tbuckley/cabot-search huggingface dataset:
Frailty and risk of metabolic dysfunction–associated steatotic liver disease and other chronic liver diseases
Authors: Qi Zhong, Rui Zhou, Yi-Ning Huang, Rui-Dian Huang, Fu-Rong Li, Hao-Wen Chen, Yan-Fei Wei, Kuan Liu, Bi-Fei Cao, Kai-Yue Liao, Zheng-Yun Xu, Shi-Ao Wang, Xian-Bo Wu
Journal: Journal of Hepatology (2024)
Dysglycemia and liver lipid content determine the relationship of insulin resistance with hepatic OXPHOS capacity in obesity
Authors: Sabine Kahl, Klaus Straßburger, Giovanni Pacini, Nina Trinks, Kalliopi Pafili, Lucia Mastrototaro, Bedair Dewidar, Theresia Sarabhai, Sandra Trenkamp, Irene Esposito, Matthias Schlensak, Frank A. Granderath, Michael Roden
Journal: Journal of Hepatology (2024)

Highlights•Glycemia and liver lipid content jointly affect the adaptation of hepatic oxidative capacity to insulin resistance•Prediabetes affects hepatic insulin signaling, mitochondrial dynamics and relates to fibrosis prevalence•Fasting plasma glucose predicts the decline of hepatic mitochondrial plasticity more robustly than 2-hour OGTT glucoseAbstractBackground & AimsHepatic mitochondrial respiration is higher in steatosis, but lower in overt type 2 diabetes. We hypothesized that hepatic OXPHOS capacity increases with a greater degree of insulin resistance in obesity, independent of other metabolic diseases.MethodsWe analysed 65 humans without diabetes (BMI 50±7 kg/m2, HbA1c 5.5±0.4%) undergoing bariatric surgery. MASLD stages were assessed by histology, whole-body insulin sensitivity (PREDIcted-M index) by oral glucose tolerance tests, and maximal ADP-stimulated mitochondrial OXPHOS capacity by high-resolution respirometry of liver samples.ResultsPrediabetes was present in 30 participants, and MASLD in 46 participants. Thereof, 25 had metabolic dysfunction-associated steatohepatitis (MASH), and seven had F2-F3 fibrosis. While simple regression did not detect an association of insulin sensitivity with hepatic OXPHOS capacity, interaction analyses revealed that the regression coefficient of OXPHOS capacity depended on fasting plasma glucose (FPG) and liver lipid content. Interestingly, the respective slopes were negative for FPG ≤100 mg/dl, but positive for FPG >100 mg/dl. Liver lipid content displayed similar behavior, with a threshold value of 24%. Post-challenge glycemia affected the association between insulin sensitivity and OXPHOS capacity normalized for citrate synthase activity. Presence of prediabetes affected hepatic insulin signaling, mitochondrial dynamics and fibrosis prevalence, while the presence of MASLD related to higher biomarkers of hepatic inflammation, cell damage and lipid peroxidation in people with normal glucose tolerance.ConclusionsRising liver lipid contents and plasma glucose concentrations, even in the non-diabetic range, are associated with a progressive decline of hepatic mitochondrial adaptation in people with obesity and insulin resistance.ClinTrials.gov identifierNCT01477957Graphical abstract
Cyclin-dependent kinase 4 drives cystic kidney disease in the absence of mTORC1 signaling activity.
Authors: Florian Grahammer, Bernhard Dumoulin, Ramila E. Gulieva, Hui Wu, Yaoxian Xu, Nurgazy Sulaimanov, Frederic Arnold, Lukas Sandner, Tomke Cordts, Abhijeet Todkar, Pierre Moulin, Wilfried Reichardt, Victor G. Puelles, Rafael Kramann, Benjamin S. Freedman, Hauke Busch, Melanie Boerries, Gerd Walz, Tobias B. Huber
Journal: Kidney International (2024)

