Sphingosine 1-phosphate modulates antigen capture by murine langerhans cells via the S1P2 receptor subtype

Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions

Considerations for preparing a randomized population health intervention trial: lessons from a South African–Canadian partnership to improve the health of health workers

Background: Community-based cluster-randomized controlled trials (RCTs) are increasingly being conducted to address pressing global health concerns. Preparations for clinical trials are well-described, as are the steps for multi-component health service trials. However, guidance is lacking for addressing the ethical and logistic challenges in (cluster) RCTs of population health interventions in low- and middle-income countries. Objective: We aimed to identify the factors that population health researchers must explicitly consider when planning RCTs within North–South partnerships. Design: We reviewed our experiences and identified key ethical and logistic issues encountered during the pre-trial phase of a recently implemented RCT. This trial aimed to improve tuberculosis (TB) and Human Immunodeficiency Virus (HIV) prevention and care for health workers by enhancing workplace assessment capability, addressing concerns about confidentiality and stigma, and providing onsite counseling, testing, and treatment. An iterative framework was used to synthesize this analysis with lessons taken from other studies. Results: The checklist of critical factors was grouped into eight categories: 1) Building trust and shared ownership; 2) Conducting feasibility studies throughout the process; 3) Building capacity; 4) Creating an appropriate information system; 5) Conducting pilot studies; 6) Securing stakeholder support, with a view to scale-up; 7) Continuously refining methodological rigor; and 8) Explicitly addressing all ethical issues both at the start and continuously as they arise. Conclusion: Researchers should allow for the significant investment of time and resources required for successful implementation of population health RCTs within North–South collaborations, recognize the iterative nature of the process, and be prepared to revise protocols as challenges emerge

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

The effect of disgust-related side-effects on symptoms of depression and anxiety in people treated for cancer: a moderated mediation model

As maladaptive disgust responses are linked to mental health problems, and cancer patients may experience heightened disgust as a result of treatments they receive, we explored the associations between disgust-related side-effects and symptoms of depression and anxiety in people treated for cancer. One hundred and thirty two (83 women, Mage = 57.48 years) participants answered questions about their treatments, side-effects, disgust responding, and mental health. Experiencing bowel and/or bladder problems, sickness and/or nausea (referred to here as “core” disgust-related side-effects) was significantly related to greater symptoms of depression and borderline increased anxiety. Further, these links were explained by a moderated mediation model, whereby the effects of core disgust side-effects on depression and anxiety were mediated by (physical and behavioural) self-directed disgust, and disgust propensity moderated the effect of core disgust side-effects on self-disgust. These findings stress the importance of emotional responses, like disgust, in psychological adaptation to the side-effects of cancer treatments

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Search for new physics in the multijet and missing transverse momentum final state in proton-proton collisions at √s=8 Tev

Peer reviewe

Measurement of Higgs boson production and properties in the WW decay channel with leptonic final states

Peer reviewe

Study of double parton scattering using W+2-jet events in proton-proton collisions at √s=7 TeV

Peer reviewe