tbuckley/cabot-search huggingface dataset:
Protein arginine methyltransferase 6 enhances immune checkpoint blockade efficacy via the STING pathway in MMR-proficient colorectal cancer
Authors: Jinlin Duan, Tao Chen, Qiwei Li, Yu Zhang, Ting Lu, Junyan Xue, Yang Sun, Ling Gao, Yonglong Zhang
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The emergence of immunotherapy has revolutionized the paradigm of cancer treatment with immune checkpoint blockades (ICB) in solid cancers, including colorectal cancer (CRC). However, only a small subset of CRC patients harboring deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) benefits from ICB therapy. A very limited response to ICB therapy has been achieved in MMR-proficient CRC, representing a significant challenge limiting the clinical application of immunotherapy. MMR is the critical DNA repair pathway that maintains genomic integrity by correcting DNA mismatches, which is mediated by the MutSα or MutSβ complex consisting of MSH2 with MSH6 and MSH3, respectively. Given that MMR status directs effective immune response, we sought to determine whether targeting MMR capacity boosts ICB efficacy. Methods Azoxymethane/dextran sodium sulfate (AOM/DSS)‐induced CRC and xenograft model were used to evaluate the function of PRMT6 and response to PRMT6 inhibitor EPZ020411 and combination therapy of PD1 and EPZ020411. Biochemical assays were performed to elucidate the underlying mechanism of PRMT6-mediated MSH2 methylation and immune evasion. Results We have identified PRMT6 as a crucial regulator of MMR capacity via MSH2 dimethylation at R171 and R219. Such a modification abrogates its MMR capacity and prevents the recruitment of MSH3 and MSH6. PRMT6 loss or inhibition triggers cytosolic DNA accumulation and cGAS-STING signaling activation, leading to enhanced immune response in PRMT6-deficient colon tumors or xenografts. Pharmacological inhibition of PRMT6 using EPZ020411 promotes mutagenesis and destabilizes MutSα or MutSβ assembly, and prolonged EPZ020411 exposure maintains an MSI-like phenotype in microsatellite stability (MSS) cells. EPZ020411 treatment sensitizes ICB efficacy of MSS cells, but not MSI cells in vivo. Similar effects have been observed in MSS colon tumors induced by AOM/DSS. Conclusions Our study provides a preclinical proof of concept to overcome resistance to immunotherapy by targeting PRMT6 in CRC with MSS.
Optimization of Adcitmer, a Monomethyl-Auristatin E bearing antibody-drug conjugate for the treatment of CD56-expressing cancers
Authors: Aurelie Drouin, Laurine Durand, Clara Esnault, Pauline Gaboriaud, Valérie Leblond, Shawk Karim, Morgane Fouché, Christine Dhommée, Christine B Baltus, Fanny Boursin, Nicolas Aubrey, Roland Houben, David Schrama, Serge Guyétant, Audrey Desgranges, Marie Claude Viaud-Massuard, Valérie Gouilleux-Gruart, Mahtab Samimi, Thibault Kervarrec, Antoine Touzé
Journal: Journal for ImmunoTherapy of Cancer (2025)

The cell adhesion protein CD56 has been identified as a potential therapeutic target in several solid tumors and hematological malignancies. Recently, we developed a CD56-directed antibody-drug conjugate (ADC), called Adcitmer and demonstrated its antitumor properties in preclinical models of the rare and aggressive skin cancer Merkel cell carcinoma (MCC). The present study aims to further optimize Adcitmer to overcome the therapeutic limitations observed with previously evaluated CD56-targeting ADCs, which were partially related to toxic effects on leukocytes. To this end, we aimed to avoid interaction of Adcitmer with immune cells via Fc gamma receptor (FcγR) binding. Since glycosylation is essential for FcγR binding, an aglycosylated form of Adcitmer was generated and evaluated on human leukocytes and MCC cell lines using cell death (annexin V/ 7-aminoactinomycine D ) and proliferation (2,3-Bis-(2-methoxy-4Nitro-5-sulfophenyl)-2H-tetrazolium-5carboxanilide) assays. Finally, the therapeutic performance of Adcitmer and its aglycosylated form was assessed in an MCC xenograft mouse model. Investigating the Adcitmer interaction with immune cells demonstrated that it is mostly mediated by Fc recognition. Accordingly, Adcitmer aglycosylation led to reduced immune cell toxicity and strikingly also to improved therapeutic performance even in an MCC xenograft model using immunodeficient mice. Our study suggests that aglycosylated Adcitmer should be considered as a therapeutic option in patients with advanced MCC or other CD56-positive tumors.
Endothelial TDP-43 depletion disrupts core blood–brain barrier pathways in neurodegeneration
Authors: Omar M. F. Omar, Amy L. Kimble, Ashok Cheemala, Jordan D. Tyburski, Swati Pandey, Qian Wu, Bo Reese, Evan R. Jellison, Bing Hao, Yunfeng Li, Riqiang Yan, Patrick A. Murphy
Journal: Nature Neuroscience (2025)

