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Sample records for hcc genetic heterogeneity

  1. Clear cell HCC: an imitator of hepatic adenoma

    International Nuclear Information System (INIS)

    Incedayi, M.; Sivrioglu, A.

    2012-01-01

    Full text: A 60-year old male patient was complaining of a postprandial heartburn and of abdominal distension. Physical examination was normal except for nodular, painless hepatomegaly. Ultrasonographic examination of the liver showed diffuse increased echogenicity and coarse echotexture. A large mixed echogenic mass is seen in the right hepatic lobe. Computerized tomography showed heterogeneously hypodense mass lesions with fatty change on non-contrast scans and enhance heterogeneously on both arterial phase and venous phase postcontrast scans. Following true-cut biopsy, it was ascertained to be a clear cell HCC. Clear cell HCC may include large fatty areas and this is often misdiagnosed to be an adenoma. Clear cell HCC is characterized by high female prevalence, high rate of association with liver cirrhosis and has no significant difference in prognosis compared with non-clear cell HCC

  2. An Overview of Biomarkers and Molecular Signatures in HCC

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    Yim, Seon-Hee [Integrated Research Center for Genome Polymorphism, The Catholic University of Korea School of Medicine, 505 Banpo-dong, Seocho-gu, Seoul 137-701 (Korea, Republic of); Chung, Yeun-Jun, E-mail: yejun@catholic.ac.kr [Integrated Research Center for Genome Polymorphism, The Catholic University of Korea School of Medicine, 505 Banpo-dong, Seocho-gu, Seoul 137-701 (Korea, Republic of); Department of Microbiology, The Catholic University of Korea School of Medicine, 505 Banpo-dong, Seocho-gu, Seoul 137-701 (Korea, Republic of)

    2010-05-07

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Although most HCCs seem to originate from the accumulation of genetic abnormalities induced by various risk factors, underlying mechanisms of hepatocarcinogenesis remain unclear. Long-term survival of HCC patients is also poor, partly due to HCC recurrence. Although serum alpha-fetoprotein (AFP) level is a useful marker for the detection and monitoring of HCC, AFP levels may remain normal in the patients even with advanced HCC. To identify useful biomarkers for HCC, many studies have been conducted on molecular events such as genetic and epigenetic alterations, and gene expression. This review summarizes recent studies of potential molecular markers for diagnosis and monitoring metastasis or recurrence of HCC.

  3. Genetic heterogeneity of retinitis pigmentosa

    OpenAIRE

    Hartono, Hartono

    2015-01-01

    Genetic heterogeneity is a phenomenon in which a genetic disease can be transmitted by several modes of inheritance. The understanding of genetic heterogeneity is important in giving genetic counselling.The presence of genetic heterogeneity can be explained by the existence of:1.different mutant alleles at a single locus, and2.mutant alleles at different loci affecting the same enzyme or protein, or affecting different enzymes or proteins.To have an overall understanding of genetic heterogene...

  4. HCC Biomarkers in China and Taiwan

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    Regina M. Santella

    2007-02-01

    Full Text Available

    A number of different types of biomarkers have been used to understand the etiology and progression of hepatocellular cancer (HCC. Perhaps the most well known are the serum/ plasma markers of HBV or HCV infection. These markers include analysis of viral DNA or proteins or antibodies produced against the viral proteins. HBV surface antigen (HBsAg is most frequently used to determine chronic infection with high or low viral replication, while HBeAg is a measure of chronic infection with high viral replication. Analysis of antibodies includes measurement of anti-HBV core antigen, anti-HBV e antigen and anti-HBsAg. The response to immunization can be monitored by analysis of anti-HBsAg. The other major classes of biomarkers used in studies of HCC are biomarkers of exposure to environmental, lifestyle or dietary carcinogens, biomarkers of oxidative stress and early biologic response. In addition, studies of genetic susceptibility have studied polymorphisms in a number of pathways and their role in HCC risk. The biomarkers of exposure include the measurement of carcinogens in urine and carcinogen-DNA and protein adducts. Examples are measurement of aflatoxin and polycyclic aromatic hydrocarbon metabolites, and DNA and protein adducts.

    Biomarkers of oxidative stress include urinary isoprostanes and 8-oxodeoxyguanosine and oxidized plasma proteins. Most of these assays are immunologic although the use of high performance liquid chromatograph (HPLC as well as gas chromatography/mass spectroscopy (GC/MS have been utilized. In nested case-control studies, many of these markers are associated with elevated risk. For example, elevated aflatoxin and polycyclic aromatic hydrocarbon-albumin adducts, aflatoxin metabolites in urine and urinary isoprostanes were observed in baseline samples from

  5. How to measure genetic heterogeneity

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    Yamada, Ryo

    2009-01-01

    Genetic information of organisms is coded as a string of four letters, A, T, G and C, a sequence in macromolecules called deoxyribonucleic acid (DNA). DNA sequence offers blueprint of organisms and its heterogeneity determines identity and variation of species. The quantitation of this genetic heterogeneity is fundamental to understand biology. We compared previously-reported three measures, covariance matrix expression of list of loci (pair-wise r 2 ), the most popular index in genetics, and its multi-dimensional form, Ψ, and entropy-based index, ε. Thereafter we proposed two methods so that we could handle the diplotypic heterogeneity and quantitate the conditions where the number of DNA sequence samples is much smaller than the number of possible variants.

  6. HCV and HCC molecular epidemiology

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    Flor H. Pujol

    2007-02-01

    -infected cirrhotic patients than for HBVinfected ones.

    HCV genotype 1b has also been more frequently associated with a more severe liver disease. However, this association seems to be due to the fact that individuals infected with this genotype have a longer mean duration of infection. An heterogeneity in the IFN sensitivity determining region (ISDR of HCV genotype 1b isolates has been observed in patients presenting with HCC, compared with the isolates of patients presenting with liver cirrhosis without HCC, which exhibit a more homogeneous ISDR region, although an opposite observation has been reported by others. Some nucleotides in the 5' non-coding region and specific amino acid substitutions within the entire HCV genome have been also found in the HCV strains infecting patients with HCC. Hepatic steatosis is a common consequence of HCV infection, particularly HCV genotype 3, and has been recently associated with the development of HCC. Steatosis might be contributing to the progression of fibrosis in HCV-related disease. More studies are needed to evaluate an eventual correlation between HCV genotype 3, the presence of steatosis, and progression to HCC.

    Even if it seems that an effective vaccine against HCV will not be readily obtained in the near future, available therapeutic approaches seem to delay the progression to HCC in infected patients who respond at least transiently to treatment. The evolution to HCC associated with infection by HCV seems to be a multifactor process. Although the role of chronic infection with HCV in the etiology of liver cancer is well established, more studies are needed to assess the individual contribution of specific viral strains in the development of HCC. The limited arsenal available against HCV (improving therapeutic agents is crucial since it might prevent or delay

  7. Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis.

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    Cheng, Yue; Yu, Chengxiao; Huang, Mingtao; Du, Fangzhi; Song, Ci; Ma, Zijian; Zhai, Xiangjun; Yang, Yuan; Liu, Jibin; Bei, Jin-Xin; Jia, Weihua; Jin, Guangfu; Li, Shengping; Zhou, Weiping; Liu, Jianjun; Dai, Juncheng; Hu, Zhibin

    2017-10-01

    Observational studies show an association between telomere length and Hepatocellular carcinoma (HCC) risk, but the relationship is controversial. Particularly, it remains unclear whether the association is due to confounding or biases inherent in conventional epidemiological studies. Here, we applied Mendelian randomization approach to evaluate whether telomere length is causally associated with HCC risk. Individual-level data were from HBV-related HCC Genome-wide association studies (1,538 HBV positive HCC patients and 1,465 HBV positive controls). Genetic risk score, as proxy for actual measured telomere length, derived from nine telomere length-associated genetic variants was used to evaluate the effect of telomere length on HCC risk. We observed a significant risk signal between genetically increased telomere length and HBV-related HCC risk (OR=2.09, 95% CI 1.32-3.31, P=0.002). Furthermore, a U-shaped curve was fitted by the restricted cubic spline curve, which indicated that either short or long telomere length would increase HCC risk (P=0.0022 for non-linearity test). Subgroup analysis did not reveal significant heterogeneity between different age, gender, smoking status and drinking status groups. Our results indicated that a genetic background that favors longer or shorter telomere length may increase HBV-related HCC risk-a U-shaped association. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Genetic variants influencing phenotypic variance heterogeneity.

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    Ek, Weronica E; Rask-Andersen, Mathias; Karlsson, Torgny; Enroth, Stefan; Gyllensten, Ulf; Johansson, Åsa

    2018-03-01

    Most genetic studies identify genetic variants associated with disease risk or with the mean value of a quantitative trait. More rarely, genetic variants associated with variance heterogeneity are considered. In this study, we have identified such variance single-nucleotide polymorphisms (vSNPs) and examined if these represent biological gene × gene or gene × environment interactions or statistical artifacts caused by multiple linked genetic variants influencing the same phenotype. We have performed a genome-wide study, to identify vSNPs associated with variance heterogeneity in DNA methylation levels. Genotype data from over 10 million single-nucleotide polymorphisms (SNPs), and DNA methylation levels at over 430 000 CpG sites, were analyzed in 729 individuals. We identified vSNPs for 7195 CpG sites (P mean DNA methylation levels. We further showed that variance heterogeneity between genotypes mainly represents additional, often rare, SNPs in linkage disequilibrium (LD) with the respective vSNP and for some vSNPs, multiple low frequency variants co-segregating with one of the vSNP alleles. Therefore, our results suggest that variance heterogeneity of DNA methylation mainly represents phenotypic effects by multiple SNPs, rather than biological interactions. Such effects may also be important for interpreting variance heterogeneity of more complex clinical phenotypes.

  9. Association between platelet to lymphocyte ratio (PLR) and overall survival (OS) of hepatocellular carcinoma (HCC): A meta-analysis.

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    Hu, D-H; Yu, S-M

    2017-08-30

    Some studies investigated the association between platelet-to-lymphocyte ratio (PLR) and the survival of hepatocellular carcinoma (HCC). However, the results remained inconclusive. Thus, we performed this meta-analysis. Published studies were searched in PubMed and EMBASE. The strength of association was assessed by calculating odds ratios (OR) and 95% confidence interval (CI). In total, 6 studies with 1446 HCC patients were included in this meta-analysis. HCC with higher PLR showed an increased death risk (OR = 1.59; 95%CI, 1.15-2.20; P < 0.0001). However, the heterogeneity was high (I2=89.2%). When the study by Li et al. was excluded, the heterogeneity decreased (I2=20%). Further, the result was still positive (OR = 1.70; 95%CI, 1.42-2.04; P < 0.00001). In conclusion, this meta-analysis suggested that PLR was significantly associated with the OS of HCC.

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

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    Julien Fitamant

    2015-03-01

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

  11. A weighted U statistic for association analyses considering genetic heterogeneity.

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    Wei, Changshuai; Elston, Robert C; Lu, Qing

    2016-07-20

    Converging evidence suggests that common complex diseases with the same or similar clinical manifestations could have different underlying genetic etiologies. While current research interests have shifted toward uncovering rare variants and structural variations predisposing to human diseases, the impact of heterogeneity in genetic studies of complex diseases has been largely overlooked. Most of the existing statistical methods assume the disease under investigation has a homogeneous genetic effect and could, therefore, have low power if the disease undergoes heterogeneous pathophysiological and etiological processes. In this paper, we propose a heterogeneity-weighted U (HWU) method for association analyses considering genetic heterogeneity. HWU can be applied to various types of phenotypes (e.g., binary and continuous) and is computationally efficient for high-dimensional genetic data. Through simulations, we showed the advantage of HWU when the underlying genetic etiology of a disease was heterogeneous, as well as the robustness of HWU against different model assumptions (e.g., phenotype distributions). Using HWU, we conducted a genome-wide analysis of nicotine dependence from the Study of Addiction: Genetics and Environments dataset. The genome-wide analysis of nearly one million genetic markers took 7h, identifying heterogeneous effects of two new genes (i.e., CYP3A5 and IKBKB) on nicotine dependence. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  12. The heterogeneous HLA genetic makeup of the Swiss population.

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    Buhler, Stéphane; Nunes, José Manuel; Nicoloso, Grazia; Tiercy, Jean-Marie; Sanchez-Mazas, Alicia

    2012-01-01

    This study aims at investigating the HLA molecular variation across Switzerland in order to determine possible regional differences, which would be highly relevant to several purposes: optimizing donor recruitment strategies in hematopoietic stem cell transplantation (HSCT), providing reliable reference data in HLA and disease association studies, and understanding the population genetic background(s) of this culturally heterogeneous country. HLA molecular data of more than 20,000 HSCT donors from 9-13 recruitment centers of the whole country were analyzed. Allele and haplotype frequencies were estimated by using new computer tools adapted to the heterogeneity and ambiguity of the data. Non-parametric and resampling statistical tests were performed to assess Hardy-Weinberg equilibrium, selective neutrality and linkage disequilibrium among different loci, both in each recruitment center and in the whole national registry. Genetic variation was explored through genetic distance and hierarchical analysis of variance taking into account both geographic and linguistic subdivisions in Switzerland. The results indicate a heterogeneous genetic makeup of the Swiss population: first, allele frequencies estimated on the whole national registry strongly deviate from Hardy-Weinberg equilibrium, by contrast with the results obtained for individual centers; second, a pronounced differentiation is observed for Ticino, Graubünden, and, to a lesser extent, Wallis, suggesting that the Alps represent(ed) a barrier to gene flow; finally, although cultural (linguistic) boundaries do not represent a main genetic differentiation factor in Switzerland, the genetic relatedness between population from south-eastern Switzerland and Italy agrees with historical and linguistic data. Overall, this study justifies the maintenance of a decentralized donor recruitment structure in Switzerland allowing increasing the genetic diversity of the national--and hence global--donor registry. It also

  13. Image-based computational quantification and visualization of genetic alterations and tumour heterogeneity.

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    Zhong, Qing; Rüschoff, Jan H; Guo, Tiannan; Gabrani, Maria; Schüffler, Peter J; Rechsteiner, Markus; Liu, Yansheng; Fuchs, Thomas J; Rupp, Niels J; Fankhauser, Christian; Buhmann, Joachim M; Perner, Sven; Poyet, Cédric; Blattner, Miriam; Soldini, Davide; Moch, Holger; Rubin, Mark A; Noske, Aurelia; Rüschoff, Josef; Haffner, Michael C; Jochum, Wolfram; Wild, Peter J

    2016-04-07

    Recent large-scale genome analyses of human tissue samples have uncovered a high degree of genetic alterations and tumour heterogeneity in most tumour entities, independent of morphological phenotypes and histopathological characteristics. Assessment of genetic copy-number variation (CNV) and tumour heterogeneity by fluorescence in situ hybridization (ISH) provides additional tissue morphology at single-cell resolution, but it is labour intensive with limited throughput and high inter-observer variability. We present an integrative method combining bright-field dual-colour chromogenic and silver ISH assays with an image-based computational workflow (ISHProfiler), for accurate detection of molecular signals, high-throughput evaluation of CNV, expressive visualization of multi-level heterogeneity (cellular, inter- and intra-tumour heterogeneity), and objective quantification of heterogeneous genetic deletions (PTEN) and amplifications (19q12, HER2) in diverse human tumours (prostate, endometrial, ovarian and gastric), using various tissue sizes and different scanners, with unprecedented throughput and reproducibility.

  14. Initial assessment of a model relating intratumoral genetic heterogeneity to radiological morphology

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    Noterdaeme, O; Kelly, M; Friend, P; Soonowalla, Z; Steers, G; Brady, M

    2010-01-01

    Tumour heterogeneity has major implications for tumour development and response to therapy. Tumour heterogeneity results from mutations in the genes responsible for mismatch repair or maintenance of chromosomal stability. Cells with different genetic properties may grow at different rates and exhibit different resistance to therapeutic interventions. To date, there exists no approach to non-invasively assess tumour heterogeneity. Here we present a biologically inspired model of tumour growth, which relates intratumoral genetic heterogeneity to gross morphology visible on radiological images. The model represents the development of a tumour as a set of expanding spheres, each sphere representing a distinct clonal centre, with the sprouting of new spheres corresponding to new clonal centres. Each clonal centre may possess different characteristics relating to genetic composition, growth rate and response to treatment. We present a clinical example for which the model accurately tracks tumour growth and shows the correspondence to genetic variation (as determined by array comparative genomic hybridisation). One clinical implication of our work is that the assessment of heterogeneous tumours using Response Evaluation Criteria In Solid Tumours (RECIST) or volume measurements may not accurately reflect tumour growth, stability or the response to treatment. We believe that this is the first model linking the macro-scale appearance of tumours to their genetic composition. We anticipate that our model will provide a more informative way to assess the response of heterogeneous tumours to treatment, which is of increasing importance with the development of novel targeted anti-cancer treatments. PMID:19690073

  15. Pharmacogenomics Bias - Systematic distortion of study results by genetic heterogeneity

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    Zietemann, Vera

    2008-04-01

    Full Text Available Background: Decision analyses of drug treatments in chronic diseases require modeling the progression of disease and treatment response beyond the time horizon of clinical or epidemiological studies. In many such models, progression and drug effect have been applied uniformly to all patients; heterogeneity in progression, including pharmacogenomic effects, has been ignored. Objective: We sought to systematically evaluate the existence, direction and relative magnitude of a pharmacogenomics bias (PGX-Bias resulting from failure to adjust for genetic heterogeneity in both treatment response (HT and heterogeneity in progression of disease (HP in decision-analytic studies based on clinical study data. Methods: We performed a systematic literature search in electronic databases for studies regarding the effect of genetic heterogeneity on the validity of study results. Included studies have been summarized in evidence tables. In the case of lacking evidence from published studies we sought to perform our own simulation considering both HT and HP. We constructed two simple Markov models with three basic health states (early-stage disease, late-stage disease, dead, one adjusting and the other not adjusting for genetic heterogeneity. Adjustment was done by creating different disease states for presence (G+ and absence (G- of a dichotomous genetic factor. We compared the life expectancy gains attributable to treatment resulting from both models and defined pharmacogenomics bias as percent deviation of treatment-related life expectancy gains in the unadjusted model from those in the adjusted model. We calculated the bias as a function of underlying model parameters to create generic results. We then applied our model to lipid-lowering therapy with pravastatin in patients with coronary atherosclerosis, incorporating the influence of two TaqIB polymorphism variants (B1 and B2 on progression and drug efficacy as reported in the DNA substudy of the REGRESS

  16. The genetic validation of heterogeneity in schizophrenia.

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    Tsutsumi, Atsushi; Glatt, Stephen J; Kanazawa, Tetsufumi; Kawashige, Seiya; Uenishi, Hiroyuki; Hokyo, Akira; Kaneko, Takao; Moritani, Makiko; Kikuyama, Hiroki; Koh, Jun; Matsumura, Hitoshi; Yoneda, Hiroshi

    2011-10-07

    Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

  17. Genetic alterations in hepatocellular carcinoma: An update

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    Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Wen-Hong

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC. PMID:27895396

  18. TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients

    International Nuclear Information System (INIS)

    Körner, Christian; Nattermann, Jacob; Spengler, Ulrich; Nischalke, Hans Dieter; Riesner, Katarina; Krämer, Benjamin; Eisenhardt, Marianne; Glässner, Andreas; Wolter, Franziska; Berg, Thomas; Müller, Tobias; Sauerbruch, Tilman

    2012-01-01

    Tumour surveillance via induction of TRAIL-mediated apoptosis is a key mechanism, how the immune system prevents malignancy. To determine if gene variants in the TRAIL receptor I (DR4) gene affect the risk of hepatitis C virus (HCV)-induced liver cancer (HCC), we analysed DR4 mutations C626G (rs20575) and A683C (rs20576) in HCV-infected patients with and without HCC. Frequencies of DR4 gene polymorphisms were determined by LightSNiP assays in 159 and 234 HCV-infected patients with HCC and without HCC, respectively. 359 healthy controls served as reference population. Distribution of C626G and A683C genotypes were not significantly different between healthy controls and HCV-positive patients without HCC. DR4 variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor by Cox regression analysis (Odds ratio 1.975, 95% CI 1.205-3.236; p = 0.007). Furthermore HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors (2.69 ± 0.36 × 10 6 IU/ml vs. 1.81 ± 0.23 × 10 6 IU/ml, p = 0.049). The increased prevalence of patients with a 626C allele and the homozygous 683AA genotype in HCV-infected patients with HCC suggests that these genetic variants are a risk factor for HCC in chronic hepatitis C

  19. Histological heterogeneity in primary and metastatic classic combined hepatocellular-cholangiocarcinoma: a case series.

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    De Vito, Claudio; Sarker, Debashis; Ross, Paul; Heaton, Nigel; Quaglia, Alberto

    2017-11-01

    Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare and aggressive primary liver cancer with both hepatocellular and cholangiocellular differentiation. Due to its bi-phenotypic component, cHCC-CC is a heterogeneous tumour and histopathological analysis of metastatic deposits is poorly characterized. In this retrospective study, we describe four patients in whom the histology from resected specimens of both primary and recurrent and/or metastatic tumour was available for comparison and immunohistochemical characterization. Our study shows that recurrent or metastatic deposits replicate the heterogeneity of the primary cHCC-CC, that even originally small foci of divergent differentiation can become predominant later on and that hepatocellular and cholangiocellular components can show different tropism in distant organs. In our experience, the behaviour of recurrent/metastatic cHCC-CC is unpredictable and histological examination is necessary to guide treatment options at present.

  20. Hepatitis B Virus Infection, Genetic Susceptibility and Hepatocellular Carcinoma

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    Juan Wen

    2015-12-01

    Full Text Available Liver cancer is a sever cancer burden in the world, especially in developing countries. Its late diagnosis and high mortality rate urges early prediction. Hepatocellular carcinoma (HCC is the major histopathological type of liver cancer. Chronic infection with hepatitis B virus (HBV is a well-established risk factor for HCC. On one side, HBV sequence variation may influence the outcome of HBV infection and the development of HCC. At least ten HBV genotypes (A to J are identified. Several HBV genotypes and mutations in pre-S and pre-core/core promoter regions are closely associated with HCC pathogenesis, and have been regarded as biomarkers to predict the occurrence of HCC. On the other side, only a small fraction of chronic hepatitis B patients developed HCC, and some HCC cases were diagnosed with no known predisposing risk factors, suggesting host genetic variations may also play important roles in the carcinogenesis. In this review, we summarized current findings of HBV genotypes and mutations, host genetic variations and their interactions involved in HCC carcinogenesis. Understanding the key viral and host genetic variations is essential for generating effective predictive biomarkers for HCC development.

  1. Genetic heterogeneity of within-family variance of body weight in Atlantic salmon (Salmo salar).

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    Sonesson, Anna K; Odegård, Jørgen; Rönnegård, Lars

    2013-10-17

    Canalization is defined as the stability of a genotype against minor variations in both environment and genetics. Genetic variation in degree of canalization causes heterogeneity of within-family variance. The aims of this study are twofold: (1) quantify genetic heterogeneity of (within-family) residual variance in Atlantic salmon and (2) test whether the observed heterogeneity of (within-family) residual variance can be explained by simple scaling effects. Analysis of body weight in Atlantic salmon using a double hierarchical generalized linear model (DHGLM) revealed substantial heterogeneity of within-family variance. The 95% prediction interval for within-family variance ranged from ~0.4 to 1.2 kg2, implying that the within-family variance of the most extreme high families is expected to be approximately three times larger than the extreme low families. For cross-sectional data, DHGLM with an animal mean sub-model resulted in severe bias, while a corresponding sire-dam model was appropriate. Heterogeneity of variance was not sensitive to Box-Cox transformations of phenotypes, which implies that heterogeneity of variance exists beyond what would be expected from simple scaling effects. Substantial heterogeneity of within-family variance was found for body weight in Atlantic salmon. A tendency towards higher variance with higher means (scaling effects) was observed, but heterogeneity of within-family variance existed beyond what could be explained by simple scaling effects. For cross-sectional data, using the animal mean sub-model in the DHGLM resulted in biased estimates of variance components, which differed substantially both from a standard linear mean animal model and a sire-dam DHGLM model. Although genetic differences in canalization were observed, selection for increased canalization is difficult, because there is limited individual information for the variance sub-model, especially when based on cross-sectional data. Furthermore, potential macro

  2. Hepatocellular carcinoma (HCC) and diagnostic significance of alpha-fetoprotein (AFP)

    International Nuclear Information System (INIS)

    Baig, J.A.; Alam, J.M.; Baig, M.; Mahmood, S.R.; Shaheen, R.; Waheed, A.

    2009-01-01

    Alpha-fetoprotein (alpha-fetoprotein, AFP) is a Glycoprotein, belonging to the intriguing class of onco-development protein. Generally designated as tumour marker, AFP is recognized as an important blood component, having specific diagnostic utilities Elevation of its level up to pathological range in adults correlate with the appearance of several malignant and chronic conditions, such as hepatocellular carcinoma (HCC) and chronic liver disease, respectively. To evaluate the diagnostic significance of AFP in HCC, a study was carried out for a period of two years (Jan. 2004 to Dec. 2005) A brief history of Patients was taken with clinical symptoms and signs and initial diagnosis. Patients admitted in wards or visiting OPDs with diagnosis or suspicions of HCC and additional conditions of Chronic Liver disease (CLDs), hepatitis C (HCV) and hepatitis B viral (HBV) infections, were selected and classified according to gender. When confirmed, their HCC status was evaluated and classified according to clinical condition. In 1012 adults including, males 762 (75.3%) and females 250 (24.7%) patients suspected of or diagnosed with HCC and presence of HBV and HCV infections. Out of 480 males, who depicted elevated AFP levels, 39 (8.13%) were diagnosed with HCC. Similarly, 7 (5.34%) females out of 131 with elevated levels of AFP were diagnosed with HCC. Mean elevated AFP levels in all HCC patients were, 421+-59 mu g/ml (range 157-4019 mu g/ml) in males and 163+-32 mu g/ml (range 101-2341 mu g/ml) in females. In males, the overall estimated mean AFP elevated values were analyzed to be 514 mu g/ml (range 67-4019+-59 mu g/ml), whereas in females it was 396+-42 mu g/ml (range 21-2341 mu g/ml). It was also noted that 43 (8.96%) males and 7 (5.34%) female patients, exhibited elevated levels of AFP, however, found negative for HCV and HBV infections. It is concluded that AFP is a significant markers for Hepatocellular carcinoma, helpful in assessing problems in management of HCC and

  3. Genetic dissection of the Drosophila melanogaster female head transcriptome reveals widespread allelic heterogeneity.

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    King, Elizabeth G; Sanderson, Brian J; McNeil, Casey L; Long, Anthony D; Macdonald, Stuart J

    2014-05-01

    Modern genetic mapping is plagued by the "missing heritability" problem, which refers to the discordance between the estimated heritabilities of quantitative traits and the variance accounted for by mapped causative variants. One major potential explanation for the missing heritability is allelic heterogeneity, in which there are multiple causative variants at each causative gene with only a fraction having been identified. The majority of genome-wide association studies (GWAS) implicitly assume that a single SNP can explain all the variance for a causative locus. However, if allelic heterogeneity is prevalent, a substantial amount of genetic variance will remain unexplained. In this paper, we take a haplotype-based mapping approach and quantify the number of alleles segregating at each locus using a large set of 7922 eQTL contributing to regulatory variation in the Drosophila melanogaster female head. Not only does this study provide a comprehensive eQTL map for a major community genetic resource, the Drosophila Synthetic Population Resource, but it also provides a direct test of the allelic heterogeneity hypothesis. We find that 95% of cis-eQTLs and 78% of trans-eQTLs are due to multiple alleles, demonstrating that allelic heterogeneity is widespread in Drosophila eQTL. Allelic heterogeneity likely contributes significantly to the missing heritability problem common in GWAS studies.

  4. Genetic heterogeneity in Pakistani microcephaly families

    DEFF Research Database (Denmark)

    Sajid Hussain, M; Bakhtiar, Syeda Marriam; Farooq, Muhammad

    2013-01-01

    Autosomal recessive primary microcephaly (MCPH) is caused by mutations in at least eight different genes involved either in cell division or DNA repair. Most mutations are identified in consanguine families from Pakistan, Iran and India. To further assess their genetic heterogeneity and mutational...... mutation. One third of the families were linked to ASPM followed by WDR62 confirming previous data. We identified three novel ASPM mutations, four novel WDR62 mutations, one novel MCPH1 mutation and two novel CEP152 mutations. CEP152 mutations have not been described before in the Pakistani population....

  5. Genetically heterogeneous and selected lines of rats: behavioral and reproductive comparison.

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    Satinder, K P

    1980-03-01

    Avoidance learning, open-field, and reproductive behaviors of a genetically heterogeneous stock (derived from a four-way cross of selected lines) were compared with the corresponding behaviors of the parental lines. The heterogeneous stock showed heterosis on the body development, fertility rate, litter size at birth and at weaning, and directional dominance on the avoidance learning and open-field measures.

  6. TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication.

    Science.gov (United States)

    Ho, Daniel W H; Chan, Lo K; Chiu, Yung T; Xu, Iris M J; Poon, Ronnie T P; Cheung, Tan T; Tang, Chung N; Tang, Victor W L; Lo, Irene L O; Lam, Polly W Y; Yau, Derek T W; Li, Miao X; Wong, Chun M; Ng, Irene O L

    2017-08-01

    We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC -mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2 -mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  7. Genetic dissection of the Drosophila melanogaster female head transcriptome reveals widespread allelic heterogeneity.

    Directory of Open Access Journals (Sweden)

    Elizabeth G King

    2014-05-01

    Full Text Available Modern genetic mapping is plagued by the "missing heritability" problem, which refers to the discordance between the estimated heritabilities of quantitative traits and the variance accounted for by mapped causative variants. One major potential explanation for the missing heritability is allelic heterogeneity, in which there are multiple causative variants at each causative gene with only a fraction having been identified. The majority of genome-wide association studies (GWAS implicitly assume that a single SNP can explain all the variance for a causative locus. However, if allelic heterogeneity is prevalent, a substantial amount of genetic variance will remain unexplained. In this paper, we take a haplotype-based mapping approach and quantify the number of alleles segregating at each locus using a large set of 7922 eQTL contributing to regulatory variation in the Drosophila melanogaster female head. Not only does this study provide a comprehensive eQTL map for a major community genetic resource, the Drosophila Synthetic Population Resource, but it also provides a direct test of the allelic heterogeneity hypothesis. We find that 95% of cis-eQTLs and 78% of trans-eQTLs are due to multiple alleles, demonstrating that allelic heterogeneity is widespread in Drosophila eQTL. Allelic heterogeneity likely contributes significantly to the missing heritability problem common in GWAS studies.

  8. Linking transcriptional and genetic tumor heterogeneity through allele analysis of single-cell RNA-seq data.

    Science.gov (United States)

    Fan, Jean; Lee, Hae-Ock; Lee, Soohyun; Ryu, Da-Eun; Lee, Semin; Xue, Catherine; Kim, Seok Jin; Kim, Kihyun; Barkas, Nikolas; Park, Peter J; Park, Woong-Yang; Kharchenko, Peter V

    2018-06-13

    Characterization of intratumoral heterogeneity is critical to cancer therapy, as presence of phenotypically diverse cell populations commonly fuels relapse and resistance to treatment. Although genetic variation is a well-studied source of intratumoral heterogeneity, the functional impact of most genetic alterations remains unclear. Even less understood is the relative importance of other factors influencing heterogeneity, such as epigenetic state or tumor microenvironment. To investigate the relationship between genetic and transcriptional heterogeneity in a context of cancer progression, we devised a computational approach called HoneyBADGER to identify copy number variation and loss-of-heterozygosity in individual cells from single-cell RNA-sequencing data. By integrating allele and normalized expression information, HoneyBADGER is able to identify and infer the presence of subclone-specific alterations in individual cells and reconstruct underlying subclonal architecture. Examining several tumor types, we show that HoneyBADGER is effective at identifying deletion, amplifications, and copy-neutral loss-of-heterozygosity events, and is capable of robustly identifying subclonal focal alterations as small as 10 megabases. We further apply HoneyBADGER to analyze single cells from a progressive multiple myeloma patient to identify major genetic subclones that exhibit distinct transcriptional signatures relevant to cancer progression. Surprisingly, other prominent transcriptional subpopulations within these tumors did not line up with the genetic subclonal structure, and were likely driven by alternative, non-clonal mechanisms. These results highlight the need for integrative analysis to understand the molecular and phenotypic heterogeneity in cancer. Published by Cold Spring Harbor Laboratory Press.

  9. Diagnostic and therapeutic implications of genetic heterogeneity in myeloid neoplasms uncovered by comprehensive mutational analysis

    Directory of Open Access Journals (Sweden)

    Sarah M. Choi

    2017-01-01

    Full Text Available While growing use of comprehensive mutational analysis has led to the discovery of innumerable genetic alterations associated with various myeloid neoplasms, the under-recognized phenomenon of genetic heterogeneity within such neoplasms creates a potential for diagnostic confusion. Here, we describe two cases where expanded mutational testing led to amendment of an initial diagnosis of chronic myelogenous leukemia with subsequent altered treatment of each patient. We demonstrate the power of comprehensive testing in ensuring appropriate classification of genetically heterogeneous neoplasms, and emphasize thoughtful analysis of molecular and genetic data as an essential component of diagnosis and management.

  10. Type conversion of secretomes in a 3D TAM2 and HCC cell co-culture system and functional importance of CXCL2 in HCC.

    Science.gov (United States)

    Lu, Yu; Li, Shan; Ma, Liping; Li, Yan; Zhang, Xiaolian; Peng, Qiliu; Mo, Cuiju; Huang, Li; Qin, Xue; Liu, Yinkun

    2016-04-27

    Macrophages play important roles in the tumor microenvironment, driving cancer progression and metastasis, particularly in hepatocellular carcinoma (HCC). However, few studies have assessed the exact secretome composition in HCC. In the present study, the impact of different phenotype of macrophages on HCC cells was investigated. Alternatively activated macrophages (M2) were found to significantly increase the proliferation, migration, and invasion abilities of SMMC7721 cells (all P cultured with SMMC7721 cells to reconstruct the tumor microenvironment. Conditioned medium from 3D single cultures of M2, SMMC7721 cells, and their co-culture system were analyzed using quantitative proteomics via iTRAQ labeling combined with mass spectrometric analysis. Secretome analysis revealed a total of 159 differential secreted proteins in the co-culture system compared to the single culture systems, with 63 being up-regulated (>1.3-fold) and 96 down-regulated (culture system and HCC tissues, and was selected for further investigation. Functional effects data suggested that recombinant human CXCL2 significantly enhanced the migration, invasion ability of SMMC7721 cells, and weakened adhesion ability. While CXCL2 neutralization and CXCR2 blockage significantly inhibited the effects of CXCL2 on SMMC7721 cells, indicating that CXCL2 may play pivotal role in HCC metastasis.

  11. The genetic validation of heterogeneity in schizophrenia

    Directory of Open Access Journals (Sweden)

    Moritani Makiko

    2011-10-01

    Full Text Available Abstract Introduction Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Methods Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p Results No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57 was slightly lower than among controls (6.6+/-1.39. Conclusion The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

  12. Establishment of monoclonal HCC cell lines with organ site-specific tropisms

    International Nuclear Information System (INIS)

    Wan, Jinliang; Wen, Duo; Dong, Lili; Tang, Jun; Liu, Dongli; Liu, Yang; Tao, Zhonghua; Gao, Dongmei; Sun, Huichuan; Cao, Ya; Fan, Jia; Wu, Weizhong

    2015-01-01

    Organ site-specific metastasis is an ominous feature for most poor-prognostic hepatocellular carcinoma (HCC) patients. Cancer cell lines and animal models are indispensable for investigating the molecular mechanisms of organ specific tropism. However, till now, little is known about the drivers in HCC metastatic tropism, and also no effective way has been developed to block the process of tropistic metastasis. In this study, we established several monoclonal HCC cell lines from HCCLM3-RFP together with their xenograft models, and then analyzed their metastatic potentials and tropisms using in-vitro and in-vivo assays, and finally elucidated the driving forces of HCC tropistic metastases. Six monoclonal cell lines with different organ site-specific tropism were established successfully. SPARC, VCAM1 and ANGPTL4 were found positively correlated with the potentials of lung metastasis, while ITGA1 had a positive relation to lymph node metastasis of enterocoelia. By our powerful platforms, HCC metastatic tropisms in clinic could be easily mimicked and recapitulated for exploring the bilateral interactions between tumor and its microenvironment, elucidating the drivers of HCC metastatic tropisms, and testing anti-cancer effects of newly developed agent in pre-clinical stage. The online version of this article (doi:10.1186/s12885-015-1692-0) contains supplementary material, which is available to authorized users

  13. Spatial heterogeneity as a genetic mixing mechanism in highly philopatric colonial seabirds.

    Science.gov (United States)

    Cristofari, Robin; Trucchi, Emiliano; Whittington, Jason D; Vigetta, Stéphanie; Gachot-Neveu, Hélène; Stenseth, Nils Christian; Le Maho, Yvon; Le Bohec, Céline

    2015-01-01

    How genetic diversity is maintained in philopatric colonial systems remains unclear, and understanding the dynamic balance of philopatry and dispersal at all spatial scales is essential to the study of the evolution of coloniality. In the King penguin, Aptenodytes patagonicus, return rates of post-fledging chicks to their natal sub-colony are remarkably high. Empirical studies have shown that adults return year after year to their previous breeding territories within a radius of a few meters. Yet, little reliable data are available on intra- and inter-colonial dispersal in this species. Here, we present the first fine-scale study of the genetic structure in a king penguin colony in the Crozet Archipelago. Samples were collected from individual chicks and analysed at 8 microsatellite loci. Precise geolocation data of hatching sites and selective pressures associated with habitat features were recorded for all sampling locations. We found that despite strong natal and breeding site fidelity, king penguins retain a high degree of panmixia and genetic diversity. Yet, genetic structure appears markedly heterogeneous across the colony, with higher-than-expected inbreeding levels, and local inbreeding and relatedness hotspots that overlap predicted higher-quality nesting locations. This points towards heterogeneous population structure at the sub-colony level, in which fine-scale environmental features drive local philopatric behaviour, while lower-quality patches may act as genetic mixing mechanisms at the colony level. These findings show how a lack of global genetic structuring can emerge from small-scale heterogeneity in ecological parameters, as opposed to the classical model of homogeneous dispersal. Our results also emphasize the importance of sampling design for estimation of population parameters in colonial seabirds, as at high spatial resolution, basic genetic features are shown to be location-dependent. Finally, this study stresses the importance of

  14. Spatial heterogeneity as a genetic mixing mechanism in highly philopatric colonial seabirds.

    Directory of Open Access Journals (Sweden)

    Robin Cristofari

    Full Text Available How genetic diversity is maintained in philopatric colonial systems remains unclear, and understanding the dynamic balance of philopatry and dispersal at all spatial scales is essential to the study of the evolution of coloniality. In the King penguin, Aptenodytes patagonicus, return rates of post-fledging chicks to their natal sub-colony are remarkably high. Empirical studies have shown that adults return year after year to their previous breeding territories within a radius of a few meters. Yet, little reliable data are available on intra- and inter-colonial dispersal in this species. Here, we present the first fine-scale study of the genetic structure in a king penguin colony in the Crozet Archipelago. Samples were collected from individual chicks and analysed at 8 microsatellite loci. Precise geolocation data of hatching sites and selective pressures associated with habitat features were recorded for all sampling locations. We found that despite strong natal and breeding site fidelity, king penguins retain a high degree of panmixia and genetic diversity. Yet, genetic structure appears markedly heterogeneous across the colony, with higher-than-expected inbreeding levels, and local inbreeding and relatedness hotspots that overlap predicted higher-quality nesting locations. This points towards heterogeneous population structure at the sub-colony level, in which fine-scale environmental features drive local philopatric behaviour, while lower-quality patches may act as genetic mixing mechanisms at the colony level. These findings show how a lack of global genetic structuring can emerge from small-scale heterogeneity in ecological parameters, as opposed to the classical model of homogeneous dispersal. Our results also emphasize the importance of sampling design for estimation of population parameters in colonial seabirds, as at high spatial resolution, basic genetic features are shown to be location-dependent. Finally, this study stresses the

  15. Deciphering cancer heterogeneity: the biological space

    Directory of Open Access Journals (Sweden)

    Stephanie eRoessler

    2014-04-01

    Full Text Available Most lethal solid tumors including hepatocellular carcinoma (HCC are considered incurable due to extensive heterogeneity in clinical presentation and tumor biology. Tumor heterogeneity may result from different cells of origin, patient ethnicity, etiology, underlying disease and diversity of genomic and epigenomic changes which drive tumor development. Cancer genomic heterogeneity thereby impedes treatment options and poses a significant challenge to cancer management. Studies of the HCC genome have revealed that although various genomic signatures identified in different HCC subgroups share a common prognosis, each carries unique molecular changes which are linked to different sets of cancer hallmarks whose misregulation has been proposed by Hanahan and Weinberg to be essential for tumorigenesis. We hypothesize that these specific sets of cancer hallmarks collectively occupy different tumor biological space representing the misregulation of different biological processes. In principle, a combination of different cancer hallmarks can result in new convergent molecular networks that are unique to each tumor subgroup and represent ideal druggable targets. Due to the ability of the tumor to adapt to external factors such as treatment or changes in the tumor microenvironment, the tumor biological space is elastic. Our ability to identify distinct groups of cancer patients with similar tumor biology who are most likely to respond to a specific therapy would have a significant impact on improving patient outcome. It is currently a challenge to identify a particular hallmark or a newly emerged convergent molecular network for a particular tumor. Thus, it is anticipated that the integration of multiple levels of data such as genomic mutations, somatic copy number aberration, gene expression, proteomics, and metabolomics, may help us grasp the tumor biological space occupied by each individual, leading to improved therapeutic intervention and outcome.

  16. Lipid Biomarkers Identified for Liver Cancer | Center for Cancer Research

    Science.gov (United States)

    Hepatocellular carcinoma (HCC) is an aggressive cancer of the liver with poor prognosis and growing incidence in developed countries. Pathology and genetic profiles of HCC are heterogeneous, suggesting that it can begin growing in different cell types. Although human tumors such as HCC have been profiled in-depth by genomics-based studies, not much is known about their overall

  17. Evidence for nonallelic genetic heterogeneity in autosomal recessive retinitis pigmentosa

    NARCIS (Netherlands)

    Bleeker-Wagemakers, L. M.; Gal, A.; Kumar-Singh, R.; van den Born, L. I.; Li, Y.; Schwinger, E.; Sandkuijl, L. A.; Bergen, A. A.; Kenna, P.; Humphries, P.

    1992-01-01

    Recent evidence suggesting the involvement of mutant rhodopsin proteins in the pathogenesis of autosomal recessive retinitis pigmentosa has prompted us to investigate whether this form of the disease shows non-allelic genetic heterogeneity, as has previously been shown to be the case in autosomal

  18. Heterogeneity of schizophrenia: Genetic and symptomatic factors.

    Science.gov (United States)

    Takahashi, Sakae

    2013-10-01

    Schizophrenia may have etiological heterogeneity, and may reflect common symptomatology caused by many genetic and environmental factors. In this review, we show the potential existence of heterogeneity in schizophrenia based on the results of our previous studies. In our study of the NOTCH4 gene, there were no significant associations between any single nucleotide polymorphisms (SNPs) of NOTCH4 and schizophrenia. However, exploratory analyses suggested that the SNP, rs3134928 may be associated with early-onset schizophrenia, and that rs387071 may be associated with schizophrenia characterized by negative symptoms. In our highly familial schizophrenia study, the African-American cohort without environmental exposure showed a possible linkage at marker 8p23.1 in the dominant model and in the European-American cohort, a marker at 22q13.32 showed a probable linkage in the recessive model. In the less familial schizophrenia families, these linkages were not shown. Based on our eye movement study, a putative subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization may be associated with chromosome 22q11. We consider that a sample stratification approach may clarify the heterogeneity of schizophrenia. Therefore, this approach may lead to a more straightforward way of identifying susceptibility genes of schizophrenia. © 2013 Wiley Periodicals, Inc.

  19. Prediction of breeding values and selection responses with genetic heterogeneity of environmental variance

    NARCIS (Netherlands)

    Mulder, H.A.; Bijma, P.; Hill, W.G.

    2007-01-01

    There is empirical evidence that genotypes differ not only in mean, but also in environmental variance of the traits they affect. Genetic heterogeneity of environmental variance may indicate genetic differences in environmental sensitivity. The aim of this study was to develop a general framework

  20. Differences in antiproliferative effect of STAT3 inhibition in HCC cells with versus without HBV expression

    International Nuclear Information System (INIS)

    Hong, Yun; Zhou, Lin; Xie, Haiyang; Wang, Weilin; Zheng, Shusen

    2015-01-01

    Chronic infection with hepatitis B virus (HBV) plays an important role in the etiology of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 3 (STAT3) inactivation could inhibit the tumor growth of HCC. In this study, differential antiproliferative effect of STAT3 inhibition was observed with HBV-related HCC cells being more resistant than non-HBV-related HCC cells. Resistance of HBV-related HCC cells to STAT3 inhibition was positively correlated to the expression of HBV. Enhanced ERK activation after STAT3 blockade was detected in HBV-related HCC cells but not in non-HBV-related HCC cells. Combined ERK and STAT3 inhibition eliminates the discrepancy between the two types of HCC cells. Moderate reduced HBV expression was found after STAT3 inhibition. These findings disclose a discrepancy in cellular response to STAT3 inhibition between non-HBV-related and HBV-related HCC cells and underscore the complexity of antiproliferative effect of STAT3 inactivation in HBV-related HCC cells. - Highlights: • HBV endows HCC cells with resistance to STAT3 inactivation on proliferation. • Abnormal ERK activation after STAT3 inhibition in HBV-related HCC cells. • Combined ERK and STAT3 inhibition eliminates the discrepancy. • STAT3 inhibition moderately reduces HBV expression

  1. Differences in antiproliferative effect of STAT3 inhibition in HCC cells with versus without HBV expression

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Yun; Zhou, Lin; Xie, Haiyang; Wang, Weilin [Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Qingchun Road 79, Hangzhou, Zhejiang 310003 (China); Key Laboratory of Combined Multi-organ Transplantation of Ministry of Public Health, Qingchun Road 79, Hangzhou, Zhejiang 310003 (China); Zheng, Shusen, E-mail: shusenzheng@zju.edu.cn [Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Qingchun Road 79, Hangzhou, Zhejiang 310003 (China); Key Laboratory of Combined Multi-organ Transplantation of Ministry of Public Health, Qingchun Road 79, Hangzhou, Zhejiang 310003 (China)

    2015-06-05

    Chronic infection with hepatitis B virus (HBV) plays an important role in the etiology of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 3 (STAT3) inactivation could inhibit the tumor growth of HCC. In this study, differential antiproliferative effect of STAT3 inhibition was observed with HBV-related HCC cells being more resistant than non-HBV-related HCC cells. Resistance of HBV-related HCC cells to STAT3 inhibition was positively correlated to the expression of HBV. Enhanced ERK activation after STAT3 blockade was detected in HBV-related HCC cells but not in non-HBV-related HCC cells. Combined ERK and STAT3 inhibition eliminates the discrepancy between the two types of HCC cells. Moderate reduced HBV expression was found after STAT3 inhibition. These findings disclose a discrepancy in cellular response to STAT3 inhibition between non-HBV-related and HBV-related HCC cells and underscore the complexity of antiproliferative effect of STAT3 inactivation in HBV-related HCC cells. - Highlights: • HBV endows HCC cells with resistance to STAT3 inactivation on proliferation. • Abnormal ERK activation after STAT3 inhibition in HBV-related HCC cells. • Combined ERK and STAT3 inhibition eliminates the discrepancy. • STAT3 inhibition moderately reduces HBV expression.

  2. HCC-DETECT: a combination of nuclear, cytoplasmic, and oncofetal proteins as biomarkers for hepatocellular carcinoma.

    Science.gov (United States)

    Attallah, Abdelfattah M; El-Far, Mohamed; Malak, Camelia A Abdel; Omran, Mohamed M; Shiha, Gamal E; Farid, Khaled; Barakat, Lamiaa A; Albannan, Mohamed S; Attallah, Ahmed A; Abdelrazek, Mohamed A; Elbendary, Mohamed S; Sabry, Refaat; Hamoda, Gehan A; Elshemy, Mohamed M; Ragab, Abdallah A; Foda, Basma M; Abdallah, Sanaa O

    2015-09-01

    Currently, the search for suitable hepatocellular carcinoma (HCC) biomarkers is very intensive. Besides, efficacy and cost/effectiveness of screening and surveillance of cirrhotics for the diagnosis of HCC is still debated. So, the present study is concerned with the evaluation of cytokeratin-1 (CK-1) and nuclear matrix protein-52 (NMP-52) for identifying HCC. Two-hundred and eighty individuals categorized into three groups [liver fibrosis (F1-F3), cirrhosis (F4), and HCC] constituted this study. Western blot was used for identifying CK-1 and NMP-52 in serum samples. As a result, a single immunoreactive band was shown at 67 and 52 kDa corresponding to CK-1 and NMP-52, respectively. Both CK-1 and NMP-52 bands were cut and electroeluted separately. These markers were quantified in sera using ELISA. Patients with HCC were associated with higher concentrations of CK-1 and NMP-52 than those without HCC with a significant difference (P < 0.0001). CK-1 showed an area under receiver-operating characteristic curve (AUC) of 0.83 with 75 % sensitivity and 82 % specificity while NMP-52 yielded 0.72 AUC with 62 % sensitivity and 70 % specificity for identifying HCC. HCC-DETECT comprising CK-1 and NMP-52 together with AFP was then constructed yielding 0.90 AUC for identifying HCC with 80 % sensitivity and 92 % specificity. HCC-DETECT was then tested for separating HCC from F1-F3 showing 0.94 AUC with 80 % sensitivity and 93 % specificity. In conclusion, CK-1 in conjunction with NMP-52 and AFP could have a potential role for improving the detection of HCC with a high degree of accuracy.

  3. MEK-ERK inhibition potentiates WAY-600-induced anti-cancer efficiency in preclinical hepatocellular carcinoma (HCC) models

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Kaifeng, E-mail: kaifeng_wangdr@sina.com [Cancer center, the Affiliated Hospital of Hangzhou Normal University, Hangzhou (China); Fan, Yaohua [Oncology Department, No. 1 Hospital of Jiaxing, Zhejiang Province, Jiaxing (China); Chen, Gongying [Oncology Department, The Affiliated Hospital Hangzhou Normal University, Hangzhou (China); Wang, Zhengrong [Taizhou Hospital, Zhejiang Province, Taizhou (China); Kong, Dexin; Zhang, Peng [Oncology Department, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou (China)

    2016-05-27

    The search for novel anti-hepatocellular carcinoma (HCC) agents is important. Mammalian target of rapamycin (mTOR) hyper-activation plays a pivotal role in promoting HCC tumorigenesis and chemoresistance. The current preclinical study evaluated the potential anti-HCC activity by a potent mTOR kinase inhibitor, WAY-600. We showed that WAY-600 inhibited survival and proliferation of HCC cell lines (HepG2 and Huh7) and primary human HCC cells. Caspase-dependent apoptosis was activated by WAY-600 in above HCC cells. Reversely, caspase inhibitors largely attenuated WAY-600's lethality against HCC cells. At the signaling level, WAY-600 blocked mTOR complex 1/2 (mTORC1/2) assemble and activation, yet activated MEK-ERK pathway in HCC cells. MEK-ERK inhibitors, PD-98059 and MEK-162, or MEK1/2 shRNA significantly potentiated WAY-600's cytotoxicity in HCC cells. Further studies showed that WAY-600 intraperitoneal (i.p.) administration in nude mice inhibited p-AKT Ser-473 and displayed significant anti-cancer activity against HepG2 xenografts. Remarkably, co-administration of MEK-162 further potentiated WAY-600's anti-HCC activity in vivo. These preclinical results demonstrate the potent anti-HCC activity by WAY-600, either alone or with MEK-ERK inhibitors. -- Highlights: •WAY-600 inhibits HCC cell survival and proliferation in vitro. •WAY-600 activates caspase-dependent apoptosis in HCC cells. •WAY-600 blocks mTORC1/2 activation, but activates MEK-ERK in HCC cells. •MEK-ERK inhibitors or MEK1/2 shRNA enhances WAY-600's cytotoxicity against HCC cells. •MEK-162 co-administration potentiates WAY-600-induced the anti-HepG2 tumor efficacy.

  4. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma.

    Science.gov (United States)

    Nahon, Pierre; Nault, Jean-Charles

    2017-11-01

    Exploration of the constitutional genetics of hepatocellular carcinoma (HCC) has identified numerous variants associated with a higher risk of liver cancer in alcoholic cirrhotic patients. Although Genome-Wide Association studies have not been carried out in the field of alcohol-related HCC, common single nucleotide polymorphisms conferring a small increase in the risk of liver cancer risk have been identified and shown to modulate ethanol metabolism, inflammation, oxidative stress, iron or lipid metabolism. Specific patterns of gene mutations including CTNNB1, TERT, ARID1A and SMARCA2 exist in alcohol-related HCC. Moreover, a specific mutational process observed at the nucleotide level by next generation sequencing has revealed cooperation between alcohol and tobacco in the development of HCC. Combining this genetic information with epidemiological and clinical data that might define specific HCC risk classes and refine surveillance strategies needs to be assessed in large prospective cohorts of patients with alcoholic cirrhosis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Scale-dependent effects of a heterogeneous landscape on genetic differentiation in the Central American squirrel monkey (Saimiri oerstedii.

    Directory of Open Access Journals (Sweden)

    Mary E Blair

    Full Text Available Landscape genetic studies offer a fine-scale understanding of how habitat heterogeneity influences population genetic structure. We examined population genetic structure and conducted a landscape genetic analysis for the endangered Central American Squirrel Monkey (Saimiri oerstedii that lives in the fragmented, human-modified habitats of the Central Pacific region of Costa Rica. We analyzed non-invasively collected fecal samples from 244 individuals from 14 groups for 16 microsatellite markers. We found two geographically separate genetic clusters in the Central Pacific region with evidence of recent gene flow among them. We also found significant differentiation among groups of S. o. citrinellus using pairwise F(ST comparisons. These groups are in fragments of secondary forest separated by unsuitable "matrix" habitats such as cattle pasture, commercial African oil palm plantations, and human residential areas. We used an individual-based landscape genetic approach to measure spatial patterns of genetic variance while taking into account landscape heterogeneity. We found that large, commercial oil palm plantations represent moderate barriers to gene flow between populations, but cattle pastures, rivers, and residential areas do not. However, the influence of oil palm plantations on genetic variance was diminished when we restricted analyses to within population pairs, suggesting that their effect is scale-dependent and manifests during longer dispersal events among populations. We show that when landscape genetic methods are applied rigorously and at the right scale, they are sensitive enough to track population processes even in species with long, overlapping generations such as primates. Thus landscape genetic approaches are extremely valuable for the conservation management of a diverse array of endangered species in heterogeneous, human-modified habitats. Our results also stress the importance of explicitly considering the heterogeneity of

  6. Estimation of the frequency of occult mutations for an autosomal recessive disease in the presence of genetic heterogeneity: application to genetic hearing loss disorders.

    Science.gov (United States)

    Kimberling, William J

    2005-11-01

    The routine testing for pathologic mutation(s) in a patient's DNA has become the foundation of modern molecular genetic diagnosis. It is especially valuable when the phenotype shows genetic heterogeneity, and its importance will grow as treatments become genotype specific. However, the technology of mutation detection is imperfect and mutations are often missed. This can be especially troublesome when dealing with a recessive disorder where the combination of genetic heterogeneity and missed mutation creates an imprecision in the genotypic assessment of individuals who do not appear to have the expected complement of two pathologic mutations. This article describes a statistical approach to the estimation of the likelihood of a genetic diagnosis under these conditions. In addition to providing a means of testing for missed mutations, it also provides a method of estimating and testing for the presence of genetic heterogeneity in the absence of linkage data. Gene frequencies as well as estimates of sensitivity and specificity can be obtained as well. The test is applied to GJB2 recessive nonsyndromic deafness, Usher syndrome types Ib and IIa, and Pendred-enlarged vestibular aqueduct syndrome. Copyright 2005 Wiley-Liss, Inc.

  7. Analysis of a genetically structured variance heterogeneity model using the Box-Cox transformation.

    Science.gov (United States)

    Yang, Ye; Christensen, Ole F; Sorensen, Daniel

    2011-02-01

    Over recent years, statistical support for the presence of genetic factors operating at the level of the environmental variance has come from fitting a genetically structured heterogeneous variance model to field or experimental data in various species. Misleading results may arise due to skewness of the marginal distribution of the data. To investigate how the scale of measurement affects inferences, the genetically structured heterogeneous variance model is extended to accommodate the family of Box-Cox transformations. Litter size data in rabbits and pigs that had previously been analysed in the untransformed scale were reanalysed in a scale equal to the mode of the marginal posterior distribution of the Box-Cox parameter. In the rabbit data, the statistical evidence for a genetic component at the level of the environmental variance is considerably weaker than that resulting from an analysis in the original metric. In the pig data, the statistical evidence is stronger, but the coefficient of correlation between additive genetic effects affecting mean and variance changes sign, compared to the results in the untransformed scale. The study confirms that inferences on variances can be strongly affected by the presence of asymmetry in the distribution of data. We recommend that to avoid one important source of spurious inferences, future work seeking support for a genetic component acting on environmental variation using a parametric approach based on normality assumptions confirms that these are met.

  8. An alternative covariance estimator to investigate genetic heterogeneity in populations.

    Science.gov (United States)

    Heslot, Nicolas; Jannink, Jean-Luc

    2015-11-26

    For genomic prediction and genome-wide association studies (GWAS) using mixed models, covariance between individuals is estimated using molecular markers. Based on the properties of mixed models, using available molecular data for prediction is optimal if this covariance is known. Under this assumption, adding individuals to the analysis should never be detrimental. However, some empirical studies showed that increasing training population size decreased prediction accuracy. Recently, results from theoretical models indicated that even if marker density is high and the genetic architecture of traits is controlled by many loci with small additive effects, the covariance between individuals, which depends on relationships at causal loci, is not always well estimated by the whole-genome kinship. We propose an alternative covariance estimator named K-kernel, to account for potential genetic heterogeneity between populations that is characterized by a lack of genetic correlation, and to limit the information flow between a priori unknown populations in a trait-specific manner. This is similar to a multi-trait model and parameters are estimated by REML and, in extreme cases, it can allow for an independent genetic architecture between populations. As such, K-kernel is useful to study the problem of the design of training populations. K-kernel was compared to other covariance estimators or kernels to examine its fit to the data, cross-validated accuracy and suitability for GWAS on several datasets. It provides a significantly better fit to the data than the genomic best linear unbiased prediction model and, in some cases it performs better than other kernels such as the Gaussian kernel, as shown by an empirical null distribution. In GWAS simulations, alternative kernels control type I errors as well as or better than the classical whole-genome kinship and increase statistical power. No or small gains were observed in cross-validated prediction accuracy. This alternative

  9. Assessment of Genetic Heterogeneity in Structured Plant Populations Using Multivariate Whole-Genome Regression Models.

    Science.gov (United States)

    Lehermeier, Christina; Schön, Chris-Carolin; de Los Campos, Gustavo

    2015-09-01

    Plant breeding populations exhibit varying levels of structure and admixture; these features are likely to induce heterogeneity of marker effects across subpopulations. Traditionally, structure has been dealt with as a potential confounder, and various methods exist to "correct" for population stratification. However, these methods induce a mean correction that does not account for heterogeneity of marker effects. The animal breeding literature offers a few recent studies that consider modeling genetic heterogeneity in multibreed data, using multivariate models. However, these methods have received little attention in plant breeding where population structure can have different forms. In this article we address the problem of analyzing data from heterogeneous plant breeding populations, using three approaches: (a) a model that ignores population structure [A-genome-based best linear unbiased prediction (A-GBLUP)], (b) a stratified (i.e., within-group) analysis (W-GBLUP), and (c) a multivariate approach that uses multigroup data and accounts for heterogeneity (MG-GBLUP). The performance of the three models was assessed on three different data sets: a diversity panel of rice (Oryza sativa), a maize (Zea mays L.) half-sib panel, and a wheat (Triticum aestivum L.) data set that originated from plant breeding programs. The estimated genomic correlations between subpopulations varied from null to moderate, depending on the genetic distance between subpopulations and traits. Our assessment of prediction accuracy features cases where ignoring population structure leads to a parsimonious more powerful model as well as others where the multivariate and stratified approaches have higher predictive power. In general, the multivariate approach appeared slightly more robust than either the A- or the W-GBLUP. Copyright © 2015 by the Genetics Society of America.

  10. Pathway-based Analysis of the Hidden Genetic Heterogeneities in Cancers

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    Xiaolei Zhao

    2014-02-01

    Full Text Available Many cancers apparently showing similar phenotypes are actually distinct at the molecular level, leading to very different responses to the same treatment. It has been recently demonstrated that pathway-based approaches are robust and reliable for genetic analysis of cancers. Nevertheless, it remains unclear whether such function-based approaches are useful in deciphering molecular heterogeneities in cancers. Therefore, we aimed to test this possibility in the present study. First, we used a NCI60 dataset to validate the ability of pathways to correctly partition samples. Next, we applied the proposed method to identify the hidden subtypes in diffuse large B-cell lymphoma (DLBCL. Finally, the clinical significance of the identified subtypes was verified using survival analysis. For the NCI60 dataset, we achieved highly accurate partitions that best fit the clinical cancer phenotypes. Subsequently, for a DLBCL dataset, we identified three hidden subtypes that showed very different 10-year overall survival rates (90%, 46% and 20% and were highly significantly (P = 0.008 correlated with the clinical survival rate. This study demonstrated that the pathway-based approach is promising for unveiling genetic heterogeneities in complex human diseases.

  11. Genetic heterogeneity of L-Zagreb mumps virus vaccine strain.

    Science.gov (United States)

    Kosutic-Gulija, Tanja; Forcic, Dubravko; Santak, Maja; Ramljak, Ana; Mateljak-Lukacevic, Sanja; Mazuran, Renata

    2008-07-10

    The most often used mumps vaccine strains Jeryl Lynn (JL), RIT4385, Urabe-AM9, L-Zagreb and L-3 differ in immunogenicity and reactogenicity. Previous analyses showed that JL, Urabe-AM9 and L-3 are genetically heterogeneous. We identified the heterogeneity of L-Zagreb throughout the entire genome. Two major variants were defined: variant A being identical to the consensus sequence of viral seeds and vaccine(s) and variant B which differs from variant A in three nucleotide positions. The difference between viral variants in L-Zagreb strain is insufficient for distinct viral strains to be defined. We demonstrated that proportion of variants in L-Zagreb viral population depends on cell substrate used for viral replication in vitro and in vivo. L-Zagreb strain should be considered as a single strain composed of at least two variant viral genomes.

  12. 4 gene expression in hepatocellular carcinoma (HCC)

    African Journals Online (AJOL)

    Gamalat El Gedawy

    2016-06-06

    Jun 6, 2016 ... Subjects and methods: This study was conducted on 30 HCC patients, 20 chronic liver disease ...... [26] Huang CS, Yu W, Cui H, Wang YJ, Zhang L, Han F, et al. ... Y. Involvement of programmed cell death 4 in transforming.

  13. Environmental heterogeneity explains the genetic structure of Continental and Mediterranean populations of Fraxinus angustifolia Vahl.

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    Martina Temunović

    Full Text Available Tree species with wide distributions often exhibit different levels of genetic structuring correlated to their environment. However, understanding how environmental heterogeneity influences genetic variation is difficult because the effects of gene flow, drift and selection are confounded. We investigated the genetic variation and its ecological correlates in a wind-pollinated Mediterranean tree species, Fraxinus angustifolia Vahl, within a recognised glacial refugium in Croatia. We sampled 11 populations from environmentally divergent habitats within the Continental and Mediterranean biogeographical regions. We combined genetic data analyses based on nuclear microsatellite loci, multivariate statistics on environmental data and ecological niche modelling (ENM. We identified a geographic structure with a high genetic diversity and low differentiation in the Continental region, which contrasted with the significantly lower genetic diversity and higher population divergence in the Mediterranean region. The positive and significant correlation between environmental and genetic distances after controlling for geographic distance suggests an important influence of ecological divergence of the sites in shaping genetic variation. The ENM provided support for niche differentiation between the populations from the Continental and Mediterranean regions, suggesting that contemporary populations may represent two divergent ecotypes. Ecotype differentiation was also supported by multivariate environmental and genetic distance analyses. Our results suggest that despite extensive gene flow in continental areas, long-term stability of heterogeneous environments have likely promoted genetic divergence of ashes in this region and can explain the present-day genetic variation patterns of these ancient populations.

  14. Delineating the genetic heterogeneity of OCA in Hungarian patients

    OpenAIRE

    F?bos, Be?ta; Farkas, Katalin; T?th, Lola; Sul?k, Adrienn; Tripolszki, Korn?lia; Tihanyi, Mariann; N?meth, R?ka; Vas, Krisztina; Csoma, Zsanett; Kem?ny, Lajos; Sz?ll, M?rta; Nagy, Nikoletta

    2017-01-01

    Background Oculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities characterized by variable hair, skin, and ocular hypopigmentation. Six known genes and a locus on human chromosome 4q24 have been implicated in the etiology of isolated OCA forms (OCA 1?7). Methods The most frequent OCA types among Caucasians are OCA1, OCA2, and OCA4. We aimed to investigate genes responsible for the development of these OCA forms in Hungarian OCA patients ...

  15. Genetic heterogeneity of L-Zagreb mumps virus vaccine strain

    Directory of Open Access Journals (Sweden)

    Mateljak-Lukacevic Sanja

    2008-07-01

    Full Text Available Abstract Background The most often used mumps vaccine strains Jeryl Lynn (JL, RIT4385, Urabe-AM9, L-Zagreb and L-3 differ in immunogenicity and reactogenicity. Previous analyses showed that JL, Urabe-AM9 and L-3 are genetically heterogeneous. Results We identified the heterogeneity of L-Zagreb throughout the entire genome. Two major variants were defined: variant A being identical to the consensus sequence of viral seeds and vaccine(s and variant B which differs from variant A in three nucleotide positions. The difference between viral variants in L-Zagreb strain is insufficient for distinct viral strains to be defined. We demonstrated that proportion of variants in L-Zagreb viral population depends on cell substrate used for viral replication in vitro and in vivo. Conclusion L-Zagreb strain should be considered as a single strain composed of at least two variant viral genomes.

  16. Genetic heterogeneity of L-Zagreb mumps virus vaccine strain

    Science.gov (United States)

    Kosutic-Gulija, Tanja; Forcic, Dubravko; Šantak, Maja; Ramljak, Ana; Mateljak-Lukacevic, Sanja; Mazuran, Renata

    2008-01-01

    Background The most often used mumps vaccine strains Jeryl Lynn (JL), RIT4385, Urabe-AM9, L-Zagreb and L-3 differ in immunogenicity and reactogenicity. Previous analyses showed that JL, Urabe-AM9 and L-3 are genetically heterogeneous. Results We identified the heterogeneity of L-Zagreb throughout the entire genome. Two major variants were defined: variant A being identical to the consensus sequence of viral seeds and vaccine(s) and variant B which differs from variant A in three nucleotide positions. The difference between viral variants in L-Zagreb strain is insufficient for distinct viral strains to be defined. We demonstrated that proportion of variants in L-Zagreb viral population depends on cell substrate used for viral replication in vitro and in vivo. Conclusion L-Zagreb strain should be considered as a single strain composed of at least two variant viral genomes. PMID:18616793

  17. Identification of Key Pathways and Genes in the Dynamic Progression of HCC Based on WGCNA.

    Science.gov (United States)

    Yin, Li; Cai, Zhihui; Zhu, Baoan; Xu, Cunshuan

    2018-02-14

    Hepatocellular carcinoma (HCC) is a devastating disease worldwide. Though many efforts have been made to elucidate the process of HCC, its molecular mechanisms of development remain elusive due to its complexity. To explore the stepwise carcinogenic process from pre-neoplastic lesions to the end stage of HCC, we employed weighted gene co-expression network analysis (WGCNA) which has been proved to be an effective method in many diseases to detect co-expressed modules and hub genes using eight pathological stages including normal, cirrhosis without HCC, cirrhosis, low-grade dysplastic, high-grade dysplastic, very early and early, advanced HCC and very advanced HCC. Among the eight consecutive pathological stages, five representative modules are selected to perform canonical pathway enrichment and upstream regulator analysis by using ingenuity pathway analysis (IPA) software. We found that cell cycle related biological processes were activated at four neoplastic stages, and the degree of activation of the cell cycle corresponded to the deterioration degree of HCC. The orange and yellow modules enriched in energy metabolism, especially oxidative metabolism, and the expression value of the genes decreased only at four neoplastic stages. The brown module, enriched in protein ubiquitination and ephrin receptor signaling pathways, correlated mainly with the very early stage of HCC. The darkred module, enriched in hepatic fibrosis/hepatic stellate cell activation, correlated with the cirrhotic stage only. The high degree hub genes were identified based on the protein-protein interaction (PPI) network and were verified by Kaplan-Meier survival analysis. The novel five high degree hub genes signature that was identified in our study may shed light on future prognostic and therapeutic approaches. Our study brings a new perspective to the understanding of the key pathways and genes in the dynamic changes of HCC progression. These findings shed light on further investigations.

  18. Significance of genetic variants in DLC1 and their association with hepatocellular carcinoma

    Science.gov (United States)

    XIE, CHENG-RONG; SUN, HONG-GUANG; SUN, YU; ZHAO, WEN-XIU; ZHANG, SHENG; WANG, XIAO-MIN; YIN, ZHEN-YU

    2015-01-01

    DLC1 has been shown to be downregulated or absent in hepatocellular carcinoma (HCC) and is associated with tumorigenesis and development. However, only a small number of studies have focused on genetic variations of DLC1. The present study performed exon sequencing for the DLC1 gene in HCC tissue samples from 105 patients to identify functional genetic variation of DLC1 and its association with HCC susceptibility, clinicopathological features and prognosis. A novel missense mutation and four non-synonymous single nucleotide polymorphisms (SNPs; rs3816748, rs11203495, rs3816747 and rs532841) were identified. A significant correlation of rs3816747 polymorphisms with HCC susceptibility was identified. Compared to individuals with the GG genotype of rs3816747, those with the GA (odds ratio (OR)=0.486; P=0.037) or GA+AA genotype (OR=0.51; P=0.039) were associated with a significantly decreased HCC risk. Furthermore, patients with the GC+CC genotype of rs3816748, the TC+CC genotype of rs11203495 or the GA+AA genotype of rs3816747 had small-sized tumors compared with those carrying the wild-type genotype. No significant association of DLC1 SNPs with the patients' prognosis was found. These results indicated that genetic variations in the DLC1 gene may confer a risk for HCC. PMID:26095787

  19. Sousse: extreme genetic heterogeneity in North Africa.

    Science.gov (United States)

    Fadhlaoui-Zid, Karima; Garcia-Bertrand, Ralph; Alfonso-Sánchez, Miguel A; Zemni, Ramzi; Benammar-Elgaaied, Amel; Herrera, Rene J

    2015-01-01

    The male genetic landscape of the territory currently known as Tunisia is hampered by the scarcity of data, especially from cosmopolitan areas such as the coastal city of Sousse. In order to alleviate this lacuna, 220 males from Sousse were examined, for the first time, for more than 50 Y-chromosome single-nucleotide polymorphisms (Y-SNPs) markers and compared with 3099 individuals from key geographically targeted locations in North Africa, Europe and the Near East. The paternal lineages observed belong to a common set of Y haplogroups previously described in North Africa. In addition to the prominent autochthonous North African E-M81 haplogroup which is exclusively represented by its subclade E-M183 (44.55% of Y-chromosomes), a number of Near Eastern Neolithic lineages including E-M78, J-M267 and J-M172 account for 39% of the Y-chromosomes detected. Principal component analysis based on haplogroup frequencies, multidimensional scaling based on Rst genetic distances and analyses of molecular variance using both Y-chromosome short tandem repeat haplotypes and Y-SNP haplogroup data revealed that the Tunisian and North African groups, as a whole, are intra- and inter-specific diverse with Sousse being highly heterogeneous.

  20. Gadoxetate Acid-Enhanced MR Imaging for HCC: A Review for Clinicians

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    Jendana Chanyaputhipong

    2011-01-01

    Full Text Available Hepatocellular carcinoma (HCC is increasingly being detected at an earlier stage, owing to the screening programs and regular imaging follow-up in high-risk populations. Small HCCs still pose diagnostic challenges on imaging due to decreased sensitivity and increased frequency of atypical features. Differentiating early HCC from premalignant or benign nodules is important as management differs and has implications on both the quality of life and the overall survival for the patients. Gadoxetate acid (Gd-EOB-DTPA, Primovist®, Bayer Schering Pharma is a relatively new, safe and well-tolerated liver-specific contrast agent for magnetic resonance (MR imaging of the liver that has combined perfusion- and hepatocyte-specific properties, allowing for the acquisition of both dynamic and hepatobiliary phase images. Its high biliary uptake and excretion improves lesion detection and characterization by increasing liver-to-lesion conspicuity in the added hepatobiliary phase imaging. To date, gadoxetate acid-enhanced MRI has been mostly shown to be superior to unenhanced MRI, computed tomography, and other types of contrast agents in the detection and characterization of liver lesions. This review article focuses on the evolving role of gadoxetate acid in the characterization of HCC, differentiating it from other mimickers of HCC.

  1. Summary of the 2010 AHPBA/SSO/SSAT Consensus Conference on HCC

    Directory of Open Access Journals (Sweden)

    Gitonga Munene

    2011-01-01

    Full Text Available Under the auspices of the American Hepato-Pancreato-Biliary Association, an expert consensus conference was convened in January 2010 on the multidisciplinary management of hepatocellular carcinoma. The goals of the conference were to address knowledge gaps in the optimal preparation of patients with HCC for operative therapy, best methods to control HCC while awaiting liver transplantation, and developing a multidisciplinary approach to these patients with implementation of novel systemic therapies.

  2. Quantification of within-sample genetic heterogeneity from SNP-array data

    DEFF Research Database (Denmark)

    Martinez, Pierre; Kimberley, Christopher; Birkbak, Nicolai Juul

    2017-01-01

    Intra-tumour genetic heterogeneity (ITH) fosters drug resistance and is a critical hurdle to clinical treatment. ITH can be well-measured using multi-region sampling but this is costly and challenging to implement. There is therefore a need for tools to estimate ITH in individual samples, using...... standard genomic data such as SNP-arrays, that could be implemented routinely. We designed two novel scores S and R, respectively based on the Shannon diversity index and Ripley's L statistic of spatial homogeneity, to quantify ITH in single SNP-array samples. We created in-silico and in-vitro mixtures...... sequencing data but heterogeneity in the fraction of tumour cells present across samples hampered accurate quantification. The prognostic potential of both scores was moderate but significantly predictive of survival in several tumour types (corrected p = 0.03). Our work thus shows how individual SNP...

  3. Genetic variation in the Cytb gene of human cerebral Taenia solium cysticerci recovered from clinically and radiologically heterogeneous patients with neurocysticercosis

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    Hector Palafox-Fonseca

    2013-11-01

    Full Text Available Neurocysticercosis (NC is a clinically and radiologically heterogeneous parasitic disease caused by the establishment of larval Taenia solium in the human central nervous system. Host and/or parasite variations may be related to this observed heterogeneity. Genetic differences between pig and human-derived T. solium cysticerci have been reported previously. In this study, 28 cysticerci were surgically removed from 12 human NC patients, the mitochondrial gene that encodes cytochrome b was amplified from the cysticerci and genetic variations that may be related to NC heterogeneity were characterised. Nine different haplotypes (Ht, which were clustered in four haplogroups (Hg, were identified. Hg 3 and 4 exhibited a tendency to associate with age and gender, respectively. However, no significant associations were found between NC heterogeneity and the different T. solium cysticerci Ht or Hg. Parasite variants obtained from patients with similar NC clinical or radiological features were genetically closer than those found in groups of patients with a different NC profile when using the Mantel test. Overall, this study establishes the presence of genetic differences in the Cytb gene of T. solium isolated from human cysticerci and suggests that parasite variation could contribute to NC heterogeneity.

  4. Genetic heterogeneity in Alzheimer disease and implications for treatment strategies.

    Science.gov (United States)

    Ringman, John M; Goate, Alison; Masters, Colin L; Cairns, Nigel J; Danek, Adrian; Graff-Radford, Neill; Ghetti, Bernardino; Morris, John C

    2014-11-01

    Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.

  5. Progression of liver cirrhosis to HCC: an application of hidden Markov model

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    Serio Gabriella

    2011-04-01

    Full Text Available Abstract Background Health service databases of administrative type can be a useful tool for the study of progression of a disease, but the data reported in such sources could be affected by misclassifications of some patients' real disease states at the time. Aim of this work was to estimate the transition probabilities through the different degenerative phases of liver cirrhosis using health service databases. Methods We employed a hidden Markov model to determine the transition probabilities between two states, and of misclassification. The covariates inserted in the model were sex, age, the presence of comorbidities correlated with alcohol abuse, the presence of diagnosis codes indicating hepatitis C virus infection, and the Charlson Index. The analysis was conducted in patients presumed to have suffered the onset of cirrhosis in 2000, observing the disease evolution and, if applicable, death up to the end of the year 2006. Results The incidence of hepatocellular carcinoma (HCC in cirrhotic patients was 1.5% per year. The probability of developing HCC is higher in males (OR = 2.217 and patients over 65 (OR = 1.547; over 65-year-olds have a greater probability of death both while still suffering from cirrhosis (OR = 2.379 and if they have developed HCC (OR = 1.410. A more severe casemix affects the transition from HCC to death (OR = 1.714. The probability of misclassifying subjects with HCC as exclusively affected by liver cirrhosis is 14.08%. Conclusions The hidden Markov model allowing for misclassification is well suited to analyses of health service databases, since it is able to capture bias due to the fact that the quality and accuracy of the available information are not always optimal. The probability of evolution of a cirrhotic subject to HCC depends on sex and age class, while hepatitis C virus infection and comorbidities correlated with alcohol abuse do not seem to have an influence.

  6. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances

    Science.gov (United States)

    Dhanasekaran, Renumathy; Bandoh, Salome; Roberts, Lewis R.

    2016-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and has an increasing incidence worldwide. HCC can be induced by multiple etiologies, is influenced by many risk factors, and has a complex pathogenesis. Furthermore, HCCs exhibit substantial heterogeneity, which compounds the difficulties in developing effective therapies against this highly lethal cancer. With advances in cancer biology and molecular and genetic profiling, a number of different mechanisms involved in the development and progression of HCC have been identified. Despite the advances in this area, the molecular pathogenesis of hepatocellular carcinoma is still not completely understood. This review aims to elaborate our current understanding of the most relevant genetic alterations and molecular pathways involved in the development and progression of HCC, and anticipate the potential impact of future advances on therapeutic drug development. PMID:27239288

  7. Loss of heterozygosity at D8S262: an early genetic event of hepatocarcinogenesis.

    Science.gov (United States)

    Zhu, Qiao; Gong, Li; Liu, Xiaoyan; Wang, Jun; Ren, Pin; Zhang, Wendong; Yao, Li; Han, Xiujuan; Zhu, Shaojun; Lan, Miao; Li, Yanhong; Zhang, Wei

    2015-06-16

    Hepatocellular carcinoma (HCC) is a multi-factor, multi-step, multi-gene and complicated process resulting from the accumulation of sequential genetic and epigenetic alterations. An important change among them is from precancerous lesions to HCC. However, only few studies have been reported about the sequential genetic changes during hepatocarcinogenesis. We observed firstly molecular karyotypes of 10 matched HCC using Affymetrix single-nucleotide polymorphism (SNP) 6.0 arrays, and found chromosomal fragments with high incidence (more than 70%) of loss of heterozygosity (LOH). Then, we selected 28 microsatellite markers at some gene spanning these chromosomal fragments, and examined the frequency of LOH of 128 matched HCC and 43 matched precancerous lesions-dysplastic nodules (DN) by a PCR-based analysis. Finally, we investigated the expression of proteins encoded by these genes in HCC, DN and the surrounding hepatic tissues. The result of Affymetrix SNP6.0 arrays demonstrated that more than 70% (7/10) cases had chromosomal fragment deletion on 4q13.3-35.1, 8p23.2-21.2, 16q11.2-24.3, and 17p13.3-12. Among 28 microsatellite markers selected, LOH frequencies at D8S262 for DN and HCC were found to be the highest, 51.2% and 72.7%, respectively. Immunohistochemically, the positive rate of its adjacent gene CSMD1 in HCC, DN, and the surrounding hepatic tissues were 27.3% (35/128), 75% (33/44), and 82% (105/128), respectively. LOH at D8S262 may be associated with an early genetic event of hepatocarcinogenesis, and a predictor for the monitor and prevention of HCC. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1557074981159099 .

  8. Low and high linear energy transfer radiation sensitization of HCC cells by metformin

    International Nuclear Information System (INIS)

    Kim, Eun Ho; Jung, Won-Gyun; Kim, Mi-Sook; Cho, Chul-Koo; Jeong, Youn Kyoung; Jeong, Jae-Hoon

    2014-01-01

    The purpose of this study was to investigate the efficacy of metformin as a radiosensitizer for use in combination therapy for human hepatocellular carcinoma (HCC). Three human HCC cell lines (Huh7, HepG2, Hep3B) and a normal human hepatocyte cell line were treated with metformin alone or with radiation followed by metformin. In vitro tests were evaluated by clonogenic survival assay, FACS analysis, western blotting, immunofluorescence and comet assay. Metformin significantly enhanced radiation efficacy under high and low Linear Energy Transfer (LET) radiation conditions in vitro. In combination with radiation, metformin abrogated G2/M arrest and increased the cell population in the sub-G1 phase and the ROS level, ultimately increasing HCC cellular apoptosis. Metformin inhibits the repair of DNA damage caused by radiation. The radiosensitizing effects of metformin are much higher in neutron (high LET)-irradiated cell lines than in γ (low LET)-irradiated cell lines. Metformin only had a moderate effect in normal hepatocytes. Metformin enhances the radiosensitivity of HCC, suggesting it may have clinical utility in combination cancer treatment with high-LET radiation. (author)

  9. Hair cortisol concentration (HCC) as a measure for prenatal psychological distress - A systematic review.

    Science.gov (United States)

    Mustonen, Paula; Karlsson, Linnea; Scheinin, Noora M; Kortesluoma, Susanna; Coimbra, Bárbara; Rodrigues, Ana João; Karlsson, Hasse

    2018-06-01

    Prenatal environment reportedly affects the programming of developmental trajectories in offspring and the modification of risks for later morbidity. Among the increasingly studied prenatal exposures are maternal psychological distress (PD) and altered maternal hypothalamus-pituitary-adrenal (HPA) axis functioning. Both prenatal PD and maternal short-term cortisol concentrations as markers for HPA axis activity have been linked to adverse child outcomes and it has been assumed that maternal PD affects the offspring partially via altered cortisol secretion patterns. Yet, the existing literature on the interrelations between these two measures is conflicting. The assessment of cortisol levels by using hair cortisol concentration (HCC) has gained interest, as it offers a way to assess long-term cortisol levels with a single non-invasive sampling. According to our review, 6 studies assessing the associations between maternal HCC during pregnancy and various types of maternal PD have been published so far. Measures of prenatal PD range from maternal symptoms of depression or anxiety to stress related to person's life situation or pregnancy. The aim of this systematic review is to critically evaluate the potential of HCC as a biomarker for maternal PD during pregnancy. We conclude that HCC appears to be inconsistently associated with self-reported symptoms of prenatal PD, especially in the range of mild to moderate symptom levels. Self-reports on PD usually cover short time periods and they seem to depict partly different phenomena than HCC. Thus, methodological aspects are in a key role in future studies evaluating the interconnections across different types of prenatal PD and maternal HPA axis functioning. Further, studies including repetitive measurements of both HCC and PD during the prenatal period are needed, as timing of the assessments is one important source of variation among current studies. The significance of prenatal HCC in the context of offspring outcomes

  10. Addressing the Externalities from Genetically Modified Pollen Drift on a Heterogeneous Landscape

    Directory of Open Access Journals (Sweden)

    Mattia C. Mancini

    2016-10-01

    Full Text Available Genetically modified (GM crops have single or multiple genes introduced to obtain crop characteristics that cannot be obtained through conventional breeding. Pollen mediated gene flow from GM to non-GM crops causes some crops planted as non-GM to become GM, and this imposes economic losses on farmers who planted a non-GM crop but then have to sell the harvest on a GM market. The economic losses that result when both crops are grown together depend on the institutional arrangements and the type of property rights in place. We analyze how the spatial heterogeneity of a farmer’s fields affects the land allocation between buffers, the GM, and the non-GM crop based on cross-pollination and initial assignment of property rights. Greater spatial heterogeneity reduces the possibility of coexistence of crops on the landscape and increases the economic losses. Buffer zones enforced to reduce cross-pollination result in less coexistence on heterogeneous landscapes.

  11. Genetic and phenotypic heterogeneity in tropical calcific pancreatitis.

    Science.gov (United States)

    Paliwal, Sumit; Bhaskar, Seema; Chandak, Giriraj R

    2014-12-14

    Tropical calcific pancreatitis (TCP) is a form of chronic non-alcoholic pancreatitis initially reported in the developing parts of the tropical world. The clinical phenotype of TCP has undergone marked changes since its first description in 1968. The disease is now seen in relatively older people with less severe symptoms. In addition, there are varying reports on the proportion of cases presenting with imaging abnormalities like calcification, ductal dilation, and glandular atrophy. Significant progress has also been made in understanding the etiopathology of TCP. The role of malnutrition and cassava toxicity in its pathogenesis is disproven and few studies have focused on the role of micronutrient deficiency and oxidative stress in the etiopathogenesis of TCP. Emerging evidence support an important role for genetic risk factors in TCP. Several studies have shown that, rather than mutations in trypsinogens, variants in serine protease inhibitor kazal type 1, cathepsin B, chymotrypsin C, cystic fibrosis transmembrane regulator, and carboxypeptidase A1, predict risk of TCP. These studies also provided evidence of mutational heterogeneity between TCP and chronic pancreatitis in Western populations. The current review summarizes recent advances that have implications in the understanding of the pathophysiology and thus, heterogeneity in genotype-phenotype correlations in TCP.

  12. Acral peeling skin syndrome: a clinically and genetically heterogeneous disorder.

    Science.gov (United States)

    Pavlovic, Sasha; Krunic, Aleksandar L; Bulj, Tanja K; Medenica, Maria M; Fong, Kenneth; Arita, Ken; McGrath, John A

    2012-01-01

    Acral peeling skin syndrome (APSS) is a rare, autosomal, recessive genodermatosis characterized by painless spontaneous exfoliation of the skin of the hands and feet at a subcorneal or intracorneal level. It usually presents at birth or appears later in childhood or early adulthood. Some cases result from mutations in the TGM5 gene that encodes transglutaminase 5, which has an important role in cross-linking cornified cell envelope proteins. We report a new APSS pedigree from Jordan that contains at least 10 affected family members, although sequencing of the TGM5 gene failed to disclose any pathogenic mutation(s). On the basis of probable consanguinity, we performed homozygosity mapping and identified areas of homozygosity on chromosomes 1, 6, 10, 13, and 16, although none of the intervals contained genes of clear relevance to cornification. APSS is a clinically and genetically heterogeneous disorder, and this Jordanian pedigree underscores the likelihood of still further heterogeneity. © 2011 Wiley Periodicals, Inc.

  13. HYDRA: Revealing heterogeneity of imaging and genetic patterns through a multiple max-margin discriminative analysis framework.

    Science.gov (United States)

    Varol, Erdem; Sotiras, Aristeidis; Davatzikos, Christos

    2017-01-15

    Multivariate pattern analysis techniques have been increasingly used over the past decade to derive highly sensitive and specific biomarkers of diseases on an individual basis. The driving assumption behind the vast majority of the existing methodologies is that a single imaging pattern can distinguish between healthy and diseased populations, or between two subgroups of patients (e.g., progressors vs. non-progressors). This assumption effectively ignores the ample evidence for the heterogeneous nature of brain diseases. Neurodegenerative, neuropsychiatric and neurodevelopmental disorders are largely characterized by high clinical heterogeneity, which likely stems in part from underlying neuroanatomical heterogeneity of various pathologies. Detecting and characterizing heterogeneity may deepen our understanding of disease mechanisms and lead to patient-specific treatments. However, few approaches tackle disease subtype discovery in a principled machine learning framework. To address this challenge, we present a novel non-linear learning algorithm for simultaneous binary classification and subtype identification, termed HYDRA (Heterogeneity through Discriminative Analysis). Neuroanatomical subtypes are effectively captured by multiple linear hyperplanes, which form a convex polytope that separates two groups (e.g., healthy controls from pathologic samples); each face of this polytope effectively defines a disease subtype. We validated HYDRA on simulated and clinical data. In the latter case, we applied the proposed method independently to the imaging and genetic datasets of the Alzheimer's Disease Neuroimaging Initiative (ADNI 1) study. The imaging dataset consisted of T1-weighted volumetric magnetic resonance images of 123 AD patients and 177 controls. The genetic dataset consisted of single nucleotide polymorphism information of 103 AD patients and 139 controls. We identified 3 reproducible subtypes of atrophy in AD relative to controls: (1) diffuse and extensive

  14. Application of data mining techniques to explore predictors of HCC in Egyptian patients with HCV-related chronic liver disease.

    Science.gov (United States)

    Omran, Dalia Abd El Hamid; Awad, AbuBakr Hussein; Mabrouk, Mahasen Abd El Rahman; Soliman, Ahmad Fouad; Aziz, Ashraf Omar Abdel

    2015-01-01

    Hepatocellular carcinoma (HCC) is the second most common malignancy in Egypt. Data mining is a method of predictive analysis which can explore tremendous volumes of information to discover hidden patterns and relationships. Our aim here was to develop a non-invasive algorithm for prediction of HCC. Such an algorithm should be economical, reliable, easy to apply and acceptable by domain experts. This cross-sectional study enrolled 315 patients with hepatitis C virus (HCV) related chronic liver disease (CLD); 135 HCC, 116 cirrhotic patients without HCC and 64 patients with chronic hepatitis C. Using data mining analysis, we constructed a decision tree learning algorithm to predict HCC. The decision tree algorithm was able to predict HCC with recall (sensitivity) of 83.5% and precession (specificity) of 83.3% using only routine data. The correctly classified instances were 259 (82.2%), and the incorrectly classified instances were 56 (17.8%). Out of 29 attributes, serum alpha fetoprotein (AFP), with an optimal cutoff value of ≥50.3 ng/ml was selected as the best predictor of HCC. To a lesser extent, male sex, presence of cirrhosis, AST>64U/L, and ascites were variables associated with HCC. Data mining analysis allows discovery of hidden patterns and enables the development of models to predict HCC, utilizing routine data as an alternative to CT and liver biopsy. This study has highlighted a new cutoff for AFP (≥50.3 ng/ml). Presence of a score of >2 risk variables (out of 5) can successfully predict HCC with a sensitivity of 96% and specificity of 82%.

  15. Systematic analysis of molecular mechanisms for HCC metastasis via text mining approach.

    Science.gov (United States)

    Zhen, Cheng; Zhu, Caizhong; Chen, Haoyang; Xiong, Yiru; Tan, Junyuan; Chen, Dong; Li, Jin

    2017-02-21

    To systematically explore the molecular mechanism for hepatocellular carcinoma (HCC) metastasis and identify regulatory genes with text mining methods. Genes with highest frequencies and significant pathways related to HCC metastasis were listed. A handful of proteins such as EGFR, MDM2, TP53 and APP, were identified as hub nodes in PPI (protein-protein interaction) network. Compared with unique genes for HBV-HCCs, genes particular to HCV-HCCs were less, but may participate in more extensive signaling processes. VEGFA, PI3KCA, MAPK1, MMP9 and other genes may play important roles in multiple phenotypes of metastasis. Genes in abstracts of HCC-metastasis literatures were identified. Word frequency analysis, KEGG pathway and PPI network analysis were performed. Then co-occurrence analysis between genes and metastasis-related phenotypes were carried out. Text mining is effective for revealing potential regulators or pathways, but the purpose of it should be specific, and the combination of various methods will be more useful.

  16. Genetic alterations of hepatocellular carcinoma by random amplified polymorphic DNA analysis and cloning sequencing of tumor differential DNA fragment

    Science.gov (United States)

    Xian, Zhi-Hong; Cong, Wen-Ming; Zhang, Shu-Hui; Wu, Meng-Chao

    2005-01-01

    AIM: To study the genetic alterations and their association with clinicopathological characteristics of hepatocellular carcinoma (HCC), and to find the tumor related DNA fragments. METHODS: DNA isolated from tumors and corresponding noncancerous liver tissues of 56 HCC patients was amplified by random amplified polymorphic DNA (RAPD) with 10 random 10-mer arbitrary primers. The RAPD bands showing obvious differences in tumor tissue DNA corresponding to that of normal tissue were separated, purified, cloned and sequenced. DNA sequences were analyzed and compared with GenBank data. RESULTS: A total of 56 cases of HCC were demonstrated to have genetic alterations, which were detected by at least one primer. The detestability of genetic alterations ranged from 20% to 70% in each case, and 17.9% to 50% in each primer. Serum HBV infection, tumor size, histological grade, tumor capsule, as well as tumor intrahepatic metastasis, might be correlated with genetic alterations on certain primers. A band with a higher intensity of 480 bp or so amplified fragments in tumor DNA relative to normal DNA could be seen in 27 of 56 tumor samples using primer 4. Sequence analysis of these fragments showed 91% homology with Homo sapiens double homeobox protein DUX10 gene. CONCLUSION: Genetic alterations are a frequent event in HCC, and tumor related DNA fragments have been found in this study, which may be associated with hepatocarcin-ogenesis. RAPD is an effective method for the identification and analysis of genetic alterations in HCC, and may provide new information for further evaluating the molecular mechanism of hepatocarcinogenesis. PMID:15996039

  17. JST Thesaurus Headwords and Synonyms: HCC [MeCab user dictionary for science technology term[Archive

    Lifescience Database Archive (English)

    Full Text Available MeCab user dictionary for science technology term HCC 名詞 一般 * * * * 肝細胞癌 カンサイボウガン カンサイボーガン Thesaurus2015 200906030566328014 C LS51 UNKNOWN_1 HCC

  18. The Role of Diffusion-Weighted Imaging (DWI in Locoregional Therapy Outcome Prediction and Response Assessment for Hepatocellular Carcinoma (HCC: The New Era of Functional Imaging Biomarkers

    Directory of Open Access Journals (Sweden)

    Johannes M. Ludwig

    2015-11-01

    Full Text Available Reliable response criteria are critical for the evaluation of therapeutic response in hepatocellular carcinoma (HCC. Current response assessment is mainly based on: (1 changes in size, which is at times unreliable and lag behind the result of therapy; and (2 contrast enhancement, which can be difficult to quantify in the presence of benign post-procedural changes and in tumors presenting with a heterogeneous pattern of enhancement. Given these challenges, functional magnetic resonance imaging (MRI techniques, such as diffusion-weighted imaging (DWI have been recently investigated, aiding specificity to locoregional therapy response assessment and outcome prediction. Briefly, DWI quantifies diffusion of water occurring naturally at a cellular level (Brownian movement, which is restricted in multiple neoplasms because of high cellularity. Disruption of cellular integrity secondary to therapy results in increased water diffusion across the injured membranes. This review will provide an overview of the current literature on DWI therapy response assessment and outcome prediction in HCC following treatment with locoregional therapies.

  19. Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib.

    Science.gov (United States)

    Zhai, Yang; Zhang, Yanjun; Nan, Kejun; Liang, Xuan

    2017-05-01

    The clinical resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been linked to EGFR T790M resistance mutations or MET amplifications. Additional mechanisms underlying EGFR-TKI drug resistance remain unclear. The present study demonstrated that icotinib significantly inhibited the proliferation and increased the apoptosis rate of HCC827 cells; the cellular mRNA and protein expression levels of phosphatase and tensin homolog (PTEN) were also significantly downregulated. To investigate the effect of PTEN expression levels on the sensitivity of HCC827 cells to icotinib, PTEN expression was silenced using a PTEN-specific small interfering RNA. The current study identified that the downregulation of PTEN expression levels may promote cellular proliferation in addition to decreasing the apoptosis of HCC827 cells, and may reduce the sensitivity of HCC827 cells to icotinib. These results suggested that reduced PTEN expression levels were associated with the decreased sensitivity of HCC827 cells to icotinib. Furthermore, PTEN expression levels may be a useful marker for predicting icotinib resistance and elucidating the resistance mechanisms underlying EGFR-mutated NSCLC.

  20. MicroRNA expression analysis in high fat diet-induced NAFLD-NASH-HCC progression: study on C57BL/6J mice.

    Science.gov (United States)

    Tessitore, Alessandra; Cicciarelli, Germana; Del Vecchio, Filippo; Gaggiano, Agata; Verzella, Daniela; Fischietti, Mariafausta; Mastroiaco, Valentina; Vetuschi, Antonella; Sferra, Roberta; Barnabei, Remo; Capece, Daria; Zazzeroni, Francesca; Alesse, Edoardo

    2016-01-05

    Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Non-alcoholic fatty liver disease (NAFLD) is a frequent chronic liver disorder in developed countries. NAFLD can progress through the more severe non alcoholic steatohepatitis (NASH), cirrhosis and, lastly, HCC. Genetic and epigenetic alterations of coding genes as well as deregulation of microRNAs (miRNAs) activity play a role in HCC development. In this study, the C57BL/6J mouse model was long term high-fat (HF) or low-fat (LF) diet fed, in order to analyze molecular mechanisms responsible for the hepatic damage progression. Mice were HF or LF diet fed for different time points, then plasma and hepatic tissues were collected. Histological and clinical chemistry assays were performed to assess the progression of liver disease. MicroRNAs' differential expression was evaluated on pooled RNAs from tissues, and some miRNAs showing dysregulation were further analyzed at the individual level. Cholesterol, low and high density lipoproteins, triglycerides and alanine aminotransferase increase was detected in HF mice. Gross anatomical examination revealed hepatomegaly in HF livers, and histological analysis highlighted different degrees and levels of steatosis, inflammatory infiltrate and fibrosis in HF and LF animals, demonstrating the progression from NAFLD through NASH. Macroscopic nodules, showing typical neoplastic features, were observed in 20% of HF diet fed mice. Fifteen miRNAs differentially expressed in HF with respect to LF hepatic tissues during the progression of liver damage, and in tumors with respect to HF non tumor liver specimens were identified. Among them, miR-340-5p, miR-484, miR-574-3p, miR-720, whose expression was never described in NAFLD, NASH and HCC tissues, and miR-125a-5p and miR-182, which showed early and significant dysregulation in the sequential hepatic damage process. In this study, fifteen microRNAs which were modulated in hepatic tissues and in tumors during

  1. The detection of hepatocellular carcinoma (HCC) from patients' breath using canine scent detection: a proof-of-concept study.

    Science.gov (United States)

    Kitiyakara, Taya; Redmond, Susan; Unwanatham, Nattawut; Rattanasiri, Sasivimol; Thakkinstian, Amarin; Tangtawee, Pongsatorn; Mingphruedhi, Somkit; Sobhonslidsuk, Abhasnee; Intaraprasong, Pongphob; Kositchaiwat, Chomsri

    2017-09-13

    Patients with hepatocellular carcinoma (HCC) have poor outcomes as a result of late detection of the disease. We investigated the possibility of using smell detection by dogs for detecting HCC from the breath of patients. Patients whose diagnosis of HCC was confirmed histologically or radiologically according to the American Association for the Study of Liver Diseases criteria had breaths collected using face masks and transported to the study test site. The numbering of the HCC samples was sent in a sealed envelope to blind the dog trainer during testing but allow for correct rewarding of the dog afterwards. One golden retriever was trained to detect HCC with positive feedback using known samples of HCC and healthy controls in a step-wise manner. The controls were selected from hospital staff and relatives of patients who were not involved in the study. They were questioned about the risks of their disease before selection. When the trainer was confident that the dog could recognize the HCC scent, blind testing was performed using 1 HCC : 3 healthy controls per test run. Once the dog signaled on a specimen, it was given a reward. The correct-detection rate was compared to the theoretical detection rate expected based on chance of 25% using the statistical one-sample test of proportions. Thirty-seven HCC patients were tested. The patients had a mean age of 58 years and 21/37 were male. Seventeen patients had hepatitis B and 14 patients had hepatitis C. Twenty-six patients had one HCC lesion; four patients had two lesions in the liver, whilst seven had many lesions. The number of patients in the very early, early, intermediate, advanced, and terminal stages of the Barcelona Clinic Liver Cancer classification was 5, 9, 21, 1, and 1, respectively. The dog detected correctly in 29 runs. The sensitivity for canine detection was 78% (95% CI: 62%-90%). Compared to the 25% correct indication expected based on chance, this was statistically significant (p canine olfaction

  2. Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor.

    Science.gov (United States)

    D'Alessandro, Rosalba; Refolo, Maria Grazia; Lippolis, Catia; Carella, Nicola; Messa, Caterina; Cavallini, Aldo; Carr, Brian Irving

    2015-06-01

    Blood platelet numbers are correlated to growth and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). We previously found that platelet lysates (hPLs) also stimulated growth and migration, and antagonized the growth-inhibitory and apoptotic effects of both Sorafenib and Regorafenib, two multikinase inhibitors, on three HCC cell lines. In this study, in vitro function of human epidermal growth factor (EGF) with and without Sorafenib or Regorafenib was investigated. An ELISA kit was used to evaluate the EGF concentrations in hPLs. In vitro function of EGF was assessed with proliferation MTT test. Apoptosis assay, scratch assays, and Transwell assays were performed for apoptosis, invasion, and migration, respectively. MAPK Activation Kit was used to explore MAPK phosphorylation. EGF antagonized the growth inhibition of Regorafenib on three HCC cell lines. Regorafenib-mediated growth inhibition was blocked by 70 % when the cells were pre-treated with EGF. EGF also blocked Regorafenib-induced apoptosis, as well as Regorafenib-induced decreases in cell migration and invasion. The EGF effects were in turn antagonized by concomitant addition to the cultures of EGF receptor antagonist Erlotinib, showing that the EGF receptor was involved in the mechanisms of EGF-mediated blocking of Regorafenib effects. Erlotinib also partially blocked the effects of hPLs in antagonizing Regorafenib-mediated growth inhibition, showing that EGF was an important component of hPL actions. All these results show that EGF antagonized Regorafenib-mediated growth and migration inhibition and apoptosis induction in HCC cells and reinforce the idea that microenvironment can influence cancer drug actions.

  3. Analysis of a genetically structured variance heterogeneity model using the Box-Cox transformation

    DEFF Research Database (Denmark)

    Yang, Ye; Christensen, Ole Fredslund; Sorensen, Daniel

    2011-01-01

    of the marginal distribution of the data. To investigate how the scale of measurement affects inferences, the genetically structured heterogeneous variance model is extended to accommodate the family of Box–Cox transformations. Litter size data in rabbits and pigs that had previously been analysed...... in the untransformed scale were reanalysed in a scale equal to the mode of the marginal posterior distribution of the Box–Cox parameter. In the rabbit data, the statistical evidence for a genetic component at the level of the environmental variance is considerably weaker than that resulting from an analysis...... in the original metric. In the pig data, the statistical evidence is stronger, but the coefficient of correlation between additive genetic effects affecting mean and variance changes sign, compared to the results in the untransformed scale. The study confirms that inferences on variances can be strongly affected...

  4. Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing.

    Directory of Open Access Journals (Sweden)

    You-Wang Lu

    Full Text Available Intratumor heterogeneity (ITH leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases. On average, 65% of all the mutations detected were common within individual tumors. KMT2C aberrations and the NCOR1 mutation were the only ubiquitous events. Subsequent phylogenetic analysis showed that the tumors evolved in a branched manner. Comparison of the primary and metastatic tumors revealed that PPP2R1A (E370X, SETD2 (I1608V, SMAD4 (G382T, and AR splicing site mutations may be specific to liver metastatic cancer. These mutations might contribute to the initiation and progression of distant metastasis. Collectively, our analysis identified a substantial level of genetic ITH in CRC, which should be considered for personalized therapeutic strategies.

  5. TACE: therapy of the HCC before liver transplantation - experiences

    International Nuclear Information System (INIS)

    Herber, S.; Schneider, J.; Brecher, B.; Thelen, M.; Pitton, M.B.; Hoehler, T.; Otto, G.

    2005-01-01

    Purpose: Analysis of the course of disease in patients with histologically proven HCC before and after orthotopic liver transplantation (LTx) who received transarterial chemoembolization (TACE). Material and Methods: Thirty-five of a total collective of 363 patients with histologically proven HCC underwent LTx. Before LTx, all patients were treated with sequential TACE. According to treatment pattern, TACE should be performed every 6 weeks, using a suspension consisting of max. 10 mg Mitomycin C as well as 10-30 ml iodized oil (Lipiodol). Patients were classified according to the Milano criteria. Criteria were called exceeded if the tumor size was >5 cm and/or >3 tumors larger than 3 cm were found. Therapy success and liver function were examined by means of spiral CT and laboratory controls. Investigation parameters included the number of tumor knots as well as the maximum tumor size. Additionally, the Lipiodol accumulation, the patency of the portal vein and the occurrence of complications were checked. Results: Altogether, 184 TACE procedures were accomplished (5.3+/-3.3, range 1-14). The waiting period up to the transplantation amounted to 366+/-255 days (range 44-1137). The average number of tumor knots for each patient was 3.1+/-2.2 before and 2.9+/-2.2 after TACE (p=0.887). The average tumor size was 4.2+/-2.5 before and 2.8+/-1.4 after TACE. The Milano criteria to LTx crossed 17/35 patients. Patients with exceeded Milan criteria showed a highly significant size reduction of the tumor after TACE (p=0.001); in 9/17 cases the transplantation criteria were secondarily fulfilled through downstaging. A successful LTx was accomplished in 35/35 cases. Follow up after LTx was 769+/-509 days. The tumor recurrence in patients with exceeded vs. fulfilled transplantation criteria was 11.1% vs. 11.8% (p=0.99). The recurrence free survival was 93.3%, 82.5% and 82.5% at 1, 3 and 5 years, respectively. There were no relevant differences between patients with exceeded vs

  6. Stattic Enhances Radiosensitivity and Reduces Radio-Induced Migration and Invasion in HCC Cell Lines through an Apoptosis Pathway

    Directory of Open Access Journals (Sweden)

    Gang Xu

    2017-01-01

    Full Text Available Purpose. Signal transducer and activator of transcription factor 3 (STAT3 is involved in tumorigenesis, development, and radioresistance of many solid tumors. The aim of this study is to investigate the effects of stattic (an inhibitor of STAT3 on the radiosensitivity and radio-induced migration and invasion ability in hepatocellular carcinoma (HCC cell lines. Methods. HCC cells were treated with stattic, and cell survival rate was analyzed through CCK-8 assay. Radiosensitivity was evaluated using cloning formation analysis; STAT3, p-STAT3, and apoptosis related proteins were detected by western blot. Radio-induced migration and invasion ability in HCC cells were analyzed by wound-healing assay and transwell test. Results. Stattic inhibits the expression of p-STAT3 and reduces cell survival in a dose-dependent manner in HCC cell lines, and the IC50 values for Hep G2, Bel-7402, and SMMC-7721 are 2.94 μM, 2.5 μM, and 5.1 μM, respectively. Cloning formation analysis shows that stattic enhances the radiosensitivity of HCC cells. Wound-healing assay and transwell test show that stattic inhibits radio-induced migration and invasion. Further study indicates that stattic promotes radio-induce apoptosis through regulating the expression of apoptosis related proteins in HCC cells. Conclusion. Stattic enhances radiosensitivity and reduces radio-induced migration and invasion ability in HCC cells probably through apoptosis pathway.

  7. PKCα expression regulated by Elk-1 and MZF-1 in human HCC cells

    International Nuclear Information System (INIS)

    Hsieh, Y.-H.; Wu, T.-T.; Tsai, J.-H.; Huang, C.-Y.; Hsieh, Y.-S.; Liu, J.-Y.

    2006-01-01

    Our previous study found that PKCα was highly expressed in the poor-differentiated human HCC cells and associated with cell migration and invasion. In this study, we further investigated the gene regulation of this enzyme. We showed that PKCα expression enhancement in the poor-differentiated human HCC cells was found neither by DNA amplification nor by increasing mRNA stability using differential PCR and mRNA decay assays. After screening seven transcription factors in the putative cis-acting regulatory elements of human PKCα promoters, only Elk-1 and MZF-1 antisense oligonucleotide showed a significant reduction in the PKCα mRNA level. They also reduced cell proliferation, cell migratory and invasive capabilities, and DNA binding activities in the PKCα promoter region. Over-expression assay confirmed that the PKCα expression may be modulated by these two factors at the transcriptional level. Therefore, these results may provide a novel mechanism for PKCα expression regulation in human HCC cells

  8. Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications

    Directory of Open Access Journals (Sweden)

    George D. Cresswell

    2016-07-01

    Full Text Available The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT; current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.

  9. Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC

    International Nuclear Information System (INIS)

    Lin, Zhong-Zhe; Jeng, Yung-Ming; Hu, Fu-Chang; Pan, Hung-Wei; Tsao, Hsin-Wei; Lai, Po-Lin; Lee, Po-Huang; Cheng, Ann-Lii; Hsu, Hey-Chi

    2010-01-01

    To investigate the significance of Aurora B expression in hepatocellular carcinoma (HCC). The Aurora B and Aurora A mRNA level was measured in 160 HCCs and the paired nontumorous liver tissues by reverse transcription-polymerase chain reaction. Mutations of the p53 and β-catenin genes were analyzed in 134 and 150 tumors, respectively, by direct sequencing of exon 2 to exon 11 of p53 and exon 3 of β-catenin. Anticancer effects of AZD1152-HQPA, an Aurora B kinase selective inhibitor, were examined in Huh-7 and Hep3B cell lines. Aurora B was overexpressed in 98 (61%) of 160 HCCs and in all 7 HCC cell lines examined. The overexpression of Aurora B was associated with Aurora A overexpression (P = 0.0003) and p53 mutation (P = 0.002) and was inversely associated with β-catenin mutation (P = 0.002). Aurora B overexpression correlated with worse clinicopathologic characteristics. Multivariate analysis confirmed that Aurora B overexpression was an independent poor prognostic factor, despite its interaction with Aurora A overexpression and mutations of p53 and β-catenin. In Huh-7 and Hep3B cells, AZD1152-HQPA induced proliferation blockade, histone H3 (Ser10) dephosphorylation, cell cycle disturbance, and apoptosis. Aurora B overexpression is an independent molecular marker predicting tumor invasiveness and poor prognosis of HCC. Aurora B kinase selective inhibitors are potential therapeutic agents for HCC treatment

  10. Expression of Plasma hsa-miR122 in HBV-related Hepatocellular Carcinoma (HCC) in Vietnamese Patients.

    Science.gov (United States)

    Quoc, Nguyen Bao; Phuong, Nguyen Doan Nguyen; Ngan, Tang Kim; Linh, Nguyen Thi Minh; Cuong, Pham Hung; Chau, Nguyen Ngoc Bao

    2018-04-27

    Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death in the world and considered as one of the most susceptible cancers in humans. The microRNA molecule, hsa-miR122, considered as a potential biological marker linked with the injury of hepatocellular tissue, is the most common microRNA in human liver cancer. Understanding the expression profile of hsa-miR122 plays an important role in the diagnosis of HCC Objective: Identification and comparison of cut-off values of plasma hsa-miR122 expression were conducted in blood samples of healthy control, HBV infected and HBV-related HCC Vietnamese patients Method and result: Fifty-two blood samples of healthy control and HBV-related HCC cases, collected between 2015 and 2017 were obtained from Ho Chi Minh City Oncology Hospital, Vietnam. Written informed consent was attained from all patients and the Human Research Ethics Committee, Oncology Hospital (#08/BVUB-HDDD) approved the research protocol. Total RNA was isolated from blood samples with TrizolTM Reagent (Thermo Fisher Scientific, USA). To analyze the expression level of hsa-miR122, miRNA specific reverse transcription was performed using SensiFASTTM¬ cDNA Synthesis Kit (Bioline, UK) as described by the manufacturer, followed by running RT-qPCR with SensiFASTTMSYBR No-ROX Kit (Bioline, UK). The housekeeping gene, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was used for normalization. The presence of hsa-miR122 and HBV-DNA were identified in human blood using RT-PCR and LAMP techniques. Downregulation of plasma hsa-miR122 was observed in HBV-related HCC patients with a ΔCt value of 7.9 ± 2.1 which was significantly lower than found in healthy control (pHBV infected patients. We also identified the difference of diagnostic values of this microRNA in different populations and provided a high diagnostic accuracy of HCC (AUC = 0.984 with sensitivity and specificity of 96% and 94%, respectively). hsa-miR122 was downregulated in HBV-related HCC

  11. VEGFR-2 expression in HCC, dysplastic and regenerative liver nodules, and correlation with pre-biopsy Dynamic Contrast Enhanced CT

    Energy Technology Data Exchange (ETDEWEB)

    Thaiss, W.M., E-mail: wolfgang.thaiss@med.uni-tuebingen.de [Eberhard Karls University, Department of Radiology, Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, D-72076 Tuebingen (Germany); Kaufmann, S., E-mail: sascha.kaufmann@med.uni-tuebingen.de [Eberhard Karls University, Department of Radiology, Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, D-72076 Tuebingen (Germany); Kloth, C., E-mail: christopher.kloth@med.uni-tuebingen.de [Eberhard Karls University, Department of Radiology, Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, D-72076 Tuebingen (Germany); Nikolaou, K., E-mail: konstantin.nikolaou@med.uni-tuebingen.de [Eberhard Karls University, Department of Radiology, Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, D-72076 Tuebingen (Germany); Bösmüller, H., E-mail: hans.boesmueller@med.uni-tuebingen.de [Eberhard Karls University, Department of Pathology, Liebermeisterstraße 8, D-72076 Tuebingen (Germany); Horger, M., E-mail: Marius.Horger@med.uni-tuebingen.de [Eberhard Karls University, Department of Radiology, Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, D-72076 Tuebingen (Germany)

    2016-11-15

    Highlights: • VEGFR-2-expression levels vary between HCC, dysplastic and regenerative liver nodules. • Perfusion parameters vary between these groups in blood flow, blood volume and HPI. • Strong correlations were observed between perfusion parameters and VEGFR-2-expression. • The results might influence diagnosis and therapy of anti-vascular therapeutic regimes. - Abstract: Purpose: To evaluate whether VEGFR-2-expression in hepatocellular carcinoma (HCC), dysplastic (DLN) and regenerative liver nodules (RLN) correlates with pre-histology, in vivo Dynamic Contrast Enhanced-Computed Tomography (DCE-CT) data as VEGFR-2-expression affects prognosis and therapeutic options. Materials and methods: 34 patients (63.6 ± 8.9 years, 7 females) underwent liver biopsy or surgery due to suspected HCC or dysplastic nodules after DCE-CT between 2009 and 2015 with no previous chemo- or interventional therapy. Immunohistochemistry staining for VEGFR-2 was performed using Immunoreactive-Remmele-Stegner-Score (IRS) for quantification. A 128-row CT-scanner was used for DCE-CT with assessment of perfusion parameters blood flow (BF), blood volume (BV), arterial liver perfusion (ALP), portal venous perfusion (PVP), and hepatic perfusion index (HPI). Results: Histology confirmed HCC (n = 10), DLN (n = 7) and RLN (n = 34). Mean IRS for VEGFR-2 in HCCs was 9.1 ± 3.0, 7.3 ± 1.6 for DLN and 5.2 ± 2.8 for RLN (p = 0.0004 for HCC vs. RLN). Perfusion values varied significantly between all three groups for BF and HPI (p < 0.001 and p < 0.0001) and for BV in HCC vs. RLN (p < 0.0001) and DLN vs. RLN (p = 0.0019). Strong correlations between VEGFR-2-IRS and perfusion parameters were observed for BF in HCC (r = 0.88, p < 0.01) and HPI in HCC and DLN (r = 0.85, p < 0.04; r = 0.9, p < 0.01). Conclusion: Immunostaining revealed different VEGFR-2-expression levels in HCC, dysplastic and regenerative liver nodules. Perfusion markers blood flow, blood volume and hepatic perfusion index

  12. Local Climate Heterogeneity Shapes Population Genetic Structure of Two Undifferentiated Insular Scutellaria Species.

    Science.gov (United States)

    Hsiung, Huan-Yi; Huang, Bing-Hong; Chang, Jui-Tse; Huang, Yao-Moan; Huang, Chih-Wei; Liao, Pei-Chun

    2017-01-01

    Spatial climate heterogeneity may not only affect adaptive gene frequencies but could also indirectly shape the genetic structure of neutral loci by impacting demographic dynamics. In this study, the effect of local climate on population genetic variation was tested in two phylogenetically close Scutellaria species in Taiwan. Scutellaria taipeiensis , which was originally assumed to be an endemic species of Taiwan Island, is shown to be part of the widespread species S. barbata based on the overlapping ranges of genetic variation and climatic niches as well as their morphological similarity. Rejection of the scenario of "early divergence with secondary contact" and the support for multiple origins of populations of S. taipeiensis from S. barbata provide strong evolutionary evidence for a taxonomic revision of the species combination. Further tests of a climatic effect on genetic variation were conducted. Regression analyses show nonlinear correlations among any pair of geographic, climatic, and genetic distances. However, significantly, the bioclimatic variables that represent the precipitation from late summer to early autumn explain roughly 13% of the genetic variation of our sampled populations. These results indicate that spatial differences of precipitation in the typhoon season may influence the regeneration rate and colonization rate of local populations. The periodic typhoon episodes explain the significant but nonlinear influence of climatic variables on population genetic differentiation. Although, the climatic difference does not lead to species divergence, the local climate variability indeed impacts the spatial genetic distribution at the population level.

  13. Histogram Analysis of CT Perfusion of Hepatocellular Carcinoma for Predicting Response to Transarterial Radioembolization: Value of Tumor Heterogeneity Assessment.

    Science.gov (United States)

    Reiner, Caecilia S; Gordic, Sonja; Puippe, Gilbert; Morsbach, Fabian; Wurnig, Moritz; Schaefer, Niklaus; Veit-Haibach, Patrick; Pfammatter, Thomas; Alkadhi, Hatem

    2016-03-01

    To evaluate in patients with hepatocellular carcinoma (HCC), whether assessment of tumor heterogeneity by histogram analysis of computed tomography (CT) perfusion helps predicting response to transarterial radioembolization (TARE). Sixteen patients (15 male; mean age 65 years; age range 47-80 years) with HCC underwent CT liver perfusion for treatment planning prior to TARE with Yttrium-90 microspheres. Arterial perfusion (AP) derived from CT perfusion was measured in the entire tumor volume, and heterogeneity was analyzed voxel-wise by histogram analysis. Response to TARE was evaluated on follow-up imaging (median follow-up, 129 days) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results of histogram analysis and mean AP values of the tumor were compared between responders and non-responders. Receiver operating characteristics were calculated to determine the parameters' ability to discriminate responders from non-responders. According to mRECIST, 8 patients (50%) were responders and 8 (50%) non-responders. Comparing responders and non-responders, the 50th and 75th percentile of AP derived from histogram analysis was significantly different [AP 43.8/54.3 vs. 27.6/34.3 mL min(-1) 100 mL(-1)); p 0.05) was not. Further heterogeneity parameters from histogram analysis (skewness, coefficient of variation, and 25th percentile) did not differ between responders and non-responders (p > 0.05). If the cut-off for the 75th percentile was set to an AP of 37.5 mL min(-1) 100 mL(-1), therapy response could be predicted with a sensitivity of 88% (7/8) and specificity of 75% (6/8). Voxel-wise histogram analysis of pretreatment CT perfusion indicating tumor heterogeneity of HCC improves the pretreatment prediction of response to TARE.

  14. Intra-tumor genetic heterogeneity and mortality in head and neck cancer: analysis of data from the Cancer Genome Atlas.

    Science.gov (United States)

    Mroz, Edmund A; Tward, Aaron D; Tward, Aaron M; Hammon, Rebecca J; Ren, Yin; Rocco, James W

    2015-02-01

    Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity's associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having

  15. Activation of Anti-tumor Immune Response by Ablation of HCC with Nanosecond Pulsed Electric Field.

    Science.gov (United States)

    Xu, Xiaobo; Chen, Yiling; Zhang, Ruiqing; Miao, Xudong; Chen, Xinhua

    2018-03-28

    Locoregional therapy is playing an increasingly important role in the non-surgical management of hepatocellular carcinoma (HCC). The novel technique of non-thermal electric ablation by nanosecond pulsed electric field has been recognized as a potential locoregional methodology for indicated HCC. This manuscript explores the most recent studies to indicate its unique anti-tumor immune response. The possible immune mechanism, termed as nano-pulse stimulation, was also analyzed.

  16. Adjusting for heterogeneity of experimental data in genetic evaluation of dry matter intake in dairy cattle.

    Science.gov (United States)

    Uddin, M E; Meuwissen, T; Veerkamp, R F

    2018-02-01

    The objectives of the present study were (i) to find the best fitted model for repeatedly measured daily dry matter intake (DMI) data obtained from different herds and experiments across lactations and (ii) to get better estimates of the genetic parameters and better genetic evaluations. After editing, there were 572,512 daily DMI records of 3,495 animals (Holstein cows) from 11 different herds across 13 lactations and the animals were under 110 different nutritional experiments. The fitted model for this data set was a univariate repeated-measure animal model (called model 1) in which additive genetic and permanent environmental (within and across lactations) effects were fitted as random. Model 1 was fitted as two distinct models (called models 2 and 3) based on alternative fixed effect corrections. For unscaled data, each model (models 2 and 3) was fitted as a homoscedastic (HOM) model first and then as a heteroscedastic (HET) model. Then, data were scaled by multiplying with particular herd-scaling factors, which were calculated by accounting for heterogeneity of phenotypic within-herd variances. Models were selected based on cross-validation and prediction accuracy results. Scaling factors were re-estimated to determine the effectiveness of accounting for herd heterogeneity. Variance components and respective heritability and repeatability were estimated based on a pedigree-based relationship matrix. Results indicated that the model fitted for scaled data showed better fit than the models (HOM or HET) fitted for unscaled data. The heritability estimates of the models 2 and 3 fitted for scaled data were 0.30 and 0.08, respectively. The repeatability estimates of the model fitted for scaled data ranged from 0.51 to 0.63. The re-estimated scaling factor after accounting for heterogeneity of residual variances was close to 1.0, indicating the stabilization of residual variances and herd accounted for most of the heterogeneity. The rank correlation of EBVs between

  17. Prediction of recurrence after HCC resection. Faint oily deposits in preoperative Lipiodol-CT of remnant liver tissue

    International Nuclear Information System (INIS)

    Yamamoto, M.; Iimuro, Y.; Mogaki, M.; Kachi, K.; Fujii, H.; Matsumoto, Y.

    1994-01-01

    In trying to clarify the high recurrence rate after removal of small hepatocellular carconoma (HCC), we assessed the postoperative evolution of minute hepatic Lipiodol deposits which had been diagnosed as artifacts on the preoperative Lipiodol-CT. Of 27 patients with solitary HCC less than 5 cm in diameter, 14 had such Lipiodol deposits in the preoperative CT and 9 of them (64%) developed recurrent tumors. On the other hand, 6 of the 13 patients without deposits (46%) suffered recurrence, but in 5 of these 6 patients the HCC was metachronous multicentric. The cumulative survival rate of the non-deposit group was better than that of the deposit group (p<0.1). The present study suggested that, even in patients with small HCC, minute concomitant tumors invisible by conventional imaging techniques may exist at the time of surgery. Some of these lesions without sufficient tumor vasculature showing a hypervascular blush on angiography appear to retain small, vague Lipiodol deposits. (orig.)

  18. Mechanisms of population heterogeneity among molting common mergansers on Kodiak Island, Alaska: Implications for genetic assessments of migratory connectivity

    Science.gov (United States)

    Pearce, John M.; Zwiefelhofer, Denny; Maryanski, Nate

    2009-01-01

    Quantifying population genetic heterogeneity within nonbreeding aggregations can inform our understanding of patterns of site fidelity, migratory connectivity, and gene flow between breeding and nonbreeding areas. However, characterizing mechanisms that contribute to heterogeneity, such as migration and dispersal, is required before site fidelity and migratory connectivity can be assessed accurately. We studied nonbreeding groups of Common Mergansers (Mergus merganser) molting on Kodiak Island, Alaska, from 2005 to 2007, using banding data to assess rates of recapture, mitochondrial (mt) DNA to determine natal area, and nuclear microsatellite genotypes to assess dispersal. Using baseline information from differentiated mtDNA haplogroups across North America, we were able to assign individuals to natal regions and document population genetic heterogeneity within and among molting groups. Band-recovery and DNA data suggest that both migration from and dispersal among natal areas contribute to admixed groups of males molting on Kodiak Island. A lack of differentiation in the Common Merganser's nuclear, bi-parentally inherited DNA, observed across North America, implies that dispersal can mislead genetic assessments of migratory connectivity and assignments of nonbreeding individuals to breeding areas. Thus multiple and independent data types are required to account for such behaviors before accurate assessments of migratory connectivity can be made.

  19. CD147 is increased in HCC cells under starvation and reduces cell death through upregulating p-mTOR in vitro.

    Science.gov (United States)

    Gou, Xingchun; Tang, Xu; Kong, Derek Kai; He, Xinying; Gao, Xingchun; Guo, Na; Hu, Zhifang; Zhao, Zhaohua; Chen, Yanke

    2016-01-01

    Transarterial chemoembolization (TACE) is the standard of care for treatment of intermediate hepatocellular carcinoma (HCC), however, key molecules involved in HCC cell survival and tumor metastasis post-TACE remain unclear. CD147 is a member of the immunoglobulin superfamily that is overexpressed on the surface of HCC cells and is associated with malignant potential and poor prognosis in HCC patients. In this study, using an Earle's Balanced Salt Solution medium culture model that mimics nutrient deprivation induced by TACE, we investigated the regulation of CD147 expression on HCC cells under starvation conditions and its functional effects on HCC cell death. During early stages of starvation, the expression of CD147 was considerably upregulated in SMMC7721, HepG2 and HCC9204 hepatoma cell lines at the protein levels. Downregulation of CD147 by specific small interfering RNA (siRNA) significantly promoted starvation-induced cell death. In addition, CD147 siRNA-transfected SMMC7721 cells demonstrated significantly increased levels of both apoptosis and autophagy as compared to cells transfected with control siRNA under starvation conditions, whereas no difference was observed between the two treatment groups under normal culture conditions. Furthermore, silencing of CD147 resulted in a remarkable downregulation of phosphorylated mammalian target of rapamycin (p-mTOR) in starved SMMC7721 cells. Finally, the combined treatment of starvation and anti-CD147 monoclonal antibody exhibited a synergistic HCC cell killing effect. Our study suggests that upregulation of CD147 under starvation may reduce hepatoma cell death by modulating both apoptosis and autophagy through mTOR signaling, and that CD147 may be a novel potential molecular target to improve the efficacy of TACE.

  20. Using genetic data to estimate diffusion rates in heterogeneous landscapes.

    Science.gov (United States)

    Roques, L; Walker, E; Franck, P; Soubeyrand, S; Klein, E K

    2016-08-01

    Having a precise knowledge of the dispersal ability of a population in a heterogeneous environment is of critical importance in agroecology and conservation biology as it can provide management tools to limit the effects of pests or to increase the survival of endangered species. In this paper, we propose a mechanistic-statistical method to estimate space-dependent diffusion parameters of spatially-explicit models based on stochastic differential equations, using genetic data. Dividing the total population into subpopulations corresponding to different habitat patches with known allele frequencies, the expected proportions of individuals from each subpopulation at each position is computed by solving a system of reaction-diffusion equations. Modelling the capture and genotyping of the individuals with a statistical approach, we derive a numerically tractable formula for the likelihood function associated with the diffusion parameters. In a simulated environment made of three types of regions, each associated with a different diffusion coefficient, we successfully estimate the diffusion parameters with a maximum-likelihood approach. Although higher genetic differentiation among subpopulations leads to more accurate estimations, once a certain level of differentiation has been reached, the finite size of the genotyped population becomes the limiting factor for accurate estimation.

  1. Carrier detection in X-linked retinitis pigmentosa by multipoint DNA analysis. Problems due to genetic heterogeneity

    NARCIS (Netherlands)

    Bergen, A. A.; Platje, E. J.; Craig, I.; Bakker, E.; Bleeker-Wagemakers, E. M.; van Ommen, G. J.

    1991-01-01

    DNA diagnosis of X-linked retinitis pigmentosa (XLRP) is hampered by its genetic heterogeneity, while a clinical subdivision is almost impossible to make. So far, diagnostic services have been offered only to those families in which linkage to one RP locus (RP2 or RP3) has been clearly established.

  2. Developing cross entropy genetic algorithm for solving Two-Dimensional Loading Heterogeneous Fleet Vehicle Routing Problem (2L-HFVRP)

    Science.gov (United States)

    Paramestha, D. L.; Santosa, B.

    2018-04-01

    Two-dimensional Loading Heterogeneous Fleet Vehicle Routing Problem (2L-HFVRP) is a combination of Heterogeneous Fleet VRP and a packing problem well-known as Two-Dimensional Bin Packing Problem (BPP). 2L-HFVRP is a Heterogeneous Fleet VRP in which these costumer demands are formed by a set of two-dimensional rectangular weighted item. These demands must be served by a heterogeneous fleet of vehicles with a fix and variable cost from the depot. The objective function 2L-HFVRP is to minimize the total transportation cost. All formed routes must be consistent with the capacity and loading process of the vehicle. Sequential and unrestricted scenarios are considered in this paper. We propose a metaheuristic which is a combination of the Genetic Algorithm (GA) and the Cross Entropy (CE) named Cross Entropy Genetic Algorithm (CEGA) to solve the 2L-HFVRP. The mutation concept on GA is used to speed up the algorithm CE to find the optimal solution. The mutation mechanism was based on local improvement (2-opt, 1-1 Exchange, and 1-0 Exchange). The probability transition matrix mechanism on CE is used to avoid getting stuck in the local optimum. The effectiveness of CEGA was tested on benchmark instance based 2L-HFVRP. The result of experiments shows a competitive result compared with the other algorithm.

  3. Prohibitin-induced, obesity-associated insulin resistance and accompanying low-grade inflammation causes NASH and HCC.

    Science.gov (United States)

    Ande, Sudharsana R; Nguyen, K Hoa; Grégoire Nyomba, B L; Mishra, Suresh

    2016-03-23

    Obesity increases the risk for nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. However, the underlying mechanisms involved in the disease process remain unclear. Recently, we have developed a transgenic obese mouse model (Mito-Ob) by prohibitin mediated mitochondrial remodeling in adipocytes. The Mito-Ob mice develop obesity in a sex-neutral manner, but obesity-associated adipose inflammation and metabolic dysregulation in a male sex-specific manner. Here we report that with aging, the male Mito-Ob mice spontaneously develop obesity-linked NASH and hepatocellular carcinoma (HCC). In contrast, the female Mito-Ob mice maintained normal glucose and insulin levels and did not develop NASH and HCC. The anti-inflammatory peptide ghrelin was significantly upregulated in the female mice and down regulated in the male mice compared with respective control mice. In addition, a reduction in the markers of mitochondrial content and function was found in the liver of male Mito-Ob mice with NASH/HCC development. We found that ERK1/2 signaling was significantly upregulated whereas STAT3 signaling was significantly down regulated in the tumors from Mito-Ob mice. These data provide a proof-of-concept that the metabolic and inflammatory status of the adipose tissue and their interplay at the systemic and hepatic level play a central role in the pathogenesis of obesity-linked NASH and HCC.

  4. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

    Science.gov (United States)

    Chaste, Pauline; Klei, Lambertus; Sanders, Stephan J; Hus, Vanessa; Murtha, Michael T; Lowe, Jennifer K; Willsey, A Jeremy; Moreno-De-Luca, Daniel; Yu, Timothy W; Fombonne, Eric; Geschwind, Daniel; Grice, Dorothy E; Ledbetter, David H; Mane, Shrikant M; Martin, Donna M; Morrow, Eric M; Walsh, Christopher A; Sutcliffe, James S; Lese Martin, Christa; Beaudet, Arthur L; Lord, Catherine; State, Matthew W; Cook, Edwin H; Devlin, Bernie

    2015-05-01

    Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Assigning Treatment to HCC Patients for Transplantation: Utility of a New Decision-Making Tool.

    Science.gov (United States)

    Shah, Najmul Hassan; Dar, Faisal Saud; Bhatti, Abu Bakar Hafeez; Rana, Atif; Salih, Mohammad

    2016-10-28

    BACKGROUND The Barcelona clinic liver cancer (BCLC) staging system is considered the standard of care for hepatocellular carcinoma (HCC) management. It has various limitations, including lack of second-line treatment options and combination therapy. We prospectively collected data on our HCC patients based on a new decision-making tool (NDT). The objective of this study was to determine the applicability of this tool and compare it with BCLC for treatment allocation, in particular with respect to liver transplantation. MATERIAL AND METHODS We retrospectively reviewed HCC patients who were managed based on an NDT that was developed in 2012. All patients whose treatment decision was based on this tool between 2012 and 2015 were included. Comparison was made with BCLC. Survival was compared for patients who underwent liver transplantation. RESULTS Based on the NDT, 406 (40.6%) patients were eligible for curative treatment versus only 22 (2.2%) patients based on BCLC. A total of 58 (5.8%) patients underwent liver transplant based on the NDT, while only 2 (0.2%) were transplantable based on BCLC. Estimated 3-year survival for transplanted patients based on the NDT was 73%. There were 41 (4.1%) stage C and 15 (1.5%) stage D BCLC patients who received transplant based on the NDT. Estimated 3-year survival for stage A, C, and D BCLC patients who received transplantation was 100%,72%, and 67%, respectively (P=0.6). CONCLUSIONS The NDT correctly identified a group of HCC patients for liver transplantation who would otherwise have received palliative treatment based on the BCLC algorithm.

  6. HCC development is associated to peripheral insulin resistance in a mouse model of NASH.

    Science.gov (United States)

    De Minicis, Samuele; Agostinelli, Laura; Rychlicki, Chiara; Sorice, Gian Pio; Saccomanno, Stefania; Candelaresi, Cinzia; Giaccari, Andrea; Trozzi, Luciano; Pierantonelli, Irene; Mingarelli, Eleonora; Marzioni, Marco; Muscogiuri, Giovanna; Gaggini, Melania; Benedetti, Antonio; Gastaldelli, Amalia; Guido, Maria; Svegliati-Baroni, Gianluca

    2014-01-01

    NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance. we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC. mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis. CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1-3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors. the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD.

  7. Tumoural Expression of Connective Tissue Growth Factor (CTGF) Impacts on Survival in Patients Diagnosed with Hepatocellular Carcinoma (HCC).

    Science.gov (United States)

    Lamarca, Angela; Mendiola, Marta; Bernal, Elsa; Heredia, Victoria; Díaz, Esther; Miguel, María; Pastrian, Laura G; Burgos, Emilio; Feliu, Jaime; Barriuso, Jorge

    2015-01-01

    Hepatocellular carcinoma (HCC) tends to develop in the liver when there is a high level of background inflammation (cirrhosis). Treatment options are limited and mainly based on systemic therapies such as anti-angiogenic drugs (e.g. sorafenib). Connective tissue growth factor (CTGF) is a matricellular protein involved in inflammation, tumour growth and angiogenesis. The aim of this study is to determine the expression of CTGF and hypoxia inducible factors (HIF) in HCC and to clarify its impact on relapse and survival. Eligibility criteria for the study consisted of patients with a diagnosis of HCC, formalin-fixed and paraffin-embedded (FFPE) biopsy tissue, as well as relapse and available survival data. A tissue microarray was constructed from ≥ 70% tumoural sections. The expressions of CTGF, HIF1α and HIF2α were analysed by immunohistochemistry. The relationship between expression of CTGF/HIF1α and CTGF/HIF2α were analysed. Univariate and multivariate analyses were performed. Fifty-three patients were screened; 39 patients were eligible for this study. Patients were treated with radical intent. At the end of follow up, 59% patients relapsed (28.2% locally, 10.3% multicentric liver relapse and 7.7% distant metastases). Estimated median disease-free survival (DFS) and overall survival (OS) were 23.4 (95%CI 7.18-39.66) and 38.6 months (95%CI 30.7-46.6), respectively. Expression of CTGF was: negative 23.1%, focal 48.7% and diffuse 23.1%. A non-statistically significant relationship between expression of CTGF and HIF was shown supporting an alternative pathway for CTGF expression in HCC. In multivariate analysis CTGF expression was an independent factor related to OS, with shorter survival in those patients with focal/diffuse CTGF expression (HR 2.46; 95%CI 1.18-5.15). Our results support that expression of CTGF is an independent factor associated with shorter OS in HCC. Further analysis of CTGF expression in a larger series of HCC patients is required to confirm

  8. Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion and growth in vitro

    Science.gov (United States)

    Carr, Brian Irving; D’Alessandro, Rosalba; Refolo, Maria Grazia; Iacovazzi, Palma Aurelia; Lippolis, Catia; Messa, Caterina; Cavallini, Aldo; Correale, Mario; Di Carlo, Antonio

    2012-01-01

    Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multi-kinase inhibitors, Regorafenib (Stivarga) and Sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1–1µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multi-kinase inhibitor concentrations thus modulate several aspects of HCC cell biology. PMID:23169148

  9. Histogram Analysis of CT Perfusion of Hepatocellular Carcinoma for Predicting Response to Transarterial Radioembolization: Value of Tumor Heterogeneity Assessment

    International Nuclear Information System (INIS)

    Reiner, Caecilia S.; Gordic, Sonja; Puippe, Gilbert; Morsbach, Fabian; Wurnig, Moritz; Schaefer, Niklaus; Veit-Haibach, Patrick; Pfammatter, Thomas; Alkadhi, Hatem

    2016-01-01

    PurposeTo evaluate in patients with hepatocellular carcinoma (HCC), whether assessment of tumor heterogeneity by histogram analysis of computed tomography (CT) perfusion helps predicting response to transarterial radioembolization (TARE).Materials and MethodsSixteen patients (15 male; mean age 65 years; age range 47–80 years) with HCC underwent CT liver perfusion for treatment planning prior to TARE with Yttrium-90 microspheres. Arterial perfusion (AP) derived from CT perfusion was measured in the entire tumor volume, and heterogeneity was analyzed voxel-wise by histogram analysis. Response to TARE was evaluated on follow-up imaging (median follow-up, 129 days) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results of histogram analysis and mean AP values of the tumor were compared between responders and non-responders. Receiver operating characteristics were calculated to determine the parameters’ ability to discriminate responders from non-responders.ResultsAccording to mRECIST, 8 patients (50 %) were responders and 8 (50 %) non-responders. Comparing responders and non-responders, the 50th and 75th percentile of AP derived from histogram analysis was significantly different [AP 43.8/54.3 vs. 27.6/34.3 mL min −1  100 mL −1 ); p < 0.05], while the mean AP of HCCs (43.5 vs. 27.9 mL min −1  100 mL −1 ; p > 0.05) was not. Further heterogeneity parameters from histogram analysis (skewness, coefficient of variation, and 25th percentile) did not differ between responders and non-responders (p > 0.05). If the cut-off for the 75th percentile was set to an AP of 37.5 mL min −1  100 mL −1 , therapy response could be predicted with a sensitivity of 88 % (7/8) and specificity of 75 % (6/8).ConclusionVoxel-wise histogram analysis of pretreatment CT perfusion indicating tumor heterogeneity of HCC improves the pretreatment prediction of response to TARE

  10. (188)Re-SSS/Lipiodol: Development of a Potential Treatment for HCC from Bench to Bedside.

    Science.gov (United States)

    Lepareur, Nicolas; Ardisson, Valérie; Noiret, Nicolas; Garin, Etienne

    2012-01-01

    Hepatocellular carcinoma (HCC) is the 5th most common tumour worldwide and has a dark prognosis. For nonoperable cases, metabolic radiotherapy with Lipiodol labelled with β-emitters is a promising therapeutic option. The Comprehensive Cancer Centre Eugène Marquis and the National Graduate School of Chemistry of Rennes (ENSCR) have jointly developed a stable and efficient labelling of Lipiodol with rhenium-188 (E(βmax) = 2.1 MeV) for the treatment of HCC. The major "milestones" of this development, from the first syntheses to the recent first injection in man, are described.

  11. HCC development is associated to peripheral insulin resistance in a mouse model of NASH.

    Directory of Open Access Journals (Sweden)

    Samuele De Minicis

    Full Text Available NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC, even in the absence of cirrhosis, that makes NAFLD of such clinical importance.we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC.mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA or its control (CSAA diet and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis.CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1-3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2 and Osteopontin (SPP-1 were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors.the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD.

  12. Reframing autism as a behavioral syndrome and not a specific mental disorder: Implications of genetic and phenotypic heterogeneity.

    Science.gov (United States)

    Tordjman, S; Cohen, D; Coulon, N; Anderson, G M; Botbol, M; Canitano, R; Roubertoux, P L

    2017-01-30

    Clinical and molecular genetics have advanced current knowledge on genetic disorders associated with autism. A review of diverse genetic disorders associated with autism is presented and for the first time discussed extensively with regard to possible common underlying mechanisms leading to a similar cognitive-behavioral phenotype of autism. The possible role of interactions between genetic and environmental factors, including epigenetic mechanisms, is in particular examined. Finally, the pertinence of distinguishing non-syndromic autism (isolated autism) from syndromic autism (autism associated with genetic disorders) will be reconsidered. Given the high genetic and etiological heterogeneity of autism, autism can be viewed as a behavioral syndrome related to known genetic disorders (syndromic autism) or currently unknown disorders (apparent non-syndromic autism), rather than a specific categorical mental disorder. It highlights the need to study autism phenotype and developmental trajectory through a multidimensional, non-categorical approach with multivariate analyses within autism spectrum disorder but also across mental disorders, and to conduct systematically clinical genetic examination searching for genetic disorders in all individuals (children but also adults) with autism. Copyright © 2017. Published by Elsevier Ltd.

  13. Implications of Heterogeneity in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Sanjay de Mel

    2014-01-01

    Full Text Available Multiple myeloma is the second most common hematologic malignancy in the world. Despite improvement in outcome, the disease is still incurable for most patients. However, not all myeloma are the same. With the same treatment, some patients can have very long survival whereas others can have very short survival. This suggests that there is underlying heterogeneity in myeloma. Studies over the years have revealed multiple layers of heterogeneity. First, clinical parameters such as age and tumor burden could significantly affect outcome. At the genetic level, there are also significant heterogeneity ranging for chromosome numbers, genetic translocations, and genetic mutations. At the clonal level, there appears to be significant clonal heterogeneity with multiple clones coexisting in the same patient. At the cell differentiation level, there appears to be a hierarchy of clonally related cells that have different clonogenic potential and sensitivity to therapies. These levels of complexities present challenges in terms of treatment and prognostication as well as monitoring of treatment. However, if we can clearly delineate and dissect this heterogeneity, we may also be presented with unique opportunities for precision and personalized treatment of myeloma. Some proof of concepts of such approaches has been demonstrated.

  14. Genetically heterogeneous glioblastoma recurring with disappearance of 1p/19q losses: case report.

    Science.gov (United States)

    Ito, Motokazu; Wakabayashi, Toshihiko; Natsume, Atsushi; Hatano, Hisashi; Fujii, Masazumi; Yoshida, Jun

    2007-07-01

    Intratumor heterogeneity is of great importance in many clinical aspects of glioma biology, including tumor grading, therapeutic response, and recurrence. Modifications in the genetic features of a specific primary tumor recurring after chemo- and radiotherapy are poorly understood. We report a recurrent glioblastoma case exhibiting loss of heterozygosity (LOH) on chromosome 10q, while the primary tumor exhibited heterogeneity in the LOH status of 1p, 19q, and 10q. To determine the relationship between such modifications and heterogeneous chemosensitivity, primary cultured cells heterogeneously showing 1p/19q/10q losses were established from a surgical specimen of oligoastrocytoma and were treated with chemotherapeutic agents. A 46-year-old woman with a 1-month history of headache and visual disturbances presented to our institution. A right temporoparietal craniotomy and gross total resection were performed. The pathological diagnosis was glioblastoma multiforme with oligodendroglial components. Whereas LOH on 10q was identified at all tumor sites, only the oligodendroglial components exhibited LOH on 1p and 19q. The tumor recurred 6 months after postoperative chemotherapy using interferon-beta and ranimustine, as well as a course of fractionated external-beam radiotherapy (total dose, 60 Gy). Gene analysis revealed no 1p/19q allelic losses but only 10q LOH. Intratumor heterogeneity might be explained by the presence of more than one subclone in the primary tumor. Here, the tumor cells exhibiting 1p/19q LOH with high chemosensitivity might have been killed by the adjuvant therapy and those exhibiting 10q LOH with chemoresistance recurred. This study and our preliminary laboratory findings might suggest an approach to brain tumor physiology, diagnosis, and therapy.

  15. Midterm follow-up after DC-BEAD™-TACE of Hepatocellular Carcinoma (HCC)

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    Skowasch, Marijke, E-mail: marijkeskowasch@aol.com [Department of Diagnostic and Interventional Radiology, Johannes Gutenberg University of Mainz, Mainz, Langenbeckstrasse 1, 55131 Mainz (Germany); Schneider, Jens, E-mail: jens.schneider@unimedizin-mainz.de [Department of Diagnostic and Interventional Radiology, Johannes Gutenberg University of Mainz, Mainz, Langenbeckstrasse 1, 55131 Mainz (Germany); Otto, Gerd, E-mail: gerd.otto@unimedizin-mainz.de [Department of Hepatobiliary Surgery, Johannes Gutenberg-University of Mainz, Langenbeckstrasse 1, 55131 Mainz (Germany); Weinmann, Arndt, E-mail: weinmann@1-med.klinik.uni-mainz.de [First Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Langenbeckstrasse 1, 55131 Mainz (Germany); Woerns, Markus Alexander, E-mail: marcus-alexander.woerns@unimedizin-mainz.de [First Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Langenbeckstrasse 1, 55131 Mainz (Germany); Dueber, Christoph, E-mail: dueber@radiologie.klinik.uni-mainz.de [Department of Diagnostic and Interventional Radiology, Johannes Gutenberg University of Mainz, Mainz, Langenbeckstrasse 1, 55131 Mainz (Germany); Pitton, Michael Bernhard, E-mail: pitton@radiologie.klinik.uni-mainz.de [Department of Diagnostic and Interventional Radiology, Johannes Gutenberg University of Mainz, Mainz, Langenbeckstrasse 1, 55131 Mainz (Germany)

    2012-12-15

    Aim: To determine local response, its predictors and survival and complication rates after DC-Bead™-TACE in patients with hepatocellular carcinoma (HCC). Materials and methods: DC-Beads™ are non-resorbable, polyvinyl-alcoholic hydrophilic microspheres. They release high amounts of chemotherapeutics directly into the tumour. Delivery is sustained over time, tumour feeders are embolised. We used beads from 100–300 to 500–700 μm loaded with Doxorubicin (max. 150 mg/4 ml). Fifty patients (mean age: 68.5 ± 8.8 years) with HCC were analysed. DC-Bead™-TACE was performed once or repeated in two-month intervals. Imaging scans (CT or MRI) were done one-month following each procedure. To evaluate tumour response EASL and RECIST criteria was applied. If eligible, every patient received a non-selective TACE. Results: 128 DC-Bead™ sessions were performed: 127 showed technical success, 120 successful stasis. Complications occurred in 7% (9/128): active bleeding into the tumour (n = 1), liver failure (n = 1), liver abscess (n = 1) ascites (n = 3), pleural effusion (n = 1), false aneurysm (n = 1) and hypoglycaemia (n = 1). At imaging after the 1st, 2nd, 3rd and 4th–8th session, objective response (complete + partial) was 49%, 67%, 67% and 31%, progressive disease was seen in n = 11/50. Baseline diameter and differentiation significantly impacted response. Median overall survival was 25.1 months (95% [CI]: 18.3–31.9) with an estimated cumulative survival rate at one and two-to-four years of 66.7% and 45.7%, respectively. Conclusion: DC-Beads™ can be safely and effectively control HCC. Survival and response rates are encouraging, complications are low. Many factors are involved in response to treatment like liver function or child state.

  16. Molecular signatures associated with HCV-induced hepatocellular carcinoma and liver metastasis.

    Directory of Open Access Journals (Sweden)

    Valeria De Giorgi

    Full Text Available Hepatocellular carcinomas (HCCs are a heterogeneous group of tumors that differ in risk factors and genetic alterations. In Italy, particularly Southern Italy, chronic hepatitis C virus (HCV infection represents the main cause of HCC. Using high-density oligoarrays, we identified consistent differences in gene-expression between HCC and normal liver tissue. Expression patterns in HCC were also readily distinguishable from those associated with liver metastases. To characterize molecular events relevant to hepatocarcinogenesis and identify biomarkers for early HCC detection, gene expression profiling of 71 liver biopsies from HCV-related primary HCC and corresponding HCV-positive non-HCC hepatic tissue, as well as gastrointestinal liver metastases paired with the apparently normal peri-tumoral liver tissue, were compared to 6 liver biopsies from healthy individuals. Characteristic gene signatures were identified when normal tissue was compared with HCV-related primary HCC, corresponding HCV-positive non-HCC as well as gastrointestinal liver metastases. Pathway analysis classified the cellular and biological functions of the genes differentially expressed as related to regulation of gene expression and post-translational modification in HCV-related primary HCC; cellular Growth and Proliferation, and Cell-To-Cell Signaling and Interaction in HCV-related non HCC samples; Cellular Growth and Proliferation and Cell Cycle in metastasis. Also characteristic gene signatures were identified of HCV-HCC progression for early HCC diagnosis.A diagnostic molecular signature complementing conventional pathologic assessment was identified.

  17. Mitochondrial DNA variability among eight Tikúna villages: evidence for an intratribal genetic heterogeneity pattern.

    Science.gov (United States)

    Mendes-Junior, Celso Teixeira; Simões, Aguinaldo Luiz

    2009-11-01

    To study the genetic structure of the Tikúna tribe, four major Native American mitochondrial DNA (mtDNA) founder haplogroups were analyzed in 187 Amerindians from eight Tikúna villages located in the Brazilian Amazon. The central position of these villages in the continent makes them relevant for attempts to reconstruct population movements in South America. In this geographic region, there is particular concern regarding the genetic structure of the Tikúna tribe, formerly designated "enigmatic" due to its remarkable degree of intratribal homogeneity and the scarcity of private protein variants. In spite of its large population size and geographic distribution, the Tikúna tribe presents marked genetic and linguistic isolation. All individuals presented indigenous mtDNA haplogroups. An intratribal genetic heterogeneity pattern characterized by two highly homogeneous Tikúna groups that differ considerably from each other was observed. Such a finding was unexpected, since the Tikúna tribe is characterized by a social system that favors intratribal exogamy and patrilocality that would lead to a higher female migration rate and homogenization of the mtDNA gene pool. Demographic explosions and religious events, which significantly changed the sizes and compositions of many Tikúna villages, may be reflected in the genetic results presented here.

  18. Delineating the genetic heterogeneity of OCA in Hungarian patients.

    Science.gov (United States)

    Fábos, Beáta; Farkas, Katalin; Tóth, Lola; Sulák, Adrienn; Tripolszki, Kornélia; Tihanyi, Mariann; Németh, Réka; Vas, Krisztina; Csoma, Zsanett; Kemény, Lajos; Széll, Márta; Nagy, Nikoletta

    2017-06-19

    Oculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities characterized by variable hair, skin, and ocular hypopigmentation. Six known genes and a locus on human chromosome 4q24 have been implicated in the etiology of isolated OCA forms (OCA 1-7). The most frequent OCA types among Caucasians are OCA1, OCA2, and OCA4. We aimed to investigate genes responsible for the development of these OCA forms in Hungarian OCA patients (n = 13). Mutation screening and polymorphism analysis were performed by direct sequencing on TYR, OCA2, SLC45A2 genes. Although the clinical features of the investigated Hungarian OCA patients were identical, the molecular genetic data suggested OCA1 subtype in eight cases and OCA4 subtype in two cases. The molecular diagnosis was not clearly identifiable in three cases. In four patients, two different heterozygous known pathogenic or predicted to be pathogenic mutations were present. Seven patients had only one pathogenic mutation, which was associated with non-pathogenic variants in six cases. In two patients no pathogenic mutation was identified. Our results suggest that the concomitant screening of the non-pathogenic variants-which alone do not cause the development of OCA, but might have clinical significance in association with a pathogenic variant-is important. Our results also show significant variation in the disease spectrum compared to other populations. These data also confirm that the concomitant analysis of OCA genes is critical, providing new insights to the phenotypic diversity of OCA and expanding the mutation spectrum of OCA genes in Hungarian patients.

