tbuckley/cabot-search huggingface dataset:
Targeting Innate Immune Checkpoint TREX1 is a Safe and Effective Immunotherapeutic Strategy in Cancer
Authors: Cong Xing, Xintao Tu, Wanwan Huai, Zhen Tang, Kun Song, Devon Jeltema, Kennady Knox, Nicole Dobbs, Kun Yang, Nan Yan
Journal: Cancer Research (2025)

Abstract Three-prime repair exonuclease 1 (TREX1) is the major DNase in mammalian cells that degrades cytosolic DNA to prevent activation of the cGAS-STING pathway. Genotoxic stress, DNA damage, and radiotherapy induce TREX1 expression in cancer cells, allowing them to evade innate immune activation of type I interferon (IFN-I)-mediated antitumor response. Therefore, targeting TREX1 could represent a potential approach to stimulate antitumor immunity and enhance therapeutic efficacy. Here, we conducted a high-throughput small-molecule inhibitor (SMI) screen of TREX1 using a cell-free DNase assay. Compound 296 specifically inhibited TREX1 DNase activity at low micromolar concentrations, induced IFN-I signaling in cancer cells, and inhibited tumor growth in mice in an IFNAR-dependent manner. Treatment with compound 296 also stimulated T cell infiltration into tumors and synergized with immune checkpoint blockade. Trex1 knockout cancer cells elicited robust systemic antitumor immunity through tumor-intrinsic cGAS-STING activation and functioned as autologous cancer vaccines that protected against tumor challenge and metastasis. An inducible whole-body Trex1 knockout mouse model was established to simulate “on-demand” systemic TREX1 inactivation in adult mice. Sustained TREX1 loss suppressed a broad range of solid and metastatic tumors in adult mice without incurring severe immune toxicity, even when combined with immune checkpoint blockade, demonstrating the feasibility of an immune-safe therapeutic window. Together, these data demonstrate the antitumor efficacy and immune safety of multiple therapeutic modalities, including targeting TREX1 using SMIs and employing TREX1 knockout tumor cells as an autologous cancer vaccine, which should pave the way for developing TREX1-targeted cancer immunotherapies.
Combining Multiplexed CRISPR/Cas9-Nickase and PARP Inhibitors Efficiently and Precisely Targets Cancer Cells
Authors: Soyoung Lee, Kyunghwan Kim, Hye-Jin Jeong, Subin Choi, Himchan Cheng, Dayoung Kim, Soomin Heo, Jinhee Mun, Minjong Kim, Eunjin Lee, Yoon Ji Choi, Seon-gyeong Lee, Eun A. Lee, Yewon Jang, Kayeong Lim, Heon Seok Kim, Euihwan Jeong, Seung-Jae Myung, Deok-Beom Jung, Chang Sik Yu, In Ho Song, M. Ryan Corces, Joo H. Kang, Kyungjae Myung, Taejoon Kwon, Tae-Eun Park, Jinmyoung Joo, Seung Woo Cho
Journal: Cancer Research (2025)

Abstract Triggering cancer cell death by inducing DNA damage is the primary aim of radiation therapy; however, normal cells are also damaged. Here, we showed that delivery of only four synthetic guide RNAs (sgRNAs) with Cas9 endonuclease efficiently induced simultaneous DNA double-strand breaks, resulting in efficient cell death in a cell type-specific manner. Off-target effects of Cas9 endonuclease were prevented by using Cas9-nickase to induce DNA single-strand breaks and blocking their repair with poly ADP-ribose polymerase (PARP) inhibitors. When recombinant Cas9-nickase protein and multiple sgRNAs were delivered with PARP inhibitors into cultured cells, in vivo xenografts, and patient-derived cancer organoids via lipid nanoparticles, cancer cells were unable to tolerate the induced DNA damage, even in the presence of a functional BRCA2 gene. This approach has the potential to expand the use of PARP inhibitors with verified safety and thus is a potentially powerful tool for personalized genome-based anti-cancer therapy.
