tbuckley/cabot-search huggingface dataset:
We need to focus on local solutions for health inequalities
Authors: Ara Darzi, Tetiana Lunova, Peter Howitt
Journal: BMJ (2025)

The covid-19 pandemic and the recent cost-of-living crisis have substantially exacerbated pre-existing inequalities in health and social care in the UK. 1 Marginalised populations are disproportionately affected, for example by experiencing higher rates of childhood obesity, depression, and maternal and neonatal mortality. 2Paradoxically, those who are most in need of medical care-disadvantaged populations-often face the greatest barriers to accessing it.In England, people living in the most deprived areas are twice as likely to wait over a year for non-urgent treatment compared to others. 3
Hybrid prodrug nanoassembly for hypoxia-triggered immunogenic chemotherapy and immune modulation
Authors: Beiyuan Zhang, Chao Qin, Xue Wang, Chuanhong Shen, Shuo Li, Taiyu Liu, Wenqing Li, Zhaojie Chen, Yawen Wang, Lisha Liu, Lifang Yin
Journal: Journal of Controlled Release (2025)
Endoscopic size measurement of colorectal polyps: a systematic review of techniques
Authors: Mahsa Taghiakbari, Roupen Djinbachian, Juliette Labelle, Daniel von Renteln
Journal: Endoscopy (2025)

Abstract Accurate size measurement of colorectal polyps is critical for clinical decision making and patient management. This systematic review aimed to evaluate the current techniques used for colonic polyp measurement to improve the reliability of size estimations in routine practice. A comprehensive literature search was conducted across PubMed, EMBASE, and MEDLINE to identify studies relevant to size measurement techniques published between 1980 and March 2024. The primary outcome was the accuracy of polyp sizing techniques used during colonoscopy. 61 studies were included with 34 focusing on unassisted and assisted endoscopic visual estimation and 27 on computer-based tools. There was significant variability in visual size estimation among endoscopists. The most accurate techniques identified were computer-based systems, such as virtual scale endoscopes (VSE) and artificial intelligence (AI)-based systems. The least accurate techniques were visual or snare-based polyp size estimation. VSE assists endoscopists by providing an adaptive scale for real-time, direct, in vivo polyp measurements, while AI systems offer size measurements independent of the endoscopist’s subjective judgment. This review highlights the need for standardized, accurate, and accessible techniques to optimize sizing accuracy during endoscopic procedures. There is no consensus on a gold standard for measuring polyps during colonoscopy. While biopsy forceps, snare, and graduated devices can improve the accuracy of visual size estimation, their clinical implementation is limited by practical, time, and cost challenges. Computer-based techniques will likely offer improved accuracy of polyp sizing in the near future.
Graphene oxide scaffolds promote functional improvements mediated by scaffold-invading axons in thoracic transected rats
Authors: Marta Zaforas, Esther Benayas, Raquel Madroñero-Mariscal, Ana Domínguez-Bajo, Elena Fernández-López, Yasmina Hernández-Martín, Ankor González-Mayorga, Elena Alonso-Calviño, Eduardo R Hernández, Elisa López-Dolado, Juliana M Rosa, Juan Aguilar, María C Serrano
Journal: Bioactive Materials (2025)
Characterization of a novel conditional knockout mouse model to assess efficacy of mRNA therapy in the context of severe ornithine transcarbamylase deficiency
Authors: Jenny Zhou, Shi Liang, Ling Yin, Andrea Frassetto, Anne-Renee Graham, Rebecca White, Maria Principe, Madelyn Severson, Tiffany Palmer, Shan Naidu, Eric Jacquinet, Mike Zimmer, Patrick F Finn, Paolo G V Martini
Journal: Molecular Therapy (2025)
Depletion of alloreactive B cells by drug- resistant chimeric alloantigen receptor T cells to prevent transplant rejection
Authors: Anna Christina Dragon, Agnes Bonifacius, Stefan Lienenklaus, Murielle Verboom, Jan-Phillipp Gerhards, Fabio Ius, Christian Hinze, Michael Hudecek, Constanca Figueiredo, Rainer Blasczyk, Britta Eiz-Vesper
Journal: Molecular Therapy (2025)

