tbuckley/cabot-search huggingface dataset:
SNHG17 Reprograms Energy Metabolism of Breast Cancer by Activating Mitochondrial DNAs Transcription
Authors: Lin Gao, Jingyi Huang, Jinquan Xia, Pan Zhao, Shaowei Dong, Wei Jiang, Qianqian Zhou, Zhenglei Xu, Hui Luo, Wenbin Zhou, Jichao Sun, Guangsuo Wang, Qingshan Geng, Jigang Wang, Chang Zou
Journal: Cancer Research (2025)

Abstract In most solid tumors, cellular energy metabolism is primarily dominated by aerobic glycolysis, which fulfills the high demand for biomacromolecules at the expense of reduced ATP production efficiency. Elucidation of the mechanisms by which rapidly proliferating malignant cells acquire sufficient energy in this state of inefficient ATP production from glycolysis could enable development of metabolism targeted therapeutic strategies. In this study, we observed a significant association between elevated expression levels of the long non-coding RNA (lncRNA) SNHG17 and unfavorable prognosis in breast cancer (BCa). SNHG17 promoted BCa cell proliferation by augmenting mitochondrial ATP production. Mechanistically, SNHG17 directly interacted with the p65 subunit of NF-κB and phosphorylated p65 at the threonine 505 site. SNHG17 bound to p65 at its truncated loop2 site, recruited p65 to mitochondria, and co-regulated the transcriptional activation of mitochondrial DNA to promote ATP production. Accordingly, targeting SNHG17 with an anti-sense oligonucleotide (ASO) significantly reduced BCa tumor growth both in vitro and in vivo. Overall, these results established a role for SNHG17 in promoting BCa progression by increasing ATP production and provided insight into the reprogramming of energy metabolism in solid tumors.
SMAD4 and KRAS Status Shape Cancer Cell-Stromal Crosstalk and Therapeutic Response in Pancreatic Cancer
Authors: Eloise G. Lloyd, Muntadher Jihad, Judhell S. Manansala, Wenlong Li, Priscilla S. W. Cheng, Gianluca Mucciolo, Marta Zaccaria, Sara Pinto Teles, Joaquín Araos Henríquez, Sneha Harish, Rebecca Brais, Sally Ashworth, Weike Luo, Paul M. Johnson, Lisa Veghini, Mireia Vallespinos, Vincenzo Corbo, Giulia Biffi
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on pre-clinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase understanding of malignant cell-stroma crosstalk in PDAC. Here, we used single-cell RNA-sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V in which Smad4 was wild-type or deleted. KrasG12D Smad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared to KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype impacts cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy.
PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers
Authors: Ying He, Wei Li, Meiling Zhang, Hui Wang, Peilu Lin, Ying Yu, Bin Huang, Meng Hao, Jianuo He, Weiyao Kong, Dan Luo, Tengteng Xu, Jiaqi Wang, Ying Huang, Qinwen Zhao, Ying Liu, Jie Zhang, Yong Nian, Lei Zhang, Bo Zhu, Chengqian Yin
Journal: The Journal of Experimental Medicine (2025)

BRAF mutations drive initiation and progression of various tumors. While BRAF inhibitors are effective in BRAF-mutant melanoma patients, intrinsic or acquired resistance to these therapies is common. Here, we identify non–receptor-type protein tyrosine phosphatase 23 (PTPN23) as an alternative effective target in BRAF-mutant cancer cells. Silencing PTPN23 selectively kills BRAF-mutant melanoma cells but not those with wild-type BRAF. Mechanistically, PTPN23, a catalytically inactive phosphatase, intriguingly induces WNK3-mediated phosphorylation of phosphoinositide 3-kinase class II alpha (PI3KC2α) at serine 329, enhancing its catalytic activity. This activation promotes production of PI(3,4)P2 and subsequent AKT2 activation at endosomes to support cell survival. Genetic or pharmacological targeting of the PTPN23-PI3KC2α-AKT2 signaling axis, alone or in combination with BRAF inhibitors, effectively inhibits the growth of BRAF-mutant melanoma and other cancers in vitro and in vivo. We also demonstrate that melanocyte-specific knockout of PTPN23 significantly inhibits BRAFV600E-driven melanomagenesis. Altogether, our findings demonstrate that targeting PTPN23/PI3KC2α offers a new and viable therapeutic strategy for BRAF-mutant cancers.
The XCL1–XCR1 axis supports intestinal tissue residency and antitumor immunity
Authors: Amir Ferry, Kianoosh M. Mempel, Alexander Monell, Miguel Reina-Campos, Nicole E. Scharping, Maximilian Heeg, Kennidy K. Takehara, Shiruyeh Schokrpur, Ning Kuo, Robert Saddawi-Konefka, J. Silvio Gutkind, Ananda W. Goldrath
Journal: The Journal of Experimental Medicine (2025)

Tissue-resident memory T cells (TRM) provide frontline protection against pathogens and emerging malignancies. Tumor-infiltrating lymphocytes (TIL) with TRM features are associated with improved clinical outcomes. However, the cellular interactions that program TRM differentiation and function are not well understood. Using murine genetic models and targeted spatial transcriptomics, we found that the CD8+ T cell–derived chemokine XCL1 is critical for TRM formation and conventional DC1 (cDC1) supported the positioning of intestinal CD8+ T cells during acute viral infection. In tumors, enforced Xcl1 expression by antigen-specific CD8+ T cells promoted intratumoral cDC1 accumulation and T cell persistence, leading to improved overall survival. Notably, analysis of human TIL and TRM revealed conserved expression of XCL1 and XCL2. Thus, we have shown that the XCL1–XCR1 axis plays a non-cell autonomous role in guiding intestinal CD8+ TRM spatial differentiation and tumor control.
NETs persisting in vasculature undergo self-renewal with consequences for subsequent infection: a mouse model study
Authors: Michal Santocki, Anna Such, Dominika Drab, Gabriela Burczyk, Elzbieta Kolaczkowska
Journal: Blood (2025)

While key for pathogen immobilization, neutrophil extracellular traps (NETs) often cause severe bystander cell/tissue damage. This was hypothesized to depend on their prolonged presence in the vasculature, leading to cytotoxicity. Imaging of NETs (histones, neutrophil elastase, extracellular DNA) with intravital microscopy in blood vessels of mouse livers in a pathogen-replicative-free environment (endotoxemia) led to detection of NET proteins attached to the endothelium for months despite the early disappearance of extracellular DNA. Intravascular liver macrophages (Kupffer cells) and neutrophils, but not monocytes, were involved in NET removal. They utilized scavenger receptors (SR-A) and Toll-like receptors (TLR2/4) to recognize NET components. Despite the absence of further stimuli, 14 days later a second wave of NET formation occurred, initiated by remnants of NETs from the first wave. The second burst of NET production was triggered by histones, which induced an inflammatory milieu (IL-1β) and activated platelets and coagulation-related events, including factor VII-activating protease (FSAP) activity. This in turn recruited and activated neutrophils to release the second wave of NETs. In peptidyl arginine deiminase (PAD4)-deficient mice, not forming NETs, inflammation and liver damage were reduced in comparison to their wild-type counterparts. When mice were challenged with methicillin-resistant Staphylococcus aureus (MRSA) 14 or 165 days post the second NETs, the course of infection/injury was diminished and exacerbated, respectively. Our study demonstrates that the complete removal of NETs in vivo takes much longer than hypothesized, and a vicious cycle of NET formation/disassembly impacts subsequent infection, depending on the time elapsed since its occurrence.
FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human hematopoietic stem cells
Authors: Joana L Araújo, Elvin Wagenblast, Veronique Voisin, Jessica McLeod, Olga I. Gan, Suraj Bansal, Liqing Jin, Amanda Mitchell, Blaise Gratton, Sarah Kristen Cutting, Andrea Arruda, Monica Doedens, Anthea Travas, Dennis Dong Hwan Kim, Jose-Mario Capo-Chichi, Sagi Abelson, Mark D Minden, Jean CY Wang, Manuel A Sobrinho-Simões, Perpétua Pinto-do-Ó, Eric R Lechman, John E. Dick
Journal: Blood (2025)
Aging platelets shift their hemostatic properties to inflammatory functions
Authors: Afra Anjum, Magdalena Mader, Shaan Mahameed, Abhinaya Muraly, Frederik Denorme, Fabian P. Kliem, Dario Rossaro, Sezer Akgöl, Lea Di Fina, Maité Mulkers, Lisa Sophia Laun, Lukas Li, Nadja Kupper, Keyang Yue, Marie-Louise Hoffknecht, Anastassia Akhalkatsi, Quentin Loew, Joachim Pircher, Raphael Escaig, Erwin F. Strasser, Christian Wichmann, Kami Pekayvaz, Bernhard Nieswandt, Christian Schulz, Maria S. Robles, Rainer Kaiser, Steffen Massberg, Robert A. Campbell, Leo Nicolai
Journal: Blood (2025)