Progression of cystic kidney disease has been linked to activation of the mTORC1 signaling pathway. Yet the utility of mTORC1 inhibitors to treat patients with polycystic kidney disease remains controversial despite promising preclinical data. To define the cell intrinsic role of mTORC1 for cyst development, the mTORC1 subunit gene Raptor was selectively inactivated in kidney tubular cells lacking cilia due to simultaneous deletion of the kinesin family member gene Kif3A. In contrast to a rapid onset of cyst formation and kidney failure in mice with defective ciliogenesis, both kidney function, cyst formation discerned by magnetic resonance imaging and overall survival were strikingly improved in mice additionally lacking Raptor. However, these mice eventually succumbed to cystic kidney disease despite mTORC1 inactivation. In-depth transcriptome analysis revealed the rapid activation of other growth-promoting signaling pathways, overriding the effects of mTORC1 deletion and identified cyclin-dependent kinase (CDK) 4 as an alternate driver of cyst growth. Additional inhibition of CDK4-dependent signaling by the CDK4/6 inhibitor Palbociclib markedly slowed disease progression in mice and human organoid models of polycystic kidney disease and potentiated the effects of mTORC1 deletion/inhibition. Our findings indicate that cystic kidneys rapidly adopt bypass mechanisms typically observed in drug resistant cancers. Thus, future clinical trials need to consider combinatorial or sequential therapies to improve therapeutic efficacy in patients with cystic kidney disease.Graphical abstract
A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease
Authors: Viknesh Selvarajah, Darren Robertson, Lars Hansen, Lutz Jermutus, Kirsten Smith, Angela Coggi, José Sánchez, Yi-Ting Chang, Hongtao Yu, Joanna Parkinson, Anis Khan, H. Sophia Chung, Sonja Hess, Richard Dumas, Tabbatha Duck, Simran Jolly, Tom G. Elliott, John Baker, Albert Lecube, Karl-Michael Derwahl, Russell Scott, Cristobal Morales, Carl Peters, Ronald Goldenberg, Victoria E.R. Parker, Hiddo J.L. Heerspink
Journal: Kidney International (2024)

<h2>Abstract</h2> Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD ,estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m<sup>2</sup> and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks treatment with standard of care plus subcutaneous cotadutide up-titrated to100, 300, or 600 μg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once-weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m<sup>2</sup>, geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium–glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 μg (−43.9% [95%confidence interval −54.7 to −30.6]) and 600 μg (−49.9% [−59.3 to −38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 μg were comparable to semaglutide. Thus, our study shows that in patients with T2Dand CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study.
A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B
Authors: Moon Haeng Hur, Terry Cheuk-Fung Yip, Seung Up Kim, Hyun Woong Lee, Han Ah Lee, Hyung-Chul Lee, Grace Lai-Hung Wong, Vincent Wai-Sun Wong, Jun Yong Park, Sang Hoon Ahn, Beom Kyung Kim, Hwi Young Kim, Yeon Seok Seo, Hyunjae Shin, Jeayeon Park, Yunmi Ko, Youngsu Park, Yun Bin Lee, Su Jong Yu, Sang Hyub Lee, Yoon Jun Kim, Jung-Hwan Yoon, Jeong-Hoon Lee
Journal: Journal of Hepatology (2024)
Early versus Delayed Timing of Primary Repair after Open-Globe Injury
Authors: David McMaster, James Bapty, Lana Bush, Giuseppe Serra, Theo Kempapidis, Scott F. McClellan, Fasika A. Woreta, Grant A. Justin, Rupesh Agrawal, Annette K. Hoskin, Kara Cavuoto, James Leong, Andrés Rousselot Ascarza, John Cason, Kyle E. Miller, Matthew C. Caldwell, William G. Gensheimer, Tom H. Williamson, Felipe Dhawahir-Scala, Peter Shah, Andrew Coombes, Gangadhara Sundar, Robert A. Mazzoli, Malcolm Woodcock, Stephanie L. Watson, Ferenc Kuhn, Marcus Colyer, Renata S.M. Gomes, Richard J. Blanch
Journal: Ophthalmology (2024)

