tbuckley/cabot-search huggingface dataset:
Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury
Authors: Lin Wang, Nanhu Quan, Wanqing Sun, Xu Chen, Courtney Cates, Thomas Rousselle, Xinchun Zhou, Xuezhong Zhao, Ji Li
Journal: Cardiovascular Research (2018)

A longevity gene, Sirtuin 1 (SIRT1) and energy sensor AMP-activated protein kinase (AMPK) have common activators such as caloric restriction, oxidative stress, and exercise. The objective of this study is to characterize the role of cardiomyocyte SIRT1 in age-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults. Mice were subjected to ligation of left anterior descending coronary artery for in vivo ischemic models. The glucose and fatty acid oxidation were measured in a working heart perfusion system. The cardiac functions by echocardiography show no difference in young wild-type C57BL/6 J (WT, 4–6 months), aged WT C57BL/6 J (24–26 months), and young inducible cardiomyocyte-specific SIRT1 knockout (icSIRT1 KO) (4–6 months) mice under physiological conditions. However, after 45 mins ischaemia and 24-h reperfusion, the ejection fraction of aged WT and icSIRT1 KO mice was impaired. The aged WT and icSIRT1 KO hearts vs. young WT hearts also show an impaired post-ischemic contractile function in a Langendorff perfusion system. The infarct size of aged WT and icSIRT1 KO hearts was larger than that of young WT hearts. The immunoblotting data demonstrated that aged WT and icSIRT1 KO hearts vs. young WT hearts had impaired phosphorylation of AMPK and downstream acetyl-CoA carboxylase during ischaemia. Intriguingly, AMPK upstream LKB1 is hyper-acetylated in both aged WT and icSIRT1 KO hearts; this could blunt activation of LKB1, leading to an impaired AMPK activation. The working heart perfusion results demonstrated that SIRT1 deficiency significantly impaired substrate metabolism in the hearts; fatty acid oxidation is augmented and glucose oxidation is blunted during ischaemia and reperfusion. Adeno-associated virus (AAV9)-Sirt1 was delivered into the aged hearts via a coronary delivery approach, which significantly rescued the protein level of SIRT1 and the ischemic tolerance of aged hearts. Furthermore, AMPK agonist can rescue the tolerance of aged heart and icSIRT1 KO heart to ischemic insults. Cardiac SIRT1 mediates AMPK activation via LKB1 deacetylation, and AMPK modulates SIRT1 activity via regulation of NAD+ level during ischaemia. SIRT1 and AMPK agonists have therapeutic potential for treatment of aging-related ischemic heart disease.
Randomized trial of enzalutamide versus bicalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer: A Prostate Cancer Clinical Trials Consortium trial.
Authors: Ulka N. Vaishampayan, Lance K. Heilbrun, Paul Monk, Sheela Tejwani, Guru Sonpavde, Daryn Smith, Pallavi Jasti, Kimberlee Dobson, Elisabeth I. Heath, Michael L. Cher, Sreenivasa Chinni, Joseph A. Fontana
Journal: Journal of Clinical Oncology (2018)

190 Background: Addition of abiraterone or docetaxel has overall survival (OS) benefit in metastatic hormone sensitive prostate cancer (mHSPC). The clinical outcomes with early enzalutamide in mHSPC are unknown. We compared the combinations of enzalutamide (Arm A) or bicalutamide (Arm B) each with LHRH analogue therapy in mHSPC. Methods: The primary endpoint was PSA nadir &lt; 4 ng/ml after 7 months of therapy, as this has been recognized as a powerful surrogate for overall survival (OS) outcomes. A minimum of 29 African American (AA) patients were required to be enrolled to evaluate the effect of race on the primary endpoint. Secondary endpoints were toxicities, biochemical and radiologic progression free survival (PFS), and OS. Stratification was by presence of bone pain and race; AA or other. PSA was monitored monthly for first 7 months and then every 3 months. The target sample size was 82 evaluable patients but the study was stopped when early abiraterone showed OS benefit in mHSPC. Metastatic site biopsies were mandatory pretherapy and optional post therapy. Results: 71 men; 29 black, 41 white and 1 Asian were enrolled. The median age was 67 years (range 46-87 years) and median baseline PSA was 56.3 ng/ml in Arm A (4.2-10,431 ng/ml) and 60 (4.9-12,030 ng/ml) in Arm B. 27 pts (38.5%) had bone pain and 13 had visceral metastases. No seizures were noted in either arm. Grade 3+ AE’s on Arm A were: Hypertension (13%), infection (7%), and Snycope (7%) and on Arm B were: Hypertension (21%), Fatigue (7%), and Hematuria (7%). By intent to treat PSA nadir &lt; 4ng/ml at month 7 was achieved in 96.3% pts in arm A and 66.7% pts in arm B and in 71.7% of AA men and 89.7% of Caucasians. The 6-month PSA remission duration rates after month 7 on Arms A and B were 86% and 79%, respectively. 53 (75%) biopsy samples had tumor tissue available. Tmprss2-Erg fusion gene expression and androgen biosynthetic enzyme levels were determined in metastatic biopsies and will be correlated with clinical endpoints. Conclusions: Early enzalutamide use in mHSPC has the potential to improve PSA remission rates and subsequently improve PFS and OS outcomes. Clinical trial information: NCT02058706.
Whistleblowing protection for agency locums clarified by legal ruling
Authors: Abi Rimmer
Journal: BMJ (2016)

