tbuckley/cabot-search huggingface dataset:
Increased PVR Expression on Bone Marrow Macrophages May Promote Resistance to TIGIT Blockade in Multiple Myeloma
Authors: Ester Lozano, Mari-Pau Mena, Glòria Garrabou, Oriol Cardus, Tania Díaz, David F. Moreno, Joan Mañé Pujol, Aina Oliver-Caldés, Anthony Battram, Natalia Tovar, Maria Teresa Cibeira, Luis Gerardo Rodríguez-Lobato, Joan Bladé, Carlos Fernández de Larrea, Laura Rosinol
Journal: Clinical Cancer Research (2024)

Abstract Purpose: TIGIT blockade in our ex vivo model of bone marrow (BM) reduced the number of malignant plasma cells (PC) in only half of patients with multiple myeloma. Here, we wanted to investigate whether increased expression of TIGIT ligands may inhibit T-cell immune response promoting resistance to TIGIT blockade. Experimental Design: We first characterized the number and phenotype of BM macrophages in different stages of the disease by multiparameter flow cytometry. We assessed the effect of TIGIT ligands on PC survival by performing experiments in the ex vivo BM model and analyzed changes in gene expression by using NanoString technology and real-time PCR. Results: The frequency of BM macrophages was significantly decreased in multiple myeloma, which was accompanied by changes in their immunophenotype. Moreover, we found a higher number of malignant PC in ex vivo BM cells cultured onto the poliovirus receptor (PVR) and nectin-2 compared with control, suggesting that both ligands may support PC survival. In addition, the presence of PVR, but not nectin-2, overcame the therapeutic effect of TIGIT blockade or exogenous IL2. Furthermore, exogenous IL2 increased TIGIT expression on both CD4+ and CD8+ T cells and, indirectly, PVR on BM macrophages. Consistently, PVR reduced the number of cytotoxic T cells and promoted a gene signature with reduced effector molecules. Conclusions: IL2 induced TIGIT on T cells in the BM, in which increased PVR expression resulted in cytotoxic T-cell inhibition, promoting PC survival and resistance to TIGIT blockade.
Differences in the prognostic role of age, extent of resection and tumor grade between astrocytoma IDHmt and oligodendroglioma: a single center cohort study
Authors: Thijs van der Vaart, Maarten M.J. Wijnenga, Karin van Garderen, Hendrikus J. Dubbink, Pim J. French, Marion Smits, Clemens M.F. Dirven, Johan M. Kros, Arnaud J.P.E. Vincent, Martin J. van den Bent
Journal: Clinical Cancer Research (2024)

IDH-mutant glioma is classified as oligodendroglioma or astrocytoma based on 1p19q-codeletion. Whether prognostic factors are similar between these tumor types is not well understood.
Circulating Tumor DNA Assessment for Treatment Monitoring Adds Value to PSA in Metastatic Castration-Resistant Prostate Cancer
Authors: Christopher J. Sweeney, Russell Petry, Chang Xu, Merrida Childress, Jie He, David Fabrizio, Ole Gjoerup, Samantha Morley, Timothy Catlett, Zoe J. Assaf, Kobe Yuen, Matthew Wongchenko, Kalpit Shah, Pratyush Gupta, Priti Hegde, Lincoln W. Pasquina, Sanjeev Mariathasan, Ryon P. Graf, Thomas Powles
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Enzalutamide after abiraterone progression is commonly used in metastatic castration-resistant prostate cancer despite a low rate of clinical benefit. Analyzing IMbassador250, a phase III trial assessing enzalutamide with or without atezolizumab after abiraterone, we hypothesized that baseline and early changes in circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients more likely to exhibit survival benefit from enzalutamide. Experimental Design: ctDNA was quantified from plasma samples using a tissue-agnostic assay without buffy coat sequencing. Baseline ctDNA TF, changes in ctDNA TF from baseline to cycle 3 day 1 (C3D1), and detection at C3D1 alone were compared with overall response rate, radiographic progression-free survival (rPFS), median OS (mOS), and 50% reduction in PSA. Results: ctDNA TF detection at baseline and/or C3D1 was associated with shorter rPFS and OS in 494 evaluable patients. Detection of ctDNA TF at C3D1, with or without detection at cycle 1 day 1, was associated with worse rPFS and mOS than lack of detection. When ctDNA TF and PSA response at C3D1 were discordant, patients with (ctDNA TF undetected/PSA not reduced) had more favorable outcomes than (ctDNA TF detected/PSA reduced; mOS 22.1 vs. 16 months; P &amp;lt; 0.001). Conclusions: In a large cohort of patients with metastatic castration-resistant prostate cancer receiving enzalutamide after abiraterone, we demonstrate the utility of a new tissue-agnostic assay for monitoring molecular response based on ctDNA TF detection and dynamics. ctDNA TF provides a minimally invasive, complementary biomarker to PSA testing and may refine personalized treatment approaches.
Dermatological aspects of gender affirming medical treatment in transgender and gender diverse people: a systematic review
Authors: Jon Arcelus, Kamilla Kamaruddin, Walter Pierre Bouman
Journal: International Journal of Transgender Health (2024)