The timing of primary repair of open-globe injury is variable in major trauma centers worldwide, and consensus on optimal timing is lacking. Surgery is the mainstay of open-globe injury management, and appropriate timing of surgical repair may minimize the risk of potentially blinding complications such as endophthalmitis, thereby optimizing visual outcomes. A systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (International Prospective Register of Systematic Reviews identifier, CRD42023442972). The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and ISRCTN registries and ClinicalTrials.gov were searched from inception through October 29, 2023. Prospective and retrospective nonrandomized studies of patients with open-globe injury with a minimum of 1 month of follow-up after primary repair were included. Primary outcomes included visual acuity at last follow-up and the proportion of patients with endophthalmitis. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. Fifteen studies met inclusion criteria, reporting a total of 8497 eyes. The most common injury types were penetrating and intraocular foreign body (IOFB). Meta-analysis found that primary repair less than 24 hours after open-globe injury was associated with 0.30 odds of endophthalmitis compared with primary repair conducted more than 24 hours after trauma (odds ratio, 0.39; 95% confidence interval [CI], 0.19-0.79; I2 = 95%; P = 0.01). No significant difference was found in reported visual outcomes between patients whose open-globe injuries were repaired more than, compared with less than, 24 hours after trauma (odds ratio, 0.89; 95% CI, 0.61-1.29; I2 = 70%; P = 0.52). All included studies were retrospective and nonrandomized, demonstrating an overall low certainty of evidence on GRADE assessment. Only retrospective data exist around the effect of timing of open-globe repair, resulting in low certainty of the available evidence. However, this review of current evidence, predominantly including penetrating and IOFB injuries, suggests that primary repair performed less than 24 hours after open-globe injury is associated with a reduced endophthalmitis rate compared with longer delays, consistent with delay to primary repair increasing endophthalmitis risk. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Activation of Wnt/β-catenin signaling is critical for the tumorigenesis of choroid plexus
Authors: Kim Hoa Ho, Marleen Trapp, Catello Guida, Ekaterina L Ivanova, Anchel De Jaime-Soguero, Ammar Jabali, Christian Thomas, Alena Salasova, Ondřej Bernatík, Chiara Salio, Sandra Horschitz, Martin Hasselblatt, Marco Sassoè-Pognetto, Lukáš Čajánek, Hiroshi Ishikawa, Horst Schroten, Christian Schwerk, Sergio P Acebrón, Peter Angel, Philipp Koch, Annarita Patrizi
Journal: Neuro-Oncology (2024)

Abstract Background The choroid plexus (ChP) is the secretory epithelial structure located in the brain ventricles. Choroid plexus tumors (CPTs) are rare neoplasms predominantly occurring in young patients with intensified malignancy in children. CPT treatment is hindered by insufficient knowledge of tumor pathology and the limited availability of valid models. Methods Genomic and transcriptomic data from CPT patients were analyzed to identify the putative pathological pathway. Cellular and molecular techniques were employed to validate bioinformatic results in CPT patient samples. Pharmacologic inhibition of Wnt/β-catenin signaling was assessed in CPT cells. Cell-based assays of ChP cell lines were performed following CRISPR-Cas9-derived knockout and overexpression of Wnt/β-catenin pathway genes. A 3D CPT model was generated through CRISPR-Cas9-derived knockout of APC. Results We discovered that Wnt/β-catenin signaling is activated in human CPTs, likely as a consequence of large-scale chromosomal instability events of the CPT genomes. We demonstrated that CPT-derived cells depend on autocrine Wnt/β-catenin signaling for survival. Constitutive Wnt/β-catenin pathway activation, either through knockout of the negative regulator APC or overexpression of the ligand WNT3A, induced tumorigenic properties in ChP 2D in vitro models. Increased activation of the Wnt/β-catenin pathway in ChP organoids, through treatment with a potent GSK3β inhibitor, reduced the differentiation of mature ChP epithelial cells. Remarkably, the depletion of APC was sufficient to induce the oncogenic transformation of ChP organoids. Conclusions Our research identifies Wnt/β-catenin signaling as a critical driver of CPT tumorigenesis and provides the first 3D in vitro model for future pathological and therapeutic studies of CPT.
The deubiquitinase USP44 enhances cisplatin chemosensitivity through stabilizing STUB1 to promote LRPPRC degradation in neuroblastoma
Authors: Liang Zeng, Ying-Qing Li, Shi-Wei He, Hui Xu, Ruizhong Zhang, Kai Chen, Liang-Jun Qin, Xun-Hua Zhu, Yi-Lin Li, Le Li, Na Liu, Hai-Yun Wang
Journal: Neuro-Oncology (2024)

Dysregulated deubiquitinating enzymes (DUBs) execute as intrinsic oncogenes or tumor suppressors and are involved in chemoresistance in cancers. However, the functions and exact molecular mechanisms remain largely unclear in neuroblastoma.
NEJM at ESC — Inflammation, Cholesterol, Lipoprotein(a) and 30-Year Cardiovascular Outcomes in Women
Authors: Eric J. Rubin, Jane Leopold, Stephen Morrissey
Journal: New England Journal of Medicine (2024)

Audio Interview NEJM at ESC — Inflammation, Cholesterol, Lipoprotein(a) and 30-Year Cardiovascular Outcomes in Women 3m 46s Download
Prevention of Cardiovascular Disease — Don’t Stop Thinking about Tomorrow
Authors: Roger S Blumenthal, Seth S Martin
Journal: New England Journal of Medicine (2024)

Taking a long-term view of cardiovascular disease prevention is an attractive strategy since atherosclerosis begins early in life and progresses over decades. Lowering low-density lipoprotein (LDL) cholesterol levels and improving lifestyle habits are mainstay strategies for reducing the risk of cardiovascular disease.1 Moreover, emerging therapeutic targets include vascular inflammation as reflected by elevated levels of high-sensitivity C-reactive protein (CRP) and lipoprotein(a). Ridker et al. now report in the Journal the results of an examination of the long-term predictive value of a single baseline measurement of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels in nearly 28,000 healthy, female, U.S. health professionals . . .
Regulation of KIF23 by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma
Authors: Mirco Castoldi, Sanchari Roy, Carolin Angendohr, Rossella Pellegrino, Mihael Vucur, Michael T. Singer, Veronika Buettner, Matthias A. Dille, Stephanie D. Wolf, Lara R. Heij, Ahmed Ghallab, Wiebke Albrecht, Jan G. Hengstler, Georg Flügen, Wolfram T. Knoefel, Johannes G. Bode, Lars Zender, Ulf P. Neumann, Mathias Heikenwälder, Thomas Longerich, Christoph Roderburg, Tom Luedde
Journal: Journal of Hepatology (2024)
Basophil activation test is a complementary tool in the diagnosis of immediate reactions to platinum salts and taxanes
Authors: Gádor Bogas, Adriana Ariza, Paula Vázquez‐Revuelta, Marina Labella, Ricardo Madrigal‐Burgaleta, Rubén Fernández‐Santamaría, Silvia Calvo‐Serrano, Esther Villar‐Chamorro, Susana Martín‐Clavo, Clara Lebrón‐Martín, Cristobalina Mayorga, Inmaculada Doña, Maria J. Torres
Journal: Allergy (2024)

