IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer

Biliary tract cancer; Cancer immunotherapy; CholangiocarcinomaCàncer del tracte biliar; Immunoteràpia contra el càncer; ColangiocarcinomaCáncer del tracto biliar; Inmunoterapia contra el cáncer; ColangiocarcinomaBackground: Biliary tract cancers (BTCs) are heterogenous, highly aggressive tumors that harbor a dismal prognosis for which more effective treatments are needed. The role of cancer immunotherapy in BTC remains to be characterized. The tumor microenvironment (TME) of BTC is highly immunosuppressed and combination treatments are needed to promote effective anticancer immunity. Vascular endothelial growth factor (VEGF) drives immunosuppression in the TME by disrupting antigen presentation, limiting T-cell infiltration, or potentiating immune-suppressive cells. Many VEGF-regulated mechanisms are thought to be relevant to repressed antitumor immunity in BTC, making dual targeting of VEGF and programmed cell death protein 1 (PD-1)/PD-L1 pathways a rational approach. Gemcitabine and Cisplatin (Gem/Cis) can also modulate anticancer immunity through overlapping and complementary mechanisms to those regulated by VEGF. Anti-PD-L1/VEGF inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit. Methods: IMbrave 151 is a randomized, double-blind, placebo-controlled, multicenter, international phase II study to evaluate atezolizumab (a PD-L1 inhibitor) in combination with chemotherapy (gemcitabine and cisplatin) and bevacizumab (an anti-VEGF monoclonal antibody) as a first-line treatment for advanced BTC. Approximately 150 patients with previously untreated, advanced BTC will be randomized to either Arm A (atezolizumab + bevacizumab + Gem/Cis) or Arm B (atezolizumab + placebo + Gem/Cis). Randomization is stratified by the presence of metastatic disease, primary tumor location, and geographic region. The primary efficacy endpoint is investigator-assessed progression-free survival (PFS) per RECIST 1.1. Secondary endpoints include objective response rate (ORR), duration of response (DoR), disease control rate (DCR), overall survival (OS), and safety and patient reported outcomes (PROs). Tissue, blood, and stool samples will be collected at baseline and on-treatment in order to perform correlative biomarker analyses. Discussion: IMbrave 151 represents the first randomized study to evaluate combined PD-L1/VEGF blockade on a chemotherapy backbone in BTC. Trial registration: NCT identifier: NCT04677504; EUDRACT number: 2020-003759-14The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study is funded by F. Hoffmann-La Roche Ltd

Pretreatment with a 55-kDa Tumor Necrosis Factor Receptor-Immunoglobulin Fusion Protein Attenuates Activation of Coagulation, but not of Fibrinolysis, during Lethal Bacteremia in Baboons

Baboons (Papio anubis) receiving a lethal intravenous infusion with live Escherichia coli were pretreated with either a 55-kDa tumor necrosis factor (TNF) receptor-IgG fusion protein (TNFR55:IgG) (n = 4, 4.6 mg/kg) or placebo (n = 4). Neutralization of TNF activity in TNFR55:IgG-treated animals was associated with a complete prevention of mortality and a strong attenuation of coagulation activation as reflected by the plasma concentrations of thrombin-antithrombin III complexes (P < .05). Activation of fibrinolysis was not influenced by TNFR55:IgG (plasma tissue-type plasminogen activator and plasmin-a2-antiplasmin complexes), whereas TNFR55:IgG did inhibit the release of plasminogen activator inhibitor type I (P < .05). Furthermore, TNFR55:IgG inhibited neutrophil degranulation (plasma levels of elastase-α1-antitrypsin complexes, P < .05) and modestly reduced release of secretory phospholipase A2. These data suggest that endogenous TNF contributes to activation of coagulation, but not to stimulation of fibrinolysis, during severe bacteremi

