tbuckley/cabot-search huggingface dataset:
Tracking the trajectory of kidney dysfunction in cirrhosis: the acute kidney injury – chronic kidney disease spectrum
Authors: Vishnu Girish, Rakhi Maiwall
Journal: Clinical and Molecular Hepatology (2025)

Kidney disease in cirrhosis is now viewed as a continuum encompassing acute kidney injury (AKI), acute kidney disease (AKD), and chronic kidney disease (CKD), rather than three different disorders. Contemporary diagnostic criteria for AKI integrate urine output parameters and acknowledge the intricate relationship and possibility of overlap between functional and structural as well as acute and chronic entities, including hepatorenal syndrome (HRS). AKI demonstrates a propensity for progression to AKD and CKD, particularly in the context of recurrent and severe insults. The diagnostic complexity is further compounded by limitations in serum creatinine (Scr.) measurements, prompting the integration of novel biomarkers and the need to accurately estimate glomerular filtration rate (GFR). The diagnosis, phenotyping, and management of acute kidney injury should be prompt and early, the initial step should always be volume and urine output assessment, a personalized approach is needed and the possibility of co-existing structural or functional kidney disease should be borne in mind. The earlier concept of waiting for 48 hours to diagnose HRS has evolved and early diagnosis and prompt treatment are advised now. Kidney replacement therapy (KRT) and simultaneous liver and kidney transplantation may be required in resistant cases.
Double hit &amp; double expressor lymphomas: a multicenter analysis of survival outcomes with CD19-directed CAR T-cell therapy
Authors: Reem Karmali, Geoffrey Shouse, Pallawi Torka, Tamara K. Moyo, Jason Romancik, Stefan K. Barta, Rahul Bhansali, Jonathon B. Cohen, Nirav N. Shah, Joanna Zurko, Vaishalee P. Kenkre, Brian Hess, Deborah M. Stephens, Lindsey Fitzgerald, Thomas Ollila, Bukky Tabiti, Ishan Roy, Shuo Ma, Jane Winter, Barbara Pro, Jonathan Moreira, Alexey V. Danilov, Kevin David, Leo I. Gordon, Narendranath Epperla
Journal: Blood Cancer Journal (2025)

Double-hit (DHL) and double expressor (DEL) DLBCL have poor prognosis with standard therapy but CART may overcome this poor prognostic impact. In this multicenter retrospective study, we sought to confirm this observation by evaluating survival outcomes among patients with relapsed/refractory DHL and DEL treated with CART and evaluate outcomes of relapse post-CART. A total of 408 adult patients with relapsed/refractory DLBCL from 13 academic centers were included based on the availability of DHL and DEL. All 408 patients were included in the DHL (n = 80) vs non-DHL (n = 328) analysis, while 333 patients were included in the analysis of DHL (n = 80) vs DEL (n = 74) vs non (n = 179). On MVA, there were no differences for PFS for DHL vs non-DHL (HR 0.8, 95%CI 0.5–1.3, p = 0.35) or DHL vs DEL vs other (three-way p value, p = 0.5). Response rates and toxicities were similar among groups. Patients with DEL had the highest relapse rates post-CART, while DHL had the worst overall survival after CART relapse. In sum, our data support the notion that CART cell therapy can overcome the poor prognostic impact of DHL and DEL DLBCL in the relapsed/refractory setting. Additionally, patients with DHL that relapse after CART have a very poor prognosis.
Muscle Wasting and Arteriovenous Fistula Nonmaturation in Kidney Failure
Authors: Srinivasan Beddhu, Yan-Ting Shiu
Journal: Journal of the American Society of Nephrology (2025)

1Division of Nephrology and Hypertension, Department of Internal Medicine, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, Utah 2Cardiovascular, Renal, and Metabolism Center, Department of Internal Medicine, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, Utah 3George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah 4Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah Correspondence: Prof. Yan-Ting Shiu, email: [email protected] See related article, "Interplay between Skeletal Muscle Catabolism and Remodeling of Arteriovenous Fistula by Yes-Associated Protein 1 (YAP1) Signaling," on pages XXX–XXX.
Single-dose intranasal AdC68-vectored vaccines rapidly protect Syrian hamsters against lethal Nipah virus infection
Authors: Mingqing Lu, Yanfeng Yao, Hang Liu, Yun Peng, Xuejie Li, Ge Gao, Miaoyu Chen, Xuekai Zhang, Lingjing Mao, Peipei Yang, XiaoYu Zhang, Jing Miao, Zhiming Yuan, Jiaming Lan, Chao Shan
Journal: Molecular Therapy (2025)

