SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND:Programmed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy. METHODS:This retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC. RESULTS:412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC < 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC < 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC < 50%, 10.0 months, P = 0.39, respectively). CONCLUSIONS:PD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies. Trial registration ClinicalTrials.gov, NCT02543476. Registered September 4, 2015

Maverick dark matter at colliders

Assuming that dark matter is a weakly interacting massive particle (WIMP) species X produced in the early Universe as a cold thermal relic, we study the collider signal of pp or ppbar -> XXbar + jets and its distinguishability from standard-model background processes associated with jets and missing energy. We assume that the WIMP is the sole particle related to dark matter within reach of the LHC--a "maverick" particle--and that it couples to quarks through a higher dimensional contact interaction. We simulate the WIMP final-state signal XXbar + jet and dominant standard-model (SM) background processes and find that the dark-matter production process results in higher energies for the colored final state partons than do the standard-model background processes, resulting in more QCD radiation and a higher jet multiplicity. As a consequence, the detectable signature of maverick dark matter is an excess over standard-model expectations of events consisting of large missing transverse energy, together with large leading jet transverse momentum and scalar sum of the transverse momenta of the jets. Existing Tevatron data and forthcoming LHC data can constrain (or discover!) maverick dark matter.Comment: 11 pages, 7 figure

Effects of seagrasses and algae of the Caulerpa family on hydrodynamics and particle-trapping rates

The widespread decline of seagrass beds within the Mediterranean often results in the replacement of seagrasses by opportunistic green algae of the Caulerpa family. Because Caulerpa beds have a different height, stiffness and density compared to seagrasses, these changes in habitat type modify the interaction of the seafloor with hydrodynamics, influencing key processes such as sediment resuspension and particle trapping. Here, we compare the effects on hydrodynamics and particle trapping of Caulerpa taxifolia, C. racemosa, and C. prolifera with the Mediterranean seagrasses Cymodocea nodosa and Posidonia oceanica. All macrophyte canopies reduced near-bed volumetric flow rates compared to bare sediment, vertical profiles of turbulent kinetic energy revealed peak values around the top of the canopies, and maximum values of Reynolds stress increased by a factor of between 1.4 (C. nodosa) and 324.1 (P. oceanica) when vegetation was present. All canopies enhanced particle retention rates compared to bare sediment. The experimental C. prolifera canopy was the most effective at particle retention (m2 habitat); however, C. racemosa had the largest particle retention capacity per structure surface area. Hence, in terms of enhancing particle trapping and reducing hydrodynamic forces at the sediment surface, Caulerpa beds provided a similar or enhanced function compared to P.oceanica and C. nodosa. However, strong seasonality in the leaf area index of C. racemosa and C. taxifolia within the Mediterranean, combined with a weak rhizome structure, suggests that sediments maybe unprotected during winter storms, when most erosion occurs. Hence, replacement of seagrass beds with Caulerpa is likely to have a major influence on annual sediment dynamics at ecosystem scales.This research was funded by the European Network of Excellence ‘‘Marine Biodiversity and Ecosystem Function’’ (MarBEF); FP6, EC contract no. 505446 and a grant from the Fundacio ´n BBVA. EPM was supported by a European Union Marie Curie host fellowship for transfer of knowledge, MTKD-CT-2004-509254, the Spanish national project EVAMARIA (CTM2005-00395/MAR) and the regional government of Andalusia project FUNDIV(P07-RNM-2516)

Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

Occupational differences, cardiovascular risk factors and lifestyle habits in South Eastern rural Australia

BACKGROUND: In rural and remote Australia, cardiovascular mortality and morbidity rates are higher than metropolitan rates.This study analysed cardiovascular and other chronic disease risk factors and related health behaviours by occupational status, to determine whether agricultural workers have higher cardiovascular disease (CVD) risk than other rural workers. METHODS: Cross-sectional surveys in three rural regions of South Eastern Australia (2004-2006). A stratified random sample of 1001 men and women aged 25-74 from electoral rolls were categorised by occupation into agricultural workers (men = 214, women = 79), technicians (men = 123), managers (men = 148, women = 272) and 'home duties' (women = 165). Data were collected from self-administered questionnaire, physical measurements and laboratory tests. Cardiovascular disease (CVD) and coronary heart disease (CHD) risk were assessed by Framingham 5 years risk calculation. RESULTS: Amongst men, agricultural workers had higher occupational physical activity levels, healthier more traditional diet, lower alcohol consumption, lower fasting plasma glucose, the lowest proportion of daily smokers and lower age-adjusted 5 year CVD and CHD risk scores.Amongst women, managers were younger with higher HDL cholesterol, lower systolic blood pressure, less hypertension, lower waist circumference, less self-reported diabetes and better 5 year CVD and CHD risk scores.Agricultural workers did not have higher cardiovascular disease risk than other occupational groups. CONCLUSIONS: Previous studies have suggested that farmers have higher risks of cardiovascular disease but this is because the risk has been compared with non-rural populations. In this study, the comparison has been made with other rural occupations. Cardiovascular risk reduction programs are justified for all. Programs tailored only for agricultural workers are unwarranted

Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli

Gram-negative bacteria, such as Escherichia coli, expel toxic chemicals via tripartite efflux pumps spanning both the inner and outer membranes. The three parts are: 1) a membrane fusion protein connecting 2) a substrate-binding inner membrane transporter to 3) an outer membrane-anchored channel in the periplasmic space. A crystallographic model of this tripartite efflux complex has been unavailable simply because co-crystallization of different components of the system has proven to be extremely difficult. We previously described the crystal structures of both the inner membrane transporter CusA1 and membrane fusion protein CusB2 of the CusCBA efflux system3,4 from E. coli. We here report the co-crystal structure of the CusBA efflux complex, revealing the trimeric CusA efflux pump interacts with six CusB protomers at the upper half of the periplasmic domain. These six CusB molecules form a channel extending contiguously from the top of the pump. The affinity of the CusA and CusB interaction was found to be in the micromolar range. Finally, we predicted a three-dimensional structure of the trimeric CusC outer membrane channel, and develop a model of the tripartite efflux assemblage. This CusC3-CusB6-CusA3 model presents a 750 kDa efflux complex spanning the entire bacterial cell envelope to export Cu(I)/Ag(I) ions

Prospects for seasonal forecasting of iceberg distributions in the North Atlantic

An efficient approach to ocean–iceberg modelling provides a means for assessing prospects for seasonal forecasting of iceberg distributions in the northwest Atlantic, where icebergs present a hazard to mariners each spring. The stand-alone surface (SAS) module that is part of the Nucleus for European Modelling of the Ocean (NEMO) is coupled with the NEMO iceberg module (ICB) in a “SAS-ICB” configuration with horizontal resolution of 0.25°. Iceberg conditions are investigated for three recent years, 2013–2015, characterized by widely varying iceberg distributions. The relative simplicity of SAS-ICB facilitates efficient investigation of sensitivity to iceberg fluxes and prevailing environmental conditions. SAS-ICB is provided with daily surface ocean analysis fields from the global Forecasting Ocean Assimilation Model (FOAM) of the Met Office. Surface currents, temperatures and height together determine iceberg advection and melting rates. Iceberg drift is further governed by surface winds, which are updated every 3 h. The flux of icebergs from the Greenland ice sheet is determined from engineering control theory and specified as an upstream flux in the vicinity of Davis Strait for January or February. Simulated iceberg distributions are evaluated alongside observations reported and archived by the International Ice Patrol. The best agreement with observations is obtained when variability in both upstream iceberg flux and oceanographic/atmospheric conditions is taken into account. Including interactive icebergs in an ocean–atmosphere model with sufficient seasonal forecast skill, and provided with accurate winter iceberg fluxes, it is concluded that seasonal forecasts of spring/summer iceberg conditions for the northwest Atlantic are now a realistic prospect

Dynamic Emotional and Neural Responses to Music Depend on Performance Expression and Listener Experience

Apart from its natural relevance to cognition, music provides a window into the intimate relationships between production, perception, experience, and emotion. Here, emotional responses and neural activity were observed as they evolved together with stimulus parameters over several minutes. Participants listened to a skilled music performance that included the natural fluctuations in timing and sound intensity that musicians use to evoke emotional responses. A mechanical performance of the same piece served as a control. Before and after fMRI scanning, participants reported real-time emotional responses on a 2-dimensional rating scale (arousal and valence) as they listened to each performance. During fMRI scanning, participants listened without reporting emotional responses. Limbic and paralimbic brain areas responded to the expressive dynamics of human music performance, and both emotion and reward related activations during music listening were dependent upon musical training. Moreover, dynamic changes in timing predicted ratings of emotional arousal, as well as real-time changes in neural activity. BOLD signal changes correlated with expressive timing fluctuations in cortical and subcortical motor areas consistent with pulse perception, and in a network consistent with the human mirror neuron system. These findings show that expressive music performance evokes emotion and reward related neural activations, and that music's affective impact on the brains of listeners is altered by musical training. Our observations are consistent with the idea that music performance evokes an emotional response through a form of empathy that is based, at least in part, on the perception of movement and on violations of pulse-based temporal expectancies

Crystal structures of the CusA efflux pump suggest methionine-mediated metal transport

Gram-negative bacteria, such as Escherichia coli, frequently utilize tripartite efflux complexes in the resistance-nodulation-cell division (RND) family to expel diverse toxic compounds from the cell.1,2 The efflux system CusCBA is responsible for extruding biocidal Cu(I) and Ag(I) ions.3,4 No prior structural information was available for the heavy-metal efflux (HME) subfamily of the RND efflux pumps. Here we describe the crystal structures of the inner membrane transporter CusA in the absence and presence of bound Cu(I) or Ag(I). These CusA structures provide important new structural information about the HME sub-family of RND efflux pumps. The structures suggest that the metal binding sites, formed by a three-methionine cluster, are located within the cleft region of the periplasmic domain. Intriguingly, this cleft is closed in the apo-CusA form but open in the CusA-Cu(I) and CusA-Ag(I) structures, which directly suggests a plausible pathway for ion export. Binding of Cu(I) and Ag(I) triggers significant conformational changes in both the periplasmic and transmembrane domains. The crystal structure indicates that CusA has, in addition to the three-methionine metal binding site, four methionine pairs - three located in the transmembrane region and one in the periplasmic domain. Genetic analysis and transport assays suggest that CusA is capable of actively picking up metal ions from the cytosol, utilizing these methionine pairs/clusters to bind and export metal ions. These structures suggest a stepwise shuttle mechanism for transport between these sites