Where did the Y chromosome in the spiny rat go, and how did it get there?
Authors: Miki Okuno, Kentaro Matsuoka, Yuta Mochimaru, Takahiro Yamabe, Mayou Okano, Takamichi Jogahara, Atsushi Toyoda, Asato Kuroiwa, Takehiko Itoh
Journal: Molecular Biology and Evolution (2025)

Abstract The XX/XY sex chromosome system is highly conserved across mammals, with rare exceptions where males lack a Y chromosome. Among these is the genus Tokudaia, a group of spiny rats comprising three species with unique sex chromosome systems deviating from the typical XX/XY pattern. While T. osimensis and T. tokunoshimensis have completely lost the Y chromosome, they retain some Y-linked genes on the X chromosome. In contrast, T. muenninki retains large sex chromosomes where both the X and Y chromosomes have fused with an autosome pair, carrying multi-copied Y-linked genes, including Sry. In this study, we generated chromosome-level genome assemblies for male individuals of all three Tokudaia species. By investigating loci typically associated with rodent Y-linked genes, we characterized sequences derived from the Tokudaia Y-chromosomal most recent common ancestor (Tokudaia Y-MRCA) and traced their evolutionary trajectories. Our analyses revealed that an initial X-to-Y translocation of a sequence containing the Boundary-Associated Segmental Duplication (BASD) in a common ancestor of Tokudaia marked the beginning of their unique sex chromosome evolution. The BASD, uniquely multi-copied in Tokudaia, facilitated further rearrangements through non-allelic homologous recombination and duplications. These processes culminated in subsequent Y-to-X translocations and duplications, leading to the complete loss of the Y chromosome as a distinct entity while preserving Y-linked genes in a multicopy state on the X chromosome. These findings highlight Tokudaia’s rapid sex chromosome evolution within three million years and provide insights into the mechanisms underlying Y chromosome loss, contributing to a broader understanding of sex chromosome evolution in rodents.
Unique Energy Profile Associated with Persistent Thin Phenotype
Authors: Mélina Bailly, David Thivel, Laurie Isacco, Julien Verney
Journal: Annual Review of Nutrition (2025)

The concept of constitutional thinness first emerged in the scientific literature at the beginning of the 20th century. Yet, this concept of a physiologically determined thinness, which clearly differentiated it from anorexia nervosa and challenged the basic notions of metabolism, intrigued the medical community. How could a young, healthy person with normal food intake present such an underweight state that resists body-weight gain? Due to either skepticism or disinterest, the fact remains that fewer than 50 clinical studies have focused on constitutional thinness the last 90 years, contrasting with the hundreds of thousands conducted on the other end of the weight status spectrum (obesity). The aim of this review is to discuss current evidence of various aspects of this persistent thin phenotype, from its definition and diagnosis to its metabolic and physiological mechanisms. A deeper understanding of constitutional thinness would facilitate medical/societal recognition and clinical management of this condition. Greater insight into constitutional thinness could also help identify metabolic patterns that may be protective in the current context of the global obesity pandemic and its related critical health implications. Constitutional thinness stands out as a unique model questioning basic dogmatic knowledge about energy balance and metabolism.
Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV — CDC Recommendations, United States, 2025
Authors: Mary R. Tanner, Jesse G. O’Shea, Katrina M. Byrd, Marie Johnston, Gema G. Dumitru, John N. Le, Allison Lale, Kathy K. Byrd, Preetam Cholli, Emiko Kamitani, Weiming Zhu, Karen W. Hoover, Athena P. Kourtis
Journal: MMWR Recommendations and Reports (2025)

Nonoccupational postexposure prophylaxis (nPEP) for HIV is recommended when a nonoccupational (e.g., sexual, needle, or other) exposure to nonintact skin or mucous membranes that presents a substantial risk for HIV transmission has occurred, and the source has HIV without sustained viral suppression or their viral suppression information is not known. A rapid HIV test (also referred to as point-of-care) or laboratory-based antigen/antibody combination HIV test is recommended before nPEP initiation. Health care professionals should ensure the first dose of nPEP is provided as soon as possible, and ideally within 24 hours, but no later than 72 hours after exposure. The initial nPEP dose should not be delayed due to pending results of any laboratory-based testing, and the recommended length of nPEP course is 28 days. The recommendations in these guidelines update the 2016 nPEP guidelines (CDC. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV - United States, 2016. Atlanta, GA: US Department of Health and Human Services, CDC; 2017). These 2025 nPEP guidelines update recommendations and considerations for use of HIV nPEP in the United States to include newer antiretroviral (ARV) agents, updated nPEP indication considerations, and emerging nPEP implementation strategies. The guidelines also include considerations for testing and nPEP regimens for persons exposed who have received long-acting injectable ARVs in the past. Lastly, testing recommendations for persons who experienced sexual assault were updated to align with the most recent CDC sexually transmitted infection treatment guidelines. These guidelines are divided into two sections: Recommendations and CDC Guidance. The preferred regimens for most adults and adolescents are now bictegravir/emtricitabine/tenofovir alafenamide or dolutegravir plus (tenofovir alafenamide or tenofovir disoproxil fumarate) plus (emtricitabine or lamivudine). However, the regimen can be tailored to the clinical circumstances. Medical follow-up for persons prescribed nPEP also should be tailored to the clinical situation; recommended follow-up includes a visit at 24 hours (remote or in person) with a medical provider, and clinical follow-up 4-6 weeks and 12 weeks after exposure for laboratory testing. Persons initiating nPEP should be informed that pre-exposure prophylaxis for HIV (PrEP) can reduce their risk for acquiring HIV if they will have repeat or continuing exposure to HIV after the end of the nPEP course. Health care professionals should offer PrEP options to persons with ongoing indications for PrEP and create an nPEP-to-PrEP transition plan for persons who accept PrEP.
Pitavastatin-loaded procyanidins self-assembled nanoparticles alleviate advanced atherosclerosis via modulating macrophage efferocytosis and cholesterol efflux
Authors: Yizhou Wu, Hongyan Zhou, Hao Liu, Jiayao Hu, Yue Sun, Wei Yan, Chunyi Tong, Ying Kong, Bin Liu
Journal: Acta Pharmaceutica Sinica B (2025)
Understanding the Role of NOTCH2 Mutation in Centronuclear Myopathy
Authors: Youxi Lin, Hang Zhou, Wenjun Hu, Bo Gao, Tongzhou Liang, Jincheng Qiu, Pengfei Li, Yichen Que, Chipiu Wong, Xianjian Qiu, Zhihuai Deng, Huihong Shi, Song Liu, Jianan Chen, Nianchun Liao, Qihui Chen, Xiaojuan Li, Anjing Liang, Wenjie Gao, Dongsheng Huang
Journal: Molecular Therapy (2025)
LONG-TERM DEVELOPMENT OF 12- AND 15-YEAR-OLD OFFSPRING AFTER MATERNAL CANCER DIAGNOSIS DURING PREGNANCY: A PROSPECTIVE MULTICENTRE COHORT STUDY
Authors: E A Huis In 't Veld, I A Van Assche, K Van Calsteren, T Salaets, M G Slieker, E Cardonick, M van Grotel, M J Halaska, C Fontana, R Fruscio, J Lemiere, M van Gerwen, E M van Dijk-Lokkart, C L Lejeune, H van Tinteren, L Mertens, V Tomek, S Posthouwer, J Voigt, M M van den Heuvel-Eibrink, L Lagae, F Amant
Journal: Annals of Oncology (2025)
SARS-CoV-2 N protein induces hypokalemia in acute kidney injury mice via ENaC-dependent mechanism.
