tbuckley/cabot-search huggingface dataset:
Modulation of DNA double-strand break repair through ATM - dependent and - independent ERK signaling
Authors: Ashraf Khalil, Sarah Golding, Elizabeth Rosenberg, Kristoffer Valerie
Journal: Cancer Research (2005)

3520  We have shown that DNA double-strand breaks (DSBs) affect ERK signaling in both positive and negative fashion suggesting a bi-modal mechanism of regulation that likely affects DSB repair and cell survival. Low levels of DSBs resulted in ATM-dependent ERK phosphorylation (activation) whereas high levels resulted in dephosphorylation (inactivation) by an as of yet unidentified phosphatase. Dephosphorylation occured in a DSB dose-dependent and ATM-independent fashion. CDC25A is a phosphatase important for cell cycle progression through G1/S and G2/M. CDC25A is positioned downstream of the ATM→CHK2/CHK1 arm of the DSB signaling pathway. In response to DSBs, ATM phosphorylates CHK2, which in turn phosphorylates CDC25A and triggers its degradation by the proteasome resulting in cell cycle arrest. Recently, a new role for CDC25A was revealed after it was shown it binds to and negatively regulates RAF; when CDC25A is inhibited or degraded ERK is activated. To investigate the possibility that CDC25A modulates ERK signaling through ATM→CHK2→CDC25A→RAF→MEK→ERK and affects DSB repair, we used a novel CDC25A inhibitor, NCS95397, which does not cause DNA damage, and examined its effect on ERK signaling and DSB repair. We found that treatment of human glioma cells with NSC95397 resulted in a ∼2-fold increase in ERK phosphorylation comparable to that seen after low levels of DSBs (equivalent to ≤2 Gy of radiation). The MAPK kinase (MEK) inhibitor U0126 completely inhibited ERK activation by NSC 95397, suggesting that NSC95397 acts upstream of MEK1/2 in line with its role as a CDC25A inhibitor acting through RAF. Furthermore, we found that NSC95397 modulated DSB repair and homologous recombination in particular. These preliminary results show that inhibition of CDC25A, mimicking CDC25A degradation in response to DSBs, stimulates ERK signaling and affects DSB repair, suggesting a potential link between ATM signaling and the ERK survival pathway.
Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder
Authors: Annie Kathuria, Kara Lopez-Lengowski, Magdalena Vater, Donna McPhie, Bruce M. Cohen, Rakesh Karmacharya
Journal: Genome Medicine (2020)

Abstract Background Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with disease-specific genetic backgrounds. Methods Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays. Results RNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER–mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids. Conclusions Our studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission.
Correction to: Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer
Authors: Shaoquan Zheng, Lu Yang, Yutian Zou, Jie-ying Liang, Peng Liu, Guanfeng Gao, Anli Yang, Hailin Tang, Xiaoming Xie
Journal: Journal of Hematology & Oncology (2020)

The original article [1] contains an error in Fig. 5b whereby two panels have been mistakenly duplicated. The correct version of Fig. 5b can be viewed ahead alongside the rest of Fig. 5.
The AHCPR Unstable Angina Algorithm in Practice
Authors: Richard A. Young
Journal: JAMA (1997)