Abstract Endothelial cells (ECs) help maintain the blood–brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20–98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer’s disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood–brain barrier breakdown in neurodegenerative diseases.
Telephone Counseling and Messaging Guided by Mobile Profiling of Tobacco Users for Smoking Cessation
Authors: Yee Tak Derek Cheung, Min Jin Zhang, Tzu Tsun Luk, Sai Yin Ho, Tai Hing Lam, Man Ping Wang
Journal: JAMA Network Open (2025)

Evidence-based pharmacotherapy and behavioral therapy could increase tobacco abstinence but are underused and require further investigation. To evaluate the effectiveness of a novel mobile health (mHealth) profiling via ecological momentary assessment (EMA) in personalizing smoking cessation intervention for individuals who use tobacco with no intention to use smoking cessation services and medications. A 2-arm, assessor-blind, individual-randomized clinical trial was conducted. With online recruitment through social media or email advertisement, 459 adults with daily tobacco use in Hong Kong were recruited from March 23, 2022, to January 4, 2023, with follow-up completed by July 4, 2023. Individuals who had not used smoking cessation services or medications in the preceding 7 days and had no intention to use these aids in the next month were included. Participants were randomized 1:1 to intervention (n = 231) or control (n = 228) groups. Both groups completed 5 EMAs daily for 7 days to report smoking behaviors and triggers. The intervention group additionally received nurse-led telephone counseling and 10-week instant messaging support guided by mHealth profiling from EMA. Primary outcomes were biochemically validated tobacco abstinence and Incremental Behavior Change Toward Smoking Cessation (IBC-S) score at 3 months after EMA initiation. Secondary outcomes were biochemically validated tobacco abstinence and IBC-S status at 6 months, self-reported 7-day point prevalence, abstinence, and use of smoking cessation medications and services at 3 and 6 months after EMA initiation. Intention-to-treat analysis was used. The study included 459 participants (304 males [66.2%]) with a mean (SD) age of 36.7 (10.7) years. Biochemically validated tobacco abstinence rates were 8.2% in the intervention group and 3.5% in the control group (odds ratio [OR], 2.46; 95% CI, 1.06 to 5.75; P = .04) at 3-month follow-up. The corresponding rates at 6-month follow-up were 9.5% and 4.0% (OR, 2.56; 95% CI, 1.15-5.70; P = .02). The intervention group showed a greater increase in IBC-S scores from baseline to both 3-month (β = 1.03; 95% CI, 0.46-1.59; P < .001) and 6-month (β = 0.95; 95% CI, 0.37-1.53; P = .001) follow-ups. The findings of this randomized clinical trial suggest that telephone counseling and instant messaging support, guided by mHealth profiling, increased tobacco abstinence vs EMA alone. This intervention may be used to supplement conventional smoking cessation for individuals who use tobacco and are unwilling to use smoking cessation aids. ClinicalTrials.gov Identifier: NCT05212220.
Probiotics and Fever Duration in Children With Upper Respiratory Tract Infections
Authors: Silvia Bettocchi, Anna Comotti, Marina Elli, Valentina De Cosmi, Cristiana Berti, Ilaria Alberti, Alessandra Mazzocchi, Chiara Rosazza, Carlo Agostoni, Gregorio Paolo Milani
Journal: JAMA Network Open (2025)

