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Sample records for aberrant human cancer

  1. Aberrant expression of interferon regulatory factor 3 in human lung cancer

    Tokunaga, Takayuki [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Naruke, Yuki; Shigematsu, Sayuri; Kohno, Tomoko; Yasui, Kiyoshi; Ma, Yuhua; Chua, Koon Jiew [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Katayama, Ikuo; Nakamura, Takashi [Department of Radiology and Cancer Biology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Hishikawa, Yoshitaka; Koji, Takehiko [Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Yatabe, Yasushi [Department of Pathology and Clinical Oncology, Aichi Cancer Research Institute, Nagoya 464-8681 (Japan); Nagayasu, Takeshi [Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Fujita, Takashi [Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8507 (Japan); Matsuyama, Toshifumi, E-mail: tosim@nagasaki-u.ac.jp [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); The Global Center of Excellence Program at Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); and others

    2010-06-25

    We analyzed the subcellular distributions and gene structures of interferon regulatory factor 3 (IRF3) transcription factor in 50 cases of human primary lung cancer. The immunohistochemical analyses revealed substantially aberrant IRF3 expression specific to the cancer lesions (2 and 6 tumors with nuclear staining, and 4 and 5 tumors with negative staining, in adenocarcinoma and squamous cell carcinoma, respectively), while the morphologically normal region around the tumors exhibited only cytoplasmic staining. In addition, we determined the sequence of the entire IRF3 coding region, and found two novel variants with the amino acid changes (S{sup 175}(AGC) {yields} R{sup 175}(CGC) and A{sup 208}(GCC) {yields} D{sup 208}(GAC)). The R{sup 175} variant was also detected in a morphologically normal region around the nuclear staining squamous cell carcinoma, and exhibited almost the same functions as the wild type IRF3. On the other hand, the D{sup 208} variant, found in the negative staining squamous cell carcinoma cases, reduced the nuclear translocation in response to I{kappa}B kinase {epsilon} stimulation, as compared to the wild type IRF3, but the same variant was detected in the surrounding morphologically normal region. The aberrant expression of IRF3 and the novel D{sup 208} variant may provide clues to elucidate the etiology of primary lung cancer.

  2. Impact of types of lymphocyte chromosomal aberrations on human cancer risk

    Hagmar, Lars; Strömberg, Ulf; Bonassi, Stefano; Hansteen, Inger-Lise; Knudsen, Lisbeth E.; Lindholm, Carita; Norppa, Hannu

    2004-01-01

    The frequency of cells with structural chromosomal aberrations (CAs) in peripheral blood lymphocytes is the first genotoxicity biomarker that has shown an association with cancer risk. CAs are usually divided into chromosome-type (CSAs) and chromatid-type aberrations (CTAs), with different...... mechanisms of formation. From a mechanistic point of view, it is of interest to clarify whether the cancer predictivity of CAs is different with respect to CSAs and CTAs. We report here cancer risk for cytogenetically tested, healthy subjects with respect to frequency of CAs, CSAs, and CTAs in peripheral...... the Nordic cohorts and increased total cancer mortality in the Italian cohort. In the Nordic cohorts, significantly elevated cancer risks were observed for subjects with both high CSAs and high CTAs at test, and these variables showed equally strong cancer predictivity. The results of the Italian...

  3. Association between different types of chromosomal aberrations in human peripheral lymphocytes and cancer in different locations

    Šmerhovský, Zdeněk; Landa, K.; Rössner st., Pavel; Juzova, D.

    2002-01-01

    Roč. 39, č. 33 (2002), s. 59. ISSN 0893-6692. [ Environmental Mutagen Society Annual Meeting /33./. 27.04.2002-02.05.2002, Anchorage - USA] R&D Projects: GA MZd NJ5177 Grant ostatní: GA-(EC) QLK4-2000-00628 Keywords : cytogenic analysis * cancer incidence * chromosomal aberrations Subject RIV: DN - Health Impact of the Environment Quality

  4. Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression.

    Li, Min; Zhang, Yuqing; Liu, Zijuan; Bharadwaj, Uddalak; Wang, Hao; Wang, Xinwen; Zhang, Sheng; Liuzzi, Juan P; Chang, Shou-Mei; Cousins, Robert J; Fisher, William E; Brunicardi, F Charles; Logsdon, Craig D; Chen, Changyi; Yao, Qizhi

    2007-11-20

    Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth. PMID:18003899

  5. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer.

    Wang, Tianzhen; Wang, Guangyu; Hao, Dapeng; Liu, Xi; Wang, Dong; Ning, Ning; Li, Xiaobo

    2015-01-01

    RNA binding proteins (RBPs) and microRNAs (miRNAs) are two of the most important post-transcriptional regulators of gene expression, and their aberrant expression contributes to the development of human malignancies. Let-7, one of the most well-known tumor suppressors, is frequently down-regulated in a variety of human cancers. The RBP LIN28A/LIN28B, a direct target of the let-7 family of miRNAs, is an inhibitor of let-7 biogenesis and is frequently up-regulated in cancers. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors is reportedly involved in cancer development, contributing to cellular proliferation, cell death resistance, angiogenesis, metastasis, metabolism reprogramming, tumor-associated inflammation, genome instability, acquiring immortality and evading immune destruction. In this review, we summarized the mechanisms of LIN28A/LIN28B and let-7 loop aberrant regulation in human cancer and discussed the roles and potential mechanisms of the LIN28A/LIN28B and let-7 loop in regulating the hallmarks of cancer. The crosstalk between LIN28A/LIN28B and let-7 loop and certain oncogenes (such as MYC, RAS, PI3K/AKT, NF-κB and β-catenin) in regulating hallmarks of cancer has also been discussed. PMID:26123544

  6. Biphasic Effects of Nitric Oxide Radicals on Radiation-Induced Lethality and Chromosome Aberrations in Human Lung Cancer Cells Carrying Different p53 Gene Status

    Purpose: The aim of this study was to clarify the effects of nitric oxide (NO) on radiation-induced cell killing and chromosome aberrations in two human lung cancer cell lines with a different p53 gene status. Methods and Materials: We used wild-type (wt) p53 and mutated (m) p53 cell lines that were derived from the human lung cancer H1299 cell line, which is p53 null. The wtp53 and mp53 cell lines were generated by transfection of the appropriate p53 constructs into the parental cells. Cells were pretreated with different concentrations of isosorbide dinitrate (ISDN) (an NO donor) and/or 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO) (an NO scavenger) and then exposed to X-rays. Cell survival, apoptosis, and chromosome aberrations were scored by use of a colony-forming assay, Hoechst 33342 staining assay and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP [deoxyuridine triphosphate] nick end labeling) assay, and chromosomal banding techniques, respectively. Results: In wtp53 cells the induction of radioresistance and the inhibition of apoptosis and chromosome aberrations were observed in the presence of ISDN at low 2- to 10-μmol/L concentrations before X-irradiation. The addition of c-PTIO and ISDN into the culture medium 6 h before irradiation almost completely suppressed these effects. However, at high concentrations of ISDN (100-500 μmol/L), clear evidence of radiosensitization, enhancement of apoptosis, and chromosome aberrations was detected. However, these phenomena were not observed in mp53 cells at either concentration range with ISDN. Conclusions: These results indicate that low and high concentrations of NO radicals can choreograph inverse radiosensitivity, apoptosis, and chromosome aberrations in human lung cancer cells and that NO radicals can affect the fate of wtp53 cells.

  7. Aberrant methylation patterns in cancer

    Hudler, Petra; Videtič, Alja

    2016-01-01

    Epigenetic mechanisms, such as DNA methylation, DNA hydroxymethylation, post-translational modifications (PTMs) of histone proteins affecting nucleosome remodelling, and regulation by small and large non-coding RNAs (ncRNAs) work in concert with cis and trans acting elements to drive appropriate gene expression. Advances in detection methods and development of dedicated platforms and methylation arrays resulted in an explo - sion of information on aberrantly methylated sequences linking devia...

  8. Chromosomal aberrations in lymphocytes predict human cancer: a report from the European Study Group on Cytogenetic Biomarkers and Health (ESCH)

    Hagmar, L; Bonassi, S; Strömberg, U; Brøgger, A; Knudsen, Lisbeth E.; Norppa, H; Reuterwall, C

    1998-01-01

    .35-2.89) was obtained for those with a high CA frequency level, whereas the SMRs for those with medium or low did not noticeably differ from unity. Cox's proportional hazards models gave no evidence that the effect of CAs on total cancer incidence/mortality was modified by gender, age at test, or time since...... test. No association was seen between the SCEs or the MN frequencies and subsequent cancer incidence/mortality. The present study further supports our previous observation on the cancer predictivity of the CA biomarker, which seems to be independent of age at test, gender, and time since test. The risk...... patterns were similar within each national cohort. This result suggests that the frequency of CAs in peripheral blood lymphocytes is a relevant biomarker for cancer risk in humans, reflecting either early biological effects of genotoxic carcinogens or individual cancer susceptibility....

  9. Aberrantly methylated DNA as a biomarker in breast cancer

    Kristiansen, Søren; Jørgensen, Lars Mønster; Guldberg, Per;

    2013-01-01

    hypermethylation events, their use as tumor biomarkers is usually not hampered by analytical signals from normal cells, which is a general problem for existing protein tumor markers used for clinical assessment of breast cancer. There is accumulating evidence that DNA-methylation changes in breast cancer patients......Aberrant DNA hypermethylation at gene promoters is a frequent event in human breast cancer. Recent genome-wide studies have identified hundreds of genes that exhibit differential methylation between breast cancer cells and normal breast tissue. Due to the tumor-specific nature of DNA...... occur early during tumorigenesis. This may open up for effective screening, and analysis of blood or nipple aspirate may later help in diagnosing breast cancer. As a more detailed molecular characterization of different types of breast cancer becomes available, the ability to divide patients into...

  10. Radiotherapeutical chromosomal aberrations in laryngeal cancer patients

    Stošić-Divjak Svetlana L.

    2009-01-01

    Full Text Available Introduction. The authors present the results of cytogenetic analysis of 21 patients with laryngeal carcinomas diagnosed and treated in the period 1995-2000 at the Institute of Otorhinolaryngology and Maxillofacial Surgery, Clinical Center of Serbia and Clinical Center of Novi Sad. Material and methods. The patients were specially monitored and the material was analyzed at the Institute of Human Genetics of the School of Medicine in Belgrade as well as in the Laboratory for Radiological Protection of the Institute of Occupational and Radiological Health 'Dr Dragomir Karajovic' in Belgrade. Results. The incidence of chromosomal aberrations and incidence of exchange of material between sister chromatids were observed in the preparation of the metaphasic lymphocyte chromosomes of the peripheral blood obtained in the culture. Structural aberrations were found on the chromosomes in the form of breakups, rings, translocations and dicentrics as early as after a single exposure of patients to tumor radiation dose of 2 Gy in the field sized 5x7. Out of the total number of 35 cultivated blood samples obtained from 13 patients, 21 were successfully cultivated and they were proved to contain chromosomal aberrations. Some of the peripheral blood samples failed to show cell growth in vitro due to the lethal cell damages in vivo. Discussion.. We have consluded that the number of structural aberrations cannot be used as a biological measure of the absorbed ionizing radiation dose. The presence of aberrations per se is indicative of the mutagenic effect of the ionizing radiation, which was also confirmed in our series on the original model by cultivation of the peripheral blood lymphocytes in the culture of the cells of the volunteer donors upon in vitro radiation. Using the method of bromdeoxyuridylreductase, the increased incidence of SCE as a mutagenic effect was registered. Conclusion. It has been concluded that the increase of absorbed radiation dose in

  11. Genome-wide identification of significant aberrations in cancer genome

    Yuan Xiguo

    2012-07-01

    Full Text Available Abstract Background Somatic Copy Number Alterations (CNAs in human genomes are present in almost all human cancers. Systematic efforts to characterize such structural variants must effectively distinguish significant consensus events from random background aberrations. Here we introduce Significant Aberration in Cancer (SAIC, a new method for characterizing and assessing the statistical significance of recurrent CNA units. Three main features of SAIC include: (1 exploiting the intrinsic correlation among consecutive probes to assign a score to each CNA unit instead of single probes; (2 performing permutations on CNA units that preserve correlations inherent in the copy number data; and (3 iteratively detecting Significant Copy Number Aberrations (SCAs and estimating an unbiased null distribution by applying an SCA-exclusive permutation scheme. Results We test and compare the performance of SAIC against four peer methods (GISTIC, STAC, KC-SMART, CMDS on a large number of simulation datasets. Experimental results show that SAIC outperforms peer methods in terms of larger area under the Receiver Operating Characteristics curve and increased detection power. We then apply SAIC to analyze structural genomic aberrations acquired in four real cancer genome-wide copy number data sets (ovarian cancer, metastatic prostate cancer, lung adenocarcinoma, glioblastoma. When compared with previously reported results, SAIC successfully identifies most SCAs known to be of biological significance and associated with oncogenes (e.g., KRAS, CCNE1, and MYC or tumor suppressor genes (e.g., CDKN2A/B. Furthermore, SAIC identifies a number of novel SCAs in these copy number data that encompass tumor related genes and may warrant further studies. Conclusions Supported by a well-grounded theoretical framework, SAIC has been developed and used to identify SCAs in various cancer copy number data sets, providing useful information to study the landscape of cancer genomes

  12. Aberrant glycosylation associated with enzymes as cancer biomarkers

    Meany Danni L

    2011-06-01

    Full Text Available Abstract Background One of the new roles for enzymes in personalized medicine builds on a rational approach to cancer biomarker discovery using enzyme-associated aberrant glycosylation. A hallmark of cancer, aberrant glycosylation is associated with differential expressions of enzymes such as glycosyltransferase and glycosidases. The aberrant expressions of the enzymes in turn cause cancer cells to produce glycoproteins with specific cancer-associated aberrations in glycan structures. Content In this review we provide examples of cancer biomarker discovery using aberrant glycosylation in three areas. First, changes in glycosylation machinery such as glycosyltransferases/glycosidases could be used as cancer biomarkers. Second, most of the clinically useful cancer biomarkers are glycoproteins. Discovery of specific cancer-associated aberrations in glycan structures of these existing biomarkers could improve their cancer specificity, such as the discovery of AFP-L3, fucosylated glycoforms of AFP. Third, cancer-associated aberrations in glycan structures provide a compelling rationale for discovering new biomarkers using glycomic and glycoproteomic technologies. Summary As a hallmark of cancer, aberrant glycosylation allows for the rational design of biomarker discovery efforts. But more important, we need to translate these biomarkers from discovery to clinical diagnostics using good strategies, such as the lessons learned from translating the biomarkers discovered using proteomic technologies to OVA 1, the first FDA-cleared In Vitro Diagnostic Multivariate Index Assay (IVDMIA. These lessons, providing important guidance in current efforts in biomarker discovery and translation, are applicable to the discovery of aberrant glycosylation associated with enzymes as cancer biomarkers as well.

  13. Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. European Study Group on Cytogenetic Biomarkers and Health

    Bonassi, S; Hagmar, L; Strömberg, U; Montagud, A H; Tinnerberg, H; Forni, A; Heikkilä, P; Wanders, S; Wilhardt, P; Hansteen, I L; Knudsen, Lisbeth E.; Norppa, H

    2000-01-01

    played by exposure to carcinogens is still uncertain because of the requisite information concerning occupation and lifestyle was lacking. We evaluated in the present study whether CAs predicted cancer because they were the result of past exposure to carcinogens or because they were an intermediate end...... point in the pathway leading to disease. A nested case-control study was performed on 93 incident cancer cases and 62 deceased cancer cases coming from two prospective cohort studies performed in Nordic countries (Denmark, Finland, Norway, and Sweden) and Italy. For each case, four controls matched by...... compared to those with a low level in the Nordic cohort (odds ratio, 2.35; 95% confidence interval, 1.31-4.23) and in the Italian cohort (odds ratio, 2.66; 95% confidence interval, 1.26-5.62). These estimates were not affected by the inclusion of occupational exposure level and smoking habit in the...

  14. The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis

    Ben-David, Uri; Ha, Gavin; Khadka, Prasidda; Jin, Xin; Wong, Bang; Franke, Lude; Golub, Todd R.

    2016-01-01

    Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalogue of chromosomal aberrations in cancer GEMMs. Mining this resource, we find that most chromosomal aberrations accumulate late during breast tu...

  15. Chromosomal aberration frequency in lymphocytes predicts the risk of cancer

    Bonassi, Stefano; Norppa, Hannu; Ceppi, Marcello;

    2008-01-01

    Mechanistic evidence linking chromosomal aberration (CA) to early stages of cancer has been recently supported by the results of epidemiological studies that associated CA frequency in peripheral lymphocytes of healthy individuals to future cancer incidence. To overcome the limitations of single...

  16. Antimetastatic therapy targeting aberrant sialylation profiles in cancer cells

    Da Yong Lu

    2011-09-01

    Full Text Available Neoplasm metastases involve a fixed cascade of pathological processes, and are responsible for more than 60% cancer deaths worldwide and can only be controlled or inhibited by drugs now. Antimetastatic drugs targeting aberrantly sialylated in tumors have involved about a quarter of a century and might be a future therapeutic option apart from currently utilized antimetastatic drugs, such as antivascular and matrix metalloproteinase (MMP inhibitors. Since neoplasm tissues often manifest high levels of sialic acids and sialyl antigens or glycoligands, and some types of sialic acid analogue, such as N-glycolylneuraminic acid (Nau5Gc occurred in most tumor tissues, is absent in common humans, more attentions are needed to work with new therapeutic approaches to target these changes. Previously preliminary data have shown some compounds that inhibit some pathways of sialic acids can inhibit the tumor metastasis in vitro and tumor metastasis in experimental animal models. This type of pharmacological work can be helped by glycome investigations in order to deep understanding their mechanisms. As the central dogma of glycobiology is still unknown, some fundamental questions related to carbohydrate itself are even more welcoming and decisive to our understanding to nature of cancer. These types of work also need mathematical analysis of data. In this review, we will document and discuss the latest experimental therapeutic data and their clinical significance between cancer pathological profiles and therapeutics benefits.

  17. Involvement of Aberrant Glycosylation in Thyroid Cancer

    Eiji Miyoshi

    2010-01-01

    Full Text Available Glycosylation is one of the most common posttranslational modification reactions and nearly half of all known proteins in eukaryotes are glycosylated. In fact, changes in oligosaccharides structures are associated with many physiological and pathological events, including cell growth, migration and differentiation, and tumor invasion. Therefore, functional glycomics, which is a comprehensive study of the structures and functions of glycans, is attracting the increasing attention of scientists in various fields of life science. In cases of thyroid cancer, the biological characters and prognosis are completely different in each type of histopathology, and their oligosaccharide structures as well as the expression of glycosyltransferases are also different. In this review, we summarized our previous papers on oligosaccharides and thyroid cancers and discussed a possible function of oligosaccharides in the carcinogenesis in thyroid cancer.

  18. Chromosomal aberrations and SCEs as biomarkers of cancer risk

    Norppa, H; Bonassi, S; Hansteen, I-L; Hagmar, L; Strömberg, U; Rössner, P; Boffetta, P; Lindholm, C; Gundy, S; Lazutka, J; Cebulska-Wasilewska, A; Fabiánová, E; Srám, R J; Knudsen, Lisbeth E.; Barale, R; Fucic, A

    Previous studies have suggested that the frequency of chromosomal aberrations (CAs), but not of sister chromatid exchanges (SCEs), predicts cancer risk. We have further examined this relationship in European cohorts comprising altogether almost 22,000 subjects, in the framework of a European...... collaborative project (CancerRiskBiomarkers). The present paper gives an overview of some of the results of the project, especially as regards CAs and SCEs. The results confirm that a high level of CAs is associated with an increased risk of cancer and indicate that this association does not depend on the time...... between CA analysis and cancer detection, i.e., is obviously not explained by undetected cancer. The present evidence indicates that both chromatid-type and chromosome-type CAs predict cancer, even though some data suggest that chromosome-type CAs may have a more pronounced predictive value than chromatid...

  19. Aberrant Gene Promoter Methylation Associated with Sporadic Multiple Colorectal Cancer

    Victoria Gonzalo; Juan José Lozano; Jenifer Muñoz; Francesc Balaguer; Maria Pellisé; Cristina Rodríguez de Miguel; Montserrat Andreu; Rodrigo Jover; Xavier Llor; M Dolores Giráldez; Teresa Ocaña; Anna Serradesanferm; Virginia Alonso-Espinaco; Mireya Jimeno; Miriam Cuatrecasas

    2010-01-01

    BACKGROUND: Colorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-...

  20. Aberrant promoter CpG methylation and its translational applications in breast cancer

    Ting-Xiu Xiang; Ying Yuan; Li-Li Li; Zhao-Hui Wang; Liang-Ying Dan; Yan Chen; Guo-Sheng Ren; Qian Tao

    2013-01-01

    Breast cancer is a complex disease driven by multiple factors including both genetic and epigenetic alterations.Recent studies revealed that abnormal gene expression induced by epigenetic changes,including aberrant promoter methylation and histone modification,plays a critical role in human breast carcinogenesis.Silencing of tumor suppressor genes (TSGs) by promoter CpG methylation facilitates cells growth and survival advantages and further results in tumor initiation and progression,thus directly contributing to breast tumorigenesis.Usually,aberrant promoter methylation of TSGs,which can be reversed by pharmacological reagents,occurs at the early stage of tumorigenesis and therefore may serve as a potential tumor marker for early diagnosis and therapeutic targeting of breast cancer.In this review,we summarize the epigenetic changes of multiple TSGs involved in breast pathogenesis and their potential clinical applications as tumor markers for early detection and treatment of breast cancer.

  1. Aberrant expression of nuclear matrix proteins during HMBA-induced differentiation of gastric cancer cells

    2010-01-01

    AIM: To investigate the aberrant expression of nuclear matrix proteins in human gastric cancer cells before and after hexamethylene bisacetamide (HMBA) treatment.METHODS: Proteomics analysis of differential nuclear matrix proteins was performed by two dimensional electrophoresis polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.The expression levels of three nuclear matrix proteins were further confirmed by Western blotting and their location...

  2. Induction of chromosomal aberrations in human lymphocytes by fission neutrons

    Chromosome aberrations induced by sparsely ionizing radiation (low-LET) are well known and cytogenetic analyses of irradiated human lymphocytes have been widely applied to biological dosimetry. However, much less is known about chromosome aberrations induced by densely ionizing radiation (high LET), such as that of alpha particles or neutrons. Such particles induce DNA strand breaks, as well as chromosome breakage and rearrangements of high complexity. This damage is more localized and less efficiently repaired than after X- or γ-ray irradiation. This preferential production of complex aberrations by densely ionizing radiation is related to the unique energy deposition patterns, which produces highly localized multiple DNA damage at the chromosomal level. A better knowledge of the interactions between different types of radiation and cellular DNA is of importance, not only from the radiobiological viewpoint but also for dosimetric and therapeutic purposes. The objective of the present study was to analyse the cytogenetic effects of fission neutrons on peripheral blood lymphocytes in order to evaluate structural and numerical aberrations and number of cells in the different mitotic cycles. So, blood samples from five healthy donors, 22-25 years old, of both sexes, were irradiated in the Research Reactor IEA-R1 of our Institute (IPEN/CNEN-SP) with thermal and fast neutrons at doses of 0.2; 0.3; 0.5 and 1.0 Gy. The γ contribution to the total absorbed dose was about 30%. These doses were monitored by thermoluminescent dosemeters: LiF-600 (for neutrons) and LiF-700 (for γ-rays). The data concerning structural aberrations were evaluated with regard to three parameters: percentage of cells with aberrations, number of aberrations/cell and number of dicentric/cell. The cytogenetic results showed an increase in the three parameters after irradiation with neutrons, as a function of radiation dose. Apparently, there was no influence of neutrons on the kinetics of cellular

  3. Chromosomal aberrations detected by chromosome painting in lymphocytes from cancer patients given high doses of therapeutic X-rays

    Chromosome painting by fluorescence in situ hybridization (FISH) with a whole chromosome-specific DNA probe was used to detect chromosomal aberrations in lymphocytes from cancer patients given partial-body fractionated X-ray therapy. Six male patients with cancer of the stomach, prostate, lung, or hepatocellular carcinoma, received X-rays in total doses of 40.5 to 70.08 Gy. Lymphocytes were cultured for 50 h with phytohemagglutinin. The mean frequency of aberrant cells detected by chromosome 4 painting varied from 1.57% to 14.34% in the patients and was markedly higher than in healthy controls (mean=0.12%). Chromosome painting effectively detected chromosomal aberrations in lymphocytes from cancer patients. Equivalent biological doses extrapolated from a dose-response curve obtained in an in vitro human lymphocyte X-ray irradiation study are discussed as an indicator of the cytogenetic damage inducible by radiotherapy in cancer patients. (author)

  4. Aberrant splicing of the DMP1-ARF-MDM2-p53 pathway in cancer.

    Inoue, Kazushi; Fry, Elizabeth A

    2016-07-01

    Alternative splicing (AS) of mRNA precursors is a ubiquitous mechanism for generating numerous transcripts with different activities from one genomic locus in mammalian cells. The gene products from a single locus can thus have similar, dominant-negative or even opposing functions. Aberrant AS has been found in cancer to express proteins that promote cell growth, local invasion and metastasis. This review will focus on the aberrant splicing of tumor suppressor/oncogenes that belong to the DMP1-ARF-MDM2-p53 pathway. Our recent study shows that the DMP1 locus generates both tumor-suppressive DMP1α (p53-dependent) and oncogenic DMP1β (p53-independent) splice variants, and the DMP1β/α ratio increases with neoplastic transformation of breast epithelial cells. This process is associated with high DMP1β protein expression and shorter survival of breast cancer (BC) patients. Accumulating pieces of evidence show that ARF is frequently inactivated by aberrant splicing in human cancers, demonstrating its involvement in human malignancies. Splice variants from the MDM2 locus promote cell growth in culture and accelerate tumorigenesis in vivo. Human cancers expressing these splice variants are associated with advanced stage/metastasis, and thus have negative clinical impacts. Although they lack most of the p53-binding domain, their activities are mostly dependent on p53 since they bind to wild-type MDM2. The p53 locus produces splice isoforms that have either favorable (β/γ at the C-terminus) or negative impact (Δ40, Δ133 at the N-terminus) on patients' survival. As the oncogenic AS products from these loci are expressed only in cancer cells, they may eventually become targets for molecular therapies. PMID:26802432

  5. Chromosome aberrations induced in human lymphocytes by neutron irradiation

    In vitro dose-response curves of unstable chromosome aberrations in human lymphocytes have been obtained for neutron spectra of mean energies 0.7, 0.9, 7.6 and 14.7 MeV. The aberration yields have been fitted to the quadratic function Y = αD + βD2, which is consistent with the single-track and two-track model of aberration formation. However with high-LET radiation, the linear component of yield, corresponding to damage caused by single tracks, predominates, and this term becomes more dominant with increasing LET, so that for fission spectrum neutrons the relationship is linear, Y = αD. At low doses, such as those received by radiation workers, limiting r.b.e. values between 13 and 47 were obtained relative to 60Co γ-radiation. At higher doses, as used in radiotherapy, the values were much lower; ranging from 2.7 to 8 at 200 rad of equivalent γ-radiation. Both sets of r.b.e. values correlated well with track-averaged LET but not with dose-averaged LET. When the numbers of cells without aberrations were plotted against radiation dose, curves were obtained which are similar in shape to those for conventional cell-survival experiments with comparable neutron spectra. The D0 values obtained in the present study are close to those from other cell systems. (author)

  6. A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer

    Castanos-Velez Esmeralda

    2006-09-01

    Full Text Available Abstract Background Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression. Results We investigated genome-wide gene expression in colorectal carcinoma (CRC and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81 distinct chromosomal islands with aberrant gene expression. Of these, 38 islands show a gain in expression and 43 a loss of expression. In total, 7.892 genes (25.3% of all human genes are located in aberrantly expressed islands. Many chromosomal regions that are linked to hereditary colorectal cancer show deregulated expression. Also, many known tumor genes localize to chromosomal islands of misregulated expression in CRC. Conclusion An extensive comparison with published CGH data suggests that chromosomal regions known for frequent deletions in colon cancer tend to show reduced expression. In contrast, regions that are often amplified in colorectal tumors exhibit heterogeneous expression patterns: even show a decrease of mRNA expression. Because for several islands of deregulated expression chromosomal aberrations have never been observed, we speculate that additional mechanisms (like abnormal states of regional chromatin also have a substantial impact on the formation of co-expression islands in colorectal carcinoma.

  7. Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts

    Vizoso, Miguel; Puig, Marta; Carmona, F.Javier; Maqueda, María; Velásquez, Adriana; Gómez, Antonio; Labernadie, Anna; Lugo, Roberto; Gabasa, Marta; Rigat-Brugarolas, Luis G.; Trepat, Xavier; Ramírez, Josep; Moran, Sebastian; Vidal, Enrique; Reguart, Noemí; Perera, Alexandre; Esteller, Manel; Alcaraz, Jordi

    2015-01-01

    Epigenetic changes through altered DNA methylation have been implicated in critical aspects of tumor progression, and have been extensively studied in a variety of cancer types. In contrast, our current knowledge of the aberrant genomic DNA methylation in tumor-associated fibroblasts (TAFs) or other stromal cells that act as critical coconspirators of tumor progression is very scarce. To address this gap of knowledge, we conducted genome-wide DNA methylation profiling on lung TAFs and paired control fibroblasts (CFs) from non-small cell lung cancer patients using the HumanMethylation450 microarray. We found widespread DNA hypomethylation concomitant with focal gain of DNA methylation in TAFs compared to CFs. The aberrant DNA methylation landscape of TAFs had a global impact on gene expression and a selective impact on the TGF-β pathway. The latter included promoter hypermethylation-associated SMAD3 silencing, which was associated with hyperresponsiveness to exogenous TGF-β1 in terms of contractility and extracellular matrix deposition. In turn, activation of CFs with exogenous TGF-β1 partially mimicked the epigenetic alterations observed in TAFs, suggesting that TGF-β1 may be necessary but not sufficient to elicit such alterations. Moreover, integrated pathway-enrichment analyses of the DNA methylation alterations revealed that a fraction of TAFs may be bone marrow-derived fibrocytes. Finally, survival analyses using DNA methylation and gene expression datasets identified aberrant DNA methylation on the EDARADD promoter sequence as a prognostic factor in non-small cell lung cancer patients. Our findings shed light on the unique origin and molecular alterations underlying the aberrant phenotype of lung TAFs, and identify a stromal biomarker with potential clinical relevance. PMID:26449251

  8. Mechanistic modeling of aberrant energy metabolism in human disease

    Vineet eSangar

    2012-10-01

    Full Text Available Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell.

  9. Adaptive and aberrant reward prediction signals in the human brain.

    Roiser, J.P.; Stephan, K.E.; Ouden, H.E.M. den; Friston, K.J.; Joyce, E.M.

    2010-01-01

    Theories of the positive symptoms of schizophrenia hypothesize a role for aberrant reinforcement signaling driven by dysregulated dopamine transmission. Recently, we provided evidence of aberrant reward learning in symptomatic, but not asymptomatic patients with schizophrenia, using a novel paradigm

  10. Molecular Confirmation that Fasciola gigantica Can Undertake Aberrant Migrations in Human Hosts▿

    Le, Thanh Hoa; Van, Nguyen; Agatsuma, Takeshi; Blair, David; Vercruysse, Jozef; Dorny, Pierre; Nguyen, Thanh Giang Thi; McManus, Donald P.

    2006-01-01

    Two cases of aberrant migration by the liver fluke Fasciola gigantica in humans are reported. In both cases, subadult worms emerged through the skin. The identity of the worms was confirmed from their DNA sequences. This uncommon human pathogen might be more likely than F. hepatica to undertake aberrant migrations in humans.

  11. OncoScape: Exploring the cancer aberration landscape by genomic data fusion

    Andreas Schlicker; Magali Michaut; Rubayte Rahman; Wessels, Lodewyk F. A.

    2016-01-01

    Although large-scale efforts for molecular profiling of cancer samples provide multiple data types for many samples, most approaches for finding candidate cancer genes rely on somatic mutations and DNA copy number only. We present a new method, OncoScape, which exploits five complementary data types across 11 cancer types to identify new candidate cancer genes. We find many rarely mutated genes that are strongly affected by other aberrations. We retrieve the majority of known cancer genes but...

  12. Intra- and interindividual variability in lymphocyte chromosomal aberrations: implications for cancer risk assessment.

    Peters, Susan; Portengen, Lützen; Bonassi, Stefano; Sram, Radim; Vermeulen, Roel

    2011-08-15

    Chromosomal aberration frequency in peripheral lymphocytes of healthy individuals has been found to be predictive of future cancer risk. The variability of chromosomal aberrations over time, which is largely unknown, should be clarified to interpret the strength of this association and to determine its use in cancer prediction. Intra- and interindividual variability in chromosomal aberration frequency was therefore determined. From a pooled database comprising 11 national cohorts (1965-2002), the authors included 9,433 blood samples from 3,550 subjects with at least one repeated chromosomal aberration measurement. The generalized concordance correlation coefficient of 0.19 was low, indicating high intraindividual variability compared with interindividual variability, resulting in a high likelihood of misclassification. The relation between chromosomal aberration frequency and future cancer risk has probably been underestimated in previous studies. A single chromosomal aberration measurement seems not to be representative of the whole lifespan level of chromosome instability and greatly limits the use of chromosomal aberration frequency-as measured with Giemsa staining-for individual risk assessment. PMID:21652601

  13. On the spontaneous frequency of the structural chromosome aberrations (anomalies) in lymphocytes from human blood

    Chromosomal aberrations are observed both in irradiated cells and in cells which have not been irradiated but submitted to the action of the natural radioactive background. The reasons for these ''spontaneous chromosomal aberrations'' are both the natural radioactivity and a complex of physical, chemical and biological factors. A cytogenetic analysis of 6000 lymphocytes metaphases from the peripheral blood of 47 people indicates that the overall amount of the spontaneous aberrations is 2% with a ratio of chromosomal type aberrations to chromatide type aberrations of 1:5. Chromatide type aberrations are seen as the result of purely mechanical factors acting during slides preparation but yet another unknown moments cannot be excluded. They are more one hit type aberrations - chromatide and chromosomal fragments, wereas the two hit aberrations are very rare - one dicentric per 3000 cells. The chromosome type aberrations are proposed for comparison with radiation induced aberrations in human lymphocytes. They have a frequency of 0.0035 per cell or 0.0040 breakages per cell. Ionizing radiation does not induce qualitatively specific type of aberrations but increases many times the yield of anomalies, which are spontaneously observed. (A.B.)