Nipah virus (NiV) infection is highly lethal in humans, and the development of vaccines that provide rapid protection is critical for addressing NiV outbreaks. In this study, we demonstrate that a single intranasal immunization with the chimpanzee adenoviral-vectored NiV vaccine, AdC68-F, induced robust and sustained cellular and humoral responses in BALB/c mice, and provided complete protection against challenge with the NiV-Malaysia strain (NiV-M) in hamsters. Notably, AdC68-F, administered at a dose of 5 × 109 viral particles, offered a complete prophylactic protection window as short as seven days before exposure to a lethal NiV-M challenge. Furthermore, passive transfer of sera from AdC68-F or AdC68-G immunized animals conferred complete protection against NiV-M infection in naïve hamsters. These findings underscore the pivotal role of antigen-specific immunity in controlling NiV infection and highlight the potential of single-dose intranasal AdC68-based NiV vaccines for rapid protection during outbreaks. By providing rapid and effective protection, these vaccines could help reduce human-to-human transmission and aid in curbing NiV outbreaks.
The Peptide PROTAC Modality: A New Strategy for Drug Discovery
Authors: Youmin Zhu, Yu Dai, Yuncai Tian
Journal: MedComm (2025)

ABSTRACT In recent years, proteolysis targeting chimera (PROTAC) technology has made significant progress in the field of drug development. Traditional drugs mainly focus on inhibiting or activating specific proteins, while PROTAC technology provides new ideas for treating various diseases by inducing the degradation of target proteins. Especially for peptide PROTACs, due to their unique structural and functional characteristics, they have become a hot research topic. This review provides a detailed description of the key components, mechanisms, and design principles of peptide PROTACs, elaborates on their applications in skin‐related diseases, oncology, and other potential therapeutic fields, analyzes their advantages and challenges, and looks forward to their future development prospects. The development of peptide PROTAC technology not only opens up new paths for drug research and development, but also provides new ideas for solving the resistance and safety issues faced by traditional small‐molecule drugs. Compared with small‐molecule PROTACs, peptide PROTACs have advantages such as multitargeting, biodegradability, low toxicity, and flexibility in structural design. With the deepening of research and the continuous maturity of technology, peptide PROTACs are expected to become one of the important strategies for future drug discovery, providing new hope for the treatment of more intractable diseases. Peptide PROTACs are ushering in a new era of precision medicine.
ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma
Authors: Koya Yasukawa, Shu Shimada, Yoshimitsu Akiyama, Tomohiko Taniai, Yosuke Igarashi, Shu Tsukihara, Yoshiaki Tanji, Kentaro Umemura, Atsushi Kamachi, Atsushi Nara, Masahiro Yamane, Keiichi Akahoshi, Akira Shimizu, Yuji Soejima, Minoru Tanabe, Shinji Tanaka
Journal: Cell Reports Medicine (2025)
Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations
Authors: Jeannette L Tenthorey, Serena Del Banco, Ishrak Ramzan, Hayley Klingenberg, Chang Liu, Michael Emerman, Harmit S Malik
Journal: Cell Genomics (2025)

Antiviral proteins often evolve rapidly at virus-binding interfaces to defend against new viruses. We investigated whether antiviral adaptation via missense mutations might face limits, which insertion or deletion mutations (indels) could overcome. Using high-throughput saturation missense mutagenesis, we identify one such case of a nearly insurmountable evolutionary challenge: the human anti-retroviral protein TRIM5α requires more than five missense mutations in its specificity-determining v1 loop to restrict a divergent simian immunodeficiency virus (SIV). However, through a novel saturating indel scanning methodology, we find that duplicating just one amino acid in v1 enables human TRIM5α to potently restrict SIV in a single evolutionary step. Moreover, natural primate TRIM5α v1 loops have evolved indels that confer novel antiviral specificities. Thus, indels enable antiviral proteins to overcome viral challenges otherwise inaccessible by missense mutations. Our findings reveal the potential of often-overlooked indel mutations in driving protein innovation.
The prevalence, incidence, and sociodemographic risk factors of HIV among older adults in sub-Saharan Africa (AWI-Gen): a multicentre, longitudinal cohort study
Authors: Luicer A Ingasia Olubayo, Theophilous Mathema, Chodziwadziwa Kabudula, Lisa K Micklesfield, Shukri F Mohamed, Isaac Kisiangani, Cairo B Ntimane, Solomon S Choma, Brian Houle, Scott Hazelhurst, Nigel Crowther, Stephen Tollman, Furahini D Tluway, Michele Ramsay, F Xavier Gómez-Olivé
Journal: The Lancet Healthy Longevity (2025)
(−)‐Epicatechin Rescues Memory Deficits by Activation of Autophagy in a Mouse Model of Tauopathies
Authors: Yanqing Wu, Ting Li, Xingjun Jiang, Jianmin Ling, Zaihua Zhao, Jiahui Zhu, Chongyang Chen, Qian Liu, Xifei Yang, Xuefeng Shen, Rong Ma, Gang Li, Gongping Liu
Journal: MedComm (2025)

