tbuckley/cabot-search huggingface dataset:
Defects in the necroptosis machinery are a cancer resistance mechanism to checkpoint inhibitor immunotherapy
Authors: Anna Sax, Peter May, Stefan Enssle, Nardine Soliman, Tatiana Nedelko, Giada Mandracci, Fabian Stögbauer, Laura Joachim, Christof Winter, Florian Bassermann, Katja Steiger, Nadia El Khawanky, Hendrik Poeck, Simon Heidegger
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Immune checkpoint inhibitors (ICIs) of programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) reinvigorate strong polyclonal T-cell immune responses against tumor cells. For many patients, these therapies fail because the development of spontaneous immune responses is often compromised, as the tumor microenvironment (TME) lacks proinflammatory signals resulting in suboptimal activation of antigen-presenting cells (APCs). Necroptosis is a special form of programmed cell death associated with leakage of inflammatory factors that can lead to APC maturation. However, it is unclear to which extent functional necroptosis in tumor cells contributes to ICI immunotherapy. Methods With genetically engineered tumor cell lines that lack specific components of the necroptosis machinery (mixed lineage kinase domain-like pseudokinase (MLKL), receptor interacting protein kinase 3 (RIPK3)), we addressed the importance of necroptotic tumor cell death for the efficacy of ICI immunotherapy in murine models. Preclinical data were aligned with genome-wide transcriptional programs in patient tumor samples at diagnosis and during ICI treatment for the activity of these pathways and association with treatment outcome. Results Mice bearing MLKL-deficient or RIPK3-deficient tumors failed to control tumor growth in response to anti-PD-1/anti-CTLA-4 immunotherapy. Mechanistically, defects in the necroptosis pathway resulted in reduced tumor antigen cross-presentation by type 1 conventional dendritic cells (DCs) in tumor-draining lymph nodes, and subsequently impaired immunotherapy-induced expansion of circulating tumor antigen-specific CD8 + T cells and their accumulation and activation in the TME. In vitro, co-culture of tumor cells undergoing necroptotic but not apoptotic programmed cell death resulted in increased uptake by phagocytic cells, associated with maturation and activation of DCs. Treatment of tumors with the epigenetic modulator azacytidine enhanced intrinsic transcriptional activity of the necroptosis machinery, and hence their susceptibility to ICI immunotherapy. In humans, transcriptome analysis of melanoma samples revealed a strong association between high expression of MLKL and prolonged overall survival and durable clinical response to immunotherapy with anti-PD-1 and/or anti-CTLA-4 checkpoint inhibitors. Conclusions Defective necroptosis signaling in tumor cells is a cancer resistance mechanism to ICI immunotherapy. Reversion of epigenetic silencing of the necroptosis pathway can render tumors susceptible to checkpoint inhibition.
Prediction of 90-day mortality among cancer patients with unplanned hospitalisation: a retrospective validation study of three prognostic scores
Authors: Galip Can Uyar, Oriol Mirallas, Kadriye Başkurt, Berta Martin-Cullell, Enes Yeşilbaş, Jordi Recuero-Borau, Seher Kaya, Victor Navarro Garcés, Sevgi Eryıldız Yücel, Kreina Sharela Vega Cano, Diego Gómez-Puerto, Anna Pedrola Gómez, Clara Salva de Torres, Ömür Berna Çakmak Öksüzoğlu, Sonia Serradell, Rodrigo Dienstmann, Osman Sütcüoğlu
Journal: The Lancet Regional Health - Europe (2025)
Reimagining species on the move across space and time
