 SNP in the Vesicle-associated membrane protein-associated protein A (VAPA) gene was associated with five sun exposure variables whilst the rs650662 SNP in the Opioid Receptor Mu 1 (OPRM1) gene was associated with three. The remaining SNPs did not show associations beyond what was expected by chance. After Bonferroni correction one SNP in the children was associated with an increased likelihood of using sun cream whilst in the sun at 8 years old (rs60050811 in the Spermatogenesis and Centriole Associated 1 (SPATC1) gene, OR per C allele = 1.34, 95% CI 1.11-1.62, p = .003). In the mothers, rs650662 in OPRM1 was associated with the use of a lower factor of sun cream in their children, (OR per A allele = 0.89, 95% CI 0.82-0.96, p = .002). Whilst rs2073478 in the Aldehyde Dehydrogenase 1 Family Member B1 (ALDH1B1) gene was associated with a reduced odds of their child using a sun block or cream with a 4 star rating (OR per T allele = 0.68, 95% CI 0.53-0.88, p = .003). Similar but weaker associations were observed for the main findings in

  18. Should metacognition be measured by logistic regression?

    Science.gov (United States)

    Rausch, Manuel; Zehetleitner, Michael

    2017-03-01

    Are logistic regression slopes suitable to quantify metacognitive sensitivity, i.e. the efficiency with which subjective reports differentiate between correct and incorrect task responses? We analytically show that logistic regression slopes are independent from rating criteria in one specific model of metacognition, which assumes (i) that rating decisions are based on sensory evidence generated independently of the sensory evidence used for primary task responses and (ii) that the distributions of evidence are logistic. Given a hierarchical model of metacognition, logistic regression slopes depend on rating criteria. According to all considered models, regression slopes depend on the primary task criterion. A reanalysis of previous data revealed that massive numbers of trials are required to distinguish between hierarchical and independent models with tolerable accuracy. It is argued that researchers who wish to use logistic regression as measure of metacognitive sensitivity need to control the primary task criterion and rating criteria. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Identifying Interacting Genetic Variations by Fish-Swarm Logic Regression

    Science.gov (United States)

    Yang, Aiyuan; Yan, Chunxia; Zhu, Feng; Zhao, Zhongmeng; Cao, Zhi

    2013-01-01

    Understanding associations between genotypes and complex traits is a fundamental problem in human genetics. A major open problem in mapping phenotypes is that of identifying a set of interacting genetic variants, which might contribute to complex traits. Logic regression (LR) is a powerful multivariant association tool. Several LR-based approaches have been successfully applied to different datasets. However, these approaches are not adequate with regard to accuracy and efficiency. In this paper, we propose a new LR-based approach, called fish-swarm logic regression (FSLR), which improves the logic regression process by incorporating swarm optimization. In our approach, a school of fish agents are conducted in parallel. Each fish agent holds a regression model, while the school searches for better models through various preset behaviors. A swarm algorithm improves the accuracy and the efficiency by speeding up the convergence and preventing it from dropping into local optimums. We apply our approach on a real screening dataset and a series of simulation scenarios. Compared to three existing LR-based approaches, our approach outperforms them by having lower type I and type II error rates, being able to identify more preset causal sites, and performing at faster speeds. PMID:23984382

  20. Identifying Interacting Genetic Variations by Fish-Swarm Logic Regression

    Directory of Open Access Journals (Sweden)

    Xuanping Zhang

    2013-01-01

    Full Text Available Understanding associations between genotypes and complex traits is a fundamental problem in human genetics. A major open problem in mapping phenotypes is that of identifying a set of interacting genetic variants, which might contribute to complex traits. Logic regression (LR is a powerful multivariant association tool. Several LR-based approaches have been successfully applied to different datasets. However, these approaches are not adequate with regard to accuracy and efficiency. In this paper, we propose a new LR-based approach, called fish-swarm logic regression (FSLR, which improves the logic regression process by incorporating swarm optimization. In our approach, a school of fish agents are conducted in parallel. Each fish agent holds a regression model, while the school searches for better models through various preset behaviors. A swarm algorithm improves the accuracy and the efficiency by speeding up the convergence and preventing it from dropping into local optimums. We apply our approach on a real screening dataset and a series of simulation scenarios. Compared to three existing LR-based approaches, our approach outperforms them by having lower type I and type II error rates, being able to identify more preset causal sites, and performing at faster speeds.

  1. The Gene Polymorphism of the Angiotensin I-Converting Enzyme Correlates with Tumor Size and Patient Survival in Colorectal Cancer Patients

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    Christoph Röcken

    2007-09-01

    Full Text Available We studied the putative significance of angiotensin I-converting enzyme (ACE in colorectal cancer (CRC biology. Local expression of ACE was investigated by quantitative reverse transcription- polymerase chain reaction and by immunohistochemistry in CRCs and adenomas. ACE insertion (I/deletion (D polymorphism was studied in 141 CRC patients and 189 controls. ACE mRNA was upregulated in CRCs compared to corresponding nonlesional tissues (2.5-fold; P = .009. ACE protein was more commonly expressed in adenomas [17 (81 %] and cancer epithelial cells [22 (100%] than in corresponding non-neoplastic crypt and surface epithelium [2 (10% and 2 (9%, respectively]. Thirty-seven CRC patients (26% carried II genotype, 69 (49% carried ID genotype, 35 (25% carried DD genotype. The distribution of the genotypes did not differ from that of controls. Female CRC patients more commonly carried the ID genotype and less frequently the II and DD genotypes compared with male patients (P = .033. Men heterozygous or homozygous for the D-allele had larger tumors compared to carriers of the II genotype (P < .01. Women homozygous for the D-allele lived longer than carriers of the ID and II genotypes. Our study shows that ACE is differentially expressed in CRCs and that gene polymorphism is associated with gender-specific differences in primary tumor size and patient survival.

  2. Assessment of diagnostic value of various tumors markers (CEA, CA199, CA50) for colorectal neoplasm with logistic regression and ROC curve

    International Nuclear Information System (INIS)

    Gu Ping; Huang Gang; Han Yuan

    2007-01-01

    Objective: To assess the diagnostic value of CEA, CA199 and CA50 for colorectal neoplasm by logistic regression and ROC curve. Methods: Serum CEA (with CLIA), CA199 (with ECLIA) and CA50 (with IRMA) levels were measured in 75 patients with colorectal cancer, 35 patients with benign colorectal disorders and 49 controls. The area under the ROC curve (AUC)s of CEA, CA199, CA50 from logistic regression results were compared. Results: In the cancer-benign disorder group, the AUC of CA50 was larger than the AUC of CA199. AUC of combined CEA, CA50 was largest: not only larger than any AUC of CEA, CA50, CA199 alone but also larger than the AUC of the combined three markers (0.875 vs 0.604). In cancer-control group, the AUC of combination of CEA, CA199 and CA50 was larger than any AUC of CEA, CA199 or CA50 alone. Both in the cancer-benign disorder group or cancer-control group, the AUC of CEA was larger than the AUC of CA199 or CA50. Conclusion: CEA is of definite value in the diagnosis of colorectal cancer. For differential diagnosis, the combination of CEA and CA50 can give more information, while the combination of three tumor markers is less helpful. As an advanced statistical method, logistic regression can improve the diagnostic sensitivity and specificity. (authors)

  3. Therapeutic effects and adverse drug reactions are affected by icotinib exposure and CYP2C19 and EGFR genotypes in Chinese non-small cell lung cancer patients.

    Science.gov (United States)

    Chen, Jia; Zheng, Xin; Liu, Dong-Yang; Zhao, Qian; Wu, Yi-Wen; Tan, Fen-Lai; Wang, Yin-Xiang; Jiang, Ji; Hu, Pei

    2014-01-01

    The aim of this study was to evaluate how CYP2C19 affects icotinib and metabolite' exposure, and to determine whether the exposure and EGFR genotype influences survival time, tumor metastasis and adverse drug reactions. 274 NSCLC patients who accepted 125 mg icotinib/t.i.d. were chosen from a phase III study. Blood samples were obtained in 672 nd (4th week) and 1,680 th hours (10th week), and plasma was used to quantify the concentration of icotinib and blood cells were sampled to check the genotypes. Clinical data were also collected at the same time, including EGFR genotypes. Plasma concentrations were assessed by HPLC-MS/MS and genotype by sequencing. All data were analyzed through SPSS 17.0 and SAS 9.2. CYP 2C19 genotypes affected bio-transformation from icotinib to M24 and M26, especially in poor-metabolisers. Higher icotinib concentrations (>1000 ng/mL) not only increased patient PFS and OS but also reduced tumor metastasis. Patients with mutant EGFR experienced a higher median PFS and OS (234 and 627 days), especially those with the 19del genotype demonstrating higher PR ratio. Patients who suffered grade II skin toxicity had a higher icotinib exposure than those with grade I skin toxicity or no adverse effects. Liver toxic reactions might occur in patients with greater M20 and M23 plasma concentrations. CYP2C19 polymorphisms significantly affect icotinib, M24 and M26 exposure. Patients with mutant EGFR genotype and higher icotinib concentration might have increased PFS and OS and lower tumor metastasis. Liver ADR events and serious skin effects might be respectively induced by greater M20, M23 and icotinib concentrations.

  4. Gross tumor volume dependency on phase sorting methods of four-dimensional computed tomography images for lung cancer

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    Lee, Soo Yong; Lim, Sang Wook; Ma, Sun Young; Yu, Je Sang [Dept. of Radiation Oncology, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan (Korea, Republic of)

    2017-09-15

    To see the gross tumor volume (GTV) dependency according to the phase selection and reconstruction methods, we measured and analyzed the changes of tumor volume and motion at each phase in 20 cases with lung cancer patients who underwent image-guided radiotherapy. We retrospectively analyzed four-dimensional computed tomography (4D-CT) images in 20 cases of 19 patients who underwent image-guided radiotherapy. The 4D-CT images were reconstructed by the maximum intensity projection (MIP) and the minimum intensity projection (Min-IP) method after sorting phase as 40%–60%, 30%–70%, and 0%–90%. We analyzed the relationship between the range of motion and the change of GTV according to the reconstruction method. The motion ranges of GTVs are statistically significant only for the tumor motion in craniocaudal direction. The discrepancies of GTV volume and motion between MIP and Min-IP increased rapidly as the wider ranges of duty cycles are selected. As narrow as possible duty cycle such as 40%–60% and MIP reconstruction was suitable for lung cancer if the respiration was stable. Selecting the reconstruction methods and duty cycle is important for small size and for large motion range tumors.

  5. Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer.

    Science.gov (United States)

    Osipo, Clodia; Gajdos, Csaba; Liu, Hong; Chen, Bin; Jordan, V Craig

    2003-11-05

    Long-term tamoxifen treatment of breast cancer can result in tamoxifen-stimulated breast cancer, in which estrogen inhibits tumor growth after tamoxifen withdrawal. We investigated the molecular mechanism(s) of estradiol-induced tumor regression by using an in vivo model of tamoxifen-stimulated human breast cancer. Growth of parental estradiol-stimulated MCF-7E2 and long-term tamoxifen-stimulated MCF-7TAMLT xenografts in athymic mice was measured during treatment with vehicle, estradiol, estradiol plus tamoxifen, tamoxifen alone, estradiol plus fulvestrant, or fulvestrant alone. Apoptosis was detected by the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Protein expression was assessed by western blot analysis. mRNA expression was assessed by real-time reverse transcription-polymerase chain reaction. All statistical tests were two-sided. MCF-7E2 tumor growth was stimulated by estradiol (cross-sectional area at week 13 = 1.06 cm2, 95% confidence interval [CI] = 0.82 to 1.30 cm2; Pestradiol-induced regression to 0.18 cm2 (95% CI = 0.15 to 0.21 cm2; P<.001), and tamoxifen or estradiol plus fulvestrant enhanced tumor growth to 1.00 cm2 (95% CI = 0.88 to 1.22 cm2). Estradiol increased the number of apoptotic cells in tumors by 23% (95% CI = 20% to 26%; P<.001) compared with all other treatments, decreased estrogen receptor alpha(ERalpha) protein expression, increased the expression of Fas mRNA and protein, decreased the expression of HER2/neu mRNA and protein and nuclear factor kappaB (NF-kappaB) protein but did not affect Fas ligand protein expression compared with control. Paradoxically, fulvestrant reversed this effect and stimulated MCF-7TAMLT tumor growth apparently through ERalpha-mediated regulation of Fas, HER2/neu, and NF-kappaB. Physiologic levels of estradiol induced regression of tamoxifen-stimulated breast cancer tumors, apparently by inducing the death receptor Fas and suppressing the antiapoptotic

  6. A combination of p53-activating APR-246 and phosphatidylserine-targeting antibody potently inhibits tumor development in hormone-dependent mutant p53-expressing breast cancer xenografts

    Directory of Open Access Journals (Sweden)

    Liang Y

    2018-03-01

    Full Text Available Yayun Liang,1 Benford Mafuvadze,1 Cynthia Besch-Williford,2 Salman M Hyder1 1Deparment of Biomedical Sciences and Dalton Cardiovascular Research Center, Columbia, MO, USA; 2IDEXX BioResearch, Columbia, MO, USA Background: Between 30 and 40% of human breast cancers express a defective tumor suppressor p53 gene. Wild-type p53 tumor suppressor protein promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor–dependent angiogenesis, whereas mutant p53 protein (mtp53 lacks these functions, resulting in tumor cell survival and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for combating mtp53-expressing breast cancer. Methods: In this study, we sought to determine whether administration of APR-246, a small-molecule drug that restores p53 function, in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits advanced hormone-dependent breast cancer tumor growth. Results: APR-246 reduced cell viability in mtp53-expressing BT-474 and T47-D human breast cancer cells in vitro, and significantly induced apoptosis in a dose-dependent manner. However, APR-246 did not reduce cell viability in MCF-7 breast cancer cells, which express wild-type p53. We next examined APR-246’s anti-tumor effects in vivo using BT-474 and T47-D tumor xenografts established in female nude mice. Tumor-bearing mice were treated with APR-246 and/or 2aG4 and tumor volume followed over time. Tumor growth was more effectively suppressed by combination treatment than by either agent alone, and combination therapy completely eradicated some tumors. Immunohistochemistry analysis of tumor tissue sections demonstrated that combination therapy more effectively induced apoptosis and reduced cell proliferation in tumor xenografts than either agent alone. Importantly, combination therapy dramatically reduced the density of blood

  7. Ascorbate availability affects tumor implantation-take rate and increases tumor rejection in Gulo–/– mice

    Directory of Open Access Journals (Sweden)

    Campbell EJ

    2016-04-01

    Full Text Available Elizabeth J Campbell,1 Margreet CM Vissers,2 Gabi U Dachs1 1Mackenzie Cancer Research Group, 2Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand Abstract: In solid tumors, HIF1 upregulates the expression of hundreds of genes involved in cell survival, tumor growth, and adaptation to the hypoxic microenvironment. HIF1 stabilization and activity are suppressed by prolyl and asparagine hydroxylases, which require oxygen as a substrate and ascorbate as a cofactor. This has led us to hypothesize that intracellular ascorbate availability could modify the hypoxic HIF1 response and influence tumor growth. In this study, we investigated the effect of variable intracellular ascorbate levels on HIF1 induction in cancer cells in vitro, and on tumor-take rate and growth in the Gulo–/– mouse. These mice depend on dietary ascorbate, and were supplemented with 3,300 mg/L, 330 mg/L, or 33 mg/L ascorbate in their drinking water, resulting in saturating, medium, or low plasma and tissue ascorbate levels, respectively. In Lewis lung carcinoma cells (LL/2 in culture, optimal ascorbate supplementation reduced HIF1 accumulation under physiological but not pathological hypoxia. LL/2, B16-F10 melanoma, or CMT-93 colorectal cancer cells were implanted subcutaneously into Gulo–/– mice at a range of cell inocula. Establishment of B16-F10 tumors in mice supplemented with 3,300 mg/L ascorbate required an increased number of cancer cells to initiate tumor growth compared with the number of cells required in mice on suboptimal ascorbate intake. Elevated ascorbate intake was also associated with decreased tumor ascorbate levels and a reduction in HIF1α expression and transcriptional activity. Following initial growth, all CMT-93 tumors regressed spontaneously, but mice supplemented with 33 mg/L ascorbate had lower plasma ascorbate levels and grew larger tumors than optimally supplemented mice. The data from this

  8. Genotype-dependent Burst of Transposable Element Expression in Crowns of Hexaploid Wheat (Triticum aestivum L. during Cold Acclimation

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    Debbie Laudencia-Chingcuanco

    2012-01-01

    Full Text Available The expression of 1,613 transposable elements (TEs represented in the Affymetrix Wheat Genome Chip was examined during cold treatment in crowns of four hexaploid wheat genotypes that vary in tolerance to cold and in flowering time. The TE expression profiles showed a constant level of expression throughout the experiment in three of the genotypes. In winter Norstar, the most cold-hardy of the four genotypes, a subset of the TEs showed a burst of expression after vernalization saturation was achieved. About 47% of the TEs were expressed, and both Class I (retrotransposons and Class II (DNA transposons types were well represented. Gypsy and Copia were the most represented among the retrotransposons while CACTA and Mariner were the most represented DNA transposons. The data suggests that the Vrn-A1 region plays a role in the stage-specific induction of TE expression in this genotype.

  9. Parameters Estimation of Geographically Weighted Ordinal Logistic Regression (GWOLR) Model

    Science.gov (United States)

    Zuhdi, Shaifudin; Retno Sari Saputro, Dewi; Widyaningsih, Purnami

    2017-06-01

    A regression model is the representation of relationship between independent variable and dependent variable. The dependent variable has categories used in the logistic regression model to calculate odds on. The logistic regression model for dependent variable has levels in the logistics regression model is ordinal. GWOLR model is an ordinal logistic regression model influenced the geographical location of the observation site. Parameters estimation in the model needed to determine the value of a population based on sample. The purpose of this research is to parameters estimation of GWOLR model using R software. Parameter estimation uses the data amount of dengue fever patients in Semarang City. Observation units used are 144 villages in Semarang City. The results of research get GWOLR model locally for each village and to know probability of number dengue fever patient categories.

  10. Outcome and histopathologic regression in oral squamous cell carcinoma after preoperative radiochemotherapy

    International Nuclear Information System (INIS)

    Driemel, Oliver; Ettl, Tobias; Reichert, Torsten E.; Koelbl, Oliver; Dresp, Bernd V.; Reuther, Juergen; Pistner, Hans

    2009-01-01

    Background and purpose: preoperative radiochemotherapy has been reported to enhance tumor response and to improve long-term survival in advanced squamous cell carcinoma of the head and neck. This retrospective study evaluates regression rate and long-term survival in 228 patients with primary oral squamous cell carcinoma treated by neoadjuvant radiochemotherapy and radical surgery. Patients and methods: all patients with biopsy-proven, resectable oral squamous cell carcinoma - TNM stages II-IV without distant metastasis - received preoperative treatment consisting of fractioned irradiation of the primary and the regional lymph nodes with a total dose of 40 Gy and additional cisplatin (n = 160) or carboplatin (n = 68) during the 1st week of treatment. Radical surgery and neck dissection followed after a delay of 10-14 days. The study only included cases with histologically negative resection margins. Results: after a median follow-up of 5.2 years, 53 patients (23.2%) had experienced local-regional recurrence. The median 2-year disease-specific survival (DSS) rate was 86.2%. 5-year DSS and 10-year DSS were 76.3% and 66.7%, respectively. Complete histological local tumor regression after surgery (ypTO) was observed in 50 patients (21.9%) and was independent of pretreatment tumor classification. Uni- and multivariate survival analysis revealed that ypT- and ypN-stage were the most decisive predictors for DSS. Conclusion: preoperative radiochemotherapy with cisplatin/carboplatin followed by radical surgery attains favorable long-term survival rates. This applies especially to cases with complete histological tumor regression after radiochemotherapy, which can be assumed for one of five patients. (orig.)

  11. Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes.

    Science.gov (United States)

    Markowitz, Geoffrey J; Yang, Pengyuan; Fu, Jing; Michelotti, Gregory A; Chen, Rui; Sui, Jianhua; Yang, Bin; Qin, Wen-Hao; Zhang, Zheng; Wang, Fu-Sheng; Diehl, Anna Mae; Li, Qi-Jing; Wang, Hongyang; Wang, Xiao-Fan

    2016-04-15

    Chronic inflammation in liver tissue is an underlying cause of hepatocellular carcinoma. High levels of inflammatory cytokine IL18 in the circulation of patients with hepatocellular carcinoma correlates with poor prognosis. However, conflicting results have been reported for IL18 in hepatocellular carcinoma development and progression. In this study, we used tissue specimens from hepatocellular carcinoma patients and clinically relevant mouse models of hepatocellular carcinoma to evaluate IL18 expression and function. In a mouse model of liver fibrosis that recapitulates a tumor-promoting microenvironment, global deletion of the IL18 receptor IL18R1 enhanced tumor growth and burden. Similarly, in a carcinogen-induced model of liver tumorigenesis, IL18R1 deletion increased tumor burden. Mechanistically, we found that IL18 exerted inflammation-dependent tumor-suppressive effects largely by promoting the differentiation, activity, and survival of tumor-infiltrating T cells. Finally, differences in the expression of IL18 in tumor tissue versus nontumor tissue were more predictive of patient outcome than overall tissue expression. Taken together, our findings resolve a long-standing contradiction regarding a tumor-suppressive role for IL18 in established hepatocellular carcinoma and provide a mechanistic explanation for the complex relationship between its expression pattern and hepatocellular carcinoma prognosis. Cancer Res; 76(8); 2394-405. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. Rapid targeted somatic mutation analysis of solid tumors in routine clinical diagnostics.

    Science.gov (United States)

    Magliacane, Gilda; Grassini, Greta; Bartocci, Paola; Francaviglia, Ilaria; Dal Cin, Elena; Barbieri, Gianluca; Arrigoni, Gianluigi; Pecciarini, Lorenza; Doglioni, Claudio; Cangi, Maria Giulia

    2015-10-13

    Tumor genotyping is an essential step in routine clinical practice and pathology laboratories face a major challenge in being able to provide rapid, sensitive and updated molecular tests. We developed a novel mass spectrometry multiplexed genotyping platform named PentaPanel to concurrently assess single nucleotide polymorphisms in 56 hotspots of the 5 most clinically relevant cancer genes, KRAS, NRAS, BRAF, EGFR and PIK3CA for a total of 221 detectable mutations. To both evaluate and validate the PentaPanel performance, we investigated 1025 tumor specimens of 6 different cancer types (carcinomas of colon, lung, breast, pancreas, and biliary tract, and melanomas), systematically addressing sensitivity, specificity, and reproducibility of our platform. Sanger sequencing was also performed for all the study samples. Our data showed that PentaPanel is a high throughput and robust tool, allowing genotyping for targeted therapy selection of 10 patients in the same run, with a practical turnaround time of 2 working days. Importantly, it was successfully used to interrogate different DNAs isolated from routinely processed specimens (formalin-fixed paraffin embedded, frozen, and cytological samples), covering all the requirements of clinical tests. In conclusion, the PentaPanel platform can provide an immediate, accurate and cost effective multiplex approach for clinically relevant gene mutation analysis in many solid tumors and its utility across many diseases can be particularly relevant in multiple clinical trials, including the new basket trial approach, aiming to identify appropriate targeted drug combination strategies.

  13. Logistic regression applied to natural hazards: rare event logistic regression with replications

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    M. Guns

    2012-06-01

    Full Text Available Statistical analysis of natural hazards needs particular attention, as most of these phenomena are rare events. This study shows that the ordinary rare event logistic regression, as it is now commonly used in geomorphologic studies, does not always lead to a robust detection of controlling factors, as the results can be strongly sample-dependent. In this paper, we introduce some concepts of Monte Carlo simulations in rare event logistic regression. This technique, so-called rare event logistic regression with replications, combines the strength of probabilistic and statistical methods, and allows overcoming some of the limitations of previous developments through robust variable selection. This technique was here developed for the analyses of landslide controlling factors, but the concept is widely applicable for statistical analyses of natural hazards.

  14. Evaluating Imputation Algorithms for Low-Depth Genotyping-By-Sequencing (GBS Data.

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    Ariel W Chan

    Full Text Available Well-powered genomic studies require genome-wide marker coverage across many individuals. For non-model species with few genomic resources, high-throughput sequencing (HTS methods, such as Genotyping-By-Sequencing (GBS, offer an inexpensive alternative to array-based genotyping. Although affordable, datasets derived from HTS methods suffer from sequencing error, alignment errors, and missing data, all of which introduce noise and uncertainty to variant discovery and genotype calling. Under such circumstances, meaningful analysis of the data is difficult. Our primary interest lies in the issue of how one can accurately infer or impute missing genotypes in HTS-derived datasets. Many of the existing genotype imputation algorithms and software packages were primarily developed by and optimized for the human genetics community, a field where a complete and accurate reference genome has been constructed and SNP arrays have, in large part, been the common genotyping platform. We set out to answer two questions: 1 can we use existing imputation methods developed by the human genetics community to impute missing genotypes in datasets derived from non-human species and 2 are these methods, which were developed and optimized to impute ascertained variants, amenable for imputation of missing genotypes at HTS-derived variants? We selected Beagle v.4, a widely used algorithm within the human genetics community with reportedly high accuracy, to serve as our imputation contender. We performed a series of cross-validation experiments, using GBS data collected from the species Manihot esculenta by the Next Generation (NEXTGEN Cassava Breeding Project. NEXTGEN currently imputes missing genotypes in their datasets using a LASSO-penalized, linear regression method (denoted 'glmnet'. We selected glmnet to serve as a benchmark imputation method for this reason. We obtained estimates of imputation accuracy by masking a subset of observed genotypes, imputing, and

  15. Evaluating Imputation Algorithms for Low-Depth Genotyping-By-Sequencing (GBS) Data.

    Science.gov (United States)

    Chan, Ariel W; Hamblin, Martha T; Jannink, Jean-Luc

    2016-01-01

    Well-powered genomic studies require genome-wide marker coverage across many individuals. For non-model species with few genomic resources, high-throughput sequencing (HTS) methods, such as Genotyping-By-Sequencing (GBS), offer an inexpensive alternative to array-based genotyping. Although affordable, datasets derived from HTS methods suffer from sequencing error, alignment errors, and missing data, all of which introduce noise and uncertainty to variant discovery and genotype calling. Under such circumstances, meaningful analysis of the data is difficult. Our primary interest lies in the issue of how one can accurately infer or impute missing genotypes in HTS-derived datasets. Many of the existing genotype imputation algorithms and software packages were primarily developed by and optimized for the human genetics community, a field where a complete and accurate reference genome has been constructed and SNP arrays have, in large part, been the common genotyping platform. We set out to answer two questions: 1) can we use existing imputation methods developed by the human genetics community to impute missing genotypes in datasets derived from non-human species and 2) are these methods, which were developed and optimized to impute ascertained variants, amenable for imputation of missing genotypes at HTS-derived variants? We selected Beagle v.4, a widely used algorithm within the human genetics community with reportedly high accuracy, to serve as our imputation contender. We performed a series of cross-validation experiments, using GBS data collected from the species Manihot esculenta by the Next Generation (NEXTGEN) Cassava Breeding Project. NEXTGEN currently imputes missing genotypes in their datasets using a LASSO-penalized, linear regression method (denoted 'glmnet'). We selected glmnet to serve as a benchmark imputation method for this reason. We obtained estimates of imputation accuracy by masking a subset of observed genotypes, imputing, and calculating the

  16. Calculating the tumor volume of acoustic neuromas: comparison of ABC/2 formula with planimetry method.

    Science.gov (United States)

    Yu, Yi-Lin; Lee, Meei-Shyuan; Juan, Chun-Jung; Hueng, Dueng-Yuan

    2013-08-01

    The ABC/2 equation is commonly applied to measure the volume of intracranial hematoma. However, the precision of ABC/2 equation in estimating the tumor volume of acoustic neuromas is less addressed. The study is to evaluate the accuracy of the ABC/2 formula by comparing with planimetry method for estimating the tumor volumes. Thirty-two patients diagnosed with acoustic neuroma received contrast-enhanced magnetic resonance imaging of brain were recruited. The volume was calculated by the ABC/2 equation and planimetry method (defined as exact volume) at the same time. The 32 patients were divided into three groups by tumor volume to avoid volume-dependent overestimation (6 ml). The tumor volume by ABC/2 method was highly correlated to that calculated by planimetry method using linear regression analysis (R2=0.985). Pearson correlation coefficient (r=0.993, pABC/2 formula is an easy method in estimating the tumor volume of acoustic neuromas that is not inferior to planimetry method. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Prevalence of hepatitis-C virus genotypes and potential transmission risks in Malakand Khyber Pakhtunkhwa, Pakistan.

    Science.gov (United States)

    Nazir, Nausheen; Jan, Muhammad Rasul; Ali, Amjad; Asif, Muhammad; Idrees, Muhammad; Nisar, Mohammad; Zahoor, Muhammad; Abd El-Salam, Naser M

    2017-08-22

    Hepatitis C virus (HCV) is a leading cause of chronic liver disease and frequently progresses towards liver cirrhosis and Hepatocellular Carcinoma (HCC). This study aimed to determine the prevalence of HCV genotypes and their association with possible transmission risks in the general population of Malakand Division. Sum of 570 serum samples were collected during March 2011 to January 2012 from suspected patients visited to different hospitals of Malakand. The suspected sera were tested using qualitative PCR and were then subjected to molecular genotype specific assay. Quantitative PCR was also performed for determination of pre-treatment viral load in confirmed positive patients. Out of 570 serum samples 316 sera were seen positive while 254 sera were found negative using qualitative PCR. The positive samples were then subjected to genotyping assay out of 316, type-specific PCR fragments were seen in 271 sera while 45 samples were found untypable genotypes. Genotype 3a was seen as a predominant genotype (63.3%) with a standard error of ±2.7%. Cramer's V statistic and Liklihood-Ratio statistical procedures are used to measure the strength and to test the association, respectively, between the dependent variable, genotype, and explanatory variables (e.g. gender, risk, age and area/districts). The dependent variable, genotype, is observed statistically significant association with variable risk factors. This implies that the genotype is highly dependent on how the patient was infected. In contrast, the other covariates, for example, gender, age, and district (area) no statistical significant association are observed. The association between gender-age indicates that the mean age of female was older by 10.5 ± 2.3 years with 95% confidence level using t-statistic. It was concluded from the present study that the predominant genotype was 3a in the infected population of Malakand. This study also highlights the high prevalence rate of untypable genotypes which an

  18. Asthma: Effect of Genotype on Response to Therapy in the Emergency Department

    Directory of Open Access Journals (Sweden)

    Henderson, Sean

    2007-08-01

    Full Text Available Objective: We examined the effect of two β2-adrenoreceptor (β2AR polymorphisms (A46G and C79G in asthmatics presenting to the Emergency Department (ED in relation to their response to standard therapy measured by change in Forced Expiratory Volume at one second (FEV1. Our hypothesis was that the polymorphisms in the β2AR gene would predict clinical response to therapy with 46G and 79C displaying decreased response to inhaled therapy. Methods: This was a pilot feasibility study of a convenience sample of patients seen in the ED for acute exacerbation of asthma. Baseline data collected included: age, gender, ethnicity, vital signs, baseline FEV1, body mass index (BMI, smoking history and medications taken prior to arrival to the ED. Patients received standard ED care and FEV1 was measured after each treatment. Blood was taken and genotyped. Results: Fifty-three patients were enrolled over a three-month period. Using mean improvement in FEV1 from baseline to the first treatment as the primary outcome of interest, we performed multivariable linear regression analyses, with the FEV1 change as the dependent variable. When modeled as an ordinal covariate representing the number of G alleles present, there was a significant positive trend for the C79G locus (p=0.035. Those who were GG homozygotes had a 0.284 L/min improvement in FEV1 (31% after their initial albuterol treatment compared to 0.123 L/min (12% in those who were CC homozygotes. This represents a 2.5 times relative difference and a 19% actual difference. Genotypes at the A46G locus were not associated with FEV1 change. Conclusion: In this pilot study of ED patients with acute asthma exacerbation, there was a significant effect of genotype on response to therapy.

  19. Burned-Out Testicular Tumor: A Case Report

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    N. Balalaa

    2011-01-01

    Full Text Available Germ cell tumors constitute the majority of all testicular tumors, which are relatively rare overall and are mainly encountered in young adults and teenagers. The term ‘burned-out’ germ cell tumor refers to the presence of a metastatic germ cell tumor with histological regression of the primary testicular lesion. Clinical examination of the testes and scrotal sonography is pivotal in the initial diagnosis of such neoplasms. We present a case of a 31-year-old male with a retroperitoneal mass and no palpable lesion on testicular examination.

  20. Yet another look at MIDAS regression

    NARCIS (Netherlands)

    Ph.H.B.F. Franses (Philip Hans)

    2016-01-01

    textabstractA MIDAS regression involves a dependent variable observed at a low frequency and independent variables observed at a higher frequency. This paper relates a true high frequency data generating process, where also the dependent variable is observed (hypothetically) at the high frequency,

  1. Activated Hepatic Stellate Cells Induce Tumor Progression of Neoplastic Hepatocytes in a TGF-β Dependent Fashion

    Science.gov (United States)

    MIKULA, M.; PROELL, V.; FISCHER, A.N.M.; MIKULITS, W.

