tbuckley/cabot-search huggingface dataset:
Identification of a novel synthetic microtubule depolymerizer with antitumor activity
Authors: Kimberly N. Weiderhold, Deborah A. Randall-Hlubek, Lisa Polin, Susan L. Mooberry
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

5439 

A long term goal of our work is the identification of new microtubule disrupting agents that might have utility in the treatment of cancer. Microtubule stabilizers and microtubule depolymerizers have proved to be useful anticancer agents. Although our previous efforts focused mainly on identifying microtubule disrupting compounds from natural products, we recently began screening large synthetic chemical libraries to identify small molecule inhibitors of microtubules. A novel microtubule-depolymerizing compound with a molecular weight of 365 was identified using the phenotypic screening assay. The compound, designated CB694, is a potent inhibitor of cellular proliferation with an average IC50 value of 85 nM against a wide range of cancer cell lines. The NCI/ADR cell line, which has a high level of expression of P-glycoprotein, is resistant to the vinca alkaloids and Taxol and yet it is very sensitive to inhibition by CB694, suggesting that this compound is a poor substrate for transport by P-glycoprotein. Similar to the effects of the vinca alkaloids, CB694 causes loss of interphase microtubules. The lowest concentrations of CB694 cause loss of the microtubules at the cell periphery and higher concentrations cause complete depletion of cellular microtubules. Similar to the effects of other microtubule disrupting compounds, CB694 causes micronucleation and the formation of abnormal mitotic spindles. A concentration dependent increase in multipolar mitotic spindles occurs in HeLa cells treated with this compound. As expected from the effects on mitotic spindles, CB694 causes mitotic accumulation followed by G1 aneuploidy and apoptosis. The compound was also evaluated for efficacy against a syngeneic, transplantable solid tumor model. CB694, given on a qDx6 intravenous treatment schedule, was well tolerated and produced antitumor activity against early stage Mammary Adenocarcinoma 16/C. Supported by a grant from the William Randolph Hearst Foundation to SLM.
Abstract 2106: Quantification of Doppler Flow Velocity-Derived Pulmonary Flow Reserve in Healthy Primates
Authors: Rahn Ilsar, Chirapan Chawantanpipat, Annemarie Hennessy, Richard Waugh, David S Celermajer, Martin K Ng
Journal: Circulation (2007)

Background: Pulmonary vascular disease (PVD), characterized by progressive pulmonary microvascular destruction, is only clinically evident late in its course when pulmonary artery pressure (PAP) rises. We hypothesized that changes in pulmonary flow reserve (PFR, maximal hyperemic vs. basal flow) may precede the PAP rise and thus aimed to: validate invasively-measured Doppler flow-velocity (v dopp ) as a marker of pulmonary blood flow and define the optimal hyperemic agent and dose for v dopp -derived PFR (PFR dopp ) assessment, in healthy baboons. Methods: Eight baboons were anaesthetized and a Doppler-sensing guidewire (DSG) placed in a segmental pulmonary artery. Angiographically-determined vessel diameter ( D ) and DSG-measured v dopp were obtained at baseline and at increasing intrapulmonary normal saline (NS) infusion rates and boluses. Escalating local doses of adenosine, acetylcholine &amp; papaverine were administered, v dopp obtained and PFR dopp calculated. Results: NS administration did not change D or v dopp (panels A &amp; B, p≥0.4). Adenosine produced a dose-dependent increase in v dopp maximal at 200μg/kg/min (p&lt;0.0001, panel C), papaverine to 24mg significantly increased v dopp (p&lt;0.0001, panel D) but acetylcholine to 10 − l concentration reduced v dopp (p=0.0008). Adenosine and papaverine-derived PFR dopp values were 1.5–2.0. Conclusions: As D does not vary with NS or hyperemic agent administration, v dopp is a valid marker of pulmonary blood flow. Adenosine and papaverine can be used with a Doppler-flow wire to derive PFR, with normal baboon PFR dopp being 1.5 – 2.0. Thus PFR dopp may be a potential novel marker for investigating early PVD.
Abstract 2096: Cardiovascular Risk Factors and Heart Rate Variability in an Older Cohort
Authors: Linda C Norton, Joan M Fair, Ruth E Taylor-Piliae, Mohammed H Mahbouba, Carlos Iribarren, Stephen P Fortmann
Journal: Circulation (2006)

