Month: July 2020

We identified a need to translate evidence about sex/gender to systematic reviewers. We decided to adopt briefing notes to complete this task because they allow for the synthesis of evidence and seemed well suited to the targeted users of systematic reviews. Briefing notes, communication tools commonly used by policy and decision makers, concisely describe an issue along with pertinent evidence, options and recommended actions in a user friendly format intended to increase awareness and uptake. They are sometimes NSC 136476 referred to as ‘evidence briefs’ and are widely used by leading health research groups such as National Institute for Health and Care Excellence to concisely communicate evidence for decision making. This article describes the development, pilot testing and evaluation of sex/gender briefing notes to translate evidence about how to consider sex/gender in systematic reviews. The musculoskeletal note highlights the difference in prevalence for some musculoskeletal disorders for men and women often reflecting underlying pathophysiologic mechanisms. The hypertension note provides examples related to the differing manifestation, outcomes and prevalence of hypertension among women and men. To develop the fourth section on methods, we built on existing structured guidance for systematic reviewers by appraising four current checklists for systematic reviews: 1) the Preferred Reporting Items for Systematic Reviews and Meta-analyses -Equity reporting guidelines ; 2) AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. ; 3) Methodological Standards for the Conduct of Cochrane Intervention Reviews ; and the Campbell and Cochrane Equity Methods Group Equity Checklist. The Cochrane Review Groups suggested that topic-specific examples were needed for each briefing note. We identified Cochrane and non-Cochrane peer-reviewed published systematic reviews in each topic area where elements of the reviews addressed an aspect of sex/gender. Reviews were chosen in several ways: by seeking review nominations from our collaborators in each of the review groups; searching for sex and gender in the Cochrane Database of Systematic Reviews; using the Montori search filter for sensitivity in searching for systematic reviews and using the text words “sex” and “gender” in PubMed. Significantly, we did not find exemplar reviews that served as a model for integrating sex/gender analysis but identified examples of reviews where some limited consideration was given to sex/gender issues. After a period of feedback and revision from the three collaborating review groups we moved to evaluate the briefing notes with a broader group of users. We conducted a workshop at the 2012 Canadian Cochrane Symposium and invited user feedback on the briefing notes. The Canadian Cochrane Symposium provided a very useful setting to evaluate the briefing notes as it gathers a diverse array of participants involved in systematic reviews including systematic review authors, methodologists, researchers and users of systematic reviews such as policy makers and health care practitioners. The workshop was open to all conference attendees with all levels of experience in systematic reviews in order to ensure that the comprehensibility of the briefing notes were evaluated by experts and non-experts. Participants self-selected to attend. A simple content analysis of responses was conducted and similar responses were grouped according to each evaluation question. Examples of responses are quoted verbatim below to illustrate respondents’ insights into the key areas evaluated.

In this third model, perforin forms pores in the plasma membrane of the target cell. Granzymes and perforin are then endocytosed together into large endosomes, and perforin acts on the endosomal membrane to release granzymes into the cytosol. However, the mechanism of how perforin causes release of granzymes from the endosome remains unclear. Perforin is commonly defined as providing cytolytic activity against target cells. Recently new, non-classical, mechanisms have been put forward that perforin can function in non-cytolytic pathways. Perforin has been identified, along with granzyme, as having a noncytolytic role in controlling the reactivation of HSV-1 Carfilzomib neuronal infections without inducing cytotoxicity. Additionally, in mouse model of obesity related insulin resistance and visceral adipose tissue, a lack of perforin showed reduced insulin sensitivity and changed the inflammation status within the VAT lesions, suggesting an immunoregulatory role for perforin in this disease state. Importantly, in this study, the formation of crown like structures, indicative of adipocyte death, was not changed in mice lacking perforin, further emphasizing a noncytolytic role of perforin. Other noncytolytic roles for perforin extend to contributing to CD8 T cell activation during arenavirus infection and regulating antigen presentation of dendritic cells. Previous work, in our lab, shows caspase-3 cleavage is not present until after BBB disruption has already occurred. Given these new roles for perforin and lack of evidence for apoptosis, it is possible that during BBB disruption, perforin is acting in a non-classical mechanism. However, the exact mechanism by which perforin wielding CD8 T cells can induce BBB disruption is yet to be defined. The contribution of molecules delivered by perforin beyond granzyme B also needs to be evaluated. For example, orphan granzymes have recently been proposed to play a role in pathogen clearance and cell-mediated death. Nevertheless, based on the findings put forward in this manuscript, investigating mechanisms of perforin-dependent cytotoxicity are important to the development of novel therapeutic strategies to ameliorate pathology associated with BBB disruption in several devastating neurological disorders. The demonstration that CD8 T cells can serve as a sole source of perforin to induce BBB disruption will greatly aid in this process. Essential medicines are those that satisfy the priority health care needs of a population. They are selected with regard to their public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness. The first global essential medicines list was assembled in 1977 by the World Health Organization, which is revised every other year. Medicines are identified through an evidence-based process in which quality, safety, efficacy and cost-effectiveness are key selection criteria. Although the Model List was not designed as a global standard, it has contributed to global acceptance of the concept of essential medicines and can be used by countries as a guide for the development of their own national essential medicines list. National essential medicines may be helpful in informing decisions in insurance coverage, as they help effective allocation of often limited financial resources, which is important because medicines spending in many countries amounts to about 17% of total health spending or 1.5% of gross domestic product. The WHO’s record of national medicines list has 117 countries, including most of the countries in the Central, East and South Europe.