    2010-01-01

    The development of hepatocellular carcinomas from malignant hepatocytes is frequently associated with intra- and peritumoral accumulation of connective tissue arising from activated hepatic stellate cells. For both tumorigenesis and hepatic fibrogenesis, transforming growth factor (TGF)-β signaling executes key roles and therefore is considered as a hallmark of these pathological events. By employing cellular transplantation we show that the interaction of neoplastic MIM-R hepatocytes with the tumor microenvironment, containing either activated hepatic stellate cells (M1-4HSCs) or myofibroblasts derived thereof (M-HTs), induces progression in malignancy. Cotransplantation of MIM-R hepatocytes with M-HTs yielded strongest MIM-R generated tumor formation accompanied by nuclear localization of Smad2/3 as well as of β-catenin. Genetic interference with TGF-β signaling by gain of antagonistic Smad7 in MIM-R hepatocytes diminished epithelial dedifferentiation and tumor progression upon interaction with M1-4HSCs or M-HTs. Further analysis showed that tumors harboring disrupted Smad signaling are devoid of nuclear β-catenin accumulation, indicating a crosstalk between TGF-β and β-catenin signaling. Together, these data demonstrate that activated HSCs and myofibroblasts directly govern hepatocarcinogenesis in a TGF-β dependent fashion by inducing autocrine TGF-β signaling and nuclear β-catenin accumulation in neoplastic hepatocytes. These results indicate that intervention with TGF-β signaling is highly promising in liver cancer therapy. PMID:16883581

  2. Negative frequency-dependent selection between Pasteuria penetrans and its host Meloidogyne arenaria

    Science.gov (United States)

    In negative frequency-dependant selection (NFDS), parasite genotypes capable of infecting the numerically dominant host genotype are favored, while host genotypes resistant to the dominant parasite genotype are favored, creating a cyclical pattern of resistant genotypes in the host population and, a...

  3. Genotype X/C recombinant (putative genotype I) of hepatitis B virus is rare in Hanoi, Vietnam--genotypes B4 and C1 predominate.

    Science.gov (United States)

    Phung, Thi Bich Thuy; Alestig, Erik; Nguyen, Thanh Liem; Hannoun, Charles; Lindh, Magnus

    2010-08-01

    There are eight known genotypes of hepatitis B virus, A-H, and several subgenotypes, with rather well-defined geographic distributions. HBV genotypes were evaluated in 153 serum samples from Hanoi, Vietnam. Of the 87 samples that could be genotyped, genotype B was found in 67 (77%) and genotype C in 19 (22%). All genotype C strains were of subgenotype C1, and the majority of genotype B strains were B4, while a few were B2. The genotype X/C recombinant strain, identified previously in Swedish patients of indigenous Vietnamese origin, was found in one sample. This variant, proposed to be classified as genotype I, has been found recently also by others in Vietnam and Laos. The current study indicates that the genotype X/C recombinant may represent approximately 1% of the HBV strains circulating in Vietnam. (c) 2010 Wiley-Liss, Inc.

  4. Heterogeneity index evaluated by slope of linear regression on 18F-FDG PET/CT as a prognostic marker for predicting tumor recurrence in pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Kim, Yong-il; Kim, Yong Joong; Paeng, Jin Chul; Cheon, Gi Jeong; Lee, Dong Soo; Chung, June-Key; Kang, Keon Wook

    2017-01-01

    18 F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of 18 F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and 18 F-FDG PET/CT parameters. A total of 93 pancreatic ductal adenocarcinoma patients (M:F = 60:33, mean age = 64.2 ± 9.1 years) who underwent preoperative 18 F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each 18 F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and 18 F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence. Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence = 9.4 ± 8.4 months). Comparing the recurrence and no recurrence patients, all of the 18 F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox-regression analyses, MTV (P = 0.013), TLG (P = 0.007), and heterogeneity index-2 (P = 0.027) were significant. Among the clinicopathologic parameters, CA19-9 (P = 0.025) and venous invasion (P = 0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P = 0.005), TLG (P = 0.004), and heterogeneity index-2 (P = 0.016) with venous invasion (P < 0.001, 0.001, and 0.001, respectively) demonstrated significant results

  5. Existence of various human parvovirus B19 genotypes in Chinese plasma pools: genotype 1, genotype 3, putative intergenotypic recombinant variants and new genotypes.

    Science.gov (United States)

    Jia, Junting; Ma, Yuyuan; Zhao, Xiong; Huangfu, Chaoji; Zhong, Yadi; Fang, Chi; Fan, Rui; Lv, Maomin; Zhang, Jingang

    2016-09-17

    Human parvovirus B19 (B19V) is a frequent contaminant of blood and plasma-derived medicinal products. Three distinct genotypes of B19V have been identified. The distribution of the three B19V genotypes has been investigated in various regions or countries. However, in China, data on the existence of different B19V genotypes are limited. One hundred and eighteen B19V-DNA positive source plasma pool samples collected from three Chinese blood products manufacturers were analyzed. The subgenomic NS1/VP1u region junction of B19V was amplified by nested PCR. These amplified products were then cloned and subsequently sequenced. For genotyping, their phylogenetic inferences were constructed based on the NS1/VP1-unique region. Then putative recombination events were analyzed and identified. Phylogenetic analysis of 118 B19V sequences attributed 61.86 % to genotype 1a, 10.17 % to genotype 1b, and 17.80 % to genotype 3b. All the genotype 3b sequences obtained in this study grouped as a specific, closely related cluster with B19V strain D91.1. Four 1a/3b recombinants and 5 new atypical B19V variants with no recombination events were identified. There were at least 3 subtypes (1a, 1b and 3b) of B19V circulating in China. Furthermore, putative B19V 1a/3b recombinants and unclassified strains were identified as well. Such recombinant and unclassified strains may contribute to the genetic diversity of B19V and consequently complicate the B19V infection diagnosis and NAT screening. Further studies will be required to elucidate the biological significance of the recombinant and unclassified strains.

  6. Chemical composition, nutritional value and antioxidant properties of Mediterranean okra genotypes in relation to harvest stage.

    Science.gov (United States)

    Petropoulos, Spyridon; Fernandes, Ângela; Barros, Lillian; Ferreira, Isabel C F R

    2018-03-01

    The aim of the present study was to determine the effect of fruit size on nutritional value, chemical composition and antioxidant properties of Mediterranean okra genotypes. For this purpose, pods from four okra cultivars and local landraces commonly cultivated in Greece, as well as pods from four commercial cultivars from North America were collected at two sizes (3-5 and>7cm). Significant differences were observed between the studied genotypes for both nutritional value and chemical composition parameters. Small fruit had a higher nutritional value, whereas chemical composition differed in a genotype dependent manner with most of the studied cultivars showing better results when harvested in small size. In conclusion, fruit size has a genotype dependent impact on chemical composition and nutritional value of okra pods and the common practice of harvesting okra fruit while they still have a small size helps to increase nutritional value for most of the studied genotypes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Clinical Effect of Human Papillomavirus Genotypes in Patients With Cervical Cancer Undergoing Primary Radiotherapy

    International Nuclear Information System (INIS)

    Wang, Chun-Chieh; Lai, Chyong-Huey; Huang, Huei-Jean; Chao, Angel; Chang, Chee-Jen; Chang, Ting-Chang; Chou, Hung-Hsueh; Hong, Ji-Hong

    2010-01-01

    Purpose: To study the prognostic value of the human papillomavirus (HPV) genotypes in cervical cancer patients undergoing radiotherapy. Patients and Methods: A total of 1,010 patients with cervical cancer after radiotherapy between 1993 and 2000 were eligible for this study. The HPV genotypes were determined by a genechip, which detects 38 types of HPV. The patient characteristics and treatment outcomes were analyzed using the Cox regression hazard model and classification and regression tree decision tree method. Results: A total of 25 genotypes of HPV were detected in 992 specimens (98.2%). The leading 8 types were HPV16, 58, 18, 33, 52, 39, 31, and 45. These types belong to two high-risk HPV species: alpha-7 (HPV18, 39, 45) and alpha-9 (HPV16, 31, 33, 52, 58). Three HPV-based risk groups, which were independent of established prognostic factors, such as International Federation of Gynecology and Obstetrics stage, age, pathologic features, squamous cell carcinoma antigen, and lymph node metastasis, were associated with the survival outcomes. The high-risk group consisted of the patients without HPV infection or the ones infected with the alpha-7 species only. Patients co-infected with the alpha-7 and alpha-9 species belonged to the medium-risk group, and the others were included in the low-risk group. Conclusion: The results of the present study have confirmed the prognostic value of HPV genotypes in cervical cancer treated with radiotherapy. The different effect of the alpha-7 and alpha-9 species on the radiation response deserves additional exploration.

  8. Heteroscedasticity as a Basis of Direction Dependence in Reversible Linear Regression Models.

    Science.gov (United States)

    Wiedermann, Wolfgang; Artner, Richard; von Eye, Alexander

    2017-01-01

    Heteroscedasticity is a well-known issue in linear regression modeling. When heteroscedasticity is observed, researchers are advised to remedy possible model misspecification of the explanatory part of the model (e.g., considering alternative functional forms and/or omitted variables). The present contribution discusses another source of heteroscedasticity in observational data: Directional model misspecifications in the case of nonnormal variables. Directional misspecification refers to situations where alternative models are equally likely to explain the data-generating process (e.g., x → y versus y → x). It is shown that the homoscedasticity assumption is likely to be violated in models that erroneously treat true nonnormal predictors as response variables. Recently, Direction Dependence Analysis (DDA) has been proposed as a framework to empirically evaluate the direction of effects in linear models. The present study links the phenomenon of heteroscedasticity with DDA and describes visual diagnostics and nine homoscedasticity tests that can be used to make decisions concerning the direction of effects in linear models. Results of a Monte Carlo simulation that demonstrate the adequacy of the approach are presented. An empirical example is provided, and applicability of the methodology in cases of violated assumptions is discussed.

  9. Hepatitis B virus genotypes circulating in Brazil: molecular characterization of genotype F isolates

    Directory of Open Access Journals (Sweden)

    Virgolino Helaine A

    2007-11-01

    Full Text Available Abstract Background Hepatitis B virus (HBV isolates have been classified in eight genotypes, A to H, which exhibit distinct geographical distributions. Genotypes A, D and F are predominant in Brazil, a country formed by a miscegenated population, where the proportion of individuals from Caucasian, Amerindian and African origins varies by region. Genotype F, which is the most divergent, is considered indigenous to the Americas. A systematic molecular characterization of HBV isolates from different parts of the world would be invaluable in establishing HBV evolutionary origins and dispersion patterns. A large-scale study is needed to map the region-by-region distribution of the HBV genotypes in Brazil. Results Genotyping by PCR-RFLP of 303 HBV isolates from HBsAg-positive blood donors showed that at least two of the three genotypes, A, D, and F, co-circulate in each of the five geographic regions of Brazil. No other genotypes were identified. Overall, genotype A was most prevalent (48.5%, and most of these isolates were classified as subgenotype A1 (138/153; 90.2%. Genotype D was the most common genotype in the South (84.2% and Central (47.6% regions. The prevalence of genotype F was low (13% countrywide. Nucleotide sequencing of the S gene and a phylogenetic analysis of 32 HBV genotype F isolates showed that a great majority (28/32; 87.5% belonged to subgenotype F2, cluster II. The deduced serotype of 31 of 32 F isolates was adw4. The remaining isolate showed a leucine-to-isoleucine substitution at position 127. Conclusion The presence of genotypes A, D and F, and the absence of other genotypes in a large cohort of HBV infected individuals may reflect the ethnic origins of the Brazilian population. The high prevalence of isolates from subgenotype A1 (of African origin indicates that the African influx during the colonial slavery period had a major impact on the circulation of HBV genotype A currently found in Brazil. Although most genotype F

  10. Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade.

    Science.gov (United States)

    Lipson, Evan J; Lilo, Mohammed T; Ogurtsova, Aleksandra; Esandrio, Jessica; Xu, Haiying; Brothers, Patricia; Schollenberger, Megan; Sharfman, William H; Taube, Janis M

    2017-01-01

    Monoclonal antibodies that block immune regulatory proteins such as programmed death-1 (PD-1) have demonstrated remarkable efficacy in controlling the growth of multiple tumor types. Unresectable or metastatic basal cell carcinoma, however, has largely gone untested. Because PD-Ligand-1 (PD-L1) expression in other tumor types has been associated with response to anti-PD-1, we investigated the expression of PD-L1 and its association with PD-1 expression in the basal cell carcinoma tumor microenvironment. Among 40 basal cell carcinoma specimens, 9/40 (22%) demonstrated PD-L1 expression on tumor cells, and 33/40 (82%) demonstrated PD-L1 expression on tumor-infiltrating lymphocytes and associated macrophages. PD-L1 was observed in close geographic association to PD-1+ tumor infiltrating lymphocytes. Additionally, we present, here, the first report of an objective anti-tumor response to pembrolizumab (anti-PD-1) in a patient with metastatic PD-L1 (+) basal cell carcinoma, whose disease had previously progressed through hedgehog pathway-directed therapy. The patient remains in a partial response 14 months after initiation of therapy. Taken together, our findings provide a rationale for testing anti-PD-1 therapy in patients with advanced basal cell carcinoma, either as initial treatment or after acquired resistance to hedgehog pathway inhibition.

  11. Possible Association of APOE Genotype with Working Memory in Young Adults.

    Directory of Open Access Journals (Sweden)

    Lindsey I Sinclair

    Full Text Available Possession of the ε4 allele of the Apolipoprotein E (APOE gene is associated with an increased risk of Alzheimer's disease. Early adult life effects of ε4 are less well understood. Working memory has been relatively little studied (compared to episodic memory in relation to APOE genotype despite its importance in cognitive functioning. Our hypothesis was that ε4 would lead to an impairment in working memory in young adults.We studied working memory using a computerised n-back task in the Avon Longitudinal Study of Parents and Children (ALSPAC at age 18. Data was available for 1049-1927 participants and for the 2- and 3-back versions of the task. Using multiple and multi-level regression controlling for important confounders we examined the association between APOE genotype on accuracy and reaction times.There was no evidence of a genotype effect on accuracy when the two difficulty levels were examined separately. There was some evidence to support a deleterious effect of the ε4 allele on n-back accuracy in the multi-level regression. There was weak evidence that the ε22 group were less accurate but the numbers were very low in this group. The ε34 group had faster reaction times than the reference ε33 group in all adjusted analyses but the ε44 group were only faster in the 3-back condition in multi-level analyses.There was no evidence of benefit in ε4 carriers, but there was some evidence of a detrimental effect on working memory in this large study.

  12. Commensal bacteria modulate the tumor microenvironment.

    Science.gov (United States)

    Poutahidis, Theofilos; Erdman, Susan E

    2016-09-28

    It has been recently shown that gut microbes modulate whole host immune and hormonal factors impacting the fate of distant preneoplastic lesions toward malignancy or regression. This raises the possibility that the tumor microenvironment interacts with broader systemic microbial-immune networks. These accumulated findings suggest novel therapeutic opportunities for holobiont engineering in emerging tumor microenvironments. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. CNS tumors: postoperative evaluation

    International Nuclear Information System (INIS)

    Dayanir, Y.

    2012-01-01

    Full text: Imaging assessment of brain tumors following surgery is complex and depends upon several factors, including the location of the tumor, the surgical procedure and the disease process for which it was performed. Depending upon these factors, one or a combination of complementary imaging modalities may be required to demonstrate any clinically relevant situation, to assist the surgeon in deciding if repeat surgery is necessary. Conventional magnetic resonance imaging (MRI) can show the shape, size, signal intensity, and enhancement of a brain tumor. It has been widely used to diagnose and differentiate brain tumors and to assess the surgery outcomes. Longitudinal MRI scans have also been applied for the assessment of treatment and response to surgery. The newly developed MRI techniques, including diffusion weighted imaging (DWI), perfusion weighted imaging (PWI) and magnetic resonance spectroscopy (MRS), have the potential to provide the molecular, functional and metabolic information of preoperative and postoperative brain tumors. Postoperative diffusion and perfusion magnetic resonance imaging are especially useful in predicting early functional recovery from new deficits after brain tumor surgery.This lecture will stress the principles, applications, and pitfalls of conventional as well as newly developing functional imaging techniques following operation of brain tumors

  14. Dose-dependent effects of (anti)folate preinjection on 99mTc-radiofolate uptake in tumors and kidneys

    International Nuclear Information System (INIS)

    Mueller, Cristina; Schibli, Roger; Forrer, Flavio; Krenning, Eric P.; Jong, Marion de

    2007-01-01

    Introduction: The folate receptor (FR) is frequently overexpressed in tumors and can be targeted with folate-based (radio)pharmaceuticals. However, significant accumulation of radiofolates in FR-positive kidneys represents a drawback. We have shown that preadministration of the antifolate pemetrexed (PMX) significantly improved the tumor-to-kidney ratio of radiofolates in mice. The aim of this study was to investigate the dose dependence of these effects and whether the same results could be achieved with folic acid (FA) or 5-methyl-tetrahydrofolate (5-Me-THF). Methods: Biodistribution was assessed 4 h postinjection of the organometallic 99m Tc-picolylamine monoacetic acid folate in nude mice bearing FR-positive KB tumor xenografts. PMX (50-400 μg/mouse) was injected 1 h previous to radioactivity. The effects of FA and 5-Me-THF (0.5-50 μg/mouse) were investigated likewise. Tissues and organs were collected and counted for radioactivity and the values tabulated as percentage of injected dose per gram tissue (% ID/g). Results: PMX administration reduced renal retention ( 10% ID/g), while the tumor uptake (average 1.35%±0.40% ID/g vs. control: 1.79%±0.49% ID/g) was only slightly affected independent of the PMX dose. Replacement of PMX by FA or 5-Me-THF (50 μg/mouse) resulted in a significant renal blockade (<0.1% ID/g) but at the same time in an undesired reduction of tumor uptake (<0.2% ID/g). Conclusions: Selective reduction of radiofolate uptake in kidneys under retention of high tumor accumulation could be achieved in combination with PMX over a broad dose range but not with FA or 5-Me-THF

  15. Genotype dependent radiosensitivity of autotetraploids in Trigonella foenum-graecum L

    Energy Technology Data Exchange (ETDEWEB)

    Raghuvanshi, S S; Singh, A K

    1980-01-01

    Different diploids of Trigonella foenum-graecum L. and their corresponding autotetraploids were seedtreated with 40 krad of ..gamma..-rays, and parameters such as germination, survival, growth reduction, pollen fertility, pod setting, etc. were recorded. A stimulation of seed germination due to the irradiation could be observed. Contrary to the general rule that polyploids are more radioresistant than their corresponding diploids, one 4x strain was completely killed while the 2x version survived comparatively well. Apparently gene reduplication is not the overall protective mechanism as was once earlier believed. The importance of genotypic influence on radiosensitivity was demonstrated at both the 2x and 4x level. The limitation of interphase chromosome volume and degree of ploidy in predicting radiosensitivity is discussed.

  16. Hierarchical regression analysis in structural Equation Modeling

    NARCIS (Netherlands)

    de Jong, P.F.

    1999-01-01

    In a hierarchical or fixed-order regression analysis, the independent variables are entered into the regression equation in a prespecified order. Such an analysis is often performed when the extra amount of variance accounted for in a dependent variable by a specific independent variable is the main

  17. Expression of LIGHT/TNFSF14 Combined with Vaccination against Human Papillomavirus Type 16 E7 Induces Significant Tumor Regression

    Science.gov (United States)

    Kanodia, Shreya; Da Silva, Diane M.; Karamanukyan, Tigran; Bogaert, Lies; Fu, Yang-Xin; Kast, W. Martin

    2010-01-01

    LIGHT, a ligand for the lymphotoxin-beta receptor, establishes lymphoid-like tissues inside tumor sites and recruits naïve T-cells into the tumor. However, whether these infiltrating T-cells are specific for tumor antigens is not known. We hypothesized that therapy with LIGHT can expand functional tumor-specific CD8+ T-cells that can be boosted using HPV16E6E7-Venezuelan Equine Encephalitis Virus Replicon Particles (HPV16-VRP) and that this combined therapy can eradicate HPV16-induced tumors. Our data show that forced expression of LIGHT in tumors results in an increase in expression of interferon gamma (IFNg) and chemottractant cytokines such as IL-1a, MIG and MIP-2 within the tumor and that this tumor microenvironment correlates with an increase in frequency of tumor-infiltrating CD8+ T-cells. Forced expression of LIGHT also results in the expansion of functional T-cells that recognize multiple tumor-antigens, including HPV16 E7, and these T-cells prevent the outgrowth of tumors upon secondary challenge. Subsequent boosting of E7-specific T-cells by vaccination with HPV16-VRP significantly increases their frequency in both the periphery and the tumor, and leads to the eradication of large well-established tumors, for which either treatment alone is not successful. These data establish the safety of Ad-LIGHT as a therapeutic intervention in pre-clinical studies and suggest that patients with HPV16+ tumors may benefit from combined immunotherapy with LIGHT and antigen-specific vaccination. PMID:20460520

  18. Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice

    Directory of Open Access Journals (Sweden)

    Shoya Shiromizu

    2018-04-01

    Full Text Available Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Keywords: l-asparaginase, Asparagine, Solid tumor, Chrono-pharmacotherapy

  19. Dependence of deodorant usage on ABCC11 genotype: scope for personalized genetics in personal hygiene.

    Science.gov (United States)

    Rodriguez, Santiago; Steer, Colin D; Farrow, Alexandra; Golding, Jean; Day, Ian N M

    2013-07-01

    Earwax type and axillary odor are genetically determined by rs17822931, a single-nucleotide polymorphism (SNP) located in the ABCC11 gene. The literature has been concerned with the Mendelian trait of earwax, although axillary odor is also Mendelian. Ethnic diversity in rs17822931 exists, with higher frequency of allele A in east Asians. Influence on deodorant usage has not been investigated. In this work, we present a detailed analysis of the rs17822931 effect on deodorant usage in a large (N∼17,000 individuals) population cohort (the Avon Longitudinal Study of Parents and Children (ALSPAC)). We found strong evidence (P=3.7 × 10(-20)) indicating differential deodorant usage according to the rs17822931 genotype. AA homozygotes were almost 5-fold overrepresented in categories of never using deodorant or using it infrequently. However, 77.8% of white European genotypically nonodorous individuals still used deodorant, and 4.7% genotypically odorous individuals did not. We provide evidence of a behavioral effect associated with rs17822931. This effect has a biological basis that can result in a change in the family's environment if an aerosol deodorant is used. It also indicates potential cost saving to the nonodorous and scope for personalized genetics usage in personal hygiene choices, with consequent reduction of inappropriate chemical exposures for some.

  20. Robust logistic regression to narrow down the winner's curse for rare and recessive susceptibility variants.

    Science.gov (United States)

    Kesselmeier, Miriam; Lorenzo Bermejo, Justo

    2017-11-01

    Logistic regression is the most common technique used for genetic case-control association studies. A disadvantage of standard maximum likelihood estimators of the genotype relative risk (GRR) is their strong dependence on outlier subjects, for example, patients diagnosed at unusually young age. Robust methods are available to constrain outlier influence, but they are scarcely used in genetic studies. This article provides a non-intimidating introduction to robust logistic regression, and investigates its benefits and limitations in genetic association studies. We applied the bounded Huber and extended the R package 'robustbase' with the re-descending Hampel functions to down-weight outlier influence. Computer simulations were carried out to assess the type I error rate, mean squared error (MSE) and statistical power according to major characteristics of the genetic study and investigated markers. Simulations were complemented with the analysis of real data. Both standard and robust estimation controlled type I error rates. Standard logistic regression showed the highest power but standard GRR estimates also showed the largest bias and MSE, in particular for associated rare and recessive variants. For illustration, a recessive variant with a true GRR=6.32 and a minor allele frequency=0.05 investigated in a 1000 case/1000 control study by standard logistic regression resulted in power=0.60 and MSE=16.5. The corresponding figures for Huber-based estimation were power=0.51 and MSE=0.53. Overall, Hampel- and Huber-based GRR estimates did not differ much. Robust logistic regression may represent a valuable alternative to standard maximum likelihood estimation when the focus lies on risk prediction rather than identification of susceptibility variants. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants

    DEFF Research Database (Denmark)

    Serre, Stéphanie B N; Jensen, Sanne B; Ghanem, Lubna

    2016-01-01

    , grazoprevir, paritaprevir and deldeprevir identified positions 156 and 168 as hotspots for resistance; substitution Y56H emerged for 3 newer PIs. Substitution selection also depended on the specific recombinant. Identified substitutions conferred cross-resistance to several PIs, however, most substitutions...... fitness, depending on the original recombinant and the substitution. Across genotypes, fitness impairment induced by resistance substitutions was primarily due to decreased replication. Most identified combinations of substitutions increased resistance or fitness. Combinations of resistance substitutions...... with fitness compensating substitutions either rescued replication or compensated for decreased replication with increased assembly. This comprehensive study provides insight into selection patterns and effects of PI resistance substitutions for HCV genotypes 1-6 in the context of the infectious viral life...

  2. Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity.

    Science.gov (United States)

    Garcia, Emmanuel; Becker, Veronika G C; McCullough, Danielle J; Stabley, John N; Gittemeier, Elizabeth M; Opoku-Acheampong, Alexander B; Sieman, Dietmar W; Behnke, Bradley J

    2016-07-01

    Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. Copyright © 2016 the American Physiological Society.

  3. Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab

    Science.gov (United States)

    Brand, Toni M; Dunn, Emily F; Iida, Mari; Myers, Rebecca A; Kostopoulos, Kellie T; Li, Chunrong; Peet, Chimera R

    2011-01-01

    The epidermal growth factor receptor (EGFR) is an ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab and cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical success; however, many tumors remain non-responsive or acquire resistance during therapy. To explore potential molecular mechanisms of acquired resistance to cetuximab we previously established a series of cetuximab-resistant clones by chronically exposing the NCI-H226 NSCLC cell line to escalating doses of cetuximab. Cetuximab-resistant clones exhibited a dramatic increase in the activation of EGFR, HER2 and HER3 receptors as well as increased signaling through the MAP K and AKT pathways. RNAi studies demonstrated dependence of cetuximab-resistant clones on the EGFR signaling network. These findings prompted investigation on whether or not cells with acquired resistance to cetuximab would be sensitive to the EGFR targeted TKI erlotinib. In vitro, erlotinib was able to decrease signaling through the EGFR axis, decrease cellular proliferation and induce apoptosis. To determine if erlotinib could have therapeutic benefit in vivo, we established cetuximab-resistant NCI-H226 mouse xenografts, and subsequently treated them with erlotinib. Mice harboring cetuximab-resistant tumors treated with erlotinib exhibited either a tumor regression or growth delay as compared with vehicle controls. Analysis of the erlotinib treated tumors demonstrated a decrease in cell proliferation and increased rates of apoptosis. The work presented herein suggests that (1) cells with acquired resistance to cetuximab maintain their dependence on EGFR and (2) tumors developing resistance to cetuximab can benefit from subsequent treatment with erlotinib, providing rationale

  4. Intra-tumoral Heterogeneity of KRAS and BRAF Mutation Status in Patients with Advanced Colorectal Cancer (aCRC and Cost-Effectiveness of Multiple Sample Testing

    Directory of Open Access Journals (Sweden)

    Susan D. Richman

    2011-01-01

    Full Text Available KRAS mutation status is established as a predictive biomarker of benefit from anti-EGFr therapies. Mutations are normally assessed using DNA extracted from one formalin-fixed, paraffin-embedded (FFPE tumor block. We assessed heterogeneity of KRAS and BRAF mutation status intra-tumorally (multiple blocks from the same primary tumor. We also investigated the utility and efficiency of genotyping a ‘DNA cocktail’ prepared from multiple blocks. We studied 68 consenting patients in two randomized clinical trials. DNA was extracted, from ≥2 primary tumor FFPE blocks per patient. DNA was genotyped by pyrosequencing for KRAS codons 12, 13 and 61 and BRAF codon 600. In patients with heterogeneous mutation status, DNA cocktails were prepared and genotyped. Among 69 primary tumors in 68 patients, 7 (10.1% showed intratumoral heterogeneity; 5 (7.2% at KRAS codons 12, 13 and 2 (2.9% at BRAF codon 600. In patients displaying heterogeneity, the relevant KRAS or BRAF mutation was also identified in ‘DNA cocktail’ samples when including DNA from mutant and wild-type blocks. Heterogeneity is uncommon but not insignificant. Testing DNA from a single block will wrongly assign wild-type status to 10% patients. Testing more than one block, or preferably preparation of a ‘DNA cocktail’ from two or more tumor blocks, improves mutation detection at minimal extra cost.

  5. Solid tumor models for the assessment of different treatment modalities. XIV. The evaluation of host and tumor response to cyclophosphamide and radiation

    International Nuclear Information System (INIS)

    Looney, W.B.; Hopkins, H.A.; MacLeod, M.S.; Ritenour, E.R.

    1979-01-01

    The effect of increasing doses of cyclophosphamide (50 to 250 mg/kg) on the time of occurrence of maximal and minimal tumor growth rates, tumor volume reduction, and linear doubling times (LDT) on the solid tumor model H-4-II-E has been determined. Tumor response to cyclophosphamide was classified as class I, tumor regression; class II, pseudo-regression; and class III, slow-down. The overall treatment efficiency (OTE) has been used to assess the magnitude of tumor volume changes after treatment. The maximum OTE occurred after 150 mg/kg of cyclophosphamide. Increasing the dose to 200 and 250 mg/kg of cyclophosphamide resulted in a decrease in OTE. Similar parameters were utilized to measure the effectiveness of increasing doses of local tumor radiation (750, 1500, 2000, 2500, 3000 and 3500R). The major increase in OTE occurs when the radiation dose is increased from 750R to 2000R. Increasing the dose further to 3500R results in smaller incremental increases in the OTE. Results of the study indicate that increasing the cyclophosphamide dose beyond a certain level (i.e., 150 mg/kg) increases mortality and morbidity without concomitant therapeutic benefit. The effects of increasing the dose of local tumor radiation on life span have given results which suggest that increasing the total radiation dose beyond a certain limit is less effective in increasing life span

  6. CD40 dependent exacerbation of immune mediated hepatitis by hepatic CD11b+ Gr-1+ myeloid derived suppressor cells in tumor bearing mice

    Science.gov (United States)

    Kapanadze, Tamar; Medina-Echeverz, José; Gamrekelashvili, Jaba; Weiss, Jonathan M.; Wiltrout, Robert H.; Kapoor, Veena; Hawk, Nga; Terabe, Masaki; Berzofsky, Jay A.; Manns, Michael P.; Wang, Ena; Marincola, Francesco M.; Korangy, Firouzeh; Greten, Tim F.

    2015-01-01

    Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) accumulate in the livers of tumor-bearing mice. We studied hepatic MDSC in two murine models of immune mediated hepatitis. Unexpectedly, treatment of tumor bearing mice with Concanavalin A or α-Galactosylceramide resulted in increased ALT and AST serum levels in comparison to tumor free mice. Adoptive transfer of hepatic MDSC into naïve mice exacerbated Concanavalin A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized pro-inflammatory gene signature after Concanavalin A treatment. An interferon gamma- dependent up-regulation of CD40 on hepatic CD11b+Gr-1+ cells along with an up-regulation of CD80, CD86, and CD1d after Concanavalin A treatment was observed. Concanavalin A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSC as well as enhanced reactive oxygen species-mediated hepatotoxicity. CD40 knockdown in hepatic MDSC led to increased arginase activity upon Concanavalin A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40−/− tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased reactive oxygen species production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSC act as pro-inflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner. PMID:25616156

  7. Association of the AA genotype of the BCL2 (-938C>A) promoter polymorphism with better survival in ovarian cancer.

    Science.gov (United States)

    Heubner, Martin; Wimberger, Pauline; Otterbach, Friedrich; Kasimir-Bauer, Sabine; Siffert, Winfried; Kimmig, Rainer; Nückel, Holger

    2009-01-01

    Bcl-2 plays a key role in the regulation of apoptosis. Recently, a novel regulatory single nucleotide polymorphism (-938C>A) in the inhibitory P2 BCL2 promoter was described. In this study we investigated its potential association with survival in epithelial ovarian cancer. Patients (n=110) with primary epithelial ovarian cancer were retrospectively genotyped by pyrosequencing. Genotype distribution was not significantly different between 110 ovarian cancer patients and 120 healthy controls, suggesting that genotypes of this polymorphism do not increase the susceptibility to ovarian cancer. Kaplan-Meier curves showed a significant association of the AA genotype with increased survival (p=0.002). Multivariate analysis revealed that the BCL2-938AC/CC genotype (hazard ratio 4.5; p=0.003) was an independent prognostic factor compared to other prognostic factors such as age, histological grade or tumor stage. The results suggest a role for the BCL2-938C>A polymorphism as a marker for survival in patients with epithelial ovarian cancer.

