tbuckley/cabot-search huggingface dataset:
Functional Consequences of Metabolic Zonation in Murine Livers: Insights for an Old Story
Authors: Nikolaus Berndt, Erik Kolbe, Robert Gajowski, Johannes Eckstein, Fritzi Ott, David Meierhofer, Hermann‐Georg Holzhütter, Madlen Matz‐Soja
Journal: Hepatology (2020)

Background and Aims Zone‐dependent differences in expression of metabolic enzymes along the portocentral axis of the acinus are a long‐known feature of liver metabolism. A prominent example is the preferential localization of the enzyme, glutamine synthetase, in pericentral hepatocytes, where it converts potentially toxic ammonia to the valuable amino acid, glutamine. However, with the exception of a few key regulatory enzymes, a comprehensive and quantitative assessment of zonal differences in the abundance of metabolic enzymes and, much more important, an estimation of the associated functional differences between portal and central hepatocytes is missing thus far. Approach and Results We addressed this problem by establishing a method for the separation of periportal and pericentral hepatocytes that yields sufficiently pure fractions of both cell populations. Quantitative shotgun proteomics identified hundreds of differentially expressed enzymes in the two cell populations. We used zone‐specific proteomics data for scaling of the maximal activities to generate portal and central instantiations of a comprehensive kinetic model of central hepatic metabolism (Hepatokin1). Conclusions The model simulations revealed significant portal‐to‐central differences in almost all metabolic pathways involving carbohydrates, fatty acids, amino acids, and detoxification.
Hypoxia-induced lncRNA-AC020978 promotes proliferation and glycolytic metabolism of non-small cell lung cancer by regulating PKM2/HIF-1α axis
Authors: Qian Hua, Baoming Mi, Fei Xu, Jun Wen, Li Zhao, Jianjun Liu, Gang Huang
Journal: Theranostics (2020)

Rationale: Non-small cell lung cancer (NSCLC) is a deadly disease with a hallmark of aberrant metabolism. The mechanism of glycolysis associated lncRNA underlying the aggressive behaviors of NSCLC is poorly understood. Methods: The expression level of AC020978 in NSCLC was measured by quantitative real-time PCR and fluorescence in situ hybridization (FISH) assay. The biological role of AC020978 in cell proliferation and aerobic glycolysis was determined by functional experiments in vitro and in vivo. The transcription of AC020978 was assessed by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assay. RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP) assays were used to identify the interaction protein with AC020978. Western blotting, in situ proximity ligation assay (PLA), and co-immunoprecipitation (co-IP) were performed to reveal the potential mechanism of AC020978. Results: The present study indicated that AC020978 was upregulated in NSCLC, significantly correlated with advanced TNM stage and poor clinical outcomes, representing as an independent prognostic predictor. Functional assays revealed AC020978's role in promoting cell growth and metabolic reprogramming. Moreover, AC020978 was an upregulated lncRNA under glucose starvation as well as hypoxia conditions, and directly transactivated by HIF-1α. Mechanistic investigations identified that AC020978 directly interacted with Pyruvate kinase isozymes M2 (PKM2) and enhanced PKM2 protein stability. Besides, this study uncovered that AC020978 could promote the nuclear translocation of PKM2 and regulate PKM2-enhanced HIF-1α transcription activity. Conclusions: Together, these data provided evidence that AC020978 conferred an aggressive phenotype to NSCLC and was a poor prognosticator. Targeting AC020978 might be an effective therapeutic strategy for NSCLC.
Dermatological adverse events associated with use of oral mechanistic target of rapamycin inhibitors in a cohort of individuals with tuberous sclerosis complex
Authors: D.J. Pithadia, A.M. Treichel, A.M. Jones, P. Julien‐Williams, T. Machado, J. Moss, T.N. Darling
Journal: British Journal of Dermatology (2020)
Targeted sequencing reveals the mutational landscape responsible for sorafenib therapy in advanced hepatocellular carcinoma
Authors: Jing Tang, Cheng-Jun Sui, Dong-Fang Wang, Xin-Yuan Lu, Gui-Juan Luo, Qing Zhao, Qiu-Yu Lian, Seogsong Jeong, Xi-Meng Lin, Yan-Jing Zhu, Bo Zheng, Rui Wu, Qing Wang, Xiao-Long Liu, Jing-Feng Liu, Qiang Xia, Gang Wu, Jin Gu, Hong-Yang Wang, Lei Chen
Journal: Theranostics (2020)