To  Editor.  —While  topic of  article by Katz et al1is timely, their conclusion that the [AHCPR] guideline's recommendation for triage disposition of low-risk patients would apply to less than 1% of all patients with suspected acute cardiac ischemia who present to   is overstated for 2 reasons.  First,  authors probably did not identify all eligible candidates for this study. Even though a patient with unstable angina has a history of worsening chest pain, it is usually an especially severe or prolonged episode that actually brings that patient into  ED. Often,  foremost thought on  ED physician's mind is whether that particular event was an MI. At that moment,  2-month history of worsening chest pain is secondary. At my institution, most patients admitted with possible MI or ischemia are admitted as rule out MIs, not unstable angina. To identify all possible candidates,  authors
Impact of Morphine Treatment With and Without Metoclopramide Coadministration on Ticagrelor-Induced Platelet Inhibition in Acute Myocardial Infarction
Authors: Mohammed Saad, Roza Meyer-Saraei, Suzanne de Waha-Thiele, Thomas Stiermaier, Tobias Graf, Georg Fuernau, Harald F. Langer, Thomas Kurz, Janine Pöss, Jörg Barkhausen, Steffen Desch, Ingo Eitel, Holger Thiele
Journal: Circulation (2020)
Association of rhinovirus species with nasopharyngeal metabolome in bronchiolitis infants: A multicenter study
Authors: Michimasa Fujiogi, Carlos A. Camargo, Yoshihiko Raita, Yury A. Bochkov, James E. Gern, Jonathan M. Mansbach, Pedro A. Piedra, Kohei Hasegawa
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Effect of Lung-Protective Ventilation in Organ Donors on Lung Procurement and Recipient Survival
Authors: Hervé Mal, Gaëlle Santin, Christelle Cantrelle, Louise Durand, Camille Legeai, Gaëlle Cheisson, Luc Saint-Marcel, Isabelle Pipien, Laurent Durin, Olivier Bastien, Richard Dorent
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Previous studies have shown that a lung-protective strategy, which aims at minimizing ventilator-induced lung injury (with low Vt/high positive end-expiratory pressure as the main pillars), in selected potential organ donors after brain death increased lung eligibility and procurement.Objectives: This prospective nationwide cohort study aimed to evaluate the impact of lung-protective ventilation (PV) in nonselected donors on lung procurement and recipient survival after lung transplantation.Methods: We included all reported donors aged 18-70 years after brain death without a lung recovery contraindication and with at least one organ recovered between January 2016 and December 2017. PV was defined as Vt ≤8 ml/kg predicted body weight and positive end-expiratory pressure ≥8 cm H2O. The association between PV at the time of lung proposal (T1) and lung procurement was determined by multivariable logistic regression stratified by propensity score quintile to account for PV and non-PV group differences in baseline characteristics. We studied 1-year survival of recipients from donors with or without PV at T1.Measurements and Main Results: Of 1,626 included lung donors, 1,109 (68%) had at least one lung proposed; 678 (61%) of these had at least one lung recovered. At T1, only 25.6% of donors with at least one lung proposed for lung transplantation were ventilated with a protective strategy. For donors with a lung proposal, the probability of lung procurement was increased with PV at T1 (odds ratio, 1.43; 95% confidence interval [CI], 1.03-1.98; P = 0.03). One-year survival did not differ between recipients of lungs from donors with and without PV (82.7%, 95% CI 76.0-87.8% vs. 82.3%, 95% CI 78.5-85.4%; P = 0.94).Conclusions: The use of lung PV in nonselected donors may increase lung procurement. One-year survival did not differ between recipients of lungs from donors with PV or from those without PV.
Safety and Tolerability of Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFβ and PD-L1, in Asian Patients with Pretreated Recurrent or Refractory Gastric Cancer
Authors: Yoon-Koo Kang, Yung-Jue Bang, Shunsuke Kondo, Hyun Cheol Chung, Kei Muro, Isabelle Dussault, Christoph Helwig, Motonobu Osada, Toshihiko Doi
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Patients with advanced gastric/gastroesophageal junction cancer (GC/GEJC) have limited treatment options after first-line therapy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (a TGFβ “trap”) fused to a human IgG1 antibody against programmed death ligand 1 (PD-L1), potentially offering a new treatment approach for these patients. We report results for bintrafusp alfa in GC/GEJC. Patients and Methods: Asian patients with recurrent GC/GEJC for whom standard therapy does not exist or for whom standard therapy has failed enrolled in this expansion cohort of an ongoing phase I trial and received bintrafusp alfa 1,200 mg once every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary objective was to assess safety/tolerability. Results: By July 23, 2018, 31 heavily pretreated patients received bintrafusp alfa for a median of 10.1 weeks; 3 patients remained on treatment. Six patients (19%) experienced grade 3 treatment-related adverse events (AE); no grade 4 events occurred. One on-treatment death occurred (sudden death); rupture of a preexisting thoracic aortic aneurysm was the suspected cause. Ten patients (32%) had immune-related AEs. The confirmed objective response rate per independent review committee was 16%; disease control rate was 26%. Median duration of response was 8.7 months (range, 2.4–12.4+). Responses occurred irrespective of PD-L1 expression or microsatellite instability status and appeared to correlate with high tumor TGFB1 levels. Conclusions: In this first evaluation in Asian patients with heavily pretreated advanced GC/GEJC, bintrafusp alfa demonstrated a manageable safety profile and clinical activity.
Age-Related Variations in Takotsubo Syndrome
Authors: Victoria L. Cammann, Konrad A. Szawan, Barbara E. Stähli, Ken Kato, Monika Budnik, Manfred Wischnewsky, Sara Dreiding, Rena A. Levinson, Davide Di Vece, Sebastiano Gili, Rodolfo Citro, Eduardo Bossone, Michael Neuhaus, Jennifer Franke, Benjamin Meder, Miłosz Jaguszewski, Michel Noutsias, Maike Knorr, Susanne Heiner, Fabrizio D’Ascenzo, Wolfgang Dichtl, Christof Burgdorf, Behrouz Kherad, Carsten Tschöpe, Annahita Sarcon, Jerold Shinbane, Lawrence Rajan, Guido Michels, Roman Pfister, Alessandro Cuneo, Claudius Jacobshagen, Mahir Karakas, Wolfgang Koenig, Alexander Pott, Philippe Meyer, Marco Roffi, Adrian Banning, Mathias Wolfrum, Florim Cuculi, Richard Kobza, Thomas A. Fischer, Tuija Vasankari, K.E. Juhani Airaksinen, L. Christian Napp, Rafal Dworakowski, Philip MacCarthy, Christoph Kaiser, Stefan Osswald, Leonarda Galiuto, Christina Chan, Paul Bridgman, Daniel Beug, Clément Delmas, Olivier Lairez, Ekaterina Gilyarova, Alexandra Shilova, Mikhail Gilyarov, Ibrahim El-Battrawy, Ibrahim Akin, Karolina Poledniková, Petr Toušek, David E. Winchester, Jan Galuszka, Christian Ukena, Gregor Poglajen, Pedro Carrilho-Ferreira, Christian Hauck, Carla Paolini, Claudio Bilato, Yoshio Kobayashi, Toshihiro Shoji, Iwao Ishibashi, Masayuki Takahara, Toshiharu Himi, Jehangir Din, Ali Al-Shammari, Abhiram Prasad, Charanjit S. Rihal, Kan Liu, P. Christian Schulze, Matteo Bianco, Lucas Jörg, Hans Rickli, Gonçalo Pestana, Thanh H. Nguyen, Michael Böhm, Lars S. Maier, Fausto J. Pinto, Petr Widimský, Stephan B. Felix, Ruediger C. Braun-Dullaeus, Wolfgang Rottbauer, Gerd Hasenfuß, Burkert M. Pieske, Heribert Schunkert, Martin Borggrefe, Holger Thiele, Johann Bauersachs, Hugo A. Katus, John D. Horowitz, Carlo Di Mario, Thomas Münzel, Filippo Crea, Jeroen J. Bax, Thomas F. Lüscher, Frank Ruschitzka, Jelena R. Ghadri, Grzegorz Opolski, Christian Templin
Journal: Journal of the American College of Cardiology (2020)
Saliva: potential diagnostic value and transmission of 2019-nCoV
Authors: Ruoshi Xu, Bomiao Cui, Xiaobo Duan, Ping Zhang, Xuedong Zhou, Quan Yuan
Journal: International Journal of Oral Science (2020)

