Combination immunotherapy induces distinct T-cell repertoire responses when administered to patients with different malignancies.

BackgroundCTLA-4 blockade with ipilimumab is Food and Drug Administration-approved for melanoma as a monotherapy and has been shown to modulate the circulating T-cell repertoire. We have previously reported clinical trials combining CTLA-4 blockade with granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic melanoma patients and in metastatic castration resistant prostate cancer (mCRPC) patients. Here, we investigate the effect that cancer type has on circulating T cells in metastatic melanoma and mCRPC patients, treated with ipilimumab and GM-CSF.MethodsWe used next-generation sequencing of T-cell receptors (TCR) to compare the circulating T cells of melanoma and mCRPC patients receiving the same treatment with ipilimumab and GM-CSF by Wilcoxon rank sum test. Flow cytometry was utilized to investigate specific T-cell populations. TCR sequencing results were correlated with each T-cell subpopulation by Spearman's rank correlation coefficient. Of note, 14 metastatic melanoma patients had samples available for TCR sequencing and 21 had samples available for flow cytometry analysis; 37 mCRPC patients had samples available for sequencing of whom 22 have TCR data available at both timepoints; 20 of these patients had samples available for flow cytometry analysis and 16 had data available at both timepoints.ResultsWhile melanoma and mCRPC patients had similar pretreatment circulating T-cell counts, treatment induces greater expansion of circulating T cells in melanoma patients. Metastatic melanoma patients have a higher proportion of clones that increased more than fourfold after the treatment compared with mCRPC patients (18.9% vs 11.0%, p=0.017). Additionally, melanoma patients compared with mCRPC patients had a higher ratio of convergent frequency (1.22 vs 0.60, p=0.012). Decreases in clonality induced by treatment are associated with baseline CD8+ T-cell counts in both patient groups, but are more pronounced in the melanoma patients (r=-0.81, p<0.001 vs r=-0.59, p=0.02).Trial registration numbersNCT00064129; NCT01363206

Liquid-like thermal conduction in a crystalline solid

A solid conducts heat through both transverse and longitudinal acoustic phonons, but a liquid employs only longitudinal vibrations. Here, we report that the crystalline solid AgCrSe2 has liquid-like thermal conduction. In this compound, Ag atoms exhibit a dynamic duality that they are exclusively involved in intense low-lying transverse acoustic phonons while they also undergo local fluctuations inherent in an order-to-disorder transition occurring at 450 K. As a consequence of this extreme disorder-phonon coupling, transverse acoustic phonons become damped as approaching the transition temperature, above which they are not defined anymore because their lifetime is shorter than the relaxation time of local fluctuations. Nevertheless, the damped longitudinal acoustic phonon survives for thermal transport. This microscopic insight might reshape the fundamental idea on thermal transport properties of matter and facilitates the optimization of thermoelectrics.Comment: four figures, supplemental informatio

Shear stress regulation of miR-93 and miR-484 maturation through nucleolin.

Pulsatile shear (PS) and oscillatory shear (OS) elicit distinct mechanotransduction signals that maintain endothelial homeostasis or induce endothelial dysfunction, respectively. A subset of microRNAs (miRs) in vascular endothelial cells (ECs) are differentially regulated by PS and OS, but the regulation of the miR processing and its implications in EC biology by shear stress are poorly understood. From a systematic in silico analysis for RNA binding proteins that regulate miR processing, we found that nucleolin (NCL) is a major regulator of miR processing in response to OS and essential for the maturation of miR-93 and miR-484 that target mRNAs encoding Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS). Additionally, anti-miR-93 and anti-miR-484 restore KLF2 and eNOS expression and NO bioavailability in ECs under OS. Analysis of posttranslational modifications of NCL identified that serine 328 (S328) phosphorylation by AMP-activated protein kinase (AMPK) was a major PS-activated event. AMPK phosphorylation of NCL sequesters it in the nucleus, thereby inhibiting miR-93 and miR-484 processing and their subsequent targeting of KLF2 and eNOS mRNA. Elevated levels of miR-93 and miR-484 were found in sera collected from individuals afflicted with coronary artery disease in two cohorts. These findings provide translational relevance of the AMPK-NCL-miR-93/miR-484 axis in miRNA processing in EC health and coronary artery disease

A study of the static yield stress in a binary Lennard-Jones glass

The stress-strain relations and the yield behavior of model glass (a 80:20 binary Lennard-Jones mixture) is studied by means of MD simulations. First, a thorough analysis of the static yield stress is presented via simulations under imposed stress. Furthermore, using steady shear simulations, the effect of physical aging, shear rate and temperature on the stress-strain relation is investigated. In particular, we find that the stress at the yield point (the ``peak''-value of the stress-strain curve) exhibits a logarithmic dependence both on the imposed shear rate and on the ``age'' of the system in qualitative agreement with experiments on amorphous polymers and on metallic glasses. In addition to the very observation of the yield stress which is an important feature seen in experiments on complex systems like pastes, dense colloidal suspensions and foams, further links between our model and soft glassy materials are found. An example are hysteresis loops in the system response to a varying imposed stress. Finally, we measure the static yield stress for our model and study its dependence on temperature. We find that for temperatures far below the mode coupling critical temperature of the model ($Tc = 0.435$), \sigmay decreases slowly upon heating followed by a stronger decrease as \Tc is approached. We discuss the reliability of results on the static yield stress and give a criterion for its validity in terms of the time scales relevant to the problem.Comment: 14 pages, 18 figure

