tbuckley/cabot-search huggingface dataset:
A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis
Authors: Arun J Sanyal, Pierre Bedossa, Mandy Fraessdorf, Guy W Neff, Eric Lawitz, Elisabetta Bugianesi, Quentin M Anstee, Samina Ajaz Hussain, Philip N Newsome, Vlad Ratziu, Azadeh Hosseini-Tabatabaei, Jörn M Schattenberg, Mazen Noureddin, Naim Alkhouri, Ramy Younes
Journal: New England Journal of Medicine (2024)

BackgroundDual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction–associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear.MethodsIn this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage F1 through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4, 4.8, or 6.0 mg or placebo. The trial had two phases: a 24-week rapid-dose-escalation phase, followed by a 24-week maintenance phase. The primary end point was histologic improvement (reduction) in MASH with no worsening of fibrosis. Secondary end points included a decrease in liver fat content by at least 30% and biopsy-assessed improvement (reduction) in fibrosis by at least one stage.ResultsA total of 293 randomly assigned participants received at least one dose of survodutide or placebo. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group (P<0.001 for the quadratic dose–response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events that were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo.ConclusionsSurvodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials. (Funded by Boehringer Ingelheim; 1404-0043 ClinicalTrials.gov number, NCT04771273; EudraCT number, 2020-002723-11.)
Recent Advances in Understanding the Molecular Basis of Infantile Haemangioma Development
Authors: Raka Mitra, Helen L Fitzsimons, Tracy Hale, Swee T Tan, Clint Gray, Madeleine P J White
Journal: British Journal of Dermatology (2024)

Infantile haemangioma (IH), the most common vascular tumour of infancy, is comprised of diverse cell types including endothelial cells, pericytes, fibroblasts and immune cells. IH is characterized by rapid proliferation followed by slow involution over 1 - 10 years. Most lesions regress spontaneously, but up to 10% can be disfiguring with complications that require further medical treatment. Recent research has revealed the biological characteristics of IH, highlighting the involvement of angiogenesis and vasculogenesis during tumour formation. Gene expression profiling has provided vital insights into these underlying biological processes, with some of the key IH-related pathways identified, including VEGF, RAAS, HIF-1α, Notch, PDGF, PI3K/Akt/mTOR, JAK/STAT, FGF, PPARγ, IGF. Further evidence suggests extracellular matrix factors and hormone receptors regulate IH progression. In this review, we explore the molecular mechanisms involved in the proliferating, plateau and involuting phases of IH. This involves identifying differentially expressed genes, targeted proteins, and key signalling pathways. This knowledge will increase the broader understanding of vascular development, tissue remodelling and angiogenesis.
Keeping up with the pathogens: improved antimicrobial resistance detection and prediction from Pseudomonas aeruginosa genomes
Authors: Danielle E. Madden, Timothy Baird, Scott C. Bell, Kate L. McCarthy, Erin P. Price, Derek S. Sarovich
Journal: Genome Medicine (2024)

