RESUMEN
PURPOSE Differences in cellular levels of histone modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three histone modifications in pancreatic adenocarcinoma. METHODS Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for histone H3 lysine 4 dimethylation (H3K4me2), histone H3 lysine 9 dimethylation (H3K9me2), and histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures. Results Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival in univariate and multivariate models, and combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival (hazard ratio, 2.93; 95% CI, 1.78 to 4.82) in the University of California, Los Angeles cohort. In subgroup analyses, histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil, but not gemcitabine, in RTOG 9704. CONCLUSION Cellular levels of histone modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions, including the use of fluorouracil chemotherapy.
Asunto(s)
Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Epigénesis Genética , Histonas/metabolismo , Neoplasias Pancreáticas/patología , Adenocarcinoma/genética , Adenocarcinoma/terapia , Antineoplásicos/farmacología , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Resistencia a Antineoplásicos/genética , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacología , Humanos , Análisis Multivariante , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Supervivencia , Análisis de Matrices Tisulares , GemcitabinaRESUMEN
Dengue virus (DENV) nonstructural protein-1 (NS1) is a secreted glycoprotein that is absent from viral particles but accumulates in the supernatant and on the plasma membrane of cells during infection. Immune recognition of cell surface NS1 on endothelial cells has been hypothesized as a mechanism for the vascular leakage that occurs during severe DENV infection. However, it has remained unclear how NS1 becomes associated with the plasma membrane, as it contains no membrane-spanning sequence motif. Using flow cytometric and ELISA-based binding assays and mutant cell lines lacking selective glycosaminoglycans, we show that soluble NS1 binds back to the surface of uninfected cells primarily via interactions with heparan sulfate and chondroitin sulfate E. DENV NS1 binds directly to the surface of many types of epithelial and mesenchymal cells yet attaches poorly to most peripheral blood cells. Moreover, DENV NS1 preferentially binds to cultured human microvascular compared to aortic or umbilical cord vein endothelial cells. This binding specificity was confirmed in situ as DENV NS1 bound to lung and liver but not intestine or brain endothelium of mouse tissues. Differential binding of soluble NS1 by tissue endothelium and subsequent recognition by anti-NS1 antibodies could contribute to the selective vascular leakage syndrome that occurs during severe secondary DENV infection.
Asunto(s)
Sulfatos de Condroitina/metabolismo , Virus del Dengue/metabolismo , Heparitina Sulfato/metabolismo , Proteínas no Estructurales Virales/metabolismo , Animales , Línea Celular , Electroforesis en Gel de Poliacrilamida , Células Endoteliales/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Ratones , Microscopía Confocal , Proteínas no Estructurales Virales/inmunologíaRESUMEN
BACKGROUND: Chronic hepatitis C genotypes 3 and 1 are the two most common genotypes in Thailand. OBJECTIVE: Identify the pathologically different features between genotypes 3 and land to compare the fibrosis score of Knodell HAI and Ishak modified HAI. MATERIAL AND METHOD: The pathological features of 114 liver biopsies were evaluated. RESULTS: Steatosis was more commonly found in genotype 3 than in genotype 1 (97.1% vs. 77.8%, p = 0.001). Portal lymphoid follicles were commonly found, but bile duct damage was uncommon. The majority of portal tracts showed partial involvement. The majority of patients had Knodell fibrosis 1 and Ishak fibrosis 3. CONCLUSION: Steatosis is significantly more common in genotype 3, while other features do not show any differences. The portal tracts show partial involvement because inflammatory cells tend to aggregate and form lymphoid follicles. The most comparable fibrosis scores are Knodell fibrosis 1 and Ishak fibrosis 3.