tbuckley/cabot-search huggingface dataset:
VCP regulates early tau seed amplification via specific cofactors
Authors: Sushobhna Batra, Jaime Vaquer-Alicea, Clarissa Valdez, Skyler P. Taylor, Victor A. Manon, Anthony R. Vega, Omar M. Kashmer, Sourav Kolay, Andrew Lemoff, Nigel J. Cairns, Charles L. White, Marc I. Diamond
Journal: Molecular Neurodegeneration (2025)

Abstract Background Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. Seeding into the complex cytoplasmic milieu happens within hours, implying the existence of unknown factors that regulate this process. Methods We used proximity labeling to identify proteins that control seed amplification within 5 h of seed exposure. We fused split-APEX2 to the C-terminus of tau repeat domain (RD) to reconstitute peroxidase activity 5 h after seeded intracellular tau aggregation. Valosin containing protein (VCP/p97) was the top hit. VCP harbors dominant mutations that underlie two neurodegenerative diseases, multisystem proteinopathy and vacuolar tauopathy, but its mechanistic role is unclear. We used immortalized cells and human neurons to study the effects of VCP on tau seeding. We exposed cells to fibrils or brain homogenates in cell culture media and measured effects on uptake and induction of intracellular tau aggregation following various genetic and pharmacological manipulations of VCP. Results VCP knockdown reduced tau seeding. Chemical inhibitors had opposing effects on seeding in HEK293T tau biosensor cells and human neurons: ML-240 increased seeding efficiency, whereas NMS-873 decreased it. The inhibitors only functioned when administered within 8 h of seed exposure, indicating a role for VCP early in seed processing. We screened 30 VCP co-factors in HEK293T biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding, as did NPLOC4, which also uniquely increased soluble tau levels. By contrast, reduction of FAF2 increased tau seeding. Conclusions Divergent effects on tau seeding of chemical inhibitors and cofactor reduction indicate that VCP regulates this process. This is consistent with a cytoplasmic processing complex centered on VCP that directs seeds acutely towards degradation vs. amplification.
Multimodal deep ensemble classification system with wearable vibration sensor for detecting throat-related events
Authors: Yonghun Song, Inyeol Yun, Sandra Giovanoli, Chris Awai Easthope, Yoonyoung Chung
Journal: npj Digital Medicine (2025)