  14. Aberrant gene promoter methylation associated with sporadic multiple colorectal cancer.

    Victoria Gonzalo

    Full Text Available BACKGROUND: Colorectal cancer (CRC multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect. METHODOLOGY/PRINCIPAL FINDINGS: We examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2, RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008 and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047 as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006. Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17, SFRP1 (r = 0.83, 0.06, HPP1 (r = 0.64, p = 0.17, 3OST2 (r = 0.83, p = 0.06 and GATA4 (r = 0.6, p = 0.24. Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant

  15. Azoxymethane-induced rat aberrant crypt foci: Relevance in studying chemoprevention of colon cancer

    Jayadev Raju

    2008-01-01

    The pathogenesis of colon cancer involves sequential and multistep progression of epithelial cells initiated to a cancerous state with defined precancerous intermediaries.Aberrant crypt foci (ACF) represent the earliest identifiable intermediate precancerous lesions during colon carcinogenesis in both laboratory animals and humans.ACF are easily induced by colon-specific carcinogens in rodents and can be used to learn more about the process of colon carcinogenesis.For over two decades,since its first discovery,azoxymethane(AOM)-induced rodent ACF have served as surrogate biomarkers in the screening of various anticarcinogens and carcinogens.Several dietary constituents and phytochemicals have been tested for their colon cancer chemopreventive efficacy using the ACF system.There has been substantial effort in defining and refining ACF in terms of understanding their molecular make-up,and extensive research in this field is currently in progress.In chemoprevention studies,AOM-induced rat ACF have been very successful as biomarkers,and have provided several standardized analyses of data.There have been several studies that have reported that ACF data do not correlate to actual colon tumor outcome,however,and hence there has been an ambiguity about their role as biomarkers.The scope of this mini-review is to provide valuable insights and limitations of AOM-induced rat ACF as biomarkers in colon cancer chemoprevention studies.The role of the dynamics and biological heterogeneity of ACF is critical in understanding them as biomarkers in chemoprevention studies.

  16. Prioritizing cancer-related genes with aberrant methylation based on a weighted protein-protein interaction network

    Lv Jie

    2011-10-01

    Full Text Available Abstract Background As an important epigenetic modification, DNA methylation plays a crucial role in the development of mammals and in the occurrence of complex diseases. Genes that interact directly or indirectly may have the same or similar functions in the biological processes in which they are involved and together contribute to the related disease phenotypes. The complicated relations between genes can be clearly represented using network theory. A protein-protein interaction (PPI network offers a platform from which to systematically identify disease-related genes from the relations between genes with similar functions. Results We constructed a weighted human PPI network (WHPN using DNA methylation correlations based on human protein-protein interactions. WHPN represents the relationships of DNA methylation levels in gene pairs for four cancer types. A cancer-associated subnetwork (CASN was obtained from WHPN by selecting genes associated with seed genes which were known to be methylated in the four cancers. We found that CASN had a more densely connected network community than WHPN, indicating that the genes in CASN were much closer to seed genes. We prioritized 154 potential cancer-related genes with aberrant methylation in CASN by neighborhood-weighting decision rule. A function enrichment analysis for GO and KEGG indicated that the optimized genes were mainly involved in the biological processes of regulating cell apoptosis and programmed cell death. An analysis of expression profiling data revealed that many of the optimized genes were expressed differentially in the four cancers. By examining the PubMed co-citations, we found 43 optimized genes were related with cancers and aberrant methylation, and 10 genes were validated to be methylated aberrantly in cancers. Of 154 optimized genes, 27 were as diagnostic markers and 20 as prognostic markers previously identified in literature for cancers and other complex diseases by searching Pub

  17. Chromosomal aberrations and SCEs as biomarkers of cancer risk

    Norppa, H.; Bonassi, S.; Hansteen, I. L.; Hagmar, L.; Strömberg, U.; Rössner st., Pavel; Boffetta, P.; Lindholm, C.; Gundy, S.; Lazutka, J.; Cebulska-Wasilewska, A.; Fabiánová, E.; Šrám, Radim; Knudsen, L. E.; Barale, R.; Fucic, A.

    2006-01-01

    Roč. 600, - (2006), s. 37-45. ISSN 0027-5107 Institutional research plan: CEZ:AV0Z50390512 Keywords : biomarkers * chromosomal aberration * sister chromatid exchange Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 4.111, year: 2006

  18. Inter- and Intra-Chromosomal Aberrations in Human Cells Exposed in vitro to High and Low LET Radiations

    Hada, M.; Wilkins, R.; Saganti, P. B.; Gersey, B.; Cucinotta, F. A.; Wu, H.

    2006-01-01

    Energetic heavy ions pose a health risk to astronauts in extended ISS and future Mars missions. High-LET heavy ions are particularly effective in causing various biological effects including cell inactivation, genetic mutations and cancer induction. Most of these biological endpoints are closely related to chromosomal damage, which can be utilized as a biomarker for radiation insults. Previously, we had studied chromosome aberrations in human lymphocytes and fibroblasts induced by both low- and high-LET radiation using FISH and multicolor fluorescence in situ hybridization (mFISH) techniques. In this study, we exposed human epithelial cells in vitro to gamma rays and energetic particles of varying types and energies and dose rates, and analyzed chromosomal damages using the multicolor banding in situ hybridization (mBAND) procedure. Confluent human epithelial cells (CH184B5F5/M10) were exposed to energetic heavy ions at NASA Space Radiation Laboratory (NSRL) at the Brookhaven National Laboratory, high energy neutron at the Los Alamos Nuclear Science Center (LANSCE) or Cs-137-gamma radiation source at the University of Texas, MD Anderson Cancer Center. After colcemid and Calyculin A treatment, cells were fixed and painted with XCyte3 mBAND kit (MetaSystems) and chromosome aberrations were analyzed with mBAND analysis system (MetaSystems). With this technique, individually painted chromosomal bands on one chromosome allowed the identification of interchromosomal aberrations (translocation to unpainted chromosomes) and intrachromosomal aberrations (inversions and deletions within a single painted chromosome). The results of the mBAND study showed a higher ratio of inversion involved with interchromosomal exchange in heavy ions compared to -ray irradiation. Analysis of chromosome aberrations using mBAND has the potential to provide useful information on human cell response to space-like radiation.

  19. Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers.

    Yuichi Shiraishi

    Full Text Available Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV-related hepatocellular carcinomas (HCCs and their matched controls. Comparison of whole genome sequence (WGS and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive over-expression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3, and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome.

  20. Radiation-induced chromosome aberrations in human lymphocytes

    Dose-response relationships for unstable chromosome exchange aberrations were obtained after irradiation with 200 kV X-rays and 60Co gamma rays, the doses ranging within 0.05-3.0 Gy. The data points were fitted to the linear quadratic model Y = C + αD + βD2, and after the chromosome hits leading to two-break unstable aberrations were estimated, to the model average x = C +kD. The results fitted the latter model particularly well, the index of determination being 0.988 for gamma rays and 0.997 for X-rays. The RBE of 200 kV X-rays as compared with 60Co gamma radiation was 1.6, when primary chromosome breaks leading to dicentric and centric ring aberrations were used as the biological endpoint. (author)

  1. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas.

    Sugawa, N; Ekstrand, A J; James, C D; Collins, V P

    1990-01-01

    The epidermal growth factor receptor gene has been found to be amplified and rearranged in human glioblastomas in vivo. Here we present the sequence across a splice junction of aberrant epidermal growth factor receptor transcripts derived from corresponding and uniquely rearranged genes that are coamplified and coexpressed with non-rearranged epidermal growth factor receptor genes in six primary human glioblastomas. Each of these six tumors contains aberrant transcripts derived from identical...

  2. Aberrant expression of Wnt antagonist SFRP1 in pancreatic cancer

    BU Xian-min; ZHAO Cheng-hai; DAI Xian-wei

    2008-01-01

    @@ Pancreatic cancer is one of the malignant tumor with a very poor prognosis. Both genetic and epigenetic alterations are involved in the pathogenetic mechanisms of pancreatic cancer. Hypermethylation and subsequent loss of expression of some tumor suppressor genes and tumor-related genes occur frequently in pancreatic cancer, such as loss of expression of pl6,1 RASSF1A,2 SOCS-1,3 and hMLH14 genes were repoted.

  3. [HPV-associated head and neck cancer : mutational signature and genomic aberrations].

    Wagner, S; Würdemann, N; Hübbers, C; Reuschenbach, M; Prigge, E-S; Wichmann, G; Hess, J; Dietz, A; Dürst, M; Tinhofer, I; von Knebel-Döberitz, M; Wittekindt, C; Klussmann, J P

    2015-11-01

    A significantly increasing proportion of oropharyngeal head and neck carcinomas (OSCC) in North America and Europe are associated with human papillomavirus (HPV) infections. HPV-related OSCC is regarded as a distinct tumor type with regard to its cellular, biologic, and clinical characteristics. Patients with HPV-related OSCC have significantly better local control, but higher rates of regional lymph node and distant metastases as compared to patients with HPV-negative OSCC. Classical molecular genetic investigations demonstrated specific chromosomal aberration signatures in HPV-related OSCC, and recent developments in next generation sequencing (NGS) technology have rendered possible the sequencing of entire genomes, and thus detection of specific mutations, in just a few days. Initial data from The Cancer Genome Atlas (TCGA) project obtained by using genome-wide high throughput methods have confirmed that HPV-related OSCC contain fewer, albeit more specific mutations than HPV-negative tumors. Additionally, these data revealed the presence of specific-potentially therapeutically targetable-activating driver mutations in subgroups of HPV-positive OSCC, some of which have a prognostic impact. Specific targeted NGS technologies provide new possibilities for identification of diagnostic, prognostic, and predictive biomarkers and the development of personalized cancer treatment. Patients with HPV-positive tumors are likely to profit from these developments in the future, since the genetic alterations are relatively homogenous and frequently lead to signal pathway activation. There is an urgent need for network research activities to carry out the necessary basic research in prospective cohort studies. PMID:26507715

  4. Antipain-mediated suppression of X-ray-induced chromosomal aberrations in human lymphocytes

    The protease inhibitor antipain is known to modulate the number of chromosomal aberrations induced by the S-phase-dependent alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. Experiments have now been carried out to see if antipain might also affect the yield of aberrations induced by X-rays, which are S-independent and thus produce chromosomal aberrations by a different mechanism. The results show that human lymphocytes exposed to 0.4 or 1.5 Gy of X-rays at 48 h of culture and fixed at 3, 6, 8, 10 or 12 h thereafter contain 27-52% fewer chromatid breaks if the cells are also treated with antipain before irradiation. Because previous studies postulated that antipain could affect the induction of of chromosomal aberrations by suppressing free radical reactions within cells, we also tested whether antipain affects X-ray-induced aberrations when present only during the time of irradiation, as is the case for free radical scavengers, such as L-cysteine. The results indicate that, in contrast to L-cysteine, antipain can suppress the induction of X-ray-induced aberrations even when administered as late as 2 h after irradiation, suggesting that the effects of antipain on aberrations are not attributable to its interference with short-lived radicals within the cells. These data indicate that the formation of chromosome aberrations by S-independent agents can involve an antipain-sensitive process. (author)

  5. Human Prostate Cancer Hallmarks Map.

    Datta, Dipamoy; Aftabuddin, Md; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-01-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process. PMID:27476486

  6. Combining Chromosomal Arm Status and Significantly Aberrant Genomic Locations Reveals New Cancer Subtypes

    Tal Shay

    2009-01-01

    Full Text Available Many types of tumors exhibit characteristic chromosomal losses or gains, as well as local amplifications and deletions. Within any given tumor type, sample specific amplifications and deletions are also observed. Typically, a region that is aberrant in more tumors, or whose copy number change is stronger, would be considered as a more promising candidate to be biologically relevant to cancer. We sought for an intuitive method to define such aberrations and prioritize them. We define V, the “volume” associated with an aberration, as the product of three factors: (a fraction of patients with the aberration, (b the aberration’s length and (c its amplitude. Our algorithm compares the values of V derived from the real data to a null distribution obtained by permutations, and yields the statistical significance (p-value of the measured value of V. We detected genetic locations that were significantly aberrant, and combine them with chromosomal arm status (gain/loss to create a succinct fingerprint of the tumor genome. This genomic fingerprint is used to visualize the tumors, highlighting events that are co-occurring or mutually exclusive. We apply the method on three different public array CGH datasets of Medulloblastoma and Neuroblastoma, and demonstrate its ability to detect chromosomal regions that were known to be altered in the tested cancer types, as well as to suggest new genomic locations to be tested. We identified a potential new subtype of Medulloblastoma, which is analogous to Neuroblastoma type 1.

  7. Chromosome Aberrations in Human Lymphocytes Irradiated with Ionizing Radiation

    The purpose of the present experiment was to provide data on the dose-dependent production of chromosome aberrations such as dicentrics, centric rings, and excess acentrics. Radiation is one of the more dangerous clastogens in the environment. Ionizing radiation causes chromosome breakages and various cytogenetic aberrations in exposed cells. In an investigation into radiation emergencies, it is important to estimate the dose to exposed persons for several reasons. Physical dosimeters (e. g., film badges) may misrepresent the actual radiation dose and may not be available in a radiological accident or terrorism incident. Biological dosimetry is suitable for estimating the radiation dose during such accidents. The dicentric chromosome assay is very sensitive and a reliable bio-indicator in cases of accidental overexposure

  8. Transcriptional consequences of genomic structural aberrations in breast cancer

    Inaki, Koichiro; Hillmer, Axel M.; Ukil, Leena; Yao, Fei; Woo, Xing Yi; Vardy, Leah A; Zawack, Kelson Folkvard Braaten; Lee, Charlie Wah Heng; Ariyaratne, Pramila Nuwantha; Chan, Yang Sun; Desai, Kartiki Vasant; Bergh, Jonas; Hall, Per; Putti, Thomas Choudary; Ong, Wai Loon

    2011-01-01

    Using a long-span, paired-end deep sequencing strategy, we have comprehensively identified cancer genome rearrangements in eight breast cancer genomes. Herein, we show that 40%–54% of these structural genomic rearrangements result in different forms of fusion transcripts and that 44% are potentially translated. We find that single segmental tandem duplication spanning several genes is a major source of the fusion gene transcripts in both cell lines and primary tumors involving adjacent genes ...

  9. M-Band Analysis of Chromosome Aberrations in Human Epithelial Cells Induced By Low- and High-Let Radiations

    Hada, M.; Gersey, B.; Saganti, P. B.; Wilkins, R.; Gonda, S. R.; Cucinotta, F. A.; Wu, H.

    2007-01-01

    Energetic primary and secondary particles pose a health risk to astronauts in extended ISS and future Lunar and Mars missions. High-LET radiation is much more effective than low-LET radiation in the induction of various biological effects, including cell inactivation, genetic mutations, cataracts and cancer. Most of these biological endpoints are closely correlated to chromosomal damage, which can be utilized as a biomarker for radiation insult. In this study, human epithelial cells were exposed in vitro to gamma rays, 1 GeV/nucleon Fe ions and secondary neutrons whose spectrum is similar to that measured inside the Space Station. Chromosomes were condensed using a premature chromosome condensation technique and chromosome aberrations were analyzed with the multi-color banding (mBAND) technique. With this technique, individually painted chromosomal bands on one chromosome allowed the identification of both interchromosomal (translocation to unpainted chromosomes) and intrachromosomal aberrations (inversions and deletions within a single painted chromosome). Results of the study confirmed the observation of higher incidence of inversions for high-LET irradiation. However, detailed analysis of the inversion type revealed that all of the three radiation types in the study induced a low incidence of simple inversions. Half of the inversions observed in the low-LET irradiated samples were accompanied by other types of intrachromosome aberrations, but few inversions were accompanied by interchromosome aberrations. In contrast, Fe ions induced a significant fraction of inversions that involved complex rearrangements of both the inter- and intrachromosome exchanges.

  10. Aberrant Expression of Notch1 in Cervical Cancer

    Li Sun; Qimin Zhan; Wenhua Zhang; Yongmei Song; Tong Tong

    2007-01-01

    OBJECTIVE To investigate the putative role of the Notch1 receptor in cervical cancer carcinogenesis and progression.METHODS The expression of the Notch1 protein was analyzed by a Western-blotting approach in 40 cervical cancer and 30 normal cervical tissues.Some tissues were examined using RT-PCR To determine Mrna levels.Celluar localization of the Notch1 protein in the paraffin-embedded cervical tissues was also analyzed by immunohistochemistry.RESULTS The Notch1 protein was detected in all 30 normal cervical tissues.In contrast.only 6 samples of 40 cervical cancer tissues showed Notch1 expression.The level of the Notch1 protein expression was significantly lower in cervical cancer tissues than that in normal tissue samples.In agreement with these observations.levels of Notch1 Mrna were found to be substantially down-regulated in cervical cancer tissues.In the immunohistochemistry staining assay,the Notch1 protein was shown to localize predominantly in the cytoplasm and nucleoli of the normal cervical squamous epithelium of the cervix,but no staining was observed in the cervical cancer cells.Notch1 expression was observed to correlate with the clinical disease stage.but there were no correlations with age,tumor size,grade or lymph node metastasis (P>0.05).The levels of Notchl protein expression were significantly higher in early stages(I~lla,66.7%) compared to those in the advanced stages (Iib~IV,12.6%)(P=0.001).CONCLUSION Notch1 may play a role as a tumor suppressor in cervical tumorigenesis.Determination of Notch1 expression may be helpful for preoperative diagnosis and accuracy of staging.But its clinical use for cervical cancer requires further investigation.

  11. Retrieval of wave aberration of human eyes from actual point-spread-function data.

    Artal, Pablo; Santamaría, J.; Bescós, J.

    1988-01-01

    The wave aberration of human eyes is retrieved from actual point-spread-function (PSF) data and the modulus of the pupil function. The PSF had been obtained previously by application of a hybrid optical-digital method developed recently. The retrieval is done by using a bidimensional Gerchberg-Saxton phase-retrieval algorithm joined to an iterative phase-unwrapping algorithm. To obtain an adequate convergence, the initial wave aberration for starting the retrieval-unwrapping algorithm is esti...

  12. Aberrant allele-specific replication, independent of parental origin, in blood cells of cancer patients

    Allelic counterparts of biallelically expressed genes display an epigenetic symmetry normally manifested by synchronous replication, different from genes subjected to monoallelic expression, which normally are characterized by an asynchronous mode of replication (well exemplified by the SNRPN imprinted locus). Malignancy was documented to be associated with gross modifications in the inherent replication-timing coordination between allelic counterparts of imprinted genes as well as of biallelically expressed loci. The cancer-related allelic replication timing aberrations are non-disease specific and appear in peripheral blood cells of cancer patients, including those with solid tumors. As such they offer potential blood markers for non-invasive cancer test. The present study was aimed to gain some insight into the mechanism leading to the replication timing alterations of genes in blood lymphocytes of cancer patients. Peripheral blood samples derived from patients with prostate cancer were chosen to represent the cancerous status, and samples taken from patients with no cancer but with benign prostate hyperplasia were used to portray the normal status. Fluorescence In Situ Hybridization (FISH) replication assay, applied to phytohemagglutinin (PHA)-stimulated blood lymphocytes, was used to evaluate the temporal order (either synchronous or asynchronous) of genes in the patients' cells. We demonstrated that: (i) the aberrant epigenetic profile, as delineated by the cancer status, is a reversible modification, evidenced by our ability to restore the normal patterns of replication in three unrelated loci (CEN15, SNRPN and RB1) by introducing an archetypical demethylating agent, 5-azacytidine; (ii) following the rehabilitating effect of demethylation, an imprinted gene (SNRPN) retains its original parental imprint; and (iii) the choice of an allele between early or late replication in the aberrant asynchronous replication, delineated by the cancer status, is not

  13. Prognostic significance of aberrantly silenced ANPEP expression in prostate cancer

    Sørensen, Karina Dalsgaard; Abildgaard, Mette Opstrup; Haldrup, Christa;

    2013-01-01

    Background:Novel biomarkers for prostate cancer (PC) are urgently needed. This study investigates the expression, epigenetic regulation, and prognostic potential of ANPEP in PC.Methods:Aminopeptidase N (APN; encoded by ANPEP) expression was analysed by immunohistochemistry using tissue microarrays...

  14. Genomic aberrations relate early and advanced stage ovarian cancer

    A. Zaal; W.J. Peyrot (Wouter ); P.M.J.J. Berns (Els); M.E.L. van der Burg (Maria); J.H.W. Veerbeek (Jan ); J.B. Trimbos; I. Cadron (Isabelle); P.J. van Diest (Paul); W.N. Wieringen (Wessel); O. Krijgsman (Oscar); G.A. Meijer (Gerrit); J.M.J. Piek (Jurgen ); P.J. Timmers (Petra); I. Vergote (Ignace); R.H.M. Verheijen (René); B. Ylstra (Bauke); R.P. Zweemer (Ronald )

    2012-01-01

    textabstractBackground Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. Methods Sixteen early and sixteen advanced

  15. Hedgehog pathway aberrations and gastric cancer; evaluation of prognostic impact and exploration of therapeutic potentials.

    Abdel-Rahman, Omar

    2015-03-01

    Gastric cancer is an important cause for mortality and morbidity worldwide; it lies in the fourt rank as a cause of cancer-related death in males and in the fifth rank of cancer-related death in women. The prognosis of advanced/metastatic gastric cancer cases looks poor with the majority of available therapeutics. Thus, novel therapeutic strategies in this setting have been considered a priority for leading cooperative oncology groups. Hedgehog(Hh) pathway aberrations have sparked particular interest as prognostic markers with data from multiple studies showing consistent evidence of a poor prognostic value of Gli over expression in gastric cancer while on the other hand the prognostic significance of Hh protein over expression (particularly SHH) was not consistent among different studies. This review article revises the prognostic and potential therapeutic opportunities in the targeting of hedgehog pathway in gastric cancer. PMID:25680409

  16. EFFECT OF SHORT-TERM SOFT CONTACT LENS WEAR ON HUMAN OCULAR ABERRATIONS

    YU Jing; CHEN Yi-hui; CHEN Hui; SHENG Min-jie

    2009-01-01

    Objective To evaluate the effect of short-term soft contact lens (SCLs) wearing on human ocular aberrations (HOA).Methods This prospective study included 50 eyes of 50 young volunteers wearing SCLs for 1month. The ocular aberrations were measured by Allegretto Wavefront Analyzer. The root-mean-square (RMS) values of the general (RMSG), higher-order (RMSH), first to sixth order (RMS1 to RMS6) and aberration coefficients were analyzed.Results There were no significant differences in the mean values of RMSG, RMSH, RMS1 to RMS6 (P>0.05) and changes of absolute values of aberration coefficients between baseline and various visits after SCLs discontinuation. However, at d1 after the discontinuation of SCLs, changes in coefficient values of the third-order aberrations (C6 to C9) were slightly higher than others, and C7 was the highest. The increase factors of RMS values were higher at 1 week and lower at the 2 week visit after SCLs discontinuation. The uniformity of dominating type in HOA and the corneal topography form was both about 60% after discontinuation of SCLs. The corneal thickness increased after SCLs wear and gradually decreased to baseline until 1month discontinuation of SCLs.Conclusion The effect of short-term SCLs wear on human ocular aberrations is slight but profound. A month or more wait should be allowed before the short-term SCLs wearers are scheduled for wavefronted-guided LASIK.

  17. Regulation of MYC gene expression by aberrant Wnt/β-catenin signaling in colorectal cancer

    Sherri; Rennoll; Gregory; Yochum

    2015-01-01

    The Wnt/β-catenin signaling pathway controls intestinal homeostasis and mutations in components of this pathway are prevalent in human colorectal cancers(CRCs).These mutations lead to inappropriate expression of genes controlled by Wnt responsive DNA elements(WREs). T-cell factor/Lymphoid enhancer factor transcription factors bind WREs and recruit the β-catenin transcriptional co-activator to activate target gene expression. Deregulated expression of the c-MYC proto-oncogene(MYC) by aberrant Wnt/β-catenin signaling drives colorectal carcinogenesis. In this review,we discuss the current literature pertaining to the identification and characterization of WREs that control oncogenic MYC expression in CRCs. A common theme has emerged whereby these WREs often map distally to the MYC genomic locus and control MYC gene expression through long-range chromatin loops with the MYC proximal promoter. We propose that by determining which of these WREs is critical for CRC pathogenesis,novel strategies can be developed to treat individuals suffering from this disease.

  18. A comparison of chromosomal aberrations induced by in vivo radiotherapy in human sperm and lymphocytes

    Chromosomal aberrations in human sperm and lymphocytes were compared before and after in vivo radiation treatment of 13 cancer patients. The times of analyses after radiotherapy (RT) were 1, 3, 12, 24, 36, 48 and 60 months. The median total radiation dose was 30 Gy and the testicular dose varied from 0.4 to 5.0 Gy. Human sperm chromosome complements were analysed after fusion with golden hamster eggs. There were no abnormalities in sperm or lymphocytes before RT. Following RT there was an increase in the frequency of numerical and structural chromosomal abnormalities in both lymphocytes and sperm. For structural abnormalities there were more rejoined lesions (dicentrics, rings) in lymphocytes and more unrejoined lesions (chromosome breaks, fragments) in sperm. It appears that the frequency of lymphocyte chromosomal abnormalities had an initial marked increase after RT followed by a gradual decrease with time whereas the frequency of sperm chromosomal abnormalities was elevated when sperm production recovered and remained elevated from 24 to 60 mo. post-RT. This difference in the effect of time makes it very difficult to compare abnormality rates in lymphocytes and sperm and to use analysis of induced damage in somatic cells as surrogates for germ cells since the ratio between sperm and lymphocytes varied from 1:1 (at 24 mo. post-RT) to 5:1 (at 60 mo. post-RT). (author). 14 refs.; 2 figs.; 5 tabs

  19. Human cancer databases (Review)

    Pavlopoulou, Athanasia; Spandidos, Demetrios A.; Michalopoulos, Ioannis

    2014-01-01

    Cancer is one of the four major non-communicable diseases (NCD), responsible for ~14.6% of all human deaths. Currently, there are >100 different known types of cancer and >500 genes involved in cancer. Ongoing research efforts have been focused on cancer etiology and therapy. As a result, there is an exponential growth of cancer-associated data from diverse resources, such as scientific publications, genome-wide association studies, gene expression experiments, gene-gene or protein-protein in...

  20. Circadian Dysrhythmias, Physiological Aberrations, and the Link to Skin Cancer

    Daniel Gutierrez

    2016-04-01

    Full Text Available Circadian rhythms are core regulators of a variety of mammalian physiologic processes and oscillate in a 24-h pattern. Many peripheral organs possess endogenous rhythmicity that is then modulated by a master clock; the skin is one of these peripheral organs. The dysregulation of rhythms is associated with decreased ability to ameliorate cellular stressors at a local and global level, which then increases the propensity for the development of neoplastic growths. In this article, we review the implications of altered circadian rhythms on DNA repair as well as modified gene expression of core clock proteins with particular focus on skin models. These findings are then correlated with epidemiologic data regarding skin cancer to showcase the effects of circadian disruption on this phenomenon.

  1. Replication stress, a source of epigenetic aberrations in cancer?

    Jasencakova, Zusana; Groth, Anja

    2010-01-01

    . Chromatin organization is transiently disrupted during DNA replication and maintenance of epigenetic information thus relies on faithful restoration of chromatin on the new daughter strands. Acute replication stress challenges proper chromatin restoration by deregulating histone H3 lysine 9 mono......-methylation on new histones and impairing parental histone recycling. This could facilitate stochastic epigenetic silencing by laying down repressive histone marks at sites of fork stalling. Deregulation of replication in response to oncogenes and other tumor-promoting insults is recognized as a significant source...... of genome instability in cancer. We propose that replication stress not only presents a threat to genome stability, but also jeopardizes chromatin integrity and increases epigenetic plasticity during tumorigenesis....

  2. Unstable chromosome aberrations on peripheral blood lymphocytes from patients with cervical uterine cancer following radiotherapy

    Absorbed dose determination is an important step for risk assessment related to an exposure to ionizing radiation. However, physical dosimetry cannot be always performed, principally in the case of retrospective estimates. In this context, the use of bioindicators (biological effects) has been proposed, which defines the so-called biological dosimetry. In particular, scoring of unstable chromosomes aberrations (dicentrics, centric rings and fragments) of peripheral blood lymphocytes, while is the most reliable biological method for estimating individual exposure to ionizing radiation. In this work, blood samples from 5 patients, with cervical uterine cancer, were evaluated after partial-body radiotherapy with a source of 69 Co. For this, conventional cytogenetic method was employed, based on Giemsa coloration and fluorescence in situ hybridization, in order to correlate the frequency of unstable chromosome aberrations of blood lymphocytes with absorbed dose, as a result of the radiotherapy. A good agreement was observed between the frequency of chromosome aberrations scored and the values of dose previously calculated by physical dosimetry during patient's radiotherapy. The results presented in this work point out the importance of concerning analyses of unstable chromosome aberrations as biological dosimeter in the investigation of partial-body exposure to ionizing radiation. (author)

  3. Frequency of unstable chromosome aberrations in peripheral lymphocytes of women with breast cancer treated with radiotherapy

    This study proposes to obtain information about the behavior of the frequency and distribution of radiation induced lymphocyte dicentric chromosome aberrations with therapeutic doses in women with breast cancer treated only with radiotherapy, about which there are no existing works in Chile. Blood samples were taken from 6 women volunteers included in the study, with their informed consent, treated in the Fundacion Arturo Lopez Perez, aged 24 to 65 years old, without prior or parallel chemotherapy, nor prior radiotherapy. Three peripheral blood samples were taken from each patient in 0, 16.2 and 43.2 Gy doses. The lymphocytes obtained from each sample were cultivated using the micro-culture technique following the protocol in IAEA Technical Report No. 405, 2001. The samples were evaluated under a microscope and the unstable chromosome aberrations for lymphocytes were counted. A total of 500 cells per sample was evaluated in most cases, which were distributed depending on the number of aberrations that they had. The results were analyzed by treatment dose for each of the study patients, using the Papworth u test, Dolphin's 'Contaminated Poisson' method and Sasaki's 'QDR'. Great variations were observed in the frequency distribution of aberrations among the patients studied, which could be due to the influence of factors related to the patients' partial irradiations (C.Wood)

  4. Types of structural chromosome aberrations and their incidences in human spermatozoa X-irradiated in vitro

    The authors studied the effects of in vitro X-irradiation on human sperm chromosomes, using our interspecific in vitro fertilization system between human spermatozoa and zona-free hamster oocytes. 28 semen samples from 5 healthy men were exposed to 0.23, 0.45, 0.91 and 1.82 Gy of X-rays. Totals of 2098 and 2862 spermatozoa were karyotyped in the control and the irradiated groups, respectively. The indicence of spermatozoa with X-ray-induced structural chromosome aberrations (Y) increased linearly with increasing dosage (D), being best expressed by the equation, Y = 0.08 + 34.52 D. The incidence of breakage-type aberrations was moe than 9 times higher than that of exchange-type aberrations. Both of them showed linear dose-dependent increases, which were expressed by the regression lines, Y = -0.014 + 0.478 D and Y -0.010 + 0.057 D, respectively. The incidence of chromosome-ltype aberrations was about 6 times higher than that of chromatid-type aberrations. Their dose-dependent increases were expressed by the regression lines, Y = -0.015 + 0.462 D and Y = -0.006 + 0.079 D, respectively. These results are discussed in relation to the previous data obtained with γ-rays. The repair mechanism of X-ray-induced sperm DNA lesions is also discussed. (author). 21 refs.; 4 figs.; 4 tabs

  5. Metabolic Gene Variants Associated with Chromosomal Aberrations in Healthy Humans

    Hemminki, K.; Frank, Ch.; Försti, A.; Musak, L.; Kazimírová, A.; Barančoková, M.; Horská, A.; Vymetálková, Veronika; Smerhovský, Z.; Naccarati, Alessio; Souček, P.; Vodičková, Ludmila; Buchancová, J.; Smolková, B.; Dusinska, M.; Vodička, Pavel

    2015-01-01

    Roč. 54, č. 4 (2015), s. 260-266. ISSN 1045-2257 Institutional support: RVO:68378041 Keywords : DNA-damage * cancer * polymorphisms * risk * lymphocytes * exposure * repair * susceptibility * markers * GSTT1 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.041, year: 2014

  6. A biophysical model applied to survival of tumor cells and chromosomal aberrations in human lymphocytes

    Investigations on survival of tumor cells E.M.T.6 and chromosomal aberrations in human lymphocytes irradiated in vitro and microdosimetric studies were made using a helion beam. The results obtained were compared in order to see if the Dual Radiation Action Theory of ROSSI and KELLERER can explain these radiobiological phenomena

  7. Prediction of human cell radiosensitivity: Comparison of clonogenic assay with chromosome aberrations scored using premature chromosome condensation with fluorescence in situ hybridization

    The purpose of the present investigation was to determine whether chromosome aberrations scored by premature chromosome condensation (PCC) and fluorescence in situ hybridization (FISH) can predict the radiosensitivity of human cell lines, thereby providing a possible means of assessing the in situ radiosensitivity of normal tissues and the radiocurability of individual human cancers. We used four cells lines of different radiosensitivity: normal human fibroblasts (AG1522), ataxia-telangiectasia fibroblasts (AT2052), a human fibrosarcoma cell line (HT1080), and a human melanoma cell line (melanoma 903). These were irradiated in plateau phase with a range of doses and assessed both for clonogenic cell survival and for aberrations in a single chromosome (number 4) immediately after, and 24 h after irradiation. The initial number of breaks in chromosome 4 was proportional to irradiation dose and was identical for all the different human cell lines, irrespective of radiosensitivity. On the other hand, the number of chromosome 4 breaks remaining 24 h after irradiation reflected the radiosensitivity of the cells such that the relationship between residual chromosome aberrations and cell survival was the same for the different cell lines. These results suggest that the scoring of chromosome aberrations in interphase using FISH with PCC holds considerable promise for predicting the radiosensitivity of normal and tumor tissues in situ. 28 refs., 4 figs