Upper respiratory tract infections (URTIs) are prevalent in children, prompting frequent health care consultations, especially among those with fever. Probiotics show potential as an adjuvant treatment for URTIs, but evidence in children is limited. To evaluate the efficacy of a probiotic mixture containing Bifidobacterium breve M-16V, Bifidobacterium lactis HN019, and Lactobacillus rhamnosus HN001 in shortening fever duration among children with URTIs. This randomized clinical trial was conducted between November 19, 2021, and June 20, 2023, at the pediatric emergency department of the Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy. Patients between 28 days and 4 years of age with a fever (≥38.5 °C) and URTI were eligible. Exclusion criteria included recent probiotic use, chronic autoimmune diseases, immunosuppressive treatment, and requirement for hospitalization. Randomization was computer generated and assigned participants to either the intervention (probiotics) or control (placebo) group. Participants, parents or caregivers, and investigators were masked to the group assignments. The primary analysis followed the intention-to-treat approach. The probiotic group received daily single dose of 0.5 mL probiotic mixture containing Bifidobacterium breve M-16V, Bifidobacterium lactis HN019, and Lactobacillus rhamnosus HN001 for 14 days. The placebo group received daily single dose of 0.5 mL placebo for 14 days. The primary outcome was fever duration, defined as the number of days between the first and the last days with fever. Of the 128 patients enrolled (69 males [54%]; mean [SD] age 2.5 [1.3] years), 65 (51%) were randomly assigned to receive placebo and 63 (49%) to receive probiotics. The median (IQR) fever duration was shorter in the probiotic group than the placebo group (median [IQR], 3 [2-4] days vs 5 [4-6] days; adjusted risk ratio, 0.64; 95% CI, 0.51-0.80). Few mild adverse events were reported and did not significantly differ between the probiotic and placebo groups, including constipation (6 [16%] and 6 [12%]; P = .80) and abdominal pain (3 [8%] and 2 [4%]; P = .65). In this randomized clinical trial, administering a probiotic mixture reduced fever duration by 2 days compared with placebo, with no meaningful safety concerns. The probiotic mixture under investigation could be an effective adjuvant for shortening fever duration in children with URTIs. ClinicalTrials.gov Identifier: NCT06052540.
Intervention for Psychological Trauma in Children Impacted by War in Ukraine
Authors: Irwin Redlener, Khrystyna Dudashvili, Oksana Viontsek, Roy Grant, Eva Roca
Journal: JAMA Network Open (2025)

This cohort study describes outcomes of a 6-day psychosocial recovery camp as an intervention for psychological trauma experienced by children from front-line regions of the war in Ukraine.
Lifetime and Past-Year Defensive Gun Use
Authors: Michael D. Anestis, Kimberly Burke, Sultan Altikriti, Daniel Semenza
Journal: JAMA Network Open (2025)

Defensive gun use (DGU) is cited as a rationale for permissive firearm-carrying policies; however, no consensus exists on how frequently DGU occurs. To examine the frequency of DGU relative to gun violence exposure (GVE) in a sample of firearm owners drawn from a nationally representative sample of US adults. This survey study used data from a cross-sectional, self-reported survey administered via KnowledgePanel, a probability-based panel, between May 15 and May 28, 2024. Eligible participants were adults residing within the US reporting current firearm access who responded to DGU survey items. Data were analyzed from July to September 2024. Primary outcomes were 4 forms of DGU: telling a perceived threat about a firearm, showing a firearm to a perceived threat, firing in the vicinity of but not at a perceived threat, and firing at a perceived threat. Among 12 822 adults invited to participate, 8647 (67.4%) read the informed consent, 8009 (92.6%) consented to participate, and 3000 (37.7%; 532 [51.1%] male; 982 [32.7%] aged ≥60 years) endorsed firearm access and responded to DGU items, including 295 Black, non-Hispanic participants (9.8%); 365 Hispanic participants (12.2%); and 2178 White, non-Hispanic participants (72.6%). DGU was rare, with 91.7% (95% CI, 90.6%-92.7%) of participants reporting no lifetime history of DGU. The most reported form of DGU was showing a firearm to a perceived threat (lifetime: 4.7%; 95% CI, 4.0%-5.5%). Less than 1% of the sample reported any form of past-year DGU. GVE was more pervasive for lifetime (eg, loss of a friend or loved one to firearm suicide: 34.4%; 95% CI, 32.7%-36.1%; hearing gunshots in neighborhood: 51.8%; 95% CI, 50.0%-53.6%) and past-year exposure (eg, loss of a friend or loved one to firearm suicide: 3.2%; 95% CI, 2.6%-3.9%; hearing gunshots in neighborhood: 32.7%; 95% CI, 31.0%-34.4%). In this survey of adults with firearm access, DGU was rare relative to GVE. Perceived threats may not necessitate DGU, and given the association between DGU and GVE, the consequences of DGU may be substantial. Narratives centering DGU as a consideration in firearm policies may misstate the risk profile of firearm access.
Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis
Authors: Marco Rosina, Silvia Scaricamazza, Gianmarco Fenili, Valentina Nesci, Cristiana Valle, Alberto Ferri, Maria Paola Paronetto
Journal: Trends in Endocrinology and Metabolism (2025)

Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.
Anti-vascular endothelial growth factor treatment potentiates immune checkpoint blockade through a BAFF- and IL-12-dependent reprogramming of the TME
Authors: Mohamed-Reda Benmebarek, Cihan Oguz, Matthias Seifert, Benjamin Ruf, Yuta Myojin, Kylynda C Bauer, Patrick Huang, Chi Ma, Marina Villamor-Payà, Francisco Rodriguez-Matos, Marlaine Soliman, Rajiv Trehan, Cecilia Monge, Changqing Xie, David E Kleiner, Bradford J Wood, Elliot B Levy, Anuradha Budhu, Noemi Kedei, Christian T Mayer, Xin Wei Wang, Justin Lack, William Telford, Firouzeh Korangy, Tim F Greten
Journal: Immunity (2025)
NNMT promotes acquired EGFR-TKI resistance by forming EGR1 and lactate-mediated double positive feedback loops in non-small cell lung cancer
Authors: Jiali Dai, Xiyi Lu, Chang Zhang, Tianyu Qu, Wei Li, Jun Su, Renhua Guo, Dandan Yin, Pingping Wu, Liang Han, Erbao Zhang
Journal: Molecular Cancer (2025)

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, patients inevitably develop acquired drug resistance, resulting in recurrence or metastasis. It is important to identify novel effective therapeutic targets to reverse acquired TKI resistance. Bioinformatics analysis revealed that nicotinamide N-methyltransferase (NNMT) was upregulated in EGFR-TKI resistant cells and tissues via EGR1-mediated transcriptional activation. High NNMT levels were correlated with poor prognosis in EGFR-mutated NSCLC patients, which could promote resistance to EGFR-TKIs in vitro and in vivo. Mechanistically, NNMT catalyzed the conversion of nicotinamide to 1-methyl nicotinamide by depleting S-adenosyl methionine (the methyl group donor), leading to a reduction in H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3) and subsequent epigenetic activation of EGR1 and ALDH3A1. In addition, ALDH3A1 activation increased lactic acid levels, which further promoted NNMT expression via p300-mediated histone H3K18 lactylation on its promoter. Thus, NNMT mediates the formation of a double positive feedback loop via EGR1 and lactate, EGR1/NNMT/EGR1 and NNMT/ALDH3A1/lactate/NNMT. Moreover, the combination of a small-molecule inhibitor for NNMT (NNMTi) and osimertinib exhibited promising potential for the treatment of TKI resistance in an NSCLC osimertinib-resistant xenograft model. The combined contribution of these two positive feedback loops promotes EGFR-TKI resistance in NSCLC. Our findings provide new insight into the role of histone methylation and histone lactylation in TKI resistance. The pivotal NNMT-mediated positive feedback loop may serve as a powerful therapeutic target for overcoming EGFR-TKI resistance in NSCLC.
A Single‐Nucleus Transcriptomic Atlas Reveals Cellular and Genetic Characteristics of Alzheimer's‐Like Pathology in Aging Tree Shrews
Authors: Liu‐Lin Xiong, Rong He, Ruo‐Lan Du, Rui‐Ze Niu, Lu‐Lu Xue, Li Chen, Li‐Ren Huangfu, Qiu‐Xia Xiao, Jing Li, Yong‐Ping Li, Si‐Min Zhang, Chang‐Yin Yu, Xiao‐He Tian, Ting‐Hua Wang
Journal: MedComm (2025)

ABSTRACT The lack of natural aging‐inducing Alzheimer's disease (AD) model presents a significant gap in the current preclinical research. Here, we identified a unique cohort of 10 naturally aging tree shrews (TSs) displaying distinct Alzheimer's‐like pathology (ALP) from a population of 324, thereby establishing a novel model that closely mirrors human AD progression. Using single‐nucleus RNA sequencing, we generated a comprehensive transcriptome atlas, revealing the cellular diversity and gene expression changes underlying AD pathology in aged TSs. Particularly, distinct differentiation trajectories of neural progenitor cells were highly associated with AD pathology. Intriguingly, cross‐species comparisons among humans, TSs, monkeys, and mice highlighted a greater cellular homogeneity of TSs to primates and humans than to mice. Our extended cross‐species analysis by including a direct comparison between human and TS hippocampal tissue under AD conditions uncovered conserved cell types, enriched synaptic biological processes, and elevated excitatory/inhibitory imbalance across species. Cell–cell communication analysis unveiled parallel patterns between AD human and ALP TSs, with both showing reduced interaction strength and quantity across most cell types. Overall, our study provides rich, high‐resolution resources on the cellular and molecular landscape of the ALP TS hippocampus, reinforcing the utility of TSs as a robust model for AD research.
Refining precision prognostics in multiple myeloma: loss of miR-221/222 cluster in CD138+ plasma cells results in short-term progression and worse treatment outcome
Authors: Konstantinos Soureas, Panagiotis Malandrakis, Maria-Alexandra Papadimitriou, Christos Minopoulos, Ioannis Ntanasis-Stathopoulos, Christine-Ivy Liacos, Maria Gavriatopoulou, Efstathios Kastritis, Meletios-Athanasios Dimopoulos, Andreas Scorilas, Margaritis Avgeris, Evangelos Terpos
Journal: Blood Cancer Journal (2025)

Abstract The persistence of high relapse rates and therapy resistance continues to challenge the effective management of multiple myeloma (MM). The identification of novel MM-specific molecular markers could ameliorate risk-stratification tools and accurately identify high-risk patients towards personalized prognosis and therapy. miRNA-seq analysis of CD138+ plasma cells (n = 24) unveiled miR-221-3p and miR-222-3p (miR-221/222 cluster) as the most downregulated miRNAs in R-ISS III compared to R-ISS I/II patients. Subsequently, miR-221/222 levels were quantified by RT-qPCR in CD138+ plasma cells of our screening cohort (n = 141), assessing patients’ mortality and disease progression as clinical endpoints. Internal validation was performed by bootstrap analysis, while clinical benefit was estimated by decision curve analysis. Kryukov et al. (n = 149) and Aass et al. (n = 86) served as institutional-independent validation cohorts. Loss of miR-221/222 cluster was strongly associated with patients’ short-term progression and poor overall survival, which was confirmed by Kryukov et al. and Aass et al. validation cohorts. Intriguingly, miR-221/222-fitted multivariate models offered superior risk-stratification within R-ISS staging and risk-based cytogenetics. Moreover, miR-221/222 loss could effectively discriminate optimal 1st-line treatment responders with inferior treatment outcome. Our study identified the loss of miR-221/222 cluster as a powerful independent predictor of patients’ post-treatment progression, ameliorating prognosis and supporting precision medicine in MM.
Utilizing ctDNA to discover mechanisms of resistance to targeted therapies in patients with metastatic NSCLC: towards more informative trials
Authors: Sophie M. Ernst, Mihaela Aldea, Jan H. von der Thüsen, Adrianus J. de Langen, Egbert F. Smit, Marthe S. Paats, Joachim G. J. V. Aerts, Laura Mezquita, Sanjay Popat, Benjamin Besse, Jordi Remon, Christian Rolfo, Hendrikus J. Dubbink, Anne-Marie C. Dingemans
Journal: Nature Reviews Clinical Oncology (2025)
Noninvasive method for achieving the regeneration of damaged nerves via ultrasonic nasal drops
Authors: Ning Zhu, Fan Wang, Zeyu Han, Shifeng Ling, Duo Wai-Chi Wong, Shenglin Ye, Mingyue Liu, Yanyang Chen, Gracie Shen, Ming Ni, Huitong Ruan, Yan Qiu, Wenguo Cui
Journal: Bioactive Materials (2025)
Protective functions of liver X receptor α on calcified aortic valve: involvement of regulating endoplasmic reticulum-mediated osteogenic differentiation
Authors: Lishan Zeng, Xin Chen, Kai Kang, Yifei Lin, Zhongxing Zhou, Shuaijie Chen, Chunkai Huang, Qingqing Lin, Hongzhuang Wang, Longqing Chen, Liangliang Yan, HanFan Qiu, Jinxiu Lin, Xiaoyan Lin, Dajun Chai
Journal: Cardiovascular Research (2025)

Abstract Aims Effective therapeutic drugs for calcific aortic valve disease (CAVD) are lacking, although its incidence has been increasing over the past decade, and is predicted to continue rising in the future. This study aimed to explore the role and potential mechanisms of liver X receptor α (LXRα) in CAVD, which offers a promising approach for treating CAVD. Methods and results Osteogenic stimulation was performed following which a substantial downregulation of LXRα was observed in human calcific aortic valves and in valvular interstitial cells. Further functional investigations revealed that silencing LXRα exacerbated calcification both in vitro and in vivo. We showed that LXRα suppressed the protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 (elF2α)/activating transcription factor 4 (ATF4) pathway, which controls endoplasmic reticulum stress (ERS) and promotes osteogenic differentiation thereby slowing the course of CAVD. Conclusion Our research offers fresh perspectives on how LXRα controls the pathophysiology of CAVD via regulating ERS. The findings suggest that targeting LXRα is a potential treatment strategy for treating aortic valve calcification.