Platelets are crucial players in hemostasis and thrombosis, but also contribute to immune regulation and host defense, using different receptors, signaling pathways and effector functions, respectively. Whether distinct subsets of platelets specialize in these diverse tasks is insufficiently understood. Here, we employed an in vivo pulse-labelling method in Mus musculus models for tracking in vivo platelet ageing and its functional implications. Using in vitro and in vivo assays, we reveal that young, reticulated platelets show heightened responses in the setting of clot formation, with corresponding, increased responses to agonists, adhesion, and retractile function. Unexpectedly, aged platelets lose their hemostatic proficiency but are more prone to react to inflammatory challenge: compared to reticulated platelets, this cohort was more likely to form platelet-leukocyte aggregates and showed increased adhesion to neutrophils in vitro, as well as enhanced bactericidal function. In vivo, this was reflected in increased pulmonary recruitment of aged platelets in an acute lung injury model. Proteomic analyses confirmed upregulation of immune pathways in this cohort, including enhanced procoagulant function. In mouse models of prolonged platelet half-life, this resulted in increased pulmonary leukocyte infiltration and inflammation upon acute lung injury. Similarly, human platelet concentrates decreased their hemostatic function and elevated their putative immunomodulatory potential in vitro over time, and in a mouse model of platelet transfusion, aged platelet concentrates resulted in augmented inflammation. In summary, we show that platelets exhibit age-dependent phenotypic shifts allowing them to fulfill their diverse tasks in the vasculature. As functional alterations of aging platelets extend to platelet concentrates, this may hold important implications for transfusion medicine.
Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells
Authors: Charlotte Rothfuß, Tobias Baumann, Sainitin Donakonda, Bettina Brauchle, Anetta Marcinek, Christian Urban, Julia Mergner, Anna-Marie Pedde, Anna Hirschberger, Christina Krupka, Anne-Sophie Neumann, Gerulf Hänel, Camilla Merten, Rupert Öllinger, Judith S. Hecker, Tanja Bauer, Christian Rudolf Schmid, Katharina S Götze, Jennifer Altomonte, Veit L. Bücklein, Roland Jacobs, Roland Rad, Corinna Dawid, Luca Simeoni, Burkhart Schraven, Andreas Pichlmair, Marion Subklewe, Percy Alexander Knolle, Jan P Böttcher, Bastian Höchst
Journal: Blood (2025)