  8. Cytogenetic biological dosimetry in radiological protection: chromosome aberration analysis in human lymphocyties

    The effects of ionizing radiation on chromosomes have been know for several decades and dose effect relationships are also fairly well established for several doses and dose rates. Apart from its biological significance, the interpretation of chromosome aberration frequency associated with human exposure to radiation plays an important role in dose assessment, particularly in cases where exposure is though to have occurred but no physical dose monitoring system was present. Based on the cytogenetic data obtained from seven cases of exposure to radiation the aberration frequency have been fitted to the quadratic function Y= αD + βD2 as the dose response curves from literature. The dose equivalent estimate by frequency of chromosomic aberration found here was compared with 60Co and 192Ir already published curves obtained at almost similar dose rate together with some hematological data. (author)

  9. Protective Effect of Curcumin on γ - radiation Induced Chromosome Aberrations in Human Blood Lymphocytes

    The present work is aimed at evaluating the radioprotective effect of curcumin on γ radiation induced genetic toxicity. The DNA damage was analyzed by the frequencies of chromosome aberrations assay. Human lymphocytes were treated in vitro with 5.0 γg/ml of curcumin for 30 min at 37 degree C then exposed to 1, 2 and 4 Gy gamma-radiation. The lymphocytes which were pre-treated with curcumin exhibited a significant decrease in the frequency of chromosome aberration at 1 and 2 Gy radiation-induced chromosome damage as compared with the irradiated cells which did not receive the curcumin pretreatment. Thus, pretreatment with curcumin gives protection to lymphocytes against γ-radiation induced chromosome aberration at certain doses. (author)

  10. Biological radiation dose estimation by chromosomal aberrations analysis in human peripheral blood (dose-effect curve)

    In order to draw a dose-effect curve, experimentally gamma ray induced chromosomal aberrations in human peripheral lymphocytes from eight healthy people were studied. Samples from 4 males and 4 females were irradiated in tubes with 0.15, 0.25, 0.5, 1, 1.5, 2, 2.5 gray of gamma ray (Co60 at dose rate 0.3 Gy/min). Irradiated and control samples were incubated in 37 centigrade for 48 hours cell cultures. Cell cultures then were stopped and metaphases spread, Giemsa stained to score the induced chromosomal aberrations. Chromosomal aberrations from 67888 metaphases were scored. Curves from the total number of dicentrics, dicentrics + rings and total numbers of breaks in cell for each individual or for all people were drawn. An increase of all chromosomal aberrations types with the elevation of the doses was observed. The yield of chromosome aberrations is related to the dose used. These curves give a quick useful estimation of the accidentally radiation exposure. (author)

  11. The effects of biological and life-style factors on baseline frequencies of chromosome aberrations in human lymphocytes

    Hilada Nefic

    2014-01-01

    Full Text Available Objective: This study investigated the influence of sex and ageing on chromosomal damage and the role of life-style habits on the frequency of chromosomal aberrations (CAs in peripheral blood lymphocytes (PBLs of healthy Bosnian subjects. Materials and Methods: Peripheral blood samples were obtained from 100 healthy, unrelated individuals in Bosnia and Herzegovina during 2010 and 2011. Chromosome preparations were made by dropping and air drying and slides were stained with 10% Giemsa solution (pH 6.8. The cytogenetic analysis was carried out in a cytogenetic laboratory in the Department of Biology of the Faculty of Science in Sarajevo. The category of total structural CAs was sub classified as chromosome-type aberrations (CSAs and chromatid-type aberrations (CTAs while the category of total numerical CAs was sub classified as aneuploid and polyploid mitoses. All statistical analyses were carried out using Microsoft Excel 2010 (Microsoft Corporation and the Windows Kwikstat Winks SDA 7.0.2 statistical software package (Texa Soft Cedar Hill, Texas. Results: Cytogenetic analysis revealed the average number of structural CAs was 2.84 and of numerical CAs was 9.56. There was a significant increase in the frequency of chromosome-type aberrations (1.92 compared with chromatid-type aberrations (CTAs (0.92 and a significant increase in the frequency of aneuploid (8.83 compared with polyploid (0.73 mitoses. Significant positive correlations between age and CTAs in human PBLs were also demonstrated. Additional statistical analysis showed that ageing increase number of numerical CAs in lymphocytes of drinkers. The frequency of structural CAs of females exposed to radiation was significantly greater than in males. Analysis indicates the presence of a positive association between CAs and smoking in younger subjects but a negative correlation between aberrant cells frequencies and alcohol in older drinkers. Conclusion: The results of the study support the

  12. Expression and aberrant promoter methylation of Wnt inhibitory factor-1 in human astrocytomas

    Wu Jun; Liu Jinfang; Chen Fenghua; Fang Jiasheng; Wang Ying; Yang Zhuanyi; Wang Yanjin

    2010-01-01

    Abstract Background Wnt inhibitory factor-1(WIF-1) acts as a Wnt-antagonists and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression activate Wnt signaling aberrantly and induce the development of various human tumors. With this work we intended to investigate the expression and promoter methylation status of WIF-1 gene in human astrocytomas. Methods The tissue samples consisted of 53 astrocytomas and 6 normal brain tissues. The expression levels of WIF-1 were det...

  13. Aberrant cyclooxygenase isozyme expression in human intrahepatic cholangiocarcinoma

    Chariyalertsak, S.; Sirikulchayanonta, V; Mayer, D.; Kopp-Schneider, A; Furstenberger, G; F. Marks; Muller-Decker, K

    2001-01-01

    METHODS—Cellular localisation of the cyclooxygenase (COX) isozymes COX-1 and COX-2 was analysed in 24 cholangiocarcinomas, including 17 matched tissues originating from non-tumorous liver tissue adjacent to tumours and seven biopsies of normal human liver, by immunohistochemistry using isozyme selective antibodies.
RESULTS—In normal liver, constitutive expression of COX-2 protein was a characteristic feature of hepatocytes whereas no COX-2 immunosignal was detectable in normal bile duct epith...

  14. Hypermethylation and aberrant expression of secreted fizzled-related protein genes in pancreatic cancer

    Xian-Min Bu; Cheng-Hai Zhao; Ning Zhang; Feng Gao; Shuai Lin; Xian-Wei Dai

    2008-01-01

    AIM:To determine the methylation status and aberrant expression of some secreted frizzled-related protein (SFRP) genes in pancreatic cancer and explore their role in pancreatic carcinogenesis. METHODS:Methylation status and expression of SFRP genes were detected by methylation-specific PCR (MSPCR) and reverse-transcription PCR (RT-PCR) respectively. RESULTS:The frequencies of methylation for SFRP genes 1,2,4,5 were 70%, 48.3%,60% and 76.7% in pancreatic cancer samples, and 21.7%, 20%,10% and 36.7% in matched cancer adjacent normal tissue samples,respectively (χ2=28.23,P<0.0001 for SFRP gene 1; χ2=10.71,P=0.001 for SFRP gene 2;χ2=32.97,P<0.0001 for SFRP gene 4;χ2=19.55,P<0.0001 for SFRP gene 5). Expression loss of SFRP genes 1,2,4 and 5 was found in 65%,40%,55% and 71.7% of 60 pancreatic cancer samples, and 25%,15%,18.3% and 31.7% of matched cancer adjacent normal tissue samples,respectively (χ2=19.39,P<0.0001 for SFRP gene 1;χ2=9.40,P=0.002 for SFRP gene 2;χ2=17.37,P<0.0001 for SFRP gene 4;χ2=19.22,P<0.0001 for SFRP gene 5).SFRP gene 1 was methylated but not expressed in PC-3 and PANC-1,SFRP gene 2 was methylated but not expressed in PANC-1 and CFPAC-1,SFRP gene 4 was methylated but not expressed in PC-3,and SFRP gene 5 was methylated but not expressed in CFPAC-1. CONCLUSION:Hypermethylation and aberrant expression of SFRP genes are common in pancreatic cancer,which may be involved in pancreatic carcinogenesis.

  15. Chromosome Aberrations Induced in Human Peripheral Blood by 2-MeV X-Irradiation to the Whole Body and In Vitro

    In recent years it has proved possible to correlate the incidence of ring and dicentric chromosomes in cultured human peripheral blood lymphocytes with given radiation doses both in vitro and following partial or whole body irradiation exposure in vivo In the present study a comparison is made between the yield of aberrations in six men with advanced cancer who received whole body irradiation in doses varying between 36 and 50 rads and the yield of aberrations in samples of their blood drawn before exposure and irradiated in vitro simultaneously to the same dose A comparison is also made between the yield of aberrations following in vitro irradiation to much higher doses of blood derived from these same cancer patients and blood from non cancer controls The significance of these findings is discussed with reference to biological dosimetry using chromosome aberrations as the parameter for both external and internal irradiation Apart from such a practical application it also appears possible to develop this technique to study the sensitivity of cells to chromosome breakage by radiation in selected populations such as mongols or persons with Fancom s anaemia where there is a higher than normal incidence of malignant disease. (author)

  16. Aberrant DNA methylation of cancer-related genes in giant breast fibroadenoma: a case report

    Orozco Javier I

    2011-10-01

    Full Text Available Abstract Introduction Giant fibroadenoma is an uncommon variant of benign breast lesions. Aberrant methylation of CpG islands in promoter regions is known to be involved in the silencing of genes (for example, tumor-suppressor genes and appears to be an early event in the etiology of breast carcinogenesis. Only hypermethylation of p16INK4a has been reported in non-giant breast fibroadenoma. In this particular case, there are no previously published data on epigenetic alterations in giant fibroadenomas. Our previous results, based on the analysis of 49 cancer-related CpG islands have confirmed that the aberrant methylation is specific to malignant breast tumors and that it is completely absent in normal breast tissue and breast fibroadenomas. Case presentation A 13-year-old Hispanic girl was referred after she had noted a progressive development of a mass in her left breast. On physical examination, a 10 × 10 cm lump was detected and axillary lymph nodes were not enlarged. After surgical removal the lump was diagnosed as a giant fibroadenoma. Because of the high growth rate of this benign tumor, we decided to analyze the methylation status of 49 CpG islands related to cell growth control. We have identified the methylation of five cancer-related CpG islands in the giant fibroadenoma tissue: ESR1, MGMT, WT-1, BRCA2 and CD44. Conclusion In this case report we show for the first time the methylation analysis of a giant fibroadenoma. The detection of methylation of these five cancer-related regions indicates substantial epigenomic differences with non-giant fibroadenomas. Epigenetic alterations could explain the higher growth rate of this tumor. Our data contribute to the growing knowledge of aberrant methylation in breast diseases. In this particular case, there exist no previous data regarding the role of methylation in giant fibroadenomas, considered by definition as a benign breast lesion.

  17. Biomarker for Space Radiation Risk: Painting Analysis of Chromosome Aberrations Induced by Energetic Heavy Ions in Human Cells

    Hada, Megumi; George, Kerry; Cucinotta, Francis A.; Wu, Honglu

    2007-01-01

    Energetic heavy ions pose a great health risk to astronauts in extended ISS and future Lunar and Mars missions. High-LET heavy ions are particularly effective in causing various biological effects, including cell inactivation, genetic mutations, cataracts and cancer induction. Most of these biological endpoints are closely related to chromosomal damage, which can be utilized as a biomarker for radiation insults. Over the years, we have studied chromosomal damage in human fibroblast, epithelia and lymphocyte cells exposed in vitro to energetic charged particles generated at several accelerator facilities in the world. We have also studied chromosome aberrations in astronaut s peripheral blood lymphocytes before and after space flight. Various fluorescence in situ hybridization painting techniques have been used to identify from only the telomere region of the chromosome to every chromosome in a human cell. We will summarize the results of the investigations, and discuss the unique radiation signatures and biomarkers for space radiation exposure.

  18. High-throughput detection of aberrant imprint methylation in the ovarian cancer by the bisulphite PCR-Luminex method

    Hiura Hitoshi

    2012-03-01

    Full Text Available Abstract Background Aberrant DNA methylation leads to loss of heterozygosity (LOH or loss of imprinting (LOI as the first hit during human carcinogenesis. Recently we developed a new high-throughput, high-resolution DNA methylation analysis method, bisulphite PCR-Luminex (BPL, using sperm DNA and demonstrated the effectiveness of this novel approach in rapidly identifying methylation errors. Results In the current study, we applied the BPL method to the analysis of DNA methylation for identification of prognostic panels of DNA methylation cancer biomarkers of imprinted genes. We found that the BPL method precisely quantified the methylation status of specific DNA regions in somatic cells. We found a higher frequency of LOI than LOH. LOI at IGF2, PEG1 and H19 were frequent alterations, with a tendency to show a more hypermethylated state. We detected changes in DNA methylation as an early event in ovarian cancer. The degree of LOI (LOH was associated with altered DNA methylation at IGF2/H19 and PEG1. Conclusions The relative ease of BPL method provides a practical method for use within a clinical setting. We suggest that DNA methylation of H19 and PEG1 differentially methylated regions (DMRs may provide novel biomarkers useful for screening, diagnosis and, potentially, for improving the clinical management of women with human ovarian cancer.

  19. Persistence of unstable and stable chromosome aberrations in lymphocytes of cancer patients treated with radiotherapy

    Background: Radiation-induced DNA damage in human lymphocytes has equal probability of producing both stable or unstable chromosome aberrations (C.A.). Reports of its in vivo persistence show considerable variations. The quantification of unstable C.A. (dicentrics) in peripheral blood lymphocytes (P.B.L.) is the most reliable biological method for estimating whole-body doses of recent overexposures to ionizing radiation. Given that during the division of T cell precursors, proliferative death of cells containing dicentrics reduces the number of such lymphocytes in peripheral blood, dicentric methodology should be modified to account for past exposures. Micronuclei (M.N.) in cytokinesis-blocked human P.B.L. are well established bio markers for assessing radiation damage in vivo. However, persistence of radiation induced M.N. is limited. Unlike dicentrics and M.N., stable C.A. (translocations) identified at present by the FISH technique, seem to be an adequate indicator for the dosimetric evaluation of past exposures, since translocations are not selected against during mitotic division in the haematopoietic stem cells compartment. Nevertheless, for partial -body exposures with high dose there is some evidence that the decline with time of dicentrics causes some reduction in the yield of translocations. Purpose: To assess the persistence along time of dicentrics, M.N. and translocations in lymphocytes of cancer patients after radiotherapy in order to model changes in C.A. frequencies with partial-body exposures. Materials and methods: 22 cancer patients with different tumor sites, treated with radiotherapy, were evaluated through dicentric chromosome, M.N. and FISH techniques with a follow-up time of up to 90 months after the end of radiotherapy. Regression analysis were performed: 1) for dicentric and for M.N. frequencies in relation to time after the end of radiotherapy and total tumor dose; 2) for the percentage of uns table cells in relation to time after the end

  20. Aberrant phenotypes of transgenic mice expressing dimeric human erythropoietin

    Yun Seong-Jo

    2012-01-01

    Full Text Available Abstract Background Dimeric human erythropoietin (dHuEPO peptides are reported to exhibit significantly higher biological activity than the monomeric form of recombinant EPO. The objective of this study was to produce transgenic (tg mice expressing dHuEPO and to investigate the characteristics of these mice. Methods A dHuEPO-expressing vector under the control of the goat beta-casein promoter, which produced a dimer of human EPO molecules linked by a 2-amino acid peptide linker (Asp-Ile, was constructed and injected into 1-cell fertilized embryos by microinjection. Mice were screened using genomic DNA samples obtained from tail biopsies. Blood samples were obtained by heart puncture using heparinized tubes, and hematologic parameters were assessed. Using the microarray analysis tool, we analyzed differences in gene expression in the spleens of tg and control mice. Results A high rate of spontaneous abortion or death of the offspring was observed in the recipients of dHuEPO embryos. We obtained 3 founder lines (#4, #11, and #47 of tg mice expressing the dHuEPO gene. However, only one founder line showed stable germline integration and transmission, subsequently establishing the only transgenic line (#11. We obtained 2 F1 mice and 3 F2 mice from line #11. The dHuEPO protein could not be obtained because of repeated spontaneous abortions in the tg mice. Tg mice exhibited symptoms such as short lifespan and abnormal blood composition. The red blood cell count, white blood cell count, and hematocrit levels in the tg mice were remarkably higher than those in the control mice. The spleens of the tg mice (F1 and F2 females were 11- and -21-fold larger than those of the control mice. Microarray analysis revealed 2,672 spleen-derived candidate genes; more genes were downregulated than upregulated (849/764. Reverse transcriptase-polymerase chain reaction (RT-PCR and quantitative real-time PCR (qRT-PCR were used for validating the results of the microarray

  1. Dose-dependence of the chromosome aberration yield in a human lymphocyte culture after. gamma. -irradiation with high doses

    Sevan' kaev, A.V. (Akademiya Meditsinskikh Nauk SSSR, Obninsk. Nauchno-Issledovatel' skij Inst. Meditsinskoj Radiologii)

    A study was made of the yield of chromosome aberrations in a human lymphocyte culture at the G/sub 0/ stage after /sup 60/Co-..gamma..-irradiation with doses of 5-12 Gy. It was shown that a linear-quadratic dependence of the aberration frequency observed with median doses became purely linear at high doses.

  2. Cosmic radiation induced chromosomal aberrations in human lymphocytes

    Since decades, elevated frequencies of dicentric chromosomes (DIC) in human lymphocytes have successfully been used as a biological dosimeter in cases of acute, often accidental exposures to ionizing radiation. As long as duration and time lags after exposure are small compared to the lifetime of DIC, their frequencies can also be used to assess doses from protracted, chronic irradiation. E.g., within the substantial range of uncertainties, the frequencies of DIC observed in cosmonauts are compatible with the frequencies expected from doses of low and high LET radiation to which they were exposed in low earth orbit (LEO). On the other hand, frequencies of DIC detected in lymphocytes of civilian aviation crewmembers rarely correlate with the doses accumulated all along their professional career. For such long duration exposures with relatively low induction rates, the concomitant decay of DIC frequencies due to the removal during exposure of lymphocytes carrying DIC has to be taken into account. We present temporal profiles of frequencies of DIC during the exposure calculated with a model of exponential decay of DIC for some scenarios of chronic exposure to cosmic radiation. E.g., even after a 'heavily' shielded Mars mission, the expected frequencies of DIC in lymphocytes of astronauts will be 10 to 40 times higher than the terrestrial control levels. For air flight personnel we calculated the time profiles of frequencies of DIC in lymphocytes of a 'typical' pilot, a male cabin attendant and a female cabin attendant whose professional radiation exposures were recalculated for the actual flight routes flown during their entire flight career as recorded in detailed duty logs. These results demonstrate that experimental (epidemiological) studies concerning DIC in air or space flight personnel must explicitly take into consideration the temporal exposure profiles in the prospective study population and that the point in time at which blood samples are to be drawn must

  3. The effect of x-ray induced mitotic delay on chromosome aberration yields in human lymphocytes

    The extent to which X-ray induced mitotic delay at 150 and 400 rad influences chromosome aberration yields was examined in human peripheral blood lymphocytes. The dicentric was used as a marker and aberration yields were obtained for mixed cultures prepared from equal numbers of normal and irradiated cells. The cultures were terminated following incubation times of 36-120 h. Greater mitotic delay of the order of a few hours was observed at the higher dose. However most reduction in the numbers of lymphocytes arriving at metaphase by 48 h may be ascribed to interphase death of failure to transform. Analysis of the dicentric distributions which were expected to follow Poisson statistics indicated that cells containing dicentrics were delayed relative to irradiated but aberration-free cells. Cells with one dicentric moved more easily through the first cell cycle than cells containing two dicentrics. Following accidental partial body irradiation, selection in culture favouring the unirradiated lymphocytes does not distort the aberration yield sufficiently to warrant incubation times in excess of the standard 48-52 h

  4. Painting Analysis of Chromosome Aberrations Induced by Energetic Heavy Ions in Human Cells

    Wu, Honglu; Hada, Megumi; Cucinotta, Francis

    2007-01-01

    This viewgraph presentation reviews some of the techniques used to analyze the damage done to chromosome from ion radiation. Fluorescence in situ hybridization (FISH), mFISH, mBAND, telomere and centromereprobes have been used to study chromosome aberrations induced in human cells exposed to low-and high-LET radiation in vitro. There is some comparison of the different results from the various techniques. The results of the study are summarized.

  5. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

    Guenther, Matthew G.; Lawton, Lee N.; Rozovskaia, Tatiana; Frampton, Garrett M.; Levine, Stuart S.; Thomas L Volkert; Croce, Carlo M.; Nakamura, Tatsuya; Canaani, Eli; Young, Richard A.

    2008-01-01

    Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending acr...

  6. Space Radiation Effects on Human Cells: Modeling DNA Breakage, DNA Damage Foci Distribution, Chromosomal Aberrations and Tissue Effects

    Ponomarev, A. L.; Huff, J. L.; Cucinotta, F. A.

    2011-01-01

    Future long-tem space travel will face challenges from radiation concerns as the space environment poses health risk to humans in space from radiations with high biological efficiency and adverse post-flight long-term effects. Solar particles events may dramatically affect the crew performance, while Galactic Cosmic Rays will induce a chronic exposure to high-linear-energy-transfer (LET) particles. These types of radiation, not present on the ground level, can increase the probability of a fatal cancer later in astronaut life. No feasible shielding is possible from radiation in space, especially for the heavy ion component, as suggested solutions will require a dramatic increase in the mass of the mission. Our research group focuses on fundamental research and strategic analysis leading to better shielding design and to better understanding of the biological mechanisms of radiation damage. We present our recent effort to model DNA damage and tissue damage using computational models based on the physics of heavy ion radiation, DNA structure and DNA damage and repair in human cells. Our particular area of expertise include the clustered DNA damage from high-LET radiation, the visualization of DSBs (DNA double strand breaks) via DNA damage foci, image analysis and the statistics of the foci for different experimental situations, chromosomal aberration formation through DSB misrepair, the kinetics of DSB repair leading to a model-derived spectrum of chromosomal aberrations, and, finally, the simulation of human tissue and the pattern of apoptotic cell damage. This compendium of theoretical and experimental data sheds light on the complex nature of radiation interacting with human DNA, cells and tissues, which can lead to mutagenesis and carcinogenesis later in human life after the space mission.

  7. Preventing E-cadherin aberrant N-glycosylation at Asn-554 improves its critical function in gastric cancer.

    Carvalho, S; Catarino, T A; Dias, A M; Kato, M; Almeida, A; Hessling, B; Figueiredo, J; Gärtner, F; Sanches, J M; Ruppert, T; Miyoshi, E; Pierce, M; Carneiro, F; Kolarich, D; Seruca, R; Yamaguchi, Y; Taniguchi, N; Reis, C A; Pinho, S S

    2016-03-31

    E-cadherin is a central molecule in the process of gastric carcinogenesis and its posttranslational modifications by N-glycosylation have been described to induce a deleterious effect on cell adhesion associated with tumor cell invasion. However, the role that site-specific glycosylation of E-cadherin has in its defective function in gastric cancer cells needs to be determined. Using transgenic mice models and human clinical samples, we demonstrated that N-acetylglucosaminyltransferase V (GnT-V)-mediated glycosylation causes an abnormal pattern of E-cadherin expression in the gastric mucosa. In vitro models further indicated that, among the four potential N-glycosylation sites of E-cadherin, Asn-554 is the key site that is selectively modified with β1,6 GlcNAc-branched N-glycans catalyzed by GnT-V. This aberrant glycan modification on this specific asparagine site of E-cadherin was demonstrated to affect its critical functions in gastric cancer cells by affecting E-cadherin cellular localization, cis-dimer formation, molecular assembly and stability of the adherens junctions and cell-cell aggregation, which was further observed in human gastric carcinomas. Interestingly, manipulating this site-specific glycosylation, by preventing Asn-554 from receiving the deleterious branched structures, either by a mutation or by silencing GnT-V, resulted in a protective effect on E-cadherin, precluding its functional dysregulation and contributing to tumor suppression. PMID:26189796

  8. Mouse Lymphoblastic Leukemias Induced by Aberrant Prdm14 Expression Demonstrate Widespread Copy Number Alterations Also Found in Human ALL

    Aberrant expression and activation of oncogenes in somatic cells has been associated with cancer initiation. Required for reacquisition of pluripotency in the developing germ cell, PRDM14 initiates lymphoblastic leukemia when misexpressed in murine bone marrow. Activation of pluripotency in somatic cells can lead to aneuploidy and copy number alterations during iPS cell generation, and we hypothesized that PRDM14-induced lymphoblastic leukemias would demonstrate significant chromosomal damage. High-resolution oligo array comparative genomic hybridization demonstrated infrequent aneuploidy but frequent amplification and deletion, with amplifications occurring in a 5:1 ratio with deletions. Many deletions (i.e., Cdkn2a, Ebf1, Pax5, Ikzf1) involved B-cell development genes and tumor suppressor genes, recapitulating deletions occurring in human leukemia. Pathways opposing senescence were frequently deactivated via Cdkn2a deletion or Tbx2 amplification, with corollary gene expression. Additionally, gene expression studies of abnormal pre-leukemic B-precursors showed downregulation of genes involved in chromosomal stability (i.e., Xrcc6) and failure to upregulate DNA repair pathways. We propose a model of leukemogenesis, triggered by pluripotency genes like Prdm14, which involves ongoing DNA damage and failure to activate non-homologous end-joining secondary to aberrant gene expression

  9. A method to design aspheric spectacles for correction of high-order aberrations of human eye

    LI Rui; WANG ZhaoQi; LIU YongJi; MU GuoGuang

    2012-01-01

    Aiming at the correction of high-order aberrations of human eye with spectacles,a design method of aspheric spectacles is proposed based on the eye's wavefront aberrations data.Regarding the eyeball and the spectacles as a whole system-the lens-eye system-the surface profiles of the spectacles are achieved by optimization procedure of lens design.Different from the conventional optometry,in which the refraction prescription is acquired with a visual chart,the design takes into account the two aspects of actual human viewing,eyeball rolling and certain distinct viewing field.The rotation angle of eyeball is set to be ±20° as wearing spectacles,and the field of view is set to be ∧7° which is especially important as watching screen display.The individual eye model is constructed as the main part of the lens-eye system.The Liou eye model is modified by sticking a thin meniscus lens to the crystalline lens.Then the defocus of the individual eye is transferred to the front surface of the meniscus lens,and the astigmatism and high-order aberrations are transferred to the front surface of the cornea.50 eyes are involved in this research,among which 36 eyes have good enough visual performance already after sphero-cylindrical correction.10 eyes have distinct improvement in vision and 4 eyes have no visual improvement by further aspheric correction.6 typical subject eyes are selected for the aberrations analysis and the spectacles design in this paper.It is shown that the validity of visual correction of aspheric lens depends on the characteristics of the eye's wavefront aberrations,and it is effective for the eye with larger astigmatism or spherical aberration.Compared with sphero-cylindrical correction only,the superiority taken by the aspheric correction is mainly on the improvement of MTF at a larger field of view.For the best aspheric correction,the MTF values increase by 18.87%,38.34%,44.36%,51.29% and 57.32% at the spatial frequencies of 40

  10. Studies on chromosome aberrations induced in human lymphocytes by very low-dose exposure to tritium

    Assessment of potential hazard from environmental tritium to man becomes very important with increasing the development of nuclear-power industry. However, little data are available as to the determination on the genetic effect of tritium especially at the low levels. The object of the present study is to obtain quantitative data for chromosome aberrations in human lymphocytes, as an indicator for genetic risk estimation, induced by tritium at very low dose levels. Leukocyte cultures of human peripheral blood were chronically exposed for 48h to tritiated water and 3H-thymidine using a wide range of tritium doses, and aberrations in lymphocyte chromosomes at the first metaphases were examined. In the experimental conditions, the types of aberrations induced by radiation emitted from both tritiated water and 3H-thymidine were mostly chromatid types, such as chromatid gaps and deletions. The dose-response relations for chromatid breaks per cell exhibited unusual dose-dependency in both cases. It was demonstrated that at higher dose range the yields of chromatid breaks increased linearly with dose, while those at lower dose range were significantly higher than would be expected by a downward extraporation from the linear relation. Partial-hit or partial-target kinetics events appeared at very low dose exposure. (author)

  11. Chromosome aberrations induced in human lymphocytes by U-235 fission neutrons. Pt. 1

    A set-up for irradiation of biological samples in the TRIGA Mark II research reactor in Ljubljana is described. Threshold activation detectors were used for characterisation of the neutron flux, and the accompanying gamma dose was measured by TLDs. Human peripheral blood samples were irradiated 'in vitro' and biological effects evaluated according to the unstable chromosomal aberrations induced. Biological effects of two types of cultivation of irradiated blood samples, the first immediately after irradiation and the second after 96 h storage, were studied. A significant difference in the incidence of chromosomal aberrations between these two types of samples was obtained, while our dose-response curve fitting coefficients are in both cases lower than could be found in the literature. (orig./MG)

  12. Germline DNA copy number aberrations identified as potential prognostic factors for breast cancer recurrence.

    Yadav Sapkota

    Full Text Available Breast cancer recurrence (BCR is a common treatment outcome despite curative-intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up after breast cancer diagnosis of 6.35 years (range = 0.60-21.78 and 8.60 years (range = 3.08-13.57, respectively. Whole genome CNA genotyping was performed on the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with ≥1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log-rank tests identified seven CNAs (two copy number gains and five copy neutral-loss of heterozygosities, CN-LOHs showing significant differences (P<2.01×10(-5 in recurrence-free survival (RFS probabilities with and without CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2.86×10(-5 when analyses were restricted to stratified cases (luminal A, n = 208 only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models, all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA

  13. Induction of aberrations in human lymphocytes by γ-rays and fast heavy ions

    Frequencies of aberrations induced by different doses of γ-rays and 14N ions (LET ∼ 77 keV/μm) in the chromosomes 1 and 2 of human lymphocytes as detected by FISH were compared with those detected by conventional staining in the whole genome. The results have shown that the induction of aberrations in the chromosomes 1 and 2 is more frequent than that in the rest of genome. The frequencies of dicentrics detected by FISH in the chromosomes 1 and 2 recalculated for the whole genome are in good agreement with those detected by conventional staining at different doses of 14N, but they are about 2 times lower at low doses of γ-rays. Translocation frequencies calculated in the same manner from the frequencies induced in the chromosome 1 by γ-rays correspond to the frequencies of dicentrics detected by conventional staining, however, they are about 2 times higher than those detected by convectional staining at doses lower than 2 Gy of 14N. The differences between the frequencies of these aberration types increase at higher doses of both radiation types

  14. Drinking beer reduces radiation-induced chromosome aberrations in human lymphocytes

    We here investigated and reported the effects of beer drinking on radiation-induced chromosome aberrations in blood lymphocytes. Human blood that was collected either before or after drinking a 700 ml beer was in vitro irradiated with 200 kVp X rays or 50 keV/μm carbon ions. The relation between the radiation dose and the aberration frequencies (fragments and dicentrics) was significantly (P<0.05) lower for lymphocytes collected 3 h after beer drinking than those before drinking. Fitting the dose response to a linear quadratic model showed that the alpha term of carbon ions was significantly (P<0.05) decreased by beer drinking. A decrease of dicentric formation was detected as early as 0.5 h after beer drinking, and lasted not shorter than 4.5 h. The mitotic index of lymphocytes was higher after beer drinking than before, indicating that a division delay would not be responsible for the low aberrations induced by beer drinking. An in vitro treatment of normal lymphocytes with 0.1 M ethanol, which corresponded to a concentration of 6-times higher than the maximum ethanol concentration in the blood after beer drinking, reduced the dicentric formation caused by X-ray irradiation, but not by carbon-ion irradiation. The beer-induced reduction of dicentric formation was not affected by serum. It is concluded that beer could contain non-ethanol elements that reduce the chromosome damage of lymphocytes induced by high-LET radiation. (author)

  15. Aberrant nocturnal cortisol and disease progression in women with breast cancer.

    Zeitzer, Jamie M; Nouriani, Bita; Rissling, Michelle B; Sledge, George W; Kaplan, Katherine A; Aasly, Linn; Palesh, Oxana; Jo, Booil; Neri, Eric; Dhabhar, Firdaus S; Spiegel, David

    2016-07-01

    While a relationship between disruption of circadian rhythms and the progression of cancer has been hypothesized in field and epidemiologic studies, it has never been unequivocally demonstrated. We determined the circadian rhythm of cortisol and sleep in women with advanced breast cancer (ABC) under the conditions necessary to allow for the precise measurement of these variables. Women with ABC (n = 97) and age-matched controls (n = 24) took part in a 24-h intensive physiological monitoring study involving polysomnographic sleep measures and high-density plasma sampling. Sleep was scored using both standard clinical metrics and power spectral analysis. Three-harmonic regression analysis and functional data analysis were used to assess the 24-h and sleep-associated patterns of plasma cortisol, respectively. The circadian pattern of plasma cortisol as described by its timing, timing relative to sleep, or amplitude was indistinguishable between women with ABC and age-matched controls (p's > 0.11, t-tests). There was, however, an aberrant spike of cortisol during the sleep of a subset of women, during which there was an eightfold increase in the amount of objectively measured wake time (p sleep disruption. A greater understanding of this sleep-related cortisol abnormality, possibly a vulnerability trait, is likely important in our understanding of individual variation in the progression of cancer. PMID:27314577

  16. Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter is associated with the inflammatory breast cancer phenotype

    Van der Auwera, I; Laere, S.J.; Van den Bosch, S M; Van den Eynden, G. G.; Trinh, B X; van Dam, P A; Colpaert, C G; van Engeland, M; Van Marck, E A; Vermeulen, P B; Dirix, L Y

    2008-01-01

    Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter occurs in about 40% of breast tumours and has been correlated with reduced APC protein levels. To what extent epigenetic alterations of the APC gene may differ according to specific breast cancer phenotypes, remains to be elucidated. Our aim was to explore the role of APC methylation in the inflammatory breast cancer (IBC) phenotype. The status of APC gene promoter hypermethylation was investigated in DNA from normal b...