Background: Lower heart rate variability (HRV) has been associated with CVD events in persons with CAD, diabetes and metabolic syndrome (MS). However, the role of HRV in predicting CVD risk in asym...
Genomic heterogeneity in primary breast cancer: Clinical implications.
Authors: Lucy Rebecca Connolly, Stian Knappskog, Christine Desmedt, David Wedge, Peter Van Loo, Moritz Gerstung, Aquila Fatima, Andrea Richardson, Per Eystein Lonning, Christos Sotiriou, Michael R. Stratton, Peter J. Campbell
Journal: Journal of Clinical Oncology (2014)

11004 Background: The targeting of new cancer therapeutics will be driven by genomic analysis of an individual’s tumor. It is questionable that standard sampling approaches that utilize slices from single ‘tissue blocks’ or clinical biopsies would always reflect the full spectrum of clinically relevant changes in the breast tumor landscape. Methods: We explore the diversity between multiple samples (n=294) from 49 patient’s primary breast tumors. Using a combination of targeted gene screens (n=285) and/or whole genome sequencing (n=25) mutation catalogues were compiled for each tumor. Results: To assess geographical heterogeneity within primary tumors we obtained multiple spatially separated samples (7-17) from 13 patients’ primary surgical specimens. Somatic point mutation and insertion/deletion analysis identified branching heterogeneity in 11/13 surgical samples (including ER positive, triple negative and HER2+ subtypes). In 4 cases, potentially ‘druggable’ targets such as PIK3CA mutations occur in a single sampled region – indicating frequent sub-clonality, and spatial confinement, of cancer driver mutations. We observe divergent and convergent evolution involving cancer drivers within individual tumors. We exploit the resolution of whole genome sequencing to demonstrate that even when homogeneity of driver mutations is observed, mutational processes such as kataegis continue to operate independently in spatially distinct regions. The analysis is extended to clinical samples: Pre-treatment biopsies and post-surgical blocks from 36 patients who underwent neo-adjuvant chemotherapy were analyzed. Initial findings reveal genomic heterogeneity within cases of both complete response (n=10) and residual disease (n=26), but interestingly, sub-clonal driver mutations so far appear to be limited to those with residual disease. Our ongoing analysis incorporates copy number analysis, and explores the relationship between chemotherapy response and heterogeneity and compares the genomic landscape pre and post neo-adjuvant chemotherapy. Conclusions: Current sampling approaches can be expected to under-report clinically actionable genomic events in a significant proportion of breast cancers.
Abstract 409: Effects of Angiotensin II Receptor Blocker (ARB) and PPAR-gamma Agonist on Vascular Failure in Patients with Hypertension, Diabetic Mellitus and Chronic Kidney Disease
Authors: Hideki Watanabe, Kunio Nakagawa, Masaaki Kakihana
Journal: Circulation (2008)

Background: Hypertension (HT), diabetes mellitus (DM), and chronic kidney disease (CKD) are known to be associated with “vascular failure”, which is defined as the integration of endothelial dysfunction and metabolic abnormalities of the vessel wall including inflammation, oxidative stress. We evaluated effects of ARB, calcium channel blocker (CCB), and PPAR-γ agonist on vascular failure in patients with HT, DM and CKD. Methods: Forty eight patients with untreated HT, type 2 DM (HbA1c 6.0 – 6.5%), and CKD (stage 3 or 4) were randomized to receive telmisartan ( