tbuckley/cabot-search huggingface dataset:
Functional Validation of Doxorubicin-Induced Cardiotoxicity-Related Genes
Authors: Hananeh Fonoudi, Mariam Jouni, Romina B. Cejas, Tarek Magdy, Malorie Blancard, Ning Ge, Disheet A. Shah, Davi M. Lyra-Leite, Achal Neupane, Mennat Gharib, Zhengxin Jiang, Yadav Sapkota, Paul W. Burridge
Journal: JACC CardioOncology (2024)

Genome-wide association studies and candidate gene association studies have identified more than 180 genetic variants statistically associated with anthracycline-induced cardiotoxicity (AIC). However, the lack of functional validation has hindered the clinical translation of these findings. The aim of this study was to functionally validate all genes associated with AIC using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). Through a systemic literature search, 80 genes containing variants significantly associated with AIC were identified. Additionally, 3 more genes with potential roles in AIC (GSTM1, CBR1, and ERBB2) were included. Of these, 38 genes exhibited expression in human fetal heart, adult heart, and hiPSC-CMs. Using clustered regularly interspaced short palindromic repeats/Cas9–based genome editing, each of these 38 genes was systematically knocked out in control hiPSC-CMs, and the resulting doxorubicin-induced cardiotoxicity (DIC) phenotype was assessed using hiPSC-CMs. Subsequently, functional assays were conducted for each gene knockout on the basis of hypothesized mechanistic implications in DIC. Knockout of 26 genes increased the susceptibility of hiPSC-CMs to DIC. Notable genes included efflux transporters (ABCC10, ABCC2, ABCB4, ABCC5, and ABCC9), well-established DIC-associated genes (CBR1, CBR3, and RAC2), and genome-wide association study–discovered genes (RARG and CELF4). Conversely, knockout of ATP2B1, HNMT, POR, CYBA, WDR4, and COL1A2 had no significant effect on the in vitro DIC phenotype of hiPSC-CMs. Furthermore, knockout of the uptake transporters (SLC28A3, SLC22A17, and SLC28A1) demonstrated a protective effect against DIC. The present findings establish a comprehensive platform for the functional validation of DIC-associated genes, providing insights for future studies in DIC variant associations and potential mechanistic targets for the development of cardioprotective drugs.
Factors influencing clinician and patient interaction with machine learning-based risk prediction models: a systematic review
Authors: Rebecca Giddings, Anabel Joseph, Thomas Callender, Sam M Janes, Mihaela van der Schaar, Jessica Sheringham, Neal Navani
Journal: The Lancet Digital Health (2024)

<h2>Summary</h2> Machine learning (ML)-based risk prediction models hold the potential to support the health-care setting in several ways; however, use of such models is scarce. We aimed to review health-care professional (HCP) and patient perceptions of ML risk prediction models in published literature, to inform future risk prediction model development. Following database and citation searches, we identified 41 articles suitable for inclusion. Article quality varied with qualitative studies performing strongest. Overall, perceptions of ML risk prediction models were positive. HCPs and patients considered that models have the potential to add benefit in the health-care setting. However, reservations remain; for example, concerns regarding data quality for model development and fears of unintended consequences following ML model use. We identified that public views regarding these models might be more negative than HCPs and that concerns (eg, extra demands on workload) were not always borne out in practice. Conclusions are tempered by the low number of patient and public studies, the absence of participant ethnic diversity, and variation in article quality. We identified gaps in knowledge (particularly views from under-represented groups) and optimum methods for model explanation and alerts, which require future research.
Membrane transporters in drug development and as determinants of precision medicine
Authors: Aleksandra Galetin, Kim L. R. Brouwer, Donald Tweedie, Kenta Yoshida, Noora Sjöstedt, Lauren Aleksunes, Xiaoyan Chu, Raymond Evers, Michael J. Hafey, Yurong Lai, Pär Matsson, Andrew Riselli, Hong Shen, Alex Sparreboom, Manthena V. S. Varma, Jia Yang, Xinning Yang, Sook Wah Yee, Maciej J. Zamek-Gliszczynski, Lei Zhang, Kathleen M. Giacomini
Journal: Nature Reviews Drug Discovery (2024)
Neoadjuvant and adjuvant therapy for biliary tract cancer: Advances and limitations
Authors: H. Catherine Wilbur, Heloisa P. Soares, Nilofer S. Azad
Journal: Hepatology (2024)