ABSTRACT In tauopathies, defects in autophagy‐lysosomal protein degradation are thought to contribute to the abnormal accumulation of aggregated tau. Recent studies have shown that (−)‐Epicatechin (Epi), a dietary flavonoid belonging to the flavan‐3‐ol subgroup, improves blood flow, modulates metabolic profiles, and prevents oxidative damage. However, less research has explored the effects of Epi on tauopathies. Here, we found that Epi rescued cognitive deficits in P301S tau transgenic mice, a model exhibiting characteristics of tauopathies like frontotemporal dementia and Alzheimer's disease, and attenuated tau pathology through autophagy activation. Proteomic and biochemical analyses revealed that P301S mice exhibit deficits in autophagosome formation via modulating mTOR, consequently inhibiting autophagy. Epi inhibited the mTOR signaling pathway to promote autophagosome formation, which is essential for the clearance of tau aggregation. By using chloroquine (CQ) to inhibit autophagy in vivo, we further confirmed that Epi induced tau degradation via the autophagy pathway. Lastly, Epi administration was also found to improve cognition by reversing spine decrease and neuron loss, as well as attenuating neuroinflammation. Our findings suggest that Epi promoted tau clearance by activating autophagy, indicating its potential as a promising therapeutic candidate for tauopathies.
Intranasal Inoculation of Cationic Crosslinked Carbon Dots‐Adjuvanted Respiratory Syncytial Virus F Subunit Vaccine Elicits Mucosal and Systemic Humoral and Cellular Immunity
Authors: Hong Lei, Aqu Alu, Jingyun Yang, Cai He, Jie Shi, Weiqi Hong, Dandan Peng, Yu Zhang, Jian Liu, Furong Qin, Xiya Huang, Chunjun Ye, Lijiao Pei, Xuemei He, Hong Yan, Guangwen Lu, Xiangrong Song, Xiawei Wei, Yuquan Wei
Journal: MedComm (2025)

ABSTRACT Respiratory syncytial virus (RSV) causes severe acute lower respiratory tract infections, especially in infants and the elderly. Developing an RSV vaccine that promotes a robust mucosal immune response is necessary to successfully prevent viral transmission and the development of severe disease. We previously reported that crosslinked carbon dots (CCD) may be an excellent adjuvant candidate for intranasal (IN) protein subunit vaccines. Considering the strong immunogenicity of RSV prefused F protein (preF), we prepared an IN RSV vaccine composed of the CCD adjuvant and the preF protein as antigen (CCD/preF) and evaluated the induced antigen‐specific humoral and cellular immunity. We found that IN immunization with the CCD/preF vaccine elicited strong serum IgG responses and mucosal immunity, including secreted IgA antibodies, tissue‐resident memory T (T RM ) cells, and antigen‐specific B cells, which lasted for at least 1 year. In addition, a combination of intramuscular and IN immunization with CCD/preF vaccine induced stronger systemic and mucosal immunity. Together, this study proved the high immunogenicity of the CCD/preF vaccines and supported the university of the mucosal CCD adjuvant, supporting further development of the CCD/preF vaccine in larger animal models and clinical studies.
Living Myocardial Slices as Model for Testing Cardiac Pro-Reparative Gene Therapies
Authors: Rocco Caliandro, Azra Husetic, Merel L Ligtermoet, Arie R Boender, Lorena Zentilin, Gerard J J Boink, Mauro Giacca, Monika M Gladka
Journal: Molecular Therapy (2025)
Amount and intensity of daily total physical activity, step count and risk of incident cancer in the UK Biobank
Authors: Alaina H Shreves, Scott R Small, Rosemary Walmsley, Shing Chan, Pedro F Saint-Maurice, Steven C Moore, Keren Papier, Kezia Gaitskell, Ruth C Travis, Charles E Matthews, Aiden Doherty
Journal: British Journal of Sports Medicine (2025)