Authors: Alexa L Fredston, Morgan W Tingley, Montague H C Neate-Clegg, Luke J Evans, Laura H Antão, Natalie C Ban, I-Ching Chen, Yi-Wen Chen, Lise Comte, David P Edwards, Birgitta Evengard, Belen Fadrique, Sophie H Falkeis, Robert Guralnick, David H Klinges, Jonas J Lembrechts, Jonathan Lenoir, Juliano Palacios-Abrantes, Aníbal Pauchard, Gretta Pecl, Malin L Pinsky, Rebecca A Senior, Jennifer E Smith, Lydia G Soifer, Jennifer M Sunday, Ken D Tape, Peter Washam, Brett R Scheffers
Journal: Trends in Ecology & Evolution (2025)
The Therapeutic Potential of Melatonin and Its Novel Synthetic Analogs in Circadian Rhythm Sleep Disorders, Inflammation‐Associated Pathologies, and Neurodegenerative Diseases
Authors: Rodrigo F. N. Ribeiro, Marco Rios Santos, Maria Aquino, Luis Pereira de Almeida, Cláudia Cavadas, Maria Manuel C. Silva
Journal: Medicinal Research Reviews (2025)

ABSTRACT Melatonin, N ‐acetyl‐5‐methoxytryptamine, is a tryptophan‐derived hormone mostly produced in the pineal gland, despite being synthesized locally at several tissues and organs. This production is rhythmically controlled by complex clock gene networks in the master pacemaker located in the suprachiasmatic nucleus of the hypothalamus. Melatonin is usually secreted only during the dark phase of the day and is essential to synchronize circadian rhythms and neuroendocrine physiological processes. Its main clinical use is associated with the treatment of jet lag and other circadian rhythm sleep disorders, with a growing number of other promising therapeutic applications due to the diverse physiological roles of melatonin. In this review, we explore melatonin and its receptors and provide an updated overview on research concerning the role of melatonin, either as an endogenous molecule or as a drug, in: sleep–wake cycle regulation; circadian rhythms; inflammatory processes that may compromise cardiovascular, respiratory, gastrointestinal, renal, and reproductive system functions; and neurodegenerative disorders such as Alzheimer's and Parkinson's disease. The most recent and promising research findings concerning melatonin synthetic analogs such as agomelatine and ramelteon are highlighted, pointing toward new compounds with promising pharmacological activity while emphasizing their structural differences and advantages when compared to melatonin.
Engineered bacteria as an orally administered anti-viral treatment and immunization system
Authors: Nitin S. Kamble, Shindu Thomas, Tushar Madaan, Nadia Ehsani, Saqib Sange, Kiersten Tucker, Alexis Muhumure, Sarah Kunkler, Nalinikanth Kotagiri
Journal: Gut Microbes (2025)

The emergence of new viral pathogens necessitates innovative antiviral therapies and vaccines. Traditional approaches, such as monoclonal antibodies and vaccines, are often hindered by resistance, limited effectiveness, and high costs. Here, we develop an engineered probiotic-based antiviral platform using Escherichia coli Nissle 1917 (EcN), capable of providing both mucosal and systemic immunity via oral administration. EcN was engineered to display anti-spike nanobodies or express the Spike-Receptor Binding Domain on its surface. Our findings reveal that EcN with nanobodies effectively inhibits the interaction between spike protein-expressing pseudoviruses and the ACE2 receptor. Furthermore, we observed the translocation of nanobodies to distant organs, facilitated by outer membrane vesicles (OMVs). The oral administration of EcN expressing spike proteins induced a robust immune response characterized by the production of both IgG and IgA, antibodies that blocked the pseudovirus-ACE2 interaction. While SARS-CoV-2 served as a model, this versatile probiotic platform holds potential for developing customizable biotherapeutics against a wide range of emerging pathogens such as influenza virus or respiratory syncytial virus (RSV) by engineering EcN to express viral surface protein or neutralizing nanobodies demonstrating its versatility as a next-generation mucosal vaccine strategy.
