tbuckley/cabot-search huggingface dataset:
Abstract 11417: Bempedoic Acid and Glycemic Control: A Pooled Analysis of 4 Phase 3 Clinical Trials
Authors: Lawrence A Leiter, Maciej Banach, Alberico L Catapano, P. Barton Duell, Antonio Gotto, Ulrich Laufs, G. B. John Mancini, Kausik K Ray, Jeffrey C Hanselman, Zhan Ye, Harold E Bays
Journal: Circulation (2019)

Introduction: Many statins have demonstrated the potential to accelerate the transition from prediabetes to diabetes. We evaluated the effect of bempedoic acid (BA), a first-in-class, oral, ATP-cit...
The Emerging Science of Interoception: Sensing, Integrating, Interpreting, and Regulating Signals within the Self
Authors: Wen G. Chen, Dana Schloesser, Angela M. Arensdorf, Janine M. Simmons, Changhai Cui, Rita Valentino, James W. Gnadt, Lisbeth Nielsen, Coryse St. Hillaire-Clarke, Victoria Spruance, Todd S. Horowitz, Yolanda F. Vallejo, Helene M. Langevin
Journal: Trends in Neurosciences (2020)

Interoception refers to the representation of the internal states of an organism, and includes the processes by which it senses, interprets, integrates, and regulates signals from within itself. This review presents a unified research framework and attempts to offer definitions for key terms to describe the processes involved in interoception. We elaborate on these definitions through illustrative research findings, and provide brief overviews of central aspects of interoception, including the anatomy and function of neural and non-neural pathways, diseases and disorders, manipulations and interventions, and predictive modeling. We conclude with discussions about major research gaps and challenges.
LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors
Authors: Kelli-Ann Monaco, Scott Delach, Jing Yuan, Yuji Mishina, Paul Fordjour, Emma Labrot, Daniel McKay, Ribo Guo, Stacy Higgins, Hui Qin Wang, Jinsheng Liang, Karen Bui, John Green, Peter Aspesi, Jessi Ambrose, Felipa Mapa, Lesley Griner, Mariela Jaskelioff, John Fuller, Kenneth Crawford, Gwynn Pardee, Stephania Widger, Peter S. Hammerman, Jeffrey A. Engelman, Darrin D. Stuart, Vesselina G. Cooke, Giordano Caponigro
Journal: Clinical Cancer Research (2020)

Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe in detail novel properties of the type II RAF inhibitor, LXH254.LXH254 was profiled in biochemical, in vitro, and in vivo assays, including examining the activities of the drug in a large panel of cancer-derived cell lines and a comprehensive set of in vivo models. In addition, activity of LXH254 was assessed in cells where different sets of RAF paralogs were ablated, or that expressed kinase-impaired and dimer-deficient variants of ARAF.We describe an unexpected paralog selectivity of LXH254, which is able to potently inhibit BRAF and CRAF, but has less activity against ARAF. LXH254 was active in models harboring BRAF alterations, including atypical BRAF alterations coexpressed with mutant K/NRAS, and NRAS mutants, but had only modest activity in KRAS mutants. In RAS-mutant lines, loss of ARAF, but not BRAF or CRAF, sensitized cells to LXH254. ARAF-mediated resistance to LXH254 required both kinase function and dimerization. Higher concentrations of LXH254 were required to inhibit signaling in RAS-mutant cells expressing only ARAF relative to BRAF or CRAF. Moreover, specifically in cells expressing only ARAF, LXH254 caused paradoxical activation of MAPK signaling in a manner similar to dabrafenib. Finally, in vivo, LXH254 drove complete regressions of isogenic variants of RAS-mutant cells lacking ARAF expression, while parental lines were only modestly sensitive.LXH254 is a novel RAF inhibitor, which is able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF.
The Evolution of Thienopyridine Therapy: Clopidogrel Duration, Diabetes, and Drug-Eluting Stents⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Seung-Hyuk Choi, Anand Prasad, Sotirios Tsimikas
Journal: Journal of the American College of Cardiology (2008)
<i>USP24</i> Is a Cancer-Associated Ubiquitin Hydrolase, Novel Tumor Suppressor, and Chromosome Instability Gene Deleted in Neuroblastoma
Authors: Tibor Bedekovics, Sajjad Hussain, Ying Zhang, Asma Ali, Young J. Jeon, Paul J. Galardy
Journal: Cancer Research (2020)

Abstract Deubiquitinating enzymes are increasingly recognized to play important roles in cancer, with many acting as oncogenes or tumor suppressors. In this study, we employed a bioinformatics approach to screen for enzymes from this family involved in cancer and found USP24 as a potent predictor of poor outcomes in neuroblastoma, an aggressive childhood cancer. USP24 resides in a region commonly deleted in neuroblastoma, yet was independently associated with poor outcomes in this disease. Deletion of Usp24 in a murine model resulted in degradation of collapsin response mediator protein 2 (CRMP2), a regulator of axon growth, guidance, and neuronal polarity. Cells lacking USP24 had significant increases in spindle defects, chromosome missegregation, and aneuploidy, phenotypes that were rescued by the restoration of CRMP2. USP24 prevented aneuploidy by maintaining spindle-associated CRMP2, which is required for mitotic accuracy. Our findings further indicate that USP24 is a tumor suppressor that may play an important role in the pathogenesis of neuroblastoma. Significance: This study identifies the chromosome instability gene USP24 as frequently deleted in neuroblastoma and provides important insight into the pathogenesis of this aggressive childhood cancer.
Assessment of Filled Buprenorphine Prescriptions for Opioid Use Disorder During the Coronavirus Disease 2019 Pandemic
Authors: Thuy D. Nguyen, Sumedha Gupta, Engy Ziedan, Kosali I. Simon, G. Caleb Alexander, Brendan Saloner, Bradley D. Stein
Journal: JAMA Internal Medicine (2020)

Treatment of Opioid Use Disorder Among Commercially Insured Patients Before and During the COVID-19 Pandemic
Contrast-Enhanced CMR in HCM: What Lies Behind the Bright Light of LGE and Why it Now Matters⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Martin S. Maron
Journal: JACC. Cardiovascular imaging (2013)
Association of Chronic Immune-Mediated Diarrhea and Colitis With Favorable Cancer Response
Authors: Fangwen Zou, Hamzah Abu-Sbeih, Weijie Ma, Yuanzun Peng, Wei Qiao, Jianbo Wang, Amishi Y. Shah, Isabella C. Glitza Oliva, Sarina A. Piha-Paul, John A. Thompson, Hao Chi Zhang, Anusha S. Thomas, Yinghong Wang
Journal: Journal of the National Comprehensive Cancer Network (2021)

Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes.We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis.In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018).Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.
Effect of COVID-19 Infection in Three Patients Treated with Rituximab
Authors: Anushya Jeyabalan, Reza Zonozi, Jillian Rosenthal, Karen A. Laliberte, John Niles
Journal: Journal of the American Society of Nephrology (2020)

Jeyabalan, Anushya; Zonozi, Reza; Rosenthal, Jillian; Laliberte, Karen A.; Niles, John Author Information
Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration
Authors: Swetha Mohan, Paul J. Sampognaro, Andrea R. Argouarch, Jason C. Maynard, Mackenzie Welch, Anand Patwardhan, Emma C. Courtney, Jiasheng Zhang, Amanda Mason, Kathy H. Li, Eric J. Huang, William W. Seeley, Bruce L. Miller, Alma Burlingame, Mathew P. Jacobson, Aimee W. Kao
Journal: Molecular Neurodegeneration (2021)

Abstract Background Progranulin loss-of-function mutations are linked to frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP- Pgrn ). Progranulin (PGRN) is an intracellular and secreted pro-protein that is proteolytically cleaved into individual granulin peptides, which are increasingly thought to contribute to FTLD-TDP- Pgrn disease pathophysiology. Intracellular PGRN is processed into granulins in the endo-lysosomal compartments. Therefore, to better understand the conversion of intracellular PGRN into granulins, we systematically tested the ability of different classes of endo-lysosomal proteases to process PGRN at a range of pH setpoints. Results In vitro cleavage assays identified multiple enzymes that can process human PGRN into multi- and single-granulin fragments in a pH-dependent manner. We confirmed the role of cathepsin B and cathepsin L in PGRN processing and showed that these and several previously unidentified lysosomal proteases (cathepsins E, G, K, S and V) are able to process PGRN in distinctive, pH-dependent manners. In addition, we have demonstrated a new role for asparagine endopeptidase (AEP) in processing PGRN, with AEP having the unique ability to liberate granulin F from the pro-protein. Brain tissue from individuals with FTLD-TDP- Pgrn showed increased PGRN processing to granulin F and increased AEP activity in degenerating brain regions but not in regions unaffected by disease. Conclusions This study demonstrates that multiple lysosomal proteases may work in concert to liberate multi-granulin fragments and granulins. It also implicates both AEP and granulin F in the neurobiology of FTLD-TDP- Pgrn . Modulating progranulin cleavage and granulin production may represent therapeutic strategies for FTLD- Pgrn and other progranulin-related diseases.
Remote Peritoneal Dialysis Training in a COVID-19-Positive Patient
Authors: Aditya V. Jain, Tina S. Samuel, Leslie A. Jansto, Erwin E. Morales, Cybele Ghossein
Journal: Journal of the American Society of Nephrology (2020)

Jain, Aditya V.; Samuel, Tina S.; Jansto, Leslie A.; Morales, Erwin E.; Ghossein, Cybele Author Information
Association of Histologic Regression With a Favorable Outcome in Patients With Stage 1 and Stage 2 Cutaneous Melanoma
Authors: Mary-Ann El Sharouni, Karina Aivazian, Arjen J. Witkamp, Vigfús Sigurdsson, Carla H. van Gils, Richard A. Scolyer, John F. Thompson, Paul J. van Diest, Serigne N. Lo
Journal: JAMA Dermatology (2020)

<h3>Importance</h3> Although regression is commonly observed in cutaneous melanoma, it is uncertain whether it is associated with patient prognosis. <h3>Objective</h3> To determine whether histologically confirmed regression was associated with better or worse survival in patients with primary cutaneous melanoma. <h3>Design, Setting, and Participants</h3> This cohort study analyzed data from 2 large cohorts of adults (one in the Netherlands and the other in Australia) with histologically proven, stage 1 and 2 primary, invasive cutaneous melanoma with known regression status treated between 2000 and 2014, with median follow-up times of 4.5 and 11.1 years for the Dutch and Australian cohorts, respectively. For the Dutch patients, population-based data from PALGA, the Dutch Pathology Registry, were used, and follow-up data were retrieved from the Netherlands Cancer Registry. For the Australian patients, data from the database of a large, specialized melanoma treatment center were used. <h3>Main Outcomes and Measures</h3> Multivariable Cox proportional hazards analyses were performed per cohort to assess recurrence-free survival (RFS) and overall survival (OS), and subgroup analyses according to Breslow thickness category and melanoma subtype were performed. <h3>Results</h3> A total of 17 271 Dutch patients and 4980 Australian patients were included. In both cohorts, survival outcomes were better for patients with disease regression. For Dutch patients, the hazard ratio (HR) for those with disease regression was 0.55 (95% CI, 0.48-0.63;<i>P</i> &lt; .001) for RFS and 0.87 (95% CI, 0.79-0.96;<i>P</i> = .004) for OS; for the Australian patients, the HR was 0.61 (95% CI, 0.52-0.72;<i>P</i> &lt; .001) for RFS and 0.73 (95% CI, 0.64-0.84;<i>P</i> &lt; .001) for OS. Subgroup analyses showed that the presence of regression improved RFS within thin and intermediate Breslow thickness melanomas in both cohorts. For patients with superficial spreading melanoma (SSM) subtype, regression improved RFS and OS in both cohorts. For Dutch patients with SSM, the HR for those with disease regression was 0.54 (95% CI, 0.46-0.63;<i>P</i> &lt; .001) for RFS and 0.86 (95% CI, 0.76-0.96;<i>P</i> = .009) for OS; for the Australian patients with SSM, the HR was 0.67 (95% CI, 0.52-0.85;<i>P</i> = .001) for RFS and 0.72 (95% CI, 0.59-0.88;<i>P</i> = .001) for OS. <h3>Conclusions and Relevance</h3> In 2 large patient cohorts from 2 different continents, regression was a favorable prognostic factor for patients with stage 1 and 2 melanomas, especially in those with thin and intermediate thickness tumors and those with SSM subtype.
Enteral broad-spectrum antibiotics antagonize the effect of fecal microbiota transplantation in preterm pigs
Authors: Anders Brunse, Simone Margaard Offersen, Josefine Juliane Mosegaard, Ling Deng, Peter Damborg, Dennis Sandris Nielsen, Per Torp Sangild, Thomas Thymann, Duc Ninh Nguyen
Journal: Gut Microbes (2020)

