tbuckley/cabot-search huggingface dataset:
Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors
Authors: Leo Mascarenhas, Steven G. DuBois, Catherine M. Albert, Stefan Bielack, Daniel Orbach, Noah Federman, Birgit Geoerger, Ramamoorthy Nagasubramanian, Yizhou Zhang, Julia Chisholm, Soledad Gallego Melcon, Hiroaki Goto, Daniel A. Morgenstern, Cormac Owens, Alberto S. Pappo, Sébastien Perreault, Johannes H. Schulte, Neerav Shukla, Christian Michel Zwaan, Natascha Neu, Vadim Bernard-Gauthier, Esther De La Cuesta, Cornelis M. van Tilburg, Theodore W. Laetsch
Journal: Journal of Clinical Oncology (2025)

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma. This cohort included 91 patients (younger than 18 years) from two clinical trials: infantile fibrosarcoma (49), other soft tissue sarcomas or related mesenchymal tumors (41), and bone sarcoma (1). Treatment-related adverse events were of maximum grade 1 or 2 in 25% and 25% of patients, respectively. The overall response rate was 87% (95% CI, 78 to 93). In the wait-and-see analysis, 47 patients discontinued larotrectinib. Median time from discontinuation to disease progression was not reached. Sixteen patients had tumor progression during the wait-and-see period. All 16 patients resumed larotrectinib, and 15 (94%) achieved disease control, with 11 objective responses. Larotrectinib continues to demonstrate durable responses with favorable safety in children with TRK fusion sarcomas. Treatment discontinuation is feasible in select patients with objective response and clinical benefit noted in those who have disease progression after elective treatment discontinuation.
IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening.
Authors: Marcel F. Pohly, Kerstin Putzker, Sebastian Scheinost, Lena Ben Taarit, Tatjana Walther, Sandra Kummer, Tobias Wertheimer, Minqi Lin, Thi Huong Lan Do, Kristina Handler, Jan Michler, Jarno Kivioja, Karsten Bach, Samanta Kisele, James Kim, Sascha Dietrich, Beat Bornhauser, Wendy Wei-Lynn Wong, Burkhard Becher, Andreas Moor, Joe David Lewis, Xenia Maria Ficht, Junyan Lu, Wolfgang Huber, Thorsten Zenz
Journal: Blood (2025)
Babesiosis and Sickle Red blood Cells: Loss of Deformability, Heightened Osmotic fragility, and Hypervesiculation
Authors: Divya Beri, Marilis A Rodriguez, Manpreet Singh, Daniel McLaughlin, Yunfeng Liu, Hui Zhong, Avital Mendelson, Xiuli An, Deepa G Manwani, Karina Yazdanbakhsh, Cheryl A Lobo
Journal: Blood (2025)

Babesiosis in sickle cell disease (SCD) is marked by severe anemia but the underlying red blood cell (RBC) rheological parameters remain largely undefined. Here, we describe altered RBC deformability from both primary (host RBC sickle hemoglobin mediated) and secondary changes (Babesia parasite infection mediated) to the RBC membrane using wild type AA, sickle trait AS and sickle SS RBCs. Our ektacytometry (LORRCA) analysis demonstrates that the changes in the host RBC bio-mechanical properties, pre- and post- Babesia infection, reside on a spectrum of severity, with wild type infected AA cells, despite showing a significant reduction of deformability under both shear and osmolarity gradients, exhibiting only a mild phenotype; compared to infected AS RBCs which show median changes in deformability and infected SS RBCs which exhibit the most dramatic impact of infection on cellular rheology, including an increase in Point of Sickling values. Further, using Image stream cytometric technology to quantify changes in cellular shape and area along with a tunable resistive pulse sensor to measure release of extra-cellular vesicles (EV) from these host RBCs, before and after infection, we offer a potential mechanistic basis for this extreme SS RBC rheologic profile, which include enhanced sickling rates and osmotic fragility, loss of RBC surface area and hypervesiculation in infected SS host RBCs. These results underly the importance of understanding the impact of intra-erythrocytic parasitic infections of SCD RBCs, especially on their cellular membranes and studying the mechanisms that lead to hyper hemolysis and extreme anemia in the SCD patient population.
Advances in RNA editing in hematopoiesis and associated malignancies
Authors: Shuangshuang Pu, Tao Cheng, Hui Cheng
Journal: Blood (2025)

