Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma

Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA)

Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma

Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA)

Altered expression and activation of signal transducers and activators of transcription (STATs) in hepatitis C virus infection: in vivo and in vitro studies

BACKGROUND: Signal transducers and activators of transcription (STATs) play a critical role in antiviral defence. STAT3 is also important in cell protection against inflammatory damage. STAT proteins are activated by interferons and by hepatoprotective cytokines of the interleukin 6 superfamily, including cardiotrophin 1. METHODS: We analysed the status of STATs in hepatitis C virus (HCV) infected livers and the relationship between expression and activation of STATs and HCV replication in Huh7 cells transfected with HCV genomic replicon. RESULTS: STAT3alpha expression was reduced in HCV infected livers showing an inverse correlation with serum alanine aminotransferase. In patients with HCV infection, nuclear staining for phosphorylated STAT3 was faint in parenchymal cells (although conspicuous in infiltrating leucocytes), in contrast with strong nuclear staining in hepatocytes from control livers. Expression and activation of STAT1 (a factor activated by both interferon (IFN)-alpha and IFN-gamma) were increased in HCV infected livers, particularly in those with high inflammatory activity. Conversely, phosphorylated STAT2 (a factor selectively activated by IFN-alpha) was undetectable in livers with HCV infection, a finding that was associated with marked downregulation of the two functional subunits of the IFN-alpha receptor. HCV replication in Huh7 cells caused STAT3alpha downregulation and blocked STAT3 phosphorylation by either IFN-alpha or cardiotrophin 1. HCV replication in Huh7 cells also inhibited STAT1 and STAT2 activation by IFN-alpha while there was no impairment of STAT1 phosphorylation by the proinflammatory cytokine IFN-gamma. CONCLUSIONS: STAT3 is downregulated in HCV infected livers and in Huh7 cells bearing the full length HCV replicon. HCV replication is associated with impaired Jak-STAT signalling by antiviral and cytoprotective cytokines. These effects may favour viral replication while facilitating the progression of liver diseas

Methylthioadenosine phosphorylase gene expression is impaired in human liver cirrhosis and hepatocarcinoma

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine and adenine salvage pathways. In mammals, the liver plays a central role in methionine metabolism, and this essential function is lost in the progression from liver cirrhosis to hepatocarcinoma. Deficient MTAP gene expression has been recognized in many transformed cell lines and tissues. In the present work, we have studied the expression of MTAP in human and experimental liver cirrhosis and hepatocarcinoma. We observe that MTAP gene expression is significantly reduced in human hepatocarcinoma tissues and cell lines. Interestingly, MTAP gene expression was also impaired in the liver of CCl4-cirrhotic rats and cirrhotic patients. We provide evidence indicating that epigenetic mechanisms, involving DNA methylation and histone deacetylation, may play a role in the silencing of MTAP gene expression in hepatocarcinoma. Given the recently proposed tumor suppressor activity of MTAP, our observations can be relevant to the elucidation of the molecular mechanisms of multistep hepatocarcinogenesis

The Progress Test of the European Hematology Association: A New Tool for Continuous Learning.

info:eu-repo/semantics/publishedVersio

Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma.

Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA)

Risk of gastric cancer in the environs of industrial facilities in the MCC-Spain study

