tbuckley/cabot-search huggingface dataset:
Medical Education Theme Issue 2006
Authors: Robert M. Golub
Journal: JAMA (2006)

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
Cessation of strontium ranelate supply
Authors: Mark J Bolland, Andrew Grey
Journal: BMJ (2017)

To our knowledge, there has been no response to our article1 from the European Medicines Agency (EMA), the manufacturer of strontium ranelate (Servier), or the academics involved in the phase III trials of strontium.

A news release on the Servier website dated 14 March 2017, however, says that Servier sent a letter on 10 February 2017 to …
GPs urge BMA to explore copayments for some services
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Local GP representatives have urged the BMA to explore the possibility of introducing copayments for some services in general practice, after a vote at the annual conference of local medical committees in Edinburgh last week.

The conference voted to instruct the BMA’s General Practitioners Committee to produce a discussion paper “outlining alternative funding options for general practice, including copayments,” as part of efforts to safeguard the future of general practice in the UK.

GPs passed the potentially controversial motion by 146 votes to 100 after an electronic vote. It was carried despite a warning by the General Practice Committee’s Alan McDevitt about …
Does absolute gain in progression-free survival (PFS) half-life (t½) translate into absolute overall survival (OS) benefit?
Authors: Dominick Bosse, Julie Boucher, Michael M. Vickers, David J. Stewart
Journal: Journal of Clinical Oncology (2016)

e18135 Background: OS is the “gold standard” for approval of new cancer drugs. While OS can be measured precisely, results can be misleading due to impact of crossover (CO), post-progression survival (PPS), etc. Also median OS is often used to judge drug benefit but this can vary substantially based on just a few patients at the midpoint of OS curves. PFS is not impacted by CO or PPS but many consider PFS to be an inadequate surrogate of OS. We hypothesized that an absolute gain in PFS can predict absolute gain in OS, and that calculation of PFS and OS t½ would be better than use of median PFS/OS. Methods: To test our hypothesis we used randomized controlled trials of bevacizumab (Bev) vs placebo in advanced breast and ovarian cancers. We did literature searches through Medline, EMBASE and conference proceedings. We used published survival curves, to measure PFS and OS at monthly intervals. We used GraphPad v6 to calculate PFS and OS t½s, calculated t½ differentials between Bev and placebo arms, and weighted studies according to study size. Results: 15 trials were identified, with 8710 and 7792 patients for PFS and OS respectively. OS curves were not available for 2 trials. The mean ± weighted standard deviation (SD) PFS t½ for Bev arms was 2.63 ±1.09 months longer than placebo, whereas OS was 1.83 ±3.27 months in favour of Bev. Mean difference in median PFS was 3.49 ±1.56 months. CO was reported in 7 trials. In studies without CO, mean PFS t½ was 2.61 ±1.26 months favouring Bev compared to 2.75 ±3.85 months for OS. The gap between PFS and OS t½ was greater in trials with CO, with means of 2.72 ±0.88 and 1.32 ±2.65 months, respectively. Conclusions: 1) Absolute gain in PFS t½ predicts absolute gain in OS in studies without CO, with less across-study variability in PFS than OS. 2) Absolute PFS gain may be a reasonable surrogate for OS gain, and would have advantages over OS hazard ratio as a trial endpoint. 3) Limited CO impacted OS differences. 4) CO impact suggests that Bev efficacy might be similar in 2nd and 1st line therapy. 5) Some studies showed high median PFS differences that were not seen with t½s, and differences were less variable for t½ than medians, suggesting an advantage for t½ use. Further validation of this method will be needed.
Lifetime cost-effectiveness of denosumab versus zoledronic for prevention of skeletal-related events (SREs) in patients (pts) with castrate-resistant prostate cancer (CRPC) and bone metastases (BM): United States managed care perspective.
Authors: Michael E. Rader, Mark Danese, Ze Cong, Marc Halperin, Yi Qian, Carsten Dietrich Goessl, Karen Chung
Journal: Journal of Clinical Oncology (2012)