Dysphagia, a swallowing disorder, requires continuous monitoring of throat-related events to obtain comprehensive insights into the patient's pharyngeal and laryngeal functions. However, conventional assessments were performed by medical professionals in clinical settings, limiting persistent monitoring. We demonstrate feasibility of a ubiquitous monitoring system for autonomously detecting throat-related events utilizing a soft skin-attachable throat vibration sensor (STVS). The STVS accurately records throat vibrations without interference from surrounding noise, enabling measurement of subtle sounds such as swallowing. Out of the continuous data stream, we automatically classify events of interest using an ensemble-based deep learning model. The proposed model integrates multiple deep neural networks based on multi-modal acoustic features of throat-related events to enhance robustness and accuracy of classification. The performance of our model outperforms previous studies with a classification accuracy of 95.96%. These results show the potential of wearable solutions for improving dysphagia management and patient outcomes outside of clinical environments.
Targeting Senescent Stemlike Subpopulations in Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia
Authors: Yang-Yang Ding, Jonathan H Sussman, Kellyn Madden, Joseph P Loftus, Robert K Chen, Catherine D Falkenstein, Diego Alberto Barcenas Lopez, David A Hottman, Benjamin Mathier, Wenbao Yu, Jason Xu, Changya Chen, Chia-Hui Chen, Bing He, Shovik Bandyopadhyay, Zhan Zhang, DongGeun Lee, Hong Wang, Junmin Peng, Chi V Dang, Kai Tan, Sarah K Tasian
Journal: Blood (2025)
Selenoprotein-Mediated Redox Regulation Shapes the Cell Fate of HSCs and Mature Lineages
Authors: Yumi Aoyama, Hiromi Yamazaki, Koutarou Nishimua, Masaki Nomura, Tsukasa Shigehiro, Takafumi Suzuki, Weijia Zang, Yota Tatara, Hiromi Ito, Yasutaka Hayashi, Yui Koike, Miki Fukumoto, Atsushi Tanaka, Yifan Zhang, Wataru Saika, Chihiro Hasegawa, Shuya Kasai, Yingyi Kong, Yohei Minakuchi, Ken Itoh, Masayuki Yamamoto, Shinya Toyokuni, Atsushi Toyoda, Tomokatsu Ikawa, Akifumi Takaori-Kondo, Daichi Inoue
Journal: Blood (2025)
Potentiating CD20 monoclonal antibody therapy by targeting complement C3 fragment covalently deposited on lymphoma cells
Authors: Sivasubramanian Baskar, Haiyong Peng, Erika M Gaglione, Elizabeth J Carstens, Margaret A Lindorfer, Inhye E. Ahn, Sarah E.M. Herman, Martin Skarzynski, Jing Chang, Keyvan Keyvanfar, Vicent Butera, Amy Z Blackburn, Berengere Vire, Irina Maric, Maryalice Stetler-Stevenson, Constance M Yuan, Michael A Eckhaus, Susan Soto, Mohammed Z.H. Farooqui, Ronald P Taylor, Christoph Rader, Adrian Wiestner
Journal: Blood (2025)
Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML
Authors: Mark J. Levis, Mehdi Hamadani, Brent R. Logan, Richard J. Jones, Anurag K Singh, Mark R Litzow, John R. Wingard, Esperanza B. Papadopoulos, Alexander E. Perl, Robert J. Soiffer, Celalettin Ustun, Masumi Ueda Oshima, Geoffrey L Uy, Edmund K. Waller, Sumithira Vasu, Melhem M Solh, Asmita Mishra, Lori Muffly, Hee-Je Kim, Matthias Stelljes, Yuho Najima, Masahiro Onozawa, Kirsty J Thomson, Arnon Nagler, Andrew H Wei, Guido Marcucci, Caroline Chen, Nahla Hasabou, Matt Rosales, Jason E. Hill, Stanley C. Gill, Rishita Nuthethi, Denise King, Adam M Mendizabal, Steven M. Devine, Mary M Horowitz, Yi-Bin Chen
Journal: Blood (2025)

BMT CTN 1506 ("MORPHO"; NCT02997202) was a randomized phase 3 study of gilteritinib compared to placebo as maintenance therapy after hematopoietic stem cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary endpoint was to determine the impact on survival of pre- and/or post-HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post-hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively impacted RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared to 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild type clones (as assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multi-clonal disease. These data demonstrate the potential of using FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML.
Pharmacological treatment for metabolic dysfunction–associated steatotic liver disease and related disorders: Current and emerging therapeutic options
Authors: Xiang Zhang, Harry Cheuk-Hay Lau, Jun Yu
Journal: Pharmacological Reviews (2025)