Background: Gastric cancer is the fifth most frequent tumor worldwide. In Spain, it presents a large geographic variability in incidence, suggesting a possible role of environmental factors in its etiology. Therefore, epidemiologic research focused on environmental exposures is necessary. Objectives: To assess the association between risk of gastric cancer (by histological type and tumor site) and residential proximity to industrial installations, according to categories of industrial groups and specific pollutants released, in the context of a population-based multicase-control study of incident cancer conducted in Spain (MCC-Spain). Methods: In this study, 2664 controls and 137 gastric cancer cases from 9 provinces, frequency matched by province of residence, age, and sex were included. Distances from the individuals' residences to the 106 industries located in the study areas were computed. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1 km to 3 km) to industries, adjusting for matching variables and potential confounders. Results: Overall, no excess risk of gastric cancer was observed in people living close to the industrial installations, with ORs ranging from 0.73 (at ≤2.5 km) to 0.93 (at ≤1.5 km). However, by industrial sector, excess risks (OR; 95%CI) were found near organic chemical industry (3.51; 1.42-8.69 at ≤2 km), inorganic chemical industry (3.33; 1.12-9.85 at ≤2 km), food/beverage sector (2.48; 1.12-5.50 at ≤2 km), and surface treatment using organic solvents (3.59; 1.40-9.22 at ≤3 km). By specific pollutant, a statistically significant excess risk (OR; 95%CI) was found near (≤3 km) industries releasing nonylphenol (6.43; 2.30-17.97) and antimony (4.82; 1.94-12.01). Conclusions: The results suggest no association between risk of gastric cancer and living in the proximity to the industrial facilities as a whole. However, a few associations were detected near some industrial sectors and installations releasing specific pollutants.The authors thank all those who took part in this study by providing questionnaire data. This study was funded by: Scientific Foundation of the Spanish Association Against Cancer (Fundación Científica de la Asociación Española Contra el Cáncer (AECC) e grants EVP-1178/14 and GCTRA18022MORE); “Acción Transversal del Cáncer”, approved on the Spanish Ministry Council on October 11, 2007; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP); Spain’s Health Research Fund (Fondo de Investigación Sanitaria - FIS 12/01416); Carlos III Institute of Health (ISCIII) grants, co-funded by ERDF fundsea way to build Europee (grants PI08/0533, PI08/1359, PI08/1770, PS09/00773, PS09/01286, PS09/01662, PS09/01903, PS09/02078, PI11/00226, PI11/01403, PI11/01810, PI11/01889, PI11/02213, PI12/00150, PI12/00265, PI12/00488, PI12/00715, PI12/01270, PI14/00613, PI14/01219, PI15/00069, PI15/00914, PI15/01032, PI17-00092, PI17CIII/00034); the Fundación Marqués de Valdecilla (API 10/09); the Junta de Castilla y León (LE22A10-2); the Consejería de Salud of the Junta de Andalucía (PI-0571-2009, PI-0306-2011, salud201200057018tra); the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10); the Recercaixa (2010ACUP 00310); the European Commission grants FOOD-CT-2006-036224-HIWATE; the Catalan Government-Agency for Management of University and Research Grants (AGAUR) grants 2017SGR723 and 2014SGR850; the Catalan Government DURSI grant 2014SGR647; the Fundación Caja de Ahorros de Asturias; and the University of Oviedo. ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.N

Effect of killer immunoglobulin-like receptors in the response to combined treatment in patients with chronic hepatitis C virus infection

Killer immunoglobulin-like receptors (KIRs) are related to the activation and inhibition of NK cells and may play an important role in the innate response against infection with viruses such as hepatitis C virus (HCV). We examined whether the different combinations of KIRs with their HLA class I ligands influenced the response to combined treatment (pegylated alpha interferon and ribavirin) of patients infected by HCV. A total of 186 consecutive patients diagnosed with chronic HCV infection were analyzed. Seventy-seven patients exhibited HCV RNA levels at 6 months posttreatment and were called nonresponders (NR), while 109 cleared viral RNA and were named sustained viral responders (SVR). Patients were typed for HLA-B, HLA-Cw, KIR genes, and HCV genotype. In our study, the frequency of the KIR2DL2 allele was significantly increased in NR (P < 0.001; odds ratio [OR] = 1.95), as was the frequency of the KIR2DL2/KIR2DL2 genotype (P < 0.005; OR = 2.52). In contrast, the frequencies of the KIR2DL3 genotype (P < 0.001) and KIR2DL3/KIR2DL3 genotype (P < 0.05; OR = 0.54) were significantly increased in the SVR. Different combinations of KIR2DL2 and KIR2DL3 alleles with their ligands were analyzed. The frequency of the KIR2DL2/KIR2DL2-HLA-C1C2 genotype was significantly increased in the NR (P < 0.01; OR = 3.15). Additionally, we found a higher frequency of the KIR2DL3/KIR2DL3-HLA-C1C1 genotype in the SVR group (P < 0.05; OR = 0.33). These results were not affected by the HCV genotype. In conclusion, patients who carried the KIR2DL2/KIR2DL2-HLA-C1C2 genotype were less prone to respond to treatment. However, the KIR2DL3/KIR2DL3-HLA-C1C1 genotype clearly correlated with a satisfactory response to treatment, defined by the clearance of HCV RNA

Family Firms and Firm Performance: Evidence from Japan

Corrigendum: Nature Structural and Molecular Biology 16 (12), 1331 (2009) doi:10.1038/nsmb1209-1331bInternational audienceThioredoxins (Trxs) are oxidoreductase enzymes, present in all organisms, that catalyze the reduction of disulfide bonds in proteins. By applying a calibrated force to a substrate disulfide, the chemical mechanisms of Trx catalysis can be examined in detail at the single-molecule level. Here we use single-molecule force-clamp spectroscopy to explore the chemical evolution of Trx catalysis by probing the chemistry of eight different Trx enzymes. All Trxs show a characteristic Michaelis-Menten mechanism that is detected when the disulfide bond is stretched at low forces, but at high forces, two different chemical behaviors distinguish bacterial-origin from eukaryotic-origin Trxs. Eukaryotic-origin Trxs reduce disulfide bonds through a single-electron transfer reaction (SET), whereas bacterial-origin Trxs show both nucleophilic substitution (SN2) and SET reactions. A computational analysis of Trx structures identifies the evolution of the binding groove as an important factor controlling the chemistry of Trx catalysis