e15172 Background: Denosumab (Dmab) is superior to zoledronic acid (ZA) for prevention of SREs in pts with CRPC and BM. As Dmab is not cleared renally, it can be used in pts regardless of renal status or concomitant use of nephrotoxic drugs. Previous economic analyses were limited as the analyses were based on short duration-trial based perspectives and/or did not account for disutility associated with IV vs SC administration of ZA and Dmab, respectively. These analyses assess the lifetime cost-effectiveness of Dmab vs ZA in pts with CRPC and BM from a US managed care perspective, with extensive scenario and sensitivity analyses. Methods: A lifetime Markov model was developed, with efficacy of Dmab vs ZA in SRE prevention from a head-to-head phase 3 trial; clinical practice SRE rate in ZA pts from a large commercial claims database analysis; SRE and mode of administration (IV vs SC) quality adjusted life-year (QALY) decrements estimated using the time trade-off method; and SRE costs estimated from a nationally representative commercial claims database. Drug, drug administration, and renal monitoring costs were also included. Costs and QALYs were discounted at 3% per year. Scenario analyses (including adverse events, drug discontinuation, etc), one-way and multivariate probabilistic sensitivity analyses were conducted. Results: Dmab reduced the number of SREs and increased pts’ QALY vs ZA. In the base case and the scenario analyses, cost per QALY gained was below $50,000, which is commonly considered good value. Cost per SRE avoided was below $9,000. In one-way sensitivity analyses, drug costs and SRE rate were the most influential variables. Probabilistic sensitivity analyses showed the probabilities of Dmab being cost-effective vs ZA were 0.83, 0.94, and 0.98 with willingness-to-pay of $100,000, $150,000 and $200,000 per QALY gained, respectively. Conclusions: Dmab is a cost-effective treatment option in preventing SREs in pts with CRPC and BM compared with ZA from a US managed care perspective. The overall value of Denosumab is based on superior efficacy and more efficient administration.
Routine use of beta blockers in MI patients without heart failure is questioned
Authors: Jacqui Wise
Journal: BMJ (2017)

Patients who have had a myocardial infarction (MI) but do not have heart failure or left ventricular systolic dysfunction do not seem to benefit from beta blockers, a large UK study published in the Journal of the American College of Cardiology has found.1

Current UK guidelines from the National Institute for Health and Care Excellence recommend that beta blockers are prescribed to all patients who have had an MI, irrespective of the amount of damage done to the heart muscle.2

The study found that beta blocker use was not associated with lower all cause mortality in the following year among patients with MI but without heart failure or systolic dysfunction. …
Novel insights into the HLA class I immunopeptidome and T-cell immunosurveillance
Authors: Cornelis J. M. Melief, Jan H. Kessler
Journal: Genome Medicine (2017)

Advances in mass spectrometry have allowed the high-throughput quantitative identification of human leukocyte antigen (HLA) class I ligands, and recent studies have reported on the breadth and diversity of the HLA class I immunopeptidome. These findings have far-reaching implications for immunosurveillance by T cells and translational value for immunotherapy.
Identification and function of DAX-1 agonists.
Authors: Sabitha Papineni, Sudhakar Chintharlapalli, Enzo Lalli, Stephen S. Safe
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5347 