Authors: Dan-Dan Zhang, Yang Liu, Wenbiao Wang, Wenjing Wu, Junzhe Chen, Lin Wan, Liumei Wu, Xiao-Ru Huang, Hui-Yao Lan, Xueqing Yu
Journal: Molecular Therapy (2025)
Virus-mimicking nanoparticles potentiate in-situ cancer vaccines by reversing intratumoral DCs via stimulating cytosolic nucleic acid sensors
Authors: Ya Chu, Luyao Wang, Xi Huang, Cenxi Lao, Lin Luo, Jingyi Chen, Fangfei Jin, Lili Zhao, Kaiyuan Hu, Miao Lv, Xianjing Li, Yong Yang, Weijun Zhao, Wenguang Wang
Journal: Journal of Controlled Release (2025)
Maternal and child FUT2 secretor status affect gastroenteritis risk and gut microbiota composition in early life
Authors: Yang Luo, Casper-Emil T Pedersen, Anders Ulrik Eliasen, Nicklas Brustad, Liang Chen, Ni Wang, Jie Jiang, Urvish Trivedi, Xuanji Li, Søren Johannes Sørensen, Bo L Chawes, Jakob Stokholm, Jonathan Thorsen, Klaus Bønnelykke
Journal: Clinical Microbiology and Infection (2025)
Clinicopathologic Features, Molecular Landscape, and Prognostic Implications of Ovarian Low-Grade Serous Tumors with Histologic Transformation
Authors: M. Herman Chui, Eun-Young Kang, Ryan M. Kahn, Sarah Chiang, Qin Zhou, Alexia Iasonos, Beryl Manning-Geist, Pier Selenica, Arnaud Da Cruz Paula, Kara Long Roche, Britta Weigelt, Rachel N. Grisham
Journal: Clinical Cancer Research (2025)

Abstract Purpose: To characterize the clinicopathologic features, molecular genetic landscape, and clinical behavior of ovarian low-grade serous tumors with histologic transformation (LGS-HT) to indeterminate/high-grade carcinoma. Experimental Design: LGS-HTs were retrospectively identified from an institutional cohort of ovarian cancer patients and underwent central pathology re-review. Data on clinicopathologic characteristics, including age, stage, surgical outcomes, systemic treatments, and overall survival (OS) were collected. Immunohistochemical profiling and next-generation sequencing were performed. OS comparisons were performed with our institutional cohorts of ovarian low-grade serous carcinoma (LGSC, n=109) and high-grade serous carcinoma (HGSC, n=1672). Results: From 4371 ovarian serous cancers, 40 (0.9%) LGS-HTs were identified: 30 with synchronous low-grade and higher-grade tumor components at initial diagnosis (LGS-HT-Sync) and 10 with an ovarian low-grade serous neoplasm that recurred as a higher-grade carcinoma (LGS-HT-Metac). The most common somatic driver mutations included TP53 (38.5%), KRAS (21.8%), NF1 (15.6%), BRAF (15.6%) and NRAS (12.5%), with co-existing TP53 and RAS/RAF mutations in 18.8% of cases. Alterations of DNA damage response genes (BRCA2, PALB2, CHEK2, ATM, NBN, RECQL4) were identified in LGS-HTs lacking TP53 genetic alterations. LGS-HT-Sync was associated with poorer OS (median 59.7 months) compared to LGSC (median 105.4 months; p=0.026), and was similar to HGSC (median 48.8 months, p=0.61). Severe nuclear atypia and absence of RAS/RAF-driver mutations were significant adverse prognostic factors. Conclusions: LGS-HT exhibit both low-grade and high-grade morphologic and molecular features, representing an exception to the dualistic classification of ovarian serous neoplasms.