Background Transgender and gender diverse (TGD) people face specific dermatological conditions related to the cutaneous effects of gender affirming medical treatment (GAMT). Dermatological conditions in TGD people are often underdiagnosed and underrecognized despite its potential for treatment to improve quality of life and mental health in this population. There is paucity of literature guiding health care professionals (HCP), including dermatologists, regarding the dermatological aspects that TGD people can experience during medical transition.
Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery
Authors: Xiaolei Zhang, Pantazis I. Theotokis, Nicholas Li, Euan Ashley, Steven D. Colan, Sharlene M. Day, Adam Helms, Carolyn Y. Ho, Jodie Ingles, Daniel Jacoby, Neal K. Lakdawala, Michelle Michels, Iacopo Olivotto, Anjali Owens, Victoria N. Parikh, Alexandre C. Pereira, Joseph Rossano, Sara Saberi, Chris Semsarian, Samuel Wittekind, Caroline F. Wright, Kaitlin E. Samocha, Nicola Whiffin, James S. Ware
Journal: Genome Medicine (2024)

Abstract Background One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as “genetic constraint”. Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes. Methods We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues. Results We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism. Conclusions Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.
Plasma metabolomics of immune-related adverse events for patients with lung cancer treated with PD-1/PD-L1 inhibitors
Authors: Juan Chen, Jia-Si Liu, Jun-Yan Liu, Lei She, Ting Zou, Fan Yang, Xiang-Ping Li, Zhan Wang, Zhaoqian Liu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Metabolomics has the characteristics of terminal effects and reflects the physiological state of biological diseases more directly. Several current biomarkers of multiple omics were revealed to be associated with immune-related adverse events (irAEs) occurrence. However, there is a lack of reliable metabolic biomarkers to predict irAEs. This study aims to explore the potential metabolic biomarkers to predict risk of irAEs and to investigate the association of plasma metabolites level with survival in patients with lung cancer receiving PD-1/PD-L1 inhibitor treatment. Methods The study collected 170 plasmas of 85 patients with lung cancer who received immune checkpoint inhibitors (ICIs) treatment. 58 plasma samples of 29 patients with irAEs were collected before ICIs treatment and at the onset of irAEs. 112 plasma samples of 56 patients who did not develop irAEs were collected before ICIs treatment and plasma matched by treatment cycles to onset of irAEs patients. Untargeted metabolomics analysis was used to identify the differential metabolites before initiating ICIs treatment and during the process that development of irAEs. Kaplan-Meier curves analysis was used to detect the associations of plasma metabolites level with survival of patients with lung cancer. Results A total of 24 differential metabolites were identified to predict the occurrence of irAEs. Baseline acylcarnitines and steroids levels are significantly higher in patients with irAEs, and the model of eight acylcarnitine and six steroid metabolites baseline level predicts irAEs occurrence with area under the curve of 0.91. Patients with lower concentration of baseline decenoylcarnitine(AcCa(10:1) 2, decenoylcarnitine(AcCa(10:1) 3 and hexanoylcarnitine(AcCa(6:0) in plasma would have better overall survival (OS). Moreover, 52 differential metabolites were identified related to irAEs during ICIs treatment, dehydroepiandrosterone sulfate, corticoserone, cortisol, thyroxine and sphinganine 1-phaosphate were significantly decreased in irAEs group while oxoglutaric acid and taurocholic acid were significantly increased in irAEs group. Conclusions High levels of acylcarnitines and steroid hormone metabolites might be risk factor to development of irAEs, and levels of decenoylcarnitine (AcCa(10:1) 2, decenoylcarnitine (AcCa(10:1) 3 and hexanoylcarnitine (AcCa(6:0) could be used to predict OS for patients with lung cancer received ICIs treatment.
Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer: phase 2 trial interim results
Authors: Maria Parkhurst, Stephanie L Goff, Frank J Lowery, Rachel K Beyer, Hyunmi Halas, Paul F Robbins, Todd D Prickett, Jared J Gartner, Sivasish Sindiri, Sri Krishna, Nikolaos Zacharakis, Lien Ngo, Satyajit Ray, Alakesh Bera, Ryan Shepherd, Noam Levin, Sanghyun P Kim, Amy Copeland, Shirley Nah, Shoshana Levi, Neilesh Parikh, Mei Li M Kwong, Nicholas D Klemen, James C Yang, Steven A Rosenberg
Journal: Nature Medicine (2024)
A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance
Authors: Christopher E. Whitehead, Elizabeth K. Ziemke, Christy L. Frankowski-McGregor, Rachel A. Mumby, June Chung, Jinju Li, Nathaniel Osher, Oluwadara Coker, Veerabhadran Baladandayuthapani, Scott Kopetz, Judith S. Sebolt-Leopold
Journal: Nature Cancer (2024)

