tbuckley/cabot-search huggingface dataset:
BSG/ACPGBI guidance on the management of colorectal polyps in patients with limited life expectancy
Authors: Matthew D Rutter, Ravi Ranjan, Clare Westwood, Jamie Barbour, Adam Biran, Helen Blackett, Nicholas Ewin Burr, John Carlisle, Barry Clare, Neil Cripps, Peter Coyne, Sunil Dolwani, Rachel Hodson, Stephen Holtham, Noor Mohammed, Eva J A Morris, Laura Neilson, Raymond Oliphant, John Painter, Anand Prakash, Rupert Pullan, Sanchoy Sarkar, Marion Sloan, Michael Swart, Siwan Thomas-Gibson, Nigel J Trudgill, Margaret Vance, Katie Yeadon, Linda Sharp
Journal: Gut (2025)

Background Determining optimal management of colorectal polyps in patients with limited life expectancy of under 10 years can be difficult, due to challenges balancing an uncertain natural history of polyp progression to symptomatic malignancy versus the increased risk and consequences of polypectomy complications. Aim This British Society of Gastroenterology and Association of Coloproctologists of Great Britain and Ireland guidance aims to help clinicians and patients consider these risks to aid decision-making for polypectomy versus a conservative approach. Methods A guidance development group comprising 28 members was established, including gastroenterologists, colorectal surgeons, elderly care physicians, anaesthetists, epidemiologists, nurse endoscopists, a general practitioner and patient representatives. Estimates on life expectancy stratified by age and comorbidity, polyp dwell time for differing polyp sizes, cancer sojourn time and polypectomy complication rates for comorbid/elderly patients both on and off antithrombotic medication were collated from various literature searches. A model was created to compare the risk of symptomatic malignancy in a patient’s lifetime against the risk of significant complications. Results Following a modified Delphi consensus process and after three rounds of voting, 33 recommendations were made within 10 domains (principles, diagnostic investigation, life expectancy, polyp and cancer natural history, polypectomy risks, management recommendations, follow-up, decision-making practicalities, training and education, future research). A table was created, summarising whether polypectomy or conservative management might be the favoured option for 40 clinical scenarios of patients with differing life expectancy, polyp sizes and use of antithrombotic medication. Conclusions This guidance provides a framework to facilitate more objective and informed decision-making, from which an individualised plan can be developed between the patient and their clinician.
Integrated multimodel analysis of intestinal inflammation exposes key molecular features of preclinical and clinical IBD
Authors: Miguel Gonzalez-Acera, Jay V Patankar, Lena Erkert, Roodline Cineus, Reyes Gamez-Belmonte, Tamara Leupold, Marvin Bubeck, Li-Li Bao, Martin Dinkel, Ru Wang, Laura Schickedanz, Heidi Limberger, Iris Stolzer, Katharina Gerlach, Leonard Diemand, Fabrizio Mascia, Pooja Gupta, Elisabeth Naschberger, Kristina Koop, Christina Plattner, Gregor Sturm, Benno Weigmann, Claudia Günther, Stefan Wirtz, Michael Stürzl, Kai Hildner, Anja A Kühl, Britta Siegmund, Andreas Gießl, Raja Atreya, Ahmed N Hegazy, Zlatko Trajanoski, Markus F Neurath, Christoph Becker
Journal: Gut (2025)

