tbuckley/cabot-search huggingface dataset:
A gain-of-function mutation in ATP6V0A4 drives primary distal renal tubular alkalosis with enhanced V-ATPase activity
Authors: Si-Qi Peng, Qian-Qian Wu, Wan-Yi Wang, Yi-Lin Zhang, Rui-Ning Zhou, Jun Liao, Jin-Xuan Wei, Yan Yang, Wen Shi, Jun-Lan Yang, Xiao-Xu Wang, Zhi-Yuan Wei, Jia-Xuan Sun, Lu Huang, Hong Fan, Hui Cai, Cheng-Kun Wang, Xin-Hua Li, Ting-Song Li, Bi-Cheng Liu, Xiao-Liang Zhang, Bin Wang
Journal: Journal of Clinical Investigation (2025)

The ATP6V0A4 gene encodes the a4 subunit of Vacuolar H+-ATPase (V-ATPase), which mediates hydrogen ion transport across the membrane. Previous studies have suggested that mutations in ATP6V0A4 consistently result in a loss of function (LOF), impairing the hydrogen ion transport efficacy of V-ATPase and leading to distal renal tubular acidosis (dRTA) and sensorineural hearing loss. Here, we identified a 32-year-old male patient and his father, both of whom harbored a heterozygous ATP6V0A4 p.V512L mutation, and both exhibited with hypochloremic metabolic alkalosis, acidic urine and hypokalemia. Through a series of protein structural analyses and functional experiments, the V512L mutation was confirmed as a gain-of-function (GOF) mutation in the ATP6V0A4 gene. V512-a4 increased a4 subunit expression abundance by enhancing V512L-a4 stability and reducing its degradation, which in turn potentiated V-ATPase's capacity to acidify the tubular lumen, leading to acidic urine and metabolic alkalosis. Through mutant V512L-a4 subunit structure-based virtual and experimental screening, we discovered F351 (C25H26FN3O2S), a small-molecule inhibitor specifically targeting the V512L-a4 mutant. In conclusion, we identify a GOF mutation in the ATP6V0A4 gene, broadening its phenotypic and mutational spectrum, and provide valuable insights into potential therapeutic approaches for diseases associated with ATP6V0A4 mutations.
A Novel AMD Severity Scoring System Leveraging the AREDS Studies and Routine Clinical Electronic Medical Records
Authors: Cecilia S Lee, Yu-Ru Su, Rod L Walker, Chloe Krakauer, Marian Blazes, Eric A Johnson, David Cronkite, Will Bowers, Chantelle Hess, David Arterburn, Elvira Agrón, Emily Y Chew, Paul K Crane
Journal: Ophthalmology (2025)
Corrigendum to “High-efficiency antioxidant ROS-responsive thermosensitive hydrogel encapsulated Fenofibrate for the treatment of corneal neovascularization” [Journal of Controlled Release, Volume 382, 2025, 113650]
Authors: Kai Fan, Dejun Yang, Xinyi Zhu, Lan Zheng, Yi Han, Jingwei Lin, Zixun Xiang, Yafei Guo, Keyue Tao, Juntong Li, Jia Qu, Yunlong Wu, Huaqiong Li, Cheng Li
Journal: Journal of Controlled Release (2025)
UNISOM: Unified Somatic Calling and Machine Learning-based Classification Enhance the Discovery of CHIP
Authors: Shulan Tian, Garrett Jenkinson, Alejandro Ferrer, Huihuang Yan, Joel A Morales-Rosado, Kevin L Wang, Terra L Lasho, Benjamin B Yan, Saurabh Baheti, Janet E Olson, Linda B Baughn, Wei Ding, Susan L Slager, Mrinal S Patnaik, Konstantinos N Lazaridis, Eric W Klee
Journal: Genomics Proteomics & Bioinformatics (2025)