Abstract Background Antimicrobial resistance (AMR) is an intensifying threat that requires urgent mitigation to avoid a post-antibiotic era. Pseudomonas aeruginosa represents one of the greatest AMR concerns due to increasing multi- and pan-drug resistance rates. Shotgun sequencing is gaining traction for in silico AMR profiling due to its unambiguity and transferability; however, accurate and comprehensive AMR prediction from P. aeruginosa genomes remains an unsolved problem. Methods We first curated the most comprehensive database yet of known P. aeruginosa AMR variants. Next, we performed comparative genomics and microbial genome-wide association study analysis across a Global isolate Dataset ( n = 1877) with paired antimicrobial phenotype and genomic data to identify novel AMR variants. Finally, the performance of our P. aeruginosa AMR database, implemented in our AMR detection and prediction tool, ARDaP, was compared with three previously published in silico AMR gene detection or phenotype prediction tools—abritAMR, AMRFinderPlus, ResFinder—across both the Global Dataset and an analysis-naïve Validation Dataset ( n = 102). Results Our AMR database comprises 3639 mobile AMR genes and 728 chromosomal variants, including 75 previously unreported chromosomal AMR variants, 10 variants associated with unusual antimicrobial susceptibility, and 281 chromosomal variants that we show are unlikely to confer AMR. Our pipeline achieved a genotype-phenotype balanced accuracy (bACC) of 85% and 81% across 10 clinically relevant antibiotics when tested against the Global and Validation Datasets, respectively, vs. just 56% and 54% with abritAMR, 58% and 54% with AMRFinderPlus, and 60% and 53% with ResFinder. ARDaP’s superior performance was predominantly due to the inclusion of chromosomal AMR variants, which are generally not identified with most AMR identification tools. Conclusions Our ARDaP software and associated AMR variant database provides an accurate tool for predicting AMR phenotypes in P. aeruginosa , far surpassing the performance of current tools. Implementation of ARDaP for routine AMR prediction from P. aeruginosa genomes and metagenomes will improve AMR identification, addressing a critical facet in combatting this treatment-refractory pathogen. However, knowledge gaps remain in our understanding of the P. aeruginosa resistome, particularly the basis of colistin AMR.
Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy
Authors: Marc Zuckermann, Chen He, Jared Andrews, Aditi Bagchi, Roketa Sloan-Henry, Brandon Bianski, Jia Xie, Yingzhe Wang, Nathaniel Twarog, Arzu Onar-Thomas, Kati J. Ernst, Lei Yang, Yong Li, Xiaoyan Zhu, Jennifer K. Ocasio, Kaitlin M. Budd, James Dalton, Xiaoyu Li, Divyabharathi Chepyala, Junyuan Zhang, Ke Xu, Laura Hover, Jordan T. Roach, Kenneth Chun-Ho Chan, Nina Hofmann, Peter J. McKinnon, Stefan M. Pfister, Anang A. Shelat, Zoran Rankovic, Burgess B. Freeman, Jason Chiang, David T. W. Jones, Christopher L. Tinkle, Suzanne J. Baker
Journal: Molecular Cancer (2024)

Abstract Background Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. Methods To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. Results Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. Conclusions We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.
Gut microbiota depletion delays somatic peripheral nerve development and impairs neuromuscular junction maturation
Authors: Matilde Cescon, Giovanna Gambarotta, Sonia Calabrò, Chiara Cicconetti, Francesca Anselmi, Svenja Kankowski, Luisa Lang, Marijana Basic, Andre Bleich, Silvia Bolsega, Matthias Steglich, Salvatore Oliviero, Stefania Raimondo, Dario Bizzotto, Kirsten Haastert-Talini, Giulia Ronchi
Journal: Gut Microbes (2024)