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.
Large language models for the mental health community: framework for translating code to care
Authors: Matteo Malgaroli, Katharina Schultebraucks, Keris Jan Myrick, Alexandre Andrade Loch, Laura Ospina-Pinillos, Tanzeem Choudhury, Roman Kotov, Munmun De Choudhury, John Torous
Journal: The Lancet Digital Health (2025)
Tamuzimod in patients with moderately-to-severely active ulcerative colitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 induction trial
Authors: Bruce E Sands, Remo Panaccione, Geert D'Haens, Stefan Schreiber, Vipul Jairath, Aaron DuVall, Jaroslaw Kierkus, Michael Walczak, Snehal Naik, Kye Gilder, Beatriz Lindstrom, Kathleen Ogilvie, William J Sandborn, Severine Vermeire, David T Rubin, Laurent Peyrin-Biroulet, Silvio Danese
Journal: The Lancet. Gastroenterology & hepatology (2025)
Neuropathology, pathomechanism, and transmission in zoonotic Borna disease virus 1 infection: a systematic review
Authors: Nicola Jungbäck, Yannik Vollmuth, Tatiana Mögele, Przemyslaw Grochowski, Jürgen Schlegel, Tina Schaller, Bruno Märkl, Christiane Herden, Kaspar Matiasek, Dennis Tappe, Friederike Liesche-Starnecker
Journal: The Lancet Infectious Diseases (2025)
Advanced therapies in US veterans with rheumatoid arthritis-associated interstitial lung disease: a retrospective, active-comparator, new-user, cohort study
Authors: Bryant R England, Joshua F Baker, Michael D George, Tate M Johnson, Yangyuna Yang, Punyasha Roul, Halie Frideres, Harlan Sayles, Fang Yu, Scott M Matson, Jorge Rojas, Brian C Sauer, Grant W Cannon, Jeffrey R Curtis, Ted R Mikuls
Journal: The Lancet Rheumatology (2025)
Anticoagulants: from chance discovery to structure-based design
Authors: Noel Chan, Stephanie Carlin, Jack Hirsh
Journal: Pharmacological Reviews (2025)

Taking a historical perspective, we review the discovery, pharmacology, and clinical evaluation of the old and new anticoagulants that have been approved for clinical use. The drugs are discussed chronologically, starting in the 1880s, and progressing through to 2024. The innovations in technology used to develop novel anticoagulants came in fits and starts and reflected the advances in science and technology over these decades, whereas the shift from anecdote to evidence-based use of anticoagulants was delayed until the principles of epidemiology and biostatistics were introduced into clinical trial design and to the approval process. Hirudin, heparin, and vitamin K antagonists were discovered by chance, and were used clinically before their mechanism of action was elucidated and before their net clinical benefits were evaluated in randomized clinical trials. Subsequent anticoagulants were designed based on a better understanding of the structure and function of coagulation proteins, including antithrombin, thrombin, and factor Xa, and underwent more rigorous preclinical and clinical evaluation before regulatory approval. By simplifying oral anticoagulation, the direct oral anticoagulants have revolutionized anticoagulation care and have enhanced the uptake of anticoagulation, but bleeding has not been eliminated and there is a need for more effective and convenient anticoagulants for thrombosis triggered by the contact pathway of coagulation. The newly developed factor XIa and XIIa inhibitors have the potential to address these unmet clinical needs and are undergoing clinical evaluation for several indications. SIGNIFICANCE STATEMENT: Anticoagulant therapy is the cornerstone of treatment and prevention of thrombosis, which remains a leading cause of morbidity and mortality worldwide. Elucidation of the structure and function of coagulation enzymes, their cofactors, and inhibitors, coupled with advances in structure-based design led to the discovery of more convenient, safer, and more effective anticoagulants that have revolutionized the management of thrombotic disorders.
Dermal fibroblast-derived extracellular matrix (ECM) synergizes with keratinocytes in promoting re-epithelization and scarless healing of skin wounds: Towards optimized skin tissue engineering
Authors: Xiangyu Dong, Han Xiang, Jiajia Li, Ailing Hao, Hao Wang, Yannian Gou, Aohua Li, Saidur Rahaman, Yiheng Qiu, Jiahao Li, Ou Mei, Jiamin Zhong, Wulin You, Guowei Shen, Xingye Wu, Jingjing Li, Yi Shu, Lewis L Shi, Yi Zhu, Russell R Reid, Tong-Chuan He, Jiaming Fan
Journal: Bioactive Materials (2025)
Stress granule formation is regulated by signaling machinery involving Sch9/Ypk1, sphingolipids, and Ubi4
Authors: Lihua Chen, Yuan Gao, Xinxin Hao, Xiaoxue Yang, Michelle Lindström, Shan Jiang, Xiuling Cao, Huisheng Liu, Thomas Nyström, Per Sunnerhagen, Beidong Liu
Journal: Theranostics (2025)

