tbuckley/cabot-search huggingface dataset:
Repression of the ERRγ-CYP2E1 pathway by fibroblast growth factor 4 mitigates alcoholic liver injury
Authors: Luyao Wang, Wenliya Dong, Lei Fan, Hongru Kong, Siyu Liang, Zhuobing Huang, Jie Chen, Sisi Zhi, Siyan Xu, Qiaoling Qiu, Miaomiao Yang, Yushu Hou, Yue Hu, Tongtong Pan, Minghua Zheng, Xiaokun Li, Zhifeng Huang, Lintao Song
Journal: Hepatology (2025)

Background and Aims: Alcoholic liver disease (ALD) represents a critical global health challenge characterized by liver damage resulting from excessive alcohol consumption. Early detection and timely intervention are essential for optimizing patient outcomes. However, the mechanisms underlying alcohol-induced liver injury have not been fully elucidated. Fibroblast growth factor 4 (FGF4) has been implicated in the progression of various liver diseases. This study aims to elucidate the role of FGF4 in the pathogenesis of ALD. Approach and Results: We analyzed human liver specimens and observed significant upregulation of FGF4 mRNA and protein levels in patients with ALD. Consistent findings were noted in mouse models subjected to a Lieber-DeCarli liquid diet. Importantly, hepatic FGF4 expression exhibited a positively correlated with ALD severity in both human subjects and murine models. Hepatocyte-specific deletion of Fgf4 ( Fgf4 -LKO) exacerbated alcohol-induced liver injury through increased oxidative stress, inflammation, and apoptosis. Specifically, Fgf4 -LKO mice demonstrated heightened susceptibility to ethanol plus CCl 4 -induced fibrosis and liver injury. However, treatment with the ERRγ inverse agonist GSK5182 and CYP2E1 inhibitor chlormethiazole (CMZ) mitigated the exacerbated liver injury associated with Fgf4 deficiency. Mechanistic investigations revealed that FGFR4 phosphorylates ERRγ, promoting its ubiquitination and degradation in hepatocytes. Hepatic-specific knockout of Fgfr4 intensified alcohol-induced liver injury and nullified the protective conferred of recombinant FGF4 △NT . Conclusions: Our study identifies FGF4 as a stress-responsive regulator in liver pathophysiology, operating via an FGFR4-mediated ERRγ-CYP2E1 signaling pathway. These results underscore the potential of FGF4 and its downstream pathways as therapeutic targets for ALD treatment.
<i>BCKDHA-BCKDHB</i> digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease
Authors: Jiaming Wang, Laura E. Poskitt, Jillian Gallagher, Erik G. Puffenberger, R. Max Wynn, Gauri Shishodia, David T. Chuang, Jonathan Beever, Donald L. Hardin, Karlla W. Brigatti, William C. Baker, Rachael Gately, Stephanie Bertrand, Ashlin Rodrigues, Hector R Benatti, Toloo Taghian, Erin Hall, Rachel Prestigiacomo, Jialing Liang, Gong Chen, Xuntao Zhou, Lingzhi Ren, Nan Liu, Ran He, Qin Su, Jun Xie, Zhong Jiang, Alisha Gruntman, Heather Gray-Edwards, Guangping Gao, Kevin A. Strauss, Dan Wang
Journal: Science Translational Medicine (2025)

Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1 α ( BCKDHA ), E1 β ( BCKDHB ), or dihydrolipoamide branched-chain transacylase ( DBT ) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.h A -BiP-h B ) to the liver, muscle, heart, and brain. rAAV9.h A -BiP-h B restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA −/− HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 10 14 vector genomes per kilogram. In two models of severe MSUD ( Bckdha −/− and Bckdhb −/− mice) and a newborn calf homozygous for BCKDHA c.248C&gt;T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.
An electroadhesive hydrogel interface prolongs porcine gastrointestinal mucosal theranostics
Authors: Binbin Ying, Kewang Nan, Qing Zhu, Tom Khuu, Hana Ro, Sophia Qin, Shubing Wang, Karen Jiang, Yonglin Chen, Guangyu Bao, Josh Jenkins, Andrew Pettinari, Johannes Kuosmanen, Keiko Ishida, Niora Fabian, Aaron Lopes, Flavia Codreanu, Joshua Morimoto, Jason Li, Alison Hayward, Robert Langer, Giovanni Traverso
Journal: Science Translational Medicine (2025)

Establishing a robust and intimate mucosal interface that allows medical devices to remain within lumen-confined organs for extended periods has valuable applications, particularly for gastrointestinal theranostics. Here, we report the development of an electroadhesive hydrogel interface for robust and prolonged mucosal retention after electrical activation (e-GLUE). The e-GLUE device is composed of cationic polymers interpenetrated within a tough hydrogel matrix. An e-GLUE electrode design eliminated the need for invasive submucosal placement of ground electrodes for electrical stimulation during endoscopic delivery. With an electrical stimulation treatment of about 1 minute, the cationic polymers diffuse and interact with polyanionic proteins that have a relatively slow cellular turnover rate in the deep mucosal tissue. This mucosal adhesion mechanism increased the adhesion energy of hydrogels on the mucosa by up to 30-fold and enabled in vivo gastric retention of e-GLUE devices in a pig stomach for up to 30 days. The adhesion strength was modulated by polycationic chain length, electrical stimulation time, gel thickness, cross-linking density, voltage amplitude, polycation concentration, and perimeter-to-area ratio of the electrode assembly. In porcine studies, e-GLUE demonstrated rapid mucosal adhesion in the presence of luminal fluid and mucus exposure. In proof-of-concept studies, we demonstrated e-GLUE applications for mucosal hemostasis, sustained local delivery of therapeutics, and intimate biosensing in the gastrointestinal tract, which is an ongoing clinical challenge for commercially available alternatives, such as endoclips and mucoadhesive. The e-GLUE platform could enable theranostic applications across a range of digestive diseases, including recurrent gastrointestinal bleeding and inflammatory bowel disease.
A gut <i>Eggerthella lenta</i> –derived metabolite impairs neutrophil function to aggravate bacterial lung infection
Authors: Le-Le Wang, Xiyue Shen, Yingzhou Xie, Ai Ge, Haiwen Lu, Shuyi Gu, Lingxin Kong, Jayanth Kumar Narayana, Jochen Mattner, Sanjay H. Chotirmall, Jin-Fu Xu
Journal: Science Translational Medicine (2025)

The composition of the gut microbiota in patients with bronchiectasis has been proven to be distinct from that of healthy individuals, and this disrupted gut microbiota can exacerbate lung infections. However, the responsible microbes and mechanisms in the “gut-lung” axis in bronchiectasis remain unknown. Here, we report that Eggerthella lenta was enriched in the gut, and taurine ursodeoxycholic acid (TUDCA) was enriched in both the guts and sera of patients with bronchiectasis, with both being associated with disease severity. Fecal microbiota transfer from patients with bronchiectasis as well as administration of E. lenta independently exacerbated pulmonary Pseudomonas aeruginosa infections in murine models. E. lenta –associated TUDCA bound adenosine monophosphate–activated protein kinase (AMPK) within neutrophils and interfered with the interaction between liver kinase B1 and AMPK, with a consequential decrease in AMPK phosphorylation. This ultimately reduced ATP production in neutrophils, inhibited their function, and compromised P. aeruginosa elimination from the lung, aggravating tissue injury. Metformin treatment improved disease severity and outcome in the mouse models. In sum, the gut bacterium E. lenta raises the stakes of bacterial lung infection because it causes dysfunction of neutrophils circulated from serum to lung via the metabolite TUDCA. Interventions targeting E. lenta or AMPK phosphorylation may serve as adjunctive strategies to complement existing approaches for managing chronic pulmonary infection in bronchiectasis and other chronic respiratory disease states.
Reduced cerebellar rhythm by climbing fiber denervation is linked to motor rhythm deficits in mice and ataxia severity in patients
Authors: Chih-Chun Lin, Ke-Chu Fang, Ilaria Balbo, Ting-Yu Liang, Chia-Wei Liu, Wen-Chuan Liu, Yi-Mei Wang, Yen-Ling Hung, Kai-Chien Yang, Scott Kun Geng, Chun-Lun Ni, Christopher P. Driscoll, David S. Ruff, Ami Kumar, Nadia Amokrane, Natasha Desai, Phyllis L. Faust, Elan D. Louis, Sheng-Han Kuo, Ming-Kai Pan
Journal: Science Translational Medicine (2025)