  17. In silico analysis and DHPLC screening strategy identifies novel apoptotic gene targets of aberrant promoter hypermethylation in prostate cancer.

    Murphy, Therese M

    2011-01-01

    Aberrant DNA methylation has been implicated as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many cellular processes including apoptosis. Limited data is available on the methylation profile of apoptotic genes in prostate cancer (CaP). The aim of this study was to profile methylation of apoptotic-related genes in CaP using denaturing high performance liquid chromatography (DHPLC).

  18. Human papillomaviruses and cancer

    Human papillomaviruses (HPV) are small oncogenic DNA viruses of which more than 200 types have been identified to date. A small subset of these is etiologically linked to the development of anogenital malignancies such as cervical cancer. In addition, recent studies established a causative relationship between these high-risk HPV types and tonsillar and oropharyngeal cancer. Clinical management of cervical cancer and head and neck squamous cell carcinomas (HNSCCs) is largely standardized and involves surgical removal of the tumor tissue as well as adjuvant chemoradiation therapy. Notably, the response to therapeutic intervention of HPV-positive HNSCCs has been found to be better as compared to HPV-negative tumors. Although the existing HPV vaccine is solely licensed for the prevention of cervical cancer, it might also have prophylactic potential for the development of high-risk HPV-associated HNSCCs. Another group of viruses, which belongs to the beta-HPV subgroup, has been implicated in nonmelanoma skin cancer, however, the etiology remains to be established. Treatment of HPV-induced nonmelanoma skin cancer is based on local excision. However, topically applied immune-modulating substances represent non-surgical alternatives for the management of smaller cutaneous tumors. In this review we present the current knowledge of the role of HPV in cancer development and discuss clinical management options as well as targets for the development of future intervention therapies

  19. The aberrant asynchronous replication — characterizing lymphocytes of cancer patients — is erased following stem cell transplantation

    Aberrations of allelic replication timing are epigenetic markers observed in peripheral blood cells of cancer patients. The aberrant markers are non-cancer-type-specific and are accompanied by increased levels of sporadic aneuploidy. The study aimed at following the epigenetic markers and aneuploidy levels in cells of patients with haematological malignancies from diagnosis to full remission, as achieved by allogeneic stem cell transplantation (alloSCT). TP53 (a tumor suppressor gene assigned to chromosome 17), AML1 (a gene assigned to chromosome 21 and involved in the leukaemia-abundant 8;21 translocation) and the pericentomeric satellite sequence of chromosome 17 (CEN17) were used for replication timing assessments. Aneuploidy was monitored by enumerating the copy numbers of chromosomes 17 and 21. Replication timing and aneuploidy were detected cytogenetically using fluorescence in situ hybridization (FISH) technology applied to phytohemagglutinin (PHA)-stimulated lymphocytes. We show that aberrant epigenetic markers are detected in patients with hematological malignancies from the time of diagnosis through to when they are scheduled to undergo alloSCT. These aberrations are unaffected by the clinical status of the disease and are displayed both during accelerated stages as well as in remission. Yet, these markers are eradicated completely following stem cell transplantation. In contrast, the increased levels of aneuploidy (irreversible genetic alterations) displayed in blood lymphocytes at various stages of disease are not eliminated following transplantation. However, they do not elevate and remain unchanged (stable state). A demethylating anti-cancer drug, 5-azacytidine, applied in vitro to lymphocytes of patients prior to transplantation mimics the effect of transplantation: the epigenetic aberrations disappear while aneuploidy stays unchanged. The reversible nature of the replication aberrations may serve as potential epigenetic blood markers for evaluating

  20. The aberrant asynchronous replication — characterizing lymphocytes of cancer patients — is erased following stem cell transplantation

    Korenstein-Ilan Avital

    2010-05-01

    Full Text Available Abstract Background Aberrations of allelic replication timing are epigenetic markers observed in peripheral blood cells of cancer patients. The aberrant markers are non-cancer-type-specific and are accompanied by increased levels of sporadic aneuploidy. The study aimed at following the epigenetic markers and aneuploidy levels in cells of patients with haematological malignancies from diagnosis to full remission, as achieved by allogeneic stem cell transplantation (alloSCT. Methods TP53 (a tumor suppressor gene assigned to chromosome 17, AML1 (a gene assigned to chromosome 21 and involved in the leukaemia-abundant 8;21 translocation and the pericentomeric satellite sequence of chromosome 17 (CEN17 were used for replication timing assessments. Aneuploidy was monitored by enumerating the copy numbers of chromosomes 17 and 21. Replication timing and aneuploidy were detected cytogenetically using fluorescence in situ hybridization (FISH technology applied to phytohemagglutinin (PHA-stimulated lymphocytes. Results We show that aberrant epigenetic markers are detected in patients with hematological malignancies from the time of diagnosis through to when they are scheduled to undergo alloSCT. These aberrations are unaffected by the clinical status of the disease and are displayed both during accelerated stages as well as in remission. Yet, these markers are eradicated completely following stem cell transplantation. In contrast, the increased levels of aneuploidy (irreversible genetic alterations displayed in blood lymphocytes at various stages of disease are not eliminated following transplantation. However, they do not elevate and remain unchanged (stable state. A demethylating anti-cancer drug, 5-azacytidine, applied in vitro to lymphocytes of patients prior to transplantation mimics the effect of transplantation: the epigenetic aberrations disappear while aneuploidy stays unchanged. Conclusions The reversible nature of the replication aberrations may

  1. mBAND Analysis of Late Chromosome Aberrations in Human Lymphocytes Induced by Gamma Rays and Fe Ions

    Sunagawa, Mayumi; Zhang, Ye; Yeshitla, Samrawit; Kadhim, Munira; Wilson, Bobby; Wu, Honglu

    2014-01-01

    Chromosomal translocations and inversions are considered stable, and cells containing these types of chromosome aberrations can survive multiple cell divisions. An efficient method to detect an inversion is multi-color banding fluorescent in situ hybridization (mBAND) which allows identification of both inter- and intrachromosome aberrations simultaneously. Post irradiation, chromosome aberrations may also arise after multiple cell divisions as a result of genomic instability. To investigate the stable or late-arising chromosome aberrations induced after radiation exposure, we exposed human lymphocytes to gamma rays and Fe ions ex vivo, and cultured the cells for multiple generations. Chromosome aberrations were analyzed in cells collected at first mitosis and at several time intervals during the culture period post irradiation. With gamma irradiation, about half of the damages observed at first mitosis remained after 7 day- and 14 day- culture, suggesting the transmissibility of damages to the surviving progeny. Detailed analysis of chromosome break ends participating in exchanges revealed a greater fraction of break ends involved in intrachromosome aberrations in the 7- and 14-day samples in comparison to the fraction at first mitosis. In particular, simple inversions were found at 7 and 14 days, but not at the first mitosis, suggesting that some of the aberrations might be formed days post irradiation. In contrast, at the doses that produced similar frequencies of gamma-induced chromosome aberrations as observed at first mitosis, a significantly lower yield of aberrations remained at the same population doublings after Fe ion exposure. At these equitoxic doses, more complex type aberrations were observed for Fe ions, indicating that Fe ion-induced initial chromosome damages are more severe and may lead to cell death. Comparison between low and high doses of Fe ion irradiation in the induction of late damages will also be discussed.

  2. Selective Cancer Targeting via Aberrant Behavior of Cancer Cell-associated Glucocorticoid Receptor

    Mukherjee, Amarnath; Narayan, Kumar P; Pal, Krishnendu; Kumar, Jerald M.; Rangaraj, Nandini; Shasi V Kalivendi; Banerjee, Rajkumar

    2009-01-01

    Glucocorticoid receptors (GRs) are ubiquitous, nuclear hormone receptors residing in cell types of both cancer and noncancerous origin. It is not known whether cancer cell–associated GR alone can be selectively manipulated for delivery of exogenous genes to its nucleus for eliciting anticancer effect. We find that GR ligand, dexamethasone (Dex) in association with cationic lipoplex (termed as targeted lipoplex) could selectively manipulate GR in cancer cells alone for the delivery of transgen...

  3. Human cancer databases (review).

    Pavlopoulou, Athanasia; Spandidos, Demetrios A; Michalopoulos, Ioannis

    2015-01-01

    Cancer is one of the four major non‑communicable diseases (NCD), responsible for ~14.6% of all human deaths. Currently, there are >100 different known types of cancer and >500 genes involved in cancer. Ongoing research efforts have been focused on cancer etiology and therapy. As a result, there is an exponential growth of cancer‑associated data from diverse resources, such as scientific publications, genome‑wide association studies, gene expression experiments, gene‑gene or protein‑protein interaction data, enzymatic assays, epigenomics, immunomics and cytogenetics, stored in relevant repositories. These data are complex and heterogeneous, ranging from unprocessed, unstructured data in the form of raw sequences and polymorphisms to well‑annotated, structured data. Consequently, the storage, mining, retrieval and analysis of these data in an efficient and meaningful manner pose a major challenge to biomedical investigators. In the current review, we present the central, publicly accessible databases that contain data pertinent to cancer, the resources available for delivering and analyzing information from these databases, as well as databases dedicated to specific types of cancer. Examples for this wealth of cancer‑related information and bioinformatic tools have also been provided. PMID:25369839

  4. Functional annotation of rare gene aberration drivers of pancreatic cancer | Office of Cancer Genomics

    As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC).

  5. Clinical Omics Analysis of Colorectal Cancer Incorporating Copy Number Aberrations and Gene Expression Data

    Tsuyoshi Yoshida

    2010-07-01

    Full Text Available Background: Colorectal cancer (CRC is one of the most frequently occurring cancers in Japan, and thus a wide range of methods have been deployed to study the molecular mechanisms of CRC. In this study, we performed a comprehensive analysis of CRC, incorporating copy number aberration (CRC and gene expression data. For the last four years, we have been collecting data from CRC cases and organizing the information as an “omics” study by integrating many kinds of analysis into a single comprehensive investigation. In our previous studies, we had experienced difficulty in finding genes related to CRC, as we observed higher noise levels in the expression data than in the data for other cancers. Because chromosomal aberrations are often observed in CRC, here, we have performed a combination of CNA analysis and expression analysis in order to identify some new genes responsible for CRC. This study was performed as part of the Clinical Omics Database Project at Tokyo Medical and Dental University. The purpose of this study was to investigate the mechanism of genetic instability in CRC by this combination of expression analysis and CNA, and to establish a new method for the diagnosis and treatment of CRC. Materials and methods: Comprehensive gene expression analysis was performed on 79 CRC cases using an Affymetrix Gene Chip, and comprehensive CNA analysis was performed using an Affymetrix DNA Sty array. To avoid the contamination of cancer tissue with normal cells, laser micro-dissection was performed before DNA/RNA extraction. Data analysis was performed using original software written in the R language. Result: We observed a high percentage of CNA in colorectal cancer, including copy number gains at 7, 8q, 13 and 20q, and copy number losses at 8p, 17p and 18. Gene expression analysis provided many candidates for CRC-related genes, but their association with CRC did not reach the level of statistical significance. The combination of CNA and gene

  6. Analysis of molecular aberrations of Wnt pathway gladiators in colorectal cancer in the Kashmiri population

    Sameer A

    2011-07-01

    Full Text Available Abstract The development and progression of colorectal cancer (CRC is a multi-step process, and the Wnt pathways with its two molecular gladiators adenomatous polyposis coli (APC and β-catenin plays an important role in transforming a normal tissue into a malignant one. In this study, we aimed to investigate the role of aberrations in the APC and β-catenin genes in the pathogenesis of CRC in the Kashmir valley, and to correlate it with various clinicopathological variables. We examined the paired tumour and normal-tissue specimens of 86 CRC patients for the occurrence of aberrations in the mutation cluster region (MCR of the APC gene and exon 3 of the β-catenin gene by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP and/or PCR-direct sequencing. Analysis of promoter hypermethylation of the APC gene was also carried out using methylation-specific PCR (MS-PCR. The overall mutation rate of the MCR of the APC gene among 86 CRC cases was 12.8 per cent (11 of 86. Promoter hypermethylation of APC was observed in 54.65 per cent (47 of 86 of cases. Furthermore, we found a significant association between tumour location, tumour grade and node status and the methylation status of the APC gene (p ≤ 0.05. Although the number of mutations in the APC and β-catenin genes in our CRC cases was very low, the study confirms the role of epigenetic gene silencing of the pivotal molecular gladiator, APC, of the Wnt pathway in the development of CRC in the Kashmiri population.

  7. Serglycin in human cancers

    Xin-Jian Li; Chao-Nan Qian

    2011-01-01

    Serglycin belongs to a family of small proteoglycans with Ser-Gly dipeptide repeats,and it is modified with different types of glycosaminoglycan side chains.Intracellular serglycin affects the retention and secretion of proteases,chemokines,or other cytokines by physically binding to these factors in secretory granules.Extracellular serglycin has been found to be released by several types of human cancer cells,and it is able to promote the metastasis of nasopharyngeal carcinoma cells.Serglycin can bind to CD44,which is another glycoprotein located in cellular membrane.Serglycin's function of promoting cancer cell metastasis depends on glycosylation of its core protein,which can be achieved by autocrine as well as paracrine secretion mechanisms.Further investigations are warranted to elucidate serglycin signaling mechanisms with the goal of targeting them to prevent cancer cell metastasis.

  8. Expression and aberrant promoter methylation of Wnt inhibitory factor-1 in human astrocytomas

    Wu Jun

    2010-03-01

    Full Text Available Abstract Background Wnt inhibitory factor-1(WIF-1 acts as a Wnt-antagonists and tumor suppressor, but hypermethylation of WIF-1 gene promoter and low expression activate Wnt signaling aberrantly and induce the development of various human tumors. With this work we intended to investigate the expression and promoter methylation status of WIF-1 gene in human astrocytomas. Methods The tissue samples consisted of 53 astrocytomas and 6 normal brain tissues. The expression levels of WIF-1 were determined by immunohistochemistry and semiquantitative RT-PCR. The results were analyzed in correlation with clinicopathological data. Methylation status of WIF-1 gene promoter was investigated using methylation specific PCR. The relationship between methylation and expression of the genes was analyzed. Results The average expression levels of WIF-1 protein and mRNA in astrocytomas were decreased significantly compared with normal control tissues. The protein and mRNA expression of WIF-1 gene in astrocytomas was decreased with the increase of pathological grade. Furthermore, WIF-1 promoter methylation was observed by MS-PCR in astrocytomas which showed significant reduction of WIF-1 expression. The WIF-1 promoter hypermethylation was associated with reduced expression of WIF-1 expression. Conclusion Our results demonstrate that the WIF-1 gene is frequently down-regulated or silenced in astrocytomas by aberrant promoter methylation. This may be an important mechanism in astrocytoma carcinogenesis.

  9. Study of chromosome aberration repair after acute or fractionated X-irradiation in human peripheral lymphocytes

    Pure human peripheral blood has been subjected to a single irradiation with the dose of 125 and 250R and by fractions with the doses of 125+125 R in the following periods of the cell cycle: 0, 2, 4, 6, 8, 12, 16, 24, 30, 40 and 45 hrs. The following types of structural chromosome aberrations are counted on metaphase plates with a good chromosome scattering: dicentrics, rings, interstitial deletions, symmetric translocations, chromatide and chromosome fragments. The data on polycentrics and rings prove to be most characteristic: the frequency of these aberrations in the case of single irradiation for all periods of the ''presynthetic'' Gsub(I) period is stable varying in the range of 17-20% in the case of a 125 R dose and 66-73% in the case of a 250 R dose. Their frequency decreased for both doses of irradiation in later periods and reached 1% by the end of the synthetic period. The fractionated effect of two doses 125 R each gives the following values of polycentric and ring formation: second hour - 44,15%, fourth - 50,82%, sixth - 55,15% eighth -58,32% (maximum), twelfth - 55,48%. The descending tendency is preserved till the end of the presynthetic period and in the synthetic period. The statistic processing of results shows statistically authentic differences between fractionated and single irradiation in the output of polycentrics and rings, as well as other types of aberrations and breaks per cell. The data obtained permit to conclude that repair processes are undulatory and are characterized by maximum intensity in the first hours of presynthetic period which weakens to the 8th hour and then strengthens again almost to the end of the synthetic period

  10. Thymosin beta-10 is aberrantly expressed in pancreatic cancer and induces JNK activation.

    Li, Min; Zhang, Yuqing; Zhai, Qihui; Feurino, Louis W; Fisher, William E; Chen, Changyi; Yao, Qizhi

    2009-03-01

    Thymosin beta-10 (T beta 10) has been shown to be associated with several cancers; however, its role in pancreatic cancer is not understood. The expression of T beta 10 was determined by immunohistochemistry and real-time polymerase chain reaction. The phosphorylation of JNK and the cytokine secretion was determined by using the Bio-Plex phosphoprotein and cytokines assays. Pancreatic cancer tissues and cells expressed higher amounts of T beta 10 than normal surrounding tissues and human pancreatic duct epithelial cells. Exogenous T beta 10 caused the phosphorylation of JNK and increased the secretion of cytokines interleukin (IL)-7 and IL-8 in BxPC-3 cells. T beta 10 might be a promising marker and a novel therapeutic target for pancreatic cancer. PMID:19194824

  11. Chromosome aberration yields in human lymphocytes induced by fractionated doses of x-radiation

    Unstimulated (G0) human peripheral blood lymphocytes were exposed at 37degC to doses of 200 or 500 rad of X-rays delivered in two equal fractions. The dose fractions were separated by intervals of up to 7 h in the 200 rad study and up to 48 h for 500 rad. In both studies the mean levels of dicentrics and total unstable aberrations began to decline when fractions were delivered with intervals of greater than 2 h. With 200 rad the yield had decreased to an additive baseline (i.e. equal to only twice the yield of a single 100-rad fraction) by an interval of 4 h. Following 500 rad the yield declined until 8 h and then remained 20% above the expected additive baseline even when 48 h separated the fractions. Possible explanations for this discrepancy are discussed. In a second experiment PHA stimulated lymphocyte cultures were exposed to 2 doses of 125 rad of X-rays up to 7 h apart in an attempt to demonstrate the late peak in aberration yield originally reported by Lane. Control cultures received unsplit doses of 250 rad at the time of the corresponding second 125-rad fraction. No evidence of a late peak in dicentric yield was observed. The yield remained approximately the same irrespective of the time interval between fractions but these split dose yields were significantly different from the accompanying unsplit controls

  12. Effects of cryopreservation on the recovery of radiation-induced chromosome aberrations in human lymphocytes

    Littlefield, L.G.; Joiner, E.E.; Colyer, S.P.; Frome, E.L.

    1987-01-01

    Experiments were conducted to determine whether irradiated blood samples may be preserved by freezing without compromising the accurate assessment of radiation-induced chromosome aberrations in lymphocyte cultures initiated at later dates. Human whole blood at 37/sup 0/C was exposed in vitro to 0, 1, 2, or 4 Gy cobalt-60 gamma radiation, and lymphocytes were cultured immediately after exposure or after one weeks storage at -70/sup 0/C. A slight depression in cellular proliferation and a significant increase in chromatid breakages were observed in cultures initiated from the previously frozen lymphocytes. In preparations from both fresh and frozen lymphocytes the dose response relationships for radiation-induced dicentrics and acentrics were adequately described by the linear-quadratic dose response model (Y ..cap alpha..D + ..beta..D/sup 2/) with no significant differences in the values of the alpha or beta coefficients between the two sets of cultures. This finding provides evidence that lymphocytes bearing radiation-induced chromosome aberrations are not at selective risk for cell death as a result of cryopreservation.

  13. Human peripheral blood lymphocytes for the analysis of chromosome aberrations in mutagen tests

    Studies on exposed individuals, and on cultured cells, have shown that the human peripheral blood lymphocyte is an extremely sensitive indicator of both in vivo and in vitro induced chromosome structural change. These changes in chromosome structure offer readily scored morphological evidence of damage to the genetic material. Although problems exist in the extrapolation from in vitro results to the in vivo situation, the lymphocyte offers several advantages as a test system. The types of chromosome damage which can be cytologically distinguished at metaphase can be divided into two main groups: chromosome type and chromatid type. The circulating lymphocyte is in the G/sub 0/ or G/sub 1/ phase of mitosis and exposure to ionising radiations and certain other mutagenic agents during this stage produces chromosome-type damage where the unit of breakage and reunion is the whole chromosome (i.e. both chromatids at the same locus). However, cells exposed to these agents while in the S or G/sub 2/ stages of the cell cycle, after the chromosome has divided into two sister chromatids, yield chromatid-type aberrations and only the single chromatid is involved in breakage or exchange. Other agents (e.g. some of the alkylating agents) will usually produce only chromatid-type aberrations in cells in cycle although the cells are exposed to the mutagen whilst in G/sub 1/

  14. Effects of colcemid concentration on chromosome aberration analysis in human lymphocytes

    Kanda, Reiko; Hayata, Isamu; Kobayashi, Sadayoshi (National Inst. of Radiological Sciences, Chiba (Japan)); Jiang, Tao

    1994-03-01

    As a part of technical improvements of chromosome aberration analysis on human peripheral lymphocytes for biological radiation dosimetry, we examined the optimal conditions for the use of colcemid in chromosome preparation in order to obtain enough number of cells at metaphase in the first cell division. When treated with colcemid at concentrations below 0.01 [mu]g/ml from the beginning of culture, cultures harvested at 48 hours had low mitotic indices. Colcemid treatment at 0.025 to 0.05 [mu]g/ml during 48 hours resulted in high mitotic indices (8 to 15%) and almost of the mitotic cells remaining in the 1st cell division, suggesting that this range of colcemid concentration was appropriate for continuous treatment with colcemid. We further examined the effect of colcemid concentration on the quantitative consistency of the yields of radiation-induced chromosome aberration. Repeated experiments showed that the yield of dicentrics and centric rings in the culture having colcemid at 0.025 [mu]g/ml concentration were larger than that at 0.05 [mu]g/ml. These data indicate the importance of assuring the accuracy of colcemid concentration in the lymphocyte culture for cytogenetic radiation dosimetry. (author).

  15. Aberrant crypt foci in patients with a positive family history of sporadic colorectal cancer.

    Stevens, Richard G; Swede, Helen; Heinen, Christopher D; Jablonski, Melissa; Grupka, Michael; Ross, Barry; Parente, Melissa; Tirnauer, Jennifer S; Giardina, Charles; Rajan, Thiruchandurai V; Rosenberg, Daniel W; Levine, Joel

    2007-04-18

    Early detection is crucial in the prevention of colorectal cancer (CRC) deaths. The earliest detectable neoplastic lesion in the colon is the aberrant crypt foci (ACF). A major question is whether ACF are precursors of CRC, and thus, early biomarkers for CRC risk. If so, we hypothesized that the number of ACF would be higher in patients who had a family history of CRC compared to patients without. We counted ACF in the distal 20cm of colon/rectum during 103 colonoscopic examinations using a prototype Close Focus Colonoscope (Olympus Corp.) with methylene blue chromendoscopy. Each patient was asked whether they had a family history of CRC in a first degree relative, or a personal history of CRC or adenoma. Patients answering 'no' to these questions (n=17) had a mean number of ACF of 4.4; the mean was significantly higher in the patients with a positive family history of CRC (9.0, p<0.01; n=43) or a personal history of advanced adenoma (7.5, p<0.05; n=34). PMID:16950561

  16. The production of micronuclei from chromosome aberrations in irradiated cultures of human lymphocytes

    The characteristics of an assay for chromosomal damage - micronuclei produced in cultured human lymphocytes - are given together with the evidence that the assay accurately measures X-ray-induced chromosomal damage. In the experiments the response of lymphocytes from different donors was very uniform: (1) the increase in micronucleus frequency begins at the time of the first mitoses, 48 hours after the cultures are started, (2) the exponent of the dose response equation (y = kDsup(n)) was 1.2 for micronulei, (3) the frequency of micronuclei was decreased by a factor of about two when the dose was fractionated. The rejoining time for four of five donors was between 30 and 60 minutes, (4) the X-ray-induced micronucleus frequency in cells from people with Down's syndrome (trisomy-21) was twice that of control donors. Since the micronucleus assay reflects the aberration so well and is so fast, it is suitable for a rapid assessment of chromosomal damage

  17. Antioxidant Supplementation Reduces Genomic Aberrations in Human Induced Pluripotent Stem Cells

    Junfeng Ji

    2014-01-01

    Full Text Available Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs using oncogenic transcription factors. However, this method leads to genetic aberrations in iPSCs via unknown mechanisms, which may limit their clinical use. Here, we demonstrate that the supplementation of growth media with antioxidants reduces the genome instability of cells transduced with the reprogramming factors. Antioxidant supplementation did not affect transgene expression level or silencing kinetics. Importantly, iPSCs made with antioxidants had significantly fewer de novo copy number variations, but not fewer coding point mutations, than iPSCs made without antioxidants. Our results suggest that the quality and safety of human iPSCs might be enhanced by using antioxidants in the growth media during the generation and maintenance of iPSCs.

  18. Effect of cysteamine on chromosomal aberrations yield in gamma irradiated lymphocytes from human blood

    Cytogenetic analysis is made of lymphocyte cultures following in vitro gamma-irradiation of human whole venous blood with 93, 188, 372 and 448 rad from ''Rocos'' gamma-therapeutic apparatus, with or without chemical protection. The radioprotector - cysteamine - is added to the blood 15 minutes before irradiation in a dose of 200 micrograms per milliliter of blood. Lymphocyte cultures are fixed 52 hours after stimulation. No quantitative differences are found between the patterns of chromosomal anomalies induced in nonprotected and in protected lymphocyte cultures. There are less chromosomal fragments, dicentrics, interstitial deletions, rings and chromosomal interchanges, aberrant cells and breaks after irradiation in the presence of cysteamine. The protective effect varied depending on the radiation dose: very weak (18.4 per cent) after irradiation with 93 rad, increasing to 75.7 per cent after exposure to 448 rad. (A.B.)

  19. Nonhomologous DNA end joining and chromosome aberrations in human embryonic lung fibroblasts treated with environmental pollutants

    Highlights: • We analyzed the effect of air pollutants on NHEJ and chromosome aberrations. • In HEL12469 cells B[a]P and extractable organic matter induced DSBs. • The compounds induced XRCC4 expression and a weak Ku70/80 response. • We found increased frequency of aberrations of chromosomes 1, 2, 4, 5, 7 and 17. • The tested compounds preferentially affected chromosome 7. - Abstract: In order to evaluate the ability of a representative polycyclic aromatic hydrocarbon (PAH) and PAH-containing complex mixtures to induce double strand DNA breaks (DSBs) and repair of damaged DNA in human embryonic lung fibroblasts (HEL12469 cells), we investigated the effect of benzo[a]pyrene (B[a]P) and extractable organic matter (EOM) from ambient air particles <2.5 μm (PM2.5) on nonhomologous DNA end joining (NHEJ) and induction of stable chromosome aberrations (CAs). PM2.5 was collected in winter and summer 2011 in two Czech cities differing in levels and sources of air pollutants. The cells were treated for 24 h with the following concentrations of tested chemicals: B[a]P: 1 μM, 10 μM, 25 μM; EOMs: 1 μg/ml, 10 μg/ml, 25 μg/ml. We tested several endpoints representing key steps leading from DSBs to the formation of CAs including histone H2AX phosphorylation, levels of proteins Ku70, Ku80 and XRCC4 participating in NHEJ, in vitro ligation activity of nuclear extracts of the HEL12469 cells and the frequency of stable CAs assessed by whole chromosome painting of chromosomes 1, 2, 4, 5, 7 and 17 using fluorescence in situ hybridization. Our results show that 25 μM of B[a]P and most of the tested doses of EOMs induced DSBs as indicated by H2AX phosphorylation. DNA damage was accompanied by induction of XRCC4 expression and an increased frequency of CAs. Translocations most frequently affected chromosome 7. We observed only a weak induction of Ku70/80 expression as well as ligation activity of nuclear extracts. In summary, our data suggest the induction of DSBs and

  20. A transcriptome anatomy of human colorectal cancers

    Accumulating databases in human genome research have enabled integrated genome-wide study on complicated diseases such as cancers. A practical approach is to mine a global transcriptome profile of disease from public database. New concepts of these diseases might emerge by landscaping this profile. In this study, we clustered human colorectal normal mucosa (N), inflammatory bowel disease (IBD), adenoma (A) and cancer (T) related expression sequence tags (EST) into UniGenes via an in-house GetUni software package and analyzed the transcriptome overview of these libraries by GOTree Machine (GOTM). Additionally, we downloaded UniGene based cDNA libraries of colon and analyzed them by Xprofiler to cross validate the efficiency of GetUni. Semi-quantitative RT-PCR was used to validate the expression of β-catenin and. 7 novel genes in colorectal cancers. The efficiency of GetUni was successfully validated by Xprofiler and RT-PCR. Genes in library N, IBD and A were all found in library T. A total of 14,879 genes were identified with 2,355 of them having at least 2 transcripts. Differences in gene enrichment among these libraries were statistically significant in 50 signal transduction pathways and Pfam protein domains by GOTM analysis P < 0.01 Hypergeometric Test). Genes in two metabolic pathways, ribosome and glycolysis, were more enriched in the expression profiles of A and IBD than in N and T. Seven transmembrane receptor superfamily genes were typically abundant in cancers. Colorectal cancers are genetically heterogeneous. Transcription variants are common in them. Aberrations of ribosome and glycolysis pathway might be early indicators of precursor lesions in colon cancers. The electronic gene expression profile could be used to highlight the integral molecular events in colorectal cancers

  1. Epigenetic changes in virus-associated human cancers

    Hsin Pai LI; Yu Wei LEU; Yu Sun CHANG

    2005-01-01

    Epigenetics of human cancer becomes an area of emerging research direction due to a growing understanding of specific epigenetic pathways and rapid development of detection technologies. Aberrant promoter hypermethylation is a prevalent phenonmena in human cancers. Tumor suppressor genes are often hypermethylated due to the increased activity or deregulation of DNMTs. Increasing evidence also reveals that viral genes are one of the key players in regulating DNA methylation. In this review, we will focus on hypermethylation and tumor suppressor gene silencing and the signal pathways that are involved, particularly in cancers closely associated with the hepatitis B virus, simian virus 40 (SV40), and Epstein-Barr virus. In addition, we will discuss current technologies for genome-wide detection of epigenetically regulated targets, which allow for systematic DNA hypermethylation analysis. The study of epigenetic changes should provide a global view of gene profile in cancer, and epigenetic markers could be used for early detection,prognosis, and therapy of cancer.

  2. Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells.

    Pei, Shanshan; Minhajuddin, Mohammad; Callahan, Kevin P; Balys, Marlene; Ashton, John M; Neering, Sarah J; Lagadinou, Eleni D; Corbett, Cheryl; Ye, Haobin; Liesveld, Jane L; O'Dwyer, Kristen M; Li, Zheng; Shi, Lei; Greninger, Patricia; Settleman, Jeffrey; Benes, Cyril; Hagen, Fred K; Munger, Joshua; Crooks, Peter A; Becker, Michael W; Jordan, Craig T

    2013-11-22

    The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34(+)) leukemic versus normal specimens. Our data indicate that CD34(+) AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34(+) AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34(+) cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34(+) AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34(+) cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells. PMID:24089526

  3. Analysis of the frequency of unstable chromosome aberrations in human lymphocytes irradiated with 60Co

    The aim of this study was to analyze the frequency of unstable chromosomal aberrations induced by gamma radiation from a 60Co source at two different doses. Samples were obtained from a healthy donor and exposed to 60Co source (Gammacel 220 ) located in the Department of Nuclear Energy of Pernambuco Federal University (DEN/UFPe/Brazil) with a rate of air Kerma to 3,277 Gy/h. Exposures resulted in absorbed dose 0.51 Gy and 0.77 Gy. Mitotic metaphases were obtained by culturing lymphocytes for chromosome analysis and the slides were stained with 5% Giemsa. Among the unstable chromosomal aberrations the dicentric chromosomes, ring chromosomes and acentric fragments were analyzed. To calculate the significance level the chi - square test was used, considering relevant differences between the frequencies when the value of p < 0.05. To calculate the significance level of the chi - square test was used, considering relevant differences between the frequencies when the value of p < 0.05. The results showed that there was significant difference of the frequencies of dicentric chromosomes (from 0.18 to 0.51 to 0.37 Gy to 0.77 Gy), however there was no statistically significant difference between the frequencies of acentric fragments ( 0.054 to 0, 51 Gy to 0.063 to 0.77 Gy) and ring chromosomes (0.001 to 0.51 Gy to 0.003 to 0.77 Gy). The low number of rings is found justified, considering that in irradiated human lymphocytes, its appearance is rare relative to dicentrics. The results confirm that dicentrics are the most reliable biomarkers in estimating dose after exposure to gamma radiation. These two points will make the calibration curve dose-response being built for Biological Dosimetry Laboratory of CRCN-NE/CNEN

  4. The effect of caffeine posttreatment on X-ray-induced chromosomal aberrations in human blood lymphocytes in vitro

    The potentiating effect of caffeine on X-ray-induced chromosomal aberrations in human blood lymphocytes has been investigated, with special reference to cell cycle stages (G0 and G2). Both quantitative and qualitative differences in the yield of chromosomal aberrations were detected in caffeine-posttreated cells, depending on the cell stage irradiated. The studies on caffeine potentiating effects on X-irradiated G0 lymphocytes from normal adults, newborns, Down syndrome patients, and an ataxia telangiectasia patient pointed to interindividual variations in the response to caffeine potentiation among normal probands and a very profound effect in ataxia cells. (orig.)

