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.
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.
It is unknown whether pathological reports of ischemia obtained from gastroduodenal biopsy suggests a diagnosis, prognosis or requires additional evaluation. The aim of this study was to review the natural history, clinical presentation, endoscopic appearance, treatments and major clinical outcomes of patients with gastroduodenal ischemia. Case series of fourteen patients with variable etiologies, seven patients with gastric and seven patients with duodenal origin were obtained from a search of our endoscopic pathologic database for reports of histological ischemia. The most common indication for upper endoscopy was upper gastrointestinal bleeding (71%). Half of the endoscopic lesions appeared very severe. There were six cases of rebleeding (43%) and four deaths (29%). CT scanning was frequently used (12 cases, 86%), but was diagnostic in only three cases. Patients with underlying vascular pathology have substantial 6-month mortality (29%).
e14051 Background: The role of BRAF gene mutation has been studied for its association with prognosis of colorectal cancer (CRC). The prevalence was reported 10-15% in Caucasian patients. However, there is no existing data in Thai patients. This study aimed to determine the prevalence of BRAF V600E mutation, association with various clinicopathological features and outcome in Thai sporadic CRC patients. Methods: DNA was extracted from randomly selected formalin-fixed paraffin-embedded tumor blocks of CRC patients with stage I-IV receiving surgery of the primary tumors at Siriraj Hospital between 2006 and 2007. BRAF V600E mutation was performed by two-round allele-specific PCR and analysis using high sensitivity DHPLC. The association between patient characteristics and BRAF status with overall survival (OS) and disease free survival (DFS) were explored by Kaplan-Meier estimation and log-rank test together with Cox’s proportional hazard regression. Results: BRAF V600E mutation was identified in 7 out of 188 patients (3.7%). Four patients were female. There were more likely to found in tumors on the left side (n=4) compared with right side (n=2) and rectum (n=1). All patients with mutation had stage I-III diseases; one with stage I and 3 with stage II and III each. Four had moderately differentiated tumors. Six patients had neither lymphovascular nor perineural invasion. Patients with mutation seemed to have better survival. In multivariate analysis, BRAF mutation did not have major prognostic value regarding DFS or OS. Conclusions: The prevalence of BRAF V600E mutation in Thai sporadic CRC was 3.7% which was lower than what reported in Caucasian patients. Further study with larger number of patients is warranted to determine whether BRAF mutation has significant prognostic value.
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