Androgen receptor activity in T cells limits checkpoint blockade efficacy.

Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1-5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.

Rising Prevalence of Mild Chronic Gastritis in Children: A Single Center Experience.

OBJECTIVES AND METHODS: We analyzed upper endoscopic and histological findings in 3 cohorts of children undergoing upper gastrointestinal endoscopy over a 10-year period. Five hundred seventy-nine patients were identified, with 244 (42%), 199 (35%), and 136 (23%) in the 2011, 2015, and 2019 cohorts, respectively. The most common symptoms and signs were abdominal pain, vomiting, failure to thrive, and diarrhea. RESULTS: The number of patients who had histological evidence of chronic gastritis increased from 2011 (n = 70, 29%) to 2015 (n = 106, 53%) and 2019 (n = 92, 68%; P < .001). The prevalence of "normal" endoscopic gastric findings was higher in controls (n = 247, 90%) compared to cases (n = 201, 76%; P < .001). There was a small but statistically significant difference in endoscopic esophageal grading (P = .008) over time, with lower grades being more prevalent in 2011 compared to 2015 (P = .026) and 2019 (P = .001). Crude comparisons of the predictors (sex, weight percentile, payor type, month of endoscopy, symptom duration, PPI exposure, and endoscopic stomach findings) yielded no difference between cases and controls. CONCLUSIONS: There has been a significant rise in the prevalence of mild chronic gastritis or non-specific gastritis over the last decade in our population.

Adsorption Behavior of the Coenzyme NADH at the Carbon/Electrolyte Interface Determined by Neutron Reflectometry.

The adsorption behavior of ß-nicotinamide adenine dinucleotide (NADH) at the carbon/electrolyte interface has been studied using a combination of neutron reflectometry (NR) and solution depletion isotherms. Coupling the NR technique with an electrochemical cell allowed in situ observation of the reversible adsorption and desorption of the molecule at the electrode surface over a range of applied potentials. The overall surface coverage was low (30-50%), suggesting adsorption only at specific defect sites on the surface. Isotherms conducted over a range of temperatures were used to extract thermodynamic parameters, which implied strong physisorption via electrostatic interactions. In addition, changes in the outermost layer of the carbon electrode were observed as the applied potential was varied, which were confirmed with ex situ X-ray reflectivity measurements (XRR). X-ray photoelectron spectroscopy (XPS) measurements of the carbon surface demonstrated the majority of carbon atoms were in an sp2 state.

Effect of Anionic Lipids on Mammalian Plasma Cell Membrane Properties.

The effect of lipid composition on models of the inner leaflet of mammalian cell membranes has been investigated. Grazing incidence X-ray diffraction and X-ray and neutron reflectivity have been used to characterize lipid packing and solvation, while electrochemical and infrared spectroscopic methods have been employed to probe phase behavior in an applied electric field. Introducing a small quantity of the anionic lipid dimyristoylphosphatidylserine (DMPS) into bilayers of zwitterionic dimyristoylphosphatidylethanolamine (DMPE) results in a significant change in the bilayer response to an applied field: the tilt of the hydrocarbon chains increases before returning to the original tilt angle on detachment of the bilayer. Equimolar mixtures, with slightly closer chain packing, exhibit a similar but weaker response. The latter also tend to incorporate more solvent during this electrochemical phase transition, at levels similar to those of pure DMPS. Reflectivity measurements reveal greater solvation of lipid layers for DMPS > 30 mol %, matching the greater propensity for DMPS-rich bilayers to incorporate water. Taken together, the data indicate that the range of 10-35 mol % DMPS provides optimum bilayer properties (in flexibility and function as a barrier), which may explain why the DMPS content of cell membranes tends to be found within this range.

pepsickle rapidly and accurately predicts proteasomal cleavage sites for improved neoantigen identification.

MOTIVATION: Proteasomal cleavage is a key component in protein turnover, as well as antigen processing and presentation. Although tools for proteasomal cleavage prediction are available, they vary widely in their performance, options and availability. RESULTS: Herein, we present pepsickle, an open-source tool for proteasomal cleavage prediction with better in vivo prediction performance (area under the curve) and computational speed than current models available in the field and with the ability to predict sites based on both constitutive and immunoproteasome profiles. Post hoc filtering of predicted patient neoepitopes using pepsickle significantly enriches for immune-responsive epitopes and may improve current epitope prediction and vaccine development pipelines. AVAILABILITY AND IMPLEMENTATION: pepsickle is open source and available at https://github.com/pdxgx/pepsickle. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Legal Admissibility of the Competence Assessment for Standing Trial for Defendants with Mental Retardation (CAST-MR).

The Competence Assessment for Standing Trial for Defendants with Mental Retardation (CAST-MR) was developed to assess competence to stand trial in defendants with Intellectual Disability. Although it remains the only validated instrument for this population, previous research has suggested it is rarely used by forensic examiners, a finding our survey of legal cases confirms. Initial validation studies provided some support for the instrument's reliability and validity. However, in both these and subsequent studies, there were significant limitations with respect to the size and representativeness of study samples, and therefore the associated interpretation of scores, such that questions remain as to whether the tool adequately assesses competence to stand trial in this population. In this paper, we review the research on the CAST-MR, discuss the strengths and limitations of the instrument, and debate its legal admissibility.

Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2.

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.

neoepiscope improves neoepitope prediction with multivariant phasing.

MOTIVATION: The vast majority of tools for neoepitope prediction from DNA sequencing of complementary tumor and normal patient samples do not consider germline context or the potential for the co-occurrence of two or more somatic variants on the same mRNA transcript. Without consideration of these phenomena, existing approaches are likely to produce both false-positive and false-negative results, resulting in an inaccurate and incomplete picture of the cancer neoepitope landscape. We developed neoepiscope chiefly to address this issue for single nucleotide variants (SNVs) and insertions/deletions (indels). RESULTS: Herein, we illustrate how germline and somatic variant phasing affects neoepitope prediction across multiple datasets. We estimate that up to ∼5% of neoepitopes arising from SNVs and indels may require variant phasing for their accurate assessment. neoepiscope is performant, flexible and supports several major histocompatibility complex binding affinity prediction tools. AVAILABILITY AND IMPLEMENTATION: neoepiscope is available on GitHub at https://github.com/pdxgx/neoepiscope under the MIT license. Scripts for reproducing results described in the text are available at https://github.com/pdxgx/neoepiscope-paper under the MIT license. Additional data from this study, including summaries of variant phasing incidence and benchmarking wallclock times, are available in Supplementary Files 1, 2 and 3. Supplementary File 1 contains Supplementary Table 1, Supplementary Figures 1 and 2, and descriptions of Supplementary Tables 2-8. Supplementary File 2 contains Supplementary Tables 2-6 and 8. Supplementary File 3 contains Supplementary Table 7. Raw sequencing data used for the analyses in this manuscript are available from the Sequence Read Archive under accessions PRJNA278450, PRJNA312948, PRJNA307199, PRJNA343789, PRJNA357321, PRJNA293912, PRJNA369259, PRJNA305077, PRJNA306070, PRJNA82745 and PRJNA324705; from the European Genome-phenome Archive under accessions EGAD00001004352 and EGAD00001002731; and by direct request to the authors. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Inpatient Pediatric Foreign Body Ingestion: National Estimates and Resource Utilization.

OBJECTIVE: We generated national estimates of patient and hospitalization characteristics for pediatric inpatient admissions for foreign body ingestion (FBI) and compared these to admissions for other reasons. We further identified characteristics that were independently associated with length of stay (LOS). Finally, we hypothesized that endoscopy within 24 hours of admission was independently associated with a shorter LOS in patients admitted for FBI. METHODS: In this retrospective study, we used data from the Kids' Inpatient Database for 2016. Admissions for FBI were identified and national estimates of patient and hospitalization characteristics were generated. Patients admitted for FBI were compared to patients admitted for other causes. Data were analyzed for independent associations with LOS. Subgroup analysis was performed to determine whether early endoscopy was associated with a shorter LOS. RESULTS: A total of 2464 admissions for FBI were identified in the database. The median (interquartile range) patient age was 4 (1-11) years with a slight male predominance. Most patients (82.6%) had an endoscopy performed during admission. Independent factors associated with increased LOS included: airway procedures, intra-abdominal surgery, psychiatric diagnosis, esophageal disorder, and developmental delay. Among patients who required endoscopy, 56.7% were performed early (within 24 hours). Early endoscopy was independently associated with a 35% shorter LOS (incidence rate ratio = 0.65, 95% confidence interval 0.54-0.80; P=0.009). CONCLUSIONS: Inpatient admissions for FBI frequently require endoscopy and have a short LOS. In patients who require endoscopy during the admission, early endoscopy (within 24 hours of admission) may be associated with a shorter LOS.

Preliminary examination of an insanity defense typology: Prevalence rates and correlates.

The present investigation was designed to systematically examine the insanity defense typology proposed by Brown (2018) using a large sample of cases wherein there was support for the insanity defense. A total of 187 court-ordered cases in which an insanity defense was supported were categorized based on the typology. The sample comprised of mostly single, middle-aged males who had been charged with a felony and diagnosed with a psychotic disorder. About half the sample was ultimately adjudicated not guilty by reason of insanity by the court. About two-thirds of the cases were categorized into one of the seven insanity defense subtypes using a coding scheme developed by the author of the typology. Inter-rater agreement occurred 82% of the time. The most frequent subtype was Paranoid Self-Defense, followed by "But It's Mine" and Paranoid Protection of Others. There were few differences among these subtypes based on demographic, clinical, offense, and outcome variables, except for presence of a primary psychotic disorder and offense type. Implications and ideas for future research are discussed.

Pathogen-mediated selection in free-ranging elk populations infected by chronic wasting disease.

Pathogens can exert a large influence on the evolution of hosts via selection for alleles or genotypes that moderate pathogen virulence. Inconsistent interactions between parasites and the host genome, such as those resulting from genetic linkages and environmental stochasticity, have largely prevented observation of this process in wildlife species. We examined the prion protein gene (PRNP) in North American elk (Cervus elaphus nelsoni) populations that have been infected with chronic wasting disease (CWD), a contagious, fatal prion disease, and compared allele frequency to populations with no history of exposure to CWD. The PRNP in elk is highly conserved and a single polymorphism at codon 132 can markedly extend CWD latency when the minor leucine allele (132L) is present. We determined population exposure to CWD, genotyped 1,018 elk from five populations, and developed a hierarchical Bayesian model to examine the relationship between CWD prevalence and PRNP 132L allele frequency. Populations infected with CWD for at least 30-50 y exhibited 132L allele frequencies that were on average twice as great (range = 0.23-0.29) as those from uninfected populations (range = 0.04-0.17). Despite numerous differences between the elk populations in this study, the consistency of increase in 132L allele frequency suggests pathogen-mediated selection has occurred due to CWD. Although prior modeling work predicted that selection will continue, the potential for fitness costs of the 132L allele or new prion protein strains to arise suggest that it is prudent to assume balancing selection may prevent fixation of the 132L allele in populations with CWD.

Structural Changes in Adsorbed Cytochrome c upon Applied Potential Characterized by Neutron Reflectometry.

The structural behavior of an electron-transfer protein, cytochrome c, at the 316L stainless steel electrode/aqueous interface was investigated over a range of applied potentials using neutron reflectometry supported by solution depletion isotherms, X-ray reflectometry, and quartz crystal microbalance measurements. A custom-made electrochemical cell allowed in situ observation of the adsorbed protein across a range of applied potentials; models fitted to the NR data showed a compact inner protein layer at the metal/electrolyte interface and a further thicker but highly diffuse layer that could be removed by rinsing. The overall amount adsorbed was found to be strongly dependent on the applied potential and buffer pH. Subtle but significant changes in the structure of the adsorbed protein layer were seen as the potential was swept between ±0.40 V, reflecting changing attractive/repulsive interactions between the protein's charged side groups and the surface. At greater applied potentials, irreversible changes in the stainless steel film structure were also observed and attributed to deuterium absorption into the metal.

Adsorption of 4-n-Nonylphenol, Carvacrol, and Ethanol onto Iron Oxide from Nonaqueous Hydrocarbon Solvents.

The adsorption of 4-n-nonylphenol (4NP), carvacrol, and ethanol onto the surface of iron oxide from nonaqueous solutions is presented. It is found that adsorption of 4NP from alkanes is strong and proceeds to monolayer formation, where the molecules are essentially "upright". However, at high relative concentrations, ethanol successfully out-competes 4NP for the iron oxide surface. Estimates of the enthalpy and entropy of binding of 4NP were found to be exothermic and entropically disfavored. Sum frequency generation vibrational spectroscopy data indicate some evidence of binding through a phenolate anion, despite the nonpolar, nonaqueous solvent. Carvacrol is also found to adsorb as a monolayer where the molecules are lying "flat". The adsorption of ethanol onto iron oxide from dodecane was investigated through the use of quantitative NMR, which is a convenient analytical technique for measuring adsorption isotherms. It was concluded that ethanol does not form adsorbed monolayers on the surface. Instead, it partitions onto the surface as a surface-enhanced local phase separation related to its poor solubility in alkane solvents.

Population-level distribution and putative immunogenicity of cancer neoepitopes.

BACKGROUND: Tumor neoantigens are drivers of cancer immunotherapy response; however, current prediction tools produce many candidates requiring further prioritization. Additional filtration criteria and population-level understanding may assist with prioritization. Herein, we show neoepitope immunogenicity is related to measures of peptide novelty and report population-level behavior of these and other metrics. METHODS: We propose four peptide novelty metrics to refine predicted neoantigenicity: tumor vs. paired normal peptide binding affinity difference, tumor vs. paired normal peptide sequence similarity, tumor vs. closest human peptide sequence similarity, and tumor vs. closest microbial peptide sequence similarity. We apply these metrics to neoepitopes predicted from somatic missense mutations in The Cancer Genome Atlas (TCGA) and a cohort of melanoma patients, and to a group of peptides with neoepitope-specific immune response data using an extension of pVAC-Seq (Hundal et al., pVAC-Seq: a genome-guided in silico approach to identifying tumor neoantigens. Genome Med 8:11, 2016). RESULTS: We show neoepitope burden varies across TCGA diseases and HLA alleles, with surprisingly low repetition of neoepitope sequences across patients or neoepitope preferences among sets of HLA alleles. Only 20.3% of predicted neoepitopes across TCGA patients displayed novel binding change based on our binding affinity difference criteria. Similarity of amino acid sequence was typically high between paired tumor-normal epitopes, but in 24.6% of cases, neoepitopes were more similar to other human peptides, or bacterial (56.8% of cases) or viral peptides (15.5% of cases), than their paired normal counterparts. Applied to peptides with neoepitope-specific immune response, a linear model incorporating neoepitope binding affinity, protein sequence similarity between neoepitopes and their closest viral peptides, and paired binding affinity difference was able to predict immunogenicity (AUROC = 0.66). CONCLUSIONS: Our proposed prioritization criteria emphasize neoepitope novelty and refine patient neoepitope predictions for focus on biologically meaningful candidate neoantigens. We have demonstrated that neoepitopes should be considered not only with respect to their paired normal epitope, but to the entire human proteome, and bacterial and viral peptides, with potential implications for neoepitope immunogenicity and personalized vaccines for cancer treatment. We conclude that putative neoantigens are highly variable across individuals as a function of cancer genetics and personalized HLA repertoire, while the overall behavior of filtration criteria reflects predictable patterns.

Characterizing Surfaces of Garnet and Steel, and Adsorption of Organic Additives.

This work reports that abrasive blasting of a structural steel results in significant retention of garnet abrasive residues. A comparative study of the adsorption behavior of a number of organic species, relevant to paint components and additives, onto the surfaces of garnet and S355 steel from nonaqueous solutions is also presented. Areas per adsorbed molecule, estimated from the isotherm data, suggest a range of molecular orientations on the surfaces. Pronounced differences in the adsorption strength to the garnet and steel were observed, particularly that most additives bind more strongly to steel than to garnet. Surface characterization data from acid-base titrations, photoelectron spectroscopy, and backscattered electron diffraction were used to rationalize the adsorption data obtained. The ramifications of these findings for particular industrial processes, with regards the strength of paint adhesion and paint additive formulations, are highlighted.

An X-ray and Neutron Reflectometry Study of Iron Corrosion in Seawater.

The corrosive breakdown of thin iron films supported on silicon substrates under a number of conditions is presented-in particular to understand better how iron, and hence ferritic steel, behaves in a salty water environment. A combination of X-ray and neutron reflectometry was used to monitor the structures of both metal and oxide surface layers and also organic corrosion inhibitors adsorbed at the iron/aqueous interface. A range of behavior in seawater was observed, including complete dissolution and void formation under the metal surface. Importantly, two simple treatments-UV/ozone or soaking in ultrapure water-were found to significantly protect the iron surface for considerable lengths of time, although evidence of pitting corrosion began after around 10 days. The underlying causes of the efficacies of these treatments were further investigated using X-ray photoelectron spectroscopy. In addition, three potential corrosion inhibitors were investigated: (i) dodecyltrimethylammonium bromide (DTAB) demonstrated no ability to protect the surface; (ii) sodium dodecyl sulfate (SDS) appeared to accelerate corrosion; and (iii) bis(2-ethylhexyl)phosphate showed an impressive level of protection (the neutron reflectometry results indicated a thick diffuse layer of surfactant of 23% surface coverage). These findings have been interpreted in terms of preferential inhibitor adsorption at cathodic and anodic surface sites (depending on the nature of the inhibitor).

Pain Assessment Recommendations for Women, Made by Women: A Mixed Methods Study.

Objective: To quantitatively describe women's priorities for pain assessment and qualitatively explain unique features of women's pain experiences. Design: Mixed-methods study that included a three-round Delphi study followed by in-depth interviews. Setting: Clinical research study. Participants: Twenty-three women with chronic pain recruited from three women's pain treatment facilities and one interdisciplinary chronic pain clinic. Methods: Phase 1 (Delphi) involved completion of a questionnaire that rated agreement with the importance of 32 commonly used pain assessment measures. Answers were compiled, and controlled feedback was provided after each round. This iterative process continued until acceptable stability was reached. Stability was defined as proportion agreement for each response that reached the a priori cutoff score of 75%. Phase 2 (qualitative) involved one-to-one telephone interviews that followed a semistructured interview guide partially informed from phase 1 findings. A descriptive approach summarized and described participants' perspectives while avoiding abstractions. Textual data were analyzed using content analysis. Results: Phase 1 identified 15 pain assessments as important. Some commonly used pain assessment measures such as the numeric pain intensity rating scale did not reach agreement as important. However, no pain assessments reached agreement as unimportant. Ten additional women completed face-to-face interviews, and an overall theme of stigmatization emerged that highlighted the importance of soliciting the pain narrative and why some aspects of psychosocial pain assessment did not reach agreement. Conclusions: Priorities identified by women for the assessment of pain were largely consistent with expert recommendations; however, important differences were raised that merit consideration for clinicians to reduce stigma.

An Anionic Surfactant on an Anionic Substrate: Monovalent Cation Binding.

Neutron reflectometry has been used to study the adsorption of the anionic surfactant bis(2-ethylhexyl) sulfosuccinate cesium salt on the anionic surface of mica. Evidence of significant adsorption is reported. The adsorption is reversible and changes little with pH. This unexpected adsorption behavior of an anionic molecule on an anionic surface is discussed in terms of recent models for surfactant adsorption such as cation bridging, where adsorption has been reported with the divalent ion calcium but not previously observed with monovalent ions.

"No Ordinary Lawsuit": Climate Change, Due Process, and the Public Trust Doctrine.

On November 10, 2016, just two days after the election of President Donald Trump, the federal district court in Oregon handed down Juliana v. United States. This remarkable decision refused to dismiss a lawsuit brought by youth plaintiffs who claimed that the federal government's fossil fuel policies over the years, which have produced an atmosphere with dangerous levels of greenhouse gases (GHGs), violated the federal public trust doctrine (PTD) and their federal constitutional rights to due process and equal protection. The court found a constitutional right to a stable climate system, determining that the PTD was an implicit part of due process and enforceable through the Constitution's due process clause. At trial, if the youth plaintiffs are able to prove that for decades the government willfully disregarded information about the potential catastrophic effects of GHG pollution, or abdicated its public trust duties, the decision could be transformative in global efforts to shift to an energy policy that does not threaten young people and future generations. This Article examines Juliana, its context as part of a worldwide campaign of "atmospheric trust" litigation, its path-breaking reasoning, and its implications in the United States and abroad. The case has been described as "the case of the century" and, because of the harm it aims to address and the fundamental rights approach endorsed by the court, it just may be that. Pending the forthcoming trial and almost certain appeals, we think the case is, as the trial judge accurately recognized, "no ordinary lawsuit."