A tela em limites: projeções sobre a superfície urbana

Trabalho de Conclusão de Curso apresentado ao Instituto Latino-Americano de Arte, Cultura e História da Universidade Federal da Integração Latino-Americana, como requisito parcial à obtenção do título de Bacharel em Cinema e Audiovisual. Orientador: Fabio Allan Mendes RamalhoNestas últimas décadas, houve um crescente avanço tecnológico digital em diversas áreas do ramo, gerou-se assim um barateamento considerável em equipamentos eletrônicos, principalmente em relação ao audiovisual. Esse baixo custo bem como as inovações tecnológicas, fizeram com que o audiovisual pudesse alcançar outros modos de exibição, e desta maneira, abrindo um leque de possibilidades para diferentes jeitos de se fazer arte com as imagens, com o vídeo e com o áudio. O VJ é um desses artistas desta nova safra, que se utiliza de diversas linguagens audiovisuais e traz consigo um apanhado de novas representações artísticas tanto visuais quanto sonoras, como é o caso do VJing e projeções mapeadas por exemplo. Esta pesquisa faz questão de apresentar esse universo do audiovisual, proporcionando assim uma maior visibilidade à algumas performances pouco conhecidas pelo público em geral. Deste modo, foi escolhido dentre tantos artistas audiovisuais contemporâneo, o duo VJ Suave, sua performance Suaveciclo e seu curta-metragem Homeless, para poder contextualizar esses novos meios audiovisuais contemporâneos de se fazer arte.En estas últimas décadas, hubo un creciente avance tecnológico digital en diversas áreas del campo, se generó así un abaratamiento considerable en equipos electrónicos, principalmente con relación al audiovisual. Este bajo costo, así como las innovaciones tecnológicas, hicieron que el audiovisual pudiera alcanzar otros modos de exhibición, y de esta manera, se abrió un abanico de posibilidades para diferentes maneras de hacer arte con las imágenes, con el vídeo y con el audio. El VJ es uno de esos artistas de esta nueva generación, que utiliza diversos lenguajes audiovisuales y trae consigo un repertorio de nuevas representaciones artísticas tanto visuales como sonoras, como es el caso del VJing y proyecciones mapeadas por ejemplo. Esta investigación hace cuestión de presentar ese universo del audiovisual, proporcionando así una mayor visibilidad a algunas performances poco conocidas por el público en general. De este modo, fue elegido entre tantos artistas audiovisuales contemporáneos, el dúo VJ Suave, su performance Suaveciclo y su cortometraje Homeless, para poder contextualizar esos nuevos medios audiovisuales contemporáneos de hacerse art

Unfinished Decolonisation and Globalisation

This article locates John Darwin’s work on decolonisation within an Oxbridge tradition which portrays a British world system, of which formal empire was but one part, emerging to increasing global dominance from the early nineteenth century. In this mental universe, decolonisation was the mirror image of that expanding global power. According to this point of view, it was not the sloughing off of individual territories, but rather the shrinking away of the system and of the international norms that supported it, until only its ghost remained by the end of the 1960s. The article then asks, echoing the title of Darwin’s Unfinished Empire, whether the decolonisation project is all but complete, or still ongoing. In addition, what is the responsibility of the imperial historian to engage with, inform, or indeed refrain from, contemporary debates that relate to some of these issues? The answer is twofold. On the one hand, the toolkit that the Oxbridge tradition and Darwin provide remains relevant, and also useful in thinking about contemporary issues such as China’s move towards being a global power, the United States’ declining hegemony, and some states and groups desires to rearticulate their relationship with the global. On the other hand, the decline of world systems of power needs to be recognised as just one of several types of, and approaches to, analysing ‘decolonisation’. One which cannot be allowed to ignore or marginalise the study of others, such as experience, first nations issues, the shaping of the postcolonial state, and empire legacies. The article concludes by placing the Oxbridge tradition into a broader typology of types and methodologies of decolonisation, and by asking what a new historiography of decolonisation might look like. It suggests that it would address the Oxbridge concern with the lifecycles of systems of power and their relationship to global changes, but also place them alongside, and in dialogue with, a much broader set of perspectives and analytical approaches

Mean biases, variability, and trends in air–sea fluxes and sea surface temperature in the CCSM4

Author Posting. © American Meteorological Society, 2012. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Climate 25 (2012): 7781–7801, doi:10.1175/JCLI-D-11-00442.1.Air–sea fluxes from the Community Climate System Model version 4 (CCSM4) are compared with the Coordinated Ocean-Ice Reference Experiment (CORE) dataset to assess present-day mean biases, variability errors, and late twentieth-century trend differences. CCSM4 is improved over the previous version, CCSM3, in both air–sea heat and freshwater fluxes in some regions; however, a large increase in net shortwave radiation into the ocean may contribute to an enhanced hydrological cycle. The authors provide a new baseline for assessment of flux variance at annual and interannual frequency bands in future model versions and contribute a new metric for assessing the coupling between the atmospheric and oceanic planetary boundary layer (PBL) schemes of any climate model. Maps of the ratio of CCSM4 variance to CORE reveal that variance on annual time scales has larger error than on interannual time scales and that different processes cause errors in mean, annual, and interannual frequency bands. Air temperature and specific humidity in the CCSM4 atmospheric boundary layer (ABL) follow the sea surface conditions much more closely than is found in CORE. Sensible and latent heat fluxes are less of a negative feedback to sea surface temperature warming in the CCSM4 than in the CORE data with the model’s PBL allowing for more heating of the ocean’s surface.The CESM project is supported by the National Science Foundation and the Office of Science (BER) of the U.S. Department of Energy. S. Stevensonwas supported byNASAGrantNNX09A020H and B. Fox-Kemper by Grants NSF 0934737 and NASA NNX09AF38G.2013-05-1

