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1.  Molecular signature of adipose tissue in patients with both Non-Alcoholic Fatty Liver Disease (NAFLD) and Polycystic Ovarian Syndrome (PCOS) 
Background
Polycystic ovarian syndrome (PCOS) is one of the most common reproductive disorders with strong association with both insulin resistance and non-alcoholic fatty liver disease (NAFLD). To untangle the complex relationship between PCOS and NAFLD, we analyzed serum biomarkers of apoptosis, some adipokines and mRNA profiles in the visceral adipose tissue of obese patients with NAFLD who were also diagnosed with PCOS and compared to a group with NAFLD only.
Methods
We included patients with biopsy-proven NAFLD and PCOS (N = 12) and BMI-matched biopsy-proven NAFLD patients without PCOS (N = 12). Expression levels of individual mRNAs and soluble serum biomarkers were compared by non-parametric Mann–Whitney test. The analysis also included Spearman rank correlation tests and multiple regression analysis. For co-correlated genes, the factor analysis was performed.
Results
The total serum levels of apoptotic biomarker M30 were significantly elevated in PCOS patients with liver steatosis as compared to non-PCOS NAFLD controls (P < 0.02), pointing that androgen-dependent proapoptotic PCOS environment that may directly contribute to NAFLD progression in these patients. Similarly, hyperandrogenism may explain the observed PCOS-specific decrease (P < 0.04) in adipose LDLR mRNA expression that may be connected to the proneness of PCOS patients to NAFLD. The levels of mRNA encoding angiogenesis-associated GSK-3B interacting protein ninein were also significantly increased in the adipose tissue of NAFLD patients with PCOS (P < 0.007). Furthermore, the levels of resistin positively correlated with expression levels of LDLR and prothrombin time (PT).
Conclusion
An androgen-dependent proapoptotic PCOS environment may directly contribute to NAFLD progression in these patients. Hyperandrogenism may explain an observed decrease in adipose LDLR mRNA expression. An inflammation-associated increase in the release of resistin into circulation might contribute to the prothrombotic state observed under conditions associated with insulin resistance, including PCOS. The studies of larger cohorts of NAFLD with and without PCOS patients are needed to further assess these potential interactions.
doi:10.1186/1479-5876-11-133
PMCID: PMC3681627  PMID: 23721173
NAFLD; PCOS; LDLR; M30; Apoptosis; Ninein; Resistin
2.  Knowledge-Based Identification of Soluble Biomarkers: Hepatic Fibrosis in NAFLD as an Example 
PLoS ONE  2013;8(2):e56009.
The discovery of biomarkers is often performed using high-throughput proteomics-based platforms and is limited to the molecules recognized by a given set of purified and validated antigens or antibodies. Knowledge-based, or systems biology, approaches that involve the analysis of integrated data, predominantly molecular pathways and networks may infer quantitative changes in the levels of biomolecules not included by the given assay from the levels of the analytes profiled. In this study we attempted to use a knowledge-based approach to predict biomarkers reflecting the changes in underlying protein phosphorylation events using Nonalcoholic Fatty Liver Disease (NAFLD) as a model. Two soluble biomarkers, CCL-2 and FasL, were inferred in silico as relevant to NAFLD pathogenesis. Predictive performance of these biomarkers was studied using serum samples collected from patients with histologically proven NAFLD. Serum levels of both molecules, in combination with clinical and demographic data, were predictive of hepatic fibrosis in a cohort of NAFLD patients. Our study suggests that (1) NASH-specific disruption of the kinase-driven signaling cascades in visceral adipose tissue lead to detectable changes in the levels of soluble molecules released into the bloodstream, and (2) biomarkers discovered in silico could contribute to predictive models for non-malignant chronic diseases.
doi:10.1371/journal.pone.0056009
PMCID: PMC3566090  PMID: 23405244
3.  Gene expression profiles associated with depression in patients with chronic hepatitis C (CH-C) 
Brain and Behavior  2012;2(5):525-531.
The standard treatment for CH-C, pegylated interferon-α and ribavirin (PEG-IFN + RBV), is associated with depression. Recent studies have proposed a new role for cytokines in the pathogenesis of depression. We aimed to assess differential gene expression related to depression in CH-C patients treated with PEG-IFN + RBV. We included 67 CH-C patients being treated with PEG-IFN+RBV. Of the entire study cohort, 22% had pre-existing depression, while another 37% developed new depression in course of the treatment. Pretreatment blood samples were collected into PAXgene™ RNA tubes, the RNAs extracted from peripheral blood mononuclear cells (PBMCs) were used for one step RT-PCR to profile 160 mRNAs. Differentially expressed genes were separated into up- and down-regulated genes according to presence or absence of depression at baseline (pre-existing depression) or following the initiation of treatment (treatment-related depression). The mRNA expression profile associated with any depression and with treatment-related depression included four and six genes, respectively. Our data demonstrate a significant down-regulation of TGF-β1 and the shift of Th1-Th2 cytokine balance in the depression associated with IFN-based treatment of HCV infection. We propose that TGF-β1 plays an important role in the imbalance of Th1/Th2 in patients with CH-C and depression. With further validation, TGF-β1 and other components of Th1/Th2 regulation pathway may provide a future marker for CH-C patients predisposed to depression.
doi:10.1002/brb3.72
PMCID: PMC3489805  PMID: 23139898
Depression; hepatitis C; interferon; ribavirin; TGFβ1; Th1/Th2 cytokines; treatment
4.  The impact of IL28B genotype on the gene expression profile of patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin 
Background
Recent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients.
