bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-18 Is Critical for Mucosa-Associated Invariant T Cell Gamma Interferon Responses to Francisella SpeciesIn Vitrobut NotIn Vivo
Authors: Jesteadt Eric , Zhang Irma , Yu Huifeng , Meierovics Anda , Chua Yankelevich Wei-Jen , Cowley Siobhan 
Published: March 2018

ABSTRACTMucosa-associated invariant T (MAIT) cells are a subset of innate T cells that express a semi-invariant Vα chain paired with limited Vβ chains. MAIT cells are activated by riboflavin metabolite derivatives presented by the nonpolymorphic major histocompatibility complex class I (MHC-I)-like molecule MR1. The precise mechanisms required to activate MAIT cells are an area of intense interest. Here we used two closely related intracellular pathogens with distinct inflammasome activation phenotypes to probe the role of innate cytokines in MAIT cell activation. Using anin vitroassay containing transgenic murine MAIT cells, we show that macrophages infected withFrancisella novicida, a strong inflammasome activator, released high levels of interleukin-18 (IL-18) and stimulated high levels of MAIT cell gamma interferon (IFN-γ) through a partially MR1-independent pathway. In contrast, macrophages infected withFrancisella tularensislive vaccine strain (LVS), a weak inflammasome activator, generated little IL-18 and stimulated low MAIT cell IFN-γ through an MR1-dependent pathway. By manipulating the quantities of IL-18 in these cultures, we show that the IL-18 concentration is sufficient to influence the magnitude of MAIT cell IFN-γ production. Correspondingly, infected IL-18-deficient macrophages failed to induce substantial MAIT cell IFN-γ. In contrast, we found that MAIT cell IFN-γ production in the lungs of IL-18-deficient mice was not significantly different from that in WT mice duringF. tularensisLVS pulmonary infection. Overall, we demonstrate that while IL-18 is essential for the MAIT cell IFN-γ responsein vitro, it is not essential for MAIT cell IFN-γ production duringin vivoLVS pulmonary infection, suggesting that additional signals can drive MAIT cell IFN-γ productionin vivo.
Caspase-Dependent Suppression of Type I Interferon Signaling Promotes Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication
Authors: Tabtieng Tate , Degterev Alexei , Gaglia Marta M. 
Published: March 2018

ABSTRACT
An important component of lytic infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is the ability of the virus to evade the innate immune response, specifically type I interferon (IFN) responses that are triggered by recognition of viral nucleic acids. Inhibition of type I IFN responses by the virus promotes viral replication. Here, we report that KSHV uses a caspase-dependent mechanism to block type I IFN, in particular IFN-β, responses during lytic infection. Inhibition of caspases during KSHV reactivation resulted in increased TBK1/IKKε-dependent phosphorylation of IRF3 as well as elevated levels of IFN-β transcription and secretion. The increased secretion of IFN-β upon caspase inhibition reduced viral gene expression, viral DNA replication, and virus production. Blocking IFN-β production or signaling restored viral replication. Overall, our results show that caspase-mediated regulation of pathogen sensing machinery is an important mechanism exploited by KSHV to evade innate immune responses.

IMPORTANCE
KSHV is the causative agent of Kaposi's sarcoma (KS), an AIDS-defining tumor that is one of the most common causes of cancer death in sub-Saharan Africa. In this study, we examined the role of a set of cellular proteases, called caspases, in the regulation of immune responses during KSHV infection. We demonstrate that caspases prevent the induction and secretion of the antiviral factor IFN-β during replicative KSHV infection. The reduced IFN-β production allows for high viral gene expression and viral replication. Therefore, caspases are important for maintaining KSHV replication. Overall, our results suggest that KSHV utilizes caspases to evade innate immune responses, and that inhibiting caspases could boost the innate immune response to this pathogen and potentially be a new antiviral strategy.
Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection
Authors: Brown Judy J. , Short Sarah P. , Stencel-Baerenwald Jennifer , Urbanek Kelly , Pruijssers Andrea J. , McAllister Nicole , Ikizler Mine , Taylor Gwen , Aravamudhan Pavithra , Khomandiak Solomiia , Jabri Bana , Williams Christopher S. , Dermody Terence S. 
Published: March 2018

ABSTRACT
Several viruses induce intestinal epithelial cell death during enteric infection. However, it is unclear whether proapoptotic capacity promotes or inhibits replication in this tissue. We infected mice with two reovirus strains that infect the intestine but differ in the capacity to alter immunological tolerance to new food antigen. Infection with reovirus strain T1L, which induces an inflammatory immune response to fed antigen, is prolonged in the intestine, whereas T3D-RV, which does not induce this response, is rapidly cleared from the intestine. Compared with T1L, T3D-RV infection triggered apoptosis of intestinal epithelial cells and subsequent sloughing of dead cells into the intestinal lumen. We conclude that the infection advantage of T1L derives from its capacity to subvert host restriction by epithelial cell apoptosis, providing a possible mechanism by which T1L enhances inflammatory signals during antigen feeding. Using a panel of T1L × T3D-RV reassortant viruses, we identified the viral M1 and M2 gene segments as determinants of reovirus-induced apoptosis in the intestine. Expression of the T1L M1 and M2 genes in a T3D-RV background was sufficient to limit epithelial cell apoptosis and enhance viral infection to levels displayed by T1L. These findings define additional reovirus gene segments required for enteric infection of mice and illuminate the antiviral effect of intestinal epithelial cell apoptosis in limiting enteric viral infection. Viral strain-specific differences in the capacity to infect the intestine may be useful in identifying viruses capable of ameliorating tolerance to fed antigen in autoimmune conditions like celiac disease.

IMPORTANCE
Acute viral infections are thought to be cleared by the host with few lasting consequences. However, there may be much broader and long-lasting effects of viruses on immune homeostasis. Infection with reovirus, a common, nonpathogenic virus, triggers inflammation against innocuous food antigens, implicating this virus in the development of celiac disease, an autoimmune intestinal disorder triggered by exposure to dietary gluten. Using two reovirus strains that differ in the capacity to abrogate oral tolerance, we found that strain-specific differences in the capacity to replicate in the intestine inversely correlate with the capacity to induce apoptotic death of intestinal epithelial cells, providing a host-mediated process to restrict intestinal infection. This work contributes new knowledge about virus-host interactions in the intestine and establishes a foundation for future studies to define mechanisms by which viruses break oral tolerance in celiac disease.
p16INK4a overexpression as a predictor of survival in ocular surface squamous neoplasia
Authors: Chauhan Sheetal , Sen Seema , Sharma Anjana , Kashyap Seema , Tandon Radhika , Bajaj Mandeep S , Pushker Neelam , Vanathi Murugesan , Chauhan Shyam S 
Published: March 2018

AimsTo evaluate the expression and methylation status of the p16INK4a gene in early and advanced American Joint Committee on Cancer (AJCC) stages of ocular surface squamous neoplasia (OSSN) and to correlate its association with clinicopathological features and survival.MethodsSixty-four (35 early and 29 advanced AJCC stage) patients with OSSN formed part of this study and were followed up for 36–58 (mean 48±3.6) months. Immunohistochemical expression of the p16INK4a protein and methylation status of the p16INK4a gene were determined by methylation-specific PCR.ResultsOverexpression of p16INK4a was observed in 18/64 (28%) and hypermethylation in 35/64 (54.7%) OSSN cases. A gradual significant increase in the expression of p16INK4a (0%–48%, P=0.03) and decrease in its methylation (75%–16%, P=0.001) was observed with disease progression from early to advanced tumour stage. Overexpression of p16INK4a was significantly associated with palpebral location and diffuse growth pattern in both early and advanced T stage. Hypermethylation of p16INK4a was significantly associated with history of longer sunlight exposure in both early and advanced T stage of OSSN cases. In advanced T stage, p16INK4a overexpression was associated with reduced disease-free survival (P=0.02) and poor prognosis (HR, 0.2; P=0.03).ConclusionsOSSN patients presenting at an advanced AJCC stage with p16INK4a overexpression may require more aggressive treatment. Epigenetic inactivation of the p16INK4a gene due to sunlight exposure could be responsible for pathogenesis of OSSN.
Human rights versus societal norms: a mixed methods study among healthcare providers on social stigma related to adolescent abortion and contraceptive use in Kisumu, Kenya
Authors: Håkansson Miranda , Oguttu Monica , Gemzell-Danielsson Kristina , Makenzius Marlene 
Published: March 2018

IntroductionAdolescent pregnancy represents a serious public health issue in sub-Saharan Africa, and stigmatising attitudes are contributing factors. This study investigates stigmatising attitudes related to adolescent pregnancy, abortion and contraceptive use among healthcare providers working with postabortion care (PAC) in a low-resource setting in Kenya.MethodsA mixed methods approach in a convergent design was utilised to capture attitudes related to abortion and contraceptive use among 86 (f=62; m=19) PAC providers in Kisumu, Kenya. Two Likert-scale questionnaires were used: the 18-item Stigmatising Attitudes, Beliefs and Actions Scale (SABAS) and the 7-item Contraceptive Use Stigma Scale (CUSS). 74 PAC providers responded to the SABAS, 44 to the CUSS and 12 participated in two focus group discussions. Descriptive statistics, psychometric tests of instruments and qualitative content analysis were conducted and reported in accordance with Consolidated Criteria for Reporting Qualitative Research.ResultsCronbach’s α coefficients for the total instrument was 0.88 (SABAS) and 0.84 (CUSS). The majority, 92% (68/74) agreed that a woman who has had an abortion should be treated equally to everyone else, 27% (20/74) considered abortion a sin and 30% (22/74) believed she will make abortion a habit. Contraceptive use among adolescent women was associated with promiscuity (39%; 17/44), hence contraceptives should only be available to married women (36%; 16/44), and 20% (9/44) believed that contraceptive use causes infertility. The providers encouraged women’s autonomy and their rights to sexual and reproductive health; however, unclear regulations reinforce religious and cultural beliefs, which hampers implementation of evidence-based contraceptive counselling.ConclusionStigmatising attitudes towards young women in need of abortion and contraception is common among PAC providers. Their work is characterised by a conflict between human rights and societal norms, thus highlighting the need for interventions targeting PAC providers to reduce stigma and misconceptions related to abortion and contraception among adolescent women.
Relationship between stress-related psychosocial work factors and suboptimal health among Chinese medical staff: a cross-sectional study
Authors: Liang Ying-Zhi , Chu Xi , Meng Shi-Jiao , Zhang Jie , Wu Li-Juan , Yan Yu-Xiang 
Published: March 2018

ObjectivesThe study aimed to develop and validate a model to measure psychosocial factors at work among medical staff in China based on confirmatory factor analysis (CFA). The second aim of the current study was to clarify the association between stress-related psychosocial work factors and suboptimal health status.DesignThe cross-sectional study was conducted using clustered sampling method.SettingXuanwu Hospital, a 3A grade hospital in Beijing.ParticipantsNine hundred and fourteen medical staff aged over 40 years were sampled. Seven hundred and ninety-seven valid questionnaires were collected and used for further analyses. The sample included 94% of the Han population.Main outcome measuresThe Copenhagen Psychosocial Questionnaire (COPSOQ) and the Suboptimal Health Status Questionnaires-25 were used to assess the psychosocial factors at work and suboptimal health status, respectively. CFA was conducted to establish the evaluating method of COPSOQ. A multivariate logistic regression model was used to estimate the relationship between suboptimal health status and stress-related psychosocial work factors among Chinese medical staff.ResultsThere was a strong correlation among the five dimensions of COPSOQ based on the first-order factor model. Then, we established two second-order factors including negative and positive psychosocial work stress factors to evaluate psychosocial factors at work, and the second-order factor model fit well. The high score in negative (OR (95% CI)=1.47 (1.34 to 1.62), P<0.001) and positive (OR (95% CI)=0.96 (0.94 to 0.98), P<0.001) psychosocial work factors increased and decreased the risk of suboptimal health, respectively. This relationship remained statistically significant after adjusting for confounders and when using different cut-offs of suboptimal health status.ConclusionsAmong medical staff, the second-order factor model was a suitable method to evaluate the COPSOQ. The negative and positive psychosocial work stress factors might be the risk and protective factors of suboptimal health, respectively. Moreover, negative psychosocial work stress was the most associated factor to predict suboptimal health.
Factor structure and convergent validity of the Derriford Appearance Scale-24 using standard scoring versus treating ‘not applicable’ responses as missing data: a Scleroderma Patient-centered Intervention Network (SPIN) cohort study
Authors: Merz Erin L , Kwakkenbos Linda , Carrier Marie-Eve , Gholizadeh Shadi , Mills Sarah D , Fox Rina S , Jewett Lisa R , Williamson Heidi , Harcourt Diana , Assassi Shervin , Furst Daniel E , Gottesman Karen , Mayes Maureen D , Moss Tim P , Thombs Brett D , Malcarne Vanessa L 
Published: March 2018

ObjectiveValid measures of appearance concern are needed in systemic sclerosis (SSc), a rare, disfiguring autoimmune disease. The Derriford Appearance Scale-24 (DAS-24) assesses appearance-related distress related to visible differences. There is uncertainty regarding its factor structure, possibly due to its scoring method.DesignCross-sectional survey.SettingParticipants with SSc were recruited from 27 centres in Canada, the USA and the UK. Participants who self-identified as having visible differences were recruited from community and clinical settings in the UK.ParticipantsTwo samples were analysed (n=950 participants with SSc; n=1265 participants with visible differences).Primary and secondary outcome measuresThe DAS-24 factor structure was evaluated using two scoring methods. Convergent validity was evaluated with measures of social interaction anxiety, depression, fear of negative evaluation, social discomfort and dissatisfaction with appearance.ResultsWhen items marked by respondents as ‘not applicable’ were scored as 0, per standard DAS-24 scoring, a one-factor model fit poorly; when treated as missing data, the one-factor model fit well. Convergent validity analyses revealed strong correlations that were similar across scoring methods.ConclusionsTreating ‘not applicable’ responses as missing improved the measurement model, but did not substantively influence practical inferences that can be drawn from DAS-24 scores. Indications of item redundancy and poorly performing items suggest that the DAS-24 could be improved and potentially shortened.
Systematic review and meta-analysis of global birth prevalence of clubfoot: a study protocol
Authors: Ansar Adnan , Rahman Ahmed Ehsanur , Romero Lorena , Haider Mohammad Rifat , Rahman Mohammad Masudur , Moinuddin Md , Siddique Md Abu Bakkar , Mamun Md Al , Mazumder Tapas , Pirani Shafique Pyarali , Mathias Richard Gordon , Arifeen Shams EI , Hoque Dewan Md Emdadul 
Published: March 2018

IntroductionClubfoot is a common congenital birth defect, with an average prevalence of approximately 1 per 1000 live births, although this rate is reported to vary among different countries around the world. If it remains untreated, clubfoot causes permanent disability, limits educational and employment opportunities, and personal growth. The aim of this systematic review and meta-analysis is to estimate the global birth prevalence of congenital clubfoot.Methods and analysisElectronic databases including MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Global Health, Latin American & Caribben Health Science Literature (LILACS), Maternity and Infant Care, Web of Science, Scopus and Google Scholar will be searched for observational studies based on predefined criteria and only in English language from inception of database in 1946 to 10 November 2017. A standard data extraction form will be used to extract relevant information from included studies. The Joanna Briggs Institute appraisal checklist will be used to assess the overall quality of studies reporting prevalence. All included studies will be assessed for risk of bias using a tool developed specifically for prevalence studies. Forest plots will be created to understand the overall random effects of pooled estimates with 95% CIs. An I2test will be done for heterogeneity of the results (P>0.05), and to identify the source of heterogeneity across studies, subgroup or meta-regression will be used to assess the contribution of each variable to the overall heterogeneity. A funnel plot will be used to identify reporting bias, and sensitivity analysis will be used to assess the impact of methodological quality, study design, sample size and the impact of missing data.Ethics and disseminationThis review will be conducted completely based on published data, so approval from an ethics committee or written consent will not be required. The results will be disseminated through a peer-reviewed publication and relevant conference presentations.PROSPERO registration numberCRD42016041922.
Measurement and monitoring of safety: impact and challenges of putting a conceptual framework into practice
Authors: Chatburn Eleanor , Macrae Carl , Carthey Jane , Vincent Charles 
Published: March 2018

BackgroundThe Measurement and Monitoring of Safety Framework provides a conceptual model to guide organisations in assessing safety. The Health Foundation funded a large-scale programme to assess the value and impact of applying the Framework in regional and frontline care settings. We explored the experiences and reflections of key participants in the programme.MethodsThe study was conducted in the nine healthcare organisations in England and Scotland testing the Framework (three regional improvement bodies, six frontline settings). Post hoc interviews with clinical and managerial staff were analysed using template analysis.FindingsParticipants reported that the Framework promoted a substantial shift in their thinking about how safety is actively managed in their environment. It provided a common language, facilitated a more inquisitive approach and encouraged a more holistic view of the components of safety. These changes in conceptual understanding, however, did not always translate into broader changes in practice, with many sites only addressing some aspects of the Framework. One of the three regions did embrace the Framework in its entirety and achieved wider impact with a range of interventions. This region had committed leaders who took time to fully understand the concepts, who maintained a flexible approach to exploring the utility of the Framework and who worked with frontline staff to translate the concepts for local settings.ConclusionsThe Measuring and Monitoring of Safety Framework has the potential to support a broader and richer approach to organisational safety. Such a conceptually based initiative requires both committed leaders who themselves understand the concepts and more time to establish understanding and aims than might be needed in a standard improvement programme.
Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program
Authors: Luan Haitao , Mohapatra Bhopal , Bielecki Timothy A. , Mushtaq Insha , Mirza Sameer , Jennings Tameka A. , Clubb Robert J. , An Wei , Ahmed Dena , El-Ansari Rokaya , Storck Matthew D. , Mishra Nitish K. , Guda Chittibabu , Sheinin Yuri M. , Meza Jane L. , Raja Srikumar , Rakha Emad A. , Band Vimla , Band Hamid 
Published: March 2018

Abstract
CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two thirds of ErbB2+ and triple-negative breast cancers (TNBC) and in one third of ER+ breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2+ and TNBC cell lines. Ectopic CHIP expression in ErbB2+ lines suppressed in vitro oncogenic traits and in vivo xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up- or downregulated by CHIP. We characterized myeloid zinc finger 1 (MZF1) as a CHIP target, given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L)-mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2+ and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2+ breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression.
Significance: These findings reveal a novel targetable pathway of breast oncogenesis unleashed by the loss of tumor suppressor ubiquitin ligase CHIP/STUB1. Cancer Res; 78(10); 2524–35. ©2018 AACR.