tbuckley/cabot-search huggingface dataset:
Atrial Fibrillation as a Prognostic Factor for All-Cause Mortality in Patients With Transthyretin Amyloid Cardiomyopathy
Authors: Ronald Witteles, John L. Jefferies, Suraj Kapa, Francesco Cappelli, Marla B. Sultan, Balarama Gundapaneni, Margot K. Davis, Pablo Garcia-Pavia
Journal: JACC CardioOncology (2024)

Atrial fibrillation/atrial flutter (AF/AFL) are common manifestations of transthyretin amyloid cardiomyopathy (ATTR-CM) but have not been found to be predictive of mortality. This analysis aimed to examine whether baseline or historical AF/AFL at enrollment was prognostic for all-cause mortality. In the ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), a 30-month study of tafamidis vs placebo for ATTR-CM, AF/AFL was evaluated as an independent prognostic factor for all-cause mortality using Cox proportional hazards modelling. The impact of AF/AFL on tafamidis efficacy was explored by adding an interaction term for AF/AFL status and treatment. ATTR-ACT enrolled 441 patients with ATTR-CM (median age 75 years; 90% male); 314 (71.2%) had baseline or historical AF/AFL at enrollment. AF/AFL was an independent prognostic factor for all-cause mortality after adjusting for covariates prespecified in the ATTR-ACT model (treatment, genotype, New York Heart Association functional class; HR: 0.550; 95% CI: 0.368-0.821) but not in an expanded stepwise model selection analysis including 23 covariates (blood urea nitrogen and N-terminal pro–B-type natriuretic peptide concentration, 6-minute walk test distance, genotype, treatment, and global longitudinal strain were prognostic [P < 0.01]). The interactions between tafamidis treatment and AF/AFL for all-cause mortality (P = 0.33) and changes in Kansas City Cardiomyopathy Questionnaire Overall Summary score (P = 0.83) and 6-minute walk test distance (P = 0.82) were not significant. In ATTR-ACT, baseline or historical AF/AFL was prognostic for all-cause mortality in analyses with limited adjustment but not after accounting for additional indicators of disease severity. Baseline or historical AF/AFL did not impact the efficacy of tafamidis treatment. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy [ATTR-ACT]; NCT01994889)
Circulating Proteins and IgA Nephropathy
Authors: Chen Tang, Pei Chen, Lin-Lin Xu, Ji-Cheng Lv, Su-Fang Shi, Xu-Jie Zhou, Li-Jun Liu, Hong Zhang
Journal: Journal of the American Society of Nephrology (2024)

Key Points A multiancestry proteome-wide Mendelian randomization analysis was conducted for IgA nephropathy. The findings from the study would help prioritize new drug targets and drug-repurposing opportunities. Background The therapeutic options for IgA nephropathy are rapidly evolving, but early diagnosis and targeted treatment remain challenging. We aimed to identify circulating plasma proteins associated with IgA nephropathy by proteome-wide Mendelian randomization studies across multiple ancestry populations. Methods In this study, we applied Mendelian randomization and colocalization analyses to estimate the putative causal effects of 2615 proteins on IgA nephropathy in Europeans and 235 proteins in East Asians. Following two-stage network Mendelian randomization, multitrait colocalization analysis and protein-altering variant annotation were performed to strengthen the reliability of the results. A protein–protein interaction network was constructed to investigate the interactions between the identified proteins and the targets of existing medications. Results Putative causal effects of 184 and 13 protein–disease pairs in European and East Asian ancestries were identified, respectively. Two protein–disease pairs showed shared causal effects across them (CFHR1 and FCRL2). Supported by the evidence from colocalization analysis, potential therapeutic targets were prioritized and four drug-repurposing opportunities were suggested. The protein–protein interaction network further provided strong evidence for existing medications and pathways that are known to be therapeutically important. Conclusions Our study identified a number of circulating proteins associated with IgA nephropathy and prioritized several potential drug targets that require further investigation.
Femtosecond Laser Maskless Optical Projection Lithography of Cartilage PCM Inspired 3D Protein Matrix to Chondrocyte Phenotype
Authors: Teng Li, Jie Liu, Min Guo, Fan‐Chun Bin, Qi Duan, Xian‐Zi Dong, Feng Jin, Katsumasa Fujita, Mei‐Ling Zheng
Journal: Advanced Healthcare Materials (2024)