Suppression of the 2010 Alexandrium fundyense bloom by changes in physical, biological, and chemical properties of the Gulf of Maine

Author Posting. © American Society of Limnology and Oceanography, 2011. This article is posted here by permission of American Society of Limnology and Oceanography for personal use, not for redistribution. The definitive version was published in Limnology and Oceanography 56 (2011): 2411-2426, doi:10.4319/lo.2011.56.6.2411.For the period 2005–2009, the abundance of resting cysts in bottom sediments from the preceding autumn was a first-order predictor of the overall severity of spring–summer blooms of Alexandrium fundyense in the western Gulf of Maine and southern New England. Cyst abundance off mid-coast Maine was significantly higher in autumn 2009 than it was preceding a major regional bloom in 2005. A seasonal ensemble forecast was computed using a range of forcing conditions for the period 2004–2009, suggesting that a large bloom was likely in the western Gulf of Maine in 2010. This did not materialize, perhaps because environmental conditions in spring–summer 2010 were not favorable for growth of A. fundyense. Water mass anomalies indicate a regional-scale change in circulation with direct influence on A. fundyense's niche. Specifically, near-surface waters were warmer, fresher, more stratified, and had lower nutrients than during the period of observations used to construct the ensemble forecast. Moreover, a weaker-than-normal coastal current lessened A. fundyense transport into the western Gulf of Maine and Massachusetts Bay. Satellite ocean color observations indicate the 2010 spring phytoplankton bloom was more intense than usual. Early season nutrient depletion may have caused a temporal mismatch with A. fundyense's endogenous clock that regulates the timing of cyst germination. These findings highlight the difficulties of ecological forecasting in a changing oceanographic environment, and underscore the need for a sustained observational network to drive such forecasts.We gratefully acknowledge support of the National Oceanic Atmospheric Administration (grant NA06NOS4780245 for the Gulf of Maine Toxicity (GOMTOX) program) and the Woods Hole Center for Oceans and Human Health through National Science Foundation grants OCE-0430724 and OCE-0911031 and National Institute of Environmental Health Sciences grant 1P50- ES01274201

Impact of Tobacco-Related Health Warning Labels across Socioeconomic, Race and Ethnic Groups: Results from a Randomized Web-Based Experiment

Background: The U.S. Family Smoking Prevention and Tobacco Control Act of 2009 requires updating of the existing text-only health warning labels on tobacco packaging with nine new warning statements accompanied by pictorial images. Survey and experimental research in the U.S. and other countries supports the effectiveness of pictorial health warning labels compared with text-only warnings for informing smokers about the risks of smoking and encouraging cessation. Yet very little research has examined differences in reactions to warning labels by race/ethnicity, education or income despite evidence that population subgroups may differ in their ability to process health information. The purpose of the present study was to evaluate the potential impact of pictorial warning labels compared with text-only labels among U.S. adult smokers from diverse racial/ethnic and socioeconomic subgroups. Methods/Findings: Participants were adult smokers recruited from two online research panels (n = 3,371) into a web-based experimental study to view either the new pictorial warnings or text-only warnings. Participants viewed the labels and reported their reactions. Adjusted regression models demonstrated significantly stronger reactions for the pictorial condition for each outcome salience (b = 0.62, p<.001); perceived impact (b = 0.44, p<.001); credibility (OR = 1.41, 95% CI = 1.22−1.62), and intention to quit (OR = 1.30, 95% CI = 1.10−1.53). No significant results were found for interactions between condition and race/ethnicity, education, or income. The only exception concerned the intention to quit outcome, where the condition-by-education interaction was nearly significant (p = 0.057). Conclusions: Findings suggest that the greater impact of the pictorial warning label compared to the text-only warning is consistent across diverse racial/ethnic and socioeconomic populations. Given their great reach, pictorial health warning labels may be one of the few tobacco control policies that have the potential to reduce communication inequalities across groups. Policies that establish strong pictorial warning labels on tobacco packaging may be instrumental in reducing the toll of the tobacco epidemic, particularly within vulnerable communities

Supersymmetric Contributions to Bs->K+K-

Inspired by the existing calculation of B->piK decays in supersymmetry (SUSY), we evaluate the dominant SUSY contributions to Bs->K+K-. We show that the observables of this process can be significantly modified in the presence of SUSY. In particular, the branching ratio can be increased considerably compared to the prediction of the standard model (SM). The effect is even more dramatic for the CP-violating asymmetries A_dir and A_mix. These asymmetries, expected to be small in the SM (A_dir is predicted to take only positive values), change drastically with SUSY contributions. The measurement of these observables can therefore be used to detect the presence of physics beyond the SM, and put constraints on its parameters.Comment: 17 pages, 2 figures. This new version contains one added reference and some minor style change

New Physics Signals in Longitudinal Gauge Boson Scattering at the LHC

We introduce a novel technique designed to look for signatures of new physics in vector boson fusion processes at the TeV scale. This functions by measuring the polarization of the vector bosons to determine the relative longitudinal to transverse production. In studying this ratio we can directly probe the high energy E^2-growth of longitudinal vector boson scattering amplitudes characteristic of models with non-Standard Model (SM) interactions. We will focus on studying models parameterized by an effective Lagrangian that include a light Higgs with non-SM couplings arising from TeV scale new physics associated with the electroweak symmetry breaking, although our technique can be used in more general scenarios. We will show that this technique is stable against the large uncertainties that can result from variations in the factorization scale, improving upon previous studies that measure cross section alone