A further intriguing possibility is that Hes6 may act to alter the fluctuating expression patterns of neurogenins and Hes proteins that accompany neural differentiation. In neural progenitors, transcription of Hes1, neurogenin 2 and the Notch WZ4002 ligand Deltalike-1 oscillate. On differentiation, Ngn2 and Dll1 expression are maintained at a high level and Hes1 expression is downregulated. Hes6 may play a role in the dynamic interactions between Hes1 and neurogenin that control their reciprocal oscillations, which in turn plays an essential role in progenitor maintenance. We conclude that Hes6 is a mutltifaceted regulator of neuronal differentiation in diverse systems where it plays distinct roles both at the level of regulation of gene expression, and at the level of regulation of proneural protein function. Sensitivity to pain varies greatly across humans and growing evidence suggests that genetic factors might explain part of this variability. Among the few single nucleotide polymorphisms that have been suggested to be associated with pain, one that has recently attracted significant attention is Catechol-Omethyltransferase val158met. COMT is an enzyme that is involved in a number of physiological functions, including the degradation of catecholamine neurotransmitters after their release in the synaptic cleft. The val108/158met SNP is associated with a valine-to-methionine substitution at position 108 or 158, which leads to a four-fold decrease in enzyme activity in met homozygotes, with the heterozygotes demonstrating intermediate activity. The first direct evidence that this polymorphism affects neural processing of pain came from Zubieta and colleagues, who showed that 158met homozygotes were characterized by higher pain sensitivity, diminished regional muopioid system responses to pain, as well as a higher mu-opioid receptor binding potential, compared with heterozygotes. Despite these intriguing results, the existence of an effect of COMT variation on pain sensitivity is still strongly debated, as some subsequent behavioral studies using larger sample size have failed to show a substantial association. In the last few years, evidence produced by several groups has suggested that the effect of COMT polymorphism on pain sensitivity is generally not observed for the initial pain provocations, but rather becomes apparent in later phases of a testing session. Thus, it is possible that the inconsistency in the literature on the effects of COMT is attributable to the delayed onset of this effect, which some studies might have failed to capture. The aim of the present study was to test the hypothesis that the effect of COMT on pain modulation emerges in the setting of a repeated pain challenge, as proposed by Jensen and colleagues. In order to test our hypothesis we reanalyzed the fMRI activations in response to early and late stimuli in a series of repeated heat pain stimulations, using data from three previous experiments from our laboratory.

