tbuckley/cabot-search huggingface dataset:
Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR)
Authors: David S Kessler, Stephanie J MacNeill, Deborah Tallon, Glyn Lewis, Tim J Peters, William Hollingworth, Jeff Round, Alison Burns, Carolyn A Chew-Graham, Ian M Anderson, Tom Shepherd, John Campbell, Chris M Dickens, Mary Carter, Caroline Jenkinson, Una Macleod, Helen Gibson, Simon Davies, Nicola J Wiles
Journal: BMJ (2018)

Abstract Objective To investigate the effectiveness of combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants for treatment resistant depression in primary care. Design Two parallel group multicentre phase III randomised placebo controlled trial. Setting 106 general practices in four UK sites; Bristol, Exeter, Hull, and Keele/North Staffs, August 2013 to October 2015. Participants 480 adults aged 18 or more years who scored 14 or more on the Beck depression inventory, second revision, fulfilled ICD-10 (international classification of diseases, 10th revision) criteria for depression, and had used an SSRI or SNRI for at least six weeks but were still depressed. 241 were randomised to mirtazapine and 239 to placebo, both given in addition to usual SSRI or SNRI treatment. Participants were stratified by centre and minimised by baseline Beck depression inventory score, sex, and current psychological therapy. They were followed up at 12, 24, and 52 weeks. 431 (89.8%) were included in the (primary) 12 week follow-up. Main outcome measures Depressive symptoms at 12 weeks after randomisation, measured using the Beck depression inventory II score as a continuous variable. Secondary outcomes included measures of anxiety, quality of life, and adverse effects at 12, 24, and 52 weeks. Results Beck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means −1.83 (95% confidence interval −3.92 to 0.27); P=0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug. Conclusion This study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where evidence of effective treatment options is limited. Trial registration Current Controlled Trials ISRCTN06653773 .
Preliminary Phase 2 Results Demonstrate Engraftment with Minimal Neutropenia with MGTA-456, a CD34+ Expanded Cord Blood (CB) Product in Patients Transplanted for Inherited Metabolic Disorders (IMD)
Authors: Paul Orchard, Glen D. Raffel, Carolyn H Condon, Catherine A Monaghan, Demetra Vernet, Suzanne Tracey Sheirr, Jennifer Braun, Ryan Shanley, Troy C Lund, Anthony E. Boitano, Michael P. Cooke, John C Davis, John E. Wagner
Journal: Blood (2018)
Abstract 19163: Rapid Progressive Thoracic and Abdominal Aneurysm Model in Fbn1C1039G/+ Mice Treated With Angiotensin Ii
Authors: Mamoru Arakawa, Tiffnay K Koyano, Fabian Emrich, Albert J Pedroza, Emma Magavern, Tetsuya Sato, Kiril Penov, Hideo Adachi, Michael P Fischbein
Journal: Circulation (2015)

Rationale: Marfan syndrome patients typically develop aortic root aneurysms with ensuing aortic dissection remaining the leading cause of death. Although losartan (Angiotensin 1 receptor blocker) has been shown to reduce aneurysms in mice, the role Angiotensin II (AngII) plays during aneurysm formation in MFS remains unknown. Objective: We hypothesized that AngII may exacerbate aneurysm growth in Fbn1 C1039G/+ mice. Moreover, we predicted AngII would induce abdominal aneurysms, creating a novel model to study the pathophysiology of aneurysm formation with two different embryonic origins. Method and results: Fbn1 C1039G/+ mice (n = 7) were treated with either (a) AngII (500 ng/min/kg) or (b) vehicle control and compared to ApoE-/- mice treated with Ang II (1000 ng/min/kg). Aortic root, ascending and abdominal diameters are measured with echo on POD 3, 7 and 14. Following dose-response curve experiments, optimal survival rate is 70%, 14 days after treatment. The average aortic root/ascending (AS) aortic diameter in Ang II Fbn1 C1039G/+ mice was 2.08 ± 0.31 mm, compared to 1.48 ± 0.25 mm in vehicle control Fbn1 C1039G/+ mice (p&lt;.05). Interestingly, in addition to AS aortic aneurysms, 50% developed abdominal aneurysms. Cause of death in Ang II Fbn1 C1039G/+ mice were due to either AS or abdominal aneurysm dissection. Immunohistochemistry on POD 14 showed severe elastic layer disruption in aneurysmal tissue from both aneurysms. Quantitative PCR was performed to measure the expression of matrix-metalloproteinase (MMP) gene expression. When comparing AS and abdominal aneurysms in AngII Fbn1 C1039G/+ mice, MMP-2 was highly up-regulated in AS aneurysms (Fold change: 3.03 ± 0.69, p&lt;0.05), whereas MMP-9 was up-regulated in abdominal aneurysms (Fold change: 1.86 ± 0.15, p&lt;0.05). In contrast, MMP-9 was down-regulated in abdominal aneurysms in AngII ApoE-/- mice (Fold change: 0.18 ± 0.13, p&lt;0.05). Conclusions: Fbn1 C1039G/+ mice treated with AngII develop severe aortic root/ascending aortic aneurysms. Ang II treatment results in abdominal aneurysm formation. Interestingly, gene expression analyses suggest different mechanisms of aneurysm development in aortic segments of different embryonic origin.
Is ctDNA the Road Map to the Landscape of the Clonal Mutational Evolution in Drug Resistance? Lessons from the PALOMA-3 Study and Implications for Precision Medicine
Authors: Rachel Schiff, Rinath Jeselsohn
Journal: Cancer Discovery (2018)

Abstract Summary: The correlative circulating tumor DNA (ctDNA) studies of the PALOMA-3 clinical trial showed that acquired resistance to fulvestrant and palbociclib is associated with clonal evolution and acquired mutations in RB1, PIK3CA, and ESR1, with the latter two related to fulvestrant resistance. These results highlight the potential of ctDNA as a tool to detect mechanisms of resistance and infer the next line of treatment. Cancer Discov; 8(11); 1352–4. ©2018 AACR. See related article by O'Leary et al., p. 1390.
Fas activation alters tight junction proteins in acute lung injury
Authors: Raquel Herrero, Lucia Prados, Antonio Ferruelo, Ferranda Puig, Rachele Pandolfi, Raquel Guillamat-Prats, Laura Moreno, Gustavo Matute-Bello, Antonio Artigas, Andres Esteban, José Ángel Lorente
Journal: Thorax (2018)

Background: The acute respiratory distress syndrome (ARDS) is characterized by protein-rich oedema in the alveolar spaces, a feature in which Fas-mediated apoptosis of the alveolar epithelium has been involved. Objective: To determine whether Fas activation increases protein permeability by mechanisms involving disruption of the paracellular tight junction (TJ) proteins in the pulmonary alveoli. Methods: Protein permeability and the expression of TJ proteins were assessed in vivo in wild-type and Fas-deficient lpr mice 16 hours after the intratracheal instillation of recombinant human soluble Fas ligand (rh-sFasL), and at different time points in vitro in human pulmonary alveolar epithelial cells (HPAEpiC) exposed to rh-sFasL Results: Activation of the Fas pathway increased protein permeability in mouse lungs and altered the expression of the TJ proteins occludin and zonula occludens-1 in the alveolar–capillary membrane in vivo and in human alveolar epithelial cell monolayers in vitro. Blockade of caspase-3, but not inhibition of tyrosine kinase dependent pathways, prevented the alterations in TJ protein expression and permeability induced by the Fas/FasL system in human alveolar cell monolayers in vitro. We also observed that both the Fas-induced increase of protein permeability and disruption of TJ proteins occurred before cell death could be detected in the cell monolayers in vitro. Conclusion: Targeting caspase pathways could prevent the disruption of TJs and reduce the formation of lung oedema in the early stages of ARDS.
Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a
Authors: Ying Cheng, Zhi-Meng Wang, Weiqi Tan, Xiaona Wang, Yujing Li, Bing Bai, Yuxin Li, Shuang-Feng Zhang, Hai-Liang Yan, Zuo-Lun Chen, Chang-Mei Liu, Ting-Wei Mi, Shuting Xia, Zikai Zhou, An Liu, Gang-Bin Tang, Cong Liu, Zhi-Jie Dai, Ying-Ying Wang, Hong Wang, Xusheng Wang, Yunhee Kang, Li Lin, Zhenping Chen, Nina Xie, Qinmiao Sun, Wei Xie, Junmin Peng, Dahua Chen, Zhao-Qian Teng, Peng Jin
Journal: Nature Neuroscience (2018)
A Single Intravenous Infusion of FLT180a Results in Factor IX Activity Levels of More Than 40% and Has the Potential to Provide a Functional Cure for Patients with Haemophilia B
Authors: Pratima Chowdary, Susie Shapiro, Andrew M. Davidoff, Ulrike Reiss, Rebecca Alade, Geoff Brooks, Allison Dane, Jenny McIntosh, Gerard Short, Edward Tuddenham, Amit C Nathwani
Journal: Blood (2018)
Abstract MP08: Coffee Consumption and Incident Kidney Disease: Results From the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Emily A Hu, Elizabeth Selvin, Morgan E Grams, Lyn M Steffen, Josef Coresh, Casey M Rebholz
Journal: Circulation (2018)

Background: Moderate coffee consumption has been consistently associated with a lower risk of diabetes, a major precursor to chronic kidney disease (CKD). However, the association between coffee and CKD has not been fully established. Hypothesis: We hypothesized that coffee consumption was associated with a lower risk of incident CKD after adjustment for major covariates among adults in the Atherosclerosis Risk in Communities (ARIC) study. Methods: We conducted a prospective analysis of 14,209 participants aged 45-64 years from the ARIC study. Coffee consumption (cups/day) was assessed at visit 1 (1987-89) and visit 3 (1993-95) using food frequency questionnaires. Our primary outcome was incident CKD defined as eGFR &lt;60 mL/min/1.73 m 2 accompanied by ≥25% eGFR decline, CKD-related hospitalization or death, or end-stage renal disease. Results: There were 3,845 cases of incident CKD over a median of 24 years of follow-up. Men, whites, current smokers, and participants without comorbidities were more likely to consume higher amounts of coffee per day. After adjustment for demographic, clinical, and dietary factors, higher categories of coffee consumption were associated with lower risk of incident CKD ( Table ). Compared to participants who never consumed coffee, participants who consumed any amount of coffee had an 11% lower risk of CKD (HR: 0.89; 95% CI: 0.82-0.96; p for trend&lt;0.001). In the continuous analysis, for each additional cup of coffee consumed per day, the risk of incident CKD was lower by 3% (HR: 0.97, 95% CI: 0.95-0.99, p&lt;0.001). Results were consistent across the three progressively adjusted models and in a sensitivity analysis using a secondary definition of CKD. Stratification of analyses by smoking status suggested an inverse association among never smokers and former smokers. Conclusions: Coffee consumption was inversely associated with incident CKD after adjusting for covariates. Coffee consumption may not adversely affect kidney disease risk and may instead be protective.
Abstract 15001: Stimulation of P2Y11 Receptor Affords Cardioprotection Against Hypoxia/Reoxygenation Injury in Cultured Cardiomyocytes and Improves Allogeneic Heart Graft Survival
Authors: Lauriane Benoist, Thierry Bourguignon, Thibaud Genet, Stéphanie Chadet, Claudie Lefort, Christophe Baron, Dominique Babuty, Denis Angoulvant, Fabrice Ivanes
Journal: Circulation (2016)