Abstract 2019-nCoV epidemic was firstly reported at late December of 2019 and has caused a global outbreak of COVID-19 now. Saliva, a biofluid largely generated from salivary glands in oral cavity, has been reported 2019-nCoV nucleic acid positive. Besides lungs, salivary glands and tongue are possibly another hosts of 2019-nCoV due to expression of ACE2. Close contact or short-range transmission of infectious saliva droplets is a primary mode for 2019-nCoV to disseminate as claimed by WHO, while long-distance saliva aerosol transmission is highly environment dependent within indoor space with aerosol-generating procedures such as dental practice. So far, no direct evidence has been found that 2019-nCoV is vital in air flow for long time. Therefore, to prevent formation of infectious saliva droplets, to thoroughly disinfect indoor air and to block acquisition of saliva droplets could slow down 2019-nCoV dissemination. This review summarizes diagnostic value of saliva for 2019-nCoV, possibly direct invasion into oral tissues, and close contact transmission of 2019-nCoV by saliva droplets, expecting to contribute to 2019-nCoV epidemic control.
Techniques for Treatment of Carotid Stenosis—Reply
Authors: Marc L. Schermerhorn, Patric Liang
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Pleiotropy in the Genetic Predisposition to Rheumatoid Arthritis: A Phenome‐Wide Association Study and Inverse Variance–Weighted Meta‐Analysis
Authors: Vivian K. Kawai, Mingjian Shi, Qiping Feng, Cecilia P. Chung, Ge Liu, Nancy J. Cox, Gail P. Jarvik, Ming T. M. Lee, Scott J. Hebbring, John B. Harley, Kenneth M. Kaufman, Bahram Namjou, Eric Larson, Adam S. Gordon, Dan M. Roden, C. Michael Stein, Jonathan D. Mosley
Journal: Arthritis & Rheumatology (2020)

