tbuckley/cabot-search huggingface dataset:
Gene therapy for genetic diseases: challenges and future directions
Authors: Beibei Qie, Jianghua Tuo, Feilong Chen, Haili Ding, Lei Lyu
Journal: MedComm (2025)

Abstract Genetic diseases constitute the majority of rare human diseases, resulting from abnormalities in an individual's genetic composition. Traditional treatments offer limited relief for these challenging conditions. In contrast, the rapid advancement of gene therapy presents significant advantages by directly addressing the underlying causes of genetic diseases, thereby providing the potential for precision treatment and the possibility of curing these disorders. This review aims to delineate the mechanisms and outcomes of current gene therapy approaches in clinical applications across various genetic diseases affecting different body systems. Additionally, genetic muscular disorders will be examined as a case study to investigate innovative strategies of novel therapeutic approaches, including gene replacement, gene suppression, gene supplementation, and gene editing, along with their associated advantages and limitations at both clinical and preclinical levels. Finally, this review emphasizes the existing challenges of gene therapy, such as vector packaging limitations, immunotoxicity, therapy specificity, and the subcellular localization and immunogenicity of therapeutic cargos, while discussing potential optimization directions for future research. Achieving delivery specificity, as well as long‐term effectiveness and safety, will be crucial for the future development of gene therapies targeting genetic diseases.
Cannabidiol restores hematopoietic stem cell stemness in mouse through Atf2–Lrp6 axis after acute irradiation
Authors: Zhijie Bai, Congshu Huang, Huanhua Xu, Yuxin Wang, Zebin Liao, Pan Shen, Zhexin Ni, Chaoji Huangfu, Dezhi Sun, Yangyi Hu, Ningning Wang, Pengfei Zhang, Lei Zhou, Wei Zhou, Yue Gao
Journal: MedComm (2025)

Abstract Bone marrow serves as the residence of hematopoietic stem cells and is recognized as one of the most radiosensitive tissues. Exposure to acute radiation leads to severe damage to bone marrow hematopoiesis which can be fatal, while few clinically applicable medication or specific therapeutic targets have been discovered. In this study, we found that the administration of cannabidiol significantly enhanced individual survival and restored the reconstitution capacity of bone marrow hematopoietic stem cells within 14 days after irradiation. Single‐cell RNA sequencing analysis demonstrated that the expression levels of genes associated with stemness along with Wnt and BMP signaling pathways were restored by the cannabidiol treatment through the upregulation of Atf2 , a transcription factor possessing multifunctional properties. Atf2 upregulation induced by cannabidiol treatment potentially upregulated the expression of Lrp6 to improve the stemness of hematopoietic stem cells. Further functional experiments validated the crucial role of Atf2 in regulating multilineage differentiation potential of bone marrow hematopoietic stem and progenitor cells. Overall, our findings provide evidence for a promising radioprotective function of cannabidiol and Atf2 as a candidate therapeutic target for acute radiation‐induced hematopoietic injury, thereby paving the way for future research in the field.
Endothelial monocarboxylate transporter 1 drives atherosclerosis via a lactate/NADH/CtBP‐mediated transrepression pathway
Authors: Zou Li, Shuai Guo, Kaixiang Cao, Yuxi Duan, Yuan Zhao, Yuting Zhang, Shihui Yu, Zaixia Bai, Runfa Yu, Yixin Chen, Ziling Li, Shuqi Huang, Mingchuan Song, Cailing Wang, Wenzhong Hou, Jun He, Bin Yang, Yiming Xu
Journal: MedComm (2025)