Abstract Background Delabelling pathways offer confirmatory diagnosis and can prevent unnecessary second‐line therapies or drug desensitization procedures after chemotherapeutic hypersensitivity reactions (CHT‐HSRs). However, these pathways rely on risky in vivo tests. Data on whether in vitro tests could be helpful are scarce. We assessed the role of basophil activation test (BAT) in the diagnosis of HSRs to platin salts (PSs) and taxanes (TXs) in a well‐defined population featuring varied endophenotypes and severities of HSRs. Methods We conducted a 3‐year‐long multicentric, prospective study with 121 suspected‐immediate CHT‐HSR patients. The allergy workup included clinical history (initial reaction based on Type I, cytokine release syndrome, and mixed phenotype's symptoms and if unable to fit in any of these, as “indeterminate”), skin testing (ST), and drug provocation testing (DPT), provided risk assessment was favorable. Final diagnosis classified patients as “hypersensitive,” “non‐hypersensitive,” or “inconclusive.” We performed BAT using CD63 and CD203c as activation markers in patients and controls. Patients underwent DPT regardless of BAT results to prevent bias. Results ST positivity significantly correlated with skin involvement, Type I phenotype, cancer recurrence, and lifetime exposures before reactions. DPTs were negative in all indeterminate phenotype patients ( p = .02) and those considered low‐risk, whereas they were negative in 62% moderate‐risk patients. 55% were confirmed as hypersensitive (mainly Type I reactions, p &lt; .0001), 24% as non‐hypersensitive (mainly TXs and indeterminate phenotypes), and 21% as inconclusive. BAT showed 79% sensitivity in Type I IgE‐mediated reactions to PSs with a high correlation to ST. Conclusions BAT is a promising tool for delabelling and endotyping CHT‐HSRs, especially Type I reactions to PSs, possibly identifying patients at risk of positive DPT. ST seems useful in confirming CHT‐HSRs, especially PS‐induced reactions, and DPT remains the gold standard, being essential even in moderate‐risk patients.
Diverse origins of near-identical antifreeze proteins in unrelated fish lineages provide insights into evolutionary mechanisms of new gene birth and protein sequence convergence
Authors: Nathan Rives, Vinita Lamba, C -H Christina Cheng, Xuan Zhuang
Journal: Molecular Biology and Evolution (2024)

Abstract Determining the origins of novel genes and the mechanisms driving the emergence of new functions is challenging yet crucial for understanding evolutionary innovations. Recently evolved fish antifreeze proteins (AFPs) offer a unique opportunity to explore these processes, particularly the near-identical type I AFP (AFPI) found in four phylogenetically divergent fish taxa. This study tested the hypothesis of protein sequence convergence beyond functional convergence in three unrelated AFPI-bearing fish lineages. Through comprehensive comparative analyses of newly sequenced genomes of winter flounder and grubby sculpin, along with available high-quality genomes of cunner and 14 other related species, the study revealed that near-identical AFPI proteins originated from distinct genetic precursors in each lineage. Each lineage independently evolved a de novo coding region for the novel ice-binding protein while repurposing fragments from their respective ancestors into potential regulatory regions, representing partial de novo origination—a process that bridges de novo gene formation and the neofunctionalization of duplicated genes. The study supports existing models of new gene origination and introduces new ones: the Innovation-Amplification-Divergence (IAD) model, where novel changes precede gene duplication; the newly proposed Duplication-Degeneration-Divergence (DDD) model, which describes new functions arising from degenerated pseudogenes; and the DDD gene fission model, where each new sibling gene differentially degenerate and renovate distinct functional domains from their parental gene. These findings highlight the diverse evolutionary pathways through which a novel functional gene with convergent sequences at the protein level can evolve across divergent species, advancing our understanding of the mechanistic intricacies in new gene formation.
ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in HER2-positive breast cancer
Authors: Liliana Santos, Francesca Tomatis, Hugo R S Ferreira, Sara F F Almeida, Edward Ciputra, José Sereno, Rui Almeida, Paulo Teixeira, Ana Sofia Ribeiro, João N Moreira, Ana P Silva, Lino Ferreira, Antero J Abrunhosa, Célia M Gomes
Journal: Neuro-Oncology (2024)

Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation. We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20 kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model. Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3β/β-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival. We demonstrated that metastatic BC cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ BC.