Adenosine-to-inosine (A-to-I) RNA editing is a prevalent RNA modification essential for cell survival. The process is catalyzed by the Adenosine Deaminase Acting on RNA (ADAR) enzyme family that converts adenosines in double-stranded RNAs (dsRNAs) into inosines, which are read as guanosines during translation. Deep sequencing has helped to reveal that A-to-I editing occurs across various types of RNAs to affect their functions. RNA editing detection is now so sophisticated that we can achieve a high level of accuracy and sensitivity to identify low abundance edited events. Consequently, A-to-I editing has been implicated in various biological processes, including immune and stress responses, cancer progression and stem cell fate determination. In particular, a crucial role for this process has been recently reported in hematopoietic cell development and hematologic malignancy progression. Results from genetic mouse models have demonstrated the impact of ADARs' catalytic activity on hematopoietic cells, complemented by insights from human cell studies. Meanwhile clinical studies have implicated ADAR enzymes and RNA editing events in hematologic malignancies and highlighted their potential as prognostic indicators. In this review, we outline the regulatory mechanisms of RNA editing in both normal hematopoiesis and hematologic malignancies. We then speculate on how targeting ADAR expression and site-specific RNA substrates might serve as a therapeutic avenue for affected patients.
Multimodal machine learning enables AI chatbot to diagnose ophthalmic diseases and provide high-quality medical responses
Authors: Ruiqi Ma, Qian Cheng, Jing Yao, Zhiyu Peng, Mingxu Yan, Jie Lu, Jingjing Liao, Lejin Tian, Wenjun Shu, Yunqiu Zhang, Jinghan Wang, Pengfei Jiang, Weiyi Xia, Xiaofeng Li, Lu Gan, Yue Zhao, Jiang Zhu, Bing Qin, Qin Jiang, Xiawei Wang, Xintong Lin, Haifeng Chen, Weifang Zhu, Dehui Xiang, Baoqing Nie, Jingtao Wang, Jie Guo, Kang Xue, Hongguang Cui, Jinwei Cheng, Xiangjia Zhu, Jiaxu Hong, Fei Shi, Rui Zhang, Xinjian Chen, Chen Zhao
Journal: npj Digital Medicine (2025)

Chatbot-based multimodal AI holds promise for collecting medical histories and diagnosing ophthalmic diseases using textual and imaging data. This study developed and evaluated the ChatGPT-powered Intelligent Ophthalmic Multimodal Interactive Diagnostic System (IOMIDS) to enable patient self-diagnosis and self-triage. IOMIDS included a text model and three multimodal models (text + slit-lamp, text + smartphone, text + slit-lamp + smartphone). The performance was evaluated through a two-stage cross-sectional study across three medical centers involving 10 subspecialties and 50 diseases. Using 15640 data entries, IOMIDS actively collected and analyzed medical history alongside slit-lamp and/or smartphone images. The text + smartphone model showed the highest diagnostic accuracy (internal: 79.6%, external: 81.1%), while other multimodal models underperformed or matched the text model (internal: 69.6%, external: 72.5%). Moreover, triage accuracy was consistent across models. Multimodal approaches enhanced response quality and reduced misinformation. This proof-of-concept study highlights the potential of chatbot-based multimodal AI for self-diagnosis and self-triage. (The clinical trial was registered on June 26, 2023, on ClinicalTrials.gov under the registration number NCT05930444.).
Small molecule modulators of B56-PP2A restore 4E-BP function to suppress eIF4E-dependent translation in cancer cells
Authors: Michelle A. Lum, Kayla A. Jonas, Shreya Parmar, Adrian R. Black, Caitlin M. O'Connor, Stephanie Dobersch, Naomi Yamamoto, Tess M. Robertson, Aidan Schutter, Miranda Giambi, Rita A. Avelar, Analisa DiFeo, Nicholas T. Woods, Sita Kugel, Goutham Narla, Jennifer D. Black
Journal: Journal of Clinical Investigation (2025)

