bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of Hepatitis C Virus-Specific CD8 Effector T-Cell Function with Antiviral Effect in Infectious Hepatitis C Virus Coculture Model
Authors: Ojiro Keisuke , Qu Xiaowang , Cho Hyosun , Park Jang-June , Vuidepot Annelise , Lissin Nikolai , Molloy Peter E. , Bennett Alan , Jakobsen Bent K. , Kaplan David E. , Riley James L. , Chang Kyong-Mi 
Published: March 2017

ABSTRACT

The antiviral effects of hepatitis C virus (HCV)-specific CD8 T cells have been shown in an HCV replicon system but not in an authentic infectious HCV cell culture (HCVcc) system. Here, we developed tools to examine the antigenicity of HCV-infected HLA-A2-positive Huh7.5 hepatoma cells (Huh7.5A2 cells) in activating HCV-specific CD8 T cells and the downstream antiviral effects. Infectious HCV epitope mutants encoding the well-defined genotype 1a-derived HLA-A2-restricted HCV NS3-1073 or NS5-2594 epitope were generated from a genotype 2a-derived HCV clone (Jc1Gluc2A) by site-directed mutagenesis. CD8 T-cell lines specific for NS3-1073 and NS5-2594 were expanded from HCV-seropositive persons by peptide stimulation
in vitro
or engineered from HCV-seronegative donor T cells by transduction of a lentiviral vector expressing HCV-specific T-cell receptors. HCV-specific CD8 T cells were cocultured with Huh7.5 cells that were pulsed with titrating doses of HCV epitope peptides or infected with HCV epitope mutants. HCV-specific CD8 T-cell activation (CD107a, gamma interferon, macrophage inflammatory protein 1β, tumor necrosis factor alpha) was dependent on the peptide concentrations and the relative percentages of HCV-infected Huh7.5A2 cells. HCV-infected Huh7.5A2 cells activated HCV-specific CD8 T cells at levels comparable to those achieved with 0.1 to 2 μM pulsed peptides, providing a novel estimate of the level at which endogenously processed HCV epitopes are presented on HCV-infected cells. While HCV-specific CD8 T-cell activation with cytolytic and antiviral effects was blunted by PD-L1 expression on HCV-infected Huh7.5A2 cells, resulting in the improved viability of Huh7.5A2 cells, PD-1 blockade reversed this effect, producing enhanced cytolytic elimination of HCV-infected Huh7.5A2 cells. Our findings, obtained using an infectious HCVcc system, show that the HCV-specific CD8 T-cell function is modulated by antigen expression levels, the percentage of HCV-infected cells, and the PD-1/PD-L1 pathways and has antiviral and cytotoxic effects.

IMPORTANCE
We developed several novel molecular and immunological tools to study the interactions among HCV, HCV-infected hepatocytes, and HCV-specific CD8 T cells. Using these tools, we show the level at which HCV-infected hepatoma cells present endogenously processed HCV epitopes to HCV-specific CD8 T cells with antiviral and cytotoxic effects. We also show the marked protective effect of PD-L1 expression on HCV-infected hepatoma cells against HCV-specific CD8 T cells.
Glycolysis, Glutaminolysis, and Fatty Acid Synthesis Are Required for Distinct Stages of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication
Authors: Sanchez Erica L. , Pulliam Thomas H. , Dimaio Terri A. , Thalhofer Angel B. , Delgado Tracie , Lagunoff Michael 
Published: March 2017

ABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). KSHV infection induces and requires multiple metabolic pathways, including the glycolysis, glutaminolysis, and fatty acid synthesis (FAS) pathways, for the survival of latently infected endothelial cells. To determine the metabolic requirements for productive KSHV infection, we induced lytic replication in the presence of inhibitors of different metabolic pathways. We found that glycolysis, glutaminolysis, and FAS are all required for maximal KSHV virus production and that these pathways appear to participate in virus production at different stages of the viral life cycle. Glycolysis and glutaminolysis, but not FAS, inhibit viral genome replication and, interestingly, are required for different early steps of lytic gene expression. Glycolysis is necessary for early gene transcription, while glutaminolysis is necessary for early gene translation but not transcription. Inhibition of FAS resulted in decreased production of extracellular virions but did not reduce intracellular genome levels or block intracellular virion production. However, in the presence of FAS inhibitors, the intracellular virions are noninfectious, indicating that FAS is required for virion assembly or maturation. KS tumors support both latent and lytic KSHV replication. Previous work has shown that multiple cellular metabolic pathways are required for latency, and we now show that these metabolic pathways are required for efficient lytic replication, providing novel therapeutic avenues for KS tumors.

