tbuckley/cabot-search huggingface dataset:
Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists
Authors: Giovanni Targher, Alessandro Mantovani, Christopher D Byrne, Herbert Tilg
Journal: Gut (2024)

Clinically effective pharmacological treatment(s) for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form metabolic dysfunction-associated steatohepatitis (MASH) represent a largely unmet need in medicine. Since glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been licensed for the treatment of type 2 diabetes mellitus and obesity, they were one of the first drug classes to be examined in individuals with MASLD/MASH. Successful phase 2 randomised clinical trials with these agents have resulted in progression to phase 3 clinical trials (principally testing the long-term efficacy of subcutaneous semaglutide). Over the last few years, in addition to GLP-1RAs, newer agents with glucose-dependent insulinotropic peptide and/or glucagon receptor agonist functions have been tested, with increasing evidence from phase 2 randomised clinical trials of histological improvements in MASLD/MASH, as well as benefits on MASLD-related extrahepatic complications. Based on this background of evidence, single, dual or triple incretin receptor agonists are becoming an attractive and promising treatment option for MASLD or MASH, particularly in individuals with coexisting obesity or type 2 diabetes mellitus. In this narrative review, we examine the rapidly expanding body of clinical evidence supporting a role of incretin-based pharmacotherapies in delaying or reversing MASH progression. We also discuss the biology of incretins and the putative hepatoprotective mechanisms of incretin-based pharmacotherapies for managing MASLD or MASH.
Medium-term results of arthroscopic hip surgery compared with physiotherapy and activity modification for the treatment of femoroacetabular impingement syndrome: a multi-centre randomised controlled trial
Authors: Antony Palmer, Scott Fernquest, Ines Rombach, Alice Harin, Ramy Mansour, Susan Dutton, H Paul Dijkstra, Tony Andrade, Sion Glyn-Jones
Journal: British Journal of Sports Medicine (2024)

Objective To report a 3-year follow-up from the FemoroAcetabular Impingement Trial, comparing arthroscopic surgery with physiotherapy in the management of femoroacetabular impingement (FAI) syndrome for the dual primary outcomes of radiographic hip osteoarthritis (OA) and patient-reported outcome measures of activities of daily living. Methods Two-group parallel, assessor-blinded, pragmatic randomised controlled trial across seven sites. 222 participants aged 18–60 years with FAI syndrome confirmed clinically and radiologically were randomised (1:1) to receive arthroscopic hip surgery (n=112) or physiotherapy (n=110). Dual primary outcome measure was minimum joint space width (mJSW) on anteroposterior radiograph at 38 months post-randomisation and Hip Outcome Score ADL (HOS ADL) (higher score indicates superior outcomes). Secondary outcome measures were Scoring Hip Osteoarthritis with MRI (SHOMRI) (lower score indicates less pathology). Results mJSW, HOS ADL and MRI data were available for 45%, 77% and 62% of participants at 38 months, respectively. No significant difference in mJSW was seen between groups at 38 months. HOS ADL was higher in the arthroscopy group (mean (SD) 84.2 (17.4)) compared with the physiotherapy group (74.2 (21.9)), difference 8.9 (95% CI 7.0, 10.8)). SHOMRI score total at 38 months was lower in the arthroscopy group (mean (SD) 9.22 (11.43)) compared with the physiotherapy group (22.76 (15.26)), differences (95% CIs) −15.94 (–18.69, –13.19). Conclusions No difference was seen between groups on radiographic measures of OA progression. Patients with FAI syndrome treated surgically may experience superior pain and function outcomes, and less MRI-measured cartilage damage compared with physiotherapy. Trial registration number NCT01893034 .
Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma
Authors: Timothy I. Shaw, Stanley Pounds, Xueyuan Cao, Jing Ma, Gustavo Palacios, John Mason, Sherrie Perkins, Gang Wu, Yiping Fan, Jian Wang, Xin Zhou, Alyssa Obermayer, Marsha C. Kinney, Jacqueline Kraveka, Thomas Gross, John Sandlund, Jinghui Zhang, Charles Mullighan, Megan S. Lim, Vasiliki Leventaki
Journal: Leukemia (2024)
Routine measurement of cardiometabolic disease risk factors in primary care in England before, during, and after the COVID-19 pandemic: A population-based cohort study
Authors: Frederick K. Ho, Caroline Dale, Mehrdad A. Mizani, Thomas Bolton, Ewan R. Pearson, Jonathan Valabhji, Christian Delles, Paul Welsh, Shinya Nakada, Daniel Mackay, Jill P. Pell, Chris Tomlinson, Steffen E. Petersen, Benjamin Bray, Mark Ashworth, Kazem Rahimi, Mamas Mamas, Julian Halcox, Cathie Sudlow, Reecha Sofat, Naveed Sattar
Journal: PLoS Medicine (2024)

