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The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0–19·7) and followed up for a median of 9·9 months (4·3–12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11–24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1–2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Merck KGaA, and Pfizer Inc.

PurposeObesity and poor diet quality (DQ) are associated with increased risk of morbidity/mortality among breast cancer survivors. This study explored DQ changes during a weight loss maintenance intervention in a cohort of rural female breast cancer survivors (n = 131) who lost ≥ 5% body weight in a weight loss intervention. Previous analyses demonstrated significant DQ improvements during weight loss.MethodsDQ was calculated using the alternate Healthy Eating Index (aHEI)-2010. Differences in scores across time for the cohort and between those that maintained weight loss within 5% (low regainers) and those that regained > 5% (high regainers) were analyzed by linear mixed models.ResultsSignificant improvements in aHEI total score were observed from baseline (M = 52.3 ± 11) to 6 months (M = 60.7 ± 8; p < 0.001); these improvements were sustained from 6 to 18 months (M = 58.4 ± 11; p = 0.16). Total aHEI-2010 score at 18 months was higher in low regainers, compared with high regainers (60.7 vs. 56.0, p = 0.03), with healthier component scores for red meat (p = 0.01) and fruit (p = 0.04), and a trend for a healthier score for sugar-sweetened beverages (p = 0.08).ConclusionsOverall DQ improvements made during a weight loss intervention for rural breast cancer survivors were sustained during a weight loss maintenance intervention; this intervention was effective in helping low regainers maintain healthier scores in fruit, red meat, and sugar-sweetened beverage components.Implications for Cancer SurvivorsMaintaining higher DQ may help breast cancer survivors maintain weight loss, thereby reducing risk of breast cancer recurrence and premature death from comorbidities.

The γ-clade of class I homeodomain-leucine zipper (HD-Zip I) transcription factors (TFs) constitute members which play a role in adapting plant growth to conditions of water deficit. Given the importance of wheat (Triticum aestivum L.) as a global food crop and the impact of water deficit upon grain yield, we focused on functional aspects of wheat drought responsive HD-Zip I TFs. While the wheat γ-clade HD-Zip I TFs share significant sequence similarities with homologous genes from other plants, the clade-specific features in transcriptional response to abiotic stress were detected. We demonstrate that wheat TaHDZipI-3, TaHDZipI-4, and TaHDZipI-5 genes respond differentially to a variety of abiotic stresses, and that proteins encoded by these genes exhibit pronounced differences in oligomerisation, strength of DNA binding, and trans-activation of an artificial promoter. Three-dimensional molecular modelling of the protein-DNA interface was conducted to address the ambiguity at the central nucleotide in the pseudo-palindromic cis-element CAATNATTG that is recognised by all three HD-Zip I proteins. The co-expression of these genes in the same plant tissues together with the ability of HD-Zip I TFs of the γ-clade to hetero-dimerise suggests a role in the regulatory mechanisms of HD-Zip I dependent transcription. Our findings highlight the complexity of TF networks involved in plant responses to water deficit. A better understanding of the molecular complexity at the protein level during crop responses to drought will enable adoption of efficient strategies for production of cereal plants with enhanced drought tolerance.

Neighbourhood differences in access to fresh fruit and vegetables may explain social inequalities in diet. Investigations have focused on variations in cost and availability as barriers to the purchase and consumption of fresh produce; investigations of quality have been neglected. Here we investigate whether produce quality systematically varies by food store type, rural-urban location and neighbourhood deprivation in a selection of communities across Scotland. Cross-sectional survey of twelve fresh fruit and vegetable items in 288 food stores in ten communities across Scotland. Communities were selected to reflect a range of urban-rural settings and a food retail census was conducted in each location. The quality of twelve fruit and vegetable items within each food store was evaluated. Data from the Scottish Executive were used to characterise each small area by deprivation and urban-rural classification. Scotland. Quality of fruit and vegetables within the surveyed stores was high. Medium-sized stores, stores in small town and rural areas, and stores in more affluent areas tended to have the highest-quality fresh fruit and vegetables. Stores where food is secondary, stores in urban settings and stores in more deprived areas tended have the lowest-quality fresh produce. Although differences in quality were not always statistically significant, patterns were consistent for the majority of fruit and vegetable items. The study provides evidence that variations in food quality may plausibly be a micro-environmental mediating variable in food purchase and consumption and help partially explain neighbourhood differences in food consumption patterns.