Abstract The accumulation of lactate in tissue microenvironments is associated with atherosclerosis, but its precise role in atherogenesis remains largely unknown. This study demonstrated that lactate accumulation in aortic tissues and blood is correlated with increased monocarboxylate transporter 1 (Mct1) expression in endothelial cells (ECs) within atherosclerotic plaques. Lactate uptake via Mct1 triggers an inflammatory response in ECs. The administration of endothelial‐targeting nanoparticles containing siRNA against Mct1 reduces endothelial inflammation and atherogenesis in Apoe −/− mice. Mechanistic studies revealed that the conversion of lactate to pyruvate, along with NADH production and oligomerization of the NADH‐sensitive transcriptional corepressor C‐terminal binding protein 1 (CtBP1), is necessary for the proinflammatory effects of lactate. Monomeric CtBP1 interacts with the transcriptional repressor forkhead box P1 (FOXP1) to suppress endothelial adhesion molecule expression. However, NADH‐induced oligomerization of CtBP1 prevents its binding to FOXP1, significantly reducing FOXP1‐mediated transrepression of endothelial adhesion molecules. Moreover, silencing Foxp1 in ECs negates the atheroprotective effect of endothelial Mct1 knockdown in Apoe −/− mice. These findings suggest that lactate/MCT1‐induced epigenetic reprogramming represents a potential therapeutic target in atherosclerosis.
Once‐weekly glucagon‐like peptide receptor agonist polyethylene glycol loxenatide protects against major adverse cardiovascular events in patients with type 2 diabetes: a multicenter ambispective cohort study (FLYING trial)
Authors: Jilin Li, Yu Tian, Liping Li, Yanyan Zhao, Shuhui Yang, Wencan Xu, Dan Zhu, Junjun Ye, Jingxian Chen, Weiting Liu, Haibo Xue, Wei Wu, Feiying Deng, Yale Duan, Zhizhen Hu, Bin Xie, Zhe‐Sheng Chen, Kaijian Hou
Journal: MedComm (2025)

Abstract This study aimed to determine the effects of polyethylene glycol loxenatide (PEG‐Loxe), a glucagon‐like peptide‐1 receptor agonist, on a three‐point major adverse cardiovascular event (3P‐MACE) in patients with type 2 diabetes mellitus (T2DM). The study was conducted in six tertiary hospitals in three cities in China. Large language models were used to retrospectively screen and include 12,341 patients with T2DM who had either cardiovascular disease or cardiovascular risk factors. The patients were divided into the PEG‐Loxe cohort (treated with PEG‐Loxe, n = 1282) and the control cohort (treated with incretin glucose‐lowering agents, n = 11,059). After a median follow‐up of 4.0 years, 3P‐MACE occurred in 51 (4.0%) and 1263 (11.4%) patients in PEG‐Loxe and control cohorts, respectively (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.49–0.94; p = 0.019). In the PEG‐Loxe versus control cohorts, 21 (1.6%) versus 476 (4.3%) patients experienced nonfatal stroke (HR 0.63; p = 0.041), whereas 22 (1.7%) versus 545 (4.9%) experienced nonfatal myocardial infarction (HR 0.66; p = 0.058), and the incidence of cardiovascular death was 8 (0.6%) versus 240 (2.2%), respectively (HR 0.56; p = 0.118). We found a significantly lower incidence of first nonfatal myocardial infarction, nonfatal stroke, or cardiovascular deaths in the PEG‐Loxe cohort than the control cohort.
Microbiota‐derived 3‐Methyl‐L‐histidine mediates the proatherogenic effect of high chicken protein diet
Authors: Shanshan Zhu, Ludi Liu, Yawen Zhao, Bingqi Ye, Jialin He, Wenkang Li, Yingxi Xu, Jiangyuan Zhu, Min Xia, Yan Liu
Journal: MedComm (2025)

Abstract Diet rich in chicken protein has gained a widespread popularity for its profound effect on weight loss and glycemic control; however, its long‐term effect on cardiovascular health and the underlying mechanisms remains obscure. Here, we demonstrated that higher intake of chicken protein was an independent risk factor for sub‐clinical atherosclerosis. Adherence to high chicken protein diet (HCD) alleviated excessive weight gain and glycemic control regardless of the presence of gut microbiota in apolipoprotein E–deficient mice. In contrast, long‐term HCD administration enhanced intestinal cholesterol absorption and accelerated atherosclerotic plaque formation in a gut microbiota‐dependent manner. Integrative analysis of 16S rDNA sequencing and metabolomics profiling identified 3‐Methyl‐L‐histidine (3‐MH), resulting from an enrichment of Lachnospiraceae , as the key microbial effector to the atherogenic effect of HCD. Mechanistically, 3‐MH facilitated the binding of hepatocyte nuclear factor 1A (HNF1A) to the promoter of NPC1‐like intracellular cholesterol transporter 1 (NPC1L1), whereas inhibition of HNF1A–NPC1L1 axis abolished the atherogenic effect of 3‐MH. Our findings uncovered a novel link between microbiota‐derived 3‐MH and disturbed cholesterol homeostasis, which ultimately accelerated atherosclerosis, and argued against the recommendation of HCD as weight loss regimens considering its adverse role in vascular health.
Prognostic and predictive effects of new steatotic liver disease nomenclatures: a large population‐based study
Authors: Huixian Zeng, Letian Fang, Zhiyu Yang, Xinyu Zhao, Hongsen Chen, Puyi Xing, Zheyun Niu, Zheng Li, Zishuai Li, Jiayi Zhao, Wenbin Liu, Chunxia Jing, Hong You, Guangwen Cao
Journal: MedComm (2025)

