tbuckley/cabot-search huggingface dataset:
Abstract 107: Acetyl-coa Carboxylase 2 Prevents Cardiomyocyte Hypertrophy by Reducing Glucose Reliance
Authors: Julia Ritterhoff, Dan Shao, Rong Tian
Journal: Circulation Research (2016)

In cardiac hypertrophy, the adult heart switches from mainly using fatty acids to increased reliance on glucose to maintain its energetic demands. Reducing fatty acid overload and further increasing glucose reliance has been suggested to be beneficial in the diseased state. Recently, however, it has been shown that increasing fatty acid oxidation (FAO) by cardiac-specific deletion of Acetyl-CoA Carboxylase 2 (ACC2) maintains cardiac energetics and prevents cardiac dysfunction as well as cardiomyocyte hypertrophy during chronic pressure overload. However, it remained unclear, how increased FAO specifically prevented cardiomyocyte hypertrophy. Thus, the goal of this study was to determine the impact of ACC2 deletion on cardiomyocyte hypertrophy in vitro . Adenoviral-mediated knock-down (KD) of ACC2 in adult rat ventricular cardiomyocytes (CMs) resulted in a 70% downregulation of ACC2 mRNA. In standard CM medium (medium M199, 5.5mM glucose) ACC2 KD resulted in a similar increase in CM growth after phenylephrine (PE) treatment as control CMs (+39±10% in control vs. 41±16% in ACC2 KD CMs). Supplementation of 0.4 mM mixed long-chain fatty acids (FA) and 0.1 mU/ml insulin had no effect on cardiomyocyte morphology or hypertrophic response after PE treatment (+42±6%). However, ACC2 KD effectively prevented CM hypertrophy after PE stimulation in the presence of FA/insulin (+9±6%). Whereas PE stimulation in control CMs increased glucose uptake (+28±8%) and reduced fatty acid uptake (-25±6%), both were normalized after ACC2 KD. Inhibiting FAO by etomoxir or increasing glucose utilization by dichloroacetate abolished the beneficial effects of ACC2 KD after PE stimulation. When cultured in glucose-free medium supplemented with FA, ACC2 KD was incapable of preventing cardiomyocyte hypertrophy. Together, these data indicate that increased FAO after ACC2 deletion prevents cardiomyocyte hypertrophy by reducing glucose reliance, suggesting that rather increasing than reducing FAO is beneficial in cardiac hypertrophy.
Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors
Authors: Jayesh Desai, Sanjeev Deva, Jong Seok Lee, Chia-Chi Lin, Chia-Jui Yen, Yee Chao, Bhumsuk Keam, Michael Jameson, Ming-Mo Hou, Yoon-Koo Kang, Ben Markman, Chang-Hsien Lu, Kun-Ming Rau, Kyung-Hun Lee, Lisa Horvath, Michael Friedlander, Andrew Hill, Shahneen Sandhu, Paula Barlow, Chi-Yuan Wu, Yun Zhang, Liang Liang, John Wu, Virginia Paton, Michael Millward
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors. Methods Patients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay. Results Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity; anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials. Conclusions Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies. Trial registration number NCT02407990 .
Mechanism of succinate efflux upon reperfusion of the ischaemic heart
Authors: Hiran A Prag, Anja V Gruszczyk, Margaret M Huang, Timothy E Beach, Timothy Young, Laura Tronci, Efterpi Nikitopoulou, John F Mulvey, Raimondo Ascione, Anna Hadjihambi, Michael J Shattock, Luc Pellerin, Kourosh Saeb-Parsy, Christian Frezza, Andrew M James, Thomas Krieg, Michael P Murphy, Dunja Aksentijević
Journal: Cardiovascular Research (2020)