Whistleblowing protection for agency workers, including locum doctors, has been clarified by a legal ruling that ensures that they have the same protection as employees, a legal expert has said.

Tom Long, legal director at law firm Shakespeare Martineau, said that an appeal tribunal hearing involving an agency nurse working at University Hospital Bristol, had clarified the rules around whistleblowing …
HDL3C IS THE MOST EFFECTIVE HDL PHENOTYPE IN THE ATTENUATION OF MYOCARDIAL ISCHEMIA AND REPERFUSION INJURY
Authors: Vitor Wilson De Moura Virginio, Isabella B. Oliveira, Michele Santana, Joaquim Oliveira, Orlando Petrucci, Andrei C. Sposito
Journal: Journal of the American College of Cardiology (2018)
Investigational NEDD8-activating enzyme inhibitor pevonedistat (Pev) plus chemotherapy in patients (Pts) with solid tumors (Phase 1b study): Antitumor activity of pev plus carboplatin (Carbo)/paclitaxel (Pac).
Authors: Todd Michael Bauer, R Donald Harvey, Carrie B. Lee, Charu Aggarwal, Roger B. Cohen, Farhad Sedarati, Zhaoyang Teng, Hélène M. Faessel, Ajeeta Dash, Bruce J. Dezube, Sergio Santillana, Afshin Dowlati, Albert C. Lockhart
Journal: Journal of Clinical Oncology (2016)

2580 Background: This is an open-label, multi-arm, dose-escalation study (NCT01862328) of pev (TAK-924/MLN4924) plus chemotherapy in pts with solid tumors. Safety and preliminary efficacy results have been reported (Lockhart et al, AACR-NCI-EORTC 2015); common adverse events in pts treated with pev + carbo/pac were fatigue (50%), nausea (38%), and G3 elevated AST/ALT (19%). We present previously unreported antitumor activity in pts treated with this combination. Methods: Twenty-six pts received pev IV 15, 20, or 25 mg/m2 on d 1, 3, and 5 with carbo AUC5 + pac 175 mg/m2 on d 1 (lead-in cohort, n = 6: pev 15 mg/m2 + carbo AUC6) every 21 d. The combination appeared tolerable; MTD pev 20 mg/m2 + carbo AUC5 + pac 175 mg/m2. Response was assessed per RECIST v1.1; sparse PK sampling was carried out during C1. ERCC1 expression was assessed by IHC. Results: Nine responses were observed in 32 pts (28%) including those resistant to prior platinum/taxane therapy. Two pts (1 endometrial carcinoma, 1 bladder cancer) achieved a complete response (CR), and remain on study ( > 12 cycles). Seven pts (3 head and neck, 1 cholangiocarcinoma, 1 NSCLC, 1 sarcoma, 1 breast cancer) achieved a partial response (PR). The 9 responders received 4–18 cycles and had a median of 4 (range 1–8) prior therapies, including 4 with prior taxane (best response: 1 CR, 1 PR, 1 stable disease [SD], 1 unknown) and 8 with prior platinum (best response: 1 PR, 6 SD, 1 unknown). The majority had response within 2 cycles. Prolonged SD was seen in 3 pts (1 sarcoma, 1 endometrial cancer, 1 ovarian cancer), all 3 discontinued chemotherapy due to toxicity but continued to benefit from single-agent pev (SD duration 4.9–14.7 mos). Pev PK was unaffected in the presence of carbo/pac. Archival tumor sections from 23/30 pts were evaluable for ERCC1 staining. Conclusions: Pev+ carbo/pac showed broad-based antitumor activity in heavily pre-treated pts with solid tumors. Consistent with preclinical synergy between agents, lengthy treatment durations and improved responses in pts resistant to prior platinum/taxane therapy suggest the potential reversal of resistance by the addition of pev. Clinical trial information: NCT01862328.
RIGHT VENTRICULAR FUNCTIONAL AND STRUCTURAL CHANGES MIRROR THOSE OF THE LEFT VENTRICLE IN HEART FAILURE WITH PRESERVED EJECTION FRACTION
Authors: Karl-Philipp Rommel, Christian Besler, Maximilian Von Roeder, Stephan Blazek, Karl Fengler, Karin Klingel, Holger Thiele, Volker Adams, Philipp Lurz
Journal: Journal of the American College of Cardiology (2018)
A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets
Authors: Ángel F. Álvarez-Prado, Pablo Pérez-Durán, Arantxa Pérez-García, Alberto Benguria, Carlos Torroja, Virginia G. de Yébenes, Almudena R. Ramiro
Journal: The Journal of Experimental Medicine (2018)