Abstract Clonal hematopoiesis (CH) of indeterminate potential (CHIP), driven by somatic mutations in leukemia-associated genes, confers increased risk of hematologic malignancies, cardiovascular disease, and all-cause mortality. In blood of healthy individuals, small CH clones can expand over time to reach 2% variant allele frequency (VAF), the current threshold for CHIP. Nevertheless, reliable detection of low-VAF CHIP mutations is challenging, often relying on deep targeted sequencing. Here, we present UNISOM, a streamlined workflow for enhancing CHIP detection from whole-genome and whole-exome sequencing data that are underpowered, especially for low VAFs. UNISOM utilizes a meta-caller for variant detection, in couple with machine learning models which classify variants into CHIP, germline, and artifact. In whole-exome data, UNISOM recovered nearly 80% of the CHIP mutations identified via deep targeted sequencing in the same cohort. Applied to whole-genome sequencing data from Mayo Clinic Biobank, it recapitulated the patterns previously established in much larger cohorts, including the most frequently mutated CHIP genes, predominant mutation types and signatures, as well as strong associations of CHIP with age and smoking status. Notably, 30% of the identified CHIP mutations had &amp;lt; 5% VAFs, demonstrating its high sensitivity toward small mutant clones. This workflow is applicable to CHIP screening in population genomic studies. The UNISOM pipeline is freely available at https://github.com/shulanmayo/UNISOM and https://ngdc.cncb.ac.cn/biocode/tool/7816.
Tissue mechanics in tumor heterogeneity and aggression
Authors: Anna-Marie Finger, Audrey Marie Hendley, Diego Figueroa, Hugo Gonzalez, Valerie Marie Weaver
Journal: Trends in cancer (2025)

Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.
Annals of the Rheumatic Diseases collection on axial spondyloarthritis (2022-2024): advances in the field
Authors: Sofia Ramiro, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2025)

During the period from 2022 to 2024, Annals of the Rheumatic Diseases published a series of articles dedicated to significant advancements in axial spondyloarthritis (axSpA). These articles spanned across diverse areas including translational science, epidemiology, disease outcomes, imaging, management, and updated clinical recommendations and consensus statements supported by new evidence.
Identifying Leukemia-related Genes based on Time-series Dynamical Network by Integrating Differential Genes
Authors: Jin A, Ju Xiang, Xiangmao Meng, Yue Sheng, Hongling Peng, Min Li
Journal: Genomics Proteomics & Bioinformatics (2025)

Abstract Leukemia is a malignant disease of progressive accumulation characterized by high morbidity and mortality rates, and investigating its disease genes is crucial for understanding its etiology and pathogenesis. Network propagation methods have emerged and been widely employed in disease gene prediction, but most of them focus on static biological networks, which hinders their applicability and effectiveness in the study of progressive diseases. Moreover, there is currently a lack of special algorithms for the identification of leukemia disease genes. Here, we proposed DyNDG, a novel dynamic network-based model, which integrates differentially expressed genes to identify leukemia-related genes. Initially, we constructed a time-series dynamic network to model the development trajectory of leukemia. Then, we built a background–temporal multilayer network by integrating both the dynamic network and the static background network, which was initialized with differentially expressed genes at each stage. To quantify the associations between genes and leukemia, we extended a random walk process to the background–temporal multilayer network. The experimental results demonstrate that DyNDG achieves superior accuracy compared to several state-of-the-art methods. Moreover, after excluding housekeeping genes, DyNDG yields a set of promising candidate genes associated with leukemia progression or potential biomarkers, indicating the value of dynamic network information in identifying leukemia-related genes. The implementation of DyNDG is available at both https://ngdc.cncb.ac.cn/biocode/tool/BT7617 and https://github.com/CSUBioGroup/D yNDG.
Integrated Computational and Functional Screening Identify G9a Inhibitors for <i>SETD2</i>-Mutant Leukemia
Authors: Ya Zhang, Mengfang Xia, Zhenyi Yi, Pinpin Sui, Xudong He, Liping Wang, Qiyi Chen, Hong-Hu Zhu, Gang Huang, Qian-Fei Wang
Journal: Genomics Proteomics & Bioinformatics (2025)