  5. Chromosome Aberrations by Heavy Ions

    Ballarini, Francesca; Ottolenghi, Andrea

    It is well known that mammalian cells exposed to ionizing radiation can show different types of chromosome aberrations (CAs) including dicentrics, translocations, rings, deletions and complex exchanges. Chromosome aberrations are a particularly relevant endpoint in radiobiology, because they play a fundamental role in the pathways leading either to cell death, or to cell conversion to malignancy. In particular, reciprocal translocations involving pairs of specific genes are strongly correlated (and probably also causally-related) with specific tumour types; a typical example is the BCR-ABL translocation for Chronic Myeloid Leukaemia. Furthermore, aberrations can be used for applications in biodosimetry and more generally as biomarkers of exposure and risk, that is the case for cancer patients monitored during Carbon-ion therapy and astronauts exposed to space radiation. Indeed hadron therapy and astronauts' exposure to space radiation represent two of the few scenarios where human beings can be exposed to heavy ions. After a brief introduction on the main general features of chromosome aberrations, in this work we will address key aspects of the current knowledge on chromosome aberration induction, both from an experimental and from a theoretical point of view. More specifically, in vitro data will be summarized and discussed, outlining important issues such as the role of interphase death/mitotic delay and that of complex-exchange scoring. Some available in vivo data on cancer patients and astronauts will be also reported, together with possible interpretation problems. Finally, two of the few available models of chromosome aberration induction by ionizing radiation (including heavy ions) will be described and compared, focusing on the different assumptions adopted by the authors and on how these models can deal with heavy ions.

  6. Report: Human cancer genetics

    LI Marilyn; ALBERTSON Donna

    2006-01-01

    The short report will be focused on the genetic basis and possible mechanisms of tumorigenesis, common types of cancer, the importance of genetic diagnosis of cancer, and the methodology of cancer genetic diagnosis. They will also review presymptomatic testing of hereditary cancers, and the application of expression profiling to identify patients likely to benefit from particular therapeutic approaches.

  7. HSulf-1 suppresses cell growth and down-regulates Hedgehog signaling in human gastric cancer cells

    MA, HUI-YAN; Zhang, Fang; Li, Jie; Mo, Min-Li; Chen, Zhao; Liu, Lili; Zhou, Hai-Meng; Sheng, Qing

    2011-01-01

    Gastric cancer is the second most lethal cancer worldwide. Despite the current surgical and adjuvant therapies, 5-year survival remains less than 20–25% in the US, Europe and China. Therefore, there is an urgent need to identify new therapeutic targets for treating this malignant disease. Accumulating evidence has supported that aberrant activation of the Hedgehog signaling pathway plays a crucial role in tumorigenesis and progression of gastric cancer. Human sulfatase-1 (HSulf-1) is a recent...

  8. Optical study on the vision correction and supernormal vision based on the wave-front aberrations of human eye

    MU GuoGuang; WANG ZhaoQi; LIU YongJi; QUAN Wei; WANG Yang; WANG Wei

    2007-01-01

    In this paper we present the recent research results in the field of vision correction and supernormal vision according to the actual measurements of the wave-front aberrations and the corneal surface topography, the clinical detection of the visual function and the laser corneal refractive surgery, and the optimization of the optical system. These include the features of the aberrations of human eye with different pupil sizes, different fields of view and temporal accommodation, the influence of the polychromatic illumination of the visible wavelength on the supernormal vision,and the effect of the existing laser corneal refractive surgery on the wave-front aberrations of the eye. It is shown that the wave-front aberration of human eye is of temporal variation and of synthesis with multi impact factors. To achieve supernormal vision, an optimum engineering data for the customized laser corneal surgery should be firstly acquired, which may involve the dynamic free-form optical surface. Although the myopia can be corrected by the laser in situ keratomileusis (LASlK) in a certain degree, it brings about negative effects under scotopic conditions.

  9. Optical study on the vision correction and supernormal vision based on the wave-front aberrations of human eye

    2007-01-01

    In this paper we present the recent research results in the field of vision correction and supernormal vision according to the actual measurements of the wave-front aberrations and the corneal surface topography,the clinical detection of the visual function and the laser corneal refractive surgery,and the optimization of the optical system. These include the features of the aberrations of human eye with different pupil sizes,different fields of view and temporal accommodation,the influence of the polychromatic illumination of the visible wavelength on the supernormal vision,and the effect of the existing laser corneal refractive surgery on the wave-front ab-errations of the eye. It is shown that the wave-front aberration of human eye is of temporal variation and of synthesis with multi impact factors. To achieve super-normal vision,an optimum engineering data for the customized laser corneal sur-gery should be firstly acquired,which may involve the dynamic free-form optical surface. Although the myopia can be corrected by the laser in situ keratomileusis(LASIK) in a certain degree,it brings about negative effects under scotopic condi-tions.

  10. Human Rif1 protein binds aberrant telomeres and aligns along anaphase midzone microtubules

    Xu, Lifeng; Blackburn, Elizabeth H.

    2004-01-01

    We identified and characterized a human orthologue of Rif1 protein, which in budding yeast interacts in vivo with the major duplex telomeric DNA binding protein Rap1p and negatively regulates telomere length. Depletion of hRif1 by RNA interference in human cancer cells impaired cell growth but had no detectable effect on telomere length, although hRif1 overexpression in S. cerevisiae interfered with telomere length control, in a manner specifically dependent on the presence of yeast Rif1p. No...

  11. Correction of monochromatic aberrations in human eyes - report on work in progress

    In the excimer laser photorefractive keratectomy the laser removes tissues across the anterior corneal surface. The result is a change in the anterior corneal curvature which is used to correct ocular image errors such as myopia and astigmatism. Unfortunately, there are additional aberrations as higher order coma-like and spherical aberration-like image errors limiting the visual acuity. Actually we are investigating how to fit the excimer laser photorefractive ablation profiles for correction of myopia and astigmatism to those for minimizing higher order coma and spherical aberration. Our approach is an aberrometry-guided corneal refractive surgery using a scanning spot ArF excimer laser. (author)

  12. The effects of oxygen and hypoxic cell sensitizers on chromosome aberration induction in human lymphocytes

    Normal human blood was exposed at 370C to 250 kVp X-rays under conditions of anoxia and of equilibration with oxygen. The numbers of observed dicentric aberrations were fitted to the expression Y = αD + βD2 and from these curves an OER estimate of 2.8 at 5.0 Gy was obtained. The dicentric yield was also measured after blood held at various oxygen tensions was exposed to 3.0 Gy or 0.75 Gy X-rays. No difference was observed between the values at the lowest oxygen concentration of less than 2 ppm and at 250 ppm. Above 250 ppm there was a steep rise in the number of dicentrics observed but at oxygen levels above 1% the dicentric yield was again much less dependent on the oxygen concentration. The experiments were repeated using different concentrations of 'Flagyl' and Ro 07 0582 which both showed a maximum effect at 4 to 8 mM. Dose response data obtained in the presence of 8 mM sensitizer were again fitted to the quadratic expression and enhancement ratios of 2.2 and 1.4 estimated for Ro 07 0582 and 'Flagyl' respectively. Blood irradiated at venous oxygen tension in the presence of each of these chemicals showed an unchanged dicentric yield in the case of 'Flagyl' and a slight increase with Ro 07 0582 at a dose of 1.0 Gy. (Auth.)

  13. Aberrant Phenotype in Human Endothelial Cells of Diabetic Origin: Implications for Saphenous Vein Graft Failure?

    Anna C. Roberts

    2015-01-01

    Full Text Available Type 2 diabetes (T2DM confers increased risk of endothelial dysfunction, coronary heart disease, and vulnerability to vein graft failure after bypass grafting, despite glycaemic control. This study explored the concept that endothelial cells (EC cultured from T2DM and nondiabetic (ND patients are phenotypically and functionally distinct. Cultured human saphenous vein- (SV- EC were compared between T2DM and ND patients in parallel. Proliferation, migration, and in vitro angiogenesis assays were performed; western blotting was used to quantify phosphorylation of Akt, ERK, and eNOS. The ability of diabetic stimuli (hyperglycaemia, TNF-α, and palmitate to modulate angiogenic potential of ND-EC was also explored. T2DM-EC displayed reduced migration (~30% and angiogenesis (~40% compared with ND-EC and a modest, nonsignificant trend to reduced proliferation. Significant inhibition of Akt and eNOS, but not ERK phosphorylation, was observed in T2DM cells. Hyperglycaemia did not modify ND-EC function, but TNF-α and palmitate significantly reduced angiogenic capacity (by 27% and 43%, resp., effects mimicked by Akt inhibition. Aberrancies of EC function may help to explain the increased risk of SV graft failure in T2DM patients. This study highlights the importance of other potentially contributing factors in addition to hyperglycaemia that may inflict injury and long-term dysfunction to the homeostatic capacity of the endothelium.

  14. Cyclin D1 splice site variant triggers chromosomal aberrations in healthy humans

    Hemminki, K.; Mušák, L.; Vymetálková, Veronika; Šmerhovský, Z.; Halásová, E.; Osina, O.; Letková, L.; Försti, A.; Vodičková, Ludmila; Buchancová, J.; Vodička, Pavel

    2014-01-01

    Roč. 28, č. 3 (2014), s. 721-722. ISSN 0887-6924 Institutional support: RVO:68378041 Keywords : chromosomal aberrations * DNA repair Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 10.431, year: 2014

  15. Dose-dependence of the yield of chromosomal aberrations in human lymphocytes after irradiation of peripheral blood with monoenergetic neutrons of 2, 4 and 6 MeV

    Sevan' kaev, A.V.; Obaturov, G.M.; Nasonova, V.A.; Izmajlova, N.N. (Akademiya Meditsinskikh Nauk SSSR, Obninsk. Nauchno-Issledovatel' skij Inst. Meditsinskoj Radiologii)

    A study was made of the dose-dependence of the yield of chromosome aberrations in human lymphocyte culture irradiated at the G/sub 0/ stage with monoenergetic neutrons of 2, 4 and 6 MeV. The dose dependence was found to be linear all types of aberrations. The RBE of neutrons under study increased with the decrease in their energy.

  16. In Vitro genotoxic and antigenotoxic studies of Thai Noni fruit juice by chromosomal aberration and sister chromatid exchange assays in human lymphocytes

    Treetip Ratanavalachai; Sumon Thitiorul; Pranee Nandhasri

    2008-01-01

    The genotoxic and antigenotoxic effects of Noni fruit juice produced in Thailand have been studied in human lymphocytes for chromosome aberration assay and sister chromatid exchange (SCE) assay in vitro. Treatment of Noni fruit juice(3.1-50 mg/ml) alone for 3 h did not significantly induce chromosomal aberration or SCE (p

  17. Chromosomal aberrations in lymphocytes of healthy subjects and risk of cancer

    Rössner st., Pavel; Boffetta, P.; Ceppi, M.; Bonassi, S.; Šmerhovský, Zdeněk; Jůzova, D.; Šrám, Radim

    2005-01-01

    Roč. 113, č. 5 (2005), s. 517-520. ISSN 0091-6765 Institutional research plan: CEZ:AV0Z50390512 Keywords : chromosomal aberrations * cytogenetic assay Subject RIV: EA - Cell Biology Impact factor: 5.342, year: 2005

  18. Genotoxic and antigenotoxic effects of Fucus vesiculosus extract on cultured human lymphocytes using the chromosome aberration and Comet assays

    Cleide Leite-Silva

    2007-01-01

    Full Text Available The brown seaweed Fucus vesiculosus (Fucales, Fucaceae was screened for its protective activity using doxorubicin-induced DNA damage in human lymphocytes. In this study, we assessed the genotoxic and antigenotoxic potential of three different concentrations (0.25, 0.5 and 1.0 mg mL-1 of F. vesiculosus aqueous extract using the chromosome aberration and Comet assays. Treatment of human lymphocyte cultures with 0.25, 0.5 and 1.0 mg mL-1 F. vesiculosus aqueous extract had no effect on the chromosome aberration frequency or on the extent of DNA damage detected by the Comet assay. The antigenotoxic effects of the extract were tested in human lymphocyte cultures treated with 15 µg mL-1 of doxorubicin, either alone or combined with the different concentrations of the extract, which was added to the cultures before, simultaneously with or after the doxorubicin. Only when lymphocytes were pre-treated with extract there was a reduction in doxorubicin-induced chromosome aberrations and DNA damage as detected by the Comet assay. These results demonstrate that F. vesiculosus aqueous extract is not genotoxic in cultured human lymphocytes and indicate that when added to lymphocyte cultures before doxorubicin it has antigenotoxic activity against doxorubicin-induced DNA damage.

  19. An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer

    Lockwood William W

    2010-05-01

    Full Text Available Abstract Background Genomics has substantially changed our approach to cancer research. Gene expression profiling, for example, has been utilized to delineate subtypes of cancer, and facilitated derivation of predictive and prognostic signatures. The emergence of technologies for the high resolution and genome-wide description of genetic and epigenetic features has enabled the identification of a multitude of causal DNA events in tumors. This has afforded the potential for large scale integration of genome and transcriptome data generated from a variety of technology platforms to acquire a better understanding of cancer. Results Here we show how multi-dimensional genomics data analysis would enable the deciphering of mechanisms that disrupt regulatory/signaling cascades and downstream effects. Since not all gene expression changes observed in a tumor are causal to cancer development, we demonstrate an approach based on multiple concerted disruption (MCD analysis of genes that facilitates the rational deduction of aberrant genes and pathways, which otherwise would be overlooked in single genomic dimension investigations. Conclusions Notably, this is the first comprehensive study of breast cancer cells by parallel integrative genome wide analyses of DNA copy number, LOH, and DNA methylation status to interpret changes in gene expression pattern. Our findings demonstrate the power of a multi-dimensional approach to elucidate events which would escape conventional single dimensional analysis and as such, reduce the cohort sample size for cancer gene discovery.

  20. Human papillomavirus and genital cancer

    Rapose Alwyn

    2009-01-01

    Human papillomavirus (HPV) is one of the most common sexually transmitted infections world-wide. Low-risk HPV-types are associated with genital warts. Persistent infection with high-risk HPV-types is associated with genital cancers. Smoking and HIV infection have consistently been associated with longer duration of HPV infection and risk for genital cancer. There is an increasing incidence of anal cancers, and a close association with HPV infection has been demonstrated. Receptive anal sex an...

  1. Human Papillomavirus and Cervical Cancer

    D. Jenkins(University of York, UK)

    2003-01-01

    Of the many types of human papillomavirus (HPV), more than 30 infect the genital tract. The association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Although HPV is essential to the transformation of cervical epithelial cells, it is not sufficient, and a variety of cofactors and molecular events influence whether cervical cancer will develop. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Ident...

  2. Comparison of effects of six tritiated compounds on chromosomal aberrations in human lymphocytes in vitro and dose-response relationships

    The effects of six tritiated compounds on chromosomal aberrations were compared in cultured human lymphocytes, and dose-response relationships were analysed. According to the efficiency of inducing aberrations, these compounds could be arranged in decreasing order as follows: 3H-TdR > 3H-UdR > 3H-lysine > 3H-thymine > 3H-leucine > HTO, when the dose-response relationship was expressed in radioactivity/ml of the medium. This order is determined mainly by the radioactivities incorporated into the nuclei or the cells. However, when compared in terms of the dose absorbed by the nuclei or the cells, the differences among various compounds would be much more reduced. The data of aberration yields for different tritium activities (or absorbed dsoes) were fitted satisfactorily to the linear-quadratic dose-response equation Y = A + BX + CX2. The yields of chromatid-type and chromosometype aberrations induced by various tritiated compounds were quite different. These differences are related to the metabolism of the compounds

  3. HUMAN PROSTATE CANCER RISK FACTORS

    Prostate cancer has the highest prevalence of any non-skin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating an...

  4. Unstable chromosome aberrations on peripheral blood lymphocytes from patients with cervical uterine cancer following radiotherapy; Aberracoes cromossomicas instaveis em linfocitos de pacientes com cancer de colo de utero

    Magnata, Simey de Souza Leao Pereira

    2002-09-01

    Absorbed dose determination is an important step for risk assessment related to an exposure to ionizing radiation. However, physical dosimetry cannot be always performed, principally in the case of retrospective estimates. In this context, the use of bioindicators (biological effects) has been proposed, which defines the so-called biological dosimetry. In particular, scoring of unstable chromosomes aberrations (dicentrics, centric rings and fragments) of peripheral blood lymphocytes, while is the most reliable biological method for estimating individual exposure to ionizing radiation. In this work, blood samples from 5 patients, with cervical uterine cancer, were evaluated after partial-body radiotherapy with a source of {sup 69} Co. For this, conventional cytogenetic method was employed, based on Giemsa coloration and fluorescence in situ hybridization, in order to correlate the frequency of unstable chromosome aberrations of blood lymphocytes with absorbed dose, as a result of the radiotherapy. A good agreement was observed between the frequency of chromosome aberrations scored and the values of dose previously calculated by physical dosimetry during patient's radiotherapy. The results presented in this work point out the importance of concerning analyses of unstable chromosome aberrations as biological dosimeter in the investigation of partial-body exposure to ionizing radiation. (author)

  5. Identification of O-glycosylated Proteins That Are Aberrantly Excreted in the Urine of Patients with Early Stage Ovarian Cancer

    Adawiyah Suriza Shuib

    2013-04-01

    Full Text Available Cancer is known to induce or alter the O-glycosylation of selective proteins that may eventually be excreted in the patients’ urine. The present study was performed to identify O-glycosylated proteins that are aberrantly excreted in the urine of patients with early stage ovarian cancer (OCa. These urinary glycoproteins are potential biomarkers for early detection of OCa. In this study, urinary proteins of patients with early stage OCa and age-matched OCa negative women were subjected to two-dimensional gel electrophoresis and detection using a lectin that binds to the O-glycosylated proteins. Our analysis demonstrated significant enhanced expression of clusterin and leucine-rich alpha-2-glycoprotein, but lower levels of kininogen in the urine of the OCa patients compared to the controls. The different altered levels of these urinary glycoproteins were further confirmed using competitive ELISA. Our data are suggestive of the potential use of the aberrantly excreted urinary O-glycosylated proteins as biomarkers for the early detection of OCa, although this requires further validation in a large clinically representative population.

  6. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Dose of High Let Radiation

    Hada, M.; George, K.; Chappell, L.; Cucinotta, F. A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (0.01 - 0.20 Gy) of 170 MeV/u Si-28 ions or 600 MeV/u Fe-56 ions, including doses where on average less than one direct ion traversal per cell nucleus occurs. Chromosomes were analyzed using the whole-chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The responses for doses above 0.1 Gy (more than one ion traverses a cell) showed linear dose responses. However, for doses less than 0.1 Gy, both Si-28 ions and Fe-56 ions showed a dose independent response above background chromosome aberrations frequencies. Possible explanations for our results are non-targeted effects due to aberrant cell signaling [1], or delta-ray dose fluctuations [2] where a fraction of cells receive significant delta-ray doses due to the contributions of multiple ion tracks that do not directly traverse cell nuclei where chromosome aberrations are scored.

  7. Chromosome Aberrations in Human Epithelial Cells Exposed Los Alamos High-Energy Secondary Neutrons: M-BAND Analysis

    Hada, M.; Saganti, P. B.; Gersey, B.; Wilkins, R.; Cucinotta, F. A.; Wu, H.

    2007-01-01

    High-energy secondary neutrons, produced by the interaction of galactic cosmic rays (GCR) with the atmosphere, spacecraft structure and planetary surfaces, contribute a significant fraction to the dose equivalent radiation measurement in crew members and passengers of commercial aviation travel as well as astronauts in space missions. The Los Alamos Nuclear Science Center (LANSCE) neutron facility's 30L beam line (4FP30L-A/ICE House) is known to generate neutrons that simulate the secondary neutron spectrum of the Earth's atmosphere at high altitude. The neutron spectrum is also similar to that measured onboard spacecrafts like the MIR and the International Space Station (ISS). To evaluate the biological damage, we exposed human epithelial cells in vitro to the LANSCE neutron beams with an entrance dose rate of 2.5 cGy/hr, and studied the induction of chromosome aberrations that were identified with multicolor-banding in situ hybridization (mBAND) technique. With this technique, individually painted chromosomal bands on one chromosome allowed the identification of inter-chromosomal aberrations (translocation to unpainted chromosomes) and intra-chromosomal aberrations (inversions and deletions within a single painted chromosome). Compared to our previous results with gamma-rays and 600 MeV/nucleon Fe ions of high dose rate at NSRL (NASA Space Radiation Laboratory at Brookhaven National Laboratory), the neutron data from the LANSCE experiments showed significantly higher frequency of chromosome aberrations. However, detailed analysis of the inversion type revealed that all of the three radiation types in the study induced a low incidence of simple inversions. Most of the inversions in gamma-ray irradiated samples were accompanied by other types of intrachromosomal aberrations but few inversions were accompanied by interchromosomal aberrations. In contrast, neutrons and Fe ions induced a significant fraction of inversions that involved complex rearrangements of both

  8. Aberrant Wnt/β-catenin signaling can induce chromosomal instability in colon cancer

    Hadjihannas, Michel V; Brückner, Martina; Jerchow, Boris; Birchmeier, Walter; Dietmaier, Wolfgang; Behrens, Jürgen

    2006-01-01

    Chromosomal instability (CIN), a hallmark of most colon tumors, may promote tumor progression by increasing the rate of genetic aberrations. CIN is thought to arise as a consequence of improper mitosis and spindle checkpoint activity, but its molecular basis remains largely elusive. The majority of colon tumors develop because of mutations in the tumor suppressor APC that lead to Wnt/β-catenin signaling activation and subsequent transcription of target genes, including conductin/AXIN2. Here w...

  9. Cancer Grafted in Aberrant Breast Tissue Cáncer injertado en tejido mamario aberrante

    Lidia Torres Ajá

    2012-03-01

    Full Text Available Among the anomalies during embryonic development of the breasts we may find supernumerary breasts and aberrant ectopic tissue. In both of them, malignant tumors of the breast can proliferate, mostly in aberrant tissue. We present the case of a female patient aged 73, who refers to have always had a "little mammary gland in the left submammary that never caused discomfort to the last two months when its volume increased and the skin retracted". Excisional biopsy allowed diagnosing an infiltrating ductal carcinoma, the first case of carcinoma grafted in aberrant breast tissue diagnosed in the province.

    Entre las anomalías del desarrollo embrionario de las mamas se encuentran las mamas supernumerarias y el tejido ectópico aberrante. Ambas pueden ser asiento de tumores malignos de la mama, en mayor número  el tejido aberrante. Se presenta el caso de una paciente femenina de 73 años, que refiere tiene desde siempre una “mamita pequeña en el surco submamario izquierdo la cual nunca le ocasiono molestias hasta hace 2 meses en que aumentó de volumen y se le retrajo la piel". Mediante biopsia escisional se le diagnostica un carcinoma ductal infiltrante, siendo así  el primer caso de carcinoma injertado en tejido mamario aberrante diagnosticado en nuestra provincia.

  10. Analysis of Chromosomal Aberrations after Low and High Dose Rate Gamma Irradiation in ATM or NBS Suppressed Human Fibroblast Cells

    Hada, M.; Huff, J. L.; Patel, Z.; Pluth, J. M.; George, K. A.; Cucinotta, F. A.

    2009-01-01

    A detailed understanding of the biological effects of heavy nuclei is needed for space radiation protection and for cancer therapy. High-LET radiation produces more complex DNA lesions that may be non-repairable or that may require additional processing steps compared to endogenous DSBs, increasing the possibility of misrepair. Interplay between radiation sensitivity, dose, and radiation quality has not been studied extensively. Previously we studied chromosome aberrations induced by low- and high- LET radiation in several cell lines deficient in ATM (ataxia telangactasia mutated; product of the gene that is mutated in ataxia telangiectasia patients) or NBS (nibrin; product of the gene mutated in the Nijmegen breakage syndrome), and gliomablastoma cells that are proficient or lacking in DNA-dependent protein kinase (DNA-PK) activity. We found that the yields of both simple and complex chromosomal aberrations were significantly increased in the DSB repair defective cells compared to normal cells. The increased aberrations observed for the ATM and NBS defective lines was due to a significantly larger quadratic dose-response term compared to normal fibroblasts for both simple and complex aberrations, while the linear dose-response term was significantly higher in NBS cells only for simple exchanges. These results point to the importance of the functions of ATM and NBS in chromatin modifications that function to facilitate correct DSB repair and minimize aberration formation. To further understand the sensitivity differences that were observed in ATM and NBS deficient cells, in this study, chromosomal aberration analysis was performed in normal lung fibroblast cells treated with KU-55933, a specific ATM kinase inhibitor, or Mirin, an MRN complex inhibitor involved in activation of ATM. We are also testing siRNA knockdown of these proteins. Normal and ATM or NBS suppressed cells were irradiated with gamma-rays and chromosomes were collected with a premature chromosome

  11. Chromosome aberrations induced in human lymphocytes by U-235 fission neutrons. Pt. 2

    Blood samples were spiked with Na-24 to study the separate effect of this nuclide on the incidence of chromosomal aberrations in neutron irradiated blood samples. A delay of 96 h was allowed before cultivation, so the results of chromosomal aberration analysis could be compared with the results obtained by direct irradiation of blood samples with U-235 fission neutrons. The absorbed dose was calculated using a simple conservative model. From the results obtained we can conclude that Na-24 alone was not the reason for the difference in the incidence of chromosomal aberrations between blood samples cultivated immediately after 'in vitro' irradiation by U-235 fission neutrons and samples which were cultivated after 96 h storage. (orig.)

  12. Chromosome aberrations in human lymphocytes, chronically exposed to different doses of gamma radiation in vitro

    Man's blood, not stimulated with phytohemagglutinin has been subjected to a chronic gamma irradiation from the 226Ra(99 mg) source at the temperature of 37 deg C. The obtained metaphase plates have been used to carry out the quantitative analysis of separate types of structural chromosomal aberrations. Quantitative results on aberrant cells have been statistically processed. It is established, that the increase of dose rate lends to the increase in the share of those dicentrics, that appeared as a result of one-trail process, while that output of two-trail dicentrics remains constant

  13. Aberrant expression of ether à go-go potassium channel in colorectal cancer patients and cell lines

    Xiang-Wu Ding; Juan-Juan Yan; Ping An; Peng Lü; He-Sheng Luo

    2007-01-01

    AIM: To study the expression of ether à go-go (Eag1) potassium channel in colorectal cancer and the relation ship between their expression and clinico-pathological features.METHODS: The expression levels of Eag1 protein were determined in 76 cancer tissues with paired noncancerous matched tissues as well as 9 colorectal adenoma tissues by immunohistochemistry. Eag1 mRNA expression was detected in 13 colorectal cancer tissues with paired non-cancerous matched tissues and 4 colorectal adenoma tissues as well as two colorectal cancer cell lines (LoVo and HT-29) by reverse transcription PCR.RESULTS: The frequency of positive expression of Eag1 protein was 76.3% (58/76) and Eag1 mRNA was 76.9% (10/13) in colorectal cancer tissue. Expression level of Eag1 protein was dependent on the tumor size,lymphatic node metastasis, other organ metastases and Dukes' stage (P < 0.05), while not dependent on age,sex, site and degree of differentiation. Eag1 protein and mRNA were negative in normal colorectal tissue, and absolutely negative in colorectal adenomas except that one case was positively stained for Eag1 protein.CONCLUSION: Eag1 protein and mRNA are aberrantly expressed in colorectal cancer and occasionally expressed in colorectal adenoma. The high frequency of expression of Eag1 in tumors and the restriction of normal expression to the brain suggest the potential of this protein for diagnostic, prognostic and therapeutic purposes.

  14. Nonhomologous DNA end joining and chromosome aberrations in human embryonic lung fibroblasts treated with environmental pollutants

    Rössner ml., Pavel; Rössnerová, Andrea; Beskid, Olena; Tabashidze, Nana; Líbalová, Helena; Uhlířová, Kateřina; Topinka, Jan; Šrám, Radim

    763-764, MAY-JUN 2014 (2014), s. 28-38. ISSN 0027-5107 R&D Projects: GA ČR GAP503/11/0084 Institutional support: RVO:68378041 Keywords : benzo[a]pyrene * chromosome aberrations * double-strand DNA breaks Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 3.680, year: 2014

  15. Overexpression of human sperm protein 17 increases migration and decreases the chemosensitivity of human epithelial ovarian cancer cells

    Most deaths from ovarian cancer are due to metastases that are resistant to conventional therapies. But the factors that regulate the metastatic process and chemoresistance of ovarian cancer are poorly understood. In the current study, we investigated the aberrant expression of human sperm protein 17 (HSp17) in human epithelial ovarian cancer cells and tried to analyze its influences on the cell behaviors like migration and chemoresistance. Immunohistochemistry and immunocytochemistry were used to identify HSp17 in paraffin embedded ovarian malignant tumor specimens and peritoneal metastatic malignant cells. Then we examined the effect of HSp17 overexpression on the proliferation, migration, and chemoresistance of ovarian cancer cells to carboplatin and cisplatin in a human ovarian carcinoma cell line, HO8910. We found that HSp17 was aberrantly expressed in 43% (30/70) of the patients with primary epithelial ovarian carcinomas, and in all of the metastatic cancer cells of ascites from 8 patients. The Sp17 expression was also detected in the metastatic lesions the same as in ovarian lesions. None of the 7 non-epithelial tumors primarily developed in the ovaries was immunopositive for HSp17. Overexpression of HSp17 increased the migration but decreased the chemosensitivity of ovarian carcinoma cells to carboplatin and cisplatin. HSp17 is aberrantly expressed in a significant proportion of epithelial ovarian carcinomas. Our results strongly suggest that HSp17 plays a role in metastatic disease and resistance of epithelial ovarian carcinoma to chemotherapy

  16. A comparative analysis of chromosomal aberrations in cultured human lymphocytes due to fluoroquinolone drugs at different expression periods.

    Anupama, M; Seiler, J P; Murthy, P B

    2010-05-01

    Fluoroquinolones (FQ) are broad-spectrum antibacterial agents widely used for the treatment of infections with various types of gram negative and gram positive bacteria. Specifically, gatifloxacin (GFX) is under development as a component in a new antituberculosis fixed-dose drug combination. In the context of this project, GFX was also tested for genotoxic activity in human peripheral lymphocytes, and the induction of chromosomal aberrations by GFX in PHA-M stimulated cultured human lymphocytes, investigated under conditions of conventional and increased expression times, was further compared to the analogous effects induced by some other second- and third-generation FQ antibacterial agents, namely ofloxacin (OFX), ciprofloxacin (CFX) and sparfloxacin (SFX). OFX did not induce any significant chromosomal aberrations in human lymphocytes. CFX and SFX exhibited slight to moderate clastogenic potential at cytotoxic concentrations (150, 175, 200 and 225 microg/ml), and GFX, a third-generation FQ, induced a clear, concentration-dependent increase in the frequency of chromosomal aberrations at cytotoxic concentrations (150, 200 and 250 microg/ml). These effects were not apparent when metaphases were analysed at the conventionally used sampling time of 24 h, but only after prolongation of the expression time between treatment and harvesting to a sampling time of 36 h (4 h exposure and 32 h expression period). Also, an increased incidence of numerical aberrations (polyploidy and endoreduplication) was seen with GFX at non-cytotoxic concentrations (12.5, 25, 50 and 75 microg/ml). These effects can be attributed to the slight cross-reactivity of FQs between their inhibitory activity towards their intended targets, the prokaryotic type II topoisomerase enzymes DNA gyrase and topoisomerase IV, and the analogous mammalian enzyme topoisomerase II. We have also observed the formation of polycentrics, i.e., chromosomes with five to six centromeres, a rarely reported structural

  17. Widespread parainflammation in human cancer

    Aran, Dvir; Lasry, Audrey; Zinger, Adar; Biton, Moshe; Pikarsky, Eli; Hellman, Asaf; Butte, Atul J; Ben-Neriah, Yinon

    2016-01-01

    Background Chronic inflammation has been recognized as one of the hallmarks of cancer. We recently showed that parainflammation, a unique variant of inflammation between homeostasis and chronic inflammation, strongly promotes mouse gut tumorigenesis upon p53 loss. Here we explore the prevalence of parainflammation in human cancer and determine its relationship to certain molecular and clinical parameters affecting treatment and prognosis. Results We generated a transcriptome signature to iden...

  18. Human papilloma virus, DNA methylation and microRNA expression in cervical cancer (Review)

    JIMÉNEZ-WENCES, HILDA; Peralta-Zaragoza, Oscar; Fernández-Tilapa, Gloria

    2014-01-01

    Cancer is a complex disease caused by genetic and epigenetic abnormalities that affect gene expression. The progression from precursor lesions to invasive cervical cancer is influenced by persistent human papilloma virus (HPV) infection, which induces changes in the host genome and epigenome. Epigenetic alterations, such as aberrant miRNA expression and changes in DNA methylation status, favor the expression of oncogenes and the silencing of tumor-suppressor genes. Given that some miRNA genes...