Rationale:The existence of primary and acquired drug resistance is the main obstacle for the effect of multi-kinase inhibitor sorafenib and regorafenib in advanced hepatocellular carcinoma (HCC).However, plenty of patients did not significantly benefit from sorafenib treatment and little is known about the mechanism of drug resistance.Methods: Laser capture microdissection was used to acquire matched normal liver and tumor tissues on formalin-fixed paraffin-embedded specimens collected before sorafenib therapy from the first surgery of 119 HCC patients.Ultra-deep sequencing (~1000×) targeting whole exons of 440 genes in microdissected specimens and siRNA screen in 7 cell lines were performed to find mutations associated with differential responses to sorafenib.Patient-derived xenograft models were employed to determine the role of TP53 in response to sorafenib.Lentiviruses harboring wild-type and c.G52C-mutant OCT4 were applied to explore the function of OCT4 in resistance to sorafenib.ChIP-PCR assay for analysis of OCT4 transcriptional activity was performed to explore the affinity with the KITLG promoter.Statistical analyses were used to associate levels of p53 and OCT4 with tumor features and patient outcomes. Ivyspring International
Characteristics of human metapneumovirus infection in adults hospitalized for community-acquired influenza-like illness in France, 2012–2018: a retrospective observational study
Authors: P. Loubet, P. Mathieu, N. Lenzi, F. Galtier, F. Lainé, Z. Lesieur, P. Vanhems, X. Duval, D. Postil, S. Amour, S. Rogez, G. Lagathu, A.-S. L'Honneur, V. Foulongne, N. Houhou, B. Lina, F. Carrat, O. Launay
Journal: Clinical Microbiology and Infection (2020)
A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity
Authors: Kathryn L. Simpson, Ruth Stoney, Kristopher K. Frese, Nicole Simms, William Rowe, Simon P. Pearce, Sam Humphrey, Laura Booth, Derrick Morgan, Marek Dynowski, Francesca Trapani, Alessia Catozzi, Mitchell Revill, Thomas Helps, Melanie Galvin, Luc Girard, Daisuke Nonaka, Louise Carter, Matthew G. Krebs, Natalie Cook, Mathew Carter, Lynsey Priest, Alastair Kerr, Adi F. Gazdar, Fiona Blackhall, Caroline Dive
Journal: Nature Cancer (2020)
Hypothalamic oestrogen receptor alpha establishes a sexually dimorphic regulatory node of energy expenditure
Authors: J. Edward van Veen, Laura G. Kammel, Patricia C. Bunda, Michael Shum, Michelle S. Reid, Megan G. Massa, Douglas V. Arneson, Jae W. Park, Zhi Zhang, Alexia M. Joseph, Haley Hrncir, Marc Liesa, Arthur P. Arnold, Xia Yang, Stephanie M. Correa
Journal: Nature Metabolism (2020)
Alcohol or Benzodiazepine Co-involvement With Opioid Overdose Deaths in the United States, 1999-2017
Authors: Marco E. Tori, Marc R. Larochelle, Timothy S. Naimi
Journal: JAMA Network Open (2020)