Dosage sensitive sex reversal, adrenal hypoplasia congenital (AHC) critical region on the X-chromosome gene 1(DAX-1) is an orphan receptor that represses nuclear receptor/transcription factor-mediated gene expression. Mutations of DAX-1 compromise the DAX-1-dependent regulation of steroidgenic genes leading to serious genetic disorders and related health problems. DAX-1 activates silencing of several genes and Gal4-DAX-1 E-domain (207-470) chimera exhibits decreased activity compared to Gal4 alone in LNCaP prostrate cancer cells transfected with a construct (p GAL45) containing 5 tandem Gal4 response elements linked to a luciferase reporter gene. In contrast, this inhibitory response was not observed in cells transfected with Gal4-DAX-1 or chimeric constructs containing point or deletion mutants in the E-domain of DAX-1. Ligand-dependent activation of DAX-1 in LNCaP and other cancer cells was investigated using a series of 1.1-bis (3’-indolyl)-1-(substituted phenyl) methanes and among the methylene-substituted diindolylmethanes (C-DIMs) , compounds containing p-fluorophenyl (DIM-C-pPhF) and p-cyanophenyl (DIM-C-pPhCN) activated Gal4-DAX-1. The effects of these DAX-1 agonists were structure-dependent and the ortho-and meta-substituted analogs were inactive. Mammalian two hybrid studies using Gal4-coactivator and VP-DAX-1 chimeras demonstrated that only the para-substituted analogs were active and induced coactivator specific interactions with steroid receptor coactivator-1(SRC-1),SRC-2,TRAP 220 and PGC-1 but not with SRC-2,the methyltransferase CARM-1 or the corepressor SMRT. These results are consistent with the identification of C-DIM compounds as DAX-1 agonists and these compounds also activate DAX-1-dependent silencing of androgen receptor(AR) mediated transactivation without disrupting AR distribution in LNCaP cells.Current studies are investigating silencing of AR and other genes by DAX-1 -active-C-DIMs and determining the mechanisms of these inhibitory responses.
MEDU-49. TARGETING FRS2 RESTRICTS BRAIN TISSUE INFILTRATION IN MEDULLOBLASTOMA
Authors: Karthiga Santhana Kumar, Anuja Neve, Dimitra Tripolitsioti, Lena Harder, Elisabeth Rushing, Dominique Bruns, Ryan Byrne, Gisbert Schneider, Michael Grotzer, Martin Baumgartner
Journal: Neuro-Oncology (2017)

How pediatric medulloblastoma (MB), a metastatic tumor of the cerebellum, infiltrates the brain tissue prior to recurrence or distant spreading is poorly understood. We hypothesized that growth factors released from the tumor microenvironment trigger tumor cell migration and brain tissue infiltration. Using a medium-throughput in vitro 3D cell migration screen and ex vivo organotypic cerebellum slice culture, we identified and validated novel potential drug targets for preventing brain tissue infiltration and growth of MB. We found that the FGFR1 ligand bFGF, which we detected in the tumor microenvironment of clinical samples and in organotypic cultures, promoted tumor cell infiltration through the adaptor protein FRS2. Interestingly, FRS2 function was antagonized by TGFβ, which induced a contractile, non-motile cell phenotype through ROCK activation and direct FRS2 repression. In the absence of TGFβ, however, bFGF-FRS2 function attenuated ROCK and enabled motility and invasiveness through Rac-PAK and ERK1/2. In contrast, at high concentrations of bFGF as observed in certain areas of MB tumor tissue, TGFβ rescued tumor cell motility impeded by a FGFR1-dependent negative feed-back and triggered invasiveness. Using organotypic cerebellum slice culture, we demonstrated that pharmacological inhibition of FGFR or genetic ablation of FRS2 prevented infiltration and proliferation of MB cells. Using a computer-assisted molecular design approach, we are currently exploring low molecular weight compounds that might selectively block FRS2 function. Together, we describe an antagonistic crosstalk between bFGF and TGFβ signaling pathways in MB that tunes the motile and invasive properties of the tumor cells for brain infiltration under varying environmental conditions. Furthermore, we identified the FRS2 adaptor protein as a novel and promising drug target in this process.
Abstract 277: Acute Cardiac Insulin Resistance During Cardiopulmonary Bypass in Mini-pigs: Role of Hexosamine Biosynthesis and Protein O-Glycosylation
Authors: Kun Zhao, Jia Li, Qijun Zheng, Feng Fu, Zhenxiao Jin, Wensheng Chen, Xinli Wang, Yue Zhang, Yan Jin, Min Chen, Hailong Zhu, Jianyu Feng, Fuen Qin, Qin Cui, Dinghua Yi, Feng Gao
Journal: Circulation Research (2013)