Ischemia reperfusion injuries are involved in the physiopathology of heart transplantation where they will increase graft rejection. Ischemia generates cellular stress leading to ATP release in the extracellular medium that may activate purinergic receptors. These receptors may play important regulatory roles. We already showed that the purinergic receptor P2Y11 (P2Y11R) exhibited an immunosuppressive role in human dendritic cells in vitro (Chadet et al., 2015). We sought here for a possible role of P2Y11R in the cellular response of cardiomyocytes to ischemia/reperfusion. We used a human cell line of adult ventricular cardiomyocytes (AC16) and a rat cardiomyoblast cell line (H9c2). Both were subjected to 5h of hypoxia (1% O2, PBS) and 1h of reoxygenation (21% O2, DMEM) (H/R). Viability/mortality was assessed by MTT Assay, ATPi level and LDH release. We then confirmed our in vitro data in an in vivo model of allogeneic heterotopic heart transplantation in mice. Hearts from BalbC mice were intra-abdominall...
High Throughput Drug Screening of Leukemia Stem Cells Reveals Resistance to Standard Therapies and Sensitivity to Other Agents in Acute Myeloid Leukemia
Authors: Frances Linzee Mabrey, Sylvia S Chien, Timothy S Martins, James Annis, Taylor S Sekizaki, Jin Dai, Robert A. Beckman, Lawrence A. Loeb, Andrew Carson, Bradley Patay, Carl Anthony Blau, Vivian G. Oehler, Safiye S Celik, Su-In Lee, Raymond J. Monnat, Janis L. Abkowitz, Frederick R. Appelbaum, Elihu H. Estey, Pamela S Becker
Journal: Blood (2018)
MiTES 中等位基因 PRDM12 突变
Authors: C. Moss, S. M. Srinivas, N. Sarveswaran, M. Nahorski, V. K. Gowda, F. M. Browne, G. Woods
Journal: British Journal of Dermatology (2018)

中面部幼儿剥脱综合征 (MiTES) 是一种新被认识的疾病, 在此病中, 表面健康儿童持续搔抓鼻梁中央的局部面部。这一问题在出生后第一年开始, 导致深在伤口和严重瘢痕。这可能易被误认为虐待儿童。此病的原因不明, 但一篇发表于 2015 年的论文提供了线索, 这篇论文描述了 11 个对疼痛先天不敏感家庭, 这些家庭在一个新认识的名为 PRDM12 的基因存在突变, 该基因负责编码疼痛受体神经发生必须的一种蛋白。大部分 PRDM12 突变患者的肢体发生切断性伤害, 因为他们缺乏避免伤害的疼痛反应。但是, 11 个家庭中有一个受到的伤害较轻, 5 名受影响的兄弟姐妹存在一种被描述为“鼻周搔抓”的疾病(与 MiTES 看起来相同)。因此, 来自英国、印度和爱尔兰团队分析了 5 例新发 MiTES 病例中的PRDM12。4 名儿童, 其中 2 名为手足, 存在与在早期报告中相同的 PRDM12 的突变, 但在第 5 名儿童中未见任何突变。在大多数病例中, 父母有亲属关系, 在一个基因上携带突变, 而受影响儿童的两个基因均受到影响。这项研究证实 MiTES 为一种遗传性疾病, 在某些情况下因 PRDM12 隐性突变导致。这一新的发现将帮助我们了解这一使人痛苦的毁容疾病, 并有望对其进行管理。 Linked Article:Moss et al. Br J Dermatol 2018; 179:1135–1140
Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic hepatitis C virus genotype 5 or 6 infection (ENDURANCE-5,6): an open-label, multicentre, phase 3b trial
Authors: Tarik Asselah, Samuel S Lee, Betty B Yao, Tuan Nguyen, Florence Wong, Adam Mahomed, Seng Gee Lim, Armand Abergel, Joe Sasadeusz, Edward Gane, Neddie Zadeikis, Gretja Schnell, Zhenzhen Zhang, Ariel Porcalla, Federico J Mensa, Kinh Nguyen
Journal: The Lancet. Gastroenterology & hepatology (2018)
OC-049 Exaggerated acute inflammation in ulcerative colitis, and promotion of its resolution by 5-aminosalicylates through anti-inflammatory hydroxy fatty acid biosynthesis
Authors: DJ Marks, R Wysoczanski, AC Kendall, M Motwani, R Vega, FZ Rahman, S McCartney, SL Bloom, A Nicolaou, DW Gilroy, AW Segal
Journal: Gut (2017)