Death‐Associated Protein 3 Triggers Intrinsic Apoptosis via Miro1 Upon Inducing Intracellular Calcium Changes
Authors: Dongxue Hu, Qiaoyun Yang, Hongxu Xian, Minghao Wang, Hong Zheng, Karthik Babu Mallilankaraman, Victor C. Yu, Yih‐Cherng Liou
Journal: MedComm (2025)

ABSTRACT Mitochondrial homeostasis is essential for cell survival and function, necessitating quality control mechanisms to ensure a healthy mitochondrial network. Death‐associated protein 3 (DAP3) serves as a subunit of the mitochondrial ribosome, playing a pivotal role in the translation of mitochondrial‐encoded proteins. Apart from its involvement in protein synthesis, DAP3 has been implicated in the process of cell death and mitochondrial dynamics. In this study, we demonstrate that DAP3 mediates cell death via intrinsic apoptosis by triggering excessive mitochondrial fragmentation, loss of mitochondrial membrane potential (Δ Ψ m), ATP decline, and oxidative stress. Notably, DAP3 induces mitochondrial fragmentation through the Mitochondrial Rho GTPase 1 (Miro1), independently of the canonical fusion/fission machinery. Mechanistically, DAP3 promotes mitochondrial calcium accumulation through the MCU complex, leading to decreased cytosolic Ca 2+ levels. This reduction in cytosolic Ca 2+ is sensed by Miro1, which subsequently drives mitochondrial fragmentation. Depletion of Miro1 or MCU alleviates mitochondrial fragmentation, oxidative stress, and cell death. Collectively, our findings reveal a novel function of the mitoribosomal protein DAP3 in regulating calcium signalling and maintaining mitochondrial homeostasis.
The Role of CPX-351 in the Acute Myeloid Leukemia Treatment Landscape: Mechanism of Action, Efficacy, and Safety
Authors: Livio Pagano, Romano Danesi, Edoardo Benedetti, Riccardo Morgagni, Luigina Romani, Adriano Venditti
Journal: Drugs (2025)

CPX-351 (also known as VYXEOS® or Vyxeos liposomal) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin in a synergistic 5:1 molar ratio and was the first example that utilized CombiPlex®, a combination drug technology platform. Superior efficacy with CPX-351 in the pivotal phase 3 randomized clinical trial versus its conventional free-drug counterpart led to its approval for the treatment of newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in multiple countries. Emerging evidence indicates that CPX-351 affords additional benefits compared with conventional chemotherapy, including protection against intestinal dysbiosis and fungal colonization, fewer infectious complications, and a lower incidence of cardiotoxicity. This review examines the mechanisms underlying CPX-351's therapeutic effects and highlights its expanding role in AML treatment by summarizing efficacy and safety data from preclinical models, the pivotal clinical trial, and real-world studies. Particular focus is given to recent findings on CPX-351's intestinal and cardioprotective properties, which together strengthen its safety and efficacy profile compared with conventional chemotherapy.
A Wet‐Adhesive Hydrogel Patch with Rapid‐Adhesion, Anti‐Swelling, and Pro‐Healing Properties for Sutureless Repair of Dural Tear
Authors: Hao Zhou, Yue Fan, Jiajun Huang, Hanwen Huang, He Li, Zhi Liang, Zhaopeng Cai, Youchen Tang, Peng Wang
Journal: Advanced Healthcare Materials (2025)

Abstract Dural tears and subsequent cerebrospinal fluid leakage are common and intractable in spinal surgery. However, the existing clinical treatments are still unsatisfactory and the effective closure and repair of dural tears remain a huge challenge. Herein, a bilayer wet‐adhesive hydrogel patch (denoted as BMTP) with rapid‐adhesion, anti‐swelling, and pro‐healing properties is developed, which comprises a tough poly(vinyl alcohol) (PVA) dissipative layer and a functionalized poly(acrylic acid)‐based wet‐adhesive layer modified with methyl acrylate (MA) and tannic acid (TA). Owing to the hydrophobic effect of MA moieties and the strong intermolecular hydrogen bonding interaction facilitated by TA, BMTP has a unique low swelling property (24.2%) without compromising wet adhesion. Meanwhile, attributed to the high mechanical strength of the PVA dissipative layer and its mechanical interlocking with the wet‐adhesive layer, BMTP exhibits durable sealing capacities with a burst pressure tolerance of 325 mm Hg. Moreover, the TA‐mediated promotion of fibroblast proliferation enables BMTP to accelerate the healing of dura wounds. The rabbit dural tear model demonstrates that the BMTP can effectively seal and promote the healing of the damaged dura without postoperative adhesion within 3 weeks. Therefore, this work may offer a promising solution for the sutureless treatment of dural tears.