  19. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus–related hepatocellular carcinoma

    Science.gov (United States)

    Jiang, De-Ke; Sun, Jielin; Cao, Guangwen; Liu, Yao; Lin, Dongxin; Gao, Yu-Zhen; Ren, Wei-Hua; Long, Xi-Dai; Zhang, Hongxing; Ma, Xiao-Pin; Wang, Zhong; Jiang, Wei; Chen, Tao-Yang; Gao, Yong; Sun, Liang-Dan; Long, Ji-Rong; Huang, Hui-Xing; Wang, Dan; Yu, Hongjie; Zhang, Pengyin; Tang, Li-Sha; Peng, Bo; Cai, Hao; Liu, Ting-Ting; Zhou, Ping; Liu, Fang; Lin, Xiaoling; Tao, Sha; Wan, Bo; Sai-Yin, He-Xi Ge; Qin, Lun-Xiu; Yin, Jianhua; Liu, Li; Wu, Chen; Pei, Yan; Zhou, Yuan-Feng; Zhai, Yun; Lu, Pei-Xin; Tan, Aihua; Zuo, Xian-Bo; Fan, Jia; Chang, Jiang; Gu, Xiaoli; Wang, Neng-Jin; Li, Yang; Liu, Yin-Kun; Zhai, Kan; Zhang, Hongwei; Hu, Zhibin; Liu, Jun; Yi, Qing; Xiang, Yongbing; Shi, Rong; Ding, Qiang; Zheng, Wei; Shu, Xiao-Ou; Mo, Zengnan; Shugart, Yin Yao; Zhang, Xue-Jun; Zhou, Gangqiao; Shen, Hongbing; Zheng, S Lilly; Xu, Jianfeng; Yu, Long

    2013-01-01

    To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, Pmeta = 2.48 × 10−10, odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, Pmeta = 2.72 × 10−17, OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (Ptrend = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10−14). PMID:23242368

  20. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma.

    Science.gov (United States)

    Jiang, De-Ke; Sun, Jielin; Cao, Guangwen; Liu, Yao; Lin, Dongxin; Gao, Yu-Zhen; Ren, Wei-Hua; Long, Xi-Dai; Zhang, Hongxing; Ma, Xiao-Pin; Wang, Zhong; Jiang, Wei; Chen, Tao-Yang; Gao, Yong; Sun, Liang-Dan; Long, Ji-Rong; Huang, Hui-Xing; Wang, Dan; Yu, Hongjie; Zhang, Pengyin; Tang, Li-Sha; Peng, Bo; Cai, Hao; Liu, Ting-Ting; Zhou, Ping; Liu, Fang; Lin, Xiaoling; Tao, Sha; Wan, Bo; Sai-Yin, He-Xi Ge; Qin, Lun-Xiu; Yin, Jianhua; Liu, Li; Wu, Chen; Pei, Yan; Zhou, Yuan-Feng; Zhai, Yun; Lu, Pei-Xin; Tan, Aihua; Zuo, Xian-Bo; Fan, Jia; Chang, Jiang; Gu, Xiaoli; Wang, Neng-Jin; Li, Yang; Liu, Yin-Kun; Zhai, Kan; Zhang, Hongwei; Hu, Zhibin; Liu, Jun; Yi, Qing; Xiang, Yongbing; Shi, Rong; Ding, Qiang; Zheng, Wei; Shu, Xiao-Ou; Mo, Zengnan; Shugart, Yin Yao; Zhang, Xue-Jun; Zhou, Gangqiao; Shen, Hongbing; Zheng, S Lilly; Xu, Jianfeng; Yu, Long

    2013-01-01

    To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, P(meta) = 2.48 × 10(-10), odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, P(meta) = 2.72 × 10(-17), OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (P(trend) = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10(-14)).

  1. The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling

    International Nuclear Information System (INIS)

    Sankin, Alexander; Hakimi, Abraham A; Mikkilineni, Nina; Ostrovnaya, Irina; Silk, Mikhail T; Liang, Yupu; Mano, Roy; Chevinsky, Michael; Motzer, Robert J; Solomon, Stephen B; Cheng, Emily H; Durack, Jeremy C; Coleman, Jonathan A; Russo, Paul; Hsieh, James J

    2014-01-01

    Primary clear cell renal cell carcinoma (ccRCC) genetic heterogeneity may lead to an underestimation of the mutational burden detected from a single site evaluation. We sought to characterize the extent of clonal branching involving key tumor suppressor mutations in primary ccRCC and determine if genetic heterogeneity could limit the mutation profiling from a single region assessment. Ex vivo core needle biopsies were obtained from three to five different regions of resected renal tumors at a single institution from 2012 to 2013. DNA was extracted and targeted sequencing was performed on five genes associated with ccRCC (von-Hippel Lindau [VHL], PBRM1, SETD2, BAP1, and KDM5C). We constructed phylogenetic trees by inferring clonal evolution based on the mutations present within each core and estimated the predictive power of detecting a mutation for each successive tumor region sampled. We obtained 47 ex vivo biopsy cores from 14 primary ccRCC's (median tumor size 4.5 cm, IQR 4.0–5.9 cm). Branching patterns of various complexities were observed in tumors with three or more mutations. A VHL mutation was detected in nine tumors (64%), each time being present ubiquitously throughout the tumor. Other genes had various degrees of regional mutational variation. Based on the mutations' prevalence we estimated that three different tumor regions should be sampled to detect mutations in PBRM1, SETD2, BAP1, and/or KDM5C with 90% certainty. The mutational burden of renal tumors varies by region sampled. Single site assessment of key tumor suppressor mutations in primary ccRCC may not adequately capture the genetic predictors of tumor behavior

  2. Genetic alterations and epigenetic changes in hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    Luz Stella Hoyos Giraldo

    2007-02-01

    Full Text Available

    Hepatocarcinogenesis as hepatocellular carcinoma (HCC is associated with background of chronic liver disease usually in association with cirrhosis, marked hepatic fibrosis, hepatitis B virus (HBV and/or hepatitis virus (HCV infection, chronic inflammation, Aflatoxin B1(AFB1 exposure, chronic alcoholism, metabolic disorder of the liver and necroinflamatory liver disease. Hepatocarcinogenesis involve two mechanisms, genetic alterations (with changes in the cell's DNA sequence and epigenetic changes (without changes in the cell's DNA sequence, but changes in the pattern of gene expression that can persist through one or more generations (somatic sense. Hepatocarcinogenesis is associated with activation of oncogenes and decreased expression of tumor suppressor genes (TSG; include those involved in cell cycle control, apoptosis, DNA repair, immortalization and angiogenesis. AFB1 is metabolized in the liver into a potent carcinogen, aflatoxin 8, 9-epoxide, which is detoxified by epoxide hydrolase (EPHX and glutathione S-transferase M1 (GSTM1.

    A failure of detoxification processes can allow to mutagenic metabolite to bind to DNA and inducing P53 mutation. Genetic polymorphism of EPHX and GSTM1 can make individuals more susceptible to AFB1. Epigenetic inactivation of GSTP1 by promoter hypermethylation plays a role in the development of HCC because, it leads that electrophilic metabolite increase DNA damage and mutations. HBV DNA integration into the host chromosomal DNA of hepatocytes has been detected in HBV-related HCC.

    DNA tumor viruses cause cancer mainly by interfering with cell cycle controls, and activating the cell's replication machinery by blocking the action of key TSG. HBx protein is a

  3. Study of Preoperative Antiviral Treatment of Patients with HCC Negative for HBV-DNA.

    Science.gov (United States)

    Liu, Xiao-Fang; Zhang, Tong; Tang, Kun; Sui, Lu-Lu; Xu, Gang; Liu, Qiang

    2017-08-01

    To study preoperative HBV-DNA negative HBV-related hepatocellular carcinoma (HCC) which was reactivated after surgery and could influence liver function and HCC recurrence. Patients were divided into two groups according to preoperative antiviral therapy status. The control group comprised of 102 preoperative HBV-DNA-negative patients who had not undergone antiviral therapy before surgery. In the treatment group, all HBV-DNA-negative patients (n=63) received entecavir 3-5 days before surgery and for 12 months after surgery. Patients were followed-up regularly, during the preoperative period, and at 1, 3, 6, 12, 18, 24, 30 and 36 months postoperatively. The data for the two groups were analyzed including the level of HBV-DNA and HBV-DNA activation; liver function; 1-, 2- and 3-year survival rate; cumulative survival time; and tumor recurrence. Liver function in the treatment group was better than that of the control group12 months after surgery. Compared to the control group, total bilirubin in the treatment group was significantly better at 6 and 12 months after surgery (pHBV-DNA activation while there were 13 cases (12.75%) with HBV-DNA activation in the control group (pHBV-related HCC with negative HBV-DNA is beneficial to liver function, coagulation function, disease control, prevention of tumor recurrence, improvement of patient quality of life, reduces the death rate and prolongs survival duration. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  4. Human choice and ICT policy: Introduction to the HCC8 Conference proceedings

    NARCIS (Netherlands)

    Avgerou, C.; Smith, M.L.; van den Besselaar, P.; Avgerou, C.; Smith, M.L.; van den Besselaar, P.

    2008-01-01

    Since its launching in 1974, the Human Choice and Computers (HCC) series of conferences of the IFIP Technical Committee 9 (TC9)1 has provided a forum for the study of the multiple facets of the dynamics of social change associated with information and communication technologies (ICTs). These

  5. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

    International Nuclear Information System (INIS)

    Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng; Xia, Qiang

    2012-01-01

    Highlights: ► miR-199a-5p levels were significantly decreased after cisplatin treatment. ► Cisplatin treatment induced autophagy activation. ► Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  6. Non-hypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI as a predictor of outcomes for early-stage HCC.

    Science.gov (United States)

    Toyoda, Hidenori; Kumada, Takashi; Tada, Toshifumi; Sone, Yasuhiro; Maeda, Atsuyuki; Kaneoka, Yuji

    2015-01-01

    In patients with hepatocellular carcinoma (HCC), gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) often identifies non-hypervascular hypointense hepatic nodules during the hepatobiliary phase, but their prognostic significance is unclear. We conducted a prospective observational study to investigate the impact of non-hypervascular hypointense hepatic nodules detected by Gd-EOB-DTPA-enhanced MRI on the outcome of patients with early-stage HCC. Post-treatment recurrence and survival rates were analyzed in 138 patients with non-recurrent, early-stage HCC [Barcelona Clinic Liver Cancer (BCLC) stage 0 or A] and Child-Pugh A liver function according to the presence of non-hypervascular hypointense nodules on pretreatment Gd-EOB-DTPA-enhanced MRI. Non-hypervascular hypointense hepatic nodules were detected in 51 (37.0%) patients with early-stage HCC on pretreatment Gd-EOB-DTPA-enhanced MRI. Recurrence rates were significantly higher in patients with non-hypervascular hypointense nodules (p DTPA-enhanced MRI was independently associated with an increased recurrence rate, independent of tumor progression or treatment (p = 0.0005). The survival rate was significantly lower in patients with non-hypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI (p = 0.0108). In patients with early-stage typical HCC (BCLC 0 or A), the presence of concurrent non-hypervascular hypointense hepatic nodules in the hepatobiliary phase of pretreatment Gd-EOB-DTPA-enhanced MRI is an indicator of higher likelihood of recurrence after treatment and may be a marker for unfavorable outcome.

  7. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China); Xia, Qiang, E-mail: xiaqiang1@yahoo.com.cn [Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People' s Republic of China (China)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer miR-199a-5p levels were significantly decreased after cisplatin treatment. Black-Right-Pointing-Pointer Cisplatin treatment induced autophagy activation. Black-Right-Pointing-Pointer Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  8. 3-Bromopyruvate induces endoplasmic reticulum stress, overcomes autophagy and causes apoptosis in human HCC cell lines.

    Science.gov (United States)

    Ganapathy-Kanniappan, Shanmugasundaram; Geschwind, Jean-Francois H; Kunjithapatham, Rani; Buijs, Manon; Syed, Labiq H; Rao, Pramod P; Ota, Shinichi; Kwak, Byung Kook; Loffroy, Romaric; Vali, Mustafa

    2010-03-01

    Autophagy, a cellular response to stress, plays a role in resistance to chemotherapy in cancer cells. Resistance renders systemic chemotherapy generally ineffective against human hepatocellular carcinoma (HCC). Recently, we reported that the pyruvate analog 3-bromopyruvate (3-BrPA) promoted tumor cell death by targeting GAPDH. In continuance, we investigated the intracellular response of two human HCC cell lines (Hep3B and SK-Hep1) that differ in their status of key apoptotic regulators, p53 and Fas. 3-BrPA treatment induced endoplasmic reticulum (ER) stress, translation inhibition and apoptosis based on Western blot and qPCR, pulse labeling, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and active caspase-3 in both the cell lines. However, electron microscopy revealed that 3-BrPA treated SK-Hep1 cells underwent classical apoptotic cell death while Hep3B cells initially responded with the protective autophagy that failed to prevent eventual apoptosis. 3-BrPA treatment promotes apoptosis in human HCC cell lines, irrespective of the intracellular response.

  9. ANGIOGENESIS INHIBITORS FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA

    Directory of Open Access Journals (Sweden)

    Massimiliano Berretta

    2016-11-01

    Full Text Available Background: Angiogenesis inhibitors have become an important therapeutic approach in the treatment of hepatocellular carcinoma (HCC patients. The achievement of Sorafenib in prolonging overall survival of patients with HCC makes therapeutic inhibition of angiogenesis a fundamental element of the treatment of HCC. Considering the heterogeneous aspects of HCC and to enhance therapeutic efficacy, overcome drug resistance and reduce toxicity, the combination of antiangiogenic drugs with antiblastic chemotherapy (AC, radiotherapy or other targeted drugs have been evaluated. The issue is further complicated by the combination of antiangiogenesis with other AC or biologic drugs. To date, there is no planned approach to determine which patients are more responsive to a given type of antiangiogenic treatment. Conclusion: Large investments in the clinical research are essential to improve treatment response and minimize toxicities for patients with HCC. Future investigations will need to focus on utilizing patterns of genetic information to classify HCC into groups that display similar prognosis and treatment sensitivity, and combining targeted therapies with AC producing enhanced anti-tumor effect. In this review the current panel of available antiangiogenic therapies for the treatment of HCC have been analyzed. In addition current clinical trials are also reported herein.

  10. Expanding the genetic heterogeneity of intellectual disability

    KAUST Repository

    Anazi, Shams; Maddirevula, Sateesh; Salpietro, Vincenzo; Asi, Yasmine T.; Alsahli, Saud; Alhashem, Amal; Shamseldin, Hanan E.; AlZahrani, Fatema; Patel, Nisha; Ibrahim, Niema; Abdulwahab, Firdous M.; Hashem, Mais; Alhashmi, Nadia; Al Murshedi, Fathiya; Al Kindy, Adila; Alshaer, Ahmad; Rumayyan, Ahmed; Al Tala, Saeed; Kurdi, Wesam; Alsaman, Abdulaziz; Alasmari, Ali; Banu, Selina; Sultan, Tipu; Saleh, Mohammed M.; Alkuraya, Hisham; Salih, Mustafa A.; Aldhalaan, Hesham; Ben-Omran, Tawfeg; Al Musafri, Fatima; Ali, Rehab; Suleiman, Jehan; Tabarki, Brahim; El-Hattab, Ayman W.; Bupp, Caleb; Alfadhel, Majid; Al Tassan, Nada; Monies, Dorota; Arold, Stefan T.; Abouelhoda, Mohamed; Lashley, Tammaryn; Houlden, Henry; Faqeih, Eissa; Alkuraya, Fowzan S.

    2017-01-01

    Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

  11. Expanding the genetic heterogeneity of intellectual disability

    KAUST Repository

    Anazi, Shams

    2017-09-22

    Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

  12. Expanding the genetic heterogeneity of intellectual disability.

    Science.gov (United States)

    Anazi, Shams; Maddirevula, Sateesh; Salpietro, Vincenzo; Asi, Yasmine T; Alsahli, Saud; Alhashem, Amal; Shamseldin, Hanan E; AlZahrani, Fatema; Patel, Nisha; Ibrahim, Niema; Abdulwahab, Firdous M; Hashem, Mais; Alhashmi, Nadia; Al Murshedi, Fathiya; Al Kindy, Adila; Alshaer, Ahmad; Rumayyan, Ahmed; Al Tala, Saeed; Kurdi, Wesam; Alsaman, Abdulaziz; Alasmari, Ali; Banu, Selina; Sultan, Tipu; Saleh, Mohammed M; Alkuraya, Hisham; Salih, Mustafa A; Aldhalaan, Hesham; Ben-Omran, Tawfeg; Al Musafri, Fatima; Ali, Rehab; Suleiman, Jehan; Tabarki, Brahim; El-Hattab, Ayman W; Bupp, Caleb; Alfadhel, Majid; Al Tassan, Nada; Monies, Dorota; Arold, Stefan T; Abouelhoda, Mohamed; Lashley, Tammaryn; Houlden, Henry; Faqeih, Eissa; Alkuraya, Fowzan S

    2017-11-01

    Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

  13. Genetic heterogeneity in supratentorial and infratentorial primitive neuroectodermal tumours of the central nervous system.

    Science.gov (United States)

    Inda, M M; Perot, C; Guillaud-Bataille, M; Danglot, G; Rey, J A; Bello, M J; Fan, X; Eberhart, C; Zazpe, I; Portillo, E; Tuñón, T; Martínez-Peñuela, J M; Bernheim, A; Castresana, J S

    2005-12-01

    Medulloblastoma (MB), a kind of infratentorial primitive neuroectodermal tumour (PNET), is the most frequent malignant brain tumour in childhood. In contrast, supratentorial PNET (sPNET) are very infrequent tumours, but they are histologically similar to MB, although they present a worse clinical outcome. We investigated the differences in genetic abnormalities between sPNET and MB. We analysed 20 central PNET (14 MB and six sPNET) by conventional comparative genomic hybridization (CGH) in order to determine whether a different genetic profile for each tumour exists. Isochromosome 17q was detected in four of the 14 MB cases, but not in any sPNET. Gains at 17q and 7 happened more frequently in MB, and those at 1q in sPNET. Losses at chromosome 10 were detected only in MB, while losses at 16p and 19p happened more frequently in sPNET. A new amplification site, on 4q12, was detected in two MB. Central PNET are a heterogeneous group of tumours from the genetic point of view. The present and previous data, together with further results from larger series, might contribute to the establishment of specific treatments for supratentorial and infratentorial PNET.

  14. Histogram Analysis of CT Perfusion of Hepatocellular Carcinoma for Predicting Response to Transarterial Radioembolization: Value of Tumor Heterogeneity Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Reiner, Caecilia S., E-mail: caecilia.reiner@usz.ch; Gordic, Sonja; Puippe, Gilbert; Morsbach, Fabian; Wurnig, Moritz [University Hospital Zurich, Institute of Diagnostic and Interventional Radiology (Switzerland); Schaefer, Niklaus; Veit-Haibach, Patrick [University Hospital Zurich, Division of Nuclear Medicine (Switzerland); Pfammatter, Thomas; Alkadhi, Hatem [University Hospital Zurich, Institute of Diagnostic and Interventional Radiology (Switzerland)

    2016-03-15

    PurposeTo evaluate in patients with hepatocellular carcinoma (HCC), whether assessment of tumor heterogeneity by histogram analysis of computed tomography (CT) perfusion helps predicting response to transarterial radioembolization (TARE).Materials and MethodsSixteen patients (15 male; mean age 65 years; age range 47–80 years) with HCC underwent CT liver perfusion for treatment planning prior to TARE with Yttrium-90 microspheres. Arterial perfusion (AP) derived from CT perfusion was measured in the entire tumor volume, and heterogeneity was analyzed voxel-wise by histogram analysis. Response to TARE was evaluated on follow-up imaging (median follow-up, 129 days) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results of histogram analysis and mean AP values of the tumor were compared between responders and non-responders. Receiver operating characteristics were calculated to determine the parameters’ ability to discriminate responders from non-responders.ResultsAccording to mRECIST, 8 patients (50 %) were responders and 8 (50 %) non-responders. Comparing responders and non-responders, the 50th and 75th percentile of AP derived from histogram analysis was significantly different [AP 43.8/54.3 vs. 27.6/34.3 mL min{sup −1} 100 mL{sup −1}); p < 0.05], while the mean AP of HCCs (43.5 vs. 27.9 mL min{sup −1} 100 mL{sup −1}; p > 0.05) was not. Further heterogeneity parameters from histogram analysis (skewness, coefficient of variation, and 25th percentile) did not differ between responders and non-responders (p > 0.05). If the cut-off for the 75th percentile was set to an AP of 37.5 mL min{sup −1} 100 mL{sup −1}, therapy response could be predicted with a sensitivity of 88 % (7/8) and specificity of 75 % (6/8).ConclusionVoxel-wise histogram analysis of pretreatment CT perfusion indicating tumor heterogeneity of HCC improves the pretreatment prediction of response to TARE.

  15. Functional role of CCL5/RANTES for HCC progression during chronic liver disease

    NARCIS (Netherlands)

    Mohs, Antje; Kuttkat, Nadine; Reissing, Johanna; Zimmermann, Henning Wolfgang; Sonntag, Roland; Proudfoot, Amanda; Youssef, Sameh A.; de Bruin, Alain; Cubero, Francisco Javier; Trautwein, Christian

    Background & Aims: During liver inflammation, triggering fibrogenesis and carcinogenesis immune cells play a pivotal role. In the present study we investigated the role of CCL5 in human and in murine models of chronic liver inflammation leading to hepatocellular carcinoma (HCC) development. Methods:

  16. Inhibition of mTORC2 Induces Cell-Cycle Arrest and Enhances the Cytotoxicity of Doxorubicin by Suppressing MDR1 Expression in HCC Cells.

    Science.gov (United States)

    Chen, Bryan Wei; Chen, Wei; Liang, Hui; Liu, Hao; Liang, Chao; Zhi, Xiao; Hu, Li-Qiang; Yu, Xia-Zhen; Wei, Tao; Ma, Tao; Xue, Fei; Zheng, Lei; Zhao, Bin; Feng, Xin-Hua; Bai, Xue-Li; Liang, Ting-Bo

    2015-08-01

    mTOR is aberrantly activated in hepatocellular carcinoma (HCC) and plays pivotal roles in tumorigenesis and chemoresistance. Rapamycin has been reported to exert antitumor activity in HCC and sensitizes HCC cells to cytotoxic agents. However, due to feedback activation of AKT after mTOR complex 1 (mTORC1) inhibition, simultaneous targeting of mTORC1/2 may be more effective. In this study, we examined the interaction between the dual mTORC1/2 inhibitor OSI-027 and doxorubicin in vitro and in vivo. OSI-027 was found to reduce phosphorylation of both mTORC1 and mTORC2 substrates, including 4E-BP1, p70S6K, and AKT (Ser473), and inhibit HCC cell proliferation. Similar to OSI-027 treatment, knockdown of mTORC2 induced G0-G1 phase cell-cycle arrest. In contrast, rapamycin or knockdown of mTORC1 increased phosphorylation of AKT (Ser473), yet had little antiproliferative effect. Notably, OSI-027 synergized with doxorubicin for the antiproliferative efficacy in a manner dependent of MDR1 expression in HCC cells. The synergistic antitumor effect of OSI-027 and doxorubicin was also observed in a HCC xenograft mouse model. Moreover, AKT was required for OSI-027-induced cell-cycle arrest and downregulation of MDR1. Our findings provide a rationale for dual mTORC1/mTORC2 inhibitors, such as OSI-027, as monotherapy or in combination with cytotoxic agents to treat HCC. Mol Cancer Ther; 14(8); 1805-15. ©2015 AACR. ©2015 American Association for Cancer Research.

  17. The role of genetic factors in patients with hepatocellular carcinoma and iron overload - a prospective series of 234 patients.

    Science.gov (United States)

    Funakoshi, Natalie; Chaze, Iphigénie; Alary, Anne-Sophie; Tachon, Gaëlle; Cunat, Séverine; Giansily-Blaizot, Muriel; Bismuth, Michael; Larrey, Dominique; Pageaux, Georges-Philippe; Schved, Jean-François; Donnadieu-Rigole, Hélène; Blanc, Pierre; Aguilar-Martinez, Patricia

    2016-05-01

    Iron overload (IO) in HFE-related hereditary haemochromatosis is associated with increased risk of liver cancer. This study aimed to investigate the role of other genes involved in hereditary IO among patients with hepatocellular carcinoma (HCC). Patients with HCC diagnosed in our institution were included in this prospective study. Those with ferritin levels ≥300 μg/L (males) or ≥200 μg/L (females) and/or transferrin saturation ≥50% (males) or ≥45% (females) had liver iron concentration (LIC) evaluated by MRI. HFE C282Y and H63D mutations were screened. Genetic analyses of genes involved in hereditary IO (HFE, HJV/HFE2, HAMP, TFR2, SLC40A1, GNPAT) were performed in patients with increased LIC. A total of 234 patients were included; 215 (92%) had common acquired risk factors of HCC (mainly alcoholism or chronic viral hepatitis). 119 patients had abnormal iron parameters. Twelve (5.1%) were C282Y homozygotes, three were compound C282Y/H63D heterozygotes. LIC was measured by MRI in 100 patients. Thirteen patients with a LIC>70 μmol/g were enrolled in further genetic analyses: two unrelated patients bore the HAMP:c.-153C>T mutation at the heterozygous state, which is associated with increased risk of IO and severe haemochromatosis. Specific haplotypes of SLC40A1 were also studied. Additional genetic risk factors of IO were found in 18 patients (7.7%) among a large series of 234 HCC patients. Screening for IO and the associated at-risk genotypes in patients who have developed HCC, is useful for both determining etiologic diagnosis and enabling family screening and possibly primary prevention in relatives. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Repint of "Reframing autism as a behavioral syndrome and not a specific mental disorder: Implications of genetic and phenotypic heterogeneity".

    Science.gov (United States)

    Tordjman, S; Cohen, D; Anderson, G M; Botbol, M; Canitano, R; Coulon, N; Roubertoux, P L

    2018-06-01

    Clinical and molecular genetics have advanced current knowledge on genetic disorders associated with autism. A review of diverse genetic disorders associated with autism is presented and for the first time discussed extensively with regard to possible common underlying mechanisms leading to a similar cognitive-behavioral phenotype of autism. The possible role of interactions between genetic and environmental factors, including epigenetic mechanisms, is in particular examined. Finally, the pertinence of distinguishing non-syndromic autism (isolated autism) from syndromic autism (autism associated with genetic disorders) will be reconsidered. Given the high genetic and etiological heterogeneity of autism, autism can be viewed as a behavioral syndrome related to known genetic disorders (syndromic autism) or currently unknown disorders (apparent non-syndromic autism), rather than a specific categorical mental disorder. It highlights the need to study autism phenotype and developmental trajectory through a multidimensional, non-categorical approach with multivariate analyses within autism spectrum disorder but also across mental disorders, and to conduct systematically clinical genetic examination searching for genetic disorders in all individuals (children but also adults) with autism. Copyright © 2018. Published by Elsevier Ltd.

  19. Role of EPI in diagnosing cavernous hemangioma and small HCC : comparison with fast T2-weighted MR Imaging

    International Nuclear Information System (INIS)

    Kim, Suk; Lee, Jun Woo; Kim, Chang Won; Jung, Hyun Woo; Choi, Sang Yoel; Lee, Suck Hong; Kim, Byung Soo

    1998-01-01

    The purpose of this study is to compare single-shot echo-planar MR imaging (EPI) with breath-hold fast T2-weighted imaging (HASTE or Turbo spin-echo T2WI) for evaluation of the role of EPI in distinguishing small hepatocellular carcinoma from cavernous hemangioma. We retrospectively evaluated MR images of 35 patients (21 cases of small HCC and 14 cases of cavernous hemangioma). EPI and breath-hold fast T2WI images were obtained and compared on the basis of lesion detection sensitivity, lesion-to-liver signal intensity ratio (SIR), contrast ratio (CR), and lesion-to-liver contrast to noise ratio (CNR). For the detection of small HCC, the sensitivity of EPI and breath-hold fast T2WI were equal in 14 of 21 cases (71.4%). The detection sensitivity of cavernous hemangioma with EPI and breath-hold fast T2WI was 100 % (14/14). Mean SIR on breath-hold fast T2WI was 2.02 ± 0.45 for small HCC and 3.65 ± 0.97 for cavernous hemangioma; on EPI, the corresponding figures were 2.91 ± 0.57 for cavernous hemangioma; On EPI, the figures obtained were 2.27 ± 0.52 and 6.26 ± 2.19, respectively. Mean CNR on breath-hold fast T2WI was 14.24 ± 4.098 for small HCC and 50.28 ± 10.96 for cavernous hemangioma, while on EPI, the corresponding figures were 13.84 ± 3.02 and 45.44 ± 11.21. In detecting focal hepatic mass, the sensitivity of EPI and breath-hold fast T2WI are comparable for the diagnosis of small HCC and cavernous hemangioma, EPI can provided additional information. (author). 20 refs., 2 tabs., 4 figs

  20. Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity

    Directory of Open Access Journals (Sweden)

    Mohit Kumar Jolly

    2018-03-01

    Full Text Available It is well known that genetic mutations can drive drug resistance and lead to tumor relapse. Here, we focus on alternate mechanisms—those without mutations, such as phenotypic plasticity and stochastic cell-to-cell variability that can also evade drug attacks by giving rise to drug-tolerant persisters. The phenomenon of persistence has been well-studied in bacteria and has also recently garnered attention in cancer. We draw a parallel between bacterial persistence and resistance against androgen deprivation therapy in prostate cancer (PCa, the primary standard care for metastatic disease. We illustrate how phenotypic plasticity and consequent mutation-independent or non-genetic heterogeneity possibly driven by protein conformational dynamics can stochastically give rise to androgen independence in PCa, and suggest that dynamic phenotypic plasticity should be considered in devising therapeutic dosing strategies designed to treat and manage PCa.

  1. Regorafenib in advanced hepatocellular carcinoma (HCC): considerations for treatment.

    Science.gov (United States)

    Kim, Kyung; Jha, Reena; Prins, Petra A; Wang, Hongkun; Chacha, Monica; Hartley, Marion L; He, Aiwu Ruth

    2017-11-01

    We report our institutional observations of ten patients with advanced hepatocellular carcinoma (HCC) (seven and three were Child-Pugh class A and B, respectively) who received compassionate regorafenib therapy between June 2016 and January 2017. These patients did not fit the rigid criteria of a clinical trial and represented the use of regorafenib in an everyday clinic situation. Regorafenib (160 mg P.O. daily) was administered to patients on a 4-week cycle (3 weeks on, 1 week off) until disease progression (assessed using mRECIST criteria) or discontinuation secondary to toxicity (assessed using CTCAE criteria). Relevant clinical data were abstracted from patient medical records and reviewed retrospectively. The median duration of patient treatment was 6.6 weeks, and the median time to disease progression was 12.5 weeks. Most common treatment emergent adverse events were fatigue, diarrhea, and hand-foot skin reaction. Elevated AST and ALT were the most commonly observed laboratory-assessed adverse events, which reached grade 3 status in the Child-Pugh class B patients only. We observed intolerance to regorafenib treatment in one patient who had previously received a liver transplant. We also saw lithium toxicity in one patient receiving long-term lithium treatment, suggesting a potential and unexpected drug-drug interaction with regorafenib. Taken together, our observations indicate that regorafenib is beneficial in the treatment of patients with advanced HCC who progressed on or demonstrated intolerance to sorafenib therapy; however, careful selection and close monitoring of patients is necessary to maximize the benefit while minimizing the toxicities of regorafenib treatment.

  2. Intra-tumor heterogeneity in head and neck cancer and its clinical implications

    Directory of Open Access Journals (Sweden)

    Edmund A. Mroz

    2016-06-01

    Full Text Available The presence of heritable differences among cancer cells within a tumor, called intra-tumor genetic heterogeneity, has long been suspected of playing a role in poor responses to therapy. Research over the past decade has documented the existence of such heterogeneity within tumors of individual patients and documented its potential clinical significance. The research methods for identifying this heterogeneity were not, however, readily adaptable to widespread clinical application. After a brief review of this background, we describe the development of a measure of intra-tumor genetic heterogeneity, based on whole-exome sequencing of individual tumor samples, that could be applied to biopsy specimens in a clinical setting. This measure has now been used in head and neck squamous cell carcinoma (HNSCC to document, for the first time, a relation of high intra-tumor genetic heterogeneity to shorter overall survival in a large, multi-institutional study. The implications of heterogeneity for research and clinical care thus now need to be addressed. Keywords: Head and neck squamous cell carcinoma, Intra-tumor genetic heterogeneity, Next-generation sequencing, Targeted therapy

  3. Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity.

    Science.gov (United States)

    Grünewald, Inga; Vollbrecht, Claudia; Meinrath, Jeannine; Meyer, Moritz F; Heukamp, Lukas C; Drebber, Uta; Quaas, Alexander; Beutner, Dirk; Hüttenbrink, Karl-Bernd; Wardelmann, Eva; Hartmann, Wolfgang; Büttner, Reinhard; Odenthal, Margarete; Stenner, Markus

    2015-07-20

    Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.

  4. The role of HBV-induced autophagy in HBV replication and HBV related-HCC.

    Science.gov (United States)

    Xie, Mingjie; Yang, Zhenggang; Liu, Yanning; Zheng, Min

    2018-04-27

    Hepatitis B virus (HBV) is infecting about 364 million people around the world. It can cause various diseases, such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). However, the present anti-viral treatment in clinics is limited; studies for new therapies are highly desired. Autophagy is a crucial and major catabolic process in the maintenance of normal intracellular homeostasis in host cells. Host cells use this unique process to degrade and recycle long-lived proteins, damaged organelles, and various pathogens for keeping the normal physiological functions. Recently, published studies indicated that HBV can induce autophagy in host cells; this autophagic response is involved in viral replication and pathogenesis. Several viral proteins, such as surface and X proteins, are assumed to be responsible for inducing autophagy in HBV infection. This review briefly summarizes some important mechanisms involved in HBV-induced autophagy and provides a novel perspective on therapies of HBV infection and HBV-related HCC. Copyright © 2017. Published by Elsevier Inc.

  5. FDG uptake on PET and enhancement on CT or MRI in hepatocellular carcinoma (HCC)

    International Nuclear Information System (INIS)

    Ko, K. H.; Yun, M.; Kim, M. J.; Ryu, Y. H.; Lee, J. D.

    2002-01-01

    To correlate between FDG PET and enhancement pattern on CT and MRI and assess the factors affecting FDG uptake in HCC. Thirty seven nontreated HCC from 34 pts (M:F=30:4, mean age 53) were enrolled. All cases were histologically diagnosed and classified according to Edmonson and Steiner's grading. Tumor FDG uptake was visually assessed on a scale of 0 to 3 compared to the adjacent liver. (0 liver and 3>>liver) and was semi-quantitatively analyzed using SUV. Enhancement pattern on CT and MRI was classified into 3 groups according to signal intensity or density in arterial and portal phase (GroupI: hyperintense-hypointense, GroupII: isointense-hypointense, GroupIII: hypointense-hypointense). Tumor FDG uptake was correlated with enhancement pattern, grade, size and serum aFP level. The tumor ranged from 1.5cm to 20cm. Of the 37 cases, 19(51%) had positive FDG uptake (2 or 3), while 18(49%) were negative (0 or 1). The correlation between FDG uptake and enhancement pattern was statistically insignificant. Lower FDG uptake was associated with lower tumor grade and/or smaller tumor size (P<0.005). FDG uptake of HCC seems to be useful in predicting the differentiation of the tumor and may be prognostic. Although the significance of dynamic enhancement pattern on CT or MRI is yet controversial, it has no specific correlation with FDG uptake and grade on the tumor in this study

  6. Differential neural representation of oral ethanol by central taste-sensitive neurons in ethanol-preferring and genetically heterogeneous rats.

    Science.gov (United States)

    Lemon, Christian H; Wilson, David M; Brasser, Susan M

    2011-12-01

    In randomly bred rats, orally applied ethanol stimulates neural substrates for appetitive sweet taste. To study associations between ethanol's oral sensory characteristics and genetically mediated ethanol preference, we made electrophysiological recordings of oral responses (spike density) by taste-sensitive nucleus tractus solitarii neurons in anesthetized selectively bred ethanol-preferring (P) rats and their genetically heterogeneous Wistar (W) control strain. Stimuli (25 total) included ethanol [3%, 5%, 10%, 15%, 25%, and 40% (vol/vol)], a sucrose series (0.01, 0.03, 0.1, 0.3, 0.5, and 1 M), and other sweet, salt, acidic, and bitter stimuli; 50 P and 39 W neurons were sampled. k-means clustering applied to the sucrose response series identified cells showing high (S(1)) or relatively low (S(0)) sensitivity to sucrose. A three-way factorial analysis revealed that activity to ethanol was influenced by a neuron's sensitivity to sucrose, ethanol concentration, and rat line (P = 0.01). Ethanol produced concentration-dependent responses in S(1) neurons that were larger than those in S(0) cells. Although responses to ethanol by S(1) cells did not differ between lines, neuronal firing rates to ethanol in S(0) cells increased across concentration only in P rats. Correlation and multivariate analyses revealed that ethanol evoked responses in W neurons that were strongly and selectively associated with activity to sweet stimuli, whereas responses to ethanol by P neurons were not easily associated with activity to representative sweet, sodium salt, acidic, or bitter stimuli. These findings show differential central neural representation of oral ethanol between genetically heterogeneous rats and P rats genetically selected to prefer alcohol.

  7. IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines.

    Science.gov (United States)

    Refolo, Maria Grazia; D'Alessandro, Rosalba; Lippolis, Catia; Carella, Nicola; Cavallini, Aldo; Messa, Caterina; Carr, Brian Irving

    2017-11-28

    The recent RESORCE trial showed that treatment with Regorafenib after Sorafenib failure provided a significant improvement in overall survival in HCC patients. Preclinical and clinical trial data showed that Regorafenib is a more potent drug than Sorafenib. In this study we aimed at improving Regorafenib actions and at reducing its toxicity, by targeting parallel pathways or by combination with Vitamins K (VKs). We investigated the effects of Regorafenib administrated at low concentrations and in combination with either VK1 and/or with GSK1838705A or OSI-906, two IGF1-R inhibitors, on HCC cell growth and motility. Our results showed that both IGF1-R inhibitors potentiated the antiproliferative and pro-apoptotic effects of Regorafenib and/or VK1 in HCC cell lines. Moreover we provide evidence that the combined treatment with IG1-R antagonists and Regorafenib (and/or VK1) also caused a significant reduction and depolymerization of actin resulting in synergistic inhibition exerted on cell migration. Thus, simultaneous blocking of MAPK and PI3K/Akt cascades with IGF1-R inhibitors plus Regorafenib could represent a more potent approach for HCC treatment.

  8. Heterogeneity in the multiple myeloma tumor clone

    NARCIS (Netherlands)

    Guikema, JEJ; Hovenga, S; Vellenga, E; Bos, NA

    Multiple Myeloma ( MM) is a plasma cell malignancy which is characterized by a very heterogeneous disease outcome. Heterogeneity in plasma cell characteristics, including morphology, maturation status, immunophenotype and genetic abnormalities partly account for the variable disease outcome.

  9. Consecutive five-year analysis of paternal and maternal gene flow and contributions of gametic heterogeneities to overall genetic composition of dispersed seeds of Pinus densiflora (Pinaceae).

    Science.gov (United States)

    Iwaizumi, Masakazu G; Takahashi, Makoto; Isoda, Keiya; Austerlitz, Frédéric

    2013-09-01

    Genetic variability in monoecious woody plant populations results from the assemblage of individuals issued from asymmetrical male and female reproductive functions, produced during spatially and temporarily heterogeneous reproductive and dispersal events. Here we investigated the dispersal patterns and levels of genetic diversity and differentiation of both paternal and maternal gametes in a natural population of Pinus densiflora at the multiple-year scale as long as five consecutive years. • We analyzed the paternity and maternity for 1576 seeds and 454 candidate adult trees using nuclear DNA polymorphisms of diploid biparental embryos and haploid maternal megagametophytes at eight microsatellite loci. • Despite the low levels of genetic differentiation among gamete groups, a two-way AMOVA analysis showed that the parental origin (paternal vs. maternal gametes), the year of gamete production and their interaction had significant effects on the genetic composition of the seeds. While maternal gamete groups showed a significant FST value across the 5 years, this was not true for their paternal counterparts. Within the population, we found that the relative reproductive contributions of the paternal vs. the maternal parent differed among adult trees, the maternal contributions showing a larger year-to-year fluctuation. • The overall genetic variability of dispersed seeds appeared to result from two sources of heterogeneity: the difference between paternal and maternal patterns of reproduction and gamete dispersal and year-to-year heterogeneity of reproduction of adult trees, especially in their maternal reproduction.

  10. Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry

    DEFF Research Database (Denmark)

    Taylor, Kimberly E; Wong, Quenna; Levine, David M

    2017-01-01

    common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets. METHODS: We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all......OBJECTIVE: The Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using...... subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations. RESULTS: We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10(-42) , P = 3 × 10(-14) , and P = 9 × 10...

  11. Heterogeneity in the multiple myeloma tumor clone

    NARCIS (Netherlands)

    Guikema, Jeroen E. J.; Hovenga, Sjoerd; Vellenga, Edo; Bos, Nicolaas A.

    2004-01-01

    Multiple Myeloma (MM) is a plasma cell malignancy which is characterized by a very heterogeneous disease outcome. Heterogeneity in plasma cell characteristics, including morphology, maturation status, immunophenotype and genetic abnormalities partly account for the variable disease outcome. Although

  12. Evidence of genetic heterogeneity in Alberta Hutterites with Usher syndrome type I.

    Science.gov (United States)

    Zhou, Qi; Lenger, Chaeli; Smith, Richard; Kimberling, William J; Ye, Ming; Lehmann, Ordan; MacDonald, Ian

    2012-01-01

    To identify the genetic defect in a Hutterite population from northern Alberta with Usher syndrome type I. Complete ophthalmic examinations were conducted on two boys and two girls from two related Hutterite families diagnosed with Usher syndrome type I. DNA from patients and their parents was first evaluated for a mutation in exon 10 of the protocadherin-related 15 (PCDH15) gene (c.1471delG), previously reported in southern Alberta Hutterite patients with Usher syndrome (USH1F). Single nucleotide polymorphic linkage analysis was then used to confirm another locus, and DNA was analyzed with the Usher Chip v4.0 platform. Severe hearing impairment, unintelligible speech, and retinitis pigmentosa with varying degrees of visual acuity and visual field loss established a clinical diagnosis of Usher syndrome type I. The patients did not carry the exon 10 mutation in the PCDH15 gene; however, with microarray analysis, a previously reported mutation (c.52C>T; p.Q18X) in the myosin VIIA (MYO7A) gene was found in the homozygous state in the affected siblings. The finding of a MYO7A mutation in two related Hutterite families from northern Alberta provides evidence of genetic heterogeneity in Hutterites affected by Usher syndrome type I.

  13. Population dynamics on heterogeneous bacterial substrates

    Science.gov (United States)

    Mobius, Wolfram; Murray, Andrew W.; Nelson, David R.

    2012-02-01

    How species invade new territories and how these range expansions influence the population's genotypes are important questions in the field of population genetics. The majority of work addressing these questions focuses on homogeneous environments. Much less is known about the population dynamics and population genetics when the environmental conditions are heterogeneous in space. To better understand range expansions in two-dimensional heterogeneous environments, we employ a system of bacteria and bacteriophage, the viruses of bacteria. Thereby, the bacteria constitute the environment in which a population of bacteriophages expands. The spread of phage constitutes itself in lysis of bacteria and thus formation of clear regions on bacterial lawns, called plaques. We study the population dynamics and genetics of the expanding page for various patterns of environments.

  14. Clinical values of AFP, GPC3 mRNA in peripheral blood for prediction of hepatocellular carcinoma recurrence following OLT: AFP, GPC3 mRNA for prediction of HCC.

    Science.gov (United States)

    Wang, Yuliang; Shen, Zhongyang; Zhu, Zhijun; Han, Ruifa; Huai, Mingsheng

    2011-03-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Annually, about 200,000 patients died of HCC in China. Liver transplantation (LT) holds great theoretical appeal in treating HCC. However, the high recurrence rate after transplantation is the most important limiting factor for long-term survival. To assess the value of alpha-fetoprotein (AFP) messenger RNA (mRNA), Glypican-3 (GPC3) mRNA-expressing cells in the peripheral blood (PB) for prediction of HCC recurrence following orthotopic liver transplantation (OLT). 29 patients with HCC who underwent OLT with a minimum clinical follow-up of 12 months were included in this retrospective study. We detected AFP mRNA, GPC3 mRNA-expressing cells in the PB by TaqMan real-time reverse transcriptase-polymerase chain reaction (RT-PCR), pre-, intra- and post-operatively. The early recurrence of patients was evaluated. 8 (28%), 15 (52%), and 9 (31%) patients had AFP mRNA detected pre-, intra-, and post-operatively, respectively. With 12 months of follow-up, HCC recurred in 7 (24%) patients. Univariate analysis revealed that positive pre- and post-operative AFP mRNA, TNM stage as well as vascular invasion were significant predictors for the HCC recurrence. Multivariate analysis revealed that being positive for AFP mRNA pre-operatively remained a significant risk factor for HCC recurrence after OLT. GPC3 mRNA was expressed in all PB samples. There was no significant difference in the expression levels of GPC3 mRNA between the HCC and control groups. There were no significant differences in GPC3 mRNA expression values between those patients with and without tumor recurrence. The pre-operative detection of circulating AFP mRNA-expressing cells could be a useful predictor for HCC recurrence following OLT. GPC3 mRNA-expressing cells in PB seem to have no diagnostic value.

  15. Implantation port-catheter permanent indwelling of pulmonary artery in treating lung metastasis from HCC

    International Nuclear Information System (INIS)

    Cheng Jiemin; Wang Jianhua; Yan Zhiping; Wang Xiaolin; Gong Gaoquan; Liu Qingxin

    2000-01-01

    Objective: To observe the efficacy of a percutaneous implantation port-catheter permanent indwelling pulmonary artery for regional chemotherapy of the metastatic lung cancer from HCC. Methods: Between 1995 and 1999, 62 patients (42 males, 20 females; mean age 46 years) suffering from the metastatic lung cancer from HCC underwent percutaneous implantation of port-catheter permanent indwelling pulmonary artery using the right subclavian vein. In 19 patients with metastatic tumor located on one side of the lung, an indwelling catheter was placed into the ipsilateral side pulmonary artery. With metastasis of both sides, the catheter was inserted into the main trunk of pulmonary artery. The regimens of the chemotherapy were 5-FU + CDDP + MMC(FDM) or 5-FU + CDDP + MMC(FDA). Results: The interventional procedure was successfully completed in all 62 cases (100%). The complications occurred in 8% cases, including infections (3.2%), unhealed wound (1.6%) and pneumothorax (3.2%). The treatment effects of 3-months after the procedure were as follows: the obvious decrease of lung tumor size was 35.5%; stable disease (SD) 32.3% and progressive disease (PD) 32.3%. 6 months follow-up: 12 patients were dead (12/62) and the others are still doing well. The response rates were 22.6%, partial response (PR) 32.3%; stable disease (SD) 25.8% and progressive disease (PD) 32.3%. Conclusions: The percutaneous implantation techniques of pulmonary arterial port-catheter could be a good method in the treatment of metastatic lung cancer from HCC because of it is simple, with few complications and positive effect

  16. Design and rationale of the HCC BRIDGE study in China: a longitudinal, multicenter cohort trial in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Qiao You-Lin

    2011-05-01

    Full Text Available Abstract Background More than 50% of the worldwide cases of hepatocellular carcinoma occur in China, and this malignancy currently represents the country's second leading cause of cancer death in cities and the leading cause in rural areas. Despite recent advances in the control and management of hepatocellular carcinoma within China, this disease remains a major health care issue. The global HCC BRIDGE study, designed to assess patterns of hepatocellular carcinoma therapy use and associated outcomes across real-world clinical practice, has recently been expanded as a national study in China, allowing a detailed analysis of hepatocellular carcinoma in this important country. Methods/Design The global HCC BRIDGE study is a multiregional longitudinal cohort trial including patients newly diagnosed with hepatocellular carcinoma between January 1, 2005, and June 30, 2011, who are receiving treatment for hepatocellular carcinoma via sites in the Asia-Pacific, European, and North American regions. The HCC BRIDGE China national study comprises the portion of the global HCC BRIDGE study conducted within mainland China. Patients will be followed from time of diagnosis of hepatocellular carcinoma (post-January 1, 2005 to time of death or December 31, 2011, whichever comes first. Data will be collected on demographic/clinical characteristics, relevant laboratory values, hepatocellular carcinoma/underlying liver disease treatment, tumor response, adverse events, hospitalizations, and overall survival. The primary study end point is overall survival; secondary end points are disease progression, treatment-limiting adverse events, and treatment failure. Results At the time of writing, 15 sites have selected for participation across all 7 traditional regions of China (North, North-East, East, South, South-West, North-West, and Central. The anticipated study population from the China national study is approximately 9000 patients. Discussion Findings from the

  17. Phenotypic and genetic heterogeneity in a genome-wide linkage study of asthma families

    Directory of Open Access Journals (Sweden)

    Schuster Antje

    2005-01-01

    Full Text Available Abstract Background Asthma is a complex genetic disease with more than 20 genome-wide scans conducted so far. Regions on almost every chromosome have been linked to asthma and several genes have been associated. However, most of these associations are weak and are still awaiting replication. Methods In this study, we conducted a second-stage genome-wide scan with 408 microsatellite markers on 201 asthma-affected sib pair families and defined clinical subgroups to identify phenotype-genotype relations. Results The lowest P value for asthma in the total sample was 0.003 on chromosome 11, while several of the clinical subsets reached lower significance levels than in the overall sample. Suggestive evidence for linkage (p = 0.0007 was found for total IgE on chromosomes 1, 7 and again on chromosome 11, as well as for HDM asthma on chromosome 12. Weaker linkage signals could be found on chromosomes 4 and 5 for early onset and HDM, and, newly described, on chromosome 2 for severe asthma and on chromosome 9 for hay fever. Conclusions This phenotypic dissection underlines the importance of detailed clinical characterisations and the extreme genetic heterogeneity of asthma.

  18. The Transmission Disequilibrium/Heterogeneity Test with Parental-Genotype Reconstruction for Refined Genetic Mapping of Complex Diseases

    Directory of Open Access Journals (Sweden)

    Jing Han

    2012-01-01

    Full Text Available In linkage analysis for mapping genetic diseases, the transmission/disequilibrium test (TDT uses the linkage disequilibrium (LD between some marker and trait loci for precise genetic mapping while avoiding confounding due to population stratification. The sib-TDT (S-TDT and combined-TDT (C-TDT proposed by Spielman and Ewens can combine data from families with and without parental marker genotypes (PMGs. For some families with missing PMG, the reconstruction-combined TDT (RC-TDT proposed by Knapp may be used to reconstruct missing parental genotypes from the genotypes of their offspring to increase power and to correct for potential bias. In this paper, we propose a further extension of the RC-TDT, called the reconstruction-combined transmission disequilibrium/heterogeneity (RC-TDH test, to take into account the identical-by-descent (IBD sharing information in addition to the LD information. It can effectively utilize families with missing or incomplete parental genetic marker information. An application of this proposed method to Genetic Analysis Workshop 14 (GAW14 data sets and extensive simulation studies suggest that this approach may further increase statistical power which is particularly valuable when LD is unknown and/or when some or all PMGs are not available.

  19. Hepatocyte SLAMF3 reduced specifically the multidrugs resistance protein MRP-1 and increases HCC cells sensitization to anti-cancer drugs.

    Science.gov (United States)

    Fouquet, Grégory; Debuysscher, Véronique; Ouled-Haddou, Hakim; Eugenio, Mélanie Simoes; Demey, Baptiste; Singh, Amrathlal Rabbind; Ossart, Christèle; Al Bagami, Mohammed; Regimbeau, Jean-Marc; Nguyen-Khac, Eric; Naassila, Mickael; Marcq, Ingrid; Bouhlal, Hicham

    2016-05-31

    Multidrug resistance MDR proteins (MRPs) are members of the C family of a group of proteins named ATP binding cassette (ABC) transporters. MRPs can transport drugs including anticancer drugs, nucleoside analogs, antimetabolites and tyrosine kinase inhibitors. Drugs used in HCC therapy, such as tyrosine kinase inhibitor sorafenib, are substrates of uptake and/or efflux transporters. Variable expression of MRPs at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. Recently, we reported that the hepatocyte SLAMF3 expression (Signaling Lymphocytic Activation Molecule Family member 3) was reduced in tumor cells from hepatocellular carcinoma (HCC) compared to its high expression in adjacent tissues. In the present study, we make a strong correlation between induced SLAMF3 overexpression and the specific loss of MRP-1 expression and its functionalities as a drugs resistance transporter. No changes were observed on expression of ABCG2 and MDR. More importantly, we highlight a strong inverse correlation between MRP-1 and SLAMF3 expression in patients with HCC. We propose that the SLAMF3 overexpression in cancerous cells could represent a potential therapeutic strategy to improve the drugs sensibility of resistant cells and thus control the therapeutic failure in HCC patients.

  20. Genetic heterogeneity of Escherichia coli isolated from pasteurized milk in State of Paraná, Brazil

    Directory of Open Access Journals (Sweden)

    Karine Oltramari

    2014-04-01

    Full Text Available Food contamination caused by enteric pathogens is a major cause of diarrheal disease worldwide, resulting in high morbidity and mortality and significant economic losses. Bacteria are important agents of foodborne diseases, particularly diarrheagenic Escherichia coli. The present study assessed the genetic diversity and antimicrobial resistance of E. coli isolates from pasteurized milk processed in 21 dairies in northwestern State of Parana, Brazil. The 95 E. coli isolates were subjected to antimicrobial susceptibility testing according to the recommendations of the Clinical and Laboratory Standards Institute and assessed genotypically by Enterobacterial Repetitive Intergenic Consensus-Polymerase Chain Reaction (ERIC-PCR. The highest rate of resistance was observed for cephalothin (55.78%. ERIC-PCR revealed high genetic diversity, clustering the 95 bacterial isolates into 90 different genotypic patterns. These results showed a heterogeneous population of E. coli in milk samples produced in the northwestern region of Paraná and the need for good manufacturing practices throughout the processing of pasteurized milk to reduce the risk of foodborne illnesses.

  1. Osler-Weber-Rendu disease presenting with hepatocellular carcinoma: radiologic and genetic findings.

    Science.gov (United States)

    Lee, Joo Ho; Lee, Yung Sang; Kim, Pyo Nyun; Lee, Beom Hee; Kim, Gu Whan; Yoo, Han Wook; Heo, Nae Yun; Lim, Young Suk; Lee, Han Chu; Chung, Young Hwa; Suh, Dong Jin

    2011-12-01

    This is a case report of a 68-year-old man with hepatocellular carcinoma (HCC) accompanied by hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, and hepatic vascular malformation. HHT is an autosomal dominant disorder of the fibrovascular tissue that is characterized by recurrent epistaxis, mucocutaneous telangiectasias, and visceral arteriovenous malformations. HHT is caused by mutation of the genes involved in the signaling pathway of transforming growth factor-β, which plays an important role in the formation of vascular endothelia. Hepatic involvement has been reported as occurring in 30-73% of patients with HHT. However, symptomatic liver involvement is quite rare, and the representative clinical presentations of HHT in hepatic involvement are high-output heart failure, portal hypertension, nodular regenerative hyperplasia, and symptoms of biliary ischemia. Some cases of HCC in association with HHT have been reported, but are very rare. We present herein the characteristic radiologic and genetic findings of HHT that was diagnosed during the evaluation and treatment of HCC.

  2. Variance heterogeneity in Saccharomyces cerevisiae expression data: trans-regulation and epistasis.

    Science.gov (United States)

    Nelson, Ronald M; Pettersson, Mats E; Li, Xidan; Carlborg, Örjan

    2013-01-01

    Here, we describe the results from the first variance heterogeneity Genome Wide Association Study (VGWAS) on yeast expression data. Using this forward genetics approach, we show that the genetic regulation of gene-expression in the budding yeast, Saccharomyces cerevisiae, includes mechanisms that can lead to variance heterogeneity in the expression between genotypes. Additionally, we performed a mean effect association study (GWAS). Comparing the mean and variance heterogeneity analyses, we find that the mean expression level is under genetic regulation from a larger absolute number of loci but that a higher proportion of the variance controlling loci were trans-regulated. Both mean and variance regulating loci cluster in regulatory hotspots that affect a large number of phenotypes; a single variance-controlling locus, mapping close to DIA2, was found to be involved in more than 10% of the significant associations. It has been suggested in the literature that variance-heterogeneity between the genotypes might be due to genetic interactions. We therefore screened the multi-locus genotype-phenotype maps for several traits where multiple associations were found, for indications of epistasis. Several examples of two and three locus genetic interactions were found to involve variance-controlling loci, with reports from the literature corroborating the functional connections between the loci. By using a new analytical approach to re-analyze a powerful existing dataset, we are thus able to both provide novel insights to the genetic mechanisms involved in the regulation of gene-expression in budding yeast and experimentally validate epistasis as an important mechanism underlying genetic variance-heterogeneity between genotypes.

  3. A challenge to the striking genotypic heterogeneity of retinitis pigmentosa: a better understanding of the pathophysiology using the newest genetic strategies

    Science.gov (United States)

    Sorrentino, F S; Gallenga, C E; Bonifazzi, C; Perri, P

    2016-01-01

    Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by a complex association between tremendous genotypic multiplicity and great phenotypic heterogeneity. The severity of the clinical manifestation depends on penetrance and expressivity of the disease-gene. Also, various interactions between gene expression and environmental factors have been hypothesized. More than 250 genes with ~4500 causative mutations have been reported to be involved in different RP-related mechanisms. Nowadays, not more than the 50% of RPs are attributable to identified genes, whereas the rest of molecular defects are still undetectable, especially in populations where few genetic screenings have been performed. Therefore, new genetic strategies can be a remarkably useful tool to aid clinical diagnosis, potentially modifying treatment options, and family counseling. Genome-wide analytical techniques (array comparative genomic hybridization and single-nucleotide polymorphism genotyping) and DNA sequencing strategies (arrayed primer extension, Sanger sequencing, and ultra high-throughput sequencing) are successfully used to early make molecular diagnosis detecting single or multiple mutations in the huge heterogeneity of RPs. To date, further research needs to be carried out to better investigate the genotype/phenotype correlation, putting together genetic and clinical findings to provide detailed information concerning the risk of RP development and novel effective treatments. PMID:27564722

  4. The Number of Candidate Variants in Exome Sequencing for Mendelian Disease under No Genetic Heterogeneity

    Directory of Open Access Journals (Sweden)

    Jo Nishino

    2013-01-01

    Full Text Available There has been recent success in identifying disease-causing variants in Mendelian disorders by exome sequencing followed by simple filtering techniques. Studies generally assume complete or high penetrance. However, there are likely many failed and unpublished studies due in part to incomplete penetrance or phenocopy. In this study, the expected number of candidate single-nucleotide variants (SNVs in exome data for autosomal dominant or recessive Mendelian disorders was investigated under the assumption of “no genetic heterogeneity.” All variants were assumed to be under the “null model,” and sample allele frequencies were modeled using a standard population genetics theory. To investigate the properties of pedigree data, full-sibs were considered in addition to unrelated individuals. In both cases, particularly regarding full-sibs, the number of SNVs remained very high without controls. The high efficacy of controls was also confirmed. When controls were used with a relatively large total sample size (e.g., N=20, 50, filtering incorporating of incomplete penetrance and phenocopy efficiently reduced the number of candidate SNVs. This suggests that filtering is useful when an assumption of no “genetic heterogeneity” is appropriate and could provide general guidelines for sample size determination.

  5. Section 4. Further expanding the criteria for HCC in living donor liver transplantation: the Tokyo University experience.

    Science.gov (United States)

    Tamura, Sumihito; Sugawara, Yasuhiko; Kokudo, Norihiro

    2014-04-27

    In Asia, evidence-based guidelines for the management of hepatocellular carcinoma (HCC) have evolved, including the option of liver transplantation. Because of the continuing serious organ shortage, however, living donor liver transplantation (LDLT) remains the mainstream in Japan. Unlike deceased donor transplantation, living donor transplantation is not always limited by the restrictions imposed by the nationwide organ allocation system. The decision for transplantation may depend on institutional or case-by-case considerations, balancing the will of the donor, the operative risk, and the overall survival benefit. Cumulative data from the Japanese national multicenter registry analysis as well as individual center experiences suggest further expanding the criteria for LDLT for HCC from the Milan criteria is feasible with acceptable outcomes.

  6. Regional heterogeneity and gene flow maintain variance in a quantitative trait within populations of lodgepole pine

    Science.gov (United States)

    Yeaman, Sam; Jarvis, Andy

    2006-01-01

    Genetic variation is of fundamental importance to biological evolution, yet we still know very little about how it is maintained in nature. Because many species inhabit heterogeneous environments and have pronounced local adaptations, gene flow between differently adapted populations may be a persistent source of genetic variation within populations. If this migration–selection balance is biologically important then there should be strong correlations between genetic variance within populations and the amount of heterogeneity in the environment surrounding them. Here, we use data from a long-term study of 142 populations of lodgepole pine (Pinus contorta) to compare levels of genetic variation in growth response with measures of climatic heterogeneity in the surrounding region. We find that regional heterogeneity explains at least 20% of the variation in genetic variance, suggesting that gene flow and heterogeneous selection may play an important role in maintaining the high levels of genetic variation found within natural populations. PMID:16769628

  7. Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design

    Science.gov (United States)

    Diaz-Cano, Salvador J.

    2012-01-01

    Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma), mechanisms of intercellular transference of genetic information (exosomes), and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning. PMID:22408433

  8. Comparison of the performance of the CMS Hierarchical Condition Category (CMS-HCC) risk adjuster with the Charlson and Elixhauser comorbidity measures in predicting mortality.

    Science.gov (United States)

    Li, Pengxiang; Kim, Michelle M; Doshi, Jalpa A

    2010-08-20

    The Centers for Medicare and Medicaid Services (CMS) has implemented the CMS-Hierarchical Condition Category (CMS-HCC) model to risk adjust Medicare capitation payments. This study intends to assess the performance of the CMS-HCC risk adjustment method and to compare it to the Charlson and Elixhauser comorbidity measures in predicting in-hospital and six-month mortality in Medicare beneficiaries. The study used the 2005-2006 Chronic Condition Data Warehouse (CCW) 5% Medicare files. The primary study sample included all community-dwelling fee-for-service Medicare beneficiaries with a hospital admission between January 1st, 2006 and June 30th, 2006. Additionally, four disease-specific samples consisting of subgroups of patients with principal diagnoses of congestive heart failure (CHF), stroke, diabetes mellitus (DM), and acute myocardial infarction (AMI) were also selected. Four analytic files were generated for each sample by extracting inpatient and/or outpatient claims for each patient. Logistic regressions were used to compare the methods. Model performance was assessed using the c-statistic, the Akaike's information criterion (AIC), the Bayesian information criterion (BIC) and their 95% confidence intervals estimated using bootstrapping. The CMS-HCC had statistically significant higher c-statistic and lower AIC and BIC values than the Charlson and Elixhauser methods in predicting in-hospital and six-month mortality across all samples in analytic files that included claims from the index hospitalization. Exclusion of claims for the index hospitalization generally led to drops in model performance across all methods with the highest drops for the CMS-HCC method. However, the CMS-HCC still performed as well or better than the other two methods. The CMS-HCC method demonstrated better performance relative to the Charlson and Elixhauser methods in predicting in-hospital and six-month mortality. The CMS-HCC model is preferred over the Charlson and Elixhauser methods

  9. Metformin radiosensitization effect of low and high linear energy transfer radiation in HCC

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Ho; Jung, Won Gyun [Division of Heavy Ion Clinical Research, Korea University, Seoul (Korea, Republic of); Kim, Mi Sook; Cho, Chul Koo; Jeong, Youn Kyoung [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2014-04-15

    Metformin (1,1-dimethylbiguanide hydrochloride), the most widely used treatment for type 2 diabetes, provides a good tolerability profile and low cost and has recently sparked keen interest as a potential anticancer agent. Recent evidence has suggested Metformin provides a synergistic benefit with chemotherapy or radiotherapy against certain cancers in several clinical cohort studies.Treatment response rates are higher in patients treated with metformin in cohort studies of breast cancer treated with neoadjuvant chemotherapy in head and neck cancer treated with radiation and in esophageal cancer treated with chemoradiotherapy. As the sensitizing effect of Metformin in HCC has been characterized in vitro and in vivo, we investigated the radio-sensitizing effect of Metformin in HCC cells in combination with γ-ray (low LET) and neutron (high LET) radiation. The radiosensitizing effect of Metformin was much higher in neutron-irradiated than in γ -irradiated cell lines. Fortunately, Metformin had little effect on normal tissues. Our studies revealed no interaction between Metformin and radiation in normal hepatocytes. High LET radiation,including neutron and carbon ion, would produce more complicated and different cellular effects; indeed, the molecular biological mechanism of high LET radiation remains a topic of investigation.

  10. Metformin radiosensitization effect of low and high linear energy transfer radiation in HCC

    International Nuclear Information System (INIS)

    Kim, Eun Ho; Jung, Won Gyun; Kim, Mi Sook; Cho, Chul Koo; Jeong, Youn Kyoung

    2014-01-01

    Metformin (1,1-dimethylbiguanide hydrochloride), the most widely used treatment for type 2 diabetes, provides a good tolerability profile and low cost and has recently sparked keen interest as a potential anticancer agent. Recent evidence has suggested Metformin provides a synergistic benefit with chemotherapy or radiotherapy against certain cancers in several clinical cohort studies.Treatment response rates are higher in patients treated with metformin in cohort studies of breast cancer treated with neoadjuvant chemotherapy in head and neck cancer treated with radiation and in esophageal cancer treated with chemoradiotherapy. As the sensitizing effect of Metformin in HCC has been characterized in vitro and in vivo, we investigated the radio-sensitizing effect of Metformin in HCC cells in combination with γ-ray (low LET) and neutron (high LET) radiation. The radiosensitizing effect of Metformin was much higher in neutron-irradiated than in γ -irradiated cell lines. Fortunately, Metformin had little effect on normal tissues. Our studies revealed no interaction between Metformin and radiation in normal hepatocytes. High LET radiation,including neutron and carbon ion, would produce more complicated and different cellular effects; indeed, the molecular biological mechanism of high LET radiation remains a topic of investigation

  11. The innovator's dilemma revisited: The Home Communication Concept (HCC)

    DEFF Research Database (Denmark)

    Madsen, Arne Stjernholm; Ulhøi, John Parm

    of analysing the actual events. In this respect, it not only demonstrates the classical dilemma of management during disruptive technological development, but also illustrates the internal problem of allowing a creative BDD to become 'sectarian', i.e. blindly believing in itself and suspicious of the rest......The case described in this article is based on an innovation project at Ericsson Denmark. The project has been called the home communication concept (HCC), and represents the response of a major ICT manufacturer to the reshaping of the telecom market, paved by internet technology. The project...... of the world. Using the framework presented in this paper, several fundamental concerns regarding existing research are identified and discussed. In closing, implications for research and management are addressed....

  12. Genetic heterogeneity and minor CYP1B1 involvement in the molecular basis of primary congenital glaucoma in Gypsies.

    Science.gov (United States)

    Sivadorai, P; Cherninkova, S; Bouwer, S; Kamenarova, K; Angelicheva, D; Seeman, P; Hollingsworth, K; Mihaylova, V; Oscar, A; Dimitrova, G; Kaneva, R; Tournev, I; Kalaydjieva, L

    2008-07-01

    Primary congenital glaucoma (PCG) is a genetically heterogeneous disorder of autosomal recessive inheritance, with mutations in the cytochrome P450 1B1 (CYP1B1) gene detected in an average of approximately 50% of cases worldwide. The Roma/Gypsies are considered to be a rare example of a single founder CYP1B1 mutation, E387K (identified in the Slovak Roma), accounting for 100% of disease alleles. Contrary to this concept, unusual genetic heterogeneity was revealed in this study of 21 Gypsy PCG patients from Bulgaria and 715 controls from the general Gypsy population. In our small sample of affected subjects, we identified five different CYP1B1 mutations - four known (E229K, R368H, E387K and R390C) and one novel and potentially pathogenic (F445I), which together accounted for approximately 30% of disease alleles. E387K was rare in both the patient and the control group, indicating that its high frequency in the Slovak Roma is the product of local founder effect not representative of the overall molecular pattern of PCG in the Gypsy population. Data on other Mendelian disorders and on the population genetics of the Gypsies suggest that a true founder mutation is likely to exist and has remained undetected. Our analysis of another candidate gene, MYOC, and the GLC3B and GLC3C loci did not provide support for their involvement. The molecular basis of PCG in the Gypsies is thus unresolved, and diagnostic analyses should be extended beyond the E387K mutation.

  13. Imaging metabolic heterogeneity in cancer.

    Science.gov (United States)

    Sengupta, Debanti; Pratx, Guillem

    2016-01-06

    As our knowledge of cancer metabolism has increased, it has become apparent that cancer metabolic processes are extremely heterogeneous. The reasons behind this heterogeneity include genetic diversity, the existence of multiple and redundant metabolic pathways, altered microenvironmental conditions, and so on. As a result, methods in the clinic and beyond have been developed in order to image and study tumor metabolism in the in vivo and in vitro regimes. Both regimes provide unique advantages and challenges, and may be used to provide a picture of tumor metabolic heterogeneity that is spatially and temporally comprehensive. Taken together, these methods may hold the key to appropriate cancer diagnoses and treatments in the future.

  14. Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design

    Directory of Open Access Journals (Sweden)

    Salvador J. Diaz-Cano

    2012-02-01

    Full Text Available Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma, mechanisms of intercellular transference of genetic information (exosomes, and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning.

  15. Endogenous network states predict gain or loss of functions for genetic mutations in hepatocellular carcinoma.

    Science.gov (United States)

    Wang, Gaowei; Su, Hang; Yu, Helin; Yuan, Ruoshi; Zhu, Xiaomei; Ao, Ping

    2016-02-01

    Cancers have been typically characterized by genetic mutations. Patterns of such mutations have traditionally been analysed by posteriori statistical association approaches. One may ponder the possibility of a priori determination of any mutation regularity. Here by exploring biological processes implied in a mechanistic theory recently developed (the endogenous molecular-cellular network theory), we found that the features of genetic mutations in cancers may be predicted without any prior knowledge of mutation propensities. With hepatocellular carcinoma (HCC) as an example, we found that the normal hepatocyte and cancerous hepatocyte can be represented by robust stable states of one single endogenous network. These stable states, specified by distinct patterns of expressions or activities of proteins in the network, provide means to directly identify a set of most probable genetic mutations and their effects in HCC. As the key proteins and main interactions in the network are conserved through cell types in an organism, similar mutational features may also be found in other cancers. This analysis yielded straightforward and testable predictions on accumulated and preferred mutation spectra in normal tissue. The validation of predicted cancer state mutation patterns demonstrates the usefulness and potential of a causal dynamical framework to understand and predict genetic mutations in cancer. © 2016 The Author(s).

  16. Journal of Genetics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Keywords. antagonistic pleiotropy; balancer chromosomes; environmental heterogeneity; maintenance of genetic variation; trade-offs. Abstract. A fundamental assumption of models for the maintenance of genetic variation by environmental heterogeneity is that selection favours different genotypes in different environments.

  17. Patients with liver FNH and HCC patients with negative AFP: plain and dynamic enhanced MRI and CT findings

    Directory of Open Access Journals (Sweden)

    LI Mingtong

    2015-05-01

    Full Text Available ObjectiveTo investigate plain and dynamic enhanced magnetic resonance imaging (MRI and computed tomography (CT findings in patients with focal nodular hyperplasia (FNH of the liver and hepatocellular carcinoma (HCC patients with negative alpha-fetoprotein (AFP. MethodsA statistical analysis was performed on the clinical data of 124 cases of liver tumor admitted to Beijing Miyun County Hospital from April 2012 to April 2014. ResultsFifty-five of the 74 patients with FNH underwent CT examination, among whom 38 patients received three-phase dynamic enhanced scan and 16 received only plain scan; 62 cases had plain and enhanced MRI with the application of contrast agent Gd-BOPTA in 42 patients. Among the 50 HCC patients with negative AFP, CT examination was performed in 40 and 10 only had plain scan; 46 patients received plain and enhanced MRI with the use of contrast agent Gd-BOPTA in 30. Delayed scan after 1-2 h demonstrated low signal in 30 lesions of the 30 cases. ConclusionFor patients with liver FNH and AFP-negative HCC patients, their plain and dynamic enhanced MRI and CT scan have respective characteristics. A combination of multiple examination methods can significantly improve diagnostic yield of the two diseases.

  18. An estimating function approach to linkage heterogeneity

    Indian Academy of Sciences (India)

    Testing linkage heterogeneity between two loci is an important issue in genetics. Currently, there are ... on linkage heterogeneity can help people to better understand complex .... χ2(F − 2) + cχ2 (1), where c is a constant (see Appendix). Here, it can be ..... gin, ancestry, gender, age, etc., for purpose of dividing sub- groups to ...

  19. Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I.

    Science.gov (United States)

    Astuto, L M; Weston, M D; Carney, C A; Hoover, D M; Cremers, C W; Wagenaar, M; Moller, C; Smith, R J; Pieke-Dahl, S; Greenberg, J; Ramesar, R; Jacobson, S G; Ayuso, C; Heckenlively, J R; Tamayo, M; Gorin, M B; Reardon, W; Kimberling, W J

    2000-12-01

    Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.

  20. Population specific genetic heterogeneity of familial hypercholesterolemia in South Africa.

    Science.gov (United States)

    Smyth, Natalie; Ramsay, Michèle; Raal, Frederick J

    2018-04-01

    To describe the prevalence and population-specific genetic heterogeneity of familial hypercholesterolemia in South Africa. This review highlights the paucity of data on familial hypercholesterolemia in South Africa, and the urgent need to uncover the mutation profiles in lipid-associated genes, causing an increase in LDL-cholesterol in the different ethnic groups. Case reports and small studies have shown that familial hypercholesterolemia, although apparently uncommon, is present in black Africans. Local founder effects have led to an increased prevalence of familial hypercholesterolemia in several South African populations: Afrikaner founder mutations (c.681 C>G, c.1285 G>A, c.523 G>A), Ashkenazi founder mutation (c.654_656del) and possible Indian founder mutation (c.2054 C>T). Preliminary data in black Africans with elevated LDL-cholesterol identified a possible common mutation, c.137_142del. The South African multiethnic society and well described founder effects emphasize the need for differential approaches to diagnosis and management of familial hypercholesterolemia. Studies involving larger cohorts and inclusive of different ethnicities are paramount to establishing an accurate prevalence of familial hypercholesterolemia in black Africans, not only in South Africa but in the Sub-Saharan African region. It is clear that the estimated world prevalence of one in 250 cannot be generally applied across African populations.

  1. VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study.

    Science.gov (United States)

    Scartozzi, Mario; Faloppi, Luca; Svegliati Baroni, Gianluca; Loretelli, Cristian; Piscaglia, Fabio; Iavarone, Massimo; Toniutto, Pierluigi; Fava, Giammarco; De Minicis, Samuele; Mandolesi, Alessandra; Bianconi, Maristella; Giampieri, Riccardo; Granito, Alessandro; Facchetti, Floriana; Bitetto, Davide; Marinelli, Sara; Venerandi, Laura; Vavassori, Sara; Gemini, Stefano; D'Errico, Antonietta; Colombo, Massimo; Bolondi, Luigi; Bearzi, Italo; Benedetti, Antonio; Cascinu, Stefano

    2014-09-01

    Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways. © 2014 UICC.

  2. New Algorithm and Software (BNOmics) for Inferring and Visualizing Bayesian Networks from Heterogeneous Big Biological and Genetic Data.