Methods
Clinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort.
Results
The most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype.
Conclusions
IL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.
doi:10.1186/1479-5876-10-25
PMCID: PMC3296607  PMID: 22313623
HCV; Gene Expression; Pathway Analysis; IL28B; SOCS1; IRF2; chronic hepatitis C; HCV treatment
5.  Non-Invasive markers for hepatic fibrosis 
BMC Gastroenterology  2011;11:91.
With great advancements in the therapeutic modalities used for the treatment of chronic liver diseases, the accurate assessment of liver fibrosis is a vital need for successful individualized management of disease activity in patients. The lack of accurate, reproducible and easily applied methods for fibrosis assessment has been the major limitation in both the clinical management and for research in liver diseases. However, the problem of the development of biomarkers capable of non-invasive staging of fibrosis in the liver is difficult due to the fact that the process of fibrogenesis is a component of the normal healing response to injury, invasion by pathogens, and many other etiologic factors. Current non-invasive methods range from serum biomarker assays to advanced imaging techniques such as transient elastography and magnetic resonance imaging (MRI). Among non-invasive methods that gain strongest clinical foothold are FibroScan elastometry and serum-based APRI and FibroTest. There are many other tests that are not yet widely validated, but are none the less, promising. The rate of adoption of non-invasive diagnostic tests for liver fibrosis differs from country to country, but remains limited. At the present time, use of non-invasive procedures could be recommended as pre-screening that may allow physicians to narrow down the patients' population before definitive testing of liver fibrosis by biopsy of the liver. This review provides a systematic overview of these techniques, as well as both direct and indirect biomarkers based approaches used to stage fibrosis and covers recent developments in this rapidly advancing area.
doi:10.1186/1471-230X-11-91
PMCID: PMC3176189  PMID: 21849046
6.  Validation of endogenous reference genes for qRT-PCR analysis of human visceral adipose samples 
BMC Molecular Biology  2010;11:39.
Background
Given the epidemic proportions of obesity worldwide and the concurrent prevalence of metabolic syndrome, there is an urgent need for better understanding the underlying mechanisms of metabolic syndrome, in particular, the gene expression differences which may participate in obesity, insulin resistance and the associated series of chronic liver conditions. Real-time PCR (qRT-PCR) is the standard method for studying changes in relative gene expression in different tissues and experimental conditions. However, variations in amount of starting material, enzymatic efficiency and presence of inhibitors can lead to quantification errors. Hence the need for accurate data normalization is vital. Among several known strategies for data normalization, the use of reference genes as an internal control is the most common approach. Recent studies have shown that both obesity and presence of insulin resistance influence an expression of commonly used reference genes in omental fat. In this study we validated candidate reference genes suitable for qRT-PCR profiling experiments using visceral adipose samples from obese and lean individuals.
Results
Cross-validation of expression stability of eight selected reference genes using three popular algorithms, GeNorm, NormFinder and BestKeeper found ACTB and RPII as most stable reference genes.
Conclusions
We recommend ACTB and RPII as stable reference genes most suitable for gene expression studies of human visceral adipose tissue. The use of these genes as a reference pair may further enhance the robustness of qRT-PCR in this model system.
doi:10.1186/1471-2199-11-39
PMCID: PMC2886049  PMID: 20492695
7.  Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region 
Tumour Biology  2009;31(1):33-45.
Deletion of 13q14.3 and a candidate gene KCNRG (potassium channel regulating gene) is the most frequent chromosomal abnormality in B-cell chronic lymphocytic leukemia and is a common finding in multiple myeloma (MM). KCNRG protein may interfere with the normal assembly of the K+ channel proteins causing the suppression of Kv currents. We aimed to examine possible role of KCNRG haploinsufficiency in chronic lymphocytic leukemia (CLL) and MM cells. We performed detailed genomic analysis of the KCNRG locus; studied effects of the stable overexpression of KCNRG isoforms in RPMI-8226, HL-60, and LnCaP cells; and evaluated relative expression of its transcripts in various human lymphomas. Three MM cell lines and 35 CLL PBL samples were screened for KCNRG mutations. KCNRG exerts growth suppressive and pro-apoptotic effects in HL-60, LnCaP, and RPMI-8226 cells. Direct sequencing of KCNRG exons revealed point mutation delT in RPMI-8226 cell line. Levels of major isoform of KCNRG mRNA are lower in DLBL lymphomas compared to normal PBL samples, while levels of its minor mRNA are decreased across the broad range of the lymphoma types. The haploinsufficiency of KCNRG might be relevant to the progression of CLL and MM at least in a subset of patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s13277-009-0005-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s13277-009-0005-0
PMCID: PMC2803748  PMID: 20237900
Tumor suppressor candidate; Potassium channels; 13q14; Chronic lymphocytic leukemia; Multiple myeloma; KCNRG

Results 1-7 (7)