Medical Therapy for Acute Severe Ulcerative Colitis: A Systematic Review with Meta-analysis
Authors: Sudheer K Vuyyuru, Nader Shaban, Yuhong Yuan, Sailish Honap, Lotus Alphonsus, Theshani Amalka De Silva, Abdulaziz Alajmi, John K MacDonald, Christopher Ma, Parambir S Dulai, Laurent Peyrin Biroulet, Vipul Jairath
Journal: Clinical Gastroenterology and Hepatology (2025)
REPAIR: Reciprocal Assistance Imputation-Representation Learning for Glioma Diagnosis with Incomplete MRI Sequences
Authors: Chuixing Wu, Jincheng Xie, Fangrong Liang, Weixiong Zhong, Ruimeng Yang, Yuankui Wu, Tao Liang, Linjing Wang, Xin Zhen
Journal: Medical Image Analysis (2025)
Regulation of podocyte surface proteins by the enzyme A Disintegrin And Metalloproteinase 10 (ADAM10)
Authors: David Rosenbaum, Julia Reichelt, Simonas Gudaitis, Stine Kühne, Stephanie Zielinski, Desiree Loreth, Lukas Blume, Johannes Brand, Helga Vitzthum, Wiebke Sachs, Alina Lampert, Lisa Seipold, Matthias Voss, Catherine Meyer-Schwesinger, Paul Saftig
Journal: Kidney International (2025)
Practical Considerations for Using the TITE-BOIN Design to Handle Late-onset Toxicity or Fast Accrual in Phase I Trials
Authors: Kai Chen, Ting-Yu Chen, Yiming Zhang, Ruitao Lin, Ying Yuan
Journal: Clinical Cancer Research (2025)

Abstract Conducting phase I trials is particularly challenging when dealing with late-onset dose-limiting toxicity (DLT) or when patient accrual is rapid relative to the DLT assessment window. In such cases, a new cohort may be ready for enrollment before the DLT assessments are complete for the current cohort, complicating dose assignment decisions. The Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design was developed to address this issue by enabling real-time dose assignment for new cohorts, even when some enrolled patients’ DLT data are still pending. Upon reviewing trial protocols utilizing TITE-BOIN, we observed considerable variation on dosing decision criteria, ranging from no requirements to requiring that at least two third of enrolled patients’ DLT data should be available before enrolling the next cohort. This article systematically evaluates how such variation affects the operating characteristics of the TITE-BOIN design. Based on these evaluations, we generally recommend suspending accrual to allow longer safety follow-up if fewer than 51% of patients at the current dose have their DLT data ascertained, or if TITE-BOIN recommends dose escalation and the shortest follow-up time for pending patients at the current dose is less than 25% of the DLT assessment window. The rules should be further calibrated to suit specific trial considerations. Equipped with these rules, TITE-BOIN achieves similar accuracy in identifying the MTD and comparable safety to the fully staggered approach, while substantially reducing trial duration and increasing patient access by enabling real-time dose decisions when some patients' DLT data are still pending.
Uncovering hidden transmission pathways of Klebsiella pneumoniae: Is there a need to reevaluate the necessity for toilet disinfection?
Authors: Aila Caplunik-Pratsch, Livia Grancicova, Bärbel Kieninger, Anja Eichner, Wulf Schneider-Brachert, Anca Rath
Journal: Clinical Microbiology and Infection (2025)
Regulation of Adipose Tissue Metabolism During Fasting
Authors: Philip M.M. Ruppert, Sander Kersten
Journal: Annual Review of Nutrition (2025)

There is widespread interest in fasting as a therapeutic or preventive regimen for improving health. This review provides an overview of the impact of fasting on adipose tissue metabolism, with special attention to sexually dimorphic regulation. During fasting, the storage of triacylglycerols in adipose tissue is inhibited via suppression of the extracellular lipolytic enzyme lipoprotein lipase. By contrast, the breakdown of stored triacylglycerols and subsequent release of fatty acids and glycerol in the blood are enhanced via stimulation of the intracellular lipolytic enzymes adipose triglyceride lipase and hormone-sensitive lipase. These metabolic alterations are driven by changes in humoral factors such as insulin, glucagon, corticosteroids, growth hormone, and catecholamines, as well as by neuronal pathways, and are mediated by transcriptional and posttranscriptional regulation of critical enzymes. Overall, fasting profoundly influences adipose tissue metabolism and leads to mobilization of stored triacylglycerols and the repartitioning of circulating triacylglycerols to nonadipose tissues.