Preterm infants are at risk of multiple morbidities including necrotizing enterocolitis (NEC). Suspected NEC patients receive intravenous antibiotics (AB) to prevent sepsis, although enteral AB is arguably more effective at reducing NEC but is rarely used due to the risk of AB resistance. Fecal microbiota transplantation (FMT) has shown protective effects against NEC in animal experiments, but the interaction between AB and FMT has not been investigated in neonates. We hypothesized that administration of enteral AB followed by rectal FMT would effectively prevent NEC with negligible changes in AB resistance and systemic immunity. Using preterm piglets, we examined host and gut microbiota responses to AB, FMT, or a sequential combination thereof, with emphasis on NEC development. In a saline-controlled experiment, preterm piglets (n = 67) received oro-gastric neomycin (50 mg/kg/d) and amoxicillin-clavulanate (50/12.5 mg/kg/d) (hereafter AB) for four days after cesarean delivery, and were subsequently given rectal FMT from healthy suckling piglet donors. Whereas AB protected the stomach and small intestine, and FMT primarily protected the colon, the sequential combination treatment surprisingly provided no NEC protection. Furthermore, minor changes in the gut microbiota composition were observed in response to either treatment, although AB treatment decreased species diversity and increased AB resistance among coliform bacteria and Enterococci, which were both partly reversed by FMT. Besides, enteral AB treatment suppressed cellular and functional systemic immune development, which was not prevented by subsequent FMT. We discovered an antagonistic relationship between enteral AB and FMT in terms of NEC development. The outcome may depend on choice of AB compounds, FMT composition, doses, treatment duration, and administration routes, but these results challenge the applicability of enteral AB and FMT in preterm infants.
Natriuretic Peptide Assays Revisited: Do We Need Pro–B-Type Natriuretic Peptide?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Michele Emdin, Claudio Passino, Aldo Clerico
Journal: Journal of the American College of Cardiology (2011)
Stability of eosinophilic inflammation in COPD bronchial biopsies
Authors: E. Haydn Walters, Shakti D. Shukla, Chris Ward
Journal: European Respiratory Journal (2020)

<b>A claim for cellular inflammation in tissues needs the full picture, with total cell count and full differential counts, and not just data on one specific cell type, in addition to details of what normal looks like</b>https://bit.ly/2G0Tpob
DNA methylation is associated with airflow obstruction in patients living with HIV
Authors: Ana I Hernandez Cordero, Chen Xi Yang, Maen Obeidat, Julia Yang, Julie MacIsaac, Lisa McEwen, David Lin, Michael Kobor, Richard Novak, Fleur Hudson, Hartwig Klinker, Nila Dharan, SF Paul Man, Don D Sin, Ken Kunisaki, Janice Leung
Journal: Thorax (2020)

Introduction People living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH. Methods Using blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV 1 , FEV 1 /FVC ratio and FEV 1 decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing. Results Airflow obstruction as defined by a FEV 1 /FVC&lt;0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV 1 /FVC&lt;lower limit of normal. These DMPs were enriched for biological pathways associated with chronic viral infections. The airflow obstruction group was globally hypomethylated compared with those without airflow obstruction. 103 and 7112 DMPs were associated with FEV 1 and FEV 1 /FVC, respectively. No positions were associated with FEV 1 decline. Conclusion A large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.
Abstract 12153: Urinary N-terminal Fragment of Titin Distinguishes Muscular Dystrophy From Other Types of Cardiomyopathy
Authors: Takatoyo Kiko, Akiomi Yoshihisa, Yusuke Kimishima, Yu Sato, Shunsuke Watanabe, Yuki Kanno, Makiko Tatsumi, Satoshi Abe, Takamasa Sato, Satoshi Suzuki, Masayoshi Oikawa, Atsushi Kobayashi, Takayoshi Yamaki, Hiroyuki Kunii, Kazuhiko Nakazato, Shu-ichi Saitoh, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2017)

Background: Titin, a giant sarcomeric protein, is involved in myocardial passive tension and viscoelasticity, and associated with myocardial stiffness and hypertrophy. Mutations in titin gene have ...
Abstract 10935: Impact of Protein Losing Enteropathy in Children Who Underwent the Fontan Operation: A Single Large Institution Experience
Authors: Baneen Alkofair, Abdulmajeed Alruwaili, Jiaxiang Gai, Ashraf S Harahsheh
Journal: Circulation (2019)

Background: Post-Fontan Protein-losing enteropathy (PLE) is associated with significant morbidity and mortality. Previous reports have identified clinical, hemodynamic and echocardiographic risk fa...
Niche-specific functional heterogeneity of intestinal resident macrophages
Authors: Maria Francesca Viola, Guy Boeckxstaens
Journal: Gut (2020)

Intestinal resident macrophages are at the front line of host defence at the mucosal barrier within the gastrointestinal tract and have long been known to play a crucial role in the response to food antigens and bacteria that are able to penetrate the mucosal barrier. However, recent advances in single-cell RNA sequencing technology have revealed that resident macrophages throughout the gut are functionally specialised to carry out specific roles in the niche they occupy, leading to an unprecedented understanding of the heterogeneity and potential biological functions of these cells. This review aims to integrate these novel findings with long-standing knowledge, to provide an updated overview on our understanding of macrophage function in the gastrointestinal tract and to speculate on the role of specialised subsets in the context of homoeostasis and disease.
Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes
Authors: Adriana Estrada-Bernal, Anh T. Le, Andrea E. Doak, Vijaya G. Tirunagaru, Shevan Silva, Matthew R. Bull, Jeff B. Smaill, Adam V. Patterson, Chul Kim, Stephen V. Liu, Robert C. Doebele
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Approved therapies for EGFR exon 20, ERBB2 mutations, and NRG1 fusions are currently lacking for non–small cell lung cancer and other cancers. Tarloxotinib is a prodrug that harnesses tumor hypoxia to generate high levels of a potent, covalent pan-HER tyrosine kinase inhibitor, tarloxotinib-effector (tarloxotinib-E), within the tumor microenvironment. This tumor-selective delivery mechanism was designed to minimize the dose-limiting toxicities that are characteristic of systemic inhibition of wild-type EGFR. Experimental Design: Novel and existing patient-derived cell lines and xenografts harboring EGFR exon 20 insertion mutations, ERBB2 mutations and amplification, and NRG1 fusions were tested in vitro and in vivo with tarloxotinib to determine its impact on cancer cell proliferation, apoptosis, and cell signaling. Results: Tarloxotinib-E inhibited cell signaling and proliferation in patient-derived cancer models in vitro by directly inhibiting phosphorylation and activation of EGFR, HER2, and HER2/HER3 heterodimers. In vivo, tarloxotinib induced tumor regression or growth inhibition in multiple murine xenograft models. Pharmacokinetic analysis confirmed markedly higher levels of tarloxotinib-E in tumor tissue than plasma or skin. Finally, a patient with lung adenocarcinoma harboring an ERBB2 exon 20 p.A775_G776insYVMA mutation demonstrated a dramatic clinical response to tarloxotinib. Conclusions: Experimental data with tarloxotinib validate the novel mechanism of action of a hypoxia-activated prodrug in cancer models by concentrating active drug in the tumor versus normal tissue, and this activity can translate into clinical activity in patients.