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Polybromo-1 (PBRM1) is a component of the PBAF (Polybromo-associated-BRG1- or BRM-associated factors) chromatin remodeling complex and is the second most frequently mutated gene in clear-cell renal cell Carcinoma (ccRCC). Mutation of PBRM1 is believed to be an early event in carcinogenesis, however its function as a tumor suppressor is not understood. In this study, we have employed Next Generation Sequencing to profile the differentially expressed genes upon PBRM1 re-expression in a cellular model of ccRCC. PBRM1 re-expression led to upregulation of genes involved in cellular adhesion, carbohydrate metabolism, apoptotic process and response to hypoxia, and a downregulation of genes involved in different stages of cell division. The decrease in cellular proliferation upon PBRM1 re-expression was confirmed, validating the functional role of PBRM1 as a tumor suppressor in a cell-based model. In addition, we identified a role for PBRM1 in regulating metabolic pathways known to be important for driving ccRCC, including the regulation of hypoxia response genes, PI3K signaling, glucose uptake, and cholesterol homeostasis. Of particular novelty is the identification of cell adhesion as a major downstream process uniquely regulated by PBRM1 expression. Cytoskeletal reorganization was induced upon PBRM1 reexpression as evidenced from the increase in the number of cells displaying cortical actin, a hallmark of epithelial cells. Genes involved in cell adhesion featured prominently in our transcriptional dataset and overlapped with genes uniquely regulated by PBRM1 in clinical specimens of ccRCC. Genes involved in cell adhesion serve as tumor suppressor and maybe involved in inhibiting cell migration. Here we report for the first time genes linked to cell adhesion serve as downstream targets of PBRM1, and hope to lay the foundation of future studies focusing on the role of chromatin remodelers in bringing about these alterations during malignancies.

Purpose The purpose of this study was to determine the effects of a nonselective cyclooxygenase (cox) inhibitor and of a selective cox-2 inhibitor on the renal toxicity of cisplatin. Methods Cisplatin with or without a cox-1 inhibitor (SC560), a cox-2 inhibitor (SC236), or a nonselective cox inhibitor (piroxicam) was administered to Sprague-Dawley rats. Renal toxicity was assessed by serum creatinine concentration (SCR), urine specific gravity (USG), and histopathologic lesion score (HLS). Results Acutely, the SCR was significantly higher in rats receiving cisplatin/SC560 (1.62 ± 0.34 mg/dl) or cisplatin/piroxicam (2.0 ± 0.41 mg/dl) than in rats receiving cisplatin alone (1.09 ± 0.40 mg/dl). The apparent increase in SCR in the rats receiving cisplatin/SC236 (1.58 ± 0.31) was not significantly different from that of rats receiving cisplatin alone (1.09 ± 0.40 mg/dl). No significant differences in USG or HLSs were noted between rats receiving cisplatin alone and cisplatin combined with any cox inhibitor. In a chronic study, no differences in renal toxicity were found between rats treated with cisplatin alone and cisplatin/SC236 or cisplatin/piroxicam. Conclusions The acute rise in SCR following cisplatin treatment can be worsened by the addition of cox inhibitors, especially those that inhibit cox-1.

Polybromo1 (PBRM1) is a chromatin remodeler subunit highly mutated in cancer, particularly renal clear cell carcinoma. PBRM1 is a member of the SWI/SNF subcomplex, PBAF (PBRM1-Brg1/Brm Associated Factors) and is characterized by six tandem bromodomains. Here we establish a role for PBRM1 in epithelial cell maintenance through the expression of genes involved in cell adhesion, metabolism, stress response, and apoptosis. In support of a general role for PBRM1 in stress response and apoptosis, we observe that loss of PBRM1 results in an increase in reactive oxygen species generation and a decrease in cellular viability under stress conditions. We find that loss of PBRM1 promotes cell growth under favorable conditions but is required for cell survival under conditions of cellular stress.

Mechanistic investigation of host-microbe interactions in the human gut are hindered by difficulty of co-culturing microbes with intestinal epithelial cells. On one hand the gut bacteria are a mix of facultative, aerotolerant or obligate anaerobes, while the intestinal epithelium requires oxygen for growth and function. Thus, a coculture system that can recreate these contrasting oxygen requirements is critical step towards our understanding microbial-host interactions in the human gut. Here, we demonstrate Intestinal Organoid Physoxic Coculture (IOPC) system, a simple and cost-effective method for coculturing anaerobic intestinal bacteria with human intestinal organoids (HIOs). Using commensal anaerobes with varying degrees of oxygen tolerance, such as nano-aerobe Bacteroides thetaiotaomicron and strict anaerobe Blautia sp., we demonstrate that IOPC can successfully support 24–48 hours HIO-microbe coculture. The IOPC recapitulates the contrasting oxygen conditions across the intestinal epithelium seen in viv o. The IOPC cultured HIOs showed increased barrier integrity, and induced expression of immunomodulatory genes. A transcriptomic analysis suggests that HIOs from different donors show differences in the magnitude of their response to coculture with anaerobic bacteria. Thus, the IOPC system provides a robust coculture setup for investigating host-microbe interactions in complex, patient-derived intestinal tissues, that can facilitate the study of mechanisms underlying the role of the microbiome in health and disease.

A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program. Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.