Loss of anticancer NK cell function in AML patients is associated with fatal disease progression and remains poorly understood. Here, we demonstrate that AML-blasts isolated from patients rapidly inhibit NK cell function and escape NK cell-mediated killing. Transcriptome analysis of NK cells exposed to AML-blasts revealed increased CREM expression and transcriptional activity, indicating enhanced cAMP signalling, confirmed by uniform production of the cAMP-inducing prostanoid PGE2 by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE2 induced a blockade of LCK-ERK signalling that is crucial for NK cell activation, indicating a two-layered escape of AML-blasts with low expression of NK cell-activating ligands and inhibition of NK cell signalling. To evaluate the therapeutic potential to target PGE2 inhibition, we combined Fcg-receptor-mediated activation with the prevention of inhibitory PGE2-signalling. This rescued NK cell function and restored the killing of AML-blasts. Thus, we identify the PGE2-LCK signalling axis as the key barrier for NK cell activation in two-layered immune escape of AML-blasts that can be targeted for immune therapy to reconstitute anti-cancer NK cell immunity in AML patients.
Bacterial extracellular vesicles in the initiation, progression and treatment of atherosclerosis
Authors: Yuling Lin, Jingyu Wang, Fan Bu, Ruyi Zhang, Junhui Wang, Yubing Wang, Mei Huang, Yiyi Huang, Lei Zheng, Qian Wang, Xiumei Hu
Journal: Gut Microbes (2025)

Atherosclerosis is the primary cause of cardiovascular and cerebrovascular diseases. However, current anti-atherosclerosis drugs have shown conflicting therapeutic outcomes, thereby spurring the search for novel and effective treatments. Recent research indicates the crucial involvement of oral and gastrointestinal microbiota in atherosclerosis. While gut microbiota metabolites, such as choline derivatives, have been extensively studied and reviewed, emerging evidence suggests that bacterial extracellular vesicles (BEVs), which are membrane-derived lipid bilayers secreted by bacteria, also play a significant role in this process. However, the role of BEVs in host-microbiota interactions remains insufficiently explored. This review aims to elucidate the complex communication mediated by BEVs along the gut-heart axis. In this review, we summarize current knowledge on BEVs, with a specific focus on how pathogen-derived BEVs contribute to the promotion of atherosclerosis, as well as how BEVs from gut symbionts and probiotics may mitigate its progression. We also explore the potential and challenges associated with engineered BEVs in the prevention and treatment of atherosclerosis. Finally, we discuss the benefits and challenges of using BEVs in atherosclerosis diagnosis and treatment, and propose future research directions to address these issues.
CpG island methylator phenotype classification improves risk assessment in pediatric T-cell Acute Lymphoblastic Leukemia
Authors: Fernanda Schäfer Hackenhaar, Nina Refhagen, Melanie M Hagleitner, Frank N. van Leeuwen, Hanne Vibeke Marquart, Hans Ole Madsen, Mattias Landfors, Pia Osterman, Kjeld Schmiegelow, Trond Flaegstad, Olafur G Jonsson, Jukka Kanerva, Jonas Abrahamsson, Mats Heyman, Ulrika Noren-Nystrom, Magnus Hultdin, Sofie Degerman
Journal: Blood (2025)
The Pharmacology of Vitamin C
Authors: Jens Lykkesfeldt, Anitra C Carr, Pernille Tveden-Nyborg
Journal: Pharmacological Reviews (2025)