Biliary tract cancers (BTC) are a rare and aggressive consortium of malignancies, consisting of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma. While most patients present with metastatic disease, a minority of patients with BTC are eligible for curative surgical resection at the time of presentation. However, these patients have poor 5-year overall survival rates and high rates of recurrence, necessitating the improvement of the neoadjuvant and adjuvant treatment of BTC. In this review, we assess the neoadjuvant and adjuvant clinical trials for the treatment of BTC and discuss the challenges and limitations of clinical trials, as well as future directions for the treatment of BTC.
Quartet metabolite reference materials for inter-laboratory proficiency test and data integration of metabolomics profiling
Authors: Naixin Zhang, Qiaochu Chen, Peipei Zhang, Kejun Zhou, Yaqing Liu, Haiyan Wang, Shumeng Duan, Yongming Xie, Wenxiang Yu, Ziqing Kong, Luyao Ren, Wanwan Hou, Jingcheng Yang, Xiaoyun Gong, Lianhua Dong, Xiang Fang, Leming Shi, Ying Yu, Yuanting Zheng
Journal: Genome biology (2024)

Various laboratory-developed metabolomic methods lead to big challenges in inter-laboratory comparability and effective integration of diverse datasets.
Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of HSC
Authors: Yujia Xia, Yu Wang, Qi Xiong, Jiayi He, Han Wang, Mozaffarul Islam, Xinyu Zhou, Alex Kim, Hongji Zhang, Hai Huang, Allan Tsung
Journal: Hepatology (2024)

Background and Aims: Metabolic dysfunction–associated steatohepatitis (MASH) fibrosis is a reversible stage of liver disease accompanied by inflammatory cell infiltration. Neutrophils extrude a meshwork of chromatin fibers to establish neutrophil extracellular traps (NETs), which play important roles in inflammatory response regulation. Our previous work demonstrated that NETs promote HCC in MASH. However, it is still unknown if NETs play a role in the molecular mechanisms of liver fibrosis. Approach and Results: Following 12 weeks of Western diet/carbon tetrachloride, MASH fibrosis was identified in C57BL/6 mice with increased NET formation. However, NET depletion using DNase I treatment or mice knocked out for peptidyl arginine deaminase type IV significantly attenuated the development of MASH fibrosis. NETs were demonstrated to induce HSCs activation, proliferation, and migration through augmented mitochondrial and aerobic glycolysis to provide additional bioenergetic and biosynthetic supplies. Metabolomic analysis revealed markedly an altered metabolic profile upon NET stimulation of HSCs that were dependent on arachidonic acid metabolism. Mechanistically, NET stimulation of toll-like receptor 3 induced cyclooxygenase-2 activation and prostaglandin E2 production with subsequent HSC activation and liver fibrosis. Inhibiting cyclooxygenase-2 with celecoxib reduced fibrosis in our MASH model. Conclusions: Our findings implicate NETs playing a critical role in the development of MASH hepatic fibrosis by inducing metabolic reprogramming of HSCs through the toll-like receptor 3/cyclooxygenase-2/cyclooxygenase-2 pathway. Therefore, NET inhibition may represent an attractive treatment target for MASH liver fibrosis.
The unusual gene architecture of polyubiquitin is created by dual-specific splice sites
Authors: Chaorui Duan, Truman Mooney, Luke Buerer, Cory Bowers, Stephen Rong, Seong Won Kim, Alger M. Fredericks, Sean F. Monaghan, William G. Fairbrother
Journal: Genome biology (2024)