Background This study estimated to what extent the number of measurements of cardiometabolic risk factors (e.g., blood pressure, cholesterol, glycated haemoglobin) were impacted by the COVID-19 pandemic and whether these have recovered to expected levels. Methods and findings A cohort of individuals aged ≥18 years in England with records in the primary care—COVID-19 General Practice Extraction Service Data for Pandemic Planning and Research (GDPPR) were identified. Their records of 12 risk factor measurements were extracted between November 2018 and March 2024. Number of measurements per 1,000 individuals were calculated by age group, sex, ethnicity, and area deprivation quintile. The observed number of measurements were compared to a composite expectation band, derived as the union of the 95% confidence intervals of 2 estimates: (1) a projected trend based on data prior to the COVID-19 pandemic; and (2) an assumed stable trend from before pandemic. Point estimates were calculated as the mid-point of the expectation band. A cohort of 49,303,410 individuals aged ≥18 years were included. There was sharp drop in all measurements in March 2020 to February 2022, but overall recovered to the expected levels during March 2022 to February 2023 except for blood pressure, which had prolonged recovery. In March 2023 to March 2024, blood pressure measurements were below expectation by 16% (−19 per 1,000) overall, in people aged 18 to 39 (−23%; −18 per 1,000), 60 to 79 (−17%; −27 per 1,000), and ≥80 (−31%; −57 per 1,000). There was suggestion that recovery in blood pressure measurements was socioeconomically patterned. The second most deprived quintile had the highest deviation (−20%; −23 per 1,000) from expectation compared to least deprived quintile (−13%; −15 per 1,000). Conclusions There was a substantial reduction in routine measurements of cardiometabolic risk factors following the COVID-19 pandemic, with variable recovery. The implications for missed diagnoses, worse prognosis, and health inequality are a concern.
IL-2-inducible T cell kinase deficiency sustains chimeric antigen receptor T cell therapy against tumor cells
Authors: Zheng Fu, Zineng Huang, Hao Xu, Qingbai Liu, Jing Li, Keqing Song, Yating Deng, Yujia Tao, Huifang Zhang, Peilong Wang, Heng Li, Yue Sheng, Aijun Zhou, Lianbin Han, Yan Fu, Chen-Zhi Wang, Saurav Kumar Choudhary, Kaixiong Ye, Gianluca Veggiani, Zhihong Li, Avery August, Weishan Huang, Qiang Shan, Hongling Peng
Journal: Journal of Clinical Investigation (2024)

