bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individual, social and environmental determinants of sleep among women: protocol for a systematic review and meta-analysis
Authors: Vézina-Im Lydi-Anne , Moreno Jennette P , Thompson Debbe , Nicklas Theresa A , Baranowski Tom 
Published: August 2017

IntroductionSleep is important to promote optimal health and avoid negative health outcomes. Short-duration and low-quality sleep may be more common and more detrimental among women compared with men. Identifying the determinants of behaviour is one of the first steps in designing effective interventions. To our knowledge, no systematic review has identified the individual, social and environmental determinants of sleep among adult women.Methods and analysisStudies reporting data on adult women from 18 to 64 years of age will be included. On the basis of ecological models of health behaviour and sleep, the types of determinants that will be included in the review are individual (eg, demographic, psychological and behavioural), social (eg, family) and environmental (eg, physical environment and policies) determinants. Observational (cross-sectional and longitudinal) and experimental studies will be included. MEDLINE/PubMed, PsycINFO, CINAHL, EMBASE and Proquest Dissertations and Theses will be investigated. Data will be extracted independently by two reviewers using a standardised data extraction form. The quality of observational studies will be assessed using the National Institute of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies and the quality of experimental studies will be assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Study. If there is a sufficient number of studies reporting data on a similar determinant among a similar population (k>5), a meta-analysis of the results will be performed with a random-effects model. If between-study heterogeneity is high (I2≥75%), it will be investigated through sensitivity analyses and meta-regression.Ethics and disseminationFormal ethical approval is not required as no primary data will be collected. The results will be published in a peer-reviewed journal. This review will provide valuable information to those interested in developing empirically based sleep interventions among women.PROSPERO registration numberCRD42017056894.
Factors influencing career intentions on completion of general practice vocational training in England: a cross-sectional study
Authors: Dale Jeremy , Russell Rachel , Scott Emma , Owen Katherine 
Published: August 2017

ObjectivesGeneral practice is experiencing a growing crisis with the numbers of doctors who are training and then entering the profession in the UK failing to keep pace with workforce needs. This study investigated the immediate to medium term career intentions of those who are about to become general practitioners (GPs) and the factors that are influencing career plans.DesignOnline questionnaire survey, with quantitative answers analysed using descriptive statistics and free text data analysed using a thematic framework approach.Setting and participantsDoctors approaching the end of 3-year GP vocational training in the West Midlands, England.Results178 (57.2%) doctors completed the survey. Most participants planned to work as salaried GPs or locums rather than entering a general practice partnership for at least the first 5 years post-completion of training; others failed to express a career plan or planned to leave general practice completely or work overseas. Many were interested in developing portfolio careers.The quality of general practice experience across undergraduate, foundation and vocational training were reported as influencing personal career plans, and in particular perceptions about workload pressure and morale within the training practices in which they had been placed. Experience of a poor work–life balance as a trainee had a negative effect on career intentions, as did negative perceptions about how general practice is portrayed by politicians and the media.ConclusionThis study describes a number of potentially modifiable factors related to training programmes that are detrimentally influencing the career plans of newly trained GPs. In addition, there are sociodemographic factors, such as age, gender and having children, which are also influencing career plans and so need to be accommodated. With ever-increasing workload in general practice, there is an urgent need to understand and where possible address these issues at national and local level.
Vibrotactile feedback as a tool to improve motor learning and sports performance: a systematic review
Authors: van Breda Eric , Verwulgen Stijn , Saeys Wim , Wuyts Katja , Peeters Thomas , Truijen Steven 
Published: August 2017

BackgroundEvidence concerning the use of vibrotactile feedback for acquiring and learning new motor skills is limited. Although various concepts and applications for tactile feedback have been proposed, little is known about the suitability of this feedback mechanism in sports training.AimThe goal of this systematic review was to gather knowledge on the efficacy of the use of vibrotactile feedback in improving sports performance skills.DesignSystematic review.MethodsComprehensively searched databases were: PubMed, Cochrane and Web of Science. Studies investigating the effects of using vibrotactile feedback in sports training in healthy subjects were included in this review.ResultsNo consensus was found regarding the positive effectiveness on performance using vibrotactile feedback in a sports context. No evidence was found that the addition of tactile feedback is effective for acquiring new motor skills. None of the studies show a significant learning effect.
O13 ‘I was struggling to feel intimate, the drugs just helped’. chemsex and HIV-risk among men who have sex with men (MSM) in the uk: syndemics of stigma, minority-stress, maladaptive coping and risk environments
Authors: Pollard Alex , Nadarzynski Tom , Llewellyn Carrie 
Published: August 2017

IntroductionThere has been a steep rise in the use of drugs during sex by some men who have sex with men (MSM), with associated increases in sexual risk for HIV and other STIs. This ‘Chemsex’ has been described, but there is a lack of theoretical perspectives applied to this particular phenomenon.We aimed to assess participants’ reasoning and conceptualisation of Chemsex and situate this within theoretical frameworks.MethodsThis study presents data from telephone interviews with 15 MSM attending sexual health clinics following a risk of HIV and accessing post-exposure prophylaxis (PEP). Interviews were conducted as part of a larger interventional study, which used an adapted version of Motivational Interviewing to explore risk behaviour and support change. We used Framework analysis on interview transcripts in order to understand participants’ perspectives on the use of chemsex.ResultsParticipants conceptualised their chemsex and HIV risks in their psycho-social context, highlighting the influence of the psycho-socio-cultural challenges of homophobic marginalisation and the ‘gay scene’ on their behaviour. Narratives of loneliness and difficulties in forming satisfying social and sexual relationships were repeatedly identified.DiscussionMultiple influences of stigma, minority stress and maladaptive coping (including drug-use) are seen to contribute to syndemic ‘risk-environments’ in which chemsex and risk behaviours are played out. Interventions to address the harms of chemsex must recognise the complex psychosocial context of risk, and shift the responsibility for change from vulnerable individuals to a shared responsibility distributed across social, political and institutional contexts.
O14 Chemsex, consent and the rise in sexual assault
Authors: Ward Chris , McQuillan Orla , Evans Rebecca 
Published: August 2017

IntroductionWithin the chemsex population reports of sexual assault, non-consensual sex and coercion are rising. We looked at consent among our chemsex clinic users.MethodsRetrospective data review of patients from April 2015 to March 2017. Data was collected on sexual assault, coercion, exploitation, risk taking, sexually transmitted infections and drug use.Results72 men were seen with a median age of 32. 41 (56.9%) were HIV positive, and 11 (15.3%) had Hepatitis C. 53 (73.6%) patients used Mephedrone, 40 (55.6%) GHB and 22 (30.6%) Crystal Meth. 13 (18.1%) patients reported self-harm. In total 23 (31.9%) patients reported non-consensual sex. A minority 5/30 (16.7%) were identified from April 2015 to Jan 2016 when using the terminology ‘forced into sex’. After realising that addressing consent is more complex in this cohort, we prioritised consent discussions around unwanted sexual attention and from Jan 2016 to March 2017 18/42 (42.9%) reported non-consensual sex (Table 1).Abstract O14 Table 1ChemsexAssault/coercionN/42 (%)Non-consensual sex18 (42.9%)Reported as sexual assault6 (14.3%)Coercive sex4 (9.5%)Sex while unconscious3 (7.1%)Assaulted > once2 (4.8%)Allegations of organised assault2 (4.8%)Injected/filmed while unconscious1 (2.4%)DiscussionOur data shows rates of non-consensual sex among chemsex users of up to 42.9%. There is a lack of patient understanding around what sexual assault and consent are and exploring this in a sensitive manner is paramount. Sexual assault discussions must be reviewed in both standard sexual health and chemsex clinics.
Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells
Authors: Gall Victor A. , Philips Anne V. , Qiao Na , Clise-Dwyer Karen , Perakis Alexander A. , Zhang Mao , Clifton Guy T. , Sukhumalchandra Pariya , Ma Qing , Reddy Sangeetha M. , Yu Dihua , Molldrem Jeffrey J. , Peoples George E. , Alatrash Gheath , Mittendorf Elizabeth A. 
Published: August 2017

AbstractEarly-phase clinical trials evaluating CD8+ T cell–eliciting, HER2-derived peptide vaccines administered to HER2+ breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein, an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. On the basis of these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy. Cancer Res; 77(19); 5374–83. ©2017 AACR.
PADI2-Mediated Citrullination Promotes Prostate Cancer Progression
Authors: Wang Lin , Song Guanhua , Zhang Xiang , Feng Tingting , Pan Jihong , Chen Weiwen , Yang Muyi , Bai Xinnuo , Pang Yu , Yu Jindan , Han Jinxiang , Han Bo 
Published: August 2017

Abstract
Onset of castration-resistance prostate cancer (CRPC) after long-term androgen deprivation therapy remains a major obstacle in the treatment of prostate cancer. The peptidylarginine deiminase PADI2 has been implicated in chronic inflammatory diseases and cancer. Here we show that PADI2 is an androgen-repressed gene and is upregulated in CRPC. PADI2 expression was required for survival and cell-cycle progression of prostate cancer cells, and PADI2 promoted proliferation of prostate cancer cells under androgen-deprived or castration conditions in vitro and in vivo. Cytoplasmic PADI2 protected the androgen receptor (AR) against proteasome-mediated degradation and facilitated AR binding to its target genes after nuclear translocation and citrullination of histone H3 amino acid residue R26. In contrast, mutant PADI2 D180A failed to affect AR stability, nuclear translocation, or transcriptional activity. PADI2 mediated AR control in a manner dependent on its enzymatic activity and nuclear localization, as correlated with increased histone H3 citrullination. Notably, coadministration of the PADI inhibitor Cl-Amidine and the AR signaling inhibitor enzalutamide synergized in inhibiting CRPC cell proliferation in vitro and tumor growth in vivo. Overall, our results establish PADI2 as a key mediator for AR in prostate cancer progression, especially CRPC, and they suggest PADI as novel therapeutic targets in this disease setting. Cancer Res; 77(21); 5755–68. ©2017 AACR.
β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy
Authors: Bucsek Mark J. , Qiao Guanxi , MacDonald Cameron R. , Giridharan Thejaswini , Evans Lauren , Niedzwecki Brian , Liu Haichao , Kokolus Kathleen M. , Eng Jason W.-L. , Messmer Michelle N. , Attwood Kristopher , Abrams Scott I. , Hylander Bonnie L. , Repasky Elizabeth A. 
Published: August 2017

Abstract
The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T-cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies—physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intratumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of programmed death receptor-1 (PD-1), in addition to an elevated effector CD8+ T-cell to CD4+ regulatory T-cell ratio (IFNγ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy. Cancer Res; 77(20); 5639–51. ©2017 AACR.
Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells
Authors: Daniloski Zharko , Smith Susan 
Published: August 2017

Abstract
Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. STAG2 silencing in normal human cells that lack telomerase led to increased recombination at telomeres, delayed telomere shortening, and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of STAG2 could promote tumorigenesis by extending the period during which tumor-driving mutations occur. Cancer Res; 77(20); 5530–42. ©2017 AACR.
Phenotypic Heterogeneity of Circulating Tumor Cells Informs Clinical Decisions between AR Signaling Inhibitors and Taxanes in Metastatic Prostate Cancer
Authors: Scher Howard I. , Graf Ryon P. , Schreiber Nicole A. , McLaughlin Brigit , Jendrisak Adam , Wang Yipeng , Lee Jerry , Greene Stephanie , Krupa Rachel , Lu David , Bamford Pascal , Louw Jessica E. , Dugan Lyndsey , Vargas Hebert A. , Fleisher Martin , Landers Mark , Heller Glenn , Dittamore Ryan 
Published: August 2017

AbstractThe heterogeneity of an individual patient's tumor has been linked to treatment resistance, but quantitative biomarkers to rapidly and reproducibly evaluate heterogeneity in a clinical setting are currently lacking. Using established tools available in a College of American Pathologists–accredited and Clinical Laboratory Improvement Amendments–certified clinical laboratory, we quantified digital pathology features on 9,225 individual circulating tumor cells (CTC) from 179 unique metastatic castration-resistant prostate cancer (mCRPC) patients to define phenotypically distinct cell types. Heterogeneity was quantified on the basis of the diversity of cell types in individual patient samples using the Shannon index and associated with overall survival (OS) in the 145 specimens collected prior to initiation of the second or later lines of therapy. Low CTC phenotypic heterogeneity was associated with better OS in patients treated with androgen receptor signaling inhibitors (ARSI), whereas high heterogeneity was associated with better OS in patients treated with taxane chemotherapy. Overall, the results show that quantifying CTC phenotypic heterogeneity can help inform the choice between ARSI and taxanes in mCRPC patients. Cancer Res; 77(20); 5687–98. ©2017 AACR.
MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress
Authors: Spehalski Elizabeth , Capper Kayla M. , Smith Cheryl J. , Morgan Mary J. , Dinkelmann Maria , Buis Jeffrey , Sekiguchi JoAnn M. , Ferguson David O. 
Published: August 2017

Abstract
Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double-strand breaks, where it functions in repair and triggers cell-cycle checkpoints via activation of the ataxia-telangiectasia mutated kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus. These preneoplastic B lymphocytes did not progress to detectable B lineage lymphoma, even in the absence of p53. Moreover, Mre11 deficiencies prevented tumorigenesis in a mouse model strongly predisposed to spontaneous B-cell lymphomas. Our findings indicate that MRN cannot be considered a standard tumor suppressor and instead imply that nuclease activities of MRE11 are required for oncogenesis. Inhibition of MRE11 nuclease activity increased DNA damage and selectively induced apoptosis in cells overexpressing oncogenes, suggesting MRE11 serves an important role in countering oncogene-induced replication stress. Thus, MRE11 may offer a target for cancer therapeutic development. More broadly, our work supports the idea that subtle enhancements of endogenous genome instability can exceed the tolerance of cancer cells and be exploited for therapeutic ends. Cancer Res; 77(19); 5327–38. ©2017 AACR.
New Horizons for Precision Medicine in Biliary Tract Cancers
Authors: Valle Juan W. , Lamarca Angela , Goyal Lipika , Barriuso Jorge , Zhu Andrew X. 
Published: August 2017

AbstractBiliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943–62. ©2017 AACR.
The Tumor Microenvironment Regulates Sensitivity of Murine Lung Tumors to PD-1/PD-L1 Antibody Blockade
Authors: Li Howard Y. , McSharry Maria , Bullock Bonnie , Nguyen Teresa T. , Kwak Jeff , Poczobutt Joanna M. , Sippel Trisha R. , Heasley Lynn E. , Weiser-Evans Mary C. , Clambey Eric T. , Nemenoff Raphael A. 
Published: August 2017

Abstract
Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 induce tumor regression in a subset of non–small cell lung cancer patients. However, clinical response rates are less than 25%. Evaluation of combinations of immunotherapy with existing therapies requires appropriate preclinical animal models. In this study, murine lung cancer cells (CMT167 and LLC) were implanted either orthotopically in the lung or subcutaneously in syngeneic mice, and response to anti–PD-1/PD-L1 therapy was determined. Anti–PD-1/PD-L1 therapy inhibited CMT167 orthotopic lung tumors by 95%. The same treatments inhibited CMT167 subcutaneous tumors by only 30% and LLC orthotopic lung tumors by 35%. CMT167 subcutaneous tumors had more Foxp3+ CD4+ T cells and fewer PD-1+ CD4+ T cells compared with CMT167 orthotopic tumors. Flow cytometric analysis also demonstrated increased abundance of PD-L1high cells in the tumor microenvironment in CMT167 tumor–bearing lungs compared with CMT167 subcutaneous tumors or LLC tumor–bearing lungs. Silencing PD-L1 expression in CMT167 cells resulted in smaller orthotopic tumors that remained sensitive to anti–PD-L1 therapy, whereas implantation of CMT167 cells into PD-L1− mice blocked orthotopic tumor growth, indicating a role for PD-L1 in both the cancer cell and the microenvironment. These findings indicate that the response of cancer cells to immunotherapy will be determined by both intrinsic properties of the cancer cells and specific interactions with the microenvironment. Experimental models that accurately recapitulate the lung tumor microenvironment are useful for evaluation of immunotherapeutic agents. Cancer Immunol Res; 5(9); 767–77. ©2017 AACR.