Investigating endogenous immune-mediated monocyte memory in rheumatoid arthritis
Authors: Anna M Marzeda, Anja Schwenzer, Bogdan S Didov, Kieran Woolcock, Jean-Baptiste Richard, Libby K Jennings, Amélie M Julé, Nan Yang, Sarah Davidson, Steve Sansom, Adam P Cribbs, Calliope A Dendrou, Wyatt W Yue, Carl S Goodyear, Karim Raza, Kim S Midwood
Journal: Annals of the Rheumatic Diseases (2025)

Inflammation triggered by endogenous stimuli that signal cellular stress or tissue injury must be tightly controlled to balance robust protection from intrinsic danger while avoiding catastrophic destruction of healthy tissues. Here, we assess the contribution of innate memory to this balance. Memory evoked by the extracellular matrix protein tenascin-C, a damage-associated, toll-like receptor 4 (TLR4) agonist, was compared to that induced by the pathogenic TLR4 agonist lipopolysaccharide (LPS) by transcriptomic and epigenetic profiling of monocytes from healthy individuals or people wirh rheumatoid arthritis (RA), and tissue macrophages from the RA synovium. Tenascin-C reprograms monocyte response to subsequent threats, inducing concomitantly suppressed and enhanced responses to rechallenge. Comparative analysis of tenascin-C and LPS revealed common and distinct gene expression signatures, effects controlled transcriptionally and associated with stimulus-specific epigenetic mediators. Altered responses following rechallenge after priming with tenascin-C were not limited to subsequent TLR4 activation but were evident in response to various pathogenic and endogenous stimuli detected by different receptors. In healthy monocytes primed with tenascin-C, rechallenge with stimuli found at high levels in the joints of people with RA resulted in trained responses that were not induced by LPS, including genes associated with chronic inflammation, tissue destruction, altered metabolism, and poor treatment response in RA. The expression of a large subset of these genes was elevated in monocytes from people with RA in the absence of any stimulation and in RA synovial macrophage populations associated with disease flare. Moreover, higher levels of permissive complexes within key epigenetic nodes and increased bivalent modification creating poised loci within endogenously trained genes were observed in RA cells. These data highlight how innate reprogramming during 'sterile' inflammatory diseases contributes to chronicity, uncovering pathways unique to endogenous immune triggers that could provide disease-specific points of intervention without engendering global immune suppression.
Anti-TFAM antibodies link mitochondrial damage with antiphospholipid syndrome and thrombosis in SLE
Authors: Eduardo Gómez-Bañuelos, Alessandra Ida Celia, Maria Isabel Trejo-Zambrano, Jesus Aureliano Robles-De Anda, Merlin Paz, Shruti Chaturvedi, Fabrizio Conti, Cristiano Alessandri, Eleni Tiniakou, Daniel W Goldman, Robert A Brodsky, Michelle Petri, Felipe Andrade
Journal: Annals of the Rheumatic Diseases (2025)

Mitochondria are a source of autoantigens and damage-associated molecular patterns (DAMPs) in systemic lupus erythematosus (SLE). Nucleoids carrying TFAM (transcription factor A, mitochondrial) and mitochondrial DNA (mtDNA) are important DAMPs in SLE. While mtDNA has been associated with anti-double-stranded (ds)DNA antibodies and type I interferon (IFN-I), the immunogenic role of TFAM in SLE pathogenesis is unknown. Here, we characterised the clinical and transcriptional phenotypes linked to anti-TFAM antibodies in SLE. Anti-TFAM antibodies were discovered in an exploratory sample of 22 SLE patients and 9 healthy controls. To define the prevalence, clinical significance, and associations with transcriptional profiles and IFN levels, anti-TFAM antibodies were detected using enzyme-linked immunosorbent assay (ELISA) in 98 healthy controls and 158 SLE patients. Sera from patients with dermatomyositis, rheumatoid arthritis, and primary antiphospholipid syndrome (PAPS) were also tested. Anti-TFAM antibodies were discovered in patients with SLE while analysing neutrophil autoantigens and confirmed by ELISA and immunoblotting. One-third of SLE patients (48/158) were positive for anti-TFAM antibodies. Unlike anti-dsDNA antibodies, anti-TFAM antibodies were not associated with disease activity or the IFN signature. Instead, anti-TFAM antibodies were associated with thrombosis, antiphospholipid syndrome (APS) (odds ratio [OR], 2.9 and 5.4, respectively), thrombosis-associated transcriptional profiles, and elevated IFN-III. Anti-TFAM antibodies were also found in PAPS, supporting their role in APS but not SLE pathogenesis. Lupus anticoagulant increased the risk of thrombosis associated with anti-TFAM antibodies (OR, 8.71), indicating they are markers of independent prothrombotic pathways. Anti-TFAM antibodies identify a distinct clinical and transcriptional disease subset associated with mitochondrial damage, thrombosis, and APS in SLE.