  8. Polymorphisms of Tumor Necrosis Factor Alpha in Moroccan Patients with Gastric Pathology: New Single-Nucleotide Polymorphisms in TNF-α−193 (G/A

    Directory of Open Access Journals (Sweden)

    A. Essadik

    2015-01-01

    Full Text Available Polymorphisms in tumor necrosis factor alpha (TNF-α gene are emerging as key determinants of gastric diseases. The TNF-α−308 (G/A and TNF-α−238 (G/A single-nucleotide polymorphisms SNPs are the most extensively studied. However, all these studies are conducted in Caucasian and Asian populations. Thus, for the first time in Africa, we sought to investigate whether polymorphisms in TNF-α gene were associated with the development of gastric pathology in Morocco. Two SNPs located in the promoter region (positions −308 and −238 in TNF-α gene were genotyped in 244 individuals (170 patients and 74 healthy controls. Odds ratios (ORs and 95% confidence intervals (CI were estimated using logistic regression analysis. The TNF-α−238 (G/A genotype was significantly associated with a high risk of gastritis and gastric cancer (GC (P=0.001 and P=0.002, resp.. Furthermore, a new polymorphism located in the promoter region at position −193 in TNF-α gene was identified. The distribution of this SNP was markedly different in patients suffering from ulcers. The association between TNF-α−193 (G/A genotype and high risk of ulcer was significant (P=0.03. These results suggest that the TNF-α−193 (G/A allele has a protective function against gastric cancer by developing ulcer.

  9. Characterization of genotypic variability associated to the phosphorus bioavailability in peanut (Arachis hypogaea L.

    Directory of Open Access Journals (Sweden)

    Mohamed Kraimat

    2017-06-01

    Full Text Available In order to assess genotypic variability in some peanut genotypes depending on phosphorus availability, both effects of tri-calcium phosphate (TCP and inoculation by Bradyrhizobium strain (BR on morphological and physiological parameters were studied in five peanut genotypes (Arachis hypogaea L., originated from two Algerian areas (Northern and Southern. The results obtained during the flowering stage of crop development, confirmed the positive effect of the contribution of tri-calcium phosphate (TCP with Bradyrhizobium strains on the morphological characters (shoot biomass, root biomass, nodular biomass and leaf and the physiological (nitrogenase activity, phosphorus absorption efficiency by roots (RPAE and phosphorus use efficiency (PUE for the peanut genotypes cultivated in this experiment. Among five genotypes tested, it was noted that the Southern genotypes were more efficient to use TCP in the presence of Bradyrhizobium strain after a screening of these local genotypes, in particular, with phosphorus use efficiency (PUE and shoot biomass production.

  10. Comparison between linear and non-parametric regression models for genome-enabled prediction in wheat.

    Science.gov (United States)

    Pérez-Rodríguez, Paulino; Gianola, Daniel; González-Camacho, Juan Manuel; Crossa, José; Manès, Yann; Dreisigacker, Susanne

    2012-12-01

    In genome-enabled prediction, parametric, semi-parametric, and non-parametric regression models have been used. This study assessed the predictive ability of linear and non-linear models using dense molecular markers. The linear models were linear on marker effects and included the Bayesian LASSO, Bayesian ridge regression, Bayes A, and Bayes B. The non-linear models (this refers to non-linearity on markers) were reproducing kernel Hilbert space (RKHS) regression, Bayesian regularized neural networks (BRNN), and radial basis function neural networks (RBFNN). These statistical models were compared using 306 elite wheat lines from CIMMYT genotyped with 1717 diversity array technology (DArT) markers and two traits, days to heading (DTH) and grain yield (GY), measured in each of 12 environments. It was found that the three non-linear models had better overall prediction accuracy than the linear regression specification. Results showed a consistent superiority of RKHS and RBFNN over the Bayesian LASSO, Bayesian ridge regression, Bayes A, and Bayes B models.

  11. Brown tumor of secondary hyperparathyroidism: surgical approach and clinical outcome.

    Science.gov (United States)

    Queiroz, Isaac Vieira; Queiroz, Samara Pereira; Medeiros, Rui; Ribeiro, Rodolfo Bonfim; Crusoé-Rebello, Iêda Margarida; Leão, Jair Carneiro

    2016-12-01

    Secondary hyperparathyroidism is a frequent complication of chronic renal failure. The brown tumor is an unusual presentation of fibrous osteitis that represents a serious complication of renal osteodystrophy, affecting predominantly the hands, feet, skull, and facial bones. The aim of this paper is to describe the case of a 53-year-old female patient, with renal failure who has been on dialysis for 6 years and developed severe secondary hyperparathyroidism and brown tumor of the maxilla and mandible, confirmed by incisional biopsy. Parathyroidectomy was indicated as a result of rapid growth of the tumor and the maintenance of laboratory findings. Despite the normalization of serum parathyroid hormone and alkaline phosphatase, tumor regression was slow and patient's important functional and esthetic deficits persisted. Excision of the mandible tumor was conservative. Osteoplasty was recommended because during a 5-year follow-up there was regression of the lesion, decreased pain, bleeding, and tooth mobility.

  12. A Tumor-stroma Targeted Oncolytic Adenovirus Replicated in Human Ovary Cancer Samples and Inhibited Growth of Disseminated Solid Tumors in Mice

    Science.gov (United States)

    Lopez, M Veronica; Rivera, Angel A; Viale, Diego L; Benedetti, Lorena; Cuneo, Nicasio; Kimball, Kristopher J; Wang, Minghui; Douglas, Joanne T; Zhu, Zeng B; Bravo, Alicia I; Gidekel, Manuel; Alvarez, Ronald D; Curiel, David T; Podhajcer, Osvaldo L

    2012-01-01

    Targeting the tumor stroma in addition to the malignant cell compartment is of paramount importance to achieve complete tumor regression. In this work, we modified a previously designed tumor stroma-targeted conditionally replicative adenovirus (CRAd) based on the SPARC promoter by introducing a mutated E1A unable to bind pRB and pseudotyped with a chimeric Ad5/3 fiber (Ad F512v1), and assessed its replication/lytic capacity in ovary cancer in vitro and in vivo. AdF512v1 was able to replicate in fresh samples obtained from patients: (i) with primary human ovary cancer; (ii) that underwent neoadjuvant treatment; (iii) with metastatic disease. In addition, we show that four intraperitoneal (i.p.) injections of 5 × 1010 v.p. eliminated 50% of xenografted human ovary tumors disseminated in nude mice. Moreover, AdF512v1 replication in tumor models was enhanced 15–40-fold when the tumor contained a mix of malignant and SPARC-expressing stromal cells (fibroblasts and endothelial cells). Contrary to the wild-type virus, AdF512v1 was unable to replicate in normal human ovary samples while the wild-type virus can replicate. This study provides evidence on the lytic capacity of this CRAd and highlights the importance of targeting the stromal tissue in addition to the malignant cell compartment to achieve tumor regression. PMID:22948673

  13. Heterogeneity index evaluated by slope of linear regression on {sup 18}F-FDG PET/CT as a prognostic marker for predicting tumor recurrence in pancreatic ductal adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yong-il [CHA University, Department of Nuclear Medicine, CHA Bundang Medical Center, Seongnam (Korea, Republic of); Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Kim, Yong Joong [Veterans Health Service Medical Center, Seoul (Korea, Republic of); Paeng, Jin Chul; Cheon, Gi Jeong; Lee, Dong Soo [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Chung, June-Key [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University, Cancer Research Institute, Seoul (Korea, Republic of); Kang, Keon Wook [Seoul National University Hospital, Department of Nuclear Medicine, Seoul (Korea, Republic of); Seoul National University, Cancer Research Institute, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Biomedical Sciences, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of)

    2017-11-15

    {sup 18}F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of {sup 18}F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and {sup 18}F-FDG PET/CT parameters. A total of 93 pancreatic ductal adenocarcinoma patients (M:F = 60:33, mean age = 64.2 ± 9.1 years) who underwent preoperative {sup 18}F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each {sup 18}F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and {sup 18}F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence. Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence = 9.4 ± 8.4 months). Comparing the recurrence and no recurrence patients, all of the {sup 18}F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox-regression analyses, MTV (P = 0.013), TLG (P = 0.007), and heterogeneity index-2 (P = 0.027) were significant. Among the clinicopathologic parameters, CA19-9 (P = 0.025) and venous invasion (P = 0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P = 0.005), TLG (P = 0.004), and heterogeneity index-2 (P = 0.016) with venous invasion (P < 0.001, 0.001, and 0

  14. Dietary rice bran component γ-oryzanol inhibits tumor growth in tumor-bearing mice.

    Science.gov (United States)

    Kim, Sung Phil; Kang, Mi Young; Nam, Seok Hyun; Friedman, Mendel

    2012-06-01

    We investigated the effects of rice bran and components on tumor growth in mice. Mice fed standard diets supplemented with rice bran, γ-oryzanol, Ricetrienol®, ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet for two additional weeks. Tumor mass was significantly lower in the γ-oryzanol and less so in the phytic acid group. Tumor inhibition was associated with the following biomarkers: increases in cytolytic activity of splenic natural killer (NK) cells; partial restoration of nitric oxide production and phagocytosis in peritoneal macrophages increases in released the pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 from macrophages; and reductions in the number of blood vessels inside the tumor. Pro-angiogenic biomarkers vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and 5-lipoxygenase-5 (5-LOX) were also significantly reduced in mRNA and protein expression by tumor genes. ELISA of tumor cells confirmed reduced expression of COX-2 and 5-LOX up to 30%. Reduced COX-2 and 5-LOX expression downregulated VEGF and inhibited neoangiogenesis inside the tumors. Induction of NK activity, activation of macrophages, and inhibition of angiogenesis seem to contribute to the inhibitory mechanism of tumor regression by γ-oryzanol. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Enhanced responses to tumor immunization following total body irradiation are time-dependent.

    Directory of Open Access Journals (Sweden)

    Adi Diab

    Full Text Available The development of successful cancer vaccines is contingent on the ability to induce effective and persistent anti-tumor immunity against self-antigens that do not typically elicit immune responses. In this study, we examine the effects of a non-myeloablative dose of total body irradiation on the ability of tumor-naïve mice to respond to DNA vaccines against melanoma. We demonstrate that irradiation followed by lymphocyte infusion results in a dramatic increase in responsiveness to tumor vaccination, with augmentation of T cell responses to tumor antigens and tumor eradication. In irradiated mice, infused CD8(+ T cells expand in an environment that is relatively depleted in regulatory T cells, and this correlates with improved CD8(+ T cell functionality. We also observe an increase in the frequency of dendritic cells displaying an activated phenotype within lymphoid organs in the first 24 hours after irradiation. Intriguingly, both the relative decrease in regulatory T cells and increase in activated dendritic cells correspond with a brief window of augmented responsiveness to immunization. After this 24 hour window, the numbers of dendritic cells decline, as does the ability of mice to respond to immunizations. When immunizations are initiated within the period of augmented dendritic cell activation, mice develop anti-tumor responses that show increased durability as well as magnitude, and this approach leads to improved survival in experiments with mice bearing established tumors as well as in a spontaneous melanoma model. We conclude that irradiation can produce potent immune adjuvant effects independent of its ability to induce tumor ablation, and that the timing of immunization and lymphocyte infusion in the irradiated host are crucial for generating optimal anti-tumor immunity. Clinical strategies using these approaches must therefore optimize such parameters, as the correct timing of infusion and vaccination may mean the difference

  16. Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.

    Science.gov (United States)

    Shiromizu, Shoya; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

    2018-04-01

    Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  17. Bounded Gaussian process regression

    DEFF Research Database (Denmark)

    Jensen, Bjørn Sand; Nielsen, Jens Brehm; Larsen, Jan

    2013-01-01

    We extend the Gaussian process (GP) framework for bounded regression by introducing two bounded likelihood functions that model the noise on the dependent variable explicitly. This is fundamentally different from the implicit noise assumption in the previously suggested warped GP framework. We...... with the proposed explicit noise-model extension....

  18. Signaling Pathways Related to Protein Synthesis and Amino Acid Concentration in Pig Skeletal Muscles Depend on the Dietary Protein Level, Genotype and Developmental Stages.

    Science.gov (United States)

    Liu, Yingying; Li, Fengna; Kong, Xiangfeng; Tan, Bie; Li, Yinghui; Duan, Yehui; Blachier, François; Hu, Chien-An A; Yin, Yulong

    2015-01-01

    Muscle growth is regulated by the homeostatic balance of the biosynthesis and degradation of muscle proteins. To elucidate the molecular interactions among diet, pig genotype, and physiological stage, we examined the effect of dietary protein concentration, pig genotype, and physiological stages on amino acid (AA) pools, protein deposition, and related signaling pathways in different types of skeletal muscles. The study used 48 Landrace pigs and 48 pure-bred Bama mini-pigs assigned to each of 2 dietary treatments: lower/GB (Chinese conventional diet)- or higher/NRC (National Research Council)-protein diet. Diets were fed from 5 weeks of age to respective market weights of each genotype. Samples of biceps femoris muscle (BFM, type I) and longissimus dorsi muscle (LDM, type II) were collected at nursery, growing, and finishing phases according to the physiological stage of each genotype, to determine the AA concentrations, mRNA levels for growth-related genes in muscles, and protein abundances of mechanistic target of rapamycin (mTOR) signaling pathway. Our data showed that the concentrations of most AAs in LDM and BFM of pigs increased (Prelated AA, including Met, Phe, Tyr, Pro, and Ser, compared with Landrace pigs. The mRNA levels for myogenic determining factor, myogenin, myocyte-specific enhancer binding factor 2 A, and myostatin of Bama mini-pigs were higher (P<0.05) than those of Landrace pigs, while total and phosphorylated protein levels for protein kinase B, mTOR, and p70 ribosomal protein S6 kinases (p70S6K), and ratios of p-mTOR/mTOR, p-AKT/AKT, and p-p70S6K/p70S6K were lower (P<0.05). There was a significant pig genotype-dependent effect of dietary protein on the levels for mTOR and p70S6K. When compared with the higher protein-NRC diet, the lower protein-GB diet increased (P<0.05) the levels for mTOR and p70S6K in Bama mini-pigs, but repressed (P<0.05) the level for p70S6K in Landrace pigs. The higher protein-NRC diet increased ratio of p-mTOR/mTOR in

  19. Common genotypes of hepatitis B virus

    International Nuclear Information System (INIS)

    Idrees, M.; Khan, S.; Riazuddin, S.

    2004-01-01

    Objective: To find out the frequency of common genotypes of hepatitis-B virus (HBV). Subjects and Methods: HBV genotypes were determined in 112 HBV DNA positive sera by a simple and precise molecular genotyping system base on PCR using type-specific primers for the determination of genotypes of HBV A through H. Results: Four genotypes (A,B,C and D) out of total eight reported genotypes so far were identified. Genotypes A, B and C were predominant. HBV genotype C was the most predominant in this collection, appearing in 46 samples (41.7%). However, the genotypes of a total of 5 (4.46%) samples could not be determined with the present genotyping system. Mixed genotypes were seen in 8(7.14% HBV) isolates. Five of these were infected with genotypes A/D whereas two were with genotypes C/D. One patient was infected with 4 genotypes (A/B/C/D). Genotype A (68%) was predominant in Sindh genotype C was most predominant in North West Frontier Province (NWFP) (68.96) whereas genotype C and B were dominant in Punjab (39.65% and 25.86% respectively). Conclusion: All the four common genotypes of HBV found worldwide (A,B,C and D) were isolated. Genotype C is the predominant Genotypes B and C are predominant in Punjab and N.W.F.P. whereas genotype A is predominant in Sindh. (author)

  20. Multicollinearity and Regression Analysis

    Science.gov (United States)

    Daoud, Jamal I.

    2017-12-01

    In regression analysis it is obvious to have a correlation between the response and predictor(s), but having correlation among predictors is something undesired. The number of predictors included in the regression model depends on many factors among which, historical data, experience, etc. At the end selection of most important predictors is something objective due to the researcher. Multicollinearity is a phenomena when two or more predictors are correlated, if this happens, the standard error of the coefficients will increase [8]. Increased standard errors means that the coefficients for some or all independent variables may be found to be significantly different from In other words, by overinflating the standard errors, multicollinearity makes some variables statistically insignificant when they should be significant. In this paper we focus on the multicollinearity, reasons and consequences on the reliability of the regression model.

  1. Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli.

    Science.gov (United States)

    Rea, Kieran; Olango, Weredeselam M; Okine, Bright N; Madasu, Manish K; McGuire, Iseult C; Coyle, Kathleen; Harhen, Brendan; Roche, Michelle; Finn, David P

    2014-01-01

    Pain is both a sensory and an emotional experience, and is subject to modulation by a number of factors including genetic background modulating stress/affect. The Wistar-Kyoto (WKY) rat exhibits a stress-hyper-responsive and depressive-like phenotype and increased sensitivity to noxious stimuli, compared with other rat strains. Here, we show that this genotype-dependent hyperalgesia is associated with impaired pain-related mobilisation of endocannabinoids and transcription of their synthesising enzymes in the rostral ventromedial medulla (RVM). Pharmacological blockade of the Cannabinoid1 (CB1) receptor potentiates the hyperalgesia in WKY rats, whereas inhibition of the endocannabinoid catabolising enzyme, fatty acid amide hydrolase, attenuates the hyperalgesia. The latter effect is mediated by CB1 receptors in the RVM. Together, these behavioural, neurochemical, and molecular data indicate that impaired endocannabinoid signalling in the RVM underpins hyper-responsivity to noxious stimuli in a genetic background prone to heightened stress/affect. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  2. Testing GxG interactions between coinfecting microbial parasite genotypes within hosts

    Directory of Open Access Journals (Sweden)

    Rebecca D Schulte

    2014-05-01

    Full Text Available Host-parasite interactions represent one of the strongest selection pressures in nature. They are often governed by genotype-specific (GxG interactions resulting in host genotypes that differ in resistance and parasite genotypes that differ in virulence depending on the antagonist’s genotype. Another type of GxG interactions, which is often neglected but which certainly influences host-parasite interactions, are those between coinfecting parasite genotypes. Mechanistically, within-host parasite interactions may range from competition for limited host resources to cooperation for more efficient host exploitation. The exact type of interaction, i.e. whether competitive or cooperative, is known to affect life-history traits such as virulence. However, the latter has been shown for chosen genotype combinations only, not considering whether the specific genotype combination per se may influence the interaction (i.e. GxG interactions. Here, we want to test for the presence of GxG interactions between coinfections of the bacterium Bacillus thuringiensis infecting the nematode Caenorhabditis elegans by combining two non-pathogenic and five pathogenic strains in all possible ways. Furthermore, we evaluate whether the type of interaction, reflected by the direction of virulence change of multiple compared to single infections, is genotype-specific. Generally, we found no indication for GxG interactions between non-pathogenic and pathogenic bacterial strains, indicating that virulence of pathogenic strains is equally affected by both non-pathogenic strains. Specific genotype combinations, however, differ in the strength of virulence change, indicating that the interaction type between coinfecting parasite strains and thus the virulence mechanism is specific for different genotype combinations. Such interactions are expected to influence host-parasite interactions and to have strong implications for coevolution.

  3. William Bradley Coley, MD, and the phenomenon of spontaneous regression

    Directory of Open Access Journals (Sweden)

    Vernon LF

    2018-04-01

    Full Text Available Leonard F Vernon Sherman College of Chiropractic, Spartanburg, SC, USA Abstract: The standard definition of spontaneous regression (SR of cancer is as follows, “…when a malignant tumor partially or completely disappears without treatment or in the presence of therapy which is considered inadequate to exert a significant influence on neoplastic disease.” SR is also known as Saint Peregrine tumor, the name taken from a young priest, Peregrine Laziosi (1260 [5]–1345, exact date is unknown, who had been diagnosed with a tumor of the tibia. The mass eventually grew so large that it broke through the skin and became severely infected. The available treatment for this condition was limited to amputation. Historical records report that on the day of surgery, physicians found that the tumor had disappeared and reportedly never returned. To date, the medical literature consists only of individual case studies and overviews of this phenomenon. The most cited work on the subject was done by surgeons Tilden Everson and Warren Cole who reviewed 176 published cases of SR from 1900 to 1960. While a percentage of these were found not to be cases of SR, there remained a number of unexplained cases. A frequent theme in many cases of SR is the co-occurrence of infection. Given the current interest in immunotherapy in the treatment of cancer, this article discusses one of the very early pioneers of this theory, William Bradley Coley, MD, a surgeon who was clearly ahead of his time. Ostracized by colleagues for his belief that stimulation of the immune system could in fact produce a regression of cancer, Coley remained convinced that his theory was right and, while he was not familiar with cytokines such as tumor necrosis factor (TNF, interferons, and streptokinase, he knew instinctively that an innate immune response was taking place. Keywords: autoimmunity, cancer, fever, infection, immunotherapy, tumor, cytokines

  4. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Jatin Roper

    Full Text Available To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC.PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined.In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC(50 = 9.0-14.3 nM. Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01 vs. a 43% decrease (p = 0.008 in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003, no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013.These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC.

  5. Effect of Planting Date on Cold Tolerance of Winter and Spring Barley Genotypes

    Directory of Open Access Journals (Sweden)

    A. R. Eivazi

    2015-01-01

    Full Text Available In order to evaluate cold tolerance of twenty barley genotypes under field conditions, an experiment was carried out in a randomized complete block design at 3 sowing dates of October 5, November 5, and December 5 in Saatlu Agricultural Research Station, West Azarbaijan, Iran, during 2010-11 seasons. Also, another experiment was conducted on the same genotypes based on a completely randomized design under greenhouse conditions. in wich Cold stress was applied up to -25°C at two, four and six leaf development stages. LT50, ion leakage and dry matter were measured and apex photographed. Field experiment results showed the lowest significant differences at p≤0.05 between different levels of sowing date, genotype, and interaction between them for plant height, spike/m2, kernel per spike, 1000-kernel weight, grain yield and total dry matter. Genotypes of winter growth type had higher grain yield (4250kg/ha than those with spring growth type (4190kg/ha. There were significant differences for ion leakage and dry matter at 4 and 6 leaf development stages under greenhouse conditions. Genotype 1 (winter growth type with lowest values of range and standard deviation for grain yield, total dry matter and LT50 = -38 °C showed a relatively low ion leakage. In contrast, genotypes 5, 10 and 14 (spring growth type were identified sensitive to cold stress due to having more values of range, standard deviation for grain yield and total dry matter, LT50 = -18 to -27 °C and ion leakage from 25 to 33µS/m. Regression analysis showed 1000-kernel weight and total dry matter to remain at final model. Cluster analysis indicated that genotypes 2, 18, 1, 17 and 19 were superior genotypes. In principal component analysis, four components showed 80% of total variations, and the first component with 26% of variation was an important yield component for improving grain yield of barley genotypes. In conclusion, grain yields of winter and spring barley genotypes were

  6. Power calculations for likelihood ratio tests for offspring genotype risks, maternal effects, and parent-of-origin (POO) effects in the presence of missing parental genotypes when unaffected siblings are available.

    Science.gov (United States)

    Rampersaud, E; Morris, R W; Weinberg, C R; Speer, M C; Martin, E R

    2007-01-01

    Genotype-based likelihood-ratio tests (LRT) of association that examine maternal and parent-of-origin effects have been previously developed in the framework of log-linear and conditional logistic regression models. In the situation where parental genotypes are missing, the expectation-maximization (EM) algorithm has been incorporated in the log-linear approach to allow incomplete triads to contribute to the LRT. We present an extension to this model which we call the Combined_LRT that incorporates additional information from the genotypes of unaffected siblings to improve assignment of incompletely typed families to mating type categories, thereby improving inference of missing parental data. Using simulations involving a realistic array of family structures, we demonstrate the validity of the Combined_LRT under the null hypothesis of no association and provide power comparisons under varying levels of missing data and using sibling genotype data. We demonstrate the improved power of the Combined_LRT compared with the family-based association test (FBAT), another widely used association test. Lastly, we apply the Combined_LRT to a candidate gene analysis in Autism families, some of which have missing parental genotypes. We conclude that the proposed log-linear model will be an important tool for future candidate gene studies, for many complex diseases where unaffected siblings can often be ascertained and where epigenetic factors such as imprinting may play a role in disease etiology.

  7. TH-E-BRF-01: Exploiting Tumor Shrinkage in Split-Course Radiotherapy

    International Nuclear Information System (INIS)

    Unkelbach, J; Craft, D; Hong, T; Papp, D; Wolfgang, J; Bortfeld, T; Ramakrishnan, J; Salari, E

    2014-01-01

    Purpose: In split-course radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated by radiobiological considerations. However, using modern image-guidance, it also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. In this work, we consider the optimal design of split-course treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. Methods: We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cell repopulation. The design of splitcourse radiotherapy is formulated as a mathematical optimization problem in which the total dose to the liver is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. Results: We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one third of the dose should be delivered in the first stage. The projected benefit of split-course treatments in terms of liver sparing depends on model assumptions. However, the model predicts large liver dose reductions by more than a factor of two for plausible model parameters. Conclusion: The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at split-course radiotherapy for selected disease sites where substantial tumor regression translates into reduced

  8. TH-E-BRF-01: Exploiting Tumor Shrinkage in Split-Course Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Unkelbach, J; Craft, D; Hong, T; Papp, D; Wolfgang, J; Bortfeld, T [Massachusetts General Hospital, Boston, MA (United States); Ramakrishnan, J [University of Wisconsin, Madison, Wisconsin (United States); Salari, E [Wichita State University, Wichita, KS (United States)

    2014-06-15

    Purpose: In split-course radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated by radiobiological considerations. However, using modern image-guidance, it also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. In this work, we consider the optimal design of split-course treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. Methods: We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cell repopulation. The design of splitcourse radiotherapy is formulated as a mathematical optimization problem in which the total dose to the liver is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. Results: We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one third of the dose should be delivered in the first stage. The projected benefit of split-course treatments in terms of liver sparing depends on model assumptions. However, the model predicts large liver dose reductions by more than a factor of two for plausible model parameters. Conclusion: The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at split-course radiotherapy for selected disease sites where substantial tumor regression translates into reduced

  9. An improved multiple linear regression and data analysis computer program package

    Science.gov (United States)

    Sidik, S. M.

    1972-01-01

    NEWRAP, an improved version of a previous multiple linear regression program called RAPIER, CREDUC, and CRSPLT, allows for a complete regression analysis including cross plots of the independent and dependent variables, correlation coefficients, regression coefficients, analysis of variance tables, t-statistics and their probability levels, rejection of independent variables, plots of residuals against the independent and dependent variables, and a canonical reduction of quadratic response functions useful in optimum seeking experimentation. A major improvement over RAPIER is that all regression calculations are done in double precision arithmetic.

  10. Genotypic to expression profiling of bovine calcium channel, voltage-dependent, alpha-2/delta subunit 1 gene, and their association with bovine mastitis among Frieswal (HFX Sahiwal) crossbred cattle of Indian origin.

    Science.gov (United States)

    Deb, Rajib; Singh, Umesh; Kumar, Sushil; Kumar, Arun; Singh, Rani; Sengar, Gyanendra; Mann, Sandeep; Sharma, Arjava

    2014-04-03

    Calcium channel, voltage-dependent, alpha-2/delta subunit 1 (CACNA2D1) gene is considered to be an important noncytokine candidate gene influencing mastitis. Scanty of reports are available until today regarding the role play of CACNA2D1 gene on the susceptibility of bovine mastitis. We interrogated the CACNA2D1 G519663A [A>G] SNP by PCR-RFLP among two hundreds Frieswal (HF X Sahiwal) crossbred cattle of Indian origin. Genotypic frequency of AA (51.5, n=101) was comparatively higher than AG (35, n=70) and GG (14.5, n=29). Association of Somatic cell score (SCS) with genotypes revealed that, GG genotypes showing lesser count (less susceptible to mastitis) compare to AA and AG. Relative expression of CACNA2D1 transcript (in milk samples) was significantly higher among GG than AG and AA. Further we have also isolated blood sample from the all groups and PBMCs were cultured from each blood sample as per the standard protocol. They were treated with Calcium channel blocker and the expression level of the CACNA2D1 gene was evaluated by Real Time PCR. Results show that expression level decline in each genotypic group after treatment and expression level of GG are again significantly higher than AA and AG. Thus, it may be concluded that GG genotypic animals are favorable for selecting disease resistant breeds.

  11. Direction of Effects in Multiple Linear Regression Models.

    Science.gov (United States)

    Wiedermann, Wolfgang; von Eye, Alexander

    2015-01-01

    Previous studies analyzed asymmetric properties of the Pearson correlation coefficient using higher than second order moments. These asymmetric properties can be used to determine the direction of dependence in a linear regression setting (i.e., establish which of two variables is more likely to be on the outcome side) within the framework of cross-sectional observational data. Extant approaches are restricted to the bivariate regression case. The present contribution extends the direction of dependence methodology to a multiple linear regression setting by analyzing distributional properties of residuals of competing multiple regression models. It is shown that, under certain conditions, the third central moments of estimated regression residuals can be used to decide upon direction of effects. In addition, three different approaches for statistical inference are discussed: a combined D'Agostino normality test, a skewness difference test, and a bootstrap difference test. Type I error and power of the procedures are assessed using Monte Carlo simulations, and an empirical example is provided for illustrative purposes. In the discussion, issues concerning the quality of psychological data, possible extensions of the proposed methods to the fourth central moment of regression residuals, and potential applications are addressed.

  12. Impact of inter-genotypic recombination and probe cross-reactivity on the performance of the Abbott RealTime HCV Genotype II assay for hepatitis C genotyping.

    Science.gov (United States)

    Sridhar, Siddharth; Yip, Cyril C Y; Chan, Jasper F W; To, Kelvin K W; Cheng, Vincent C C; Yuen, Kwok-Yung

    2018-05-01

    The Abbott RealTime HCV Genotype II assay (Abbott-RT-HCV assay) is a real-time PCR based genotyping method for hepatitis C virus (HCV). This study measured the impact of inter-genotypic recombination and probe cross-reactivity on the performance of the Abbott-RT-HCV assay. 517 samples were genotyped using the Abbott-RT-HCV assay over a one-year period, 34 (6.6%) were identified as HCV genotype 1 without further subtype designation raising the possibility of inaccurate genotyping. These samples were subjected to confirmatory sequencing. 27 of these 34 (79%) samples were genotype 1b while five (15%) were genotype 6. One HCV isolate was an inter-genotypic 1a/4o recombinant. This is a novel natural HCV recombinant that has never been reported. Inter-genotypic recombination and probe cross-reactivity can affect the accuracy of the Abbott-RT-HCV assay, both of which have significant implications on antiviral regimen choice. Confirmatory sequencing of ambiguous results is crucial for accurate genotyping. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Photodynamic Therapy of the Murine LM3 Tumor Using Meso-Tetra (4-N,N,N-Trimethylanilinium) Porphine.

    Science.gov (United States)

    Colombo, L L; Juarranz, A; Cañete, M; Villanueva, A; Stockert, J C

    2007-12-01

    Photodynamic therapy (PDT) of cancer is based on the cytotoxicity induced by a photosensitizer in the presence of oxygen and visible light, resulting in cell death and tumor regression. This work describes the response of the murine LM3 tumor to PDT using meso-tetra (4-N,N,N-trimethylanilinium) porphine (TMAP). BALB/c mice with intradermal LM3 tumors were subjected to intravenous injection of TMAP (4 mg/kg) followed 24 h later by blue-red light irradiation (λmax: 419, 457, 650 nm) for 60 min (total dose: 290 J/cm(2)) on depilated and glycerol-covered skin over the tumor of anesthetized animals. Control (drug alone, light alone) and PDT treatments (drug + light) were performed once and repeated 48 h later. No significant differences were found between untreated tumors and tumors only treated with TMAP or light. PDT-treated tumors showed almost total but transitory tumor regression (from 3 mm to less than 1 mm) in 8/9 animals, whereas no regression was found in 1/9. PDT response was heterogeneous and each tumor showed different regression and growth delay. The survival of PDT-treated animals was significantly higher than that of TMAP and light controls, showing a lower number of lung metastasis but increased tumor-draining lymph node metastasis. Repeated treatment and reduction of tissue light scattering by glycerol could be useful approaches in studies on PDT of cancer.