  19. Chromosomal aberration

    Chromosomal aberrations are classified into two types, chromosome-type and chromatid-type. Chromosom-type aberrations include terminal deletion, dicentric, ring and interstitial deletion, and chromatid-type aberrations include achromatic lesion, chromatid deletion, isochromatid deletion and chromatid exchange. Clastogens which induce chromosomal aberration are divided into ''S-dependent'' agents and ''S-independent''. It might mean whether they can induce double strand breaks independent of the S phase or not. Double strand breaks may be the ultimate lesions to induce chromosomal aberrations. Caffeine added even in the G2 phase appeared to modify the frequency of chromatid aberrations induced by X-rays and mitomycin C. Those might suggest that the G2 phase involves in the chromatid aberration formation. The double strand breaks might be repaired by ''G2 repair system'', the error of which might yield breakage types of chromatid aberrations and the by-pass of which might yield chromatid exchanges. Chromosome-type aberrations might be formed in the G1 phase. (author)

  20. Effects of 60Co γ-ray partial radiation on chromosome aberration in human peripheral blood in vitro

    Objective: To investigate the effects of 60Co γ-ray partial radiation on chromosome aberration in human peripheral blood in vitro. Methods: The samples of heparinized peripheral whole blood from 3 healthy persons were exposed to 60Co γ-rays at the doses between 0 and 8 Gy with the dose rate of 0.35 Gy/min at the temperature of 37 ℃ ,and then mixed with the unirradiated blood samples of the Microscopy was used to observe the chromosome aberration double (centromere + centromere) and the biological dose was estimated thereby. Results: The amounts of double centromere + centromere were increased along with the dose of irradiation in all groups. The estimated biological dose was higher than the 1/3 of the irradiation dose when the dose was between 0.5 to 2 Gy, and was close to the 1/3 of the irradiation dose when the dose was between 4 to 8 Gy. Conclusion: Chromosome aberration can be used as a biomarker in estimation of uneven irradiation. (authors)

  1. Influence of the shielding on the induction of chromosomal aberrations in human lymphocytes exposed to high-energy iron ions

    Computer code calculations based on biophysical models are commonly used to evaluate the effectiveness of shielding in reducing the biological damage caused by cosmic radiation in space flights. Biological measurements are urgently needed to benchmark the codes. We have measured the induction of chromosomal aberrations in human peripheral blood lymphocytes exposed in vitro to 56Fe-ion beams accelerated at the Heavy for Medical Accelerator in Chiba (HIMAC) synchrotron in Chiba. Isolated lymphocytes were exposed to the 500 MeV/n iron beam (dose range 0.1-1 Gy)after traversal of 0 to 8 g/cm2 of either polymethylmethacrylate (PMMA) (lucite, a common plastic material) or aluminum. Three PMMA shield thickness and one Al shield thickness were used. For comparison, cells were exposed to 200 MeV/n iron ions and to X-rays. Chromosomes were prematurely condensed by a phosphatase inhibitor (calyculin A) to avoid cell-cycle selection produced by the exposure to high-linear energy transfer (LET) heavy ion beams. Aberrations were scored in chromosomes 1, 2,and 4 following fluorescence in situ hybridization. The yield of chromosomal aberrations per unit dose at the sample position was poorly dependent on the shield thickness and material. However, the yield of aberrations per unit ion incident on the shield was increased by the shielding. This increase is associated to the increased dose-rate measured behind the shield as compared to the direct beam. These preliminary results prove that shielding can increase the effectiveness of heavy ions, and the damage is dependent upon shield thickness and material. (author)

  2. Status of human chromosome aberrations as a biological radiation dosimeter in the nuclear industry

    It seems that the determination of peripheral lymphocyte chriomosome aberration levels is now firmly established as a means of biological dosimetry of great value in many phases of the nuclear industry. In the case of large external exposure it can provide valuable quantitative estimates, as well as information on dose distribution and radiation quality. In the case of routine occupational exposures the technique is more qualitative, but is of value particularly in resolving uncertainties as to whether suspected overexposures did in fact occur. Where workers accumulate burdens of internal emitters, aberration analysis provides a valuable, though at present quite qualitative indicator. In spite of the expense of cytogenetic analyses, they are of sufficient value to justify much more widespread application, particularly in high risk situations

  3. Determination of chromatic aberration in the human eye by means of Fresnel propagation theory

    Mas Candela, David; Pérez Rodríguez, Jorge; Illueca Contri, Carlos; Espinosa Tomás, Julián; Hernández Poveda, Consuelo; Vázquez Ferri, Carmen; Miret Marí, Juan José

    2005-01-01

    In this communication, the authors have determined the longitudinal chromatic aberrations in real eyes. The method that has been used combines real data of corneal morphology, central thickness of crystalline lens and biometric measures of axial length together with numerical calculation of the propagation process. The curvature of the crystalline lens has been adjusted to different curvature models and refractive index distributions. The wavelength dependence of all ocular media has been mod...

  4. Influence of diagnostic roentgen doses on human chromosomes and influence of age on the aberration yield

    Urography was performed in 2 groups of patients (one comprising patients aged 7-18 years, the other patients aged 8-32 months) under constant conditions. The skin dose ranged between 1 and 4 R. Blood samples were taken before, immediately after and 24 hours after the irradiation. A significantly increased number of aberrant cells was found only in the blood samples taken 24 hours after irradiation. No age-dependent influence on the radiation sensitivity in vivo was found. (author)

  5. Immune checkpoints aberrations and gastric cancer; assessment of prognostic value and evaluation of therapeutic potentials.

    Abdel-Rahman, Omar

    2016-01-01

    Till now, the prognosis of advanced gastric cancer looked dreadful; thus the search for newer better approaches for this lethal disease has been a strategic target for cancer researchers. In recent years, important immunobiological aspects of the tumor have been revealed with the subsequent proposal of immune check point inhibitors to target these pathways. Clinically, unselected use of immune checkpoint inhibitors in gastric cancer has been deemed with failure; in contrast to the clear success of more recent studies reporting on the use of pembrolizumab in molecularly selected patients. This may illustrate that any future use of immune checkpoint inhibitors in gastric cancer has to be molecularly supported. This review provides a delicate dissection of the clinical and immunobiological considerations underlying the use of these agents in addition to a thorough review of the published clinical data of immune checkpoint inhibitors in gastric cancer. PMID:26321371

  6. Viruses and human cancer

    Gallo, R.C.; Haseltine, W.; Klein, G.; Zur Hausen, H.

    1987-01-01

    This book contains papers on the following topics: Immunology and Epidemiology, Biology and Pathogenesis, Models of Pathogenesis and Treatment, Simian and Bovine Retroviruses, Human Papilloma Viruses, EBV and Herpesvirus, and Hepatitis B Virus.

  7. DBGC: A Database of Human Gastric Cancer

    Chao Wang; Jun Zhang; Mingdeng Cai; Zhenggang Zhu; Wenjie Gu; Yingyan Yu; Xiaoyan Zhang

    2015-01-01

    The Database of Human Gastric Cancer (DBGC) is a comprehensive database that integrates various human gastric cancer-related data resources. Human gastric cancer-related transcriptomics projects, proteomics projects, mutations, biomarkers and drug-sensitive genes from different sources were collected and unified in this database. Moreover, epidemiological statistics of gastric cancer patients in China and clinicopathological information annotated with gastric cancer cases were also integrated...

  8. Human papillomavirus and genital cancer

    Rapose Alwyn

    2009-01-01

    Full Text Available Human papillomavirus (HPV is one of the most common sexually transmitted infections world-wide. Low-risk HPV-types are associated with genital warts. Persistent infection with high-risk HPV-types is associated with genital cancers. Smoking and HIV infection have consistently been associated with longer duration of HPV infection and risk for genital cancer. There is an increasing incidence of anal cancers, and a close association with HPV infection has been demonstrated. Receptive anal sex and HIV-positive status are associated with a high risk for anal cancer. Two HPV vaccines are now available and offer protection from infection by the HPV-types included in the vaccine. This benefit is maximally seen in young women who were uninfected prior to vaccination.

  9. Induction of chromosome aberrations in human lymphocytes by technetium-99m. In vitro and in vivo studies

    In Nuclear Medicine, total body dose calculated after a technetium 99m labeled pharmaceutical administration was very low. Nevertheless, risks evaluation of the radio-induced genetics damages at low doses has become a public health priority. Peripheral lymphocytes can be used to study the effects of ionizing radiations on human cells. The induction by ionizing radiations of unstable structural chromosome aberrations (dicentrics, centrics, and fragments) in peripheral blood lymphocytes is considered to be a useful technique to complete physical dosimetry, and presently is the most advanced biological dosimeter. The aim of the study was to evaluate the potential cytogenetic effects of in vitro and in vivo exposure to technetium 99m (99mTc). Firstly, to evaluate the level of 99mTc activity able to produce a significant number of unstable chromosomal aberrations, specific relationships between activity and number of unstable chromosomal aberrations was established in vitro. The whole blood in vitro irradiation procedure has been performed during 3 hours using microspheres labeled with increasing activities of 99mTc (0, 37, 74, 148, 296, and 444 MBq). Secondly, blood samples from 5 patients scheduled for benign bone disease scintigraphy were collected before and 6 hours after administration of 925 MBq of 99mTc-HDP. Both irradiated whole-blood samples obtained in vitro or in vivo are prepared for conventional scoring by classical Fluorescence Plus Giemsa. For in vivo study, 250 and 500 metaphases were scored respectively before and 6 hours after a bone scan undergone. For in vitro studies, 750 cells were scored per activity. The distribution of unstable chromosome aberrations after in vitro 99mTc irradiation follows a Poisson law. We observed no cytogenetic effect induced by clinical exposure to 99mTc 6 hours after administration versus the control point, as predicted by the in vitro results. Nevertheless, unstable anomalies are lethal to the cell and therefore are

  10. Induction of chromosome aberrations in human lymphocytes by technetium-99m. In vitro and in vivo studies

    Jacquet, N.; Petiet, A.; Colas-Linhart, N. [Universit Paris-7 (France). Faculte de Medecine Xavier Bichat; Guiraud-Vitaux, F.; Leroy, A.; Voisin, P.

    2000-05-01

    In Nuclear Medicine, total body dose calculated after a technetium 99m labeled pharmaceutical administration was very low. Nevertheless, risks evaluation of the radio-induced genetics damages at low doses has become a public health priority. Peripheral lymphocytes can be used to study the effects of ionizing radiations on human cells. The induction by ionizing radiations of unstable structural chromosome aberrations (dicentrics, centrics, and fragments) in peripheral blood lymphocytes is considered to be a useful technique to complete physical dosimetry, and presently is the most advanced biological dosimeter. The aim of the study was to evaluate the potential cytogenetic effects of in vitro and in vivo exposure to technetium 99m (99mTc). Firstly, to evaluate the level of 99mTc activity able to produce a significant number of unstable chromosomal aberrations, specific relationships between activity and number of unstable chromosomal aberrations was established in vitro. The whole blood in vitro irradiation procedure has been performed during 3 hours using microspheres labeled with increasing activities of 99mTc (0, 37, 74, 148, 296, and 444 MBq). Secondly, blood samples from 5 patients scheduled for benign bone disease scintigraphy were collected before and 6 hours after administration of 925 MBq of 99mTc-HDP. Both irradiated whole-blood samples obtained in vitro or in vivo are prepared for conventional scoring by classical Fluorescence Plus Giemsa. For in vivo study, 250 and 500 metaphases were scored respectively before and 6 hours after a bone scan undergone. For in vitro studies, 750 cells were scored per activity. The distribution of unstable chromosome aberrations after in vitro 99mTc irradiation follows a Poisson law. We observed no cytogenetic effect induced by clinical exposure to 99mTc 6 hours after administration versus the control point, as predicted by the in vitro results. Nevertheless, unstable anomalies are lethal to the cell and therefore are

  11. Structural Aberrations of Cellular Sialic Acids and TheirFunctions in Cancer Metastases

    2001-01-01

    Sialic acids (neuraminic acids) are a special series of 9-carbon ring negatively charged carbohydrates, which has been found to be selectively changed in malignant cells from structures (both synthesis and structure modifications) to functions (up and down regulation in cells). Sialic acids, in single forms or conjugates, have been systematically studied both in lab and in clinics by GC, GCMS, NMR, HPTLC, HPLC and other modern analytical means. Sialic acids and related conjugates are predicted to be used in cancer diagnosis, cancer prognostic forecasting, designing of cancer chemotherapy regimens, uncovering carcinogenetic processes and neoplasm metastasis. Tumor cell regulative systems and pathways are correlated with sialic acids, which can be applied to prognostic evaluation of cancer patients, and antimetastatic chemotherapy by sialic acid derivatives and analogues. Searching for new biological characteristics of sialic acids in cells have also been extensively studied these days. In this paper, main stream discoveries and advancements are provided , also discussions of possible mechanisms and hypotheses are invoked.

  12. HCSD: the human cancer secretome database

    Feizi, Amir; Banaei-Esfahani, Amir; Nielsen, Jens

    2015-01-01

    database is limiting the ability to query the increasing community knowledge. We therefore developed the Human Cancer Secretome Database (HCSD) to fulfil this gap. HCSD contains >80 000 measurements for about 7000 nonredundant human proteins collected from up to 35 high-throughput studies on 17 cancer......The human cancer secretome database (HCSD) is a comprehensive database for human cancer secretome data. The cancer secretome describes proteins secreted by cancer cells and structuring information about the cancer secretome will enable further analysis of how this is related with tumor biology. The...... secreted proteins from cancer cells are believed to play a deterministic role in cancer progression and therefore may be the key to find novel therapeutic targets and biomarkers for many cancers. Consequently, huge data on cancer secretome have been generated in recent years and the lack of a coherent...

  13. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells

    Lee, JK; Phillips, JW; Smith, BA; Park, JW; Stoyanova, T; McCaffrey, EF; Baertsch, R.; Sokolov, A.; Meyerowitz, JG; Mathis, C.; Cheng, D; Stuart, JM; Shokat, KM; Gustafson, WC; Huang, J.

    2016-01-01

    MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarci...

  14. Human Breast Cancer Cell Lines Co-Express Neuronal, Epithelial, and Melanocytic Differentiation Markers In Vitro and In Vivo

    Qingbei Zhang; Hanli Fan; Jikun Shen; Hoffman, Robert M.; H Rosie Xing

    2010-01-01

    Differentiation programs are aberrant in cancer cells allowing them to express differentiation markers in addition to their tissue of origin. In the present study, we demonstrate the multi-lineage differentiation potential of breast cancer cell lines to express multiple neuronal/glial lineage-specific markers as well as mammary epithelial and melanocytic-specific markers. Multilineage expression was detected in luminal (MCF-7 and SKBR3) and basal (MDA-MB-231) types of human breast cancer cell...

  15. Induction of chromosome aberration in human lymphocytes and its dependence on X ray energy

    The variations of dose response with X ray energy observed with the human lymphocyte dicentric assay is examined. In order to determine reliably the initial slopes (RBEm) many cells need to be analysed at low doses. Insufficient analysis may explain some reported interlaboratory differences in fitted dose-response coefficients. One such discrepancy at 150 kVp, E(mean) = 70 keV is examined. Data are also presented for an X ray spectrum of 80 kVp, E(mean) = 58 keV. Over the photon energy range 20 keV X rays to 1.25 MeV gamma rays RBEm varies by about a factor of 5, with the lower energies being more effective. This is consistent with microdosimetric theory. By contrast, in radiological protection a radiation weighting factor of 1.0 is assumed for all photons when assessing the risk of inducing cancer at low doses. The measured variations of biological effect with photon energy have led to suggestions that the lower energies, as used for some diagnostic radiology, carry a greater risk per unit dose than is normally assumed by those involved in radiological protection. Interpretation of the data reported in this paper does not support this view. (author)

  16. Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells.

    Choi, Dongwon; Ramu, Swapnika; Park, Eunkyung; Jung, Eunson; Yang, Sara; Jung, Wonhyeuk; Choi, Inho; Lee, Sunju; Kim, Kyu Eui; Seong, Young Jin; Hong, Mingu; Daghlian, George; Kim, Daniel; Shin, Eugene; Seo, Jung In; Khatchadourian, Vicken; Zou, Mengchen; Li, Wei; De Filippo, Roger; Kokorowski, Paul; Chang, Andy; Kim, Steve; Bertoni, Ana; Furlanetto, Tania Weber; Shin, Sung; Li, Meng; Chen, Yibu; Wong, Alex; Koh, Chester; Geliebter, Jan; Hong, Young-Kwon

    2016-02-01

    Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/β-catenin signaling but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 reexpression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression. PMID:26609053

  17. Aberrant promoter methylation of PPP1R3C and EFHD1 in plasma of colorectal cancer patients

    Aberrant DNA methylation is a common epigenetic alteration involved in colorectal cancer (CRC). In our previous study, we performed methylated DNA immunoprecipitation-on-chip analysis combined with gene re-expression analysis by 5-aza-2′-deoxycytidine treatment, to identify methylation genes in CRC genome widely. Among these genes, 12 genes showed aberrant hypermethylation frequently in >75% of 149 CRC samples but did not in normal samples. In this study, we aim to find out any of these methylation genes to be utilized for CRC detection using plasma DNA samples. Primers for methylation-specific PCR and pyrosequencing were designed for seven of the 12 genes. Among them, PPP1R3C and EFHD1 were rarely hypermethylated in peripheral blood cells, but frequently hypermethylated in 24 CRC tissue samples and their corresponding plasma samples. In plasma samples, PPP1R3C was methylated in 81% (97/120) of CRC patients, but only in 19% (18/96) of noncancer patients (P = 6 × 10−20, Fisher's exact test). In combined analysis with EFHD1, both genes were methylated in 53% (64/120) of CRC patients, but only in 4% (4/96) of noncancer patients (P = 2 × 10−16), giving high specificity of 96%. At least one of the two genes was methylated in 90% (108/120) of CRC patients, and 36% (35/96) of control patients, giving high sensitivity of 90%. Compared with low sensitivity of carcinoembryonic antigen (17% at stage I, 40% at stage II) and CA19-9 (0% at stage I, 13% at stage II) for early-stage CRCs, sensitivity of aberrant methylation was significantly higher: PPP1R3C methylation at 92% (11/12) for stage I and 77% (23/30) for stage II, and methylation of at least one gene at 100% (12/12) for stage I and 87% (26/30) for stage II. PPP1R3C methylation or its combined use of EFHD1 methylation was highly positive in CRC plasma samples, and they might be useful in detection of CRC, especially for early-stage CRCs

  18. In vitro radioprotective effects of histamine H2 receptor antagonists against gamma-rays induced chromosomal aberrations in human lymphocytes

    Background: Radioprotective capability of histamine H2 receptor antagonists have been shown in several in vivo studies mainly using animal models. However, to verify the effectiveness of these agents in clinical applications, studies should be performed on human lymphocytes using metaphase analysis. Materials and Methods: In vitro metaphase analysis technique was used to test the effects of cimetidine, ranitidine and famotidine on radiation induced clastogenic effects. Lymphocytes in whole peripheral blood were exposed to 3 Gy gamma-rays at a dose rate of 73.7 c Gy/min in the presence or absence of various doses of the drugs used in this study. The frequency of chromosomal aberrations were determined after standard metaphase preparations and staining slides in 5% Giemsa. Results: Results show that radiation produced a high number of chromosomal aberrations in lymphocytes compared to controls (p2-receptor antagonists used in this study effectively reduced the clastogenic effects of radiation with a dose reduction factor of 1.5-2 in human lymphocytes in vitro. The way in which these drugs reduce the clastogenic effects of radiation might be via radical scavenging mechanism

  19. Theoretical effect of refractive error and accommodation on longitudinal chromatic aberration of the human eye.

    Atchison, D A; Smith, G; Waterworth, M D

    1993-09-01

    Simple formulas based on reduced eyes have been developed to predict the variation in longitudinal chromatic aberration with variation in ametropia or accommodation. Two formulas were developed, one for axial ametropia and one for refractive ametropia. The latter also served as a model for accommodation. The results using the formulas are in close agreement with results obtained using raytracing through more sophisticated models. Combining the results of different methods gives the following predictions of change in chromatic difference of focus, between wavelengths of 400 and 700 nm, with change in each diopter of refractive error or accommodation: axial ametropia 0.012 to 0.017 D (0.6 to 0.9%), refractive ametropia 0.05 D (2.2 to 2.4%), and accommodation 0.04 to 0.05 D (2.1 to 2.6%). The chromatic aberration effects of correcting lenses with low dispersion are intermediate in effect and opposite in sign to the effects of corresponding degrees of axial ametropia and refractive ametropia. PMID:8233365

  20. Topoisomerase-1 gene copy aberrations are frequent in patients with breast cancer

    Kümler, Iben; Balslev, Eva; Poulsen, Tim S.; Nielsen, Signe Lykke; Nygård, Sune Boris; Rømer, Maria Unni; Christensen, Ib Jarle; Høgdall, Estrid; Moreira, José; Nielsen, Dorte Lisbet; Brünner, Nils; Stenvang, Jan

    2015-01-01

    Topoisomerase-1 (Top1) targeting drugs have shown promising efficacy in patients with metastatic breast cancer (BC). However, these drugs are rather toxic calling for development and validation of predictive biomarkers to increase the therapeutic index. As these drugs are targeting the Top1 prote....../centromere ratio. This article is protected by copyright. All rights reserved....

  1. Modulation of gamma ray induced chromosome aberrations in human peripheral blood lymphocytes by Hippophae rhammnoides leaf extract, SBL-1

    Hippophae rhammnoides L. commonly known as seabuckthorn is a temperate shrub and native of Asia and Europe. It has high antioxidant potential and is known to the traditional Indian, Chinese and Tibetan medicinal system for treatment of multiple disorders viz., circulatory and digestive disorders, hepatic injuries, neoplasia etc. One time treatment with the standardized leaf extract from H. rhammnoides (SBL-1) before whole body irradiation with 60Co (10 Gy), rendered more than 90% survival in non SBL-1 treated irradiated animals (J herbs, spices medi plants, 2009). Present study investigated the effects of SBL-1 treatment on chromosomal damage in human peripheral blood lymphocytes (PBL), with or without 60Co-gamma-radiation. The lymphocytes were isolated from the blood drawn from different donors. The isolated lymphocytes were divided into several groups: Group 1-untreated control, Group 2-irradiated (2 Gy), Group 3, 4 and 5 were treated with different concentration of SBL-1, 30 min. after irradiation with 60Co-gamma-rays (2 Gy). Group 6 was treated with the maximum concentration of SBL-1 used in the study. The metaphase spreading technique was used as per standard procedure to record chromosome breaks, dicentrics, acentrics and rings. The results were also recorded in terms of total aberrant metaphase and frequency of aberrant metaphase per 100 cells. In comparison to the untreated control, in the irradiated PBL culture, there was 8-fold increase in breaks, 211-folds in dicentrics, 75-folds in acentrics and 3-folds in rings (average data). SBL-1 alone at the highest concentration did not cause any significant change in number of breaks, dicentrics, acentrics and rings. The radiation induced aberrations decreased significantly by treatment with SBL-1 and the maximum decrease was observed when the cells were treated with 22μg/ml of SBL-1. These results demonstrated the anti-clastogenic activity of SBL-1 against gamma radiation induced damage. (author)

  2. MIR-9-1 ABERRANT METHYLATION IS A FREQUENT EVENT IN BREAST CANCER AND IS ASSOCIATED WITH BONE METASTASES

    Anca Florescu

    2012-03-01

    Full Text Available Abstract:Background. Aberrant promoter methylation of classical tumor suppressor genes occurs frequently during carcinogenesis. Several lines of evidences suggest that this epigenetic change also regulates microRNAs expression and may represent a potential molecular marker for cancer.Methods. We examined the methylation status at the hsa-miR-9-1 gene promoter in a series of 66 breast cancer cases by methylation sensitive PCR (MSP analysis. For 43 of the 66 patients paired normal breast tissue and/or pre invasive (ADH, DCIS lesions were also available. As control methylation status was determined on 6 normal breast tissues obtained from reductive mammoplasty.  Results. Methylation at mir-9-1 gene was detected in 32 out of 66 breast tumours (49% and in none of the 6 normal breast tissues derived from reductive mammoplasty (P=0.02 χ2- Test. In all cases the same methylation status was demonstrated in tumour specimen, paired normal breast tissues and/or pre-invasive (ADH and DCIS lesions. An higher frequency of methylation was found in patients showing metastases at diagnosis as compared with non metastatic patients (P=0.03 χ2-Test. Moreover, methylation at mir-9-1 gene was more frequent in patients showing bone metastases as first metastatic sites (P=0.04 χ2-Test, and in the subgroup of patients developing only bone metastases as compared with patients developing metastases  to visceral organs (P=0.03 χ2-Test.Conclusions. This study give further evidence of epigenetic mechanisms as regulators of miR-9 expression in breast cancer. Moreover, our results suggest an association between hypermethylation  at the miR-9-1 gene and metastatic site.

  3. Chromosome aberrations induced in human lymphocytes by U-235 fission neutrons: I. Irradiation of human blood samples in the "dry cell" of the TRIGA Mark II nuclear reactor.

    Fajgelj, A; Lakoski, A; Horvat, D; Remec, I; Skrk, J; Stegnar, P

    1991-11-01

    A set-up for irradiation of biological samples in the TRIGA Mark II research reactor in Ljubljana is described. Threshold activation detectors were used for characterisation of the neutron flux, and the accompanying gamma dose was measured by TLDs. Human peripheral blood samples were irradiated "in vitro" and biological effects evaluated according to the unstable chromosomal aberrations induced. Biological effects of two types of cultivation of irradiated blood samples, the first immediately after irradiation and the second after 96 h storage, were studied. A significant difference in the incidence of chromosomal aberrations between these two types of samples was obtained, while our dose-response curve fitting coefficients alpha 1 = (7.71 +/- 0.09) x 10(-2) Gy-1 (immediate cultivation) and alpha 2 = (11.03 +/- 0.08) x 10(-2) Gy-1 (96 h delayed cultivation) are in both cases lower than could be found in the literature. PMID:1962281

  4. Outsmarting androgen receptor: creative approaches for targeting aberrant androgen signaling in advanced prostate cancer

    Karen E Knudsen; Kelly, William Kevin

    2011-01-01

    Prostatic adenocarcinomas are reliant on androgen receptor (AR) activity for survival and progression. Therefore, first-line therapeutic intervention for disseminated disease entails the use of AR-directed therapeutics, achieved through androgen deprivation and direct AR antagonists. While initially effective, recurrent, ‘castrate-resistant’ prostate cancers arise, for which there is no durable means of treatment. An abundance of clinical study and preclinical modeling has led to the revelati...

  5. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts after Exposure to Very Low Doses of High LET Radiation

    Hada, M.; George, Kerry; Cucinotta, Francis A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivors with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (1-20 cGy) of 170 MeV/u Si-28- ions or 600 MeV/u Fe-56-ions. Chromosomes were analyzed using the whole chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving greater than 2 breaks in 2 or more chromosomes). The curves for doses above 10 cGy were fitted with linear or linear-quadratic functions. For Si-28- ions no dose response was observed in the 2-10 cGy dose range, suggesting a non-target effect in this range.

  6. Aberrant Free Radical Biology Is a Unifying Theme in the Etiology and Pathogenesis of Major Human Diseases

    Frederick E. Domann

    2013-04-01

    Full Text Available The seemingly disparate areas of oxygen toxicity, radiation exposure, and aging are now recognized to share a common feature—the aberrant production and/or removal of biologically derived free radicals and other reactive oxygen and nitrogen species (ROS/RNS. Advances in our understanding of the effects of free radicals in biology and medicine have been, and continue to be, actively translated into clinically tractable diagnostic and therapeutic applications. This issue is dedicated to recent advances, both basic discoveries and clinical applications, in the field of free radicals in biology and medicine. As more is understood about the proximal biological targets of aberrantly produced or removed reactive species, their sensors, and effectors of compensatory response, a great deal more will be learned about the commonalities in mechanisms underlying seemingly disparate disease states. Together with this deeper understanding, opportunities will arise to devise rational therapeutic interventions to decrease the incidence and severity of these diseases and positively impact the human healthspan.

  7. A Mouse Model for Human Anal Cancer

    Stelzer, Marie K.; Pitot, Henry C.; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F.

    2010-01-01

    Human anal cancers are associated with high-risk human papillomaviruses (HPVs) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncoge...

  8. Involvement of evolutionarily plastic regions in cancer associated CHR3 aberrations

    Darai-Ramqvist, Eva

    2007-01-01

    A functional test to identify tumor antagonizing regions on chromosome 3 (chr3), called the Elimination Test, was developed in our group. It is based on microcell mediated transfer of human chr3 into mouse or human tumor cells and analysis of the monochromosomal hybrids after their growth in vivo. We identified three regions on 3p14-p22, which were frequently lost in derived tumors (common or frequently eliminated regions). In order to understand the role of these regions in...

  9. Proteogenomic strategies for identification of aberrant cancer peptides using large-scale Next Generation Sequencing data

    Woo, Sunghee; Cha, Seong Won; Na, Seungjin; Guest, Clark; Liu, Tao; Smith, Richard D.; Rodland, Karin D.; Payne, Samuel H.; Bafna, Vineet

    2014-11-17

    Cancer is driven by the acquisition of somatic DNA lesions. Distinguishing the early driver mutations from subsequent passenger mutations is key to molecular sub-typing of cancers, and the discovery of novel biomarkers. The availability of genomics technologies (mainly wholegenome and exome sequencing, and transcript sampling via RNA-seq, collectively referred to as NGS) have fueled recent studies on somatic mutation discovery. However, the vision is challenged by the complexity, redundancy, and errors in genomic data, and the difficulty of investigating the proteome using only genomic approaches. Recently, combination of proteomic and genomic technologies are increasingly employed. However, the complexity and redundancy of NGS data remains a challenge for proteogenomics, and various trade-offs must be made to allow for the searches to take place. This paperprovides a discussion of two such trade-offs, relating to large database search, and FDR calculations, and their implication to cancer proteogenomics. Moreover, it extends and develops the idea of a unified genomic variant database that can be searched by any mass spectrometry sample. A total of 879 BAM files downloaded from TCGA repository were used to create a 4.34 GB unified FASTA database which contained 2,787,062 novel splice junctions, 38,464 deletions, 1105 insertions, and 182,302 substitutions. Proteomic data from a single ovarian carcinoma sample (439,858 spectra) was searched against the database. By applying the most conservative FDR measure, we have identified 524 novel peptides and 65,578 known peptides at 1% FDR threshold. The novel peptides include interesting examples of doubly mutated peptides, frame-shifts, and non-sample-recruited mutations, which emphasize the strength of our approach.

  10. Cancer associated aberrant protein o-glycosylation can modify antigen processing and immune response

    Madsen, Caroline B; Petersen, Cecilie; Lavrsen, Kirstine;

    2012-01-01

    response to a cancer related tumor antigen, Balb/c or B6.Cg(CB)-Tg(HLA-A/H2-D)2Enge/J (HLA-A2 transgenic) mice were immunized with a non-glycosylated or GalNAc-glycosylated MUC1 derived peptide followed by comparison of T cell proliferation, IFN-¿ release, and antibody induction. Gal...... abolished MUC1 specific CD8+ T cell responses in HLA-A2 transgenic mice. GalNAc glycosylation of MUC1 antigen therefore facilitates uptake, MHC class II presentation, and antibody response but might block the antigen presentation to CD8+ T cells....

  11. Identification of new cancer biomarkers based on aberrant mucin glycoforms by in situ proximity ligation

    Pinto, Rita; Carvalho, Ana S; Conze, Tim;

    2012-01-01

    ) based on existing monoclonal antibodies directed to MUC1, MUC2, MUC5AC and MUC6 mucins and to cancer-associated carbohydrate antigens Tn, Sialyl-Tn (STn), T, Sialyl-Le(a) (SLe(a) ) and Sialyl-Le(x) (SLe(x) ) we screened a series of 28 mucinous adenocarcinomas from different locations (stomach, ampulla...... of Vater, colon, lung, breast and ovary) to detect specific mucin glycoforms. We detected Tn/STn/SLe(a) /SLe(x) -MUC1 and STn/SLe(a) /SLe(x) -MUC2 glycoforms in $50% of the cases, with a variable distribution among organs. Some new glycoforms-T/SLe(a) -MUC2, STn/T/SLe(a) /SLe(x) -MUC5AC and STn......Mucin glycoproteins are major secreted or membrane-bound molecules that, in cancer, show modifications in both the mucin proteins expression and in the O-glycosylation profile, generating some of the most relevant tumour markers in clinical use for decades. Thus far, the identification of these...

  12. MUC1-C ONCOPROTEIN INDUCES TAMOXIFEN RESISTANCE IN HUMAN BREAST CANCER CELLS

    Kharbanda, Akriti; Rajabi, Hasan; Jin, Caining; Raina, Deepak; Kufe, Donald

    2013-01-01

    Resistance of estrogen receptor positive (ER+) breast cancer cells to tamoxifen has been linked in part to activation of (i) certain receptor tyrosine kinases, such as HER2, and (ii) the PI3K→AKT pathway. Mucin 1 (MUC1) is aberrantly overexpressed in about 90% of human breast cancers and the oncogenic MUC1-C subunit associates with ERα. The present studies using HER2 overexpressing BT-474 breast cancer cells, which are constitutively resistant to tamoxifen, demonstrate that silencing MUC1-C i...

  13. Aberrant septin 9 DNA methylation in colorectal cancer is restricted to a single CpG island

    The septin 9 gene (SEPT9) codes for a GTP-binding protein associated with filamentous structures and cytoskeleton formation. SEPT9 plays a role in multiple cancers as either an oncogene or a tumor suppressor gene. Regulation of SEPT9 expression is complex and not well understood; however, hypermethylation of the gene was recently introduced as a biomarker for early detection of colorectal cancer (CRC) and has been linked to cancer of the breast and of the head and neck. Because the DNA methylation landscape of different regions of SEPT9 is poorly understood in cancer, we analyzed the methylation patterns of this gene in distinct cell populations from normal and diseased colon mucosa. Laser capture microdissection was performed to obtain homogeneous populations of epithelial and stromal cells from normal, adenomatous, and tumorous colon mucosa. Microdissected samples were analyzed using direct bisulfite sequencing to determine the DNA methylation status of eight regions within and near the SEPT9 gene. Septin-9 protein expression was assessed using immunohistochemistry (IHC). Regions analyzed in SEPT9 were unmethylated in normal tissue except for a methylation boundary detected downstream of the largest CpG island. In adenoma and tumor tissues, epithelial cells displayed markedly increased DNA methylation levels (>80%, p <0.0001) in only one of the CpG islands investigated. SEPT9 methylation in stromal cells increased in adenomatous and tumor tissues (≤50%, p <0.0001); however, methylation did not increase in stromal cells of normal tissue close to the tumor. IHC data indicated a significant decrease (p <0.01) in Septin-9 protein levels in epithelial cells derived from adenoma and tumor tissues; Septin-9 protein levels in stromal cells were low in all tissues. Hypermethylation of SEPT9 in adenoma and CRC specimens is confined to one of several CpG islands of this gene. Tumor-associated aberrant methylation originates in epithelial cells; stromal cells appear to

  14. Dose-rate effect on chromosomal aberrations induced by 60Co γ-rays irradiation in human peripheral blood lymphocyte

    To estimate exactly the biological dose of persons exposed to different dose rate, human peripheral blood was exposed to 60Co γ-rays in vitro at low, middle and high dose rates respectively and chromosome samples were prepared, then dose-response curves were established according to the dicentrics and ring frequencies. The result showed that the aberration frequency at same dose level increased with dose rate and there was an obvious dose-rate effect. Absorbed dose estimated with low dose-rate dose-response curve was higher markedly than that with high dose-rate dose-response curve. So, considering the effect of dose-rate, approximate dose-rate dose-response curve should be chosen when absorbed dose estimation and the result will be credible. (authors)

  15. Structural chromosomal aberrations as potential risk markers in incident cancer patients

    Vodenková, Soňa; Polívková, Z.; Musak, L.; Smerhovský, Z.; Zoubková, H.; Sytarová, S.; Kavcová, E.; Halasová, E.; Vodičková, Ludmila; Jirásková, Kateřina; Svoboda, Miroslav; Ambruš, M.; Hemminki, K.; Vodička, Pavel

    2015-01-01

    Roč. 30, č. 4 (2015), s. 557-563. ISSN 0267-8357 R&D Projects: GA MŠk(CZ) LD14050 Institutional support: RVO:68378041 Keywords : peripheral-blood lymphocytes * dna-repair genes * healthy humans * polymorphisms * frequency * damage * biomarkers * association * carcinogens * instability Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.793, year: 2014

  16. Aberrant expression of Cx43 is associated with the peritoneal metastasis of gastric cancer and Cx43-mediated gap junction enhances gastric cancer cell diapedesis from peritoneal mesothelium.