Introduction  Acute inflammation in ulcerative colitis (UC) is protracted. Using an in vivo bacterial challenge model, we characterised the cellular and molecular determinants and consequences of the early inflammatory response in UC, and the functional impacts of 5-ASA on this process.  Method  Acute inflammation was provoked in 23 healthy controls (HC) and 26 UC patients off treatment or on 5-ASAs, by intradermal injection with killed E. coli or S. pneumoniae. Local vascular reactions were quantified by laser Doppler. Early and resolving inflammatory exudates were sampled by raising suction blisters over inoculation sites after 4 hour or 48 hour. Cells were characterised by polychromatic flow cytometry; cytokines by multiplex array; and lipid mediators by mass spectrometry. In vivo findings were confirmed by in vitro stimulation of cultured peripheral blood-derived macrophages with killed E. coli.  Results  UC patients had enhanced local blood flow within 24 hour of bacterial exposure, and impaired inflammation resolution, to both Gram-negative and Gram-positive bacteria (p=0.01). Neutrophil accumulation (p=0.04) and PGE2 production (p=0.02) were increased within 4 hour, and were not cytokine-driven phenomena. At 48 hour, UC patients had persistent neutrophils (p=0.001) and T lymphocytes (p=0.03). Findings were replicated in cultured macrophages, which also exhibited higher COX-1 up-regulation, supporting the primary impact of these abnormalities. Exaggerated onset was normalised in patients taking 5-ASAs, although these individuals had greater numbers of macrophages at 48 hour (p=0.03). This was accompanied by increased concentrations of the hydroxy fatty acids 9-oxo-octadecadienoic acid (OxoODE) and 13-OxoODE. To characterise their effects, macrophages were co-incubated with E. coli and these mediators. Both led to dose-dependent suppression of TNF-α (p=0.0001 and p=0.01, respectively), at concentrations reflective of those in vivo. These effects were completely reversed by GW9662, a PPARγ antagonist (p=0.006). The in vivo profile of lipid mediators in HC treated with 5-ASAs differed from UC, with subtle differences in resolving inflammatory cellular and cytokine constituents; this has important implications for understanding generation of these hydroxy fatty acids in vivo.  Conclusion  Acute inflammation in UC is exaggerated and slow to resolve, associated with perturbed production of inflammatory lipid mediators. 5-ASAs normalise this reaction, partly through generation of hydroxy fatty acids that act through the PPAR-γ receptor.  Disclosure of Interest  None Declared
Decline of Increased Risk Donor Offers on Waitlist Survival in Heart Transplantation
Authors: Michael S. Mulvihill, Morgan L. Cox, Muath Bishawi, Asishana A. Osho, Babatunde A. Yerokun, Cameron R. Wolfe, Adam D. DeVore, Chetan B. Patel, Matthew G. Hartwig, Carmelo A. Milano, Jacob N. Schroder
Journal: Journal of the American College of Cardiology (2018)
Focus on the Number of Radiation Oncology Trials or on Clinical Relevance—Reply
Authors: Xu Liu, Quynh Thu Le, Jun Ma
Journal: JAMA Oncology (2018)

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 Oncology 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 Oncology journal
Felicity Clare Edwards
Authors: Krishna Somers
Journal: BMJ (2018)

Felicity Clare Edwards (nee Toussaint) was born in London. Her father, Charles Hugh Christie Toussaint, was a specialist in respiratory medicine who took care of tuberculosis patients in the prewar and postwar years. Her mother, Nora Cecilia, was an artist, she trained as an auxiliary during the war. She volunteered as a braille translator. Felicity was a Quaker by upbringing. She attended at Sidcot School in Somerset and Somerville College in Oxford, followed by the Middlesex Hospital in London.