Dysregulated eIF4E-dependent translation is a central driver of tumorigenesis and therapy resistance. eIF4E binding proteins (4E-BP1/2/3) are major negative regulators of eIF4E-dependent translation that are inactivated in tumors through inhibitory phosphorylation or downregulation. Previous studies have linked PP2A phosphatase(s) to activation of 4E-BP1. Here, we leveraged biased small molecule activators of PP2A (SMAPs) to explore the role of B56-PP2A(s) in 4E-BP regulation and the potential of B56-PP2A activation for restoring translational control in tumors. SMAP treatment promoted PP2A-dependent hypophosphorylation of 4E-BP1/2, supporting a role for B56-PP2As (e.g., B56α-PP2A) as 4E-BP phosphatases. Unexpectedly, SMAPs induced transcriptional upregulation of 4E-BP1 through a B56 PP2A→TFE3/TFEB→ATF4 axis. Cap-binding and co-immunoprecipitation assays showed that B56-PP2A(s) activation blocks assembly of the eIF4F translation initiation complex, and cap-dependent translation assays confirmed the translation inhibitory effects of SMAPs. Thus, B56-PP2A(s) orchestrate a translation repressive program involving transcriptional induction and activation of 4E-BP1. Notably, SMAPs promoted 4E-BP1-dependent apoptosis in tumor cells and potentiated 4E-BP1 function in the presence of ERK or mTOR inhibitors, agents that rely on inhibition of eIF4E-dependent translation for antitumor activity. These findings, combined with the ability of SMAPs to regulate 4E-BP1 in vivo, highlight the potential of PP2A activators for cancer therapy and overcoming therapy resistance.
Adopting a complex systems approach to functional ageing: bridging the gap between gerontological theory and empirical research
Authors: Almar A L Kok, Martijn Huisman, Erik J Giltay, Gabriela Lunansky
Journal: The Lancet Healthy Longevity (2025)

Functional ageing, related to but distinct from biological and environmental systems, is defined as the changes in physical, psychological, cognitive, and social functioning, as well as behavioural factors of individuals as they age. In this Personal View, we propose that a complex systems perspective to functional ageing can show how outcomes such as quality of life and longevity, and success in prevention and treatment, emerge from dynamic interactions among these domains, rather than from single causes. We support this view in three ways. First, we explain how three key principles of complex systems science-namely, resilience, non-linearity, and heterogeneity-apply to functional ageing. Second, we show how established gerontological theories and geriatric models align with these principles. Third, we illustrate the use of novel methodological tools available from complex systems science for studying functional ageing. Finally, we offer a glossary of key concepts and recommendations for researchers to adopt this perspective in future studies on functional ageing.
Clinical Practices and Educational Interests of Dermatologists in Caribbean Countries
Authors: Chrislene Olukoga, Antonella Tosti, Jonathan Ho, Brian W Morrison
Journal: British Journal of Dermatology (2025)

This manuscript holds particular significance for a global health and equity dermatology journal as it addresses critical considerations for continuing medical education and relevant epidemiology of the Caribbean. Our survey’s aim was to determine the perspective and needs of Caribbean dermatologists to better support this community. Our focus was to identify common conditions seen in clinical practice and the educational interests of the group. We hope our data helps guide local and international efforts to identify and address the needs of this diverse and unique region.
Lipidome disruption in Alzheimer’s disease brain: detection, pathological mechanisms, and therapeutic implications
Authors: Sijia He, Ziying Xu, Xianlin Han
Journal: Molecular Neurodegeneration (2025)

Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to the involvement of lipid dysregulation in the development of AD. Nevertheless, the precise lipidomic landscape and the mechanistic roles of lipids in disease pathology remain poorly understood. This review aims to highlight the significance of lipidomics and lipid-targeting approaches in the diagnosis and treatment of AD. We summarized the connection between lipid dysregulation in the human brain and AD at both genetic and lipid species levels. We briefly introduced lipidomics technologies and discussed potential challenges and areas of future advancements in the lipidomics field for AD research. To elucidate the central role of lipids in converging multiple pathological aspects of AD, we reviewed the current knowledge on the interplay between lipids and major AD features, including amyloid beta, tau, and neuroinflammation. Finally, we assessed the progresses and obstacles in lipid-based therapeutics and proposed potential strategies for leveraging lipidomics in the treatment of AD.
Machine learning meta-analysis identifies individual characteristics moderating cognitive intervention efficacy for anxiety and depression symptoms
Authors: Thalia Richter, Reut Shani, Shachaf Tal, Nazanin Derakshan, Noga Cohen, Philip M. Enock, Richard J. McNally, Nilly Mor, Shimrit Daches, Alishia D. Williams, Jenny Yiend, Per Carlbring, Jennie M. Kuckertz, Wenhui Yang, Andrea Reinecke, Christopher G. Beevers, Brian E. Bunnell, Ernst H. W. Koster, Sigal Zilcha-Mano, Hadas Okon-Singer
Journal: npj Digital Medicine (2025)
Fasting-mimicking diet-enriched<i>Bifidobacterium pseudolongum</i>suppresses colorectal cancer by inducing memory CD8<sup>+</sup>T cells
Authors: Ke Nan, Ziwen Zhong, Ying Yue, Yang Shen, Hao Zhang, Zhiqiang Wang, Kameina Zhuma, Baichao Yu, Ying Fu, Luman Wang, Xingfeng Sun, Mengdi Qu, Zhaoyuan Chen, Miaomiao Guo, Jie Zhang, Yiwei Chu, Ronghua Liu, Changhong Miao
Journal: Gut (2025)

Background Fasting-mimicking diet (FMD) boosts the antitumour immune response in patients with colorectal cancer (CRC). The gut microbiota is a key host immunity regulator, affecting physiological homeostasis and disease pathogenesis. Objective We aimed to investigate how FMD protects against CRC via gut microbiota modulation. Design We assessed probiotic species enrichment in FMD-treated CRC mice using faecal metagenomic sequencing. The candidate species were verified in antibiotic-treated conventional and germ-free mouse models. Immune landscape alterations were evaluated using single-cell RNA sequencing and multicolour flow cytometry. The microbiota-derived antitumour metabolites were identified using metabolomic profiling. Results Faecal metagenomic profiling revealed Bifidobacterium pseudolongum enrichment in FMD-treated CRC mice. B. pseudolongum mediates the FMD antitumour effects by increasing the tissue-resident memory CD8 + T-cell (TRM) population in CRC mice. The level of L-arginine, a B. pseudolongum functional metabolite, increased in FMD-treated CRC mice; furthermore, L-arginine induced the TRM phenotype in vivo and in vitro. Mechanistically, L-arginine is transported by the solute carrier family 7-member 1 (SLC7A1) receptor in CD8 + T cells. Both FMD and B. pseudolongum improved anti-CTLA-4 efficacy in the orthotopic mouse CRC model. In FMD-treated patients with CRC, the CD8 + TRM cell number increased as B. pseudolongum and L-arginine accumulated. The abundance of CD8 + TRM cells and B. pseudolongum was associated with a better prognosis in patients with CRC. Conclusion B. pseudolongum contributes to the FMD antitumour effects in CRC by producing L-arginine. This promotes CD8 + T-cell differentiation into memory cells. B. pseudolongum administration is a potential CRC therapeutic strategy.
Respiratory syncytial virus vaccination in older adults and patients with chronic disorders: A position paper from the Portuguese Society of Pulmonology, the Portuguese Association of General and Family Medicine, the Portuguese Society of Cardiology, the Portuguese Society of Infectious Diseases and Clinical Microbiology, the Portuguese Society of Endocrinology, Diabetes and Metabolism, and the Portuguese Society of Internal Medicine
Authors: Tiago Alfaro, Filipe Froes, Cláudia Vicente, Rui Costa, Cristina Gavina, Rui Baptista, António Maio, Saraiva da Cunha, João Sérgio Neves, Pedro Leuschner, Sofia Duque, Paula Pinto
Journal: Pulmonology (2025)