Our previous study as well as others has demonstrated a strong positive correlation between cardiac insulin signaling and myocardial function in ischemic/reperfused hearts. This study was designed to determine whether cardiac insulin signaling is impaired during cardiopulmonary bypass (CPB) and the possible mechanisms involved. Twelve male mini-pigs were anesthetized and subjected to CPB for 30 min. Blood samples and left ventricle biopsies were taken at pre-bypass (control), aortic cross clamp (AXC) 5 min and AXC release 120 min. Compared with sham-operated group, both blood glucose and insulin levels went up at 120 min after AXC release. Glucose uptake in heart dropped significantly as measured by attenuated coronary arterio-venous glucose difference and reduced cardiac 18 F-fluorodeoxyglucose uptake by Positron Emission Tomography imaging. Furthermore, myocardial insulin signaling was blunted as manifested by decreased phosphorylation of IRS-1, Akt and GSK-3beta (P&lt;0.01, n=4). Interestingly, these changes were associated with a substantial increase of GFAT activity (the rate-limiting enzyme for hexosamine biosynthesis) and a significant increase in protein O-GlcNAcylation in cardiac tissues (P&lt;0.05, n=6). Moreover, pretreatment with Alloxan, an inhibitor of O-GlcNAc-transferase, blocked both the impaired GSK-3beta phosphorylation and the increase in O-GlcNAcylation. Enhancement of cardiac insulin signaling with glucose-insulin-potassium before AXC decreased protein O-GlcNAcylation and ameliorated myocardial dysfunction after CPB. These data indicate the existence of acute myocardial insulin resistance during CPB which is attributable to elevated hexosamine biosynthesis and protein O-glycosylation.
Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution
Authors: Shaon Chakrabarti, Franziska Michor
Journal: Cancer Research (2017)

The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908-21. ©2017 AACR.
Abstract P077: Ischemic Preconditioning Improves Postischemic Cardiac Function by Preserving PTEN Activity
Authors: Xiaoxu Zheng, Lingyun Zu, Zheqing P Cai
Journal: Circulation Research (2011)

Background Ischemic preconditioning (IPC) increases post-ischemic functional recovery. Although reduced infarct size is associated with the better outcome, its underlying mechanism is not fully understood. The phosphatase and tensin homologue deleted on chromosome ten (PTEN) promotes cell death and increases myocardial contractility. We recently reported that IPC attenuates loss of PTEN activity in post-ischemic hearts. In the present study, we have investigated the hypothesis that IPC improves post-ischemic cardiac function by preserving PTEN activity. Methods and Results Isolated mouse hearts were exposed to no ischemia as control (CON) or IPC, consisting of 10-min ischemia and 5-min reperfusion (I-10/R-5), followed by I-30/R-120. bpV(phen) (10 µM), a PTEN inhibitor, or vehicle was added into the perfusion line in IPC group following reperfusion. Isolated hearts from muscle-specific PTEN knockout mice ( Pten loxp/loxp ;ckm +/− ) and control mice ( Pten loxp/loxp ;ckm −/− ) were exposed to I-30/R-30. Left ventricular (LV) pressure was monitored by a pressure catheter. Myocardial infarct size was measured by triphenyltetrazolium chloride staining. After I-30/R-120, IPC increased LV developed pressure (LVDP) and maximal +dp/dt (+dp/dtm) compared with CON. bpV blocked the effects of IPC (LVDP: 42±4 vs. 63±4 mmHg, p&lt;0.01; +dp/dtm: 1209±101 vs. 1880±155 mmHg/sec, p&lt;0.01). However, it did not increase infarct size compared with vehicle. Muscle-specific PTEN knockout modestly decreased LVDP and +dp/dtm in isolated perfused hearts under basal conditions, but it markedly impaired their recovery after I-30/R-30 compared with control (LVDP: 21±4 vs. 45±5 mmHg, p&lt;0.01; +dp/dtm: 784±146 vs. 1795±154 mmHg/sec, p&lt;0.01). Myocardial infarct size was decreased in PTEN knockout hearts after I/R. Conclusions: PTEN inhibition blocks the improvement of cardiac functional recovery induced by IPC. Loss of PTEN exacerbates post-ischemic dysfunction in isolated hearts. Therefore, our studies suggest that IPC attenuates post-ischemic cardiac dysfunction by preserving PTEN activity.
<i>Modern Death, How Medicine Changed the End of Life</i>—A Book Review
Authors: Joshua R. Lakin
Journal: JAMA Internal Medicine (2017)