Background IBD is a chronic inflammatory condition driven by complex genetic and immune interactions, yet preclinical models often fail to fully recapitulate all aspects of the human disease. A systematic comparison of commonly used IBD models is essential to identify conserved molecular mechanisms and improve translational relevance. Objective We performed a multimodel transcriptomic analysis of 13 widely used IBD mouse models to uncover coregulatory gene networks conserved between preclinical colitis/ileitis and human IBD and to define model-specific and conserved cellular, subcellular and molecular signatures. Design We employed comparative transcriptomic analyses with curated and a priori statistical correlative methods between mouse models versus IBD patient datasets at both bulk and single-cell levels. Results We identify IBD-related pathways, ontologies and cellular compositions that are translatable between mouse models and patient cohorts. We further describe a conserved core inflammatory signature of IBD-associated genes governing T-cell homing, innate immunity and epithelial barrier that translates into the new mouse gut Molecular Inflammation Score (mMIS). Moreover, specific mouse IBD models have distinct signatures for B-cell, T-cell and enteric neurons. We discover that transcriptomic relatedness of models is a function of the mode of induction, not the canonical immunotype (Th1/Th2/Th17). Moreover, the model compendium database is made available as a web explorer ( http://trr241.hosting.rrze.uni-erlangen.de/SEPIA/ ). Conclusion This integrated multimodel approach provides a framework for systematically assessing the molecular landscape of intestinal inflammation. Our findings reveal conserved inflammatory circuits, refine model selection, offering a valuable resource for the IBD research community.
DUOX2 activation drives bacterial translocation and subclinical inflammation in IBD-associated dysbiosis
Authors: Hajar Hazime, Gloria Michelle Ducasa, Ana M Santander, Nivis Brito, Eddy Ernesto Gonzalez-Horta, Maria A Quintero, Stephen Barnes, Landon Wilson, Yanping Zhang, Fahong Yu, Raad Z Gharaibeh, Christian Jobin, Katerina M Faust, Oriana M Damas, Amar Deshpande, David H Kerman, Siobhan Proksell, Judith Pignac-Kobinger, Irina Fernández, Juan F Burgueño, Maria T Abreu
Journal: Gut (2025)

Background Inflammatory bowel diseases (IBDs) are characterised by dysbiosis and a leaky gut. The NADPH oxidase dual oxidase 2 (DUOX2) is upregulated in patients with IBD, yet its role in driving the disease remains unclear. Objective We interrogated the functional consequences of epithelial DUOX2 activity for the host and microbiome. Design DUOX2 function was studied in mice with epithelial-specific DUOX2 overactivation (vTLR4), inactivation (vTLR4 DUOXA IEC-KO) and wild-type controls. We assessed the effect of dysbiosis on DUOX2 signalling and intestinal permeability (FITC-dextran, serum zonulin, bacterial translocation) with germ-free (GF) mice engrafted with IBD or healthy microbiota. RNA sequencing of colonic mucosa and microbiota and faecal metabolomics were used to characterise the host–microbe interface. Mechanistic studies were conducted in mouse colonoids, IBD biopsies and patient serum samples. Results DUOX2 activity increased permeability and bacterial translocation and induced subclinical inflammation in vTLR4 mice. GF vTLR4 mice had increased DUOX2 activity and permeability but no subclinical inflammation. In patients with IBD, DUOX2 expression was positively associated with plasma zonulin levels and negatively associated with ZO-1 expression. Engraftment of GF mice with IBD stool increased DUOX2 activity and triggered low-grade inflammation and permeability defects in mice. DUOX2 activity functionally altered the microbiome, reduced butyrate metabolism and promoted proinflammatory and pro-oncogenic bacterial metabolites. Butyrate and histone deacetylase (HDAC) inhibitors blocked DUOX2 activation and reversed its effects. Conclusions Elevated DUOX2 signalling contributes to epithelial barrier dysfunction, microbiome alterations and subclinical inflammation. Butyrate and HDAC inhibitors reversed these effects, indicating that DUOX2 may be a therapeutic target in IBD.
Systemic treatment in patients with hepatocellular carcinoma and advanced liver dysfunction
Authors: Matthias Pinter, Claudia A M Fulgenzi, David J Pinato, Bernhard Scheiner
Journal: Gut (2025)

Systemic therapy represents the standard of care treatment for patients with advanced hepatocellular carcinoma (HCC). Given the increased risk of death from cirrhosis-related complications in patients with advanced liver dysfunction, pivotal phase III trials traditionally limited inclusion to patients with Child-Pugh class A, where death is more likely to be attributed to HCC progression. Therefore, Western guidelines recommend the use of systemic therapies primarily in patients with preserved liver function. However, patients with HCC and Child-Pugh class B are commonly encountered in clinical practice, but due to limited prospective evidence, there is no clear guidance on their optimal management. In this recent advances article, we discuss how the clinical course of cirrhosis can affect eligibility to treatment in the modern era of systemic therapy for HCC, elaborate on strategies to improve liver function in HCC patients by targeting cirrhosis-related and tumour-related factors and summarise the current literature on systemic therapy in HCC patients with Child-Pugh class B. Based on this information, we finally propose a clinical algorithm on how to systematically approach patients with HCC and advanced liver dysfunction in clinical practice.
Translational strategies for oral delivery of faecal microbiota transplantation
Authors: Srinivas Kamath, Robert V Bryant, Samuel P Costello, Alice S Day, Ben Forbes, Craig Haifer, Georgina Hold, Colleen R Kelly, Anna Li, Evance Pakuwal, Andrea Stringer, Emily C Tucker, Hannah Rose Wardill, Paul Joyce
Journal: Gut (2025)