Abstract We aimed to compare the association of metabolic dysfunction‐associated fatty liver disease (MAFLD), metabolic dysfunction‐associated steatotic liver disease (MASLD), alcohol‐related liver disease (ALD), metabolic dysfunction and ALD (MetALD), and MASLD with viral hepatitis (MASLD‐Viral) with risks of cirrhosis, liver cancer, and mortality. The data of 464,556 adults from the UK Biobank (UKB), 13,526 adults from the National Health and Nutrition Examination Survey (NHANES), and 2554 adults from BeijngFH Health Cohort Study (FHCS) were included. Adjusted hazard ratios (aHR) and odds ratios were calculated using Cox and Logistic regression models, respectively. Compared with non‐SLD, the risk of liver cancer increased from MetALD (aHR 1.70 [95% CI 1.37, 2.09]), MASLD (1.91 [1.66, 2.21]), MAFLD (2.01 [1.76, 2.29]), ALD (3.16 [2.54, 3.93]), to MASLD‐Viral (22.0 [10.8, 44.4]) in a stepwise manner in the UKB; the risk of all‐cause mortality increased from MetALD, MASLD, MAFLD, ALD, to MASLD‐Viral in the NHANES. The odds ratio of liver fibrosis increased from MASLD, MAFLD, to MASLD‐Viral in the FHCS. In patients with diabetes, metformin plus other drugs were associated with higher risks of cirrhosis, liver cancer, and all‐cause mortality in MASLD or MAFLD. Prevention rather than antiglycemic treatment is important for patients with diabetic MASLD or MAFLD.
German Asthma Net: Characterisation of responders to anti-IL-5 and anti-IL-5(R) therapy
Authors: Christina Bal, Slagjana Stoshikj, Andreas Renner, Katrin Milger, Dirk Skowasch, Christian Schulz, Margret Jandl, Olaf Schmidt, Rainer Ehmann, Sonja Zehetmayer, Christian Taube, Eckard Hamelmann, Roland Buhl, Stephanie Korn, Marco Idzko
Journal: Pulmonology (2025)

Introduction Previous studies of anti-IL-5/IL-5(R) therapies in severe asthma found that response was mainly predicted by indicators of good baseline disease control. However, long-term response predictors remain unclear.
Copper in cancer: friend or foe? Metabolism, dysregulation, and therapeutic opportunities
Authors: Dan Shan, Jinling Song, Yuqing Ren, Yuyuan Zhang, Yuhao Ba, Peng Luo, Quan Cheng, Hui Xu, Siyuan Weng, Anning Zuo, Shutong Liu, Xinwei Han, Jinhai Deng, Zaoqu Liu
Journal: Cancer Communications (2025)

Abstract Copper, one of the essential nutrients for the human body, acts as an electron relay in multiple pathways due to its redox properties. Both deficiencies and excesses of copper lead to cellular fragility. Therefore, it can manifest pro‐ and anti‐cancer properties in tumors. Therefore, it is crucial to clarify the copper activity within the cell. We have thoughtfully summarized the metabolic activities of copper from a macro and micro perspective. Cuproptosis, as well as other forms of cell death, is directly or indirectly interfered with by Cu 2+ , causing cancer cell death. Meanwhile, we did pan‐cancer analysis of cuproptosis‐related genes to further clarify the roles of these genes. In addition, copper has been found to be involved in multiple pathways within the metastasis of cancer cells. Given the complexity of copper's role, we are compelled to ask: is copper a friend or a foe? Up to now, copper has been used in various clinical applications, including protocols for measurement of copper concentration and bioimaging of radioactive 64 Cu. But therapeutically it is still a continuation of the old medicine, and new possibilities need to be explored, such as the use of nanomaterials. Some studies have also shown that copper has considerable interventional power in metabolic cancers, which provides the great applications potential of copper therapy in specific cancer types. This paper reviews the dual roles played by cuproptosis in cancer from the new perspectives of oxidative stress, cell death, and tumor metastasis, and points out the value of its application in specific cancer types, summarizes the value of its testing and imaging from the perspective of clinical application as well as the current feasible options for the new use of the old drugs, and emphasizes the prospects for the application of nano‐copper.
Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis
Authors: Sean Wen, Pablo Kuri-Morales, Fengyuan Hu, Abhishek Nag, Ioanna Tachmazidou, Sri V. V. Deevi, Haeyam Taiy, Katherine R. Smith, Douglas P. Loesch, Oliver S. Burren, Ryan S. Dhindsa, Sebastian Wasilewski, Jesus Alegre-Díaz, Jaime Berumen, Jonathan Emberson, Jason M. Torres, Rory Collins, Keren Carss, Quanli Wang, Slavé Petrovski, Roberto Tapia-Conyer, Margarete A. Fabre, Andrew R. Harper, George S. Vassiliou, Jonathan Mitchell
Journal: Nature Genetics (2025)
Targeting vaccines to dendritic cells by mimicking the processing and presentation of antigens in xenotransplant rejection
Authors: Jinjin Wang, Yuxuan Zhang, Yaru Jia, Haonan Xing, Fengfei Xu, Bozhang Xia, Wenjia Lai, Yuan Yuan, Xianlei Li, Shaobo Shan, Junge Chen, Weisheng Guo, Jinchao Zhang, Aiping Zheng, Jinghong Li, Ningqiang Gong, Xing-Jie Liang
Journal: Nature Biomedical Engineering (2025)
Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis
Authors: Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan M. Adrian Segarra, Ignacio L. Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Böse, Marco Breinig, Danijela Heide, Suchira Gallage, Jose E. Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Mäkinen, Darjus F. Tschaharganeh, Mathias Heikenwalder, Judith B. Zaugg, Moritz Mall
Journal: Nature Genetics (2025)

Abstract Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.
Cardiovascular Disease in Anabolic Androgenic Steroid Users
Authors: Josefine Windfeld-Mathiasen, Ida M. Heerfordt, Kim Peder Dalhoff, Jon Trærup Andersen, Michael Asger Andersen, Karl Sebastian Johansson, Tor Biering-Sørensen, Flemming Javier Olsen, Henrik Horwitz
Journal: Circulation (2025)

BACKGROUND: Use of anabolic androgenic steroids (AASs) is associated with increased mortality, and case reports have suggested that some of these deaths are due to cardiovascular disease. However, the epidemiology of cardiovascular disease in AAS users is still relatively unexplored. This study aimed to measure the incidence of cardiovascular disease in male AAS users and to compare these rates with those of a cohort from the general population matched by age and sex. METHODS: Men sanctioned in an antidoping program for AAS use in Danish fitness centers between 2006 and 2018 were included and matched for age and sex with 50 times as many controls from the general Danish population. The cohort was followed until June 30, 2023. Using the nationwide registries, we obtained information on admissions, prescriptions, educational length, and occupational status for both the AAS users and controls. This study investigated the incidence of acute myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft, venous thromboembolism, ischemic stroke, arrhythmia, cardiomyopathy, heart failure, and cardiac arrest during the follow-up period. RESULTS: During an average of 11 years of follow-up, AAS users (n=1189) demonstrated a significantly higher incidence of several cardiovascular events compared with controls (n=59 450). Correspondingly, AASs were associated with an increased risk of acute myocardial infarction (adjusted hazard ratio [aHR] 3.00 [95% CI, 1.67–5.39]), percutaneous coronary intervention or coronary artery bypass graft (aHR 2.95 [95% CI, 1.68–5.18]), venous thromboembolism (aHR 2.42 [95% CI, 1.54–3.80]), arrhythmias (aHR 2.26 [95% CI, 1.53–3.32]), cardiomyopathy (aHR 8.90 [95% CI, 4.99–15.88]), and heart failure (aHR 3.63 [95% CI, 2.01–6.55]). Due to the limited number of ischemic stroke and cardiac arrest cases among AAS users, these outcomes were not reportable. CONCLUSIONS: AAS use is associated with a substantially increased risk of cardiovascular disease in a large cohort with a long follow-up period.
Novel Directly Reprogrammed Smooth Muscle Cells Promote Vascular Regeneration as Microvascular Mural Cells
Authors: Cholomi Jung, Ji Woong Han, Shin-Jeong Lee, Kyung Hee Kim, Jee Eun Oh, Seongho Bae, Sangho Lee, Young-Jae Nam, Sangsung Kim, Chaewon Dang, Jaehyun Kim, Nakhyung Chu, Eun Jig Lee, Young-sup Yoon
Journal: Circulation (2025)

BACKGROUND: Although cell therapy has emerged as a promising approach to promote neovascularization, its effects are mostly limited to capillaries. To generate larger or stable vessels, layering of mural cells such as smooth muscle cells (SMCs) or pericytes is required. Recently, direct reprogramming approaches have been developed for generating SMCs. However, such reprogrammed SMCs lack genuine features of contractile SMCs, a native SMC phenotype; thus, their therapeutic and vessel-forming potential in vivo was not explored. Therefore, we aimed to directly reprogram human dermal fibroblasts toward contractile SMCs (rSMCs) and investigated their role for generating vascular mural cells in vivo and their therapeutic effects on ischemic disease. METHODS: We applied myocardin and all- trans retinoic acid with specific culture conditions to directly reprogram human dermal fibroblasts into rSMCs. We characterized their phenotype as contractile SMCs through quantitative reverse-transcriptase polymerase chain reaction, flow cytometry, and immunostaining. We then explored their contractility using a vasoconstrictor, carbachol, and through transmission electron microscope and bulk RNA sequencing. Next, we evaluated whether transplantation of rSMCs improves blood flow and induces vessel formation as mural cells in a mouse model of hind-limb ischemia with laser Doppler perfusion imaging and histological analysis. We also determined their paracrine effects. RESULTS: Our novel culture conditions using myocardin and all- trans retinoic acid efficiently reprogrammed human dermal fibroblasts into SMCs. These rSMCs displayed characteristics of contractile SMCs at the mRNA, protein, and cellular levels. Transplantation of rSMCs into ischemic mouse hind limbs enhanced blood flow recovery and vascular repair and improved limb salvage. Histological examination showed that vascular density was increased and the engrafted rSMCs were incorporated into the vascular wall as pericytes and vascular SMCs, thereby contributing to formation of stabler and larger microvessels. Quantitative reverse-transcriptase polymerase chain reaction analysis revealed that these transplanted rSMCs exerted pleiotropic effects, including angiogenic, arteriogenic, vessel-stabilizing, and tissue regenerative effects, on ischemic limbs. CONCLUSIONS: A combination of myocardin and all- trans retinoic acid in defined culture conditions efficiently reprogrammed human fibroblasts into contractile and functional SMCs. The rSMCs were shown to be effective for vascular repair and contributed to neovascularization through mural cells and various paracrine effects. These human rSMCs could represent a novel source for cell-based therapy and research.
The Efficacy of Pediatric‐Inspired Regimens vs. Hyper‐<scp>CVAD</scp> in the Treatment of Adolescents and Young Adults With Acute Lymphoblastic Leukemia: A Systematic Review and Meta‐Analysis
Authors: Wenqing Su, Melisa Stricherz, Alison Martin, Jonathan Belsey, Eric Kemadjou, Daniel J. DeAngelo
Journal: American Journal of Hematology (2025)

ABSTRACT Adults with acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) have poorer outcomes than pediatric patients. The aim of this systematic literature review and meta‐analysis was to compare asparaginase (ASP)‐containing pediatric‐inspired regimens (PIRs) with hyper‐fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD) in adolescents and young adults (AYAs) with ALL/LBL. Searches included relevant publications up to April 21, 2022. A meta‐analysis was conducted in four studies with comparable demographics, to estimate the effects of intervention on rates of response and survival. Patients receiving PIRs were approximately twice as likely to achieve complete response and 1.8 times more likely to survive than patients receiving hyper‐CVAD. These results suggest ASP‐containing PIRs are associated with improved outcomes in AYAs compared with hyper‐CVAD.