tbuckley/cabot-search huggingface dataset:
Abstract 4456: Biochemical and structural characteristics of crizotinib-resistant ALK mutants.
Authors: Sergei Timofeevski, Wei Liu, Ya-Li Deng, Alexei Brooun, Simon Bergqvist, Shannon Karlicek, Brion Murray, Ben Bolaños, Michele McTigue
Journal: Cancer Research (2013)

Abstract Anaplastic lymphoma kinase (ALK), when aberrantly regulated through gene translocations or mutations, has been implicated as an oncogenic driver in a variety of cancers. XALKORI (crizotinib) is an FDA-approved therapy for locally advanced or metastatic (ALK)-positive non-small cell lung cancer (NSCLC). Mutations of certain residues within the ALK kinase domain have been associated with crizotinib resistance. To understand the molecular basis of mutational resistance, we have kinetically and structurally characterized several clinical mutations of ALK kinase domain. In the basal-state (nonphosphorylated) proteins, mutations C1156Y, F1174L, L1152R and L1196M resulted in 14 to 52-fold increase in catalytic efficiency of phosphorylation of an activation loop peptide. Accordingly, these mutants were more rapidly autophosphorylated, compared to wild-type enzyme. In addition, F1174L, C1156Y and L1156Y had 2 to 6-fold higher catalytic efficiencies when fully activated by autophosphorylation. Conversely, catalytic efficiencies of nonphosphorylated and phosphorylated G1269A variant decreased by 1.2 and 1.6-fold, respectively. Inhibition of L1152R, L1196M and G1269A by crizotinib was reduced by 3-28-fold, compared to wild-type enzyme, from Ki determinations. From direct binding studies of the L1196M “gatekeeper” mutation, the loss of crizotinib binding occurred 6 and 13-fold for phosphorylated and nonphosphorylated proteins, respectively. By crystallographic studies apoenzyme and crizotinib complexes of ALK kinase domain displayed an inactive kinase conformation that is stabilized by an extended hydrophobic network of residues. F1174 and L1196 are part of this hydrophobic core, and mutations of these residues are predicted to destabilize the inactive ALK conformation. Taken together, these results suggest that most of the resistant mutations (e.g. L1196M, F1174L, C1156Y, L1152R) result in a more dynamic protein that increases substrate turnover. In addition, the reduction of crizotinib binding for the mutations in the vicinity of the inhibitor binding site (L1196M, G1269A) is likely a contributing factor for the resistance. This structural and kinetic analysis of mutational resistance may be useful for design of new inhibitors targeting multiple clinical mutations of ALK. Citation Format: Sergei Timofeevski, Wei Liu, Ya-Li Deng, Alexei Brooun, Simon Bergqvist, Shannon Karlicek, Brion Murray, Ben Bolaños, Michele McTigue. Biochemical and structural characteristics of crizotinib-resistant ALK mutants. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4456. doi:10.1158/1538-7445.AM2013-4456
Relapsing linear acantholytic dermatosis
Authors: F. VAKILZADEH, G. KOLDE
Journal: British Journal of Dermatology (1985)

Journal Article Relapsing linear acantholytic dermatosis Get access F. VAKILZADEH, F. VAKILZADEH Department of Dermatology, University of Münster, Federal Republic of Germany Prof. Dr F.Vakilzadeh, Department of Dermatology, University of Münster, Von‐Esmarch‐Str. 56, D‐4400 Münster, F.R.G. Search for other works by this author on: Oxford Academic Google Scholar G. KOLDE G. KOLDE Department of Dermatology, University of Münster, Federal Republic of Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 112, Issue 3, 1 March 1985, Pages 349–355, https://doi.org/10.1111/j.1365-2133.1985.tb04864.x Published: 01 March 1985 Article history Accepted: 11 July 1984 Published: 01 March 1985
A 3-Year Randomized Controlled Study with Sublingual Immunotherapy in Mite-Induced Respiratory Allergy
Authors: G. Passalacqua, C. Lombardi, R. Ariano, M. Pasquali, I. Baiardini, A. Giardini, G. Maiani, M. Bruno, P. Falagiani, G.W. Canonica
Journal: Journal of Allergy and Clinical Immunology (2006)
Minimal Hepatic Encephalopathy Is Associated with Motor Vehicle Crashes
Authors: Jasmohan S. Bajaj, Kia Saeian, Christine M. Schubert, Muhammad Hafeezullah, Jose Franco, Rajiv R. Varma, Douglas P. Gibson, Raymond G. Hoffmann, Todd R. Stravitz, Douglas M. Heuman, Richard K. Sterling, Mitchell Shiffman, Allyne Topaz, Sherry Boyett, Debulon Bell, Arun J. Sanyal
Journal: Hepatology (2009)