  14. Evaluation of the Abbott Real Time HCV genotype II assay for Hepatitis C virus genotyping.

    Science.gov (United States)

    Sariguzel, Fatma Mutlu; Berk, Elife; Gokahmetoglu, Selma; Ercal, Baris Derya; Celik, Ilhami

    2015-01-01

    The determination of HCV genotypes and subtypes is very important for the selection of antiviral therapy and epidemiological studies. The aim of this study was to evaluate the performance of Abbott Real Time HCV Genotype II assay in HCV genotyping of HCV infected patients in Kayseri, Turkey. One hundred patients with chronic hepatitis C admitted to our hospital were evaluated between June 2012 and December 2012, HCV RNA levels were determined by the COBAS® AmpliPrep/COBAS® TaqMan® 48 HCV test. HCV genotyping was investigated by the Abbott Real Time HCV Genotype II assay. With the exception of genotype 1, subtypes of HCV genotypes could not be determined by Abbott assay. Sequencing analysis was used as the reference method. Genotypes 1, 2, 3 and 4 were observed in 70, 4, 2 and 24 of the 100 patients, respectively, by two methods. The concordance between the two systems to determine HCV major genotypes was 100%. Of 70 patients with genotype 1, 66 showed infection with subtype 1b and 4 with subtype 1a by Abbott Real Time HCV Genotype II assay. Using sequence analysis, 61 showed infection with subtype 1b and 9 with subtype 1a. In determining of HCV genotype 1 subtypes, the difference between the two methods was not statistically significant (P>0.05). HCV genotype 4 and 3 samples were found to be subtype 4d and 3a, respectively, by sequence analysis. There were four patients with genotype 2. Sequence analysis revealed that two of these patients had type 2a and the other two had type 2b. The Abbott Real Time HCV Genotype II assay yielded results consistent with sequence analysis. However, further optimization of the Abbott Real Time HCV Genotype II assay for subtype identification of HCV is required.

  15. Association between number of cell phone contracts and brain tumor incidence in nineteen U.S. States.

    Science.gov (United States)

    Lehrer, Steven; Green, Sheryl; Stock, Richard G

    2011-02-01

    Some concern has arisen about adverse health effects of cell phones, especially the possibility that the low power microwave-frequency signal transmitted by the antennas on handsets might cause brain tumors or accelerate the growth of subclinical tumors. We analyzed data from the Statistical Report: Primary Brain Tumors in the United States, 2000-2004 and 2007 cell phone subscription data from the Governing State and Local Sourcebook. There was a significant correlation between number of cell phone subscriptions and brain tumors in nineteen US states (r = 0.950, P cell phone subscriptions and brain tumors could be due solely to the fact that some states, such as New York, have much larger populations than other states, such as North Dakota, multiple linear regression was performed with number of brain tumors as the dependent variable, cell phone subscriptions, population, mean family income and mean age as independent variables. The effect of cell phone subscriptions was significant (P = 0.017), and independent of the effect of mean family income (P = 0.894), population (P = 0.003) and age (0.499). The very linear relationship between cell phone usage and brain tumor incidence is disturbing and certainly needs further epidemiological evaluation. In the meantime, it would be prudent to limit exposure to all sources of electro-magnetic radiation.

  16. Regression modeling of ground-water flow

    Science.gov (United States)

    Cooley, R.L.; Naff, R.L.

    1985-01-01

    Nonlinear multiple regression methods are developed to model and analyze groundwater flow systems. Complete descriptions of regression methodology as applied to groundwater flow models allow scientists and engineers engaged in flow modeling to apply the methods to a wide range of problems. Organization of the text proceeds from an introduction that discusses the general topic of groundwater flow modeling, to a review of basic statistics necessary to properly apply regression techniques, and then to the main topic: exposition and use of linear and nonlinear regression to model groundwater flow. Statistical procedures are given to analyze and use the regression models. A number of exercises and answers are included to exercise the student on nearly all the methods that are presented for modeling and statistical analysis. Three computer programs implement the more complex methods. These three are a general two-dimensional, steady-state regression model for flow in an anisotropic, heterogeneous porous medium, a program to calculate a measure of model nonlinearity with respect to the regression parameters, and a program to analyze model errors in computed dependent variables such as hydraulic head. (USGS)

  17. Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development.

    Science.gov (United States)

    Metzler, Veronika M; de Brot, Simone; Robinson, Robert S; Jeyapalan, Jennie N; Rakha, Emad; Walton, Thomas; Gardner, David S; Lund, Emma F; Whitchurch, Jonathan; Haigh, Daisy; Lochray, Jack M; Robinson, Brian D; Allegrucci, Cinzia; Fray, Rupert G; Persson, Jenny L; Ødum, Niels; Miftakhova, Regina R; Rizvanov, Albert A; Hughes, Ieuan A; Tadokoro-Cuccaro, Rieko; Heery, David M; Rutland, Catrin S; Mongan, Nigel P

    2017-08-01

    The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases. Therefore the development of novel angiogenesis inhibitors has been an area of active research in oncology. A subset of the molecular processes regulating angiogenesis are well understood in the context of both early placentation and tumorigenesis. In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR are essential for normal male embryonic development, puberty and lifelong health. Defects in androgen signalling are associated with a diverse range of clinical disorders in men and women including disorders of sex development (DSD), polycystic ovary syndrome in women and many cancers. We summarize the diverse molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further delineate the role of androgen signalling in placental function and maternal and offspring health in animal models. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Robust Image Regression Based on the Extended Matrix Variate Power Exponential Distribution of Dependent Noise.

    Science.gov (United States)

    Luo, Lei; Yang, Jian; Qian, Jianjun; Tai, Ying; Lu, Gui-Fu

    2017-09-01

    Dealing with partial occlusion or illumination is one of the most challenging problems in image representation and classification. In this problem, the characterization of the representation error plays a crucial role. In most current approaches, the error matrix needs to be stretched into a vector and each element is assumed to be independently corrupted. This ignores the dependence between the elements of error. In this paper, it is assumed that the error image caused by partial occlusion or illumination changes is a random matrix variate and follows the extended matrix variate power exponential distribution. This has the heavy tailed regions and can be used to describe a matrix pattern of l×m dimensional observations that are not independent. This paper reveals the essence of the proposed distribution: it actually alleviates the correlations between pixels in an error matrix E and makes E approximately Gaussian. On the basis of this distribution, we derive a Schatten p -norm-based matrix regression model with L q regularization. Alternating direction method of multipliers is applied to solve this model. To get a closed-form solution in each step of the algorithm, two singular value function thresholding operators are introduced. In addition, the extended Schatten p -norm is utilized to characterize the distance between the test samples and classes in the design of the classifier. Extensive experimental results for image reconstruction and classification with structural noise demonstrate that the proposed algorithm works much more robustly than some existing regression-based methods.

  19. Tumor clone dynamics in lethal prostate cancer.

    Science.gov (United States)

    Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane; Grist, Emily; Ferraldeschi, Roberta; Miranda, Susana; Prandi, Davide; Lorente, David; Frenel, Jean-Sebastien; Pezaro, Carmel; Omlin, Aurelius; Rodrigues, Daniel Nava; Flohr, Penelope; Tunariu, Nina; S de Bono, Johann; Demichelis, Francesca; Attard, Gerhardt

    2014-09-17

    It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers. Copyright © 2014, American Association for the Advancement of Science.

  20. Regression of a vaginal leiomyoma after ovariohysterectomy in a dog: a case report.

    Science.gov (United States)

    Sathya, Suresh; Linn, Kathleen

    2014-01-01

    An 11 yr old female mixed-breed Siberian husky was presented with a history of sanguineous vaginal discharge, swelling of the perineal area, decreased appetite, and lethargy. A single, large vaginal leiomyoma and multiple mammary tumors were diagnosed. Mastectomy and ovariohysterectomy were performed. The vaginal leiomyoma regressed completely after ovariohysterectomy. This is the first reported case of spontaneous regression of a vaginal leiomyoma after ovariohysterectomy in a dog.

  1. Preoperative intraluminal irradiation of the extrahepatic bile duct tumor

    International Nuclear Information System (INIS)

    Kamada, Tadashi; Tsujii, Hirohiko; Arimoto, Takuro; Irie, Goro.

    1991-01-01

    From 1984 through 1986, six patients with extrahepatic bile duct tumor were treated preoperatively with intraluminal irradiation of the bile duct. There were no unresectable cases and pathological examination of the surgical specimens showed moderate to remarkable tumor regression in all cases. Postoperative biliary tract hemorrhage occurred in 2 of 3 patients who received 60 Gy at a point 7.5 mm from the center of the source. With accurate preoperative diagnosis of the tumor extent and careful setting of the target area of intraluminal irradiation, improved local tumor control of extrahepatic bile duct tumor can be expected with this method. (author)

  2. PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.

    Science.gov (United States)

    Sherenian, M G; Cho, S H; Levin, A; Min, J-Y; Oh, S S; Hu, D; Galanter, J; Sen, S; Huntsman, S; Eng, C; Rodriguez-Santana, J R; Serebrisky, D; Avila, P C; Kalhan, R; Smith, L J; Borrell, L N; Seibold, M A; Keoki Williams, L; Burchard, E G; Kumar, R

    2017-09-01

    PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma. We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function. There was an interaction between asthma status and the PAI-1 polymorphism on FEV 1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV 1 /FVC in subjects with asthma (β=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV 1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. The decrease in the FEV 1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation. © 2017

  3. Interaction between parental environment and genotype affects plant and seed performance in Arabidopsis

    NARCIS (Netherlands)

    He, H.; Souza Vidigal, De D.; Snoek, L.B.; Schnabel, S.K.; Nijveen, H.; Hilhorst, H.; Bentsink, L.

    2014-01-01

    Seed performance after dispersal is highly dependent on parental environmental cues, especially during seed formation and maturation. Here we examine which environmental factors are the most dominant in this respect and whether their effects are dependent on the genotypes under investigation. We

  4. Model-Independent Evaluation of Tumor Markers and a Logistic-Tree Approach to Diagnostic Decision Support

    Directory of Open Access Journals (Sweden)

    Weizeng Ni

    2014-01-01

    Full Text Available Sensitivity and specificity of using individual tumor markers hardly meet the clinical requirement. This challenge gave rise to many efforts, e.g., combing multiple tumor markers and employing machine learning algorithms. However, results from different studies are often inconsistent, which are partially attributed to the use of different evaluation criteria. Also, the wide use of model-dependent validation leads to high possibility of data overfitting when complex models are used for diagnosis. We propose two model-independent criteria, namely, area under the curve (AUC and Relief to evaluate the diagnostic values of individual and multiple tumor markers, respectively. For diagnostic decision support, we propose the use of logistic-tree which combines decision tree and logistic regression. Application on a colorectal cancer dataset shows that the proposed evaluation criteria produce results that are consistent with current knowledge. Furthermore, the simple and highly interpretable logistic-tree has diagnostic performance that is competitive with other complex models.

  5. A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of PTEN Status on Tumor Response.

    Science.gov (United States)

    Xiao, Zhan; Carrasco, Rosa A; Schifferli, Kevin; Kinneer, Krista; Tammali, Ravinder; Chen, Hong; Rothstein, Ray; Wetzel, Leslie; Yang, Chunning; Chowdhury, Partha; Tsui, Ping; Steiner, Philipp; Jallal, Bahija; Herbst, Ronald; Hollingsworth, Robert E; Tice, David A

    2016-04-01

    HER3/ERBB3 is a kinase-deficient member of the EGFR family receptor tyrosine kinases (RTK) that is broadly expressed and activated in human cancers. HER3 is a compelling cancer target due to its important role in activation of the oncogenic PI3K/AKT pathway. It has also been demonstrated to confer tumor resistance to a variety of cancer therapies, especially targeted drugs against EGFR and HER2. HER3 can be activated by its ligand (heregulin/HRG), which induces HER3 heterodimerization with EGFR, HER2, or other RTKs. Alternatively, HER3 can be activated in a ligand-independent manner through heterodimerization with HER2 in HER2-amplified cells. We developed a fully human mAb against HER3 (KTN3379) that efficiently suppressed HER3 activity in both ligand-dependent and independent settings. Correspondingly, KTN3379 inhibited tumor growth in divergent tumor models driven by either ligand-dependent or independent mechanisms in vitro and in vivo Most intriguingly, while investigating the mechanistic underpinnings of tumor response to KTN3379, we discovered an interesting dichotomy in that PTEN loss, a frequently occurring oncogenic lesion in a broad range of cancer types, substantially blunted the tumor response in HER2-amplified cancer, but not in the ligand-driven cancer. To our knowledge, this represents the first study ascertaining the impact of PTEN loss on the antitumor efficacy of a HER3 mAb. KTN3379 is currently undergoing a phase Ib clinical trial in patients with advanced solid tumors. Our current study may help us optimize patient selection schemes for KTN3379 to maximize its clinical benefits. Mol Cancer Ther; 15(4); 689-701. ©2016 AACR. ©2016 American Association for Cancer Research.

  6. Cow genotyping strategies for genomic selection in a small dairy cattle population.

    Science.gov (United States)

    Jenko, J; Wiggans, G R; Cooper, T A; Eaglen, S A E; Luff, W G de L; Bichard, M; Pong-Wong, R; Woolliams, J A

    2017-01-01

    This study compares how different cow genotyping strategies increase the accuracy of genomic estimated breeding values (EBV) in dairy cattle breeds with low numbers. In these breeds, few sires have progeny records, and genotyping cows can improve the accuracy of genomic EBV. The Guernsey breed is a small dairy cattle breed with approximately 14,000 recorded individuals worldwide. Predictions of phenotypes of milk yield, fat yield, protein yield, and calving interval were made for Guernsey cows from England and Guernsey Island using genomic EBV, with training sets including 197 de-regressed proofs of genotyped bulls, with cows selected from among 1,440 genotyped cows using different genotyping strategies. Accuracies of predictions were tested using 10-fold cross-validation among the cows. Genomic EBV were predicted using 4 different methods: (1) pedigree BLUP, (2) genomic BLUP using only bulls, (3) univariate genomic BLUP using bulls and cows, and (4) bivariate genomic BLUP. Genotyping cows with phenotypes and using their data for the prediction of single nucleotide polymorphism effects increased the correlation between genomic EBV and phenotypes compared with using only bulls by 0.163±0.022 for milk yield, 0.111±0.021 for fat yield, and 0.113±0.018 for protein yield; a decrease of 0.014±0.010 for calving interval from a low base was the only exception. Genetic correlation between phenotypes from bulls and cows were approximately 0.6 for all yield traits and significantly different from 1. Only a very small change occurred in correlation between genomic EBV and phenotypes when using the bivariate model. It was always better to genotype all the cows, but when only half of the cows were genotyped, a divergent selection strategy was better compared with the random or directional selection approach. Divergent selection of 30% of the cows remained superior for the yield traits in 8 of 10 folds. Copyright © 2017 American Dairy Science Association. Published by

  7. Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy.

    Science.gov (United States)

    Kaliff, Malin; Sorbe, Bengt; Mordhorst, Louise Bohr; Helenius, Gisela; Karlsson, Mats G; Lillsunde-Larsson, Gabriella

    2018-04-10

    Cervical cancer (CC) is one of the most common cancers in women and virtually all cases of CC are a result of a persistent infection of human papillomavirus (HPV). For disease detected in early stages there is curing treatment but when diagnosed late with recurring disease and metastasis there are limited possibilities. Here we evaluate HPV impact on treatment resistance and metastatic disease progression. Prevalence and distribution of HPV genotypes and HPV16 variants in a Swedish CC patient cohort (n=209) was evaluated, as well as HPV influence on patient prognosis. Tumor samples suitable for analysis (n=204) were genotyped using two different real-time PCR methods. HPV16 variant analysis was made using pyrosequencing. Results showed that HPV prevalence in the total series was 93%. Of the HPV-positive samples, 13% contained multiple infections, typically with two high-risk HPV together. Primary cure rate for the complete series was 95%. Recurrence rate of the complete series was 28% and distant recurrences were most frequent (20%). Patients with tumors containing multiple HPV-strains and particularly HPV genotypes belonging to the alpha 7 and 9 species together had a significantly higher rate of distant tumor recurrences and worse cancer-specific survival rate.

  8. The association of complex liver disorders with HBV genotypes prevalent in Pakistan

    Directory of Open Access Journals (Sweden)

    Qureshi Huma

    2007-11-01

    Full Text Available Abstract Background Genotyping of HBV is generally used for determining the epidemiological relationship between various virus strains and origin of infection mostly in research studies. The utility of genotyping for clinical applications is only beginning to gain importance. Whether HBV genotyping will constitute part of the clinical evaluation of Hepatitis B patients depends largely on the availability of the relevance of the evidence based information. Since Pakistan has a HBV genotype distribution which has been considered less virulent as investigated by earlier studies from south East Asian countries, a study on correlation between HBV genotypes and risk of progression to further complex hepatic infection was much needed Methods A total of 295 patients with HBsAg positive were selected from the Pakistan Medical Research Council's (PMRC out patient clinics. Two hundred and twenty six (77% were males, sixty nine (23% were females (M to F ratio 3.3:1. Results Out of 295 patients, 156 (53.2% had Acute(CAH, 71 (24.2% were HBV Carriers, 54 (18.4% had Chronic liver disease (CLD Hepatitis. 14 (4.7% were Cirrhosis and HCC patients. Genotype D was the most prevalent genotype in all categories of HBV patients, Acute (108, Chronic (39, and Carrier (53. Cirrhosis/HCC (7 were HBV/D positive. Genotype A was the second most prevalent with 28 (13% in acute cases, 12 (22.2% in chronics, 14 (19.7% in carriers and 5 (41.7 in Cirrhosis/HCC patients. Mixed genotype (A/D was found in 20 (12.8% of Acute patients, 3 (5.6% of Chronic and 4 (5.6% of carriers, none in case of severe liver conditions. Conclusion Mixed HBV genotypes A, D and A/D combination were present in all categories of patients except that no A/D combination was detected in severe conditions. Genotype D was the dominant genotype. However, genotype A was found to be more strongly associated with severe liver disease. Mixed genotype (A/D did not significantly appear to influence the clinical outcome.

  9. Enhancement of radioresponse by combined treatment with flavopiridol, a cycline dependent kinase (CDK) inhibitor, in oral cancer cells

    International Nuclear Information System (INIS)

    Mihara, Mariko; Mano, Takamitsu; Ueyama, Yoshiya; Shintani, Satoru; Li, Syunnann; Klosek, S.; Hamakawa, Hiroyuki

    2005-01-01

    Cyclin dependent kinases (CDKs) play a pivotal role in cell cycle regulation. Flavopiridol is known to potently inhibit such CDKs as CDK1, CDK2, CDK4, CDK7. We already reported that flavopiridol inhibited the growth of oral squamous cell carcinoma (OSCC) cells and induced apoptosis in OSCC cells. In the present study, we investigated whether the treatment with flavopiridol improves the response to radiosensitivity in OSCC cell lines. In an in vitro study, there was a cooperative antiproliferative effect of combined treatment with flavopiridol and radiation in OSCC cell lines. Tumor xenograft studies demonstrated that the combination of flavopiridol and radiation caused growth inhibition and tumor regression of well-established OSCC tumor in athymic mice. Overall, we concluded that flavopiridol enhances tumor radioresponse and it is considered a suitable candidate drug in the treatment of oral cancer. (author)

  10. Connecting functional and statistical definitions of genotype by genotype interactions in coevolutionary studies

    Directory of Open Access Journals (Sweden)

    Katy Denise Heath

    2014-04-01

    Full Text Available Predicting how species interactions evolve requires that we understand the mechanistic basis of coevolution, and thus the functional genotype-by-genotype interactions (G × G that drive reciprocal natural selection. Theory on host-parasite coevolution provides testable hypotheses for empiricists, but depends upon models of functional G × G that remain loosely tethered to the molecular details of any particular system. In practice, reciprocal cross-infection studies are often used to partition the variation in infection or fitness in a population that is attributable to G × G (statistical G × G. Here we use simulations to demonstrate that within-population statistical G × G likely tells us little about the existence of coevolution, its strength, or the genetic basis of functional G × G. Combined with studies of multiple populations or points in time, mapping and molecular techniques can bridge the gap between natural variation and mechanistic models of coevolution, while model-based statistics can formally confront coevolutionary models with cross-infection data. Together these approaches provide a robust framework for inferring the infection genetics underlying statistical G × G, helping unravel the genetic basis of coevolution.

  11. Genotypic frequency of Caveolin-1 (CAV1 T29107A polymorphism in the Iranian patients with breast cancer

    Directory of Open Access Journals (Sweden)

    Ahmad Hamta

    2016-09-01

    Full Text Available Introduction: Caveolin-1 (Cav-1 is a scaffolding protein found in special structures of plasma membrane, known as Caveolae. Cav-1 can regulate many intracellular processes, including signal transmission and cholesterol metabolism. This protein plays an important role in the growth and differentiation of breast tissue and acts as a tumor suppressor gene as well. The aim of this study was to determine the genotypic frequency of Cav-1 T29107A (rs7804372 polymorphism and its association with susceptibility to breast cancer among the female population in Kermanshah, Iran. Methods: A total of 120 patients with breast cancer and an equal number of non-cancer individuals (control group, matched for age and gender with the patients, were selected in this study. The paraffin tissues of the patients from 2006 to 2013 were collected from Imam Reza hospital, Kermanshah, and 2.5 cc blood sample was taken from non-cancer individuals. The genomic DNA was extracted from paraffin tissues and blood by salting out method. The genotype of samples was determined by RFLP-PCR method, and Sau3A1 enzyme was used for RFLP analysis. Results: The distribution of Cav-1 T29107A genotype was found to be significantly different between breast cancer patients and control group (p=0.004. Among the patients, 84 (70% samples had genotype TT, 29 (24.78% genotype AT and 7 (5.83% genotype AA. As for the control group, however, 59 (49.17% samples had genotype TT, 49 (40.83% genotype AT and 12 (10% genotype AA. Conclusion: The results of this study showed that genotype TT is associated with an increased risk of susceptibility to breast cancer.

  12. A case of intracranial malignant lymphoma with pure akinesia and repeated regression on CT scans

    International Nuclear Information System (INIS)

    Suzuki, Takeo; Yamamoto, Mari; Saitoh, Mitsunori; Aoki, Akira; Imai, Hisamasa; Narabayashi, Hirotaro.

    1984-01-01

    In a case of primary reticulum cell sarcoma in the brain, histologically verified by biopsy, the tumor regressed twice on a CT scan without radiotherapy. The systemic freezing phenomenon was seen as a main clinical symptom. The patient, a 44 year-old male, first complained of decreased livido and festinating speech. He also showed frozen gait, micrographia, a decrease in spontaneity and urinary incontinence. Four months after onset he was hospitalized. Neurological findings on admission revealed freezing of gait, writing, and speech, but there was no weakness of muscles with normal tendon reflexes, and normal muscular tone. In the CT scan on admission, there were high density areas mainly in the head of the right caudate nucleus, the medial deep portion of the right frontal lobe, the right side of the hypothalamus, the anterior thalamus, the globus pallidus. There were also nodular-type enhanced effects in the same areas. Regression of the tumor was seen on the CT scans after administration of betamethasone. The tumor which had again incrased in size regressed spontaneously without the use of steroids after 3 months. Thereafter, the tumor gradually became larger and an open biopsy was perfomed. Histopathological findings showed a reticulum cell sarcoma. There were no findings of systemic malignant lymphoma. Such intracrainal malignant lymphomas showing repeated regression including spontaneous one are very rare in the literature. The freezing phenomenon in this case started with festinating speech and spread to writing and gait. L-DOPA had no effect. This systemic freezing phenomenon was considered to be the same as that in the cases of pure akinesia without rigidity and tremor reported by Narabayashi and Imai, which did not respond to L-DOPA at all. But on the other hand, L-Threo-3, 4-Dihydroxyphenylserine was effective to the frozen gait of this patient. (J.P.N.)

  13. Tumor cell proliferation kinetics and tumor growth rate

    Energy Technology Data Exchange (ETDEWEB)

    Tubiana, M

    1989-01-01

    The present knowledge on the growth rate and the proliferation kinetics of human tumor is based on the measurement of the tumor doubling times (DT) in several hundred patients and on the determination of the proportion of proliferating cells with radioactive thymidine or by flow cytometry in large numbers of patients. The results show that the DT of human tumor varies widely, from less than one week to over one year with a median value of approximately 2 months. The DTs are significantly correlated with the histological type. They depend upon (1) the duration of the cell cycle whose mean duration is 2 days with small variations from tumor to tumor, (2) the proportion of proliferating cells and consequently the cell birth rate which varies widely among tumors and which is significantly correlated to the DT, (3) the cell loss factors which also vary widely and which are the greatest when proliferation is most intensive. These studies have several clinical implications: (a) they have further increased our understanding of the natural history of human tumor, (b) they have therapeutic implications since tumor responsiveness and curability by radiation and drugs are strongly influenced by the cell kinetic parameters of the tumor, (c) the proportion of proliferating cells is of great prognostic value in several types of human cancers. The investigation of the molecular defects, which are correlated with the perturbation of control of cell proliferation, should lead to significant fundamental and therapeutic advances. (orig.).

  14. Genotype 3 is the predominant hepatitis C genotype in a multi-ethnic Asian population in Malaysia.

    Science.gov (United States)

    Ho, Shiaw-Hooi; Ng, Kee-Peng; Kaur, Harvinder; Goh, Khean-Lee

    2015-06-01

    Genotypes of hepatitis C virus (HCV) are distributed differently across the world. There is a paucity of such data in a multi-ethnic Asian population like Malaysia. The objectives of this study were to determine the distribution of HCV genotypes between major ethnic groups and to ascertain their association with basic demographic variables like age and gender. This was a cross-sectional prospective study conducted from September 2007 to September 2013. Consecutive patients who were detected to have anti-HCV antibodies in the University of Malaya Medical Centre were included and tested for the presence of HCV RNA using Roche Cobas Amplicor Analyzer and HCV genotype using Roche single Linear Array HCV Genotyping strip. Five hundred and ninety-six subjects were found to have positive anti-HCV antibodies during this period of time. However, only 396 (66.4%) were HCV RNA positive and included in the final analysis. Our results showed that HCV genotype 3 was the predominant genotype with overall frequency of 61.9% followed by genotypes 1 (35.9%), 2 (1.8%) and 6 (0.5%). There was a slightly higher prevalence of HCV genotype 3 among the Malays when compared to the Chinese (P=0.043). No other statistical significant differences were observed in the distribution of HCV genotypes among the major ethnic groups. There was also no association between the predominant genotypes and basic demographic variables. In a multi-ethnic Asian society in Malaysia, genotype 3 is the predominant genotype among all the major ethnic groups with genotype 1 as the second commonest genotype. Both genotypes 2 and 6 are uncommon. Neither genotype 4 nor 5 was detected. There is no identification of HCV genotype according to ethnic origin, age and gender.

  15. Cell proliferation markers in the transplanted canine transmissible venereal tumor

    Directory of Open Access Journals (Sweden)

    F.G.A. Santos

    2011-12-01

    Full Text Available Adult male mongrel dogs were subcutaneously transplanted with the canine transmissible venereal tumor (TVT on the hypogastric region. Twelve specimens of tumors were collected, half during the proliferative phase and the other half during the regressive phase. Fragments of the tumor were fixed in 10% buffered formalin and routinely processed for light microscopy. Sections of 4µm were stained by Schorr or AgNOR or either immunostained for MIB1 (Ki67. Schorr stain, AgNOR and MIB1 showed an increased proliferative activity through mitotic index, nuclear argyrophilic protein stain and cycling tumoral cells in the growing tumors, respectively. All of the three cell proliferation markers were able to distinguish the TVT in both evolution phases. MIB1 monoclonal antibody was the best in the morphologic evaluation of growth and regression of TVT. This resulted in higher values than AgNORs counting and mitotic index. MIB1 immunostaining was the most effective parameter of the proliferative activity of TVT. However, a significant correlation has been detected only between mitosis counting and AgNORs.

  16. Mathematical models of tumor growth: translating absorbed dose to tumor control probability

    International Nuclear Information System (INIS)

    Sgouros, G.

    1996-01-01

    Full text: The dose-rate in internal emitter therapy is low and time-dependent as compared to external beam radiotherapy. Once the total absorbed dose delivered to a target tissue is calculated, however, most dosimetric analyses of radiopharmaceuticals are considered complete. To translate absorbed dose estimates obtained for internal emitter therapy to biologic effect, the growth characteristics, repair capacity, and radiosensitivity of the tumor must be considered. Tumor growth may be represented by the Gompertz equation in which tumor cells increase at an exponential growth rate that is itself decreasing at an exponential rate; as the tumor increases in size, the growth rate diminishes. The empirical Gompertz expression for tumor growth may be derived from a mechanistic model in which growth is represented by a balance between tumor-cell birth and loss. The birth rate is assumed to be fixed, while the cell loss rate is time-dependent and increases with tumor size. The birth rate of the tumors may be related to their potential doubling time. Multiple biopsies of individual tumors have demonstrated a heterogeneity in the potential doubling time of tumors. By extending the mechanistic model described above to allow for sub-populations of tumor cells with different birth rates, the effect of kinetic heterogeneity within a tumor may be examined. Model simulations demonstrate that the cell kinetic parameters of a tumor are predicted to change over time and measurements obtained using a biopsy are unlikely to reflect the kinetics of the tumor throughout its growth history. A decrease in overall tumor mass, in which each sub-population is reduced in proportion to its cell number, i.e., the log-kill assumption, leads to re-growth of a tumor that has a greater proliferation rate. Therapy that is linked to the potential doubling time or to the effective proliferation rate of the tumor may lead to re-growth of a tumor that is kinetically unchanged. The simplest model of

  17. Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp transcription factors

    Directory of Open Access Journals (Sweden)

    Pathi Satya

    2011-08-01

    Full Text Available Abstract Background Betulinic acid (BA inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells. Methods The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a and ZBTB10 mRNA expression. Results BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS, ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10. Conclusions These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent.

  18. Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors

    International Nuclear Information System (INIS)

    Chintharlapalli, Sudhakar; Papineni, Sabitha; Lei, Ping; Pathi, Satya; Safe, Stephen

    2011-01-01

    Betulinic acid (BA) inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells. The effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a) and ZBTB10 mRNA expression. BA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS), ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10. These results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent

  19. Procedures for identifying S-allele genotypes of Brassica.

    Science.gov (United States)

    Wallace, D H

    1979-11-01

    Procedures are described for efficient selection of: (1) homozygous and heterozygous S-allele genotypes; (2) homozygous inbreds with the strong self- and sib-incompatibility required for effective seed production of single-cross F1 hybrids; (3) heterozygous genotypes with the high self- and sib-incompatibility required for effective seed production of 3- and 4-way hybrids.From reciprocal crosses between two first generation inbred (I1) plants there are three potential results: both crosses are incompatible; one is incompatible and the other compatible; and both are compatible. Incompatibility of both crosses is useful information only when combined with data from other reciprocal crosses. Each compatible cross, depending on whether its reciprocal is incompatible or compatible, dictates alternative reasoning and additional reciprocal crosses for efficiently and simultaneously identifying: (A) the S-allele genotype of all individual I1 plants, and (B) the expressions of dominance or codominance in pollen and stigma (sexual organs) of an S-allele heterozygous genotype. Reciprocal crosses provide the only efficient means of identifying S-allele genotypes and also the sexual-organ x S-allele-interaction types.Fluorescent microscope assay of pollen tube penetration into the style facilitates quantitation within 24-48 hours of incompatibility and compatibility of the reciprocal crosses. A procedure for quantitating the reciprocal difference is described that maximizes informational content of the data about interactions between S alleles in pollen and stigma of the S-allele-heterozygous genotype.Use of the non-inbred Io generation parent as a 'known' heterozygous S-allele genotype in crosses with its first generation selfed (I1) progeny usually reduces at least 7 fold the effort required for achieving objectives 1, 2, and 3, compared to the method of making reciprocal crosses only among I1 plants.Identifying the heterozygous and both homozygous S-allele genotypes during

  20. Signaling Pathways Related to Protein Synthesis and Amino Acid Concentration in Pig Skeletal Muscles Depend on the Dietary Protein Level, Genotype and Developmental Stages.

    Directory of Open Access Journals (Sweden)

    Yingying Liu

    Full Text Available Muscle growth is regulated by the homeostatic balance of the biosynthesis and degradation of muscle proteins. To elucidate the molecular interactions among diet, pig genotype, and physiological stage, we examined the effect of dietary protein concentration, pig genotype, and physiological stages on amino acid (AA pools, protein deposition, and related signaling pathways in different types of skeletal muscles. The study used 48 Landrace pigs and 48 pure-bred Bama mini-pigs assigned to each of 2 dietary treatments: lower/GB (Chinese conventional diet- or higher/NRC (National Research Council-protein diet. Diets were fed from 5 weeks of age to respective market weights of each genotype. Samples of biceps femoris muscle (BFM, type I and longissimus dorsi muscle (LDM, type II were collected at nursery, growing, and finishing phases according to the physiological stage of each genotype, to determine the AA concentrations, mRNA levels for growth-related genes in muscles, and protein abundances of mechanistic target of rapamycin (mTOR signaling pathway. Our data showed that the concentrations of most AAs in LDM and BFM of pigs increased (P<0.05 gradually with increasing age. Bama mini-pigs had generally higher (P<0.05 muscle concentrations of flavor-related AA, including Met, Phe, Tyr, Pro, and Ser, compared with Landrace pigs. The mRNA levels for myogenic determining factor, myogenin, myocyte-specific enhancer binding factor 2 A, and myostatin of Bama mini-pigs were higher (P<0.05 than those of Landrace pigs, while total and phosphorylated protein levels for protein kinase B, mTOR, and p70 ribosomal protein S6 kinases (p70S6K, and ratios of p-mTOR/mTOR, p-AKT/AKT, and p-p70S6K/p70S6K were lower (P<0.05. There was a significant pig genotype-dependent effect of dietary protein on the levels for mTOR and p70S6K. When compared with the higher protein-NRC diet, the lower protein-GB diet increased (P<0.05 the levels for mTOR and p70S6K in Bama mini-pigs, but

  1. Post-processing through linear regression

    Science.gov (United States)

    van Schaeybroeck, B.; Vannitsem, S.