IMPORTANCE
KSHV is the etiologic agent of Kaposi's sarcoma, the most common tumor of AIDS patients. KS spindle cells, the main tumor cells, all contain KSHV, mostly in the latent state, during which there is limited viral gene expression. However, a percentage of spindle cells support lytic replication and production of virus and these cells are thought to contribute to overall tumor formation. Our previous findings showed that latently infected cells are sensitive to inhibitors of cellular metabolic pathways, including glycolysis, glutaminolysis, and fatty acid synthesis. Here we found that these same inhibitors block the production of infectious virus from lytically infected cells, each at a different stage of viral replication. Therefore, inhibition of specific cellular metabolic pathways can both eliminate latently infected cells and block lytic replication, thereby inhibiting infection of new cells. Inhibition of metabolic pathways provides novel therapeutic approaches for KS tumors.
Identifying opportunities for nature engagement in cancer care practice and design: protocol for four-round modified electronic Delphi
Authors: Blaschke Sarah , O'Callaghan Clare C , Schofield Penelope 
Published: March 2017

IntroductionOpportunities to engage with nature have shown relevance in experiences of health and recovery of patients with cancer and are attracting interest in cancer care practice and design. Such healthcare innovations can widen the horizon of possible supportive care solutions but require deliberate and rigorous investigation to ensure responsible action is taken and wastage avoided. This protocol outlines a study designed to solicit knowledge from relevant experts drawn from a range of healthcare practitioners, management representatives, designers and researchers to explore levels of opinion consensus for determining opportunities for, and barriers to, providing helpful nature engagement in cancer care settings.Methods and analysisA 4-round modified electronic Delphi methodology will be used to conduct a structured, iterative feedback process for querying and synthesising expert opinion. Round 1 administers an open-ended questionnaire to a panel of selected, relevant experts who will consider the own recommendations of patients with cancer for nature engagement (drawn from a preceding investigation) before contributing salient issues (items) with relevance to the topic. Round 2 circulates anonymised summaries of responses back to the experts who verify and, if they wish, reconsider their own responses. Rounds 3 and 4 determine and rank experts' top 10 items using a 10-point Likert-type scale. Descriptive statistics (median and mean scores) will be calculated to indicate the items' relative importance. Levels of consensus will be explored with consensus defined as 75% agreement.Ethics and disseminationEthics approval for this study was obtained from the Institution's Human Research Ethics Committee (blinded for review). It is anticipated that the results will be published in peer-reviewed journals and presented in a variety of forums.
Effect of using cardiovascular risk scoring in routine risk assessment in primary prevention of cardiovascular disease: protocol for an overview of systematic reviews
Authors: Studziński Krzysztof , Tomasik Tomasz , Krzysztoń Janusz , Jóźwiak Jacek , Windak Adam 
Published: March 2017

IntroductionMajor clinical practice guidelines recommend assessing risk of cardiovascular disease (CVD) using absolute/global/total CVD risk scores. However, the effectiveness of using them in clinical practice, despite publication of numerous randomised controlled trials (RCTs), is still poorly understood. To summarise and analyse current knowledge in this field, we will carry out an overview of existing systematic reviews (SRs). The objective of this overview will be to assess the effect of using cardiovascular risk scoring in routine risk assessment in primary prevention of CVD compared with standard care.Methods and analysisWe will include SRs and meta-analyses which take into account RCTs and quasi-RCTs investigating the effect of using cardiovascular risk scoring in routine risk assessment in primary prevention of CVD. SRs will be retrieved from 4 bibliographical databases and reference lists of identified reviews. Additionally, the PROSPERO database will be searched for unpublished, ongoing or recently completed SRs. 2 reviewers will assess the SRs independently for eligibility and bias. The data will be extracted to a special form. Any disagreement will be resolved by discussion. In case of lack of consensus, a third author will arbitrate. The overview of SRs will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement.Ethics and disseminationEthics approval is not required for overview of SRs. We will summarise evidence concerning whether use of the absolute/global/total CVD risk scoring tools in primary prevention of CVD is effective and supported with scientific data or not. If we face unsatisfactory confirmation, we will highlight a need for further research and advice on how to plan such a study. We will submit the results of our study for peer-review publication in a journal indexed in the international bibliographic database of biomedical information.
Reduced muscular fatigue after a 12-week leucine-rich amino acid supplementation combined with moderate training in elderly: a randomised, placebo-controlled, double-blind trial
Authors: Reule Claudia A , Scholz Claudia , Schoen Christiane , Brown Niklas , Siepelmeyer Anne , Alt Wilfried W 
Published: March 2017