Abstract SETD2, a frequently mutated epigenetic tumor suppressor in acute leukemia, is associated with chemotherapy resistance and poor patient outcomes. To explore potential therapeutics for SETD2-mutant leukemia, we employed an integrated approach combining computational prediction with epigenetic compound library screening. This approach identified G9a inhibitors as promising candidates, capable of reversing gene expression signatures associated with Setd2 deficiency and selectively inhibiting SETD2-deficient cells. RNA-sequencing analysis revealed that G9a inhibitor significantly downregulated Myc and Myc-regulated genes involved in translation, DNA replication, and G1/S transition in Setd2-mutant cells. Further chromatin immunoprecipitation sequencing analysis showed that G9a inhibition reduced H3K9me2 levels at the long non-coding RNA Mir100hg locus, coinciding with specific upregulation of the embedded microRNA let-7a-2 in Setd2-mutant cells. Given the established role of let-7a in MYC suppression, these findings suggest a potential mechanism by which G9a inhibitors induce MYC downregulation in SETD2-mutant leukemia. Additionally, correlation analysis between computational prediction and phenotypic outcomes highlighted the MYC signature as a key predictor of drug efficacy. Collectively, our study identifies G9a inhibitors as a promising therapeutic avenue for SETD2-mutant leukemia and provides novel insights into refining drug prediction strategies.
Perivascular Niche–Resident Alveolar Macrophages Promote Interstitial Pneumonitis Related to Trastuzumab Deruxtecan Treatment
Authors: Qing Wei, Teng Yang, Ziwen Zhang, Fei Wang, Yuxuan Yang, Jiayu Zhu, Xiu Zhu, Yuanzheng Li, Yun Xing, Ye Lu, Xuefei Tian, Mengyang Fan, Yuchao Zhang, Xiru Xue, Meng Li, Chuanfei Yu, Lan Wang, Takaya Shimura, Jianmin Fang, Zhiwei Cao, Jieer Ying, Peng Guo, Xiangdong Cheng
Journal: Cancer Research (2025)

Abstract Trastuzumab deruxtecan (T-DXd) is a transformative HER2-targeting antibody–drug conjugate (ADC) for treating breast cancer. Unfortunately, T-DXd has also been implicated in causing fatal interstitial lung disease (ILD) in multiple clinical trials. A better understanding of the mechanistic basis of these ADC-induced adverse effects could enable development of strategies to prevent or treat T-DXd–related ILD. In this study, we determined that T-DXd–induced ILD represents an off-target adverse event rather than an on-target off-tumor adverse event. To further investigate this phenomenon, an immunocompetent murine model that recapitulates T-DXd–induced ILD events was developed, facilitating in-depth mechanistic studies. Single-cell RNA sequencing in this model implicated alveolar macrophages (AM) as the primary cell type impacted by T-DXd in the lung microenvironment. Intravital microscopy further revealed that AMs resident in perivascular niches directly engulfed blood-circulating T-DXd via Fc–FcγR engagement. This Fc–FcγR interaction with T-DXd triggered a phenotypic shift in AMs from an immunosuppressive to a pro-ILD state, characterized by inflammation and immune activation, mediated through the SPP1 pathways. Finally, mitigating nonspecific T-DXd uptake in the lung by preconditioning perivascular AMs with IgG1 or the parental antibody of T-DXd significantly reduced unintended ADC absorption. These findings elucidate a mechanism by which T-DXd ignites the lung immune microenvironment and underscore the importance of off-target endocytosis by innate immune cells in the development of ADC-related toxicities. Significance: Preconditioning the perivascular niche can prevent lung inflammation induced by antibody-drug conjugate phagocytosis by alveolar macrophages and subsequent SPP1high macrophage differentiation, providing a clinically viable strategy for mitigating interstitial lung disease.
Evolving CAR T-Cell Therapy to Overcome the Barriers in Treating Pediatric Central Nervous System Tumors
Authors: Andrea Timpanaro, Edward Z. Song, Nour Amwas, Chu-Hsuan Chiu, Rebecca Ronsley, Mallory R. Taylor, Jessica B. Foster, Leo D. Wang, Nicholas A. Vitanza
Journal: Cancer Discovery (2025)