Gut microbiota is responsible for essential functions in human health. Several communication axes between gut microbiota and other organs via neural, endocrine, and immune pathways have been described, and perturbation of gut microbiota composition has been implicated in the onset and progression of an emerging number of diseases. Here, we analyzed peripheral nerves, dorsal root ganglia (DRG), and skeletal muscles of neonatal and young adult mice with the following gut microbiota status: a) germ-free (GF), b) gnotobiotic, selectively colonized with 12 specific gut bacterial strains (Oligo-Mouse-Microbiota, OMM12), or c) natural complex gut microbiota (CGM). Stereological and morphometric analyses revealed that the absence of gut microbiota impairs the development of somatic median nerves, resulting in smaller diameter and hypermyelinated axons, as well as in smaller unmyelinated fibers. Accordingly, DRG and sciatic nerve transcriptomic analyses highlighted a panel of differentially expressed developmental and myelination genes. Interestingly, the type III isoform of Neuregulin1 (NRG1), known to be a neuronal signal essential for Schwann cell myelination, was overexpressed in young adult GF mice, with consequent overexpression of the transcription factor Early Growth Response 2 (
Chaperone- and PTM-mediated activation of IRF1 tames radiation-induced cell death and the inflammatory response
Authors: Fenghao Geng, Jianhui Chen, Bin Song, Zhicheng Tang, Xiaoqian Li, Shuaijun Zhang, Tingyi Yang, Yulan Liu, Wei Mo, Yining Zhang, Chuntang Sun, Lei Tan, Wenling Tu, Daojiang Yu, Jianping Cao, Shuyu Zhang
Journal: Cellular and Molecular Immunology (2024)
Characteristics of a cost-effective blood test for colorectal cancer screening
Authors: Pedro Nascimento de Lima, Rosita van den Puttelaar, Amy B Knudsen, Anne I Hahn, Karen M Kuntz, Jonathan Ozik, Nicholson Collier, Fernando Alarid-Escudero, Ann G Zauber, John M Inadomi, Iris Lansdorp-Vogelaar, Carolyn M Rutter
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Blood-based biomarker tests can potentially change the landscape of colorectal cancer (CRC) screening. We characterize the conditions under which blood test screening would be as effective and cost-effective as annual fecal immunochemical testing or decennial colonoscopy. Methods We used the 3 Cancer Information and Surveillance Modeling Network–Colon models to compare scenarios of no screening, annual fecal immunochemical testing, decennial colonoscopy, and a blood test meeting Centers for Medicare &amp; Medicaid (CMS) coverage criteria (74% CRC sensitivity and 90% specificity). We varied the sensitivity to detect CRC (74%-92%), advanced adenomas (10%-50%), screening interval (1-3 years), and test cost ($25-$500). Primary outcomes included quality-adjusted life-years (QALY) gained from screening and costs for a US average-risk cohort of individuals aged 45 years. Results Annual fecal immunochemical testing yielded 125-163 QALY gained per 1000 at a cost of $3811-$5384 per person, whereas colonoscopy yielded 132-177 QALY gained at a cost of $5375-$7031 per person. A blood test with 92% CRC sensitivity and 50% advanced adenoma sensitivity yielded 117-162 QALY gained if used every 3 years and 133-173 QALY gained if used every year but would not be cost-effective if priced above $125 per test. If used every 3 years, a $500 blood test only meeting CMS coverage criteria yielded 83-116 QALY gained at a cost of $8559-$9413 per person. Conclusion Blood tests that only meet CMS coverage requirements should not be recommended to patients who would otherwise undergo screening by colonoscopy or fecal immunochemical testing because of lower benefit. Blood tests need higher advanced adenoma sensitivity (above 40%) and lower costs (below $125) to be cost-effective.
Co-existing Neuroendocrine Tumors in the Ileum and Pancreas: A Clinico-Pathological Challenge
Authors: Alice Laffi, Alexia Francesca Bertuzzi, Silvia Carrara, Alessandro Zerbi, Andrea Lania, Elisabetta Lavezzi, Giuseppe Ferrillo, Jelena Jandric, Carlo Carnaghi, Roberta Elisa Rossi, Maria Susanna Grimaudo, Paola Spaggiari, Silvia Uccella
Journal: Endocrine Pathology (2024)
Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets
Authors: Shenglan Liu, Wei Dai, Bei Jin, Feng Jiang, Hao Huang, Wen Hou, Jinxia Lan, Yanli Jin, Weijie Peng, Jingxuan Pan
Journal: Molecular Cancer (2024)