    Bo Tang

    Full Text Available The process of peritoneal metastasis involves the diapedesis of intra-abdominal exfoliated gastric cancer cells through the mesothelial cell monolayers; however, the related molecular mechanisms for this process are still unclear. Heterocellular gap-junctional intercellular communication (GJIC between gastric cancer cells and mesothelial cells may play an active role during diapedesis. In this study we detected the expression of connexin 43 (Cx43 in primary gastric cancer tissues, intra-abdominal exfoliated cancer cells, and matched metastatic peritoneal tissues. We found that the expression of Cx43 in primary gastric cancer tissues was significantly decreased; the intra-abdominal exfoliated cancer cells and matched metastatic peritoneal tissues exhibited increasing expression compared with primary gastric cancer tissues. BGC-823 and SGC-7901 human gastric cancer cells were engineered to express Cx43 or Cx43T154A (a mutant protein that only couples gap junctions but provides no intercellular communication and were co-cultured with human peritoneal mesothelial cells (HPMCs. Heterocellular GJIC and diapedesis through HPMC monolayers on matrigel-coated coverslips were investigated. We found that BGC-823 and SGC-7901 gastric cancer cells expressing Cx43 formed functional heterocellular gap junctions with HPMC monolayers within one hour. A significant increase in diapedesis was observed in engineered Cx43-expressing cells compared with Cx43T154A and control group cells, which suggested that the observed upregulation of diapedesis in Cx43-expressing cells required heterocellular GJIC. Further study revealed that the gastric cancer cells transmigrated through the intercellular space between the mesothelial cells via a paracellular route. Our results suggest that the abnormal expression of Cx43 plays an essential role in peritoneal metastasis and that Cx43-mediated heterocellular GJIC between gastric cancer cells and mesothelial cells may be an

  17. Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in gastric cancer

    Song, Binbin; Ai, Jiang; Kong, Xianghong; Liu, Dexin; Li, Jun

    2013-01-01

    Objective: We aimed to explore the association of P16, MGMT and HMLH1 with gastric cancer and their relation with Methylenetetrahydrofolate reductase (MTHFR). Methods: 322 gastric patients who were confirmed with pathological diagnosis were included in our study. Aberrant DNA methylation of P16, MGMT and HMLH1 and polymorphisms of MTHFR C677T and A1298C were detected using PCR-RFLP. Results: The proportions of DNA hypermethylation in P16, MGMT and hMLH1 genes in gastric cancer tissues were 75...

  18. Chromosome aberrations induced in human lymphocytes by U-235 fission neutrons. Pt. 3. Evaluation of the effect of the induced α and β activity on the chromosomal aberration yield

    Aim: Further experiments were performed to explain a difference in chromosomal aberration yield found between samples cultivated immediately after fission neutron irradiation and samples which were cultivated with 96 h delay after irradiation. Material and Method: Human peripheral blood samples were irradiated in mixed fission neutron/gamma field (1800 s) and biological effect assessed in the mean of analysis of unstable chromosome aberrations with a time delay in culturing cells of 12, 24, 48 and 96 h. Additional measurements were performed on irradiated and blank blood samples with the aim to detect any increase in α and β activity after fission neutron irradiation. No difference was found. Results were compared to theoretically calculated values of the α and β activity released from natural radioactive isotopes. Result and Conclusion: As a conclusion it is shown that in our experimental conditions the secondary effects resulting from nuclear transformations of natural or induced radioactive isotopes, recoil reactions and accompanying α, β, and γ radiation are not the reason for the increase observed in chromosomal aberration yield in blood samples cultured with a time delay of at least 24 hours. (orig.)

  19. Aberrant methylation frequency of TNFRSF10C promoter in pancreatic cancer cell lines

    Hui-Hua Cai; Yue-Ming Sun; Yi Miao; Wen-Tao Gao; Quan Peng; JieYao; Han-Lin Zhao

    2011-01-01

    BACKGROUND: A growing body of evidence suggests that many tumors are initiated by both epigenetic abnormalities and gene mutations, which promote tumor progression. Epigenetic abnormalities include changes in DNA methylation and in the modification of histones. This study aimed to assess the status of methylation in the CpG island (CGI) of the tumor necrosis factor receptor superfamily member 10c (TNFRSF10C) with combined bisulfite restriction analysis (COBRA) and to evaluate its role in the progression of pancreatic cancer (PC). METHODS: The methylation status of four PC cell lines was assessed using COBRA and/or bisulfite genomic sequencing (BGS). Changes in methylation and TNFRSF10C expression in PC cell lines before and after treatment with 5-aza-2'-deoxycytidine (5-aza-dC) and/or trichostatin A (TSA) were assessed by BGS and real-time RT-PCR. Apoptosis in the four cell lines was tested by flow cytometry (FCM) and TUNEL assay. RESULTS: The methylation status of the TNFRSF10C promoter was assessed in PC cells (BxPC-3: 68.84±8.71%; CFPAC-1: 0;PANC-1: 96.77±4.57%; SW1990: 54.97±7.33%) with the COBRA assay, which was confirmed by the results of BGS. After treatment with 5-aza-dC and/or TSA, apoptosis was induced in PC cells to different degrees, and the levels of TNFRSF10C transcriptional expression in the PC cell lines (except CFPAC-1) increased markedly after 5-aza-dC treatment. CONCLUSIONS: A high frequency of CGI methylation in the TNFRSF10C promoter results in inactivation of the gene and enhancement of tumor growth in most PC cell lines (except CFPAC-1). Inactivation of TNFRSF10C by CGI hypermethylation can play an important role in PC progression and be potentially useful as a diagnostic marker and a new therapeutic approach for PC.

  20. Influence of duration of fixation on the yield of chromosome aberrations in human lumphocyte culture exposed to γ-radiation at different mitotic cycle stages

    A comparative study was made of the yield of chromosome aberrations in human lymphocyte culture exposed to 60Co- γ-rays (2 Gy) at different mitotic cycle stages the cells being fixed after 52 and 60 hr. It was shown that with the latter fixation time (60 hr) the frequency of chromosome aberrations after irradiation in G1 stage was substantially lower than that with the former one (52 hr) and, vice versa, it was higher after irradiation in S and G2 stages. The authors discuss the probable causes of the distinctions observed

  1. Influence of duration of fixation on the yield of chromosome aberrations in human lumphocyte culture exposed to. gamma. -radiation at different mitotic cycle stages

    Sevan' kaev, A.V.; Bogatykh, B.A.; Lychev, V.A. (Akademiya Meditsinskikh Nauk SSSR, Obninsk. Nauchno-Issledovatel' skij Inst. Meditsinskoj Radiologii)

    A comparative study was made of the yield of chromosome aberrations in human lymphocyte culture exposed to /sup 60/Co- ..gamma..-rays (2 Gy) at different mitotic cycle stages the cells being fixed after 52 and 60 hr. It was shown that with the latter fixation time (60 hr) the frequency of chromosome aberrations after irradiation in G/sub 1/ stage was substantially lower than that with the former one (52 hr) and, vice versa, it was higher after irradiation in S and G/sub 2/ stages. The authors discuss the probable causes of the distinctions observed.

  2. Screening human populations for chromosome aberrations. Final report, March 1, 1982-August 31, 1985

    The potential use of screening lymphocytes for micronuclei for estimating radiation doses in human populations was evaluated. A modified harlequin stain was developed which permitted direct recognition of lymphocytes which had proliferated. 4 refs. (DT)

  3. Identification of Novel Breast Cancer Subtype-Specific Biomarkers by Integrating Genomics Analysis of DNA Copy Number Aberrations and miRNA-mRNA Dual Expression Profiling

    Dongguo Li

    2015-01-01

    Full Text Available Breast cancer is a heterogeneous disease with well-defined molecular subtypes. Currently, comparative genomic hybridization arrays (aCGH techniques have been developed rapidly, and recent evidences in studies of breast cancer suggest that tumors within gene expression subtypes share similar DNA copy number aberrations (CNA which can be used to further subdivide subtypes. Moreover, subtype-specific miRNA expression profiles are also proposed as novel signatures for breast cancer classification. The identification of mRNA or miRNA expression-based breast cancer subtypes is considered an instructive means of prognosis. Here, we conducted an integrated analysis based on copy number aberrations data and miRNA-mRNA dual expression profiling data to identify breast cancer subtype-specific biomarkers. Interestingly, we found a group of genes residing in subtype-specific CNA regions that also display the corresponding changes in mRNAs levels and their target miRNAs’ expression. Among them, the predicted direct correlation of BRCA1-miR-143-miR-145 pairs was selected for experimental validation. The study results indicated that BRCA1 positively regulates miR-143-miR-145 expression and miR-143-miR-145 can serve as promising novel biomarkers for breast cancer subtyping. In our integrated genomics analysis and experimental validation, a new frame to predict candidate biomarkers of breast cancer subtype is provided and offers assistance in order to understand the potential disease etiology of the breast cancer subtypes.

  4. Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer.

    Dimitra T Stefanou

    Full Text Available Ovarian carcinoma (OC is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780 and one resistant (A2780/C30 to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs from OC patients, sensitive (n = 7 or resistant (n = 4 to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9 were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05. Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03. Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05. We conclude

  5. Telomerase activity in human cancer

    Griffith, J.

    2000-10-01

    The overall goal of this collaborative project was to investigate the role in malignant cells of both chromosome telomeres, and telomerase, the enzyme that replicates telomeres. Telomeres are highly conserved nucleoprotein complexes located at the ends of eucaryotic chromosomes. Telomere length in somatic cells is reduced by 40--50 nucleotide pairs with every cell division due to incomplete replication of terminal DNA sequences and the absence of telomerase, the ribonucleoprotein that adds telomere DNA to chromosome ends. Although telomerase is active in cells with extended proliferative capacities, including more than 85% of tumors, work performed under this contract demonstrated that the telomeres of human cancer cells are shorter than those of paired normal cells, and that the length of the telomeres is characteristic of particular types of cancers. The extent of telomere shortening ostensibly is related to the number of cell divisions the tumor has undergone. It is believed that ongoing cell proliferation leads to the accumulation and fixation of new mutations in tumor cell lineages.Therefore, it is not unreasonable to assume that the degree of phenotypic variability is related to the proliferative history of the tumor, and therefore to telomere length, implying a correlation with prognosis. In some human tumors, short telomeres are also correlated with genomic instabilities, including interstitial chromosome translocation, loss of heterozygosity, and aneuoploidy. Moreover, unprotected chromosome ends are highly recombinogenic and telomere shortening in cultured human cells correlates with the formation of dicentric chromosomes, suggesting that critically short telomeres not only identify, but also predispose, cells to genomic instability, again implying a correlation with prognosis. Therefore, telomere length or content could be an important predictor of metastatic potential or responsiveness to various therapeutic modalities.

  6. Aberrant upregulation of 14-3-3ơ expression serves as an inferior prognostic biomarker for gastric cancer

    Li Hai-gang

    2011-09-01

    Full Text Available Abstract Background 14-3-3ơ is an intracellular, phosphoserine binding protein and proposed to be involved in tumorigenesis. However, the expression dynamics of 14-3-3ơ and its clinicopathological/prognostic significance in human tumors are still controversial. Methods The method of immunohistochemistry (IHC and Western blot were utilized to examine the protein expression of 14-3-3ơ in gastric cancer and paired normal adjacent gastric mucosal tissues. Receive operating characteristic (ROC curve analysis was employed to determine a cutoff score for 14-3-3ơ expression in a training set (n = 66. For validation, the ROC-derived cutoff score was subjected to analysis of the association of 14-3-3ơ expression with patient outcome and clinical characteristics in a testing set (n = 86 and overall patients (n = 152. Results The expression frequency and expression levels of 14-3-3ơ were significantly higher in gastric cancer than in normal gastric mucosal tissues. Correlation analysis demonstrated that high expression of 14-3-3ơ in gastric cancer was significantly correlated with clinical stage and tumor invasion. Furthermore, in the testing set and overall patients, Kaplan-Meier analysis showed that elevated 14-3-3ơ expression predicted poorer overall survival (OS and progression-free survival (PFS. Importantly, high 14-3-3ơ expression was also associated with shortened survival time in stage III and stage IV gastric cancer patients. Multivariate analyses revealed that 14-3-3ơ expression was an independent prognostic parameter in gastric cancer. Conclusions These findings provide evidence that high expression of 14-3-3ơ may be important in the tumor progression and servers as an independent molecular marker for poor prognosis of gastric cancer. Thus, overexpression of 14-3-3ơ identifies patients at high risk and is a novel therapeutic molecular target for this tumor.

  7. Human sperm chromosomes. Long-term effect of cancer treatment

    The long-term cytogenetic effect of radio- or chemotherapy or both on male germ cells was evaluated by study of the chromosomal abnormalities in spermatozoa of four men treated for cancer 5-18 years earlier. The cytogenetic analysis of 422 sperm metaphases showed no differences in the aneuploidy rate. The incidence of structural chromosome aberrations was 14.0%, however, which is much higher than in controls. Thus, the high incidence of structurally aberrant spermatozoa observed in our long-term study indicates that antitumoral treatments affect stem-cell spermatogonia and that aberrant cells can survive germinal selection and produce abnormal spermatozoa

  8. Somatic Mutaome Profile in Human Cancer Tissues

    Kim, Nayoung; Hong, Yourae; Kwon, Doyoung; Yoon, Sukjoon

    2013-01-01

    Somatic mutation is a major cause of cancer progression and varied responses of tumors against anticancer agents. Thus, we must obtain and characterize genome-wide mutational profiles in individual cancer subtypes. The Cancer Genome Atlas database includes large amounts of sequencing and omics data generated from diverse human cancer tissues. In the present study, we integrated and analyzed the exome sequencing data from ~3,000 tissue samples and summarized the major mutant genes in each of t...

  9. Stem cells in human breast cancer

    Roberto Oliveira, Lucinei; Jeffrey, Stefanie S; Ribeiro Silva, Alfredo

    2010-01-01

    Increasing data support cancer as a stem cell-based disease. Cancer stem cells (CSCs) have beenfound in different human cancers, and recent evidenceindicates that breast cancer originates from and ismaintained by its own CSCs, as well as the normalmammary gland. Mammary stem cells and breast CSCshave been identified and purified in in vitroculturesystems, transplantation assays and/or by cell surfaceantigen identification. Cell surface markers enable thefunctional isolation of stem cells that...

  10. Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells

    Björkman, Andrea; Qvist, Per; Du, Likun;

    2015-01-01

    machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of...... underlying BRCA1’s function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis....

  11. Effect of phenylhexyl isothiocyanate on aberrant histone H3 methylation in primary human acute leukemia

    Zou Yong

    2012-07-01

    Full Text Available Abstract Background We have previously studied the histone acetylation in primary human leukemia cells. However, histone H3 methylation in these cells has not been characterized. Methods This study examined the methylation status at histone H3 lysine 4 (H3K4 and histone H3 lysine 9 (H3K9 in primary acute leukemia cells obtained from patients and compared with those in the non-leukemia and healthy cells. We further characterized the effect of phenylhexyl isothiocyanate (PHI, Trichostatin A (TSA, and 5-aza-2’-deoxycytidine (5-Aza on the cells. Results We found that methylation of histone H3K4 was virtually undetectable, while methylation at H3K9 was significantly higher in primary human leukemia cells. The histone H3K9 hypermethylation and histone H3K4 hypomethylation were observed in both myeloid and lymphoid leukemia cells. PHI was found to be able to normalize the methylation level in the primary leukemia cells. We further showed that PHI was able to enhance the methyltransferase activity of H3K4 and decrease the activity of H3K9 methyltransferase. 5-Aza had similar effect on H3K4, but minimal effect on H3K9, whereas TSA had no effect on H3K4 and H3K9 methyltransferases. Conclusions This study revealed opposite methylation level of H3K4 and H3K9 in primary human leukemia cells and demonstrated for the first time that PHI has different effects on the methyltransferases for H3K4 and H3K9.

  12. Estrogen induces Vav1 expression in human breast cancer cells.

    Ming-juan Du

    Full Text Available Vav1, a guanine nucleotide exchange factor (GEF for Rho family GTPases, is a hematopoietic protein involved in a variety of cellular events. In recent years, aberrant expression of Vav1 has been reported in non-hematopoietic cancers including human breast cancer. It remains to be answered how Vav1 is expressed and what Vav1 does in its non-resident tissues. In this study, we aimed to explore the mechanism for Vav1 expression in breast cancer cells in correlation with estrogen-ER pathway. We not only verified the ectopic expression of Vav1 in human breast cancer cell lines, but also observed that Vav1 expression was induced by 17β-estradiol (E2, a typical estrogen receptor (ER ligand, in ER-positive cell lines. On the other hand, Tamoxifen, a selective estrogen receptor modulator (SERM, and ICI 182,780, an ER antagonist, suppressed the expression of Vav1. The estrogen receptor modulating Vav1 expression was identified to be α form, not β. Furthermore, treatment of E2 increased the transcription of vav1 gene by enhancing the promoter activity, though there was no recognizable estrogen response element (ERE. Nevertheless, two regions at the vav1 gene promoter were defined to be responsible for E2-induced activation of vav1 promoter. Chromatin immunoprecipitation (ChIP and co-immunoprecipitation (Co-IP analyses suggested that ERα might access to the vav1 promoter via interacting with transcription factors, c-Myb and ELF-1. Consequently, the enhanced expression of Vav1 led to the elevation of Cyclin D1 and the progression of cell cycle. The present study implies that estrogen-ER modulates the transcription and expression of Vav1, which may contribute to the proliferation of cancerous cells.

  13. Enhanced oxidative stress and aberrant mitochondrial biogenesis in human neuroblastoma SH-SY5Y cells during methamphetamine induced apoptosis

    Methamphetamine (METH) is an abused drug that may cause psychiatric and neurotoxic damage, including degeneration of monoaminergic terminals and apoptosis of non-monoaminergic cells in Brain. The cellular and molecular mechanisms underlying these METH-induced neurotoxic effects remain to be clarified. In this study, we performed a time course assessment to investigate the effects of METH on intracellular oxidative stress and mitochondrial alterations in a human dopaminergic neuroblastoma SH-SY5Y cell line. We characterized that METH induces a temporal sequence of several cellular events including, firstly, a decrease in mitochondrial membrane potential within 1 h of the METH treatment, secondly, an extensive decline in mitochondrial membrane potential and increase in the level of reactive oxygen species (ROS) after 8 h of the treatment, thirdly, an increase in mitochondrial mass after the drug treatment for 24 h, and finally, a decrease in mtDNA copy number and mitochondrial proteins per mitochondrion as well as the occurrence of apoptosis after 48 h of the treatment. Importantly, vitamin E attenuated the METH-induced increases in intracellular ROS level and mitochondrial mass, and prevented METH-induced cell death. Our observations suggest that enhanced oxidative stress and aberrant mitochondrial biogenesis may play critical roles in METH-induced neurotoxic effects

  14. Optimization of human cancer radiotherapy

    Swan, George W

    1981-01-01

    The mathematical models in this book are concerned with a variety of approaches to the manner in which the clinical radiologic treatment of human neoplasms can be improved. These improvements comprise ways of delivering radiation to the malignan­ cies so as to create considerable damage to tumor cells while sparing neighboring normal tissues. There is no unique way of dealing with these improvements. Accord­ ingly, in this book a number of different presentations are given. Each presentation has as its goal some aspect of the improvement, or optimization, of radiotherapy. This book is a collection of current ideas concerned with the optimization of human cancer radiotherapy. It is hoped that readers will build on this collection and develop superior approaches for the understanding of the ways to improve therapy. The author owes a special debt of thanks to Kathy Prindle who breezed through the typing of this book with considerable dexterity. TABLE OF CONTENTS Chapter GENERAL INTRODUCTION 1. 1 Introduction 1...

  15. Aberrant sialylation of a prostate-specific antigen: Electrochemical label-free glycoprofiling in prostate cancer serum samples.

    Pihikova, Dominika; Kasak, Peter; Kubanikova, Petra; Sokol, Roman; Tkac, Jan

    2016-08-31

    Electrochemical detection method allowing to detect prostate-specific antigen (PSA), a biomarker of prostate cancer (PCa), with PSA glycoprofiling was applied in an analysis of PCa serum samples for the first time. Electrochemical impedance spectroscopy (EIS) as a label-free method with immobilized anti-PSA was applied for PSA detection and lectins to glycoprofile captured PSA on the same surface. A proper choice of blocking agent providing high selectivity of biosensor detection with the immobilized anti-PSA antibody was done. The biosensor could detect PSA down to 100 ag/mL with a linear concentration working range from 100 ag/mL up to 1 μg/mL, i.e. 10 orders of concentration magnitude and the sensitivity of (5.5 ± 0.2)%/decade. The results showed that a commercial carbo-free blocking solution was the best one, reducing non-specific binding 55-fold when compared to the immunosensor surface without any blocking agent applied, while allowing to detect PSA. The biosensor response obtained after addition of lectin (i.e. proportional to the amount of a particular glycan on PSA) divided by the biosensor response obtained after incubation with a sample (i.e. proportional to the PSA level in the sample) was applied to distinguish serum samples of PCa patients from those of healthy individuals. The results showed that Maackia amurensis agglutinin (MAA) recognizing α-2,3-terminal sialic acid can be applied to distinguish between these two sets of samples since the MAA/PSA response obtained from the analysis of the PCa samples was significantly higher (5.3-fold) compared to the MAA/PSA response obtained by the analysis of samples from healthy individuals. Thus, combined analysis of serological PSA levels together with PSA glycoprofiling of aberrant glycosylation of PSA (i.e. increase in the level of α-2,3-terminal sialic acid) has a potential to improve detection of PCa. PMID:27506346

  16. Relationship of immunohistochemistry, copy number aberrations and epigenetic disorders with BRCAness pattern in hereditary and sporadic breast cancer.

    Murria Estal, Rosa; Palanca Suela, Sarai; de Juan Jiménez, Inmaculada; Alenda Gonzalez, Cristina; Egoavil Rojas, Cecilia; García-Casado, Zaida; López Guerrero, Jose Antonio; Juan Fita, María José; Sánchez Heras, Ana Beatriz; Segura Huerta, Ángel; Santaballa Bertrán, Ana; Chirivella González, Isabel; Llop García, Marta; Pérez Simó, Gema; Barragán González, Eva; Bolufer Gilabert, Pascual

    2016-04-01

    The study aims to identify the relevance of immunohistochemistry (IHC), copy number aberrations (CNA) and epigenetic disorders in BRCAness breast cancers (BCs). We studied 95 paraffin included BCs, of which 41 carried BRCA1/BRCA2 germline mutations and 54 were non hereditary (BRCAX/Sporadic). Samples were assessed for BRCA1ness and CNAs by Multiplex Ligation-dependent Probe Amplification (MLPA); promoter methylation (PM) was assessed by methylation-specific-MLPA and the expression of miR-4417, miR-423-3p, miR-590-5p and miR-187-3p by quantitative RT-PCR. IHC markers Ki67, ER, PR, HER2, CK5/6, EGFR and CK18 were detected with specific primary antibodies (DAKO, Denmark). BRCAness association with covariates was performed using multivariate binary logistic regression (stepwise backwards Wald option). BRCA1/2 mutational status (p = 0.027), large tumor size (p = 0.041) and advanced histological grade (p = 0.017) among clinic-pathological variables; ER (p < 0.001) among IHC markers; MYC (p < 0.001) among CNA; APC (p = 0.065), ATM (p = 0.014) and RASSF1 (p = 0.044) among PM; and miR-590-5p (p = 0.001), miR-4417 (p = 0.019) and miR-423 (p = 0.013) among microRNA expression, were the selected parameters significantly related with the BRCAness status. The logistic regression performed with all these parameters selected ER+ as linked with the lack of BRCAness (p = 0.001) and MYC CNA, APC PM and miR-590-5p expression with BRCAness (p = 0.014, 0.045 and 0.007, respectively). In conclusion, the parameters ER expression, APC PM, MYC CNA and miR-590-5p expression, allowed detection of most BRCAness BCs. The identification of BRCAness can help establish a personalized medicine addressed to predict the response to specific treatments. PMID:26723934

  17. Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in gastric cancer

    Song, Binbin; Ai, Jiang; Kong, Xianghong; Liu, Dexin; Li, Jun

    2013-01-01

    Objective: We aimed to explore the association of P16, MGMT and HMLH1 with gastric cancer and their relation with Methylenetetrahydrofolate reductase (MTHFR). Methods: 322 gastric patients who were confirmed with pathological diagnosis were included in our study. Aberrant DNA methylation of P16, MGMT and HMLH1 and polymorphisms of MTHFR C677T and A1298C were detected using PCR-RFLP. Results: The proportions of DNA hypermethylation in P16, MGMT and hMLH1 genes in gastric cancer tissues were 75.2% (242/322), 27.6% (89/322) and 5.3% (17/322), respectively. In the remote normal-appearing tissues, 29.5% (95/322) and 16.1%(52/322) showed hypermethylation in P16 and MGMT genes, respectively. We found a significantly higher proportion of DNA hypermethylation of P16 in patients with N1 TNM stage in cancer tissues and remote normal-appearing tissues (P<0.05). Similarly, we found DNA hypermethylation of MGMT had significantly higher proportion in N1 and M1 TNM stage (P<0.05). Individuals with homozygotes (TT) of MTHFR C677T had significant risk of DNA hypermethylation of MGMT in cancer tissues [OR (95% CI)=4.27(1.76-7.84)], and a significant risk was also found in those carrying MTHFR 677CT/TT genotype [OR (95% CI)= 3.27(1.21-4.77)]. Conclusion: We found the aberrant hypermethylation of cancer-related genes, such as P16, MGMT and HMLH1, could be predictive biomarkers for detection of gastric cancer. PMID:24550949

  18. Aberrant Promoter Methylation of p16 and MGMT Genes in Lung Tumors from Smoking and Never-Smoking Lung Cancer Patients

    Yang Liu

    2006-01-01

    Full Text Available Aberrant methylation in gene promoter regions leads to transcriptional inactivation of cancer-related genes and plays an integral role in tumorigenesis. This alteration has been investigated in lung tumors primarily from smokers, whereas only a few studies involved never-smokers. Here, we applied methylation-specific polymerase chain reaction to compare the frequencies of the methylated promoter of p16 and O6-methylguanine-DNA methyltransferase (MGMT genes in lung tumors from 122 patients with non-small cell lung cancer, including 81 smokers and 41 never-smokers. Overall, promoter methylation was detected in 52.5% (64 of 122 and 30.3°/a (37 of 122 of the p16 and MGMT genes, respectively. Furthermore, the frequency of promoter methylation was significantly higher among smokers, compared with never-smokers, for both the p16 [odds ratio (OR = 3.28; 95% confidence interval (CI = 1.28-8.39; P = .013] and MGMT (OR = 3.93; 95% CI =1.27-12.21; P = .018 genes. The trend for a higher promoter methylation frequency of these genes was also observed among female smokers compared with female never-smokers. Our results suggest an association between tobacco smoking and an increased incidence of aberrant promoter methylation of the p16 and MGMT genes in non-small cell lung cancer.

  19. Optical Aberrations and Wavefront

    Nihat Polat

    2014-08-01

    Full Text Available The deviation of light to create normal retinal image in the optical system is called aberration. Aberrations are divided two subgroup: low-order aberrations (defocus: spherical and cylindrical refractive errors and high-order aberrations (coma, spherical, trefoil, tetrafoil, quadrifoil, pentafoil, secondary astigmatism. Aberrations increase with aging. Spherical aberrations are compensated by positive corneal and negative lenticular spherical aberrations in youth. Total aberrations are elevated by positive corneal and positive lenticular spherical aberrations in elderly. In this study, we aimed to analyze the basic terms regarding optic aberrations which have gained significance recently. (Turk J Ophthalmol 2014; 44: 306-11

  20. Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites

    Pierce Levi CT; Williams Laura E; Burrow Allison A; Wang Yuh-Hwa

    2009-01-01

    Abstract Background Gene rearrangements such as chromosomal translocations have been shown to contribute to cancer development. Human chromosomal fragile sites are regions of the genome especially prone to breakage, and have been implicated in various chromosome abnormalities found in cancer. However, there has been no comprehensive and quantitative examination of the location of fragile sites in relation to all chromosomal aberrations. Results Using up-to-date databases containing all cancer...

  1. Aberrantly Over-Expressed TRPM8 Channels in Pancreatic Adenocarcinoma: Correlation with Tumor Size/Stage and Requirement for Cancer Cells Invasion

    Nelson S. Yee

    2014-05-01

    Full Text Available The transient receptor potential melastatin-subfamily member 8 (TRPM8 channels control Ca2+ homeostasis. Recent studies indicate that TRPM8 channels are aberrantly expressed and required for cellular proliferation in pancreatic adenocarcinoma. However, the functional significance of TRPM8 in pancreatic tissues is mostly unknown. The objectives of this study are to examine the expression of TRPM8 in various histopathological types of pancreatic tissues, determine its clinical significance in pancreatic adenocarcinoma, and investigate its functional role in cancer cells invasion. We present evidence that, in normal pancreatic tissues, anti-TRPM8 immunoreactivity is detected in the centroacinar cells and the islet endocrine cells. In pre-malignant pancreatic tissues and malignant neoplasms, TRPM8 is aberrantly expressed to variable extents. In the majority of pancreatic adenocarcinoma, TRPM8 is expressed at moderate or high levels, and anti-TRPM8 immunoreactivity positively correlates with the primary tumor size and stage. In the pancreatic adenocarcinoma cell lines that express relatively high levels of TRPM8, short hairpin RNA-mediated interference of TRPM8 expression impaired their ability of invasion. These data suggest that aberrantly expressed TRPM8 channels play contributory roles in pancreatic tumor growth and metastasis, and support exploration of TRPM8 as a biomarker and target of pancreatic adenocarcinoma.

  2. Prevalence of Human Papillomavirus in endometrial cancer

    Olesen, Tina Bech; Svahn, Malene Frøsig; Faber, Mette Tuxen; Duun-Henriksen, Anne Katrine; Junge, Jette; Norrild, Bodil; Kjaer, Susanne K

    2014-01-01

    HPV is a common sexually transmitted infection and is considered to be a necessary cause of cervical cancer. The anatomical proximity to the cervix has led researchers to investigate whether Human Papillomavirus (HPV) has a role in the etiology of endometrial cancer.......HPV is a common sexually transmitted infection and is considered to be a necessary cause of cervical cancer. The anatomical proximity to the cervix has led researchers to investigate whether Human Papillomavirus (HPV) has a role in the etiology of endometrial cancer....