And labor came to us: making use of an opportune workforce - enhancing migrant integration into British economy

This article considers the opportunities presented by the availability of migrant labor in the U.K. employment market and its utilization. The research found that despite their qualifications, migrant labor is underutilized, thereby resulting in a readily available workforce being shunned and excluded from participative integration. This raises economic and ethical questions whose exploration revealed structural barriers (individually, communally, and institutionally) that impeded migrants’ fulfillment of citizenship obligations to host communities and U.K. businesses. The article’s key contribution is to highlight a skills mismatch and the persistent absence of institutional, communal, and strategic frameworks to support migrants’ integration

The value of predicting restriction of fetal growth and compromise of its wellbeing: Systematic quantitative overviews (meta-analysis) of test accuracy literature

BACKGROUND: Restriction of fetal growth and compromise of fetal wellbeing remain significant causes of perinatal death and childhood disability. At present, there is a lack of scientific consensus about the best strategies for predicting these conditions before birth. Therefore, there is uncertainty about the best management of pregnant women who might have a growth restricted baby. This is likely to be due to a dearth of clear collated information from individual research studies drawn from different sources on this subject. METHODS/DESIGN: A series of systematic reviews and meta-analyses will be undertaken to determine, among pregnant women, the accuracy of various tests to predict and/or diagnose fetal growth restriction and compromise of fetal wellbeing. We will search Medline, Embase, Cochrane Library, MEDION, citation lists of review articles and eligible primary articles and will contact experts in the field. Independent reviewers will select studies, extract data and assess study quality according to established criteria. Language restrictions will not be applied. Data synthesis will involve meta-analysis (where appropriate), exploration of heterogeneity and publication bias. DISCUSSION: The project will collate and synthesise the available evidence regarding the value of the tests for predicting restriction of fetal growth and compromise of fetal wellbeing. The systematic overviews will assess the quality of the available evidence, estimate the magnitude of potential benefits, identify those tests with good predictive value and help formulate practice recommendations

Survivorship and improving quality of life in men with prostate cancer

Context: Long-term survival following a diagnosis of cancer is improving in developed nations. However, living longer does not necessarily equate to living well. Objective: To search systematically and synthesise narratively the evidence from randomised controlled trials (RCTs) of supportive interventions designed to improve prostate cancer (PCa)-specific quality of life (QoL). Evidence acquisition: A systematic search of Medline and Embase was carried out from inception to July 2014 to identify interventions targeting PCa QoL outcomes. We did not include nonrandomised studies or trials of mixed cancer groups. In addition to database searches, citations from included papers were hand-searched for any potentially eligible trials. Evidence synthesis: A total of 2654 PCa survivors from 20 eligible RCTs were identified from our database searches and reference checks. Disease-specific QoL was assessed most frequently by the Functional Assessment of Cancer Therapy-Prostate questionnaire. Included studies involved men across all stages of disease. Supportive interventions that featured individually tailored approaches and supportive interaction with dedicated staff produced the most convincing evidence of a benefit for PCa-specific QoL. Much of these data come from lifestyle interventions. Our review found little supportive evidence for simple literature provision (either in booklets or via online platforms) or cognitive behavioural approaches. Conclusions: Physical and psychological health problems can have a serious negative impact on QoL in PCa survivors. Individually tailored supportive interventions such as exercise prescription/referral should be considered by multidisciplinary clinical teams where available. Cost-effectiveness data and an understanding of how to sustain benefits over the long term are important areas for future research. Patient summary: This review of supportive interventions for improving quality of life in prostate cancer survivors found that supervised and individually tailored patient-centred interventions such as lifestyle programmes are of benefit.</p

Combined Vemurafenib and Combimetinib in BRAF-Mutated Melanoma

Background The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.Methods We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival.Results The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68;

Sound Signalling in Orthoptera

The sounds produced by orthopteran insects are very diverse. They are widely studied for the insight they give into acoustic behaviour and the biophysical aspects of sound production and hearing, as well as the transduction of sound to neural signals in the ear and the subsequent processing of information in the central nervous system. The study of sound signalling is a multidisciplinary area of research, with a strong physiological contribution. This review considers recent research in physiology and the links with related areas of acoustic work on the Orthoptera