    Science.gov (United States)

    Gogoshin, Grigoriy; Boerwinkle, Eric; Rodin, Andrei S

    2017-04-01

    Bayesian network (BN) reconstruction is a prototypical systems biology data analysis approach that has been successfully used to reverse engineer and model networks reflecting different layers of biological organization (ranging from genetic to epigenetic to cellular pathway to metabolomic). It is especially relevant in the context of modern (ongoing and prospective) studies that generate heterogeneous high-throughput omics datasets. However, there are both theoretical and practical obstacles to the seamless application of BN modeling to such big data, including computational inefficiency of optimal BN structure search algorithms, ambiguity in data discretization, mixing data types, imputation and validation, and, in general, limited scalability in both reconstruction and visualization of BNs. To overcome these and other obstacles, we present BNOmics, an improved algorithm and software toolkit for inferring and analyzing BNs from omics datasets. BNOmics aims at comprehensive systems biology-type data exploration, including both generating new biological hypothesis and testing and validating the existing ones. Novel aspects of the algorithm center around increasing scalability and applicability to varying data types (with different explicit and implicit distributional assumptions) within the same analysis framework. An output and visualization interface to widely available graph-rendering software is also included. Three diverse applications are detailed. BNOmics was originally developed in the context of genetic epidemiology data and is being continuously optimized to keep pace with the ever-increasing inflow of available large-scale omics datasets. As such, the software scalability and usability on the less than exotic computer hardware are a priority, as well as the applicability of the algorithm and software to the heterogeneous datasets containing many data types-single-nucleotide polymorphisms and other genetic/epigenetic/transcriptome variables, metabolite

  3. Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry.

    Science.gov (United States)

    Taylor, Kimberly E; Wong, Quenna; Levine, David M; McHugh, Caitlin; Laurie, Cathy; Doheny, Kimberly; Lam, Mi Y; Baer, Alan N; Challacombe, Stephen; Lanfranchi, Hector; Schiødt, Morten; Srinivasan, M; Umehara, Hisanori; Vivino, Frederick B; Zhao, Yan; Shiboski, Stephen C; Daniels, Troy E; Greenspan, John S; Shiboski, Caroline H; Criswell, Lindsey A

    2017-06-01

    The Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets. We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all participants (1,405 cases, 1,622 SICCA controls, and 3,125 external controls), one using European participants (585, 966, and 580, respectively), and one using Asian participants (460, 224, and 901, respectively) with ancestry adjustments via principal components analyses. We also investigated whether subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations. We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10 -42 , P = 3 × 10 -14 , and P = 9 × 10 -10 , respectively), and several novel suggestive regions (those with 2 or more associations at P ancestry (P = 4 × 10 -15 and P = 4 × 10 -5 , respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations. Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes. © 2017, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

  4. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

    Science.gov (United States)

    Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I.; Taylor, Kent D.; Azziz, Ricardo; Goodarzi, Mark O.

    2015-01-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS. PMID:26305227

  5. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

    Science.gov (United States)

    Jones, Michelle R; Brower, Meredith A; Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I; Taylor, Kent D; Azziz, Ricardo; Goodarzi, Mark O

    2015-08-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

  6. Framework for Interpretation of Trypsin–antitrypsin Imbalance and Genetic Heterogeneity in Pancreatitis

    Science.gov (United States)

    Lin, Kun; Gao, Feng; Chen, Qingquan; Liu, Qicai; Chen, Shu

    2015-01-01

    Early intracellular premature trypsinogen activation was interpreted as the key initiator of pancreatitis. When the balance in the homeostasis of trypsin and antitrypsin system is disequilibrated, elevated aggressive enzymes directly attack the pancreatic tissue, which leads to pancreatic destruction and inflammation. However, trypsin alone is not enough to cause complications in pancreatitis, which may play a crucial role in modulating signaling events in the initial phase of the disease. NFκB activation is the major inflammatory pathway involved in the occurrence and development of pancreatitis and it can be induced by intrapancreatic activation of trypsinogen. Synthesis of trypsinogen occurs in endoplasmic reticulum (ER), and ER stress is an important early acinar cell event. Components of ER stress response are known to be able to trigger cell death as well as NFκB signaling cascade. The strongest evidence supporting the trypsin-centered theory is that gene mutations, which lead to the generation of more trypsin, or reduce the activity of trypsin inhibitors or trypsin degradation, are associated with pancreatitis. Thus, trypsin–antitrypsin imbalance may be the first step leading to pancreatic autodigestion and inducing other pathways. Continued experimental studies are necessary to determine the specific relationships between trypsin–antitrypsin imbalance and genetic heterogeneity in pancreatitis. In this article, we review the latest advances that contributed to the understanding of the basic mechanisms behind the occurrence and development of pancreatitis with a focus on the interpretation of trypsin–antitrypsin imbalance and their relationships with other inflammation pathways. We additionally highlight genetic predispositions to pancreatitis and possible mechanisms associated with them. PMID:26228362

  7. Influence of plasminogen activator inhibitor-1 (SERPINE1) 4G/5G polymorphism on circulating SERPINE-1 antigen expression in HCC associated with viral infection.

    Science.gov (United States)

    Divella, Rosa; Mazzocca, Antonio; Gadaleta, Cosimo; Simone, Giovanni; Paradiso, Angelo; Quaranta, Michele; Daniele, Antonella

    2012-01-01

    Hepatocarcinogenesis is heavily influenced by chronic hepatitis B (HBV) and C (HCV) infection. Elevated levels of plasminogen activator inhibitor-1 (SERPINE1/PAI-1) have been reported in patients with hepatocellular carcinoma (HCC) associated with viral infection. The gene encoding SERPINE1 is highly polymorphic and the frequently associated 4/5 guanosine (4G/5G) polymorphism in the gene promoter may influence its expression. Here, we investigated the distribution of genotypes and the frequency of alleles of the 4G/5G polymorphism in patients with HCC, the influence of the 4G/5G polymorphism on plasma SERPINE1 levels and its association with viral infection. A total of 75 patients with HCC were enrolled: 32 (42.6%) were HBV(+)/HCV(+), 11 (14.6%) were only HCV(+), and 32 (42.6%) were negative for both viruses. A control group of healthy donors was also enrolled (n=50). SERPINE1 plasma concentrations were determined by ELISA and the detection of the promoter 4G/5G polymorphism was performed by an allele-specific PCR analysis. We found that the frequency of both the 4G/4G genotype (p=0.02) and the 4G allele (p=0.006) were significantly higher in patients with HCC compared to the control group, and particularly higher in patients with HCC co-infected with HBV(+)/HCV(+) than in those with no viral infection. We also found that patients with the 4G/4G genotype had significantly higher plasma SERPINE1 protein levels when compared with patients with the 4G/5G or 5G/5G genotype (p5G SERPINE1 polymorphism with a higher level of SERPINE1 protein in patients with HCC with HBV(+)/HCV(+) than those without infection, suggest the presence of two distinct pathogenic mechanisms in hepatocarcinogenesis, depending on the etiology.

  8. Genetic Drift Linked to Heterogeneous Landscape and Ecological Specialization Drives Diversification in the Alpine Endemic Columbine Aquilegia thalictrifolia.

    Science.gov (United States)

    Lega, Margherita; Fior, Simone; Li, Mingai; Leonardi, Stefano; Varotto, Claudio

    2014-01-01

    The European Alpine system is an extensive mountain range, whose heterogeneous landscape together with Quaternary climatic oscillations significantly affected organismal diversity and distribution in Europe. The model genus Aquilegia represents a textbook example of a rapid and recent radiation through the Northern hemisphere, with the majority of the European taxa occuring in the Alpine system. However, the processes governing genetic differentiation of the genus in this complex geographic area are still widely unexplored. In this work, we used 9 microsatellite loci to study the genetic structure and diversity of 11 populations of Aquilegia thalictrifolia Schott & Kotschy, an alpine taxon characterized by a marked ecological specificity. We found that, despite the endemic and fragmented distribution, A. thalictrifolia has overall high levels of heterozygosity, which is consistent to the substantial inbreeding depression that characterizes the genus. Strong spatial genetic structuring of populations suggests a historical prevalence of genetic drift over gene flow, with natural barriers and ecological niche hindering migration. An analytical comparison of fixation and population differentiation indexes allowed us to infer hypotheses of the postglacial history and more recent demographic events that have influenced the genetics of the species. Overall, our results indicate allopatry as a major force of differentiation in the European scenario, likely to underlie the development of taxonomic boundaries in a broader geographic context. This adds to previous notions on the primary evolutionary forces shaping the Aquilegia radiation in Europe. © The American Genetic Association 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. An overview of posttraumatic stress disorder genetic studies by analyzing and integrating genetic data into genetic database PTSDgene

    NARCIS (Netherlands)

    Zhang, Kunlin; Qu, Susu; Chang, Suhua; Li, Gen; Cao, Chengqi; Fang, Kechi; Olff, Miranda; Wang, Li; Wang, Jing

    2017-01-01

    Posttraumatic stress disorder (PTSD) is a debilitating psychiatric syndrome with complex etiology. Studies aiming to explore genetic susceptibility and environmental triggers of PTSD have been increasing. However, the results are limited and highly heterogeneous. To understand the genetic study

  10. A study of heterogeneity of environmental variance for slaughter weight in pigs

    DEFF Research Database (Denmark)

    Ibánez-Escriche, N; Varona, L; Sorensen, D

    2008-01-01

    This work presents an analysis of heterogeneity of environmental variance for slaughter weight (175 days) in pigs. This heterogeneity is associated with systematic and additive genetic effects. The model also postulates the presence of additive genetic effects affecting the mean and environmental...... variance. The study reveals the presence of genetic variation at the level of the mean and the variance, but an absence of correlation, or a small negative correlation, between both types of additive genetic effects. In addition, we show that both, the additive genetic effects on the mean and those...... on environmental variance have an important influence upon the future economic performance of selected individuals...

  11. Intratumor heterogeneity alters most effective drugs in designed combinations.

    Science.gov (United States)

    Zhao, Boyang; Hemann, Michael T; Lauffenburger, Douglas A

    2014-07-22

    The substantial spatial and temporal heterogeneity observed in patient tumors poses considerable challenges for the design of effective drug combinations with predictable outcomes. Currently, the implications of tissue heterogeneity and sampling bias during diagnosis are unclear for selection and subsequent performance of potential combination therapies. Here, we apply a multiobjective computational optimization approach integrated with empirical information on efficacy and toxicity for individual drugs with respect to a spectrum of genetic perturbations, enabling derivation of optimal drug combinations for heterogeneous tumors comprising distributions of subpopulations possessing these perturbations. Analysis across probabilistic samplings from the spectrum of various possible distributions reveals that the most beneficial (considering both efficacy and toxicity) set of drugs changes as the complexity of genetic heterogeneity increases. Importantly, a significant likelihood arises that a drug selected as the most beneficial single agent with respect to the predominant subpopulation in fact does not reside within the most broadly useful drug combinations for heterogeneous tumors. The underlying explanation appears to be that heterogeneity essentially homogenizes the benefit of drug combinations, reducing the special advantage of a particular drug on a specific subpopulation. Thus, this study underscores the importance of considering heterogeneity in choosing drug combinations and offers a principled approach toward designing the most likely beneficial set, even if the subpopulation distribution is not precisely known.

  12. Quantitative comparison of tumor vascularity of HCC after intravenous contrast Agent: Conventional versus harmonic power Doppler US

    International Nuclear Information System (INIS)

    Park, Seong Ho; Kim, Tae Kyoung; Lee, Kyoung Ho; Kim, Ah Young; Han, Joon Koo; Choi, Byung Ihn

    1999-01-01

    For the quantitative comparison of the degree of enhancement in nodular hepatocellular carcinoma (HCC) at conventional and harmonic Power Doppler (PD) ultrasound (US). The average of %PDA of ten nodules gradually increased until 60 seconds after contrast injection and then gradually decreased. The average %PDA on conventional and harmonic PD US at 60 seconds were 34.9% and 19.5%, respectively. The average %PDA were significantly higher on conventional PD US than those on harmonic PD US at all times except at 20 seconds. The ratio of average %pda on conventional PD US to those on harmonic PD US became gradually larger after 120 seconds. Although contrast-enhanced harmonic PD US can be an effective method in evaluating the tumor vascularity of HCC because of less PD artifacts, the duration of effective enhancement was shorter and degree of enhancement is less than that of conventional PD US.

  13. Automated Image Analysis of HER2 Fluorescence In Situ Hybridization to Refine Definitions of Genetic Heterogeneity in Breast Cancer Tissue.

    Science.gov (United States)

    Radziuviene, Gedmante; Rasmusson, Allan; Augulis, Renaldas; Lesciute-Krilaviciene, Daiva; Laurinaviciene, Aida; Clim, Eduard; Laurinavicius, Arvydas

    2017-01-01

    Human epidermal growth factor receptor 2 gene- (HER2-) targeted therapy for breast cancer relies primarily on HER2 overexpression established by immunohistochemistry (IHC) with borderline cases being further tested for amplification by fluorescence in situ hybridization (FISH). Manual interpretation of HER2 FISH is based on a limited number of cells and rather complex definitions of equivocal, polysomic, and genetically heterogeneous (GH) cases. Image analysis (IA) can extract high-capacity data and potentially improve HER2 testing in borderline cases. We investigated statistically derived indicators of HER2 heterogeneity in HER2 FISH data obtained by automated IA of 50 IHC borderline (2+) cases of invasive ductal breast carcinoma. Overall, IA significantly underestimated the conventional HER2, CEP17 counts, and HER2/CEP17 ratio; however, it collected more amplified cells in some cases below the lower limit of GH definition by manual procedure. Indicators for amplification, polysomy, and bimodality were extracted by factor analysis and allowed clustering of the tumors into amplified, nonamplified, and equivocal/polysomy categories. The bimodality indicator provided independent cell diversity characteristics for all clusters. Tumors classified as bimodal only partially coincided with the conventional GH heterogeneity category. We conclude that automated high-capacity nonselective tumor cell assay can generate evidence-based HER2 intratumor heterogeneity indicators to refine GH definitions.

  14. Comparison of information-theoretic to statistical methods for gene-gene interactions in the presence of genetic heterogeneity

    Directory of Open Access Journals (Sweden)

    Sucheston Lara

    2010-09-01

    Full Text Available Abstract Background Multifactorial diseases such as cancer and cardiovascular diseases are caused by the complex interplay between genes and environment. The detection of these interactions remains challenging due to computational limitations. Information theoretic approaches use computationally efficient directed search strategies and thus provide a feasible solution to this problem. However, the power of information theoretic methods for interaction analysis has not been systematically evaluated. In this work, we compare power and Type I error of an information-theoretic approach to existing interaction analysis methods. Methods The k-way interaction information (KWII metric for identifying variable combinations involved in gene-gene interactions (GGI was assessed using several simulated data sets under models of genetic heterogeneity driven by susceptibility increasing loci with varying allele frequency, penetrance values and heritability. The power and proportion of false positives of the KWII was compared to multifactor dimensionality reduction (MDR, restricted partitioning method (RPM and logistic regression. Results The power of the KWII was considerably greater than MDR on all six simulation models examined. For a given disease prevalence at high values of heritability, the power of both RPM and KWII was greater than 95%. For models with low heritability and/or genetic heterogeneity, the power of the KWII was consistently greater than RPM; the improvements in power for the KWII over RPM ranged from 4.7% to 14.2% at for α = 0.001 in the three models at the lowest heritability values examined. KWII performed similar to logistic regression. Conclusions Information theoretic models are flexible and have excellent power to detect GGI under a variety of conditions that characterize complex diseases.

  15. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

    Directory of Open Access Journals (Sweden)

    Michelle R Jones

    2015-08-01

    Full Text Available Genome wide association studies (GWAS have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS, a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

  16. ORIGINAL ARTICLES Huntington's disease: Genetic heterogeneity ...

    African Journals Online (AJOL)

    2008-03-01

    Mar 1, 2008 ... African origin.5 HD is considered rare among South African blacks, with an ... functions, syphilis, HIV and other tests in selected patients. We .... The discovery of a second genetic locus, resulting in HDL2,7 suggests the need ...

  17. Genomic and transcriptome profiling identified both human and HBV genetic variations and their interactions in Chinese hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Hua Dong

    2015-12-01

    Full Text Available Interaction between HBV and host genome integrations in hepatocellular carcinoma (HCC development is a complex process and the mechanism is still unclear. Here we described in details the quality controls and data mining of aCGH and transcriptome sequencing data on 50 HCC samples from the Chinese patients, published by Dong et al. (2015 (GEO#: GSE65486. In additional to the HBV-MLL4 integration discovered, we also investigated the genetic aberrations of HBV and host genes as well as their genetic interactions. We reported human genome copy number changes and frequent transcriptome variations (e.g. TP53, CTNNB1 mutation, especially MLL family mutations in this cohort of the patients. For HBV genotype C, we identified a novel linkage disequilibrium region covering HBV replication regulatory elements, including basal core promoter, DR1, epsilon and poly-A regions, which is associated with HBV core antigen over-expression and almost exclusive to HBV-MLL4 integration.

  18. Tumor Heterogeneity and Drug Resistance

    International Nuclear Information System (INIS)

    Kucerova, L.; Skolekova, S.; Kozovska, Z.

    2015-01-01

    New generation of sequencing methodologies revealed unexpected complexity and genomic alterations linked with the tumor subtypes. This diversity exists across the tumor types, histologic tumor subtypes and subsets of the tumor cells within the same tumor. This phenomenon is termed tumor heterogeneity. Regardless of its origin and mechanisms of development it has a major impact in the clinical setting. Genetic, phenotypic and expression pattern diversity of tumors plays critical role in the selection of suitable treatment and also in the prognosis prediction. Intratumoral heterogeneity plays a key role in the intrinsic and acquired chemoresistance to cytotoxic and targeted therapies. In this review we focus on the mechanisms of intratumoral and inter tumoral heterogeneity and their relationship to the drug resistance. Understanding of the mechanisms and spatiotemporal dynamics of tumor heterogeneity development before and during the therapy is important for the ability to design individual treatment protocols suitable in the given molecular context. (author)

  19. Measurement of tumor volumes of hepatocellular carcinoma (HCC) by computed tomography (CT). Correlation with several tumor markers

    Energy Technology Data Exchange (ETDEWEB)

    Yoneshima, Manabu; Sawabu, Norio; Toya, Daishu

    1984-09-01

    Tumor volumes of HCC were measured by CT using planimeter and the clinical value of this measurement was evaluated by comparing several tumor markers. Tumor volumes measured by CT roughly agreed with those measured by angiography. In some cases, volumes from ultrasonography were smaller than those from CT and angiography. Tumor volumes measured by CT correlated significantly with the levels of ..cap alpha..-fetoprotein (AFP) but didn't relate to the presence of hepatoma specific ..gamma..-GTP isoenzyme (novel ..gamma..-GTP) nor to the values and positivities of LAI assay. In small HCCs (<=30 cm/sup 3/), the presence of novel ..gamma..-GTP and the levels of AFP were significantly lower than for larger tumors of HCC, but LAI assay wasn't lower. The non-tumorous volumes and the ratio of the non-tumorous volume to the whole liver volume didn't relate to the tests of liver function except for the presence of ascites.

  20. Genetic polymorphisms in DNA double-strand break repair genes XRCC5, XRCC6 and susceptibility to hepatocellular carcinoma.

    Science.gov (United States)

    Li, Rui; Yang, Yuan; An, Yu; Zhou, Yun; Liu, Yanhong; Yu, Qing; Lu, Daru; Wang, Hongyang; Jin, Li; Zhou, Weiping; Qian, Ji; Shugart, Yin Yao

    2011-04-01

    Environmental risk factors cause DNA damages. Imprecise DNA repair leads to chromosome aberrations, genome destabilization and hepatocarcinogenesis. Ku is a key DNA double-strand break repair protein. We hypothesized that the genetic variants in Ku subunits encoding genes, XRCC5/XRCC6, may contribute to hepatocellular carcinoma (HCC) susceptibility. We genotyped 13 common single nucleotide polymorphisms (SNPs) in XRCC5 and XRCC6 and evaluated their associations with HCC risk in 689 pathologically confirmed cases and 690 cancer-free controls from a Chinese population. We found that a significantly reduced risk for HCC was associated with XRCC5 rs16855458 [odds ratio (OR)=0.59; 95% confidence interval (CI)=0.43-0.81; CA+AA versus CC] and a significantly increased risk for HCC was associated with XRCC5 rs9288516 (OR=2.02; 95% CI=1.42-2.86; TA+AA versus TT) even after Bonferroni correction (Pcorrected=0.026 and 0.002, respectively). The effects of rs16855458 (OR=0.57; 95% CI=0.37-0.86, P=0.008) and rs9288516 (OR=1.86; 95% CI=1.19-2.90, P=0.007) were more significant in hepatitis B surface antigen-infected subjects than non-infected subjects. The haplotype-based analysis revealed that in XRCC5, AA in block 1 (OR=0.63; 95% CI=0.48-0.83) and CGGTT in block 2 (OR=0.52; 95% CI=0.39-0.69) were associated with decreased HCC risk (Pcorrected=0.013 and analysis. In conclusion, XRCC5 variants may play a role in determining individual's HCC susceptibility, which warranted validation in larger studies.

  1. Prognosis of patients with hepatocellular carcinoma. Validation and ranking of established staging-systems in a large western HCC-cohort.

    Directory of Open Access Journals (Sweden)

    Mark op den Winkel

    Full Text Available HCC is diagnosed in approximately half a million people per year, worldwide. Staging is a more complex issue than in most other cancer entities and, mainly due to unique geographic characteristics of the disease, no universally accepted staging system exists to date. Focusing on survival rates we analyzed demographic, etiological, clinical, laboratory and tumor characteristics of HCC-patients in our institution and applied the common staging systems. Furthermore we aimed at identifying the most suitable of the current staging systems for predicting survival.Overall, 405 patients with HCC were identified from an electronic medical record database. The following seven staging systems were applied and ranked according to their ability to predict survival by using the Akaike information criterion (AIC and the concordance-index (c-index: BCLC, CLIP, GETCH, JIS, Okuda, TNM and Child-Pugh. Separately, every single variable of each staging system was tested for prognostic meaning in uni- and multivariate analysis. Alcoholic cirrhosis (44.4% was the leading etiological factor followed by viral hepatitis C (18.8%. Median survival was 18.1 months (95%-CI: 15.2-22.2. Ascites, bilirubin, alkaline phosphatase, AFP, number of tumor nodes and the BCLC tumor extension remained independent prognostic factors in multivariate analysis. Overall, all of the tested staging systems showed a reasonable discriminatory ability. CLIP (closely followed by JIS was the top-ranked score in terms of prognostic capability with the best values of the AIC and c-index (AIC 2286, c-index 0.71, surpassing other established staging systems like BCLC (AIC 2343, c-index 0.66. The unidimensional scores TNM (AIC 2342, c-index 0.64 and Child-Pugh (AIC 2369, c-index 0.63 performed in an inferior fashion.Compared with six other staging systems, the CLIP-score was identified as the most suitable staging system for predicting prognosis in a large German cohort of predominantly non-surgical HCC-patients.

  2. Heterogeneous Patterns of Genetic Diversity and Differentiation in European and Siberian Chiffchaff (Phylloscopus collybita abietinus/P. tristis)

    Science.gov (United States)

    Talla, Venkat; Kalsoom, Faheema; Shipilina, Daria; Marova, Irina; Backström, Niclas

    2017-01-01

    Identification of candidate genes for trait variation in diverging lineages and characterization of mechanistic underpinnings of genome differentiation are key steps toward understanding the processes underlying the formation of new species. Hybrid zones provide a valuable resource for such investigations, since they allow us to study how genomes evolve as species exchange genetic material and to associate particular genetic regions with phenotypic traits of interest. Here, we use whole-genome resequencing of both allopatric and hybridizing populations of the European (Phylloscopus collybita abietinus) and the Siberian chiffchaff (P. tristis)—two recently diverged species which differ in morphology, plumage, song, habitat, and migration—to quantify the regional variation in genome-wide genetic diversity and differentiation, and to identify candidate regions for trait variation. We find that the levels of diversity, differentiation, and divergence are highly heterogeneous, with significantly reduced global differentiation, and more pronounced differentiation peaks in sympatry than in allopatry. This pattern is consistent with regional differences in effective population size and recurrent background selection or selective sweeps reducing the genetic diversity in specific regions prior to lineage divergence, but the data also suggest that postdivergence selection has resulted in increased differentiation and fixed differences in specific regions. We find that hybridization and backcrossing is common in sympatry, and that phenotype is a poor predictor of the genomic composition of sympatric birds. The combination of a differentiation scan approach with identification of fixed differences pinpoint a handful of candidate regions that might be important for trait variation between the two species. PMID:29054864

  3. Rethinking the evolution of specialization: A model for the evolution of phenotypic heterogeneity.

    Science.gov (United States)

    Rubin, Ilan N; Doebeli, Michael

    2017-12-21

    Phenotypic heterogeneity refers to genetically identical individuals that express different phenotypes, even when in the same environment. Traditionally, "bet-hedging" in fluctuating environments is offered as the explanation for the evolution of phenotypic heterogeneity. However, there are an increasing number of examples of microbial populations that display phenotypic heterogeneity in stable environments. Here we present an evolutionary model of phenotypic heterogeneity of microbial metabolism and a resultant theory for the evolution of phenotypic versus genetic specialization. We use two-dimensional adaptive dynamics to track the evolution of the population phenotype distribution of the expression of two metabolic processes with a concave trade-off. Rather than assume a Gaussian phenotype distribution, we use a Beta distribution that is capable of describing genotypes that manifest as individuals with two distinct phenotypes. Doing so, we find that environmental variation is not a necessary condition for the evolution of phenotypic heterogeneity, which can evolve as a form of specialization in a stable environment. There are two competing pressures driving the evolution of specialization: directional selection toward the evolution of phenotypic heterogeneity and disruptive selection toward genetically determined specialists. Because of the lack of a singular point in the two-dimensional adaptive dynamics and the fact that directional selection is a first order process, while disruptive selection is of second order, the evolution of phenotypic heterogeneity dominates and often precludes speciation. We find that branching, and therefore genetic specialization, occurs mainly under two conditions: the presence of a cost to maintaining a high phenotypic variance or when the effect of mutations is large. A cost to high phenotypic variance dampens the strength of selection toward phenotypic heterogeneity and, when sufficiently large, introduces a singular point into

  4. The impact of distance and a shifting temperature gradient on genetic connectivity across a heterogeneous landscape

    Directory of Open Access Journals (Sweden)

    Offord Catherine A

    2011-05-01

    Full Text Available Abstract Background Inter-population distance and differences in breeding times are barriers to reproduction that can contribute to genotypic differentiation between populations. Temporal changes in environmental conditions and local selective processes can further contribute to the establishment of reproductive barriers. Telopea speciosissima (Proteaceae is an excellent subject for studying the effect of geographic, edaphic and phenological heterogeneity on genotypic differentiation because previous studies show that these factors are correlated with morphological variation. Molecular, morphological and environmental datasets were combined to characterise the relative influence of these factors on inter-population differentiation, and Bayesian analyses were used to investigate current levels of admixture between differentiated genomes. Results A landscape genetic approach involving molecular and morphological analyses identified three endpoints of differentiated population groups: coastal, upland and southern. The southern populations, isolated from the other populations by an edaphic barrier, show low migration and no evidence of admixture with other populations. Amongst the northern populations, coastal and upland populations are connected along a skewed altitudinal gradient by genetically intermediate populations. The strong association between temperature and flowering time in Telopea speciosissima was shown to maintain a temporally unstable reproductive barrier between coastal and upland populations. Conclusions Substrate-mediated allopatry appears to be responsible for long-term genetic isolation of the southern populations. However, the temperature-dependent reproductive barrier between upland and coastal populations bears the genetic signature of temporal adjustments. The extreme climatic events of the last glacial maximum are likely to have caused more complete allochronic isolation between upland and coastal populations, as well as

  5. [Genetic differentiation of Isaria farinosa populations in Anhui Province of East China].

    Science.gov (United States)

    Sun, Zhao-Hong; Luan, Feng-Gang; Zhang, Da-Min; Chen, Ming-Jun; Wang, Bin; Li, Zeng-Zhi

    2011-11-01

    Isaria farinosa is an important entomopathogenic fungus. By using ISSR, this paper studied the genetic heterogeneity of six I. farinosa populations at different localities of Anhui Province, East China. A total of 98.5% polymorphic loci were amplified with ten polymorphic primers, but the polymorphism at population level varied greatly, within the range of 59.6%-93.2%. The genetic differentiation index (G(st)) between the populations based on Nei's genetic heterogenesis analysis was 0.3365, and the gene flow (N(m)) was 0.4931. The genetic differentiation between the populations was lower than that within the populations, suggesting that the genetic variation of I. farinosa mainly come from the interior of the populations. The UPGMA clustering based on the genetic similarities between the isolates revealed that the Xishan population was monophylectic, while the other five populations were polyphylectic, with the Yaoluoping population being the most heterogenic and the Langyashan population being the least heterogenic. No correlations were observed between the geographic distance and the genetic distance of the populations. According to the UPGMA clustering based on the genetic distance between the populations, the six populations were classified into three groups, and this classification was accorded with the clustering based on geographic environment, suggesting the effects of environmental heterogeneity on the population heterogeneity.

  6. Genetic Heterogeneity in Spondylo- epi- metaphyseal Dysplasias

    African Journals Online (AJOL)

    rme

    Human Genetics & Genome Research Division, National Research Centre and3 ... assessment, IQ, echocardiography, abdominopelvic ultrasound, serum level of calcium, phosphorus, alkaline ..... the brain showed cortical brain atrophy.

  7. Working memory training promotes general cognitive abilities in genetically heterogeneous mice.

    Science.gov (United States)

    Light, Kenneth R; Kolata, Stefan; Wass, Christopher; Denman-Brice, Alexander; Zagalsky, Ryan; Matzel, Louis D

    2010-04-27

    In both humans and mice, the efficacy of working memory capacity and its related process, selective attention, are each strongly predictive of individuals' aggregate performance in cognitive test batteries [1-9]. Because working memory is taxed during most cognitive tasks, the efficacy of working memory may have a causal influence on individuals' performance on tests of "intelligence" [10, 11]. Despite the attention this has received, supporting evidence has been largely correlational in nature (but see [12]). Here, genetically heterogeneous mice were assessed on a battery of five learning tasks. Animals' aggregate performance across the tasks was used to estimate their general cognitive abilities, a trait that is in some respects analogous to intelligence [13, 14]. Working memory training promoted an increase in animals' selective attention and their aggregate performance on these tasks. This enhancement of general cognitive performance by working memory training was attenuated if its selective attention demands were reduced. These results provide evidence that the efficacy of working memory capacity and selective attention may be causally related to an animal's general cognitive performance and provide a framework for behavioral strategies to promote those abilities. Furthermore, the pattern of behavior reported here reflects a conservation of the processes that regulate general cognitive performance in humans and infrahuman animals. Copyright © 2010 Elsevier Ltd. All rights reserved.

  8. Demographic variability and heterogeneity among individuals within and among clonal bacteria strains

    DEFF Research Database (Denmark)

    Jouvet, Lionel; Rodriguez-Rojas, Alexandro; Steiner, Ulrich

    2018-01-01

    to accurately decompose the drivers of heterogeneity among individuals as genetically fixed or selectively neutral. Rather than working on wild populations we present here data from a simple bacterial system in the lab, Escherichia coli. Our system, based on cutting-edge microfluidic techniques, provides high...... control over the genotype and the environment. It therefore allows to unambiguously decompose and quantify fixed genetic variability and dynamic stochastic variability among individuals. We show that within clonal individual variability (dynamic heterogeneity) in lifespan and lifetime reproduction...

  9. Genetic and phylogenetic evolution of HIV-1 in a low subtype heterogeneity epidemic: the Italian example

    Directory of Open Access Journals (Sweden)

    Tornesello Maria

    2007-05-01

    Full Text Available Abstract The Human Immunodeficiency Virus type 1 (HIV-1 is classified into genetic groups, subtypes and sub-subtypes which show a specific geographic distribution pattern. The HIV-1 epidemic in Italy, as in most of the Western Countries, has traditionally affected the Intra-venous drug user (IDU and Homosexual (Homo risk groups and has been sustained by the genetic B subtype. In the last years, however, the HIV-1 transmission rate among heterosexuals has dramatically increased, becoming the prevalent transmission route. In fact, while the traditional risk groups have high levels of knowledge and avoid high-risk practices, the heterosexuals do not sufficiently perceive the risk of HIV-1 infection. This misperception, linked to the growing number of immigrants from non-Western Countries, where non-B clades and circulating recombinant forms (CRFs are prevalent, is progressively introducing HIV-1 variants of non-B subtype in the Italian epidemic. This is in agreement with reports from other Western European Countries. In this context, the Italian HIV-1 epidemic is still characterized by low subtype heterogeneity and represents a paradigmatic example of the European situation. The continuous molecular evolution of the B subtype HIV-1 isolates, characteristic of a long-lasting epidemic, together with the introduction of new subtypes as well as recombinant forms may have significant implications for diagnostic, treatment, and vaccine development. The study and monitoring of the genetic evolution of the HIV-1 represent, therefore, an essential strategy for controlling the local as well as global HIV-1 epidemic and for developing efficient preventive and therapeutic strategies.

  10. Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial

    International Nuclear Information System (INIS)

    Hoffmann, Katrin; Ganten, Tom; Gotthardtp, Daniel; Radeleff, Boris; Settmacher, Utz; Kollmar, Otto; Nadalin, Silvio; Karapanagiotou-Schenkel, Irini; Kalle, Christof von; Jäger, Dirk; Büchler, Markus W; Schemmer, Peter

    2015-01-01

    Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT. Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT). The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs. The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group

  11. Refining and defining riverscape genetics: How rivers influence population genetic structure

    Science.gov (United States)

    Chanté D. Davis; Clinton W. Epps; Rebecca L. Flitcroft; Michael A. Banks

    2018-01-01

    Traditional analysis in population genetics evaluates differences among groups of individuals and, in some cases, considers the effects of distance or potential barriers to gene flow. Genetic variation of organisms in complex landscapes, seascapes, or riverine systems, however, may be shaped by many forces. Recent research has linked habitat heterogeneity and landscape...

  12. Correlation of Multislice CT and Histomorphology in HCC Following TACE: Predictors of Outcome

    International Nuclear Information System (INIS)

    Herber, S.; Biesterfeld, S.; Franz, U.; Schneider, J.; Thies, J.; Schuchmann, M.; Dueber, C.; Pitton, M. B.; Otto, G.

    2008-01-01

    The purpose of this study was to correlate histopathological with CT findings in patients suffering from hepatocellular carcinoma (HCC) eligible for orthotopic liver transplantation (OLT), with a special focus on the antitumoral effect of transarterial chemoembolization (TACE) therapy. A total of 42 consecutive patients suffering from HCC had been treated prior to OLT by means of TACE. TACE was carried out with a mixture of Lipiodol (10-20 ml) and mitomycin C (max. dosage, 10 mg). TACE was performed at 6- to 8-week intervals. Follow-up investigation included contrast-enhanced multislice CT controls and laboratory control. Liver explants were evaluated macroscopically and microscopically to determine the number and size of the tumor lesions as well as the degree of tumor necrosis. Necrosis was investigated in H and E-stained sections. The degree of necrosis was classified as follows: 0-25%, 26-50%, 51-75%, 75-99%, and complete necrosis. Two hundred thirty-one TACE procedures (5.5 ± 2.9; range, 1-14) were performed. Mean tumor size in CT before and after TACE was 4.1 ± 2.4 (range, 1.0-12.0 cm) and 2.7 ± 1.2 (range, 1.0-6.0 cm; p < 0.001). Mean tumor number before and after TACE in CT was 2.5 ± 1.5 (n = 105; range, 1-8) and 2.4 ± 2.0 (n = 103; range, 1-6; p = 0.99). In the surgical specimen tumor size and tumor number were 2.8 ± 1.6 (range, 1.0-7.0 cm; p = 0.78) and 1.9 ± 1.2 (range, 1-7; p = 0.003). Mean tumor necrosis was 67.8% ± 28.1%. Tumor necrosis was subtotal or complete in 17 of 42 (40.5%) patients. Tumor necrosis correlated significantly with the degree of arterial devascularization in CT (p = 0.001), the amount of Lipiodol washout (p = 0.002), and the number of tumor lesions (i.e., unifocal vs. multifocal). Furthermore, elevated serum levels of bilirubin (p = 0.005) and decreased albumin (p = 0.004) affected the local antitumoral effect. A poor necrosis rate (< 25%) significantly correlated with the number of TACE procedures accomplished (p = 0

  13. Heterogeneity in Waardenburg syndrome.

    Science.gov (United States)

    Hageman, M J; Delleman, J W

    1977-01-01

    Heterogeneity of Waardenburg syndrome is demonstrated in a review of 1,285 patients from the literature and 34 previously unreported patients in five families in the Netherlands. The syndrome seems to consist of two genetically distinct entities that can be differentiated clinically: type I, Waardenburg syndrome with dystopia canthorum; and type II, Waardenburg syndrome without dystopia canthorum. Both types have an autosomal dominant mode of inheritance. The incidence of bilateral deafness in the two types of the syndrome was found in one-fourth with type I and about half of the patients with type II. This difference has important consequences for genetic counseling. Images Fig. 7 Fig. 8 Fig. 9 PMID:331943

  14. Unexpected Nongenetic Individual Heterogeneity and Trait Covariance in Daphnia and Its Consequences for Ecological and Evolutionary Dynamics.

    Science.gov (United States)

    Cressler, Clayton E; Bengtson, Stefan; Nelson, William A

    2017-07-01

    Individual differences in genetics, age, or environment can cause tremendous differences in individual life-history traits. This individual heterogeneity generates demographic heterogeneity at the population level, which is predicted to have a strong impact on both ecological and evolutionary dynamics. However, we know surprisingly little about the sources of individual heterogeneity for particular taxa or how different sources scale up to impact ecological and evolutionary dynamics. Here we experimentally study the individual heterogeneity that emerges from both genetic and nongenetic sources in a species of freshwater zooplankton across a large gradient of food quality. Despite the tight control of environment, we still find that the variation from nongenetic sources is greater than that from genetic sources over a wide range of food quality and that this variation has strong positive covariance between growth and reproduction. We evaluate the general consequences of genetic and nongenetic covariance for ecological and evolutionary dynamics theoretically and find that increasing nongenetic variation slows evolution independent of the correlation in heritable life-history traits but that the impact on ecological dynamics depends on both nongenetic and genetic covariance. Our results demonstrate that variation in the relative magnitude of nongenetic versus genetic sources of variation impacts the predicted ecological and evolutionary dynamics.

  15. Genetic heterogeneity of murine coronaviruses

    International Nuclear Information System (INIS)

    Lai, M.M.C.; Fleming, J.O.; Stohlman, S.A.; Fujiwara, K.

    1983-01-01

    Several mouse hepatitis viruses (MHV) with different pathogenicity were studied by oligonucleotide fingerprinting. Two strains, MHV-K and MHV-D, which were isolated in Japan and, which cause anaplasia and necrosis of bone marrow and diarrhea, respectively, were found to be closely related to MHV-A59, the prototype MHV. Two other MHV strains, isolated from nude mice, were found to have diverged extensively from the known MHV strains. The MHVs isolated from separate cloned neuroblastoma cell lines persistently infected with JHM strain were also found to have diverged more markedly than the corresponding virus maintained under the conditions of lytic infection. Genetic divergence during persistent infection may be one of the mechanisms by which the MHV diverges. (Author)

  16. Genetic heterogeneity of murine coronaviruses

    Energy Technology Data Exchange (ETDEWEB)

    Lai, M M.C.; Fleming, J O; Stohlman, S A; Fujiwara, K

    1983-12-01

    Several mouse hepatitis viruses (MHV) with different pathogenicity were studied by oligonucleotide fingerprinting. Two strains, MHV-K and MHV-D, which were isolated in Japan and, which cause anaplasia and necrosis of bone marrow and diarrhea, respectively, were found to be closely related to MHV-A59, the prototype MHV. Two other MHV strains, isolated from nude mice, were found to have diverged extensively from the known MHV strains. The MHVs isolated from separate cloned neuroblastoma cell lines persistently infected with JHM strain were also found to have diverged more markedly than the corresponding virus maintained under the conditions of lytic infection. Genetic divergence during persistent infection may be one of the mechanisms by which the MHV diverges.

  17. Cognitive and behavioral heterogeneity in genetic syndromes

    Directory of Open Access Journals (Sweden)

    Luiz F.L. Pegoraro

    2014-04-01

    Full Text Available OBJECTIVE: this study aimed to investigate the cognitive and behavioral profiles, as well as the psychiatric symptoms and disorders in children with three different genetic syndromes with similar sociocultural and socioeconomic backgrounds. METHODS: thirty-four children aged 6 to 16 years, with Williams-Beuren syndrome (n = 10, Prader-Willi syndrome (n = 11, and Fragile X syndrome (n = 13 from the outpatient clinics of Child Psychiatry and Medical Genetics Department were cognitively assessed through the Wechsler Intelligence Scale for Children (WISC-III. Afterwards, a full-scale intelligence quotient (IQ, verbal IQ, performance IQ, standard subtest scores, as well as frequency of psychiatric symptoms and disorders were compared among the three syndromes. RESULTS: significant differences were found among the syndromes concerning verbal IQ and verbal and performance subtests. Post-hoc analysis demonstrated that vocabulary and comprehension subtest scores were significantly higher in Williams-Beuren syndrome in comparison with Prader-Willi and Fragile X syndromes, and block design and object assembly scores were significantly higher in Prader-Willi syndrome compared with Williams-Beuren and Fragile X syndromes. Additionally, there were significant differences between the syndromes concerning behavioral features and psychiatric symptoms. The Prader-Willi syndrome group presented a higher frequency of hyperphagia and self-injurious behaviors. The Fragile X syndrome group showed a higher frequency of social interaction deficits; such difference nearly reached statistical significance. CONCLUSION: the three genetic syndromes exhibited distinctive cognitive, behavioral, and psychiatric patterns.

  18. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

    DEFF Research Database (Denmark)

    Reddy, Anupama; Zhang, Jenny; Davis, Nicholas S

    2017-01-01

    Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed...

  19. TACE Combined with Implantation of Irradiation Stent Versus TACE Combine with Bare Stent for HCC Complicated by IVCTT

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Qing-hui; Zhang, Wen; Liu, Qing-xin; Liu, Ling-xiao [Fudan University, Department of Interventional Radiology, Zhongshan Hospital (China); Wu, Lin-lin [Tengzhou Central People’s Hospital, Department of Oncology (China); Wang, Jian-hua; Yan, Zhi-ping, E-mail: 798373254@qq.com; Luo, Jian-jun, E-mail: 12211210022@fudan.edu.cn [Fudan University, Department of Interventional Radiology, Zhongshan Hospital (China)

    2016-09-15

    PurposeThis study was designed to evaluate the safety and efficacy of transarterial chemoembolization (TACE) combined with intra-IVC implantation of an irradiation stent for the treatment of hepatocellular carcinoma (HCC) complicated by inferior vena cava tumor thrombosis (IVCTT).MethodsSixty-one consecutive patients with HCC complicated by IVCTT treated by TACE combined with IVC stenting were retrospectively analysed. IVC stenting was performed using a stent loaded with {sup 125}I seeds strands (the irradiation stent) in 33 patients (Group A) and 28 patients with a bare stent (Group B). Propensity score matching eliminated the baseline differences. Overall survival, oedema related to IVC obstruction remission rate and procedure-related adverse events were compared between the two groups.ResultsThe adverse effect rate was similar for both Group A and Group B patients, and complications were adequately handled by medical treatment. TACE combined with implantation of an irradiation stent showed a significant median survival benefit over TACE combined with a bare stent, with a median survival time of 203.0 ± 28.135 days versus 93.0 ± 24.341 days (p = 0.006). The propensity score-matched (24 pairs) cohort analyses (200 ± 31.231 days vs. 66 ± 23.270 days, p = 0.019). The oedema remission rate was 97.0 % in group A patients and 96.4 % in group B, respectively. TACE-irradiation stent and object tumor response were the independent prognostic factors of favorable survival.ConclusionsTACE combined with irradiation stent implantation is a safe and effective treatment modality for patients with HCC complicated by IVCTT and may extend their survival time.

  20. Radiofrequency Thermoablation of HCC Larger Than 3 cm and Less Than 5 cm Proximal to the Gallbladder without Gallbladder Isolation: A Single Center Experience

    Directory of Open Access Journals (Sweden)

    Antonio Orlacchio

    2014-01-01

    Full Text Available Radiofrequency ablation (RFA is an effective minimally invasive treatment for nonsurgical hepatocellular carcinoma (HCC, but ablation of tumors close to the gallbladder could be associated with several complications. We report our experience on the treatment of HCC close to the gallbladder with RFA. Eight RFA procedures were performed in eight patients with HCC larger than 3 cm and less than 5 cm close to the gallbladder. In all cases, a percutaneous approach was used. There were no major complications. Only in two patients a minimal wall thickening of the gallbladder was observed. Contrast enhanced computed tomography carried out after 30 days from the first procedure showed complete necrosis in seven patients (87%. Only one patient had local recurrence at 11 months of followup. Although limited, our experience suggests that, after careful preprocedural planning, in experienced hands and with appropriate technology, percutaneous RFA could be safely performed even for lesions larger than 3 cm located in close adjacency to the gallbladder.

  1. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing.

    LENUS (Irish Health Repository)

    Murphy, Sinead M

    2012-07-01

    Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims of this study were to determine the frequency of different genes in a large cohort of patients with CMT and devise guidelines for genetic testing in practice.

  2. Programming strategy for efficient modeling of dynamics in a population of heterogeneous cells

    DEFF Research Database (Denmark)

    Hald, Bjørn Olav; Hendriksen, Morten; Sørensen, Preben Graae

    2013-01-01

    Heterogeneity is a ubiquitous property of biological systems. Even in a genetically identical population of a single cell type, cell-to-cell differences are observed. Although the functional behavior of a given population is generally robust, the consequences of heterogeneity are fairly unpredict...

  3. [Molecular heterogeneity of malignant pleural mesotheliomas].

    Science.gov (United States)

    Tranchant, Robin; Montagne, François; Jaurand, Marie-Claude; Jean, Didier

    2018-01-01

    Malignant pleural mesothelioma (MPM) is predominantly an occupational cancer, most often linked to asbestos exposure. Malignant pleural mesothelioma prognosis is poor with a short survival median, due to the aggressiveness of tumor cells and the weak efficiency of conventional anti-cancer therapies. Clinical, histological, and molecular data suggest tumor heterogeneity between patients as it was also shown for other cancer types. Consequently, there is an urgent need to develop new therapies that take into account this heterogeneity and the molecular characteristics of malignant pleural mesothelioma, in particular by identifying new anti-cancer drugs targeting the molecular specificities of each malignant pleural mesothelioma. Malignant pleural mesothelioma is characterized by numerous molecular alterations at the chromosomal, genetic and epigenetic levels. Molecular classification based on gene expression profile has firstly defined two tumor groups, C1 and C2, and more recently, four groups. By integrating genetic and transcriptomic analysis, a C2 LN tumor subgroup of the C2 group has been identified and characterized. In addition to tumor heterogeneity between patients, intra-tumor heterogeneity is supported by several evidences. Most therapeutic strategies that take into account the tumor molecular characteristics have focused on targeted therapies based on mutated genes. A more appropriate strategy would be to consider better-defined tumor groups on the basis of several molecular alterations types as it has been proposed for the C2 LN subgroup. A robust definition of homogeneous tumor groups sharing common molecular characteristics is necessary for the development of effective precision medicine for malignant pleural mesothelioma. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  4. Higher rates of sex evolve in spatially heterogeneous environments.

    Science.gov (United States)

    Becks, Lutz; Agrawal, Aneil F

    2010-11-04

    The evolution and maintenance of sexual reproduction has puzzled biologists for decades. Although this field is rich in hypotheses, experimental evidence is scarce. Some important experiments have demonstrated differences in evolutionary rates between sexual and asexual populations; other experiments have documented evolutionary changes in phenomena related to genetic mixing, such as recombination and selfing. However, direct experiments of the evolution of sex within populations are extremely rare (but see ref. 12). Here we use the rotifer, Brachionus calyciflorus, which is capable of both sexual and asexual reproduction, to test recent theory predicting that there is more opportunity for sex to evolve in spatially heterogeneous environments. Replicated experimental populations of rotifers were maintained in homogeneous environments, composed of either high- or low-quality food habitats, or in heterogeneous environments that consisted of a mix of the two habitats. For populations maintained in either type of homogeneous environment, the rate of sex evolves rapidly towards zero. In contrast, higher rates of sex evolve in populations experiencing spatially heterogeneous environments. The data indicate that the higher level of sex observed under heterogeneity is not due to sex being less costly or selection against sex being less efficient; rather sex is sufficiently advantageous in heterogeneous environments to overwhelm its inherent costs. Counter to some alternative theories for the evolution of sex, there is no evidence that genetic drift plays any part in the evolution of sex in these populations.

  5. Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Shen Xi-Zhong

    2010-03-01

    Full Text Available Abstract Background Hereditary hemochromatosis (HH is an autosomal recessive disorder mainly associated with homozygosity for the C282Y and H63D mutations in the hemochromatosis (HFE gene. The reports about the C282Y and H63D mutations and hepatocellular carninoma (HCC were controversial. To clarify the relationship between C282Y and H63D mutations and HCC, a meta-analysis including nine studies (1102 HCC cases and 3766 controls, mainly came from European populations was performed. Methods The association was measured using random-effect (RE or fixed-effect (FE odds ratios (ORs combined with 95% confidence intervals (CIs according to the studies' heterogeneity. Results Meta-analysis of nine studies showed that Y allele of C282Y was associated with HCC risk: RE OR reached 1.50 (95%CI: 1.05-2.14, p for heterogeneity = 0.02, I2 = 0.57. Subgroup analysis of seven studies also showed Y allele was associated with HCC risk in healthy populations: RE OR reached 1.61 (95%CI: 1.08-2.39, p for heterogeneity = 0.04, I2 = 0.55. We further did subgroup analysis in alcoholic liver cirrhosis (LC patients of four studies (224 cases and 380 controls and found that both the dominant model and Y allele of C282Y were associated with HCC risk (FE OR reached 4.06, 95%CI: 2.08-7.92 and 3.41, 95%CI: 1.81-6.41, respectively. There was no distinct heterogeneity among the studies (I2 = 0. Sensitivity analyses showed the results were robust in the subgroup analysis of alcoholic LC patients. Conclusions C282Y mutation was associated with HCC in European alcoholic LC patients.

  6. Tumor heterogeneity and progression: conceptual foundations for modeling.

    Science.gov (United States)

    Greller, L D; Tobin, F L; Poste, G

    1996-01-01

    A conceptual foundation for modeling tumor progression, growth, and heterogeneity is presented. The purpose of such models is to aid understanding, test ideas, formulate experiments, and to model cancer 'in machina' to address the dynamic features of tumor cell heterogeneity, progression, and growth. The descriptive capabilities of such an approach provides a consistent language for qualitatively reasoning about tumor behavior. This approach provides a schema for building conceptual models that combine three key phenomenological driving elements: growth, progression, and genetic instability. The growth element encompasses processes contributing to changes in tumor bulk and is distinct from progression per se. The progression element subsumes a broad collection of processes underlying phenotypic progression. The genetics elements represents heritable changes which potentially affect tumor character and behavior. Models, conceptual and mathematical, can be built for different tumor situations by drawing upon the interaction of these three distinct driving elements. These models can be used as tools to explore a diversity of hypotheses concerning dynamic changes in cellular populations during tumor progression, including the generation of intratumor heterogeneity. Such models can also serve to guide experimentation and to gain insight into dynamic aspects of complex tumor behavior.

  7. Correlation between LDH levels and response to sorafenib in HCC patients: an analysis of the ITA.LI.CA database.

    Science.gov (United States)

    Sacco, Rodolfo; Mismas, Valeria; Granito, Alessandro; Musettini, Gianna; Masi, Gianluca; Caparello, Chiara; Vivaldi, Caterina; Felder, Martina; Bresci, Giampaolo; Fornaro, Lorenzo

    2015-02-24

    Lactate dehydrogenase (LDH) is a predictor of clinical outcome in hepatocellular carcinoma (HCC) patients. However, its predictive role in the clinical outcomes of sorafenib treatment has been poorly documented. The correlation between LDH levels and clinical outcomes in HCC patients treated with sorafenib and included in the nationwide Italian database ITA.LI.CA was investigated here. The ITA.LI.CA database contains data for 5,136 HCC patients. All patients treated with sorafenib treatment and with available LDH values were considered. Overall survival (OS) and time to progression (TTP) were compared in patients with LDH levels above and below a defined threshold, determined through an ROC analysis. An explorative analysis investigated the relationship between the variation of LDH levels during treatment and response to sorafenib. Baseline LDH levels were available for 97 patients. The most accurate cutoff value for LDH concentration was 297 U/L. Patients with LDH values above (n=45) and below (n=52) this threshold showed equal OS (12.0 months) and TTP (4.0 months) values. Data on LDH levels during sorafenib treatment were reported for 10 patients. LDH values decreased in 3 patients (mean difference = -219 U/L) who also reported a prolonged OS and TTP versus those with unmodified/increased LDH (OS: NE (not evaluated) vs. 8.0 months, p=0.0083; TTP: 19.0 vs. 3.0 months, p=0.008). The clinical benefits of sorafenib do not seem to be influenced by baseline LDH. According to the results of an explorative analysis, however, a decreased LDH concentration during sorafenib might be associated with improved clinical outcomes.

  8. Cone-Beam Computed Tomography Correlates with Conventional Helical Computed Tomography in Evaluation of Lipiodol Accumulation in HCC after Chemoembolization.

    Directory of Open Access Journals (Sweden)

    Toru Ishikawa

    Full Text Available The amount of drug-loaded lipiodol in an HCC tumor post-transarterial chemoembolization (TACE correlates with the risk of local tumor recurrence. Lipiodol enhancement of a tumor on conventional CT, measured in Hounsfield units (HU, can predict tumor response. Here we investigate whether cone-beam CT (CBCT can also be used to predict tumor response, providing the benefit of being able to optimize the patient's treatment plan intra-procedurally.A total of 82 HCC nodules (82 patients, ≤5 cm in diameter, were treated with balloon-occluded TACE using miriplatin between December 2013 and November 2014. For each patient, both CBCT and conventional CT images were obtained post-TACE. The degree of correlation between CBCT and conventional CT was determined by comparing identical regions of interest for each imaging modality using pixel values.The pixel values from conventional CT and CBCT were highly correlated, with a Pearson correlation coefficient of 0.912 (p<0.001. The location of the nodules within the liver did not affect the results; the correlation coefficient was 0.891 (p<0.001 for the left lobe and 0.926 (p<0.001 for the right lobe. The mean pixel value for conventional CT was 439 ± 279 HU, and the mean pixel value for CBCT was 416 ± 311 HU.CBCT may be used as a substitute for conventional CT to quantitatively evaluate the amount of drug-loaded lipiodol within an HCC nodule and, hence, the efficacy of TACE treatment. The major benefit of using CBCT is the ability to predict the likelihood of local recurrence intra-procedurally, enabling subsequent treatment optimization.

  9. Inference of Cell Mechanics in Heterogeneous Epithelial Tissue Based on Multivariate Clone Shape Quantification

    Science.gov (United States)

    Tsuboi, Alice; Umetsu, Daiki; Kuranaga, Erina; Fujimoto, Koichi

    2017-01-01

    Cell populations in multicellular organisms show genetic and non-genetic heterogeneity, even in undifferentiated tissues of multipotent cells during development and tumorigenesis. The heterogeneity causes difference of mechanical properties, such as, cell bond tension or adhesion, at the cell–cell interface, which determine the shape of clonal population boundaries via cell sorting or mixing. The boundary shape could alter the degree of cell–cell contacts and thus influence the physiological consequences of sorting or mixing at the boundary (e.g., tumor suppression or progression), suggesting that the cell mechanics could help clarify the physiology of heterogeneous tissues. While precise inference of mechanical tension loaded at each cell–cell contacts has been extensively developed, there has been little progress on how to distinguish the population-boundary geometry and identify the cause of geometry in heterogeneous tissues. We developed a pipeline by combining multivariate analysis of clone shape with tissue mechanical simulations. We examined clones with four different genotypes within Drosophila wing imaginal discs: wild-type, tartan (trn) overexpression, hibris (hbs) overexpression, and Eph RNAi. Although the clones were previously known to exhibit smoothed or convoluted morphologies, their mechanical properties were unknown. By applying a multivariate analysis to multiple criteria used to quantify the clone shapes based on individual cell shapes, we found the optimal criteria to distinguish not only among the four genotypes, but also non-genetic heterogeneity from genetic one. The efficient segregation of clone shape enabled us to quantitatively compare experimental data with tissue mechanical simulations. As a result, we identified the mechanical basis contributed to clone shape of distinct genotypes. The present pipeline will promote the understanding of the functions of mechanical interactions in heterogeneous tissue in a non-invasive manner. PMID

  10. A Retrospective Study on Genetic Heterogeneity within Treponema Strains: Subpopulations Are Genetically Distinct in a Limited Number of Positions.

    Directory of Open Access Journals (Sweden)

    Darina Čejková

    Full Text Available Pathogenic uncultivable treponemes comprise human and animal pathogens including agents of syphilis, yaws, bejel, pinta, and venereal spirochetosis in rabbits and hares. A set of 10 treponemal genome sequences including those of 4 Treponema pallidum ssp. pallidum (TPA strains (Nichols, DAL-1, Mexico A, SS14, 4 T. p. ssp. pertenue (TPE strains (CDC-2, Gauthier, Samoa D, Fribourg-Blanc, 1 T. p. ssp. endemicum (TEN strain (Bosnia A and one strain (Cuniculi A of Treponema paraluisleporidarum ecovar Cuniculus (TPLC were examined with respect to the presence of nucleotide intrastrain heterogeneous sites.The number of identified intrastrain heterogeneous sites in individual genomes ranged between 0 and 7. Altogether, 23 intrastrain heterogeneous sites (in 17 genes were found in 5 out of 10 investigated treponemal genomes including TPA strains Nichols (n = 5, DAL-1 (n = 4, and SS14 (n = 7, TPE strain Samoa D (n = 1, and TEN strain Bosnia A (n = 5. Although only one heterogeneous site was identified among 4 tested TPE strains, 16 such sites were identified among 4 TPA strains. Heterogeneous sites were mostly strain-specific and were identified in four tpr genes (tprC, GI, I, K, in genes involved in bacterial motility and chemotaxis (fliI, cheC-fliY, in genes involved in cell structure (murC, translation (prfA, general and DNA metabolism (putative SAM dependent methyltransferase, topA, and in seven hypothetical genes.Heterogeneous sites likely represent both the selection of adaptive changes during infection of the host as well as an ongoing diversifying evolutionary process.

  11. A Retrospective Study on Genetic Heterogeneity within Treponema Strains: Subpopulations Are Genetically Distinct in a Limited Number of Positions.

    Science.gov (United States)

    Čejková, Darina; Strouhal, Michal; Norris, Steven J; Weinstock, George M; Šmajs, David

    2015-01-01

    Pathogenic uncultivable treponemes comprise human and animal pathogens including agents of syphilis, yaws, bejel, pinta, and venereal spirochetosis in rabbits and hares. A set of 10 treponemal genome sequences including those of 4 Treponema pallidum ssp. pallidum (TPA) strains (Nichols, DAL-1, Mexico A, SS14), 4 T. p. ssp. pertenue (TPE) strains (CDC-2, Gauthier, Samoa D, Fribourg-Blanc), 1 T. p. ssp. endemicum (TEN) strain (Bosnia A) and one strain (Cuniculi A) of Treponema paraluisleporidarum ecovar Cuniculus (TPLC) were examined with respect to the presence of nucleotide intrastrain heterogeneous sites. The number of identified intrastrain heterogeneous sites in individual genomes ranged between 0 and 7. Altogether, 23 intrastrain heterogeneous sites (in 17 genes) were found in 5 out of 10 investigated treponemal genomes including TPA strains Nichols (n = 5), DAL-1 (n = 4), and SS14 (n = 7), TPE strain Samoa D (n = 1), and TEN strain Bosnia A (n = 5). Although only one heterogeneous site was identified among 4 tested TPE strains, 16 such sites were identified among 4 TPA strains. Heterogeneous sites were mostly strain-specific and were identified in four tpr genes (tprC, GI, I, K), in genes involved in bacterial motility and chemotaxis (fliI, cheC-fliY), in genes involved in cell structure (murC), translation (prfA), general and DNA metabolism (putative SAM dependent methyltransferase, topA), and in seven hypothetical genes. Heterogeneous sites likely represent both the selection of adaptive changes during infection of the host as well as an ongoing diversifying evolutionary process.

  12. Analysis of heterogeneity and epistasis in physiological mixed populations by combined structural equation modelling and latent class analysis

    DEFF Research Database (Denmark)

    Fenger, Mogens; Linneberg, A.; Werge, Thomas Mears

    2008-01-01

    and genetic variations of such networks. METHODS: In this study on type 2 diabetes mellitus, heterogeneity was resolved in a latent class framework combined with structural equation modelling using phenotypic indicators of distinct physiological processes. We modelled the clinical condition "the metabolic......BACKGROUND: Biological systems are interacting, molecular networks in which genetic variation contributes to phenotypic heterogeneity. This heterogeneity is traditionally modelled as a dichotomous trait (e.g. affected vs. non-affected). This is far too simplistic considering the complexity...

  13. Comparison of detection pattern of HCC by ferumoxide-enhanced MRI and intratumoral blood flow pattern

    International Nuclear Information System (INIS)

    Itou, Naoki; Kotake, Fumio; Saitou, Kazuhiro; Abe, Kimihiko

    2000-01-01

    We compared the detection rate and pattern of ferumoxide-enhanced magnetic resonance imaging (Fe-MRI) with the intratumoral blood flow pattern determined by CT angiography (CTA) and CT portography (CTAP) in 124 nodes (34 cases) diagnosed as hepatocellular carcinoma (HCC) or borderline HCC, based on the clinical course. Sequences to obtain a T1-weighted images (T1W), proton density-weighted images (PDW), T2-weighted images (T2W), T2*-weighted images (T2*W) were used in Fe-MRI. In nodes shown to be hypervascular on CTA, the detection rate by Fe-MRI was 69.7%. In nodes shown to be avascular by CTAP, the detection rate by Fe-MRI was 67.3%. These rates were higher than with other flow patterns. In nodes showing high signal intensity (HSI) on any sequences, arterial blood flow was increased and portal blood flow decreased in comparison with nodes without high signal intensity. All nodes showing HSI, both on Fe-MRI T2W and T2*W, were hypervascular on CTA, and portal blood flow was absent on CTAP. Nodes showing HSI on both T2*W and T2W were considered to have greater arterial blood flow and decreased portal blood flow compared with nodes appearing as HSI on T2*W, but only as iso- or low signal intensity on T2W (Mann-Whitney U-test; p<0.05). (author)

  14. Origins and implications of pluripotent stem cell variability and heterogeneity

    Science.gov (United States)

    Cahan, Patrick; Daley, George Q.

    2014-01-01

    Pluripotent stem cells constitute a platform to model disease and developmental processes and can potentially be used in regenerative medicine. However, not all pluripotent cell lines are equal in their capacity to differentiate into desired cell types in vitro. Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within clones. These genetic and epigenetic variations could ‘lock’ the pluripotency network resulting in residual pluripotent cells or alter the signalling response of developmental pathways leading to lineage bias. The molecular contributors to functional variability and heterogeneity in both embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are only beginning to emerge, yet they are crucial to the future of the stem cell field. PMID:23673969

  15. Genetic variants in the exon region of versican predict survival of patients with resected early-stage hepatitis B virus-associated hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Liu X

    2018-05-01

    Full Text Available Xiaoguang Liu,* Chuangye Han,* Xiwen Liao, Long Yu, Guangzhi Zhu, Hao Su, Wei Qin, Sicong Lu, Xinping Ye, Tao Peng Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China *These authors contributed equally to this work Background: The upregulated expression of versican (VCAN promotes the proliferation, invasion, and metastasis of various types of human cancer cells, including hepatocellular carcinoma (HCC cells. Patients and methods: In this study, genetic variants in the exon region of VCAN were genotyped by DNA sequencing. Prognostic values of VCAN exon single nucleotide polymorphisms (SNPs were assessed by Kaplan–Meier with the log-rank test, and uni- and multivariate Cox proportional hazard regression model. Results: A total of 111 patients with resected hepatitis B virus-associated early-stage HCC were collected for genotyping VCAN exon SNPs using Sanger DNA sequencing. Haplotype analysis was performed using Haploview 4.2. Survival data were analyzed using Kaplan–Meier curves and Cox proportional hazards regression analyses. The rs2652098, rs309559, rs188703, rs160278, and rs160277 SNPs were significantly associated with overall patient survival (p<0.001, p=0.012, p=0.010, p=0.007, and p=0.007, respectively. Patients carrying the TAGTG haplotype had a poorer prognosis than those with the most common CGAAT haplotype, after adjusting for tumor size, tumor capsule, and regional invasion (adjusted hazard ratio [HR] =2.06, 95% CI: 1.27–3.34, p=0.003. Meanwhile, patients with the TAGTG haplotype and a larger tumor size or an incomplete tumor capsule had an increased risk of death, compared with the others (adjusted HR =3.00, 95% CI: 1.67–5.36, p<0.001; and adjusted HR = 1.99, 95% CI = 1.12–3.55, p = 0.02, respectively. The online database mining analysis showed that upregulated VCAN expression in HCC tissues was associated with a poor overall

  16. Utility of computer simulations in landscape genetics

    Science.gov (United States)

    Bryan K. Epperson; Brad H. McRae; Kim Scribner; Samuel A. Cushman; Michael S. Rosenberg; Marie-Josee Fortin; Patrick M. A. James; Melanie Murphy; Stephanie Manel; Pierre Legendre; Mark R. T. Dale

    2010-01-01

    Population genetics theory is primarily based on mathematical models in which spatial complexity and temporal variability are largely ignored. In contrast, the field of landscape genetics expressly focuses on how population genetic processes are affected by complex spatial and temporal environmental heterogeneity. It is spatially explicit and relates patterns to...

  17. Exploring Task Mappings on Heterogeneous MPSoCs using a Bias-Elitist Genetic Algorithm

    NARCIS (Netherlands)

    Quan, W.; Pimentel, A.D.

    2014-01-01

    Exploration of task mappings plays a crucial role in achieving high performance in heterogeneous multi-processor system-on-chip (MPSoC) platforms. The problem of optimally mapping a set of tasks onto a set of given heterogeneous processors for maximal throughput has been known, in general, to be

  18. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Chaisaingmongkol, Jittiporn; Budhu, Anuradha; Dang, Hien

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integratio...

  19. Genetic heterogeneity in Usher syndrome.

    Science.gov (United States)

    Keats, Bronya J B; Savas, Sevtap

    2004-09-15

    Mutations in seven different genes have been associated with Usher syndrome, and an additional four loci have been mapped. The identified genes encode myosin VIIa, harmonin (a PDZ-domain protein), cadherin 23, protocadherin 15, sans (a scaffold-like protein), usherin and clarin. Three clinical types of Usher syndrome have been described: USH1 patients have severe to profound congenital hearing loss, vestibular dysfunction, and retinal degeneration beginning in childhood, those with USH2 have moderate to severe congenital hearing loss, normal vestibular function, and later onset of retinitis pigmentosa, and USH3 patients have progressive hearing loss, which distinguishes them from the other two types. The shaker-1, waltzer, Ames waltzer, and Jackson shaker mice provide murine models for four of the genetic forms of Usher syndrome. Ongoing studies are enabling early diagnosis of Usher syndrome in children who present with hearing loss, thus providing time to prepare for the onset of visual loss. Copyright 2004 Wiley-Liss, Inc.

  20. N-glycosylation by N-acetylglucosaminyltransferase V enhances the interaction of CD147/basigin with integrin β1 and promotes HCC metastasis.

    Science.gov (United States)

    Cui, Jian; Huang, Wan; Wu, Bo; Jin, Jin; Jing, Lin; Shi, Wen-Pu; Liu, Zhen-Yu; Yuan, Lin; Luo, Dan; Li, Ling; Chen, Zhi-Nan; Jiang, Jian-Li

    2018-05-01

    While the importance of protein N-glycosylation in cancer cell migration is well appreciated, the precise mechanisms by which N-acetylglucosaminyltransferase V (GnT-V) regulates cancer processes remain largely unknown. In the current study, we report that GnT-V-mediated N-glycosylation of CD147/basigin, a tumor-associated glycoprotein that carries β1,6-N-acetylglucosamine (β1,6-GlcNAc) glycans, is upregulated during TGF-β1-induced epithelial-to-mesenchymal transition (EMT), which correlates with tumor metastasis in patients with hepatocellular carcinoma (HCC). Interruption of β1,6-GlcNAc glycan modification of CD147/basigin decreased matrix metalloproteinase (MMP) expression in HCC cell lines and affected the interaction of CD147/basigin with integrin β1. These results reveal that β1,6-branched glycans modulate the biological function of CD147/basigin in HCC metastasis. Moreover, we showed that the PI3K/Akt pathway regulates GnT-V expression and that inhibition of GnT-V-mediated N-glycosylation suppressed PI3K signaling. In summary, β1,6-branched N-glycosylation affects the biological function of CD147/basigin and these findings provide a novel approach for the development of therapeutic strategies targeting metastasis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

  1. Identification of resistance mechanisms in erlotinib-resistant subclones of the non-small cell lung cancer cell line HCC827 by exome sequencing

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine; Alcaraz, Nicolas; Lund, Rikke Raaen

    the SeqCap EZ Human Exome Library v3.0 kit and whole-exome sequencing of these (100 bp paired-end) were performed on an Illumina HiSeq 2000 platform. Using a recently developed in-house analysis pipeline the sequencing data were analyzed. The analysis pipeline includes quality control using Trim......Background: Erlotinib (Tarceva®, Roche) has significantly changed the treatment of non-small cell lung cancer (NSCLC) as 70% of patients show significant tumor regression upon treatment (Santarpia et. al., 2013). However, all patients relapse due to development of acquired resistance, which...... mutations in erlotinib-resistant subclones of the NSCLC cell line, HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20, 30 µM erlotinib, respectively). DNA libraries of each subclone and the parental HCC827 cell line were prepared in biological duplicates using...

  2. Genetic Heterogeneity of Benign Thyroid Lesions

    Directory of Open Access Journals (Sweden)

    O. Ferrer-Roca

    1998-01-01

    Full Text Available The present series includes 75 thyroid lesions (38 goiters, 30 adenomas, 3 follicullo‐papillary encapsulated carcinomas and 4 normal thyroid that were studied by static and flow cytometry. Four cases were also analyzed by in situ hybridization (centromeric probes for chromosomes 1 and 17 and 10 cases by G‐banding cytogenetics. Results demonstrate a polymorphysm and genetic instability in the thyroid tissue that may be related to the spontaneous polyploidization of their cells. The most consistent finding in cytometry was the presence of two clones associated with clinical or histological hyperactivity (46% versus 23% in non‐functioning cases; X2 distribution with a p < 0.05.

  3. The prune belly anomaly: heterogeneity and superficial X-linkage mimicry.

    Science.gov (United States)

    Riccardi, V M; Grum, C M

    1977-01-01

    The genetic, clinical, and necropsy findings of 2 brothers with the prune belly anomaly are presented and the literature reviewed. The combined data emphasise the clinical and genetic heterogeneity of the disorder and show that in at least some instances a heritable component may be the primary insult. The most likely heritable explanation involves a two-step autosomal dominant mutation with sex-limited expression that partially mimics X-linkage. PMID:144797

  4. Origins and implications of pluripotent stem cell variability and heterogeneity

    OpenAIRE

    Cahan, Patrick; Daley, George Q.

    2013-01-01

    Pluripotent stem cells constitute a platform to model disease and developmental processes and can potentially be used in regenerative medicine. However, not all pluripotent cell lines are equal in their capacity to differentiate into desired cell types in vitro. Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within clones. These genetic and epigenetic variations could ‘lock’ the pluripotency network resulting in residual pluripotent...

  5. Expansion Under Climate Change: The Genetic Consequences.

    Science.gov (United States)

    Garnier, Jimmy; Lewis, Mark A

    2016-11-01

    Range expansion and range shifts are crucial population responses to climate change. Genetic consequences are not well understood but are clearly coupled to ecological dynamics that, in turn, are driven by shifting climate conditions. We model a population with a deterministic reaction-diffusion model coupled to a heterogeneous environment that develops in time due to climate change. We decompose the resulting travelling wave solution into neutral genetic components to analyse the spatio-temporal dynamics of its genetic structure. Our analysis shows that range expansions and range shifts under slow climate change preserve genetic diversity. This is because slow climate change creates range boundaries that promote spatial mixing of genetic components. Mathematically, the mixing leads to so-called pushed travelling wave solutions. This mixing phenomenon is not seen in spatially homogeneous environments, where range expansion reduces genetic diversity through gene surfing arising from pulled travelling wave solutions. However, the preservation of diversity is diminished when climate change occurs too quickly. Using diversity indices, we show that fast expansions and range shifts erode genetic diversity more than slow range expansions and range shifts. Our study provides analytical insight into the dynamics of travelling wave solutions in heterogeneous environments.

  6. Deconstructing transcriptional heterogeneity in pluripotent stem cells

    Science.gov (United States)

    Shalek, Alex K.; Satija, Rahul; DaleyKeyser, AJay; Li, Hu; Zhang, Jin; Pardee, Keith; Gennert, David; Trombetta, John J.; Ferrante, Thomas C.; Regev, Aviv; Daley, George Q.; Collins, James J.

    2014-01-01

    SUMMARY Pluripotent stem cells (PSCs) are capable of dynamic interconversion between distinct substates, but the regulatory circuits specifying these states and enabling transitions between them are not well understood. We set out to characterize transcriptional heterogeneity in PSCs by single-cell expression profiling under different chemical and genetic perturbations. Signaling factors and developmental regulators show highly variable expression, with expression states for some variable genes heritable through multiple cell divisions. Expression variability and population heterogeneity can be influenced by perturbation of signaling pathways and chromatin regulators. Strikingly, either removal of mature miRNAs or pharmacologic blockage of signaling pathways drives PSCs into a low-noise ground state characterized by a reconfigured pluripotency network, enhanced self-renewal, and a distinct chromatin state, an effect mediated by opposing miRNA families acting on the c-myc / Lin28 / let-7 axis. These data illuminate the nature of transcriptional heterogeneity in PSCs. PMID:25471879

  7. Unravelling tumour heterogeneity using next-generation imaging: radiomics, radiogenomics, and habitat imaging.

    Science.gov (United States)

    Sala, E; Mema, E; Himoto, Y; Veeraraghavan, H; Brenton, J D; Snyder, A; Weigelt, B; Vargas, H A

    2017-01-01

    Tumour heterogeneity in cancers has been observed at the histological and genetic levels, and increased levels of intra-tumour genetic heterogeneity have been reported to be associated with adverse clinical outcomes. This review provides an overview of radiomics, radiogenomics, and habitat imaging, and examines the use of these newly emergent fields in assessing tumour heterogeneity and its implications. It reviews the potential value of radiomics and radiogenomics in assisting in the diagnosis of cancer disease and determining cancer aggressiveness. This review discusses how radiogenomic analysis can be further used to guide treatment therapy for individual tumours by predicting drug response and potential therapy resistance and examines its role in developing radiomics as biomarkers of oncological outcomes. Lastly, it provides an overview of the obstacles in these emergent fields today including reproducibility, need for validation, imaging analysis standardisation, data sharing and clinical translatability and offers potential solutions to these challenges towards the realisation of precision oncology. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  8. Oligonodular hepatocellular carcinoma (HCC): MR-guided laser-induced thermotherapy (LITT)

    International Nuclear Information System (INIS)

    Eichler, K.; Mack, M.G.; Straub, R.; Engelmann, K.; Zangos, S.; Woitaschek, D.; Vogl, T.J.

    2001-01-01

    Purpose. To prospectively evaluate the therapeutic potential of MR-guided laser-induced thermotherapy (LITT) in patients with oligonodular hepatocellular carcinoma. Material and methods. 39 patients with 61 intrahepatic lesions were treated with LITT. The Nd:YAG laser fiber was introduced with a percutaneously positioned irrigated laser application system. Qualitative and quantitative MR parameters and clinical data were evaluated. Results. All patients tolerated the procedure well under local anesthesia. All observed complications were minor and no further treatment was necessary. Online MR thermometry allowed exact visualization. Lesions p to 2 cm in diameter could be efficiently treated with a single laser application, larger lesions were treated simultaneous multiapplication. In 97.5% we achieved a complete necrosis of the tumor and a 5 mm safety margin, resulting in a complete destruction of the tumor without local recurrences. Mean survival was 4.4 years (95% Cl: 3.6-5.2 years) after the time of diagnoses of the HCC (Kaplan-Meier-method). Conclusion. In intrahepatic oligonodular involvement of hepatocellular carcinoma LITT appears to be an effective therapeutic procedure with a high tumor contol rate and better survival data. (orig.) [de

  9. Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge.

    Science.gov (United States)

    Lynch, Henry T; Lanspa, Stephen; Shaw, Trudy; Casey, Murray Joseph; Rendell, Marc; Stacey, Mark; Townley, Theresa; Snyder, Carrie; Hitchins, Megan; Bailey-Wilson, Joan

    2018-07-01

    Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy.