Cerebellar ataxia results from various genetic and nongenetic disorders and is characterized by involuntary movements that impair precision and motor rhythm. Here, we report that climbing fiber (CF) denervation is a common pathophysiology underlying motor rhythm loss in cerebellar ataxia. By examining cerebellar pathology in patients with spinocerebellar ataxia (SCA) types 1, 2, and 6 and multiple system atrophy, we identified CF degeneration with synaptic loss as a shared pathophysiology. Optogenetic silencing of CF synaptic activity in mice induced ataxia-like motor dysfunctions and loss of motor precision. In addition, CF silencing resulted in cerebellar and motor rhythm loss, another core feature of ataxia. This rhythm loss was predominantly CF dependent and resistant to Purkinje cell–specific lesioning by diphtheria toxin. Correspondingly, two patients with inferior olive pathology, the brain site that provides CFs to Purkinje cells, presented with ataxia and cerebellar rhythm loss. Patients with genetic or nongenetic cerebellar ataxia exhibited cerebellar rhythm loss that correlated with the Scale for the Assessment and Rating of Ataxia. Chemogenetic stimulation of CFs improved cerebellar and motor rhythms as well as motor performance in the SCA type 1 mouse model of ataxia. These results suggest that CF-dependent cerebellar rhythm loss occurs across different types of cerebellar ataxia, contributing to motor imprecision and motor rhythm loss, two defining features of ataxia.
Bone marrow transplant protects mice from sickle cell–mediated large artery remodeling
Authors: Liana Hatoum, Hannah Song, David Alexander, Victor O. Omojola, Hannah Moore, Julia N. Frank, Edward A. Botchwey, Manu O. Platt
Journal: Science Translational Medicine (2025)

Sickle cell disease (SCD) is a hereditary blood disorder that causes sickling of red blood cells under deoxygenation, which stiffens and damages the cells. Individuals homozygous for the mutant β-globin S allele (SS) endure complications including progressive arterial damage and heightened risk of stroke. The effectiveness of bone marrow transplantation (BMT), now the only curative treatment for SCD, in halting or reversing SCD-mediated arteriopathy remains unclear. This study used two distinct conditioning regimens, x-ray irradiation and chemotherapy, in a Townes humanized murine model of SCD. Mice homozygous for the SS allele underwent BMT at 2 or 4 months of age, time points that we deemed early or late, respectively. Label-free magnetic resonance angiography (MRA) was performed to longitudinally monitor common carotid artery luminal areas in living mice pre- and repeatedly post-BMT, followed by histological analysis of the arteries at euthanasia. Myeloablative chemotherapy demonstrated higher survivability in SS mice compared with x-ray irradiation. SS mice exhibited arterial outward expansion by 3 months and thinning of the medial layer at 5 months, which are characteristics of a weakened arterial wall. BMT at 2 months effectively halted this expansion, maintaining smaller luminal areas in SS mice. However, BMT at 4 months did not reverse arteriopathy, indicating the importance of early intervention. This work emphasizes how MRA can be used as a noninvasive method for assessing arteriopathy progression and demonstrates that the timing of BMT is crucial in mitigating sickle cell–induced large artery remodeling.
How is 3D modeling in metabolic surgery utilized and what is its clinical benefit: a systematic review and meta-analysis
Authors: Henry Douglas Robb, Aksaan Arif, Rithvik Mahadev Narendranath, Bibek Das, Khaled Alyaqout, William Lynn, Yasser Abul Aal, Hutan Ashrafian, Matyas Fehervari
Journal: International Journal of Surgery (2025)

Background: Three-dimensional (3D) modeling is an emerging technology in surgery, with applications in operative planning, surgical education, and patient engagement. Metabolic surgery, the most effective treatment for obesity, is increasingly prevalent leading to new complex clinical challenges. This systematic review aims to understand the use of 3D modeling in metabolic surgery and its impact on clinical outcomes. Methods: Following a registered protocol (PROSPERO: XXX), a comprehensive search using MEDLINE, Embase, and CENTRAL Cochrane Library was conducted. Eligible papers underwent screening and full-text review. A qualitative thematic analysis was performed alongside meta-analyses on available volumetric data. Results were reported as directed by the PRISMA guidelines. Results: Twenty-nine studies were included, with most at Level II evidence ( n = 19, 66%). Studies focused on operative planning and surgical practice (90%, n = 26) and were subdivided into preoperative planning (14%, n = 4), postoperative diagnosis (31%, n = 9), and postoperative assessment and prediction (45%, n = 13). Only three papers addressed surgical education (10%). 3D modeling for patient education was unexplored. To assess 3D modeling’s cross-study consistency, pooled meta-analyses on preoperative and postoperative 3D gastric volumetry and abdominal circumference were performed. Average preoperative stomach volume was 794.93 mL (95% confidence interval [CI]: 518.61–1071.26 mL). Postoperative LSG and RYGB/OAGB gastric volumes were 171.71 mL (95% CI: 113.37–288.58 mL) and 35.73 mL (95% CI: 29.32–42.14 mL) respectively. Average abdominal circumference was 120.04 cm (95% CI: 100.72–139.35 cm). All volumes were consistent with published data. Conclusions: This systematic review highlighted the accuracy of 3D modeling for volumetric assessments and its developing role in surgical planning and training. However, its potential benefits in AR or 3DP models, in patient education or for answering bariatric surgical debates using 3D volumetric studies remain underutilized.
The role of indocyanine green in fluorescence-guided pancreatic surgery: a comprehensive review
Authors: Andrea Tufo, Anna Caterina Milanetto, Roberto Valente, Enrico Spalice, Loredana Sodano, Claudio Pasquali, Maria Chiara Scandavini, Alessandro Coppola
Journal: International Journal of Surgery (2025)