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 Internal Medicine 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 Internal Medicine journal
Income inequality and mental illness-related morbidity and resilience: a systematic review and meta-analysis
Authors: Wagner Silva Ribeiro, Annette Bauer, Mário César Rezende Andrade, Marianna York-Smith, Pedro Mario Pan, Luca Pingani, Martin Knapp, Evandro Silva Freire Coutinho, Sara Evans-Lacko
Journal: The Lancet Psychiatry (2017)
Haploidentical Allogeneic Hemopoietic Stem Cell Transplant for High Risk Myelodysplastic Syndrome
Authors: Anna Maria Raiola, Sara Aquino, Germana Beltrami, Stefania Bregante, Fabio Cruciani, Carmen Di Grazia, Alida Dominietto, Anna Ghiso, Francesca Gualandi, Adalberto Ibatici, Teresa Lamparelli, Carlo Marani, Maria Teresa van Lint, Riccardo Varaldo, Andrea Bacigalupo, Emanuele Angelucci
Journal: Blood (2016)
Nonclinical Safety of SHP 826 (BAX 826), a Next Generation Extended Half-Life Recombinant Factor VIII Product
Authors: Veronika Ehrlich, Peter Leidenmuehler, Barbara Dietrich, Gerald Hoebarth, Tanja Ruthsatz, Peter L. Turecek, Martin Wolfsegger, Alfred Weber, Herbert Gritsch, Werner Hoellriegl, Marietta Turecek
Journal: Blood (2016)
Le clip ‘over-the-scope’ (OTSC) diminue le recours à la chirurgie lors des perforations digestives per-endoscopiques. Une étude cas contrôle temporelle
Authors: S Khater, G Rahmi, E Samaha, H Benosman, L Abbes, S Scialom-han, G Malamut, C Cellier
Journal: Endoscopy (2016)

La perforation est une complication grave des endoscopies digestives diagnostiques et thérapeutiques. Le clip ‘over-the-scope’ (OTSC, Ovesco®, Tûbingen, Allemagne) est une technique récente permettant de fermer une perforation lors d'une endoscopie digestive. Il se distingue des clips classiques qui passent dans le canal opérateur de l'endoscope par la forte préhension de toute la paroi digestive réalisant une véritable suture endoscopique. L'objectif de cette étude a été de comparer le recours à la chirurgie lors des perforations digestives per endoscopiques avant et depuis le début de l'utilisation du clip OTSC.
Sign, language, and gesture in the brain: Some comments
Authors: Ruth Campbell, Bencie Woll
Journal: Behavioral and Brain Sciences (2017)

Abstract In contrast with two widely held and contradictory views – that sign languages of deaf people are “just gestures,” or that sign languages are “just like spoken languages” – the view from sign linguistics and developmental research in cognition presented by Goldin-Meadow &amp; Brentari (G-M&amp;B) indicates a more complex picture. We propose that neuroscience research suggests that a similar approach needs to be taken and offer some examples from research on the brain bases of sign language perception.
Set size slope still does not distinguish parallel from serial search
Authors: Daniel R. Little, Ami Eidels, Joseph W. Houpt, Cheng-Ta Yang
Journal: Behavioral and Brain Sciences (2017)

Abstract Much of the evidence for theories in visual search (including Hulleman &amp; Olivers' [H&amp;O's]) comes from inferences made using changes in mean RT as a function of the number of items in a display. We have known for more than 40 years that these inferences are based on flawed reasoning and obscured by model mimicry. Here we describe a method that avoids these problems.