Abstract Aims Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known. Methods and results To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart. Conclusion Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.
High-Resolution CRISPR Functional Genomics Reveals Critical Vulnerabilities of the NuRD Complex for Fetal Hemoglobin Control
Authors: Falak Sher, Vivien Schoonenberg, Mitchel A. Cole, Claudio Macias-Trevino, Paolo Cifani, Patrick G Schupp, Matthew C. Canver, Ryo Kurita, Yukio Nakamura, Stuart Orkin, Alex Kentsis, Luca Pinello, Takahiro Maeda, Daniel E. Bauer
Journal: Blood (2017)
Lipid metabolism alteration contributes to and maintains the properties of cancer stem cells
Authors: Huangcan Li, Zhuoying Feng, Ming-Liang He
Journal: Theranostics (2020)

Lipids, the basic components of the cell membrane, execute fundamental roles in almost all the cell activities including cell-cell recognition, signalling transduction and energy supplies.Lipid metabolism is elementary for life sustentation that balances activity between synthesis and degradation.An accumulating amount of data has indicated abnormal lipid metabolism in cancer stem cells (CSCs), and that the alteration of lipid metabolism exerts a great impact on CSCs' properties such as the capability of self-renewal, differentiation, invasion, metastasis, and drug sensitivity and resistance.CSCs' formation and maintenance cannot do without the regulation of fatty acids and cholesterol.In normal cells and embryonic development, fatty acids and cholesterol metabolism are regulated by some important signalling pathways (such as Hedgehog, Notch, Wnt signalling pathways); these signalling pathways also play crucial roles in initiating and/or maintaining CSCs' properties, and such signalling is shown to be commonly modulated by the abnormal lipid metabolism in CSCs; on the other hand, the altered lipid metabolism in turn modifies the cell signalling and generates additional impacts on CSCs.Metabolic rewiring is considered as an ideal hallmark of CSCs, and metabolic alterations would be promising therapeutic targets of CSCs for aggressive tumors.In this review, we summarize the most updated findings of lipid metabolic abnormalities in CSCs and prospect the potential applications of targeting lipid metabolism for anticancer treatment.
Keep the Worms in the Mud
Authors: Daniel Ontaneda, Jeffrey A. Cohen
Journal: JAMA Neurology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Individualized 6-Mercaptopurine Increments in Consolidation Treatment of Childhood Acute Lymphoblastic Leukemia: A NOPHO ALL2008 Randomized Controlled Trial
Authors: Morten Tulstrup, Thomas Leth Frandsen, Jonas Abrahamsson, Bendik Lund, Kim Vettenranta, Olafur G. Jonsson, Hanne Vibeke Marquart, Birgitte Klug Albertsen, Mats Heyman, Kjeld Schmiegelow
Journal: Blood (2017)
SARS-CoV-2 infection in farmed minks, the Netherlands, April and May 2020
Authors: Nadia Oreshkova, Robert Jan Molenaar, Sandra Vreman, Frank Harders, Bas B Oude Munnink, Renate W Hakze-van der Honing, Nora Gerhards, Paulien Tolsma, Ruth Bouwstra, Reina S Sikkema, Mirriam GJ Tacken, Myrna MT de Rooij, Eefke Weesendorp, Marc Y Engelsma, Christianne JM Bruschke, Lidwien AM Smit, Marion Koopmans, Wim HM van der Poel, Arjan Stegeman
Journal: Eurosurveillance (2020)

Respiratory disease and increased mortality occurred in minks on two farms in the Netherlands, with interstitial pneumonia and SARS-CoV-2 RNA in organ and swab samples. On both farms, at least one worker had coronavirus disease-associated symptoms before the outbreak. Variations in mink-derived viral genomes showed between-mink transmission and no infection link between the farms. Inhalable dust contained viral RNA, indicating possible exposure of workers. One worker is assumed to have attracted the virus from mink.
Abstract 158: Association Between Initial Body Temperature and Neurologic Outcomes of Out-Of-Hospital Cardiac Arrest Undergoing Targeted Temperature Management
Authors: Jong Hwan Kim, Jeong Ho Park, Sun Young Lee, Sang Do Shin, Jieun Pak, Tae Han Kim
Journal: Circulation (2019)