Background Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection, hospitalisation and death in adults.
A randomised non-inferiority trial investigating antibiotic adjustments based on blood culture in acute cholangitis
Authors: Tae Seung Lee, Jin Ho Choi, Jae Min Lee, Hankyu Jeon, Woo Hyun Paik, Kwang Bum Cho, Yoon Suk Lee, Joung-Ho Han, Jong Seok Joo, Min Kyu Jung, Jonghyun Lee, Dong-Won Ahn, Jin Myung Park, Jaihwan Kim, Jongchan Lee, Eun Ae Cho, Sang Hyub Lee
Journal: Clinical Microbiology and Infection (2025)
Long-Term Risks of Living Kidney Donation: State of the Evidence and Strategies to Resolve Knowledge Gaps
Authors: Vidya A. Fleetwood, Ngan N. Lam, Krista L. Lentine
Journal: Annual Review of Medicine (2025)

Living-donor kidney transplantation is the preferred treatment for kidney failure. In the United States, rates of living kidney donation have been stagnant, which is partly related to concerns over medical and financial risks. Recent research has better characterized the risks of living kidney donation, although the field is limited by a lack of robust registries. Available evidence supports small increases in the risks of end-stage kidney disease and hypertensive disorders of pregnancy in living donors. For most donors, the 15-year risk of kidney failure is less than 1%, but for certain populations this risk may be higher. New tools such as genetic kidney disease panels may assist with risk stratification. Living kidney donors generally have similar or improved psychosocial health following donation compared to prior to donation and nondonor experience. Postdonation care allows for preventative care measures to mitigate risk as well as ongoing surveillance of donor outcomes. Continuing efforts to capture and report outcomes of living donation are necessary to safely expand living donation worldwide.
Underrepresentation of Climate Change and Sustainability Manuscripts in High Impact Dermatology Journals
Authors: Eugene Tan, Misha Rosenbach
Journal: British Journal of Dermatology (2025)

Earth’s changing climate is impacting the health of people worldwide. Dermatology is particularly impacted by climate change due to the skin’s direct contact with the environment. The majority of physicians do not feel prepared to address climate change's impact on health or to take action
Dense stroma activates the TGF-β1/FBW7 axis to induce metabolic subtype switching in pancreatic cancer
Authors: Zeyin Rong, Jianhui Yang, Jiang Liu, Qingcai Meng, Jie Hua, Zhen Tan, Bo Zhang, Yuan Liu, Qiong Du, Wei Wang, Xianjun Yu, Jin Xu, Chen Liang
Journal: International Journal of Surgery (2025)

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Although several chemotherapy regimens have been developed over the past decades, few targeted therapies have shown a significant improvement in overall survival, partly due to the identification of PDAC as a single disease. Methods: Combining metabolomic analysis and immunohistochemistry staining with Oil Red O staining, analysis for the oxygen consumption rate and extracellular acidification rate, we stratified pancreatic cancer cells into two subtypes. The impact of transforming growth factor β (TGF-β)-1/F-box and WD repeat domain-containing 7 (FBW7) on the switch of the metabolic subtype was further validated in vitro and in vivo . Finally, cell growth was performed to identify the TGF-β1/FBW7 ratio as a molecular marker for gemcitabine resistance. Results: PDAC was stratified into the glycolytic subtype and lipogenic subtype. Furthermore, pancreatic cancer-associated fibroblasts-derived TGF-β1 and tumor cell-derived FBW7 were demonstrated to co-determine the metabolic phenotypes in PDAC. A high TGF-β1/FBW7 ratio always represented the glycolytic PDAC with dense stroma. This subtype of PDAC exhibited mesenchymal features and was predictive of unfavorable prognoses, despite being more sensitive than the lipogenic subtype to combination treatment with gemcitabine and an inhibitor of TGF-β receptor I (TGF-βR1). Conclusions: The TGF-β1/FBW7 ratio could be regarded as a molecular marker of metabolic phenotypes in PDAC and may contribute to the development of effective therapeutic strategies to improve the survival of PDAC patients.
Approach to Therapy for Chronic Pouchitis
Authors: Maia Kayal, Brigid Boland
Journal: Annual Review of Medicine (2025)

Chronic pouchitis (CP) occurs in approximately 20% of patients with ulcerative colitis after total proctocolectomy with ileal pouch anal anastomosis and is categorized as antibiotic dependent, antibiotic refractory, or Crohn's disease–like. The management of CP is challenging because of limited evidence and few randomized controlled trials. In this review, we discuss the medical management of CP and its supporting data delineated by type of therapy.