CNS tumors are the leading cause of cancer-related death in children, highlighting the dire need for new treatment strategies. CAR T cells represent a unique approach, distinct from the cytotoxic chemotherapies and small-molecule inhibitors that have dominated the clinical trial space for decades. Phase I CAR T-cell trials have shown feasibility and possible efficacy against pediatric CNS tumors; however, many challenges must be overcome if these therapeutics are going to be beneficial to most affected children. Although rapid translational development and early-phase trials have quickly evolved our understanding, the pediatric CNS CAR T-cell community now yearns for critical assessments and open dialogue about overcoming the remaining obstacles ahead.
INTERLINK-1: A Phase III, Randomized, Placebo-Controlled Study of Monalizumab Plus Cetuximab in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Jérôme Fayette, Lisa Licitra, Kevin Harrington, Robert Haddad, Lillian L. Siu, Yi-Chun Liu, Makoto Tahara, Jean-Pascal Machiels, Danny Rischin, Tanguy Y. Seiwert, Robert L. Ferris, Ulrich Keilholz, Amanda Psyrri, Bhumsuk Keam, Paolo Bossi, Robert Metcalf, Ching-Yun Hsieh, Paul M.J. Clement, Pavel Isaev, Ali Mudunov, José Dinis, Ann Hoeben, Stefan Kasper, Konrad Klinghammer, Michael Hwang, Jorge Blando, Olivier Serrano, Dario Ruscica, Roger B. Cohen
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Treatment options for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) after failure of immune checkpoint inhibitor (ICI) treatment and platinum-based chemotherapy are limited. Preliminary data suggested monalizumab plus cetuximab had clinical activity in R/M HNSCC. Participants and methods: INTERLINK-1 (NCT04590963) was a double-blind, phase III study. Participants with R/M HNSCC who had received ICI therapy and progressed despite platinum-based chemotherapy were randomized 2:1 to monalizumab (750 mg, fortnightly) or placebo, plus cetuximab (400 mg/m2 loading dose, then 250 mg/m2, weekly). The primary endpoint was overall survival (OS) in participants with non-oropharyngeal cancer (OPC) or human papillomavirus (HPV)-negative OPC (HPV-unrelated analysis set). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Results: At data cut-off, 216 participants were randomized in the HPV-unrelated analysis set; 145 to monalizumab plus cetuximab and 71 to placebo plus cetuximab. Median OS was 8.8 months for monalizumab plus cetuximab versus 8.6 months for placebo plus cetuximab (hazard ratio [HR], 1.00; 95% CI, 0.66–1.54); median PFS was 3.6 versus 3.8 months, respectively (HR, 1.11; 95% CI, 0.79–1.57); and ORR was 15.2% versus 23.9%, respectively. INTERLINK-1 was terminated after a preplanned interim analysis showed futility criteria were met (predetermined futility HR &amp;gt;0.874). Grade 3–4 treatment-related adverse events were reported in 18.3% and 17.2% of participants treated in the monalizumab and placebo arms, respectively. Conclusions: Monalizumab plus cetuximab did not improve OS compared with placebo plus cetuximab. The safety profile of the combination was consistent with safety observations for cetuximab monotherapy.
High Incidence of Severe TA-TMA Increases Mortality in adult Allogeneic Transplant recipients: A prospective MIDAS Consortium study
Authors: Sumithira Vasu, Qiuhong Zhao, Elizabeth Greer Miller, Patrick Elder, Lucille Langenberg, Spero R. Cataland, Stella M Davies, Nelli Bejanyan, Theresa Hahn
Journal: Blood (2025)
The mitochondrial protease ClpP is a metabolic vulnerability and an immunogenic trigger against multiple myeloma.
Authors: Tommaso Perini, Paola Zordan, Rossella Del Pizzo, Massimo Resnati, Lisa Viviani, Davide Stefanoni, Laura Cassina, Ugo Paolo Orfanelli, Matteo Trudu, laura oliva, Daniel Lacidogna, Mehmet K. Samur, Maria Materozzi, Denise Drago, Annapaola Andolfo, Marco Patrone, Massimo Degano, Alessandra Boletta, Enrico Milan, Fabio Ciceri, Nikhil C. Munshi, Matteo Bellone, Simone Cenci
Journal: Blood (2025)
Tailoring CAR surface density and dynamics to improve CAR-T cell therapy
Authors: Ana Hinckley-Boned, Carmen Barbero-Jiménez, Maria Tristán-Manzano, Noelia Maldonado-Perez, Michael Hudecek, Pedro Justicia-Lirio, Francisco Martin
Journal: Journal for ImmunoTherapy of Cancer (2025)