We previously observed that reduced NESG1 protein levels were inversely associated with lymph node metastasis and clinical stage of NPC which suggested its downregulation favored the development of NPC. However, due to the limited patient sample size and the absence of clinical prognosis information, we did not investigate the detailed correlation of NESG1 expression with clinical features and prognosis of NPC. In this report, we used a larger cohort of 204 patients with clinical prognosis information to analyze this relationship. Similar to our previous results, we found that decreased expression of NESG1 inversely correlated with lymph node metastasis and clinical stage of NPC. We further observed that decreased NESG1 expression was correlated with distant metastases and statistically lower in the M1 group compared to the M0 group. Together these studies suggest downregulated NESG1 levels play an unfavorable role in NPC pathogenesis, a correlation which has not been previously reported. Our investigation provides data that reduced NESG1 protein expression is correlated with decreased NPC patient overall survival. According to univariate analyses, overall survival was significantly correlated with age, TNM classification, and NESG1 expression. Multivariate analyses showed that decreased expression of NESG1 alone could be a significant predictor of poor prognosis for NPC patients. Our data are the first to report the clinical significance of decreased NESG1 expression as an unfavorable prognosis TWS119 GSK-3 inhibitor biomarker in NPC. In a prior study, NESG1 overexpression had been observed to suppress cell proliferation, migration, invasion, and cell cycle progression, thus we further examined the biological functions of NESG1 in NPC. We used a loss-of-function approach to knock down the overexpressed NESG1 in 2F4 NPC cells, and confirmed its role in promoting cell proliferation, migration, and invasion in vitro. These results are consistent with our previous investigation. Our studies strongly suggest a suppressive role of NESG1 in the development of NPC. To fully understand the molecular mechanism of NESG1- mediated suppressive pathways in NPC, we analyzed differential expression of NESG1-regulated genes against the pathway-collected database KEGG. Our computational pathway analysis of 1442 differentially expressed genes strongly supported that multiple biological signaling pathways were involved in NESG1-mediated NPC oncogenesis including MAPK, insulin, actin cytoskeleton, focal adhesion, and cell cycle progression. In our recent report, NESG1 altered expression of cell cycle regulators CCNA1 and p21, a finding we confirmed through an inverse approach. We found that inhibition of NESG1 could markedly restore expression of cell cycle promoting CCNA1 while downregulating tumor suppressor p21. Including cell proliferation, differentiation migration, and invasion. MAPK was considered to be an important pathway regulated by NESG1 based on its ranking after computer analysis. Real-time PCR was used to validate the diffe

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Among these changes, the activation of oncogenes and inactivation of tumor suppressor genes may be key steps for initiating tumor formation and development. We previously compared normal human nasopharynx mucosa and oral cavity mucosa of the soft palate using differential display and identified full-length NESG1 specifically expressed in human nasopharynx and trachea. In a subsequent investigation, we revised the open reading frame sequence of NESG1 and updated its version number from NM_012337.1 to NM_012337.2 in the NCBI GeneBank database. NESG1 was found to be specifically expressed in the nasopharynx epithelium and decreased or absent in NPC tissues and cell lines compared to normal tissue. In addition, the levels of NESG1 protein were significantly greater in the lower-grade NPC tissues versus highergrade NPC. Elevated HhAntag691 expression of NESG1 in NPC cells not only significantly decreased cell proliferation and G1-S phase transition, but also markedly inhibited cell migration, invasion, and in vivo tumorigenesis. NESG1 also significantly regulated the expression of cell cycle regulators CCNA1 and p21. Our findings provided evidence that NESG1 may act as a tumor suppressor in NPC. In this study, we present further evidence that NESG1 protein is downregulated in human NPC tissues and NPC cells compared to noncancerous nasopharynx tissues. We also show that reduced protein expression of NESG1 is inversely associated with NPC progression and poor prognosis. Downregulation of overexpressed NESG1 in 2F4 NPC cells significantly regained cell proliferation, migration, and invasion. Furthermore, NESG1 knockdown elevated CCNA1 expression and suppressed p21 expression. Gene expression profile analysis indicated that NESG1 participates in multiple pathways, such as MAPK signaling and tight junction formation regulation. Finally, an epigenetic evaluation of the NESG1 promoter revealed a lack of methylation, suggesting involvement of other mechanisms in NESG1 suppression during NPC. Our studies firstly demonstrate that NESG1 as a potential tumor suppressor is an unfavorable prognostic factor for NPC. Nasopharyngeal epithelium-specific gene NESG1 was initially isolated from human normal nasopharynx mucosa using an improved differential display approach, and its sequences was submitted to the Genbank database by our research group in 1999. In a recent investigation, we updated the NESG1 ORF sequence and studied its role in NPC cells. Our results preliminarily suggested NESG1 function as a tumor suppressor in NPC. In the present study, we presented additional support for this notion as NESG1 protein was downregulated in human NPC tissues and cells compared to noncancerous nasopharynx tissues by western blot. Furthermore, we also found that protein expression of NESG1 was progressively decreased in atypical hyperplasia and cancer tissues compared to normal and squamous epithelium by immunohistochemistry.