  10. Genetic subclone architecture of tumor clone-initiating cells in colorectal cancer.

    Science.gov (United States)

    Giessler, Klara M; Kleinheinz, Kortine; Huebschmann, Daniel; Balasubramanian, Gnana Prakash; Dubash, Taronish D; Dieter, Sebastian M; Siegl, Christine; Herbst, Friederike; Weber, Sarah; Hoffmann, Christopher M; Fronza, Raffaele; Buchhalter, Ivo; Paramasivam, Nagarajan; Eils, Roland; Schmidt, Manfred; von Kalle, Christof; Schneider, Martin; Ulrich, Alexis; Scholl, Claudia; Fröhling, Stefan; Weichert, Wilko; Brors, Benedikt; Schlesner, Matthias; Ball, Claudia R; Glimm, Hanno

    2017-07-03

    A hierarchically organized cell compartment drives colorectal cancer (CRC) progression. Genetic barcoding allows monitoring of the clonal output of tumorigenic cells without prospective isolation. In this study, we asked whether tumor clone-initiating cells (TcICs) were genetically heterogeneous and whether differences in self-renewal and activation reflected differential kinetics among individual subclones or functional hierarchies within subclones. Monitoring genomic subclone kinetics in three patient tumors and corresponding serial xenografts and spheroids by high-coverage whole-genome sequencing, clustering of genetic aberrations, subclone combinatorics, and mutational signature analysis revealed at least two to four genetic subclones per sample. Long-term growth in serial xenografts and spheroids was driven by multiple genomic subclones with profoundly differing growth dynamics and hence different quantitative contributions over time. Strikingly, genetic barcoding demonstrated stable functional heterogeneity of CRC TcICs during serial xenografting despite near-complete changes in genomic subclone contribution. This demonstrates that functional heterogeneity is, at least frequently, present within genomic subclones and independent of mutational subclone differences. © 2017 Giessler et al.

  11. Emerging understanding of multiscale tumor heterogeneity

    Directory of Open Access Journals (Sweden)

    Michael J Gerdes

    2014-12-01

    Full Text Available Cancer is a multifaceted disease characterized by heterogeneous genetic alterations and cellular metabolism, at the organ, tissue, and cellular level. Key features of cancer heterogeneity are summarized by ten acquired capabilities, which govern malignant transformation and progression of invasive tumors. The relative contribution of these hallmark features to the disease process varies between cancers. At the DNA and cellular level, germ-line and somatic gene mutations are found across all cancer types, causing abnormal protein production, cell behavior, and growth. The tumor microenvironment and its individual components (immune cells, fibroblasts, collagen, and blood vessels can also facilitate or restrict tumor growth and metastasis. Oncology research is currently in the midst of a tremendous surge of comprehension of these disease mechanisms. This will lead not only to novel drug targets, but also to new challenges in drug discovery. Integrated, multi-omic, multiplexed technologies are essential tools in the quest to understand all of the various cellular changes involved in tumorigenesis. This review examines features of cancer heterogeneity and discusses how multiplexed technologies can facilitate a more comprehensive understanding of these features.

  12. Hair Cortisol in Twins

    DEFF Research Database (Denmark)

    Rietschel, Liz; Streit, Fabian; Zhu, Gu

    2017-01-01

    Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors...

  13. Allelic heterogeneity and genetic modifier loci contribute to clinical variation in males with X-linked retinitis pigmentosa due to RPGR mutations.

    Directory of Open Access Journals (Sweden)

    Abigail T Fahim

    Full Text Available Mutations in RPGR account for over 70% of X-linked retinitis pigmentosa (XlRP, characterized by retinal degeneration and eventual blindness. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of clinical severity, and female carriers may or may not be affected. This study describes the phenotypic diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and demonstrates the contribution of genetic factors (i.e., allelic heterogeneity and genetic modifiers to this diversity. Patients were categorized as grade 1 (mild, 2 (moderate or 3 (severe according to specific clinical criteria. Patient DNAs were genotyped for coding SNPs in 4 candidate modifier genes with products known to interact with RPGR protein: RPGRIP1, RPGRIP1L, CEP290, and IQCB1. Family-based association testing was performed using PLINK. A wide range of clinical severity was observed both between and within families. Patients with mutations in exons 1-14 were more severely affected than those with ORF15 mutations, and patients with predicted null alleles were more severely affected than those predicted to make RPGR protein. Two SNPs showed association with severe disease: the minor allele (N of I393N in IQCB1 (p = 0.044 and the common allele (R of R744Q in RPGRIP1L (p = 0.049. These data demonstrate that allelic heterogeneity contributes to phenotypic diversity in XlRP and suggest that this may depend on the presence or absence of RPGR protein. In addition, common variants in 2 proteins known to interact with RPGR are associated with severe disease in this cohort.

  14. Spatial phenotypic and genetic structure of threespine stickleback (Gasterosteus aculeatus) in a heterogeneous natural system, Lake Mývatn, Iceland.

    Science.gov (United States)

    Millet, Antoine; Kristjánsson, Bjarni K; Einarsson, Arni; Räsänen, Katja

    2013-09-01

    Eco-evolutionary responses of natural populations to spatial environmental variation strongly depend on the relative strength of environmental differences/natural selection and dispersal/gene flow. In absence of geographic barriers, as often is the case in lake ecosystems, gene flow is expected to constrain adaptive divergence between environments - favoring phenotypic plasticity or high trait variability. However, if divergent natural selection is sufficiently strong, adaptive divergence can occur in face of gene flow. The extent of divergence is most often studied between two contrasting environments, whereas potential for multimodal divergence is little explored. We investigated phenotypic (body size, defensive structures, and feeding morphology) and genetic (microsatellites) structure in threespine stickleback (Gasterosteus aculeatus) across five habitat types and two basins (North and South) within the geologically young and highly heterogeneous Lake Mývatn, North East Iceland. We found that (1) North basin stickleback were, on average, larger and had relatively longer spines than South basin stickleback, whereas (2) feeding morphology (gill raker number and gill raker gap width) differed among three of five habitat types, and (3) there was only subtle genetic differentiation across the lake. Overall, our results indicate predator and prey mediated phenotypic divergence across multiple habitats in the lake, in face of gene flow.

  15. Monte-Carlo model development for evaluation of current clinical target volume definition for heterogeneous and hypoxic glioblastoma.

    Science.gov (United States)

    Moghaddasi, L; Bezak, E; Harriss-Phillips, W

    2016-05-07

    Clinical target volume (CTV) determination may be complex and subjective. In this work a microscopic-scale tumour model was developed to evaluate current CTV practices in glioblastoma multiforme (GBM) external radiotherapy. Previously, a Geant4 cell-based dosimetry model was developed to calculate the dose deposited in individual GBM cells. Microscopic extension probability (MEP) models were then developed using Matlab-2012a. The results of the cell-based dosimetry model and MEP models were combined to calculate survival fractions (SF) for CTV margins of 2.0 and 2.5 cm. In the current work, oxygenation and heterogeneous radiosensitivity profiles were incorporated into the GBM model. The genetic heterogeneity was modelled using a range of α/β values (linear-quadratic model parameters) associated with different GBM cell lines. These values were distributed among the cells randomly, taken from a Gaussian-weighted sample of α/β values. Cellular oxygen pressure was distributed randomly taken from a sample weighted to profiles obtained from literature. Three types of GBM models were analysed: homogeneous-normoxic, heterogeneous-normoxic, and heterogeneous-hypoxic. The SF in different regions of the tumour model and the effect of the CTV margin extension from 2.0-2.5 cm on SFs were investigated for three MEP models. The SF within the beam was increased by up to three and two orders of magnitude following incorporation of heterogeneous radiosensitivities and hypoxia, respectively, in the GBM model. However, the total SF was shown to be overdominated by the presence of tumour cells in the penumbra region and to a lesser extent by genetic heterogeneity and hypoxia. CTV extension by 0.5 cm reduced the SF by a maximum of 78.6  ±  3.3%, 78.5  ±  3.3%, and 77.7  ±  3.1% for homogeneous and heterogeneous-normoxic, and heterogeneous hypoxic GBMs, respectively. Monte-Carlo model was developed to quantitatively evaluate SF for genetically

  16. Heterogeneity in genetic admixture across different regions of Argentina.

    Directory of Open Access Journals (Sweden)

    Sergio Avena

    Full Text Available The population of Argentina is the result of the intermixing between several groups, including Indigenous American, European and African populations. Despite the commonly held idea that the population of Argentina is of mostly European origin, multiple studies have shown that this process of admixture had an impact in the entire Argentine population. In the present study we characterized the distribution of Indigenous American, European and African ancestry among individuals from different regions of Argentina and evaluated the level of discrepancy between self-reported grandparental origin and genetic ancestry estimates. A set of 99 autosomal ancestry informative markers (AIMs was genotyped in a sample of 441 Argentine individuals to estimate genetic ancestry. We used non-parametric tests to evaluate statistical significance. The average ancestry for the Argentine sample overall was 65% European (95%CI: 63-68%, 31% Indigenous American (28-33% and 4% African (3-4%. We observed statistically significant differences in European ancestry across Argentine regions [Buenos Aires province (BA 76%, 95%CI: 73-79%; Northeast (NEA 54%, 95%CI: 49-58%; Northwest (NWA 33%, 95%CI: 21-41%; South 54%, 95%CI: 49-59%; p<0.0001] as well as between the capital and immediate suburbs of Buenos Aires city compared to more distant suburbs [80% (95%CI: 75-86% versus 68% (95%CI: 58-77%, p = 0.01]. European ancestry among individuals that declared all grandparents born in Europe was 91% (95%CI: 88-94% compared to 54% (95%CI: 51-57% among those with no European grandparents (p<0.001. Our results demonstrate the range of variation in genetic ancestry among Argentine individuals from different regions in the country, highlighting the importance of taking this variation into account in genetic association and admixture mapping studies in this population.

  17. Heterogeneity in Genetic Admixture across Different Regions of Argentina

    Science.gov (United States)

    Avena, Sergio; Via, Marc; Ziv, Elad; Pérez-Stable, Eliseo J.; Gignoux, Christopher R.; Dejean, Cristina; Huntsman, Scott; Torres-Mejía, Gabriela; Dutil, Julie; Matta, Jaime L.; Beckman, Kenneth; Burchard, Esteban González; Parolin, María Laura; Goicoechea, Alicia; Acreche, Noemí; Boquet, Mariel; Ríos Part, María Del Carmen; Fernández, Vanesa; Rey, Jorge; Stern, Mariana C.; Carnese, Raúl F.; Fejerman, Laura

    2012-01-01

    The population of Argentina is the result of the intermixing between several groups, including Indigenous American, European and African populations. Despite the commonly held idea that the population of Argentina is of mostly European origin, multiple studies have shown that this process of admixture had an impact in the entire Argentine population. In the present study we characterized the distribution of Indigenous American, European and African ancestry among individuals from different regions of Argentina and evaluated the level of discrepancy between self-reported grandparental origin and genetic ancestry estimates. A set of 99 autosomal ancestry informative markers (AIMs) was genotyped in a sample of 441 Argentine individuals to estimate genetic ancestry. We used non-parametric tests to evaluate statistical significance. The average ancestry for the Argentine sample overall was 65% European (95%CI: 63–68%), 31% Indigenous American (28–33%) and 4% African (3–4%). We observed statistically significant differences in European ancestry across Argentine regions [Buenos Aires province (BA) 76%, 95%CI: 73–79%; Northeast (NEA) 54%, 95%CI: 49–58%; Northwest (NWA) 33%, 95%CI: 21–41%; South 54%, 95%CI: 49–59%; pcapital and immediate suburbs of Buenos Aires city compared to more distant suburbs [80% (95%CI: 75–86%) versus 68% (95%CI: 58–77%), p = 0.01]. European ancestry among individuals that declared all grandparents born in Europe was 91% (95%CI: 88–94%) compared to 54% (95%CI: 51–57%) among those with no European grandparents (p<0.001). Our results demonstrate the range of variation in genetic ancestry among Argentine individuals from different regions in the country, highlighting the importance of taking this variation into account in genetic association and admixture mapping studies in this population. PMID:22506044

  18. Replication the association of 2q32.2-q32.3 and 14q32.11 with hepatocellular carcinoma.

    Science.gov (United States)

    Chen, Wei; Wang, Mingquan; Zhang, Zhen; Tang, Huayang; Zuo, Xianbo; Meng, Xiangling; Xiong, Maoming; Zhou, Fusheng; Liang, Bo; Dai, Fen; Fang, Jun; Gao, Jinping; Zhu, Jun; Zhu, Yong; Wan, Hong; Wang, Miaofeng; Chan, Shixin; Sun, Liangdan

    2015-04-25

    Hepatocellular carcinoma (HCC) is a malignant tumor. The morbidity and mortality of HCC tend to ascend and become a serious threat to the population health. Genetic studies of HCC have identified several susceptibility loci of HCC. In this study, we aim to replicate the association of these loci in our samples from Chinese population and further investigate the genetic interaction. We selected 16 SNPs within 1p36.22, 2q32.2-q32.3, 3p21.33, 8p12, 14q32.11 and 21q21.3 and genotyped in 507 HCC patients and 3014 controls by using Sequenom MassARRAY system. Association analyses were performed by using PLINK 1.07. We observed that the STAT4 (2q32.2-q32.3) at rs7574865 (P=1.17×10(-3), OR=0.79) and EFCAB11 (14q32.11) at rs8013403 (P=1.54×10(-3), OR=0.80) were significantly associated with HCC in this study. In 3p21.33, genetic variant rs6795737 within GLB1 was also observed with suggestive evidence (P=9.98×10(-3), OR=0.84). In the interaction analysis, the pair of associated SNPs (rs7574865 within STAT4, rs8013403 within EFCAB11) generated evidence for interaction (P=4.10×10(-3)). In summary, our work first reported the association of 14q32.11 (EFCAB11) with HCC in Chinese Han population and revealed the genetic interaction between STAT4 (2q32.2-q32.3) and EFCAB11 (14q32.11) in HCC. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Strategies for MCMC computation inquantitative genetics

    DEFF Research Database (Denmark)

    Waagepetersen, Rasmus; Ibánēz-Escriche, Noelia; Sorensen, Daniel

    another extension of the linear mixed model introducing genetic random effects influencing the log residual variances of the observations thereby producing a genetically structured variance heterogeneity. Considerable computational problems arise when abandoning the standard linear mixed model. Maximum...... the various algorithms in the context of the heterogeneous variance model. Apart from being a model of great interest in its own right, this model has proven to be a hard test for MCMC methods. We compare the performances of the different algorithms when applied to three real datasets which differ markedly...... results of applying two MCMC schemes to data sets with pig litter sizes, rabbit litter sizes, and snail weights. Some concluding remarks are given in Section 5....

  20. Heterogeneous silicon mesostructures for lipid-supported bioelectric interfaces

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Yuanwen; Carvalho-de-Souza, João L.; Wong, Raymond C. S.; Luo, Zhiqiang; Isheim, Dieter; Zuo, Xiaobing; Nicholls, Alan W.; Jung, Il Woong; Yue, Jiping; Liu, Di-Jia; Wang, Yucai; De Andrade, Vincent; Xiao, Xianghui; Navrazhnykh, Luizetta; Weiss, Dara E.; Wu, Xiaoyang; Seidman, David N.; Bezanilla, Francisco; Tian, Bozhi

    2016-06-27

    Silicon-based materials have widespread application as biophysical tools and biomedical devices. Here we introduce a biocompatible and degradable mesostructured form of silicon with multi-scale structural and chemical heterogeneities. The material was synthesized using mesoporous silica as a template through a chemical vapour deposition process. It has an amorphous atomic structure, an ordered nanowire-based framework and random submicrometre voids, and shows an average Young’s modulus that is 2–3 orders of magnitude smaller than that of single-crystalline silicon. In addition, we used the heterogeneous silicon mesostructures to design a lipid-bilayer-supported bioelectric interface that is remotely controlled and temporally transient, and that permits non-genetic and subcellular optical modulation of the electrophysiology dynamics in single dorsal root ganglia neurons. Our findings suggest that the biomimetic expansion of silicon into heterogeneous and deformable forms can open up opportunities in extracellular biomaterial or bioelectric systems.

  1. Study of mitochondria D-loop gene to detect the heterogeneity of gemak in Turnicidae family

    Science.gov (United States)

    Setiati, N.; Partaya

    2018-03-01

    As a part of life biodiversity, birds in Turnicidae family should be preserved from the extinction and its type heterogeneity decline. One effort for giving the strategic base of plasma nutfah conservation is through genetic heterogeneity study. The aim of the research is to analyze D-loop gen from DNA mitochondria of gemak bird in Turnicidae family molecularly. From the result of the analysis, it may be known the genetic heterogeneity of gemak bird based on the sequence of D-loop gen. The collection of both types of gemak of Turnicidae family is still easy since we can find them in ricefield area after harvest particularly for Gemakloreng (Turnix sylvatica), it means while gemak tegalan (Turnixsusciator) is getting difficult to find. Based on the above DNA quantification standard, the blood sample of Gemak in this research is mostly grouped into pure blood (ranges from 1,63 – 1,90), and it deserves to be used for PCR analysis. The sequencing analysis has not detected the sequence of nucleotide completely. However, it indicates sequence polymorphism of base as the arranger of D-loop gen. D-loop gen may identify genetic heterogeneity of gemak bird of Turnicidae family, but it is necessary to perform further sequencing analysis with PCR-RFLP technique. This complete nucleotide sequence is obtained and easy to detect after being cut restriction enzyme.

  2. Sex-specific genetic effects in physical activity: results from a quantitative genetic analysis.

    Science.gov (United States)

    Diego, Vincent P; de Chaves, Raquel Nichele; Blangero, John; de Souza, Michele Caroline; Santos, Daniel; Gomes, Thayse Natacha; dos Santos, Fernanda Karina; Garganta, Rui; Katzmarzyk, Peter T; Maia, José A R

    2015-08-01

    The objective of this study is to present a model to estimate sex-specific genetic effects on physical activity (PA) levels and sedentary behaviour (SB) using three generation families. The sample consisted of 100 families covering three generations from Portugal. PA and SB were assessed via the International Physical Activity Questionnaire short form (IPAQ-SF). Sex-specific effects were assessed by genotype-by-sex interaction (GSI) models and sex-specific heritabilities. GSI effects and heterogeneity were tested in the residual environmental variance. SPSS 17 and SOLAR v. 4.1 were used in all computations. The genetic component for PA and SB domains varied from low to moderate (11% to 46%), when analyzing both genders combined. We found GSI effects for vigorous PA (p = 0.02) and time spent watching television (WT) (p < 0.001) that showed significantly higher additive genetic variance estimates in males. The heterogeneity in the residual environmental variance was significant for moderate PA (p = 0.02), vigorous PA (p = 0.006) and total PA (p = 0.001). Sex-specific heritability estimates were significantly higher in males only for WT, with a male-to-female difference in heritability of 42.5 (95% confidence interval: 6.4, 70.4). Low to moderate genetic effects on PA and SB traits were found. Results from the GSI model show that there are sex-specific effects in two phenotypes, VPA and WT with a stronger genetic influence in males.

  3. Heritability and genetics of lipid metabolism

    DEFF Research Database (Denmark)

    Fenger, Mogens

    2007-01-01

    In this article, the concept of heritability and genetic effect will be reviewed and our current knowledge of the genetics of lipid metabolism summarized. The concepts of polygenic conditions and epistasis are discussed at length, and an effort is made to put the biological processes in context...... in the search for genetic factors influencing the metabolic pathways. Particular physiological heterogeneity is addressed and procedures to handle this complex issue are suggested....

  4. An R package "VariABEL" for genome-wide searching of potentially interacting loci by testing genotypic variance heterogeneity

    Directory of Open Access Journals (Sweden)

    Struchalin Maksim V

    2012-01-01

    Full Text Available Abstract Background Hundreds of new loci have been discovered by genome-wide association studies of human traits. These studies mostly focused on associations between single locus and a trait. Interactions between genes and between genes and environmental factors are of interest as they can improve our understanding of the genetic background underlying complex traits. Genome-wide testing of complex genetic models is a computationally demanding task. Moreover, testing of such models leads to multiple comparison problems that reduce the probability of new findings. Assuming that the genetic model underlying a complex trait can include hundreds of genes and environmental factors, testing of these models in genome-wide association studies represent substantial difficulties. We and Pare with colleagues (2010 developed a method allowing to overcome such difficulties. The method is based on the fact that loci which are involved in interactions can show genotypic variance heterogeneity of a trait. Genome-wide testing of such heterogeneity can be a fast scanning approach which can point to the interacting genetic variants. Results In this work we present a new method, SVLM, allowing for variance heterogeneity analysis of imputed genetic variation. Type I error and power of this test are investigated and contracted with these of the Levene's test. We also present an R package, VariABEL, implementing existing and newly developed tests. Conclusions Variance heterogeneity analysis is a promising method for detection of potentially interacting loci. New method and software package developed in this work will facilitate such analysis in genome-wide context.

  5. Exploiting Genetic Interference for Antiviral Therapy.

    Directory of Open Access Journals (Sweden)

    Elizabeth J Tanner

    2016-05-01

    Full Text Available Rapidly evolving viruses are a major threat to human health. Such viruses are often highly pathogenic (e.g., influenza virus, HIV, Ebola virus and routinely circumvent therapeutic intervention through mutational escape. Error-prone genome replication generates heterogeneous viral populations that rapidly adapt to new selection pressures, leading to resistance that emerges with treatment. However, population heterogeneity bears a cost: when multiple viral variants replicate within a cell, they can potentially interfere with each other, lowering viral fitness. This genetic interference can be exploited for antiviral strategies, either by taking advantage of a virus's inherent genetic diversity or through generating de novo interference by engineering a competing genome. Here, we discuss two such antiviral strategies, dominant drug targeting and therapeutic interfering particles. Both strategies harness the power of genetic interference to surmount two particularly vexing obstacles-the evolution of drug resistance and targeting therapy to high-risk populations-both of which impede treatment in resource-poor settings.

  6. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

    Science.gov (United States)

    McKay, James D.; Hung, Rayjean J.; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A.; Wilkens, Lynne R.; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F.M.; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael PA; Marcus, Michael W.; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C.; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A.; Barnett, Matt P.; Chen, Chu; Goodman, Gary E.; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H.-Erich; Manz, Judith; Muley, Thomas R.; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A.; Tsao, Ming-Sound; Arnold, Susanne M.; Haura, Eric B.; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M.; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J.; Butler, Lesley M.; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S.; McLaughlin, John; Stevens, Victoria L.; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C.; Obeidat, Ma’en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D.; Wain, Louise V.; Rafnar, Thorunn; Thorgeirsson, Thorgeir E.; Reginsson, Gunnar W.; Stefansson, Kari; Hancock, Dana B.; Bierut, Laura J.; Spitz, Margaret R.; Gaddis, Nathan C.; Lutz, Sharon M.; Gu, Fangyi; Johnson, Eric O.; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F.; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I.

    2017-01-01

    Summary While several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer. PMID:28604730

  7. Genetic mapping of retinitis pigmentosa implications for South ...

    African Journals Online (AJOL)

    of hereditary degenerative disorders of the retina, which are both genetically and clinically heterogeneous. The finding of ... causes of genetic blindness. The condition may be transmitted as an autosomal dominant, .... throughout the country conduct home visits in order to obtain blood specimens and collect pedigree data.

  8. Hyccin, the Molecule Mutated in the Leukodystrophy Hypomyelination and Congenital Cataract (HCC), Is a Neuronal Protein

    Science.gov (United States)

    Giacomini, Caterina; Musante, Veronica; Fruscione, Floriana; La Padula, Veronica; Biancheri, Roberta; Scarfì, Sonia; Prada, Valeria; Sotgia, Federica; Duncan, Ian D.; Zara, Federico; Werner, Hauke B.; Lisanti, Michael P.; Nobbio, Lucilla; Corradi, Anna; Minetti, Carlo

    2012-01-01

    “Hypomyelination and Congenital Cataract”, HCC (MIM #610532), is an autosomal recessive disorder characterized by congenital cataract and diffuse cerebral and peripheral hypomyelination. HCC is caused by deficiency of Hyccin, a protein whose biological role has not been clarified yet. Since the identification of the cell types expressing a protein of unknown function can contribute to define the physiological context in which the molecule is explicating its function, we analyzed the pattern of Hyccin expression in the central and peripheral nervous system (CNS and PNS). Using heterozygous mice expressing the b-galactosidase (LacZ) gene under control of the Hyccin gene regulatory elements, we show that the gene is primarily expressed in neuronal cells. Indeed, Hyccin-LacZ signal was identified in CA1 hippocampal pyramidal neurons, olfactory bulb, and cortical pyramidal neurons, while it did not colocalize with oligodendroglial or astrocytic markers. In the PNS, Hyccin was detectable only in axons isolated from newborn mice. In the brain, Hyccin transcript levels were higher in early postnatal development (postnatal days 2 and 10) and then declined in adult mice. In a model of active myelinogenesis, organotypic cultures of rat Schwann cells (SC)/Dorsal Root Ganglion (DRG) sensory neurons, Hyccin was detected along the neurites, while it was absent from SC. Intriguingly, the abundance of the molecule was upregulated at postnatal days 10 and 15, in the initial steps of myelinogenesis and then declined at 30 days when the process is complete. As Hyccin is primarily expressed in neurons and its mutation leads to hypomyelination in human patients, we suggest that the protein is involved in neuron-to-glia signalling to initiate or maintain myelination. PMID:22461884

  9. Hyccin, the molecule mutated in the leukodystrophy hypomyelination and congenital cataract (HCC, is a neuronal protein.

    Directory of Open Access Journals (Sweden)

    Elisabetta Gazzerro

    Full Text Available "Hypomyelination and Congenital Cataract", HCC (MIM #610532, is an autosomal recessive disorder characterized by congenital cataract and diffuse cerebral and peripheral hypomyelination. HCC is caused by deficiency of Hyccin, a protein whose biological role has not been clarified yet. Since the identification of the cell types expressing a protein of unknown function can contribute to define the physiological context in which the molecule is explicating its function, we analyzed the pattern of Hyccin expression in the central and peripheral nervous system (CNS and PNS. Using heterozygous mice expressing the b-galactosidase (LacZ gene under control of the Hyccin gene regulatory elements, we show that the gene is primarily expressed in neuronal cells. Indeed, Hyccin-LacZ signal was identified in CA1 hippocampal pyramidal neurons, olfactory bulb, and cortical pyramidal neurons, while it did not colocalize with oligodendroglial or astrocytic markers. In the PNS, Hyccin was detectable only in axons isolated from newborn mice. In the brain, Hyccin transcript levels were higher in early postnatal development (postnatal days 2 and 10 and then declined in adult mice. In a model of active myelinogenesis, organotypic cultures of rat Schwann cells (SC/Dorsal Root Ganglion (DRG sensory neurons, Hyccin was detected along the neurites, while it was absent from SC. Intriguingly, the abundance of the molecule was upregulated at postnatal days 10 and 15, in the initial steps of myelinogenesis and then declined at 30 days when the process is complete. As Hyccin is primarily expressed in neurons and its mutation leads to hypomyelination in human patients, we suggest that the protein is involved in neuron-to-glia signalling to initiate or maintain myelination.

  10. Molecular genetic differentiation in earthworms inhabiting a heterogeneous Pb-polluted landscape

    International Nuclear Information System (INIS)

    Andre, J.; King, R.A.; Stuerzenbaum, S.R.; Kille, P.; Hodson, M.E.; Morgan, A.J.

    2010-01-01

    A Pb-mine site situated on acidic soil, but comprising of Ca-enriched islands around derelict buildings was used to study the spatial pattern of genetic diversity in Lumbricus rubellus. Two distinct genetic lineages ('A' and 'B'), differentiated at both the mitochondrial (mtDNA COII) and nuclear level (AFLPs) were revealed with a mean inter-lineage mtDNA sequence divergence of approximately 13%, indicative of a cryptic species complex. AFLP analysis indicates that lineage A individuals within one central 'ecological island' site are uniquely clustered, with little genetic overlap with lineage A individuals at the two peripheral sites. FTIR microspectroscopy of Pb-sequestering chloragocytes revealed different phosphate profiles in residents of adjacent acidic and calcareous islands. Bioinformatics found over-representation of Ca pathway genes in EST Pb libraries. Subsequent sequencing of a Ca-transport gene, SERCA, revealed mutations in the protein's cytosolic domain. We recommend the mandatory genotyping of all individuals prior to field-based ecotoxicological assays, particularly those using discriminating genomic technologies. - Landscapes punctuated by Pb-polluted islands have engendered local genetic differentiation in resident earthworms.

  11. Genetic inactivation of the Fanconi anemia gene FANCC identified in the hepatocellular carcinoma cell line HuH-7 confers sensitivity towards DNA-interstrand crosslinking agents

    Directory of Open Access Journals (Sweden)

    Bassermann Florian

    2010-05-01

    Full Text Available Abstract Background Inactivation of the Fanconi anemia (FA pathway through defects in one of 13 FA genes occurs at low frequency in various solid cancer entities among the general population. As FA pathway inactivation confers a distinct hypersensitivity towards DNA interstrand-crosslinking (ICL-agents, FA defects represent rational targets for individualized therapeutic strategies. Except for pancreatic cancer, however, the prevalence of FA defects in gastrointestinal (GI tumors has not yet been systematically explored. Results A panel of GI cancer cell lines was screened for FA pathway inactivation applying FANCD2 monoubiquitination and FANCD2/RAD51 nuclear focus formation and a newly identified FA pathway-deficient cell line was functionally characterized. The hepatocellular carcinoma (HCC line HuH-7 was defective in FANCD2 monoubiquitination and FANCD2 nuclear focus formation but proficient in RAD51 focus formation. Gene complementation studies revealed that this proximal FA pathway inactivation was attributable to defective FANCC function in HuH-7 cells. Accordingly, a homozygous inactivating FANCC nonsense mutation (c.553C > T, p.R185X was identified in HuH-7, resulting in partial transcriptional skipping of exon 6 and leading to the classic cellular FA hypersensitivity phenotype; HuH-7 cells exhibited a strongly reduced proliferation rate and a pronounced G2 cell cycle arrest at distinctly lower concentrations of ICL-agents than a panel of non-isogenic, FA pathway-proficient HCC cell lines. Upon retroviral transduction of HuH-7 cells with FANCC cDNA, FA pathway functions were restored and ICL-hypersensitivity abrogated. Analyses of 18 surgical HCC specimens yielded no further examples for genetic or epigenetic inactivation of FANCC, FANCF, or FANCG in HCC, suggesting a low prevalence of proximal FA pathway inactivation in this tumor type. Conclusions As the majority of HCC are chemoresistant, assessment of FA pathway function in HCC could

  12. Genetics of complex diseases

    DEFF Research Database (Denmark)

    Mellerup, Erling; Møller, Gert Lykke; Koefoed, Pernille

    2012-01-01

    A complex disease with an inheritable component is polygenic, meaning that several different changes in DNA are the genetic basis for the disease. Such a disease may also be genetically heterogeneous, meaning that independent changes in DNA, i.e. various genotypes, can be the genetic basis...... for the disease. Each of these genotypes may be characterized by specific combinations of key genetic changes. It is suggested that even if all key changes are found in genes related to the biology of a certain disease, the number of combinations may be so large that the number of different genotypes may be close...... to the number of patients suffering from the disease. This hypothesis is based on a study of bipolar disorder....

  13. Heterogeneity maintenance in glioblastoma: a social network.

    Science.gov (United States)

    Bonavia, Rudy; Inda, Maria-del-Mar; Cavenee, Webster K; Furnari, Frank B

    2011-06-15

    Glioblastoma multiforme (GBM), the most common intracranial tumor in adults, is characterized by extensive heterogeneity at the cellular and molecular levels. This insidious feature arises inevitably in almost all cancers and has great significance for the general outcome of the malignancy, because it confounds our understanding of the disease and also intrinsically contributes to the tumor's aggressiveness and poses an obstacle to the design of effective therapies. The classic view that heterogeneity arises as the result of a tumor's "genetic chaos" and the more contemporary cancer stem cell (CSC) hypothesis tend to identify a single cell population as the therapeutic target: the prevailing clone over time in the first case and the CSC in the latter. However, there is growing evidence that the different tumor cell populations may not be simple bystanders. Rather, they can establish a complex network of interactions between each other and with the tumor microenvironment that eventually strengthens tumor growth and increases chances to escape therapy. These differing but complementary ideas about the origin and maintenance of tumor heterogeneity and its importance in GBM are reviewed here.

  14. Characterizing the genetic influences on risk aversion.

    Science.gov (United States)

    Harrati, Amal

    2014-01-01

    Risk aversion has long been cited as an important factor in retirement decisions, investment behavior, and health. Some of the heterogeneity in individual risk tolerance is well understood, reflecting age gradients, wealth gradients, and similar effects, but much remains unexplained. This study explores genetic contributions to heterogeneity in risk aversion among older Americans. Using over 2 million genetic markers per individual from the U.S. Health and Retirement Study, I report results from a genome-wide association study (GWAS) on risk preferences using a sample of 10,455 adults. None of the single-nucleotide polymorphisms (SNPs) are found to be statistically significant determinants of risk preferences at levels stricter than 5 × 10(-8). These results suggest that risk aversion is a complex trait that is highly polygenic. The analysis leads to upper bounds on the number of genetic effects that could exceed certain thresholds of significance and still remain undetected at the current sample size. The findings suggest that the known heritability in risk aversion is likely to be driven by large numbers of genetic variants, each with a small effect size.

  15. Linking movement behavior and fine-scale genetic structure to model landscape connectivity for bobcats (Lynx rufus)

    Science.gov (United States)

    Dawn M. Reding; Samuel A. Cushman; Todd E. Gosselink; William R. Clark

    2013-01-01

    Spatial heterogeneity can constrain the movement of individuals and consequently genes across a landscape, influencing demographic and genetic processes. In this study, we linked information on landscape composition, movement behavior, and genetic differentiation to gain a mechanistic understanding of how spatial heterogeneity may influence movement and gene flow of...

  16. Preliminary Groundwater Simulations To Compare Different Reconstruction Methods of 3-d Alluvial Heterogeneity

    Science.gov (United States)

    Teles, V.; de Marsily, G.; Delay, F.; Perrier, E.

    Alluvial floodplains are extremely heterogeneous aquifers, whose three-dimensional structures are quite difficult to model. In general, when representing such structures, the medium heterogeneity is modeled with classical geostatistical or Boolean meth- ods. Another approach, still in its infancy, is called the genetic method because it simulates the generation of the medium by reproducing sedimentary processes. We developed a new genetic model to obtain a realistic three-dimensional image of allu- vial media. It does not simulate the hydrodynamics of sedimentation but uses semi- empirical and statistical rules to roughly reproduce fluvial deposition and erosion. The main processes, either at the stream scale or at the plain scale, are modeled by simple rules applied to "sediment" entities or to conceptual "erosion" entities. The model was applied to a several kilometer long portion of the Aube River floodplain (France) and reproduced the deposition and erosion cycles that occurred during the inferred climate periods (15 000 BP to present). A three-dimensional image of the aquifer was gener- ated, by extrapolating the two-dimensional information collected on a cross-section of the floodplain. Unlike geostatistical methods, this extrapolation does not use a statis- tical spatial analysis of the data, but a genetic analysis, which leads to a more realistic structure. Groundwater flow and transport simulations in the alluvium were carried out with a three-dimensional flow code or simulator (MODFLOW), using different rep- resentations of the alluvial reservoir of the Aube River floodplain: first an equivalent homogeneous medium, and then different heterogeneous media built either with the traditional geostatistical approach simulating the permeability distribution, or with the new genetic model presented here simulating sediment facies. In the latter case, each deposited entity of a given lithology was assigned a constant hydraulic conductivity value. Results of these

  17. Genetics of aggression.

    Science.gov (United States)

    Anholt, Robert R H; Mackay, Trudy F C

    2012-01-01

    Aggression mediates competition for food, mating partners, and habitats and, among social animals, establishes stable dominance hierarchies. In humans, abnormal aggression is a hallmark of neuropsychiatric disorders and can be elicited by environmental factors acting on an underlying genetic susceptibility. Identifying the genetic architecture that predisposes to aggressive behavior in people is challenging because of difficulties in quantifying the phenotype, genetic heterogeneity, and uncontrolled environmental conditions. Studies on mice have identified single-gene mutations that result in hyperaggression, contingent on genetic background. These studies can be complemented by systems genetics approaches in Drosophila melanogaster, in which mutational analyses together with genome-wide transcript analyses, artificial selection studies, and genome-wide analysis of epistasis have revealed that a large segment of the genome contributes to the manifestation of aggressive behavior with widespread epistatic interactions. Comparative genomic analyses based on the principle of evolutionary conservation are needed to enable a complete dissection of the neurogenetic underpinnings of this universal fitness trait.

  18. Genetic heterogeneity of motor neuropathies.

    Science.gov (United States)

    Bansagi, Boglarka; Griffin, Helen; Whittaker, Roger G; Antoniadi, Thalia; Evangelista, Teresinha; Miller, James; Greenslade, Mark; Forester, Natalie; Duff, Jennifer; Bradshaw, Anna; Kleinle, Stephanie; Boczonadi, Veronika; Steele, Hannah; Ramesh, Venkateswaran; Franko, Edit; Pyle, Angela; Lochmüller, Hanns; Chinnery, Patrick F; Horvath, Rita

    2017-03-28

    To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  19. Molecular genetic differentiation in earthworms inhabiting a heterogeneous Pb-polluted landscape

    Energy Technology Data Exchange (ETDEWEB)

    Andre, J., E-mail: Andrej@cardiff.ac.u [Cardiff School of Biosciences, Cardiff University, BIOSI 1, Museum Avenue, Cardiff CF10 3TL (United Kingdom); Department of Soil Science, School of Human and Environmental Sciences, University of Reading, Whiteknights, Reading RG6 6DW (United Kingdom); King, R.A. [Cardiff School of Biosciences, Cardiff University, BIOSI 1, Museum Avenue, Cardiff CF10 3TL (United Kingdom); Stuerzenbaum, S.R. [King' s College London, School of Biomedical and Health Sciences, Pharmaceutical Sciences Division, London SE1 9NH (United Kingdom); Kille, P. [Cardiff School of Biosciences, Cardiff University, BIOSI 1, Museum Avenue, Cardiff CF10 3TL (United Kingdom); Hodson, M.E. [Department of Soil Science, School of Human and Environmental Sciences, University of Reading, Whiteknights, Reading RG6 6DW (United Kingdom); Morgan, A.J. [Cardiff School of Biosciences, Cardiff University, BIOSI 1, Museum Avenue, Cardiff CF10 3TL (United Kingdom)

    2010-03-15

    A Pb-mine site situated on acidic soil, but comprising of Ca-enriched islands around derelict buildings was used to study the spatial pattern of genetic diversity in Lumbricus rubellus. Two distinct genetic lineages ('A' and 'B'), differentiated at both the mitochondrial (mtDNA COII) and nuclear level (AFLPs) were revealed with a mean inter-lineage mtDNA sequence divergence of approximately 13%, indicative of a cryptic species complex. AFLP analysis indicates that lineage A individuals within one central 'ecological island' site are uniquely clustered, with little genetic overlap with lineage A individuals at the two peripheral sites. FTIR microspectroscopy of Pb-sequestering chloragocytes revealed different phosphate profiles in residents of adjacent acidic and calcareous islands. Bioinformatics found over-representation of Ca pathway genes in EST{sub Pb} libraries. Subsequent sequencing of a Ca-transport gene, SERCA, revealed mutations in the protein's cytosolic domain. We recommend the mandatory genotyping of all individuals prior to field-based ecotoxicological assays, particularly those using discriminating genomic technologies. - Landscapes punctuated by Pb-polluted islands have engendered local genetic differentiation in resident earthworms.

  20. Genetics of frontotemporal lobar degeneration

    Directory of Open Access Journals (Sweden)

    Aswathy P

    2010-10-01

    Full Text Available Frontotemporal lobar degeneration (FTLD is a highly heterogenous group of progressive neurodegenerative disorders characterized by atrophy of prefrontal and anterior temporal cortices. Recently, the research in the field of FTLD has gained increased attention due to the clinical, neuropathological, and genetic heterogeneity and has increased our understanding of the disease pathogenesis. FTLD is a genetically complex disorder. It has a strong genetic basis and 50% of patients show a positive family history for FTLD. Linkage studies have revealed seven chromosomal loci and a number of genes including MAPT, PGRN, VCP, and CHMB-2B are associated with the disease. Neuropathologically, FTLD is classified into tauopathies and ubiquitinopathies. The vast majority of FTLD cases are characterized by pathological accumulation of tau or TDP-43 positive inclusions, each as an outcome of mutations in MAPT or PGRN, respectively. Identification of novel proteins involved in the pathophysiology of the disease, such as progranulin and TDP-43, may prove to be excellent biomarkers of disease progression and thereby lead to the development of better therapeutic options through pharmacogenomics. However, much more dissections into the causative pathways are needed to get a full picture of the etiology. Over the past decade, advances in research on the genetics of FTLD have revealed many pathogenic mutations leading to different clinical manifestations of the disease. This review discusses the current concepts and recent advances in our understanding of the genetics of FTLD.

  1. Heterogeneous genetic diversity pattern in Plasmodium vivax genes encoding merozoite surface proteins (MSP) -7E, -7F and -7L.

    Science.gov (United States)

    Garzón-Ospina, Diego; Forero-Rodríguez, Johanna; Patarroyo, Manuel A

    2014-12-13

    The msp-7 gene has become differentially expanded in the Plasmodium genus; Plasmodium vivax has the highest copy number of this gene, several of which encode antigenic proteins in merozoites. DNA sequences from thirty-six Colombian clinical isolates from P. vivax (pv) msp-7E, -7F and -7L genes were analysed for characterizing and studying the genetic diversity of these pvmsp-7 members which are expressed during the intra-erythrocyte stage; natural selection signals producing the variation pattern so observed were evaluated. The pvmsp-7E gene was highly polymorphic compared to pvmsp-7F and pvmsp-7L which were seen to have limited genetic diversity; pvmsp-7E polymorphism was seen to have been maintained by different types of positive selection. Even though these copies seemed to be species-specific duplications, a search in the Plasmodium cynomolgi genome (P. vivax sister taxon) showed that both species shared the whole msp-7 repertoire. This led to exploring the long-term effect of natural selection by comparing the orthologous sequences which led to finding signatures for lineage-specific positive selection. The results confirmed that the P. vivax msp-7 family has a heterogeneous genetic diversity pattern; some members are highly conserved whilst others are highly diverse. The results suggested that the 3'-end of these genes encode MSP-7 proteins' functional region whilst the central region of pvmsp-7E has evolved rapidly. The lineage-specific positive selection signals found suggested that mutations occurring in msp-7s genes during host switch may have succeeded in adapting the ancestral P. vivax parasite population to humans.

  2. PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation.

    Science.gov (United States)

    Gedaly, Roberto; Angulo, Paul; Hundley, Jonathan; Daily, Michael F; Chen, Changguo; Evers, B Mark

    2012-08-01

    Deregulated Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study aimed to test the inhibitory effects of PKI-587 and sorafenib as single agents or in combination on HCC (Huh7 cell line) proliferation. (3)H-thymidine incorporation and MTT assay were used to assess Huh7 cell proliferation. Phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways was detected by Western blot. We found that PKI-587 is a more potent PI3K/mTOR inhibitor than PI-103. Combination of PKI-587 and sorafenib was a more effective inhibitor of Huh7 proliferation than the combination of PI-103 and sorafenib. Combination of PKI-587 and sorafenib synergistically inhibited epidermal growth factor (EGF)-stimulated Huh7 proliferation compared with monodrug therapy. EGF increased phosphorylation of Ras/Raf downstream signaling proteins MEK and ERK; EGF-stimulated activation was inhibited by sorafenib. However, sorafenib, as a single agent, increased AKT (Ser473) phosphorylation. EGF-stimulated AKT (ser473) activation was inhibited by PKI-587. PKI-587 is a potent inhibitor of AKT (Ser473), mTOR (Ser2448), and S6K (Thr389) phosphorylation; in contrast, rapamycin stimulated mTOR complex 2 substrate AKT(Ser473) phosphorylation although it inhibited mTOR complex 1 substrate S6K phosphorylation. PKI-587, as a single agent, stimulated MEK and ERK phosphorylation. However, when PKI-587 and sorafenib were used in combination, they inhibited all the tested kinases in the Ras/Raf /MAPK and PI3K/AKT/mTOR pathways. The combination of PKI-587 and sorafenib has the advantage over monodrug therapy on inhibition of HCC cell proliferation by blocking both PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. SMAD7 loci contribute to risk of hepatocellular carcinoma and clinicopathologic development among Chinese Han population.

    Science.gov (United States)

    Ji, Jiansong; Xu, Min; Zhao, Zhongwei; Tu, Jianfei; Gao, Jun; Lu, Chenying; Song, Jingjing; Chen, Weiqian; Chen, Minjiang; Fan, Xiaoxi; Cheng, Xingyao; Lan, Xilin; Li, Jie

    2016-04-19

    Genome-wide association studies (GWAS) have identified three loci at 18q21 (rs4939827, rs7240004, and rs7229639), which maps to SMAD7 loci, were associated with risk of diseases of the digestive system. However, their associations with hepatocellular carcinoma (HCC) risk remain unknown. A case-control study was conducted to assess genetic associations with HCC risk and clinicopathologic development among Chinese Han population. Three SNPs were genotyped among 1,000 HCC cases and 1,000 controls using Sequenom Mass-ARRAY technology. We observed statistically significant associations for the three SMAD7 loci and HCC risk. Each copy of minor allele was associated with a 1.24-1.36 fold increased risk of HCC. We also found that significant differences were observed between rs4939827 and clinical TNM stage and vascular invasion, as well as rs7240004 and vascular invasion. We also established a genetic risk score (GRS) by summing the risk alleles. The GRS was significantly associated with increased risk of HCC and vascular invasion. Our data revealed the SMAD7 loci is associated with HCC susceptibility and its clinicopathologic development.

  4. Huntington\\'s disease: Genetic heterogeneity in black African patients

    African Journals Online (AJOL)

    Objective. Huntington's disease (HD) has been reported to occur rarely in black patients. A new genetic variant– Huntington's disease-like 2 (HDL2) – occurring more frequently in blacks, has recently been described. The absence of an expanded trinucleotide repeat at the chromosome 4 HD locus was previously regarded ...

  5. Selection for uniformity in livestock by exploiting genetic heterogeneity of residual variance

    NARCIS (Netherlands)

    Mulder, H.A.; Veerkamp, R.F.; Vereijken, A.; Bijma, P.; Hill, W.G.

    2008-01-01

    some situations, it is worthwhile to change not only the mean, but also the variability of traits by selection. Genetic variation in residual variance may be utilised to improve uniformity in livestock populations by selection. The objective was to investigate the effects of genetic parameters,

  6. Selection for uniformity in livestock by exploiting genetic heterogeneity of environmental variance

    NARCIS (Netherlands)

    Mulder, H.A.; Bijma, P.; Hill, W.G.

    2008-01-01

    In some situations, it is worthwhile to change not only the mean, but also the variability of traits by selection. Genetic variation in residual variance may be utilised to improve uniformity in livestock populations by selection. The objective was to investigate the effects of genetic parameters,

  7. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

    Science.gov (United States)

    McKay, James D; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C; Caporaso, Neil E; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A; Qian, David C; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N; Bojesen, Stig E; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A; Wilkens, Lynne R; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F M; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael P A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A; Barnett, Matt P; Chen, Chu; Goodman, Gary E; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H-Erich; Manz, Judith; Muley, Thomas R; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Tsao, Ming-Sound; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S; McLaughlin, John; Stevens, Victoria L; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C; Obeidat, Ma'en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D; Wain, Louise V; Rafnar, Thorunn; Thorgeirsson, Thorgeir E; Reginsson, Gunnar W; Stefansson, Kari; Hancock, Dana B; Bierut, Laura J; Spitz, Margaret R; Gaddis, Nathan C; Lutz, Sharon M; Gu, Fangyi; Johnson, Eric O; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I

    2017-07-01

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

  8. Capturing heterogeneity in gene expression studies by surrogate variable analysis.

    Directory of Open Access Journals (Sweden)

    Jeffrey T Leek

    2007-09-01

    Full Text Available It has unambiguously been shown that genetic, environmental, demographic, and technical factors may have substantial effects on gene expression levels. In addition to the measured variable(s of interest, there will tend to be sources of signal due to factors that are unknown, unmeasured, or too complicated to capture through simple models. We show that failing to incorporate these sources of heterogeneity into an analysis can have widespread and detrimental effects on the study. Not only can this reduce power or induce unwanted dependence across genes, but it can also introduce sources of spurious signal to many genes. This phenomenon is true even for well-designed, randomized studies. We introduce "surrogate variable analysis" (SVA to overcome the problems caused by heterogeneity in expression studies. SVA can be applied in conjunction with standard analysis techniques to accurately capture the relationship between expression and any modeled variables of interest. We apply SVA to disease class, time course, and genetics of gene expression studies. We show that SVA increases the biological accuracy and reproducibility of analyses in genome-wide expression studies.

  9. Gene expression profiling, pathway analysis and subtype classification reveal molecular heterogeneity in hepatocellular carcinoma and suggest subtype specific therapeutic targets.

    Science.gov (United States)

    Agarwal, Rahul; Narayan, Jitendra; Bhattacharyya, Amitava; Saraswat, Mayank; Tomar, Anil Kumar

    2017-10-01

    A very low 5-year survival rate among hepatocellular carcinoma (HCC) patients is mainly due to lack of early stage diagnosis, distant metastasis and high risk of postoperative recurrence. Hence ascertaining novel biomarkers for early diagnosis and patient specific therapeutics is crucial and urgent. Here, we have performed a comprehensive analysis of the expression data of 423 HCC patients (373 tumors and 50 controls) downloaded from The Cancer Genome Atlas (TCGA) followed by pathway enrichment by gene ontology annotations, subtype classification and overall survival analysis. The differential gene expression analysis using non-parametric Wilcoxon test revealed a total of 479 up-regulated and 91 down-regulated genes in HCC compared to controls. The list of top differentially expressed genes mainly consists of tumor/cancer associated genes, such as AFP, THBS4, LCN2, GPC3, NUF2, etc. The genes over-expressed in HCC were mainly associated with cell cycle pathways. In total, 59 kinases associated genes were found over-expressed in HCC, including TTK, MELK, BUB1, NEK2, BUB1B, AURKB, PLK1, CDK1, PKMYT1, PBK, etc. Overall four distinct HCC subtypes were predicted using consensus clustering method. Each subtype was unique in terms of gene expression, pathway enrichment and median survival. Conclusively, this study has exposed a number of interesting genes which can be exploited in future as potential markers of HCC, diagnostic as well as prognostic and subtype classification may guide for improved and specific therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Change in contrast enhancement of HCC on 1-month follow-up CT after local radiotherapy: An early predictor of final treatment response

    International Nuclear Information System (INIS)

    Kim, Eun Young; Choi, Dongil; Lim, Do Hoon; Lee, Won Jae; Yoo, Byung Chul; Paik, Seung Woon

    2009-01-01

    Background: The purpose of this study was to evaluate the change in contrast enhancement of HCC on 1-month follow-up CT after local radiotherapy (RT) as an early predictor of final treatment response. Materials: Fifty patients who underwent local RT for HCCs had both pre-RT and post-RT CT scans including 1-month follow-up CT. We assessed the final treatment response by using the change in maximal tumor size on 6-12-month follow-up CT scan after RT. We also evaluated the change in tumor enhancement between pre-RT and 1-month follow-up CT scans. Results: A final treatment response was achieved in 27 (54%) of 50 patients, who showed either a complete response (n = 11) or a partial response (n = 16). Compared with non-responsive patients (n = 23), responsive patients showed a significant decrease in tumor enhancement on 1-month follow-up CT after RT in both objective and subjective analyses (each P < 0.001). Conclusion: The change in contrast enhancement of HCC seen on the 1-month follow-up CT in patients after local RT may be used as an early predictor of final treatment response.

  11. Genetic diversity and striatal gene networks: focus on the heterogeneous stock-collaborative cross (HS-CC mouse

    Directory of Open Access Journals (Sweden)

    Belknap John

    2010-10-01

    Full Text Available Abstract Background The current study focused on the extent genetic diversity within a species (Mus musculus affects gene co-expression network structure. To examine this issue, we have created a new mouse resource, a heterogeneous stock (HS formed from the same eight inbred strains that have been used to create the collaborative cross (CC. The eight inbred strains capture > 90% of the genetic diversity available within the species. For contrast with the HS-CC, a C57BL/6J (B6 × DBA/2J (D2 F2 intercross and the HS4, derived from crossing the B6, D2, BALB/cJ and LP/J strains, were used. Brain (striatum gene expression data were obtained using the Illumina Mouse WG 6.1 array, and the data sets were interrogated using a weighted gene co-expression network analysis (WGCNA. Results Genes reliably detected as expressed were similar in all three data sets as was the variability of expression. As measured by the WGCNA, the modular structure of the transcriptome networks was also preserved both on the basis of module assignment and from the perspective of the topological overlap maps. Details of the HS-CC gene modules are provided; essentially identical results were obtained for the HS4 and F2 modules. Gene ontology annotation of the modules revealed a significant overrepresentation in some modules for neuronal processes, e.g., central nervous system development. Integration with known protein-protein interactions data indicated significant enrichment among co-expressed genes. We also noted significant overlap with markers of central nervous system cell types (neurons, oligodendrocytes and astrocytes. Using the Allen Brain Atlas, we found evidence of spatial co-localization within the striatum for several modules. Finally, for some modules it was possible to detect an enrichment of transcription binding sites. The binding site for Wt1, which is associated with neurodegeneration, was the most significantly overrepresented. Conclusions Despite the marked

  12. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castrationresistant prostate cancer: a report from the PETRUS prospective study

    Science.gov (United States)

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-01-01

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients. PMID:27391263

  13. Endogenous Molecular-Cellular Network Cancer Theory: A Systems Biology Approach.

    Science.gov (United States)

    Wang, Gaowei; Yuan, Ruoshi; Zhu, Xiaomei; Ao, Ping

    2018-01-01

    In light of ever apparent limitation of the current dominant cancer mutation theory, a quantitative hypothesis for cancer genesis and progression, endogenous molecular-cellular network hypothesis has been proposed from the systems biology perspective, now for more than 10 years. It was intended to include both the genetic and epigenetic causes to understand cancer. Its development enters the stage of meaningful interaction with experimental and clinical data and the limitation of the traditional cancer mutation theory becomes more evident. Under this endogenous network hypothesis, we established a core working network of hepatocellular carcinoma (HCC) according to the hypothesis and quantified the working network by a nonlinear dynamical system. We showed that the two stable states of the working network reproduce the main known features of normal liver and HCC at both the modular and molecular levels. Using endogenous network hypothesis and validated working network, we explored genetic mutation pattern in cancer and potential strategies to cure or relieve HCC from a totally new perspective. Patterns of genetic mutations have been traditionally analyzed by posteriori statistical association approaches in light of traditional cancer mutation theory. One may wonder the possibility of a priori determination of any mutation regularity. Here, we found that based on the endogenous network theory the features of genetic mutations in cancers may be predicted without any prior knowledge of mutation propensities. Normal hepatocyte and cancerous hepatocyte stable states, specified by distinct patterns of expressions or activities of proteins in the network, provide means to directly identify a set of most probable genetic mutations and their effects in HCC. As the key proteins and main interactions in the network are conserved through cell types in an organism, similar mutational features may also be found in other cancers. This analysis yielded straightforward and testable

  14. Genetics of ischemic stroke: future clinical applications.

    Science.gov (United States)

    Wang, Michael M

    2006-11-01

    Ischemic stroke has long been thought to have a genetic component that is independent of conventional vascular risk factors. It has been estimated that over one half of stroke risk is determined by inherited genes. However, until recently, strong evidence of genetic influence on ischemic stroke has been subject to criticism because the risk factors for stroke are also inherited and because previous studies suffered from limitations imposed by this highly heterogeneous neurological disorder. Recent advances in molecular genetics have led to the identification of specific genetic loci that impart susceptibility to ischemic stroke. We review the studies of these genes and discuss the future potential applications of genetic markers on the management of ischemic stroke patients.

  15. Phylogeography of Pinus armandii and its relatives: heterogeneous contributions of geography and climate changes to the genetic differentiation and diversification of Chinese white pines.

    Directory of Open Access Journals (Sweden)

    Liu Liu

    Full Text Available Geographic barriers and Quaternary climate changes are two major forces driving the evolution, speciation, and genetic structuring of extant organisms. In this study, we used Pinus armandii and eleven other Asian white pines (subsection Strobus, subgenus Pinus to explore the influences of geographic factors and Pleistocene climatic oscillations on species in South China, a region known to be centers of plant endemism and biodiversity hotspots. Range-wide patterns of genetic variation were investigated using chloroplast and mitochondrial DNA markers, with extensive sampling throughout the entire range of P. armandii. Both cpDNA and mtDNA revealed that P. armandii exhibits high levels of genetic diversity and significant population differentiation. Three geographically distinct subdivisions corresponding to the Qinling-Daba Mountains (QDM, Himalaya-Hengduan Mountains (HHM and Yungui Plateau (YGP were revealed in mainland China by cpDNA. Their break zone was located in the southeastern margin of the Qinghai-Tibetan Plateau (QTP. A series of massive mountains, induced by the QTP uplift, imposed significant geographic barriers to genetic exchange. The disjunct distribution patterns of ancestral haplotypes suggest that a large continuous population of the white pines may have existed from southwest to subtropical China. Repeated range shifts in response to the Pleistocene glaciations led to the isolation and diversification of the subtropical species. The two Taiwanese white pines share a common ancestor with the species in mainland China and obtain their chloroplasts via long-distance pollen dispersal from North Asian pines. Distinct genetic patterns were detected in populations from the Qinling-Daba Mountains, Yungui Plateau, Himalaya-Hengduan Mountains, and subtropical China, indicating significant contributions of geographic factors to the genetic differentiation in white pines. Our study depicts a clear picture of the evolutionary history of

  16. Heterogeneity mapping of protein expression in tumors using quantitative immunofluorescence.

    Science.gov (United States)

    Faratian, Dana; Christiansen, Jason; Gustavson, Mark; Jones, Christine; Scott, Christopher; Um, InHwa; Harrison, David J

    2011-10-25

    Morphologic heterogeneity within an individual tumor is well-recognized by histopathologists in surgical practice. While this often takes the form of areas of distinct differentiation into recognized histological subtypes, or different pathological grade, often there are more subtle differences in phenotype which defy accurate classification (Figure 1). Ultimately, since morphology is dictated by the underlying molecular phenotype, areas with visible differences are likely to be accompanied by differences in the expression of proteins which orchestrate cellular function and behavior, and therefore, appearance. The significance of visible and invisible (molecular) heterogeneity for prognosis is unknown, but recent evidence suggests that, at least at the genetic level, heterogeneity exists in the primary tumor(1,2), and some of these sub-clones give rise to metastatic (and therefore lethal) disease. Moreover, some proteins are measured as biomarkers because they are the targets of therapy (for instance ER and HER2 for tamoxifen and trastuzumab (Herceptin), respectively). If these proteins show variable expression within a tumor then therapeutic responses may also be variable. The widely used histopathologic scoring schemes for immunohistochemistry either ignore, or numerically homogenize the quantification of protein expression. Similarly, in destructive techniques, where the tumor samples are homogenized (such as gene expression profiling), quantitative information can be elucidated, but spatial information is lost. Genetic heterogeneity mapping approaches in pancreatic cancer have relied either on generation of a single cell suspension(3), or on macrodissection(4). A recent study has used quantum dots in order to map morphologic and molecular heterogeneity in prostate cancer tissue(5), providing proof of principle that morphology and molecular mapping is feasible, but falling short of quantifying the heterogeneity. Since immunohistochemistry is, at best, only semi

  17. The association between donor genetic variations in one-carbon metabolism pathway genes and hepatitis B recurrence after liver transplantation.

    Science.gov (United States)

    Lu, Di; Zhuo, Jianyong; Yang, Modan; Wang, Chao; Linhui, Pan; Xie, Haiyang; Xu, Xiao; Zheng, Shusen

    2018-04-05

    Hepatitis B recurrence adversely affects patients' survival after liver transplantation. This study aims to find association between donor gene variations of one carbon metabolism and post-transplant hepatitis B recurrence. This study enrolled 196 patients undergoing liver transplantation for HBV related end-stage liver diseases. We detected 11 single nucleotide polymorphisms (SNP) of 7 one-carbon metabolism pathway genes (including MTHFR, MTR, MTRR, ALDH1L1, GART, SHMT1 and CBS) in donor livers and analyzed their association with HBV reinfection after liver transplantation. Hepatitis B recurrence was observed in 19 of the 196 patients (9.7%) undergoing liver transplantation. Hepatitis B recurrence significantly affected post-transplant survival in the 196 patients (p = 0.018), and correlate with tumor recurrence in the subgroup of HCC patients (n = 99, p = 0.006). Among the 11 SNPs, donor liver mutation in rs1979277 (G > A) was adversely associated with post-transplant hepatitis B recurrence (p = 0.042). In the subgroup of HCC patients, survival analysis showed donor liver mutations in rs1801133 (G > A) and rs1979277 (G > A) were risk factors for hepatitis B recurrence (p B recurrence in non-HCC patients (n = 97, p > 0.05). Hepatitis B recurrence impaired post-transplant survival. Donor liver genetic variations in one-carbon metabolism pathway genes were significantly associated with post-transplant hepatitis B recurrence. Copyright © 2017. Published by Elsevier B.V.

  18. Fibroblast growth factor receptor 4 polymorphism is associated with liver cirrhosis in hepatocarcinoma.

    Directory of Open Access Journals (Sweden)

    Ming-Jen Sheu

    Full Text Available Fibroblast growth factor receptor 4 (FGFR4 polymorphisms are positively correlated with tumor progression in numerous malignant tumors. However, the association between FGFR4 genetic variants and the risk of hepatocellular carcinoma (HCC has not yet been determined. In this study, we investigated the potential associations of FGFR4 single nucleotide polymorphisms (SNPs with HCC susceptibility and its clinicopathological characteristics.Four SNPs in FGFR4 (rs1966265, rs351855, rs2011077, and rs7708357 were analyzed among 884 participants, including 595 controls and 289 patients with HCC. The samples were further analyzed to clarify the associations between these gene polymorphisms and the risk of HCC, and the impact of these SNPs on the susceptibility and clinicopathological characteristics of HCC. After adjusting for other covariants, HCC patients who carrying at least one A genotype (GA and AA at rs351855 were observed to have a higher risk of liver cirrhosis compared with those carrying the wild-type genotype (GG (OR: 2.113, 95% CI: 1.188-3.831. Moreover, the patients with at least one A genotype were particularly showed a high level of alpha-fetoprotein (AFP.Our findings suggest that genetic polymorphism in FGFR4 rs351855 may be associated with the risk of HCC coupled with liver cirrhosis and may markedly increase the AFP level in Taiwanese patients with HCC. In addition, this is the first study that evaluated the risk factors associated with FGFR4 polymorphism variants in Taiwanese patients with HCC.

  19. Methodological approach for substantiating disease freedom in a heterogeneous small population. Application to ovine scrapie, a disease with a strong genetic susceptibility.

    Science.gov (United States)

    Martinez, Marie-José; Durand, Benoit; Calavas, Didier; Ducrot, Christian

    2010-06-01

    Demonstrating disease freedom is becoming important in different fields including animal disease control. Most methods consider sampling only from a homogeneous population in which each animal has the same probability of becoming infected. In this paper, we propose a new methodology to calculate the probability of detecting the disease if it is present in a heterogeneous population of small size with potentially different risk groups, differences in risk being defined using relative risks. To calculate this probability, for each possible arrangement of the infected animals in the different groups, the probability that all the animals tested are test-negative given this arrangement is multiplied by the probability that this arrangement occurs. The probability formula is developed using the assumption of a perfect test and hypergeometric sampling for finite small size populations. The methodology is applied to scrapie, a disease affecting small ruminants and characterized in sheep by a strong genetic susceptibility defining different risk groups. It illustrates that the genotypes of the tested animals influence heavily the confidence level of detecting scrapie. The results present the statistical power for substantiating disease freedom in a small heterogeneous population as a function of the design prevalence, the structure of the sample tested, the structure of the herd and the associated relative risks. (c) 2010 Elsevier B.V. All rights reserved.

  20. Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech.

    Science.gov (United States)

    Worthey, Elizabeth A; Raca, Gordana; Laffin, Jennifer J; Wilk, Brandon M; Harris, Jeremy M; Jakielski, Kathy J; Dimmock, David P; Strand, Edythe A; Shriberg, Lawrence D

    2013-10-02

    Childhood apraxia of speech (CAS) is a rare, severe, persistent pediatric motor speech disorder with associated deficits in sensorimotor, cognitive, language, learning and affective processes. Among other neurogenetic origins, CAS is the disorder segregating with a mutation in FOXP2 in a widely studied, multigenerational London family. We report the first whole-exome sequencing (WES) findings from a cohort of 10 unrelated participants, ages 3 to 19 years, with well-characterized CAS. As part of a larger study of children and youth with motor speech sound disorders, 32 participants were classified as positive for CAS on the basis of a behavioral classification marker using auditory-perceptual and acoustic methods that quantify the competence, precision and stability of a speaker's speech, prosody and voice. WES of 10 randomly selected participants was completed using the Illumina Genome Analyzer IIx Sequencing System. Image analysis, base calling, demultiplexing, read mapping, and variant calling were performed using Illumina software. Software developed in-house was used for variant annotation, prioritization and interpretation to identify those variants likely to be deleterious to neurodevelopmental substrates of speech-language development. Among potentially deleterious variants, clinically reportable findings of interest occurred on a total of five chromosomes (Chr3, Chr6, Chr7, Chr9 and Chr17), which included six genes either strongly associated with CAS (FOXP1 and CNTNAP2) or associated with disorders with phenotypes overlapping CAS (ATP13A4, CNTNAP1, KIAA0319 and SETX). A total of 8 (80%) of the 10 participants had clinically reportable variants in one or two of the six genes, with variants in ATP13A4, KIAA0319 and CNTNAP2 being the most prevalent. Similar to the results reported in emerging WES studies of other complex neurodevelopmental disorders, our findings from this first WES study of CAS are interpreted as support for heterogeneous genetic origins of

  1. Quantification of type I error probabilities for heterogeneity LOD scores.

    Science.gov (United States)

    Abreu, Paula C; Hodge, Susan E; Greenberg, David A

    2002-02-01

    Locus heterogeneity is a major confounding factor in linkage analysis. When no prior knowledge of linkage exists, and one aims to detect linkage and heterogeneity simultaneously, classical distribution theory of log-likelihood ratios does not hold. Despite some theoretical work on this problem, no generally accepted practical guidelines exist. Nor has anyone rigorously examined the combined effect of testing for linkage and heterogeneity and simultaneously maximizing over two genetic models (dominant, recessive). The effect of linkage phase represents another uninvestigated issue. Using computer simulation, we investigated type I error (P value) of the "admixture" heterogeneity LOD (HLOD) score, i.e., the LOD score maximized over both recombination fraction theta and admixture parameter alpha and we compared this with the P values when one maximizes only with respect to theta (i.e., the standard LOD score). We generated datasets of phase-known and -unknown nuclear families, sizes k = 2, 4, and 6 children, under fully penetrant autosomal dominant inheritance. We analyzed these datasets (1) assuming a single genetic model, and maximizing the HLOD over theta and alpha; and (2) maximizing the HLOD additionally over two dominance models (dominant vs. recessive), then subtracting a 0.3 correction. For both (1) and (2), P values increased with family size k; rose less for phase-unknown families than for phase-known ones, with the former approaching the latter as k increased; and did not exceed the one-sided mixture distribution xi = (1/2) chi1(2) + (1/2) chi2(2). Thus, maximizing the HLOD over theta and alpha appears to add considerably less than an additional degree of freedom to the associated chi1(2) distribution. We conclude with practical guidelines for linkage investigators. Copyright 2002 Wiley-Liss, Inc.

  2. Zebrafish as a model to assess cancer heterogeneity, progression and relapse

    Science.gov (United States)

    Blackburn, Jessica S.; Langenau, David M.

    2014-01-01

    Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays. PMID:24973745

  3. Heterogeneity and renal mass biopsy: a review of its role and reliability

    International Nuclear Information System (INIS)

    Tomaszewski, Jeffrey J.; Uzzo, Robert G.; Smaldone, Marc C.

    2014-01-01

    Increased abdominal imaging has led to an increase in the detection of the incidental small renal mass (SRM). With increasing recognition that the malignant potential of SRMs is heterogeneous, ranging from benign (15%-20%) to aggressive (20%), enthusiasm for more conservative management strategies in the elderly and infirmed, such as active surveillance (AS), have grown considerably. As the management of the SRM evolves to incorporate ablative techniques and AS for low risk disease, the role of renal mass biopsy (RMB) to help guide individualized therapy is evolving. Historically, the role of RMB was limited to the evaluation of suspected metastatic disease, renal abscess, or lymphoma. However, in the contemporary era, the role of biopsy has grown, most notably to identify patients who harbor benign lesions and for whom treatment, particularly the elderly or frail, may be avoided. When performing a RMB to guide initial clinical decision making for small, localized tumors, the most relevant questions are often relegated to proof of malignancy and documentation (if possible) of grade. However, significant intratumoral heterogeneity has been identified in clear cell renal cell carcinoma (ccRCC) that may lead to an underestimation of the genetic complexity of a tumor when single-biopsy procedures are used. Heterogeneous genomic landscapes and branched parallel evolution of ccRCCs with spatially separated subclones creates an illusion of clonal dominance when assessed by single biopsies and raises important questions regarding how tumors can be optimally sampled and whether future evolutionary tumor branches might be predictable and ultimately targetable. This work raises profound questions concerning the genetic landscape of cancer and how tumor heterogeneity may affect, and possibly confound, targeted diagnostic and therapeutic interventions. In this review, we discuss the current role of RMB, the implications of tumor heterogeneity on diagnostic accuracy, and

  4. Transcatheter chemoembolization in patients with HCC

    International Nuclear Information System (INIS)

    Lkhagvasuren, Z.; Gonchigsuren, D.; Tserendash, O.; Badamsed, Ts.P.

    2007-01-01

    Full text: Purpose: Liver cancer is considered one of the most widespread diseases around the world and every year approximately 1 million people are dying from it. 315.0 thousand people are afflicted. In Mongolia the cancer is occurring in 39.2% of 100.000 people and the main causes of the cancer are cirrhosis and viral hepatitis of which 96.6% of liver cancer is caused by virus and only 3.4% of it is not. 80% of people who have liver cancer are combined with cirrhosis and 90 % of them are getting medical help when the cancer is in the last stage. Therefore we aimed to evaluate and safety of chemoembolization in patients with Hepatocellular Carcinoma (HCC). Materials and Methods: In our study we included a total of 401 patients with liver cancer and their diagnoses were confirmed by high levels of serum alpha-fetoprotein (AFP) values, ultrasonography, computer tomography (CT), and angiographic findings. We selected another 165 patients with liver cancer who was not treated either TAE or chemotherapy as a control group and used Hitachi HD1520TM, Philips TV monitoring system for the angiographic diagnostic and embolization by Seldinger's method. Statistical analysis was performed using the χ2 test to compare differences between groups. Results were given as the mean ± standard deviation. Comparisons between group means were performed using Student's test. The level of significance was set at P<0.05. Results: The transcatheter embolization (TAE) was done in 291 patients experiencing the last stage of cancer with cancer sizes of 3.0-9.0 cm and in 43 inoperable cancer patients with cancer sizes of 1.0-3.0 cm From our research 60 patients who had cancer in left lobe of liver especially 1-4th segment and 23 (74.1 %) out of 31(51.7%) patients whose cancer size was 5,1-7,0 cm the result of operation wasn't very effective and they were able to live only 6 months to 1 year. Out of 22 patients whose cancer was in the 6, 7, and 8th segments of the right lobe, 17 of them were

  5. Breast cancer as heterogeneous disease: contributing factors and carcinogenesis mechanisms.

    Science.gov (United States)

    Kravchenko, Julia; Akushevich, Igor; Seewaldt, Victoria L; Abernethy, Amy P; Lyerly, H Kim

    2011-07-01

    The observed bimodal patterns of breast cancer incidence in the U.S. suggested that breast cancer may be viewed as more than one biological entity. We studied the factors potentially contributing to this phenomenon, specifically focusing on how disease heterogeneity could be linked to breast carcinogenesis mechanisms. Using empirical analyses and population-based biologically motivated modeling, age-specific patterns of incidence of ductal and lobular breast carcinomas from the SEER registry (1990-2003) were analyzed for heterogeneity and characteristics of carcinogenesis, stratified by race, stage, grade, and estrogen (ER)/progesterone (PR) receptor status. The heterogeneity of breast carcinoma age patterns decreased after stratification by grade, especially for grade I and III tumors. Stratification by ER/PR status further reduced the heterogeneity, especially for ER(+)/PR(-) and ER(-)/(-) tumors; however, the residual heterogeneity was still observed. The number of rate-limiting events of carcinogenesis and the latency of ductal and lobular carcinomas differed, decreasing from grade I to III, with poorly differentiated tumors associated with the least number of carcinogenesis stages and the shortest latency. Tumor grades play important role in bimodal incidence of breast carcinoma and have distinct mechanisms of carcinogenesis. Race and cancer subtype could play modifying role. ER/PR status contributes to the observed heterogeneity, but is subdominant to tumor grade. Further studies on sources of "remaining" heterogeneity of population with breast cancer (such as genetic/epigenetic characteristics) are necessary. The results of this study could suggest stratification rather than unification of breast cancer prevention strategies, risk assessment, and treatment.

  6. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia

    OpenAIRE

    Guièze, Romain; Wu, Catherine J.

    2015-01-01

    Defining features of chronic lymphocytic leukemia (CLL) are not only its immunophenotype of CD19+CD5+CD23+sIgdim expressing clonal mature B cells but also its highly variable clinical course. In recent years, advances in massively parallel sequencing technologies have led to rapid progress in our understanding of the CLL genome and epigenome. Overall, these studies have clearly demarcated not only the vast degree of genetic and epigenetic heterogeneity among individuals with CLL but also even...

  7. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castration-resistant prostate cancer: A report from the PETRUS prospective study.

    Science.gov (United States)

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-08-23

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs.Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients.

  8. Genetic heterogeneity and consanguinity lead to a "double hit": homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa.

    Science.gov (United States)

    Goldenberg-Cohen, Nitza; Banin, Eyal; Zalzstein, Yael; Cohen, Ben; Rotenstreich, Ygal; Rizel, Leah; Basel-Vanagaite, Lina; Ben-Yosef, Tamar

    2013-01-01

    Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. THE FAMILY WAS FOUND TO SEGREGATE NOVEL MUTATIONS OF TWO DIFFERENT GENES: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient.

  9. Assessing the scale of tumor heterogeneity by complete hierarchical segmentation of MRI.

    Science.gov (United States)

    Gensheimer, Michael F; Hawkins, Douglas S; Ermoian, Ralph P; Trister, Andrew D

    2015-02-07

    In many cancers, intratumoral heterogeneity has been found in histology, genetic variation and vascular structure. We developed an algorithm to interrogate different scales of heterogeneity using clinical imaging. We hypothesize that heterogeneity of perfusion at coarse scale may correlate with treatment resistance and propensity for disease recurrence. The algorithm recursively segments the tumor image into increasingly smaller regions. Each dividing line is chosen so as to maximize signal intensity difference between the two regions. This process continues until the tumor has been divided into single voxels, resulting in segments at multiple scales. For each scale, heterogeneity is measured by comparing each segmented region to the adjacent region and calculating the difference in signal intensity histograms. Using digital phantom images, we showed that the algorithm is robust to image artifacts and various tumor shapes. We then measured the primary tumor scales of contrast enhancement heterogeneity in MRI of 18 rhabdomyosarcoma patients. Using Cox proportional hazards regression, we explored the influence of heterogeneity parameters on relapse-free survival. Coarser scale of maximum signal intensity heterogeneity was prognostic of shorter survival (p = 0.05). By contrast, two fractal parameters and three Haralick texture features were not prognostic. In summary, our algorithm produces a biologically motivated segmentation of tumor regions and reports the amount of heterogeneity at various distance scales. If validated on a larger dataset, this prognostic imaging biomarker could be useful to identify patients at higher risk for recurrence and candidates for alternative treatment.