This study was undertaken to investigate the hypothesis that a genetic predisposition toward rheumatoid arthritis (RA) increases the risk of 10 cardiometabolic and autoimmune disorders previously associated with RA in epidemiologic studies, and to define new genetic pleiotropy present in RA.Two approaches were used to test our hypothesis. First, we constructed a weighted genetic risk score (wGRS) and then examined its association with 10 prespecified disorders. Additionally, a phenome-wide association study (PheWAS) was carried out to identify potential new associations. Second, inverse variance-weighted regression (IVWR) meta-analysis was used to characterize the association between genetic susceptibility to RA and the prespecified disorders, with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs).The wGRS for RA was significantly associated with type 1 diabetes mellitus (DM) (OR 1.10 [95% CI 1.04-1.16]; P = 9.82 × 10-4 ) and multiple sclerosis (OR 0.82 [95% CI 0.77-0.88]; P = 1.73 × 10-8 ), but not with other cardiometabolic phenotypes. In the PheWAS, wGRS was also associated with an increased risk of several autoimmune phenotypes including RA, thyroiditis, and systemic sclerosis, and with a decreased risk of demyelinating disorders. In the IVWR meta-analyses, RA was significantly associated with an increased risk of type 1 DM (P = 1.15 × 10-14 ), with evidence of horizontal pleiotropy (Mendelian Randomization-Egger intercept estimate P = 0.001) likely driven by rs2476601, a PTPN22 variant. The association between type 1 DM and RA remained significant (P = 9.53 × 10-9 ) after excluding rs2476601, with no evidence of horizontal pleiotropy (intercept estimate P = 0.939). RA was also significantly associated with type 2 DM and C-reactive protein levels. These associations were driven by variation in the major histocompatibility complex region.This study presents evidence of pleiotropy between the genetic predisposition to RA and associated phenotypes found in other autoimmune and cardiometabolic disorders, including type 1 DM.
Maintenance Alemtuzumab in Refractory B-Cell Chronic Lymphocytic Leukemia Patients: Updated Data.
Authors: Catherine Thieblemont, Roch Houot, Boubacari Ali Toure, Catherine Traulle, Anne-Sophie Michallet, Fadhela Bouafia, Daniel Espinouse, Gilles Salles, Bertrand Coiffier
Journal: Blood (2005)
First Case of Covid-19 in the United States
Authors: Chuanli Ren, Hui Chen, Hou-Zao Chen
Journal: New England Journal of Medicine (2020)