Despite the revolutionary achievements of chimeric antigen receptor (CAR) T cell therapy in treating cancers, especially leukemia, several key challenges still limit its therapeutic efficacy. Of particular relevance is the relapse of cancer in large part, as a result of exhaustion and short persistence of CAR-T cells in vivo. IL-2-inducible T cell kinase (ITK) is a critical modulator of the strength of T-cell receptor (TCR) signaling, while its role in CAR signaling is unknown. By electroporation of clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) ribonucleoprotein (RNP) complex into CAR-T cells, we successfully deleted ITK in CD19-CAR-T cells with high efficiency. Bulk and single-cell RNA sequencing (scRNA-seq) analyses revealed down-regulation of exhaustion and up-regulation of memory gene signatures in ITK-deficient CD19-CAR-T cells. Our results further demonstrated a significant reduction of T cell exhaustion and enhancement of T cell memory, with significant improvement of CAR-T cell expansion and persistence both in vitro and in vivo. Moreover, ITK-deficient CD19-CAR-T cells showed better control of tumor relapse. Our work provides a promising strategy of targeting ITK to develop sustainable CAR-T products for clinical use.
Chromatin Helicase CHD6 Establishes Pro-inflammatory Enhancers and is a Synthetic Lethal Target in FH-Deficient Renal Cell Carcinoma
Authors: Juan Jin, Jun Luo, Xiaodong Jin, Kiat Shenq Lim, Yang He, Jiawei Ding, Yan Shen, Yuchen Hou, Hanqing Liu, Xiaoyu Zhu, Jing Zhao, Wenjie Zhou, Hai Huang, Yi Gao, Jun Xiao, Hongchao He, Qunyi Li, Lianxin Liu, Li Chen, Qiang He, Chuanjie Zhang
Journal: Cancer Research (2024)

Abstract Fumarate hydratase (FH) deficiency causes hereditary leiomyomatosis and renal cell carcinoma (RCC). FH-deficient tumors lack effective therapeutic options. Here, we utilized an epigenetic-focused single-guide RNA library to elucidate potential drug targets in FH-deficient tumors. The screen identified chromodomain helicase DNA binding protein 6 (CHD6) as an essential regulator of the growth of FH-mutated RCC. Mechanically, FH loss induced fumarate-mediated succinylation and inactivation of KEAP1, blocking subsequent ubiquitin-proteasome degradation of CHD6. Stabilized CHD6 formed a complex with p65 to establish pro-inflammatory enhancers and thereby regulate NF-κB-mediated transcription. Moreover, CHD6 recruited mSWI/SNF ATPases to maintain chromatin accessibility at CHD6-bound enhancers. The PROTAC degrader of SMARCA2/4 AU-15330 effectively abolished structures of cis-regulatory elements bound by CHD6 and suppressed the growth of FH-mutated, but not FH-intact, RCC in vivo. Collectively, these data indicate that CHD6 is a molecular bridge between FH deficiency and pro-inflammatory enhancers assembly that endows FH-deficient tumors with epigenetic vulnerabilities.
Adapt or Perish: Efficient Selenocysteine Insertion is Critical for Metastasizing Cancer Cells
Authors: Namgyu Lee, Dohoon Kim
Journal: Cancer Research (2024)

Abstract During metastasis, cancer cells detach from the primary tumor, circulate through the bloodstream, and establish themselves at distant sites, facing increased levels of reactive oxygen species (ROS) that act as significant barriers to metastatic progression. Adapting to and surviving in these high-ROS environments is thus crucial for successful metastasis. A recent study by Nease and colleagues identified FTSJ1 as the methyltransferase responsible for methylation of the U34 position wobble uridine modification of selenocysteine (Sec) tRNA. This methylation enables efficient Sec insertion, leading to increased translation of a subset of stress-responsive selenoproteins that combat the oxidative stress encountered during the metastatic process. This study establishes FTSJ1 as an essential redox regulator during metastasis through its role in enhancing Sec insertion efficiency, and introduces a potential therapeutic strategy against metastasis.
Structural characterization of human monoclonal antibodies targeting uncommon antigenic sites on spike glycoprotein of SARS-CoV
Authors: Naveenchandra Suryadevara, Nurgun Kose, Sandhya Bangaru, Elad Binshtein, Jennifer Munt, David R. Martinez, Alexandra Schäfer, Luke Myers, Trevor D. Scobey, Robert H. Carnahan, Andrew B. Ward, Ralph S. Baric, James E. Crowe
Journal: Journal of Clinical Investigation (2024)

