Role of Alcohol Metabolism in Non-Alcoholic Steatohepatitis

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD), associated with obesity and insulin resistance. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals. METHODOLOGY/PRINCIPAL FINDINGS: To investigate whether alcohol is involved in the pathogenesis of NASH, the expression of inflammation, fibrosis and alcohol metabolism related genes in the liver tissues of NASH patients and normal controls (NCs) were examined by microarray (NASH, n = 7; NC, n = 4) and quantitative real-time PCR (NASH, n = 6; NC, n = 6). Genes related to liver inflammation and fibrosis were found to be elevated in NASH livers compared to normal livers. The most striking finding is the increased gene transcription of alcohol dehydrogenase (ADH) genes, genes for catalase and cytochrome P450 2E1, and aldehyde dehydrogenase genes. Immunoblot analysis confirmed the increased expression of ADH1 and ADH4 in NASH livers (NASH, n = 9; NC, n = 4). CONCLUSIONS/SIGNIFICANCE: The augmented activity of all the available genes of the pathways for alcohol catabolism suggest that 1) alcohol concentration was elevated in the circulation of NASH patients; 2) there was a high priority for the NASH livers to scavenge alcohol from the circulation. Our data is the first human evidence that suggests alcohol may contribute to the development of NAFLD

aCGHViewer: A Generic Visualization Tool For aCGH data

Array-Comparative Genomic Hybridization (aCGH) is a powerful high throughput technology for detecting chromosomal copy number aberrations (CNAs) in cancer, aiming at identifying related critical genes from the affected genomic regions. However, advancing from a dataset with thousands of tabular lines to a few candidate genes can be an onerous and time-consuming process. To expedite the aCGH data analysis process, we have developed a user-friendly aCGH data viewer (aCGHViewer) as a conduit between the aCGH data tables and a genome browser. The data from a given aCGH analysis are displayed in a genomic view comprised of individual chromosome panels which can be rapidly scanned for interesting features. A chromosome panel containing a feature of interest can be selected to launch a detail window for that single chromosome. Selecting a data point of interest in the detail window launches a query to the UCSC or NCBI genome browser to allow the user to explore the gene content in the chromosomal region. Additionally, aCGHViewer can display aCGH and expression array data concurrently to visually correlate the two. aCGHViewer is a stand alone Java visualization application that should be used in conjunction with separate statistical programs. It operates on all major computer platforms and is freely available at http://falcon.roswellpark.org/aCGHview/

Common Genetic Variants Are Associated with Accelerated Bone Mineral Density Loss after Hematopoietic Cell Transplantation

BACKGROUND: Bone mineral density (BMD) loss commonly occurs after hematopoietic cell transplantation (HCT). Hypothesizing that genetic variants may influence post-HCT BMD loss, we conducted a prospective study to examine the associations of single nucleotide polymorphisms (SNP) in bone metabolism pathways and acute BMD loss after HCT. METHODS AND FINDINGS: We genotyped 122 SNPs in 45 genes in bone metabolism pathways among 121 autologous and allogeneic HCT patients. BMD changes from pre-HCT to day +100 post-HCT were analyzed in relation to these SNPs in linear regression models. After controlling for clinical risk factors, we identified 16 SNPs associated with spinal or femoral BMD loss following HCT, three of which have been previously implicated in genome-wide association studies of bone phenotypes, including rs2075555 in COL1A1, rs9594738 in RANKL, and rs4870044 in ESR1. When multiple SNPs were considered simultaneously, they explained 5-35% of the variance in post-HCT BMD loss. There was a significant trend between the number of risk alleles and the magnitude of BMD loss, with patients carrying the most risk alleles having the greatest loss. CONCLUSION: Our data provide the first evidence that common genetic variants play an important role in BMD loss among HCT patients similar to age-related BMD loss in the general population. This infers that the mechanism for post-HCT bone loss is a normal aging process that is accelerated during HCT. A limitation of our study comes from its small patient population; hence future larger studies are warranted to validate our findings

Gene-resolution analysis of DNA copy number variation using oligonucleotide expression microarrays

<p>Abstract</p> <p>Background</p> <p>Array-based comparative genomic hybridization (aCGH) is a high-throughput method for measuring genome-wide DNA copy number changes. Current aCGH methods have limited resolution, sensitivity and reproducibility. Microarrays for aCGH are available only for a few organisms and combination of aCGH data with expression data is cumbersome.</p> <p>Results</p> <p>We present a novel method of using commercial oligonucleotide expression microarrays for aCGH, enabling DNA copy number measurements and expression profiles to be combined using the same platform. This method yields aCGH data from genomic DNA without complexity reduction at a median resolution of approximately 17,500 base pairs. Due to the well-defined nature of oligonucleotide probes, DNA amplification and deletion can be defined at the level of individual genes and can easily be combined with gene expression data.</p> <p>Conclusion</p> <p>A novel method of gene resolution analysis of copy number variation (graCNV) yields high-resolution maps of DNA copy number changes and is applicable to a broad range of organisms for which commercial oligonucleotide expression microarrays are available. Due to the standardization of oligonucleotide microarrays, graCNV results can reliably be compared between laboratories and can easily be combined with gene expression data using the same platform.</p

