Impact of depth of response on survival in patients treated with cobimetinib ± vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM.

BackgroundThis pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with vemurafenib or cobimetinib plus vemurafenib.MethodsThe data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures.ResultsGreater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with vemurafenib; not estimable with cobimetinib plus vemurafenib). Cobimetinib plus vemurafenib improved depth of response versus vemurafenib monotherapy regardless of other prognostic factors, including gene signatures.ConclusionsGreater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses

The molecular characterisation of Cryptosporidium species in relinquished dogs in Great Britain: a novel zoonotic risk?

Surveillance was conducted to investigate the occurrence of protozoan parasites of the genus Cryptosporidium in dogs newly admitted to a dog rehoming charity in London, Great Britain. Voided faecal samples were collected from all new admissions between 2011 and 2012 during six separate 4-week sampling periods. Information on host signalment, including age, breed and reason for submission and faecal consistency, was collected. Polymerase Chain Reaction (PCR) targeting the 18S ribosomal RNA gene, confirmed by sequencing, was conducted on the faecal samples to detect Cryptosporidium genomic DNA and determine Cryptosporidium identity. In total, 677 dogs were included in the study. The prevalence of Cryptosporidium-positive faecal samples was 4.6% (31/676). There were positive samples in all of the six sampling periods. Cryptosporidium canis (n = 28), C. parvum (n = 2) and C. andersoni (n = 1) were identified. Sixty KDa glycoprotein (gp60) gene amplicon sequencing of the C. parvum samples identified genotypes IIaA17G1R1 and IIaA15G2R1 for the first time from a dog. There were no significant associations between signalment data and Cryptosporidium status. While this was a study of one rehoming shelter, the presence of the potentially zoonotic C. parvum and C. canis in dogs highlights a public health concern. Further research is needed to better understand the epidemiology and potential impacts of Cryptosporidium infection in dogs

How different data sources and definitions of neighbourhood influence the association between food outlet availability and body mass index: a cross-sectional study.

Inconsistencies in methodologies continue to inhibit understanding of the impact of the environment on body mass index (BMI). To estimate the effect of these differences, we assessed the impact of using different definitions of neighbourhood and data sets on associations between food outlet availability within the environment and BMI. Previous research has not extended this to show any differences in the strength of associations between food outlet availability and BMI across both different definitions of neighbourhood and data sets. Descriptive statistics showed differences in the number of food outlets, particularly other food retail outlets between different data sets and definitions of neighbourhood. Despite these differences, our key finding was that across both different definitions of neighbourhood and data sets, there was very little difference in size of associations between food outlets and BMI. Researchers should consider and transparently report the impact of methodological choices such as the definition of neighbourhood and acknowledge any differences in associations between the food environment and BMI

Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Political Leadership as Statecraft? Aligning Theory with Praxis in Conversation with British Party Leaders

How should prime ministerial and party leadership be understood and assessed? One leading approach posits that we should assess them in terms of whether they achieve statecraft, that is, winning and maintain office in government. This article supplements and then assesses that theory by drawing from Pawson and Tilley’s (1997) concept of the realistic interview, in which practitioners are deployed as co-researchers to assess and revise theory. Unprecedented interviews with British party leaders were therefore undertaken. The article provides new empirical support for the framework because many of the key generative mechanisms identified within the neo-statecraft model were present in an analysis of the interviews. The interviews also allowed the limitations of the model to be demarcated. Statecraft focusses purely on cunning leadership where the aim is to maximise power and influence. This differs from leadership by conscious where the aim is to achieve normative goals

The Community Climate System Model version 3 (CCSM3)

Author Posting. © American Meteorological Society 2006. 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 19 (2006): 2122–2143, doi:10.1175/JCLI3761.1.The Community Climate System Model version 3 (CCSM3) has recently been developed and released to the climate community. CCSM3 is a coupled climate model with components representing the atmosphere, ocean, sea ice, and land surface connected by a flux coupler. CCSM3 is designed to produce realistic simulations over a wide range of spatial resolutions, enabling inexpensive simulations lasting several millennia or detailed studies of continental-scale dynamics, variability, and climate change. This paper will show results from the configuration used for climate-change simulations with a T85 grid for the atmosphere and land and a grid with approximately 1° resolution for the ocean and sea ice. The new system incorporates several significant improvements in the physical parameterizations. The enhancements in the model physics are designed to reduce or eliminate several systematic biases in the mean climate produced by previous editions of CCSM. These include new treatments of cloud processes, aerosol radiative forcing, land–atmosphere fluxes, ocean mixed layer processes, and sea ice dynamics. There are significant improvements in the sea ice thickness, polar radiation budgets, tropical sea surface temperatures, and cloud radiative effects. CCSM3 can produce stable climate simulations of millennial duration without ad hoc adjustments to the fluxes exchanged among the component models. Nonetheless, there are still systematic biases in the ocean–atmosphere fluxes in coastal regions west of continents, the spectrum of ENSO variability, the spatial distribution of precipitation in the tropical oceans, and continental precipitation and surface air temperatures. Work is under way to extend CCSM to a more accurate and comprehensive model of the earth's climate system.We would like to acknowledge the substantial contributions to and support for the CCSM project from the National Science Foundation (NSF), the Department of Energy (DOE), the National Oceanic and Atmospheric Administration, and the National Aeronautics and Space Administration

X-ray harmonic comb from relativistic electron spikes

X-ray devices are far superior to optical ones for providing nanometre spatial and attosecond temporal resolutions. Such resolution is indispensable in biology, medicine, physics, material sciences, and their applications. A bright ultrafast coherent X-ray source is highly desirable, for example, for the diffractive imaging of individual large molecules, viruses, or cells. Here we demonstrate experimentally a new compact X-ray source involving high-order harmonics produced by a relativistic-irradiance femtosecond laser in a gas target. In our first implementation using a 9 Terawatt laser, coherent soft X-rays are emitted with a comb-like spectrum reaching the 'water window' range. The generation mechanism is robust being based on phenomena inherent in relativistic laser plasmas: self-focusing, nonlinear wave generation accompanied by electron density singularities, and collective radiation by a compact electric charge. The formation of singularities (electron density spikes) is described by the elegant mathematical catastrophe theory, which explains sudden changes in various complex systems, from physics to social sciences. The new X-ray source has advantageous scalings, as the maximum harmonic order is proportional to the cube of the laser amplitude enhanced by relativistic self-focusing in plasma. This allows straightforward extension of the coherent X-ray generation to the keV and tens of keV spectral regions. The implemented X-ray source is remarkably easily accessible: the requirements for the laser can be met in a university-scale laboratory, the gas jet is a replenishable debris-free target, and the harmonics emanate directly from the gas jet without additional devices. Our results open the way to a compact coherent ultrashort brilliant X-ray source with single shot and high-repetition rate capabilities, suitable for numerous applications and diagnostics in many research fields

Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness.

BACKGROUND: Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support. METHODS: To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients. RESULTS: We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors' FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups. CONCLUSION: Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies.MRC, Evelyn Trust, Intensive Care Society, Royal Free Charit

Novel Role of Prostate Apoptosis Response-4 Tumor Suppressor in B-Cell Chronic Lymphocytic Leukemia

Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Eμ-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)–approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors