Dysregulation of IFN System Can Lead to Poor Response to Pegylated Interferon and Ribavirin Therapy in Chronic Hepatitis C

Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)- α and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome

Pimasertib Versus Dacarbazine in Patients With UnresectableNRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2 ; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42–0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00–4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61–1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068

Dysregulation of IFN System Can Lead to Poor Response to Pegylated Interferon and Ribavirin Therapy in Chronic Hepatitis C

Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)- α and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome

Intradermal Electroporation of Naked Replicon RNA Elicits Strong Immune Responses

RNA-based vaccines represent an interesting immunization modality, but suffer from poor stability and a lack of efficient and clinically feasible delivery technologies. This study evaluates the immunogenic potential of naked in vitro transcribed Semliki Forest virus replicon RNA (RREP) delivered intradermally in combination with electroporation. Replicon-immunized mice showed a strong cellular and humoral response, contrary to mice immunized with regular mRNA. RREP-elicited induction of interferon-γ secreting CD8+ T cells and antibody responses were significantly increased by electroporation. CD8+ T cell responses remained substantial five weeks post vaccination, and antigen-specific CD8+ T cells with phenotypic characteristics of both effector and central memory cells were identified. The immune response during the contraction phase was further increased by a booster immunization, and the proportion of effector memory cells increased significantly. These results demonstrate that naked RREP delivered via intradermal electroporation constitute an immunogenic, safe and attractive alternative immunization strategy to DNA-based vaccines

ASIRI : an ocean–atmosphere initiative for Bay of Bengal

Author Posting. © American Meteorological Society, 2016. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 97 (2016): 1859–1884, doi:10.1175/BAMS-D-14-00197.1.Air–Sea Interactions in the Northern Indian Ocean (ASIRI) is an international research effort (2013–17) aimed at understanding and quantifying coupled atmosphere–ocean dynamics of the Bay of Bengal (BoB) with relevance to Indian Ocean monsoons. Working collaboratively, more than 20 research institutions are acquiring field observations coupled with operational and high-resolution models to address scientific issues that have stymied the monsoon predictability. ASIRI combines new and mature observational technologies to resolve submesoscale to regional-scale currents and hydrophysical fields. These data reveal BoB’s sharp frontal features, submesoscale variability, low-salinity lenses and filaments, and shallow mixed layers, with relatively weak turbulent mixing. Observed physical features include energetic high-frequency internal waves in the southern BoB, energetic mesoscale and submesoscale features including an intrathermocline eddy in the central BoB, and a high-resolution view of the exchange along the periphery of Sri Lanka, which includes the 100-km-wide East India Coastal Current (EICC) carrying low-salinity water out of the BoB and an adjacent, broad northward flow (∼300 km wide) that carries high-salinity water into BoB during the northeast monsoon. Atmospheric boundary layer (ABL) observations during the decaying phase of the Madden–Julian oscillation (MJO) permit the study of multiscale atmospheric processes associated with non-MJO phenomena and their impacts on the marine boundary layer. Underway analyses that integrate observations and numerical simulations shed light on how air–sea interactions control the ABL and upper-ocean processes.This work was sponsored by the U.S. Office of Naval Research (ONR) in an ONR Departmental Research Initiative (DRI), Air–Sea Interactions in Northern Indian Ocean (ASIRI), and in a Naval Research Laboratory project, Effects of Bay of Bengal Freshwater Flux on Indian Ocean Monsoon (EBOB). ASIRI–RAWI was funded under the NASCar DRI of the ONR. The Indian component of the program, Ocean Mixing and Monsoons (OMM), was supported by the Ministry of Earth Sciences of India.2017-04-2

Hepatitis C Virus (HCV) Evades NKG2D-Dependent NK Cell Responses through NS5A-Mediated Imbalance of Inflammatory Cytokines

Understanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by HCV to evade NK-cell mediated responses. We show that chronic HCV infection is associated with expression of ligands for NKG2D, the MHC class I-related Chain (MIC) molecules, on hepatocytes. However, NKG2D expression is downmodulated on circulating NK cells, and consequently NK cell-mediated cytotoxic capacity and interferon-γ production are impaired. Using an endotoxin-free recombinant NS5A protein, we show that NS5A stimulation of monocytes through Toll-like Receptor 4 (TLR4) promotes p38- and PI3 kinase-dependent IL-10 production, while inhibiting IL-12 production. In turn, IL-10 triggers secretion of TGFβ which downmodulates NKG2D expression on NK cells, leading to their impaired effector functions. Moreover, culture supernatants of HCV JFH1 replicating Huh-7.5.1 cells reproduce the effect of recombinant NS5A on NKG2D downmodulation. Exogenous IL-15 can antagonize the TGFβ effect and restore normal NKG2D expression on NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention

Risk Factors for Hepatitis C Infection Among Sexually Transmitted Disease-Infected, Inner City Obstetric Patients