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.
Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes
Authors: Yuanyuan You, Josefine Dunst, Kewei Ye, Patrick A. Sandoz, Annika Reinhardt, Inga Sandrock, Natalia R. Comet, Rupak Dey Sarkar, Emily Yang, Estelle Duprez, Judith Agudo, Brian D. Brown, Paul J. Utz, Wolfgang Kastenmüller, Carmen Gerlach, Immo Prinz, Björn Önfelt, Taras Kreslavsky
Journal: Nature Immunology (2024)

Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8
ERJ Advances: interventional bronchoscopy
Authors: Justin L. Garner, Pallav L. Shah, Felix Herth, Dirk-Jan Slebos
Journal: European Respiratory Journal (2024)

The field of interventional bronchoscopy is rapidly growing, with the development of minimally invasive approaches and innovative devices to diagnose and treat a spectrum of respiratory diseases (figure 1), often as outpatient procedures, and supported by high quality collaborative research. This short review covers aspects related to COPD, peripheral pulmonary nodules, interstitial lung disease, and airway stenosis and malacia. This ERJ Advances article summarises the latest developments in the rapidly advancing field of interventional bronchoscopy <https://bit.ly/44Qvgrm>
Allergen‐specific B cell responses in oral immunotherapy‐induced desensitization, remission, and natural outgrowth in cow's milk allergy
Authors: Pattraporn Satitsuksanoa, Willem van de Veen, Ge Tan, Juan‐Felipe Lopez, Oliver Wirz, Kirstin Jansen, Milena Sokolowska, David Mirer, Anna Globinska, Tadech Boonpiyathad, Stephan R. Schneider, Elena Barletta, Hergen Spits, Iris Chang, Huseyn Babayev, İlhan Tahralı, Gunnur Deniz, Esra Özek Yücel, Ayca Kıykım, Scott D. Boyd, Cezmi A. Akdis, Kari Nadeau, Mübeccel Akdis
Journal: Allergy (2024)

Abstract Background Antigen‐specific memory B cells play a key role in the induction of desensitization and remission to food allergens in oral immunotherapy and in the development of natural tolerance (NT). Here, we characterized milk allergen Bos d 9‐specific B cells in oral allergen‐specific immunotherapy (OIT) and in children spontaneously outgrowing cow's milk allergy (CMA) due to NT. Methods Samples from children with CMA who received oral OIT (before, during, and after), children who naturally outgrew CMA (NT), and healthy individuals were received from Stanford biobank. Bos d 9‐specific B cells were isolated by flow cytometry and RNA‐sequencing was performed. Protein profile of Bos d 9‐specific B cells was analyzed by proximity extension assay. Results Increased frequencies of circulating milk allergen Bos d 9‐specific B cells were observed after OIT and NT. Milk‐desensitized subjects showed the partial acquisition of phenotypic features of remission, suggesting that desensitization is an earlier stage of remission. Within these most significantly expressed genes, IL10RA and TGFB3 were highly expressed in desensitized OIT patients. In both the remission and desensitized groups, B cell activation‐, Breg cells‐, BCR‐signaling‐, and differentiation‐related genes were upregulated. In NT, pathways associated with innate immunity characteristics, development of marginal zone B cells, and a more established suppressor function of B cells prevail that may play a role in long‐term tolerance. The analyses of immunoglobulin heavy chain genes in specific B cells demonstrated that IgG2 in desensitization, IgG1 , IgA1 , IgA2 , IgG4 , and IgD in remission, and IgD in NT were predominating. Secreted proteins from allergen‐specific B cells revealed higher levels of regulatory cytokines, IL‐10, and TGF‐β after OIT and NT. Conclusion Allergen‐specific B cells are essential elements in regulating food allergy towards remission in OIT‐received and naturally resolved individuals.
A composite reference standard is needed for bedaquiline antimicrobial susceptibility testing for<i>Mycobacterium tuberculosis</i>complex
Authors: Claudio U. Köser, Paolo Miotto, Nabila Ismail, Richard M. Anthony, Christian Utpatel, Matthias Merker, Stefan Niemann, Sabira Tahseen, Leen Rigouts, Camilla Rodrigues, Shaheed V. Omar, Maha R. Farhat, Uladzimir Antonenka, Harald Hoffmann, Daniela M. Cirillo, Thomas Schön
Journal: European Respiratory Journal (2024)