Activation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering mutations or chromosome translocations, with major implications for oncogenic transformation. However, understanding the specificity of AID has proved extremely challenging. We have sequenced at very high depth &amp;gt;1,500 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets. We have also identified the most highly mutated hotspot for AID activity described to date. Furthermore, integrative analysis of the molecular features of mutated genes coupled to machine learning has produced a powerful predictive tool for AID targets. We also have found that base excision repair and mismatch repair back up each other to faithfully repair AID-induced lesions. Finally, our data establish a novel link between AID mutagenic activity and lymphomagenesis.
How can I find out which are the “topmost hospitals” in the anaesthesia training programme at senior house officer level?
Authors: Leyla Sanai
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.</i>
High prevalence of MYD88 and CD79B mutations in intravascular large B-cell lymphoma
Authors: Anne M. R. Schrader, Patty M. Jansen, Rein Willemze, Maarten H. Vermeer, Anne-Marie Cleton-Jansen, Sebastiaan F. Somers, Hendrik Veelken, Ronald van Eijk, Willem Kraan, Marie José Kersten, Michiel van den Brand, Wendy B. C. Stevens, Daphne de Jong, Myrurgia Abdul Hamid, Bea C. Tanis, Eduardus F. M. Posthuma, Marcel Nijland, Arjan Diepstra, Steven T. Pals, Arjen H. G. Cleven, Joost S. P. Vermaat
Journal: Blood (2018)
Unrecognized Cardiovascular Emergencies Among Medicare Patients
Authors: Daniel A. Waxman, Hemal K. Kanzaria, David L. Schriger
Journal: JAMA Internal Medicine (2018)

<h3>Importance</h3> The Institute of Medicine described diagnostic error as the next frontier in patient safety and highlighted a critical need for better measurement tools. <h3>Objectives</h3> To estimate the proportions of emergency department (ED) visits attributable to symptoms of imminent ruptured abdominal aortic aneurysm (AAA), acute myocardial infarction (AMI), stroke, aortic dissection, and subarachnoid hemorrhage (SAH) that end in discharge without diagnosis; to evaluate longitudinal trends; and to identify patient characteristics independently associated with missed diagnostic opportunities. <h3>Design, Setting, and Participants</h3> This was a retrospective cohort study of all Medicare claims for 2006 to 2014. The setting was hospital EDs in the United States. Participants included all fee-for-service Medicare patients admitted to the hospital during 2007 to 2014 for the conditions of interest. Hospice enrollees and patients with recent skilled nursing facility stays were excluded. <h3>Main Outcomes and Measures</h3> The proportion of potential diagnostic opportunities missed in the ED was estimated using the difference between observed and expected ED discharges within 45 days of the index hospital admissions as the numerator, basing expected discharges on ED use by the same patients in earlier months. The denominator was estimated as the number of recognized emergencies (index hospital admissions) plus unrecognized emergencies (excess discharges). <h3>Results</h3> There were 1 561 940 patients, including 17 963 hospitalized for ruptured AAA, 304 980 for AMI, 1 181 648 for stroke, 19 675 for aortic dissection, and 37 674 for SAH. The mean (SD) age was 77.9 (10.3) years; 8.9% were younger than 65 years, and 54.1% were female. The proportions of diagnostic opportunities missed in the ED were as follows: ruptured AAA (3.4%; 95% CI, 2.9%-4.0%), AMI (2.3%; 95% CI, 2.1%-2.4%), stroke (4.1%; 95% CI, 4.0%-4.2%), aortic dissection (4.5%; 95% CI, 3.9%-5.1%), and SAH (3.5%; 95% CI, 3.1%-3.9%). Longitudinal trends were either nonsignificant (AMI and aortic dissection) or increasing (ruptured AAA, stroke, and SAH). Patient characteristics associated with unrecognized emergencies included age younger than 65 years, dual eligibility for Medicare and Medicaid coverage, female sex, and each of the following chronic conditions: end-stage renal disease, dementia, depression, diabetes, cerebrovascular disease, hypertension, coronary artery disease, and chronic obstructive pulmonary disease. <h3>Conclusions and Relevance</h3> Among Medicare patients, opportunities to diagnose ruptured AAA, AMI, stroke, aortic dissection, and SAH are missed in less than 1 in 20 ED presentations. Further improvement may prove difficult.
Multimorbidity and survival for patients with acute myocardial infarction in England and Wales: Latent class analysis of a nationwide population-based cohort
Authors: Marlous Hall, Tatendashe B. Dondo, Andrew T. Yan, Mamas A. Mamas, Adam D. Timmis, John E. Deanfield, Tomas Jernberg, Harry Hemingway, Keith A. A. Fox, Chris P. Gale
Journal: PLoS Medicine (2018)