Abstract Metastasis remains the principal cause of cancer-related lethality despite advancements in cancer treatment. Dysfunctional epigenetic alterations are crucial in the metastatic cascade. Among these, super-enhancers (SEs), emerging as new epigenetic regulators, consist of large clusters of regulatory elements that drive the high-level expression of genes essential for the oncogenic process, upon which cancer cells develop a profound dependency. These SE-driven oncogenes play an important role in regulating various facets of metastasis, including the promotion of tumor proliferation in primary and distal metastatic organs, facilitating cellular migration and invasion into the vasculature, triggering epithelial-mesenchymal transition, enhancing cancer stem cell-like properties, circumventing immune detection, and adapting to the heterogeneity of metastatic niches. This heavy reliance on SE-mediated transcription delineates a vulnerable target for therapeutic intervention in cancer cells. In this article, we review current insights into the characteristics, identification methodologies, formation, and activation mechanisms of SEs. We also elaborate the oncogenic roles and regulatory functions of SEs in the context of cancer metastasis. Ultimately, we discuss the potential of SEs as novel therapeutic targets and their implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies.
Evaluating a blood test for Colon cancer screening: how simulation modeling can inform clinical policy making and research
Authors: David F Ransohoff
Journal: JNCI Journal of the National Cancer Institute (2024)

Screening for colorectal cancer (CRC) has been shown to reduce cancer specific mortality in several randomized controlled clinical trials (RCT) involving stool blood tests and endoscopy.Absent direct evidence from RCTs, new screening tests are often evaluated by simulation modeling that can project impact on outcome.Blood tests for CRC, measuring tumor-associated analytes including from DNA, RNA, and proteins, may provide improved convenience and adherence compared to current tests, but cancer signal may be diluted compared to stool-based tests or direct examination by colonoscopy.Colonoscopy serves as a primary screening test and also in follow-up when a triage test, stool-based or blood-based, is positive.A triage test needs high sensitivity for early cancer or important precancerous lesions like advanced adenomas
Serum and Urine Metabolites and Kidney Function
Authors: Wan-Jin Yeo, Aditya L. Surapaneni, Denise C. Hasson, Insa M. Schmidt, Peggy Sekula, Anna Köttgen, Kai-Uwe Eckardt, Casey M. Rebholz, Bing Yu, Sushrut S. Waikar, Eugene P. Rhee, Sarah J. Schrauben, Harold I. Feldman, Ramachandran S. Vasan, Paul L. Kimmel, Josef Coresh, Morgan E. Grams, Pascal Schlosser
Journal: Journal of the American Society of Nephrology (2024)

Key Points We provide an atlas of cross-sectional and longitudinal serum and urine metabolite associations with eGFR and urine albumin-creatinine ratio in an older community-based cohort. Metabolic profiling in serum and urine provides distinct and complementary insights into disease. Background Metabolites represent a read-out of cellular processes underlying states of health and disease. Methods We evaluated cross-sectional and longitudinal associations between 1255 serum and 1398 urine known and unknown (denoted with “X” in name) metabolites (Metabolon HD4, 721 detected in both biofluids) and kidney function in 1612 participants of the Atherosclerosis Risk in Communities study. All analyses were adjusted for clinical and demographic covariates, including for baseline eGFR and urine albumin-creatinine ratio (UACR) in longitudinal analyses. Results At visit 5 of the Atherosclerosis Risk in Communities study, the mean age of participants was 76 years (SD 6); 56% were women, mean eGFR was 62 ml/min per 1.73 m 2 (SD 20), and median UACR level was 13 mg/g (interquartile range, 25). In cross-sectional analysis, 675 serum and 542 urine metabolites were associated with eGFR (Bonferroni-corrected P &lt; 4.0E-5 for serum analyses and P &lt; 3.6E-5 for urine analyses), including 248 metabolites shared across biofluids. Fewer metabolites (75 serum and 91 urine metabolites, including seven metabolites shared across biofluids) were cross-sectionally associated with albuminuria. Guanidinosuccinate; N2,N2-dimethylguanosine; hydroxy-N6,N6,N6-trimethyllysine; X-13844; and X-25422 were significantly associated with both eGFR and albuminuria. Over a mean follow-up of 6.6 years, serum mannose (hazard ratio [HR], 2.3 [1.6–3.2], P = 2.7E-5) and urine X-12117 (HR, 1.7 [1.3–2.2], P = 1.9E-5) were risk factors of UACR doubling, whereas urine sebacate (HR, 0.86 [0.80–0.92], P = 1.9E-5) was inversely associated. Compared with clinical characteristics alone, including the top five endogenous metabolites in serum and urine associated with longitudinal outcomes improved the outcome prediction (area under the receiver operating characteristic curves for eGFR decline: clinical model=0.79, clinical+metabolites model=0.87, P = 8.1E-6; for UACR doubling: clinical model=0.66, clinical+metabolites model=0.73, P = 2.9E-5). Conclusions Metabolomic profiling in different biofluids provided distinct and potentially complementary insights into the biology and prognosis of kidney diseases.
Glomerular Endothelial Cell Receptor ADGRF5 and the Integrity of the Glomerular Filtration Barrier
Authors: Miki Nagase, Hikaru Ando, Yoshiaki Beppu, Hidetake Kurihara, Souta Oki, Fumimasa Kubo, Kazuki Yamamoto, Takashi Nagase, Shinya Kaname, Yoshihiro Akimoto, Hiroshi Fukuhara, Tatsuo Sakai, Shigehisa Hirose, Nobuhiro Nakamura
Journal: Journal of the American Society of Nephrology (2024)