Patients with minimal hepatic encephalopathy (MHE) have impaired driving skills, but association of MHE with motor vehicle crashes is unclear. Standard psychometric tests (SPT) or inhibitory control test (ICT) can be used to diagnose MHE. The aim was to determine the association of MHE with crashes and traffic violations over the preceding year and on 1-year follow-up. Patients with cirrhosis were diagnosed with MHE by ICT (MHEICT) and SPT (MHESPT). Self and department-of-transportation (DOT)-reports were used to determine crashes and violations over the preceding year. Agreement between self and DOT-reports was analyzed. Patients then underwent 1-year follow-up for crash/violation occurrence. Crashes in those with/without MHEICT and MHESPT were compared. 167 patients with cirrhosis had DOT-reports, of which 120 also had self-reports. A significantly higher proportion of MHEICT patients with cirrhosis experienced crashes in the preceding year compared to those without MHE by self-report (17% vs 0.0%, P = 0.0004) and DOT-reports (17% vs 3%, P = 0.004, relative risk: 5.77). SPT did not differentiate between those with/without crashes. A significantly higher proportion of patients with crashes had MHEICT compared to MHESPT, both self-reported (100% vs 50%, P = 0.03) and DOT-reported (89% vs 44%, P = 0.01). There was excellent agreement between self and DOT-reports for crashes and violations (Kappa 0.90 and 0.80). 109 patients were followed prospectively. MHEICT patients had a significantly higher future crashes/violations compared to those without (22% vs 7%, P = 0.03) but MHESPT did not. MHEICT (Odds ratio: 4.51) and prior year crash/violation (Odds ratio: 2.96) were significantly associated with future crash/violation occurrence. Conclusion: Patients with cirrhosis and MHEICT have a significantly higher crash rate over the preceding year and on prospective follow-up compared to patients without MHE. ICT, but not SPT performance is significantly associated with prior and future crashes and violations. There was an excellent agreement between self- and DOT-reports. (Hepatology 2009.)
Do Patients Prefer Physiologic Pacing?
Authors: Jay W. Mason, Mark A. Hlatky
Journal: New England Journal of Medicine (1998)

Cardiac pacemakers have become increasingly sophisticated during their half-century of clinical use. Each new component has been designed to simulate normal physiology more precisely. Is such complexity necessary? In this issue of the Journal, Lamas and colleagues1 report the results of the Pacemaker Selection in the Elderly (PASE) trial, a comparison of sophisticated dual-chamber pacing with less complex ventricular pacing in patients with bradycardia. The investigators conclude that dual-chamber pacing improved the quality of life, but the benefit was seen only in the subgroup with sinus-node dysfunction.On the surface, it seems obvious that dual-chamber pacing would be superior to . . .
Restoring Science to the National Children's Study
Authors: Nigel Paneth
Journal: JAMA (2013)

