tbuckley/cabot-search huggingface dataset:
Stable‐Dynamic Hydrogels Mimicking the Pericellular Matrix for Articular Cartilage Repair
Authors: Yixin Li, Tiancheng Li, Cheng Zhu, Hairui Li, Runzhe Fang, Ruomei Li, Yu Jin, Zhiyu Zhu, Lunguo Xia, Bing Fang
Journal: Advanced Healthcare Materials (2025)

Abstract Cartilage regeneration requires a specialized biomechanical environment. Macroscopically, cartilage repair requires a protracted, stable mechanical environment, whereas microscopically, it involves dynamic interactions between cells and the extracellular matrix. Therefore, this study aims to design a hydrogel that meets the complex biomechanical requirements for cartilage repair. Dynamic hybrid hydrogels with temporal stability at the macroscale and dynamic properties at the microscale are successfully synthesized. The dynamic hybrid hydrogel simulates the stress relaxation and viscoelasticity of the pericellular matrix, facilitating effective interactions between the extracellular matrix and cells. The in vitro and in vivo experiments demonstrated that the hybrid hydrogel significantly promoted cartilage repair. The dynamic hybrid hydrogel alleviates abnormal actin polymerization, reduces intracellular stress, and increases the volume of individual cells. By modulating the cytoskeleton, the hybrid hydrogel inhibits Notch signal transduction in both the receptor and ligand cells, resulting in an improved cartilage phenotype. This study introduces an effective hybrid hydrogel scaffold that modulates the chondrocyte cytoskeleton and Notch signaling pathways by establishing an appropriate biomechanical environment, thus offering a promising material for cartilage repair.
Iron overload in HFE-related hemochromatosis severely impairs Vδ2 γδ T-cell homeostasis
Authors: Derya Erdogdu, Ina Becoku, Valerie Huber, Yao Wang, Matthias Eyrich, Hisayoshi Hashimoto, Michaela Döring, Johannes H. Schulte, Karin Schilbach
Journal: Blood (2025)
Efficacy of a Novel BCL-xL Degrader, DT2216, in Preclinical Models of JAK2-mutated Post-MPN AML
Authors: Zhe Wang, Anna Skwarska, Gowri Poigaialwar, Sovira Chaudhry, Alba Rodriguez-Meira, Pinpin Sui, Emmanuel Olivier, Yannan Jia, Varun Gupta, Warren Fiskus, Cassandra L. Ramage, Guangrong Zheng, Alexandra Schurer, Kira Gritsman, Eirini P Papapetrou, Kapil N Bhalla, Daohong Zhou, Adam J. Mead, Raajit K. Rampal, Jeffrey W. Tyner, Hussein A. Abbas, Naveen Pemmaraju, Qi Zhang Tatarata, Marina Y. Konopleva
Journal: Blood (2025)

Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments don't significantly extend survival beyond 12 months. BCL-xL has been found to be overexpressed in leucocytes from MPN patients, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera (PROTAC), in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in post-MPN AML patients compared to those with de novo AML. Single-cell multi-omics analysis revealed that leukemia cells harboring both MPN-driver and TP53 mutations exhibited higher BCL2L1 expression, elevated scores for leukemia stem cell, megakaryocyte development, and erythroid progenitor than wild-type cells. BH3 profiling confirmed a strong dependence on BCL-xL in post-MPN AML cells. DT2216 alone, or in combination with standard AML/MPN therapies, effectively degraded BCL-xL, reduced the apoptotic threshold, and induced apoptosis in post-MPN AML cells. DT2216 effectively eliminated viable cells in JAK2-mutant AML cell lines, induced pluripotent stem cell-derived hematopoietic progenitor cells (iPSC-HPCs), primary samples, and reduced tumor burden in cell line-derived xenograft model in vivo by degrading BCL-xL. DT2216, either as a single agent or in combination with azacytidine, effectively inhibited the clonogenic potential of CD34+ leukemia cells from post-MPN AML patients. In summary, our data indicate that the survival of post-MPN AML is BCL-xL dependent, and DT2216 may offer therapeutic advantage in this high-risk leukemia subset with limited treatment options.
A quiescence-like/TGF-β1-specific CRISPRi screen reveals drug uptake transporters as secondary targets of kinase inhibitors in AML
Authors: Elahe Rahimian, Masoud Koochak, Sofia Traikov, Michael Schroeder, Silke Brilloff, Silvia Schäfer, Vida Kufrin, Sandra Küchler, Alexander Krüger, Peter Mirtschink, Gustavo Baretton, Evelin Schröck, Denis M Schewe, Claudia R Ball, Martin Bornhäuser, Hanno Glimm, Marius Bill, Alexander A Wurm
Journal: Drug Resistance Updates (2025)

