Acute Caffeine Supplementation in Regular Caffeine Consumers Minimally Affects Strength in Knee Flexors

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Four Days of Caffeine Withdrawal in Caffeine Consumers Lowers Strength in Knee Flexors and Extensors

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The role of the RACK1 ortholog Cpc2p in modulating pheromone-induced cell cycle arrest in fission yeast

The detection and amplification of extracellular signals requires the involvement of multiple protein components. In mammalian cells the receptor of activated C kinase (RACK1) is an important scaffolding protein for signal transduction networks. Further, it also performs a critical function in regulating the cell cycle by modulating the G1/S transition. Many eukaryotic cells express RACK1 orthologs, with one example being Cpc2p in the fission yeast Schizosaccharomyces pombe. In contrast to RACK1, Cpc2p has been described to positively regulate, at the ribosomal level, cells entry into M phase. In addition, Cpc2p controls the stress response pathways through an interaction with Msa2p, and sexual development by modulating Ran1p/Pat1p. Here we describe investigations into the role, which Cpc2p performs in controlling the G protein-mediated mating response pathway. Despite structural similarity to Gβ-like subunits, Cpc2p appears not to function at the G protein level. However, upon pheromone stimulation, cells overexpressing Cpc2p display substantial cell morphology defects, disorientation of septum formation and a significantly protracted G1 arrest. Cpc2p has the potential to function at multiple positions within the pheromone response pathway. We provide a mechanistic interpretation of this novel data by linking Cpc2p function, during the mating response, with its previous described interactions with Ran1p/Pat1p. We suggest that overexpressing Cpc2p prolongs the stimulated state of pheromone-induced cells by increasing ste11 gene expression. These data indicate that Cpc2p regulates the pheromone-induced cell cycle arrest in fission yeast by delaying cells entry into S phase

The impact of networks on clinical trials in the United Kingdom

The conduct of clinical trials in the UK has been affected by the recent introduction of managed clinical networks, clinical research networks and rigorous governance regulations. This commentary considers the challenges that these changes have posed for clinical triallists in the UK, based on experiences derived in the conduct of a multicentre neonatal clinical trial under the conditions that now prevail. We conclude that the considerable skills and knowledge that are now required to be an effective Principal Investigator should be recognised and that application processes, including issuing honorary contracts, should be simplified and centralised

Association Between Intravenous Thrombolysis and Clinical Outcomes Among Patients With Ischemic Stroke and Unsuccessful Mechanical Reperfusion.

IMPORTANCE Clinical evidence of the potential treatment benefit of intravenous thrombolysis preceding unsuccessful mechanical thrombectomy (MT) is scarce. OBJECTIVE To determine whether intravenous thrombolysis (IVT) prior to unsuccessful MT improves functional outcomes in patients with acute ischemic stroke. DESIGN, SETTING, AND PARTICIPANTS Patients were enrolled in this retrospective cohort study from the prospective, observational, multicenter German Stroke Registry-Endovascular Treatment between May 1, 2015, and December 31, 2021. This study compared IVT plus MT vs MT alone in patients with acute ischemic stroke due to anterior circulation large-vessel occlusion in whom mechanical reperfusion was unsuccessful. Unsuccessful mechanical reperfusion was defined as failed (final modified Thrombolysis in Cerebral Infarction grade of 0 or 1) or partial (grade 2a). Patients meeting the inclusion criteria were matched by treatment group using 1:1 propensity score matching. INTERVENTIONS Mechanical thrombectomy with or without IVT. MAIN OUTCOMES AND MEASURES Primary outcome was functional independence at 90 days, defined as a modified Rankin Scale score of 0 to 2. Safety outcomes were the occurrence of symptomatic intracranial hemorrhage and death. RESULTS After matching, 746 patients were compared by treatment arms (median age, 78 [IQR, 68-84] years; 438 women [58.7%]). The proportion of patients who were functionally independent at 90 days was 68 of 373 (18.2%) in the IVT plus MT and 42 of 373 (11.3%) in the MT alone group (adjusted odds ratio [AOR], 2.63 [95% CI, 1.41-5.11]; P = .003). There was a shift toward better functional outcomes on the modified Rankin Scale favoring IVT plus MT (adjusted common OR, 1.98 [95% CI, 1.35-2.92]; P < .001). The treatment benefit of IVT was greater in patients with partial reperfusion compared with failed reperfusion. There was no difference in symptomatic intracranial hemorrhages between treatment groups (AOR, 0.71 [95% CI, 0.29-1.81]; P = .45), while the death rate was lower after IVT plus MT (AOR, 0.54 [95% CI, 0.34-0.86]; P = .01). CONCLUSIONS AND RELEVANCE These findings suggest that prior IVT was safe and improved functional outcomes at 90 days. Partial reperfusion was associated with a greater treatment benefit of IVT, indicating a positive interaction between IVT and MT. These results support current guidelines that all eligible patients with stroke should receive IVT before MT and add a new perspective to the debate on noninferiority of combined stroke treatment

HPV16 oncogene expression levels during early cervical carcinogenesis are determined by the balance of epigenetic chromatin modifications at the integrated virus genome.