Pancreatic surgery is a complex and challenging field, with patients facing a high risk of postoperative complications. In recent years, indocyanine green (ICG) has gained prominence as a valuable tool used in various aspects of pancreatic surgery. ICG is a fluorescent dye thatoffers real-time imaging capabilities that enhance the surgeon’s ability to accurately localise tumours and critical anatomical structures, thereby improving surgical precision and potentially reducing operative time and complications. One of the most significant advantages of ICG is its ability to provide enhanced visualisation of the biliary tract and vascular structures, which is particularly beneficial in complex pancreatic resections, in which the anatomy can be highly variable and challenging to navigate. Furthermore, ICG can be instrumental in ensuring the adequate perfusion of anastomoses, thereby reducing the risk of postoperative leaks and associated morbidity. This comprehensive review aims to provide an in-depth analysis of the current applications, advantages, and limitations of ICG in pancreatic surgery.
Selective genetic inactivation of Caspase 8 in hepatocytes ameliorates progression of MASH following Jnk deficiency
Authors: Ines Volkert, Julia Grube, Marius Maximilian Woitok, Mohamed Ramadan Mohamed, Karolina Edlund, Julia Christin Duda, Jana Dietrich, Ursula Schneider, Guo Yin, Cheng Lin, Stephanie Erschfeld, Hilmar Berger, Lena Candels, Roger J. Davis, Matthias Bartneck, Mark Phillip Kühnel, Adrien Guillot, Kai Markus Schneider, Carolin Victoria Schneider, Danny Jonigk, Jörg Rahnenführer, Frank Tacke, Jan Hengstler, Christian Trautwein
Journal: Hepatology (2025)

Background and Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is associated with c-Jun N-terminal kinases (JNK) activation across various cell types, but its hepatocyte-specific function in steatotic liver disease remains unclear. Our study investigates the role of JNK1/JNK2 during MASH progression and dissect its hepatocyte-specific function. Approach and Results: We showed that UK biobank patients with a predicted-loss-of-function (pLOF) variant of JNK1 presented an increased prevalence of MASLD and liver damage. Analysis of a pathology cohort of patients with steatotic liver disease revealed increased oxidative stress response and apoptosis. After subjecting mice deficient for Jnk1 and Jnk2 in hepatocytes ( Jnk1/2 Δhepa ) to two different MASH models, we observed enhanced liver injury, fibrosis and oxidative stress. RNA sequencing revealed highly up-regulated pathways in Jnk1/2 Δhepa livers, including inflammatory signals and apoptotic pathways. Additional blocking of Caspase 8 signaling improved HFD-induced liver damage, fibrogenesis and oxidative stress. Ultimately, a therapeutic approach using lipid nanoparticles containing small interfering RNA (siRNA) targeting Caspase 8 during MASH progression attenuated liver injury and cell death in mice. Conclusions: Our findings define a protective role of JNK1/JNK2 in hepatocytes during the oxidative stress response driving progression of MASH. This process is mainly mediated by Caspase 8-dependent apoptosis, thereby discovering that Caspase 8 is a downstream target of JNK1/2. Caspase 8 directed therapy in hepatocytes might be a promising treatment for patients with an increased oxidative stress response and MASH.
Intracorporeal versus extracorporeal anastomosis in laparoscopic total gastrectomy: a systematic review and meta-analysis
Authors: Shafquat Zaman, Mohammad Iqbal Hussain, Maria Kausar, Omar E.S. Mostafa, Ali Yasen Mohamedahmed, Shahab Hajibandeh, Shahin Hajibandeh, Ricardo Camprodon, Chaminda Sellahewa
Journal: International Journal of Surgery (2025)