Relapse in acute myeloid leukemia (AML) is driven by resistant subclones that survive chemotherapy. It is assumed that these resilient leukemic cells can modify their proliferative behavior by entering a quiescent-like state, similar to healthy hematopoietic stem cells (HSCs). These dormant cells can evade the effects of cytostatic drugs that primarily target actively dividing cells. Although quiescence has been extensively studied in healthy hematopoiesis and various solid cancers, its role in AML has remained unexplored. In this study, we applied an HSC-derived quiescence-associated gene signature to an AML patient cohort and found it to be strongly correlated with poor prognosis and active TGF-β signaling. In vitro treatment with TGF-β1 induces a quiescence-like phenotype, resulting in a G0 shift and reduced sensitivity to cytarabine. To find potential therapeutic targets that prevent AML-associated quiescence and improve response to cytarabine, we conducted a comprehensive CRISPR interference (CRISPRi) screen combined with TGF-β1 stimulation. This approach identified TGFBR1 inhibitors, like vactosertib, as effective agents for preventing the G0 shift in AML cell models. However, pretreatment with vactosertib unexpectedly induced complete resistance to cytarabine. To elucidate the underlying mechanism, we performed a multi-faceted approach combining a second CRISPRi screen, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and in silico analysis. Our findings revealed that TGFBR1 inhibitors unintentionally target the nucleoside transporter SLC29A1 (ENT1), leading to reduced intracellular cytarabine levels. Importantly, we found that this drug interaction is not unique to TGFBR1 inhibitors, but extends to other clinically significant kinase inhibitors, such as the FLT3 inhibitor midostaurin. These findings may have important implications for optimizing combination therapies in AML treatment.
Crossover Trial of Exogenous Ketones on Cardiometabolic Endpoints in Heart Failure with Preserved Ejection Fraction
Authors: Senthil Selvaraj, Antoneta Karaj, Julio A Chirinos, Nicole Denney, Gabby Grosso, Melissa Fernando, Kishon Chambers, Cassandra Demastus, Ravinder Reddy, Michael Langham, Dushyant Kumar, Hannah Maynard, Bianca Pourmussa, Stuart B Prenner, Jordana B Cohen, Harry Ischiropoulos, Michael R Rickels, David C Poole, David D Church, Robert R Wolfe, Daniel P Kelly, Mary Putt, Kenneth B Margulies, Payman Zamani
Journal: JACC Heart Failure (2025)
Inclusion of Participants with Non-English Language Preference in Heart Failure Clinical Trials
Authors: Zara Latif, Elena M Donald, Tracy T Makuvire, Adhya Mehta, Mansi K Shah, Christy N Taylor, Fabian Vargas, Zeyad Elgammal, Vanessa Blumer, Nasrien E Ibrahim, Ersilia M DeFilippis
Journal: JACC Heart Failure (2025)
HoxBlinc: a key driver of chromatin dynamics in NUP98 fusion–driven leukemia
Authors: Jian Xu, Wei Du
Journal: Journal of Clinical Investigation (2025)

Nucleoporin 98 (NUP98) fusion oncogenes are known to promote aggressive pediatric leukemia by disrupting chromatin structure and modulating the expression of homeobox (HOX) genes, yet the precise molecular events are unclear. In this issue of the JCI, K. Hamamoto et al. explore the mechanistic underpinnings of NUP98 fusion-driven pediatric leukemia, with a focus on aberrant activation of the Hoxb-associated long, noncoding RNA (lncRNA) HoxBlinc. The authors provide compelling evidence that HoxBlinc plays a central role in the oncogenic transformation associated with NUP98 fusion protein. The study underscores a CTCF-independent role of HoxBlinc in the regulation of topologically associated domains (TADs) and chromatin accessibility, which has not been fully appreciated in previous research on the NUP98 fusion oncogenes. The discovery of HoxBlinc lncRNA as a downstream regulator of NUP98 fusion oncoproteins offers a potential target for therapeutic intervention in pediatric leukemia.
Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake
Authors: Lu Sun, Ruixue Leng, Monan Liu, Meiming Su, Qingze He, Zhidan Zhang, Zhenghong Liu, Zhihua Wang, Hui Jiang, Li Wang, Shuai Guo, Yiming Xu, Yuqing Huo, Clint L Miller, Maciej Banach, Yu Huang, Paul C Evans, Jaroslav Pelisek, Giovanni G Camici, Bradford C Berk, Stefan Offermanns, Junbo Ge, Suowen Xu, Jianping Weng
Journal: Journal of Clinical Investigation (2025)