Faecal microbiota transplantation (FMT) has emerged as a transformative therapy for Clostridioides difficile infections and shows promise for various GI and systemic diseases. However, the poor patient acceptability and accessibility of ‘conventional’ FMT, typically administered via colonoscopies or enemas, hinders its widespread clinical adoption, particularly for chronic conditions. Oral administration of FMT (OralFMT) overcomes these limitations, yet faces distinct challenges, including a significant capsule burden, palatability concerns and poor microbial viability during gastric transit. This review provides a comprehensive analysis of emerging strategies that aim to advance OralFMT by: (1) refining processing technologies (eg, lyophilisation) that enable manufacturing of low-volume FMT formulations for reducing capsule burden and (2) developing delivery technologies that improve organoleptic acceptability and safeguard the microbiota for targeted colonic release. These advancements present opportunities for OralFMT to expand its therapeutic scope, beyond C. difficile infections, towards chronic GI conditions requiring frequent dosing regimens. While this review primarily focuses on optimising OralFMT delivery, it is important to contextualise these advancements within the broader shift towards defined microbial consortia. Live biotherapeutic products (LBPs) offer an alternative approach, yet the interplay between OralFMT and LBPs in clinical practice remains unresolved. We postulate that continued innovation in OralFMT and LBPs via a multidisciplinary approach can further increase therapeutic efficacy and scalability by enabling disease site targeting, co-delivery of therapeutic compounds and overcoming colonisation resistance. Realising these goals positions OralFMT as a cornerstone of personalised care across a range of diseases rooted in microbiome health.
Harnessing the Power of Natural Products for Targeted Protein Degradation
Authors: Bo Zhu, Zheng Wu, Yiwen Shou, Kaili Zhao, Qinpei Lu, Jiang‐Jiang Qin, Hongwei Guo
Journal: Medicinal Research Reviews (2025)

ABSTRACT Natural products have garnered significant attention due to their complex chemical structures and remarkable pharmacological activities. With inherent recognition capabilities for protein surfaces, natural products serve as ideal candidates for designing proteolysis‐targeting chimeras (PROTACs). The utilization of natural products in PROTAC development offers distinct advantages, including their rich chemical diversity, multitarget activities, and sustainable sourcing. This comprehensive review explores the vast potential of harnessing natural products in PROTAC research. Moreover, the review discusses the application of natural degradant technology, which involves utilizing natural product‐based compounds to selectively degrade disease‐causing proteins, as well as the implementation of computer‐aided drug design (CADD) technology in identifying suitable targets for degradation within the realm of natural products. By harnessing the power of natural products and leveraging computational tools, PROTACs derived from natural products have the potential to revolutionize drug discovery and provide innovative therapeutic interventions for various diseases.
Brain-wide microglia replacement using a nonconditioning strategy ameliorates pathology in mouse models of neurological disorders
Authors: Dadian Chen, Chen Wang, Xi Chen, Jiayu Li, Shuai Chen, Yanzhong Li, Fangling Ma, Tingting Li, Mengling Zou, Xin Li, Xiaohua Huang, Yun-wu Zhang, Yingjun Zhao, Guojun Bu, Honghua Zheng, Xiao-Fen Chen, Jie Zhang, Li Zhong
Journal: Science Translational Medicine (2025)