Key Points Deletion of endothelial receptor adhesion G-protein–coupled receptor F5 in mice led to abnormal structural and functional properties of the glomerular filtration barrier. Adhesion G-protein–coupled receptor F5 regulates gene expression of glomerular basement membrane components and a mechanosensitive transcription factor. Background Glomerular endothelial cells are recognized to be important for maintaining the glomerular filtration barrier. Adhesion G-protein–coupled receptor F5 (ADGRF5), an adhesion G protein–coupled receptor, has been suggested to be involved in endothelial cell function. However, the role of ADGRF5 in the glomerular filtration barrier integrity remains elusive. Methods Cellular expression of ADGRF5 in mouse glomerulus was determined by histological analyses. The effect of ADGRF5 deletion on the glomerular morphology, kidney function, and glomerular endothelial gene/protein expression was then analyzed using ADGRF5 knockout ( Adgrf5 −/− ) mice and human primary glomerular endothelial cells. Results ADGRF5 was specifically expressed in the capillary endothelial cells within the glomerulus. Adgrf5 −/− mice developed albuminuria and impaired kidney function with morphological defects in the glomeruli, namely glomerular hypertrophy, glomerular basement membrane splitting and thickening, diaphragmed fenestration and detachment of the glomerular endothelial cells, and mesangial interposition. These defects were accompanied by the altered expression of genes responsible for glomerular basement membrane organization (type 4 collagens and laminins) and Krüppel-like factor 2 ( Klf2 ) in glomerular endothelial cells. Moreover, ADGRF5 knockdown decreased COL4A3 and COL4A4 expression and increased KLF2 expression in human primary glomerular endothelial cells. Conclusions The loss of ADGRF5 resulted in altered gene expression in glomerular endothelial cells and perturbed the structure and permselectivity of the glomerular filtration barrier.
Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH
Authors: Ziqi Huang, Kun Zhang, Yurui Jiang, Mengmeng Wang, Mei Li, Yuda Guo, Ruolin Gao, Ning Li, Chenyang Wang, Jia Chen, Jiefu Wang, Ning Liu, Xiang Liu, Shuangwei Liu, Mingming Wei, Cheng Yang, Guang Yang
Journal: Acta Pharmaceutica Sinica B (2024)

Cancer stem cells (CSCs) play a pivotal role in tumor initiation, proliferation, metastasis, drug resistance, and recurrence. Consequently, targeting CSCs has emerged as a promising avenue for cancer therapy. Recently, 3-phosphoglycerate dehydrogenase (PHGDH) has been identified as being intricately associated with the regulation of numerous cancer stem cells. Yet, reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited. In this study, the novel "molecular glue" LXH-3-71 was identified, and it robustly induced degradation of PHGDH, thereby modulating the stemness of colorectal cancer cells (CRCs) both