Holshue et al. (March 5 issue) 1 describe the management of the first case of Covid-19 in the United States.We disagree that remdesivir should be used on the 11th day after the onset of symptoms.Few data on the viral load kinetics in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of Covid-19, are available. 2However, a study of changes in viral load over time in patients with severe Middle East respiratory syndrome coronavirus 3 showed that copies of RNA peaked before the 11th day of illness.We doubt that the dramatic improvement in the clinical condition of the patient described by Holshue et al. was associated with remdesivir.Readers may have a very misleading impression that remdesivir should be administered as a salvage therapy for Covid-19.We do agree that randomized, controlled trials are needed to evaluate the efficacy and safety of remdesivir.However, in a clinical trial of therapies for Ebola virus disease that was terminated early, the mortality in the remdesivir group was significantly higher than that in the other groups. 4 More safety information should be disclosed by the pharmaceutical industry before a new trial of remdesivir is launched, 5 since most cases of Covid-19 are mild or moderate.
Neurobehavioural characterisation and stratification of reinforcement-related behaviour
Authors: Tianye Jia, Alex Ing, Erin Burke Quinlan, Nicole Tay, Qiang Luo, Biondo Francesca, Tobias Banaschewski, Gareth J. Barker, Arun L. W. Bokde, Uli Bromberg, Christian Büchel, Sylvane Desrivières, Jianfeng Feng, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Gunter Schumann, Tianye Jia, Alex Ing, Erin Burke Quinlan, Biondo Francesca, Tobias Banaschewski, Gareth J. Barker, Arun L. W. Bokde, Uli Bromberg, Christian Büchel, Sylvane Desrivières, Herta Flor, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Gunter Schumann
Journal: Nature Human Behaviour (2020)
Cannabis-based medicinal products: summary of NICE guidance
Authors: Stacey Chang-Douglass, Caroline Mulvihill, Steve Pilling
Journal: BMJ (2020)

### What you need to know

In September 2018, in light of the UK chief medical officer’s review and in response to the Advisory Council on the Misuse of Drugs advice, ministers in the UK announced changes to the existing regulations on cannabis-based medicinal products (CBMPs). CBMPs would be rescheduled from Schedule 1 of the Misuse of Drugs Regulations 200112 to Schedule 2 controlled drugs and that prescribing would be restricted to doctors on the Specialist Register of the General Medical Council (GMC). Rescheduling allows CBMPs to be legally prescribed. However, many CBMPs currently do not have marketing authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA), and so existing prescribing guidance and governance arrangements in place for unlicensed medicines continue to apply. Unlicensed medications should not be considered as first line treatments and should be used only when there is …
Beneficial effects of combination therapy of canagliflozin and teneligliptin on diabetic polyneuropathy and β-cell volume density in spontaneously type 2 diabetic Goto-Kakizaki rats
Authors: Danyang Guo, Hiroki Mizukami, Sho Osonoi, Kazuhisa Takahashi, Saori Ogasawara, Kazuhiro Kudo, Takanori Sasaki, Soroku Yagihashi
Journal: Metabolism (2020)

AimsParasympathetic nerve (PN) signaling plays a crucial role in the maintenance of pancreatic β-cell volume density (Vβ). PN may be pathologically affected in diabetic polyneuropathy (DPN). However, the association between the reduction of PNs in islets and Vβ and the therapeutic effects of a DPP4 inhibitor (DPP4i) and an SGLT2 inhibitor (SGLT2i) in nonobese type 2 diabetes mellitus (T2DM) Goto-Kakizaki rats (GK) have not been investigated.Materials and methodsWe divided 5-week old male GK and Wistar rats (W) into a DPP4i-treated group (GKTe), SGLT2i-treated group (GKCa), and combination-treated group (GKCaTe). After 25 weeks, the pancreata was pathologically evaluated.ResultsVβ in GK was significantly decreased (p < 0.01 vs. W), whereas Vβ was the most well preserved in GKCaTe (p < 0.05 vs. GKTe), followed by GKTe (p < 0.05 vs. GK). The decreased amount of PNs in the islets and intraepidermal nerve fiber density (IENFD) in GK was significantly improved in the treated groups compared with GK (p < 0.05 vs. GKCa and GKTe and p < 0.01 vs. GKCaTe). PN density and IENFD were significantly correlated with Vβ (r = 0.55, p < 0.01 and r = 0.54, p < 0.01, respectively). IENFD was identified as a surrogate marker for the prediction of Vβ (cutoff value, 16.39).ConclusionsThe combination therapy of DPP4i and SGLT2i improved Vβ accompanied by PNs density and IENFD. IENFD was proportionally correlated with Vβ. Therefore, the prevention of DPN development may be concurrently beneficial for the preservation of Vβ in nonobese T2DM.