    2011-03-01

    Various post-processing techniques are compared for both deterministic and ensemble forecasts, all based on linear regression between forecast data and observations. In order to evaluate the quality of the regression methods, three criteria are proposed, related to the effective correction of forecast error, the optimal variability of the corrected forecast and multicollinearity. The regression schemes under consideration include the ordinary least-square (OLS) method, a new time-dependent Tikhonov regularization (TDTR) method, the total least-square method, a new geometric-mean regression (GM), a recently introduced error-in-variables (EVMOS) method and, finally, a "best member" OLS method. The advantages and drawbacks of each method are clarified. These techniques are applied in the context of the 63 Lorenz system, whose model version is affected by both initial condition and model errors. For short forecast lead times, the number and choice of predictors plays an important role. Contrarily to the other techniques, GM degrades when the number of predictors increases. At intermediate lead times, linear regression is unable to provide corrections to the forecast and can sometimes degrade the performance (GM and the best member OLS with noise). At long lead times the regression schemes (EVMOS, TDTR) which yield the correct variability and the largest correlation between ensemble error and spread, should be preferred.

  2. Study of correlation between polymorphism of angiotensin II-1 receptor gene A1166 genotype and complications in atrial fibrillation

    International Nuclear Information System (INIS)

    Wang Yueping; Gong Wuxing; Shi Li

    2010-01-01

    Objective: To investigate the effect of genetic polymorphism on atrial fibrillation. Methods: Polymerase chain reaction-restrictive fragment length polymorphism(PCR-RFLP) was used to identify and compare the genotype of the location of AT1R gene 1166, and color echo-ultrasound was performed with logistic regression used to analyse the independent risk of various genotypes for atrial fibrillation in 121 patients with atrial fibrillation and 100 controls. Results: (1) Frequency of genotype AC + CC, iso-gene C in atrial fibrillation group was higher than that in control group (P=0.017, 0.013), the risk ratio in patients with genotype AC + CC to develop atrial fibrillation was 3.657 compared with genotype AA (95% CI:1.181∼11.322), and genotype difference as well as systolic pressure were involved in occurrence of overall atrial fibrillation. The OR to develop atrial fibrillation in patients with genotype AC + CC was 4.132 compared with genotype AA (95% CI:1.263∼13.513). (2) There were no significant differences of clinical manifestation (heart failure, cerebral embolism) or ultrasonic parameters among patients with different genotypes (AA vs AC + CC)(P>0.05). Conclusion: People carrying iso-gene C in AT1R gene 1166 were more liable to develop atrial fibrillation, but there were no correlationship with development of complications. (authors)

  3. Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.

    Science.gov (United States)

    Ruud, Johan; Nilsson, Anna; Engström Ruud, Linda; Wang, Wenhua; Nilsberth, Camilla; Iresjö, Britt-Marie; Lundholm, Kent; Engblom, David; Blomqvist, Anders

    2013-03-01

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE(2) levels in plasma - a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE(2)-levels in the cerebrospinal fluid. Neutralization of plasma PGE(2) with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP(4) receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE(2) and neuronal EP(4) signaling. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility.

    Science.gov (United States)

    Adel Fahmideh, Maral; Lavebratt, Catharina; Schüz, Joachim; Röösli, Martin; Tynes, Tore; Grotzer, Michael A; Johansen, Christoffer; Kuehni, Claudia E; Lannering, Birgitta; Prochazka, Michaela; Schmidt, Lisbeth S; Feychting, Maria

    2015-08-01

    The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. We hypothesized that single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) on adult glioma would also be associated with PBT risk. The study is based on the Cefalo study, a population-based multicenter case-control study. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was extracted and genotyped for 29 SNPs reported by GWAS to be significantly associated with risk of adult glioma. Data were analyzed using unconditional logistic regression. Stratified analyses were performed for two histological subtypes: astrocytoma alone and the other tumor types combined. The results indicated that four SNPs, CDKN2BAS rs4977756 (p = 0.036), rs1412829 (p = 0.037), rs2157719 (p = 0.018) and rs1063192 (p = 0.021), were associated with an increased susceptibility to PBTs, whereas the TERT rs2736100 was associated with a decreased risk (p = 0.018). Moreover, the stratified analyses showed a decreased risk of astrocytoma associated with RTEL1 rs6089953, rs6010620 and rs2297440 (p trend = 0.022, p trend = 0.042, p trend = 0.029, respectively) as well as an increased risk of this subtype associated with RTEL1 rs4809324 (p trend = 0.033). In addition, SNPs rs10464870 and rs891835 in CCDC26 were associated with an increased risk of non-astrocytoma tumor subtypes (p trend = 0.009, p trend = 0.007, respectively). Our findings indicate that SNPs in CDKN2BAS, TERT, RTEL1 and CCDC26 may be associated with the risk of PBTs. Therefore, we suggest that pediatric and adult brain tumors might share common genetic risk factors and similar etiological pathways. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. [Non-metastatic clear cell renal cancer: dependence of the tumour stage on clinico-anatomic and morphologic factors; prognostic value of macro- and karyometric characteristics].

    Science.gov (United States)

    Iurin, A G

    2010-01-01

    Non-metastatic clear-cell renal cancer: dependence of the tumour stage on clinico-anatomic and morphologic factors; prognostic value of macro- and karyometric characteristics Sankt Peterburg Pathology Bureau, Sankt Peterburg It was shown based on multivariate regression analysis that pT1a3bN0MO stages of non-metastatic clear-cell renal cancer significantly correlate not only with the tumor size and invasion into the fatty tissue and/or renal vein but also with the invasion into the renal capsule and with the mean maximum diameter and mean nucleus area of tumor cells. There was no correlation of clear-cell renal cancer stages with tumor proliferative activity, gene p53 mutation, oncosuppressor gene PTEN expression, fraction of tumour clear-cell component, and such clinical characteristics as patients' sex, age, and body mass index. Taking into account statistically significant differences between the patients' survival rates, the regression equations developed in this work may be used for the prediction of disease outcome.

  6. Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

    DEFF Research Database (Denmark)

    Wang, Z; Pedersen, Esben Ditlev Kølle; Basse, A

    2010-01-01

    that Rac1 is essential for DMBA/TPA-induced skin tumor formation. This corresponded to a decreased keratinocyte hyperproliferation, although apoptosis was not detectably altered. Activated Rac1 promoted Erk-dependent hyperproliferation by Pak1-mediated Mek activation independent of Mek1 phosporylation...

  7. Dependence of radiotherapeutic results on tumor size in patients with cervix uteri carcinoma

    International Nuclear Information System (INIS)

    Gabelov, A.A.; Zharinov, G.M.

    1981-01-01

    A method is suggested that permits specifying the primary tumor size on the basis of clinical examination of patients with cervix uteri carcinoma. The values of tumor size have been correlated with long-term results of concomitant radiotherapy in 1358 patients with cervix uteri carcinoma. The data obtained have shown that the primary tumor size is a factor that determines to a large extent radiotherapeutic results in patients with cervix uteri carcinoma. The specification of tumor size values makes it possible to considerably lessen prognostic uncertainty of present-day staging classifications. The structure of radiotherapeutic failures also turned out to be closely associated with the primary tumor size

  8. Expression profiles of amhy and major sex-related genes during gonadal sex differentiation and their relation with genotypic and temperature-dependent sex determination in pejerrey Odontesthes bonariensis.

    Science.gov (United States)

    Zhang, Yan; Hattori, Ricardo S; Sarida, Munti; García, Estefany L; Strüssmann, Carlos Augusto; Yamamoto, Yoji

    2018-03-15

    To shed light on the mechanisms of and interactions of GSD and TSD in pejerrey, we investigated how the transcriptional profiles of amhy and amha are affected by feminizing (17 °C) and masculinizing (29 °C) temperatures during the critical period of sex determination/differentiation and their relation with the expression profiles of AMH receptor type II (amhrII), gonadal aromatase (cyp19a1a), and 11 beta-hydroxysteroid dehydrogenase 2 (hsd11b2). Careful consideration of the results of this study and all information currently available for this species, including similar analyzes for an intermediate, mixed-sex promoting temperature (25 °C), suggests a model for genotypic/temperature-dependent sex determination and gonadal sex differentiation that involves a) cyp19a1a-dependent, developmentally-programmed ovarian development as the default state that becomes self-sustaining in the absence of a potent and timely masculinizing stimulus, b) early, developmentally-programmed amhy expression and high temperature as masculinization signals that antagonize the putative female pathway by suppressing cyp19a1a expression, c) increasing stress response, cortisol, and the synthesis of the masculinizing androgen 11-keto-testosterone via hsd11b2 with increasing temperature that is important for masculinization in both genotypes but particularly so in XX individuals, and d) an endocrine network with positive/negative feedback mechanisms that ensure fidelity of the male/female pathway once started. The proposed model, albeit tentative and non-all inclusive, accounts for the continuum of responses, from all-females at low temperatures to all-males at high temperatures and for the balanced-, genotype-linked sex ratios obtained at intermediate temperatures, and therefore supports the coexistence of TSD and GSD in pejerrey across the range of viable temperatures for this species. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Differences in viral load among human respiratory syncytial virus genotypes in hospitalized children with severe acute respiratory infections in the Philippines.

    Science.gov (United States)

    Kadji, Francois Marie Ngako; Okamoto, Michiko; Furuse, Yuki; Tamaki, Raita; Suzuki, Akira; Lirio, Irene; Dapat, Clyde; Malasao, Rungnapa; Saito, Mariko; Pedrera-Rico, Gay Anne Granada; Tallo, Veronica; Lupisan, Socorro; Saito, Mayuko; Oshitani, Hitoshi

    2016-06-27

    Human respiratory syncytial virus (HRSV) is a leading viral etiologic agent of pediatric lower respiratory infections, including bronchiolitis and pneumonia. Two antigenic subgroups, HRSV-A and B, each contain several genotypes. While viral load may vary among HRSV genotypes and affect the clinical course of disease, data are scarce regarding the actual differences among genotypes. Therefore, this study estimated and compared viral load among NA1 and ON1 genotypes of HRSV-A and BA9 of HRSV-B. ON1 is a newly emerged genotype with a 72-nucleotide duplication in the G gene as observed previously with BA genotypes in HRSV-B. Children <5 years of age with an initial diagnosis of severe or very severe pneumonia at a hospital in the Philippines from September 2012 to December 2013 were enrolled. HRSV genotypes were determined and the viral load measured from nasopharyngeal swabs (NPS). The viral load of HRSV genotype NA1 were significantly higher than those of ON1 and BA9. Regression analysis showed that both genotype NA1 and younger age were significantly associated with high HRSV viral load. The viral load of NA1 was higher than that of ON1 and BA9 in NPS samples. HRSV genotypes may be associated with HRSV viral load. The reasons and clinical impacts of these differences in viral load among HRSV genotypes require further evaluation.

  10. Mitigating Errors in External Respiratory Surrogate-Based Models of Tumor Position

    Energy Technology Data Exchange (ETDEWEB)

    Malinowski, Kathleen T. [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); Fischell Department of Bioengineering, University of Maryland, College Park, MD (United States); McAvoy, Thomas J. [Fischell Department of Bioengineering, University of Maryland, College Park, MD (United States); Department of Chemical and Biomolecular Engineering and Institute of Systems Research, University of Maryland, College Park, MD (United States); George, Rohini [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); Dieterich, Sonja [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); D' Souza, Warren D., E-mail: wdsou001@umaryland.edu [Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD (United States); Fischell Department of Bioengineering, University of Maryland, College Park, MD (United States)

    2012-04-01

    Purpose: To investigate the effect of tumor site, measurement precision, tumor-surrogate correlation, training data selection, model design, and interpatient and interfraction variations on the accuracy of external marker-based models of tumor position. Methods and Materials: Cyberknife Synchrony system log files comprising synchronously acquired positions of external markers and the tumor from 167 treatment fractions were analyzed. The accuracy of Synchrony, ordinary-least-squares regression, and partial-least-squares regression models for predicting the tumor position from the external markers was evaluated. The quantity and timing of the data used to build the predictive model were varied. The effects of tumor-surrogate correlation and the precision in both the tumor and the external surrogate position measurements were explored by adding noise to the data. Results: The tumor position prediction errors increased during the duration of a fraction. Increasing the training data quantities did not always lead to more accurate models. Adding uncorrelated noise to the external marker-based inputs degraded the tumor-surrogate correlation models by 16% for partial-least-squares and 57% for ordinary-least-squares. External marker and tumor position measurement errors led to tumor position prediction changes 0.3-3.6 times the magnitude of the measurement errors, varying widely with model algorithm. The tumor position prediction errors were significantly associated with the patient index but not with the fraction index or tumor site. Partial-least-squares was as accurate as Synchrony and more accurate than ordinary-least-squares. Conclusions: The accuracy of surrogate-based inferential models of tumor position was affected by all the investigated factors, except for the tumor site and fraction index.

  11. Joint genome-wide prediction in several populations accounting for randomness of genotypes: A hierarchical Bayes approach. I: Multivariate Gaussian priors for marker effects and derivation of the joint probability mass function of genotypes.

    Science.gov (United States)

    Martínez, Carlos Alberto; Khare, Kshitij; Banerjee, Arunava; Elzo, Mauricio A

    2017-03-21

    It is important to consider heterogeneity of marker effects and allelic frequencies in across population genome-wide prediction studies. Moreover, all regression models used in genome-wide prediction overlook randomness of genotypes. In this study, a family of hierarchical Bayesian models to perform across population genome-wide prediction modeling genotypes as random variables and allowing population-specific effects for each marker was developed. Models shared a common structure and differed in the priors used and the assumption about residual variances (homogeneous or heterogeneous). Randomness of genotypes was accounted for by deriving the joint probability mass function of marker genotypes conditional on allelic frequencies and pedigree information. As a consequence, these models incorporated kinship and genotypic information that not only permitted to account for heterogeneity of allelic frequencies, but also to include individuals with missing genotypes at some or all loci without the need for previous imputation. This was possible because the non-observed fraction of the design matrix was treated as an unknown model parameter. For each model, a simpler version ignoring population structure, but still accounting for randomness of genotypes was proposed. Implementation of these models and computation of some criteria for model comparison were illustrated using two simulated datasets. Theoretical and computational issues along with possible applications, extensions and refinements were discussed. Some features of the models developed in this study make them promising for genome-wide prediction, the use of information contained in the probability distribution of genotypes is perhaps the most appealing. Further studies to assess the performance of the models proposed here and also to compare them with conventional models used in genome-wide prediction are needed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Plasma homocysteine in adolescents depends on the interaction between methylenetetrahydrofolate reductase genotype, lipids and folate: a seroepidemiological study

    Science.gov (United States)

    Gil-Prieto, Ruth; Hernández, Valentín; Cano, Beatriz; Oya, Manuel; Gil, Ángel

    2009-01-01

    Background Many publications link high homocysteine levels to cardiovascular disease. In Spain there is little information on the prevalence of hyperhomocysteinaemia and associated vitamin factors among the general population, and less still among children. Cardiovascular risk factors in the childhood population may be related to the appearance of cardiovascular disease at adult age. The aim of this study is to establish a definition of hyperhomocysteinaemia in adolescents and to analyze the influence of vitamin and metabolic factors in homocysteine levels in this population group. Methods Descriptive, cross-sectional epidemiological study to estimate serum homocysteine, vitamin B12 and folate levels, as well as plasma total, HDL- and LDL- cholesterol in a schoolgoing population aged 13 to 17 years in Madrid, Spain. Spearman correlation analysis was performed to ascertain quantitative comparison, Pearson's χ2 test (frequency < 5, Fisher) was used for comparison of prevalences, Mann-Whitney U and Kruskal-Wallis test were used for comparison of means and Bonferroni correction was used for post-hoc tests. A multivariate logistic regression model was performed in the multivariate analysis. Results Based on the classic values for definition of hyperhomocysteinaemia in adults, prevalence of hyperhomocysteinaemia in the study population was: 1.26% for 15 μmol/L; and 2.52% for 12 μmol/L. Deficits in HDL cholesterol and serum folate levels yielded adjusted Odds Ratios (OR) for hyperhomocysteinemia of 2.786, 95% CI (1.089-7.126), and 5.140, 95% CI (2.347-11.256) respectively. Mutation of the methylenetetrahydrofolate reductase (MTHFR) C677T genotype also raises the risk of hyperhomocysteinaemia (CC→CT: OR = 2.362; 95% CI (1.107-5.042) CC→TT: OR = 6.124, 95% CI (2.301-16.303)) Conclusion A good definition of hyperhomocysteinaemia in adolescents is the 90th percentile, equivalent to 8.23 μmol/L. Risk factors for hyperhomocysteinaemia are cHDL and folate deficiency, and

  13. Oleuropein, a non-toxic olive iridoid, is an anti-tumor agent and cytoskeleton disruptor

    International Nuclear Information System (INIS)

    Hamdi, Hamdi K.; Castellon, Raquel

    2005-01-01

    Oleuropein, a non-toxic secoiridoid derived from the olive tree, is a powerful antioxidant and anti-angiogenic agent. Here, we show it to be a potent anti-cancer compound, directly disrupting actin filaments in cells and in a cell-free assay. Oleuropein inhibited the proliferation and migration of advanced-grade tumor cell lines in a dose-responsive manner. In a novel tube-disruption assay, Oleuropein irreversibly rounded cancer cells, preventing their replication, motility, and invasiveness; these effects were reversible in normal cells. When administered orally to mice that developed spontaneous tumors, Oleuropein completely regressed tumors in 9-12 days. When tumors were resected prior to complete regression, they lacked cohesiveness and had a crumbly consistency. No viable cells could be recovered from these tumors. These observations elevate Oleuropein from a non-toxic antioxidant into a potent anti-tumor agent with direct effects against tumor cells. Our data may also explain the cancer-protective effects of the olive-rich Mediterranean diet

  14. Dopamine D1 receptor gene variation modulates opioid dependence risk by affecting transition to addiction.

    Directory of Open Access Journals (Sweden)

    Feng Zhu

    Full Text Available Dopamine D1 receptor (DRD1 modulates opioid reinforcement, reward, and opioid-induced neuroadaptation. We propose that DRD1 polymorphism affects susceptibility to opioid dependence (OD, the efficiency of transition to OD, and opioid-induced pleasure response. We analyzed potential association between seven DRD1 polymorphisms with the following traits: duration of transition from the first use to dependence (DTFUD, subjective pleasure responses to opioid on first use and post-dependence use, and OD risk in 425 Chinese with OD and 514 healthy controls. DTFUD and level of pleasure responses were examined using a semi-structured interview. The DTFUD of opioid addicts ranged from 5 days to 11 years. Most addicts (64.0% reported non-comfortable response upon first opioid use, while after dependence, most addicts (53.0% felt strong opioid-induced pleasure. Survival analysis revealed a correlation of prolonged DTFUD with the minor allele-carrying genotypes of DRD1 rs4532 (hazard ratios (HR = 0.694; p = 0.001 and rs686 (HR = 0.681, p = 0.0003. Binary logistic regression indicated that rs10063995 GT genotype (vs. GG+TT, OR = 0.261 could predict decreased pleasure response to first-time use and the minor alleles of rs686 (OR = 0.535 and rs4532 (OR = 0.537 could predict decreased post-dependence pleasure. Moreover, rs686 minor allele was associated with a decreased risk for rapid transition from initial use to dependence (DTFUD≤30 days; OR = 0.603 or post-dependence euphoria (OR = 0.603 relative to major allele. In conclusion, DRD1 rs686 minor allele decreases the OD risk by prolonging the transition to dependence and attenuating opioid-induced pleasure in Chinese.

  15. Menstrual Cycle Dependent Variability for Serum Tumor Markers CEA, AFP, CA 19-9, CA 125 and CA 15-3 in Healthy Women

    Directory of Open Access Journals (Sweden)

    Ayşe Binnur Erbağci

    1999-01-01

    Full Text Available Information on menstrual cycle dependent variation of tumor markers in healthy women is a subject of diagnostic efficiency and has an impact in elucidating the normal function of these markers. In this study midfollicular and midluteal concentrations of serum CEA, AFP, CA 19-9, CA 125, CA 15-3 and their relations with LH, FSH, prolactin, estradiol and progesterone were evaluated during ovulatory cycles in a group of 23 healthy female individuals. Samples were collected on the 7th and 21st day of the same menstrual cycle. Tumor marker and hormone concentrations were determined with chemiluminescence or electrochemiluminescence EIA methods. A significant phase-dependent difference was observed for CA 15-3, midluteal concentrations (mean ± SEM; 26.33 ± 1.56 U/ml higher than the midfollicular (mean ± SEM; 19.27 ± 1.49 U/ml concentrations (p < 0.001. But an obvious difference for other tumor markers investigated did not exist. Significant correlations of follicular and luteal CA 125 levels with body mass index of the subjects were observed (r:0.52, p < 0.05 and r:0.57, p < 0.005, respectively.

  16. Haplotype association analysis of human disease traits using genotype data of unrelated individuals

    DEFF Research Database (Denmark)

    Tan, Qihua; Christiansen, Lene; Christensen, Kaare

    2005-01-01

    unphased multi-locus genotype data, ranging from the early approach by the simple gene-counting method to the recent work using the generalized linear model. However, these methods are either confined to case – control design or unable to yield unbiased point and interval estimates of haplotype effects....... Based on the popular logistic regression model, we present a new approach for haplotype association analysis of human disease traits. Using haplotype-based parameterization, our model infers the effects of specific haplotypes (point estimation) and constructs confidence interval for the risks...... on the well-known logistic regression model is a useful tool for haplotype association analysis of human disease traits....

  17. Kernel machine methods for integrative analysis of genome-wide methylation and genotyping studies.

    Science.gov (United States)

    Zhao, Ni; Zhan, Xiang; Huang, Yen-Tsung; Almli, Lynn M; Smith, Alicia; Epstein, Michael P; Conneely, Karen; Wu, Michael C

    2018-03-01

    Many large GWAS consortia are expanding to simultaneously examine the joint role of DNA methylation in addition to genotype in the same subjects. However, integrating information from both data types is challenging. In this paper, we propose a composite kernel machine regression model to test the joint epigenetic and genetic effect. Our approach works at the gene level, which allows for a common unit of analysis across different data types. The model compares the pairwise similarities in the phenotype to the pairwise similarities in the genotype and methylation values; and high correspondence is suggestive of association. A composite kernel is constructed to measure the similarities in the genotype and methylation values between pairs of samples. We demonstrate through simulations and real data applications that the proposed approach can correctly control type I error, and is more robust and powerful than using only the genotype or methylation data in detecting trait-associated genes. We applied our method to investigate the genetic and epigenetic regulation of gene expression in response to stressful life events using data that are collected from the Grady Trauma Project. Within the kernel machine testing framework, our methods allow for heterogeneity in effect sizes, nonlinear, and interactive effects, as well as rapid P-value computation. © 2017 WILEY PERIODICALS, INC.

  18. seXY: a tool for sex inference from genotype arrays.

    Science.gov (United States)

    Qian, David C; Busam, Jonathan A; Xiao, Xiangjun; O'Mara, Tracy A; Eeles, Rosalind A; Schumacher, Frederick R; Phelan, Catherine M; Amos, Christopher I

    2017-02-15

    Checking concordance between reported sex and genotype-inferred sex is a crucial quality control measure in genome-wide association studies (GWAS). However, limited insights exist regarding the true accuracy of software that infer sex from genotype array data. We present seXY, a logistic regression model trained on both X chromosome heterozygosity and Y chromosome missingness, that consistently demonstrated >99.5% sex inference accuracy in cross-validation for 889 males and 5,361 females enrolled in prostate cancer and ovarian cancer GWAS. Compared to PLINK, one of the most popular tools for sex inference in GWAS that assesses only X chromosome heterozygosity, seXY achieved marginally better male classification and 3% more accurate female classification. https://github.com/Christopher-Amos-Lab/seXY. Christopher.I.Amos@dartmouth.edu. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

  19. Genotypic and phenotypic diversity does not affect productivity and drought response in competitive stands of Trifolium repens

    Directory of Open Access Journals (Sweden)

    Heidrun eHuber

    2016-03-01

    Full Text Available Clonal plants can form dense canopies in which plants of different genetic origin are competing for the uptake of essential resources. The competitive relationships among these clones are likely to be affected by extreme environmental conditions, such as prolonged drought spells, which are predicted to occur more frequently due to global climate change. This, in turn, may alter characteristics of the ecological system and its associated functioning.We hypothesized that the relative success of individual clones will depend on the size of the ramets as ramets with larger leaves and longer petioles (large ramets were predicted to have a competitive advantage in terms of increased light interception over smaller-sized ramets. Under drier conditions the relative performances of genotypes were expected to change leading to a change in genotype ranking. We also hypothesized that increased genotypic and phenotypic diversity will increase stand performance and resistance to drought. These hypotheses and the mechanisms responsible for shifts in competitive relationships were investigated by subjecting genotypes of the important pasture legume Trifolium repens to competition with either genetically identical clones, genetically different but similarly sized clones, or genetically as well as morphologically different clones under well-watered and dry conditions.Competitive relationships were affected by ramet size with large genotypes outperforming small genotypes in diverse stands in terms of biomass production. However, large genotypes also produced relatively fewer ramets than small genotypes and could not benefit in terms of clonal reproduction from competing with smaller genotypes, indicating that evolutionary shifts in genotype composition will depend on whether ramet size or ramet number is under selection. In contrast to our hypotheses, diversity did not increase stand performance under different selection regimes and genotype ranking was hardly

  20. Genotypic and Phenotypic Diversity Does Not Affect Productivity and Drought Response in Competitive Stands of Trifolium repens.

    Science.gov (United States)

    Huber, Heidrun; During, Heinjo J; Bruine de Bruin, Fabienne; Vermeulen, Peter J; Anten, Niels P R

    2016-01-01

    Clonal plants can form dense canopies in which plants of different genetic origin are competing for the uptake of essential resources. The competitive relationships among these clones are likely to be affected by extreme environmental conditions, such as prolonged drought spells, which are predicted to occur more frequently due to global climate change. This, in turn, may alter characteristics of the ecological system and its associated functioning. We hypothesized that the relative success of individual clones will depend on the size of the ramets as ramets with larger leaves and longer petioles (large ramets) were predicted to have a competitive advantage in terms of increased light interception over smaller-sized ramets. Under drier conditions the relative performances of genotypes were expected to change leading to a change in genotype ranking. We also hypothesized that increased genotypic and phenotypic diversity will increase stand performance and resistance to drought. These hypotheses and the mechanisms responsible for shifts in competitive relationships were investigated by subjecting genotypes of the important pasture legume Trifolium repens to competition with either genetically identical clones, genetically different but similarly sized clones, or genetically as well as morphologically different clones under well-watered and dry conditions. Competitive relationships were affected by ramet size with large genotypes outperforming small genotypes in diverse stands in terms of biomass production. However, large genotypes also produced relatively fewer ramets than small genotypes and could not benefit in terms of clonal reproduction from competing with smaller genotypes, indicating that evolutionary shifts in genotype composition will depend on whether ramet size or ramet number is under selection. In contrast to our hypotheses, diversity did not increase stand performance under different selection regimes and genotype ranking was hardly affected by soil

  1. Optimization of the tumor microenvironment and nanomedicine properties simultaneously to improve tumor therapy.

    Science.gov (United States)

    Zhang, Bo; Shi, Wei; Jiang, Ting; Wang, Lanting; Mei, Heng; Lu, Heng; Hu, Yu; Pang, Zhiqing

    2016-09-20

    Effective delivery of nanomedicines to tumor tissues depends on both the tumor microenvironment and nanomedicine properties. Accordingly, tumor microenvironment modification or advanced design of nanomedicine was emerging to improve nanomedicine delivery to tumors. However, few studies have emphasized the necessity to optimize the tumor microenvironment and nanomedicine properties simultaneously to improve tumor treatment. In the present study, imatinib mesylate (IMA) was used to normalize the tumor microenvironment including platelet-derived growth factor receptor-β expression inhibition, tumor vessel normalization, and tumor perfusion improvement as demonstrated by immunofluorescence staining. In addition, the effect of tumor microenvironment normalization on tumor delivery of nanomedicines with different sizes was carefully investigated. It was shown that IMA treatment significantly reduced the accumulation of nanoparticles (NPs) around 110 nm but enhanced the accumulation of micelles around 23 nm by in vivo fluorescence imaging experiment. Furthermore, IMA treatment limited the distribution of NPs inside tumors but increased that of micelles with a more homogeneous pattern. Finally, the anti-tumor efficacy study displayed that IMA pretreatment could significantly increase the therapeutic effects of paclitaxel-loaded micelles. All-together, a new strategy to improve nanomedicine delivery to tumor was provided by optimizing both nanomedicine size and the tumor microenvironment simultaneously, and it will have great potential in clinics for tumor treatment.

  2. Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b+Ly6G+ intratumor myeloid cells through the TICAM-1 signaling pathway

    Science.gov (United States)

    Shime, Hiroaki; Matsumoto, Misako; Seya, Tsukasa

    2017-01-01

    PolyI:C, a synthetic double-stranded RNA analog, acts as an immune-enhancing adjuvant that regresses tumors in cytotoxic T lymphocyte (CTL)-dependent and CTL-independent manner, the latter of which remains largely unknown. Tumors contain CD11b+Ly6G+ cells, known as granulocytic myeloid-derived suppressor cells (G-MDSCs) or tumor-associated neutrophils (TANs) that play a critical role in tumor progression and development. Here, we demonstrate that CD11b+Ly6G+ cells respond to polyI:C and exhibit tumoricidal activity in an EL4 tumor implant model. PolyI:C-induced inhibition of tumor growth was attributed to caspase-8/3 cascade activation in tumor cells that occurred independently of CD8α+/CD103+ dendritic cells (DCs) and CTLs. CD11b+Ly6G+ cells was essential for the antitumor effect because depletion of CD11b+Ly6G+ cells totally abrogated tumor regression and caspase activation after polyI:C treatment. CD11b+Ly6G+ cells that had been activated with polyI:C showed cytotoxicity and inhibited tumor growth through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS). These responses were abolished in either Toll/interleukin-1 receptor domain-containing adaptor molecule-1 (TICAM-1)−/− or interferon (IFN)-αβ receptor 1 (IFNAR1)−/− mice. Thus, our results suggest that polyI:C activates the TLR3/TICAM-1 and IFNAR signaling pathways in CD11b+Ly6G+ cells in tumors, thereby eliciting their antitumor activity, independent of those in CD8α+/CD103+ DCs that prime CTLs. PMID:27834952

  3. Assessment of tumor control following definitive radiotherapy in carcinoma of the prostate: A continuing dilemma

    International Nuclear Information System (INIS)

    Pilepich, M.V.

    1987-01-01

    Evaluation of tumor response and tumor control after definitive radiotherapy is a relatively simple task in most malignancies arising at sites amenable to clinical examination (inspection and palpation). The rates of tumor regression following irradiation are quite variable. While some types of cancer regress completely during the radiotherapy course, some may take weeks or months to resolve. Occasionally, residual induration or a residual mass may persist for prolonged periods (many months), prompting the clinician to consider a biopsy for evaluation of the tumor status. In these circumstances histological examination may show necrotic tumor or residual fibrotic tissue. Finding viable-appearing tumor cells beyond the immediate postirradiation period (several weeks to a few months after completion of the radiotherapy course) is generally accepted as an equivalent of failure to eradicate the tumor. However, in a few types of cancer, presence of histologically identifiable and apparently viable tumor cells over protracted periods does not necessarily imply treatment failure

  4. NUC041, a Prodrug of the DNA Methytransferase Inhibitor 5-aza-2′,2′-Difluorodeoxycytidine (NUC013, Leads to Tumor Regression in a Model of Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Richard Daifuku

    2018-04-01

    Full Text Available 5-aza-2′,2′-difluorodeoxycytidine (NUC013 has been shown to be significantly safer and more effective than decitabine in xenograft models of human leukemia and colon cancer. However, it suffers from a similar short half-life as other DNA methyltransferase inhibitors with a 5-azacytosine base, which is problematic for nucleosides that primarily target tumor cells in S phase. Because of the relative instability of 5-azanucleosides, a prodrug approach was developed to improve the pharmacology of NUC013. NUC013 was conjugated with trimethylsilanol (TMS at the 3′ and 5′ position of the sugar, rendering the molecule hydrophobic and producing 3′,5′-di-trimethylsilyl-2′,2′-difluoro-5-azadeoxycytidine (NUC041. NUC041 was designed to be formulated in a hydrophobic vehicle, protecting it from deamination and hydrolysis. In contact with blood, the TMS moieties are readily hydrolyzed to release NUC013. The half-life of NUC013 administered intravenously in mice is 20.1 min, while that of NUC013 derived from intramuscular NUC041 formulated in a pegylated-phospholipid depot is 3.4 h. In a NCI-H460 xenograft of non-small cell lung cancer, NUC013 was shown to significantly inhibit tumor growth and improve survival. Treatment with NUC041 also led to significant tumor growth inhibition. However, NUC041-treated mice had significantly more tumors ulcerate than either NUC013 treated mice or saline control mice, and such ulceration occurred at significantly lower tumor volumes. In these nude mice, tumor regression was likely mediated by the derepression of the tumor suppressor gene p53 and resultant activation of natural killer (NK cells.