  10. Genetic control of residual variance of yearling weight in Nellore beef cattle.

    Science.gov (United States)

    Iung, L H S; Neves, H H R; Mulder, H A; Carvalheiro, R

    2017-04-01

    There is evidence for genetic variability in residual variance of livestock traits, which offers the potential for selection for increased uniformity of production. Different statistical approaches have been employed to study this topic; however, little is known about the concordance between them. The aim of our study was to investigate the genetic heterogeneity of residual variance on yearling weight (YW; 291.15 ± 46.67) in a Nellore beef cattle population; to compare the results of the statistical approaches, the two-step approach and the double hierarchical generalized linear model (DHGLM); and to evaluate the effectiveness of power transformation to accommodate scale differences. The comparison was based on genetic parameters, accuracy of EBV for residual variance, and cross-validation to assess predictive performance of both approaches. A total of 194,628 yearling weight records from 625 sires were used in the analysis. The results supported the hypothesis of genetic heterogeneity of residual variance on YW in Nellore beef cattle and the opportunity of selection, measured through the genetic coefficient of variation of residual variance (0.10 to 0.12 for the two-step approach and 0.17 for DHGLM, using an untransformed data set). However, low estimates of genetic variance associated with positive genetic correlations between mean and residual variance (about 0.20 for two-step and 0.76 for DHGLM for an untransformed data set) limit the genetic response to selection for uniformity of production while simultaneously increasing YW itself. Moreover, large sire families are needed to obtain accurate estimates of genetic merit for residual variance, as indicated by the low heritability estimates (Box-Cox transformation was able to decrease the dependence of the variance on the mean and decreased the estimates of genetic parameters for residual variance. The transformation reduced but did not eliminate all the genetic heterogeneity of residual variance, highlighting

  11. Genetic Modifiers of Sickle Cell Disease

    Science.gov (United States)

    Steinberg, Martin H.; Sebastiani, Paola

    2015-01-01

    Sickle cell anemia is associated with unusual clinical heterogeneity for a Mendelian disorder. Fetal hemoglobin concentration and coincident ∝ thalassemia, both which directly affect the sickle erythrocyte, are the major modulators of the phenotype of disease. Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia would be prognostically useful, could inform personalized therapeutics, and might help the discovery of new “druggable” pathophysiologic targets. Genotype-phenotype association studies have been used to identify novel genetic modifiers. In the future, whole genome sequencing with its promise of discovering hitherto unsuspected variants could add to our understanding of the genetic modifiers of this disease. PMID:22641398

  12. Genetic diversity in Trichomonas vaginalis.

    Science.gov (United States)

    Meade, John C; Carlton, Jane M

    2013-09-01

    Recent advances in genetic characterisation of Trichomonas vaginalis isolates show that the extensive clinical variability in trichomoniasis and its disease sequelae are matched by significant genetic diversity in the organism itself, suggesting a connection between the genetic identity of isolates and their clinical manifestations. Indeed, a high degree of genetic heterogeneity in T vaginalis isolates has been observed using multiple genotyping techniques. A unique two-type population structure that is both local and global in distribution has been identified, and there is evidence of recombination within each group, although sexual recombination between the groups appears to be constrained. There is conflicting evidence in these studies for correlations between T vaginalis genetic identity and clinical presentation, metronidazole susceptibility, and the presence of T vaginalis virus, underscoring the need for adoption of a common standard for genotyping the parasite. Moving forward, microsatellite genotyping and multilocus sequence typing are the most robust techniques for future investigations of T vaginalis genotype-phenotype associations.

  13. Genetic modelling in schizophrenia according to HLA typing.

    Science.gov (United States)

    Smeraldi, E; Macciardi, F; Gasperini, M; Orsini, A; Bellodi, L; Fabio, G; Morabito, A

    1986-09-01

    Studying families of schizophrenic patients, we observed that the risk of developing the overt form of the illness could be enhanced by some factors. Among these various factors we focused our attention on a biological variable, namely the presence or the absence of particular HLA antigens: partitioning our schizophrenic patients according to their HLA structure (i.e. those with HLA-A1 or CRAG-A1 antigens and those with HLA-non-CRAG-A1 antigens, respectively), revealed different illness distribution in the two groups. From a genetic point of view, this finding suggests the presence of heterogeneity in the hypothetical liability system related to schizophrenia and we evaluated the heterogeneity hypothesis by applying alternative genetic models to our data, trying to detect more biologically homogeneous subgroups of the disease.

  14. Cognitive and behavioral heterogeneity in genetic syndromes

    Directory of Open Access Journals (Sweden)

    Luiz F.L. Pegoraro

    2014-03-01

    Full Text Available Objective: this study aimed to investigate the cognitive and behavioral profiles, as well as the psychiatric symptoms and disorders in children with three different genetic syndromes with similar sociocultural and socioeconomic backgrounds. Methods: thirty-four children aged 6 to 16 years, with Williams-Beuren syndrome (n = 10, Prader-Willi syndrome (n = 11, and Fragile X syndrome (n = 13 from the outpatient clinics of Child Psychiatry and Medical Genetics Department were cognitively assessed through the Wechsler Intelligence Scale for Children (WISC-III. Afterwards, a full-scale intelligence quotient (IQ, verbal IQ, performance IQ, standard subtest scores, as well as frequency of psychiatric symptoms and disorders were compared among the three syndromes. Results: significant differences were found among the syndromes concerning verbal IQ and verbal and performance subtests. Post-hoc analysis demonstrated that vocabulary and comprehension subtest scores were significantly higher in Williams-Beuren syndrome in comparison with Prader-Willi and Fragile X syndromes, and block design and object assembly scores were significantly higher in Prader-Willi syndrome compared with Williams-Beuren and Fragile X syndromes. Additionally, there were significant differences between the syndromes concerning behavioral features and psychiatric symptoms. The Prader-Willi syndrome group presented a higher frequency of hyperphagia and self-injurious behaviors. The Fragile X syndrome group showed a higher frequency of social interaction deficits; such difference nearly reached statistical significance. Conclusion: the three genetic syndromes exhibited distinctive cognitive, behavioral, and psychiatric patterns. Resumo: Objetivo: investigar o perfil cognitivo e comportamental, sintomas e transtornos psiquiátricos em crianças com três diferentes síndromes genéticas, com antecedentes socioculturais e socioeconômicos semelhantes. Métodos: trinta e quatro

  15. Enhancement pattern of small hepatocellular carcinoma (HCC) at contrast-enhanced US (CEUS), MDCT, and MRI: Intermodality agreement and comparison of diagnostic sensitivity between 2005 and 2010 American Association for the Study of Liver Diseases (AASLD) guidelines

    International Nuclear Information System (INIS)

    Furlan, Alessandro; Marin, Daniele; Cabassa, Paolo; Taibbi, Adele; Brunelli, Elena; Agnello, Francesco; Lagalla, Roberto; Brancatelli, Giuseppe

    2012-01-01

    Objective: To evaluate agreement between contrast-enhanced ultrasound (CEUS), multi-detector row computed tomography (MDCT) and magnetic resonance imaging (MRI) for the assessment of typical and atypical enhancement patterns of small hepatocellular carcinoma (HCC); and to compare diagnostic sensitivity of 2005 and 2010 American Association for the Study of Liver Diseases (AASLD) guidelines. Materials and methods: Between January 2008 and December 2009, we included cirrhotic patients with newly diagnosed 10–20 mm HCC imaged at two contrast-enhanced imaging techniques among CEUS, MDCT, and MRI. Dynamic studies were reviewed by two radiologists to assess enhancement pattern. Percentage of cases with concordant findings and Cohen coefficient (k) were calculated. McNemar's test was used to compare sensitivity between 2005 and 2010 AASLD guidelines. Results: There were 91 patients (69 M; 22 F; mean age, 68 years) with 96 HCCs, studied with a combination of CEUS and MDCT (n = 59), CEUS and MRI (n = 26), or MDCT and MRI (n = 11). Intermodality agreement for assessment of tumor enhancement pattern was 67% (k = 0.294, P = 0.001). Typical enhancement pattern was detected coincidentally at two imaging modalities in 50 (52%) HCCs. Sensitivity for the diagnosis of HCC increased significantly using the 2010 AASLD (81/96 (84%) vs. 50/96 (52%), P < 0.001). Conclusions: Agreement between two imaging modalities for the detection of typical tumor enhancement pattern was reached in 52% of cases. The 2010 AASLD guidelines significantly increased the sensitivity for the diagnosis of HCC

  16. Genetic variations in STAT4,C2,HLA-DRB1 and HLA-DQ associated with risk of hepatitis B virus-related liver cirrhosis.

    Science.gov (United States)

    Jiang, De-Ke; Ma, Xiao-Pin; Wu, Xiaopan; Peng, Lijun; Yin, Jianhua; Dan, Yunjie; Huang, Hui-Xing; Ding, Dong-Lin; Zhang, Lu-Yao; Shi, Zhuqing; Zhang, Pengyin; Yu, Hongjie; Sun, Jielin; Lilly Zheng, S; Deng, Guohong; Xu, Jianfeng; Liu, Ying; Guo, Jinsheng; Cao, Guangwen; Yu, Long

    2015-11-05

    Recent genome-wide associated studies (GWASs) have revealed several common loci associated with the risk of hepatitis B virus (HBV)- or hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We selected 15 single nucleotide polymorphisms (SNPs) identified through GWASs on HBV- or HCV-related HCC, and genotyped them in two independent Chinese cohorts of chronic HBV carriers, including 712 LC cases and 2601 controls. The association of each SNP with the risk of HBV-related LC was assessed by meta-analysis of the two cohorts. Of the 12 SNPs reported in HBV-related HCC GWASs, five SNPs (rs7574865 in STAT4, rs9267673 near C2, rs2647073 and rs3997872 near HLA-DRB1 and rs9275319 near HLA-DQ), were found to be significantly associated with the risk of HBV-related LC (rs7574865: P = 1.79 × 10(-2), OR = 1.17, 95% CI = 1.03-1.34; rs9267673: P = 4.91 × 10(-4), OR = 1.37, 95% CI = 1.15-1.63; rs2647073: P = 3.53 × 10(-5), OR = 1.63, 95% CI = 1.29-2.06; rs3997872: P = 4.22 × 10(-4), OR = 1.86, 95% CI = 1.32-2.62; rs9275319: P = 1.30 × 10(-2), OR = 1.32, 95% CI = 1.06-1.64). However, among the three SNPs associated with the risk of HCV-related HCC in previous GWASs, none of them showed significant association with the risk of HBV-related LC. Our results suggested that genetic variants associated with HBV-related hepatocarcinogenesis may already play an important role in the progression from CHB to LC.

  17. A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

    Directory of Open Access Journals (Sweden)

    Clemens Krepler

    2017-11-01

    Full Text Available Summary: Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups. : Krepler et al. have established a collection of melanoma patient-derived xenografts (PDX. Melanoma is a very heterogeneous cancer, and this large collection includes even rare subtypes and genetic aberrations in sufficient numbers. Multiple PDX from therapy-resistant patients are characterized and tested in pre-clinical trials for second line therapies. Keywords: melanoma, patient-derived xenografts, targeted therapy, immune checkpoint blockade, melanoma brain metastasis, in vivo models, BRAF inhibitor resistance, ERK inhibitor, MDM2 inhibitor, PI3K beta inhibitor

  18. Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario.

    Science.gov (United States)

    Ali, Muhammad Umar; Rahman, Muhammad Saif Ur; Cao, Jiang; Yuan, Ping Xi

    2017-08-01

    Retinitis pigmentosa is a group of genetically transmitted disorders affecting 1 in 3000-8000 individual people worldwide ultimately affecting the quality of life. Retinitis pigmentosa is characterized as a heterogeneous genetic disorder which leads by progressive devolution of the retina leading to a progressive visual loss. It can occur in syndromic (with Usher syndrome and Bardet-Biedl syndrome) as well as non-syndromic nature. The mode of inheritance can be X-linked, autosomal dominant or autosomal recessive manner. To date 58 genes have been reported to associate with retinitis pigmentosa most of them are either expressed in photoreceptors or the retinal pigment epithelium. This review focuses on the disease mechanisms and genetics of retinitis pigmentosa. As retinitis pigmentosa is tremendously heterogeneous disorder expressing a multiplicity of mutations; different variations in the same gene might induce different disorders. In recent years, latest technologies including whole-exome sequencing contributing effectively to uncover the hidden genesis of retinitis pigmentosa by reporting new genetic mutations. In future, these advancements will help in better understanding the genotype-phenotype correlations of disease and likely to develop new therapies.

  19. The landscape genetics of infectious disease emergence and spread.

    Science.gov (United States)

    Biek, Roman; Real, Leslie A

    2010-09-01

    The spread of parasites is inherently a spatial process often embedded in physically complex landscapes. It is therefore not surprising that infectious disease researchers are increasingly taking a landscape genetics perspective to elucidate mechanisms underlying basic ecological processes driving infectious disease dynamics and to understand the linkage between spatially dependent population processes and the geographic distribution of genetic variation within both hosts and parasites. The increasing availability of genetic information on hosts and parasites when coupled to their ecological interactions can lead to insights for predicting patterns of disease emergence, spread and control. Here, we review research progress in this area based on four different motivations for the application of landscape genetics approaches: (i) assessing the spatial organization of genetic variation in parasites as a function of environmental variability, (ii) using host population genetic structure as a means to parameterize ecological dynamics that indirectly influence parasite populations, for example, gene flow and movement pathways across heterogeneous landscapes and the concurrent transport of infectious agents, (iii) elucidating the temporal and spatial scales of disease processes and (iv) reconstructing and understanding infectious disease invasion. Throughout this review, we emphasize that landscape genetic principles are relevant to infection dynamics across a range of scales from within host dynamics to global geographic patterns and that they can also be applied to unconventional 'landscapes' such as heterogeneous contact networks underlying the spread of human and livestock diseases. We conclude by discussing some general considerations and problems for inferring epidemiological processes from genetic data and try to identify possible future directions and applications for this rapidly expanding field.

  20. The evolving diagnostic and genetic landscapes of autism spectrum disorder

    Directory of Open Access Journals (Sweden)

    Mark Nicholas Ziats

    2016-04-01

    Full Text Available The autism spectrum disorders (ASD are a heterogeneous set of neurodevelopmental syndromes defined by impairments in verbal and non-verbal communication, restricted social interaction, and the presence of stereotyped patterns of behavior. The prevalence of ASD is rising, and the diagnostic criteria and clinical perspectives on the disorder continue to evolve in parallel. Although the majority of individuals with ASD will not have an identifiable genetic cause, almost 25% of cases have identifiable causative DNA variants. The rapidly improving ability to identify genetic mutations because of advances in next generation sequencing, coupled with previous epidemiological studies demonstrating high heritability of ASD, have led to many recent attempts to identify causative genetic mutations underlying the ASD phenotype. However, although hundreds of mutations have been identified to date, they are either rare variants affecting only a handful of ASD patients, or are common variants in the general population conferring only a small risk for ASD. Furthermore, the genes implicated thus far are heterogeneous in their structure and function, hampering attempts to understand shared molecular mechanisms among all ASD patients; an understanding that is crucial for the development of targeted diagnostics and therapies. However, new work is beginning to suggest that the heterogeneous set of genes implicated in ASD may ultimately converge on a few common pathways. In this review, we discuss the parallel evolution of our diagnostic and genetic understanding of autism spectrum disorders, and highlight recent attempts to infer common biology underlying this complicated syndrome.

  1. The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder.

    Science.gov (United States)

    Ziats, Mark N; Rennert, Owen M

    2016-01-01

    The autism spectrum disorders (ASD) are a heterogeneous set of neurodevelopmental syndromes defined by impairments in verbal and non-verbal communication, restricted social interaction, and the presence of stereotyped patterns of behavior. The prevalence of ASD is rising, and the diagnostic criteria and clinical perspectives on the disorder continue to evolve in parallel. Although the majority of individuals with ASD will not have an identifiable genetic cause, almost 25% of cases have identifiable causative DNA variants. The rapidly improving ability to identify genetic mutations because of advances in next generation sequencing, coupled with previous epidemiological studies demonstrating high heritability of ASD, have led to many recent attempts to identify causative genetic mutations underlying the ASD phenotype. However, although hundreds of mutations have been identified to date, they are either rare variants affecting only a handful of ASD patients, or are common variants in the general population conferring only a small risk for ASD. Furthermore, the genes implicated thus far are heterogeneous in their structure and function, hampering attempts to understand shared molecular mechanisms among all ASD patients; an understanding that is crucial for the development of targeted diagnostics and therapies. However, new work is beginning to suggest that the heterogeneous set of genes implicated in ASD may ultimately converge on a few common pathways. In this review, we discuss the parallel evolution of our diagnostic and genetic understanding of autism spectrum disorders, and highlight recent attempts to infer common biology underlying this complicated syndrome.

  2. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges

    Science.gov (United States)

    Hoshida, Yujin; Fuchs, Bryan C.; Tanabe, Kenneth K.

    2013-01-01

    Chronic fibrotic liver diseases such as viral hepatitis eventually develop liver cirrhosis, which causes occurrence of hepatocellular carcinoma (HCC). Given the limited therapeutic efficacy in advanced HCC, prevention of HCC development could be an effective strategy for improving patient prognosis. However, there is still no established therapy to meet the goal. Studies have elucidated a wide variety of molecular mechanisms and signaling pathways involved in HCC development. Genetically-engineered or chemically-treated experimental models of cirrhosis and HCC have been developed and shown their potential value in investigating molecular therapeutic targets and diagnostic biomarkers for HCC prevention. In this review, we overview potential targets of prevention and currently available experimental models, and discuss strategies to translate the findings into clinical practice. PMID:22873223

  3. Diagnosis of hepatocellular carcinoma with gadoxetic acid-enhanced MRI: 2016 Consensus Recommendations of the Korean Society of Abdominal Radiology

    International Nuclear Information System (INIS)

    Park, Mi-Suk

    2017-01-01

    Diagnosis of hepatocellular carcinoma (HCC) with gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) poses certain unique challenges beyond the scope of current guidelines. The regional heterogeneity of HCC in demographic characteristics, prevalence, surveillance, and socioeconomic status necessitates different treatment approaches, leading to variations in survival outcomes. Considering the medical practices in Korea, the Korean Society of Abdominal Radiology (KSAR) study group for liver diseases has developed expert consensus recommendations for diagnosis of HCC by gadoxetic acid-enhanced MRI with updated perspectives, using a modified Delphi method. During the 39th Scientific Assembly and Annual Meeting of KSAR (2016), consensus was reached on 12 of 16 statements. These recommendations might serve to ensure a more standardized diagnosis of HCC by gadoxetic acid-enhanced MRI

  4. Diagnosis of hepatocellular carcinoma with gadoxetic acid-enhanced MRI: 2016 Consensus Recommendations of the Korean Society of Abdominal Radiology

    Energy Technology Data Exchange (ETDEWEB)

    Park, Mi-Suk [Yonsei University College of Medicine, Severance Hospital, Seoul (Korea, Republic of)

    2017-06-15

    Diagnosis of hepatocellular carcinoma (HCC) with gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) poses certain unique challenges beyond the scope of current guidelines. The regional heterogeneity of HCC in demographic characteristics, prevalence, surveillance, and socioeconomic status necessitates different treatment approaches, leading to variations in survival outcomes. Considering the medical practices in Korea, the Korean Society of Abdominal Radiology (KSAR) study group for liver diseases has developed expert consensus recommendations for diagnosis of HCC by gadoxetic acid-enhanced MRI with updated perspectives, using a modified Delphi method. During the 39th Scientific Assembly and Annual Meeting of KSAR (2016), consensus was reached on 12 of 16 statements. These recommendations might serve to ensure a more standardized diagnosis of HCC by gadoxetic acid-enhanced MRI.

  5. Heterogeneity wavelet kinetics from DCE-MRI for classifying gene expression based breast cancer recurrence risk.

    Science.gov (United States)

    Mahrooghy, Majid; Ashraf, Ahmed B; Daye, Dania; Mies, Carolyn; Feldman, Michael; Rosen, Mark; Kontos, Despina

    2013-01-01

    Breast tumors are heterogeneous lesions. Intra-tumor heterogeneity presents a major challenge for cancer diagnosis and treatment. Few studies have worked on capturing tumor heterogeneity from imaging. Most studies to date consider aggregate measures for tumor characterization. In this work we capture tumor heterogeneity by partitioning tumor pixels into subregions and extracting heterogeneity wavelet kinetic (HetWave) features from breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to obtain the spatiotemporal patterns of the wavelet coefficients and contrast agent uptake from each partition. Using a genetic algorithm for feature selection, and a logistic regression classifier with leave one-out cross validation, we tested our proposed HetWave features for the task of classifying breast cancer recurrence risk. The classifier based on our features gave an ROC AUC of 0.78, outperforming previously proposed kinetic, texture, and spatial enhancement variance features which give AUCs of 0.69, 0.64, and 0.65, respectively.

  6. Simulation study on heterogeneous variance adjustment for observations with different measurement error variance

    DEFF Research Database (Denmark)

    Pitkänen, Timo; Mäntysaari, Esa A; Nielsen, Ulrik Sander

    2013-01-01

    of variance correction is developed for the same observations. As automated milking systems are becoming more popular the current evaluation model needs to be enhanced to account for the different measurement error variances of observations from automated milking systems. In this simulation study different...... models and different approaches to account for heterogeneous variance when observations have different measurement error variances were investigated. Based on the results we propose to upgrade the currently applied models and to calibrate the heterogeneous variance adjustment method to yield same genetic......The Nordic Holstein yield evaluation model describes all available milk, protein and fat test-day yields from Denmark, Finland and Sweden. In its current form all variance components are estimated from observations recorded under conventional milking systems. Also the model for heterogeneity...

  7. Differential network analysis reveals genetic effects on catalepsy modules.

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    Ovidiu D Iancu

    Full Text Available We performed short-term bi-directional selective breeding for haloperidol-induced catalepsy, starting from three mouse populations of increasingly complex genetic structure: an F2 intercross, a heterogeneous stock (HS formed by crossing four inbred strains (HS4 and a heterogeneous stock (HS-CC formed from the inbred strain founders of the Collaborative Cross (CC. All three selections were successful, with large differences in haloperidol response emerging within three generations. Using a custom differential network analysis procedure, we found that gene coexpression patterns changed significantly; importantly, a number of these changes were concordant across genetic backgrounds. In contrast, absolute gene-expression changes were modest and not concordant across genetic backgrounds, in spite of the large and similar phenotypic differences. By inferring strain contributions from the parental lines, we are able to identify significant differences in allelic content between the selected lines concurrent with large changes in transcript connectivity. Importantly, this observation implies that genetic polymorphisms can affect transcript and module connectivity without large changes in absolute expression levels. We conclude that, in this case, selective breeding acts at the subnetwork level, with the same modules but not the same transcripts affected across the three selections.

  8. A FAST AND ELITIST BI-OBJECTIVE EVOLUTIONARY ALGORITHM FOR SCHEDULING INDEPENDENT TASKS ON HETEROGENEOUS SYSTEMS

    Directory of Open Access Journals (Sweden)

    G.Subashini

    2010-07-01

    Full Text Available To meet the increasing computational demands, geographically distributed resources need to be logically coupled to make them work as a unified resource. In analyzing the performance of such distributed heterogeneous computing systems scheduling a set of tasks to the available set of resources for execution is highly important. Task scheduling being an NP-complete problem, use of metaheuristics is more appropriate in obtaining optimal solutions. Schedules thus obtained can be evaluated using several criteria that may conflict with one another which require multi objective problem formulation. This paper investigates the application of an elitist Nondominated Sorting Genetic Algorithm (NSGA-II, to efficiently schedule a set of independent tasks in a heterogeneous distributed computing system. The objectives considered in this paper include minimizing makespan and average flowtime simultaneously. The implementation of NSGA-II algorithm and Weighted-Sum Genetic Algorithm (WSGA has been tested on benchmark instances for distributed heterogeneous systems. As NSGA-II generates a set of Pareto optimal solutions, to verify the effectiveness of NSGA-II over WSGA a fuzzy based membership value assignment method is employed to choose the best compromise solution from the obtained Pareto solution set.

  9. Mutation inactivation of Nijmegen breakage syndrome gene (NBS1 in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

    Directory of Open Access Journals (Sweden)

    Yan Wang

    Full Text Available Nijmegen breakage syndrome (NBS with NBS1 germ-line mutation is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition. The NBS1 gene codes for a protein, Nbs1(p95/Nibrin, involved in the processing/repair of DNA double-strand breaks. Hepatocellular carcinoma (HCC is a complex and heterogeneous tumor with several genomic alterations. Recent studies have shown that heterozygous NBS1 mice exhibited a higher incidence of HCC than did wild-type mice. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of human primary liver cancer, including HBV-associated HCC and intrahepatic cholangiocarcinoma (ICC. Eight missense NBS1 mutations were identified in six of 64 (9.4% HCCs and two of 18 (11.1% ICCs, whereas only one synonymous mutation was found in 89 control cases of cirrhosis and chronic hepatitis B. Analysis of the functional consequences of the identified NBS1 mutations in Mre11-binding domain showed loss of nuclear localization of Nbs1 partner Mre11, one of the hallmarks for Nbs1 deficiency, in one HCC and two ICCs with NBS1 mutations. Moreover, seven of the eight tumors with NBS1 mutations had at least one genetic alteration in the TP53 pathway, including TP53 mutation, MDM2 amplification, p14ARF homozygous deletion and promoter methylation, implying a synergistic effect of Nbs1 disruption and p53 inactivation. Our findings provide novel insight on the molecular pathogenesis of primary liver cancer characterized by mutation inactivation of NBS1, a DNA repair associated gene.

  10. Cofactor of BRCA1: A new genetic marker for common malignant liver cancer

    Directory of Open Access Journals (Sweden)

    Editorial Office

    2016-08-01

    Full Text Available A new study has identified a vital gene in the pathogenesis and progression of liver cancer hepatocellular carcinoma (HCC, according to a team of biotechnology researchers at The American University in Cairo, Egypt, in a scientific paper published recently by AMOR. The study on human gene ‘Cofactor of BRCA1’ (dubbed COBRA1 and its potential role as a reliable cancer predictor for HCC is especially important due to the disease’s grim outlook. HCC is “ranked as the second most common cause of cancer-related deaths in the world in 2012,” the authors said. “Thus, it is considered as a highly aggressive cancer with poor prognosis,” they added. According to data from the Surveillance Epidemiology and End Results (SEER program, hepatocellular carcinoma accounts for 90% of all liver cancers worldwide. In the United States, HCC represents the fastest growing cause of cancer mortality overall and the second fastest growing cause of cancer deaths among women. Globally, the incidence of HCC in developing nations is over twice that of in developed countries – East Asia having highest incidence of HCC with the rate of 35 male cases per 100,000, followed by the continent of Africa. HCC mortality statistics in the developing countries is also more than double compared to the First World nations, with the annual loss of 33.5 and 23.73 lives per 100,000 in Asia and Africa, respectively. In addition, “HCC is usually diagnosed in the late stages of the tumor where, at some point, treatment is of limited efficacy. Thus, prognoses and follow-ups are necessary to regularly assess the patients and to predict any risks before the deterioration of patients’ condition,” said researcher Aya Youssef and her fellow team members. The behaviour of COBRA1 in the development and progression of several cancers has previously been studied and established, the researchers wrote. “For example, cell lines and tissues isolated from late-stage metastatic breast

  11. Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats

    NARCIS (Netherlands)

    Homberg, J.R.; Nijman, I.J.; Kuijpers, S.; Cuppen, E.

    2010-01-01

    BACKGROUND: Genetic variation in the regulatory region of the human serotonin transporter gene (SLC6A4) has been shown to affect brain functionality and personality. However, large heterogeneity in its biological effects is observed, which is at least partially due to genetic modifiers. To gain

  12. Heterogeneity of chromatin modifications in testicular spermatocytic seminoma point toward an epigenetically unstable phenotype

    DEFF Research Database (Denmark)

    Kristensen, Dina Graae; Mlynarska, Olga; Nielsen, John E

    2012-01-01

    Testicular spermatocytic seminoma (SS) is a rare tumor type predominantly found in elderly men. It is thought to originate from spermatogonia and shows cytological and genetic heterogeneity. In this study, we performed for the first time a comprehensive analysis of epigenetic modifications in a s...

  13. Insufficient evidence of benefit regarding mortality due to albumin substitution in HCC-free cirrhotic patients undergoing large volume paracentesis.

    Science.gov (United States)

    Kütting, Fabian; Schubert, Jens; Franklin, Jeremy; Bowe, Andrea; Hoffmann, Vera; Demir, Muenevver; Pelc, Agnes; Nierhoff, Dirk; Töx, Ulrich; Steffen, Hans-Michael

    2017-02-01

    Current guidelines for clinical practice recommend the infusion of human albumin after large volume paracentesis. After inspecting the current evidence behind this recommendation, we decided to conduct a systematic review and meta-analysis in order to address the effect of albumin on mortality and morbidity in the context of large volume paracentesis. We performed a comprehensive search of large databases and abstract books of conference proceedings up to March 15th 2016 for randomized controlled trials, testing the infusion of human albumin against alternatives (vs no treatment, vs plasma expanders; vs vasoconstrictors) in HCC-free patients suffering from cirrhosis. We analyzed these trials with regard to mortality, changes in plasma renin activity (PRA), hyponatremia, renal impairment, recurrence of ascites with consequential re-admission into hospital and additional complications. We employed trial sequential analysis in order to calculate the number of patients required in controlled trials to be able to determine a statistically significant advantage of the administration of one agent over another with regard to mortality. We were able to include 21 trials totaling 1277 patients. While the administration of albumin prevents a rise in PRA as well as hyponatremia, no improvement in strong clinical endpoints such as mortality could be demonstrated. Trial sequential analysis showed that at least 1550 additional patients need to be recruited into RCTs and analyzed with regard to this question in order to detect or disprove a 25% mortality effect. There is insufficient evidence that the infusion of albumin after LVP significantly lowers mortality in HCC-free patients with advanced liver disease. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  14. Genetic heterogeneity and consanguinity lead to a “double hit”: Homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa

    Science.gov (United States)

    Goldenberg-Cohen, Nitza; Banin, Eyal; Zalzstein, Yael; Cohen, Ben; Rotenstreich, Ygal; Rizel, Leah; Basel-Vanagaite, Lina

    2013-01-01

    Purpose Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. Methods The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. Results The family was found to segregate novel mutations of two different genes: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. Conclusions This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient. PMID:23882135

  15. Heterogeneity of D-Serine Distribution in the Human Central Nervous System

    Science.gov (United States)

    Suzuki, Masataka; Imanishi, Nobuaki; Mita, Masashi; Hamase, Kenji; Aiso, Sadakazu

    2017-01-01

    D-serine is an endogenous ligand for N-methyl-D-aspartate glutamate receptors. Accumulating evidence including genetic associations of D-serine metabolism with neurological or psychiatric diseases suggest that D-serine is crucial in human neurophysiology. However, distribution and regulation of D-serine in humans are not well understood. Here, we found that D-serine is heterogeneously distributed in the human central nervous system (CNS). The cerebrum contains the highest level of D-serine among the areas in the CNS. There is heterogeneity in its distribution in the cerebrum and even within the cerebral neocortex. The neocortical heterogeneity is associated with Brodmann or functional areas but is unrelated to basic patterns of cortical layer structure or regional expressional variation of metabolic enzymes for D-serine. Such D-serine distribution may reflect functional diversity of glutamatergic neurons in the human CNS, which may serve as a basis for clinical and pharmacological studies on D-serine modulation. PMID:28604057

  16. Large epidemic thresholds emerge in heterogeneous networks of heterogeneous nodes

    Science.gov (United States)

    Yang, Hui; Tang, Ming; Gross, Thilo

    2015-08-01

    One of the famous results of network science states that networks with heterogeneous connectivity are more susceptible to epidemic spreading than their more homogeneous counterparts. In particular, in networks of identical nodes it has been shown that network heterogeneity, i.e. a broad degree distribution, can lower the epidemic threshold at which epidemics can invade the system. Network heterogeneity can thus allow diseases with lower transmission probabilities to persist and spread. However, it has been pointed out that networks in which the properties of nodes are intrinsically heterogeneous can be very resilient to disease spreading. Heterogeneity in structure can enhance or diminish the resilience of networks with heterogeneous nodes, depending on the correlations between the topological and intrinsic properties. Here, we consider a plausible scenario where people have intrinsic differences in susceptibility and adapt their social network structure to the presence of the disease. We show that the resilience of networks with heterogeneous connectivity can surpass those of networks with homogeneous connectivity. For epidemiology, this implies that network heterogeneity should not be studied in isolation, it is instead the heterogeneity of infection risk that determines the likelihood of outbreaks.

  17. Large epidemic thresholds emerge in heterogeneous networks of heterogeneous nodes.

    Science.gov (United States)

    Yang, Hui; Tang, Ming; Gross, Thilo

    2015-08-21

    One of the famous results of network science states that networks with heterogeneous connectivity are more susceptible to epidemic spreading than their more homogeneous counterparts. In particular, in networks of identical nodes it has been shown that network heterogeneity, i.e. a broad degree distribution, can lower the epidemic threshold at which epidemics can invade the system. Network heterogeneity can thus allow diseases with lower transmission probabilities to persist and spread. However, it has been pointed out that networks in which the properties of nodes are intrinsically heterogeneous can be very resilient to disease spreading. Heterogeneity in structure can enhance or diminish the resilience of networks with heterogeneous nodes, depending on the correlations between the topological and intrinsic properties. Here, we consider a plausible scenario where people have intrinsic differences in susceptibility and adapt their social network structure to the presence of the disease. We show that the resilience of networks with heterogeneous connectivity can surpass those of networks with homogeneous connectivity. For epidemiology, this implies that network heterogeneity should not be studied in isolation, it is instead the heterogeneity of infection risk that determines the likelihood of outbreaks.

  18. Programming strategy for efficient modeling of dynamics in a population of heterogeneous cells.

    Science.gov (United States)

    Hald, Bjørn Olav; Garkier Hendriksen, Morten; Sørensen, Preben Graae

    2013-05-15

    Heterogeneity is a ubiquitous property of biological systems. Even in a genetically identical population of a single cell type, cell-to-cell differences are observed. Although the functional behavior of a given population is generally robust, the consequences of heterogeneity are fairly unpredictable. In heterogeneous populations, synchronization of events becomes a cardinal problem-particularly for phase coherence in oscillating systems. The present article presents a novel strategy for construction of large-scale simulation programs of heterogeneous biological entities. The strategy is designed to be tractable, to handle heterogeneity and to handle computational cost issues simultaneously, primarily by writing a generator of the 'model to be simulated'. We apply the strategy to model glycolytic oscillations among thousands of yeast cells coupled through the extracellular medium. The usefulness is illustrated through (i) benchmarking, showing an almost linear relationship between model size and run time, and (ii) analysis of the resulting simulations, showing that contrary to the experimental situation, synchronous oscillations are surprisingly hard to achieve, underpinning the need for tools to study heterogeneity. Thus, we present an efficient strategy to model the biological heterogeneity, neglected by ordinary mean-field models. This tool is well posed to facilitate the elucidation of the physiologically vital problem of synchronization. The complete python code is available as Supplementary Information. bjornhald@gmail.com or pgs@kiku.dk Supplementary data are available at Bioinformatics online.

  19. Assessing the scale of tumor heterogeneity by complete hierarchical segmentation of MRI

    International Nuclear Information System (INIS)

    Gensheimer, Michael F; Ermoian, Ralph P; Hawkins, Douglas S; Trister, Andrew D

    2015-01-01

    In many cancers, intratumoral heterogeneity has been found in histology, genetic variation and vascular structure. We developed an algorithm to interrogate different scales of heterogeneity using clinical imaging. We hypothesize that heterogeneity of perfusion at coarse scale may correlate with treatment resistance and propensity for disease recurrence. The algorithm recursively segments the tumor image into increasingly smaller regions. Each dividing line is chosen so as to maximize signal intensity difference between the two regions. This process continues until the tumor has been divided into single voxels, resulting in segments at multiple scales. For each scale, heterogeneity is measured by comparing each segmented region to the adjacent region and calculating the difference in signal intensity histograms. Using digital phantom images, we showed that the algorithm is robust to image artifacts and various tumor shapes. We then measured the primary tumor scales of contrast enhancement heterogeneity in MRI of 18 rhabdomyosarcoma patients. Using Cox proportional hazards regression, we explored the influence of heterogeneity parameters on relapse-free survival. Coarser scale of maximum signal intensity heterogeneity was prognostic of shorter survival (p = 0.05). By contrast, two fractal parameters and three Haralick texture features were not prognostic. In summary, our algorithm produces a biologically motivated segmentation of tumor regions and reports the amount of heterogeneity at various distance scales. If validated on a larger dataset, this prognostic imaging biomarker could be useful to identify patients at higher risk for recurrence and candidates for alternative treatment. (paper)

  20. An Update on the Genetics of Usher Syndrome

    OpenAIRE

    José M. Millán; Elena Aller; Teresa Jaijo; Fiona Blanco-Kelly; Ascensión Gimenez-Pardo; Carmen Ayuso

    2011-01-01

    Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive...

  1. Long-term results of interventional treatment of large unresectable hepatocellular carcinoma (HCC): significant survival benefit from combined transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) compared to TACE monotherapy; Langzeitergebnisse der interventionellen Therapie von grossen, inoperablen hepatozellulaeren Karzinomen (HCC): signifikanter Ueberlebensvorteil von transarterieller Chemoembolisation (TACE) und perkutaner Ethanolinjektion (PEI) gegenueber der TACE-Monotherapie

    Energy Technology Data Exchange (ETDEWEB)

    Lubienski, A.; Bitsch, R.G.; Grenacher, L.; Kauffmann, G.W. [Radiologische Universitaetsklinik Heidelberg, Abt. Radiodiagnostik, Heidelberg (Germany); Schemmer, P. [Chirurgische Universitaetsklinik Heidelberg (Germany); Duex, M. [Radiologisches Zentralinstitut Krankenhaus Nordwest Frankfurt (Germany)

    2004-12-01

    Purpose: A retrospective analysis of long-term efficacy of combined transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) and TACE monotherapy was conducted in patients with large, non-resectable hepatocellular carcinoma (HCC). Methods and Materials: Fifty patients with large, unresectable HCC lesions underwent selective TACE. Liver cirrhosis was present in 42 patients, due to alcohol abuse (n = 22) and viral infection (n = 17). In three patients, the underlying cause for liver cirrhosis remained unclear. Child A cirrhosis was found in 22 and Child B cirrhosis in 20 patients. Repeated and combined TACE and PEI were performed in 22 patients and repeated TACE monotherapy was performed in 28 patients. Survival and complication rates were determined and compared. Results: The 6-, 12-, 24- and 36-month survival rates were 61%, 21%, 4%, and 4% for TACE monotherapy and 77%, 55%, 39% and 22% for combined TACE and PEI (Kaplan-Meier method). The kind of treatment significantly affected the survival rate (p=0.002 log-rank test). Severe side effects were present in two patients of the monotherapy group and in three patients of the combination therapy group. (orig.)

  2. Genetic resources as the backbone of plant protection

    International Nuclear Information System (INIS)

    Frankel, O.H.

    1977-01-01

    The defence against parasites has come to be regarded as probably the biggest problem in the production of the plants on which our own survival depends. The problem has always been there, but in our pure-bred cultivars extending over large areas it has assumed disaster proportions. The wild ancestors of many crop species evolved in balance with parasite species, their regions of genetic diversity coinciding. Domestication led to geographical dispersal and genetic differentiation of host and, presumably, of parasite species. Genetic heterogeneity may have been the saving grace of the primitive cultivars by which fairly stable populations lived for some 5000 to 10,000 years. We are now aware of the advantages and of the dangers of genetic homogeneity, and ''genetic vulnerability'' is now more than a catch phrase. We are responding to it in a variety of ways, each involving some use of new or increased genetic variation. They extend from the search for new oligogenic resistance sources, to multiple resistance, and to the various forms of ''horizontal'' or polygenic resistance. We turn to the genetic resources accumulated in the much neglected wild and primitive gene pools which helped our ancestors to survive epidemics. And we turn further towards the full circle by deliberately adopting heterogeneity in multilines of various descriptions and in varietal blends. The rate at which resistance sources are ''used up'' in the different systems now in use is discussed, in the light of the urgent need for economizing and preserving both the now used and the as yet unexplored resistance sources, on which the future stability of crop production will depend. (author)

  3. An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options

    Institute of Scientific and Technical Information of China (English)

    Anne Masi; Marilena M.DeMayo; Nicholas Glozier; Adam J.Guastella

    2017-01-01

    Since the documented observations of Kanner in 1943,there has been great debate about the diagnoses,the sub-types,and the diagnostic threshold that relates to what is now known as autism spectrum disorder (ASD).Reflecting this complicated history,there has been continual refinement from DSM-Ⅲ with ‘Infantile Autism’ to the current DSM-Ⅴ diagnosis.The disorder is now widely accepted as a complex,pervasive,heterogeneous condition with multiple etiologies,sub-types,and developmental trajectories.Diagnosis remains based on observation of atypical behaviors,with criteria of persistent deficits in social communication and restricted and repetitive patterns of behavior.This review provides a broad overview of the history,prevalence,etiology,clinical presentation,and heterogeneity of ASD.Factors contributing to heterogeneity,including genetic variability,comorbidity,and gender are reviewed.We then explore current evidencebased pharmacological and behavioral treatments for ASD and highlight the complexities of conducting clinical trials that evaluate therapeutic efficacy in ASD populations.Finally,we discuss the potential of a new wave of research examining objective biomarkers to facilitate the evaluation of sub-typing,diagnosis,and treatment response in ASD.

  4. MetaRanker 2.0: a web server for prioritization of genetic variation data

    DEFF Research Database (Denmark)

    Pers, Tune Hannes; Dworzynski, Piotr; Thomas, Cecilia Engel

    2013-01-01

    MetaRanker 2.0 is a web server for prioritization of common and rare frequency genetic variation data. Based on heterogeneous data sets including genetic association data, protein–protein interactions, large-scale text-mining data, copy number variation data and gene expression experiments, Meta...

  5. A family-based joint test for mean and variance heterogeneity for quantitative traits.

    Science.gov (United States)

    Cao, Ying; Maxwell, Taylor J; Wei, Peng

    2015-01-01

    Traditional quantitative trait locus (QTL) analysis focuses on identifying loci associated with mean heterogeneity. Recent research has discovered loci associated with phenotype variance heterogeneity (vQTL), which is important in studying genetic association with complex traits, especially for identifying gene-gene and gene-environment interactions. While several tests have been proposed to detect vQTL for unrelated individuals, there are no tests for related individuals, commonly seen in family-based genetic studies. Here we introduce a likelihood ratio test (LRT) for identifying mean and variance heterogeneity simultaneously or for either effect alone, adjusting for covariates and family relatedness using a linear mixed effect model approach. The LRT test statistic for normally distributed quantitative traits approximately follows χ(2)-distributions. To correct for inflated Type I error for non-normally distributed quantitative traits, we propose a parametric bootstrap-based LRT that removes the best linear unbiased prediction (BLUP) of family random effect. Simulation studies show that our family-based test controls Type I error and has good power, while Type I error inflation is observed when family relatedness is ignored. We demonstrate the utility and efficiency gains of the proposed method using data from the Framingham Heart Study to detect loci associated with body mass index (BMI) variability. © 2014 John Wiley & Sons Ltd/University College London.

  6. Cancer Metabolism and Tumor Heterogeneity: Imaging Perspectives Using MR Imaging and Spectroscopy

    Directory of Open Access Journals (Sweden)

    Gigin Lin

    2017-01-01

    Full Text Available Cancer cells reprogram their metabolism to maintain viability via genetic mutations and epigenetic alterations, expressing overall dynamic heterogeneity. The complex relaxation mechanisms of nuclear spins provide unique and convertible tissue contrasts, making magnetic resonance imaging (MRI and magnetic resonance spectroscopy (MRS pertinent imaging tools in both clinics and research. In this review, we summarized MR methods that visualize tumor characteristics and its metabolic phenotypes on an anatomical, microvascular, microstructural, microenvironmental, and metabolomics scale. The review will progress from the utilities of basic spin-relaxation contrasts in cancer imaging to more advanced imaging methods that measure tumor-distinctive parameters such as perfusion, water diffusion, magnetic susceptibility, oxygenation, acidosis, redox state, and cell death. Analytical methods to assess tumor heterogeneity are also reviewed in brief. Although the clinical utility of tumor heterogeneity from imaging is debatable, the quantification of tumor heterogeneity using functional and metabolic MR images with development of robust analytical methods and improved MR methods may offer more critical roles of tumor heterogeneity data in clinics. MRI/MRS can also provide insightful information on pharmacometabolomics, biomarker discovery, disease diagnosis and prognosis, and treatment response. With these future directions in mind, we anticipate the widespread utilization of these MR-based techniques in studying in vivo cancer biology to better address significant clinical needs.

  7. Clinical implications of heterogeneity of tumor response to radiation therapy

    International Nuclear Information System (INIS)

    Suit, H.; Skates, S.; Taghian, A.; Okunieff, P.; Efird, J.T.

    1992-01-01

    Heterogeneity of response of tumor tissue to radiation clearly exists. Major parameters include histopathologic type, size (number of tumor rescue units (TRUs)), hemoglobin concentration, cell proliferation kinetics and immune rejection reaction by host. Further, normal and presumably tumor tissue response is altered in certain genetic diseases, e.g. ataxia telangiectasia. Any assessment of response of tumor tissue to a new treatment method or the testing of a new clinical response predictor is optimally based upon a narrow strata, viz., uniform with respect to known parameters of response, e.g. size, histological type. Even among tumors of such a clinical defined narrow strata, there will be residual heterogeneity with respect to inherent cellular radiation sensitivity, distributions of pO 2 , (SH), cell proliferation, etc. (author). 39 refs., 7 figs., 3 tabs

  8. Pitfalls in setting up genetic studies on preeclampsia.

    Science.gov (United States)

    Laivuori, Hannele

    2013-04-01

    This presentation will consider approaches to discover susceptibility genes for a complex genetic disorder such as preeclampsia. The clinical disease presumably results from the additive effects of multiple sequence variants from the mother and the foetus together with environmental factors. Disease heterogeneity and underpowered study designs are likely to be behind non-reproducible results in candidate gene association studies. To avoid spurious findings, sample size and characteristics of the study populations as well as replication studies in an independent study population should be an essential part of a study design. In family-based linkage studies relationship with genotype and phenotype may be modified by a variety of factors. The large number of families needed in discovering genetic variants with modest effect sizes is difficult to attain. Moreover, the identification of underlying mutations has proven difficult. When pooling data or performing meta-analyses from different populations, disease and locus heterogeneity may become a major issue. First genome-wide association studies (GWAS) have identified risk loci for preeclampsia. Adequately powered replication studies are critical in order to replicate the initial GWAS findings. This approach requires rigorous multiple testing correction. The expected effect sizes of individual sequence variants on preeclampsia are small, but this approach is likely to decipher new clues to the pathogenesis. The rare variants, gene-gene and gene-environmental interactions as well as noncoding genetic variations and epigenetics are expected to explain the missing heritability. Next-generation sequencing technologies will make large amount of data on genomes and transcriptomes available. Complexity of the data poses a challenge. Different depths of coverage might be chosen depending on the design of the study, and validation of the results by different methods is mandatory. In order to minimize disease heterogeneity in

  9. Polymeric nanoparticles as cancer-specific DNA delivery vectors to human hepatocellular carcinoma.

    Science.gov (United States)

    Zamboni, Camila G; Kozielski, Kristen L; Vaughan, Hannah J; Nakata, Maisa M; Kim, Jayoung; Higgins, Luke J; Pomper, Martin G; Green, Jordan J

    2017-10-10

    Hepatocellular carcinoma (HCC) is the third most deadly cancer in the US, with a meager 5-year survival rate of effective and cancer-specific DNA delivery to human HCC using biodegradable poly(beta-amino ester) (PBAE) nanoparticles (NPs). Varied PBAE NP formulations were evaluated for transfection efficacy and cytotoxicity to a range of human HCC cells as well as healthy human hepatocytes. To address HCC heterogeneity, nine different sources of human HCC cells were utilized. The polymeric NPs composed of 2-((3-aminopropyl)amino) ethanol end-modified poly(1,5-pentanediol diacrylate-co-3-amino-1-propanol) ('536') at a 25 polymer-to-DNA weight-to-weight ratio led to high transfection efficacy to all of the liver cancer lines, but not to hepatocytes. Each individual HCC line had a significantly higher percentage of exogenous gene expression than the healthy liver cells (Peffective DNA transfection in vivo. PBAE-based NPs enabled high and preferential DNA delivery to HCC cells, sparing healthy hepatocytes. These biodegradable and liver cancer-selective NPs are a promising technology to deliver therapeutic genes to liver cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. A compendium of genetic variant data

    DEFF Research Database (Denmark)

    Cardoso, Joao; Schöning, Lars Yannik; Herrgard, Markus

    2014-01-01

    database where the physiological characteristics of mutants can easily be queried. This database contains the experimental information sorted into normalized units. The aim of this repository is to become a golden-­standard of genetic variation information for microorganisms, providing standardized data......Laboratory strains are genetically unstable if exposed to selective pressure as encountered, for example, during molecular cloning, fermentation, or adaptive laboratory evolution experiments. This genetic variation is the consequence of an adaptation process of the microorganism to stress...... the effects of those variations, it is necessary to collect and sort this genomic information in an organized fashion, including all relevant physiological data (e.g., growth rate, metabolomics, proteomics, transcriptomics, etc.). We propose a systematic way to collect heterogeneous datasets into a coherent...

  11. Phenotypic heterogeneity in modeling cancer evolution.

    Directory of Open Access Journals (Sweden)

    Ali Mahdipour-Shirayeh

    Full Text Available The unwelcome evolution of malignancy during cancer progression emerges through a selection process in a complex heterogeneous population structure. In the present work, we investigate evolutionary dynamics in a phenotypically heterogeneous population of stem cells (SCs and their associated progenitors. The fate of a malignant mutation is determined not only by overall stem cell and non-stem cell growth rates but also differentiation and dedifferentiation rates. We investigate the effect of such a complex population structure on the evolution of malignant mutations. We derive exactly calculated results for the fixation probability of a mutant arising in each of the subpopulations. The exactly calculated results are in almost perfect agreement with the numerical simulations. Moreover, a condition for evolutionary advantage of a mutant cell versus the wild type population is given in the present study. We also show that microenvironment-induced plasticity in invading mutants leads to more aggressive mutants with higher fixation probability. Our model predicts that decreasing polarity between stem and non-stem cells' turnover would raise the survivability of non-plastic mutants; while it would suppress the development of malignancy for plastic mutants. The derived results are novel and general with potential applications in nature; we discuss our model in the context of colorectal/intestinal cancer (at the epithelium. However, the model clearly needs to be validated through appropriate experimental data. This novel mathematical framework can be applied more generally to a variety of problems concerning selection in heterogeneous populations, in other contexts such as population genetics, and ecology.

  12. A New Player in the Development of TRAIL Based Therapies for Hepatocarcinoma Treatment: ATM Kinase

    International Nuclear Information System (INIS)

    Stagni, Venturina; Santini, Simonetta; Barilà, Daniela

    2012-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCCs are genetically and phenotypically heterogeneous tumors characterized by very poor prognosis, mainly due to the lack, at present, of effective therapeutic options, as these tumors are rarely suitable for radiotherapy and often resistant to chemotherapy protocols. In the last years, agonists targeting the Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) death receptor, has been investigated as a valuable promise for cancer therapy, based on their selectivity for malignant cells and low toxicity for healthy cells. However, many cancer models display resistance to death receptor induced apoptosis, pointing to the requirement for the development of combined therapeutic approaches aimed to selectively sensitize cancer cells to TRAIL. Recently, we identified ATM kinase as a novel modulator of the ability of chemotherapeutic agents to enhance TRAIL sensitivity. Here, we review the biological determinants of HCC responsiveness to TRAIL and provide an exhaustive and updated analysis of the molecular mechanisms exploited for combined therapy in this context. The role of ATM kinase as potential novel predictive biomarker for combined therapeutic approaches based on TRAIL and chemotherapeutic drugs will be closely discussed

  13. Molecular Signature and Mechanisms of Hepatitis D Virus-Associated Hepatocellular Carcinoma.

    Science.gov (United States)

    Diaz, Giacomo; Engle, Ronald E; Tice, Ashley; Melis, Marta; Montenegro, Stephanie; Rodriguez-Canales, Jaime; Hanson, Jeffrey; Emmert-Buck, Michael R; Bock, Kevin W; Moore, Ian N; Zamboni, Fausto; Govindarajan, Sugantha; Kleiner, David; Farci, Patrizia

    2018-06-01

    There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC (n-5) and with non-HCC HDV cirrhosis (n=7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture-microdissected (LCM) malignant and non-malignant hepatocytes, tumorous and non-tumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of up-regulated transcripts associated with pathways involved in cell cycle/DNA replication, damage and repair (sonic hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell cycle regulation, cell cycle: G2/M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being over-expressed, these genes were also strongly co-regulated. Gene co-regulation was high not only when compared to non-malignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and co-regulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus-associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms. This study identifies a molecular signature of HDV

  14. A novel oncolytic adenovirus targeting Wnt signaling effectively inhibits cancer-stem like cell growth via metastasis, apoptosis and autophagy in HCC models.

    Science.gov (United States)

    Zhang, Jian; Lai, Weijie; Li, Qiang; Yu, Yang; Jin, Jin; Guo, Wan; Zhou, Xiumei; Liu, Xinyuan; Wang, Yigang

    2017-09-16

    Cancer stem cells (CSCs), which are highly differentiated and self-renewing, play an important role in the occurrence, therapeutic resistant and metastasis of hepatacellular carcinoma (HCC). Oncolytic adenoviruses have targeted killing effect on tumor cells, and are invoked as candidate drugs for cancer treatment. We designed a dual-regulated oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 that targets Wnt and Rb signaling pathways respectively, and carries the tumor suppressor gene, TSLC1. Previous studies have demonstrated that oncolytic adenovirus mediated TSLC1can target liver cancer and exhibit significant cytotoxicity. However, whether Ad.wnt-E1A(△24bp)-TSLC1 can effectively eliminate liver CSCs remains to be explored. We first used the spheroid culture to enrich the liver CSCs-like cells, and detected the self-renewal capacity, differentiation, drug resistance and tumorigenicity. The results showed that Ad-wnt-E1A(△24bp)-TSLC1 could effectively lead to autophagic death. In addition, recombinant adenovirus effectively induced the apoptosis, inhibit metastasis of hepatic CSCs-like cells in vivo. Further animal experiments indicated that Ad-wnt-E1A(△24bp)-TSLC1could effectively inhibit the growth of transplanted tumor of hepatic CSCs and prolong the survival time of mice. Therefore, the novel oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 has potential application as a therapeutic target for HCC stem cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Biology of lung cancer: genetic mutation, epithelial-mesenchymal transition, and cancer stem cells.

    Science.gov (United States)

    Aoi, Takashi

    2016-09-01

    At present, most cases of unresectable cancer cannot be cured. Genetic mutations, EMT, and cancer stem cells are three major issues linked to poor prognosis in such cases, all connected by inter- and intra-tumor heterogeneity. Issues on inter-/intra-tumor heterogeneity of genetic mutation could be resolved with recent and future technologies of deep sequencers, whereas, regarding such issues as the "same genome, different epigenome/phenotype", we expect to solve many of these problems in the future through further research in stem cell biology. We herein review and discuss the three major issues in the biology of cancers, especially from the standpoint of stem cell biology.

  16. Journal of Genetics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    the points of introduction of mutant alleles for cat coat phenotypes from Europe into Latin America,; the heterozygosity levels at these loci in the current Latin American cat populations,; the level of genetic heterogeneity among Latin American cat populations, and how this compares with levels found in North American and ...

  17. Lack of sex-biased dispersal promotes fine-scale genetic structure in alpine ungulates

    Science.gov (United States)

    Gretchen H. Roffler; Sandra L. Talbot; Gordon Luikart; George K. Sage; Kristy L. Pilgrim; Layne G. Adams; Michael K. Schwartz

    2014-01-01

    Identifying patterns of fine-scale genetic structure in natural populations can advance understanding of critical ecological processes such as dispersal and gene flow across heterogeneous landscapes. Alpine ungulates generally exhibit high levels of genetic structure due to female philopatry and patchy configuration of mountain habitats. We assessed the spatial scale...

  18. Genetic Manipulation of Outer Membrane Permeability: Generating Porous Heterogeneous Catalyst Analogs in Escherichia coli

    Energy Technology Data Exchange (ETDEWEB)

    Patel, TN; Park, AHA; Bantat, S

    2014-12-01

    The limited permeability of the E. coli outer membrane can significantly hinder whole-cell biocatalyst performance. In this study, the SARS coronavirus small envelope protein (SCVE) was expressed in E. coli cells previously engineered for periplasmic expression of carbonic anhydrase (CA) activity. This maneuver increased small molecule uptake by the cells, resulting in increased apparent CA activity of the biocatalysts. The enhancements in activity were quantified using methods developed for traditional heterogeneous catalysis. The expression of the SCVE protein was found to significantly reduce the Thiele moduli (phi), as well as increase the effectiveness factors (eta), effective diffusivities (D-e), and permeabilities (P) of the biocatalysts. These catalytic improvements translated into superior performance of the biocatalysts for the precipitation of calcium carbonate from solution which is an attractive strategy for long-term sequestration of captured carbon dioxide. Overall, these results demonstrate that synthetic biology approaches can be used to enhance heterogeneous catalysts incorporated into microbial whole-cell scaffolds.

  19. Muscle MRI in pediatrics: clinical, pathological and genetic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Cejas, Claudia P.; Serra, Maria M.; Galvez, David F.G. [Foundation for Neurological Research Dr. Raul Carrea (FLENI), Radiology Department, Buenos Aires (Argentina); Cavassa, Eliana A.; Vazquez, Gabriel A.; Massaro, Mario E.L.; Schteinschneider, Angeles V. [Foundation for Neurological Research Dr. Raul Carrea (FLENI), Department of Neuropediatrics, Buenos Aires (Argentina); Taratuto, Ana L. [Foundation for Neurological Research Dr. Raul Carrea (FLENI), Neuropathology Consultant, Buenos Aires (Argentina)

    2017-05-15

    Pediatric myopathies comprise a very heterogeneous group of disorders that may develop at different ages and affect different muscle groups. Its diagnosis is sometimes difficult and must be confirmed by muscle biopsy and/or genetic analysis. In recent years, muscle involvement patterns observed on MRI have become a valuable tool, aiding clinical diagnosis and enriching pathological and genetic assessments. We selected eight myopathy cases from our institutional database in which the pattern of muscle involvement observed on MRI was almost pathognomonic and could therefore contribute to establishing diagnosis. Muscle biopsy, genetic diagnosis or both confirmed all cases. (orig.)

  20. Muscle MRI in pediatrics: clinical, pathological and genetic correlation

    International Nuclear Information System (INIS)

    Cejas, Claudia P.; Serra, Maria M.; Galvez, David F.G.; Cavassa, Eliana A.; Vazquez, Gabriel A.; Massaro, Mario E.L.; Schteinschneider, Angeles V.; Taratuto, Ana L.

    2017-01-01

    Pediatric myopathies comprise a very heterogeneous group of disorders that may develop at different ages and affect different muscle groups. Its diagnosis is sometimes difficult and must be confirmed by muscle biopsy and/or genetic analysis. In recent years, muscle involvement patterns observed on MRI have become a valuable tool, aiding clinical diagnosis and enriching pathological and genetic assessments. We selected eight myopathy cases from our institutional database in which the pattern of muscle involvement observed on MRI was almost pathognomonic and could therefore contribute to establishing diagnosis. Muscle biopsy, genetic diagnosis or both confirmed all cases. (orig.)

  1. Genetic background impacts vaccine-induced reduction of pneumococcal colonization

    NARCIS (Netherlands)

    Kuipers, Kirsten; Van Selm, Saskia; van Opzeeland, Fred; Langereis, Jeroen D.; Verhagen, Lilly M.; Diavatopoulos, Dimitri A.; De Jonge, Marien I.

    2017-01-01

    Vaccination has been one of the most successful strategies to reduce morbidity and mortality caused by respiratory infections. Recent evidence suggests that differences in the host genetic background and environmental factors may contribute to heterogeneity in the immune response to vaccination.

  2. Congenital hydrocephalus in clinical practice : A genetic diagnostic approach

    NARCIS (Netherlands)

    Verhagen, J. M. A.; Schrander-Stumpel, C. T. R. M.; Krapels, P. C.; de Die-Smulders, C. E. M.; van Lint, F. H. M.; Willekes, C.; Weber, J. W.; Gavilanes, A. W. D.; Macville, M. V. E.; Stegmann, A. P. A.; Engelen, J. J. M.; Bakker, J.; Vos, Y. J.; Frints, S. G. M.

    2011-01-01

    Congenital hydrocephalus is a common and often disabling disorder. The etiology is very heterogeneous. Little is known about the genetic causes of congenital hydrocephalus. A retrospective survey was performed including patients with primary congenital hydrocephalus referred to the Department of

  3. Association between pretreatment retention rate of indocyanine green 15 min after administration and life prognosis in patients with HCC treated by proton beam therapy

    International Nuclear Information System (INIS)

    Mizumoto, Masashi; Oshiro, Yoshiko; Okumura, Toshiyuki; Fukuda, Kuniaki; Fukumitsu, Nobuyoshi; Abei, Masato; Ishikawa, Hitoshi; Ohnishi, Kayoko; Numajiri, Haruko; Tsuboi, Koji; Sakurai, Hideyuki

    2014-01-01

    Purpose: The Child-Pugh score is often used to judge the outcome of radiotherapy for hepatocellular carcinoma (HCC). The retention rate of indocyanine green 15 min after administration (ICG R15) can also be used to predict prognosis after liver resection. We evaluated the utility of ICG R15 for prediction of outcomes after proton beam therapy (PBT) for HCC. Methods and materials: A retrospective evaluation was performed in 250 patients who received PBT between 2002 and 2007. The patients (178 males and 72 females) had a median age of 71 years (range: 43–88). Child-Pugh categories were A (score 5–6), B (7–9), and C (10–15) in 197, 51, and 2 patients, respectively. ICG scores were 0–<10, 10–<20, 20–<30, 30–<40 and ⩾40 in 27, 99, 59, 28 and 37 patients, respectively; including 26, 92, 45, 16 and 18 Child-Pugh A patients and 1, 8, 14, 11, and 17 Child-Pugh B patients, respectively. Survival times from the start of PBT were compared between Child-Pugh A and B patients, and among each ICG group. Results: The median survival times were 61 months (95% CI: 50–72 months) in all patients, and 64 and 20 months in Child-Pugh A and B patients, respectively (p = 0.001), The 3-year survival rates were 72%, 72%, 75%, 63%, and 26% in patients with ICG scores of 0–<10, 10–<20, 20–<30, 30–<40, and ⩾40 (p = 0.001); 70%, 75%, 77%, 65%, and 38% in these respective groups in Child-Pugh A patients (p = 0.02); and 100%, 57%, 67%, 36%, and 14% in Child-Pugh B patients (p = 0.173, not significant). Multivariate analysis showed that low ICG R15 and the absence of portal vein tumor thrombus were associated with good survival. Conclusions: Pretreatment ICG R15 is a useful prognostic factor for prediction of outcome of PBT in HCC patients, especially in those with Child-Pugh A liver function

  4. Molecular Heterogeneity in Primary Breast Carcinomas and Axillary Lymph Node Metastases Assessed by Genomic Fingerprinting Analysis

    Science.gov (United States)

    Ellsworth, Rachel E; Toro, Allyson L; Blackburn, Heather L; Decewicz, Alisha; Deyarmin, Brenda; Mamula, Kimberly A; Costantino, Nicholas S; Hooke, Jeffrey A; Shriver, Craig D; Ellsworth, Darrell L

    2015-01-01

    Molecular heterogeneity within primary breast carcinomas and among axillary lymph node (LN) metastases may impact diagnosis and confound treatment. In this study, we used short tandem repeated sequences to assess genomic heterogeneity and to determine hereditary relationships among primary tumor areas and regional metastases from 30 breast cancer patients. We found that primary carcinomas were genetically heterogeneous and sampling multiple areas was necessary to adequately assess genomic variability. LN metastases appeared to originate at different time periods during disease progression from different sites of the primary tumor and the extent of genomic divergence among regional metastases was associated with a less favorable patient outcome (P = 0.009). In conclusion, metastasis is a complex process influenced by primary tumor heterogeneity and variability in the timing of dissemination. Genomic variation in primary breast tumors and regional metastases may negatively impact clinical diagnostics and contribute to therapeutic resistance. PMID:26279627

  5. Molecular Heterogeneity in Primary Breast Carcinomas and Axillary Lymph Node Metastases Assessed by Genomic Fingerprinting Analysis

    Directory of Open Access Journals (Sweden)

    Rachel E. Ellsworth

    2015-01-01

    Full Text Available Molecular heterogeneity within primary breast carcinomas and among axillary lymph node (LN metastases may impact diagnosis and confound treatment. In this study, we used short tandem repeated sequences to assess genomic heterogeneity and to determine hereditary relationships among primary tumor areas and regional metastases from 30 breast cancer patients. We found that primary carcinomas were genetically heterogeneous and sampling multiple areas was necessary to adequately assess genomic variability. LN metastases appeared to originate at different time periods during disease progression from different sites of the primary tumor and the extent of genomic divergence among regional metastases was associated with a less favorable patient outcome ( P = 0.009. In conclusion, metastasis is a complex process influenced by primary tumor heterogeneity and variability in the timing of dissemination. Genomic variation in primary breast tumors and regional metastases may negatively impact clinical diagnostics and contribute to therapeutic resistance.

  6. Cancer Metabolism and Tumor Heterogeneity: Imaging Perspectives Using MR Imaging and Spectroscopy

    OpenAIRE

    Lin, Gigin; Keshari, Kayvan R.; Park, Jae Mo

    2017-01-01

    Cancer cells reprogram their metabolism to maintain viability via genetic mutations and epigenetic alterations, expressing overall dynamic heterogeneity. The complex relaxation mechanisms of nuclear spins provide unique and convertible tissue contrasts, making magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) pertinent imaging tools in both clinics and research. In this review, we summarized MR methods that visualize tumor characteristics and its metabolic phenotypes ...

  7. Effects of soil nutrient heterogeneity on intraspecific competition in the invasive, clonal plant Alternanthera philoxeroides.

    Science.gov (United States)

    Zhou, Jian; Dong, Bi-Cheng; Alpert, Peter; Li, Hong-Li; Zhang, Ming-Xiang; Lei, Guang-Chun; Yu, Fei-Hai

    2012-03-01

    Fine-scale, spatial heterogeneity in soil nutrient availability can increase the growth of individual plants, the productivity of plant communities and interspecific competition. If this is due to the ability of plants to concentrate their roots where nutrient levels are high, then nutrient heterogeneity should have little effect on intraspecific competition, especially when there are no genotypic differences between individuals in root plasticity. We tested this hypothesis in a widespread, clonal species in which individual plants are known to respond to nutrient heterogeneity. Plants derived from a single clone of Alternanthera philoxeroides were grown in the greenhouse at low or high density (four or 16 plants per 27·5 × 27·5-cm container) with homogeneous or heterogeneous availability of soil nutrients, keeping total nutrient availability per container constant. After 9 weeks, measurements of size, dry mass and morphology were taken. Plants grew more in the heterogeneous than in the homogeneous treatment, showing that heterogeneity promoted performance; they grew less in the high- than in the low-density treatment, showing that plants competed. There was no interactive effect of nutrient heterogeneity and plant density, supporting the hypothesis that heterogeneity does not affect intraspecific competition in the absence of genotypic differences in plasticity. Treatments did not affect morphological characteristics such as specific leaf area or root/shoot ratio. Results indicate that fine-scale, spatial heterogeneity in the availability of soil nutrients does not increase competition when plants are genetically identical, consistent with the suggestion that effects of heterogeneity on competition depend upon differences in plasticity between individuals. Heterogeneity is only likely to increase the spread of monoclonal, invasive populations such as that of A. philoxeroides in China.

  8. Phenotype heterogeneity in cancer cell populations

    International Nuclear Information System (INIS)

    Almeida, Luis; Chisholm, Rebecca; Clairambault, Jean; Escargueil, Alexandre; Lorenzi, Tommaso; Lorz, Alexander; Trélat, Emmanuel

    2016-01-01

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as “bet hedging” of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  9. Phenotype heterogeneity in cancer cell populations

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Luis [CNRS UMR 7598, LJLL, & INRIA MAMBA team, Sorbonne Universités, UPMC Univ Paris 06, Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, luis@ann.jussieu.fr (France); Chisholm, Rebecca [School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia, rebecca.chisholm@gmail.com (Australia); Clairambault, Jean [INRIA MAMBA team & LJLL, UMR 7598, Sorbonne Universités, UPMC Univ Paris 06, Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, jean.clairambault@inria.fr, Corresponding author (France); Escargueil, Alexandre [INSERM “Cancer Biology and Therapeutics”, Sorbonne Universités, UPMC Univ Paris 06, UMR-S 938, CDR St Antoine, Hôpital St Antoine, 184 Fbg. St Antoine, 75571 Paris cedex 12, France, alexandre.escargueil@upmc.fr (France); Lorenzi, Tommaso [CMLA, ENS Cachan, 61, Av. du Président Wilson, 94230 Cachan cedex & INRIA MAMBA team, & LJLL, UMR 7598, UPMC Univ Paris 06, Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, tommaso.lorenzi@gmail.com (France); Lorz, Alexander [Sorbonne Universités, UPMC Univ Paris 06, LJLL, UMR 7598 & INRIA Boîte courrier 187, 4 Pl. Jussieu, 75252 Paris cedex 05, France, alex.lorz@ann.jussieu.fr (France); Trélat, Emmanuel [Institut Universitaire de France, Sorbonne Universités, UPMC Univ Paris 06, LJLL, UMR 7598, Boîte courrier 187, UPMC Univ Paris 06, 4 Pl. Jussieu, 75252 Paris cedex 05, France, emmanuel.trelat@upmc.fr (France)

    2016-06-08

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as “bet hedging” of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  10. Phenotype heterogeneity in cancer cell populations

    Science.gov (United States)

    Almeida, Luis; Chisholm, Rebecca; Clairambault, Jean; Escargueil, Alexandre; Lorenzi, Tommaso; Lorz, Alexander; Trélat, Emmanuel

    2016-06-01

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as "bet hedging" of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  11. Unraveling the hidden heterogeneities of breast cancer based on functional miRNA cluster.

    Directory of Open Access Journals (Sweden)

    Li Li

    Full Text Available It has become increasingly clear that the current taxonomy of clinical phenotypes is mixed with molecular heterogeneity, which potentially affects the treatment effect for involved patients. Defining the hidden molecular-distinct diseases using modern large-scale genomic approaches is therefore useful for refining clinical practice and improving intervention strategies. Given that microRNA expression profiling has provided a powerful way to dissect hidden genetic heterogeneity for complex diseases, the aim of the study was to develop a bioinformatics approach that identifies microRNA features leading to the hidden subtyping of complex clinical phenotypes. The basic strategy of the proposed method was to identify optimal miRNA clusters by iteratively partitioning the sample and feature space using the two-ways super-paramagnetic clustering technique. We evaluated the obtained optimal miRNA cluster by determining the consistency of co-expression and the chromosome location among the within-cluster microRNAs, and concluded that the optimal miRNA cluster could lead to a natural partition of disease samples. We applied the proposed method to a publicly available microarray dataset of breast cancer patients that have notoriously heterogeneous phenotypes. We obtained a feature subset of 13 microRNAs that could classify the 71 breast cancer patients into five subtypes with significantly different five-year overall survival rates (45%, 82.4%, 70.6%, 100% and 60% respectively; p = 0.008. By building a multivariate Cox proportional-hazards prediction model for the feature subset, we identified has-miR-146b as one of the most significant predictor (p = 0.045; hazard ratios = 0.39. The proposed algorithm is a promising computational strategy for dissecting hidden genetic heterogeneity for complex diseases, and will be of value for improving cancer diagnosis and treatment.

  12. Persistent genetic instability induced by synergistic interaction between x-irradiation and 6-thioguanine

    International Nuclear Information System (INIS)

    Grosovsky, A.J.; Nelson, S.L.; Smith, L.E.

    1995-01-01

    Clonal karyotypic analysis was performed using G-banding on four groups of clones derived from TK6 human lymphoblasts: 25 HPRT - total gene deletion mutants induced by exposure to 2 Gy of x-rays; 8 spontaneous HPRT - total gene deletion mutants; 25 clones irradiated with 2 Gy, not selected with 6-thioguanine. Ten to twenty metaphases were examined for each clone. Extensive karyotypic heterogeneity was observed among x-ray induced HPRT - mutants involving translocations, deletions, duplications and aneuploidy; recovery of chromosomal aberrations and karyotypic heterogeneity was greater than the additive effects of clones treated with x-irradiation or 6-thioguanine alone. This synergistic interaction between x-irradiation and 6-thioguanine was observed despite a 7 day phenotypic expression interval between exposure to the two agents. Thus, x-irradiated TK6 cells appear to be persistently hypersensitive to the induction of genetic instability. Several mutants appeared to exhibit evidence of clonal evolution since aberrant chromosomes observed in one metaphase, were found to be further modified in other metaphases. In order to determine if genetic instability, identified by clonal karyotypic heterogeneity, affected specific locus mutation rates, we utilized the heterozygous thymidine kinase (tk) locus as a genetic marker. Four x-ray induced HPRT - mutants with extensive karyotypic heterogeneity, exhibited mutation rates at tk ranging from 5 to 8 fold higher than the parental TK6 cells. Further analysis, using fractionated low dose radiation exposure, is currently in progress

  13. Spatial intratumoral heterogeneity of proliferation in immunohistochemical images of solid tumors

    International Nuclear Information System (INIS)

    Valous, Nektarios A.; Lahrmann, Bernd; Halama, Niels; Grabe, Niels; Bergmann, Frank; Jäger, Dirk

    2016-01-01

    Purpose: The interactions of neoplastic cells with each other and the microenvironment are complex. To understand intratumoral heterogeneity, subtle differences should be quantified. Main factors contributing to heterogeneity include the gradient ischemic level within neoplasms, action of microenvironment, mechanisms of intercellular transfer of genetic information, and differential mechanisms of modifications of genetic material/proteins. This may reflect on the expression of biomarkers in the context of prognosis/stratification. Hence, a rigorous approach for assessing the spatial intratumoral heterogeneity of histological biomarker expression with accuracy and reproducibility is required, since patterns in immunohistochemical images can be challenging to identify and describe. Methods: A quantitative method that is useful for characterizing complex irregular structures is lacunarity; it is a multiscale technique that exhaustively samples the image, while the decay of its index as a function of window size follows characteristic patterns for different spatial arrangements. In histological images, lacunarity provides a useful measure for the spatial organization of a biomarker when a sampling scheme is employed and relevant features are computed. The proposed approach quantifies the segmented proliferative cells and not the textural content of the histological slide, thus providing a more realistic measure of heterogeneity within the sample space of the tumor region. The aim is to investigate in whole sections of primary pancreatic neuroendocrine neoplasms (pNENs), using whole-slide imaging and image analysis, the spatial intratumoral heterogeneity of Ki-67 immunostains. Unsupervised learning is employed to verify that the approach can partition the tissue sections according to distributional heterogeneity. Results: The architectural complexity of histological images has shown that single measurements are often insufficient. Inhomogeneity of distribution depends

  14. Spatial intratumoral heterogeneity of proliferation in immunohistochemical images of solid tumors.

    Science.gov (United States)

    Valous, Nektarios A; Lahrmann, Bernd; Halama, Niels; Bergmann, Frank; Jäger, Dirk; Grabe, Niels

    2016-06-01

    The interactions of neoplastic cells with each other and the microenvironment are complex. To understand intratumoral heterogeneity, subtle differences should be quantified. Main factors contributing to heterogeneity include the gradient ischemic level within neoplasms, action of microenvironment, mechanisms of intercellular transfer of genetic information, and differential mechanisms of modifications of genetic material/proteins. This may reflect on the expression of biomarkers in the context of prognosis/stratification. Hence, a rigorous approach for assessing the spatial intratumoral heterogeneity of histological biomarker expression with accuracy and reproducibility is required, since patterns in immunohistochemical images can be challenging to identify and describe. A quantitative method that is useful for characterizing complex irregular structures is lacunarity; it is a multiscale technique that exhaustively samples the image, while the decay of its index as a function of window size follows characteristic patterns for different spatial arrangements. In histological images, lacunarity provides a useful measure for the spatial organization of a biomarker when a sampling scheme is employed and relevant features are computed. The proposed approach quantifies the segmented proliferative cells and not the textural content of the histological slide, thus providing a more realistic measure of heterogeneity within the sample space of the tumor region. The aim is to investigate in whole sections of primary pancreatic neuroendocrine neoplasms (pNENs), using whole-slide imaging and image analysis, the spatial intratumoral heterogeneity of Ki-67 immunostains. Unsupervised learning is employed to verify that the approach can partition the tissue sections according to distributional heterogeneity. The architectural complexity of histological images has shown that single measurements are often insufficient. Inhomogeneity of distribution depends not only on percentage

  15. Spatial intratumoral heterogeneity of proliferation in immunohistochemical images of solid tumors

    Energy Technology Data Exchange (ETDEWEB)

    Valous, Nektarios A. [Applied Tumor Immunity Clinical Cooperation Unit, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg 69120 (Germany); Lahrmann, Bernd; Halama, Niels; Grabe, Niels [Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg 69120 (Germany); Bergmann, Frank [Institute of Pathology, Heidelberg University Hospital, Heidelberg 69120 (Germany); Jäger, Dirk [Department of Medical Oncology, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg 69120, Germany and National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg 69120 (Germany)

    2016-06-15

    Purpose: The interactions of neoplastic cells with each other and the microenvironment are complex. To understand intratumoral heterogeneity, subtle differences should be quantified. Main factors contributing to heterogeneity include the gradient ischemic level within neoplasms, action of microenvironment, mechanisms of intercellular transfer of genetic information, and differential mechanisms of modifications of genetic material/proteins. This may reflect on the expression of biomarkers in the context of prognosis/stratification. Hence, a rigorous approach for assessing the spatial intratumoral heterogeneity of histological biomarker expression with accuracy and reproducibility is required, since patterns in immunohistochemical images can be challenging to identify and describe. Methods: A quantitative method that is useful for characterizing complex irregular structures is lacunarity; it is a multiscale technique that exhaustively samples the image, while the decay of its index as a function of window size follows characteristic patterns for different spatial arrangements. In histological images, lacunarity provides a useful measure for the spatial organization of a biomarker when a sampling scheme is employed and relevant features are computed. The proposed approach quantifies the segmented proliferative cells and not the textural content of the histological slide, thus providing a more realistic measure of heterogeneity within the sample space of the tumor region. The aim is to investigate in whole sections of primary pancreatic neuroendocrine neoplasms (pNENs), using whole-slide imaging and image analysis, the spatial intratumoral heterogeneity of Ki-67 immunostains. Unsupervised learning is employed to verify that the approach can partition the tissue sections according to distributional heterogeneity. Results: The architectural complexity of histological images has shown that single measurements are often insufficient. Inhomogeneity of distribution depends

  16. Update on Sporadic Colorectal Cancer Genetics.

    Science.gov (United States)

    Hardiman, Karin M

    2018-05-01

    Our understanding of the genetics of colorectal cancer has changed dramatically over recent years. Colorectal cancer can be classified in multiple different ways. Along with the advent of whole-exome sequencing, we have gained an understanding of the scale of the genetic changes found in sporadic colorectal cancer. We now know that there are multiple pathways that are commonly involved in the evolution of colorectal cancer including Wnt/β-catenin, RAS, EGFR, and PIK3 kinase. Another recent leap in our understanding of colorectal cancer genetics is the recognition that many, if not all tumors, are actually genetically heterogeneous within individual tumors and also between tumors. Recent research has revealed the prognostic and possibly therapeutic implications of various specific mutations, including specific mutations in BRAF and KRAS . There is increasing interest in the use of mutation testing for screening and surveillance through stool and circulating DNA testing. Recent advances in translational research in colorectal cancer genetics are dramatically changing our understanding of colorectal cancer and will likely change therapy and surveillance in the near future.