<h3>Importance</h3> The use of benzodiazepines or alcohol together with opioids increases overdose risk, but characterization of co-involvement by predominant opioid subtype is incomplete to date. Understanding the use of respiratory depressants in opioid overdose deaths (OODs) is important for prevention efforts and policy making. <h3>Objective</h3> To assess the prevalence and number of alcohol- or benzodiazepine-involved OODs by opioid subtypes in the United States from 1999 to 2017. <h3>Design and Setting</h3> This repeated cross-sectional analysis used data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (WONDER) database of all opioid-involved poisoning deaths from January 1, 1999, to December 31, 2017, for the United States. State-level binge drinking prevalence rates for 2015 to 2017 were obtained from the Behavior Risk Factor Surveillance System of the Centers for Disease Control and Prevention, and benzodiazepine prescribing rates for 2012 (most recent available data) were obtained from IMS Health, a commercial database. Data were analyzed from July 10, 2018, to May 16, 2019. <h3>Main Outcomes and Measures</h3> Prevalence of alcohol or benzodiazepine co-involvement for all OODs and by opioid subtype, nationally and by state. <h3>Results</h3> From 1999 to 2017, 399 230 poisoning deaths involved opioids, of which 263 601 (66.0%) were male, and 204 560 (51.2%) were aged 35 to 54 years. Alcohol co-involvement for all opioid overdose deaths increased nonlinearly from 12.4% in 1999 to 14.7% in 2017. By opioid subtype, deaths involving heroin and synthetic opioids (eg, fentanyl; excluding methadone) had the highest alcohol co-involvement at 15.5% and 14.9%, respectively, in 2017. Benzodiazepine co-involvement in all OODs increased nonlinearly from 8.7% in 1999 to 21.0% in 2017. Benzodiazepines were present in 33.1% of prescription OODs and 17.1% of synthetic OODs in 2017. State-level rates of binge drinking were significantly correlated with alcohol co-involvement in all OODs (<i>r</i> = 0.34;<i>P</i> = .02). State benzodiazepine prescribing rates were significantly correlated with benzodiazepine co-involvement in all OODs (<i>r</i> = 0.57;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> This study found that alcohol and benzodiazepine co-involvement in opioid-involved overdose deaths was common, varied by opioid subtype, and was associated with state-level binge drinking and benzodiazepine prescribing rates. These results may inform state policy initiatives in harm reduction and overdose prevention efforts.
Reduction in ST-Segment Elevation Cardiac Catheterization Laboratory Activations in the United States During COVID-19 Pandemic
Authors: Santiago Garcia, Mazen S. Albaghdadi, Perwaiz M. Meraj, Christian Schmidt, Ross Garberich, Farouc A. Jaffer, Simon Dixon, Jeffrey J. Rade, Mark Tannenbaum, Jenny Chambers, Paul P. Huang, Timothy D. Henry
Journal: Journal of the American College of Cardiology (2020)
The impact of hyperglycaemia on PKM2-mediated NLRP3 inflammasome/stress granule signalling in macrophages and its correlation with plaque vulnerability: an in vivo and in vitro study
Authors: Qinxue Li, Kunkun Leng, Yayun Liu, Haichen Sun, Jinhuan Gao, Quanxin Ren, Tian Zhou, Jing Dong, Jinggang Xia
Journal: Metabolism (2020)
Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: A prospective contact-tracing study
Authors: Lei Huang, Xiuwen Zhang, Xinyue Zhang, Zhijian Wei, Lingli Zhang, Jingjing Xu, Peipei Liang, Yuanhong Xu, Chengyuan Zhang, Aman Xu
Journal: Journal of Infection (2020)

The outbreak of coronavirus-disease-2019 (COVID-19) has rapidly spread to many places outside Wuhan. Previous studies on COVID-19 mostly included older hospitalized-adults. Little information on infectivity among and characteristics of youngsters with COVID-19 is available.A cluster of 22 close-contacts of a 22-year-old male (Patient-Index) including youngsters with laboratory-confirmed COVID-19 and hospitalized close-contacts testing negative for severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) in Anhui Province, China was prospectively-traced.Since January 23, 2020, we enrolled a cluster of eight youngsters with COVID-19 (median age [range], 22 [16-23] years; six males) originating from Patient-Index returning from Wuhan to Hefei on January 19. Patient-Index visited his 16-year-old female cousin in the evening on his return, and met 15 previous classmates in a get-together on January 21. He reported being totally asymptomatic and were described by all his contacts as healthy on January 19-21. His very first symptoms were itchy eyes and fever developed at noon and in the afternoon on January 22, respectively. Seven youngsters (his cousin and six classmates) became infected with COVID-19 after a-few-hour-contact with Patient-Index. None of the patients and contacts had visited Wuhan (except Patient-Index), or had any exposure to wet-markets, wild-animals, or medical-institutes within three months. For affected youngsters, the median incubation-period was 2 days (range, 1-4). The median serial-interval was 1 day (range, 0-4). Half or more of the eight COVID-19-infected youngsters had fever, cough, sputum production, nasal congestion, and fatigue on admission. All patients had mild conditions. Six patients developed pneumonia (all mild; one bilateral) on admission. As of February 20, four patients were discharged.SARS-CoV-2-infection presented strong infectivity during the incubation-period with rapid transmission in this cluster of youngsters outside Wuhan. COVID-19 developed in these youngsters had fast onset and various nonspecific atypical manifestations, and were much milder than in older patients as previously reported.
Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis
Authors: Vance G. Fowler, Anita F. Das, Joy Lipka-Diamond, Raymond Schuch, Roger Pomerantz, Luis Jáuregui-Peredo, Adam Bressler, David Evans, Gregory J. Moran, Mark E. Rupp, Robert Wise, G. Ralph Corey, Marcus Zervos, Pamela S. Douglas, Cara Cassino
Journal: Journal of Clinical Investigation (2020)