The function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target the SARS-CoV-2 NTD potently neutralize the virus. This finding suggests the NTD may contribute, in part, to protective immunity. Pansarbecovirus antibodies are desirable for broad protection, but the NTD region of SARS-CoV and SARS-CoV-2 exhibit a high level of sequence divergence; therefore, cross-reactive NTD-specific antibodies are unexpected, and there is no structure of a SARS-CoV NTD-specific antibody in complex with NTD. Here, we report a monoclonal antibody COV1-65, encoded by the IGHV1-69 gene, that recognizes the NTD of SARS-CoV S protein. A prophylaxis study showed the mAb COV1-65 prevented disease when administered before SARS-CoV challenge of BALB/c mice, an effect that requires intact fragment crystallizable region (Fc) effector functions for optimal protection in vivo. The footprint on the S protein of COV1-65 is near to functional components of the S2 fusion machinery, and the selection of COV1-65 escape mutant viruses identified critical residues Y886H and Q974H, which likely affect the epitope through allosteric effects. Structural features of the mAb COV1-65-SARS-CoV antigen interaction suggest critical antigenic determinants that should be considered in the rational design of sarbecovirus vaccine candidates.
A Potent, Selective, Small-Molecule Inhibitor of DHX9 Abrogates Proliferation of Microsatellite Instable Cancers with Deficient Mismatch Repair
Authors: Jennifer Castro, Matthew H. Daniels, David Brennan, Brian Johnston, Deepali Gotur, Young-Tae Lee, Kevin E. Knockenhauer, Chuang Lu, Jie Wu, Sunaina Nayak, Cindy Collins, Rishabh Bansal, Shane M. Buker, April Case, Julie Liu, Shihua Yao, Brian A. Sparling, E. Allen. Sickmier, Serena J. Silver, Stephen J. Blakemore, P. Ann Boriack-Sjodin, Kenneth W. Duncan, Scott Ribich, Robert A. Copeland
Journal: Cancer Research (2024)

Abstract DHX9 is a multifunctional DExH-box RNA helicase with important roles in the regulation of transcription, translation, and maintenance of genome stability. Elevated expression of DHX9 is evident in multiple cancer types, including colorectal cancer (CRC). Microsatellite instable-high (MSI-H) tumors with deficient mismatch repair (dMMR) display a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery. In this report, we show that DHX9 knockdown increased RNA/DNA secondary structures and replication stress, resulting in cell cycle arrest and the onset of apoptosis in cancer cells with MSI-H/dMMR. ATX968 was identified as a potent and selective inhibitor of DHX9 helicase activity. Chemical inhibition of DHX9 enzymatic activity elicited similar selective effects on cell proliferation as seen with genetic knockdown. In addition, ATX968 induced robust and durable responses in an MSI-H/dMMR xenograft model but not in a microsatellite stable (MSS)/proficient mismatch repair (pMMR) model. These preclinical data validate DHX9 as a target for the treatment of patients with MSI-H/dMMR. Additionally, this potent and selective inhibitor of DHX9 provides a valuable tool with which to further explore the effects of inhibition of DHX9 enzymatic activity on the proliferation of cancer cells in vitro and in vivo.
Fungal Influences on Cancer Initiation, Progression, and Response to Treatment
Authors: Hazrat Bilal, Muhammad Nadeem. Khan, Sabir Khan, Muhammad Shafiq, Wenjie Fang, Yuebin Zeng, Yangzhong Guo, Xiaohui Li, Bing Zhao, Qiao-Li Lv, Bin Xu
Journal: Cancer Research (2024)

Abstract Fungal dysbiosis is increasingly recognized as a key factor in cancer, influencing tumor initiation, progression, and treatment outcomes. This review explores the role of fungi in carcinogenesis, with a focus on mechanisms such as immunomodulation, inflammation induction, tumor microenvironment remodeling, and interkingdom interactions. Fungal metabolites are involved in oncogenesis, and antifungals can interact with anticancer drug, including eliciting potential adverse effects and influencing immune responses. Furthermore, mycobiota profiles have potential as diagnostic and prognostic biomarkers, emphasizing their clinical relevance. The interplay between fungi and cancer therapies can impact drug resistance, therapeutic efficacy, and risk of invasive fungal infections associated with targeted therapies. Finally, emerging strategies for modulating mycobiota in cancer care are promising approaches to improve patient outcomes.
Stayin’ Alive: Targeting chromatin regulators of clonal hematopoiesis promotes CD8 T cell stemness
Authors: Xingjian Qiu, Aaron Yang, Amanda C. Poholek
Journal: Cancer Research (2024)

Abstract T cell exhaustion remains a significant barrier to immunotherapeutic success for many patients with solid tumors. Growing evidence suggests that enhanced survival and self-renewal properties of a stem-like precursor T cell population (Tpex) is correlated with a survival advantage in immunotherapy. In a recent study published in Science, Kang and colleagues find three epigenetic regulators commonly mutated in clonal hematopoiesis also control Tpex progression to exhaustion. By leveraging the finding that patients with enhanced survival in myelodysplastic syndrome (MDS) had T cell mutations in the ASXL1 gene, this study demonstrates that loss of ASXL1 in T cells preserves their stem-cell like properties of self-renewal and survival leading to increased anti-tumor responses when combined with immunotherapy in both mouse models and human cancers. These findings have significant implications for new therapeutic options that target epigenetic modifiers promoting exhaustion together with immune checkpoint blockade to improve response rates in patients.
Breast Cancer Subtype-Specific Organotropism is Dictated by FOXF2-Regulated Metastatic Dormancy and Recovery
Authors: Wen-Jing Jiang, Tian-Hao Zhou, Huan-Jing Huang, Lin-Sen Li, Hao Tan, Rui Zhang, Qing-Shan Wang, Yu-Mei Feng
Journal: Cancer Research (2024)

Abstract Breast cancer subtypes display different metastatic organotropism. Identification of the mechanisms underlying subtype-specific organotropism could help uncover potential approaches to prevent and treat metastasis. Herein, we found that FOXF2 promoted the seeding and proliferative recovery from dormancy of luminal breast cancer (LumBC) and basal-like breast cancer (BLBC) cells in the bone by activating the NF-κB and BMP signaling pathways. Conversely, FOXF2 suppressed the seeding and proliferative recovery of BLBC cells in the lung by repressing the TGF-β signaling pathway. FOXF2 directly upregulated RelA/p65 transcription and expression in LumBC and BLBC cells by binding to the RELA proximal promoter region, and RelA/p65 bound to the FOXF2 proximal promoter region to upregulate expression, forming a positive feedback loop. Targeting the NF-κB pathway efficiently prevented the metastasis of FOXF2-overexpressing breast cancer cells to the bone, while inhibiting TGF-β signaling blocked the metastasis of BLBC with low FOXF2 expression to the lung. These findings uncover critical mechanisms of breast cancer subtype-specific organotropism and provide insight into precision assessment and treatment strategies.
NEUROPILIN-1 INHIBITION SUPPRESSES NERVE-GROWTH FACTOR SIGNALING AND NOCICEPTION IN PAIN MODELS
Authors: Chloe J. Peach, Raquel Tonello, Elisa Damo, Kimberly Gomez, Aida Calderon-Rivera, Renato Bruni, Harsh Bansia, Laura Maile, Ana-Marie Manu, Hyunggu Hahn, Alex R.B. Thomsen, Brian L. Schmidt, Steve Davidson, Amedee des Georges, Rajesh Khanna, Nigel W. Bunnett
Journal: Journal of Clinical Investigation (2024)

Nerve growth factor (NGF) monoclonal antibodies inhibit chronic pain yet failed to gain approval due to worsened joint damage in osteoarthritis patients. We report that neuropilin-1 (NRP1) is a co-receptor for NGF and tropomyosin-related kinase A (TrkA) pain signaling. NRP1 was coexpressed with TrkA in human and mouse nociceptors. NRP1 inhibitors suppressed NGF-stimulated excitation of human and mouse nociceptors and NGF-evoked nociception in mice. NRP1 knockdown inhibited NGF/TrkA signaling, whereas NRP1 overexpression enhanced signaling. NGF bound NRP1 with high affinity and interacted with and chaperoned TrkA from the biosynthetic pathway to the plasma membrane and endosomes, enhancing TrkA signaling. Molecular modeling suggested that C-terminal R/KXXR/K NGF motif interacts with extracellular "b" NRP1 domain within a plasma membrane NGF/TrkA/NRP1 of 2:2:2 stoichiometry. G Alpha Interacting Protein C-terminus 1 (GIPC1), which scaffolds NRP1 and TrkA to myosin VI, colocalized in nociceptors with NRP1/TrkA. GIPC1 knockdown abrogated NGF-evoked excitation of nociceptors and pain-like behavior. Thus, NRP1 is a nociceptor-enriched co-receptor that facilitates NGF/TrkA pain signaling. NRP binds NGF and chaperones TrkA to the plasma membrane and signaling endosomes via GIPC1 adaptor. NRP1 and GIPC1 antagonism in nociceptors offers a long-awaited non-opioid alternative to systemic antibody NGF sequestration for the treatment of chronic pain.
A large-scale population-based study reveals that gp42-IgG antibody is protective against Epstein-Barr virus-associated nasopharyngeal carcinoma
Authors: Xiang-Wei Kong, Guo-Long Bu, Hua Chen, Yu-Hua Huang, Zhiwei Liu, Yin-Feng Kang, Yan-Cheng Li, Xia Yu, Biao-Hua Wu, Zi-Qian Li, Xin-Chun Chen, Shang-Hang Xie, Dong-Feng Lin, Tong Li, Shu-Mei Yan, Run-Kun Han, Nan Huang, Qian-Yu Wang, Yan Li, Ao Zhang, Qian Zhong, Xiao-Ming Huang, Weimin Ye, Ming-Fang Ji, Yong-Lin Cai, Su-Mei Cao, Mu-Sheng Zeng
Journal: Journal of Clinical Investigation (2024)

BACKGROUND. Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), but the existence of NPC protective antibody against EBV-associated antigens remains inconclusive.
AAV9/SLC6A1 gene therapy rescues abnormal EEG patterns and cognitive behavioral deficiencies in Slc6a1-/- mice
Authors: Weirui Guo, Matthew Rioux, Frances Shaffo, Yuhui Hu, Ze Yu, Chao Xing, Steven J. Gray
Journal: Journal of Clinical Investigation (2024)

The solute carrier family 6 member 1 (SLC6A1) gene encodes the γ-aminobutyric acid (GABA) transporter GAT-1, the deficiency of which is associated with infantile encephalopathy with intellectual disability. We designed 2 AAV9 vectors, with either the JeT or MeP promoter, and conducted preclinical gene therapy studies using heterozygous and homozygous Slc6a1-KO mice at different developmental ages and various routes of administration. Neonatal intracerebroventricular administration of either vector resulted in significantly normalized EEG patterns in Slc6a1-/- or Slc6a1+/- mice as well as improvement in several behavioral phenotypes of Slc6a1-/- mice. However, some mortality and adverse effects were observed in neonatal-treated mice. Intrathecal administration of either vector at P5 normalized EEG patterns in Slc6a1+/- mice, but in Slc6a1-/- mice, the treatment only rescued nest building without impact on EEG. Both vectors were well tolerated in all mice treated at P5 or later (including WT mice), up to 1 year after injection. Overall, our data demonstrate compelling efficacy when mice are treated at an early development age. We also identified that outside of the neonatal treatment window, the severe homozygous KO model is more refractory to treatment, whereas our treatments in the heterozygous mice, which genotypically match human patients, have resulted in stronger benefits.