THE UNHAPPY STATE OF THE NATIONAL CHILDREN’S Study (NCS) has been described in several recent publications. Authorized by Congress in 2000, but not fully funded until 2007, this ambitious National Institutes of Health (NIH) study has consumed years of planning efforts, produced many reports and white papers, and spent close to a billion dollars. Yet, in 2013, the study is still in its pilot phase. The original design, proposed in 2004, was to enroll 100 000 pregnant women in a nationally representative sample of 105 communities. But in 2011, the NIH announced that sample size would be increased to “up to 250 000 women,” and in 2012 added that the NCS would use “healthcare provider networks as the primary sources for recruitment” and that the “enrolled population would no longer be a national proability sample.” Later in 2012, the NIH had second thoughts and reverted to 100 000 participants, but now at least half would be recruited at birth, not in pregnancy, and from a sampling frame of hospitals, not counties. In the meantime, approximately 4000 pilot-phase participants have been recruited with changing data-collection protocols in 40 communities and have been informed that the main study may take place elsewhere. The university teams that recruited the pilot participants have nearly all been replaced by independent research organizations. At the heart of the failure of the NCS is its abandonment of the hypothetico-deductive mode of scientific thinking. Vacillation in study design was inevitable once the NIH asserted, in 2010, that the NCS “is not designed to answer a set of specific hypotheses. It is a data-gathering platform.” Without explicit scientific goals, there is no logical way to select an optimal design. Whenthose responsible for “big science” suggest that “‘process’ expertise to maximize efficiency of high throughput operations is as important as scientific rigor,” the scientific impulse is likely to disappear in the thicket of bureaucratic management. The fundamental flaw in this thinking is the assumption that building a cohort—determining the sampling frame and sample size; deciding on the venue for recruiting study participants; choosing the times of interviews, assessments, and collections; and deciding on the content of the data collection instruments—is essentially an administrative task and not a scientific problem. When scientific questions do not drive the construction of the study, the construction of the study defines and constrains the scientific questions the study can answer. Decades ago, Weinberg warned that big science was a way of spending money instead of spending thought. But the creative scientific spirit need not be lost in big science. Dawber and Kannell, the first 2 directors of the Framingham study—the big science of its day—both insisted on the need for scientific hypotheses in designing large epidemiologic studies (Philip Landrigan, MD, Mount Sinai Hospital, New York, NY, about Kannell’s advice: “You’ve got to have a hypothesis,” oral communication, November 19, 1999).
AIDS: guidelines for barbers.
Authors: G. Bignardi
Journal: BMJ (1992)

secondary to primary care.Psychiatrists must realise this and start taking the criticisms of their clients and clients to be, the general practitioners in their area, more seriously than they do at present.This question needs to be addressed: if fundholding general practitioners are given the choice between a hospital oriented psychiatry service and other, equally effective, services that may be cheaper and are more flexible, how long before they start putting psychiatrists out of work?
SOME DISEASES COMMON TO THE FEEBLE-MINDED.
Authors: MARTIN W. BARR
Journal: JAMA (1898)

I count not the least valuable to myself of my former collaborations with the late Dr. Isaac Kerlin a study that we made together-with intent of reducing to tabulated form-of those diseases most common to the feeble-minded. This study involved the examination of medical records of 1400 cases, covering a period of twenty-five years, and I have since extended it so as to include some 3000 cases. Sifted out, we find the diseases, some eighty in number, distributed equally among the sexes, and in varying proportion in the different grades. Broadly considered, there are three conditions or classes which the feebleminded present to the eye of the medical observer, with modifications of course in different grades, causing the individual, therefore, to repel or to succumb to disease each in a different way. We have, first, a physical development according to age, susceptibilities to pain or pleasure being almost normal, and
Reply to C.S. Tam et al
Authors: Tony Panzarella, Diego Villa, John Kuruvilla
Journal: Journal of Clinical Oncology (2013)

report the survival impact of the number of regimens prior to transformation. 7Lastly, the discrepancy between univariate and MVA may be related to the greater proportion of R-chemotherapy patients receiving anthracycline rather than platinum-based chemotherapy (in this study, anthracyclines were weakly favorably associated with OS and platinums were strongly negatively associated with OS).We therefore request further clarification of the statistical methods fromthestudyauthors,includingresultsoftheunivariateanalysesandthe detailed methodology of the MVA.In particular, it would be informative for the reader to know details of how factors were entered and removed from the MVA model, and for the authors to present their MVA results after removal of nonsignificant factors.It would also be of great interest to analyze the impact of autoSCT versus R-chemotherapy on OS, as stratified by age and prior treatment status.We believe that these further analyses may provide important, practice-changing messages to help guide management of this uncommon condition.
Anti–tumor necrosis factor therapy was not associated with greater risk for mortality than standard therapy in rheumatoid arthritis
Authors: Ami Schattner
Journal: Annals of Internal Medicine (2011)