Mitochondrial dysfunction fuels vascular inflammation and atherosclerosis. Mitochondrial calcium uptake 1 (MICU1) maintains mitochondrial Ca2+ homeostasis. However, the role of MICU1 in vascular inflammation and atherosclerosis remains unknown. Here, we report that endothelial MICU1 prevents vascular inflammation and atherosclerosis by maintaining mitochondrial homeostasis. We observed that vascular inflammation was aggravated in endothelial cell-specific Micu1 knockout mice (Micu1ECKO) and attenuated in endothelial cell-specific Micu1 transgenic mice (Micu1ECTg). Furthermore, hypercholesterolemic Micu1ECKO mice also showed accelerated development of atherosclerosis, while Micu1ECTg mice were protected against atherosclerosis. Mechanistically, MICU1 depletion increased mitochondrial Ca2+ influx, thereby decreasing the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and the ensuing deacetylation of superoxide dismutase 2 (SOD2), leading to the burst of mitochondrial reactive oxygen species (mROS). Of clinical relevance, we observed decreased MICU1 expression in the endothelial layer covering human atherosclerotic plaques and in human aortic endothelial cells exposed to serum from patients with coronary artery diseases (CAD). Two-sample Wald ratio Mendelian randomization further revealed that increased expression of MICU1 was associated with decreased risk of CAD and coronary artery bypass grafting (CABG). Our findings support MICU1 as an endogenous endothelial resilience factor that protects against vascular inflammation and atherosclerosis by maintaining mitochondrial Ca2+ homeostasis.
ACAT1 regulates tertiary lymphoid structures and correlates with immunotherapy response in non–small cell lung cancer
Authors: Mengxia Jiao, Yifan Guo, Hongyu Zhang, Haoyu Wen, Peng Chen, Zhiqiang Wang, Baichao Yu, Kameina Zhuma, Yuchen Zhang, Jingbo Qie, Yun Xing, Pengyuan Zhao, Zihe Pan, Luman Wang, Dan Zhang, Fei Li, Yijiu Ren, Chang Chen, Yiwei Chu, Jie Gu, Ronghua Liu
Journal: Journal of Clinical Investigation (2025)

Tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) are emerging solid-tumor indicators of prognosis and response to immunotherapy. Considering that tumorigenesis requires metabolic reprogramming and subsequent TME remodeling, the discovery of TLS metabolic regulators is expected to produce immunotherapeutic targets. To identify such metabolic regulators, we constructed a metabolism-focused sgRNA library and performed an in vivo CRISPR screening in an orthotopic lung tumor mouse model. Combined with The Cancer Genome Atlas database analysis of TLS-related metabolic hub genes, we found that the loss of Acat1 in tumor cells sensitized tumors to anti-PD1 treatment, accompanied by increased TLS in the TME. Mechanistic studies revealed that ACAT1 resulted in mitochondrial protein hypersuccinylation in lung tumor cells and subsequently enhanced mitochondrial oxidative metabolism, which impeded TLS formation. Elimination of ROS by NAC or Acat1 knockdown promoted B cell aggregation and TLS construction. Consistently, data from tissue microassays of 305 patients with lung cancer showed that TLS were more abundant in non-small cell lung cancer (NSCLC) tissues with lower ACAT1 expression. Intratumoral ACAT1 expression was associated with poor immunotherapy outcomes in patients with NSCLC. In conclusion, our results identified ACAT1 as a metabolic regulator of TLS and a promising immunotherapeutic target in NSCLC.
Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma
Authors: Qun Chen, Hao Yuan, Michael S. Bronze, Min Li
Journal: Journal of Clinical Investigation (2025)

Metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) fosters an immunosuppressive tumor microenvironment (TME) characterized by elevated lactate levels, which contribute to immune evasion and therapeutic resistance. In this issue of the JCI, Sun, Zhang, and colleagues identified nonhistone ENSA-K63 lactylation as a critical regulator that inactivates PP2A, activates STAT3/CCL2 signaling, recruits tumor-associated macrophages (TAMs), and suppresses cytotoxic T cell activity. Targeting ENSA-K63 lactylation or CCL2/CCR2 signaling reprograms the TME and enhances the efficacy of immune checkpoint blockade (ICB) in PDAC preclinical models. This work provides critical insights into the metabolic-immune crosstalk in PDAC and highlights promising therapeutic strategies for overcoming immune resistance and improving patient outcomes.
Paternal Cardiac Lesion Induces Cardiac Adaptation in Offspring
Authors: Benedetta Coppe, María Galardi-Castilla, Andrés Sanz-Morejón, Prateek Arora, Javier Lucas, Casie Iciek, Laura Lalaguna, Enrique Lara-Pezzi, Ignacio Flores, Nadia Mercader
Journal: Circulation (2025)
Correction to: Update on Diagnosis and Management of Kawasaki Disease: A Scientific Statement From the American Heart Association
Authors: Pei-Ni Jone, Adriana Tremoulet, Nadine Choueiter, Samuel R. Dominguez, Ashraf S. Harahsheh, Yoshihide Mitani, Meghan Zimmerman, Ming-Tai Lin, Kevin G. Friedman
Journal: Circulation (2025)
Correction to: 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
Authors: Sunil V. Rao, Michelle L. O’Donoghue, Marc Ruel, Tanveer Rab, Jaqueline E. Tamis-Holland, John H. Alexander, Usman Baber, Heather Baker, Mauricio G. Cohen, Mercedes Cruz-Ruiz, Leslie L. Davis, James A. de Lemos, Tracy A. DeWald, Islam Y. Elgendy, Dmitriy N. Feldman, Abhinav Goyal, Ijeoma Isiadinso, Venu Menon, David A. Morrow, Debabrata Mukherjee, Elke Platz, Susan B. Promes, Sigrid Sandner, Yader Sandoval, Rachel Schunder, Binita Shah, Jason P. Stopyra, Amy W. Talbot, Pam R. Taub, Marlene S. Williams
Journal: Circulation (2025)
Community-Based Peer Support for Diabetes Management: 24-Month Changes Relative to Comparison Communities
Authors: Yuexing Liu, Chun Cai, Jiahe Tian, Li Shen, Patrick Y. Tang, Muchieh Maggy Coufal, Hongli Chen, Megan S. Evans, Yiqing Qian, Wenya Yu, Xiaoyu Wu, Xiaobing Wu, Edwin B. Fisher, Weiping Jia
Journal: Diabetes Care (2025)

OBJECTIVE To evaluate the effectiveness of community-based peer support for diabetes self-management with HbA1c and other clinical and psychosocial outcomes over 24 months. RESEARCH DESIGN AND METHODS This study used an intervention comparison design with 12 intervention communities and 4 comparison communities matched according to location in urban or suburban areas. A community organization approach was used to integrate standardization of key messages and patient education protocols, along with adaptation and innovation among multiple community partners. The primary outcome was HbA1c; secondary outcomes included BMI, fasting plasma glucose (FPG), systolic and diastolic blood pressure, LDL cholesterol (LDL-C), depressive symptoms (PHQ-8), diabetes distress, and general quality of life (EQ-5D). RESULTS The analyses included 967 participants completing both the baseline and follow-up assessment. Intervention communities versus comparison communities were older (mean age 66.43 vs. 63.45 years), included more women (57.1% vs. 45.5%), and had longer diabetes duration (mean 7.95 vs. 6.40 years). Significant improvements were found for HbA1c (7.42% [58 mmol/mol] vs. 7.95% [63 mmol/mol]), BMI (25.31 vs. 25.94 kg/m2), FPG (7.91 vs. 8.59 mmol/L), and depressive symptoms (PHQ-8 score 1.39 vs. 1.41), favoring intervention communities, after adjusting for baseline values of outcome measures and confounders (P ≤ 0.028). No interactions were found with age (&amp;lt;65 vs. ≥65 years). Men showed modestly greater diastolic blood pressure reduction, and women showed a minor increase of LDL-C in intervention communities. These analyses by age or sex and sensitivity analyses with missing data imputation supported the robustness of findings. CONCLUSIONS Culturally adapted and appropriate community-based peer support for diabetes management may improve clinical and psychosocial outcomes at 24 months among people with diabetes.
Correction to: Clinical Considerations for Competitive Sports Participation for Athletes With Cardiovascular Abnormalities: A Scientific Statement From the American Heart Association and American College of Cardiology
Authors: Jonathan H. Kim, Aaron L. Baggish, Benjamin D. Levine, Michael J. Ackerman, Sharlene M. Day, Elizabeth H. Dineen, J. Sawalla Guseh, Andre La Gerche, Rachel Lampert, Matthew W. Martinez, Michael Papadakis, Dermot M. Phelan, Keri M. Shafer
Journal: Circulation (2025)
Metabolic dysfunction–associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations
Authors: Bernd Schnabl, Christopher J Damman, Rotonya M Carr
Journal: Journal of Clinical Investigation (2025)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.
Insights into protection against Mycobacterium tuberculosis infection: time to officially confirm another phenotype?
Authors: Todia P Setiabudiawan, Philip C Hill, Andrew R DiNardo, Reinout van Crevel
Journal: Journal of Clinical Investigation (2025)