Rationale: Stress granules (SGs) are membraneless organelles that are formed in response to various stresses. Multiple cellular processes have been reported to be involved in SG formation. However, the signaling cascades that coordinate SG formation remain to be elucidated. Methods: By performing two high-content imaging-based phenomic screens, we identified multiple signaling components that form a possible signal transduction pathway that regulates SG formation. Results: We found that Sch9 and Ypk1 function in an early step of SG formation, leading to a decrease in intermediate long-chain base sphingolipids (LCBs). This further downregulates the polyubiquitin precursor protein Ubi4 through upregulating the deubiquitinase Ubp3. Decreased levels of cellular free ubiquitin may subsequently facilitate Lsm7 phase separation and thus trigger SG formation. Conclusion: The signaling pathway identified in this work, together with its conserved components, provides valuable clues for understanding the mechanisms underlying SG formation and SG-associated human diseases.
Pharmacovigilance insights into medication-induced risk of dural arteriovenous fistula
Authors: Hao Liu, Yujia Zou, Qiongchi Zhang, Jinghao Zhao, Jingtao Wu, Xingyu Li, Yongzhong Cheng, Hongyu Wei, Haopeng Li, Shuai Cao
Journal: International Journal of Surgery (2025)

Dural arteriovenous fistulas (DAVFs) pose a significant health threat owing to their high misdiagnosis rate. Case reports suggest that DAVFs or related acute events may follow medication use; however, drug-related risk factors remain unclear. In clinical practice, the concomitant use of multiple drugs for therapy is known as "polypharmacy situations," further increasing the risk of drug-induced DAVF. Real-world studies linking medications and DAVF can alert clinicians to their possibilities and contribute to clinical decision-making and patient education. This study investigated adverse events spanning a decade from the FAERS database, employing pharmacovigilance analysis to systematically assess the risk of drug-induced DAVF. Furthermore, the clinical characteristics of these drug-related DAVFs, such as demographic information, complications, and outcomes, were characterized. This study generated a broad spectrum of drugs associated with DAVFs. A total of 355 DAVF events, involving 161 drugs across 73 categories, were compiled from millions of records. We identified eight classes of drugs for thorough investigation. Pharmacovigilance analysis revealed that tamoxifen, methylprednisolone, betamethasone, prednisone, rebif, ustekinumab, natalizumab, baclofen, dabigatran etexilate, and bupivacaine have the potential to induce DAVFs. Cerebrovascular thrombotic and embolic events emerge as the most prominent co-adverse events of drug-induced DAVFs. Analyses based on drug-disease targets suggested that the regulation of angiogenesis could be a potential mechanism in tamoxifen-induced DAVFs. Apart from medications with gender-specific prescription patterns, most medications exhibit a high risk of DAVF in adult male cohorts. Five patients with drug-related DAVFs experienced severe (fatal) outcomes, with four reports attributed to tamoxifen. These findings highlight the diverse range of drugs implicated in the occurrence or progression of DAVF. Drugs such as tamoxifen, corticosteroids, multiple sclerosis medications, and oral anticoagulants require particular attention. Future research should focus on elucidating the underlying mechanisms and risk factors, such as thrombosis, contributing to drug-induced DAVF to inform preventive strategies and optimize patient care.
TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance
Authors: Zhi Liu, Chunyu Zhang, Jiatong Xiao, Yunbo He, Haisu Liang, Jinliang Huang, Zhiyong Cai, Zhenglin Yi, Mingfeng Chen, Yixiao Li, Jun Zhang, Fenglian liu, Peng Ren, Huihuang Li, Jinbo Chen, Benyi Fan, Jiao Hu, Xiongbing Zu, Dingshan Deng
Journal: Theranostics (2025)

Background: Identifying biomarkers that predict immunotherapy efficacy and discovering new targets for combination therapies are critical elements for improving the prognosis of bladder cancer (BLCA) patients. Methods: Firstly, we explored the expression patterns of TBX3 in normal and pan-cancer tissues and the correlation between TBX3 and the immune microenvironment using data from multiple public databases. Then, we combined various techniques, including bulk RNA sequencing, single-cell RNA sequencing, high-throughput cytokine arrays, functional experiments, ProcartaPlex multiplex immunoassays and TissueFAXS panoramic tissue quantification assays, to demonstrate that TBX3 shapes an immunosuppressive tumor microenvironment (TME) in BLCA. Results: We identified TBX3 as a key factor associated with the immunosuppressive microenvironment in BLCA through a systematic multi-omics analysis. We found that TBX3 is primarily expressed in malignant cells, where TBX3high tumor cells increase the secretion of TGFβ1, which promotes the infiltration of cancer-associated fibroblasts (CAFs), thereby forming an immunosuppressive microenvironment. We further demonstrated that TBX3 enhances TGFβ1 expression by binding to the TGFβ1 promoter, and blocking TGFβ1 counteracts the immunosuppressive effects of TBX3. Moreover, TBX3 reduced the cancer-killing efficiency of CD8+ T cells by decreasing the proportion of GZMB+ CD8+ T cells, and knocking down TBX3 combined with anti-PD-1 treatment increased CD8+ T cell infiltration and reduced CAFs in vivo. We also validated the inverse relationship between TBX3+ malignant cells and CD8+ T cells and the positive relationship with CAFs in tissue microarrays. Lastly, we found that TBX3 predicted immunotherapy efficacy in our real-world immunotherapy cohort and multiple public cohorts. Conclusion: In summary, TBX3 promotes BLCA progression and immunotherapy resistance by inducing an immunosuppressive microenvironment, and targeting TBX3 could enhance the efficacy of immunotherapy for BLCA.
Betaine inhibits the stem cell-like properties of hepatocellular carcinoma by activating autophagy via SAM/m<sup>6</sup>A/YTHDF1-mediated enhancement on ATG3 stability
Authors: Chen Wang, Meng-chu Li, Wen-ge Huang, Si-yu Huang, Maierhaba Wusiman, Zhao-yan Liu, Hui-lian Zhu
Journal: Theranostics (2025)

Background: Stem cell-like properties are known to promote the recurrence and metastasis of hepatocellular carcinoma (HCC), contributing to a poor prognosis for HCC patients. Betaine, an important phytochemical and a methyl-donor related substance, has shown protective effects against liver diseases. However, its effect on HCC stem cell-like properties and the underlying mechanisms remains uninvestigated. Methods: We measured the effects of betaine on the stem cell-like properties and malignant progression of HCC using patient-derived xenografts, cell-derived xenografts, tail vein-lung metastasis models, in vitro limiting dilution, tumor sphere formation, colony formation, and transwell assays. Mechanistic exploration was conducted using western blots, dot blots, methylated RNA immunoprecipitation-qPCR, RNA stability assays, RNA immunoprecipitation-qPCR, RNA pull-down, and gene mutation assays. Results: A cohort study of HCC found that a higher serum concentration of betaine was associated with decreased levels of stemness-related markers. Furthermore, in HCC cells and xenograft mice, betaine suppressed the stem cell-like properties of HCC by activating autophagy. Mechanistically, betaine increased the m6A modification in HCC by producing S-adenosylmethionine (SAM) via betaine-homocysteine S-methyltransferase (BHMT). This increase in SAM subsequently triggered autophagy by enhancing the stability of autophagy-related protein 3 (ATG3) via YTHDF1 in an m6A-dependent manner, thereby inhibiting the stem cell-like properties of HCC cells. Conclusions: These findings indicate that betaine inhibits the stem cell-like properties of HCC via the SAM/m6A/YTHDF1/ATG3 pathway. This study underscores the potential anti-tumor effects of betaine on HCC and offers novel therapeutic prospects for HCC patients.