Source Citation Lunt M, Watson KD, Dixon WG, et al. No evidence of association between anti-tumor necrosis factor treatment and mortality in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2010;62:3145-53. 20662063
TCTAP A-044 The Impact of the Presence of Chronic Total Occlusion in a Non-Infarct-Related Coronary Artery in Acute Myocardial Infarction Patients: Validation in a Subset of Patients with Preserved Left Ventricular Function After Successful Primary Percutaneous Coronary Intervention
Authors: Yukio Mizuguchi, Akihiko Takahashi, Takeshi Yamada, Norimasa Taniguchi, Shunsuke Nakajima, Tetsuya Hata
Journal: Journal of the American College of Cardiology (2015)
Zotarolimus- Versus Everolimus-Eluting Stents for Unprotected Left Main Coronary Artery Disease
Authors: Julinda Mehilli, Gert Richardt, Marco Valgimigli, Stefanie Schulz, Ambika Singh, Mohamed Abdel-Wahab, Klaus Tiroch, Jürgen Pache, Jörg Hausleiter, Robert A. Byrne, Ilka Ott, Tareq Ibrahim, Massimiliano Fusaro, Melchior Seyfarth, Karl-Ludwig Laugwitz, Steffen Massberg, Adnan Kastrati
Journal: Journal of the American College of Cardiology (2013)
PREDICTORS OF END–STAGE RENAL DISEASE IN OUTPATIENTS WITH STABLE SYSTOLIC HEART FAILURE
Authors: Helle Skovmand Bosselmann, Gunnar H. Gislason, Per Hildebrandt, Finn Gustafsson, Lars Videbaek, Lars Koeber, Christian Torp–Pedersen, Niels Toender, Kasper Rossing, Stefan Christensen, Anne–Lise Kamper, James Heaf, Morten Schou
Journal: Journal of the American College of Cardiology (2013)
Histone deacetylase 5 interacts with Krüppel-like factor 2 and inhibits its transcriptional activity in endothelium
Authors: Il-Sun Kwon, Weiye Wang, Suowen Xu, Zheng-Gen Jin
Journal: Cardiovascular Research (2014)

AimsVascular endothelial dysfunction and inflammation are hallmarks of atherosclerosis. Krüppel-like factor 2 (KLF2) is a key mediator of anti-inflammatory and anti-atherosclerotic properties of the endothelium. However, little is known of the molecular mechanisms for regulating KLF2 transcriptional activation.
Use of computer terminals on wards to access emergency test results: a retrospective audit
Authors: E. S Kilpatrick
Journal: BMJ (2001)

<h3>abstract</h3> <b>Objective:</b> To assess delay in clinicians obtaining emergency biochemistry test results when the telephoning of results by laboratory staff is supplanted by installation of computer ward terminals. <b>Design:</b> Retrospective observational study. <b>Setting:</b> Accident and emergency department and acute medical admissions ward of a teaching hospital. <b>Sample:</b> 3228 emergency requests for biochemistry tests sent from the accident and emergency department and 1836 from the medical admissions ward during August 1999 to January 2000 when there was no recorded telephone contact for results. <b>Main outcome measures:</b> Proportion of emergency biochemistry results accessed via a ward terminal within 1 or 3 hours of becoming available and the proportion never seen by this means. <b>Results:</b> The results from 1443/3228 (45%) of urgent requests from accident and emergency and 529/1836 (29%) from the admissions ward were never accessed via the ward terminal. Results from 794/3228 (25%) of accident and emergency requests and 413/1836 (22%) of admissions ward requests were seen within 1 hour of becoming available while a further 491/3228 (15%) and 341/1836 (19%) respectively were accessed between 1 and 3 hours. In up to 43/1443 (3%) of the accident and emergency test results that were never looked at the findings might have led to an immediate change in patient management. <b>Conclusions:</b> When used as the sole substitute for telephoning results, the provision of terminal access to laboratory results on wards can hinder rather than promote the communication of emergency blood results to healthcare staff. <h3>What is already known on this topic</h3> Providing computer terminals on wards to access laboratory results is usually regarded as a service improvement for healthcare staff Many laboratories that transmit results to ward terminals dispense with telephoning emergency blood results <h3>What this study adds</h3> Many urgently requested results are not looked at if hospital staff need to access a computer terminal to obtain them If ward terminals are used as a complete substitute for the telephone, results that would have led to an immediate change in patient management may pass unnoticed
Climato-economic livability predicts societal collectivism and political autocracy better than parasitic stress does
Authors: Evert Van de Vliert, Tom Postmes
Journal: Behavioral and Brain Sciences (2012)