Ascorbic acid, the reduced form of vitamin C, is a ubiquitous small carbohydrate. Despite decades of focused research, new metabolic functions of this universal electron donor are still being discovered and add to the complexity of our view of vitamin C in human health. Although praised as an unsurpassed water-soluble antioxidant in plasma and cells, the most interesting functions of vitamin C seem to be its roles as specific electron donor in numerous biological reactions ranging from the well-known hydroxylation of proline to cofactor for the epigenetic master regulators ten-eleven translocation enzymes and Jumonji domain-containing histone-lysine demethylases. Some of these functions may have important implications for disease prevention and treatment and have spiked renewed interest in, eg, vitamin C's potential in cancer therapy. Moreover, some fundamental pharmacokinetic properties of vitamin C remain to be established including if other mechanisms than passive diffusion governs the efflux of ascorbate anions from the cell. Taken together, there still seems to be much to learn about the pharmacology of vitamin C and its role in health and disease. This review explores new avenues of vitamin C and integrates our present knowledge of its pharmacology. SIGNIFICANCE STATEMENT: Vitamin C is involved in multiple biological reactions of which most are essential to human health. Hundreds of millions of people are considered deficient in vitamin C according to accepted guidelines, but little is known about the long-term consequences. Although the complexity of vitamin C's physiology and pharmacology has been widely disregarded in clinical studies for decades, it seems clear that a deeper understanding of particularly its pharmacology holds the key to unravel and possibly exploit the potential of vitamin C in disease prevention and therapy.
X-Mapper: fast and accurate sequence alignment via gapped x-mers
Authors: Jeffry M. Gaston, Eric J. Alm, An-Ni Zhang
Journal: Genome biology (2025)

Abstract Sequence alignment is foundational to many bioinformatic analyses. Many aligners start by splitting sequences into contiguous, fixed-length seeds, called k-mers. Alignment is faster with longer, unique seeds, but more accurate with shorter seeds avoiding mutations. Here, we introduce X-Mapper, aiming to offer high speed and accuracy via dynamic-length seeds containing gaps, called gapped x-mers. We observe 11–24-fold fewer suboptimal alignments analyzing a human reference and 3–579-fold lower inconsistency across bacterial references than other aligners, improving on 53% and 30% of reads aligned to non-target strains and species, respectively. Other seed-based analysis algorithms might benefit from gapped x-mers too.
Cyclic nucleotide phosphodiesterases as drug targets
Authors: Michy P. Kelly, Viacheslav O. Nikolaev, Leila Gobejishvili, Claire Lugnier, Christian Hesslinger, Peter Nickolaus, David A. Kass, Walma Pereira de Vasconcelos, Rodolphe Fischmeister, Stefan Brocke, Paul M. Epstein, Gary A. Piazza, Adam B. Keeton, Gang Zhou, Mohammad Abdel-Halim, Ashraf H. Abadi, George S. Baillie, Mark A. Giembycz, Graeme Bolger, Gretchen Snyder, Kjetil Tasken, Nathaniel E.B. Saidu, Martina Schmidt, Manuela Zaccolo, Ralph T. Schermuly, Hengming Ke, Rick H. Cote, Soroush Mohammadi Jouabadi, Anton J.M. Roks
Journal: Pharmacological Reviews (2025)

Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.
Granulomatosis with Polyangiitis Presenting as Strawberry Gingivitis: Diagnostic Challenges with Negative <scp>ANCA</scp>
Authors: Hanghang Liu, Wenting Qi, Qi Han, Linyi Liu, Yongle Shi, En Luo, Chongyun Bao, Xian Liu
Journal: Arthritis & Rheumatology (2025)

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Effective therapeutic targeting of tumor lineage plasticity in neuroendocrine prostate cancer by BRD4 inhibitors
Authors: Xiong Zhang, Yatian Yang, Hongye Zou, Yang Yang, Xingling Zheng, Eva Corey, Amina Zoubeidi, Nicolas Mitsiades, Ai-Ming Yu, Yuanpei Li, Hong-Wu Chen
Journal: Acta Pharmaceutica Sinica B (2025)

Tumor lineage plasticity (LP) is an emerging hallmark of cancer progression. Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids, we identified bromodomain protein BRD4 as a crucial player. Integrated ChIP-seq and RNA-seq analysis of tumors revealed, for the first time, that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis, axonogenesis, EMT and stem cells and key drivers such as POU3F2 (BRN2), ASCL1/2, NeuroD1, SOX2/9, RUNX1/2 and DLL3. Interestingly, BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1. Significantly, we demonstrated that BRD4 inhibitor AZD5153, currently at clinical development, possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action (MOA) by AZD5153. Together, our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.