Objective: To test the hypothesis that our inner city obstetric patients who have been infected with sexually transmitted diseases (STDs) will have a higher prevalence of hepatitis C virus infection than the general population and to identify specific risk factors and high-risk groups. Methods: All patients in our prenatal clinic (July 1997–April 1999) who tested positive for one or more STDs were asked to return for hepatitis C antibody testing. Medical charts of all patients who returned for hepatitis C testing were reviewed. Results: A total of 106 patients with STDs were tested for hepatitis C. Positive screening tests for anti-hepatitis C antibody were found in 6.6% (7/106) of the patients (95% CI = 2.7–13.1%). This frequency is significantly higher than the hepatitis C prevalence (1.8%) in the general United States population (p = 0.006). Multiple logistic regression analysis confirmed only older age (p = 0.016) and positive HIV status (p = 0.023) to be significant predictors of hepatitis C infection. Conclusions: Inner city STD-infected obstetric patients are at high risk for hepatitis C infection compared with the general population. Increasing age and HIV-positive status are risk factors which are significantly associated with hepatitis C infection

Investigating trophic ecology and dietary niche overlap among morphs of Lake Trout in Lake Superior

Four morphs of Lake Trout (Salvelinus namaycush, Walbaum 1792) have been identified in Lake Superior: leans, siscowets, humpers, and redfins. In this comprehensive study, the trophic ecology of Lake Trout morphs were characterized using stomach content, fatty acid, and stable isotope data. Stomach content results indicated a predominately piscivorous diet for leans, siscowets, and redfins, whereas humper diets were comprised of 50% fish and 50% Mysis by mass. Humper and siscowets were most similar in their dietary fatty acid profiles, whereas redfins had the most distinct dietary fatty acid profile. Results from stable isotope analysis revealed some among-morph differences along a pelagic-profundal consumption gradient (34S), but there were no significant differences in trophic position (15N) or basal carbon sources among morphs (13C). Using the recently developed nicheROVER software package, 4-dimensional trophic niches for each morph were quantified using stable isotope ratios (δ13C, δ15N, and δ34S) and fatty acid profiles (30 dietary fatty acids, condensed to one axis). Humpers had the largest 4-dimensional niche regions of all four morphs, and redfins had the smallest. Pairwise probability of overlap among morphs in these four-dimensional niche regions was determined to be < 50% in most cases. Overall, stomach content results indicate that humpers diets were more planktivorous than the other morphs, consistent with previous research. Results of the niche overlap analysis suggests some degree of generalist feeding for all morphs. Better characterization of seasonal variation in diet using tracers that reflect more recent feeding (e.g., fatty acids, stomach contents, and/or stable isotope analyses performed on tissues that turnover more quickly than muscle) are needed to further elucidate among-morph differences and similarities in diet and trophic ecology

Metabolites of Purine Nucleoside Phosphorylase (NP) in Serum Have the Potential to Delineate Pancreatic Adenocarcinoma

Pancreatic Adenocarcinoma (PDAC), the fourth highest cause of cancer related deaths in the United States, has the most aggressive presentation resulting in a very short median survival time for the affected patients. Early detection of PDAC is confounded by lack of specific markers that has motivated the use of high throughput molecular approaches to delineate potential biomarkers. To pursue identification of a distinct marker, this study profiled the secretory proteome in 16 PDAC, 2 carcinoma in situ (CIS) and 7 benign patients using label-free mass spectrometry coupled to 1D-SDS-PAGE and Strong Cation-Exchange Chromatography (SCX). A total of 431 proteins were detected of which 56 were found to be significantly elevated in PDAC. Included in this differential set were Parkinson disease autosomal recessive, early onset 7 (PARK 7) and Alpha Synuclein (aSyn), both of which are known to be pathognomonic to Parkinson's disease as well as metabolic enzymes like Purine Nucleoside Phosphorylase (NP) which has been exploited as therapeutic target in cancers. Tissue Microarray analysis confirmed higher expression of aSyn and NP in ductal epithelia of pancreatic tumors compared to benign ducts. Furthermore, extent of both aSyn and NP staining positively correlated with tumor stage and perineural invasion while their intensity of staining correlated with the existence of metastatic lesions in the PDAC tissues. From the biomarker perspective, NP protein levels were higher in PDAC sera and furthermore serum levels of its downstream metabolites guanosine and adenosine were able to distinguish PDAC from benign in an unsupervised hierarchical classification model. Overall, this study for the first time describes elevated levels of aSyn in PDAC as well as highlights the potential of evaluating NP protein expression and levels of its downstream metabolites to develop a multiplex panel for non-invasive detection of PDAC

Social Media, Gender and the Mediatisation of War: Exploring the German Armed Forces’ Visual Representation of the Afghanistan Operation on Facebook

Studies on the mediatisation of war point to attempts of governments to regulate the visual perspective of their involvements in armed conflict – the most notable example being the practice of ‘embedded reporting’ in Iraq and Afghanistan. This paper focuses on a different strategy of visual meaning-making, namely, the publication of images on social media by armed forces themselves. Specifically, we argue that the mediatisation of war literature could profit from an increased engagement with feminist research, both within Critical Security/Critical Military Studies and within Science and Technology Studies that highlight the close connection between masculinity, technology and control. The article examines the German military mission in Afghanistan as represented on the German armed forces’ official Facebook page. Germany constitutes an interesting, and largely neglected, case for the growing literature on the mediatisation of war: its strong antimilitarist political culture makes the representation of war particularly delicate. The paper examines specific representational patterns of Germany’s involvement in Afghanistan and discusses the implications which arise from what is placed inside the frame of visibility and what remains out of its view