  5. Phenotype prediction using regularized regression on genetic data in the DREAM5 Systems Genetics B Challenge.

    Directory of Open Access Journals (Sweden)

    Po-Ru Loh

    Full Text Available A major goal of large-scale genomics projects is to enable the use of data from high-throughput experimental methods to predict complex phenotypes such as disease susceptibility. The DREAM5 Systems Genetics B Challenge solicited algorithms to predict soybean plant resistance to the pathogen Phytophthora sojae from training sets including phenotype, genotype, and gene expression data. The challenge test set was divided into three subcategories, one requiring prediction based on only genotype data, another on only gene expression data, and the third on both genotype and gene expression data. Here we present our approach, primarily using regularized regression, which received the best-performer award for subchallenge B2 (gene expression only. We found that despite the availability of 941 genotype markers and 28,395 gene expression features, optimal models determined by cross-validation experiments typically used fewer than ten predictors, underscoring the importance of strong regularization in noisy datasets with far more features than samples. We also present substantial analysis of the training and test setup of the challenge, identifying high variance in performance on the gold standard test sets.

  6. Multiple linear regression analysis

    Science.gov (United States)

    Edwards, T. R.

    1980-01-01

    Program rapidly selects best-suited set of coefficients. User supplies only vectors of independent and dependent data and specifies confidence level required. Program uses stepwise statistical procedure for relating minimal set of variables to set of observations; final regression contains only most statistically significant coefficients. Program is written in FORTRAN IV for batch execution and has been implemented on NOVA 1200.

  7. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder.

    Science.gov (United States)

    Fehr, Stephanie; Wong, Kingsley; Chin, Richard; Williams, Simon; de Klerk, Nick; Forbes, David; Krishnaraj, Rahul; Christodoulou, John; Downs, Jenny; Leonard, Helen

    2016-11-22

    To investigate seizure outcomes and their relationships to genotype and functional abilities in individuals with the cyclin-dependent kinase-like-5 (CDKL5) disorder. Using the International CDKL5 Disorder Database, we identified 172 cases with a pathogenic CDKL5 mutation. We categorized individual mutations into 4 groups based on predicted structural and functional consequences. Negative binomial regression was used to model the linear association between current seizure rate and mutation group, current level of assistance required to walk 10 steps, and the highest level of expressive communication used to convey refusal or request. All but 3 (169/172) patients had a history of epilepsy. The median age at seizure onset was 6 weeks (range 1 week-1.5 years) and the median seizure rate at ascertainment was 2 per day (range 0-20 per day). After adjusting for walking ability and confounders including use or otherwise of polytherapy, seizure rate was lower in those with truncating mutations between aa172 and aa781 compared to those with no functional protein (incidence rate ratio [IRR] 0.57; 95% confidence interval [CI] 0.35-0.93). Ability to walk and use of spoken language were associated with lower rates of current seizures when compared to those with the least ability after adjusting for genotype (walking: IRR 0.62; 95% CI 0.39-0.99, communication: IRR 0.48; 95% CI 0.23-1.02). At a median age at questionnaire completion of 5 years, those previously treated with corticosteroids had more frequent seizures than those who have never been treated, whether or not there was a history of infantile spasms. Epilepsy is pervasive but not mandatory for the CDKL5 disorder. Genotype and functional abilities were related to seizure frequency, which appears refractory to antiepileptic drugs. © 2016 American Academy of Neurology.

  8. [From clinical judgment to linear regression model.

    Science.gov (United States)

    Palacios-Cruz, Lino; Pérez, Marcela; Rivas-Ruiz, Rodolfo; Talavera, Juan O

    2013-01-01

    When we think about mathematical models, such as linear regression model, we think that these terms are only used by those engaged in research, a notion that is far from the truth. Legendre described the first mathematical model in 1805, and Galton introduced the formal term in 1886. Linear regression is one of the most commonly used regression models in clinical practice. It is useful to predict or show the relationship between two or more variables as long as the dependent variable is quantitative and has normal distribution. Stated in another way, the regression is used to predict a measure based on the knowledge of at least one other variable. Linear regression has as it's first objective to determine the slope or inclination of the regression line: Y = a + bx, where "a" is the intercept or regression constant and it is equivalent to "Y" value when "X" equals 0 and "b" (also called slope) indicates the increase or decrease that occurs when the variable "x" increases or decreases in one unit. In the regression line, "b" is called regression coefficient. The coefficient of determination (R 2 ) indicates the importance of independent variables in the outcome.

  9. Differentiating regressed melanoma from regressed lichenoid keratosis.

    Science.gov (United States)

    Chan, Aegean H; Shulman, Kenneth J; Lee, Bonnie A

    2017-04-01

    Distinguishing regressed lichen planus-like keratosis (LPLK) from regressed melanoma can be difficult on histopathologic examination, potentially resulting in mismanagement of patients. We aimed to identify histopathologic features by which regressed melanoma can be differentiated from regressed LPLK. Twenty actively inflamed LPLK, 12 LPLK with regression and 15 melanomas with regression were compared and evaluated by hematoxylin and eosin staining as well as Melan-A, microphthalmia transcription factor (MiTF) and cytokeratin (AE1/AE3) immunostaining. (1) A total of 40% of regressed melanomas showed complete or near complete loss of melanocytes within the epidermis with Melan-A and MiTF immunostaining, while 8% of regressed LPLK exhibited this finding. (2) Necrotic keratinocytes were seen in the epidermis in 33% regressed melanomas as opposed to all of the regressed LPLK. (3) A dense infiltrate of melanophages in the papillary dermis was seen in 40% of regressed melanomas, a feature not seen in regressed LPLK. In summary, our findings suggest that a complete or near complete loss of melanocytes within the epidermis strongly favors a regressed melanoma over a regressed LPLK. In addition, necrotic epidermal keratinocytes and the presence of a dense band-like distribution of dermal melanophages can be helpful in differentiating these lesions. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Report of the Second International Workshop on molecular blood group genotyping

    NARCIS (Netherlands)

    Daniels, G.; van der Schoot, C. E.; Olsson, M. L.

    2007-01-01

    The second International Society of Blood Transfusion and International Council for Standardization in Haematology workshop on molecular blood group genotyping was held in 2006. Forty-one laboratories participated. Six samples were distributed: two representing DNA from transfusion-dependent

  11. Peculiarities in the CT findings of germ cell tumors in various tumor localizations

    International Nuclear Information System (INIS)

    Tazoe, Makoto; Miyagami, Mitsusuke; Tsubokawa, Takashi

    1991-01-01

    The CT findings of 17 germ cell tumors were studied in relation to the locations of the tumor, the pathological diagnoses, and the tumor markers (AFP and HCG). Generally, the CT findings of germ cell tumors depended on the pathological diagnoses more strongly than on the location of the tumors. On plain CT of 7 germ cell tumors in the pineal region, all of them demonstrated heterogeneous findings. Hydrocephalus was seen in 6 cases (86%) and calcification in 6 cases (86%) of the germ cell tumors in the pineal region. Calcification and hydrocephalus that appeared more often than in other regions were characteristic of germ cell tumors of the pineal region. The germ cell tumors in the basal ganglia had a slightly homogenous high density, with small cysts and calcification in most of them on plain CT. On enhanced CT, the tumors were moderately enhanced in all cases located in the basal ganglia. Four cases of germ cell tumors located in the basal ganglia revealed the dilatation of lateral ventricle due to hemispheric atrophy in the tumor side. The germ cell tumors showing an increase in the tumor markers such as AFP and HCG, which were usually malignant germ cell tumors, were strongly enhanced on enhanced CT. (author)

  12. Decoding noises in HIV computational genotyping.

    Science.gov (United States)

    Jia, MingRui; Shaw, Timothy; Zhang, Xing; Liu, Dong; Shen, Ye; Ezeamama, Amara E; Yang, Chunfu; Zhang, Ming

    2017-11-01

    Lack of a consistent and reliable genotyping system can critically impede HIV genomic research on pathogenesis, fitness, virulence, drug resistance, and genomic-based healthcare and treatment. At present, mis-genotyping, i.e., background noises in molecular genotyping, and its impact on epidemic surveillance is unknown. For the first time, we present a comprehensive assessment of HIV genotyping quality. HIV sequence data were retrieved from worldwide published records, and subjected to a systematic genotyping assessment pipeline. Results showed that mis-genotyped cases occurred at 4.6% globally, with some regional and high-risk population heterogeneities. Results also revealed a consistent mis-genotyping pattern in gp120 in all studied populations except the group of men who have sex with men. Our study also suggests novel virus diversities in the mis-genotyped cases. Finally, this study reemphasizes the importance of implementing a standardized genotyping pipeline to avoid genotyping disparity and to advance our understanding of virus evolution in various epidemiological settings. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Misregulation of Stromelysin-1 in Mouse Mammary Tumor Cells Accompanies Acquisition of Stromelysin-1 dependent Invasive Properties

    Energy Technology Data Exchange (ETDEWEB)

    Lochter, A.; Srebrow, A.; Sympson, C.J.; Terracio, N.; Werb, Z.; Bissell, M.J.

    1997-02-21

    Stromelysin-1 is a member of the metalloproteinase family of extracellular matrix-degrading enzymes that regulates tissue remodeling. We previously established a transgenic mouse model in which rat stromelysin-1 targeted to the mammary gland augmented expression of endogenous stromelysin-1, disrupted functional differentiation, and induced mammary tumors. A cell line generated from an adenocarcinoma in one of these animals and a previously described mammary tumor cell line generated in culture readily invaded both a reconstituted basement membrane and type I collagen gels, whereas a nonmalignant, functionally normal epithelial cell line did not. Invasion of Matrigel by tumor cells was largely abolished by metalloproteinase inhibitors, but not by inhibitors of other proteinase families. Inhibition experiments with antisense oligodeoxynucleotides revealed that Matrigel invasion of both cell lines was critically dependent on stromelysin-1 expression. Invasion of collagen, on the other hand, was reduced by only 40-50%. Stromelysin-1 was expressed in both malignant and nonmalignant cells grown on plastic substrata. Its expression was completely inhibited in nonmalignant cells, but up-regulated in tumor cells, in response to Matrigel. Thus misregulation of stromelysin-1 expression appears to be an important aspect of mammary tumor cell progression to an invasive phenotype. The matrix metalloproteinases (MMPs) are a family of extracellular matrix (ECM)-degrading enzymes that have been implicated in a variety of normal developmental and pathological processes, including tumorigenesis. The MMP family comprises at least 15 members with different, albeit overlapping, substrate specificities. During activation of latent MMPs, their propeptides are cleaved and they are converted to a lower molecular weight form by other enzymes, including serine proteinases, and by autocatalytic cleavage. Among the MMPs, stromelysin-1 (SL1) possesses the broadest substrate specificity. Despite

  14. Inhibition of Fungal Pathogens across Genotypes and Temperatures by Amphibian Skin Bacteria

    Directory of Open Access Journals (Sweden)

    Carly R. Muletz-Wolz

    2017-08-01

    Full Text Available Symbiotic bacteria may dampen the impacts of infectious diseases on hosts by inhibiting pathogen growth. However, our understanding of the generality of pathogen inhibition by different bacterial taxa across pathogen genotypes and environmental conditions is limited. Bacterial inhibitory properties are of particular interest for the amphibian-killing fungal pathogens (Batrachochytrium dendrobatidis and Batrachochytrium salamandrivorans, for which probiotic applications as conservation strategies have been proposed. We quantified the inhibition strength of five putatively B. dendrobatidis-inhibitory bacteria isolated from woodland salamander skin against six Batrachochytrium genotypes at two temperatures (12 and 18°C. We selected six genotypes from across the Batrachochytrium phylogeny: B. salamandrivorans, B. dendrobatidis-Brazil and four genotypes of the B. dendrobatidis Global Panzootic Lineage (GPL1: JEL647, JEL404; GPL2: SRS810, JEL423. We performed 96-well plate challenge assays in a full factorial design. We detected a Batrachochytrium genotype by temperature interaction on bacterial inhibition score for all bacteria, indicating that bacteria vary in ability to inhibit Batrachochytrium depending on pathogen genotype and temperature. Acinetobacter rhizosphaerae moderately inhibited B. salamandrivorans at both temperatures (μ = 46–53%, but not any B. dendrobatidis genotypes. Chryseobacterium sp. inhibited three Batrachochytrium genotypes at both temperatures (μ = 5–71%. Pseudomonas sp. strain 1 inhibited all Batrachochytrium genotypes at 12°C and four Batrachochytrium genotypes at 18°C (μ = 5–100%. Pseudomonas sp. strain 2 and Stenotrophomonas sp. moderately to strongly inhibited all six Batrachochytrium genotypes at both temperatures (μ = 57–100%. All bacteria consistently inhibited B. salamandrivorans. Using cluster analysis of inhibition scores, we found that more closely related Batrachochytrium genotypes grouped together

  15. Optical Coherence Tomography Angiography Characteristics of Iris Melanocytic Tumors

    Science.gov (United States)

    Skalet, Alison H.; Li, Yan; Lu, Chen D.; Jia, Yali; Lee, ByungKun; Husvogt, Lennart; Maier, Andreas; Fujimoto, James G.; Thomas, Charles R.; Huang, David

    2016-01-01

    Objective To evaluate tumor vasculature with optical coherence tomography (OCT) angiography (OCTA) in malignant iris melanomas and benign iris lesions. Design Cross-sectional observational clinical study. Participants Patients with iris lesions and healthy volunteers. Methods Eyes were imaged using OCTA systems operating at 1050 and 840 nm wavelengths. Three-dimensional OCTA scans were acquired. Iris melanomas patients treated with radiation therapy were imaged again after I-125 plaque brachytherapy at 6 and 18 months. Main Outcome Measures OCT and OCTA images, qualitative evaluation of iris and tumor vasculature and quantitative vessel density. Results One eye each of eight normal volunteers and nine patients with iris melanomas or benign iris lesions including freckles, nevi, and an iris pigment epithelial (IPE) cyst were imaged. The normal iris has radially-oriented vessels within the stroma on OCTA. Penetration of flow signal in normal iris depended on iris color, with best penetration seen in light to moderately pigmented irides. Iris melanomas demonstrated tortuous and disorganized intratumoral vasculature. In two eyes with nevi there was no increased vascularity; in another, fine vascular loops were noted near an area of ectropion uveae. Iris freckles and the IPE cyst did not have intrinsic vascularity. The vessel density was significantly higher within iris melanomas (34.5%±9.8%, piris nevi (8.0%±1.4%) or normal irides (8.0%±1.2%). Tumor regression after radiation therapy for melanomas was associated with decreased vessel density. OCTA at 1050 nm provided better visualization of tumor vasculature and penetration through thicker tumors than at 840 nm. But in very thick tumors and highly pigmented lesions even 1050 nm OCTA could not visualize their full thickness. Interpretable OCTA images were obtained in 82% participants in whom imaging was attempted. Conclusions This is the first demonstration of OCTA in iris tumors. OCTA may provide a dye-free, no

  16. Human papillomavirus genotyping and p16 expression as prognostic factors for patients with American Joint Committee on Cancer stages I to III carcinoma of the anal canal

    DEFF Research Database (Denmark)

    Serup-Hansen, Eva; Linnemann, Dorte; Skovrider-Ruminski, Wojciech

    2014-01-01

    -specific survival (DSS) in patients diagnosed with American Joint Committee on Cancer (AJCC) stages I to III carcinoma of the anal canal. PATIENTS AND METHODS: HPV genotyping polymerase chain reaction (high-risk subtypes 16, 18, 31, 33, 45, 52, and 58) and immunohistochemical expression of p16 were analyzed......PURPOSE: Carcinomas of the anal canal are strongly associated with the human papillomavirus (HPV). Expression of p16 is used as a surrogate marker of HPV infection. In a retrospective study, we evaluated HPV genotyping and p16 expression as prognostic markers of overall survival (OS) and disease...... by using paraffin-embedded tumor biopsies from 143 anal carcinomas. The patients were treated with combined chemoradiotherapy or radiotherapy alone. RESULTS: HPV16 was detected in 81.0% of the tumors, followed by HPV33 (5.1%), HPV18 (2.2%), and HPV58 (0.7%). p16 positivity was found in 92.9% of the tumors...

  17. Multiparametric classification links tumor microenvironments with tumor cell phenotype.

    Directory of Open Access Journals (Sweden)

    Bojana Gligorijevic

    2014-11-01

    Full Text Available While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which

  18. Post-processing through linear regression

    Directory of Open Access Journals (Sweden)

    B. Van Schaeybroeck

    2011-03-01

    Full Text Available Various post-processing techniques are compared for both deterministic and ensemble forecasts, all based on linear regression between forecast data and observations. In order to evaluate the quality of the regression methods, three criteria are proposed, related to the effective correction of forecast error, the optimal variability of the corrected forecast and multicollinearity. The regression schemes under consideration include the ordinary least-square (OLS method, a new time-dependent Tikhonov regularization (TDTR method, the total least-square method, a new geometric-mean regression (GM, a recently introduced error-in-variables (EVMOS method and, finally, a "best member" OLS method. The advantages and drawbacks of each method are clarified.

    These techniques are applied in the context of the 63 Lorenz system, whose model version is affected by both initial condition and model errors. For short forecast lead times, the number and choice of predictors plays an important role. Contrarily to the other techniques, GM degrades when the number of predictors increases. At intermediate lead times, linear regression is unable to provide corrections to the forecast and can sometimes degrade the performance (GM and the best member OLS with noise. At long lead times the regression schemes (EVMOS, TDTR which yield the correct variability and the largest correlation between ensemble error and spread, should be preferred.

  19. FTO genotype is associated with phenotypic variability of body mass index

    NARCIS (Netherlands)

    Yang, J.; Loos, R.J.; Powell, J.E.; Medland, S.E.; Speliotes, E.K.; Chasman, D.I.; Rose, L.M.; Thorleifsson, G.; Steinthorsdottir, V.; Mägi, R.; Waite, L.; Smith, A.V.; Yerges-Armstrong, L.M.; Monda, K.L.; Hadley, D.; Mahajan, A.; Li, G.; Kapur, K.; Vitart, V.; Huffman, J.E.; Wang, S.R.; Palmer, C.; Esko, T.; Fischer, K.; Zhao, J.H.; Demirkan, A.; Isaacs, A.; Feitosa, M.F.; Luan, J.; Heard-Costa, N.L.; White, C.; Jackson, A.U.; Preuss, M; Ziegler, A.; Eriksson, J.; Kutalik, Z.; Frau, F.; Nolte, I.M.; van Vliet-Ostaptchouk, J.V.; Hottenga, J.J.; Jacobs, K.B.; Verweij, N.; Goel, A.; Medina-Gomez, C.; Estrada, K.; Bragg-Gresham, J.L.; Sanna, S.; Sidore, C.; Tyrer, J.; Teumer, A.; Prokopenko, I.; Mangino, M.; Lindgren, C.M.; Assimes, T.L.; Shuldiner, A.R.; Hui, J.; Beilby, J.P.; McArdle, W.L.; Hall, P.; Haritunians, T.; Zgaga, L.; Kolcic, I.; Polasek, O.; Zemunik, T.; Oostra, B.A.; Junttila, M.J.; Grönberg, H.; Schreiber, S; Peters, A.; Hicks, A.A.; Stephens, J.; Foad, N.S.; Laitinen, J.; Pouta, A.; Kaakinen, M.; Willemsen, G.; Vink, J.M.; Wild, S.H.; Navis, G.; Asselbergs, F.W.; Homuth, G.; John, U.; Iribarren, C.; Harris, T.; Launer, L.J.; Gudnason, V.; O'Connell, J.R.; Boerwinkle, E.; Cadby, G.; Palmer, L.J.; James, A.L.; Musk, A.W.; Ingelsson, E.; Psaty, B.M.; Beckmann, J.S.; Waeber, G.; Vollenweider, P.; Hayward, C.; Wright, A.F.; Rudan, I.; Groop, L.C.; Metspalu, A.; Thee Khaw, K.; van Duijn, C.M.; Borecki, I.B.; Province, M.A.; Wareham, N.J.; Tardif, J.C.; Huikuri, H.V.; Cupples, L.A.; Atwood, L.D.; Fox, C.S.; Boehnke, M.; Collins, F.S.; Mohlke, K.L.; Erdmann, J.; Schunkert, H.; Hengstenberg, C.; Stark, K.; Lorentzon, M.; Ohlsson, C.; Cusi, D.; Staessen, J.A.; van der Klauw, M.M.; Pramstaller, P.P.; Kathiresan, S.; Jolley, D.J.; Ripatti, S.; Jarvelin, M.-R.; de Geus, E.J.C.; Boomsma, D.I.; Penninx, B.W.J.H.; Wilson, J.F.; Campbell, H.; Chanock, S.J.; van der Harst, P.; Hamsten, A.; Watkins, H.; Hofman, A.; Witteman, J.C.; Zillikens, M.C.; Uitterlinden, A.G.; Rivadeneira, F.; Kiemeney, L.A.; Vermeulen, S.H.; Abecasis, G.R.; Schlessinger, D.; Schipf, S.; Stumvoll, M.; Tönjes, A.; Spector, T.D.; North, K.E.; Lettre, G.; McCarthy, M.I.; Berndt, S.I.; Heath, A.C.; Madden, P.A.F.; Nyholt, DR; Montgomery, G.W.; Martin, N.G.; McKnight, B.; Strachan, D.P.; Hill, W.G.; Snieder, H.; Ridker, P.M.; Thorsteinsdottir, U.; Stefansson, K.; Frayling, T.M.; Hirschhorn, J.N.; Goddard, M.E.; Visscher, P.M.

    2012-01-01

    There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human

  20. Censored Hurdle Negative Binomial Regression (Case Study: Neonatorum Tetanus Case in Indonesia)

    Science.gov (United States)

    Yuli Rusdiana, Riza; Zain, Ismaini; Wulan Purnami, Santi

    2017-06-01

    Hurdle negative binomial model regression is a method that can be used for discreate dependent variable, excess zero and under- and overdispersion. It uses two parts approach. The first part estimates zero elements from dependent variable is zero hurdle model and the second part estimates not zero elements (non-negative integer) from dependent variable is called truncated negative binomial models. The discrete dependent variable in such cases is censored for some values. The type of censor that will be studied in this research is right censored. This study aims to obtain the parameter estimator hurdle negative binomial regression for right censored dependent variable. In the assessment of parameter estimation methods used Maximum Likelihood Estimator (MLE). Hurdle negative binomial model regression for right censored dependent variable is applied on the number of neonatorum tetanus cases in Indonesia. The type data is count data which contains zero values in some observations and other variety value. This study also aims to obtain the parameter estimator and test statistic censored hurdle negative binomial model. Based on the regression results, the factors that influence neonatorum tetanus case in Indonesia is the percentage of baby health care coverage and neonatal visits.

  1. The comparison of nuclear ubiquitous casein and cyclin-dependent kinases substrate (NUCKS) with Ki67 proliferation marker expression in common skin tumors.

    Science.gov (United States)

    Zduniak, Krzysztof; Agrawal, Siddarth; Symonowicz, Krzysztof; Jurczyszyn, Kamil; Ziółkowski, Piotr

    2014-03-01

    Nuclear ubiquitous casein and cyclin-dependent kinases substrate (NUCKS) is a chromosomal protein of unknown function. Its amino acid composition and structure of its DNA binding domain resemble those of high mobility group A (HMGA) proteins which are associated with various malignancies. Since changes in expression of HMGA are considered as a marker of tumor progression, it is possible that similar changes in expression of NUCKS could be a useful tool in diagnosis of malignant skin tumors. To investigate this assumption we used specific antibodies against NUCKS for immunohistochemistry of squamous (SCC) and basal cell carcinoma (BCC) as well as keratoacanthoma (KA). We found high expression of NUCKS in nuclei of SCC and BCC cells which exceeded expression of the well-known proliferation marker Ki67. Expression of NUCKS in benign KA was much below that of malignant tumors. With the present study and based on our previous experience we would like to suggest the NUCKS protein as a novel proliferation marker for immunohistochemical evaluation of formalin-fixed and paraffin-embedded skin tumor specimens. We would like to emphasize that NUCKS abundance in malignant skin tumors is higher than that of the well-known proliferation marker Ki67, thus allowing more precise assessment of tumor proliferation potential.

  2. Reactivity of p53 protein in canine transmissible venereal tumor Reatividade da proteína P53 no tumor venéreo transmissível canino

    Directory of Open Access Journals (Sweden)

    J.V. Moro

    2010-04-01

    Full Text Available The expression of p53 protein was evaluated in canine transmissible venereal tumor (CTVT, as following: natural occurrence (n=8; resistant to chemotherapy (n=4; and allogeneic transplanted in progression (n=8, stable (n=8, and regression (n=8stages. The collected specimens were submitted to GM1 immunohistochemical reaction. Results showed a mean percentage of immunomarked cells around 18.6% in CTVT of natural occurrence, 23.8% in CTVT resistant to chemotherapy, 22.9% in allogeneic transplanted CTVT in both progression and stable stages, and 35.8% in transplanted CTVT in regression stage. The results suggest that there is a functional abnormality in p53 gene and its products in the studied tumors; although, it is not possible to correlate the percentage of cells marked by p53 and a prognosis.A expressão da proteína p53 foi avaliada em espécimes de tumor venéreo transmissível canino (TVT de ocorrência natural (n=8; resistente à quimioterapia (n=4 e transplantado em cão nas fases de progressão tumoral (n=8, de latência (n=8 e de regressão (n=8. Os espécimes foram submetidos à reação de imunoistoquímica. Os resultados mostraram porcentagem média de células imunomarcadas de 18,6% no TVT de ocorrência natural, de 23,8% no TVT refratário, 22,9% nos TVTs transplantados nas fases de progressão e latência e de 35,8% na fase de regressão. Os resultados sugerem que há uma anormalidade funcional no gene P53 e seus produtos nos tumores estudados, apesar de não ser possível correlacionar a porcentagem de células marcadas pelo p53 ao prognóstico.

  3. Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Qingwen [Shanghai Chest Hospital, Shanghai 200433 (China); State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Jiang, Songmin [State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Han, Baohui [Shanghai Chest Hospital, Shanghai 200433 (China); Sun, Tongwen [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China); Li, Zhengnan; Zhao, Lina; Gao, Qiang [College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457 (China); Sun, Jialin, E-mail: jialin_sun@126.com [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China)

    2012-11-02

    Highlights: Black-Right-Pointing-Pointer We construct and purify a fusion protein VEGF-SEA. Black-Right-Pointing-Pointer VEGF-SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. Black-Right-Pointing-Pointer T cells driven by VEGF-SEA were accumulated around tumor cells bearing VEGFR by mice image model. Black-Right-Pointing-Pointer VEGF-SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. Black-Right-Pointing-Pointer The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF-SEA treated with 15 {mu}g, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4{sup +} and CD8{sup +} T cells driven by VEGF-SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF-SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.

  4. Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor–superantigen conjugate

    International Nuclear Information System (INIS)

    Sun, Qingwen; Jiang, Songmin; Han, Baohui; Sun, Tongwen; Li, Zhengnan; Zhao, Lina; Gao, Qiang; Sun, Jialin

    2012-01-01

    Highlights: ► We construct and purify a fusion protein VEGF–SEA. ► VEGF–SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. ► T cells driven by VEGF–SEA were accumulated around tumor cells bearing VEGFR by mice image model. ► VEGF–SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. ► The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF–SEA treated with 15 μg, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4 + and CD8 + T cells driven by VEGF–SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF–SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.

  5. Least-Squares Linear Regression and Schrodinger's Cat: Perspectives on the Analysis of Regression Residuals.

    Science.gov (United States)

    Hecht, Jeffrey B.

    The analysis of regression residuals and detection of outliers are discussed, with emphasis on determining how deviant an individual data point must be to be considered an outlier and the impact that multiple suspected outlier data points have on the process of outlier determination and treatment. Only bivariate (one dependent and one independent)…

  6. HBV genotypic variability in Cuba.

    Directory of Open Access Journals (Sweden)

    Carmen L Loureiro

    Full Text Available The genetic diversity of HBV in human population is often a reflection of its genetic admixture. The aim of this study was to explore the genotypic diversity of HBV in Cuba. The S genomic region of Cuban HBV isolates was sequenced and for selected isolates the complete genome or precore-core sequence was analyzed. The most frequent genotype was A (167/250, 67%, mainly A2 (149, 60% but also A1 and one A4. A total of 77 isolates were classified as genotype D (31%, with co-circulation of several subgenotypes (56 D4, 2 D1, 5 D2, 7 D3/6 and 7 D7. Three isolates belonged to genotype E, two to H and one to B3. Complete genome sequence analysis of selected isolates confirmed the phylogenetic analysis performed with the S region. Mutations or polymorphisms in precore region were more common among genotype D compared to genotype A isolates. The HBV genotypic distribution in this Caribbean island correlates with the Y lineage genetic background of the population, where a European and African origin prevails. HBV genotypes E, B3 and H isolates might represent more recent introductions.

  7. HBV Genotypic Variability in Cuba

    Science.gov (United States)

    Loureiro, Carmen L.; Aguilar, Julio C.; Aguiar, Jorge; Muzio, Verena; Pentón, Eduardo; Garcia, Daymir; Guillen, Gerardo; Pujol, Flor H.

    2015-01-01

    The genetic diversity of HBV in human population is often a reflection of its genetic admixture. The aim of this study was to explore the genotypic diversity of HBV in Cuba. The S genomic region of Cuban HBV isolates was sequenced and for selected isolates the complete genome or precore-core sequence was analyzed. The most frequent genotype was A (167/250, 67%), mainly A2 (149, 60%) but also A1 and one A4. A total of 77 isolates were classified as genotype D (31%), with co-circulation of several subgenotypes (56 D4, 2 D1, 5 D2, 7 D3/6 and 7 D7). Three isolates belonged to genotype E, two to H and one to B3. Complete genome sequence analysis of selected isolates confirmed the phylogenetic analysis performed with the S region. Mutations or polymorphisms in precore region were more common among genotype D compared to genotype A isolates. The HBV genotypic distribution in this Caribbean island correlates with the Y lineage genetic background of the population, where a European and African origin prevails. HBV genotypes E, B3 and H isolates might represent more recent introductions. PMID:25742179

  8. Dosimetric investigation depending on tumor location in patient breast in partial breast irradiation

    International Nuclear Information System (INIS)

    Kim, Min Joo; Park, So Hyun; Jung, Joo Young; Woong, Cho; Suh, Tae Suk

    2012-01-01

    The Partial Breast Irradiation (PBI) technique, which involves radiation beam delivery techniques that use a limited range of treatment volumes, has been a challenging approach that is worthy of consideration compared to whole-breast radiation therapy (WBRT). Because of a small target volumes used in the PBI technique, the radiation dose can be safely delivered to the targeted tissue without the unwanted delivery of radiation to normal breast tissues and organ at risk (OAR), such as contralateral breast, lung and heart.Through PBI technique, better cosmetic outcomes and minimizing damages to OARs could be expected and also the daily dose can be increased with smaller number of fractionation in radiation therapy. The purpose of this study was to evaluate the dosimetric effects according to tumor locations in patient's breast for Partial Breast Irradiation (PBI) technique using three Dimensional Conformal Radiation Therapy (3DCRT), Electron Beam Radiation therapy (EBRT) and Helical-tomotherapy (H-TOMO). Dosimetric comparisons of PBI technique for 3DCRT, EBRT, and H-TOMO depending on the classified tumor locations were performed. H-TOMO delivered the low dose to lager volume to surrounding normal tissue, such as the heart and lungs compared to 3DCRT and EBRT although it had the same degree of target coverage as the other methods (3DCRT, EBRT). EBRT had a curative effect for early-stage breast cancers located in the lower and inner sections (LIQ-S, LIQ-D)

  9. Phenotypic and Genotypic Characterization and Treatment of a Cohort with Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome

    Science.gov (United States)

    Ramnitz, Mary Scott; Gourh, Pravitt; Goldbach-Mansky, Raphaela; Wodajo, Felasfa; Ichikawa, Shoji; Econs, Michael J.; White, Kenneth; Molinolo, Alfredo; Chen, Marcus Y.; Heller, Theo; Del Rivero, Jaydira; Seo-Mayer, Patricia; Arabshahi, Bita; Jackson, Malaka B.; Hatab, Sarah; McCarthy, Edward; Guthrie, Lori C.; Brillante, Beth A.; Gafni, Rachel I.; Collins, Michael T.