Objectives To investigate associations between daily physical activity, activity intensity and step counts with incident cancer risk. Methods Prospective analysis of UK Biobank participants who wore wrist-based accelerometers for 7 days, followed for cancer incidence (mean follow-up 5.8 years, SD 1.3). Time-series machine-learning models derived total physical activity, sedentary behaviour (SB), light-intensity physical activity (LIPA), moderate-vigorous-intensity physical activity (MVPA) and step counts. The outcome was a composite of 13 cancers previously associated with low physical activity in questionnaire-based studies. Cox proportional hazard models estimated HRs and 95% CIs, adjusted for demographic, health and lifestyle factors. We also explored associations of LIPA, MVPA and SB with cancer risk. Results Among 85 394 participants (median age 63 (IQR 56–68)), 2633 were diagnosed with cancer during follow-up. Compared with individuals in the lowest quintile of total physical activity (&lt;21.6 milligravity units), those in the highest (34.3+) had a 26% lower cancer risk (HR=0.74 (95% CI 0.65 to 0.84)). After mutual adjustment, LIPA (HR=0.94 (95% CI 0.90 to 0.98)) and MVPA (HR=0.87 (95% CI 0.79 to 0.94)) were associated with lower risk, but SB was not. Similar associations were observed for substituting 1 hour/day of SB with LIPA or MVPA. Daily step counts were inversely associated with cancer, with the dose-response beginning to plateau at around 9 000 steps/day (HR=0.89 (95% CI 0.83 to 0.96) 7000 vs 5000 steps; HR=0.84 (95% CI 0.76 to 0.93) 9000 vs 5000 steps). There was no significant association between stepping intensity (peak 30-minute cadence) and cancer after adjusting for step count. Conclusion Total physical activity, LIPA, MVPA and step counts were inversely associated with incident cancer.
Stressed hepatocyte sustains alcohol-associated hepatitis progression by producing leukocyte cell-derived chemotaxin 2
Authors: Honghai Xu, Zihao Wu, Jiangfeng Qin, Xutong Li, Feng Xu, Wei Wang, Hui Zhang, HeHe Yin, Shiwei Zhu, Wenzhe Zhang, Yuanru Yang, Yuanyuan Wei, Long Gao, Jiatao Liu, Yufeng Gao, Ming-Hua Zheng, Haoxiong Zhou, Tingting Qi, Jinjun Chen, Yanhang Gao, Li Zuo, Jiong Chen, Suthat Liangpunsakul, Jiabin Li, Hua Wang
Journal: Gut (2025)

Background Neutrophil infiltration and hepatocyte damage are indispensable hallmarks in alcohol-associated hepatitis (AH), yet the underlying crosstalk between neutrophils and hepatocytes and its role in AH pathogenesis remain unclear. Objective We investigate the regulatory role of leucocyte cell-derived chemotaxin 2 (LECT2) in hepatocyte–neutrophil interaction and its impact on AH progression. Design We used bulk and single-cell RNA sequencing to identify hepatocyte-secreted factors targeting neutrophils. We analysed serum and liver samples from AH patients and employed genetically modified mice alongside in vitro studies. Results RNA-sequencing analysis identified several neutrophil chemokines that are elevated in hepatocytes from AH patients, including LECT2 whose role in AH remains largely unknown. AH patients exhibited increased levels of LECT2 in hepatocytes, positively correlating with the severity of AH. Ethanol-fed mice also exhibited elevated liver LECT2, which was abolished by inhibiting endoplasmic reticulum stress. Functional studies revealed that ethanol-induced liver injury was ameliorated in Lect2 -deficient mice but was exacerbated in mice with hepatic overexpression of Lect2 . Furthermore, LECT2 exacerbated ethanol-induced liver injury by promoting reactive oxygen species (ROS) through its interaction with prohibitin 2 (PHB2), a neutrophil membrane protein. By directly binding to PHB2, LECT2 disrupts the stable structure of PHB1/PHB2 heterodimerisation, consequently leading to PHB2 degradation, ROS accumulation, neutrophil activation and neutrophil extracellular trap formation. Moreover, therapeutic intervention of LECT2 via Lect2 shRNA ameliorated ethanol-induced liver injury. Conclusion Our studies identified a novel vicious cycle between neutrophils and hepatocytes through the LECT2–PHB2 interaction, presenting a promising therapeutic intervention by targeting LECT2 to mitigate AH in patients.
Survey of gene, lncRNA and transposon transcription patterns in four mouse organs highlights shared and organ-specific sex-biased regulation
Authors: Qinwei Kim-Wee Zhuang, Klara Bauermeister, Jose Hector Galvez, Najla Alogayil, Enkhjin Batdorj, Fernando Pardo Manuel de Villena, Teruko Taketo, Guillaume Bourque, Anna K. Naumova
Journal: Genome biology (2025)