Background: To evaluate outcomes of intracorporeal (IOJ) versus extracorporeal (EOJ) oesophagojejunostomy following laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer. Methods: A comprehensive search of various electronic databases was conducted. Comparative studies of IOJ versus EOJ following LTG in patients with gastric malignancy were included. Primary outcomes were anastomotic leak, anastomotic bleeding, and anastomotic stricture formation. Secondary outcomes included operative time, length of hospital stay (LOS), volume of intra-operative haemorrhage, number of harvested lymph nodes, time to flatus, time to soft diet, intra-abdominal infection, pulmonary infection, surgical site infection (SSI), duodenal stump leak, pancreatic fistula occurrence, postoperative ileus, re-operation, and mortality. Combined overall effect sizes were calculated using the random-effects model, and the Newcastle-Ottawa Scale was used to assess risk of bias. Results: Seventeen non-randomised studies enrolling 2,960 patients divided between an IOJ ( n = 1430) and EOJ ( n = 1530) group were included. IOJ was associated with significantly lower risk of anastomotic stricture ( P = 0.01), volume of intra-operative bleeding ( P = &lt; 0.001), and SSI (P = 0.04) compared to EOJ. No difference was found in anastomotic leak ( P = 0.93); anastomotic bleeding ( P = 0.35); operative time ( P = 0.63); LOS ( P = 0.30); lymph node yield ( P = 0.17); time to first flatus ( P = 0.77); time to resumption of soft diet ( P = 0.32); intra-abdominal infection ( P = 0.22); pulmonary infection ( P = 0.45); duodenal stump leak ( P = 0.46); pancreatic fistula occurrence ( P = 0.16); and paralytic ileus ( P = 0.59), re-operation ( P = 0.50), and mortality ( P = 0.23) between the two groups. Conclusions: LTG for gastric malignancy with IOJ may be associated with lower risk of anastomotic stricture and SSI compared to the extracorporeal approach. However, future adequately powered randomized studies are needed to compare the two techniques.
Single-cell analysis of aplastic anemia reveals a convergence of NK and NK-like CD8 <sup>+</sup> T cells with a disease-associated TCR signature
Authors: Sofie Lundgren, Jani Huuhtanen, Mikko Keränen, Xingmin Feng, Bhavisha A. Patel, Georgina L. Ryland, Lucy C. Fox, Carlos Bravo-Perez, Michael Clemente, Cassandra Kerr, Gunilla Walldin, Olli Dufva, Yoshitaka Zaimoku, Tiina Tuononen, Mikko Myllymäki, Freja Ebeling, Emmi Jokinen, Markus Heinonen, Tiina Kasanen, Jay Klievink, Hanna Lähteenmäki, Taina Jaatinen, Sari Kytölä, Sanna Siitonen, Alina Dulau-Florea, Raul Braylan, Merja Heinäniemi, Shinji Nakao, Eva Hellström-Lindberg, Jaroslaw P. Maciejewski, Piers Blombery, Neal S. Young, Harri Lähdesmäki, Satu Mustjoki
Journal: Science Translational Medicine (2025)

Immune aplastic anemia (AA) is a life-threatening bone marrow failure disorder driven by an autoimmune T cell attack against hematopoietic stem and progenitor cells (HSPCs). However, the exact autoantigen targets and role of other immune cells in the pathogenesis of AA are unknown. Here, we analyzed a cohort of 218 patients with AA using single-cell RNA and T cell receptor (TCR) αβ sequencing, TCRβ sequencing, flow cytometry, and plasma cytokine profiling. We identified natural killer (NK) cells and CD8 + terminally differentiated effector T (T EMRA ) cells expressing NK receptors with AA-associated TCRβ motifs as the most dysregulated immune cell populations in AA bone marrow. Functional coculture experiments using primary HSPCs and immune cells showed that NK cells cannot kill HSPCs alone but may sensitize HSPCs to CD8 + T cell–mediated killing through production of interferons. Furthermore, HSPCs induced activation of T cell clones with CD8 + T EMRA NK-like phenotype in coculture. Our results reveal a convergent phenotype of innate and adaptive immune cells that may drive AA.