    2016-01-01

    Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated while iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in 7 subjects; no causative mutation was found in the eighth. Biopsies from 4 subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in 1 subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the 2 subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and peri-lesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations

  10. Correlation between dose and tumor response in the radiotherapy of lung cancer of various histological types

    International Nuclear Information System (INIS)

    Koga, Kenji; Kusuhara, Toshiyuki; Nishikawa, Kiyoshi; Asada, Keiko; Watanabe, Katsushi

    1984-01-01

    Correlation between dose and tumor response by cell types was determined in 50 patients with lung cancer in order to predict the possibility of further tumor regression. The TDF (time-dose-fractionation) concept was used as dose factor. The radiation source was a cobalt-60 γ-ray or linear accelerator 10 MV X-ray. As a routine regime a fraction dose of 2 Gy five times per week was given to 39 of the 50 patients, but a dose of 2 Gy three times per week or of 1.5 Gy five times per week was given to seven and four patients, respectively. Radiation response was the best in small cell carcinoma and better in adenocarcinoma than in squamous cell carcinoma, showing a tumor regression rate of 50% or more in 90%, 80% and 58% of the patients, respectively. The correlation between tumor regression rate and TDF values was good in squamous cell carcinoma (r = 0.73) and small cell carcinoma (r = - 0.72), but poor in adenocarcinoma (r = - 0.10). These results suggest that in squamous cell carcinoma improvement of tumor regression can be expected by increasing TDF values, and in adenocarcinoma and small cell carcinoma the optimal TDF values are about 100 and 60 to 80, respectively. (author)

  11. Evaluation of Different Triticale (X Triticosecale wittmack Genotypes for Agronomic and Qualitative Characters

    Directory of Open Access Journals (Sweden)

    S Ansari

    2018-02-01

    coefficients of genotypic (41.7% and phenotypic (44.9% coefficient of variation were belonged to wet gluten content. The least coefficient of genotypic (4.5% and phenotypic (7% variation was denoted to test weight. Simple mean comparisons for seed yield of Triticale showed that the highest seed yield (11.84 ton ha-1 was denoted to Sorento genotype from Poland and the least seed yield (5.5 ton ha-1 to Beaglel and EMA genotypes (from CYMMYT. Using stepwise regression analysis, 98.8% of seed yield variation was attributed to two traits, including harvest index, and biological yield. Correlation analysis showed the significant relation of number of spikelets per spike, and spike length with grain yield. The results of the factor analysis revealed that five factors namely, plant height, grain yield and their components, biological yield, harvest index gluten content explained 80% of total variances of the grain yield. Cluster analysis of genotypes based on agronomic and protein content traits grouped the genotypes into four separate clusters. In categorization based on collected data, the fourth group included genotype from Poland origin (Prego, Lamberto, Moreno, Lasko, Dagro, Sorento, Fidelio, LAD1900, RH116, Tewo, Disco, Vero, DAD601, Pinokio and Magnat with the highest value for biological yield, seed yield, number of spikelet per spike, plant height, spike length and the length of the last internode. These clusters have beneficial characteristics and are useful for plant breeding purposes. Conclusions Based on the data reported here, the scientific use of multivariate statistical analysis including stepwise regression analysis, principle component and cluster analysis of genotypes revealed subjectivity of these methods as a suitable way to exploit intraspecific variation within triticale and evaluate its genetic resources for their agronomic value and the amount of genetic variation for specific traits to allow more efficient genetic improvement. The identified superior

  12. The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade

    Directory of Open Access Journals (Sweden)

    David A. Schaer

    2018-03-01

    Full Text Available Summary: Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6, has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control. In vitro, treatment with abemaciclib resulted in increased activation of human T cells and upregulated expression of antigen presentation genes in MCF-7 breast cancer cells. These data collectively support the clinical investigation of the combination of abemaciclib with agents such as anti-PD-L1 that modulate T cell anti-tumor immunity. : Schaer, Beckmann et al. describe unique immune-modulating properties of abemaciclib that include upregulation of antigen presentation on tumor cells and increased T cell activation. These activities synergize with anti-PD-L1 therapy to further enhance immune activation, including macrophage and DC antigen presentation, and also lead to a reciprocal increase in abemaciclib-dependent cell cycle gene regulation. Keywords: CDK4/6, abemaciclib, PD-1, PD-L1, combination immunotherapy, cancer

  13. Effects of Drought Stress on Canola (Brassica napus L. Genotypes Yield and Yield Components

    Directory of Open Access Journals (Sweden)

    R Khani

    2018-02-01

    Full Text Available Introduction Canola (Brassica napus L. genotypes with wide adaptability to environmental conditions could play a major role in Iran’s oilseed crop production. Selection of high performing genotypes is very important for developing canola cultivation. Water stress can reduce crop yield by affecting both source and sink for assimilation. Canola yield depends on genotype and environmental conditions and response of genotypes to environmental factors. Canola genotypes response to stress depends on the developmental stage and the events occurring prior to and during flowering stage. Resistance to water stress is divided to avoidance and tolerance. Some species are tolerable against water stress. In a while, other species respond ending life cycle, falling leaves and other reactions into water stress. Therefore, investigation of canola genotypes response to water stress in phenological growth stages can be valuable in order to determine resistant or tolerant genotypes. Materials and Methods In order to study the effect of drought stress on canola genotypes yield and its components, an experiment was conducted in 2013-2014 as a split plot based on randomized complete block design with three replications at the research farm, Agricultural and Natural Resources Research Center of East-Azarbaijan, Tabriz-Iran. Three levels of drought stress were considered as main plot (No-stress, stress at the flowering and pod setting growth stages and 18 canola genotypes including HW113, RS12, Karaj1, KR18, L73, L72, HW101, L146, L210, L183, SW101, L5, L201, HW118, KR4, Karaj2, Karaj3 and KS7 as subplots. Flood irrigation was scheduled at 50% field capacity, 30 and 30% field capacity for no-stress, stress at the flowering and pod setting growth stages, respectively; i.e. soil moisture capacity was maintained at 30% by irrigating to 100% field capacity when available moisture reached 30% in drought stress treatments. An ANOVA was conducted using the PROC-GLM procedure

  14. Bulk Genotyping of Biopsies Can Create Spurious Evidence for Hetereogeneity in Mutation Content.

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    Rumen Kostadinov

    2016-04-01

    Full Text Available When multiple samples are taken from the neoplastic tissues of a single patient, it is natural to compare their mutation content. This is often done by bulk genotyping of whole biopsies, but the chance that a mutation will be detected in bulk genotyping depends on its local frequency in the sample. When the underlying mutation count per cell is equal, homogenous biopsies will have more high-frequency mutations, and thus more detectable mutations, than heterogeneous ones. Using simulations, we show that bulk genotyping of data simulated under a neutral model of somatic evolution generates strong spurious evidence for non-neutrality, because the pattern of tissue growth systematically generates differences in biopsy heterogeneity. Any experiment which compares mutation content across bulk-genotyped biopsies may therefore suggest mutation rate or selection intensity variation even when these forces are absent. We discuss computational and experimental approaches for resolving this problem.

  15. Bulk Genotyping of Biopsies Can Create Spurious Evidence for Hetereogeneity in Mutation Content.

    Science.gov (United States)

    Kostadinov, Rumen; Maley, Carlo C; Kuhner, Mary K

    2016-04-01

    When multiple samples are taken from the neoplastic tissues of a single patient, it is natural to compare their mutation content. This is often done by bulk genotyping of whole biopsies, but the chance that a mutation will be detected in bulk genotyping depends on its local frequency in the sample. When the underlying mutation count per cell is equal, homogenous biopsies will have more high-frequency mutations, and thus more detectable mutations, than heterogeneous ones. Using simulations, we show that bulk genotyping of data simulated under a neutral model of somatic evolution generates strong spurious evidence for non-neutrality, because the pattern of tissue growth systematically generates differences in biopsy heterogeneity. Any experiment which compares mutation content across bulk-genotyped biopsies may therefore suggest mutation rate or selection intensity variation even when these forces are absent. We discuss computational and experimental approaches for resolving this problem.

  16. MRI features and pathologic types of benign meningiomas and their correlation with tumor recurrence

    International Nuclear Information System (INIS)

    Du Tieqiao; Zhu Mingwang; Zhao Dianjiang; Qi Xueling; Wang Lining; Zhang Xufei

    2014-01-01

    Objective: To determine MR manifestations and pathologic types of benign meningiomas and their relationship with tumor recurrence. Methods: There were 218 patients (160 females,58 males; age range 4-79 years) with benign meningiomas in the study, including 31 recurrent meningiomas (recurrence group)and 187 primary meningiomas (primary group). All patients were proved by postoperative pathology. Differences of pathological types and MRI manifestations between the recurrence group and the primary group were evaluated by using χ 2 test and rank sum test. Logistic regression analysis was performed by taking tumor recurrence as the dependent variable, and age, gender, vital structures involvement and pathologic types as independent variables. The recurrent time intervals were compared by rank sum test. Results: There were 30 patients with intracranial vital structures involvement or extreintracranial communication tumors in the recurrent group, which was obviously higher than that of the primary group (61 patients). The difference was statistically significant (χ 2 =57.672, P=0.001). The tumors located in the skull-base and juxtasinus in the recurrent group were obviously more than those in the primary group, and difference was statistically significant (χ 2 =10.990, P=0.001). Multi-logistic regression analysis showed that the recurrent risk of benign meningiomas was elevated significantly only with vital structure involvement or extreintracranial communication tumors (wald χ 2 =31.863, OR=3.820, P=0.001). The recurrent risk of dural sinus involvement was 3.820 times of cerebral artery trunk and cranial nerves involvement, and the risk of the latter was 3.820 times of the non-involved. There was no statistical difference between the two groups in pathology type, location, peritumoral edema, tumor morphology and tumor size. The relapse time of dural sinus involvement and cerebral artery trunk involvement in the recurrent group was 24(13 to 180) and 126(12 to 187

  17. Mitigating Errors in External Respiratory Surrogate-Based Models of Tumor Position

    International Nuclear Information System (INIS)

    Malinowski, Kathleen T.; McAvoy, Thomas J.; George, Rohini; Dieterich, Sonja; D'Souza, Warren D.

    2012-01-01

    Purpose: To investigate the effect of tumor site, measurement precision, tumor–surrogate correlation, training data selection, model design, and interpatient and interfraction variations on the accuracy of external marker-based models of tumor position. Methods and Materials: Cyberknife Synchrony system log files comprising synchronously acquired positions of external markers and the tumor from 167 treatment fractions were analyzed. The accuracy of Synchrony, ordinary-least-squares regression, and partial-least-squares regression models for predicting the tumor position from the external markers was evaluated. The quantity and timing of the data used to build the predictive model were varied. The effects of tumor–surrogate correlation and the precision in both the tumor and the external surrogate position measurements were explored by adding noise to the data. Results: The tumor position prediction errors increased during the duration of a fraction. Increasing the training data quantities did not always lead to more accurate models. Adding uncorrelated noise to the external marker-based inputs degraded the tumor–surrogate correlation models by 16% for partial-least-squares and 57% for ordinary-least-squares. External marker and tumor position measurement errors led to tumor position prediction changes 0.3–3.6 times the magnitude of the measurement errors, varying widely with model algorithm. The tumor position prediction errors were significantly associated with the patient index but not with the fraction index or tumor site. Partial-least-squares was as accurate as Synchrony and more accurate than ordinary-least-squares. Conclusions: The accuracy of surrogate-based inferential models of tumor position was affected by all the investigated factors, except for the tumor site and fraction index.

  18. HRM and SNaPshot as alternative forensic SNP genotyping methods.

    Science.gov (United States)

    Mehta, Bhavik; Daniel, Runa; McNevin, Dennis

    2017-09-01

    Single nucleotide polymorphisms (SNPs) have been widely used in forensics for prediction of identity, biogeographical ancestry (BGA) and externally visible characteristics (EVCs). Single base extension (SBE) assays, most notably SNaPshot® (Thermo Fisher Scientific), are commonly used for forensic SNP genotyping as they can be employed on standard instrumentation in forensic laboratories (e.g. capillary electrophoresis). High resolution melt (HRM) analysis is an alternative method and is a simple, fast, single tube assay for low throughput SNP typing. This study compares HRM and SNaPshot®. HRM produced reproducible and concordant genotypes at 500 pg, however, difficulties were encountered when genotyping SNPs with high GC content in flanking regions and differentiating variants of symmetrical SNPs. SNaPshot® was reproducible at 100 pg and is less dependent on SNP choice. HRM has a shorter processing time in comparison to SNaPshot®, avoids post PCR contamination risk and has potential as a screening tool for many forensic applications.

  19. Photodynamic therapy-generated vaccines prevent tumor recurrence after radiotherapy

    International Nuclear Information System (INIS)

    Korbelik, M.; Sun, J.

    2003-01-01

    Photodynamic therapy (PDT), an established clinical modality for a variety of malignant and non-malignant diseases, inflicts photoreactive drug-mediated oxidative stress that prompts the engagement of host inflammatory and immune responses which contribute to the therapy outcome. Recently, it has become evident that in vitro PDT-treated tumor cells or their lysates can be utilized as an effective vaccine against established tumors of the same origin. The mechanism underlying the vaccine action appears to be based on eliciting immune recognition of the tumor and developing an efficient immune response even against poorly immunogenic tumors. This study examined whether PDT-generated vaccines can be effectively combined with radiotherapy. Subcutaneous SCCVII tumors (squamous cell carcinomas) growing in syngeneic C3H/HeN mice were treated by radiotherapy (60 Gy x-ray dose). PDT-vaccine treatment, done by peritumoral injection of in vitro PDT-treated SCCVII cells (20 million/mouse), was performed either immediately after radiotherapy or ten days later. The mice were then observed for tumor regression/recurrence. The tumors treated with radiotherapy alone shrunk and became impalpable for a brief period after which they all recurred. In contrast, vaccination performed at 10 days post radiotherapy delayed tumor recurrence and prevented it in one of six mice. Even better results were obtained with mice vaccinated immediately after radiotherapy, with mice showing not only a delayed tumor recurrence but also no sign of tumor in 50% of mice. The PDT-vaccine treatment without radiotherapy produced in this trial a significant tumor growth retardation but no complete regressions. These results indicate that PDT-generated vaccines can ensure immune rejection of cancer once the lesion size is reduced by radiotherapy. Even without obtaining a systemic immunity for the elimination of disseminated malignant deposits, these findings suggest that PDT-vaccines can improve local control

  20. Sources of Wilhelm Johannsen's genotype theory.

    Science.gov (United States)

    Roll-Hansen, Nils

    2009-01-01

    death in 1927. The claim that there was a "substantial but cautious modification of Johannsen's phenotype-genotype distinction" (Churchill, 1974, p. 24) from a statistical to an individual ontological perspective derives from a misreading of the 1903 and 1909 texts. The immediate purpose of this paper is to correct this reading of the 1903 monograph by showing how its problems and results grow out of Johannsen's earlier work in heredity and plant breeding. Johannsen presented his famous selection experiment as the culmination of a line of criticism of orthodox Darwinism by William Bateson, Hugo de Vries, and others (Johannsen, 1903). They had argued that evolution is based on stepwise rather than continuous change in heredity. Johannsen's paradigmatic experiment showed how stepwise variation in heredity could be operationally distinguished from the observable, continuous morphological variation. To test Galton's law of partial regression, Johannsen deliberately chose pure lines of self-fertilizing plants, a pure line being the descendants in successive generations of one single individual. Such a population could be assumed to be highly homogeneous with respect to hereditary type, and Johannsen found that selection produced no change in this type. Galton, he explained, had experimented with populations composed of a number of stable hereditary types. The partial regression which Galton found was simply an effect of selection between types, increasing the proportion of some types at the expense of others.

  1. Diffusion-weighted MR imaging of intracranial tumors

    International Nuclear Information System (INIS)

    Bydder, G.M.; Baudouin, C.J.; Steiner, R.E.; Hajnal, J.V.; Young, I.R.

    1991-01-01

    This paper assesses the effect of anisotropic diffusion weighting on the appearances of cerebral tumors as well as vasogenic and interstitial edema. Diffusion weighting produced a reduction in signal intensity in all or part of the tumors in the majority of cases. However, a relative increase in signal intensity was apparent in four cases. The decrease in signal intensity in vasogenic edema depended on the site and direction of gradient sensitization. Marked increase in conspicuity between tumor and edema was apparent in three cases. Changes in interstitial edema depended in detail in fiber direction. Differentiation between tumor and edema can be improved with diffusion-weighted imaging. Anisotropic change is seen in both vasogenic and interstitial edema

  2. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

    DEFF Research Database (Denmark)

    Laklai, Hanane; Miroshnikova, Yekaterina A.; Pickup, Michael W.

    2016-01-01

    by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were......Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop...... stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression...

  3. Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype.

    Science.gov (United States)

    Ringman, John M; Elashoff, David; Geschwind, Daniel H; Welsh, Brian T; Gylys, Karen H; Lee, Cathy; Cummings, Jeffrey L; Cole, Greg M

    2012-06-01

    To study the effect of familial Alzheimer disease (FAD) mutations and APOE genotype on plasma signaling protein levels. Cross-sectional comparison of plasma levels of 77 proteins measured using multiplex immune assays. A tertiary referral dementia research center. Thirty-three persons from families harboring PSEN1 or APP mutations, aged 19 to 59 years. Protein levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs) and among APOE genotype groups, using multiple linear regression models. Twenty-one participants were FAD MCs and 12 were NCs. Six had the APOE ε2/3, 6 had the ε3/4, and 21 had the ε3/3 genotype. Levels of 17 proteins differed among APOE genotype groups, and there were significant interactions between age and APOE genotype for 12 proteins. Plasma levels of apolipoprotein E and superoxide dismutase 1 were highest in the ε2 carriers, lowest in ε4 carriers, and intermediate in the ε3 carriers. Levels of multiple interleukins showed the opposite pattern and, among the ε4 carriers, demonstrated significant negative correlations with age. Although there were no significant differences between FAD MCs and NCs, there were interactions between mutation status and APOE genotype for 13 proteins. We found different patterns of inflammatory markers in young and middle-aged persons among APOE genotype groups. The APOE ε4 carriers had the lowest levels of apolipoprotein E. Young ε4 carriers have increased inflammatory markers that diminish with age. We demonstrated altered inflammatory responses in young and middle adulthood in ε4 carriers that may relate to AD risk later in life.

  4. Negative social acts and pain: evidence of a workplace bullying and 5-HTT genotype interaction.

    Science.gov (United States)

    Jacobsen, Daniel Pitz; Nielsen, Morten Birkeland; Einarsen, Ståle; Gjerstad, Johannes

    2018-05-01

    Objectives Long-term exposure to systematic negative acts at work, usually labeled workplace bullying, is a prevalent problem at many workplaces. The adverse effects of such exposure may range from psychological symptoms, such as depression and anxiety to somatic ailments like cardiovascular disease and musculoskeletal complaints. In this study, we examined the relationships among exposure to negative acts, genetic variability in the 5-HTT gene SLC6A4 and pain. Methods The study was based on a nationally representative survey of 987 Norwegian employees drawn from the Norwegian Central Employee Register by Statistics Norway. Exposure to bullying in the workplace was measured with the 9-item version of the Negative Acts Questionnaire - Revised (NAQ-R) inventory. Pain was rated using an 11-point (0-10) numeric rating scale (NRS). Genotyping with regard to SLC6A4 was carried out using a combination of gel-electrophoresis and TaqMan assay. Results The data revealed a significant interaction between exposure to negative acts and the SLC6A4 genotype with regard to pain (linear regression with 5000 resamples; age, sex, tobacco use and education were included as covariates). The relationship between negative acts and pain intensity was significantly stronger for subjects with the LALA genotype than for subjects with the SLA/LALG/SLG genotype. No significant difference between subjects with the LALA genotype and SS genotype was observed. Conclusions Our data demonstrated that the relationship between bullying and pain was modified by the 5-HTT genotype, ie, genetic variation in SLC6A4. The association between negative acts and health among vulnerable individuals appeared more potent than previously reported.

  5. Distribution of genotype network sizes in sequence-to-structure genotype-phenotype maps.

    Science.gov (United States)

    Manrubia, Susanna; Cuesta, José A

    2017-04-01

    An essential quantity to ensure evolvability of populations is the navigability of the genotype space. Navigability, understood as the ease with which alternative phenotypes are reached, relies on the existence of sufficiently large and mutually attainable genotype networks. The size of genotype networks (e.g. the number of RNA sequences folding into a particular secondary structure or the number of DNA sequences coding for the same protein structure) is astronomically large in all functional molecules investigated: an exhaustive experimental or computational study of all RNA folds or all protein structures becomes impossible even for moderately long sequences. Here, we analytically derive the distribution of genotype network sizes for a hierarchy of models which successively incorporate features of increasingly realistic sequence-to-structure genotype-phenotype maps. The main feature of these models relies on the characterization of each phenotype through a prototypical sequence whose sites admit a variable fraction of letters of the alphabet. Our models interpolate between two limit distributions: a power-law distribution, when the ordering of sites in the prototypical sequence is strongly constrained, and a lognormal distribution, as suggested for RNA, when different orderings of the same set of sites yield different phenotypes. Our main result is the qualitative and quantitative identification of those features of sequence-to-structure maps that lead to different distributions of genotype network sizes. © 2017 The Author(s).

  6. Preliminary Evaluation of Some Elicited Apple Genotypes Candidate as Cultivars Using Morphological and Molecular Markers

    Directory of Open Access Journals (Sweden)

    Bayan Muzher

    2016-05-01

    Full Text Available Preliminary evaluation of 5 apple genotypes produced by seed selection in the germplasm of seed rootstocks in Sweida- Syria was carried out between 2005 and 2012, to study date of full flowering, maturity time, morphological characters of tree, shoots, leaves, flowers, and fruits, including chemical analysis. On the other hand, yield efficiency, fruit storability and the susceptibility to pests and physiological disorders were evaluated. Molecular characterization was achieved by using 8 pairs of SSR primers for the 5th genotypes in comparison with the two main commercial cultivars "Golden Delicious" and "Starking Delicious" to determine the genetic relationship between the studied genotypes and cultivars. The results divided the studied genotypes depending on the time of ripening into three groups: early, intermediate and late genotypes. All studied genotypes gave efficient and regular yield, and showed fixable fruit shape and size with variable storability due to maturity time. Molecular characterization reveled the ability of SSR technique to determine the genetic variation between the studied genotypes, the 8 primer pairs produced 22 alleles, 21 of them were polymorphic (95.45%. Cluster analysis divided the studied genotypes into 2 clusters, the first cluster included the two commercial cultivars Starking delicious and Golden delicious with one genotypes, while the second cluster contained the four remaining genotypes. Finally, the studied genotypes revealed high desired quantitative and qualitative traits, which assess to distribute these genotypes as new cultivars, and SSR technique was able to identify and revealed the genetic distance between the studied genotypes and commercial cultivars.INTERNATIONAL JOURNAL OF ENVIRONMENTVolume-5, Issue-2, March-May 2016, page: 98-109

  7. Plant genotype shapes ant-aphid interactions: implications for community structure and indirect plant defense.

    Science.gov (United States)

    Mooney, Kailen A; Agrawal, Anurag A

    2008-06-01

    Little is known about the mechanisms by which plant genotype shapes arthropod community structure. In a field experiment, we measured the effects of milkweed (Asclepias syriaca) genotype and ants on milkweed arthropods. Populations of the ant-tended aphid Aphis asclepiadis and the untended aphid Myzocallis asclepiadis varied eight- to 18-fold among milkweed genotypes, depending on aphid species and whether ants were present. There was no milkweed effect on predatory arthropods. Ants increased Aphis abundance 59%, decreased Myzocallis abundance 52%, and decreased predator abundance 56%. Milkweed genotype indirectly influenced ants via direct effects on Aphis and Myzocallis abundance. Milkweed genotype also modified ant-aphid interactions, influencing the number of ants attracted per Aphis and Myzocallis. While ant effects on Myzocallis were consistently negative, effects on Aphis ranged from antagonistic to mutualistic among milkweed genotypes. As a consequence of milkweed effects on ant-aphid interactions, ant abundance varied 13-fold among milkweed genotypes, and monarch caterpillar survival was negatively correlated with genetic variation in ant abundance. We speculate that heritable variation in milkweed phloem sap drives these effects on aphids, ants, and caterpillars. In summary, milkweed exerts genetic control over the interactions between aphids and an ant that provides defense against foliage-feeding caterpillars.

  8. Radiation effects on tumor-specific DTH response, 2

    International Nuclear Information System (INIS)

    Nobusawa, Hiroshi; Hachisu, Reiko.

    1991-01-01

    Tumor-specific immunity was induced in C3H mice by immunizing with syngeneic MH134 hepatoma cells. Radiation sensitivity of anti-tumor activity of immunized spleen cells were examined and compared with the radiation sensitivity of the delayed-type hypersensitivity (DTH)-response. The spleen cells were irradiated in vitro, then mixed with the tumor cells. DTH-response intensity was determined from the footpad increment twenty-four hours after inoculation of tumor cells with immunized spleen cells. Anti-tumor activity of the spleen cells, based on growth inhibition of tumor cells, was measured by a cytostatic test in vivo with diffusion chambers. Tumor-specific DTH response was suppressed dose-dependently in the range of 12-24 Gy irradiation. No suppression was observed below 12 Gy. Without irradiation, growth of tumor cells was inhibited by immunized spleen cells more effectively than by normal spleen cells. Anti-tumor activity of immunized and normal spleen cells was diminished by irradiation doses of 20 Gy and 10 Gy, respectively. Comparing our report with others that analyzed the type of anti-tumor effector cells induced in this experimental system, we concluded that tumor-specific anti-tumor activity (tumor growth inhibition in vivo) that was radiosensitive at 10-20 Gy depended on a DTH-response. (author)

  9. Transforming microbial genotyping: a robotic pipeline for genotyping bacterial strains.

    Directory of Open Access Journals (Sweden)

    Brian O'Farrell

    Full Text Available Microbial genotyping increasingly deals with large numbers of samples, and data are commonly evaluated by unstructured approaches, such as spread-sheets. The efficiency, reliability and throughput of genotyping would benefit from the automation of manual manipulations within the context of sophisticated data storage. We developed a medium- throughput genotyping pipeline for MultiLocus Sequence Typing (MLST of bacterial pathogens. This pipeline was implemented through a combination of four automated liquid handling systems, a Laboratory Information Management System (LIMS consisting of a variety of dedicated commercial operating systems and programs, including a Sample Management System, plus numerous Python scripts. All tubes and microwell racks were bar-coded and their locations and status were recorded in the LIMS. We also created a hierarchical set of items that could be used to represent bacterial species, their products and experiments. The LIMS allowed reliable, semi-automated, traceable bacterial genotyping from initial single colony isolation and sub-cultivation through DNA extraction and normalization to PCRs, sequencing and MLST sequence trace evaluation. We also describe robotic sequencing to facilitate cherrypicking of sequence dropouts. This pipeline is user-friendly, with a throughput of 96 strains within 10 working days at a total cost of 200,000 items were processed by two to three people. Our sophisticated automated pipeline can be implemented by a small microbiology group without extensive external support, and provides a general framework for semi-automated bacterial genotyping of large numbers of samples at low cost.

  10. Fibrogenesis and carcinoid tumor - a case report

    Directory of Open Access Journals (Sweden)

    Eduardo Fonseca Alves Filho

    2012-06-01

    Full Text Available Carcinoid tumors are rare. They may appear in the entire gastrointestinal and respiratory tracts, with single or multiple occurrences. Prognosis is dependent on the size and location. Symptoms may appear in carcinoid syndrome, related to active substances, especially serotonin. One important aspect associated with these tumors and usually ignored is fibrogenesis. This is a case report of a patient with carcinoid tumor of the terminal ileum, treated by laparoscopy, associated with fat and fibrosis infiltration.Tumores carcinoides são pouco frequentes, podem surgir em todo o trato gastrointestinal e respiratório, podem ser únicos ou múltiplos. O prognóstico depende do tamanho e da localização do tumor. Podem ocorrer sintomas relacionados à síndrome carcinoide, decorrente da produção de substâncias ativas, em especial serotonina. Um aspecto comumente ignorado associado a estes tumores é a estimulação da fibrogênese. Relatamos um caso de tumor carcinoide de íleo, tratado por videolaparoscopia, associado à infiltração fibroadiposa.

  11. Radiotherapy in glomus jugulare and glomus tympanicum tumors

    International Nuclear Information System (INIS)

    Feyerabend, T.; Richter, E.; Kapp, B.; Bohndorf, W.; Ptok, M.

    1989-01-01

    Glomus jugulare tumors are difficult to manage therapeutically due to their localisation. Operation may be successful in small tumors but can be hazardous in larger lesions mainly because of bleeding and palsy of cranial nerves. In these cases there should be used radiation therapy under the condition that it is planned by use of computed tomography. Moreover reproducibility of radiation treatment set-up is vital. In this way tumor regression may be achieved. Four own illustrative cases are demonstrated. According to the stage of disease a modified treatment strategy is presented which integrates surgical procedures, angiographic embolisation and radiotherapy. (orig.) [de

  12. Introduction to the use of regression models in epidemiology.

    Science.gov (United States)

    Bender, Ralf

    2009-01-01

    Regression modeling is one of the most important statistical techniques used in analytical epidemiology. By means of regression models the effect of one or several explanatory variables (e.g., exposures, subject characteristics, risk factors) on a response variable such as mortality or cancer can be investigated. From multiple regression models, adjusted effect estimates can be obtained that take the effect of potential confounders into account. Regression methods can be applied in all epidemiologic study designs so that they represent a universal tool for data analysis in epidemiology. Different kinds of regression models have been developed in dependence on the measurement scale of the response variable and the study design. The most important methods are linear regression for continuous outcomes, logistic regression for binary outcomes, Cox regression for time-to-event data, and Poisson regression for frequencies and rates. This chapter provides a nontechnical introduction to these regression models with illustrating examples from cancer research.

  13. Systemic Administration of Interleukin 2 Enhances the Therapeutic Efficacy of Dendritic Cell-Based Tumor Vaccines

    Science.gov (United States)

    Shimizu, K.; Fields, R. C.; Giedlin, M.; Mule, J. J.

    1999-03-01

    We have reported previously that murine bone marrow-derived dendritic cells (DC) pulsed with whole tumor lysates can mediate potent antitumor immune responses both in vitro and in vivo. Because successful therapy was dependent on host immune T cells, we have now evaluated whether the systemic administration of the T cell stimulatory/growth promoting cytokine interleukin-2 (IL-2) could enhance tumor lysate-pulsed DC-based immunizations to further promote protective immunity toward, and therapeutic rejection of, syngeneic murine tumors. In three separate approaches using a weakly immunogenic sarcoma (MCA-207), the systemic administration of non-toxic doses of recombinant IL-2 (20,000 and 40,000 IU/dose) was capable of mediating significant increases in the potency of DC-based immunizations. IL-2 could augment the efficacy of tumor lysate-pulsed DC to induce protective immunity to lethal tumor challenge as well as enhance splenic cytotoxic T lymphocyte activity and interferon-γ production in these treated mice. Moreover, treatment with the combination of tumor lysate-pulsed DC and IL-2 could also mediate regressions of established pulmonary 3-day micrometastases and 7-day macrometastases as well as established 14- and 28-day s.c. tumors, leading to either significant cure rates or prolongation in overall survival. Collectively, these findings show that nontoxic doses of recombinant IL-2 can potentiate the antitumor effects of tumor lysate-pulsed DC in vivo and provide preclinical rationale for the use of IL-2 in DC-based vaccine strategies in patients with advanced cancer.