We echo the latest calls that have been made to increase the capacity for antimicrobial susceptibility testing (AST) for bedaquiline for the Mycobacterium tuberculosis complex [1, 2]. However, we would like to highlight the limitations of using insufficiently standardised or validated phenotypic AST methods and breakpoints as the reference standard for bedaquiline AST. Moreover, we advocate for adoption of a composite reference standard that considers genotypic AST results to minimise false-susceptible results for borderline/low-level resistance mechanisms and avoid confusion during clinical decision-making. A composite reference standard minimises false-susceptible AST results for bedaquiline <https://bit.ly/3wAVvFm>
Lipidome changes due to improved dietary fat quality inform cardiometabolic risk reduction and precision nutrition
Authors: Fabian Eichelmann, Marcela Prada, Laury Sellem, Kim G. Jackson, Jordi Salas Salvadó, Cristina Razquin Burillo, Ramon Estruch, Michael Friedén, Frederik Rosqvist, Ulf Risérus, Kathryn M. Rexrode, Marta Guasch-Ferré, Qi Sun, Walter C. Willett, Miguel Angel Martinez-Gonzalez, Julie A. Lovegrove, Frank B. Hu, Matthias B. Schulze, Clemens Wittenbecher
Journal: Nature Medicine (2024)

Current cardiometabolic disease prevention guidelines recommend increasing dietary unsaturated fat intake while reducing saturated fats. Here we use lipidomics data from a randomized controlled dietary intervention trial to construct a multilipid score (MLS), summarizing the effects of replacing saturated fat with unsaturated fat on 45 lipid metabolite concentrations. In the EPIC-Potsdam cohort, a difference in the MLS, reflecting better dietary fat quality, was associated with a significant reduction in the incidence of cardiovascular disease (-32%; 95% confidence interval (95% CI): -21% to -42%) and type 2 diabetes (-26%; 95% CI: -15% to -35%). We built a closely correlated simplified score, reduced MLS (rMLS), and observed that beneficial rMLS changes, suggesting improved dietary fat quality over 10 years, were associated with lower diabetes risk (odds ratio per standard deviation of 0.76; 95% CI: 0.59 to 0.98) in the Nurses' Health Study. Furthermore, in the PREDIMED trial, an olive oil-rich Mediterranean diet intervention primarily reduced diabetes incidence among participants with unfavorable preintervention rMLS levels, suggestive of disturbed lipid metabolism before intervention. Our findings indicate that the effects of dietary fat quality on the lipidome can contribute to a more precise understanding and possible prediction of the health outcomes of specific dietary fat modifications.
A crisis in clinical research
Authors: David S Hong, Patricia LoRusso, Mario Sznol
Journal: Journal for ImmunoTherapy of Cancer (2024)

The clinical research pipeline is critical to ensuring continued development of novel treatments that can offer patients with cancer safe and effective options. Unfortunately, progress has slowed since the COVID-19 pandemic due to uncovered, systemic inefficiencies across critical processes. Towards initiating discussion on how to reinvigorate clinical research, the Society for Immunotherapy of Cancer (SITC) hosted a virtual summit that characterized issues and formed potential solutions. This commentary serves to highlight the crisis facing clinical research as well as stimulate field-wide discussion on how to better serve patients into the future.
A global initiative to deliver precision health in diabetes
Authors: W T Cefalu, P W Franks, N D Rosenblum, N A Zaghloul, J C Florez, F Giorgino, L Ji, R C W Ma, C Mathieu, S Misra, A H Ramirez, M Roden, P E Scherer, W H-H Sheu, C D A Stehouwer, M Woo, M Pragnell, S S Anand, M Carnethon, J C Chambers, J M Dennis, A L Gloyn, C Herder, R I G Holt, D G Manuel, M J Redondo, N Tandon, J S Tsang, M S Udler, S S Rich
Journal: Nature Medicine (2024)