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Despite a more proactive approach to reducing new HIV infections in infants through lifelong treatment (Option B+ policy) for infected pregnant women, prevention of mother-to-child transmission of HIV (PMTCT) has not been fully effective in Papua, Indonesia. Mother-to-child transmission (MTCT) is the second greatest risk factor for HIV infection in the community, and an elimination target of <1% MTCT has not yet been achieved. The purpose of this study was to improve understanding of the implementation of Option B+ for PMTCT in Papua through investigation of facilitators and barriers to women's uptake and adherence to antiretroviral therapy (ART) in the program. This information is vital for improving program outcomes and success of program scale up in similar settings in Papua. In-depth interviews were conducted with 20 women and 20 PMTCT health workers at two main referral hospitals for PMTCT in Papua. Development of interview guides was informed by the socio-ecological framework. Qualitative data were managed with NVivo11 software and themes were analysed using template analysis. Factors influencing women's uptake and adherence in Option B+ for PMTCT were identified through final analysis of key themes. Factors that motivated PMTCT uptake and adherence were good quality post-test HIV counselling, belief in the efficacy of antiretroviral (ARV) attained through personal or peer experiences, and a partner who did not prevent women from seeking PMTCT care. Key barriers for PMTCT participation included doubts about ARV efficacy, particularly for asymptomatic women, unsupportive partners who actively prevented women from seeking treatment, and women's concerns about community stigma and discrimination. Results suggest that PMTCT program success is determined by facilitators and barriers from across the spectrum of the socio-ecological model. While roll out of Option B+ as current national policy for pregnant women in Papua has improved detection and enrolment of HIV-positive women, health facilities need to address various existing and potential issues to ensure long-term adherence of women beyond the current PMTCT program, including during pregnancy, childbirth and breastfeeding.

Protein kinase D (PKD) binds to diacylglycerol (DAG) in the trans -Golgi network (TGN) and is activated by trimeric G-protein subunits βγ. This complex then regulates the formation of transport carriers in the TGN that traffic to the plasma membrane in non-polarized cells. Here we report specificity of different PKD isoforms in regulating protein trafficking from the TGN. Kinase-inactive forms of PKD1, PKD2 and PKD3 localize to the TGN in polarized and non-polarized cells. PKD activity is required only for the transport of proteins containing basolateral sorting information, and seems to be cargo specific.

The pathogenesis of Fabry disease is poorly understood. We used a variety of immunohistological techniques to localize globotriaosylceramide, the main glycolipid that accumulates in Fabry disease. Globotriaosylceramide immunoreactivity in a heterogenous pattern was present in all organs examined of a patient on long-term enzyme replacement therapy. In the brain, immmunopositivity was found only in the parahippocampal region. Globotriaosylceramide immunostaining was present in the cell membrane and cytoplasm of endothelial cells, even in the absence of lysosomal inclusions. In kidney tissue, globotriaosylceramide colocalized with lysosomal, endoplasmic reticulum, and nuclear markers. Pre- and postembedding immunogold electron microscopy of skin biopsies and untreated patient cultured skin fibroblasts confirmed the presence of globotriaosylceramide in the cell membrane, in various cytoplasmic structures, and in the nucleus. Control organ tissues and cultured fibroblasts from five unaffected subjects were uniformly negative for globotriaosylceramide by immunohistochemistry and immunogold electron microscopy. We conclude that a substantial amount of lysosomal and extralysosomal globotriaosylceramide immunoreactivity remains in cells and tissues even after years of enzyme replacement therapy in Fabry disease. These findings are crucial for the understanding of the disease mechanism and suggest the usefulness of immunostaining for globotriaosylceramide as a means to assess response to novel, specific therapies.

Sotorasib is a selective irreversible inhibitor of the G12C-activated KRAS oncogene, present in approximately 13% of non–small-cell lung cancers. In a single-group, phase 2 trial involving 126 patients with previously treated KRAS p.G12C–mutated NSCLC, 37% had a response (median duration, 11 months). One fifth of patients had grade 3 toxic effects, mainly liver-enzyme abnormalities and diarrhea.

Inactive state-selective KRAS(G12C) inhibitors 1 – 8 demonstrate a 30–40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer 9 . The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS , NRAS , BRAF , EGFR , FGFR2 , MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials. Multiple treatment-emergent alterations appear in patients with advanced-stage cancer who were treated with a KRAS inhibitor.

Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma. This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m2 intravenously; cisplatin 60 mg/m2 intravenously; capecitabine 625 mg/m2 orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072. Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6–12·0) for patients in the rilotumumab group and 9·4 months (5·3–13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7–10·2) in the rilotumumab group compared with 10·7 months (9·6–12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10–1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression. Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma. Amgen.