Influenza immunisation during pregnancy is recommended but not widely implemented in some low-income regions. We assessed the safety and efficacy in mothers and infants of year-round maternal influenza immunisation in Nepal, where influenza viruses circulate throughout the year. In this phase 4, randomised, placebo-controlled trial, we enrolled two consecutive sequential annual cohorts of pregnant women from the Sarlahi district in southern Nepal. We randomised mothers 1:1 to receive seasonally recommended trivalent inactivated influenza vaccine or saline placebo in blocks of eight, stratified by gestational age at enrolment (17–25 weeks vs 26–34 weeks). Women were eligible if they were married, 15–40 years of age, 17–34 weeks' gestation at enrolment, and had not previously received any influenza vaccine that season. We collected serum samples before and after immunisation, and cord blood from a subset of women and infants. Staff masked to allocation made home visits every week from enrolment to 6 months after delivery. Midnasal swabs for respiratory virus PCR testing were collected during maternal acute febrile respiratory infections, and from infants with any respiratory symptom. We assessed vaccine immunogenicity, safety, and three primary outcomes: the incidence of maternal influenza-like illness in pregnancy and 0–180 days postpartum, the incidence of low birthweight (<2500 g), and the incidence of laboratory-confirmed infant influenza disease from 0 to 180 days. This trial is registered with ClinicalTrials.gov, number NCT01034254. From April 25, 2011, to Sept 9, 2013, we enrolled 3693 women in two cohorts of 2090 (1041 assigned to placebo and 1049 to vaccine) and 1603 (805 assigned to placebo and 798 to vaccine), with 3646 liveborn infants (cohort 1, 999 in placebo group and 1010 in vaccine group; cohort 2, 805 in placebo group and 798 in vaccine group). Immunisation reduced maternal febrile influenza-like illness with an overall efficacy of 19% (95% CI 1 to 34) in the combined cohorts; 9% efficacy (−16 to 29) in the first cohort, and 36% efficacy (9 to 55) in the second cohort. For laboratory-confirmed influenza infections in infants aged 0–6 months, immunisation had an overall efficacy for the combined cohorts of 30% (95% CI 5 to 48); in the first cohort, the efficacy was 16% (−19 to 41), and in the second cohort it was 60% (26 to 88). Maternal immunisation reduced the rates of low birthweight by 15% (95% CI 3–25) in both cohorts combined. The rate of small for gestational age infants was not modified by immunisation. The number of adverse events was similar regardless of immunisation status. Miscarriage occurred in three (0·2%) participants in the placebo group versus five (0·3%) in the vaccine group, stillbirth occurred in 31 (1·7%) versus 33 (1·8%), and congenital defects occurred in 18 (1·0%) versus 20 (1·1%). Five women died in the placebo group and three died in the vaccine group. The number of infant deaths at age 0–6 months was similar in each group (50 in the placebo group and 61 in the vaccine group). No serious adverse events were associated with receipt of immunisation. Year-round maternal influenza immunisation significantly reduced maternal influenza-like illness, influenza in infants, and low birthweight over the entire course of the study, indicating the strategy could be useful in subtropical regions. Bill & Melinda Gates Foundation.

There is uncertainty around whether the risks of pelvic inflammatory disease (PID) differ following Chlamydia trachomatis (chlamydia) and Neisseria gonorrhoeae (gonorrhea) infection. We quantified the risk of PID associated with chlamydia and gonorrhea infection and subsequent repeat infections in a whole-population cohort. A cohort of 315123 Western Australian women, born during 1974-1995, was probabilistically linked to chlamydia and gonorrhea testing records and to hospitalizations and emergency department presentations for PID from 2002 to 2013. Time-updated survival analysis was used to investigate the association between chlamydia and gonorrhea testing, and positivity, and risk of PID. Over 3199135 person-years, 120748 women had pathology test records for both chlamydia and gonorrhea, 10745 chlamydia only, and 653 gonorrhea only. Among those tested, 16778 (12.8%) had ≥1 positive chlamydia test, 3195 (2.6%) ≥1 positive gonorrhea test, and 1874 (1.6%) were positive for both. There were 4819 PID presentations (2222 hospitalizations, 2597 emergency presentations). Adjusting for age, Aboriginality, year of follow-up, health area, and socioeconomic status, compared to women negative for chlamydia and gonorrhea, the relative risk (adjusted incidence rate ratio) of PID was 4.29 (95% confidence interval [CI], 3.66-5.03) in women who were both chlamydia and gonorrhea positive; 4.54 (95% CI, 3.87-5.33) in those only gonorrhea positive; and 1.77 (95% CI, 1.61-1.94) in those only chlamydia positive. Gonorrhea infection conferred a substantially higher risk than chlamydia of hospitalization or emergency department presentation for PID. The emergence of gonorrhea antimicrobial resistance may have a serious impact on rates of PID and its associated reproductive health sequelae.

Fungi are important and hyperdiverse organisms, yet chronically understudied. Most fungal clades have no reference genomes, impeding our understanding of their ecosystem functions and use as solutions in health and biotechnology. Also, opportunities for training in fungal biology and genomics are lacking, creating a bottleneck that hinders the recruitment and cultivation of a talented future mycological workforce. To address these issues, we developed Myco-Ed, an educational program offering training and scientific contributions through genome sequencing and analysis. Myco-Ed empowers students to pursue careers in fungal biology while improving fungal resources. Myco-Ed has been piloted at 12 institutions (15 classrooms) ranging from online e-Campuses to R1 universities, resulting in hundreds of fungal observations and many new high-quality reference genomes.

Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting. A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naïve individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.49-1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA ≥5,000 copies/ml) (HR 0.41; 95% CI 0.21-0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65-1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53-1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution. Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.

Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. In this multicentre, open-label, randomised controlled trial, we recruited women aged 18–40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference −0·19%; 95% CI −0·34 to −0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.