  17. Population genetic analysis of Colombian Trypanosoma cruzi isolates revealed by enzyme electrophoretic profiles

    OpenAIRE

    Ruiz-Garcia, Manuel; Montilla, Marleny; Nicholls, Sebastian; Alvarez, Diana

    2001-01-01

    Although Colombia presents an enormous biological diversity, few studies have been conducted on the population genetics of Trypanosoma cruzi. This study was carried out with 23 Colombian stocks of this protozoa analyzed for 13 isoenzymatic loci. The Hardy-Weinberg equilibrium, the genetic diversity and heterogeneity, the genetic relationships and the possible spatial structure of these 23 Colombian stocks of T. cruzi were estimated. The majority of results obtained are in agreement with a clo...

  18. Cloning of transgenic tobacco BY-2 cells; an efficient method to analyse and reduce high natural heterogeneity of transgene expression.

    Science.gov (United States)

    Nocarova, Eva; Fischer, Lukas

    2009-04-22

    Phenotypic characterization of transgenic cell lines, frequently used in plant biology studies, is complicated because transgene expression in individual cells is often heterogeneous and unstable. To identify the sources and to reduce this heterogeneity, we transformed tobacco (Nicotiana tabacum L.) BY-2 cells with a gene encoding green fluorescent protein (GFP) using Agrobacterium tumefaciens, and then introduced a simple cloning procedure to generate cell lines derived from the individual transformed cells. Expression of the transgene was monitored by analysing GFP fluorescence in the cloned lines and also in lines obtained directly after transformation. The majority ( approximately 90%) of suspension culture lines derived from calli that were obtained directly from transformation consisted of cells with various levels of GFP fluorescence. In contrast, nearly 50% of lines generated by cloning cells from the primary heterogeneous suspensions consisted of cells with homogenous GFP fluorescence. The rest of the lines exhibited "permanent heterogeneity" that could not be resolved by cloning. The extent of fluorescence heterogeneity often varied, even among genetically identical clones derived from the primary transformed lines. In contrast, the offspring of subsequent cloning of the cloned lines was uniform, showing GFP fluorescence intensity and heterogeneity that corresponded to the original clone. The results demonstrate that, besides genetic heterogeneity detected in some lines, the primary lines often contained a mixture of epigenetically different cells that could be separated by cloning. This indicates that a single integration event frequently results in various heritable expression patterns, which are probably accidental and become stabilized in the offspring of the primary transformed cells early after the integration event. Because heterogeneity in transgene expression has proven to be a serious problem, it is highly advisable to use transgenes tagged with

  19. Reducing the Diagnostic Heterogeneity of Schizoaffective Disorder.

    Science.gov (United States)

    Seldin, Katherine; Armstrong, Kristan; Schiff, Max L; Heckers, Stephan

    2017-01-01

    Clinical outcome studies of schizoaffective disorder patients have yielded conflicting results. One reason is the heterogeneity of samples drawn from the schizoaffective disorder population. Here, we studied schizoaffective disorder patients who showed marked functional impairment and continuous signs of illness for at least 6 months (i.e., DSM criteria B and C for schizophrenia). We assessed 176 chronic psychosis patients with a structured interview (SCID-IV-TR) and the Diagnostic Interview for Genetic Studies schizoaffective disorder module. We diagnosed 114 patients with schizophrenia and 62 with schizoaffective disorder. The two groups were similar with regard to age, gender, and race. We tested for group differences in antecedent risk factors, clinical features, and functional outcome. The schizoaffective disorder group differed from the schizophrenia group on two measures only: they showed higher rates of suicidality (more suicide attempts, p  schizoaffective disorder patients meet DSM criteria B and C for schizophrenia, they resemble schizophrenia patients on several measures used to assess validity. The increased rate of anxiety disorders and suicidality warrants clinical attention. Our data suggest that a more explicit definition of schizoaffective disorder reduces heterogeneity and may increase validity.

  20. The Molecular Genetics of von Willebrand Disease

    Directory of Open Access Journals (Sweden)

    Ergül Berber

    2012-12-01

    Full Text Available Quantitative and/or qualitative deficiency of von Willebrand factor (vWF is associated with the most common inherited bleeding disease von Willebrand disease (vWD. vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD.

  1. The molecular genetics of von Willebrand disease.

    Science.gov (United States)

    Berber, Ergül

    2012-12-01

    Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD. None declared.

  2. Genetic testing for patients with renal disease: procedures, pitfalls, and ethical considerations.

    Science.gov (United States)

    Korf, B R

    1999-07-01

    The Human Genome Project is rapidly producing insights into the molecular basis of human genetic disorders. The most immediate clinical benefit is the advent of new diagnostic methods. Molecular diagnostic tools are available for several genetic renal disorders and are in development for many more. Two general approaches to molecular diagnosis are linkage-based testing and direct mutation detection. The former is used when the gene has not been cloned but has been mapped in relation to polymorphic loci. Linkage-based testing is also helpful when a large diversity of mutations makes direct detection difficult. Limitations include the need to study multiple family members, the need for informative polymorphisms, and genetic heterogeneity. Direct mutation detection is limited by genetic heterogeneity and the need to distinguish nonpathogenic allelic variants from pathogenic mutations. Molecular testing raises a number of complex ethical issues, including those associated with prenatal or presymptomatic diagnosis. In addition, there are concerns about informed consent, privacy, genetic discrimination, and technology transfer for newly developed tests. Health professionals need to be aware of the technical and ethical implications of these new methods of testing, as well as the complexities in test interpretation, as molecular approaches are increasingly integrated into medical practice.

  3. Heterogeneity of mammary lesions represent molecular differences

    International Nuclear Information System (INIS)

    Namba, Ruria; Gregg, Jeffrey P; Maglione, Jeannie E; Davis, Ryan R; Baron, Colin A; Liu, Stephenie; Carmack, Condie E; Young, Lawrence JT; Borowsky, Alexander D; Cardiff, Robert D

    2006-01-01

    Human breast cancer is a heterogeneous disease, histopathologically, molecularly and phenotypically. The molecular basis of this heterogeneity is not well understood. We have used a mouse model of DCIS that consists of unique lines of mammary intraepithelial neoplasia (MIN) outgrowths, the premalignant lesion in the mouse that progress to invasive carcinoma, to understand the molecular changes that are characteristic to certain phenotypes. Each MIN-O line has distinguishable morphologies, metastatic potentials and estrogen dependencies. We utilized oligonucleotide expression arrays and high resolution array comparative genomic hybridization (aCGH) to investigate whole genome expression patterns and whole genome aberrations in both the MIN-O and tumor from four different MIN-O lines that each have different phenotypes. From the whole genome analysis at 35 kb resolution, we found that chromosome 1, 2, 10, and 11 were frequently associated with whole chromosome gains in the MIN-Os. In particular, two MIN-O lines had the majority of the chromosome gains. Although we did not find any whole chromosome loss, we identified 3 recurring chromosome losses (2F1-2, 3E4, 17E2) and two chromosome copy number gains on chromosome 11. These interstitial deletions and duplications were verified with a custom made array designed to interrogate the specific regions at approximately 550 bp resolution. We demonstrated that expression and genomic changes are present in the early premalignant lesions and that these molecular profiles can be correlated to phenotype (metastasis and estrogen responsiveness). We also identified expression changes associated with genomic instability. Progression to invasive carcinoma was associated with few additional changes in gene expression and genomic organization. Therefore, in the MIN-O mice, early premalignant lesions have the major molecular and genetic changes required and these changes have important phenotypic significance. In contrast, the changes

  4. Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma.

    Science.gov (United States)

    Inda, Maria-del-Mar; Bonavia, Rudy; Mukasa, Akitake; Narita, Yoshitaka; Sah, Dinah W Y; Vandenberg, Scott; Brennan, Cameron; Johns, Terrance G; Bachoo, Robert; Hadwiger, Philipp; Tan, Pamela; Depinho, Ronald A; Cavenee, Webster; Furnari, Frank

    2010-08-15

    Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/DeltaEGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the DeltaEGFR lesion. We hypothesized that the minor DeltaEGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by DeltaEGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express DeltaEGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically

  5. Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Abderrahim Oussalah

    2018-04-01

    Full Text Available Summary: Background: Patients with cirrhosis are at high risk of hepatocellular carcinoma (HCC. The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with liver carcinogenesis. The primary aim of this study was to evaluate the diagnostic accuracy of a PCR-based assay for the analysis of SEPT9 promoter methylation in circulating cell-free DNA (mSEPT9 for diagnosing HCC among cirrhotic patients. Methods: We report two phase II biomarker studies that included cirrhotic patients with or without HCC from France (initial study and Germany (replication study. All patients received clinical and biological evaluations, and liver imaging according to current recommendations. The primary outcome was defined as the presence of HCC according to guidelines from the American Association for the Study of Liver Diseases. The diagnosis of HCC was confirmed by abdominal contrast-enhanced computed tomography scan and systematically discussed in a multidisciplinary consultation meeting. HCC-free cirrhotic patients were recruited if the screening abdominal ultrasound showed no evidence of HCC at the time of blood sampling for the mSEPT9 test and on the next visit six months later. The adjudicating physicians were blinded to patient results associated with the mSEPT9 test. Findings: We included 289 patients with cirrhosis (initial: 186; replication: 103, among whom 98 had HCC (initial: 51; replication: 47. The mSEPT9 test exhibited high diagnostic accuracy for HCC diagnosis, with an area under the receiver operating characteristic curve (AUROC of 0.944 (0.900–0.970, p < 0.0001 in the initial study (replication: 0.930 [0.862–0.971, p < 0.0001]; meta-analysis: AUROC = 0.940 [0.910–0.970, p < 0.0001], no heterogeneity: I2 = 0%, p = 0.67; and no publication bias. In multivariate logistic regression analysis, the number of positive mSEPT9 triplicates was the only independent variable significantly

  6. Lessons learned from family history in ocular genetics.

    Science.gov (United States)

    Marino, Meghan J

    2015-07-01

    Given the vast genetic and phenotypic heterogeneity seen in ocular genetic disorders, considering a patient's clinical phenotype in the context of the family history is essential. Clinicians can improve patient care by appropriately incorporating a patient's family history into their evaluation. Obtaining, reviewing, and accurately interpreting the pedigree are skills geneticists and genetic counselors possess. However, with the field of ophthalmic genetics vastly growing, it is becoming essential for ophthalmologists to understand the utility of the pedigree and develop their abilities in eliciting this information. By not considering a patient's clinical history in the context of the family history, diagnoses can be missed or inaccurate. The purpose of this review is to inform ophthalmologists on the importance of the family history and highlight how the pedigree can aid in establishing an accurate genetic diagnosis. This review also provides to ophthalmologists helpful tips on eliciting and interpreting a patient's family history.

  7. Genetic variants in IL-6 and IL-10 genes and susceptibility to hepatocellular carcinoma in HCV infected patients.

    Science.gov (United States)

    Sghaier, Ikram; Mouelhi, Leila; Rabia, Noor A; Alsaleh, Bano R; Ghazoueni, Ezzedine; Almawi, Wassim Y; Loueslati, Besma Yacoubi

    2017-01-01

    Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC), a common primary liver malignancy, and the third leading cause of cancer-related death. The HCC risk increases with the severity of liver inflammation, and the clinical course of HCV infection depends on a balance between pro- and anti-inflammatory cytokines. The former includes interleukin (IL)-6, while the latter includes IL-10. However, the exact pathogenic mechanisms underlying IL-6 and IL-10 effects remain unclear. The present study evaluated 174 chronic HCV Tunisian patients. Polymorphisms of IL-6 (rs1880242, rs1474847, rs2069840, rs1800797, rs1800796, rs2069845, rs2069827, rs1474348, rs1800795), and IL-10 (rs1800896, rs1800871, rs1800872, rs1554286, rs1878672, rs1518111) were determined by real-time PCR. Notable differences between chronic HCV-infected patients and HCC patients were observed for the three IL-10 SNPs; rs1800871 (-819T/C), rs1800872 (-592A/C), and rs1878672. Carriage of IL-6 rs1800796 G/G genotype, IL-6 rs1474358 C-allele, and IL-6 rs1800797 A-allele was more frequent in chronic HCV-infected patients than in HCC patients. On the other hand, IL-6 rs1474358 GG genotype had a favourable factor for HCC establishment. IL-10 and IL-6 SNPs markedly influence the clinical outcomes of HCV infection. These SNPs could be used as biomarkers for early detection and molecular therapy for preventing HCC, and prognostic factors for predicting the clinical outcomes of HCC. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. The Hawk-Dove game in phenotypically homogeneous and heterogeneous populations of finite dimension

    Science.gov (United States)

    Laruelle, Annick; da Silva Rocha, André Barreira; Escobedo, Ramón

    2018-02-01

    The Hawk-Dove game played between individuals in populations of finite dimension is analyzed by means of a stochastic model. We take into account both cases when all individuals in the population are either phenotypically homogeneous or heterogeneous. A strategy in the model is a gene representing the probability of playing the Hawk strategy. Individual interactions at the microscopic level are described by a genetic algorithm where evolution results from the interplay among selection, mutation, drift and cross-over of genes. We show that the behavioral patterns observed at the macroscopic level can be reproduced as the emergent result of individual interactions governed by the rules of the Hawk-Dove game at the microscopic level. We study how the results of the genetic algorithm compare with those obtained in evolutionary game theory, finding that, although genes continuously change both their presence and frequency in the population over time, the population average behavior always achieves stationarity and, when this happens, the final average strategy played in the population oscillates around the evolutionarily stable strategy in the homogeneous population case or the neutrally stable set in the heterogeneous population case.

  9. Spatial heterogeneity, frequency-dependent selection and polymorphism in host-parasite interactions

    Directory of Open Access Journals (Sweden)

    Tellier Aurélien

    2011-11-01

    Full Text Available Abstract Background Genomic and pathology analysis has revealed enormous diversity in genes involved in disease, including those encoding host resistance and parasite effectors (also known in plant pathology as avirulence genes. It has been proposed that such variation may persist when an organism exists in a spatially structured metapopulation, following the geographic mosaic of coevolution. Here, we study gene-for-gene relationships governing the outcome of plant-parasite interactions in a spatially structured system and, in particular, investigate the population genetic processes which maintain balanced polymorphism in both species. Results Following previous theory on the effect of heterogeneous environments on maintenance of polymorphism, we analysed a model with two demes in which the demes have different environments and are coupled by gene flow. Environmental variation is manifested by different coefficients of natural selection, the costs to the host of resistance and to the parasite of virulence, the cost to the host of being diseased and the cost to an avirulent parasite of unsuccessfully attacking a resistant host. We show that migration generates negative direct frequency-dependent selection, a condition for maintenance of stable polymorphism in each deme. Balanced polymorphism occurs preferentially if there is heterogeneity for costs of resistance and virulence alleles among populations and to a lesser extent if there is variation in the cost to the host of being diseased. We show that the four fitness costs control the natural frequency of oscillation of host resistance and parasite avirulence alleles. If demes have different costs, their frequencies of oscillation differ and when coupled by gene flow, there is amplitude death of the oscillations in each deme. Numerical simulations show that for a multiple deme island model, costs of resistance and virulence need not to be present in each deme for stable polymorphism to occur

  10. Interobserver Variability in Target Definition for Hepatocellular Carcinoma With and Without Portal Vein Thrombus: Radiation Therapy Oncology Group Consensus Guidelines

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Theodore S., E-mail: tshong1@mgh.harvard.edu [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Bosch, Walter R. [Department of Radiation Oncology, Washington University in St. Louis School of Medicine, St. Louis, Missouri (United States); Krishnan, Sunil [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Kim, Tae K. [Department of Medical Imaging, University Health Network, Mount Sinai Hospital and Women' s College Hospital, University of Toronto, Toronto, Ontario (Canada); Mamon, Harvey J. [Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women' s Hospital and Harvard Medical School, Boston, Massachusetts (United States); Shyn, Paul [Department of Radiology, Brigham and Women' s Hospital and Harvard Medical School, Boston, Massachusetts (United States); Ben-Josef, Edgar [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (United States); Seong, Jinsil [Department of Radiation Oncology, Yonsei University Medical College, Seoul (Korea, Republic of); Haddock, Michael G. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Cheng, Jason C. [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Feng, Mary U. [Department of Radiation Oncology, University of Michigan Health System, Ann Arbor, Michigan (United States); Stephans, Kevin L. [Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio (United States); Roberge, David [Department of Radiation Oncology, Montreal General Hospital/McGill University Health Centre, Montreal, Quebec (Canada); Crane, Christopher [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); and others

    2014-07-15

    Purpose: Defining hepatocellular carcinoma (HCC) gross tumor volume (GTV) requires multimodal imaging, acquired in different perfusion phases. The purposes of this study were to evaluate the variability in contouring and to establish guidelines and educational recommendations for reproducible HCC contouring for treatment planning. Methods and Materials: Anonymous, multiphasic planning computed tomography scans obtained from 3 patients with HCC were identified and distributed to a panel of 11 gastrointestinal radiation oncologists. Panelists were asked the number of HCC cases they treated in the past year. Case 1 had no vascular involvement, case 2 had extensive portal vein involvement, and case 3 had minor branched portal vein involvement. The agreement between the contoured total GTVs (primary + vascular GTV) was assessed using the generalized kappa statistic. Agreement interpretation was evaluated using Landis and Koch's interpretation of strength of agreement. The S95 contour, defined using the simultaneous truth and performance level estimation (STAPLE) algorithm consensus at the 95% confidence level, was created for each case. Results: Of the 11 panelists, 3 had treated >25 cases in the past year, 2 had treated 10 to 25 cases, 2 had treated 5 to 10 cases, 2 had treated 1 to 5 cases, 1 had treated 0 cases, and 1 did not respond. Near perfect agreement was seen for case 1, and substantial agreement was seen for cases 2 and 3. For case 2, there was significant heterogeneity in the volume identified as tumor thrombus (range 0.58-40.45 cc). For case 3, 2 panelists did not include the branched portal vein thrombus, and 7 panelists contoured thrombus separately from the primary tumor, also showing significant heterogeneity in volume of tumor thrombus (range 4.52-34.27 cc). Conclusions: In a group of experts, excellent agreement was seen in contouring total GTV. Heterogeneity exists in the definition of portal vein thrombus that may impact treatment

  11. Population genetics of four heavily exploited shark species around the Arabian Peninsula

    KAUST Repository

    Spaet, Julia L.Y.; Jabado, Rima W.; Henderson, Aaron C.; Moore, Alec B. M.; Berumen, Michael L.

    2015-01-01

    The northwestern Indian Ocean harbors a number of larger marine vertebrate taxa that warrant the investigation of genetic population structure given remarkable spatial heterogeneity in biological characteristics such as distribution, behavior

  12. An aid to the diagnosis of genetic disorders underlying adult-onset renal failure : a literature review

    NARCIS (Netherlands)

    Joosten, H.; Strunk, A. L. M.; Meijer, S.; Boers, J. E.; Aries, M.J.H.; Abbes, A. P.; Engel, H.; Beukhof, J. R.

    Several genetic disorders can present in adult patients with renal insufficiency. Genetic renal disease other than ADPKD accounts for ESRD in 3% of the adult Dutch population. Because of this low prevalence and their clinical heterogeneity most adult nephrologists are less familiar with these

  13. Intrafocal heterogeneity of ERG protein expression and gene fusion pattern in prostate cancer.

    Science.gov (United States)

    Suh, Ja Hee; Park, Jeong Hwan; Lee, Cheol; Moon, Kyung Chul

    2017-10-01

    Prostate cancer is considered to be highly heterogeneous, with various morphologic features and biologic behaviors. The TMPRSS2-ERG gene fusion is the most frequently observed genetic aberration in prostate cancer. The aim of this study was to elucidate the intrafocal heterogeneity of ERG gene fusion status. ERG immunohistochemistry (IHC) was performed in samples from 168 prostate cancer patients who had undergone radical prostatectomy, and 40 cases showing ERG-positive IHC staining were selected for tissue microarray (TMA) construction. Two to six representative cores were selected from each tumor focus. In the cases with heterogeneous ERG IHC staining intensity, the areas showing different intensities were separately selected. Using the TMA blocks, IHC and fluorescence in situ hybridization (FISH) were conducted to evaluate the heterogeneity of ERG protein expression and ERG fusion gene patterns, respectively, in a single tumor focus. Heterogeneity of ERG IHC staining was defined as the simultaneous presence of negative and positive cores in the same tumor focus. Heterogeneity of ERG FISH was defined by the presence of cores with positive and negative FISH signals or cores with break-apart and interstitial deletion FISH signals in the same tumor focus. A total of 202 TMA cores were isolated from 40 ERG-positive cases. Of the 202 total cores, 19 were negative for ERG IHC staining, and 46 showed 1+, 52 showed 2+, and 85 showed 3+ ERG staining intensity. Eleven cores were negative for ERG FISH signal, 119 cores showed ERG break-apart FISH signals, and the remaining 72 cores revealed interstitial deletion. Intrafocal heterogeneity of ERG IHC staining was found in 20% (8/40) of cases, and intrafocal heterogeneity of ERG gene fusion pattern was found in 32.5% (13/40) of cases. In summary, this study showed significantly frequent intrafocal heterogeneity of ERG protein expression, gene fusion status and fusion pattern. This heterogeneity can be caused by the development

  14. Pharmacokinetic Tumor Heterogeneity as a Prognostic Biomarker for Classifying Breast Cancer Recurrence Risk.

    Science.gov (United States)

    Mahrooghy, Majid; Ashraf, Ahmed B; Daye, Dania; McDonald, Elizabeth S; Rosen, Mark; Mies, Carolyn; Feldman, Michael; Kontos, Despina

    2015-06-01

    Heterogeneity in cancer can affect response to therapy and patient prognosis. Histologic measures have classically been used to measure heterogeneity, although a reliable noninvasive measurement is needed both to establish baseline risk of recurrence and monitor response to treatment. Here, we propose using spatiotemporal wavelet kinetic features from dynamic contrast-enhanced magnetic resonance imaging to quantify intratumor heterogeneity in breast cancer. Tumor pixels are first partitioned into homogeneous subregions using pharmacokinetic measures. Heterogeneity wavelet kinetic (HetWave) features are then extracted from these partitions to obtain spatiotemporal patterns of the wavelet coefficients and the contrast agent uptake. The HetWave features are evaluated in terms of their prognostic value using a logistic regression classifier with genetic algorithm wrapper-based feature selection to classify breast cancer recurrence risk as determined by a validated gene expression assay. Receiver operating characteristic analysis and area under the curve (AUC) are computed to assess classifier performance using leave-one-out cross validation. The HetWave features outperform other commonly used features (AUC = 0.88 HetWave versus 0.70 standard features). The combination of HetWave and standard features further increases classifier performance (AUCs 0.94). The rate of the spatial frequency pattern over the pharmacokinetic partitions can provide valuable prognostic information. HetWave could be a powerful feature extraction approach for characterizing tumor heterogeneity, providing valuable prognostic information.

  15. Developmental cognitive genetics: How psychology can inform genetics and vice versa

    Science.gov (United States)

    Bishop, Dorothy V. M.

    2006-01-01

    Developmental neuropsychology is concerned with uncovering the underlying basis of developmental disorders such as specific language impairment (SLI), developmental dyslexia, and autistic disorder. Twin and family studies indicate that genetic influences play an important part in the aetiology of all of these disorders, yet progress in identifying genes has been slow. One way forward is to cut loose from conventional clinical criteria for diagnosing disorders and to focus instead on measures of underlying cognitive mechanisms. Psychology can inform genetics by clarifying what the key dimensions are for heritable phenotypes. However, it is not a one-way street. By using genetically informative designs, one can gain insights about causal relationships between different cognitive deficits. For instance, it has been suggested that low-level auditory deficits cause phonological problems in SLI. However, a twin study showed that, although both types of deficit occur in SLI, they have quite different origins, with environmental factors more important for auditory deficit, and genes more important for deficient phonological short-term memory. Another study found that morphosyntactic deficits in SLI are also highly heritable, but have different genetic origins from impairments of phonological short-term memory. A genetic perspective shows that a search for the underlying cause of developmental disorders may be misguided, because they are complex and heterogeneous and are associated with multiple risk factors that only cause serious disability when they occur in combination. PMID:16769616

  16. Cholangitis and multiple liver abscesses after percutaneous ethanol injection (PEI for recurrent hepatocellular carcinoma (HCC Colangitis y abscesos hepáticos múltiples tras la inyección percutánea de etanol (IPE en el tratamiento del carcinoma hepatocelular recurrente

    Directory of Open Access Journals (Sweden)

    Fernando Macias-García

    2013-02-01

    Full Text Available Percutaneous ablation procedures are minimally invasive treatments for unresectable early stage hepatocellular carcinoma (HCC. These techniques are usually safe, but rare and even fatal complications have been described. We present a fatal result after percutaneous ethanol injection (PEI for the treatment of a recurrent HCC in a non-cirrhotic liver, with subsequent development of diffuse cholangitis and multiple liver abscesses. Although percutaneous drainage and intensive antibiotic treatment were employed, the patient finally died. We discuss about the etiology and the physiopathology of this rare complication in which the therapeutic options are limited and usually unsuccessful.

  17. Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing.

    Science.gov (United States)

    Lalonde, Emilie; Albrecht, Steffen; Ha, Kevin C H; Jacob, Karine; Bolduc, Nathalie; Polychronakos, Constantin; Dechelotte, Pierre; Majewski, Jacek; Jabado, Nada

    2010-08-01

    Protein coding genes constitute approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., "whole exome") have the potential to contribute our understanding of human diseases. We used a method for whole-exome sequencing coupling Agilent whole-exome capture to the Illumina DNA-sequencing platform, and investigated two unrelated fetuses from nonconsanguineous families with Fowler Syndrome (FS), a stereotyped phenotype lethal disease. We report novel germline mutations in feline leukemia virus subgroup C cellular-receptor-family member 2, FLVCR2, which has recently been shown to cause FS. Using this technology, we identified three types of genetic abnormalities: point-mutations, insertions-deletions, and intronic splice-site changes (first pathogenic report using this technology), in the fetuses who both were compound heterozygotes for the disease. Although revealing a high level of allelic heterogeneity and mutational spectrum in FS, this study further illustrates the successful application of whole-exome sequencing to uncover genetic defects in rare Mendelian disorders. Of importance, we show that we can identify genes underlying rare, monogenic and recessive diseases using a limited number of patients (n=2), in the absence of shared genetic heritage and in the presence of allelic heterogeneity.

  18. Genetic variability of sorghum landraces from lower Eastern Kenya ...

    African Journals Online (AJOL)

    Reuben M. Muasya

    2016-02-24

    Feb 24, 2016 ... from the farmers and four improved varieties were analyzed using 20 SSR markers. All markers were polymorphic with ... Levels and patterns of diversity within and between cultivated and wild sorghum gene pools ..... environmental heterogeneity and/or farmer preferences and random genetic drift (Neal, ...

  19. A Practical Approach to Tumor Heterogeneity in Clinical Research and Diagnostics.

    Science.gov (United States)

    Stanta, Giorgio; Bonin, Serena

    2018-01-01

    This Pathobiology issue tries to better define the complex phenomenon of intratumor heterogeneity (ITH), mostly from a practical point of view. This topic has been chosen because ITH is a central issue in tumor development and has to be investigated directly in patient tissue and immediately applied in the treatment of the presenting patient. Different types of ITH should be considered: clonal genetic and epigenetic evolution, morphological heterogeneity, and tumor sampling, heterogeneity resulting from microenvironmental autocrine and paracrine interaction, and stochastic plasticity related to different functional cell efficiencies. For a higher level of reproducibility in clinical research and diagnostics, it is necessary to establish standardized analytical methods, including microdissection. In situ techniques can be pivotal to explore tumor microenvironment and can be improved with associated digital analysis. Liquid biopsies for plasma DNA analysis are at present the best method to study recurrent tumors with treatment adaptation, and widespread clinical use could be beneficial. The different types of tumor genomic instabilities could have pragmatic applications to rank ITH for clinical applications: treatment approaches differ in patients with a high nucleotide mutation rate and patients with high copy number alterations. © 2017 S. Karger AG, Basel.

  20. GenHtr: a tool for comparative assessment of genetic heterogeneity in microbial genomes generated by massive short-read sequencing

    Directory of Open Access Journals (Sweden)

    Yu GongXin

    2010-10-01

    Full Text Available Abstract Background Microevolution is the study of short-term changes of alleles within a population and their effects on the phenotype of organisms. The result of the below-species-level evolution is heterogeneity, where populations consist of subpopulations with a large number of structural variations. Heterogeneity analysis is thus essential to our understanding of how selective and neutral forces shape bacterial populations over a short period of time. The Solexa Genome Analyzer, a next-generation sequencing platform, allows millions of short sequencing reads to be obtained with great accuracy, allowing for the ability to study the dynamics of the bacterial population at the whole genome level. The tool referred to as GenHtr was developed for genome-wide heterogeneity analysis. Results For particular bacterial strains, GenHtr relies on a set of Solexa short reads on given bacteria pathogens and their isogenic reference genome to identify heterogeneity sites, the chromosomal positions with multiple variants of genes in the bacterial population, and variations that occur in large gene families. GenHtr accomplishes this by building and comparatively analyzing genome-wide heterogeneity genotypes for both the newly sequenced genomes (using massive short-read sequencing and their isogenic reference (using simulated data. As proof of the concept, this approach was applied to SRX007711, the Solexa sequencing data for a newly sequenced Staphylococcus aureus subsp. USA300 cell line, and demonstrated that it could predict such multiple variants. They include multiple variants of genes critical in pathogenesis, e.g. genes encoding a LysR family transcriptional regulator, 23 S ribosomal RNA, and DNA mismatch repair protein MutS. The heterogeneity results in non-synonymous and nonsense mutations, leading to truncated proteins for both LysR and MutS. Conclusion GenHtr was developed for genome-wide heterogeneity analysis. Although it is much more time

  1. C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Paulo Victor Sgobbi de Souza

    2015-03-01

    Full Text Available Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant.

  2. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma

    Science.gov (United States)

    Xu, Rui-Hua; Wei, Wei; Krawczyk, Michal; Wang, Wenqiu; Luo, Huiyan; Flagg, Ken; Yi, Shaohua; Shi, William; Quan, Qingli; Li, Kang; Zheng, Lianghong; Zhang, Heng; Caughey, Bennett A.; Zhao, Qi; Hou, Jiayi; Zhang, Runze; Xu, Yanxin; Cai, Huimin; Li, Gen; Hou, Rui; Zhong, Zheng; Lin, Danni; Fu, Xin; Zhu, Jie; Duan, Yaou; Yu, Meixing; Ying, Binwu; Zhang, Wengeng; Wang, Juan; Zhang, Edward; Zhang, Charlotte; Li, Oulan; Guo, Rongping; Carter, Hannah; Zhu, Jian-Kang; Hao, Xiaoke; Zhang, Kang

    2017-11-01

    An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive `liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.

  3. Genetically meaningful phenotypic subgroups in autism spectrum disorders.

    Science.gov (United States)

    Veatch, O J; Veenstra-Vanderweele, J; Potter, M; Pericak-Vance, M A; Haines, J L

    2014-03-01

    Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with strong evidence for genetic susceptibility. However, the effect sizes for implicated chromosomal loci are small, hard to replicate and current evidence does not explain the majority of the estimated heritability. Phenotypic heterogeneity could be one phenomenon complicating identification of genetic factors. We used data from the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, Vineland Adaptive Behavior Scales, head circumferences, and ages at exams as classifying variables to identify more clinically similar subgroups of individuals with ASD. We identified two distinct subgroups of cases within the Autism Genetic Resource Exchange dataset, primarily defined by the overall severity of evaluated traits. In addition, there was significant familial clustering within subgroups (odds ratio, OR ≈ 1.38-1.42, P definition that should increase power to detect genetic factors influencing risk for ASD. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  4. Heterogeneous network architectures

    DEFF Research Database (Denmark)

    Christiansen, Henrik Lehrmann

    2006-01-01

    is flexibility. This thesis investigates such heterogeneous network architectures and how to make them flexible. A survey of algorithms for network design is presented, and it is described how using heuristics can increase the speed. A hierarchical, MPLS based network architecture is described......Future networks will be heterogeneous! Due to the sheer size of networks (e.g., the Internet) upgrades cannot be instantaneous and thus heterogeneity appears. This means that instead of trying to find the olution, networks hould be designed as being heterogeneous. One of the key equirements here...... and it is discussed that it is advantageous to heterogeneous networks and illustrated by a number of examples. Modeling and simulation is a well-known way of doing performance evaluation. An approach to event-driven simulation of communication networks is presented and mixed complexity modeling, which can simplify...

  5. Two-generation analysis of pollen flow across a landscape. I. Male gamete heterogeneity among females.

    Science.gov (United States)

    Smouse, P E; Dyer, R J; Westfall, R D; Sork, V L

    2001-02-01

    Gene flow is a key factor in the spatial genetic structure in spatially distributed species. Evolutionary biologists interested in microevolutionary processess and conservation biologists interested in the impact of landscape change require a method that measures the real time process of gene movement. We present a novel two-generation (parent-offspring) approach to the study of genetic structure (TwoGener) that allows us to quantify heterogeneity among the male gamete pools sampled by maternal trees scattered across the landscape and to estimate mean pollination distance and effective neighborhood size. First, we describe the model's elements: genetic distance matrices to estimate intergametic distances, molecular analysis of variance to determine whether pollen profiles differ among mothers, and optimal sampling considerations. Second, we evaluate the model's effectiveness by simulating spatially distributed populations. Spatial heterogeneity in male gametes can be estimated by phiFT, a male gametic analogue of Wright's F(ST) and an inverse function of mean pollination distance. We illustrate TwoGener in cases where the male gamete can be categorically or ambiguously determined. This approach does not require the high level of genetic resolution needed by parentage analysis, but the ambiguous case is vulnerable to bias in the absence of adequate genetic resolution. Finally, we apply TwoGener to an empirical study of Quercus alba in Missouri Ozark forests. We find that phiFT = 0.06, translating into about eight effective pollen donors per female and an effective pollination neighborhood as a circle of radius about 17 m. Effective pollen movement in Q. alba is more restricted than previously realized, even though pollen is capable of moving large distances. This case study illustrates that, with a modest investment in field survey and laboratory analysis, the TwoGener approach permits inferences about landscape-level gene movements.

  6. Bet-hedging as a complex interaction among developmental instability, environmental heterogeneity, dispersal, and life-history strategy.

    Science.gov (United States)

    Scheiner, Samuel M

    2014-02-01

    One potential evolutionary response to environmental heterogeneity is the production of randomly variable offspring through developmental instability, a type of bet-hedging. I used an individual-based, genetically explicit model to examine the evolution of developmental instability. The model considered both temporal and spatial heterogeneity alone and in combination, the effect of migration pattern (stepping stone vs. island), and life-history strategy. I confirmed that temporal heterogeneity alone requires a threshold amount of variation to select for a substantial amount of developmental instability. For spatial heterogeneity only, the response to selection on developmental instability depended on the life-history strategy and the form and pattern of dispersal with the greatest response for island migration when selection occurred before dispersal. Both spatial and temporal variation alone select for similar amounts of instability, but in combination resulted in substantially more instability than either alone. Local adaptation traded off against bet-hedging, but not in a simple linear fashion. I found higher-order interactions between life-history patterns, dispersal rates, dispersal patterns, and environmental heterogeneity that are not explainable by simple intuition. We need additional modeling efforts to understand these interactions and empirical tests that explicitly account for all of these factors.

  7. Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time.

    Science.gov (United States)

    Decaens, Thomas; Roudot-Thoraval, Françoise; Hadni-Bresson, Solange; Meyer, Carole; Gugenheim, Jean; Durand, Francois; Bernard, Pierre-Henri; Boillot, Olivier; Sulpice, Laurent; Calmus, Yvon; Hardwigsen, Jean; Ducerf, Christian; Pageaux, Georges-Philippe; Dharancy, Sebastien; Chazouilleres, Olivier; Cherqui, Daniel; Duvoux, Christophe

    2006-12-01

    Orthotopic liver transplantation (OLT) indication for hepatocellular carcinoma (HCC) is currently based on the Milan criteria. The University of California, San Francisco (UCSF) recently proposed an expansion of the selection criteria according to tumors characteristics on the explanted liver. This study: 1) assessed the validity of these criteria in an independent large series and 2) tested for the usefulness of these criteria when applied to pre-OLT tumor evaluation. Between 1985 and 1998, 479 patients were listed for liver transplantation (LT) for HCC and 467 were transplanted. According to pre-OLT (imaging at date of listing) or post-OLT (explanted liver) tumor characteristics, patients were retrospectively classified according to both the Milan and UCSF criteria. The 5-yr survival statistics were assessed by the Kaplan-Meier method and compared by the log-rank test. Pre-OLT UCSF criteria were analyzed according to an intention-to-treat principle. Based on the pre-OLT evaluation, 279 patients were Milan+, 44 patients were UCSF+ but Milan- (subgroup of patients that might benefit from the expansion), and 145 patients were UCSF- and Milan-. With a short median waiting time of 4 months, 5-yr survival was 60.1 +/- 3.0%, 45.6 +/- 7.8%, and 34.7 +/- 4.0%, respectively (P OLT evaluation, the UCSF criteria are associated with a 5-yr survival below 50%. Their applicability is therefore limited, despite similar survival rates compared to the Milan criteria, when the explanted liver is taken into account.

  8. Efficient enrichment of hepatic cancer stem-like cells from a primary rat HCC model via a density gradient centrifugation-centered method.

    Directory of Open Access Journals (Sweden)

    Wei-hui Liu

    Full Text Available BACKGROUND: Because few definitive markers are available for hepatic cancer stem cells (HCSCs, based on physical rather than immunochemical properties, we applied a novel method to enrich HCSCs. METHODOLOGY: After hepatic tumor cells (HTCs were first isolated from diethylinitrosamine-induced F344 rat HCC model using percoll discontinuous gradient centrifugation (PDGC and purified via differential trypsinization and differential attachment (DTDA, they were separated into four fractions using percoll continuous gradient centrifugation (PCGC and sequentially designated as fractions I-IV (FI-IV. Morphological characteristics, mRNA and protein levels of stem cell markers, proliferative abilities, induced differentiation, in vitro migratory capacities, in vitro chemo-resistant capacities, and in vivo malignant capacities were determined for the cells of each fraction. FINDINGS: As the density of cells increased, 22.18%, 11.62%, 4.73% and 61.47% of primary cultured HTCs were segregated in FI-FIV, respectively. The cells from FIII (density between 1.041 and 1.062 g/ml displayed a higher nuclear-cytoplasmic ratio and fewer organelles and expressed higher levels of stem cell markers (AFP, EpCAM and CD133 than cells from other fractions (P<0.01. Additionally, in vitro, the cells from FIII showed a greater capacity to self-renew, differentiate into mature HTCs, transit across membranes, close scratches, and carry resistance to chemotherapy than did cells from any other fraction; in vivo, injection of only 1×10(4 cells from FIII could generate tumors not only in subcutaneous tissue but also in the livers of nude mice. CONCLUSIONS: Through our novel method, HCSC-like cells were successfully enriched in FIII. This study will greatly contribute to two important areas of biological interest: CSC isolation and HCC therapy.

  9. WE-E-17A-06: Assessing the Scale of Tumor Heterogeneity by Complete Hierarchical Segmentation On MRI

    International Nuclear Information System (INIS)

    Gensheimer, M; Trister, A; Ermoian, R; Hawkins, D

    2014-01-01

    Purpose: In many cancers, intratumoral heterogeneity exists in vascular and genetic structure. We developed an algorithm which uses clinical imaging to interrogate different scales of heterogeneity. We hypothesize that heterogeneity of perfusion at large distance scales may correlate with propensity for disease recurrence. We applied the algorithm to initial diagnosis MRI of rhabdomyosarcoma patients to predict recurrence. Methods: The Spatial Heterogeneity Analysis by Recursive Partitioning (SHARP) algorithm recursively segments the tumor image. The tumor is repeatedly subdivided, with each dividing line chosen to maximize signal intensity difference between the two subregions. This process continues to the voxel level, producing segments at multiple scales. Heterogeneity is measured by comparing signal intensity histograms between each segmented region and the adjacent region. We measured the scales of contrast enhancement heterogeneity of the primary tumor in 18 rhabdomyosarcoma patients. Using Cox proportional hazards regression, we explored the influence of heterogeneity parameters on relapse-free survival (RFS). To compare with existing methods, fractal and Haralick texture features were also calculated. Results: The complete segmentation produced by SHARP allows extraction of diverse features, including the amount of heterogeneity at various distance scales, the area of the tumor with the most heterogeneity at each scale, and for a given point in the tumor, the heterogeneity at different scales. 10/18 rhabdomyosarcoma patients suffered disease recurrence. On contrast-enhanced MRI, larger scale of maximum signal intensity heterogeneity, relative to tumor diameter, predicted for shorter RFS (p=0.05). Fractal dimension, fractal fit, and three Haralick features did not predict RFS (p=0.09-0.90). Conclusion: SHARP produces an automatic segmentation of tumor regions and reports the amount of heterogeneity at various distance scales. In rhabdomyosarcoma, RFS was

  10. Intratumor genetic heterogeneity of breast carcinomas as determined by fine needle aspiration and TaqMan low density array

    DEFF Research Database (Denmark)

    Lyng, Maria B.; Laenkholm, Anne-Vibeke; Pallisgaard, Niels

    2007-01-01

    BACKGROUND: Gene expression profiling is thought to be an important tool in determining treatment strategies for breast cancer patients. Tissues for such analysis may at a preoperative stage be obtained, by fine needle aspiration (FNA) allowing initiation of neoadjuvant treatment. To evaluate the...... of breast carcinomas, as sampled by FNA, does not prohibit generation of useful gene profiles for treatment decision making. However, sampling and analysis strategies should take heterogeneity within a tumor, and varying heterogeneity amongst the single genes, into account...

  11. Curcumin ameliorates liver damage and progression of NASH in NASH-HCC mouse model possibly by modulating HMGB1-NF-κB translocation.

    Science.gov (United States)

    Afrin, Rejina; Arumugam, Somasundaram; Rahman, Azizur; Wahed, Mir Imam Ibne; Karuppagounder, Vengadeshprabhu; Harima, Meilei; Suzuki, Hiroshi; Miyashita, Shizuka; Suzuki, Kenji; Yoneyama, Hiroyuki; Ueno, Kazuyuki; Watanabe, Kenichi

    2017-03-01

    Curcumin, a phenolic compound, has a wide spectrum of therapeutic effects such as antitumor, anti-inflammatory, anti-cancer and so on. The study aimed to investigate the underlying mechanisms of curcumin to protect liver damage and progression of non-alcoholic steatohepatitis (NASH) in a novel NASH-hepatocellular carcinoma (HCC) mouse model. To induce this model neonatal C57BL/6J male mice were exposed to low-dose streptozotocin and were fed a high-fat diet (HFD) from the age of 4weeks to 14weeks. Curcumin was given at 100mg/kg dose daily by oral gavage started at the age of 10weeks and continued until 14weeks along with HFD feeding. We found that curcumin improved the histopathological changes of the NASH liver via reducing the level of steatosis, fibrosis associated with decreasing serum aminotransferases. In addition, curcumin treatment markedly reduced the hepatic protein expression of oxidative stress, pro-inflammatory cytokines, and chemokines including interferon (IFN) γ, interleukin-1β and IFNγ-inducible protein 10, in NASH mice. Furthermore, curcumin treatment significantly reduced the cytoplasmic translocation of high mobility group box 1 (HMGB1) and the protein expression of toll like receptor 4. Nuclear translocation of nuclear factor kappa B (NF-κB) was also dramatically attenuated by the curcumin in NASH liver. Curcumin treatment effectively reduced the progression of NASH to HCC by suppressing the protein expression of glypican-3, vascular endothelial growth factor, and prothrombin in the NASH liver. Our data suggest that curcumin reduces the progression of NASH and liver damage, which may act via inhibiting HMGB1-NF-κB translocation. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Phenotypic and genetic characterization of Piscirickettsia salmonis from Chilean and Canadian salmonids.

    Science.gov (United States)

    Otterlei, Alexander; Brevik, Øyvind J; Jensen, Daniel; Duesund, Henrik; Sommerset, Ingunn; Frost, Petter; Mendoza, Julio; McKenzie, Peter; Nylund, Are; Apablaza, Patricia

    2016-03-15

    The study presents the phenotypic and genetic characterization of selected P. salmonis isolates from Atlantic salmon and rainbow trout suffering from SRS (salmonid rickettsial septicemia) in Chile and in Canada. The phenotypic characterization of the P. salmonis isolates were based on growth on different agar media (including a newly developed medium), different growth temperatures, antibiotics susceptibility and biochemical tests. This is the first study differentiating Chilean P. salmonis isolates into two separate genetic groups. Genotyping, based on 16S rRNA-ITS and concatenated housekeeping genes grouped the selected isolates into two clades, constituted by the Chilean strains, while the Canadian isolates form a branch in the phylogenetic tree. The latter consisted of two isolates that were different in both genetic and phenotypic characteristics. The phylogenies and the MLST do not reflect the origin of the isolates with respect to host species. The isolates included were heterogeneous in phenotypic tests. The genotyping methods developed in this study provided a tool for separation of P. salmonis isolates into distinct clades. The SRS outbreaks in Chile are caused by minimum two different genetic groups of P. salmonis. This heterogeneity should be considered in future development of vaccines against this bacterium in Chile. Two different strains of P. salmonis, in regards to genetic and phenotypic characteristics, can occur in the same contemporary outbreak of SRS.

  13. Genetic parameters and genetic trends in the Chinese × European Tiameslan composite pig line. I. Genetic parameters

    Directory of Open Access Journals (Sweden)

    Legault Christian

    2000-01-01

    Full Text Available Abstract Genetic parameters of body weight at 4 (W4 w, 8 (W8 w and 22 (W22 w weeks of age, days from 20 to 100 kg (DT, average backfat thickness at 100 kg (ABT, teat number (TEAT, number of good teats (GTEAT, total number of piglets born (TNB, born alive (NBA and weaned (NW per litter, and birth to weaning survival rate (SURV were estimated in the Chinese × European Tiameslan composite line using restricted maximum likelihood methodology applied to a multiple trait animal model. Performance data from a total of 4 881 males and 4 799 females from 1 341 litters were analysed. Different models were fitted to the data in order to estimate the importance of maternal effects on production traits, as well as genetic correlations between male and female performance. The results showed the existence of significant maternal effects on W4w, W8w and ABT and of variance heterogeneity between sexes for W22w, DT, ABT and GTEAT. Genetic correlations between sexes were 0.79, 0.71 and 0.82, respectively, for W22w, DT and ABT and above 0.90 for the other traits. Heritability estimates were larger than (ABT and TEAT or similar to (other traits average literature values. Some genetic antagonism was evidenced between production traits, particularly W4w, W8w and ABT, and reproductive traits.

  14. Genetic variations among Mycoplasma bovis strains isolated from Danish cattle

    DEFF Research Database (Denmark)

    Kusiluka, L.J.M.; Kokotovic, Branko; Ojeniyi, B.

    2000-01-01

    The genetic heterogeneity of Mycoplasma bovis strains isolated in Denmark over a 17-year period was investigated. Forty-two field strains isolated from different geographic locations and specimens, including strains from 21 herds involved in two outbreaks of M. bovis-induced mastitis, and the type...

  15. Understanding heterogeneity in the effects of birth weight on adult cognition and wages.

    Science.gov (United States)

    Justin Cook, C; Fletcher, Jason M

    2015-05-01

    A large economics literature has shown long term impacts of birth weight on adult outcomes, including IQ and earnings that are often robust to sibling or twin fixed effects. We examine potential mechanisms underlying these effects by incorporating findings from the genetics and neuroscience literatures. We use a sample of siblings combined with an "orchids and dandelions hypothesis", where the IQ of genetic dandelions is not affected by in utero nutrition variation but genetic orchids thrive under advantageous conditions and wilt in poor conditions. Indeed, using variation in three candidate genes related to neuroplasticity (APOE, BDNF, and COMT), we find substantial heterogeneity in the associations between birth weight and adult outcomes, where part of the population (i.e., "dandelions") is not affected by birth weight variation. Our results help uncover why birth weight affects adult outcomes. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. [Clinical and genetic aspects of albinism].

    Science.gov (United States)

    Arveiler, Benoit; Lasseaux, Eulalie; Morice-Picard, Fanny

    Albinism is a genetic disease affecting 1/17,000 person worldwide. It constitutes the second cause of congenital loss of visual acuity after optic atrophy. Albinism is heterogeneous both at the clinical and genetic levels. It is characterized by ocular development anomalies and by a variable degree of hypopigmentation. Clinically, three forms of the disease are described: oculocutaneous, ocular and syndromic (Hermansky-Pudlak syndrome, Chediak-Higashi syndrome). Nineteen genes involved in the different types of albinism have been described so far. The broad phenotypic variability between the different forms but also within a particular form renders the establishment of phenotype-genotype correlations impossible. A genetic test exploring all 19 genes is necessary to establish the diagnosis and to distinguish between syndromic and non-syndromic forms. We present the creation of an albinism-dedicated Day Hospital at the University Hospital of Bordeaux. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity.

    Directory of Open Access Journals (Sweden)

    Miles Miller

    Full Text Available Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of β-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for 'synthetic cellular heterogeneity' that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism, demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a 'phenotypic sensitivity analysis' method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a module's biochemical rate-constants, its high level functional behavior in

  18. Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity.

    Science.gov (United States)

    Miller, Miles; Hafner, Marc; Sontag, Eduardo; Davidsohn, Noah; Subramanian, Sairam; Purnick, Priscilla E M; Lauffenburger, Douglas; Weiss, Ron

    2012-01-01

    Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of β-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation) are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for 'synthetic cellular heterogeneity' that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism), demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a 'phenotypic sensitivity analysis' method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a module's biochemical rate-constants, its high level functional behavior in isolation, and

  19. Current management of hepatocellular carcinoma

    Science.gov (United States)

    Tabrizian, Parissa; Roayaie, Sasan; Schwartz, Myron E

    2014-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and leading cause of death among patients with cirrhosis. Treatment guidelines are based according to the Barcelona Clinic Liver Cancer staging system. The choice among therapeutic options that include liver resection, liver transplantation, locoregional, and systemic treatments must be individualized for each patient. The aim of this paper is to review the outcomes that can be achieved in the treatment of HCC with the heterogeneous therapeutic options currently available in clinical practice. PMID:25132740

  20. Dynamic heterogeneity in life histories

    DEFF Research Database (Denmark)

    Tuljapurkar, Shripad; Steiner, Uli; Orzack, Steven Hecht

    2009-01-01

    or no fixed heterogeneity influences this trait. We propose that dynamic heterogeneity provides a 'neutral' model for assessing the possible role of unobserved 'quality' differences between individuals. We discuss fitness for dynamic life histories, and the implications of dynamic heterogeneity...... generate dynamic heterogeneity: life-history differences produced by stochastic stratum dynamics. We characterize dynamic heterogeneity in a range of species across taxa by properties of the Markov chain: the entropy, which describes the extent of heterogeneity, and the subdominant eigenvalue, which...... distributions of lifetime reproductive success. Dynamic heterogeneity contrasts with fixed heterogeneity: unobserved differences that generate variation between life histories. We show by an example that observed distributions of lifetime reproductive success are often consistent with the claim that little...

  1. Impact of Geography and Climate on the Genetic Differentiation of the Subtropical Pine Pinus yunnanensis.

    Science.gov (United States)

    Wang, Baosheng; Mao, Jian-Feng; Zhao, Wei; Wang, Xiao-Ru

    2013-01-01

    Southwest China is a biodiversity hotspot characterized by complex topography, heterogeneous regional climates and rich flora. The processes and driving factors underlying this hotspot remain to be explicitly tested across taxa to gain a general understanding of the evolution of biodiversity and speciation in the region. In this study, we examined the role played by historically neutral processes, geography and environment in producing the current genetic diversity of the subtropical pine Pinus yunnanensis. We used genetic and ecological methods to investigate the patterns of genetic differentiation and ecological niche divergence across the distribution range of this species. We found both continuous genetic differentiation over the majority of its range, and discrete isolated local clusters. The discrete differentiation between two genetic groups in the west and east peripheries is consistent with niche divergence and geographical isolation of these groups. In the central area of the species' range, population structure was shaped mainly by neutral processes and geography rather than by ecological selection. These results show that geographical and environmental factors together created stronger and more discrete genetic differentiation than isolation by distance alone, and illustrate the importance of ecological factors in forming or maintaining genetic divergence across a complex landscape. Our findings differ from other phylogenetic studies that identified the historical drainage system in the region as the primary factor shaping population structure, and highlight the heterogeneous contributions that geography and environment have made to genetic diversity among taxa in southwest China.

  2. Genetic variance in micro-environmental sensitivity for milk and milk quality in Walloon Holstein cattle.

    Science.gov (United States)

    Vandenplas, J; Bastin, C; Gengler, N; Mulder, H A

    2013-09-01

    Animals that are robust to environmental changes are desirable in the current dairy industry. Genetic differences in micro-environmental sensitivity can be studied through heterogeneity of residual variance between animals. However, residual variance between animals is usually assumed to be homogeneous in traditional genetic evaluations. The aim of this study was to investigate genetic heterogeneity of residual variance by estimating variance components in residual variance for milk yield, somatic cell score, contents in milk (g/dL) of 2 groups of milk fatty acids (i.e., saturated and unsaturated fatty acids), and the content in milk of one individual fatty acid (i.e., oleic acid, C18:1 cis-9), for first-parity Holstein cows in the Walloon Region of Belgium. A total of 146,027 test-day records from 26,887 cows in 747 herds were available. All cows had at least 3 records and a known sire. These sires had at least 10 cows with records and each herd × test-day had at least 5 cows. The 5 traits were analyzed separately based on fixed lactation curve and random regression test-day models for the mean. Estimation of variance components was performed by running iteratively expectation maximization-REML algorithm by the implementation of double hierarchical generalized linear models. Based on fixed lactation curve test-day mean models, heritability for residual variances ranged between 1.01×10(-3) and 4.17×10(-3) for all traits. The genetic standard deviation in residual variance (i.e., approximately the genetic coefficient of variation of residual variance) ranged between 0.12 and 0.17. Therefore, some genetic variance in micro-environmental sensitivity existed in the Walloon Holstein dairy cattle for the 5 studied traits. The standard deviations due to herd × test-day and permanent environment in residual variance ranged between 0.36 and 0.45 for herd × test-day effect and between 0.55 and 0.97 for permanent environmental effect. Therefore, nongenetic effects also

  3. Improving clinical trial design for hepatocellular carcinoma treatments

    Directory of Open Access Journals (Sweden)

    Robert G. Gish

    2011-12-01

    Full Text Available Despite its place as the third leading cause of cancer deaths worldwide, there are currently no approved chemotherapeutic agents, devices or techniques to treat hepatocellular carcinoma. Importantly, there have been no phase III studies demonstrating survival benefit, nor any randomized studies of treatment except for transarterial chemoembolization and most recently sorafenib. The importance of well-designed clinical trials of agents to treat HCC has never been greater. However, general clinical study design issues, combined with HCC-specific issues pose significant challenges in structuring such studies. HCC-related challenges include the heterogeneity of this cancer and the fact that it is frequently accompanied by significant comorbidities at diagnosis, such as active hepatitis B or C virus replication, substantial past or on-going alcohol use, and cirrhosis, itself often a fatal disease. The recently published comparison of a newer treatment, nolatrexed to doxorubicin, and comments about this study’s initial HCC diagnostic criteria, staging system, comparator therapy and choice of endpoints have provided a platform to discuss the challenges unique to the design of HCC clinical trials. The difficulty in accurately framing study results obtained from the constantly changing HCC clinical landscape and approaches to meet these challenges will be reviewed.

  4. Hepatocellular carcinoma: a systems biology perspective

    Directory of Open Access Journals (Sweden)

    Lorenza Alice D'alessandro

    2013-02-01

    Full Text Available Hepatocellular carcinomas (HCC have different etiology and heterogenic genomic alterations lead to high complexity. The molecular features of HCC have largely been studied by gene expression and proteome profiling focusing on the correlations between the expression of specific markers and clinical data. Integration of the increasing amounts of data in databases has facilitated the link of genomic and proteomic profiles of HCC to disease state and clinical outcome. Despite the current knowledge, specific molecular markers remain to be identified and new strategies are required to establish novel targeted therapies. In the last years, mathematical models reconstructing gene and protein networks based on experimental data of HCC have been developed providing powerful tools to predict candidate interactions and potential targets for therapy. Furthermore, the combination of dynamic and logical mathematical models with quantitative data allows detailed mechanistic insights into system properties. To address effects at the organ level, mathematical models reconstructing the three-dimensional organization of liver lobules were developed. In the future, integration of different modeling approaches capturing the effects at the cellular up to the organ level is required to address the complex properties of HCC and to enable the discovery of new targets for HCC prevention or treatment.

  5. Contemporary paternal genetic landscape of Polish and German populations: from early medieval Slavic expansion to post-World War II resettlements

    OpenAIRE

    Rębała, Krzysztof; Martínez-Cruz, Begoña; Tönjes, Anke; Kovacs, Peter; Stumvoll, Michael; Lindner, Iris; Büttner, Andreas; Wichmann, H-Erich; Siváková, Daniela; Soták, Miroslav; Quintana-Murci, Lluís; Szczerkowska, Zofia; Comas, David

    2012-01-01

    Homogeneous Proto-Slavic genetic substrate and/or extensive mixing after World War II were suggested to explain homogeneity of contemporary Polish paternal lineages. Alternatively, Polish local populations might have displayed pre-war genetic heterogeneity owing to genetic drift and/or gene flow with neighbouring populations. Although sharp genetic discontinuity along the political border between Poland and Germany indisputably results from war-mediated resettlements and homogenisation, it re...

  6. Worldwide variation in hip fracture incidence weakly aligns with genetic divergence between populations.

    Science.gov (United States)

    Wallace, I J; Botigué, L R; Lin, M; Smaers, J B; Henn, B M; Grine, F E

    2016-09-01

    This study investigates the influence of genetic differentiation in determining worldwide heterogeneity in osteoporosis-related hip fracture rates. The results indicate that global variation in fracture incidence exceeds that expected on the basis of random genetic variance. Worldwide, the incidence of osteoporotic hip fractures varies considerably. This variability is believed to relate mainly to non-genetic factors. It is conceivable, however, that genetic susceptibility indeed differs across populations. Here, we present the first quantitative assessment of the effects of genetic differentiation on global variability in hip fracture rates. We investigate the observed variance in publically reported age-standardized rates of hip fracture among 28 populations from around the world relative to the expected variance given the phylogenetic relatedness of these populations. The extent to which these variances are similar constitutes a "phylogenetic signal," which was measured using the K statistic. Population genetic divergence was calculated using a robust array of genome-wide single nucleotide polymorphisms. While phylogenetic signal is maximized when K > 1, a K value of only 0.103 was detected in the combined-sex fracture rate pattern across the 28 populations, indicating that fracture rates vary more than expected based on phylogenetic relationships. When fracture rates for the sexes were analyzed separately, the degree of phylogenetic signal was also found to be small (females: K = 0.102; males: K = 0.081). The lack of a strong phylogenetic signal underscores the importance of factors other than stochastic genetic diversity in shaping worldwide heterogeneity in hip fracture incidence.

  7. A multiple mediator analysis approach to quantify the effects of the ADH1B and ALDH2 genes on hepatocellular carcinoma risk.

    Science.gov (United States)

    Shih, Stephannie; Huang, Yen-Tsung; Yang, Hwai-I

    2018-06-01

    Previous work suggested a genetic component affecting the risk of hepatocellular carcinoma (HCC) and mediation analyses have elucidated potential indirect pathways of these genetic effects. Specifically, the effects of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase (ALDH2) genes on HCC risk vary based on alcohol consumption habits. However, alcohol consumption may not be the only mediator in the identified pathway: factors related to alcohol consumption may contribute to the same indirect pathway. Thus, we developed a multimediator model to quantify the genetic effects on HCC risk through sequential dichotomous mediators under the counterfactual framework. Our method provided a closed form formula for the mediation effects through different indirect paths, which requires no assumption for the rarity of outcome. In simulation studies of a finite sample, we presented the utility of the method with the variance of the effects estimated using the delta method and bootstrapping. We applied our method to data from participants in Taiwan (580 cases and 3,207 controls) and quantified the mediation effects of single nucleotide polymorphisms (SNPs) in the ADH1B and ALDH2 genes on HCC through alcohol consumption (yes/no) and high alanine transaminase (ALT) levels (greater than or equal to 45 U/L or below 45 U/L). Assuming a dominant risk model, we identified that the SNPs' effects through alcohol consumption is more significant than through ALT levels on HCC risk. This new method provides insight to the magnitude of various casual mechanisms as a closed form solution and can be readily applied in other genomic studies. © 2018 WILEY PERIODICALS, INC.

  8. Multilocus Microsatellite Typing reveals intra-focal genetic diversity among strains of Leishmania tropica in Chichaoua Province, Morocco.

    Science.gov (United States)

    Krayter, Lena; Alam, Mohammad Zahangir; Rhajaoui, Mohamed; Schnur, Lionel F; Schönian, Gabriele

    2014-12-01

    In Morocco, cutaneous leishmaniasis (CL) caused by Leishmania (L.) tropica is a major public health threat. Strains of this species have been shown to display considerable serological, biochemical, molecular biological and genetic heterogeneity; and Multilocus Enzyme Electrophoresis (MLEE), has shown that in many countries including Morocco heterogenic variants of L. tropica can co-exist in single geographical foci. Here, the microsatellite profiles discerned by MLMT of nine Moroccan strains of L. tropica isolated in 2000 from human cases of CL from Chichaoua Province were compared to those of nine Moroccan strains of L. tropica isolated between 1988 and 1990 from human cases of CL from Marrakech Province, and also to those of 147 strains of L. tropica isolated at different times from different worldwide geographical locations within the range of distribution of the species. Several programs, each employing a different algorithm, were used for population genetic analysis. The strains from each of the two Moroccan foci separated into two phylogenetic clusters independent of their geographical origin. Genetic diversity and heterogeneity existed in both foci, which are geographically close to each other. This intra-focal distribution of genetic variants of L. tropica is not considered owing to in situ mutation. Rather, it is proposed to be explained by the importation of pre-existing variants of L. tropica into Morocco. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Assessing Heterogeneity of Osteolytic Lesions in Multiple Myeloma by 1H HR-MAS NMR Metabolomics

    Directory of Open Access Journals (Sweden)

    Laurette Tavel

    2016-10-01

    Full Text Available Multiple myeloma (MM is a malignancy of plasma cells characterized by multifocal osteolytic bone lesions. Macroscopic and genetic heterogeneity has been documented within MM lesions. Understanding the bases of such heterogeneity may unveil relevant features of MM pathobiology. To this aim, we deployed unbiased 1H high-resolution magic-angle spinning (HR-MAS nuclear magnetic resonance (NMR metabolomics to analyze multiple biopsy specimens of osteolytic lesions from one case of pathological fracture caused by MM. Multivariate analyses on normalized metabolite peak integrals allowed clusterization of samples in accordance with a posteriori histological findings. We investigated the relationship between morphological and NMR features by merging morphological data and metabolite profiling into a single correlation matrix. Data-merging addressed tissue heterogeneity, and greatly facilitated the mapping of lesions and nearby healthy tissues. Our proof-of-principle study reveals integrated metabolomics and histomorphology as a promising approach for the targeted study of osteolytic lesions.

  10. Confirmation of linkage of Best`s macular dystrophy to 11q13, and evidence for genetic heterogeneity

    Energy Technology Data Exchange (ETDEWEB)

    Mansergh, F.C.; Kenna, P.F.; Farrar, G.J. [Trinity College, Dublin (United Kingdom)] [and others

    1994-09-01

    Best`s macular dystrophy, also known as vitelliform macular degeneration, is an autosomal dominant, early onset form of macular degeneration. The disease is characterized by a roughly circular deposit of lipofuscin beneath the pigment epithelium of the retinal macula. Linkage studies were performed in two families, one Irish and one German, segregating typical Best`s macular dystrophy. In the Irish family (BTMD1), linkage analysis mapped the disease causing gene to chromosome 11q13, in a 10 cM region between the microsatellite markers PYGM and D11S871. Both markers showed different recombinants with the disease phenotype. This is a region that has previously shown linkage in families affected with Best`s macular dystrophy. Lod scores of 9.63, 9.12, 6.92, and 6.83 at zero recombination, were obtained with markers D11S1344, D11S1361, D11S1357 and D11S903, respectively. This data places the disease locus definitvely within the region between PYGM and D11S871. Linkage has been significantly excluded in this region in the German family (FamE), thereby providing evidence for genetic heterogeneity in this disease. The retinal specific gene, rod outer membrane protein 1 (ROM1), which maps to this region, has been screened for mutations in family BTMD1 by SSCPE analysis and by direct sequencing. Some of the promoter region, the three exons, and both introns have been sequenced; however, no mutations were found. It is likely that a gene other than ROM1 within this region may be responsible for causing the disease phenotype.

  11. Assessing liver function in patients with HBV-related HCC: a comparison of T{sub 1} mapping on Gd-EOB-DTPA-enhanced MR imaging with DWI

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Ying; Rao, Sheng-Xiang; Chen, Caizhong; Li, Renchen; Zeng, Meng-Su [Zhongshan Hospital of Fudan University, Department of Radiology, 180 Fenglin Road, Xuhui District, Shanghai (China)

    2015-05-01

    To compare the potential of T{sub 1} mapping on gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) for assessing liver function in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). One hundred consecutive patients with known HBV-related HCCs were included. T{sub 1} relaxation time and apparent diffusion coefficient (ADC) of the liver were measured, and the reduction rate of T{sub 1} relaxation time (∇%) was calculated. T{sub 1} relaxation time measurements were compared with ADC values according to the Model for End-Stage Liver Disease (MELD) score. Hepatobiliary phase (HBP) and ∇% of T{sub 1} relaxation time measurements showed significant correlations with MELD score (rho = 0.571, p < 0.0001; rho = -0.573, p < 0.0001, respectively). HBP and ∇% of T{sub 1} relaxation time were significantly different between good (MELD ≤8) and poor liver function (MELD ≥9) (p < 0.0001 for both). Areas under the receiver operating characteristic curves (AUCs) of T{sub 1} relaxation time for HBP (AUC 0.84) and ∇% (AUC 0.82) were significantly better than for ADC (AUC 0.53; p < 0.0001). T{sub 1} mapping on Gd-EOB-DTPA-enhanced MRI showed promise for evaluating liver function in patients with HBV-related HCC, while DWI was not reliable. HBP T{sub 1} relaxation time measurement was equally accurate as ∇% measurement. (orig.)

  12. Genetic Mapping in Papillon-Lefèvre Syndrome: A Report of Two Cases

    Directory of Open Access Journals (Sweden)

    Kaustubh Suresh Thakare

    2013-01-01

    Full Text Available Papillon-Lefevre syndrome (PLS is a rare autosomal recessive heterogeneous trait which is characterized by erythematous palmoplantar hyperkeratosis, early-onset periodontitis, and associated calcification of dura mater. The etiology of PLS is multifactorial with genetic, immunological, and microbial factors playing a role in etiopathogenesis. Recently identified genetic defect in PLS has been mapped to chromosome 11q14–q21, which involves mutations of cathepsin C. This paper presents a report of 2 cases of Papillon-lefevre syndrome in which diagnosis is based on clinical presentation and genetic mapping.

  13. Ankyrin-1 Gene Exhibits Allelic Heterogeneity in Conferring Protection Against Malaria

    Directory of Open Access Journals (Sweden)

    Hong Ming Huang

    2017-09-01

    Full Text Available Allelic heterogeneity is a common phenomenon where a gene exhibits a different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host–parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 (Ank-1 which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulting in an amino acid substitution (MRI95845, and the other a truncated Ank-1 protein (MRI96570. Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection against Plasmodium chabaudi infections. Upon further examination, the Ank-1(MRI96570 mutation was found to inhibit intraerythrocytic parasite maturation, whereas Ank-1(MRI95845 caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomena in achieving a better understanding of host–parasite interactions, which could be the basis of future studies.

  14. Assessing Age-Related Etiologic Heterogeneity in the Onset of Islet Autoimmunity

    Directory of Open Access Journals (Sweden)

    Brittni N. Frederiksen

    2015-01-01

    Full Text Available Type 1 diabetes (T1D, a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected. The goal of this study was to demonstrate methods for identifying exposures that differentially influence the disease process at certain ages by assessing age-related heterogeneity. The Diabetes Autoimmunity Study in the Young (DAISY has followed 2,547 children at increased genetic risk for T1D from birth since 1993 in Denver, Colorado, 188 of whom developed IA. Using the DAISY population, we evaluated putative determinants of IA, including non-Hispanic white (NHW ethnicity, maternal age at birth, and erythrocyte membrane n-3 fatty acid (FA levels, for age-related heterogeneity. A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk. NHW ethnicity, maternal age, and erythrocyte membrane n-3 FA levels demonstrated a significant age-related association with IA risk. Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.

  15. Heterogeneous cellular networks

    CERN Document Server

    Hu, Rose Qingyang

    2013-01-01

    A timely publication providing coverage of radio resource management, mobility management and standardization in heterogeneous cellular networks The topic of heterogeneous cellular networks has gained momentum in industry and the research community, attracting the attention of standardization bodies such as 3GPP LTE and IEEE 802.16j, whose objectives are looking into increasing the capacity and coverage of the cellular networks. This book focuses on recent progresses,  covering the related topics including scenarios of heterogeneous network deployment, interference management i

  16. Evolution to pathogenicity of the parvovirus minute virus of mice in immunodeficient mice involves genetic heterogeneity at the capsid domain that determines tropism.

    Science.gov (United States)

    López-Bueno, Alberto; Segovia, José C; Bueren, Juan A; O'Sullivan, M Gerard; Wang, Feng; Tattersall, Peter; Almendral, José M

    2008-02-01

    Very little is known about the role that evolutionary dynamics plays in diseases caused by mammalian DNA viruses. To address this issue in a natural host model, we compared the pathogenesis and genetics of the attenuated fibrotropic and the virulent lymphohematotropic strains of the parvovirus minute virus of mice (MVM), and of two invasive fibrotropic MVM (MVMp) variants carrying the I362S or K368R change in the VP2 major capsid protein, in the infection of severe combined immunodeficient (SCID) mice. By 14 to 18 weeks after oronasal inoculation, the I362S and K368R viruses caused lethal leukopenia characterized by tissue damage and inclusion bodies in hemopoietic organs, a pattern of disease found by 7 weeks postinfection with the lymphohematotropic MVM (MVMi) strain. The MVMp populations emerging in leukopenic mice showed consensus sequence changes in the MVMi genotype at residues G321E and A551V of VP2 in the I362S virus infections or A551V and V575A changes in the K368R virus infections, as well as a high level of genetic heterogeneity within a capsid domain at the twofold depression where these residues lay. Amino acids forming this capsid domain are important MVM tropism determinants, as exemplified by the switch in MVMi host range toward mouse fibroblasts conferred by coordinated changes of some of these residues and by the essential character of glutamate at residue 321 for maintaining MVMi tropism toward primary hemopoietic precursors. The few viruses within the spectrum of mutants from mice that maintained the respective parental 321G and 575V residues were infectious in a plaque assay, whereas the viruses with the main consensus sequences exhibited low levels of fitness in culture. Consistent with this finding, a recombinant MVMp virus carrying the consensus sequence mutations arising in the K368R virus background in mice failed to initiate infection in cell lines of different tissue origins, even though it caused rapid-course lethal leukopenia in SCID

  17. Development of sexing mechanisms in the Mediterranean fruit fly Ceratitis capitata through manipulation of radiation-induced conditional lethals and other genetic measures

    International Nuclear Information System (INIS)

    Milani, R.

    1990-05-01

    The African populations of Ceratitis capitata (Kenya and Reunion Isl.) and two Mediterranean ones (Sardinia and Procida Isl.) have been studied for genetic variability at 25 loci by electrophoresis. Parameters using gene frequencies indicate the presence of substantial geographic heterogeneity. The major part of this heterogeneity is attributable to genetic drift and is correlated with the dispersion of medfly from the source area of the species (Subsaharan Africa) to the periphery. Kenya has all the properties of a native population, as gene flow estimates, in terms of number of immigrant per generation, is significant between Kenya and the derived Mediterranean populations, supporting the hypothesis of a recent colonization. But part of the geographic heterogeneity is related to the presence of fixed alleles in Reunion population which appears particularly differentiated, although it maintains the genetic attributes of the ancestral population. Selection may have played an important role in the differentiation of this population. 12 refs, 2 figs, 2 tabs

  18. Genetic heterogeneity of hemoglobin AEBart's disease: a large cohort data from a single referral center in northeast Thailand.