Hydrogels containing chondrocytes have exhibited excellent potential in regenerating hyaline cartilage. However, chondrocytes are vulnerable to dedifferentiation during in vitro culture, leading to fibrosis and mechanical degradation of newly formed cartilage. It is proposed to modulate cartilage formation via the developed chondrocyte pericellular matrix (PCM) -like scaffolds for the first time, in which the S, M, and L-sized scaffolds are fabricated by femtosecond laser maskless optical projection lithography (FL-MOPL) of bovine serum albumin-glyceryl methacrylate hydrogel. Chondrocytes on the M PCM-like scaffold can maintain round morphology and synthesize extracellular matrix (ECM) to induce regeneration of hyaline cartilage microtissues by geometrical restriction. A series of M PCM-like scaffolds is fabricated with different stiffness and those with a high Young's modulus are more effective in maintaining the chondrocyte phenotype. The proposed PCM-like scaffolds are effective in modulating cartilage formation influenced by pore size, depth, and stiffness, which will pave the way for a better understanding of the geometric cues of mechanotransduction interactions in regulating cell fate and open up new avenues for tissue engineering.
Kupffer cell diversity maintains liver function in alcohol-associated liver disease
Authors: Kyo Sasaki, Sheetalnath Rooge, Sumedha Gunewardena, Janice Averilla Hintz, Priyanka Ghosh, Isabel Aranzazu Pulido Ruiz, Kyle Yuquimpo, Michael Schonfeld, Heer Mehta, Heather L. Stevenson, Omar A. Saldarriaga, Esteban Arroyave, Irina Tikhanovich, Ann L. Wozniak, Steven A. Weinman
Journal: Hepatology (2024)

Background and Aims: Liver macrophages are heterogeneous and play an important role in alcohol-associated liver disease (ALD) but there is limited understanding of the functions of specific macrophage subsets in the disease. We used a Western diet alcohol (WDA) mouse model of ALD to examine the hepatic myeloid cell compartment by single cell RNAseq and targeted KC ablation to understand the diversity and function of liver macrophages in ALD. Approach and Results: In the WDA liver, KCs and infiltrating monocytes/macrophages each represented about 50% of the myeloid pool. Five major KC clusters all expressed genes associated with receptor-mediated endocytosis and lipid metabolism, but most were predicted to be noninflammatory and antifibrotic with 1 minor KC cluster having a proinflammatory and extracellular matrix degradation gene signature. Infiltrating monocyte/macrophage clusters, in contrast, were predicted to be proinflammatory and profibrotic. In vivo, diphtheria toxin–based selective KC ablation during alcohol exposure resulted in a liver failure phenotype with increases in PT/INR and bilirubin, loss of differentiated hepatocyte gene expression, and an increase in expression of hepatocyte progenitor markers such as EpCAM, CK7, and Igf2bp3. Gene set enrichment analysis of whole-liver RNAseq from the KC-ablated WDA mice showed a similar pattern as seen in human alcoholic hepatitis. Conclusions: In this ALD model, KCs are anti-inflammatory and are critical for the maintenance of hepatocyte differentiation. Infiltrating monocytes/macrophages are largely proinflammatory and contribute more to liver fibrosis. Future targeting of specific macrophage subsets may provide new approaches to the treatment of liver failure and fibrosis in ALD.
Reply: Tranexamic acid in upper gastrointestinal bleed in patients with cirrhosis - A randomized controlled trial
Authors: Manoj Kumar, Shantan Venishetty
Journal: Hepatology (2024)