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment landscape for relapsed and/or refractory B-cell neoplasms, garnering Food and Drug Administration/European Medicines Agency approval for six commercial products. Despite this success, challenges persist, including a relapse rate of 30–50% in hematologic tumors, limited clinical efficacy in solid tumors, and severe side effects. This review addresses the critical need for therapeutic enhancement by focusing on the often-overlooked strategy of modulating CAR protein density on the cell membrane. We delve into the key factors influencing CAR surface expression, such as CAR downmodulation following antigen encounter and antigen-related factors. The dynamics of CAR downmodulation remain underexplored; however, recent data point to its modification as a useful tool for improving functionality. Notably, transcriptional control of CAR expression and the incorporation of specific elements into the CAR design have emerged as interesting strategies to tailor CAR expression profiles. Therefore, controlling CAR dynamic density may represent an attractive strategy for achieving optimal therapeutic outcomes.
Immunopeptidomics identified antigens for mRNA-lipid nanoparticle vaccines with alpha-galactosylceramide in multiple myeloma therapy
Authors: Arne Van der Vreken, Fabien Thery, Chenggong Tu, Kevin Mwangi, Sofie Meulewaeter, Lien De Beck, Edith Janssens, Kim De Veirman, Karin Vanderkerken, Elke De Bruyne, Lorenzo Franceschini, Francis Impens, Rein Verbeke, Ine Lentacker, Eline Menu, Karine Breckpot
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Invariant natural killer T (iNKT) cells and CD8 + T cells are key in the immune response against multiple myeloma (MM), a largely incurable blood cancer. Immunization is a promising strategy to activate these T cell populations. To our knowledge, immunization with messenger RNA (mRNA) and the iNKT agonist, α-galactosylceramide (αGC), has not been studied in MM, as knowledge on clinically relevant antigens in preclinical MM models is lacking. Methods Microarray data and immunopeptidomics (imPep) were used to identify candidate antigens for immunization in 5TMM models. Galsomes, lipid nanoparticles containing antigen mRNA and αGC were used to immunize 5T33MM-bearing mice. This treatment was combined with a CD40 agonist. Tumor burden and activation of iNKT cells and CD8 + T cells were studied using M-protein electrophoresis, flow cytometry and ELISA. Results RNA transcripts revealed survivin as a candidate antigen. Prime-boost Galsomes therapy targeting survivin significantly reduced M-protein levels despite low survivin-specific T cell responses. Further analysis showed potential T cell fratricide. ImPep revealed HSP60, Idiotype, PICALM and EF1A1 as candidate antigens. Prime-boost therapy with Galsomes targeting these antigens reduced MM growth significantly when combined with a CD40 agonist, coinciding with significantly improved antigen presentation, costimulation and cytotoxicity of iNKT cells and CD8 + T cells. Conclusion These findings highlight the potential of Galsomes, an mRNA vaccine designed to activate CD8 + T cells and iNKT cells, for MM therapy, and emphasize the importance of combinatorial approaches, addressing immune anergy for effective MM immunotherapies.
Gut reactions: harnessing microbial metabolism to fuel next-generation cancer immunotherapy
Authors: Andrew A Almonte, Laurence Zitvogel
Journal: Journal for ImmunoTherapy of Cancer (2025)

Immunotherapies, including immune checkpoint inhibitors and chimeric antigen receptor-T cell therapies, depend heavily on a healthy and diverse gut microbiome for optimal efficacy. Dysbiosis, or an imbalance in gut microbial composition and function, can diminish immunotherapy responses by altering immune cell trafficking and metabolic output. Key microbial metabolites such as short-chain fatty acids and modified bile acids shape host immunity and influence T-cell function, while their disruption can foster an immunosuppressive microenvironment. Emerging strategies to restore a balanced microbiome and boost treatment outcomes include dietary interventions, supplementation with beneficial microbes, and fecal microbiota transplantation. Despite these advances, challenges remain in defining dysbiosis, identifying reliable biomarkers, and tailoring microbiota-centered interventions. Nevertheless, as our understanding evolves, the gut microbiome holds promise as an integral component of personalized cancer immunotherapy.