Background There is limited knowledge of the scale and impact of multimorbidity for patients who have had an acute myocardial infarction (AMI). Therefore, this study aimed to determine the extent to which multimorbidity is associated with long-term survival following AMI. Methods and findings This national observational study included 693,388 patients (median age 70.7 years, 452,896 [65.5%] male) from the Myocardial Ischaemia National Audit Project (England and Wales) who were admitted with AMI between 1 January 2003 and 30 June 2013. There were 412,809 (59.5%) patients with multimorbidity at the time of admission with AMI, i.e., having at least 1 of the following long-term health conditions: diabetes, chronic obstructive pulmonary disease or asthma, heart failure, renal failure, cerebrovascular disease, peripheral vascular disease, or hypertension. Those with heart failure, renal failure, or cerebrovascular disease had the worst outcomes (39.5 [95% CI 39.0–40.0], 38.2 [27.7–26.8], and 26.6 [25.2–26.4] deaths per 100 person-years, respectively). Latent class analysis revealed 3 multimorbidity phenotype clusters: (1) a high multimorbidity class, with concomitant heart failure, peripheral vascular disease, and hypertension, (2) a medium multimorbidity class, with peripheral vascular disease and hypertension, and (3) a low multimorbidity class. Patients in class 1 were less likely to receive pharmacological therapies compared with class 2 and 3 patients (including aspirin, 83.8% versus 87.3% and 87.2%, respectively; β-blockers, 74.0% versus 80.9% and 81.4%; and statins, 80.6% versus 85.9% and 85.2%). Flexible parametric survival modelling indicated that patients in class 1 and class 2 had a 2.4-fold (95% CI 2.3–2.5) and 1.5-fold (95% CI 1.4–1.5) increased risk of death and a loss in life expectancy of 2.89 and 1.52 years, respectively, compared with those in class 3 over the 8.4-year follow-up period. The study was limited to all-cause mortality due to the lack of available cause-specific mortality data. However, we isolated the disease-specific association with mortality by providing the loss in life expectancy following AMI according to multimorbidity phenotype cluster compared with the general age-, sex-, and year-matched population. Conclusions Multimorbidity among patients with AMI was common, and conferred an accumulative increased risk of death. Three multimorbidity phenotype clusters that were significantly associated with loss in life expectancy were identified and should be a concomitant treatment target to improve cardiovascular outcomes. Trial registration ClinicalTrials.gov NCT03037255.
SMAD4 mutation acquisition in the metastatic transformation of pancreatic cancer.
Authors: Amardeep Grewal, Edgar Ben-Josef
Journal: Journal of Clinical Oncology (2018)