BACKGROUNDNovel therapeutic approaches are critically needed for Staphylococcus aureus bloodstream infections (BSIs), particularly for methicillin-resistant S. aureus (MRSA). Exebacase, a first-in-class antistaphylococcal lysin, is a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics.METHODSIn this superiority-design study, we randomly assigned 121 patients with S. aureus BSI/endocarditis to receive a single dose of exebacase or placebo. All patients received standard-of-care antibiotics. The primary efficacy endpoint was clinical outcome (responder rate) on day 14.RESULTSClinical responder rates on day 14 were 70.4% and 60.0% in the exebacase + antibiotics and antibiotics-alone groups, respectively (difference = 10.4, 90% CI [-6.3, 27.2], P = 0.31), and were 42.8 percentage points higher in the prespecified exploratory MRSA subgroup (74.1% vs. 31.3%, difference = 42.8, 90% CI [14.3, 71.4], ad hoc P = 0.01). Rates of adverse events (AEs) were similar in both groups. No AEs of hypersensitivity to exebacase were reported. Thirty-day all-cause mortality rates were 9.7% and 12.8% in the exebacase + antibiotics and antibiotics-alone groups, respectively, with a notable difference in MRSA patients (3.7% vs. 25.0%, difference = -21.3, 90% CI [-45.1, 2.5], ad hoc P = 0.06). Among MRSA patients in the United States, median length of stay was 4 days shorter and 30-day hospital readmission rates were 48% lower in the exebacase-treated group compared with antibiotics alone.CONCLUSIONThis study establishes proof of concept for exebacase and direct lytic agents as potential therapeutics and supports conduct of a confirmatory study focused on exebacase to treat MRSA BSIs.TRIAL REGISTRATIONClinicaltrials.gov NCT03163446.FUNDINGContraFect Corporation.
Radiation-induced small extracellular vesicles as “carriages” promote tumor antigen release and trigger antitumor immunity
Authors: Wanzun Lin, Yanyan Xu, Xiaochuan Chen, Jun Liu, Youliang Weng, Qingyang Zhuang, Feifei Lin, Zongwei Huang, Shihong Wu, Jianming Ding, Long Chen, Xianxin Qiu, Lurong Zhang, Junxin Wu, Duo Lin, Sufang Qiu
Journal: Theranostics (2020)

Rationale: Accumulating evidence supports the importance of radiation therapy in the induction of antitumor immunity. Small extracellular vesicles (sEVs) play essential roles in tumor antigen loading and delivery. However, the role of sEVs in radiation-induced antitumor immunity remains unclear. It is therefore important to determine the role and regulatory mechanisms of sEVs in radiation-induced immunity. Methods: Tumor cells were irradiated (8 Gy), and sEVs were purified via ultracentrifugation. Primary tumor and experimental lung metastasis models were established in mice to evaluate antitumor immunity triggered by immunization with sEVs. Proteomic and bioinformatic analyses were performed to identify altered cargos in sEVs induced by radiation. Peptides derived from up-regulated proteins in sEVs were designed and synthesized as vaccines according to major histocompatibility complex (MHC) I binding and immunogenicity. Results: Here, we demonstrated that sEVs derived from irradiated tumor cells could trigger antitumor immunity against primary tumor and experimental lung metastasis by enhancing CD8+ and CD4+ T cell infiltration. Radiation may also enrich sEVs with tumor antigens and heat-shock proteins. Furthermore, CUB domain-containing protein 1 (CDCP1) derived from radiation-induced sEVs was identified as a novel tumor-associated antigen and developed as a peptide vaccine that may generate antitumor immune responses. Conclusions: Our results demonstrate that the use of sEVs secreted by irradiated tumor cells constitutes an efficient approach for tumor antigen delivery and presentation and highlight the role of sEVs in radiation-triggered antitumor immunity.
Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study
Authors: Guillermo Garcia-Manero, Elizabeth A. Griffiths, David P. Steensma, Gail J. Roboz, Richard Wells, James McCloskey, Olatoyosi Odenike, Amy E. DeZern, Karen Yee, Lambert Busque, Casey O’Connell, Laura C. Michaelis, Joseph Brandwein, Hagop Kantarjian, Aram Oganesian, Mohammad Azab, Michael R. Savona
Journal: Blood (2020)
Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape
Authors: Meenakshi Hegde, Malini Mukherjee, Zakaria Grada, Antonella Pignata, Daniel Landi, Shoba A. Navai, Amanda Wakefield, Kristen Fousek, Kevin Bielamowicz, Kevin K.H. Chow, Vita S. Brawley, Tiara T. Byrd, Simone Krebs, Stephen Gottschalk, Winfried S. Wels, Matthew L. Baker, Gianpietro Dotti, Maksim Mamonkin, Malcolm K. Brenner, Jordan S. Orange, Nabil Ahmed
Journal: Journal of Clinical Investigation (2019)