Growing genetic and pathological evidence has identified microglial dysfunction as a key contributor to the pathogenesis and progression of various neurological disorders, positioning microglia replacement as a promising therapeutic strategy. Traditional bone marrow transplantation (BMT) methods for replenishing brain microglia have limitations, including low efficiency and the potential for brain injury because of preconditioning regimens, such as irradiation or chemotherapy. Moreover, BM-derived cells that migrate to the brain do not recapitulate the phenotypic and functional properties of resident microglia. Here, we present a microglia transplantation strategy devoid of any conditioning, termed "tricyclic microglial depletion for transplantation" (TCMDT). This approach leverages three cycles of microglial depletion using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, creating an optimal window for efficient engraftment of exogenous microglia. Transplantation of primary cultured microglia by TCMDT successfully restored the identity and functions of endogenous microglia. To evaluate the therapeutic potential of TCMDT, we applied this strategy to two distinct mouse models of neurologic disorder. In a Sandhoff disease model, a neurodegenerative lysosomal storage disorder caused by hexosaminidase subunit beta (Hexb) deficiency, TCMDT effectively replaced deficient microglia, attenuating neurodegeneration and improving motor performance. Similarly, in an Alzheimer's disease (AD)-related amyloid mouse model carrying the triggering receptor expressed on myeloid cells 2 (Trem2) R47H mutation, our transplantation strategy rescued microglial dysfunction and mitigated AD-related pathology. Overall, our study introduces TCMDT as a practical, efficient, and safe approach for microglia replacement, suggesting therapeutic potential for treating neurological disorders associated with microglial dysfunction.
Hypoglycemia promotes inner blood-retinal barrier breakdown and retinal vascular leakage in diabetic mice
Authors: Chuanyu Guo, Yueqi Niu, Xuemei Pan, Deepti Sharma, Evan Lau, Yang Jin, Guillaume Luxardi, Md Amanullah, Kevin Lo, Ala Moshiri, Jiang Qian, Silvia Montaner, Akrit Sodhi
Journal: Science Translational Medicine (2025)

The blood-retinal barrier (BRB) serves as a physiological boundary regulating the passage of nutrients, waste, ions, proteins, and water to and from the retina. In patients with diabetic retinopathy, breakdown of the inner BRB (iBRB) results in damage to the neurovascular unit and is a principal cause of vision loss in the diabetic population. Here, we demonstrate that hypoglycemia, a common consequence of tight glycemic control and high glycemic variability, results in accumulation of the transcription factors hypoxia-inducible factor-1α (HIF-1α) and HIF-2α and the expression of dozens of HIF-dependent vasoactive mediators in the mouse retina. In diabetic mice, this modest increase in HIF-dependent hyperpermeability factors was sufficient to promote vesicular transcytosis, breakdown of the iBRB, and retinal vascular permeability. Genetic inhibition of either HIF-1α or HIF-2α resulted in an incomplete inhibition of the broad increase in HIF-regulated vasoactive gene expression in response to hypoglycemia. We therefore evaluated a pharmacologic dual HIF-1 and HIF-2 inhibitor, 32-134D, as a therapeutic approach to prevent hypoglycemia-induced HIF-dependent vasoactive gene expression. 32-134D effectively inhibited HIF-1α accumulation and HIF-regulated gene expression in human retinal tissue. In diabetic mice, intravitreal administration of 32-134D prevented the increase in expression of HIF-regulated vasoactive genes after transient episodes of hypoglycemia, blocking both breakdown of the iBRB and the promotion of retinal vascular hyperpermeability. Collectively, these observations help explain why patients with diabetes initiating tight glycemic control have worsening of their diabetic retinopathy and provide the foundation for clinical studies assessing HIF inhibition with 32-134D for its prevention.
Inclusion of a retroviral protease enhances the immunogenicity of VLP-forming mRNA vaccines against HIV-1 or SARS-CoV-2 in mice
Authors: Peng Zhang, Mamta Singh, Vada A. Becker, Jacob Croft, Yaroslav Tsybovsky, Vinay Gopan, Yuna Seo, Qingbo Liu, Denise Rogers, Huiyi Miao, Yin Lin, Daniel Rogan, Courtney Shields, Sayda M. Elbashir, Samantha Calabrese, Isabella Renzi, Vladimir Preznyak, Elizabeth Narayanan, Guillaume Stewart-Jones, Sunny Himansu, Mark Connors, Kelly Lee, Andrea Carfi, Paolo Lusso
Journal: Science Translational Medicine (2025)