Her professional background was in clinical and social medicine but mid-career she changed to occupational medicine. She was …
ATF6 Regulates Cardiac Hypertrophy by Transcriptional Induction of the mTORC1 Activator, Rheb
Authors: Erik A. Blackwood, Christoph Hofmann, Michelle Santo Domingo, Alina S. Bilal, Anup Sarakki, Winston Stauffer, Adrian Arrieta, Donna J. Thuerauf, Fred W. Kolkhorst, Oliver J. Müller, Tobias Jakobi, Christoph Dieterich, Hugo A. Katus, Shirin Doroudgar, Christopher C. Glembotski
Journal: Circulation Research (2019)

Rationale: Endoplasmic reticulum (ER) stress dysregulates ER proteostasis, which activates the transcription factor, ATF6 (activating transcription factor 6α), an inducer of genes that enhance protein folding and restore ER proteostasis. Because of increased protein synthesis, it is possible that protein folding and ER proteostasis are challenged during cardiac myocyte growth. However, it is not known whether ATF6 is activated, and if so, what its function is during hypertrophic growth of cardiac myocytes. Objective: To examine the activity and function of ATF6 during cardiac hypertrophy. Methods and Results: We found that ER stress and ATF6 were activated and ATF6 target genes were induced in mice subjected to an acute model of transverse aortic constriction, or to free-wheel exercise, both of which promote adaptive cardiac myocyte hypertrophy with preserved cardiac function. Cardiac myocyte-specific deletion of Atf6 (ATF6 cKO [conditional knockout]) blunted transverse aortic constriction and exercise-induced cardiac myocyte hypertrophy and impaired cardiac function, demonstrating a role for ATF6 in compensatory myocyte growth. Transcript profiling and chromatin immunoprecipitation identified RHEB (Ras homologue enriched in brain) as an ATF6 target gene in the heart. RHEB is an activator of mTORC1 (mammalian/mechanistic target of rapamycin complex 1), a major inducer of protein synthesis and subsequent cell growth. Both transverse aortic constriction and exercise upregulated RHEB , activated mTORC1, and induced cardiac hypertrophy in wild type mouse hearts but not in ATF6 cKO hearts. Mechanistically, knockdown of ATF6 in neonatal rat ventricular myocytes blocked phenylephrine- and IGF1 (insulin-like growth factor 1)-mediated RHEB induction, mTORC1 activation, and myocyte growth, all of which were restored by ectopic RHEB expression. Moreover, adeno-associated virus 9- RHEB restored cardiac growth to ATF6 cKO mice subjected to transverse aortic constriction. Finally, ATF6 induced RHEB in response to growth factors, but not in response to other activators of ATF6 that do not induce growth, indicating that ATF6 target gene induction is stress specific. Conclusions: Compensatory cardiac hypertrophy activates ER stress and ATF6, which induces RHEB and activates mTORC1. Thus, ATF6 is a previously unrecognized link between growth stimuli and mTORC1-mediated cardiac growth.
Retraction: Low and High Dose UVB Regulation of Transcription Factor NF-E2-Related Factor 2
Authors: Sankaranarayanan Kannan, Anil K. Jaiswal
Journal: Cancer Research (2018)

[This article][1] ([1][2]) has been retracted at the request of the editors. Following an institutional investigation by the University of Maryland, Baltimore (Baltimore, MD), it was determined that the Western blot bands labeled “LaminB” and “LDH” in Figs. 2A and D have been falsified. As a