Antibody-mediated rejection (AMR) remains a major complication after solid organ transplantation (SOT). Current treatment options are inefficient and result in drastic impairment of the general immunity. To selectively eliminate responsible alloreactive B cells characterized by anti-donor-HLA B cell receptors (BCRs), we generated T cells overcoming rejection by antibodies (CORA-Ts) engineered with a novel chimeric receptor comprising a truncated donor-HLA molecule as antigen recognition domain. As proof-of-concept, CORA receptors based on HLA-A∗02 were developed. In co-cultures with anti-HLA-A∗02 B cell lines, CORA-Ts were specifically activated, released pro-inflammatory mediators, and exhibited strong cytotoxicity resulting in an effective reduction of anti-HLA-A∗02 antibody release. Significant reduction of growth of an anti-HLA-A∗02 B cell line could be confirmed using an in vivo mouse model. Modification of the CORA receptor effectively abrogated T cell binding, thereby avoiding T cell sensitization. Additionally, using CRISPR-Cas9-mediated knockout of the FKBP12 gene, CORA-Ts were able to resist immunosuppressive treatment with tacrolimus, thereby allowing high efficiency in transplant patients. Our results demonstrate that CORA-Ts are able to specifically eliminate alloreactive, anti-HLA B cells, thus selectively preventing anti-HLA antibody release even under immunosuppressive conditions. This suggests CORA-Ts as potent approach to combat AMR and improve long-term graft survival in SOT patients while preserving their overall B cell immunity.
Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.
Authors: Vicente Valenzuela, Daniela Becerra, José I. Astorga, Matías Fuentealba, Guillermo Diaz, Leslie Bargsted, Carlos Chacón, Alexis Martinez, Romina Gozalvo, Kasey Jackson, Vania Morales, Macarena Las Heras, Giovanni Tamburini, Leonard Petrucelli, Pablo Sardi, Lars Plate, Claudio Hetz
Journal: Molecular Therapy (2025)
Microbiota transplant for hepatic encephalopathy in cirrhosis: The THEMATIC trial
Authors: Jasmohan S Bajaj, Andrew Fagan, Edith A Gavis, Richard K Sterling, Mary Leslie Gallagher, Hannah Lee, Scott C Matherly, Mohammed S Siddiqui, Amy Bartels, Travis Mousel, Brian C Davis, Puneet Puri, Michael Fuchs, Daphne M Moutsoglou, Leroy R Thacker, Masoumeh Sikaroodi, Patrick M Gillevet, Alexander Khoruts
Journal: Journal of Hepatology (2025)
Donor Regulatory T-Cell Therapy to Prevent Graft-Versus-Host Disease
Authors: Everett Meyer, Anna Pavlova, Alejandro Villar-Prados, Cameron S Bader, Bryan Xie, Lori Muffly, Paige Kim, Katherine C. Sutherland, Sushma Bharadwaj, Saurabh Dahiya, Matthew J Frank, Sally Arai, Laura Johnston, David B Miklos, Andrew R. Rezvani, Parveen Shiraz, Surbhi Sidana, Judith A. Shizuru, Wen-Kai Weng, Vaibhav Agrawal, Amy Putnam, Nathanial B Fernhoff, John Tamaresis, Ying Lu, Rahul D Pawar, J Scott McClellan, Robert Lowsky, Robert S. Negrin
Journal: Blood (2025)

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy limited by graft-versus-host disease (GVHD). In preclinical studies and early-phase clinical studies enrichment of donor regulatory T cells (Tregs) appears to prevent GVHD and promote healthy immunity.We enrolled 44 patients on an open-label, single-center, phase 2 efficacy study investigating if a precision selected and highly purified Treg cell therapy manufactured from donor mobilized peripheral blood improves one-year GVHD-free relapse free survival (GRFS) after myeloablative conditioning (trial NCT 01660607). We compared this study arm to a concomitant standard of care (SOC) cohort. All donor Treg cell products were successfully manufactured and administered without cryopreservation within 72 hours. Participants had a one-year incidence of acute grade III-IV GVHD of 7%, moderate to severe chronic GVHD of 11% and non-relapse mortality rate of 4.5%. The primary endpoint of significantly improved one-year GRFS was achieved at 64% evaluated against a predicted incidence of 40% (p = 0.002) with a realized incidence of 36% in the SOC comparitor. For those trial patients whow developed grade II-IV acute GVHD, 91% responded to front-line steroid therapy wheras 50% responded in the SOC comparator group. Trial participants had a reduced incidence and burden of GVHD and improved GRFS, as compared to rates common to highly variable unmanipulated donor grafts and multi-agent immune suppression.
α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia
Authors: Scott Evan Millman, Almudena Chaves-Perez, Sudha Janaki-Raman, Yu-Jui Ho, John P Morris IV, Varun Narendra, Chi-Chao Chen, Benjamin T Jackson, Jossie J Yashinskie, Riccardo Mezzadra, Tessa I Devine, Valentin J. A. Barthet, Michelle Saoi, Timour Baslan, Sha Tian, Zohar Sachs, Lydia WS Finley, Justin R Cross, Scott W Lowe
Journal: Blood (2024)

Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.
Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases
Authors: Apeksha Singh, Jennifer J Chia, Dinesh S. Rao, Alexander Hoffmann
Journal: Blood (2024)

Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) amongst hematopoietic stem and progenitor cells (HSPCs). While HSC differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated. Here, we analyzed bone marrow data from the IκB- (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model of inflammation with elevated NFκB activity, which shows increased myeloid-biased MPPs. We interpreted these data with differential equations models of population dynamics to identify alterations of HSPC proliferation and differentiation rates. This analysis revealed that short-term (ST) HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs. To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of IκB- and wild-type HSPCs to track the continuous differentiation-trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors. Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification amongst HSCs, but also increased expansion of early myeloid-primed progenitors. Differentially expressed genes along the differentiation-trajectories supported increased proliferation amongst these progenitors. These findings were conserved when wild-type HSPCs were transplanted into IκB- recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver. We then applied our analysis pipeline to scRNA-seq measurements of HSPCs isolated from aged mice, as well as human myeloid neoplasm patients. These analyses identified the same myeloid-primed progenitor expansion as in the IκB- models, suggesting that it is a common feature across different settings of myeloid bias.
Cullin-5 controls the number of megakaryocyte-committed stem cells to prevent thrombocytosis in mice
Authors: Maria Katariina Kauppi, Craig D Hyland, Elizabeth M Viney, Christine Anne White, Carolyn A de Graaf, AnneMarie E Welch, Jumana Yousef, Laura F Dagley, Samantha J Emery-Corbin, Ladina Di Rago, Andrew J Kueh, Marco J Herold, Douglas J. Hilton, Jeffrey J Babon, Nicos A. Nicola, Kira Behrens, Warren S Alexander
Journal: Blood (2024)

Cullin-5 (Cul5) coordinates assembly of cullin-RING-E3 ubiquitin (Ub) ligase (CRL) complexes that include Suppressor of Cytokine Signaling (SOCS)-box-containing proteins. The SOCS-box proteins function to recruit specific substrates to the complex for ubiquitination and degradation. In hematopoiesis, SOCS-box proteins are best known for regulating the actions of cytokines that utilize the JAK-STAT signaling pathway. However, the roles of most SOCS-box proteins have not been studied in physiological contexts and any actions for Cul5/SOCS complexes in signaling by several hematopoietic cytokines, including thrombopoietin (TPO) and interleukin-3 (IL-3), remain unknown. To define additional potential roles for Cul5/SOCS complexes, we generated mice lacking Cul5 in hematopoiesis; the absence of Cul5 is predicted to impair the SOCS-box-dependent actions of all proteins that contain this motif. Here, we show that Cul5-deficient mice develop excess megakaryopoiesis and thrombocytosis revealing a novel mechanism of negative regulation of megakaryocyte-committed stem cells, a distinct population within the hematopoietic stem cell pool that have been shown to rapidly, perhaps directly, generate megakaryocytes, and which are produced in excess in the absence of Cul5. Cul5-deficient megakaryopoiesis is distinctive in being largely independent of TPO/Mpl and involves signaling via the beta-common and/or beta-IL-3 receptors, with evidence of deregulated responses to IL-3. This process is independent of the interferon-alpha/beta receptor (IFNARI), previously implicated in inflammation-induced activation of stem-like megakaryocyte progenitor cells.
DNTT-mediated DNA Damage Response Drives Inotuzumab Ozogamicin Resistance in B-cell Acute Lymphoblastic Leukemia
Authors: Carolin S. Escherich, Takaya Moriyama, Zhenhua Li, YuChih Hsiao, Wenjian Yang, Yizhen Li, Noemi Reyes, Megan Walker, Amit Budhraja, Sheetal Bhatara, Ernesto Diaz-Flores, Wendy Stock, Elisabeth Paietta, Marina Y. Konopleva, Steven M Kornblau, Mark R Litzow, Hiroto Inaba, Ching-Hon Pui, Joseph T. Opferman, Mignon L. Loh, Jiyang Yu, Maureen O'Brien, William E. Evans, Jun J. Yang
Journal: Blood (2024)
A Recombinant Antibody Against <scp>ALK2</scp> Promotes Tissue Iron Redistribution and Contributes to Anemia Resolution in a Mouse Model of Anemia of Inflammation
Authors: Chia‐Yu Wang, Emiliano Melgar‐Bermudez, Diana Welch, Kevin B. Dagbay, Seemana Bhattacharya, Evan Lema, Tyler Daman, Olivia Sierra, Radina Todorova, Papa Makhtar Drame, Rosa Grenha, Ffolliott M. Fisher, Dena Grayson, Lorena Lerner, Samuel M. Cadena, Jasbir Seehra, Jennifer Lachey
Journal: American Journal of Hematology (2025)

ABSTRACT Patients with chronic inflammation are burdened with anemia of inflammation (AI), where inflammatory cytokines inhibit erythropoiesis, impede erythropoietin production, and limit iron availability by inducing the iron regulator hepcidin. High hepcidin hinders iron absorption and recycling, thereby worsening the impaired erythropoiesis by restricting iron availability. AI management is important as anemia impacts quality of life and potentially affects morbidity and mortality. The bone morphogenetic protein (BMP)‐SMAD pathway is crucial for hepcidin regulation. Here, we characterized a research antibody against BMP receptor ALK2, RKER‐216, and investigated its mechanism in suppressing hepcidin and improving anemia in acute/chronic inflammation. Additive effects of RKER‐216 and recombinant human erythropoietin (rhEPO) on erythropoiesis and iron utilization were also explored. We showed that RKER‐216 neutralized ALK2 activity by competing with the binding of BMP6. RKER‐216 reduced hepcidin transcription in Hep3B cells, and a subcutaneous dose of RKER‐216 at 3 mg/kg suppressed serum hepcidin and increased circulating iron for 3–4 days in wildtype mice. Moreover, RKER‐216 decreased hepcidin by inhibiting SMAD1/5/9 signaling in lipopolysaccharide‐mediated inflammation and liberated iron from the recycling pathway to alleviate anemia in mice with adenine‐induced chronic kidney disease (CKD), a mouse model of AI. Finally, RKER‐216 reversed iron‐restricted erythropoiesis in CKD mice and supplied the iron requirement for complete resolution of anemia when coupled with rhEPO in addressing AI. Our data support that ALK2 is a key hepcidin regulator and that a neutralizing ALK2 antibody has the potential to restore iron homeostasis as monotherapy or in combination with rhEPO to ameliorate AI.
Impact of Baseline Thrombocytopenia on Early Outcomes in Patients With Acute Venous Thromboembolism
Authors: Ramón Lecumberri, Pedro Ruiz‐Artacho, Javier Trujillo‐Santos, María Marcos‐Jubilar, Montserrat Pérez‐Pinar, Isabelle Quéré, Gisela Claver, Juan Gorostidi, Behnood Bikdeli, Manuel Monreal
Journal: American Journal of Hematology (2025)

Managing acute venous thromboembolism (VTE) in patients with thrombocytopenia is challenging. We used data from the RIETE registry to investigate the impact of baseline thrombocytopenia on early VTE-related outcomes, depending on the initial presentation as pulmonary embolism (PE) or isolated lower-limb deep vein thrombosis (DVT). From March 2003 to November 2022, 90 418 patients with VTE were included. Thrombocytopenia was categorized as severe (< 50 000/μL, n = 303) or moderate (50 000-99 999/μL, n = 1882). The primary outcome, fatal PE within 15 days after diagnosis, and secondary outcomes, including major bleeding and recurrent VTE, were analyzed using multivariable-adjusted models. Among 52 703 patients with PE, the 15-day case-fatality rates from PE were 5.8% for severe thrombocytopenia, 4.5% for moderate thrombocytopenia, and 1.1% for normal platelet counts. In 37 715 patients with isolated DVT, the cumulative incidence of fatal PE were 0, 0.2%, and 0.05%, respectively. Multivariable analysis revealed a five-fold increase in the risk for fatal PE in severe thrombocytopenia (adjusted HR: 4.89; 95%CI: 2.55-9.39) without significant differences between severe and moderate thrombocytopenia. Thrombocytopenia, either moderate or severe, was also associated with increased risk for both, major bleeding and recurrent VTE at 15 days. Initial presentation with PE substantially worsened prognosis compared to isolated DVT. In conclusion, in patients with acute VTE, thrombocytopenia at baseline was associated with increased risk of early death from PE, a finding that was driven by the subgroup whose initial presentation was PE.
Frailism: a scoping review exploring discrimination against people living with frailty
Authors: Philip Braude, Emma Grace Lewis, Steve Broach KC, Edward Carlton, Sarah Rudd, Jean Palmer, Richard Walker, Ben Carter, Jonathan Benger
Journal: The Lancet Healthy Longevity (2025)