  14. SU-E-I-83: Error Analysis of Multi-Modality Image-Based Volumes of Rodent Solid Tumors Using a Preclinical Multi-Modality QA Phantom

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Y [University of Kansas Hospital, Kansas City, KS (United States); Fullerton, G; Goins, B [University of Texas Health Science Center at San Antonio, San Antonio, TX (United States)

    2015-06-15

    Purpose: In our previous study a preclinical multi-modality quality assurance (QA) phantom that contains five tumor-simulating test objects with 2, 4, 7, 10 and 14 mm diameters was developed for accurate tumor size measurement by researchers during cancer drug development and testing. This study analyzed the errors during tumor volume measurement from preclinical magnetic resonance (MR), micro-computed tomography (micro- CT) and ultrasound (US) images acquired in a rodent tumor model using the preclinical multi-modality QA phantom. Methods: Using preclinical 7-Tesla MR, US and micro-CT scanners, images were acquired of subcutaneous SCC4 tumor xenografts in nude rats (3–4 rats per group; 5 groups) along with the QA phantom using the same imaging protocols. After tumors were excised, in-air micro-CT imaging was performed to determine reference tumor volume. Volumes measured for the rat tumors and phantom test objects were calculated using formula V = (π/6)*a*b*c where a, b and c are the maximum diameters in three perpendicular dimensions determined by the three imaging modalities. Then linear regression analysis was performed to compare image-based tumor volumes with the reference tumor volume and known test object volume for the rats and the phantom respectively. Results: The slopes of regression lines for in-vivo tumor volumes measured by three imaging modalities were 1.021, 1.101 and 0.862 for MRI, micro-CT and US respectively. For phantom, the slopes were 0.9485, 0.9971 and 0.9734 for MRI, micro-CT and US respectively. Conclusion: For both animal and phantom studies, random and systematic errors were observed. Random errors were observer-dependent and systematic errors were mainly due to selected imaging protocols and/or measurement method. In the animal study, there were additional systematic errors attributed to ellipsoidal assumption for tumor shape. The systematic errors measured using the QA phantom need to be taken into account to reduce measurement

  15. Age dependency of primary tumor sites and metastases in patients with Ewing sarcoma.

    Science.gov (United States)

    Worch, Jennifer; Ranft, Andreas; DuBois, Steven G; Paulussen, Michael; Juergens, Heribert; Dirksen, Uta

    2018-06-01

    The median age of patients with Ewing sarcoma (EwS) at diagnosis is around 14-15 years. Older age is associated with a worse outcome. The correlation of age at diagnosis on sites of disease has not been fully described. The goal of this study was to evaluate the differences in sites of primary tumor and metastatic tumor involvement according to age groups. EwS data from the Gesellschaft für Pädiatrische Onkologie und Hämatology (GPOH) database of the Cooperative Ewing Sarcoma Study (CESS) 81/86 and the European Intergroup Cooperative Ewing's Sarcoma Study EICESS 92 and the EUROpean Ewing tumor Working Initiative of National Groups-99-Protocol (EURO-E.W.I.N.G.-99) study were analyzed. Patient and tumor characteristics were evaluated statistically using chi square tests. The study population included 2,635 patients with bone EwS. Sites of primary and metastatic tumors differed according to the age groups of young children (0-9 years), early adolescence (10-14 years), late adolescence (15-19 years), young adults (20-24 years), and adults (more than 24 years). Young children demonstrated the most striking differences in site of disease with a lower proportion of pelvic primary and axial tumors. They presented less often with metastatic disease at diagnosis. Site of primary and metastatic tumor involvement in EwS differs according to patient age. The biological and developmental etiology for these differences requires further investigations. © 2018 Wiley Periodicals, Inc.

  16. Malignant progressive tumor cell clone exhibits significant up-regulation of cofilin-2 and 27-kDa modified form of cofilin-1 compared to regressive clone.

    Science.gov (United States)

    Kuramitsu, Yasuhiro; Wang, Yufeng; Okada, Futoshi; Baron, Byron; Tokuda, Kazuhiro; Kitagawa, Takao; Akada, Junko; Nakamura, Kazuyuki

    2013-09-01

    QR-32 is a regressive murine fibrosarcoma cell clone which cannot grow when they are transplanted in mice; QRsP-11 is a progressive malignant tumor cell clone derived from QR-32 which shows strong tumorigenicity. A recent study showed there to be differentially expressed up-regulated and down-regulated proteins in these cells, which were identified by proteomic differential display analyses by using two-dimensional gel electrophoresis and mass spectrometry. Cofilins are small proteins of less than 20 kDa. Their function is the regulation of actin assembly. Cofilin-1 is a small ubiquitous protein, and regulates actin dynamics by means of binding to actin filaments. Cofilin-1 plays roles in cell migration, proliferation and phagocytosis. Cofilin-2 is also a small protein, but it is mainly expressed in skeletal and cardiac muscles. There are many reports showing the positive correlation between the level of cofilin-1 and cancer progression. We have also reported an increased expression of cofilin-1 in pancreatic cancer tissues compared to adjacent paired normal tissues. On the other hand, cofilin-2 was significantly less expressed in pancreatic cancer tissues. Therefore, the present study investigated the comparison of the levels of cofilin-1 and cofilin-2 in regressive QR-32 and progressive QRsP-11cells by western blotting. Cofilin-2 was significantly up-regulated in QRsP-11 compared to QR-32 cells (p<0.001). On the other hand, the difference of the intensities of the bands of cofilin-1 (18 kDa) in QR-32 and QRsP-11 was not significant. However, bands of 27 kDa showed a quite different intensity between QR-32 and QRsP-11, with much higher intensities in QRsP-11 compared to QR-32 (p<0.001). These results suggested that the 27-kDa protein recognized by the antibody against cofilin-1 is a possible biomarker for progressive tumor cells.

  17. Evaluation of High Resolution Melting for MTHFR C677T Genotyping in Congenital Heart Disease.

    Directory of Open Access Journals (Sweden)

    Ying Wang

    Full Text Available High resolution melting (HRM is a simple, flexible and low-cost mutation screening technique. The methylenetetrahydrofolate reductase (MTHFR gene encoding a critical enzyme, potentially affects susceptibility to some congenital defects like congenital heart disease (CHD. We evaluate the performance of HRM for genotyping of the MTHFR gene C677T locus in CHD cases and healthy controls of Chinese Han population.A total of 315 blood samples from 147 CHD patients (male72, female 75 and 168 healthy controls (male 92, female 76 were enrolled in the study. HRM was utilized to genotype MTHFR C677T locus of all the samples. The results were compared to that of PCR-RFLP and Sanger sequencing. The association of the MTHFR C677T genotypes and the risk of CHD was analyzed using odds ratio with their 95% confidence interval (CIs from unconditional logistic regression.All the samples were successfully genotyped by HRM within 1 hour and 30 minutes while at least 6 hours were needed for PCR-RFLP and sequencing. The genotypes of MTHFR C677T CC, CT, and TT were 9.52%, 49.66%, and 40.82% in CHD group but 29.17%, 50% and 20.83% in control group, which were identical using both methods of HRM and PCR-RFLP, demonstrating the sensitivity and specificity of HRM were all 100%.MTHFR C677T is a potential risk factor for CHD in our local residents of Shandong province in China. HRM is a fast, sensitive, specific and reliable method for clinical application of genotyping.

  18. A phase i study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas

    NARCIS (Netherlands)

    Infante, Jeffrey R.; Cassier, Philippe A.; Gerecitano, John F.; Witteveen, Petronella O.; Chugh, Rashmi; Ribrag, Vincent; Chakraborty, Abhijit; Matano, Alessandro; Dobson, Jason R.; Crystal, Adam S.; Parasuraman, Sudha; Shapiro, Geoffrey I.

    2016-01-01

    Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity,

  19. Therapeutic Non-Toxic Doses of TNF Induce Significant Regression in TNFR2-p75 Knockdown Lewis Lung Carcinoma Tumor Implants

    Science.gov (United States)

    Sasi, Sharath P.; Bae, Sanggyu; Song, Jin; Perepletchikov, Aleksandr; Schneider, Douglas; Carrozza, Joseph; Yan, Xinhua; Kishore, Raj; Enderling, Heiko; Goukassian, David A.

    2014-01-01

    Tumor necrosis factor-alpha (TNF) binds to two receptors: TNFR1/p55-cytotoxic and TNFR2/p75-pro-survival. We have shown that tumor growth in p75 knockout (KO) mice was decreased more than 2-fold in Lewis lung carcinoma (LLCs). We hypothesized that selective blocking of TNFR2/p75 LLCs may sensitize them to TNF-induced apoptosis and affect the tumor growth. We implanted intact and p75 knockdown (KD)-LLCs (>90%, using shRNA) into wild type (WT) mice flanks. On day 8 post-inoculation, recombinant murine (rm) TNF-α (12.5 ng/gr of body weight) or saline was injected twice daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 15, when study was terminated due to large tumors in LLC+TNF group. Tubular bones, spleens and peripheral blood (PB) were examined to determine possible TNF toxicity. There was no significant difference in tV or tW between LLC minus (-) TNF and p75KD/LLC-TNF tumors. Compared to 3 control groups, p75KD/LLC+TNF showed >2-5-fold decreases in tV (ptumors were 100% necrotic, the remaining revealed 40-60% necrosis. No toxicity was detected in bone marrow, spleen and peripheral blood. We concluded that blocking TNFR2/p75 in LLCs combined with intra-tumoral rmTNF injections inhibit LLC tumor growth. This could represent a novel and effective therapy against lung neoplasms and a new paradigm in cancer therapeutics. PMID:24664144

  20. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype.

    Science.gov (United States)

    de Heredia, Miguel López; Clèries, Ramón; Nunes, Virginia

    2013-07-01

    Wolfram syndrome is a degenerative, recessive rare disease with an onset in childhood. It is caused by mutations in WFS1 or CISD2 genes. More than 200 different variations in WFS1 have been described in patients with Wolfram syndrome, which complicates the establishment of clear genotype-phenotype correlation. The purpose of this study was to elucidate the role of WFS1 mutations and update the natural history of the disease. This study analyzed clinical and genetic data of 412 patients with Wolfram syndrome published in the last 15 years. (i) 15% of published patients do not fulfill the current -inclusion criterion; (ii) genotypic prevalence differences may exist among countries; (iii) diabetes mellitus and optic atrophy might not be the first two clinical features in some patients; (iv) mutations are nonuniformly distributed in WFS1; (v) age at onset of diabetes mellitus, hearing defects, and diabetes insipidus may depend on the patient's genotypic class; and (vi) disease progression rate might depend on genotypic class. New genotype-phenotype correlations were established, disease progression rate for the general population and for the genotypic classes has been calculated, and new diagnostic criteria have been proposed. The conclusions raised could be important for patient management and counseling as well as for the development of treatments for Wolfram syndrome.

  1. PROGNOSTIC VALUE OF TUMOR NECROSIS FACTOR-ALPHA IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    E. N. Zotina

    2016-01-01

    Full Text Available The prognostic value of tumor necrosis factor-alfa (TNFα, a pro-inflammatory cytokine was studied in 140 patients with a newly diagnosed chronic lymphocytic leukemia (CLL. TNFα contents in blood serum was determined using ELISA method. A significant increase of serum TNFα was shown in patients with newly diagnosed CLL, as compared to healthy individuals. Dependence of the cytokine concentration on clnical stage and course of disease was revealed: the highest levels of serum TNFα were registered in patients with advanced disease and/or CLL progression. Distinct correlations were revealed between the studied cytokine amounts and clinical laboratory parameters reflecting the cell proliferative activity and tumor clone size. Immunochemotherapy was accompanied by a significant reduction of TNFα levels. According to the data from multivariate regression analysis. TNFα level of at the time of the diagnosis was an independent predictor of overall survival. Hence, TNFα plays an important role in CLL pathogenesis and may be used as an additional predictive factor for CLL outcomes.

  2. Updating prognosis in primary biliary cirrhosis using a time-dependent Cox regression model. PBC1 and PBC2 trial groups

    DEFF Research Database (Denmark)

    Christensen, E; Altman, D G; Neuberger, J

    1993-01-01

    BACKGROUND: The precision of current prognostic models in primary biliary cirrhosis (PBC) is rather low, partly because they are based on data from just one time during the course of the disease. The aim of this study was to design a new, more precise prognostic model by incorporating follow......-up data in the development of the model. METHODS: We have performed Cox regression analyses with time-dependent variables in 237 PBC patients followed up regularly for up to 11 years. The validity of the obtained models was tested by comparing predicted and observed survival in 147 independent PBC...... patients followed for up to 6 years. RESULTS: In the obtained model the following time-dependent variables independently indicated a poor prognosis: high bilirubin, low albumin, ascites, gastrointestinal bleeding, and old age. When including histological variables, cirrhosis, central cholestasis, and low...

  3. Rotavirus genotype shifts among Swedish children and adults-Application of a real-time PCR genotyping.

    Science.gov (United States)

    Andersson, Maria; Lindh, Magnus

    2017-11-01

    It is well known that human rotavirus group A is the most important cause of severe diarrhoea in infants and young children. Less is known about rotavirus infections in other age groups, and about how rotavirus genotypes change over time in different age groups. Develop a real-time PCR to easily genotype rotavirus strains in order to monitor the pattern of circulating genotypes. In this study, rotavirus strains in clinical samples from children and adults in Western Sweden during 2010-2014 were retrospectively genotyped by using specific amplification of VP 4 and VP 7 genes with a new developed real-rime PCR. A genotype was identified in 97% of 775 rotavirus strains. G1P[8] was the most common genotype representing 34.9%, followed by G2P[4] (28.3%), G9P[8] (11.5%), G3P[8] (8.1%), and G4P[8] (7.9%) The genotype distribution changed over time, from predominance of G1P[8] in 2010-2012 to predominance of G2P[4] in 2013-2014. There were also age-related differences, with G1P[8] being the most common genotype in children under 2 years (47.6%), and G2P[4] the most common in those over 70 years of age (46.1%.). The shift to G2P[4] in 2013-2014 was associated with a change in the age distribution, with a greater number of rotavirus positive cases in elderly than in children. By using a new real-time PCR method for genotyping we found that genotype distribution was age related and changed over time with a decreasing proportion of G1P[8]. Copyright © 2017. Published by Elsevier B.V.

  4. Multiple brown tumors of the orbital walls: case report Tumor marrom múltiplo das paredes orbitárias: relato de caso

    Directory of Open Access Journals (Sweden)

    Mário Luiz Ribeiro Monteiro

    2009-02-01

    Full Text Available We report the case of a 40-year-old woman with chronic renal failure and secondary hyperparathyroidism that presented with slowly progressive proptosis of the right eye and mass sensation in the temporal and frontal orbital margins. Computerized tomography scan revealed two separate hyperdense and well-circumscribed lesions in the right orbital walls. A biopsy followed by histopathologic study revealed a dense lesion, with fibrous proliferation associated with osseous metaplasia and osteoclastic activity in the tumor, compatible with the diagnosis of brown tumor. The patient was submitted to surgical removal of the parathyroid glands that resulted in marked improvement in her condition and regression of the orbital tumors. Although the occurrence of more than one separate bone lesion in the orbit usually suggests metastasis, our case shows that brown tumors should also be included in the differential diagnosis of such lesions, particularly in patients with hyperparathyroidism.Este trabalho relata o caso de uma paciente de 40 anos, com insuficiência renal crônica e hiperparatireoidismo secundário que se apresentou com proptose progressiva e tumoração nas regiões lateral da órbita e superior da órbita. Tomografia computadorizada revelou duas lesões ósseas separadas, bem delimitadas e hiperdensas nas paredes orbitárias. Uma biópsia seguida de estudo histopatológico revelou um tumor denso, com proliferação fibrosa associada a metaplasia óssea e atividade osteoclástica no tumor, características compatíveis com tumor marrom. A paciente foi submetida a remoção das glândulas paratiróides que resultou em melhora dramática do seu estado geral e regressão dos tumores orbitais. Embora a presença de mais de uma lesão óssea separada na órbita geralmente sugira o diagnóstico de lesões metastáticas, nosso caso evidencia que tumores marrons devem também ser incluídos no diagnóstico diferencial, particularmente em pacientes com

  5. A polyethylenimine-modified carboxyl-poly(styrene/acrylamide copolymer nanosphere for co-delivering of CpG and TGF-β receptor I inhibitor with remarkable additive tumor regression effect against liver cancer in mice

    Directory of Open Access Journals (Sweden)

    Liang SY

    2016-12-01

    Full Text Available Shuyan Liang,* Jun Hu,* Yuanyuan Xie, Qing Zhou, Yanhong Zhu, Xiangliang Yang National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China *These authors contributed equally to this work Abstract: Cancer immunotherapy based on nanodelivery systems has shown potential for treatment of various malignancies, owing to the benefits of tumor targeting of nanoparticles. However, induction of a potent T-cell immune response against tumors still remains a challenge. In this study, polyethylenimine-modified carboxyl-styrene/acrylamide (PS copolymer nanospheres were developed as a delivery system of unmethylated cytosine-phosphate-guanine (CpG oligodeoxynucleotides and transforming growth factor-beta (TGF-β receptor I inhibitors for cancer immunotherapy. TGF-β receptor I inhibitors (LY2157299, LY were encapsulated to the PS via hydrophobic interaction, while CpG oligodeoxynucleotides were loaded onto the PS through electrostatic interaction. Compared to the control group, tumor inhibition in the PS-LY/CpG group was up to 99.7% without noticeable toxicity. The tumor regression may be attributed to T-cell activation and amplification in mouse models. The results highlight the additive effect of CpG and TGF-β receptor I inhibitors co-delivered in cancer immunotherapy. Keywords: CpG, TGF-β receptor I inhibitor, Pst-AAm copolymer nanosphere, immunotherapy

  6. Angiography in tumors of cartilaginous genesis

    International Nuclear Information System (INIS)

    Korolev, V.I.

    1986-01-01

    Angiography was used for 122 patients with tumors and tumor-like processes of the cartilage. Angiography was carried out by the S. Seldinger method. Normal angioarchitecture was observed in 16 patients with benign tumors (20 patients), characters of malignant tumor are determined in 4 patients. Normal angioarchitecture is determined in 9.4% of patients with chondrosarcoma (102 patients). The examination carried out showed that angiographic symptotics in chondrosarcomas varied depending on the stage, localization and the degree of morphologic differentiation

  7. Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: A role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Ajay; Kant, Shiva; Singh, Sukh Mahendra, E-mail: sukhmahendrasingh@yahoo.com

    2013-11-15

    Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. - Highlights: • DCA modulates tumor progression and chemoresistance. • DCA alters molecules regulating cell survival, glucose metabolism and MDR. • DCA reconstitutes biophysical and cellular composition of tumor microenvironment.

  8. Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: A role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation

    International Nuclear Information System (INIS)

    Kumar, Ajay; Kant, Shiva; Singh, Sukh Mahendra

    2013-01-01

    Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. - Highlights: • DCA modulates tumor progression and chemoresistance. • DCA alters molecules regulating cell survival, glucose metabolism and MDR. • DCA reconstitutes biophysical and cellular composition of tumor microenvironment.

  9. Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor.

    Science.gov (United States)

    Dahlin, Anna M; Henriksson, Maria L; Van Guelpen, Bethany; Stenling, Roger; Oberg, Ake; Rutegård, Jörgen; Palmqvist, Richard

    2011-05-01

    The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eight-gene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score ≥7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score ≤4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P=0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose

  10. Targeting Autophagy in the Tumor Microenvironment: New Challenges and Opportunities for Regulating Tumor Immunity

    Directory of Open Access Journals (Sweden)

    Bassam Janji

    2018-04-01

    Full Text Available Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Despite the remarkable and fairly rapid progress over the past two decades regarding our understanding of the role of the tumor microenvironment in cancer development, its precise contribution to cancer resistance is still fragmented. This is mainly related to the complexity of the “tumor ecosystem” and the diversity of the stromal cell types that constitute the tumor microenvironment. Emerging data indicate that several factors, such as hypoxic stress, activate a plethora of resistance mechanisms, including autophagy, in tumor cells. Hypoxia-induced autophagy in the tumor microenvironment also activates several tumor escape mechanisms, which effectively counteract anti-tumor immune responses mediated by natural killer and cytotoxic T lymphocytes. Therefore, strategies aiming at targeting autophagy in cancer cells in combination with other therapeutic strategies have inspired significant interest to overcome immunological tolerance and promote tumor regression. However, a number of obstacles still hamper the application of autophagy inhibitors in clinics. First, the lack of selectivity of the current pharmacological inhibitors of autophagy makes difficult to draw a clear statement about its effective contribution in cancer. Second, autophagy has been also described as an important mechanism in tumor cells involved in presentation of antigens to T cells. Third, there is a circumstantial evidence that autophagy activation in some innate immune cells may support the maturation of these cells, and it is required for their anti-tumor activity. In this review, we will address these aspects and discuss our current knowledge on the benefits and the drawbacks of targeting autophagy in the context of anti-tumor immunity. We believe that it is

  11. ANALYSIS OF INTERACTION OF PLANT GENOTYPE AND STRAIN AGROBACTERIUM TUMEFACIENS IN BREEDING OF POTATO RESISTANCE TO COLORADO POTATO BEETLE

    Directory of Open Access Journals (Sweden)

    Denis I Bogomaz

    2005-03-01

    Full Text Available Efficiency of potato transformation depends on plant genotype and bacterial strain. Genotypes with high regeneration ability have high transformation ability. It is shown, that transgenosis of Bt gene increases potato resistance to collorado potato beetle, transgenosis of ipt gene does not influence on resistance.

  12. Soil nutrient patchiness and genotypes interact on the quantity, quality and decomposition of roots versus shoots of Triticum aestivum.

    NARCIS (Netherlands)

    He, W.M.; Shen, Y.; Cornelissen, J.H.C.

    2012-01-01

    Aims: The purpose of this study was to test the hypotheses that soil nutrient patchiness can differentially benefit the decomposition of root and shoot litters and that this facilitation depends on plant genotypes. Methods: We grew 15 cultivars (i. e. genotypes) of winter wheat (Triticum aestivum

  13. Complete Spontaneous Regression of Merkel Cell Carcinoma After Biopsy: A Case Report and Review of the Literature.

    Science.gov (United States)

    Ahmadi Moghaddam, Parnian; Cornejo, Kristine M; Hutchinson, Lloyd; Tomaszewicz, Keith; Dresser, Karen; Deng, April; OʼDonnell, Patrick

    2016-11-01

    Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumor that typically occurs on the head and neck of the elderly and follows an aggressive clinical course. Merkel cell polyomavirus (MCPyV) has been identified in up to 80% of cases and has been shown to participate in MCC tumorigenesis. Complete spontaneous regression of MCC has been rarely reported in the literature. We describe a case of a 79-year-old man that presented with a rapidly growing, 3-cm mass on the left jaw. An incisional biopsy revealed MCC. Additional health issues were discovered in the preoperative workup of this patient which delayed treatment. One month after the biopsy, the lesion showed clinical regression in the absence of treatment. Wide excision of the biopsy site with sentinel lymph node dissection revealed no evidence of MCC 2 months later. The tumor cells in the patient's biopsy specimen were negative for MCPyV by polymerase chain reaction and immunohistochemistry (CM2B4 antibody, Santa Cruz, CA). The exact mechanism for complete spontaneous regression in MCC is unknown. To our knowledge, only 2 previous studies evaluated the presence of MCPyV by polymerase chain reaction in MCC with spontaneous regression. Whether the presence or absence of MCPyV correlates with spontaneous regression warrants further investigation.

  14. Variability in amino acid digestibility of triticale grain from diverse genotypes as studied in cecectomized laying hens.

    Science.gov (United States)

    Zuber, T; Maurer, H P; Möhring, J; Nautscher, N; Siegert, W; Rosenfelder, P; Rodehutscord, M

    2016-12-01

    Triticale, an anthropogenic hybrid grain, is increasing in importance as a feed grain for laying hens. However, our limited knowledge of its nutritional qualities and their impact on hen performance prevents optimization of its use. The present study investigated the digestibility of amino acids ( AA: ) in triticale grain in laying hens, and additionally examined relationships between AA digestibility and chemical and physical characteristics of the grain. Twenty genotypes of triticale were grown under standardized agronomic and environmental conditions and were characterized according to their physical properties (thousand-seed weight, test weight, falling number, extract viscoelasticity), chemical composition (proximate nutrients, non-starch polysaccharides, AA, minerals, inositol phosphates) and gross energy concentration. Additionally, the in vitro solubility of nitrogen was determined. The animal trial comprised 4 Latin Squares (6 × 6) distributed among 2 subsequent runs. Twelve cecectomized LSL-Classic hens were individually housed in metabolism cages and either fed a basal diet containing 500 g/kg cornstarch or one of 20 triticale diets, each replacing the cornstarch with one triticale genotype, for 8 d. During the last 4 d, feed intake was recorded and excreta were collected quantitatively. Amino acid digestibility of the triticale genotypes was calculated by linear regression. The digestibility of all AA differed significantly between the 20 genotypes, including Lys (digestibility range 68 to 80%), Met (77 to 86%), Thr (68 to 78%) and Trp (74 to 83%). However, AA digestibility only correlated with characteristics of the grain in few cases, without a consistent pattern among AA. Equations to predict AA digestibility based on the grain's physical and chemical characteristics were calculated by multiple linear regression. The explanatory power (adjusted R 2 ;) of these prediction equations was below 0.7 for most AA and thus not sufficiently precise to be

  15. Quality of life in breast cancer patients--a quantile regression analysis.

    Science.gov (United States)

    Pourhoseingholi, Mohamad Amin; Safaee, Azadeh; Moghimi-Dehkordi, Bijan; Zeighami, Bahram; Faghihzadeh, Soghrat; Tabatabaee, Hamid Reza; Pourhoseingholi, Asma

    2008-01-01

    Quality of life study has an important role in health care especially in chronic diseases, in clinical judgment and in medical resources supplying. Statistical tools like linear regression are widely used to assess the predictors of quality of life. But when the response is not normal the results are misleading. The aim of this study is to determine the predictors of quality of life in breast cancer patients, using quantile regression model and compare to linear regression. A cross-sectional study conducted on 119 breast cancer patients that admitted and treated in chemotherapy ward of Namazi hospital in Shiraz. We used QLQ-C30 questionnaire to assessment quality of life in these patients. A quantile regression was employed to assess the assocciated factors and the results were compared to linear regression. All analysis carried out using SAS. The mean score for the global health status for breast cancer patients was 64.92+/-11.42. Linear regression showed that only grade of tumor, occupational status, menopausal status, financial difficulties and dyspnea were statistically significant. In spite of linear regression, financial difficulties were not significant in quantile regression analysis and dyspnea was only significant for first quartile. Also emotion functioning and duration of disease statistically predicted the QOL score in the third quartile. The results have demonstrated that using quantile regression leads to better interpretation and richer inference about predictors of the breast cancer patient quality of life.

  16. Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Zwicker, F.; Roeder, F.; Debus, J.; Huber, P.E. [University Hospital Center Heidelberg, Heidelberg (Germany). Dept. of Radiation Oncology; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Clinical Cooperation Unit Molecular Radiation Oncology; Kirsner, A.; Weber, K.J. [University Hospital Center Heidelberg, Heidelberg (Germany). Dept. of Radiation Oncology; Peschke, P. [Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Clinical Cooperation Unit Molecular Radiation Oncology

    2013-08-15

    Background: Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. Materials and methods: The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. Results: DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. Conclusion: DCA induced tumor-specific radiosensitization in vitro but not in vivo

  17. Tumorous interstitial lung disease

    International Nuclear Information System (INIS)

    Dinkel, E.; Meyer, E.; Mundinger, A.; Helwig, A.; Blum, U.; Wuertemberger, G.

    1990-01-01

    The radiological findings in pulmonary lymphangitic carcinomatosis and in leukemic pulmonary infiltrates mirror the tumor-dependent monomorphic interstitial pathology of lung parenchyma. It is a proven fact that pulmonary lymphangitic carcinomatosis is caused by hematogenous tumor embolization to the lungs; pathogenesis by contiguous lymphangitic spread is the exception. High-resolution CT performed as a supplement to the radiological work-up improves the sensitivity for pulmonary infiltrates in general and thus makes the differential diagnosis decided easier. Radiological criteria cannot discriminate the different forms of leukemia. Plain chest X-ray allows the diagnosis of pulmonary involvement in leukemia due to tumorous infiltrates and of tumor- or therapy-induced complications. It is essential that the radiological findings be interpreted with reference to the stage of tumor disease and the clinical parameters to make the radiological differential diagnosis of opportunistic infections more reliable. (orig.) [de

  18. Association between TNF-α and IL-1β genotypes vs Helicobacter pylori infection in Indonesia

    Science.gov (United States)

    Zhao, Yang; Wang, Jing-Wen; Tanaka, Tsutomu; Hosono, Akihiro; Ando, Ryosuke; Tokudome, Shinkan; Soeripto; Triningsih, FX Ediati; Triono, Tegu; Sumoharjo, Suwignyo; Achwan, EY Wenny Astuti; Gunawan, Stephanus; Li, Yu-Min

    2013-01-01

    AIM: To investigate the correlation between the Helicobacter pylori (H. pylori) infection and host genetic background of healthy populations in Indonesia. METHODS: In March 2007, epidemiological studies were undertaken on the general population of a city in Indonesia (Mataram, Lombok). The participants included 107 men and 187 women, whose ages ranged from 6 to 74 years old, with an average age of 34.0 (± 14.4) (± SD). The H. pylori of subject by UBT method determination, and through the polymerase chain reaction with confronting two-pair primers (PCR-CTPP) method parsing the single nucleotide polymorphism of interleukin (IL)-8, IL-4, IL-1β, CD14, tumor necrosis factor (TNF-α) and tyrosine-protein phosphates non-receptor type 11 (PTPN11) genotypes. The experimental data were analyzed by the statistical software SAS. RESULTS: The H. pylori infection rates in the healthy Indonesian population studied were 8.4% for men and 12.8% for women; no obvious differences were noted for H. pylori infection rates by sex or age. TC genotypes of IL-4, TC and CC genotypes of TNF-α, and GA genotypes of PTPN11, were higher in frequency. Both CC and TC genotype of TNF-α T-1031C loci featured higher expressions in the healthy Indonesian population Indonesia studied of (OR = 1.99; 95%CI: 0.67-5.89) and (OR = 1.66; 95%CI: 0.73-3.76), respectively. C allele of IL-1β T-31C gene locus was at a higher risk (OR = 1.11; 95%CI: 0.70-1.73) of H. pylori infection, but no statistical significance was found in our study. CONCLUSION: We reveal that the association between the TNF-α and IL-1β genotypes may be the susceptibility of H. pylori in the studied population. PMID:24379597

  19. Identification of unusual Chlamydia pecorum genotypes in Victorian koalas (Phascolarctos cinereus) and clinical variables associated with infection.

    Science.gov (United States)

    Legione, Alistair R; Patterson, Jade L S; Whiteley, Pam L; Amery-Gale, Jemima; Lynch, Michael; Haynes, Leesa; Gilkerson, James R; Polkinghorne, Adam; Devlin, Joanne M; Sansom, Fiona M

    2016-05-01

    Chlamydia pecorum infection is a threat to the health of free-ranging koalas (Phascolarctos cinereus) in Australia. Utilizing an extensive sample archive we determined the prevalence of C. pecorum in koalas within six regions of Victoria, Australia. The ompA genotypes of the detected C. pecorum were characterized to better understand the epidemiology of this pathogen in Victorian koalas. Despite many studies in northern Australia (i.e. Queensland and New South Wales), prior Chlamydia studies in Victorian koalas are limited. We detected C. pecorum in 125/820 (15 %) urogenital swabs, but in only one ocular swab. Nucleotide sequencing of the molecular marker C. pecorum ompA revealed that the majority (90/114) of C. pecorum samples typed were genotype B. This genotype has not been reported in northern koalas. In general, Chlamydia infection in Victorian koalas is associated with milder clinical signs compared with infection in koalas in northern populations. Although disease pathogenesis is likely to be multifactorial, the high prevalence of genotype B in Victoria may suggest it is less pathogenic. All but three koalas had C. pecorum genotypes unique to southern koala populations (i.e. Victoria and South Australia). These included a novel C. pecorum ompA genotype and two genotypes associated with livestock. Regression analysis determined that significant factors for the presence of C. pecorum infection were sex and geographical location. The presence of 'wet bottom' in males and the presence of reproductive tract pathology in females were significantly associated with C. pecorum infection, suggesting variation in clinical disease manifestations between sexes.

  20. Clinical features and treatment outcomes of vasoproliferative tumors in Indian participants

    Directory of Open Access Journals (Sweden)

    Jaydeep Avinash Walinjkar

    2018-01-01

    Full Text Available Purpose: The aim of the study was to describe the clinical features and treatment outcomes of vasoproliferative tumors (VPT in Indian participants. Methods: This study design was a retrospective case series in a tertiary eye care center. Case records of patients diagnosed with VPT from 2011 to 2015 were reviewed, and their demographic details, clinical presentation, and treatment outcomes were documented. Baseline and follow-up visual acuity and tumor dimensions were statistically compared by applying paired t-test. Statistical analysis used SPSS version 14. Results: Twenty-two tumors from 19 eyes of 17 patients were included. Mean age at presentation was 43.5 years (range: 15–68 years. Mean presenting best-corrected visual acuity (BCVA was + 1.10 logMAR. Sixty-eight percent eyes had secondary tumors. Most common association of secondary VPT was Coats disease followed by retinal vasculitis, polypoidal choroidal vasculopathy, familial exudative vitreoretinopathy, and traumatic chorioretinopathy. Ten tumors (45% involved the inferior quadrant. Tumor-associated features were intra/subretinal exudates, vitritis, subretinal fluid, vitreous hemorrhage, preretinal fibrosis, epiretinal membrane, and subretinal blood. Treatment included cryotherapy, intravitreal or oral steroids, laser photocoagulation, cryotherapy with encirclage, cryotherapy with anti-vascular endothelial growth factor, and observation. Complications included tumor recurrence, retinal detachment, raised intraocular pressure, neovascularization of iris, and cataract. Ninety-five percent VPT regressed at mean 21 months (Median: 17 months; Range: 3–64 months. Mean final BCVA was + 1.21 logMAR. Conclusion: VPTs are commonly unilateral, unifocal, and located anterior to equator in inferior fundus. Secondary tumors are more common than primary tumors. Treatment achieves tumor regression in majority of cases.