Abstract Background The removal of introns occurs through the splicing of a 5′ splice site (5′ss) with a 3′ splice site (3′ss). These two elements are recognized by distinct components of the spliceosome. However, introns in higher eukaryotes contain many matches to the 5′ and 3′ splice-site motifs that are presumed not to be used. Results Here, we find that many of these sites can be used. We also find occurrences of the AGGT motif that can function as either a 5′ss or a 3′ss—previously referred to as dual-specific splice sites (DSSs)—within introns. Analysis of the Sequence Read Archive reveals a 3.1-fold enrichment of DSSs relative to expectation, implying synergy between the ability to function as a 5′ss and 3′ss. Despite this suggested mechanistic advantage, DSSs are 2.7- and 4.7-fold underrepresented in annotated 5′ and 3′ splice sites. A curious exception is the polyubiquitin gene UBC , which contains a tandem array of DSSs that precisely delimit the boundary of each ubiquitin monomer. The resulting isoforms splice stochastically to include a variable number of ubiquitin monomers. We found no evidence of tissue-specific or feedback regulation but note the 8.4-fold enrichment of DSS-spliced introns in tandem repeat genes suggests a driving role in the evolution of genes like UBC . Conclusions We find an excess of unannotated splice sites and the utilization of DSSs in tandem repeats supports the role of splicing in gene evolution. These findings enhance our understanding of the diverse and complex nature of the splicing process.
Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen
Authors: Samir Gupta, Nimish V. Subhedar, Jennifer L. Bell, David Field, Ursula Bowler, Elizabeth Hutchison, Sam Johnson, Wilf Kelsall, Justine Pepperell, Tracy Roberts, Sunil Sinha, Kayleigh Stanbury, Jonathan Wyllie, Pollyanna Hardy, Edmund Juszczak
Journal: New England Journal of Medicine (2024)

The cyclooxygenase inhibitor ibuprofen may be used to treat patent ductus arteriosus (PDA) in preterm infants. Whether selective early treatment of large PDAs with ibuprofen would improve short-term outcomes is not known.
Patent Ductus Arteriosus — To Close or Not to Close?
Authors: Jill L Maron
Journal: New England Journal of Medicine (2024)

The ductus arteriosus is an essential fetal cardiac conduit that allows for the diversion of blood from the pulmonary artery to the aorta for systemic circulation in utero. At term birth, separation from the placenta and expansion of the lungs leads to reduced pulmonary-artery pressure and increased oxygen saturation, which are key contributors to closure of the duct.1 However, in premature infants, birth itself is often not sufficient to close the duct, leading to patent ductus arteriosus (PDA), the most common cardiac condition in newborn infants.1 The probability of PDA is inversely proportional to gestational age at birth, with infants . . .
Hospital Prices for Physician-Administered Drugs for Patients with Private Insurance
Authors: James C Robinson, Christopher Whaley, Sanket S Dhruva
Journal: New England Journal of Medicine (2024)

BackgroundHospitals can leverage their position between the ultimate buyers and sellers of drugs to retain a substantial share of insurer pharmaceutical expenditures.MethodsIn this study, we used 2020–2021 national Blue Cross Blue Shield claims data regarding patients in the United States who had drug-infusion visits for oncologic conditions, inflammatory conditions, or blood-cell deficiency disorders. Markups of the reimbursement prices were measured in terms of amounts paid by Blue Cross Blue Shield plans to hospitals and physician practices relative to the amounts paid by these providers to drug manufacturers. Acquisition-price reductions in hospital payments to drug manufacturers were measured in terms of discounts under the federal 340B Drug Pricing Program. We estimated the percentage of Blue Cross Blue Shield drug spending that was received by drug manufacturers and the percentage retained by provider organizations.ResultsThe study included 404,443 patients in the United States who had 4,727,189 drug-infusion visits. The median price markup (defined as the ratio of the reimbursement price to the acquisition price) for hospitals eligible for 340B discounts was 3.08 (interquartile range, 1.87 to 6.38). After adjustment for drug, patient, and geographic factors, price markups at hospitals eligible for 340B discounts were 6.59 times (95% confidence interval [CI], 6.02 to 7.16) as high as those in independent physician practices, and price markups at noneligible hospitals were 4.34 times (95% CI, 3.77 to 4.90) as high as those in physician practices. Hospitals eligible for 340B discounts retained 64.3% of insurer drug expenditures, whereas hospitals not eligible for 340B discounts retained 44.8% and independent physician practices retained 19.1%.ConclusionsThis study showed that hospitals imposed large price markups and retained a substantial share of total insurer spending on physician-administered drugs for patients with private insurance. The effects were especially large for hospitals eligible for discounts under the federal 340B Drug Pricing Program on acquisition costs paid to manufacturers. (Funded by Arnold Ventures and the National Institute for Health Care Management.)
Mycophenolate mofetil inhibits Merkel cell carcinoma growth
Authors: Khalid A Garman, Nicholas Thoreson, Jennifer Strong, Patrick Hallaert, Tara Gelb, Min Shen, Matthew D Hall, Isaac Brownell
Journal: British Journal of Dermatology (2024)

The direct antitumour effects of mTOR inhibitors against cutaneous squamous cell carcinoma (SCC) have prompted a paradigm shift towards using sirolimus for allograft rejection prophylaxis in patients with high-risk SCC who have had a solid organ transplant (SOT). Patients who have had an SOT are at higher risk for Merkel cell carcinoma (MCC), yet there is little evidence concerning potential antitumour effects of immunosuppressive drugs against MCC. Screening seven immunosuppressive drugs in six MCC cell lines revealed that mycophenolate mofetil (MMF) had strong antitumour activity (surpassing mTOR inhibitors) and higher potency in MCC vs. other cancer types. MMF also inhibited MCC tumour growth in mice. Our preclinical findings strongly suggest the utility of MMF in patients with MCC who require immunosuppression.
Fluid biomarkers for amyotrophic lateral sclerosis: a review
Authors: Katherine E. Irwin, Udit Sheth, Philip C. Wong, Tania F. Gendron
Journal: Molecular Neurodegeneration (2024)

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.
Cross-Species Comparative DNA Methylation Reveals Novel Insights into Complex Trait Genetics among Cattle, Sheep, and Goats
Authors: Siqian Chen, Shuli Liu, Shaolei Shi, Hongwei Yin, Yongjie Tang, Jinning Zhang, Wenlong Li, Gang Liu, Kaixing Qu, Xiangdong Ding, Yachun Wang, Jianfeng Liu, Shengli Zhang, Lingzhao Fang, Ying Yu
Journal: Molecular Biology and Evolution (2024)

Abstract The cross-species characterization of evolutionary changes in the functional genome can facilitate the translation of genetic findings across species and the interpretation of the evolutionary basis underlying complex phenotypes. Yet, this has not been fully explored between cattle, sheep, goats, and other mammals. Here, we systematically characterized the evolutionary dynamics of DNA methylation and gene expression in 3 somatic tissues (i.e. brain, liver, and skeletal muscle) and sperm across 7 mammalian species, including 3 ruminant livestock species (cattle, sheep, and goats), humans, pigs, mice, and dogs, by generating and integrating 160 DNA methylation and transcriptomic data sets. We demonstrate dynamic changes of DNA hypomethylated regions and hypermethylated regions in tissue-type manner across cattle, sheep, and goats. Specifically, based on the phylo-epigenetic model of DNA methylome, we identified a total of 25,074 hypomethylated region extension events specific to cattle, which participated in rewiring tissue-specific regulatory network. Furthermore, by integrating genome-wide association studies of 50 cattle traits, we provided novel insights into the genetic and evolutionary basis of complex phenotypes in cattle. Overall, our study provides a valuable resource for exploring the evolutionary dynamics of the functional genome and highlights the importance of cross-species characterization of multiomics data sets for the evolutionary interpretation of complex phenotypes in cattle livestock.
Facts and Hopes in Immunotherapy Strategies Targeting Antigens Derived from KRAS mutations
Authors: Gerald P. Linette, Adham S. Bear, Beatriz M. Carreno
Journal: Clinical Cancer Research (2024)