BackgroundAge-related muscle loss is characterised by a progressing decrease in muscle mass, strength and function. Besides resistance training and physical activity, appropriate nutrition that is rich in protein, especially branched-chain amino acids, is very important to support training effects and positively influence the protein synthesis to degradation ratio.AimThe purpose of this study was to evaluate the effect of a 12-week leucine-rich amino acid supplementation in combination with moderate training.MethodsForty-eight healthy subjects exercised for 30 min three times per week and received either a leucine-rich amino acid supplementation or a placebo. Before and after supplementation, volunteers performed an exhaustive eccentric exercise protocol. Maximal concentric strength, muscle soreness, creatine kinase (CK), type II collagen collagenase cleavage neoepitope (C2C), C propeptide of type II procollagen (CP2) and safety assessments were performed before exercise and after 3, 24, 48 and 72 hours.ResultsThe supplementation with leucine resulted in reduced loss of strength at 0 and 3 hours after downhill walking compared with the placebo (p=0.0439). The reduction of C2C/CP2 ratio deflection was significantly increased (p=0.038) due to leucine compared with the placebo. The same tendency could be observed for the recovery phase. No significant supplement effects for muscle soreness and CK could be observed.ConclusionThe principle findings show that leucine-rich amino acid supplementation can counteract the negative effects of eccentric exercise. The treatment resulted in a reduction of exercise-induced strength loss.
Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour necrosis factor inhibitors
Authors: Strand Vibeke , Reaney Matthew , Chen Chieh-I , Proudfoot Clare W J , Guillonneau Sophie , Bauer Deborah , Mangan Erin , Graham Neil M H , van Hoogstraten Hubert , Lin Yong , Pacheco-Tena César , Fleischmann Roy 
Published: March 2017

ObjectiveTo evaluate effects of the anti-interleukin-6 receptor monoclonal antibody sarilumab administered with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) on patient-reported outcomes (PROs) in the TARGET trial in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitors (TNF-IR).Methods546 patients (81.9% female, mean age 52.9 years) were randomised to placebo, sarilumab 150 or 200 mg subcutaneously every 2 weeks + csDMARDs. PROs included patient global assessment (PtGA); pain and morning stiffness visual analogue scales; Health Assessment Questionnaire Disability Index (HAQ-DI); Short Form-36 Health Survey (SF-36); FACIT-Fatigue (FACIT-F); Work Productivity Survey-Rheumatoid Arthritis (WPS-RA) and Rheumatoid Arthritis Impact of Disease (RAID). Changes from baseline at weeks 12 and 24 were analysed using a mixed model for repeated measures; post hoc analyses included percentages of patients reporting improvements ≥ minimum clinically important differences (MCID) and scores ≥ normative values.ResultsSarilumab + csDMARDs doses resulted in improvements from baseline at week 12 vs placebo + csDMARDs in PtGA, pain, HAQ-DI, SF-36 and FACIT-F that were maintained at week 24. Sarilumab improved morning stiffness and reduced the impact of RA on work, family, social/leisure activities participation (WPS-RA) and on patients' lives (RAID). Percentages of patients reporting improvements ≥MCID and ≥ normative scores were greater with sarilumab than placebo.ConclusionsIn patients with TNF-IR RA, 150 and 200 mg sarilumab + csDMARDs resulted in clinically meaningful patient-reported benefits on pain, fatigue, function, participation and health status at 12 and 24 weeks that exceeded placebo + csDMARDs, and were consistent with the clinical profile previously reported.Trial registration numberNCT01709578; Results.
Measurement of the distribution of ventilation-perfusion ratios in the human lung with proton MRI: comparison with the multiple inert-gas elimination technique
Authors: Sá Rui Carlos , Henderson A. Cortney , Simonson Tatum , Arai Tatsuya J. , Wagner Harrieth , Theilmann Rebecca J. , Wagner Peter D. , Prisk G. Kim , Hopkins Susan R. 
Published: March 2017

We have developed a novel functional proton magnetic resonance imaging (MRI) technique to measure regional ventilation-perfusion (V̇A/Q̇) ratio in the lung. We conducted a comparison study of this technique in healthy subjects ( n = 7, age = 42 ± 16 yr, Forced expiratory volume in 1 s = 94% predicted), by comparing data measured using MRI to that obtained from the multiple inert gas elimination technique (MIGET). Regional ventilation measured in a sagittal lung slice using Specific Ventilation Imaging was combined with proton density measured using a fast gradient-echo sequence to calculate regional alveolar ventilation, registered with perfusion images acquired using arterial spin labeling, and divided on a voxel-by-voxel basis to obtain regional V̇A/Q̇ ratio. LogSDV̇ and LogSDQ̇, measures of heterogeneity derived from the standard deviation (log scale) of the ventilation and perfusion vs. V̇A/Q̇ ratio histograms respectively, were calculated. On a separate day, subjects underwent study with MIGET and LogSDV̇ and LogSDQ̇ were calculated from MIGET data using the 50-compartment model. MIGET LogSDV̇ and LogSDQ̇ were normal in all subjects. LogSDQ̇ was highly correlated between MRI and MIGET (R = 0.89, P = 0.007); the intercept was not significantly different from zero (−0.062, P = 0.65) and the slope did not significantly differ from identity (1.29, P = 0.34). MIGET and MRI measures of LogSDV̇ were well correlated (R = 0.83, P = 0.02); the intercept differed from zero (0.20, P = 0.04) and the slope deviated from the line of identity (0.52, P = 0.01). We conclude that in normal subjects, there is a reasonable agreement between MIGET measures of heterogeneity and those from proton MRI measured in a single slice of lung. NEW & NOTEWORTHY We report a comparison of a new proton MRI technique to measure regional V̇A/Q̇ ratio against the multiple inert gas elimination technique (MIGET). The study reports good relationships between measures of heterogeneity derived from MIGET and those derived from MRI. Although currently limited to a single slice acquisition, these data suggest that single sagittal slice measures of V̇A/Q̇ ratio provide an adequate means to assess heterogeneity in the normal lung.
Impaired sweating responses to a passive whole body heat stress in individuals with multiple sclerosis
Authors: Allen Dustin R. , Huang Mu , Parupia Iqra M. , Dubelko Ariana R. , Frohman Elliot M. , Davis Scott L. 
Published: March 2017

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS), disrupting autonomic function. The aim of this study was to test the hypothesis that individuals with MS have blunted control of thermoregulatory reflex increases in sweat rate (SR) and cutaneous vasodilation compared with controls during a passive whole body heat stress (WBH). Eighteen individuals with relapsing-remitting MS and 18 healthy controls (Con) participated in the study. Core temperature (Tcore), skin temperature, heart rate, arterial blood pressure (10-min intervals), skin blood flow (laser-Doppler flux, LDF), and SR were continuously measured during normothermic baseline (34°C water perfusing a tube-lined suit) and WBH (increased Tcore 0.8°C via 48°C water perfusing the suit). Following WBH, local heaters were warmed to 42°C, inducing peak cutaneous vasodilation at the site of LDF collection. Cutaneous vascular conductance (CVC) was calculated as the ratio of LDF to mean arterial pressure and expressed as a percentage of peak achieved during local heating. Individuals with MS had attenuated SR responses to WBH (ΔSR from baseline: Con, 0.65 ± 0.27; MS, 0.42 ± 0.17 mg·cm−2·min−1, P = 0.003), whereas Δ%CVC42C from baseline was similar between groups (Con, 42 ± 16%; MS, 38 ± 12%, P = 0.39). SR responses were blunted as a function of Tcore in MS (interaction: group × Tcore, P = 0.03), of which differences were evident at ΔTcore 0.7°C and 0.8°C ( P < 0.05). No interaction was observed in Δ%CVC42C. Taken together, the findings show MS blunts sweating responses, whereas control of the cutaneous vasculature is preserved, in response to WBH. NEW & NOTEWORTHY This study is the first to assess the reflex control of the thermoregulatory system in individuals living with multiple sclerosis (MS). The novel findings are twofold. First, attenuated increases in sweat rate in subjects with MS compared with healthy controls were observed in response to a moderate increase (0.8°C) in core temperature via passive whole body heat stress. Second, it appears the reflex control of the cutaneous vasculature is preserved in MS.
No Decreased Risk of Gastrointestinal Cancers in Users of Metformin in The Netherlands; A Time-Varying Analysis of Metformin Exposure
Authors: de Jong Roy G. , Burden Andrea M. , de Kort Sander , van Herk-Sukel Myrthe P. , Vissers Pauline A. , Janssen Paddy K. , Haak Harm R. , Masclee Ad A. , de Vries Frank , Janssen-Heijnen Maryska L. 
Published: March 2017

Abstract
Previous studies on metformin use and gastrointestinal (GI) cancer risk have yielded inconclusive results on metformin's chemoprotective effects. We aimed to evaluate GI cancer risk in users of metformin in The Netherlands using a time-varying approach in a large population-based database. A cohort study was performed using the NCR-PHARMO database. Patients using ≥1 non-insulin antidiabetic drug (NIAD) during 1998 to 2011 were included (N = 57,621). Exposure to NIADs was modeled time-varyingly. Cox regression analysis estimated HRs of GI cancers in current metformin users versus current users of other NIADs. Covariables included age, sex, drugs known to impact cancer risk, history of hospitalization, and starting year of follow-up. A sensitivity analysis was performed, applying a new-user design. Current use of metformin was not associated with a decreased risk of GI cancer [HR, 0.97; 95% confidence interval (CI), 0.82–1.15] or specific GI cancer sites. The sensitivity analysis yielded comparable results. No decreasing trends were observed with increasing cumulative dose of metformin [HR 1.05, 95% CI, 0.85–1.28; HR 0.89, 95% CI, 0.73–1.10; HR 0.96, 95% CI, 0.77–1.19 for dose tertiles low (&lt;405 g), medium (405–999 g), and high (≥999 g)]. In contrast, an increased risk of pancreatic cancer was found in current users of metformin plus insulin (HR, 4.90; 95% CI, 2.64–9.10). In conclusion, no decreased risk of GI cancer was found in current metformin users compared with current users of other NIADs. Variations in the exposure definition of metformin use may be one of the explanations of previously found reduced cancer risks in metformin users. Cancer Prev Res; 10(5); 290–7. ©2017 AACR.
Observations on a queenless colony of Plebeia saiqui (Friese) (Hymenoptera, Apidae, Meliponinae)
Authors: Fonseca Vera Lucia Imperatriz , Oliveira Maria Augusta Cabral de 
Published: March 2017

O presente trabalho descreve observações feitas em uma colônia órfã de Plebeia saqui (Friese ), com relação a construção, ao aprovisionamento, a oviposiçãoe à operculação das células. Durante três meses as operárias apresentaram umaconstrução de células regular, que poderia ser resultante do grande número deabelhas existentes na colmeia, ou uma característica do gênero.Por volta do 3.° mês os processos de aprovisionamento e oviposição modificaram-se e houve o aparecimento de operárias que se comportaram como rainha.Foram observados machos na colônia, filhos das operárias, que executavam trabalhos com cerume e desidratavam nectar.São descritas outra s observações referentes a reutilização de células vazias, oofagia, forma e tamanho de favos.
Parathyroid gland of the frog Rana tigrina
Authors: Srivastav Ajai K. , Rani Ladly 
Published: March 2017

A glândula paratiróide de Rana tigrina é composta por células epiteliais densamente agrupadas que são distribuídas em círculos. A diferença na densidade das células paratiroidais já foi registrada. As células no centro da glândula são compactamente agrupadas possuindo núcleos alongados e citoplasma denso. As células da periferia da glândula são dsitribuídas frouxamente, tendo citoplasma claramente corado e núcleos esféricos grandes.