  3. Breast cancer cell lines carry cell line-specific genomic alterations that are distinct from aberrations in breast cancer tissues: Comparison of the CGH profiles between cancer cell lines and primary cancer tissues

    Cell lines are commonly used in various kinds of biomedical research in the world. However, it remains uncertain whether genomic alterations existing in primary tumor tissues are represented in cell lines and whether cell lines carry cell line-specific genomic alterations. This study was performed to answer these questions. Array-based comparative genomic hybridization (CGH) was employed with 4030 bacterial artificial chromosomes (BACs) that cover the genome at 1.0 megabase resolution to analyze DNA copy number aberrations (DCNAs) in 35 primary breast tumors and 24 breast cancer cell lines. DCNAs were compared between these two groups. A tissue microdissection technique was applied to primary tumor tissues to reduce the contamination of samples by normal tissue components. The average number of BAC clones with DCNAs was 1832 (45.3% of spotted clones) and 971 (24.9%) for cell lines and primary tumor tissues, respectively. Gains of 1q and 8q and losses of 8p, 11q, 16q and 17p were detected in >50% of primary cancer tissues. These aberrations were also frequently detected in cell lines. In addition to these alterations, the cell lines showed recurrent genomic alterations including gains of 5p14-15, 20q11 and 20q13 and losses of 4p13-p16, 18q12, 18q21, Xq21.1 and Xq26-q28 that were barely detected in tumor tissue specimens. These are considered to be cell line-specific DCNAs. The frequency of the HER2 amplification was high in both cell lines and tumor tissues, but it was statistically different between cell lines and primary tumors (P = 0.012); 41.3 ± 29.9% for the cell lines and 15.9 ± 18.6% for the tissue specimens. Established cell lines carry cell lines-specific DCNAs together with recurrent aberrations detected in primary tumor tissues. It must therefore be emphasized that cell lines do not always represent the genotypes of parental tumor tissues

  4. Hornerin, an S100 family protein, is functional in breast cells and aberrantly expressed in breast cancer

    Fleming Jodie M

    2012-06-01

    Full Text Available Abstract Background Recent evidence suggests an emerging role for S100 protein in breast cancer and tumor progression. These ubiquitous proteins are involved in numerous normal and pathological cell functions including inflammatory and immune responses, Ca2+ homeostasis, the dynamics of cytoskeleton constituents, as well as cell proliferation, differentiation, and death. Our previous proteomic analysis demonstrated the presence of hornerin, an S100 family member, in breast tissue and extracellular matrix. Hornerin has been reported in healthy skin as well as psoriatic and regenerating skin after wound healing, suggesting a role in inflammatory/immune response or proliferation. In the present study we investigated hornerin’s potential role in normal breast cells and breast cancer. Methods The expression levels and localization of hornerin in human breast tissue, breast tumor biopsies, primary breast cells and breast cancer cell lines, as well as murine mammary tissue were measured via immunohistochemistry, western blot analysis and PCR. Antibodies were developed against the N- and C-terminus of the protein for detection of proteolytic fragments and their specific subcellular localization via fluorescent immunocytochemisty. Lastly, cells were treated with H2O2 to detect changes in hornerin expression during induction of apoptosis/necrosis. Results Breast epithelial cells and stromal fibroblasts and macrophages express hornerin and show unique regulation of expression during distinct phases of mammary development. Furthermore, hornerin expression is decreased in invasive ductal carcinomas compared to invasive lobular carcinomas and less aggressive breast carcinoma phenotypes, and cellular expression of hornerin is altered during induction of apoptosis. Finally, we demonstrate the presence of post-translational fragments that display differential subcellular localization. Conclusions Our data opens new possibilities for hornerin and its

  5. Hornerin, an S100 family protein, is functional in breast cells and aberrantly expressed in breast cancer

    Recent evidence suggests an emerging role for S100 protein in breast cancer and tumor progression. These ubiquitous proteins are involved in numerous normal and pathological cell functions including inflammatory and immune responses, Ca2+ homeostasis, the dynamics of cytoskeleton constituents, as well as cell proliferation, differentiation, and death. Our previous proteomic analysis demonstrated the presence of hornerin, an S100 family member, in breast tissue and extracellular matrix. Hornerin has been reported in healthy skin as well as psoriatic and regenerating skin after wound healing, suggesting a role in inflammatory/immune response or proliferation. In the present study we investigated hornerin’s potential role in normal breast cells and breast cancer. The expression levels and localization of hornerin in human breast tissue, breast tumor biopsies, primary breast cells and breast cancer cell lines, as well as murine mammary tissue were measured via immunohistochemistry, western blot analysis and PCR. Antibodies were developed against the N- and C-terminus of the protein for detection of proteolytic fragments and their specific subcellular localization via fluorescent immunocytochemisty. Lastly, cells were treated with H2O2 to detect changes in hornerin expression during induction of apoptosis/necrosis. Breast epithelial cells and stromal fibroblasts and macrophages express hornerin and show unique regulation of expression during distinct phases of mammary development. Furthermore, hornerin expression is decreased in invasive ductal carcinomas compared to invasive lobular carcinomas and less aggressive breast carcinoma phenotypes, and cellular expression of hornerin is altered during induction of apoptosis. Finally, we demonstrate the presence of post-translational fragments that display differential subcellular localization. Our data opens new possibilities for hornerin and its proteolytic fragments in the control of mammary cell function and breast

  6. Induction of complete and incomplete chromosome aberrations by bleomycin in human lymphocytes

    Bleomycin (BLM) is a clastogenic compound, which due to the overdispersion in the cell distribution of induced dicentrics has been compared to the effect of high-LET radiation. Recently, it has been described that in fibroblast derived cell lines BLM induces incomplete chromosome elements more efficiently than any type of ionizing radiation. The objective of the present study was to evaluate in human lymphocytes the induction of dicentrics and incomplete chromosome elements by BLM. Peripheral blood samples have been treated with different concentrations of BLM. Two cytogenetic techniques were applied, fluorescence plus Giemsa (FPG) and FISH using pan-centromeric and pan-telomeric probes. The observed frequency of dicentric equivalents increases linearly with the BLM concentration, and for all BLM concentrations the distribution of dicentric equivalents was overdispersed. In the FISH study the ratio between total incomplete elements and multicentrics was 0.27. The overdispersion in the dicentric cell distribution, and the linear BLM-concentration dependence of dicentrics can be compared to the effect of high-LET radiation, on the contrary the ratio of incomplete elements and multicentrics is similar to the one induced by low-LET radiation (∼0.40). The elevated proportion of interstitial deletions in relation to total acentric fragments, higher than any type of ionizing radiation could be a characteristic signature of the clastogenic effect of BLM

  7. Aberrant α-Adrenergic Hypertrophic Response in Cardiomyocytes from Human Induced Pluripotent Cells

    Gabor Földes

    2014-11-01

    Full Text Available Cardiomyocytes from human embryonic stem cells (hESC-CMs and induced pluripotent stem cells (hiPSC-CMs represent new models for drug discovery. Although hypertrophy is a high-priority target, we found that hiPSC-CMs were systematically unresponsive to hypertrophic signals such as the α-adrenoceptor (αAR agonist phenylephrine (PE compared to hESC-CMs. We investigated signaling at multiple levels to understand the underlying mechanism of this differential responsiveness. The expression of the normal α1AR gene, ADRA1A, was reversibly silenced during differentiation, accompanied by ADRA1B upregulation in either cell type. ADRA1B signaling was intact in hESC-CMs, but not in hiPSC-CMs. We observed an increased tonic activity of inhibitory kinase pathways in hiPSC-CMs, and inhibition of antihypertrophic kinases revealed hypertrophic increases. There is tonic suppression of cell growth in hiPSC-CMs, but not hESC-CMs, limiting their use in investigation of hypertrophic signaling. These data raise questions regarding the hiPSC-CM as a valid model for certain aspects of cardiac disease.

  8. Induction of complete and incomplete chromosome aberrations by bleomycin in human lymphocytes

    Benkhaled, L.; Xuncla, M.; Caballin, M.R. [Universitat Autonoma de Barcelona, Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, E-08193 Bellaterra (Spain); Barrios, L. [Universitat Autonoma de Barcelona, Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia (Spain); Barquinero, J.F. [Universitat Autonoma de Barcelona, Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, E-08193 Bellaterra (Spain)], E-mail: Francesc.Barquinero@uab.es

    2008-01-01

    Bleomycin (BLM) is a clastogenic compound, which due to the overdispersion in the cell distribution of induced dicentrics has been compared to the effect of high-LET radiation. Recently, it has been described that in fibroblast derived cell lines BLM induces incomplete chromosome elements more efficiently than any type of ionizing radiation. The objective of the present study was to evaluate in human lymphocytes the induction of dicentrics and incomplete chromosome elements by BLM. Peripheral blood samples have been treated with different concentrations of BLM. Two cytogenetic techniques were applied, fluorescence plus Giemsa (FPG) and FISH using pan-centromeric and pan-telomeric probes. The observed frequency of dicentric equivalents increases linearly with the BLM concentration, and for all BLM concentrations the distribution of dicentric equivalents was overdispersed. In the FISH study the ratio between total incomplete elements and multicentrics was 0.27. The overdispersion in the dicentric cell distribution, and the linear BLM-concentration dependence of dicentrics can be compared to the effect of high-LET radiation, on the contrary the ratio of incomplete elements and multicentrics is similar to the one induced by low-LET radiation ({approx}0.40). The elevated proportion of interstitial deletions in relation to total acentric fragments, higher than any type of ionizing radiation could be a characteristic signature of the clastogenic effect of BLM.

  9. Gene aberrations of RRM1 and RRM2B and outcome of advanced breast cancer after treatment with docetaxel with or without gemcitabine

    The purpose of the present study was to retrospectively evaluate whether copy number changes of the genes encoding the ribonucleotide reductase subunit M1 (RRM1) and/or subunit M2B (RRM2B) predict sensitivity to gemcitabine administered in combination with docetaxel compared to single agent docetaxel in advanced breast cancer patients. Primary tumor samples from patients randomly assigned to gemcitabine plus docetaxel or docetaxel alone were analyzed for RRM1 and RRM2B copy number changes using Fluorescence In Situ Hybridization (FISH) technology with probes covering respectively RRM1 at 11p15.5 and a reference probe covering the centromere of chromosome 11 (CEN-11), and RRM2B at 8q22.3 and a reference probe covering the centromere of chromosome 8 (CEN-8). The assays were validated in a material of 60 normal breast samples. Time to progression (TTP) was the primary endpoint. Overall survival (OS) and response rate (RR) were secondary endpoints. Associations between RRM1/CEN-11 and/or RRM2B/CEN-8 ratios and time-to-event endpoints were analyzed by unadjusted and adjusted Cox proportional hazards regression models. Heterogeneity of treatment effects on TTP and OS according to gene status were investigated by subgroup analyses, and the Wald test was applied. All statistical tests were two-sided. FISH analysis for both RRM1 and RRM2B was successful in 251 patients. RRM1 and RRM2B aberrations (deletions and amplifications) were observed in 15.9% and 13.6% of patients, respectively. RRM1 aberrations were associated with a decreased OS in the time interval 1.5-7.4 years (hazard ratio = 1.72, 95% confidence interval = 1.05-2.79, P = 0.03). RRM2B aberrations alone or in combination with RRM1 aberrations had no prognostic impact in terms of TTP or OS. RR was not different by gene status. No significant differences were detected in TTP or OS within subgroups according to gene status and chemotherapy regimen. This study demonstrated the presence of RRM1 and RRM2B copy number

  10. Inferring primary tumor sites from mutation spectra: a meta-analysis of histology-specific aberrations in cancer-derived cell lines.

    Dietlein, Felix; Eschner, Wolfgang

    2014-03-15

    Next-generation sequencing technologies have led to profound characterization of mutation spectra for several cancer types. Hence, we sought to systematically compare genomic aberrations between primary tumors and cancer lines. For this, we compiled publically available sequencing data of 1651 genes across 905 cell lines. We used them to characterize 23 distinct primary tumor sites by a novel approach that is based on Bayesian spam-filtering techniques. Thereby, we confirmed the strong overall similarity of alterations between patient samples and cell culture. However, we also identified several suspicious mutations, which had not been associated with their cancer types before. Based on these characterizations, we developed the inferring cancer origins from mutation spectra (ICOMS) tool. On our cell line collection, the algorithm reached a prediction specificity rate of 79%, which strongly variegated between primary cancer sites. On an independent validation cohort of 431 primary tumor samples, we observed a similar accuracy of 71%. Additionally, we found that ICOMS could be employed to deduce further attributes from mutation spectra, including sub-histology and compound sensitivity. Thus, thorough classification of site-specific mutation spectra for cell lines may decipher further genome-phenotype associations in cancer. PMID:24163242

  11. Antiangiogenic Steroids in Human Cancer Therapy

    Pietras, Richard J.; Weinberg, Olga K.

    2005-01-01

    Despite advances in the early detection of tumors and in the use of chemotherapy, radiotherapy and surgery for disease management, the worldwide mortality from human cancer remains unacceptably high. The treatment of cancer may benefit from the introduction of novel therapies derived from natural products. Natural products have served to provide a basis for many of the pharmaceutical agents in current use in cancer therapy. Emerging research indicates that progressive growth and spread of ...

  12. In Vitro genotoxic and antigenotoxic studies of Thai Noni fruit juice by chromosomal aberration and sister chromatid exchange assays in human lymphocytes

    Treetip Ratanavalachai

    2008-09-01

    Full Text Available The genotoxic and antigenotoxic effects of Noni fruit juice produced in Thailand have been studied in human lymphocytes for chromosome aberration assay and sister chromatid exchange (SCE assay in vitro. Treatment of Noni fruit juice(3.1-50 mg/ml alone for 3 h did not significantly induce chromosomal aberration or SCE (p<0.05. Noni fruit juice at 6.2 mg/ml is the optimum dose for cell survival and cell replication as demonstrated by the highest value of mitotic index and proliferation index (P.I.. Interestingly, pretreatment of Noni fruit juice at the same concentration of 6.2 mg/ml for 2 hfollowed by mitomycin C treatment at 3 μg/ml for 2 h significantly reduced SCE level induced by mitomycin C (p<0.05. However, these treatments did not show significant decrease in chromatid-type aberrations. Our data indicate that Thai Noni fruit juice is not genotoxic against human lymphocytes in vitro. In addition, pretreatment of Noni fruit juice at 6.2 mg/ml demonstrated no anticlastogenic effect while had some antigenotoxic effects as demonstrated by significant decrease in the SCE level induced by mitomycin C (p<0.05. Therefore, the optimum dose of Noni fruit juice used as a traditional medicine is required and needs to be studied further for the benefit of human health.

  13. HUMAN PAPILLOMAVIRUS INFECTIONS IN LARYNGEAL CANCER

    Torrente, Mariela C.; Rodrigo, Juan P.; Haigentz, Missak; Dikkers, Frederik G.; Rinaldo, Alessandra; Takes, Robert P.; Olofsson, Jan; Ferlito, Alfio

    2011-01-01

    Although the association and clinical significance of human papillomavirus (HPV) infections with a subset of head and neck cancers, particularly for oropharyngeal carcinoma, has recently been well documented, the involvement of HPV in laryngeal cancer has been inadequately evaluated. Herein we revie

  14. M-BAND Analysis of Chromosome Aberration In Human Epithelial Cells exposed to Gamma-ray and Secondary Neutrons of Low Dose Rate

    Hada, M.; Saganti, P. B.; Gersey, B.; Wilkins, R.; Cucinotta, F. A.; Wu, H.

    2007-01-01

    High-energy secondary neutrons, produced by the interaction of galactic cosmic rays with the atmosphere, spacecraft structure and planetary surfaces, contribute to a significant fraction to the dose equivalent in crew members and passengers during commercial aviation travel, and astronauts in space missions. The Los Alamos Nuclear Science Center (LANSCE) neutron facility's "30L" beam line is known to generate neutrons that simulate the secondary neutron spectrum of the Earth's atmosphere at high altitude. The neutron spectrum is also similar to that measured onboard spacecraft like the MIR and the International Space Station (ISS). To evaluate the biological damage, we exposed human epithelial cells in vitro to the LANSCE neutron beams at an entrance dose rate of 2.5 cGy/hr or gamma-ray at 1.7cGy/hr, and assessed the induction of chromosome aberrations that were identified with mBAND. With this technique, individually painted chromosomal bands on one chromosome allowed the identification of inter-chromosomal aberrations (translocation to unpainted chromosomes) and intra-chromosomal aberrations (inversions and deletions within a single painted chromosome). Compared to our previous results for gamma-rays and 600 MeV/nucleon Fe ions of high dose rate, the neutron data showed a higher frequency of chromosome aberrations. However, detailed analysis of the inversion type revealed that all of the three radiation types in the study induced a low incidence of simple inversions. The low dose rate gamma-rays induced a lower frequency of chromosome aberrations than high dose rate gamma-rays, but the inversion spectrum was similar for the same cytotoxic effect. The distribution of damage sites on chromosome 3 for different radiation types will also be discussed.

  15. Mathematical Modeling of Carcinogenesis Based on Chromosome Aberration Data

    Xiao-bo Li

    2009-01-01

    Objective: The progression of human cancer is characterized by the accumulation of genetic instability. An increasing number of experimental genetic molecular techniques have been used to detect chromosome aberrations. Previous studies on chromosome abnormalities often focused on identifying the frequent loci of chromosome alterations, but rarely addressed the issue of interrelationship of chromosomal abnormalities. In the last few years, several mathematical models have been employed to construct models of carcinogenesis, in an attempt to identify the time order and cause-and-effect relationship of chromosome aberrations. The principles and applications of these models are reviewed and compared in this paper. Mathematical modeling of carcinogenesis can contribute to our understanding of the molecular genetics of tumor development, and identification of cancer related genes, thus leading to improved clinical practice of cancer.

  16. Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer

    Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor, and stimulates growth in prostate cancer cells. The current study is to determine a potential role of Vav3 oncogene in human breast cancer and impact on estrogen receptor a (ERα)-mediated signaling axis. Immunohistochemistry analysis was performed in 43 breast cancer specimens and western blot analysis was used for human breast cancer cell lines to determine the expression level of Vav3 protein. The impact of Vav3 on breast cancer cell growth was determined by siRNA knockdown of Vav3 expression. The role of Vav3 in ERα activation was examined in luciferase reporter assays. Deletion mutation analysis of Vav3 protein was performed to localize the functional domain involved in ERα activation. Finally, the interaction of Vav3 and ERα was assessed by GST pull-down analysis. We found that Vav3 was overexpressed in 81% of human breast cancer specimens, particularly in poorly differentiated lesions. Vav3 activated ERα partially via PI3K-Akt signaling and stimulated growth of breast cancer cells. Vav3 also potentiated EGF activity for cell growth and ERα activation in breast cancer cells. More interestingly, we found that Vav3 complexed with ERα. Consistent with its function for AR, the DH domain of Vav3 was essential for ERα activation. Vav3 oncogene is overexpressed in human breast cancer. Vav3 complexes with ERα and enhances ERα activity. These findings suggest that Vav3 overexpression may aberrantly enhance ERα-mediated signaling axis and play a role in breast cancer development and/or progression

  17. Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer

    Dong Zhongyun

    2008-06-01

    Full Text Available Abstract Background Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor, and stimulates growth in prostate cancer cells. The current study is to determine a potential role of Vav3 oncogene in human breast cancer and impact on estrogen receptor a (ERα-mediated signaling axis. Methods Immunohistochemistry analysis was performed in 43 breast cancer specimens and western blot analysis was used for human breast cancer cell lines to determine the expression level of Vav3 protein. The impact of Vav3 on breast cancer cell growth was determined by siRNA knockdown of Vav3 expression. The role of Vav3 in ERα activation was examined in luciferase reporter assays. Deletion mutation analysis of Vav3 protein was performed to localize the functional domain involved in ERα activation. Finally, the interaction of Vav3 and ERα was assessed by GST pull-down analysis. Results We found that Vav3 was overexpressed in 81% of human breast cancer specimens, particularly in poorly differentiated lesions. Vav3 activated ERα partially via PI3K-Akt signaling and stimulated growth of breast cancer cells. Vav3 also potentiated EGF activity for cell growth and ERα activation in breast cancer cells. More interestingly, we found that Vav3 complexed with ERα. Consistent with its function for AR, the DH domain of Vav3 was essential for ERα activation. Conclusion Vav3 oncogene is overexpressed in human breast cancer. Vav3 complexes with ERα and enhances ERα activity. These findings suggest that Vav3 overexpression may aberrantly enhance ERα-mediated signaling axis and play a role in breast cancer development and/or progression.

  18. Aberrant reduction of telomere repetitive sequences in plasma cell-free DNA for early breast cancer detection

    Wu, Xi; Tanaka, Hiromi

    2015-01-01

    Excessive telomere shortening is observed in breast cancer lesions when compared to adjacent non-cancerous tissues, suggesting that telomere length may represent a key biomarker for early cancer detection. Because tumor-derived, cell-free DNA (cfDNA) is often released from cancer cells and circulates in the bloodstream, we hypothesized that breast cancer development is associated with changes in the amount of telomeric cfDNA that can be detected in the plasma. To test this hypothesis, we devi...

  19. Human papillomavirus testing in cervical cancer screening.

    Castle, Philip E; Cremer, Miriam

    2013-06-01

    Human papillomavirus (HPV) testing is more reliable and sensitive but less specific than Papanicolaou (Pap) testing/cervical cytology for the detection of cervical precancer and cancer. HPV-negative women are at lower risk of cervical cancer than Pap-negative women. In high-resource settings, HPV testing can be used to make cervical cancer prevention programs more efficient by focusing clinical attention on women who have HPV. In lower-resource settings, where Pap testing has not been sustained or widespread, new, lower-cost HPV tests may make cervical cancer screening feasible. PMID:23732037

  20. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

    Bartkova, J; Hamerlik, P; Stockhausen, Marie;

    2010-01-01

    brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low...... and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.......Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA...

  1. Environmental and genetic interactions in human cancer

    Humans, depending upon their genetic make-up, differ in their susceptibility to the cancer-causing effects of extrinsic agents. Clinical and laboratory studies on the hereditary disorder, ataxia telangiectasia (AT) show that persons afflicted with this are cancer-prone and unusually sensitive to conventional radiotherapy. Their skin cells, when cultured, are hypersensitive to killing by ionizing radiation, being defective in the enzymatic repair of radiation-induced damange to the genetic material, deoxyribonucleic acid (DNA). This molecular finding implicates DNA damage and its imperfect repair as an early step in the induction of human cancer by radiation and other carcinogens. The parents of AT patients are clincally normal but their cultured cells are often moderately radiosensitive. The increased radiosensitivity of cultured cells offers a means of identifying a presumed cancer-prone subpopulation that should avoid undue exposure to certain carcinogens. The radioresponse of cells from patients with other cancer-associated genetic disorders and persons suspected of being genetically predisposed to radiation-induced cancer has also been measured. Increased cell killing by γ-rays appears in the complex genetic disease, tuberous sclerosis. Cells from cancer-stricken members of a leukemia-prone family are also radiosensitive, as are cells from one patient with radiation-associated breast cancer. These radiobiological data, taken together, strongly suggest that genetic factors can interact with extrinsic agents and thereby play a greater causative role in the development of common cancers in man than previously thought. (L.L.)

  2. RBE of Energetic Iron Ions for the Induction of Early and Late Chromosome Aberrations in Different Cell Types

    Zhang, Ye; Yeshitla, Samrawit; Hada, Megumi; Kadhim, Munira; Wilson, Bobby; Wu, Honglu

    2015-01-01

    Numerous published studies have reported the Relative Biological Effectiveness (RBE) values for chromosome aberrations induced by charged particles of different LET. The RBE for chromosome aberrations in human lymphocytes exposed ex vivo has been suggested to show a similar relationship as the quality factor for cancer induction. Therefore, increased chromosome aberrations in the astronauts' white blood cells post long-duration missions are used to determine the biological doses from exposures to space radiation. However, the RBE value is known to be very different for different types of cancer. Previously, we reported that, even though the RBE for initial chromosome damages was high in human lymphocytes exposed to Fe ions, the RBE was significantly reduced after multiple cell divisions post irradiation. To test the hypothesis that RBE values for chromosome aberrations are cell type dependent, and different between early and late damages, we exposed human lymphocytes ex vivo, and human mammary epithelial cells in vitro to various charged particles. Chromosome aberrations were quantified using the samples collected at first mitosis post irradiation for initial damages, and the samples collected after multiple generations for the remaining or late arising aberrations. Results of the study suggested that the effectiveness of high-LET charged particles for late chromosome aberrations may be cell type dependent, even though the RBE values are similar for early damages.

  3. mBAND analysis of chromosome aberrations in human epithelial cells induced by gamma-rays and secondary neutrons of low dose rate.

    Hada, M; Gersey, B; Saganti, P B; Wilkins, R; Cucinotta, F A; Wu, H

    2010-08-14

    Human risks from chronic exposures to both low- and high-LET radiation are of intensive research interest in recent years. In the present study, human epithelial cells were exposed in vitro to gamma-rays at a dose rate of 17 mGy/h or secondary neutrons of 25 mGy/h. The secondary neutrons have a broad energy spectrum that simulates the Earth's atmosphere at high altitude, as well as the environment inside spacecrafts like the Russian MIR station and the International Space Station (ISS). Chromosome aberrations in the exposed cells were analyzed using the multicolor banding in situ hybridization (mBAND) technique with chromosome 3 painted in 23 colored bands that allows identification of both inter- and intrachromosome exchanges including inversions. Comparison of present dose responses between gamma-rays and neutron irradiations for the fraction of cells with damaged chromosome 3 yielded a relative biological effectiveness (RBE) value of 26+/-4 for the secondary neutrons. Our results also revealed that secondary neutrons of low dose rate induced a higher fraction of intrachromosome exchanges than gamma-rays, but the fractions of inversions observed between these two radiation types were indistinguishable. Similar to the previous findings after acute radiation exposures, most of the inversions observed in the present study were accompanied by other aberrations. The fractions of complex type aberrations and of unrejoined chromosomal breakages were also found to be higher in the neutron-exposed cells than after gamma-rays. We further analyzed the location of the breaks involved in chromosome aberrations along chromosome 3, and observed hot spots after gamma-ray, but not neutron, exposures. PMID:20338263

  4. Simulation Experiment on Wavefront Aberration of Human Eye%眼波前像差仿真实验研究

    张学勇; 唐震

    2015-01-01

    像差是衡量光学仪器成像质量的主要指标,在眼科临床波前像差检测对视觉质量评估具有重要作用。本文介绍了波前像差的基本理论,基于Zernike多项式通过仿真分别给出人眼1-4阶共14项波前像差图,可为教学服务,也可为临床医师提供科学参考。%Aberration is an essential index for determining the image quality of optical instrument,and further wavefront aberration measurement play an important role in estimating the quality of the retinal image and over-all visual performance in clinic. The theory related to wavefront aberration is briefly introduced. The contour maps of the wave aberration corresponding to the first 14 Zernike polynomials ( up to the fourth order,except the zero order) are presented using Matlab simulation. The results can serve as teaching and provide reference for clinical ophthalmologist.

  5. Aberrant p16 promoter hypermethylation in bronchial mucosae as a biomarker for the early detection of lung cancer

    XIE Guang-shun; HOU Ai-rong; LI Long-yun; GAO Yan-ning; CHENG Shu-jun

    2006-01-01

    @@ Lung cancer is the leading cause of cancer related death in the world and its mortality could be greatly reduced by diagnosis and treatment in its early stages. Effective tools for the early detection of lung cancer and its high risk factors remain a major challenge. Biomarkers that detect lung cancer in its early stages or identify its pretumour lesions,enabling early therapeutic intervention, would be invaluable to improve its dismal prognosis.

  6. Novel innate cancer killing activity in humans

    Lovato James

    2011-08-01

    Full Text Available Abstract Background In this study, we pilot tested an in vitro assay of cancer killing activity (CKA in circulating leukocytes of 22 cancer cases and 25 healthy controls. Methods Using a human cervical cancer cell line, HeLa, as target cells, we compared the CKA in circulating leukocytes, as effector cells, of cancer cases and controls. The CKA was normalized as percentages of total target cells during selected periods of incubation time and at selected effector/target cell ratios in comparison to no-effector-cell controls. Results Our results showed that CKA similar to that of our previous study of SR/CR mice was present in human circulating leukocytes but at profoundly different levels in individuals. Overall, males have a significantly higher CKA than females. The CKA levels in cancer cases were lower than that in healthy controls (mean ± SD: 36.97 ± 21.39 vs. 46.28 ± 27.22. Below-median CKA was significantly associated with case status (odds ratio = 4.36; 95% Confidence Interval = 1.06, 17.88 after adjustment of gender and race. Conclusions In freshly isolated human leukocytes, we were able to detect an apparent CKA in a similar manner to that of cancer-resistant SR/CR mice. The finding of CKA at lower levels in cancer patients suggests the possibility that it may be of a consequence of genetic, physiological, or pathological conditions, pending future studies with larger sample size.

  7. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    Chin, L.; Meyerson, M.; Aldape, K.; Bigner, D.; Mikkelsen, T.; VandenBerg, S.; Kahn, A.; Penny, R.; Gerhard, D. S.; Getz, G.; Brennan, C.; Taylor, B. S.; Winckler, W.; Park, P.; Ladanyi, M.; Hoadley, K. A.; Verhaak, R. G. W.; Hayes, D. N.; Spellman, Paul T.; Absher, D.; Weir, B. A.; Ding, L.; Wheeler, D.; Lawrence, M. S.; Cibulskis, K.; Mardis, E.; Zhang, Jinghui; Wilson, R. K.; Donehower, L.; Wheeler, D. A.; Purdom, E.; Wallis, J.; Laird, P. W.; Herman, J. G.; Schuebel, K. E.; Weisenberger, D. J.; Baylin, S. B.; Schultz, N.; Yao, Jun; Wiedemeyer, R.; Weinstein, J.; Sander, C.; Gibbs, R. A.; Gray, J.; Kucherlapati, R.; Lander, E. S.; Myers, R. M.; Perou, C. M.; McLendon, Roger; Friedman, Allan; Van Meir, Erwin G; Brat, Daniel J; Mastrogianakis, Gena Marie; Olson, Jeffrey J; Lehman, Norman; Yung, W. K. Alfred; Bogler, Oliver; Berger, Mitchel; Prados, Michael; Muzny, Donna; Morgan, Margaret; Scherer, Steve; Sabo, Aniko; Nazareth, Lynn; Lewis, Lora; Hall, Otis; Zhu, Yiming; Ren, Yanru; Alvi, Omar; Yao, Jiqiang; Hawes, Alicia; Jhangiani, Shalini; Fowler, Gerald; San Lucas, Anthony; Kovar, Christie; Cree, Andrew; Dinh, Huyen; Santibanez, Jireh; Joshi, Vandita; Gonzalez-Garay, Manuel L.; Miller, Christopher A.; Milosavljevic, Aleksandar; Sougnez, Carrie; Fennell, Tim; Mahan, Scott; Wilkinson, Jane; Ziaugra, Liuda; Onofrio, Robert; Bloom, Toby; Nicol, Rob; Ardlie, Kristin; Baldwin, Jennifer; Gabriel, Stacey; Fulton, Robert S.; McLellan, Michael D.; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.; O'Kelly, Michael; Robinson, Jim; Alexe, Gabriele; Beroukhim, Rameen; Carter, Scott; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Garraway, Levi; Golub, Todd; Protopopov, Alexei; Perna, Ilana; Aronson, Sandy; Sathiamoorthy, Narayan; Ren, Georgia; Kim, Hyunsoo; Kong, Sek Won; Xiao, Yonghong; Kohane, Isaac S.; Seidman, Jon; Cope, Leslie; Pan, Fei; Van Den Berg, David; Van Neste, Leander; Yi, Joo Mi; Li, Jun Z.; Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin; Brooks, James D.; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Choi, Yoon Gi; Han, Ju; Ray, Amrita; Wang, Victoria; Durinck, Steffen; Robinson, Mark; Wang, Nicholas J.; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Fontenay, Gerald V.; Ngai, John; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.; Speed, Terence P.; Socci, Nicholas D.; Olshen, Adam; Lash, Alex; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wang, Wei Qing; Qin, Li-Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Topal, Michael D.; Qi, Yuan; Balu, Sai; Shi, Yan; Wu, George; Bittner, Michael; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin; Schaefer, Carl; Madhavan, Subha; Buetow, Ken; Barker, Anna; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth

    2008-01-01

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular char

  8. Noncoding RNA Expression Aberration Is Associated with Cancer Progression and Is a Potential Biomarker in Esophageal Squamous Cell Carcinoma

    Hidetaka Sugihara

    2015-11-01

    Full Text Available Esophageal cancer is one of the most common cancers worldwide. Esophageal squamous cell carcinoma (ESCC is the major histological type of esophageal cancer in Eastern Asian countries. Several types of noncoding RNAs (ncRNAs function as key epigenetic regulators of gene expression and are implicated in various physiological processes. Unambiguous evidence indicates that dysregulation of ncRNAs is deeply implicated in carcinogenesis, cancer progression and metastases of various cancers, including ESCC. The current review summarizes recent findings on the ncRNA-mediated mechanisms underlying the characteristic behaviors of ESCC that will help support the development of biomarkers and the design of novel therapeutic strategies.

  9. Identification of microbial DNA in human cancer

    Vogelstein Bert

    2009-05-01

    Full Text Available Abstract Background Microorganisms have been associated with many types of human diseases; however, a significant number of clinically important microbial pathogens remain to be discovered. Methods We have developed a genome-wide approach, called Digital Karyotyping Microbe Identification (DK-MICROBE, to identify genomic DNA of bacteria and viruses in human disease tissues. This method involves the generation of an experimental DNA tag library through Digital Karyotyping (DK followed by analysis of the tag sequences for the presence of microbial DNA content using a compiled microbial DNA virtual tag library. Results To validate this technology and to identify pathogens that may be associated with human cancer pathogenesis, we used DK-MICROBE to determine the presence of microbial DNA in 58 human tumor samples, including brain, ovarian, and colorectal cancers. We detected DNA from Human herpesvirus 6 (HHV-6 in a DK library of a colorectal cancer liver metastasis and in normal tissue from the same patient. Conclusion DK-MICROBE can identify previously unknown infectious agents in human tumors, and is now available for further applications for the identification of pathogen DNA in human cancer and other diseases.

  10. Human papilloma viruses (HPV and breast cancer.

    James Sutherland Lawson

    2015-12-01

    Full Text Available Purpose: Human papillomaviruses (HPV may have a role in some breast cancers. The purpose of this study is to fill important gaps in the evidence. These gaps are: (i confirmation of the presence of high risk for cancer HPVs in breast cancers, (ii evidence of HPV infections in benign breast tissues prior to the development of HPV positive breast cancer in the same patients, (iii evidence that HPVs are biologically active and not harmless passengers in breast cancer.Methods: RNA-seq data from The Cancer Genome Atlas (TCGA was used to identify HPV RNA sequences in breast cancers. We also conducted a retrospective cohort study based on polymerase chain reaction (PCR analyses to identify HPVs in archival specimens from Australian women with benign breast biopsies who later developed breast cancer. To assess whether HPVs in breast cancer were biologically active, the expression of the oncogenic protein HPV E7 was assessed by immunohistochemistry (IHC.Results: Thirty (3.5% low risk and 20 (2.3% high risk HPV types were identified in 855 breast cancers from the TCGA data base. The high risk types were HPV 18 (48%, HPV 113 (24%, HPV 16 (10%, HPV 52 (10%. Data from the PCR cohort study, indicated that HPV type 18 was the most common type identified in breast cancer specimens (55% of 40 breast cancer specimens followed by HPV 16 (13%. The same HPV type was identified in both the benign and subsequent breast cancer in 15 patients. HPV E7 proteins were identified in 72% of benign breast specimens and 59% of invasive breast cancer specimens.Conclusions: There were 4 observations of particular interest: (i confirmation by both NGS and PCR of the presence of high risk HPV gene sequences in breast cancers, (ii a correlation between high risk HPV in benign breast specimens and subsequent HPV positive breast cancer in the same patient, (iii HPVs in breast cancer are likely to be biologically active (as shown by transcription of HPV DNA to RNA plus the expression of