The γ-clade of class I homeodomain-leucine zipper (HD-Zip I) transcription factors (TFs) constitute members which play a role in adapting plant growth to conditions of water deficit. Given the importance of wheat (Triticum aestivum L.) as a global food crop and the impact of water deficit upon grain yield, we focused on functional aspects of wheat drought responsive HD-Zip I TFs. While the wheat γ-clade HD-Zip I TFs share significant sequence similarities with homologous genes from other plants, the clade-specific features in transcriptional response to abiotic stress were detected. We demonstrate that wheat TaHDZipI-3, TaHDZipI-4, and TaHDZipI-5 genes respond differentially to a variety of abiotic stresses, and that proteins encoded by these genes exhibit pronounced differences in oligomerisation, strength of DNA binding, and trans-activation of an artificial promoter. Three-dimensional molecular modelling of the protein-DNA interface was conducted to address the ambiguity at the central nucleotide in the pseudo-palindromic cis-element CAATNATTG that is recognised by all three HD-Zip I proteins. The co-expression of these genes in the same plant tissues together with the ability of HD-Zip I TFs of the γ-clade to hetero-dimerise suggests a role in the regulatory mechanisms of HD-Zip I dependent transcription. Our findings highlight the complexity of TF networks involved in plant responses to water deficit. A better understanding of the molecular complexity at the protein level during crop responses to drought will enable adoption of efficient strategies for production of cereal plants with enhanced drought tolerance.

Optimizing froth surface area throughout the flotation circuit has a critical impact on the process performance. Launders are an essential part of any flotation cell and with the correct design and orientation for specific application, optimal performance can be achieved. Here, Bermudez et al describe the launder improvement project undertaken at Hudbay Minerals Inc's Constancia copper concentrator, located in southern Peru.

Some implants have approximately a lifetime of 15 years. The femoral stem, for example, should be made of 316L/316LN stainless steel. Fretting corrosion, friction under small displacements, should occur during human gait, due to repeated loadings and un-loadings, between stainless steel and bone for instance. Some experimental investigations of fretting corrosion have been practiced. As well known, metallic alloys and especially stainless steels are covered with a passive film that prevents from the corrosion and degradation. This passive layer of few nanometers, at ambient temperature, is the key of our civilization according to some authors. This work is dedicated to predict the passive layer thicknesses of stainless steel under fretting corrosion with a specific emphasis on the role of proteins. The model is based on the Point Defect Model (micro scale) and an update of the model on the friction process (micro-macro scale). Genetic algorithm was used for finding solution of the problem. The major results are, as expected from experimental results, albumin prevents from degradation at the lowest concentration of chlorides; an incubation time is necessary for degrading the passive film; under fretting corrosion and high concentration of chlorides the passive behavior is annihilated. Les implants orthopédiques de hanche ont une durée de vie d'environ 15 ans. Par exemple, la tige fémorale d'un tel implant peut être réalisée en acier inoxydable 316L ou 316LN. Le fretting corrosion, frottement sous petits déplacements, peut se produire pendant la marche humaine en raison des chargements répétés entre le métal de la prothèse et l'os. Plusieurs investigations expérimentales du fretting corrosion ont été entreprises. Cette couche passive de quelques nanomètres, à température ambiante, est le point clef sur lequel repose le développement de notre civilisation, selon certains auteurs. Ce travail vise à prédire les épaisseurs de cette couche passive de l'acier inoxydable soumis au fretting corrosion, avec une attention spécifique sur le rôle des protéines. Le modèle utilisé est basé sur le Point Defect Model, PDM (à une échelle microscopique) et une amélioration de ce modèle en prenant en compte le processus de frottement sous petits débattements. L'algorithme génétique a été utilisé pour optimiser la convergence du problème. Les résultats les plus importants sont, comme démontré avec les essais expérimentaux, que l'albumine, la protéine étudiée, empêche les dégradations de l'acier inoxydable aux plus faibles concentrations d'ions chlorure ; ensuite, aux plus fortes concentrations de chlorures, un temps d'incubation est nécessaire pour détruire le film passif.

Although Pullman's attack is more o n organised Christianity than faith, the aim of other strident atheists, such as Richard Dawkins, Christopher Hitchens or Daniel Dennett, is to use the hammer of science and rationality to break the chains of religious superstition. Indeed, since the Ancient World, intellectuals have predicted that faith would wither away in the face of expanding human knowledge. But the prediction was wrong. Demographic trends suggest that the proportion of the world's population who follow a major religion will rise to about 80 per cent over the coming decades. Even in countries with low religious observance - such as Britain - there has been no decline in the number who say they believe in God. Adaptationist accounts are far from universally accepted. Richard Dawkins describes the group selection theory that underlies [David Sloan Wilson]'s account as \"sheer, wanton, head-in-bag perversity\". But whatever is happening at the group level, there is something about the way individual human beings develop that makes us susceptible to religious belief. The attraction of religious explanations to young minds doesn't explain their persistence into adulthood. Grown-ups don't believe in fairies. But while we may rid ourselves of childhood myths, our susceptibility to belief in the supernatural persists. This goes beyond not walking under ladders. In one experiment, married couples were offered a hundred dollars if - after having an exact replica made of their wedding ring - they would keep one, not knowing if it was the original. Most declined.