In cervical squamous cell carcinomas, high-risk human papillomavirus (HRHPV) DNA is usually integrated into host chromosomes. Multiple integration events are thought to be present within the cells of a polyclonal premalignant lesion and the features that underpin clonal selection of one particular integrant remain poorly understood. We previously used the W12 model system to generate a panel of cervical keratinocyte clones, derived from cells of a low-grade premalignant lesion naturally infected with the major HRHPV type, HPV16. The cells were isolated regardless of their selective advantage and differed only by the site of HPV16 integration into the host genome. We used this resource to test the hypothesis that levels of HPV16 E6/E7 oncogene expression in premalignant cells are regulated epigenetically. We performed a comprehensive analysis of the epigenetic landscape of the integrated HPV16 DNA in selected clones, in which levels of virus oncogene expression per DNA template varied ~6.6-fold. Across the cells examined, higher levels of virus expression per template were associated with more open chromatin at the HPV16 long control region, together with greater loading of chromatin remodelling enzymes and lower nucleosome occupancy. There were higher levels of histone post-translational modification hallmarks of transcriptionally active chromatin and lower levels of repressive hallmarks. There was greater abundance of the active/elongating form of the RNA polymerase-II enzyme (RNAPII-Ser2P), together with CDK9, the component of positive transcription elongation factor b complex responsible for Ser2 phosphorylation. The changes observed were functionally significant, as cells with higher HPV16 expression per template showed greater sensitivity to depletion and/or inhibition of histone acetyltransferases and CDK9 and less sensitivity to histone deacetylase inhibition. We conclude that virus gene expression per template following HPV16 integration is determined through multiple layers of epigenetic regulation, which are likely to contribute to selection of individual cells during cervical carcinogenesis.This work was supported by Cancer Research UK (Programme Grant A13080); the Medical Research Council; The Pathological Society of Great Britain and Ireland (E.L.A.K.); and the Agency for Science, Technology and Research, Singapore (Q.Y.A).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/onc.2016.

Endovascular therapy versus no endovascular therapy in patients receiving best medical management for acute isolated occlusion of the posterior cerebral artery : A systematic review and meta-analysis

Background and purpose Endovascular therapy (EVT) is increasingly reported for treatment of isolated posterior cerebral artery (PCA) occlusions although its clinical benefit remains uncertain. This study-level meta-analysis investigated the functional outcomes and safety of EVT and best medical management (BMM) compared to BMM alone for treatment of PCA occlusion stroke. Methods We conducted a literature search in PubMed, Web of Science and Embase for studies in patients with isolated PCA occlusion stroke treated with EVT + BMM or BMM including intravenous thrombolysis. There were no randomized trials and all studies were retrospective. The primary outcome was modified Rankin Scale score of 0-2 at 3 months, while safety outcomes included mortality rate and incidence of symptomatic intracranial hemorrhage (sICH). Results Twelve studies with a total of 679 patients were included in the meta-analysis: 338 patients with EVT + BMM and 341 patients receiving BMM alone. Good functional outcome at 3 months was achieved in 58.0% (95% confidence interval [CI] 43.83-70.95) of patients receiving EVT + BMM and 48.1% (95% CI 40.35-55.92) of patients who received BMM alone, with respective mortality rates of 12.6% (95% CI 7.30-20.93) and 12.3% (95% CI 8.64-17.33). sICH occurred in 4.2% (95% CI 2.47-7.03) of patients treated with EVT + BMM and 3.2% (95% CI 1.75-5.92) of patients treated with BMM alone. Comparative analyses were performed on studies that included both treatments and these demonstrated no significant differences. Conclusions Our results demonstrate that EVT represents a safe treatment for patients with isolated PCA occlusion stroke. There were no differences in clinical or safety outcomes between treatments, supporting randomization of future patients into distal vessel occlusion trials.Peer reviewe

Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial-mesenchymal transition and poor overall survival.

BACKGROUND: Copy-number gain of the oncostatin-M receptor (OSMR) occurs frequently in cervical squamous cell carcinoma (SCC) and is associated with adverse clinical outcome. We previously showed that OSMR overexpression renders cervical SCC cells more sensitive to the major ligand oncostatin-M (OSM), which increases migration and invasion in vitro. We hypothesised that a major contribution to this phenotype would come from epithelial-mesenchymal transition (EMT). METHODS: We performed a comprehensive integrated study, involving in vitro cell line studies, in vivo animal models and numerous clinical samples from a variety of anatomical sites. RESULTS: In independent sets of cervical, head/neck and lung SCC tissues, OSMR expression levels correlated with multiple EMT-associated phenotypic markers and transcription factors. OSM treatment of OSMR overexpressing cervical SCC cells produced consistent EMT changes and increased tumour sphere formation in suspension culture. In a mouse model, OSMR overexpressing SCC cells treated with OSM showed significant increases in lung colonisation. The biological effects of exogenous OSM were mirrored by highly significant adverse overall survival in cervical SCCs with OSMR overexpression (N=251). CONCLUSIONS: OSM:OSMR interactions are able to induce EMT, increased cancer stem cell-like properties and enhanced lung colonisation in SCC cells. These changes are likely to contribute to the highly significant adverse outcome associated with OSMR overexpression in cervical SCCs.This work was supported by Cancer Research UK (Programme Grant A13080).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Nature Publishing Group