227 Background: SMAD4 mutations have been associated with worse prognosis and metastatic disease in patients with pancreatic cancer. It is unknown whether pancreatic cancers that metastasize acquire this mutation at disease onset or closer to the time of metastatic progression. Methods: Biopsies from 26 patients with known resectable and unresectable pancreatic cancer were analyzed via next generation DNA sequencing for 153 mutations associated with solid tumors, including SMAD4. Imaging and clinical data regarding extent of disease were reviewed at the time of each specimen collection. Results: 46% of patients had metastatic disease at the time of initial biopsy, and of these patients 83% had detectable SMAD4 mutations. Amongst patients with no evidence of metastatic disease, 11 of 14 had intact SMAD4. SMAD4 mutations were associated with metastatic spread of disease, Χ 2 = 7.46, p = .006. Eight patients with localized, SMAD4 intact pancreatic cancer had repeat biopsies at the time of metastatic progression that showed SMAD4 mutations not previously identified at the time of diagnosis. 2 of 3 patients with SMAD4 mutations and localized disease at diagnosis, developed metastatic disease within 7 months of biopsy. Mean time to metastatic disease development in localized disease patients with mutated and intact SMAD4 were 3.15 and 17 months, respectively, p = .01. Mean CA 19-9 levels in patients with mutated and intact SMAD4 were 10172 and 4117 U/mL, respectively, p = .04. Non-metastatic patients with SMAD4 mutations who developed metastatic disease shortly after initial biopsy only developed rising CA 19-9 levels once radiographic metastases were visible. Conclusions: SMAD4 mutations were ultimately acquired by each patient who presented with localized disease and then developed metastases, and are likely involved in the transformation from localized to metastatic disease. SMAD4 mutations are statistically associated with an earlier time to metastatic disease development in patients with localized disease at diagnosis. SMAD4 mutations precede CA 19-9 elevations in patients that develop metastatic disease and may represent a more sensitive biomarker to identify patients at greater risk for developing metastatic disease.
cfDNA analysis of mCRPC patients expressing mutations in Wnt signaling.
Authors: Ashkan Shahbandi, Elisa Ledet, Bryce Raymon Christensen, Marcus Marie Moses, Peter Steinwald, Lynne Chapman, Patrick Cotogno, Jodi Lyn Layton, Brian E. Lewis, Joshua Schiff, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2018)

256 Background: Alterations in Wnt signaling have been shown to play a role in the development of castrate resistant prostate cancer. Cell free DNA (cfDNA) isolated from patient plasma can provide a non-invasive way to further assess this role. The goal of this study was to identify patients with cfDNA alterations in major canonical Wnt signaling components (APC and/or beta-catenin), and relate the emergence of these mutations during treatment to alterations in other common mutations. Methods: 134 clinically progressive metastatic CRPC patients from Tulane Cancer Center underwent cfDNA analysis through Guardant360 test (Guardant Health, Redwood City, CA). This analysis consisted of exonic coverage of 70 genes as well as amplifications in 18 genes, with mutations categorized as either pathologic, non-pathologic or as variants of unknown significance (VUS). Clinical annotation of prior treatment history was recorded. Results: 21.6% (29/134) of the mCRPC patients evaluated had a canonical Wnt signaling (APC and/or CTNNB) alteration. Of these patients, 62.1% (18/29) had mutations identified as pathologic. 77.8% (14/18) of patients identified with a pathologic Wnt mutation were treated with abiraterone and/or enzalutamide prior to Guardant360 testing. To determine potential associations between Wnt signaling alterations and other detected changes in cfDNA, the relationship between Wnt mutations (APC and/or CTNNB1) with pathologic TP53 mutations, AR mutations, BRAF amplifications, and MYC amplifications was assessed using a patient’s latest Guardant360 test. A significant positive association was found between Wnt mutations (n = 18) and MYC amplifications (n = 22), (p = 0.0373). 33.3% (6/18) of patients with a pathologic Wnt mutation were found to have amplification in MYC. Other notable associations included Wnt mutations and AR mutations (n = 74), which approached statistical significance (p = 0.112). Conclusions: While the understanding of the role of Wnt signaling in the treatment of mCRPC is still evolving, co-segregation of Wnt-signaling alterations with other oncogenic alterations, particularly MYC, which has been identified as a target of canonical Wnt signaling, may provide insights with regards to future management of mCRPC.
I am a third year medic about to sit my PACES and I'm interested in doing chest medicine and intensive care medicine. How should I go about it?
Authors: Gavin Perkins
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.</i>
Editor’s Choice: Caring for doctors
Authors: Tom Moberly
Journal: BMJ (2016)

As new foundation doctors prepare to start their medical careers next Wednesday, BMJ Careers offers some guidance to those facing their first day as doctors and considers how medicine compares with other careers.

Taking a cue from the #tipsfornewdocs hashtag used in social media in the past few years, Nicola Lennard offers advice to new foundation …
Junior doctor strikes had a “significant impact” on services but did not increase deaths, study finds
Authors: Abi Rimmer
Journal: BMJ (2018)

Strike action taken by junior doctors in England in 2016 did not lead to an increase in patient deaths, researchers have found.1

However, the four periods of strike action, in protest against a new contract, did result in fewer hospital admissions, fewer emergency department attendances, and an increase in cancelled appointments, the study, published in BMJ Open , found.

The researchers compared hospital episode statistics for the four periods of industrial action, on 12 January, 10 February, …