Targeted Deletion of p73 in Mice Reveals Its Role in T Cell Development and Lymphomagenesis

Transcriptional silencing of the p73 gene through methylation has been demonstrated in human leukemias and lymphomas. However, the role of p73 in the malignant process remains to be explored. We show here that p73 acts as a T cell-specific tumor suppressor in a genetically defined mouse model, and that concomitant ablation of p53 and p73 predisposes mice to an increased incidence of thymic lymphomas compared to the loss of p53 alone. Our results demonstrate a causal role for loss of p73 in progression of T cell lymphomas to the stage of aggressive, disseminated disease. We provide evidence that tumorigenesis in mice lacking p53 and p73 proceeds through mechanisms involving altered patterns of gene expression, defects in early T cell development, impaired apoptosis, and the ensuing accumulation of chromosomal aberrations. Collectively, our data imply that tumor suppressive properties of p73 are highly dependent on cellular context, wherein p73 plays a major role in T cell development and neoplasia

Microcephaly, sensorineural deafness and Currarino triad with duplication–deletion of distal 7q

Currarino syndrome (CS) is a peculiar form of caudal regression syndrome [also known as autosomal dominant sacral agenesis (OMIM no. 176450)] characterised by (1) partial absence of the sacrum with intact first sacral vertebra, (2) a pre-sacral mass and (3) anorectal anomalies (Currarino triad). We studied a 3-year-old girl with Currarino triad who had additional systemic features and performed array comparative genomic hybridisation to look for chromosomal abnormalities. This girl had the typical spectrum of anomalies of the CS including (a) partial sacral agenesis (hemisacrum with remnants of only sacral S1–S2 vertebrae and a residual S3 vertebral body) associated with complete coccygeal agenesis, (b) pre-intrasacral dermoid, (c) intra-dural lipoma, (d) ectopic anus and (e) tethered cord. She had, in addition, pre- and post-natal growth impairment (<3rd percentile), severe microcephaly (<−3 SD) with normal gyration pattern and lack of cortical thickening associated with a hypoplastic inferior vermis, facial dysmorphism, sensorineural deafness and decreased serum levels of IGF-1. A de novo 10.3-Mb duplication of 7q34–q35 and an 8.8-Mb deletion on 7q36 were identified in this patient. The Homeobox HLXB9 (CS) gene is contained within the deletion accounting for the CS phenotype including microcephaly. The spectrums of associated abnormalities in the IGF-1 deficiency growth retardation with sensorineural deafness and mental retardation syndrome (OMIM no. 608747) are discussed. To the best of our knowledge, this is the first reported case of a patient with distal 7q chromosomal imbalance and features of CS triad (including microcephaly) and the first documented case of a patient with normal gyration pattern microcephaly. The spectrum of associated anomalies in this newly recognised phenotype complex consists of growth failure, typical facial anomalies with additional (previously unreported) nervous system abnormalities (e.g. sensorineural deafness) and somatomedin C deficiency

Upregulation of Hemoglobin Expression by Oxidative Stress in Hepatocytes and Its Implication in Nonalcoholic Steatohepatitis

Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was designed to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. Analysis of microarray gene expression data revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopsies from NASH patients. Increased hemoglobin expression in NASH was validated by quantitative real time PCR. However, the expression of hematopoietic transcriptional factors and erythrocyte specific marker genes were not increased, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, increased HBA1 and HBB expression in HepG2 and HEK293 cells. Importantly, hemoglobin overexpression suppressed oxidative stress in HepG2 cells. We concluded that hemoglobin is expressed by hepatocytes and oxidative stress upregulates its expression. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage in NASH

METHOD Open Access Cancer progression modeling using static sample data

Abstract As molecular profiling data continue to accumulate, the design of integrative computational analyses that can provide insights into the dynamic aspects of cancer progression becomes feasible. Here, we present a novel computational method for the construction of cancer progression models based on the analysis of static tumor samples. We demonstrate the reliability of the method with simulated data, and describe the application to breast cancer data. Our findings support a linear, branching model for breast cancer progression. An interactive model facilitates the identification of key molecular events in the advance of disease to malignancy