Messenger RNA (mRNA) has emerged as a highly effective and versatile platform for vaccine delivery. We previously designed a virus-like particle (VLP)-forming env-gag mRNA vaccine against human immunodeficiency virus-1 (HIV-1) that elicited envelope-specific neutralizing antibodies and protection from heterologous simian-human immunodeficiency virus (SHIV) infection in rhesus macaques. Here, we introduce a key technological advance to this platform by inclusion of mRNA encoding a retroviral protease to process Gag and produce mature VLPs. Appropriately dosed and timed expression of the protease was achieved using a full-length gag-pol mRNA transcript. Addition of gag-pol mRNA to an HIV-1 env-gag mRNA vaccine resulted in enhanced titers of envelope trimer-binding and neutralizing antibodies in a mouse model. Analogous results were obtained with a hybrid Gag-based, VLP-forming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine expressing an engineered spike protein. Thus, inclusion of a retroviral protease can increase the immunogenicity of Gag-based, VLP-forming mRNA vaccines against human pathogens.
Objective autonomic signatures of tinnitus and sound sensitivity disorders
Authors: Samuel S. Smith, Kelly N. Jahn, Jenna A. Sugai, Kenneth E. Hancock, Daniel B. Polley
Journal: Science Translational Medicine (2025)

Hypersensitivity, phantom percepts, and sensory reactivity are core features of many neurological disorders. Direct, objective measurements of these features have proven difficult to identify, leaving subjective questionnaires as the primary means of assessing sensory disorder severity. Here, we studied neurotypical adults (n = 50) or adults with sound sensitivity and tinnitus (ringing of the ears) (n = 47) and discovered a previously unidentified set of objective measurements that predicted individual differences in the Tinnitus Handicap Inventory (THI) and Hyperacusis Questionnaire (HQ). A neurophysiological assessment of central auditory gain demonstrated an elevation in participants with tinnitus and sound sensitivity but no association with symptom severity. Instead, accurate predictors of individual THI and HQ scores were identified in pupil dilations and facial movements elicited by emotionally evocative sounds. These findings highlight autonomic signatures of disrupted affective sound processing in persons with tinnitus and sound sensitivity disorders and introduce new approaches for their objective measurement.
A thin cryobiopsy device compatible with transnasal endoscopy for the gastrointestinal tract
Authors: David O. Otuya, Hamid Farrokhi, Yogesh Verma, Jing Dong, Peter Choy, Aditya Kumar, Rachel E. Shore, Sarah K. Zemlok, Evan Sevieri, Mason Schellenberg, Graham Spicer, Dan Rolando Lopez, Hany A. Osman, Joseph A. Gardecki, Alfred A. F. Kyrollos Kelada, Anna H. Gao, Anita Chung, Catriona N. Grant, Nitasha G. M. Bhat, Mireille Rosenberg, Brian C. Jacobson, Norman S. Nishioka, Yolonda Colson, Guillermo J. Tearney
Journal: Science Translational Medicine (2025)

Luminal organ biopsies are critical for disease diagnosis and are obtained using single-bite forceps inserted through the working channel of large endoscopes. Procedures using these endoscopes frequently require patient sedation or anesthesia and may not be feasible for use in pediatric patients. Additionally, forceps-derived biopsies can suffer from difficulty maintaining tissue orientation, crush artifacts, and lack of precise control of biopsy depth. The high cost and risks of anesthesia and sedation have driven the development of smaller endoscopes for unsedated procedures. However, reduced endoscope size limits working-channel dimensions, restricting biopsy forceps to sizes that may yield insufficient or nondiagnostic samples. To address these limitations, we developed an image-guided, depth-controlled, ultrasmall-diameter (1.2-millimeters) cryobiopsy device (μCryoProbe). We optimized the coolant flow profile into the device to enhance tissue freezing, optimizing device-tissue contact time and freezing depth. We tested the device for gastrointestinal biopsy collection in ex vivo preclinical tissues, in an in vivo porcine model, and in sedated human participants. Dimensions and quality of mucosal cryobiopsies from esophagus, stomach, and duodenum were compared with those of forceps-derived biopsies, and it was found that the μCryoProbe device consistently produced high-quality biopsies with optimal tissue orientation and no evidence of crush artifacts. We also demonstrated the ability to capture gastrointestinal biopsies from sedated human participants. By capturing large, well-oriented samples using a small-diameter biopsy tool, this technology has the potential to shift procedures from large to small endoscopes, reducing the need for sedation and improving patient diagnosis through the acquisition of tissue samples with better quality.