Department of Hepatology and Liver Transplantation, Institute of Liver & Biliary Sciences, New Delhi, India Correspondence Manoj Kumar, Department of Hepatology and Liver Transplantation, Institute of Liver & Biliary Sciences, D1 Vasant Kunj, New Delhi 110070 India. Email: [email protected], [email protected]
Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality
Authors: Jeremy P Gygi, Cole Maguire, Ravi K Patel, Pramod Shinde, Anna Konstorum, Casey P Shannon, Leqi Xu, Annmarie Hoch, Naresh Doni Jayavelu, Elias K Haddad, Elaine F Reed, Monica Kraft, Grace A McComsey, Jordan P Metcalf, Al Ozonoff, Denise Esserman, Charles B Cairns, Nadine Rouphael, Steven E Bosinger, Seunghee Kim-Schulze, Florian Krammer, Lindsey B Rosen, Harm van Bakel, Michael Wilson, Walter L Eckalbar, Holden T Maecker, Charles R Langelier, Hanno Steen, Matthew C Altman, Ruth R Montgomery, Ofer Levy, Esther Melamed, Bali Pulendran, Joann Diray-Arce, Kinga K Smolen, Gabriela K Fragiadakis, Patrice M Becker, Rafick P Sekaly, Lauren Ir Ehrlich, Slim Fourati, Bjoern Peters, Steven H Kleinstein, Leying Guan
Journal: Journal of Clinical Investigation (2024)

BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).
Complement regulation in the eye: implications for age-related macular degeneration
Authors: Georgia A Wilke, Rajendra S Apte
Journal: Journal of Clinical Investigation (2024)

Careful regulation of the complement system is critical for enabling complement proteins to titrate immune defense while also preventing collateral tissue damage from poorly controlled inflammation. In the eye, this balance between complement activity and inhibition is crucial, as a low level of basal complement activity is necessary to support ocular immune privilege, a prerequisite for maintaining vision. Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis. Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). In the last two decades, complement activity has been the focus of intense investigation in AMD pathogenesis, leading to the development of novel therapeutics for the treatment of atrophic AMD. This Review outlines recent advances and challenges, highlighting therapeutic approaches that have advanced to clinical trials, as well as providing a general overview of the complement system in the posterior segment of the eye and selected ocular diseases.
Therapeutic vaccines for herpesviruses
Authors: Jeffrey I. Cohen
Journal: Journal of Clinical Investigation (2024)

Herpesviruses establish latent infections, and most reactivate frequently, resulting in symptoms and virus shedding in healthy individuals. In immunocompromised patients, reactivating virus can cause severe disease. Persistent EBV has been associated with several malignancies in both immunocompromised and nonimmunocompromised persons. Reactivation and shedding occur with most herpesviruses, despite potent virus-specific antibodies and T cell immunity as measured in the blood. The licensure of therapeutic vaccines to reduce zoster indicates that effective therapeutic vaccines for other herpesviruses should be feasible. However, varicella-zoster virus is different from other human herpesviruses in that it is generally only shed during varicella and zoster. Unlike prophylactic vaccines, in which the correlate of immunity is antibody function, T cell immunity is the correlate of immunity for the only effective therapeutic herpesvirus vaccine-zoster vaccine. While most studies of therapeutic vaccines have measured immunity in the blood, cellular immunity at the site of reactivation is likely critical for an effective therapeutic vaccine for certain viruses. This Review summarizes the status of therapeutic vaccines for herpes simplex virus, cytomegalovirus, and Epstein-Barr virus and proposes approaches for future development.
A Laing distal myopathy–associated proline substitution in the β-myosin rod perturbs myosin cross-bridging activity
Authors: Massimo Buvoli, Genevieve Ck Wilson, Ada Buvoli, Jack F Gugel, Abbi Hau, Carsten G Bönnemann, Carmen Paradas, David M Ryba, Kathleen C Woulfe, Lori A Walker, Tommaso Buvoli, Julien Ochala, Leslie A Leinwand
Journal: Journal of Clinical Investigation (2024)