    Science.gov (United States)

    Chaibunruang, Attawut; Karnpean, Rossarin; Fucharoen, Goonnapa; Fucharoen, Supan

    2014-04-01

    AEBart's disease is a thalassemia intermedia usually characterized by the interaction of α(0)-thalassemia with either deletional or non-deletional α(+)-thalassemia in Hb E heterozygote. Genotypic and phenotypic features are heterogeneous. We studied the hematologic and molecular characteristics of this disease in a cohort of 173 Thai patients encountered at our center in northeast Thailand. Hemoglobin and DNA analyses identified patients with deletional AEBart's disease (n=84), Hb Constant Spring AEBart's disease (n=81), Hb Paksé-AEBart's disease (n=5), AEBart's disease with codon 30 mutation (n=1) and two hitherto un-described forms of AEBart's disease due to interaction of Hb E heterozygote and α(0)-thalassemia with the -α(16.6)kb deletional α(+)-thalassemia (n=1) and Hb Q-Thailand (n=1). Different phenotypic expression of these AEBart's diseases with low Hb, Hct and MCV and increased RDW values with marked reduction in Hb E levels were observed. It was found that all these forms of AEBart's disease showed similar thalassemia intermedia phenotypes but those with non-deletional forms were relatively more anemic. Our data confirm that in such area with high prevalence of hemoglobinopathies such as Southeast Asia, identification of rare thalassemia alleles in a thalassemia intermedia patient should not be ignored. Careful consideration of different phenotypic expression may help in providing presumptive diagnosis of this disease where access to molecular testing is limited. However, molecular diagnostic is useful for predicting the clinical outcome and improving genetic counseling of these complex hemoglobinopathies. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Application of tumor-node-metastasis staging 2002 version in locally advanced hepatocellular carcinoma: is it predictive of surgical outcome?

    International Nuclear Information System (INIS)

    Li, Binkui; Yuan, Yunfei; Chen, Guihua; He, Liru; Zhang, Yaqi; Li, Jinqing; Li, Guohui; Lau, Wan Yee

    2010-01-01

    Locally advanced (pT3-4N0M0) hepatocellular carcinoma (HCC) is a heterogeneous group of tumors, which consists of four different categories, including HCC with 'multiple tumors more than 5 cm', 'major vascular invasion', 'invasion of adjacent organs', and 'perforation of visceral peritoneum'. The aim of our study was to verify whether the 2002 version of the Tumor-Node-Metastasis staging system could predict surgical outcomes in patients with locally advanced HCC. We retrospectively reviewed 298 patients with pT3-4N0M0 HCC who underwent hepatic resection from 1993 to 2000 in an academic tertiary hospital. Overall survival (OS) and cumulative recurrence rate (CRR) of the four categories of locally advanced HCC patients were compared. In multivariate analysis, major vascular invasion was identified as the most significant factor (HR = 3.291, 95% CI 2.362-4.584, P < 0.001) followed by cirrhosis status on OS, and was found to be the only independent factor of CRR (HR = 2.242, 95% CI 1.811-3.358, P < 0.001) in patients with locally advanced HCC. Among the four categories of locally advanced HCC, OS was significantly worse, and CRR was significantly higher in patients with HCC with major vascular invasion (pT3) than with multiple tumors more than 5 cm (pT3); or tumor invasion of adjacent organs (pT4); or perforation of visceral peritoneum (pT4). No significant differences were observed in OS or CRR between the latter three groups of patients. HCC with major vascular invasion, which are classified as pT3 under the current TNM staging, have the worst prognosis when compared with the other categories of pT3-4 disease. There is a need to redefine the T classification and to stratify locally advanced HCC

  20. Nature, nurture, and item response theory: a psychometric approach to behaviour genetics

    NARCIS (Netherlands)

    Schwabe, Inga

    2016-01-01

    This dissertation discusses a number of psychometric issues that require special attention in the analysis of genetically-informative data, such as data on twins. These include heterogeneous measurement error, scaling and scale transformation, and harmonization of phenotypes. It is shown how

  1. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.

    Directory of Open Access Journals (Sweden)

    Masakazu Kohda

    2016-01-01

    Full Text Available Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4 as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3 and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21 as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.

  2. Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines.

    Science.gov (United States)

    Adalsteinsson, Viktor A; Tahirova, Narmin; Tallapragada, Naren; Yao, Xiaosai; Campion, Liam; Angelini, Alessandro; Douce, Thomas B; Huang, Cindy; Bowman, Brittany; Williamson, Christina A; Kwon, Douglas S; Wittrup, K Dane; Love, J Christopher

    2013-10-01

    Cancer is an inflammatory disease of tissue that is largely influenced by the interactions between multiple cell types, secreted factors, and signal transduction pathways. While single-cell sequencing continues to refine our understanding of the clonotypic heterogeneity within tumors, the complex interplay between genetic variations and non-genetic factors ultimately affects therapeutic outcome. Much has been learned through bulk studies of secreted factors in the tumor microenvironment, but the secretory behavior of single cells has been largely uncharacterized. Here we directly profiled the secretions of ELR+ CXC chemokines from thousands of single colorectal tumor and stromal cells, using an array of subnanoliter wells and a technique called microengraving to characterize both the rates of secretion of several factors at once and the numbers of cells secreting each chemokine. The ELR+ CXC chemokines are highly redundant, pro-angiogenic cytokines that signal via the CXCR1 and CXCR2 receptors, influencing tumor growth and progression. We find that human primary colorectal tumor and stromal cells exhibit polyfunctional heterogeneity in the combinations and magnitudes of secretions for these chemokines. In cell lines, we observe similar variance: phenotypes observed in bulk can be largely absent among the majority of single cells, and discordances exist between secretory states measured and gene expression for these chemokines among single cells. Together, these measures suggest secretory states among tumor cells are complex and can evolve dynamically. Most importantly, this study reveals new insight into the intratumoral phenotypic heterogeneity of human primary tumors.

  3. Integrative Functional Genomics for Systems Genetics in GeneWeaver.org.

    Science.gov (United States)

    Bubier, Jason A; Langston, Michael A; Baker, Erich J; Chesler, Elissa J

    2017-01-01

    The abundance of existing functional genomics studies permits an integrative approach to interpreting and resolving the results of diverse systems genetics studies. However, a major challenge lies in assembling and harmonizing heterogeneous data sets across species for facile comparison to the positional candidate genes and coexpression networks that come from systems genetic studies. GeneWeaver is an online database and suite of tools at www.geneweaver.org that allows for fast aggregation and analysis of gene set-centric data. GeneWeaver contains curated experimental data together with resource-level data such as GO annotations, MP annotations, and KEGG pathways, along with persistent stores of user entered data sets. These can be entered directly into GeneWeaver or transferred from widely used resources such as GeneNetwork.org. Data are analyzed using statistical tools and advanced graph algorithms to discover new relations, prioritize candidate genes, and generate function hypotheses. Here we use GeneWeaver to find genes common to multiple gene sets, prioritize candidate genes from a quantitative trait locus, and characterize a set of differentially expressed genes. Coupling a large multispecies repository curated and empirical functional genomics data to fast computational tools allows for the rapid integrative analysis of heterogeneous data for interpreting and extrapolating systems genetics results.

  4. High degree of genetic differentiation in marine three-spined sticklebacks (Gasterosteus aculeatus).

    Science.gov (United States)

    Defaveri, Jacquelin; Shikano, Takahito; Shimada, Yukinori; Merilä, Juha

    2013-09-01

    Populations of widespread marine organisms are typically characterized by a low degree of genetic differentiation in neutral genetic markers, but much less is known about differentiation in genes whose functional roles are associated with specific selection regimes. To uncover possible adaptive population divergence and heterogeneous genomic differentiation in marine three-spined sticklebacks (Gasterosteus aculeatus), we used a candidate gene-based genome-scan approach to analyse variability in 138 microsatellite loci located within/close to (<6 kb) functionally important genes in samples collected from ten geographic locations. The degree of genetic differentiation in markers classified as neutral or under balancing selection-as determined with several outlier detection methods-was low (F(ST) = 0.033 or 0.011, respectively), whereas average FST for directionally selected markers was significantly higher (F(ST) = 0.097). Clustering analyses provided support for genomic and geographic heterogeneity in selection: six genetic clusters were identified based on allele frequency differences in the directionally selected loci, whereas four were identified with the neutral loci. Allelic variation in several loci exhibited significant associations with environmental variables, supporting the conjecture that temperature and salinity, but not optic conditions, are important drivers of adaptive divergence among populations. In general, these results suggest that in spite of the high degree of physical connectivity and gene flow as inferred from neutral marker genes, marine stickleback populations are strongly genetically structured in loci associated with functionally relevant genes. © 2013 John Wiley & Sons Ltd.

  5. Efeitos da Heterogeneidade de Variância Residual entre Grupos de Contemporâneos na Avaliação Genética de Bovinos de Corte Effects of Heterogeneity of Residual Variance among Contemporary Groups on Genetic Evaluation of Beef Cattle

    Directory of Open Access Journals (Sweden)

    Roberto Carvalheiro

    2002-07-01

    Full Text Available O objetivo deste estudo foi investigar, por meio de dados simulados, o efeito da heterogeneidade de variância residual entre grupos de contemporâneos (GC sobre as avaliações genéticas de bovinos de corte, e comparar o uso de uma avaliação genética ponderada (R¹Isigmae² em relação à avaliação que pressupõe homogeneidade de variância (R=Isigmae². A característica estudada foi ganho de peso pós-desmame corrigido para 345 dias, sendo esta simulada com variância fenotípica de 300 kg² e herdabilidade igual a 0,4. A estrutura de um conjunto real de dados foi utilizada para fornecer os GC e os pais referentes às observações de cada animal. Cinco níveis de heterogeneidade de variância residual foram considerados de forma que os componentes de variância fossem, na média, iguais aos da situação de homogeneidade de variância. Na medida em que níveis mais acentuados de heterogeneidade de variância residual foram considerados, os animais foram selecionados dos GC com maior variabilidade, especialmente com pressão de seleção intensa. Em relação à consistência de predição, os produtos e as vacas tiveram seus valores genéticos preditos mais afetados pela heterogeneidade de variância residual do que os touros. O fator de ponderação utilizado reduziu, mas não eliminou o efeito da heterogeneidade de variância. As avaliações genéticas ponderadas apresentaram resultados iguais ou superiores àqueles obtidos pelas avaliações que assumiram homogeneidade de variância. Mesmo quando não necessário, o uso de avaliações ponderadas produziu resultados não inferiores às avaliações que assumiram homogeneidade de variância.The objective of this study was to investigate, via simulated data, the effect of heterogeneity of residual variance among contemporary groups (CG on genetic evaluation of beef cattle, and to compare a weighted genetic evaluation procedure (R¹Isigmae² with one that assumes homogeneity of

  6. Type 2-diabetes--en heterogen sygdom med kim i fostertilstanden

    DEFF Research Database (Denmark)

    Vaag, Allan

    2012-01-01

    Type 2 diabetes (T2D) is a heterogeneous disease with a multifactorial aetiology involving defects in the pancreatic beta cells, liver, muscles, adipose tissue, guts, brain, kidneys and heart. While genetics may only explain a minor proportion of T2D, the contribution of an adverse intrauterine...... environment may take centre stage in the global propagation of T2D. Impaired expandability of subcutaneous adipose tissue in persons with low birthweight may cause T2D due to lipotoxicity in non-adipose organs. Future implications include a stronger focus on individualized treatments in T2D patients...

  7. Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns

    Directory of Open Access Journals (Sweden)

    Alexander H. Li

    2017-10-01

    disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.

  8. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis.

    Science.gov (United States)

    Ghouri, Yezaz Ahmed; Mian, Idrees; Rowe, Julie H

    2017-01-01

    Since the 1970s, the epidemic of hepatocellular carcinoma (HCC) has spread beyond the Eastern Asian predominance and has been increasing in Northern hemisphere, especially in the United States (US) and Western Europe. It occurs more commonly in males in the fourth and fifth decades of life. Among all cancers, HCC is one of the fastest growing causes of death in the US and poses a significant economic burden on healthcare. Chronic liver disease due to hepatitis B virus or hepatitis C virus and alcohol accounts for the majority of HCC cases. Incidence of nonalcoholic fatty liver disease has been on the risem and it has also been associated with the development of HCC. Its pathogenesis varies based on the underlying etiological factor although majority of cases develop in the setting of background cirrhosis. Carcinogenesis of HCC includes angiogenesis, chronic inflammation, and tumor macroenvironment and microenvironment. There is a significant role of both intrinsic genetic risk factors and extrinsic influences such as alcohol or viral infections that lead to the development of HCC. Understanding its etiopathogenesis helps select appropriate diagnostic tests and treatments.

  9. Hepatocellular carcinoma and impact of aflatoxin difuranocoumarin derivative system: A case report

    Directory of Open Access Journals (Sweden)

    Ilić Miroslav

    2016-01-01

    Full Text Available Introduction. Hepatocellular carcinoma (HCC is the most frequent type of liver malignancy. As a carcinogen, aflatoxin B1 (AFB1 causes HCC by inducing deoxyribonucleic acid adducts that lead to genetic changes in liver cells and may be the cause of HCC in up to 30% of cases. The incidence of HCC has been on the rise and is an issue in the countries of the Western Balkans. Case Outline. This paper presents a case of a 37-year-old woman who was diagnosed with HCC, without hepatitis B, hepatitis C, or liver cirrhosis. The patient consumed milk and dairy products in quantities of over two liters per day over the course of 20 years, which indicates the impact of aflatoxin in milk on HCC. A positive signal for the presence of AFB1 was detected by ELISA (enzyme-linked immunosorbent assay in-house using immunoperoxidase screening test. Conclusion. As carcinogenic difuranocoumarin derivative, aflatoxin B1 is the most likely cause of malignant transformation of hepatocytes, which resulted in hepatocellular carcinoma in this patient.

  10. The Prognostic Value of Platelet Count in Patients With Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Pang, Qing; Qu, Kai; Zhang, Jing-Yao; Song, Si-Dong; Liu, Su-Shun; Tai, Ming-Hui; Liu, Hao-Chen; Liu, Chang

    2015-09-01

    Thrombocytopenia has been acknowledged to be a crucial risk factor for cirrhosis formation and hepatocarcinogenesis in chronic liver diseases. However, to date, the association between platelet count (PLT) and the prognosis of hepatocellular carcinoma (HCC) remains inconsistent and controversial. The aim of the present study was to determine whether PLT could be used as a useful predictor of survival in patients with HCC. We performed systematic review in online databases, including PubMed, EmBase, and Web of Science, from inception until 2014. Studies were included if a statistical relationship was investigated between PLT and survival for HCC, and hazard ratio (HR) and 95% confidence intervals (CIs) for overall survival (OS) or recurrence-free survival (RFS) were provided. The quality of each included study was assessed by Newcastle-Ottawa scale score. To synthesize these studies, a random-effects model or a fixed-effects model was applied as appropriate. Then, we calculated heterogeneity, performed sensitivity analysis, tested publication bias, and did subgrouped and meta-regression analysis. Finally, we identified 33 eligible articles (published from 1998 to 2014) involved 5545 patients by retrieval. A low level of preoperative PLT was found to be significantly associated with a poor survival of HCC. Irrespective of the therapy used, the pooled HRs for OS and RFS were 1.41 (95% CI, 1.14-1.75) and 1.44 (95% CI, 1.13-1.83), respectively. Specifically, in patients who underwent liver resection, the pooled HRs for OS and RFS were 1.67 (95% CI, 1.22-2.27) and 1.44 (95% CI, 1.04-1.99), respectively. Furthermore, patients with preoperative thrombocytopenia (PLT limitations of this meat-analysis were nonuniform cut-off values of PLT, high between-study heterogeneities, potential confounders, and a bias of publication year. A low preoperative PLT level results in an unfavorable outcome in HCC. PLT is a simple, inexpensive, and useful predictor of survival in patients

  11. Genetic population structure of muskellunge in the Great Lakes

    Science.gov (United States)

    Kapuscinski, Kevin L.; Sloss, Brian L.; Farrell, John M.

    2013-01-01

    We quantified genetic relationships among Muskellunge Esox masquinongy from 15 locations in the Great Lakes to determine the extent and distribution of measurable population structure and to identify appropriate spatial scales for fishery management and genetic conservation. We hypothesized that Muskellunge from each area represented genetically distinct populations, which would be evident from analyses of genotype data. A total of 691 Muskellunge were sampled (n = 10–127/site) and genetic data were collected at 13 microsatellite loci. Results from a suite of analyses (including pairwise genetic differentiation, Bayesian admixture prediction, analysis of molecular variance, and tests of isolation by distance) indicated the presence of nine distinct genetic groups, including two that were approximately 50 km apart. Geographic proximity and low habitat complexity seemed to facilitate genetic similarity among areas, whereas Muskellunge from areas of greater habitat heterogeneity exhibited high differentiation. Muskellunge from most areas contained private alleles, and mean within-area genetic variation was similar to that reported for other freshwater fishes. Management programs aimed at conserving the broader diversity and long-term sustainability of Muskellunge could benefit by considering the genetically distinct groups as independent fisheries, and individual spawning and nursery habitats could subsequently be protected to conserve the evolutionary potential of Muskellunge.

  12. Genetic heterogeneity in patients with Bartter syndrome type 1.

    Science.gov (United States)

    Sun, Mingran; Ning, Jing; Xu, Weihong; Zhang, Han; Zhao, Kaishu; Li, Wenfu; Li, Guiying; Li, Shibo

    2017-02-01

    Bartter syndrome (BS) type 1 is an autosomal recessive kidney disorder caused by loss‑of‑function mutations in the solute carrier family 12 member 1 (SLC12A1) gene. To date, 72 BS type 1 patients harboring SLC12A1 mutations have been documented. Of these 144 alleles studied, 68 different disease‑causing mutations have been detected in 129 alleles, and no mutation was detected in the remaining 15 alleles. The mutation types included missense/nonsense mutations, splicing mutations and small insertions and deletions ranging from 1 to 4 nucleotides. A large deletion encompassing a whole exon in the SLC12A1 gene has not yet been reported. The current study initially identified an undocumented homozygous frameshift mutation (c.1833delT) by Sanger sequencing analysis of a single infant with BS type 1. However, in a subsequent analysis, the mutation was detected only in the father's DNA. Upon further investigation using a next‑generation sequencing approach, a deletion in exons 14 and 15 in both the patient and patient's mother was detected. The deletion was subsequently confirmed by use of a long‑range polymerase chain reaction and was determined to be 3.16 kb in size based on sequencing of the junction fragment. The results of the present study demonstrated that pathogenic variants of SLC12A1 are heterogeneous. Large deletions appear to serve an etiological role in BS type 1, and may be more prevalent than previously thought.

  13. Organized proteomic heterogeneity in colorectal cancer liver metastases and implications for therapies.

    Science.gov (United States)

    Turtoi, Andrei; Blomme, Arnaud; Debois, Delphine; Somja, Joan; Delvaux, David; Patsos, Georgios; Di Valentin, Emmanuel; Peulen, Olivier; Mutijima, Eugène Nzaramba; De Pauw, Edwin; Delvenne, Philippe; Detry, Olivier; Castronovo, Vincent

    2014-03-01

    Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Because to date no similar information is available at the protein (phenotype) level, we employed matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the heterogeneity of extracellular and membrane subproteome in a unique collection of eight fresh human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over 1,000 proteins, we found unexpectedly that all liver metastasis lesions displayed a reproducible, zonally delineated pattern of functional and therapeutic biomarker heterogeneity. The peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis displayed increased cellular growth, movement, and drug metabolism, whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA-repair activity. From the aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally, we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. We demonstrate their in vivo antibody-based targeting and highlight their potential usefulness for clinical applications. The proteome heterogeneity of human CRC liver metastases has a distinct, organized pattern. This particular hallmark can now be used as part of the strategy for developing rational therapies based on multiple sets of targetable antigens. © 2014 by the American Association for the Study of Liver Diseases.

  14. Quantum Heterogeneous Computing for Satellite Positioning Optimization

    Science.gov (United States)

    Bass, G.; Kumar, V.; Dulny, J., III

    2016-12-01

    Hard optimization problems occur in many fields of academic study and practical situations. We present results in which quantum heterogeneous computing is used to solve a real-world optimization problem: satellite positioning. Optimization problems like this can scale very rapidly with problem size, and become unsolvable with traditional brute-force methods. Typically, such problems have been approximately solved with heuristic approaches; however, these methods can take a long time to calculate and are not guaranteed to find optimal solutions. Quantum computing offers the possibility of producing significant speed-up and improved solution quality. There are now commercially available quantum annealing (QA) devices that are designed to solve difficult optimization problems. These devices have 1000+ quantum bits, but they have significant hardware size and connectivity limitations. We present a novel heterogeneous computing stack that combines QA and classical machine learning and allows the use of QA on problems larger than the quantum hardware could solve in isolation. We begin by analyzing the satellite positioning problem with a heuristic solver, the genetic algorithm. The classical computer's comparatively large available memory can explore the full problem space and converge to a solution relatively close to the true optimum. The QA device can then evolve directly to the optimal solution within this more limited space. Preliminary experiments, using the Quantum Monte Carlo (QMC) algorithm to simulate QA hardware, have produced promising results. Working with problem instances with known global minima, we find a solution within 8% in a matter of seconds, and within 5% in a few minutes. Future studies include replacing QMC with commercially available quantum hardware and exploring more problem sets and model parameters. Our results have important implications for how heterogeneous quantum computing can be used to solve difficult optimization problems in any

  15. Quantitative proteomics identifies central players in erlotinib resistance of the non-small cell lung cancer cell line HCC827

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine; Lund, Rikke Raaen; Beck, Hans Christian

    Background: Erlotinib (Tarceva®, Roche) has significantly changed the treatment of non-small cell lung cancer (NSCLC) as 70% of patients show significant tumor regression when treated. However, all patients relapse due to development of acquired resistance, which in 43-50% of cases are caused...... by a secondary mutation (T790M) in EGFR. Importantly, a majority of resistance cases are still unexplained. Our aim is to identify novel resistance mechanisms in erlotinib-resistant subclones of the NSCLC cell line HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20...... or other EGFR or KRAS mutations, potentiating the identification of novel resistance mechanisms. We identified 2875 cytoplasmic proteins present in all 4 cell lines. Of these 87, 56 and 23 are upregulated >1.5 fold; and 117, 72 and 32 are downregulated >1.5 fold, respectively, in the 3 resistant clones...

  16. Resistance mechanisms to erlotinib in the non-small cell lung cancer cell line, HCC827 examined by RNA-seq

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine; Alcaraz, Nicolas; Ditzel, Henrik

    (Illumina) prior to sequencing on an Illumina HiSeq platform (100bp paired end). The resistant subclones were examined both in presence and absence of erlotinib. The data was analyzed by an in-house developed pipeline including quality control by Trim Galore v0.3.3, mapping of reads to HG19 by TopHat2 v.2......Background: Erlotinib, an EGFR selective reversible inhibitor, has dramatically changed the treatment of non-small cell lung cancer (NSCLC) as approximately 70% of patients show significant tumor regression upon treatment. However, all patients eventually relapse due to development of acquired...... - in erlotinib-resistant subclones of the NSCLC cell line HCC827. Materials & Methods: We established 3 erlotinib-resistant subclones (resistant to 10, 20, 30 µM erlotinib, respectively), and prepared cDNA libraries of purified RNA from biological duplicates using TruSeq® Stranded Total RNA Ribo-Zero™ Gold...

  17. Advances in molecular genetic studies of primary dystonia

    Directory of Open Access Journals (Sweden)

    MA Ling-yan

    2013-07-01

    Full Text Available Dystonias are heterogeneous hyperkinetic movement disorders characterized by involuntary muscle contractions which result in twisting, repetitive movements and abnormal postures. In recent years, there was a great advance in molecular genetic studies of primary dystonia. This paper will review the clinical characteristics and molecular genetic studies of primary dystonia, including early-onset generalized torsion dystonia (DYT1, whispering dysphonia (DYT4, dopa-responsive dystonia (DYT5, mixed-type dystonia (DYT6, paroxysmal kinesigenic dyskinesia (DYT10, myoclonus-dystonia syndrome (DYT11, rapid-onset dystonia parkinsonism (DYT12, adult-onset cervical dystonia (DYT23, craniocervical dystonia (DYT24 and primary torsion dystonia (DYT25.

  18. Long-term results of interventional treatment of large unresectable hepatocellular carcinoma (HCC): significant survival benefit from combined transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) compared to TACE monotherapy

    International Nuclear Information System (INIS)

    Lubienski, A.; Bitsch, R.G.; Grenacher, L.; Kauffmann, G.W.; Schemmer, P.; Duex, M.

    2004-01-01

    Purpose: A retrospective analysis of long-term efficacy of combined transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) and TACE monotherapy was conducted in patients with large, non-resectable hepatocellular carcinoma (HCC). Methods and Materials: Fifty patients with large, unresectable HCC lesions underwent selective TACE. Liver cirrhosis was present in 42 patients, due to alcohol abuse (n = 22) and viral infection (n = 17). In three patients, the underlying cause for liver cirrhosis remained unclear. Child A cirrhosis was found in 22 and Child B cirrhosis in 20 patients. Repeated and combined TACE and PEI were performed in 22 patients and repeated TACE monotherapy was performed in 28 patients. Survival and complication rates were determined and compared. Results: The 6-, 12-, 24- and 36-month survival rates were 61%, 21%, 4%, and 4% for TACE monotherapy and 77%, 55%, 39% and 22% for combined TACE and PEI (Kaplan-Meier method). The kind of treatment significantly affected the survival rate (p=0.002 log-rank test). Severe side effects were present in two patients of the monotherapy group and in three patients of the combination therapy group. (orig.)

  19. Potential genetic polymorphisms predicting polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Yao Chen

    2018-05-01

    Full Text Available Polycystic ovary syndrome (PCOS is a heterogenous endocrine disorder with typical symptoms of oligomenorrhoea, hyperandrogenism, hirsutism, obesity, insulin resistance and increased risk of type 2 diabetes mellitus. Extensive evidence indicates that PCOS is a genetic disease and numerous biochemical pathways have been linked with its pathogenesis. A number of genes from these pathways have been investigated, which include those involved with steroid hormone biosynthesis and metabolism, action of gonadotropin and gonadal hormones, folliculogenesis, obesity and energy regulation, insulin secretion and action and many others. In this review, we summarize the historical and recent findings in genetic polymorphisms of PCOS from the relevant publications and outline some genetic polymorphisms that are potentially associated with the risk of PCOS. This information could uncover candidate genes associating with PCOS, which will be valuable for the development of novel diagnostic and treatment platforms for PCOS patients.

  20. Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait

    Energy Technology Data Exchange (ETDEWEB)

    Dube, M.P.; Kibar, Z.; Rouleau, G.A. [McGill Univ., Quebec (Canada)] [and others

    1997-03-01

    Hereditary spastic paraplegia (HSP) is a degenerative disorder of the motor system, defined by progressive weakness and spasticity of the lower limbs. HSP may be inherited as an autosomal dominant (AD), autosomal recessive, or an X-linked trait. AD HSP is genetically heterogeneous, and three loci have been identified so far: SPG3 maps to chromosome 14q, SPG4 to 2p, and SPG4a to 15q. We have undertaken linkage analysis with 21 uncomplicated AD families to the three AD HSP loci. We report significant linkage for three of our families to the SPG4 locus and exclude several families by multipoint linkage. We used linkage information from several different research teams to evaluate the statistical probability of linkage to the SPG4 locus for uncomplicated AD HSP families and established the critical LOD-score value necessary for confirmation of linkage to the SPG4 locus from Bayesian statistics. In addition, we calculated the empirical P-values for the LOD scores obtained with all families with computer simulation methods. Power to detect significant linkage, as well as type I error probabilities, were evaluated. This combined analytical approach permitted conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity. 19 refs., 1 fig., 1 tab.

  1. Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait.

    Science.gov (United States)

    Dubé, M P; Mlodzienski, M A; Kibar, Z; Farlow, M R; Ebers, G; Harper, P; Kolodny, E H; Rouleau, G A; Figlewicz, D A

    1997-03-01

    Hereditary spastic paraplegia (HSP) is a degenerative disorder of the motor system, defined by progressive weakness and spasticity of the lower limbs. HSP may be inherited as an autosomal dominant (AD), autosomal recessive, or an X-linked trait. AD HSP is genetically heterogeneous, and three loci have been identified so far: SPG3 maps to chromosome 14q, SPG4 to 2p, and SPG4a to 15q. We have undertaken linkage analysis with 21 uncomplicated AD families to the three AD HSP loci. We report significant linkage for three of our families to the SPG4 locus and exclude several families by multipoint linkage. We used linkage information from several different research teams to evaluate the statistical probability of linkage to the SPG4 locus for uncomplicated AD HSP families and established the critical LOD-score value necessary for confirmation of linkage to the SPG4 locus from Bayesian statistics. In addition, we calculated the empirical P-values for the LOD scores obtained with all families with computer simulation methods. Power to detect significant linkage, as well as type I error probabilities, were evaluated. This combined analytical approach permitted conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity.

  2. Whole genome sequencing reveals genomic heterogeneity and antibiotic purification in Mycobacterium tuberculosis isolates

    KAUST Repository

    Black, PA

    2015-10-24

    Background Whole genome sequencing has revolutionised the interrogation of mycobacterial genomes. Recent studies have reported conflicting findings on the genomic stability of Mycobacterium tuberculosis during the evolution of drug resistance. In an age where whole genome sequencing is increasingly relied upon for defining the structure of bacterial genomes, it is important to investigate the reliability of next generation sequencing to identify clonal variants present in a minor percentage of the population. This study aimed to define a reliable cut-off for identification of low frequency sequence variants and to subsequently investigate genetic heterogeneity and the evolution of drug resistance in M. tuberculosis. Methods Genomic DNA was isolated from single colonies from 14 rifampicin mono-resistant M. tuberculosis isolates, as well as the primary cultures and follow up MDR cultures from two of these patients. The whole genomes of the M. tuberculosis isolates were sequenced using either the Illumina MiSeq or Illumina HiSeq platforms. Sequences were analysed with an in-house pipeline. Results Using next-generation sequencing in combination with Sanger sequencing and statistical analysis we defined a read frequency cut-off of 30 % to identify low frequency M. tuberculosis variants with high confidence. Using this cut-off we demonstrated a high rate of genetic diversity between single colonies isolated from one population, showing that by using the current sequencing technology, single colonies are not a true reflection of the genetic diversity within a whole population and vice versa. We further showed that numerous heterogeneous variants emerge and then disappear during the evolution of isoniazid resistance within individual patients. Our findings allowed us to formulate a model for the selective bottleneck which occurs during the course of infection, acting as a genomic purification event. Conclusions Our study demonstrated true levels of genetic diversity

  3. Genetic variations of NTCP are associated with susceptibility to HBV infection and related hepatocellular carcinoma.

    Science.gov (United States)

    Wang, Peng; Mo, Ruidong; Lai, Rongtao; Xu, Yumin; Lu, Jie; Zhao, Gangde; Liu, Yuhan; Cao, Zhujun; Wang, Xiaolin; Li, Ziqiang; Lin, Lanyi; Zhou, Huijuan; Cai, Wei; Wang, Hui; Bao, Shisan; Xiang, Xiaogang; Xie, Qing

    2017-12-01

    Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis. The frequency of rs2296651-GA was inversely correlated with CHB, LC or HCC patients [adjusted OR(95%CI)=0.16(0.11-0.23), p HBV infection [OR(95%CI)=0.532(0.287-0.986), p =0.028, codominant] or HBV-related HCC [OR(95%CI)=0.701(0.564-0.872), p =0.001, recessive]. Furthermore, the frequency of rs943277-GA was positively correlated with HBV infection [adjusted OR(95%CI)=2.42(1.05-5.54), p =0.032, codominant]. Our data suggest that NTCP mutants contribute to the susceptibility of HBV infection or HBV-related HCC.

  4. The molecular genetics of holoprosencephaly.

    Science.gov (United States)

    Roessler, Erich; Muenke, Maximilian

    2010-02-15

    Holoprosencephaly (HPE) has captivated the imagination of Man for millennia because its most extreme manifestation, the single-eyed cyclopic newborn infant, brings to mind the fantastical creature Cyclops from Greek mythology. Attempting to understand this common malformation of the forebrain in modern medical terms requires a systematic synthesis of genetic, cytogenetic, and environmental information typical for studies of a complex disorder. However, even with the advances in our understanding of HPE in recent years, there are significant obstacles remaining to fully understand its heterogeneity and extensive variability in phenotype. General lessons learned from HPE will likely be applicable to other malformation syndromes. Here we outline the common, and rare, genetic and environmental influences on this conserved developmental program of forebrain development and illustrate the similarities and differences between these malformations in humans and those of animal models. 2010 Wiley-Liss, Inc.

  5. Campora: a young genetic isolate in South Italy.

    Science.gov (United States)

    Colonna, Vincenza; Nutile, Teresa; Astore, Maria; Guardiola, Ombretta; Antoniol, Giuliano; Ciullo, Marina; Persico, M Graziella

    2007-01-01

    Genetic isolates have been successfully used in the study of complex traits, mainly because due to their features, they allow a reduction in the complexity of the genetic models underlying the trait. The aim of the present study is to describe the population of Campora, a village in the South of Italy, highlighting its properties of a genetic isolate. Both historical evidence and multi-locus genetic data (genomic and mitochondrial DNA polymorphisms) have been taken into account in the analyses. The extension of linkage disequilibrium (LD) regions has been evaluated on autosomes and on a region of the X chromosome. We defined a study sample population on the basis of the genealogy and exogamy data. We found in this population a few different mitochondrial and Y chromosome haplotypes and we ascertained that, similarly to other isolated populations, in Campora LD extends over wider region compared to large and genetically heterogeneous populations. These findings indicate a conspicuous genetic homogeneity in the genome. Finally, we found evidence for a recent population bottleneck that we propose to interpret as a demographic crisis determined by the plague of the 17th century. Overall our findings demonstrate that Campora displays the genetic characteristics of a young isolate. Copyright (c) 2007 S. Karger AG, Basel.

  6. Microbial Genetic Memory to Study Heterogeneous Soil Processes

    Science.gov (United States)

    Fulk, E. M.; Silberg, J. J.; Masiello, C. A.

    2017-12-01

    Microbes can be engineered to sense environmental conditions and produce a detectable output. These microbial biosensors have traditionally used visual outputs that are difficult to detect in soil. However, recently developed gas-producing biosensors can be used to noninvasively monitor complex soil processes such as horizontal gene transfer or cell-cell signaling. While these biosensors report on the fraction of a microbial population exposed to a process or chemical signal at the time of measurement, they do not record a "memory" of past exposure. Synthetic biologists have recently developed a suite of genetically encoded memory circuits capable of reporting on historical exposure to the signal rather than just the current state. We will provide an overview of the microbial memory systems that may prove useful to studying microbial decision-making in response to environmental conditions. Simple memory circuits can give a yes/no report of any past exposure to the signal (for example anaerobic conditions, osmotic stress, or high nitrate concentrations). More complicated systems can report on the order of exposure of a population to multiple signals or the experiences of spatially distinct populations, such as those in root vs. bulk soil. We will report on proof-of-concept experiments showing the function of a simple permanent memory system in soil-cultured microbes, and we will highlight additional applications. Finally, we will discuss challenges still to be addressed in applying these memory circuits for biogeochemical studies.

  7. Asthma in childhood: a complex, heterogeneous disease

    Directory of Open Access Journals (Sweden)

    Hai Lee Chung

    2011-01-01

    Full Text Available Asthma in childhood is a heterogeneous disease with different phenotypes and variable clinical manifestations, which depend on the age, gender, genetic background, and environmental influences of the patients. Several longitudinal studies have been conducted to classify the phenotypes of childhood asthma, on the basis of the symptoms, triggers of wheezing illness, or pathophysiological features of the disease. These studies have provided us with important information about the different wheezing phenotypes in young children and about potential mechanisms and risk factors for the development of chronic asthma. The goal of these studies was to provide a better insight into the causes and natural course of childhood asthma. It is well-known that complicated interactions between genes and environmental factors contribute to the development of asthma. Because childhood is a period of rapid growth in both the lungs and the immune system, developmental factors should be considered in the pathogenesis of childhood asthma. The pulmonary system continues to grow and develop until linear growth is completed. Longitudinal studies have reported significant age-related immune development during postnatal early life. These observations suggest that the phenotypes of childhood asthma vary among children and also in an individual child over time. Improved classification of heterogeneous conditions of the disease will help determine novel strategies for primary and secondary prevention and for the development of individualized treatment for childhood asthma.

  8. Imaging genetics paradigms in depression research: Systematic review and meta-analysis.

    Science.gov (United States)

    Pereira, Lícia P; Köhler, Cristiano A; Stubbs, Brendon; Miskowiak, Kamilla W; Morris, Gerwyn; de Freitas, Bárbara P; Thompson, Trevor; Fernandes, Brisa S; Brunoni, André R; Maes, Michael; Pizzagalli, Diego A; Carvalho, André F

    2018-05-17

    Imaging genetics studies involving participants with major depressive disorder (MDD) have expanded. Nevertheless, findings have been inconsistent. Thus, we conducted a systematic review and meta-analysis of imaging genetics studies that enrolled MDD participants across major databases through June 30th, 2017. Sixty-five studies met eligibility criteria (N = 4034 MDD participants and 3293 controls), and there was substantial between-study variability in the methodological quality of included studies. However, few replicated findings emerged from this literature with only 22 studies providing data for meta-analyses (882 participants with MDD and 616 controls). Total hippocampal volumes did not significantly vary in MDD participants or controls carrying either the BDNF Val66Met 'Met' (386 participants with MDD and 376 controls) or the 5-HTTLPR short 'S' (310 participants with MDD and 230 controls) risk alleles compared to non-carriers. Heterogeneity across studies was explored through meta-regression and subgroup analyses. Gender distribution, the use of medications, segmentation methods used to measure the hippocampus, and age emerged as potential sources of heterogeneity across studies that assessed the association of 5-HTTLPR short 'S' alleles and hippocampal volumes. Our data also suggest that the methodological quality of included studies, publication year, and the inclusion of brain volume as a covariate contributed to the heterogeneity of studies that assessed the association of the BDNF Val66Met 'Met' risk allele and hippocampal volumes. In exploratory voxel-wise meta-analyses, MDD participants carrying the 5-HTTLPR short 'S' allele had white matter microstructural abnormalities predominantly in the corpus callosum, while carriers of the BDNF Val66Met 'Met' allele had larger gray matter volumes and hyperactivation of the right middle frontal gyrus compared to non-carriers. In conclusion, few replicated findings emerged from imaging genetics studies that

  9. Treatment of hepatocellular carcinoma (HCC) with intra-arterial Yttrium-90 microspheres for down-staging patients to transplantation

    International Nuclear Information System (INIS)

    De Man, K.; Defreyne, L.; Delanghe, E.; Smeets, P.; Verhelst, X.; Geerts, A.; Van Vlierberghe, H.; Rogiers, X.; Troisi, R.; Lambert, B.

    2015-01-01

    Full text of publication follows. Introduction and aim: in our hospital, patients are referred for intra-arterial treatment with Yttrium-90 microspheres if they present with an HCC confined to the liver, but are ineligible for curative treatment options such as liver transplantation, partial hepatectomy or radio-frequent ablation. Additional eligibility criteria for radio-embolisation consist of Child-P ugh score HCC patients who were treated with Yttrium-90 microspheres in our hospital since 2008 and who presented at an age <70 and with a disease load exceeding the Milan criteria (single tumour ≤5 cm or ≤ 3 lesions ≤ 3 cm). We recorded whether the patient was down staged to a tumour load complying with the Milan criteria, and if so, whether transplantation was carried out. Results: 40 patients aged <70 years and with a tumour load exceeding the Milan criteria (all treated with TheraSphere, Nordion except 1 with SIR-Spheres, Sirtex) were evaluable. 35 had Barcelona Clinic Liver Cancer (BCLC) B stage disease and 5 had BCLC C. Overall median survival was 12.9 months. 16 out of 40 patients were down staged to the Milan criteria (40%, all BCLC B), of whom 8 were actually transplanted so far. Two patients are on the waiting list, 1 patient refuses to be listed and 1 patient suffers co-morbidity that excludes him from abdominal surgery. Unfortunately 4 patients died before or during work-out for transplantation: 1 unexplained sudden death, 1 lung embolism and 2 due to liver failure. The overall median survival was 30,4 months in the down staged patients. 24 out 40 patients (60%) did not have a tumour load within the Milan criteria at any point of their follow up and had a significant worse

  10. Social stratification in the Sikh population of Punjab (India) has a genetic basis: evidence from serological and biochemical markers.

    Science.gov (United States)

    Chahal, Sukh Mohinder Singh; Virk, Rupinder Kaur; Kaur, Sukhvir; Bansal, Rupinder

    2011-01-01

    The present study was planned to assess whether social stratification in the Sikh population inhabiting the northwest border Indian state of Punjab has any genetic basis. Blood samples were collected randomly from a total of 2851 unrelated subjects belonging to 21 groups of two low-ranking Sikh scheduled caste populations, viz. Mazhabi and Ramdasi, and a high-ranking Jat Sikh caste population of Punjab. The genetic profile of Sikh groups was investigated using a total of nine serobiochemical genetic markers, comprising two blood groups (ABO, RH(D)) and a battery of seven red cell enzyme polymorphisms (ADA, AK1, ESD, PGM1, GLO1, ACP1, GPI), following standard serological and biochemical laboratory protocols. Genetic structure was studied using original allele frequency data and statistical measures of heterozygosity, genic differentiation, genetic distance, and genetic admixture. Great heterogeneity was observed between Sikh scheduled caste and Jat Sikh populations, especially in the RH(D) blood group system, and distribution of ESD, ACP1, and PGM1 enzyme markers was also found to be significantly different between many of their groups. Genetic distance trees demonstrated little or no genetic affinities between Sikh scheduled caste and Jat Sikh populations; the Mazhabi and Ramdasi also showed little genetic relationship. Genetic admixture analysis suggested a higher element of autochthonous tribal extraction in the Ramdasi. The present study revealed much genetic heterogeneity in differently ranking Sikh caste populations of Punjab, mainly attributable to their different ethnic backgrounds, and provided a genetic basis to social stratification present in this religious community of Punjab, India.

  11. RB has a critical role in mediating the in vivo checkpoint response, mitigating secondary DNA damage and suppressing liver tumorigenesis initiated by aflatoxin B1

    OpenAIRE

    Reed, CA; Mayhew, CN; McClendon, AK; Yang, X; Witkiewicz, A; Knudsen, ES

    2009-01-01

    Hepatocellular carcinoma (HCC) is a significant worldwide health concern that is associated with discrete etiological events, encompassing viral infection, metabolic stress and genotoxic compounds. In particular, exposure to the genotoxic hepatocarcinogen aflatoxin B1 (AFB1) is a significant factor in the genesis of human liver cancer. Presumably, genetic events associated with HCC could influence the effect of environmental insults, yielding a predilection for tumor development. The retinobl...

  12. Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls.

    Directory of Open Access Journals (Sweden)

    Qing Ye

    Full Text Available Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D of human HFE (hereditary hemochromatosis gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD, liver cirrhosis and hepatocellular carcinoma (HCC.An updated systematic review and meta-analysis was conducted to evaluate the potential role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis.In total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, Passociation0.05. In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, Passociation<0.05. Moreover, a positive association between compound heterozygosity for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis, was observed.Our meta-analysis provides evidence that the HFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion.

  13. Serotonin Activated Hepatic Stellate Cells Contribute to Sex Disparity in Hepatocellular CarcinomaSummary

    Directory of Open Access Journals (Sweden)

    Qiqi Yang

    2017-05-01

    Full Text Available Background & Aims: Hepatocellular carcinoma (HCC occurs more frequently and aggressively in men than in women. Although sex hormones are believed to play a critical role in this disparity, the possible contribution of other factors largely is unknown. We aimed to investigate the role of serotonin on its contribution of sex discrepancy during HCC. Methods: By using an inducible zebrafish HCC model through hepatocyte-specific transgenic krasV12 expression, differential rates of HCC in male and female fish were characterized by both pharmaceutical and genetic interventions. The findings were validated further in human liver disease samples. Results: Accelerated HCC progression was observed in krasV12-expressing male zebrafish and male fish liver tumors were found to have higher hepatic stellate cell (HSC density and activation. Serotonin, which is essential for HSC survival and activation, similarly were found to be synthesized and accumulated more robustly in males than in females. Serotonin-activated HSCs could promote HCC carcinogenesis and concurrently increase serotonin synthesis via transforming growth factor (Tgfb1 expression, hence contributing to sex disparity in HCC. Analysis of liver disease patient samples showed similar male predominant serotonin accumulation and Tgfb1 expression. Conclusions: In both zebrafish HCC models and human liver disease samples, a predominant serotonin synthesis and accumulation in males resulted in higher HSC density and activation as well as Tgfb1 expression, thus accelerating HCC carcinogenesis in males. Keywords: Liver Cancer, TGFB1, Kras, Zebrafish

  14. Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls

    Science.gov (United States)

    Yin, Wei-Li; Wang, Feng-Mei; Han, Tao

    2016-01-01

    Background Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC). Methods An updated systematic review and meta-analysis was conducted to evaluate the potential role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis. Results In total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, PassociationHFE C282Y and H63D (all Passociation>0.05). In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, PassociationHFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion. PMID:27657935

  15. Field heritability of a plant adaptation to fire in heterogeneous landscapes.

    Science.gov (United States)

    Castellanos, M C; González-Martínez, S C; Pausas, J G

    2015-11-01

    The strong association observed between fire regimes and variation in plant adaptations to fire suggests a rapid response to fire as an agent of selection. It also suggests that fire-related traits are heritable, a precondition for evolutionary change. One example is serotiny, the accumulation of seeds in unopened fruits or cones until the next fire, an important strategy for plant population persistence in fire-prone ecosystems. Here, we evaluate the potential of this trait to respond to natural selection in its natural setting. For this, we use a SNP marker approach to estimate genetic variance and heritability of serotiny directly in the field for two Mediterranean pine species. Study populations were large and heterogeneous in climatic conditions and fire regime. We first estimated the realized relatedness among trees from genotypes, and then partitioned the phenotypic variance in serotiny using Bayesian animal models that incorporated environmental predictors. As expected, field heritability was smaller (around 0.10 for both species) than previous estimates under common garden conditions (0.20). An estimate on a subset of stands with more homogeneous environmental conditions was not different from that in the complete set of stands, suggesting that our models correctly captured the environmental variation at the spatial scale of the study. Our results highlight the importance of measuring quantitative genetic parameters in natural populations, where environmental heterogeneity is a critical aspect. The heritability of serotiny, although not high, combined with high phenotypic variance within populations, confirms the potential of this fire-related trait for evolutionary change in the wild. © 2015 John Wiley & Sons Ltd.

  16. Single nucleotide polymorphisms in MLH1 predict poor prognosis of hepatocellular carcinoma in a Chinese population.

    Science.gov (United States)

    Zhu, Xiaonian; Liu, Wei; Qiu, Xiaoqiang; Wang, Zhigang; Tan, Chao; Bei, Chunhua; Qin, Linyuan; Ren, Yuan; Tan, Shengkui

    2017-10-03

    Hepatocellular carcinoma (HCC) is a malignant cancer causing deleterious health effect worldwide, especially in China. So far clinical cure rate and long-term survival rate of HCC remains low. Most HCC patients after cancer resection have recurrence or metastasis within 5 years. This study aims to explore the genetic association of mutL homolog 1 ( MLH1 ) polymorphisms with HCC risk and prognosis. Four candidate MLH1 polymorphisms, rs1800734, rs10849, rs3774343 and rs1540354 were studied from a hospital-based case-control study including 1,036 cases (HCC patients) and 1,036 controls (non-HCC patients) in Guangxi, China. All these SNPs interacted with environmental risk factors, such as HBV infection, alcohol intake and smoking in the pathogenesis of HCC. However, only rs1800734 had significant difference between cases and controls. Compared to the AA genotype, patients with AG, GG and AG/GG genotype of rs1800734 had an increased risk of HCC [ORs (95% CI) = 1.217 (1.074∼1.536), 1.745 (1.301∼2.591) and 1.291 (1.126∼1.687)] and a decreased survival time [co-dominant, HR (95% CI) = 1.553 (1.257∼1.920); dominant, HR (95% CI) = 2.207 (1.572∼3.100)]. Furthermore, we found that tumor number, tumor staging, metastasis and rs1800734 were associated with the overall survival of HCC patients by multivariate COX regression analysis. No significant difference was found between the other three MLH1 polymorphisms with HCC risk and prognosis. Our study suggests MLH1 SNP, rs1800734 as a new predictor for poor prognosis of HCC patients.

  17. Estimation of genetic parameters and their sampling variances for quantitative traits in the type 2 modified augmented design

    OpenAIRE

    Frank M. You; Qijian Song; Gaofeng Jia; Yanzhao Cheng; Scott Duguid; Helen Booker; Sylvie Cloutier

    2016-01-01

    The type 2 modified augmented design (MAD2) is an efficient unreplicated experimental design used for evaluating large numbers of lines in plant breeding and for assessing genetic variation in a population. Statistical methods and data adjustment for soil heterogeneity have been previously described for this design. In the absence of replicated test genotypes in MAD2, their total variance cannot be partitioned into genetic and error components as required to estimate heritability and genetic ...

  18. Genetic Diversity in Natural Populations of New World Leishmania

    Directory of Open Access Journals (Sweden)

    Cupolillo Elisa

    1998-01-01

    Full Text Available Our results have shown the wide diversity of parasites within New World Leishmania. Biochemical and molecular characterization of species within the genus has revealed that much of the population heterogeneity has a genetic basis. The source of genetic diversity among Leishmania appears to arise from predominantly asexual, clonal reproduction, although occasional bouts of sexual reproduction can not be ruled out. Genetic variation is extensive with some clones widely distributed and others seemingly unique and localized to a particular endemic focus. Epidemiological studies of leishmaniasis has been directed to the ecology and dynamics of transmission of Leishmania species/variants, particularly in localized areas. Future research using molecular techniques should aim to identify and follow Leishmania types in nature and correlate genetic typing with important clinical characteristics such as virulence, pathogenicity, drug resistance and antigenic variation. The epidemiological significance of such variation not only has important implications for the control of the leishmaniases, but would also help to elucidate the evolutionary biology of the causative agents.

  19. Genetic algorithm learning in a New Keynesian macroeconomic setup.

    Science.gov (United States)

    Hommes, Cars; Makarewicz, Tomasz; Massaro, Domenico; Smits, Tom

    2017-01-01

    In order to understand heterogeneous behavior amongst agents, empirical data from Learning-to-Forecast (LtF) experiments can be used to construct learning models. This paper follows up on Assenza et al. (2013) by using a Genetic Algorithms (GA) model to replicate the results from their LtF experiment. In this GA model, individuals optimize an adaptive, a trend following and an anchor coefficient in a population of general prediction heuristics. We replicate experimental treatments in a New-Keynesian environment with increasing complexity and use Monte Carlo simulations to investigate how well the model explains the experimental data. We find that the evolutionary learning model is able to replicate the three different types of behavior, i.e. convergence to steady state, stable oscillations and dampened oscillations in the treatments using one GA model. Heterogeneous behavior can thus be explained by an adaptive, anchor and trend extrapolating component and the GA model can be used to explain heterogeneous behavior in LtF experiments with different types of complexity.

  20. Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case Study in Lynch Syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Mukherjee, Bhramar; Taylor, Jeremy M G

    2011-01-01

    Summary Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases. Its extent may vary between families and/or between mutation subtypes known to be associated with the disease phenotype....... In this article, we posit a Bayesian approach to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO. Primary interest lies in the random effects. Misspecifying the distribution of random effects may result in incorrect...... to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS). We find evidence for a decrease in AOO between generations in this article. Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk families....

  1. Hepatitis B virus mutation may play a role in hepatocellular carcinoma recurrence: A systematic review and meta-regression analysis.

    Science.gov (United States)

    Zhou, Hua-ying; Luo, Yue; Chen, Wen-dong; Gong, Guo-zhong

    2015-06-01

    A number of studies have confirmed that antiviral therapy with nucleotide analogs (NAs) can improve the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative therapy. However, what factors affected the prognosis of HBV-HCC after removal of the primary tumor and inhibition of HBV replication? A meta-regression analysis was conducted to explore the prognostic factor for this subgroup of patients. MEDLINE, EMBASE, Web of Science, and Cochrane library were searched from January 1995 to February 2014 for clinical trials evaluating the effect of NAs on the prognosis of HBV-HCC after curative therapy. Data were extracted for host, viral, and intervention information. Single-arm meta-analysis was performed to assess overall survival (OS) rates and HCC recurrence. Meta-regression analysis was carried out to explore risk factors for 1-year OS rate and HCC recurrence for HBV-HCC patients after curative therapy and antiviral therapy. Fourteen observational studies with 1284 patients met the inclusion criteria. Influential factors for prognosis of HCC were mainly baseline HBeAg positivity, cirrhotic stage, advanced Tumor-Node-Metastasis (TNM) stage, macrovascular invasion, and antiviral agent type. The 1-year OS rate decreased by more than four times (coefficient -4.45, P<0.001) and the 1-year HCC recurrence increased by more than one time (coefficient 1.20, P=0.003) when lamivudine was chosen for HCC after curative therapy, relative to entecavir for HCC. HBV mutation may play a role in HCC recurrence. Entecavir or tenofovir, a high genetic barrier to resistance, should be recommended for HBV-HCC patients. © 2015 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  2. Combined use of nuclear phosphoprotein c-Myc and cellular phosphoprotein p53 for hepatocellular carcinoma detection in high-risk chronic hepatitis C patients.

    Science.gov (United States)

    Attallah, A M; El-Far, M; Abdelrazek, M A; Omran, M M; Attallah, A A; Elkhouly, A A; Elkenawy, H M; Farid, K

    2017-10-01

    Hepatocellular carcinoma (HCC) is a multistage process resulting from various genetic changes. We aimed to determine nuclear phosphoprotein c-Myc and cellular phosphoprotein p53 expression and to evaluate their importance in HCC diagnosis. One hundred and twenty chronic hepatitis C (CHC) patients (60 non-HCC CHC patients and 60 HCC patients who had a single small (c-Myc and p53 were identified in liver tissues and serum samples using immunostaining, western blot and ELISA. Immunohistochemical detection of c-Myc and p53 with monospecific antibodies revealed intense and diffuse cytoplasmic staining patterns. Accumulated mutant proteins, released from tumour cells into the extracellular serum, were detected at 62 KDa, for c-Myc, and 53 KDa, for p53, using western blotting. In contrast to alpha feto-protein, there was a significant increase (p c-Myc (86.7% vs. 6.7%) and p53 (78.3% vs. 8.3%) in the malignant vs. non-malignant patients. The parallel combination of c-Myc and p53 reach the absolute sensitivity (100%), for more accurate and reliable HCC detection (specificity was 87%). c-Myc and p53 are potential HCC diagnostic biomarkers, and convenient combinations of them could improve diagnostic accuracy of HCC.

  3. The rapid evolution of molecular genetic diagnostics in neuromuscular diseases.

    Science.gov (United States)

    Volk, Alexander E; Kubisch, Christian

    2017-10-01

    The development of massively parallel sequencing (MPS) has revolutionized molecular genetic diagnostics in monogenic disorders. The present review gives a brief overview of different MPS-based approaches used in clinical diagnostics of neuromuscular disorders (NMDs) and highlights their advantages and limitations. MPS-based approaches like gene panel sequencing, (whole) exome sequencing, (whole) genome sequencing, and RNA sequencing have been used to identify the genetic cause in NMDs. Although gene panel sequencing has evolved as a standard test for heterogeneous diseases, it is still debated, mainly because of financial issues and unsolved problems of variant interpretation, whether genome sequencing (and to a lesser extent also exome sequencing) of single patients can already be regarded as routine diagnostics. However, it has been shown that the inclusion of parents and additional family members often leads to a substantial increase in the diagnostic yield in exome-wide/genome-wide MPS approaches. In addition, MPS-based RNA sequencing just enters the research and diagnostic scene. Next-generation sequencing increasingly enables the detection of the genetic cause in highly heterogeneous diseases like NMDs in an efficient and affordable way. Gene panel sequencing and family-based exome sequencing have been proven as potent and cost-efficient diagnostic tools. Although clinical validation and interpretation of genome sequencing is still challenging, diagnostic RNA sequencing represents a promising tool to bypass some hurdles of diagnostics using genomic DNA.

  4. The genetics of Alzheimer disease.

    Science.gov (United States)

    Tanzi, Rudolph E

    2012-10-01

    Family history is the second strongest risk factor for Alzheimer disease (AD) following advanced age. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 virtually guarantee early-onset (<60 years) familial AD, which represents ∼5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, can influence susceptibility for ∼50% of the common late-onset AD. These four genes account for 30%-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of 11 additional AD candidate genes. This paper reviews the past, present, and future attempts to elucidate the complex and heterogeneous genetic underpinnings of AD.

  5. Nucleolar TRF2 attenuated nucleolus stress-induced HCC cell-cycle arrest by altering rRNA synthesis.

    Science.gov (United States)

    Yuan, Fuwen; Xu, Chenzhong; Li, Guodong; Tong, Tanjun

    2018-05-03

    The nucleolus is an important organelle that is responsible for the biogenesis of ribosome RNA (rRNA) and ribosomal subunits assembly. It is also deemed to be the center of metabolic control, considering the critical role of ribosomes in protein translation. Perturbations of rRNA synthesis are closely related to cell proliferation and tumor progression. Telomeric repeat-binding factor 2 (TRF2) is a member of shelterin complex that is responsible for telomere DNA protection. Interestingly, it was recently reported to localize in the nucleolus of human cells in a cell-cycle-dependent manner, while the underlying mechanism and its role on the nucleolus remained unclear. In this study, we found that nucleolar and coiled-body phosphoprotein 1 (NOLC1), a nucleolar protein that is responsible for the nucleolus construction and rRNA synthesis, interacted with TRF2 and mediated the shuttle of TRF2 between the nucleolus and nucleus. Abating the expression of NOLC1 decreased the nucleolar-resident TRF2. Besides, the nucleolar TRF2 could bind rDNA and promoted rRNA transcription. Furthermore, in hepatocellular carcinoma (HCC) cell lines HepG2 and SMMC7721, TRF2 overexpression participated in the nucleolus stress-induced rRNA inhibition and cell-cycle arrest.

  6. Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma.

    Science.gov (United States)

    Kent, Lindsey N; Bae, Sooin; Tsai, Shih-Yin; Tang, Xing; Srivastava, Arunima; Koivisto, Christopher; Martin, Chelsea K; Ridolfi, Elisa; Miller, Grace C; Zorko, Sarah M; Plevris, Emilia; Hadjiyannis, Yannis; Perez, Miguel; Nolan, Eric; Kladney, Raleigh; Westendorp, Bart; de Bruin, Alain; Fernandez, Soledad; Rosol, Thomas J; Pohar, Kamal S; Pipas, James M; Leone, Gustavo

    2017-03-01

    Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.

  7. A standardized procedure for using human corpus cavernosum strips to evaluate drug activity.

    Science.gov (United States)

    Mirone, V; Sorrentino, R; di Villa Bianca, R; Imbimbo, C; Palmieri, A; Fusco, F; Tajana, G; Cirino, G

    2000-01-01

    The main problem of using human corpus cavernosum (HCC) tissue to perform bioassay is linked to its limited availability further complicated by the heterogeneous source of the tissues used. Here, we show that gender reassignment is a reliable source of human tissue without major ethical problems. Indeed, the entire corpus cavernosum is obtained from the surgery procedure, which allows creating a standardized procedure to prepare HCC strip. In addition, human tissue, if kept in the fridge in the condition described, does not loose its ability to contract to phenylephrine (PE; alpha agonist), angiotensin II (AG II) and KCl up to 4 days. Furthermore, once contracted with PE, HCC relaxes to acetylcholine (endothelium-dependent mechanism); sodium nitroprusside (endothelium-independent mechanism); cromakalim (CRK), a K(ATP) channel opener; or alprostadil, a synthetic PGE2 (ALPR). In conclusion, we have standardized a procedure that allows the use of HCC strips to evaluate drug activity and/or to study pathophysiological mechanisms with an intact functional human tissue up to 4 days from the surgery procedure.

  8. Interference, heterogeneity and disease gene mapping

    Energy Technology Data Exchange (ETDEWEB)

    Keats, B. [Louisiana State Univ. Medical Center, New Orleans, LA (United States)

    1996-12-31

    The Human Genome Project has had a major impact on genetic research over the past five years. The number of mapped genes is now over 3,000 compared with approximately 1,600 in 1989 and only about 260 ten years before that. The realization that extensive variation could be detected in anonymous DNA segments greatly enhanced the potential for mapping by linkage analysis. Previously, linkage studies had depended on polymorphisms that could be detected in red blood cell antigens, proteins (revealed by electrophoresis and isoelectric focusing), and cytogenetic heteromorphisms. The identification of thousands of polymorphic DNA markers throughout the human genome has led to the construction of high density genetic linkage maps. These maps provide the data necessary to test hypotheses concerning differences in recombination rates and levels of interference. They are also important for disease gene mapping because the existence of these genes must be inferred from the phenotype. Showing linkage of a disease gene to a DNA marker is the first step towards isolating the disease gene, determining its protein product, and developing effective therapies. However, interpretation of results is not always straightforward. Factors such as etiological heterogeneity and undetected irregular segregation can lead to confusing linkage results and incorrect conclusions about the locations of disease genes. This paper will discuss these phenomena and present examples that illustrate the problems, as well as approaches to dealing with them. 23 refs., 3 figs., 3 tabs.

  9. Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    Yuan Tian

    2016-08-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD, characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC. The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.

  10. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis

    Directory of Open Access Journals (Sweden)

    Yezaz Ahmed Ghouri

    2017-01-01

    Full Text Available Since the 1970s, the epidemic of hepatocellular carcinoma (HCC has spread beyond the Eastern Asian predominance and has been increasing in Northern hemisphere, especially in the United States (US and Western Europe. It occurs more commonly in males in the fourth and fifth decades of life. Among all cancers, HCC is one of the fastest growing causes of death in the US and poses a significant economic burden on healthcare. Chronic liver disease due to hepatitis B virus or hepatitis C virus and alcohol accounts for the majority of HCC cases. Incidence of nonalcoholic fatty liver disease has been on the risem and it has also been associated with the development of HCC. Its pathogenesis varies based on the underlying etiological factor although majority of cases develop in the setting of background cirrhosis. Carcinogenesis of HCC includes angiogenesis, chronic inflammation, and tumor macroenvironment and microenvironment. There is a significant role of both intrinsic genetic risk factors and extrinsic influences such as alcohol or viral infections that lead to the development of HCC. Understanding its etiopathogenesis helps select appropriate diagnostic tests and treatments.

  11. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase 3 RESORCE trial.

    Science.gov (United States)

    Finn, Richard S; Merle, Philippe; Granito, Alessandro; Huang, Yi-Hsiang; Bodoky, György; Pracht, Marc; Yokosuka, Osamu; Rosmorduc, Olivier; Gerolami, René; Caparello, Chiara; Cabrera, Roniel; Chang, Charissa; Sun, Weijing; LeBerre, Marie-Aude; Baumhauer, Annette; Meinhardt, Gerold; Bruix, Jordi

    2018-04-25

    The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50, 0.78; P<.0001). This exploratory analysis describes outcomes of sequential treatment with sorafenib followed by regorafenib. In RESORCE, 573 patients were randomized 2:1 to regorafenib 160mg/day or placebo for 3 weeks on/1 week off. Efficacy and safety were evaluated by last sorafenib dose. The time from the start of sorafenib to death was assessed. Time to progression (TTP) in RESORCE was analyzed by TTP during prior sorafenib treatment. HRs (regorafenib/placebo) for OS by last sorafenib dose were similar (0.67 for 800 mg/day; 0.68 for <800 mg/day). Rates of grade 3, 4, and 5 adverse events with regorafenib by last sorafenib dose (800 mg/day versus <800 mg/day) were 52%, 11%, and 15% versus 60%, 10%, and 12%, respectively. Median times (95% CI) from the start of sorafenib to death were 26.0 months (22.6, 28.1) for regorafenib and 19.2 months (16.3, 22.8) for placebo. Median time from the start of sorafenib to progression on sorafenib was 7.2 months for the regorafenib arm and 7.1 months for the placebo arm. An analysis of TTP in RESORCE in subgroups defined by TTP during prior sorafenib in quartiles (Q) showed HRs (regorafenib/placebo; 95% CI) of 0.66 (0.45, 0.96; Q1); 0.26 (0.17, 0.40; Q2); 0.40 (0.27, 0.60; Q3); and 0.54 (0.36, 0.81; Q4). These exploratory analyses show that regorafenib conferred a clinical benefit regardless of the last sorafenib dose or TTP on prior sorafenib. Rates of adverse events were generally similar regardless of the last sorafenib dose. This analysis examined characteristics and outcomes of patients with HCC who were treated with regorafenib after they had disease progression during sorafenib treatment. Regorafenib provided clinical benefit to patients regardless of the pace of their disease progression during prior sorafenib

  12. MetaRanker 2.0: a web server for prioritization of genetic variation data.

    Science.gov (United States)

    Pers, Tune H; Dworzyński, Piotr; Thomas, Cecilia Engel; Lage, Kasper; Brunak, Søren

    2013-07-01

    MetaRanker 2.0 is a web server for prioritization of common and rare frequency genetic variation data. Based on heterogeneous data sets including genetic association data, protein-protein interactions, large-scale text-mining data, copy number variation data and gene expression experiments, MetaRanker 2.0 prioritizes the protein-coding part of the human genome to shortlist candidate genes for targeted follow-up studies. MetaRanker 2.0 is made freely available at www.cbs.dtu.dk/services/MetaRanker-2.0.

  13. Heterogeneity of postpartum depression: a latent class analysis

    Science.gov (United States)

    2016-01-01

    Summary Background Maternal depression in the postpartum period confers substantial morbidity and mortality, but the definition of postpartum depression remains controversial. We investigated the heterogeneity of symptoms with the aim of identifying clinical subtypes of postpartum depression. Methods Data were aggregated from the international perinatal psychiatry consortium Postpartum Depression: Action Towards Causes and Treatment, which represents 19 institutions in seven countries. 17 912 unique subject records with phenotypic data were submitted. We applied latent class analyses in a two-tiered approach to assess the validity of empirically defined subtypes of postpartum depression. Tier one assessed heterogeneity in women with complete data on the Edinburgh postnatal depression scale (EPDS) and tier two in those with postpartum depression case status. Findings 6556 individuals were assessed in tier one and 4245 in tier two. A final model with three latent classes was optimum for both tiers. The most striking characteristics associated with postpartum depression were severity, timing of onset, comorbid anxiety, and suicidal ideation. Women in class 1 had the least severe symptoms (mean EPDS score 10·5), followed by those in class 2 (mean EPDS score 14·8) and those in class 3 (mean EPDS score 20·1). The most severe symptoms of postpartum depression were significantly associated with poor mood (mean EPDS score 20·1), increased anxiety, onset of symptoms during pregnancy, obstetric complications, and suicidal ideation. In class 2, most women (62%) reported symptom onset within 4 weeks postpartum and had more pregnancy complications than in other two classes (69% vs 67% in class 1 and 29% in class 3). Interpretation PPD seems to have several distinct phenotypes. Further assessment of PPD heterogeneity to identify more precise phenotypes will be important for future biological and genetic investigations. Funding Sources of funding are listed at the end of the

  14. An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease.

    Directory of Open Access Journals (Sweden)

    Tobias Eisenberger

    Full Text Available Renal cysts are clinically and genetically heterogeneous conditions. Autosomal dominant polycystic kidney disease (ADPKD is the most frequent life-threatening genetic disease and mainly caused by mutations in PKD1. The presence of six PKD1 pseudogenes and tremendous allelic heterogeneity make molecular genetic testing challenging requiring laborious locus-specific amplification. Increasing evidence suggests a major role for PKD1 in early and severe cases of ADPKD and some patients with a recessive form. Furthermore it is becoming obvious that clinical manifestations can be mimicked by mutations in a number of other genes with the necessity for broader genetic testing. We established and validated a sequence capture based NGS testing approach for all genes known for cystic and polycystic kidney disease including PKD1. Thereby, we demonstrate that the applied standard mapping algorithm specifically aligns reads to the PKD1 locus and overcomes the complication of unspecific capture of pseudogenes. Employing careful and experienced assessment of NGS data, the method is shown to be very specific and equally sensitive as established methods. An additional advantage over conventional Sanger sequencing is the detection of copy number variations (CNVs. Sophisticated bioinformatic read simulation increased the high analytical depth of the validation study and further demonstrated the strength of the approach. We further raise some awareness of limitations and pitfalls of common NGS workflows when applied in complex regions like PKD1 demonstrating that quality of NGS needs more than high coverage of the target region. By this, we propose a time- and cost-efficient diagnostic strategy for comprehensive molecular genetic testing of polycystic kidney disease which is highly automatable and will be of particular value when therapeutic options for PKD emerge and genetic testing is needed for larger numbers of patients.

  15. An efficient and comprehensive strategy for genetic diagnostics of polycystic kidney disease.

    Science.gov (United States)

    Eisenberger, Tobias; Decker, Christian; Hiersche, Milan; Hamann, Ruben C; Decker, Eva; Neuber, Steffen; Frank, Valeska; Bolz, Hanno J; Fehrenbach, Henry; Pape, Lars; Toenshoff, Burkhard; Mache, Christoph; Latta, Kay; Bergmann, Carsten

    2015-01-01

    Renal cysts are clinically and genetically heterogeneous conditions. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent life-threatening genetic disease and mainly caused by mutations in PKD1. The presence of six PKD1 pseudogenes and tremendous allelic heterogeneity make molecular genetic testing challenging requiring laborious locus-specific amplification. Increasing evidence suggests a major role for PKD1 in early and severe cases of ADPKD and some patients with a recessive form. Furthermore it is becoming obvious that clinical manifestations can be mimicked by mutations in a number of other genes with the necessity for broader genetic testing. We established and validated a sequence capture based NGS testing approach for all genes known for cystic and polycystic kidney disease including PKD1. Thereby, we demonstrate that the applied standard mapping algorithm specifically aligns reads to the PKD1 locus and overcomes the complication of unspecific capture of pseudogenes. Employing careful and experienced assessment of NGS data, the method is shown to be very specific and equally sensitive as established methods. An additional advantage over conventional Sanger sequencing is the detection of copy number variations (CNVs). Sophisticated bioinformatic read simulation increased the high analytical depth of the validation study and further demonstrated the strength of the approach. We further raise some awareness of limitations and pitfalls of common NGS workflows when applied in complex regions like PKD1 demonstrating that quality of NGS needs more than high coverage of the target region. By this, we propose a time- and cost-efficient diagnostic strategy for comprehensive molecular genetic testing of polycystic kidney disease which is highly automatable and will be of particular value when therapeutic options for PKD emerge and genetic testing is needed for larger numbers of patients.

  16. Genetic characterization of canine parvovirus from dogs in Pakistan.

    Science.gov (United States)

    Shabbir, M Z; Sohail, M U; Chaudhary, U N; Yaqub, W; Rashid, I; Saleem, M H; Munir, M

    Canine parvoviruses (CPV) exist as antigenic variants with varying frequencies and genetic variabilities across the globe. Given the endemicity and high prevalence in Pakistan, we characterized the CPVs originating from dogs-population to elucidate viral diversity and evolution. Fecal samples from clinically diseased pups (n = 17) of different breeds and age (2-6 months) were processed for hemagglutination assay (HA), and later for partial amplification of VP2 gene sequence and amino acid analysis. A total of 11 samples (64.71%) were found positive both in hemagglutination and PCR assays. Phylogenetic and evolutionary analysis demonstrated higher genetic heterogeneity in studied strains and constituted seven clusters within the CPV-2a group, however, they shared high level of identity with Chinese strains. Further studies are necessary to elucidate genetic analysis and epidemiology of CPV variants across a wide geographical area of the country.

  17. Population-genetic analysis of seven qualitative traits in the population of the municipality Maglaj (Bosnia and Herzegovina

    Directory of Open Access Journals (Sweden)

    Mrehić Elma

    2015-01-01

    Full Text Available On the basis of the complex seven monogenic qualitative characteristics (shape of the earlobes, hairiness of middle phalange, flexibility of lateral tongue edges, the extensiveness of the distal and proximal joint of the thumb and the flexibility of the distal phalanx of the little finger and one sexually conditioned property (digital index we analyzed the genetic structure of four populations of rural municipality Maglaj: Kosova, Novi Šeher, Jablanica, Moševac, then one isolated local population Ravna and one urban population area called Maglaj. The survey covered a total of 440 students (213 girls and 227 boys aged 11-18 years. According to the degree of genetic heterogeneity, values of Wahlund variance that are obtained for each trait belong in the category of low genetic differentiation. The maximum value of Wahlund variance was identified for the property shape of the earlobes (by Cavalli - Sforza, Bodmer = 0.0452, and the lowest for phenotypic system flexibility of lateral tongue edges (by Cavalli - Sforza, Bodmer = 0.0000. Studied set of population is the most heterogeneous according to the frequency of recessive allelogene for phenotypic characteristic shape of the earlobes, and the most homogeneous for the phenotypic trait flexibility of lateral tongue edge. Based on the analysis of genetic distance for seven phenotypic traits in populations of municipality Maglaj we established the minimum genetic distance between populations of Kosova and Maglaj (fθ = 0.0007, and the largest genetic distance between populations of Jablanica and Moševac (fθ = 0.0144. It was noted that the lowest average coefficient of kinship has a local population of Kosova (fθ = 0.0028, while the highest average coefficient of kinship has a population Moševac (fθ = 0.0081. The greatest characteristic has a population of Moševac (fθs = 0.7556, and the lowest characteristic has a population of Novi Šeher (fθs = -0.0795. Based on the obtained values of

  18. Genetic Basis of Positive and Negative Symptom Domains in Schizophrenia.

    Science.gov (United States)

    Xavier, Rose Mary; Vorderstrasse, Allison

    2017-10-01

    Schizophrenia is a highly heritable disorder, the genetic etiology of which has been well established. Yet despite significant advances in genetics research, the pathophysiological mechanisms of this disorder largely remain unknown. This gap has been attributed to the complexity of the polygenic disorder, which has a heterogeneous clinical profile. Examining the genetic basis of schizophrenia subphenotypes, such as those based on particular symptoms, is thus a useful strategy for decoding the underlying mechanisms. This review of literature examines the recent advances (from 2011) in genetic exploration of positive and negative symptoms in schizophrenia. We searched electronic databases PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature using key words schizophrenia, symptoms, positive symptoms, negative symptoms, cognition, genetics, genes, genetic predisposition, and genotype in various combinations. We identified 115 articles, which are included in the review. Evidence from these studies, most of which are genetic association studies, identifies shared and unique gene associations for the symptom domains. Genes associated with neurotransmitter systems and neuronal development/maintenance primarily constitute the shared associations. Needed are studies that examine the genetic basis of specific symptoms within the broader domains in addition to functional mechanisms. Such investigations are critical to developing precision treatment and care for individuals afflicted with schizophrenia.

  19. Heterogeneous reactors

    International Nuclear Information System (INIS)

    Moura Neto, C. de; Nair, R.P.K.

    1979-08-01

    The microscopic study of a cell is meant for the determination of the infinite multiplication factor of the cell, which is given by the four factor formula: K(infinite) = n(epsilon)pf. The analysis of an homogeneous reactor is similar to that of an heterogeneous reactor, but each factor of the four factor formula can not be calculated by the formulas developed in the case of an homogeneous reactor. A great number of methods was developed for the calculation of heterogeneous reactors and some of them are discussed. (Author) [pt

  20. Heterogeneous gas core reactor

    International Nuclear Information System (INIS)

    Han, K.I.

    1977-01-01

    Preliminary investigations of a heterogeneous gas core reactor (HGCR) concept suggest that this potential power reactor offers distinct advantages over other existing or conceptual reactor power plants. One of the most favorable features of the HGCR is the flexibility of the power producing system which allows it to be efficiently designed to conform to a desired optimum condition without major conceptual changes. The arrangement of bundles of moderator/coolant channels in a fissionable gas or mixture of gases makes a truly heterogeneous nuclear reactor core. It is this full heterogeneity for a gas-fueled reactor core which accounts for the novelty of the heterogeneous gas core reactor concept and leads to noted significant advantages over previous gas core systems with respect to neutron and fuel economy, power density, and heat transfer characteristics. The purpose of this work is to provide an insight into the design, operating characteristics, and safety of a heterogeneous gas core reactor system. The studies consist mainly of neutronic, energetic and kinetic analyses of the power producing and conversion systems as a preliminary assessment of the heterogeneous gas core reactor concept and basic design. The results of the conducted research indicate a high potential for the heterogeneous gas core reactor system as an electrical power generating unit (either large or small), with an overall efficiency as high as 40 to 45%. The HGCR system is found to be stable and safe, under the conditions imposed upon the analyses conducted in this work, due to the inherent safety of ann expanding gaseous fuel and the intrinsic feedback effects of the gas and water coolant