SummaryPeople living with frailty can experience discrimination, but unlike the characteristics of age and disability, frailty is not protected by law. Frailty is a clinical syndrome associated with ageing in which health deficits increase a person's vulnerability to illness, disability, and death. This scoping review, conducted by a team of methodologists, clinicians, lawyers, and patients, aimed to investigate the extent of discrimination against people living with frailty described in health-care literature. We searched five health-care databases from inception up to June, 2022, and grey literature, to identify 144 texts. The texts were classified by the types of discrimination (direct discrimination, indirect discrimination, harassment, and victimisation) and inductively developed into contextual themes. The median age of the participants was 77 years (IQR 69·9–82·0), and 65·4% were women. The most common types of discrimination were direct (in 90 [63%]), indirect (in 66 [46%]), and harassment (in one [1%]) of the 144 texts, with no instances of victimisation reported. Nine themes of discriminatory actions were developed. Discrimination against people living with frailty overlapped with discrimination based on established protected characteristics, including age, disability, race, and sex. Evidence indicated that frailty discrimination replaces, mediates, masks, and potentiates age discrimination. Discrimination against people with frailty seemed to be both an independent event and one that interacts with established protected characteristics. Future research should focus on preventing frailty-based discrimination and establishing whether frailty should be considered a new protected characteristic by law.
Erratum for Euro Surveill. 2024;29(50)
Journal: Eurosurveillance (2025)

© This work is licensed under a Creative Commons Attribution 4.0 International License. Closure This is a corrected article applying to the following content: Direct and indirect effects of the COVID-19 pandemic on mortality: an individual-level population-scale analysis using linked electronic health records, Wales, United Kingdom, 2016 to 2022
Detection and characterisation of high pathogenicity avian influenza virus (H5N1/H5N8) clade 2.3.4.4b, Hong Kong SAR, China, 2021 to 2024
Authors: Wanying Sun, Ka Tim Choy, Ka Man Cheng, Christopher J Brackman, Samuel MS Cheng, Thomas HC Sit, Anne CN Tse, Leslie D Sims, Haogao Gu, Amy WY Tang, Andrew NC Wong, Andrew TL Tsang, Joe CT Koo, Leo LH Luk, Hui-Ling Yen, Malik Peris, Leo LM Poon
Journal: Eurosurveillance (2025)

We isolated three genotypes of highly pathogenic avian influenza virus (HPAIV) clade 2.3.4.4b from wild birds infected with H5N1 (n = 12) and H5N8 (n = 1) in Hong Kong SAR 2021–2024. Viruses from two spoonbills from late 2022 were genetically related to a virus from a human in China. Four tested viruses exhibited variable virulence in mice but were susceptible to approved antivirals. No neutralising antibody was detected in 63 age-stratified human sera, suggesting potential risk should the virus adapt to humans.
Detection of vaccine-derived poliovirus type 2 from sewage samples and public health response, Poland, November to December 2024
Authors: Magdalena Wieczorek, Beata Gad, Arleta Krzysztoszek, Paulina Kłosiewicz, Kinga Oleksiak, Bartosz Zaborski, Paweł Grzesiowski, Katarzyna Tkaczuk, Anna Baumann-Popczyk
Journal: Eurosurveillance (2025)

In October and December 2024, circulating vaccine-derived poliovirus type 2 (cVDPV2) was detected from two wastewater samples in Poland during routine environmental surveillance. The first isolate was characterised and matched previous cVDPV2 isolates detected in Spain in September, as well as in Germany, Finland, and the United Kingdom in November and December 2024. In response to the event, active surveillance for acute flaccid paralysis (AFP) has been strengthened, and the frequency of environmental sample collection has been increased.