Proline substitutions within the coiled-coil rod region of the β-myosin gene (MYH7) are the predominant mutations causing Laing distal myopathy (MPD1), an autosomal dominant disorder characterized by progressive weakness of distal/proximal muscles. We report that the MDP1 mutation R1500P, studied in what we believe to be the first mouse model for the disease, adversely affected myosin motor activity despite being in the structural rod domain that directs thick filament assembly. Contractility experiments carried out on isolated mutant muscles, myofibrils, and myofibers identified muscle fatigue and weakness phenotypes, an increased rate of actin-myosin detachment, and a conformational shift of the myosin heads toward the more reactive disordered relaxed (DRX) state, causing hypercontractility and greater ATP consumption. Similarly, molecular analysis of muscle biopsies from patients with MPD1 revealed a significant increase in sarcomeric DRX content, as observed in a subset of myosin motor domain mutations causing hypertrophic cardiomyopathy. Finally, oral administration of MYK-581, a small molecule that decreases the population of heads in the DRX configuration, significantly improved the limited running capacity of the R1500P-transgenic mice and corrected the increased DRX state of the myofibrils from patients. These studies provide evidence of the molecular pathogenesis of proline rod mutations and lay the groundwork for the therapeutic advancement of myosin modulators.
A pipeline for senolytics
Authors: Sundeep Khosla
Journal: Journal of Clinical Investigation (2024)

There is intense interest in identifying compounds that selectively kill senescent cells, termed senolytics, for ameliorating age-related comorbidities. However, screening for senolytic compounds currently relies on primary cells or cell lines where senescence is induced in vitro. Given the complexity of senescent cells across tissues and diseases, this approach may not target the senescent cells that develop under specific conditions in vivo. In this issue of the JCI, Lee et al. describe a pipeline for high-throughput drug screening of senolytic compounds where senescence was induced in vivo and identify the HSP90 inhibitor XL888 as a candidate senolytic to treat idiopathic pulmonary fibrosis.
A pivotal phase 2 single-arm study of glecirasib (JAB-21822) in patients with NSCLC harboring KRAS G12C mutation.
Authors: Yuankai Shi, Jian Fang, Ligang Xing, Yu Yao, Jian Zhang, Lian Liu, Yongsheng Wang, Changlu Hu, Jianping Xiong, Zhihua Liu, Runxiang Yang, Zhen Wang, Enfeng Zhao, Mengzhao Wang, Yanqiu Zhao, Kejing Tang, Zhihua Li, Zhengbo Song
Journal: Journal of Clinical Oncology (2024)

468214 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancers (NSCLC) in China. Glecirasib (Jacobio, Beijing, PRC) is a potent and highly selective covalent oral inhibitor of KRAS G12C. Methods: This phase 2 single-arm study (NCT05009329) of glecirasib was conducted in China at 43 sites, enrolling participants with locally advanced or metastatic KRAS G12C mutated NSCLC. Subjects must have received prior platinum-based therapy and an immune checkpoint inhibitor (ICI) as well as appropriate targeted agents for any actionable mutations per local standards. Primary study objective is overall response rate (ORR) assessed by independent review committee (IRC). The secondary study objectives include duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Here we report topline results from this pivotal study. Results: A total of 119 patients with NSCLC harboring KRAS G12C mutation were enrolled and treated with single agent glecirasib at 800mg daily (median follow up 10.4 months). The median age was 62 years, 79% was male and 21% was female, and 80.7% had ECOG PS 1. The prior lines of therapy include 1-3, with 94.1% (112/119) patients having received prior platinum-based therapy and ICI. Confirmed ORR was 47.9% (56/117; 95% CI, 38.5%-57.3%) and confirmed DCR was 86.3% (101/117; 95% CI, 78.7%-92%) assessed by IRC. Median PFS per IRC was 8.2 months (95% CI, 5.5 – 13.1), and median OS was 13.6 months (95% CI, 10.9 – NE). Median DOR has not been reached (95% CI, 7.2 – NE ). Overall, treatment-related adverse events (TRAEs) of any grade were observed in 97.5% of subjects. Most common TRAEs [≥15%] were anemia (56.3%), blood bilirubin increased (48.7%), alanine aminotransferase increased (35.3%), aspartate aminotransferase increased (35.3%), hypertriglyceridemia (28.6%) and γ-Glutamyl transferase increased (15.1%). Grade 3 and 4 TRAEs were observed in 39.5%. No grade 5 TRAEs occurred. Most of patients can stay on the treatment and 5.0% patients discontinued the treatment due to TRAE. In contrast to other FDA approved KRAS G12C inhibitor, Gleciasib has 6.7% of nausea, 7.6% vomiting, 3.4% diarrhea in which only one grade 3 nausea is reported. Conclusion: The pivotal phase 2 study of Glecirasib has met the primary endpoints and demonstrates impressive ORR and PFS with promising clinical activity for patients with KRAS G12C mutated advanced NSCLC. Glecirasib is well tolerated, with an extremely low gastrointestinal toxicity profile, which may improve patient compliance with oral therapy. Clinical trial information: NCT05009329 .
Quantitative interferon-gamma releasing assay in predicting tuberculosis in South Korean military: a retrospective cohort study
Authors: Sung-Woon Kang, Jeongjae Lee, Seong Min Kim, Dahye Kang, Euijin Chang, Seongman Bae, Jiwon Jung, Min Jae Kim, Yong Pil Chong, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim, Sung-Han Kim
Journal: Clinical Microbiology and Infection (2024)
Reactivation of Trypanosoma cruzi infection in immunosuppressed patients: a systematic review and meta-analysis
Authors: Alba Antequera, Agustina Dal Molin-Veglia, Jesús López-Alcalde, Noelia Álvarez-Díaz, Alfonso Muriel, José Muñoz
Journal: Clinical Microbiology and Infection (2024)