In this commentary, we advance the notion that mutant KRAS (mKRAS) is an ideal tumor neoantigen that is amenable for targeting by the adaptive immune system. Recent progress highlights key advances on various fronts that validate mKRAS as a molecular target and support further pursuit as an immunological target. Because mKRAS is an intracellular membrane localized protein and not normally expressed on the cell surface, we surmise that proteasome degradation will generate short peptides that bind to HLA class I (HLA-I) molecules in the endoplasmic reticulum for transport through the Golgi for display on the cell surface. T-cell receptors (TCR)αβ and antibodies have been isolated that specifically recognize mKRAS encoded epitope(s) or haptenated-mKRAS peptides in the context of HLA-I on tumor cells. Case reports using adoptive T-cell therapy provide proof of principle that KRAS G12D can be successfully targeted by the immune system in patients with cancer. Among the challenges facing investigators is the requirement of precision medicine to identify and match patients to available mKRAS peptide/HLA therapeutics and to increase the population coverage by targeting additional mKRAS epitopes. Ultimately, we envision mKRAS-directed immunotherapy as an effective treatment option for selected patients that will complement and perhaps synergize with small-molecule mKRAS inhibitors and targeted mKRAS degraders.
TFE3-splicing factor fusions represent functional drivers and druggable targets in translocation renal cell carcinoma
Authors: Nur P. Damayanti, Ricardo A. Cordova, Christopher Rupert, Ilaria Delle Fontane, Li Shen, Sabrina Orsi, Angela J. Klunk, W. Marston Linehan, Kirk A. Staschke, Peter C. Hollenhorst, David E. Heppner, Roberto Pili
Journal: Cancer Research (2024)

Abstract TFE3 is a member of the basic helix–loop–helix leucine zipper MiT transcription factor family, and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite the variety of gene fusions, most TFE3 fusion partner genes are related to spliceosome machinery. Dissecting the function of TFE3 fused to spliceosome machinery factors (TFE3-SF) could direct the development of effective therapies for this lethal disease, which is refractory to standard treatments for kidney cancer. Here, by using a combination of in silico structure prediction, transcriptome profiling, molecular characterization, and high-throughput high-content screening (HTHCS), we interrogated a number of oncogenic mechanisms of TFE3-SF fusions. TFE3-SF fusions drove the transformation of kidney cells and promoted distinct oncogenic phenotypes in a fusion partner-dependent manner, differentially altering the transcriptome and RNA splicing landscape and activating different oncogenic pathways. Inhibiting TFE3-SF dimerization reversed its oncogenic activity and represented a potential target for therapeutic intervention. Screening the FDA-approved drugs library LOPAC and a small-molecule library (Microsource) using HTHCS combined with FRET technology identified compounds that inhibit TFE3-SF dimerization. Hit compounds were validated in 2D and 3D patient-derived xenograft models expressing TFE3-SF. The antihistamine terfenadine decreased cell proliferation and reduced in vivo tumor growth of tRCC. Overall, these results unmask therapeutic strategies to target TFE3-SF dimerization for treating patients with tRCC. Significance: TFE3-splicing factor fusions possess both transcription and splicing factor functions that remodel the transcriptome and spliceosome and can be targeted with dimerization inhibitors to suppress the growth of translocation renal cell carcinoma.
Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome
Authors: Eva Lana-Elola, Rifdat Aoidi, Miriam Llorian, Dorota Gibbins, Callan Buechsenschuetz, Claudio Bussi, Helen Flynn, Tegan Gilmore, Sheona Watson-Scales, Marie Haugsten Hansen, Darryl Hayward, Ok-Ryul Song, Véronique Brault, Yann Herault, Emmanuel Deau, Laurent Meijer, Ambrosius P. Snijders, Maximiliano G. Gutierrez, Elizabeth M. C. Fisher, Victor L. J. Tybulewicz
Journal: Science Translational Medicine (2024)

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). DS is a gene dosage disorder that results in multiple phenotypes including congenital heart defects. This clinically important cardiac pathology is the result of a third copy of one or more of the approximately 230 genes on Hsa21, but the identity of the causative dosage–sensitive genes and hence mechanisms underlying this cardiac pathology remain unclear. Here, we show that hearts from human fetuses with DS and embryonic hearts from the Dp1Tyb mouse model of DS show reduced expression of mitochondrial respiration genes and cell proliferation genes. Using systematic genetic mapping, we determined that three copies of the dual-specificity tyrosine phosphorylation–regulated kinase 1A ( Dyrk1a ) gene, encoding a serine/threonine protein kinase, are associated with congenital heart disease pathology. In embryos from Dp1Tyb mice, reducing Dyrk1a gene copy number from three to two reversed defects in cellular proliferation and mitochondrial respiration in cardiomyocytes and rescued heart septation defects. Increased dosage of DYRK1A protein resulted in impairment of mitochondrial function and congenital heart disease pathology in mice with DS, suggesting that DYRK1A may be a useful therapeutic target for treating this common human condition.