Immune correlates of protection against infection with Mycobacterium tuberculosis (Mtb) remain elusive. In this issue of the JCI, Dallmann-Sauer and authors demonstrate that lack of tuberculin skin test (TST) and interferon γ release assay (IGRA) conversion among people with HIV despite years-long Mtb exposure is associated with alveolar lymphocytosis, including specific poly-cytotoxic T cells, and M1-type alveolar macrophages with a stronger ex vivo response to the pathogen. Studies in these rare individuals, termed "TB resisters" and in tuberculosis household contacts who are repeatedly IGRA negative in the months after a specific exposure event (known as "early clearers") help elucidate manipulatable mechanisms to boost protection against Mtb infection.
ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non–small cell lung cancer
Authors: Sophie O'Keefe, Qiwei Wang
Journal: Journal of Clinical Investigation (2025)

Non-small cell lung cancer (NSCLC), the most common type of lung cancer, remains a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapy for NSCLC but only benefit a subset of patients. In this issue of the JCI, Jiao et al. revealed that acetyl-CoA acetyltransferase 1 (ACAT1) limited the efficacy of ICIs in NSCLC by impeding tertiary lymphoid structures (TLS) in the tumor microenvironment (TME). Targeting ACAT1 in tumor cells reduced mitochondrial hypersuccinylation and oxidative stress, enhancing TLS abundance and improving the efficacy of ICIs in preclinical murine models of NSCLC.
Lysyl hydroxylase 2 glucosylates collagen VI to drive lung cancer progression
Authors: Shike Wang, Houfu Guo, Reo Fukushima, Masahiko Terajima, Min Liu, Guan-Yu Xiao, Lenka Koudelková, Chao Wu, Xin Liu, Jiang Yu, Emma Burris, Jun Xu, Alvise Schiavinato, William K Russell, Mitsuo Yamauchi, Xiaochao Tan, Jonathan M Kurie
Journal: Journal of Clinical Investigation (2025)

Lysyl hydroxylase 2 (LH2) is highly expressed in multiple tumor types and accelerates disease progression by hydroxylating lysine residues on fibrillar collagen telopeptides to generate stable collagen cross links in tumor stroma. Here, we show that a galactosylhydroxylysyl glucosyltransferase (GGT) domain on LH2-modified type-VI collagen (Col6) to promote lung adenocarcinoma (LUAD) growth and metastasis. In tumors generated by LUAD cells lacking LH2 GGT domain activity, stroma was less stiff, and stable types of collagen cross links were reduced. Mass spectrometric analysis of total and glycosylated peptides in parental and GGT-inactive tumor samples identified Col6 chain α3 (Col6a3), a component of the Col6 heterotrimeric molecule, as a candidate LH2 substrate. In gain- and loss-of-function studies, high Col6a3 levels increased tumor growth and metastatic activity and enhanced the proliferative, migratory, and invasive activities of LUAD cells. LH2 coimmunoprecipitated with Col6a3, and LH2 glucosylated Col6 in an in vitro reaction. Glucosylation increased the integrin-binding and promigratory activities of Col6 in LUAD cells. Col6a3 K2049 was deglucosylated in GGT-inactive tumor samples, and mutagenesis of Col6a3 K2049 phenocopied Col6a3 deficiency or LH2 GGT domain inactivation in LUAD cells. Thus, LH2 glucosylates Col6 to drive LUAD progression. These findings show that the GGT domain of LH2 is protumorigenic, identify Col6 as a candidate effector, and provide a rationale to develop pharmacological strategies that target LH2's GGT domain in cancer cells.