Abstract A 121-nation study of societal collectivism and a 174-nation study of political autocracy show that parasitic stress does not account for any variation in these components of culture once the interactive impacts of climatic demands and income resources have been accounted for. Climato-economic livability is a viable rival explanation for the reported effects of parasitic stress on culture.
BRCA2 mutations in primary breast and ovarian cancers
Authors: Johnathan M. Lancaster, Richard Wooster, Jonathon Mangion, Catherine M. Phelan, Charles Cochran, Curtis Gumbs, Sheila Seal, Rita Barfoot, Nadine Collins, Graham Bignell, Sandeep Patel, Rifat Hamoudi, Catharina Larsson, Roger W. Wiseman, Andrew Berchuck, J. Dirk Iglehart, Jeffrey R. Marks, Alan Ashworth, Michael R. Stratton, P. Andrew Futreal
Journal: Nature Genetics (1996)
Complement in chronic cutaneous lupus erythematosus
Authors: Th. Hunziker, T.E. Mollnes, G. Misiano, P.J. Spath
Journal: British Journal of Dermatology (1988)

Journal Article Complement in chronic cutaneous lupus erythematosus Get access Th. Hunziker, Th. Hunziker Dept of Dermatology, University of Berne, Berne, Switzerland Search for other works by this author on: Oxford Academic Google Scholar T.E. Mollnes, T.E. Mollnes Institute of Immunology and Rheumatology The National Hospital, Oslo, Norway Search for other works by this author on: Oxford Academic Google Scholar G. Misiano, G. Misiano Institute of Haematology and Immunology University of Strasbourg, France Search for other works by this author on: Oxford Academic Google Scholar P.J. Späth P.J. Späth Central Laboratory of the Swiss Red Cross Blood Transfusion Service CH‐3000, Berne 22, Switzerland Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 118, Issue 1, 1 January 1988, Pages 131–133, https://doi.org/10.1111/j.1365-2133.1988.tb01762.x Published: 01 January 1988
Behavior of eosinophil leukocytes in acute inflammation. II. Eosinophil dynamics during acute inflammation.
Authors: D A Bass
Journal: Journal of Clinical Investigation (1975)

The marked diminution in the number of circulating eosinophils, which has been shown to occur during acute bacterial infections, is a distinctive aspect of eosinophil physiology and of the host response to acute infection. The mouse rendered eosinophilic by infection with trichinosis provides a suitable model for study of the eosinopenic response induced by acute inflammation. The alterations in eosinophil dynamics associated with acute inflammatory reactions in trichinous mice were studied with pneumococcal abscesses, with Escherichia coli pyelonephritis, with Coxsackie viral pancreatitis, and with acute subcutaneous inflammation due to turpentine. Each of these stimuli of acute inflammation markedly suppressed the eosinophilia of trichinosis. This suggests that the eosinopenia is a response to the acute inflammatory process rather than the response to a specific type of pathogen. These studies apply quantitative techniques to ascertain the effects of acute inflammation on eosinophil production in bone marrow and on distribution of eosinophils in the peripheral tissues. From these observations, it is apparent that the initial response to acute inflammation includes a rapid drop in numbers of circulating eosinophils, a rapid accumulation of eosinophils at the periphery of the inflammatory site, and an inhibition of egress of eosinophils from the bone marrow. With prolongation of the inflammatory process, inhibition of eosinopoiesis occurs.
Acute Geriatric Medicine
Authors: Frederick T. Sherman
Journal: JAMA (1981)

This book is written for physicians who will be diagnosing and treating acutely ill elderly patients on medical, surgical, and geriatric wards and in emergency departments and skilled nursing facilities. The chapters, written by British geriatricians and their surgical and medical subspecialty colleagues, deal with problems that are commonly seen in the acutely ill elderly: acute cardiac, gastrointestinal, metabolic, neurological, renal, respiratory, urologic, and vascular problems, septicemia, hypothermia, acute confusional states, emergency anesthesia, and acute gastrointestinal bleeding. In general, each chapter starts with a brief review of age-related changes and altered presentation of illness, followed by a description of the diagnosis and management of the condition under discussion. The emphasis is on the differences in approach to geriatric patients compared with middle-aged patients. Because each chapter is short, averaging only 20 pages, major clinical entities are dealt with briefly. The chapter on cardiac problems, for example, deals with the "A