Polarized epithelial cells maintain plasma membrane asymmetry, which is vital to their function, by sorting apical and basolateral transmembrane proteins into different post-Golgi vesicles. Although it is well established that the small GTPase Rab8 is involved in the delivery of post-Golgi vesicles to the plasma membrane in various cell types (Moritz et al. 2001, Huber et al. 1993, 1995), its association with a specific trafficking pathway remained elusive. In addition there are at least two distinguishable pathways to the basolateral plasma membrane. One is taken by LDL receptor and VSVG proteins which contain tyrosine-based sorting signals. These basolateral proteins are sorted with the help of the epithelial specific clathrin-adaptor complex AP-1B. In contrast, another basolateral protein, Fc receptor, containing a dileucine-based sorting signal, is sorted independently of AP-1B expression (Fölsch et al 1999, 2001). Here we demonstrate a functional link between Rab8 and the AP-1B pathway. We found that rab8 localizes to a post-Golgi compartment and, in its activated form, causes the missorting of VSVG and LDLR from the basolateral to the apical surface as shown by confocal immunofluorescence microscopy and radioactive pulse-labeling studies. However, activated Rab8 had no effect on sorting of FcR. Furthermore we found that expression of activated Rab8 in LLC-PK1 kidney cells exogenously expressing AP-1B dramatically changes AP-1 localization. We hypothesize that Rab8 specifically regulates the AP-1B pathway perhaps by controlling AP-1B recruitment to post-Golgi membranes, specifically recycling endosomes (RE's). Localization of AP-1B to RE's along with other components (e.g., exocyst and Rab8) involved in AP-1B-dependent transport suggested that RE's may be an intermediate between the Golgi and the plasma membrane. Although the involvement of endosomes in the secretory pathway has long been suspected, we now present direct evidence that RE's play an essential role in basolateral transport in MDCK cells using four independent methods. Newly synthesized AP-1B dependent cargo, VSV-G, was found by video microscopy, immuno-EM, and cell fractionation to enter Tfn-positive RE's immediately upon exit from the TGN. Although transient, RE entry appears essential since enzymatic inactivation of RE's almost completely blocked VSV-G delivery to the cell surface. Since an apically targeted VSV G mutant behaves in a similar fashion, these results suggest that RE's may serve not only as an intermediate, but also as an important site for polarized sorting.

For many years, SF6 has been the preferred dielectric medium in electrical power applications, particularly in high voltage gas-insulated equipment. However, with the recognition that SF6 has an extremely long atmospheric lifetime and very high global warming potential, governments have pursued emission reductions from gas-filled equipment. The electrical power industry has responded to this environmental challenge applying SF6-free technologies to an expanding range of applications which have traditionally used SF6, including gas-insulated switchgear, gas-insulated circuit breakers and gas-insulated lines or bus bars. Some of these SF6-free solutions include gas mixtures containing fluorinated compounds that have low climate impact, among them, a fluoronitrile and a fluoroketone developed as 3M™ Novec™ 4710 Insulating Gas and 3M™ Novec™ 5110 Insulating Gas, respectively. Both fluoronitrile and fluoroketone mixtures are successfully used in gas-insulated equipment currently operating on the grid where they reduce greenhouse gas emissions by more than 99% versus SF6. This paper reviews these leading components of alternative-gas mixtures with updates on the performance, safety and environmental profiles in electrical power applications.

Purpose The purpose of this paper is to evaluate the impact of delivering healthy eating messages through an interactive health corner (HC) on improving healthy dietary habits in participants. Design/methodology/approach Self-administered questionnaires were administered to participants after the education session. In total, 5,292 valid questionnaires were obtained, yielding a response rate of 93.3 per cent. In the last three months of the pilot study, a random sample of 305 from 1,493 participants was chosen and followed up six months later. Bivariate analysis was used to study the association of knowledge gained and attitude. Behavioural change was measured in terms of whether participants had reported an increase in their consumption of healthier food. Findings Majority (>98 per cent) of participants reported that the HC corner was useful, and had helped increase their awareness and knowledge of creating healthier meals and making healthier food choices. 95.7 per cent were willing to make changes after visiting the HC. At six months follow-up, 84 per cent of the participants reported positive changes in their dietary habits. Those who made positive changes were younger (mean age: 58.0 years) compared with those who did not (mean age 61.0 years, p=0.035). Research limitations/implications Incorporating cooking demonstrations as part of nutrition education is effective in inculcating healthy eating practices and changing self-reported eating habits in the short term. Further research is needed to verify actual change in eating habits and to determine if this change is sustainable in the long run. Originality/value Currently, no similar initiative has been implemented and studied to evaluate the effectiveness of this mode of health promotion in a primary care setting. This study will help the authors to evaluate if the intervention was effective in changing attitudes and behaviours after an education session at the HC.

SummaryBackground The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and preliminary efficacy of olaparib combined with carboplatin and/or paclitaxel. Methods Patients with advanced solid tumors received olaparib (capsule bid) plus carboplatin (Part A), carboplatin and paclitaxel (Part B), or paclitaxel (Part C). In each part of the study, different drug doses were given to define the most appropriate dose/drug combination to use in further studies. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs) and physical examinations. PK assessments of olaparib, carboplatin and paclitaxel were performed. Tumor responses (RECIST) were assessed every two cycles. Results Fifty-seven patients received treatment. DLTs were reported in two patients (both receiving olaparib 100 mg bid and carboplatin AUC 4; Part A, cohort 2): grade 1 thrombocytopenia with grade 2 neutropenia lasting for 16 days, and grade 2 neutropenia lasting for 7 days. Non-hematologic AEs were predominantly grade 1–2 and included fatigue (70%) and nausea (40%). Bone marrow suppression, mainly neutropenia (51%) and thrombocytopenia (25%), frequently led to dose modifications. Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications.