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PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti–PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole-genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti–PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti–PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti–PD-L1 monotherapy in bladder cancer.

\"Within these pages you'll find myriad approaches to Alice, from horror to historical, taking us from nightmarish reaches of the imagination to tales that will shock, surprise, and tug on the heart-strings. So it's time now to go down the rabbit hole, or through the looking-glass or ... But no, wait. By picking up this book and starting to read it you're already there, can't you see?\"--Provided by publisher.

Activation of systemic immune responses using PD-1 checkpoint inhibitors is an essential approach to cancer therapy. Yet, the extent of benefit relative to risk of immune related adverse events (irAE) varies widely among patients. Here, we study endocrine irAE from 7 clinical trials across 6 cancers where atezolizumab (anti-PD-L1) was combined with chemotherapies and compared to standard of care. We show that atezolizumab-induced thyroid dysfunction is associated with longer survival. We construct a polygenic risk score (PRS) for lifetime risk of hypothyroidism using a GWAS from the UK Biobank and apply this PRS to genetic data collected from 2,616 patients of European ancestry from these trials. Patients with high PRS are at increased risk of atezolizumab-induced thyroid dysfunction and lower risk of death in triple negative breast cancer. Our results indicate that genetic variation associated with thyroid autoimmunity interacts with biological pathways driving the systemic immune response to PD-1 blockade. Endocrinopathies, such as thyroid autoimmunity, are common among patients treated with immune checkpoint inhibitors. Here, by using a polygenic risk score (PRS) derived from a hypothyroidism GWAS, the authors show that cancer patients with high PRS are at increased risk of atezolizumab (anti-PD-L1)-induced thyroid dysfunction, a condition associated with systemic response to PD-1 checkpoint blockade and longer overall survival.

Diverticulosis results from herniation of mucosa and submucosa through the muscular layer of the colonic wall, whereas diverticulitis can result when these diverticula perforate.1 Although diverticulitis is a common pathological entity, it is extremely rare to encounter perforated diverticulitis that causes subcutaneous abscess. Diverticular disease of the colon is commonly encountered in clinical practice throughout the Western world, with a prevalence of approximately 65 per cent of patients aged 85 years, 30 per cent aged 60 years, and less than 5 per cent aged 40 years.1, 2 Complications occur in approximately 30 per cent of these patients, most commonly bleeding and diverticulitis.2 Suggested etiologies for colonic diverticulosis include abnormalities of smooth muscle and elevated intraluminal pressures within the colon.1 Subcutaneous abscess/emphysema resulting from a gastrointestinal source is extremely rare and usually occurs after surgical procedures.3 Our case presents a rare example of subcutaneous emphysema resulting from gastrointestinal perforation due to sigmoid diverticulitis. An increased pressure gradient between the wall of the colon and the anterior abdominal wall most likely allows for the colonic perforation in these cases to continue through the abdominal wall and into the subcutaneous tissue.1, 2 The subcutaneous emphysema can diffuse across tissue planes resulting in subcutaneous emphysema/abscess in other anatomical locations.1-4 Although rare, subcutaneous emphysema/abscess may result from perforated colonic diverticulitis.

Light volatile elements in the lunar regolith are thought to be a mixture of the solar wind and Earth’s atmosphere, the latter sourced in the absence of geomagnetic field. However, the extent to which both the current and primitive geodynamo influence the transport of terrestrial ions still remains unclear, and this uncertainty is further complicated by the enigmatic composition and poorly constrained location of the Eoarchean exosphere. Here we use three-dimensional magnetohydrodynamic numerical simulations with contemporary magnetized and Archean unmagnetized atmospheres to investigate how Earth’s intrinsic magnetic field affects this transfer, aiming to constrain how and when the lunar isotopic signature provides a record of Earth’s paleoatmosphere. We find that atmospheric transfer is efficient only when the Moon is within Earth’s magnetotail. The non-solar contribution to the lunar soil is best explained by implantation during the long history of the geodynamo under present-day solar wind conditions, rather than by any brief, putatively unmagnetized epoch of the early Archean Earth. This further suggests the history of the terrestrial atmosphere, spanning billions of years, could be preserved in buried lunar soils. Our results indicate that the elemental abundances of Apollo samples are highly sensitive to Earth’s hydrodynamic escape boundary, which, at the time of ion implantation, was never smaller than 190 km. Numerical simulations reveal that the transfer of ions from Earth’s atmosphere to the Moon is efficient only in the sustained presence of a geomagnetic field, suggesting that lunar soils may record the histories of the atmosphere, solar wind, and geodynamo.

Molecular docking studies of quinoline and 2-chloroquinoline substrates at the active site of toluene dioxygenase (TDO), were conducted using Autodock Vina, to identify novel edge-to-face interactions and to rationalize the observed stereoselective cis -dihydroxylation of carbocyclic rings and formation of isolable cis -dihydrodiol metabolites. These in silico docking results of quinoline and pyridine substrates, with TDO, also provided support for the postulated cis -dihydroxylation of electron-deficient pyridyl rings, to give transient cis -dihydrodiol intermediates and the derived hydroxyquinolines. 2-Chloroquinoline cis -dihydrodiol metabolites were used as precursors in the chemoenzymatic synthesis of enantiopure arene oxide and arene dioxide derivatives of quinoline, in the context of its possible mammalian metabolism and carcinogenicity.

Agents interacting with their environments, machine or otherwise, arrive at decisions based on their incomplete access to data and their particular cognitive architecture, including data sampling frequency and memory storage limitations. In particular, the same data streams, sampled and stored differently, may cause agents to arrive at different conclusions and to take different actions. This phenomenon has a drastic impact on polities—populations of agents predicated on the sharing of information. We show that, even under ideal conditions, polities consisting of epistemic agents with heterogeneous cognitive architectures might not achieve consensus concerning what conclusions to draw from datastreams. Transfer entropy applied to a toy model of a polity is analyzed to showcase this effect when the dynamics of the environment is known. As an illustration where the dynamics is not known, we examine empirical data streams relevant to climate and show the consensus problem manifest.

This paper introduces the Philosophical Health Compass (PHC), a quantitative assessment tool designed to complement qualitative research methods in investigating philosophical aspects of human wellbeing. The PHC evaluates six dimensions of philosophical health identified through previous research: bodily sense, sense of self, sense of belonging, sense of the possible, sense of purpose, and philosophical sense. While qualitative approaches in philosophical health excel at capturing rich individual narratives, their limitations in standardization and scalability constrain systematic research across populations. The PHC addresses this methodological gap by translating comprehensive philosophical concepts into measurable variables, enabling researchers to conduct comparative analyses, and integrate philosophical dimensions into an established wellbeing framework. This instrument is grounded in the SMILE_PH interview methodology introduced in 2023 by Luis de Miranda in the present journal, which has indicated through extensive field application that philosophical and existential health can be systematically explored through these six interrelated dimensions. We present the compass, its theoretical foundations, methodology, and potential research applications. By offering a standardized approach to evaluating philosophical wellbeing, the PHC creates new possibilities for interdisciplinary research while acknowledging that this questionnaire is not meant to replace the depth of the qualitative SMILE_PH dialogue, but rather to facilitate it.

BackgroundImmune-mediated adverse events (imAE) commonly occur in patients treated with immune checkpoint inhibitors (ICI), and pneumonitis is known to occur in 3 -5 % of patients treated with anti-PD-1 / PD-L1 antibodies.1 Most cases are grade 1 or 2 events and can be treated with immunosuppression, but high-grade events occur in a minority of patients and can be fatal.2 Since lung inflammatory phenotypes, including fibrotic idiopathic interstitial pneumonias and infectious pneumonias, were associated with allelic variation in Human Leukocyte Antigen (HLA) genes,3 4 we hypothesized that HLA variants might also be a risk factor for ICI- associated pneumonitis.MethodsOut of 1761 atezolizumab (anti-PD-L1) treated patients across nine Genentech (GNE) clinical trials with available whole-genome sequencing data, 72 (4.1%) developed pneumonitis (table 1). We inferred HLA genotypes using HLA-HD5 and performed an association study including 87 alleles with a carrier frequency of >2%. In order to confirm our results, and to test whether the association is generalizable to different classes of ICI, we genotyped two additional cohorts using an Illumina genome-wide SNP array (GSA v3), followed by HLA imputation using HIBAG6: (1) 20 ICI-treated cancer patients with pneumonitis and 20 matched controls without from a pilot study on the AEROSMITH trial from Parker Institute for Cancer Immunotherapy (PICI); (2) 15 ICI-treated melanoma patients with pneumonitis and 149 without from Peter MacCallum Cancer Centre (PMC) (table 1).ResultsTwo HLA class II alleles that are part of a common haplotype showed significant associations with pneumonitis risk after multiple testing adjustment (HLA-DRB1*15:01, HLA-DQA1*01:02), with HLA-DRB1*15:01 showing the strongest association (p = 0.0002, odds ratio (OR) =2.51). No associations were identified in the control arms (N = 1192). In the PICI pilot cohort, HLA-DRB1*15:01 did not reach statistical significance in spite of a comparable OR (p = 0.26, OR = 2.75), but the allele was significantly associated with pneumonitis risk in the PMC cohort (p = 0.03, OR = 3.92). A meta-analysis across the three cohorts yielded a highly significant p-value of 1.2x10–5 (OR = 2.67, figure 1), suggesting that the association is generalizable across ICI. Importantly, the same class II haplotype was previously shown to be associated with diverse lung inflammatory, including fibrotic, phenotypes.3,4,7,8 Abstract 811 Table 1Investigated cohortsAbstract 811 Figure 1Forest plot for HLA-DRB1*15:01 meta-analysis with ICI-associated pneumonitis. GNE, Genentech; PICI, Parker Institute for Cancer Immunotherapy; PMC, Peter MacCallum Cancer Centre; OR, odds ratio; CI, confidence interval; W, weight http://dx.doi.org/10.1136/jitc-2021-SITC2021.811ConclusionsIn summary, our findings establish HLA class II allelic variation as a potential risk factor in ICI-associated pneumonitis, and future research is warranted to determine whether this genetic association can be refined according to specific clinical presentations.ReferencesWang H, Guo X, Zhou J, Li Y, Duan L, Si X, et al. Clinical diagnosis and treatment of immune checkpoint inhibitor-associated pneumonitis. Thorac Cancer 2020;11:191–7.Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti–programmed death-1/Programmed death ligand 1 therapy. J Clin Oncol 2016;35:709–17.Tian C, Hromatka BS, Kiefer AK, Eriksson N, Noble SM, Tung JY, et al. Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. Nat Commun 2017;8:599.Fingerlin TE, Zhang W, Yang IV, Ainsworth HC, Russell PH, Blumhagen RZ, et al. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet 2016;17:74.Kawaguchi S, Higasa K, Shimizu M, Yamada R, Matsuda F. HLA-HD: An accurate HLA typing algorithm for next-generation sequencing data. Hum Mutat 2017;38:788–97.Zheng X, Shen J, Cox C, Wakefield JC, Ehm MG, Nelson MR, et al. HIBAG—HLA genotype imputation with attribute bagging. Pharmacogenomics J 2014;14:192–200.Voorter CEM, Drent M, Berg-Loonen EM van den. Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602–DRB1*150101. Hum Immunol 2005;66:826–35.Furukawa H, Oka S, Shimada K, Sugii S, Ohashi J, Matsui T, et al. Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope. Plos One 2012;7:e33133.Ethics ApprovalPatients included in this study signed an optional Research Biosample Repository (RBR) Informed Consent Form (ICF) and provided whole blood samples. By signing the optional RBR ICF, patients provided informed consent for analysis of inherited and non-inherited genetic variation from whole blood samples. Ethics Committees (EC) and Institutional Review Boards (IRB) in each country and each study site for each clinical trial approved the clinical trial protocol, the main study ICF, and theRBR ICF.