Sex-biased gene regulation is the basis of sexual dimorphism in phenotypes and has been studied across different cell types and different developmental stages. However, sex-biased expression of transposable elements (TEs), which represent nearly half of the mammalian genome and have the potential of influencing genome integrity and regulation, remains underexplored. We report a survey of gene, lncRNA, and TE expression in four organs from mice with different combinations of gonadal and genetic sex. The data show remarkable variability among organs with respect to the impact of gonadal sex on transcription with the strongest effects observed in the liver. In contrast, the X-chromosome dosage alone had a modest influence on sex-biased transcription across organs, albeit interaction between X-dosage and gonadal sex cannot be ruled out. The presence of the Y-chromosome influences TE, but not gene or lncRNA, expression in the liver. Notably, 90% of sex-biased TEs (sDETEs) reside in clusters. Moreover, 54% of these clusters overlap or reside less than 100 kb from sex-biased genes or lncRNAs, share the same sex bias, and also have higher expression levels than sDETE clusters that do not co-localize with other types of sex-biased transcripts. We test the heterochromatic sink hypothesis that predicts higher expression of TEs in XX individuals finding no evidence to support it. Our data show that sex-biased expression of TEs varies among organs with the highest numbers of sDETEs found in the liver following trends observed for genes and lncRNAs. It is enhanced by proximity to other types of sex-biased transcripts.
Tick feeding or vaccination with tick antigens elicits immunity to the <i>Ixodes scapularis</i> exoproteome in guinea pigs and humans
Authors: Thomas M. Hart, Yingjun Cui, Sam R. Telford, Alejandro Marín-López, Keith Calloway, Yile Dai, Jaqueline Matias, Kathleen DePonte, Jillian Jaycox, Melody DeBlasio, Dieuwertje Hoornstra, Alexia A. Belperron, Balasubramanian Cibichakravarthy, Emily E. Johnson, Mohamad-Gabriel Alameh, Garima Dwivedi, Joppe W. R. Hovius, Linda K. Bockenstedt, Drew Weissman, Aaron M. Ring, Erol Fikrig
Journal: Science Translational Medicine (2025)

Ixodes scapularis is a primary vector of tick-borne pathogens in North America. Repeated exposure to these ticks can induce a humoral response to tick antigens and acquired tick resistance. However, identifying antigens contributing to this resistance is challenging because of the vast number of I. scapularis proteins secreted during feeding. To address this, we developed I. scapularis rapid extracellular antigen monitoring ( Isc REAM), a technique to detect antibody responses to more than 3000 tick antigens. We validated Isc REAM with immunoglobulin G (IgG) from guinea pigs vaccinated with tick antigens, including a cement antigen cocktail that induced tick resistance. Furthermore, we explored the natural response to tick bites by profiling antigens recognized by IgG isolated from a tick-resistant individual, as well as from others with Lyme disease and tick-bitten guinea pigs and mice, to identify 199 recognized antigens. We observed that several antigens contained histamine-binding domains. This work enhances our understanding of the host immune response to I. scapularis and defines immunogen candidates for future antitick vaccines.
Variant screening of PYY <sub>3–36</sub> leads to potent long-acting PYY analogs with superior Y <sub>2</sub> receptor selectivity
Authors: Søren Østergaard, Carsten Jessen, Johan F. Paulsson, Marina A. Kasimova, Kilian W. Conde-Frieboes, Ellen Marie Straarup, Rikke Bjerring Skyggebjerg, Lars Ynddal, Annika Sanfridson, Birgitte S. Wulff, Adam P. Chambers
Journal: Science Translational Medicine (2025)

Peptide YY (PYY 3–36 ) has attracted attention in diabetes and obesity research because of its involvement in food intake regulation and glucose homeostasis. Native PYY 3–36 maintains high potency on the Y 2 receptor with a loss of potency on the Y 1 , Y 4 , and Y 5 receptors. However, PYY 3–36 has a relatively short half-life, and the selectivity displayed by the native peptide may not be optimal if a long-acting analog is to be developed. We performed variant screening of PYY 3–36 to identify key canonical amino acids that are pivotal to Y 2 receptor selectivity, potency, and peptide stability. In combination with fatty diacid derivatization, this afforded highly selective long-acting analogs against the Y 2 receptor, which improved glucose metabolism in diabetic db / db mice. When combined with a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist, these analogs showed superior blood glucose lowering in diabetic ZSF1 rats and greater body weight loss in a high-fat diet–induced mouse model of obesity compared with treatment with the GLP-1 analog alone. One of the tested analogs, PYY1875, has progressed into clinical trials for obesity. Together, our results demonstrate the power of variant screening combined with fatty diacid derivatization in the development of a long-acting, highly efficacious PYY clinical candidate.