Objectives: Targeted temperature management (TTM) is the core post-resuscitation care to minimize neurologic deficit after out-of-hospital cardiac arrest (OHCA). Uncontrolled body temperature of patients may reflect the thermoregulation ability which can be associated with neurologic damage during arrest. The aim of this study was to investigate the association between initial body temperature (BT) and neurologic outcomes in OHCA patients who underwent TTM. Methods: We used nationwide OHCA database from January 2016 to December 2017. Adult OHCA patients with presumed cardiac etiology who underwent TTM after return-of-spontaneous circulation (ROSC) were included. The main exposure was a BT at initiation of TTM which was categorized into 3 groups: low (-35.5°c), middle(35.6°c-37.4°c), and high BT (37.5°c-). The primary outcome was good neurologic outcome (cerebral performance categories (CPC) 1 or 2). Adjusted ratios (AORs) and 95% confidence intervals (CIs) were estimated to evaluate association between initial BT of TTM and outcome in multivariable logistic regression model. Stratified subgroup analyses were according to the target temperature of TTM (hypothermia vs normothermia). Results: Of a total of 744 patients, 208 (28.0%) patients were low initial BT group and 471 (63.3%) patients were normal initial BT group and 65 (8.7%) patients were high initial BT group. Good neurological recovery rate was 13.9% in low initial BT group, 41.8% in middle initial BT group and 36.9% in high initial BT group. The adjusted odds ratios for good neurologic recovery were 0.281 (95% confidence interval [CI] 0.17-0.47) in low BT group and 0.65 (95% CI 0.34-1.27) in high BT group compared with normal initial BT group. Similar results were also found regardless of target temperature of TTM. Conclusion: Low initial BT of TTM was associated with unfavorable neurologic recovery for OHCA patients who underwent TTM after ROSC.
Annals Graphic Medicine - Progress Notes: COVID
Authors: Michael Natter
Journal: Annals of Internal Medicine (2020)

Web Exclusives16 June 2020Annals Graphic Medicine - Progress Notes: COVIDFREEMichael Natter, MDMichael Natter, MDNYU School of Medicine, New York, New York (M.N.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G20-0050 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: NYU School of Medicine, New York, New York (M.N.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G19-0002.Author/Illustrator Information: Michael Natter, MD, is a current internal medicine resident at NYU School of Medicine and a graduate of Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia. His artwork is inspired by his medical training, patient encounters, and the human condition. A type 1 diabetic, Dr. Natter views himself as a patient as well as a doctor and plans to pursue a fellowship in endocrinology to help others who also share his disease. You can find more of his illustrations, stories, and comics on Instagram (www.instagram.com/mike.natter) and Twitter (@mike_natter).About Progress Notes: Progress Notes explores the everyday emotional, clinical, humorous, and ethical challenges of the medical residency training process. As implied by the title of the series, these pieces act as a visual bildungsroman, graphically dissecting the subtext of what it means to be a young doctor in today's medical world. Progress Notes appears monthly in Annals Graphic Medicine at Annals.org. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 16 June 2020Volume 172, Issue 12Page: W149-W154KeywordsConflicts of interestDisclosureEmotionsEndocrinologyFellowshipsGraduate medical educationResidency ePublished: 16 June 2020 Issue Published: 16 June 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Human milk microbiota development during lactation and its relation to maternal geographic location and gestational hypertensive status
Authors: Yi Wan, Jiajing Jiang, Mengqing Lu, Wenfeng Tong, Renke Zhou, Jiaomei Li, Jihong Yuan, Fenglei Wang, Duo Li
Journal: Gut Microbes (2020)

Bacteria in human milk could directly seed the infant intestinal microbiota, while information about how milk microbiota develops during lactation and how geographic location, gestational hypertensive status, and maternal age influence this process is limited. Here, we collected human milk samples from mothers of term infants at the first day, 2 weeks, and 6 weeks postpartum from 117 longitudinally followed-up mothers (age: 28.7 ± 3.6 y) recruited from three cities in China. We found that milk microbial diversity and richness were the highest in colostrum but gradually decreased over lactation. Microbial composition changed across lactation and exhibited more discrete compositional patterns in 2-week and 6-week milk samples compared with colostrum samples. At phylum level, the abundance of Proteobacteria increased during lactation, while Firmicutes showed the opposite trend. At genus level, Staphylococcus, Streptococcus, Acinetobacter, Pseudomonas, and Lactobacillus were predominant in colostrum samples and showed distinct variations across lactation. Maternal geographic location was significantly associated with the milk microbiota development and the abundance of predominant genus. In addition, milk from mothers with gestational prehypertension had a different and less diverse microbial community at genus level in early lactation times, and contained less Lactobacillus in the 2-week milk samples than those from normotensive mothers. Findings of our study outlined the human milk microbial diversity and community development over lactation, and underscored the importance of maternal geographic locations and gestational hypertensive status on milk microbiota, which might have important implications in the establishment of the infant intestinal microbiota via breastfeeding.
41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
Authors: Matteo Libero Baroni, Diego Sanchez Martinez, Francisco Gutierrez Aguera, Heleia Roca Ho, Maria Castella, Samanta Zanetti, Talia Velasco Hernandez, Rafael Diaz de la Guardia, Julio Castaño, Eduardo Anguita, Susana Vives, Josep Nomdedeu, Helene Lapillone, Anne E Bras, Vincent H J van der Velden, Jordi Junca, Pedro Marin, Alex Bataller, Jordi Esteve, Binje Vick, Irmela Jeremias, Angel Lopez, Marc Sorigue, Clara Bueno, Pablo Menendez
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative. Methods We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs. Results Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs. Conclusions This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.
CORM-2-entrapped ultradeformable liposomes ameliorate acute skin inflammation in an ear edema model via effective CO delivery
Authors: Gwan-Yeong Lee, Alam Zeb, Eun-Hye Kim, Beomseon Suh, Young-Jun Shin, Donghyun Kim, Kyoung-Won Kim, Yeong-Hwan Choe, Ho-Ik Choi, Cheol-Ho Lee, Omer Salman Qureshi, In-Bo Han, Sun-Young Chang, Ok-Nam Bae, Jin-Ki Kim
Journal: Acta Pharmaceutica Sinica B (2020)

The short release half-life of carbon monoxide (CO) is a major obstacle to the effective therapeutic use of carbon monoxide-releasing molecule-2 (CORM-2). The potential of CORM-2-entrapped ultradeformable liposomes (CORM-2-UDLs) to enhance the release half-life of CO and alleviate skin inflammation was investigated in the present study. CORM-2-UDLs were prepared by using soy phosphatidylcholine to form lipid bilayers and Tween 80 as an edge activator. The deformability of CORM-2-UDLs was measured and compared with that of conventional liposomes by passing formulations through a filter device at a constant pressure. The release profile of CO from CORM-2-UDLs was evaluated by myoglobin assay. In vitro and in vivo anti-inflammatory effects of CORM-2-UDLs were assessed in lipopolysaccharide-stimulated macrophages and TPA-induced ear edema model, respectively. The deformability of the optimized CORM-2-UDLs was 2.3 times higher than conventional liposomes. CORM-2-UDLs significantly prolonged the release half-life of CO from 30 s in a CORM-2 solution to 21.6 min. CORM-2-UDLs demonstrated in vitro anti-inflammatory activity by decreasing nitrite production and pro-inflammatory cytokine levels. Furthermore, CORM-2-UDLs successfully ameliorated skin inflammation by reducing ear edema, pathological scores, neutrophil accumulation, and inflammatory cytokines expression. The results demonstrate that CORM-2-UDLs could be used as promising therapeutics against acute skin inflammation.