Corrigendum to ‘A simple soft lithographic route to fabrication of poly(ethylene glycol) microstructures for protein and cell patterning’ [Biomaterials Volume 25 Issue 3, (2004) Pages 557–563]
Authors: Kahp Y Suh, Jiehyun Seong, Ali Khademhosseini, Paul E Laibinis, Robert Langer
Journal: Biomaterials (2025)
Hypoferremic Response to Chronic Inflammation Is Controlled via the Hemojuvelin/Hepcidin/Ferroportin Axis and Does Not Involve Hepcidin‐Independent Regulation of <i>Fpn</i><scp>mRNA</scp>
Authors: Siqi Liu, Sofiya Tsyplenkova, Carine Fillebeen, Kostas Pantopoulos
Journal: American Journal of Hematology (2025)

ABSTRACT The iron regulatory hormone hepcidin contributes to the pathogenesis of anemia of inflammation (AI) by inhibiting the iron exporter ferroportin in target cells, causing hypoferremia. Under acute inflammation, hepcidin induction requires hemojuvelin (Hjv), a bone morphogenetic protein co‐receptor, while Fpn mRNA is also suppressed in a hepcidin‐independent manner. However, it is unclear whether, during chronic inflammation, Hjv and hepcidin‐independent Fpn mRNA regulation are critical for hypoferremia and AI. To address these questions, wild type and Hjv −/− mice, a model of hemochromatosis, were fed for 8 weeks an adenine‐rich diet to develop chronic kidney disease (CKD). Renal inflammation, accessed by increased Il6 mRNA expression, did not differ among genotypes. Hjv disruption did not mitigate the severity of kidney injury but suppressed the inflammatory induction of liver hepcidin. CKD triggered hypoferremia and mild anemia in wild type mice; however, Hjv −/− littermates maintained high serum iron and normal hemoglobin, consistent with a protective effect of Hjv/hepcidin deficiency. Notably, tissue Fpn mRNA levels were not affected by the inflammatory milieu of CKD. Following injection of wild type or Hjv −/− mice with heat‐killed Brucella abortus , Fpn mRNA was suppressed during the acute phase of inflammation but quickly recovered and persisted in the chronic phase. We conclude that Hjv deficiency reduces hepcidin levels and mitigates anemia in the CKD model, providing further support for pharmacological targeting of Hjv for the treatment of AI. Moreover, our data demonstrate that Fpn mRNA suppression only occurs under acute but not chronic inflammatory conditions and therefore cannot substantially contribute to AI pathogenesis.
Antimicrobial resistance in Neisseria gonorrhoeae and its risk groups in 23 European countries in 2022 within the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP): a retrospective observational study
Authors: Susanne Jacobsson, Michelle J. Cole, Daniel Schröder, Melissa Jansen van Rensburg, Michaela Day, Csaba Ködmön, Magnus Unemo, Sonja Pleininger, Stefanie Schindler, Ziad El-Khatib, Irith De Baetselier, Dorien Van den Bossche, Dominique Van Beckhoven, Amaryl Lecompte, Ivva Philipova, Hana Zákoucká, Helena Žemličková, Vladislav Jakubů, Steen Hoffmann, Maria Wessman, Kairi Tõnsau, Suvi Korhonen, Jukka Torvikoski, Jari Jalava, Beatrice Bercot, Emilie Chazelle, Cheick Kounta, Gilles Delmas, Dagmar Heuer, Regina Selb, Klaus Jansen, Vivi Miriagou, Vasilios Raftopoulos, Dimitra Paraskeva, Eszter Balla, Lena Rós Ásmundsdóttir, Kristjan Orri Helgason, Anna Margret Gudmundsdottir, Marianna Thordardottir, Brendan Crowley, Sinead Saab, Candice Principe, Derval Igoe, Mark Campbell, Angeline McIntyre, Paola Stefanelli, Barbara Suligoi, Francesca Vella, Robert Cassar, Julie Haider, Alje Van Dam, Maartje Visser, Dominique Caugant, Hilde Kløvstad, Beata Młynarczyk-Bonikowska, Maria José Borrego, Peter Pavlik, Alexandra Bražinová, Tanja Kustec, Irena Klavs, Polona Maver Vodičar, Raquel Abad Torreblanca, Julio Vazquez Moreno, Javier Gómez Castellá, Magnus Unemo, Susanne Jacobsson, Daniel Golparian, Daniel Schröder
Journal: The Lancet Regional Health - Europe (2025)
Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy
Authors: Chao Wang, Xiaoqing Yu, Jamie K Teer, Jiqiang Yao, Dongliang Du, Xiaoxian Liu, Zachary J Thompson, Min Hsuan Wang, Eric A Welsh, Danish Memon, Timothy A Chan, Vladimir Makarov, Carmen M Anadon, Lamees Saeed, Theresa A Boyle, Bin Fang, John M Koomen, Cheryl Cox, Ana M Landin, Sean J Yoder, Sungjune Kim, Dung-Tsa Chen, Shari A Pilon-Thomas, Jose R Conejo-Garcia, Scott J Antonia, Eric B Haura, Benjamin C Creelan
Journal: Nature Cancer (2025)
Cellular and molecular mechanisms of pathological tau phosphorylation in traumatic brain injury: implications for chronic traumatic encephalopathy
Authors: Neil Donison, Jacqueline Palik, Kathryn Volkening, Michael J Strong
Journal: Molecular Neurodegeneration (2025)

Abstract Tau protein plays a critical role in the physiological functioning of the central nervous system by providing structural integrity to the cytoskeletal architecture of neurons and glia through microtubule assembly and stabilization. Under certain pathological conditions, tau is aberrantly phosphorylated and aggregates into neurotoxic fibrillary tangles. The aggregation and cell-to-cell propagation of pathological tau leads to the progressive deterioration of the nervous system. The clinical entity of traumatic brain injury (TBI) ranges from mild to severe and can promote tau aggregation by inducing cellular mechanisms and signalling pathways that increase tau phosphorylation and aggregation. Chronic traumatic encephalopathy (CTE), which is a consequence of repetitive TBI, is a unique tauopathy characterized by pathological tau aggregates located at the depths of the sulci and surrounding blood vessels. The mechanisms leading to increased tau phosphorylation and aggregation in CTE remain to be fully defined but are likely the result of the primary and secondary injury sequelae associated with TBI. The primary injury includes physical and mechanical damage resulting from the head impact and accompanying forces that cause blood–brain barrier disruption and axonal shearing, which primes the central nervous system to be more vulnerable to the subsequent secondary injury mechanisms. A complex interplay of neuroinflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction activate kinase and cell death pathways, increasing tau phosphorylation, aggregation and neurodegeneration. In this review, we explore the most recent insights into the mechanisms of tau phosphorylation associated with TBI and propose how multiple cellular pathways converge on tau phosphorylation, which may contribute to CTE progression. Graphical Abstract