The risk of Trypanosoma cruzi reactivation is poorly understood. Previous studies evaluating the risk of reactivation report imprecise findings, and recommendations for monitoring and management from clinical guidelines rely on consensus opinion.
Implications of the 2023-2024 MPXV Clade I Outbreak in the DRC to Global Public Health
Authors: Angel N. Desai, Marion Koopmans, Ashley Otter, Martin P. Grobusch, Pikka Jokelainen, Barry Atkinson, Flavia Cunha, Sofia R. Valdoleiros, Veronica G. Preda, Francesco Maria Fusco, Chantal P. Rovers, Gilbert Greub, Antonino Di Caro, Lone Simonsen, Francine Ntoumi, Eskild Petersen
Journal: Clinical Microbiology and Infection (2024)
ScRNA-seq reveals novel immune-suppressive T cells and investigates CMV-TCR-T cells cytotoxicity against GBM
Authors: Xinmiao Long, Zuping Zhang, Yuzhe Li, Kun Deng, Wei Gao, Meng Huang, Xiangyu Wang, Xiang Lin, Xiaoling She, Yiming Zhao, Minfu Zhang, Cheng Huang, Shiyi Wang, Yinfei Du, Peng Du, Shuai Chen, Qing Liu, Minghua Wu
Journal: Journal for ImmunoTherapy of Cancer (2024)

Glioblastoma (GBM) is a fatal primary brain malignancy in adults. Previous studies have shown that cytomegalovirus (CMV) is a risk factor for tumorigenesis and aggressiveness for glioblastoma. However, little is known about how CMV infection affects immune cells in the tumor microenvironment of GBM. Furthermore, there has been almost no engineered T-cell receptor (TCR)-T targeting CMV for GBM research to date. We evaluated the CMV infection status of patients with GBM's tumor tissue by immune electron microscopy, immunofluorescence, and droplet digital PCR. We performed single-cell RNA sequencing for CMV-infected GBM to investigate the effects of CMV on the GBM immune microenvironment. CellChat was applied to analyze the interaction between cells in the GBM tumor microenvironment. Additionally, we conducted single-cell TCR/B cell receptor (BCR) sequencing and Grouping of Lymphocyte Interactions with Paratope Hotspots 2 algorithms to acquire specific CMV-TCR sequences. Genetic engineering was used to introduce CMV-TCR into primary T cells derived from patients with CMV-infected GBM. Flow cytometry was used to measure the proportion and cytotoxicity status of T cells in vitro. We identified two novel immune cell subpopulations in CMV-infected GBM, which were bipositive CD68+SOX2+ tumor-associated macrophages and FXYD6+ T cells. We highlighted that the interaction between bipositive TAMs or cancer cells and T cells was predominantly focused on FXYD6+ T cells rather than regulatory T cells (Tregs), whereas, FXYD6+ T cells were further identified as a group of novel immunosuppressive T cells. CMV-TCR-T cells showed significant therapeutic effects on the human-derived orthotopic GBM mice model. These findings provided an insight into the underlying mechanism of CMV infection promoting the GBM immunosuppression, and provided a novel potential immunotherapy strategy for patients with GBM.