Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and confers a poor prognosis. Beyond standard systemic therapy with multikinase inhibitors, recent studies demonstrate the potential for robust and durable responses from immune checkpoint inhibition in subsets of HCC patients across disease etiologies. The majority of HCC arises in the context of chronic inflammation and from within a fibrotic liver, with many cases associated with hepatitis virus infections, toxins, and fatty liver disease. Many patients also have concomitant cirrhosis which is associated with both local and systemic immune deficiency. Furthermore, the liver is an immunologic organ in itself, which may enhance or suppress the immune response to cancer arising within it. Here, we explore the immunobiology of the liver from its native state to chronic inflammation, fibrosis, cirrhosis and then to cancer, and summarize how this unique microenvironment may affect the response to immunotherapy

The Cost of Free Assistance: Why Low-Income Individuals Do Not Access Food Pantries

Non-governmental free food assistance is available to many lowincome Americans through food pantries. However, most do not use this assistance, even though it can be worth over $2,000 per year. Survey research suggests concrete barriers, such as lack of information, account for non-use. In contrast, qualitative studies focus on the role of cultural factors, such as stigma. Drawing on interviews with 53 low-income individuals in San Francisco who did not use food pantries, we reconcile these findings by illustrating how the two types of barriers are connected. Reasons for non-use such as need, information, long lines, and food quality were rooted in respondents\u27 subjective understandings of those for whom the service was intended, those perceived to use the service, and the service\u27s respect for the community. Increasing nonprofit service utilization requires attention to how potential users relate seemingly objective barriers to subjective interpretations

Forward Modeling of Double Neutron Stars: Insights from Highly-Offset Short Gamma-Ray Bursts

We present a detailed analysis of two well-localized, highly offset short gamma-ray bursts---GRB~070809 and GRB~090515---investigating the kinematic evolution of their progenitors from compact object formation until merger. Calibrating to observations of their most probable host galaxies, we construct semi-analytic galactic models that account for star formation history and galaxy growth over time. We pair detailed kinematic evolution with compact binary population modeling to infer viable post-supernova velocities and inspiral times. By populating binary tracers according to the star formation history of the host and kinematically evolving their post-supernova trajectories through the time-dependent galactic potential, we find that systems matching the observed offsets of the bursts require post-supernova systemic velocities of hundreds of kilometers per second. Marginalizing over uncertainties in the stellar mass--halo mass relation, we find that the second-born neutron star in the GRB~070809 and GRB~090515 progenitor systems received a natal kick of $\gtrsim 200~\mathrm{km\,s}^{-1}$ at the 78\% and 91\% credible levels, respectively. Applying our analysis to the full catalog of localized short gamma-ray bursts will provide unique constraints on their progenitors and help unravel the selection effects inherent to observing transients that are highly offset with respect to their hosts.Comment: 18 pages, 7 figures, 1 table. ApJ, in pres

Short GRB Host Galaxies. II. A Legacy Sample of Redshifts, Stellar Population Properties, and Implications for their Neutron Star Merger Origins

We present the stellar population properties of 69 short gamma-ray burst (GRB) host galaxies, representing the largest uniformly-modeled sample to-date. Using the Prospector stellar population inference code, we jointly fit photometry and/or spectroscopy of each host galaxy. We find a population median redshift of $z=0.64^{+0.83}_{-0.32}$ ($68\%$ confidence), including 10 new or revised photometric redshifts at $z\gtrsim1$. We further find a median mass-weighted age of $t_m=0.8^{+2.71}_{-0.53}$Gyr, stellar mass of $\log(M_*/M_\odot)=9.69^{+0.75}_{-0.65}$, star formation rate of SFR=$1.44^{+9.37}_{-1.35}M_\odot$yr$^{-1}$, stellar metallicity of $\log(Z_*/Z_\odot)=-0.38^{+0.44}_{-0.42}$, and dust attenuation of $A_V=0.43^{+0.85}_{-0.36}$~mag (68\% confidence). Overall, the majority of short GRB hosts are star-forming ($\approx84\%$), with small fractions that are either transitioning ($\approx6\%$) or quiescent ($\approx10\%$); however, we observe a much larger fraction ($\approx40\%$) of quiescent and transitioning hosts at $z\lesssim0.25$, commensurate with galaxy evolution. We find that short GRB hosts populate the star-forming main sequence of normal field galaxies, but do not include as many high-mass galaxies, implying that their binary neutron star (BNS) merger progenitors are dependent on a combination of host star formation and stellar mass. The distribution of ages and redshifts implies a broad delay-time distribution, with a fast-merging channel at $z>1$ and a decreased BNS formation efficiency at lower redshifts. If short GRB hosts are representative of BNS merger hosts within the horizon of current gravitational wave detectors, these results can inform future searches for electromagnetic counterparts. All of the data and modeling products are available on the BRIGHT website.Comment: 32 pages, 15 figures, 3 tables, accepted to Ap

Capsular polysaccharide production and serum survival of Vibrio vulnificus are dependent on antitermination control by RfaH

© 2016 Federation of European Biochemical Societies The human pathogen Vibrio vulnificus undergoes phase variation among colonial morphotypes, including a virulent opaque form which produces capsular polysaccharide (CPS) and a translucent phenotype that produces little or no CPS and is attenuated. Here, we found that a V. vulnificus mutant defective for RfaH antitermination control showed a diminished capacity to undergo phase variation and displayed significantly reduced distal gene expression within the Group I CPS operon. Moreover, the rfaH mutant produced negligible CPS and was highly sensitive to killing by normal human serum, results which indicate that RfaH is likely essential for virulence in this bacterium

What is the Most Promising Electromagnetic Counterpart of a Neutron Star Binary Merger?

The final inspiral of double neutron star and neutron star-black hole binaries are likely to be detected by advanced networks of ground-based gravitational wave (GW) interferometers. Maximizing the science returns from such a discovery will require the identification and localization of an electromagnetic (EM) counterpart. Here we critically evaluate and compare several possible counterparts, including short-duration gamma-ray bursts (SGRBs), "orphan" optical and radio afterglows, and ~day-long optical transients powered by the radioactive decay of heavy nuclei synthesized in the merger ejecta ("kilonovae"). We assess the promise of each counterpart in terms of four "Cardinal Virtues": detectability, high fraction, identifiability, and positional accuracy. Taking into account the search strategy for typical error regions of ~10s degs sq., we conclude that SGRBs are the most useful to confirm the cosmic origin of a few GW events, and to test the association with NS mergers. However, for the more ambitious goal of localizing and obtaining redshifts for a large sample of GW events, kilonovae are instead preferred. Off-axis optical afterglows will be detectable for at most ~10% of all events, while radio afterglows are promising only for the unique combination of energetic relativistic ejecta in a high density medium, and even then will require hundreds of hours of EVLA time per event. Our main recommendations are:(i) an all-sky gamma-ray satellite is essential for temporal coincidence detections, and for GW searches of gamma-ray triggered events; (ii) LSST should adopt a 1-day cadence follow-up strategy, ideally with ~0.5 hr per pointing to cover GW error regions (the standard 4-day cadence and depth will severely limit the probability of a unique identification); and (iii) radio searches should only focus on the relativistic case, which requires observations for a few months.Comment: 16 pages, 9 figures, 3 tables, submitted to Ap

Anatomy of protein disorder, flexibility and disease-related mutations.

Integration of protein structural information with human genetic variation and pathogenic mutations is essential to understand molecular mechanisms associated with the effects of polymorphisms on protein interactions and cellular processes. We investigate occurrences of non-synonymous SNPs in ordered and disordered protein regions by systematic mapping of common variants and disease-related SNPs onto these regions. We show that common variants accumulate in disordered regions; conversely pathogenic variants are significantly depleted in disordered regions. These different occurrences of pathogenic and common SNPs can be attributed to a negative selection on random mutations in structurally highly constrained regions. New approaches in the study of quantitative effects of pathogenic-related mutations should effectively account for all the possible contexts and relative functional constraints in which the sequence variation occurs.This research was supported by the Biotechnology and Biological Sciences Research Council (BB/H018409/1 to FF), the British Heart Foundation (FS/12/41/29724 to AF and FF) and the Leukaemia & Lymphoma Research (to FF). SSC is funded by a Leukaemia & Lymphoma Research Gordon Piller PhD Studentship

The PHENIX Experiment at RHIC

The physics emphases of the PHENIX collaboration and the design and current status of the PHENIX detector are discussed. The plan of the collaboration for making the most effective use of the available luminosity in the first years of RHIC operation is also presented.Comment: 5 pages, 1 figure. Further details of the PHENIX physics program available at http://www.rhic.bnl.gov/phenix

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types