Pediatric Cancer Predisposition and Surveillance Update: Summary Perspective and Future Directions
Authors: Garrett M. Brodeur, Lisa R. Diller, Kim E. Nichols, Sharon E. Plon, Christopher C. Porter, David Malkin
Journal: Clinical Cancer Research (2025)

Abstract An increasing number of studies suggest that a significant proportion of children with cancer harbor an underlying predisposition to malignancy, and it is likely that this proportion will only increase. Targeted surveillance for these individuals would likely improve outcome. Historically however, for most predisposition syndromes, there were no standardized surveillance protocols for early detection of cancer in predisposed individuals. Therefore, the Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) convened a workshop in 2016 to develop consensus surveillance recommendations (published in 2017) for children and adolescents with the most common cancer predisposition syndromes. These recommendations provided a consistent approach for pediatric oncologists and other care providers to use as a plan for cancer surveillance in pediatric patients with these syndromes. We held a second workshop in 2023 to update recommendations based upon new data, as well as to add syndromes that were newly described or not addressed in the prior workshop. The resulting articles represent updated surveillance recommendations for currently recognized predisposition syndromes, organized along similar themes. We also address novel approaches to surveillance that are under investigation, as well as prospects for prevention trials for these high-risk populations.
CD19 CAR-T in relapsed t(8;21) AML: a single-center prospective phase II clinical trial
Authors: Jia Yin, Qing-Ya Cui, Hai-Ping Dai, Chang-Ju Qu, Zheng Li, Li-Qing Kang, Wei Cui, Xiao-Peng Tian, Xia-Ming Zhu, Lei Yu, De-Pei Wu, Xiao-Wen Tang
Journal: Journal of Hematology & Oncology (2025)
Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in <i>FLT3</i>-ITD Mutant/<i>TP53</i> Wild Type Acute Myeloid Leukemias
Authors: Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Koichi Iwanaga, Fumie Tanzawa, Masashi Numata, Dale L. Bixby, Harry P. Erba, Nikolai Podoltsev, Gary J. Schiller, Prasanna Kumar, Arnaud Lesegretain, Takeshi Isoyama, Takahiko Seki, Naval Daver, Michael Andreeff
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Acute myeloid leukemia (AML) is characterized by frequent mutation of fms-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. Here, we investigated the antileukemia efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3-internal tandem duplication (ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase 1 clinical trial. Methods: Preclinical studies used human and murine cell lines carrying FLT3-ITD, and/or TKD mutations and TP53 WT/knockdown, leukemia cell xenograft models and a PDX model. Assays were conducted using milademetan (DS-3032b) and murine-specific MDM2i (DS-5272). An open-label, phase 1, dose-escalation clinical trial (ClinicalTrials.gov NCT03552029) was conducted. Results: Dual inhibition of FLT3-ITD and MDM2 synergistically induced apoptosis in FLT3-ITD/TP53 WT AML and venetoclax-resistant cell lines, reduced tumor burden, and improved survival in xenograft and PDX models of FLT3-ITD AML. Phase 1 clinical data indicated favorable safety and tolerability for the Q/M combination treatment. Complete responses with incomplete hematologic recovery were achieved in 40% of relapsed/refractory AML patients. Unsupervised single-cell proteomics analysis showed Q/M treatment decreased the expression of prosurvival (pERK, pAKT, Mcl-1) proteins and activated protein signaling downstream of p53 including PUMA. YTHDF2 was increased post therapy in resistant cells. Q/M combination demonstrated higher activity in CD34+ versus CD34− leukemia blasts. Conclusions: Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3 targeting strategies for FLT3-mutant AML.