The corresponding author recently notified the JCI that the patient data presented in Figure 1B were not correct.Analysis of the correct patient data set does not show a significant difference in CERS6 expression in human lung adenocarcinomas with positive invasive growth (definite) compared with those with negligible invasive growth or without invasive growth (focal/none).The Editors have requested an institutional investigation into this matter, and we will inform our readers of the outcome when the investigation is complete.
Blood‐Brain–Barrier Microvasculatures: Modeling Nanocarrier Transport across a 3D In Vitro Human Blood‐Brain–Barrier Microvasculature (Adv. Healthcare Mater. 7/2020)
Authors: Sharon Wei Ling Lee, Marco Campisi, Tatsuya Osaki, Luca Possenti, Clara Mattu, Giulia Adriani, Roger Dale Kamm, Valeria Chiono
Journal: Advanced Healthcare Materials (2020)

The cover image shows the potentiality of an in vitro microfluidic 3D model of a human blood-brain–barrier microvasculature as a tool to assess the permeability of nanoparticles, surface functionalized with specific ligands, and their spatio-temporal distribution into brain tissue. This work is found in article number 1901486 by Roger Dale Kamm, Valeria Chiono, and co-workers.
Coronavirus Infections and Type 2 Diabetes—Shared Pathways with Therapeutic Implications
Authors: Daniel J Drucker
Journal: Endocrine Reviews (2020)

Abstract Abstract Individuals with diabetes are at increased risk for bacterial, mycotic, parasitic, and viral infections. The severe acute respiratory syndrome (SARS)-CoV-2 (also referred to as COVID-19) coronavirus pandemic highlights the importance of understanding shared disease pathophysiology potentially informing therapeutic choices in individuals with type 2 diabetes (T2D). Two coronavirus receptor proteins, angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase-4 (DPP4) are also established transducers of metabolic signals and pathways regulating inflammation, renal and cardiovascular physiology, and glucose homeostasis. Moreover, glucose-lowering agents such as the DPP4 inhibitors, widely used in subjects with T2D, are known to modify the biological activities of multiple immunomodulatory substrates. Here, we review the basic and clinical science spanning the intersections of diabetes, coronavirus infections, ACE2, and DPP4 biology, highlighting clinical relevance and evolving areas of uncertainty underlying the pathophysiology and treatment of T2D in the context of coronavirus infection.
Service to Others May Be the Answer to Physician Burnout
Authors: Rahul M. Jindal
Journal: JAMA Surgery (2020)

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Reverse-genetics studies of lncRNAs—what we have learnt and paths forward
Authors: Fan Gao, Ye Cai, Philipp Kapranov, Dongyang Xu
Journal: Genome biology (2020)

Long non-coding RNAs (lncRNAs) represent a major fraction of the transcriptome in multicellular organisms. Although a handful of well-studied lncRNAs are broadly recognized as biologically meaningful, the fraction of such transcripts out of the entire collection of lncRNAs remains a subject of vigorous debate. Here we review the evidence for and against biological functionalities of lncRNAs and attempt to arrive at potential modes of lncRNA functionality that would reconcile the contradictory conclusions. Finally, we discuss different strategies of phenotypic analyses that could be used to investigate such modes of lncRNA functionality.
What I learnt from studying doctors’ mental health over 20 years—an essay by Jenny Firth-Cozens
Authors: Jenny Firth-Cozens
Journal: BMJ (2020)

Covid-19 has put mental health in the spotlight more than ever. <b>Jenny Firth-Cozens</b> spent two decades following cohorts of doctors through the trials of their career. She looks back on the persisting problems from a failure to acknowledge the reality of a life in medicine—and the organisational changes needed to support it
Rationalization may improve predictability rather than accuracy
Authors: P Kyle Stanford, Ashley J Thomas, Barbara W Sarnecka
Journal: Behavioral and Brain Sciences (2020)

Abstract We present a theoretical and an empirical challenge to Cushman's claim that rationalization is adaptive because it allows humans to extract more accurate beliefs from our non-rational motivations for behavior. Rationalization sometimes generates more adaptive decisions by making our beliefs about the world less accurate. We suggest that the most important adaptive advantage of rationalization is instead that it increases our predictability (and therefore attractiveness) as potential partners in cooperative social interactions.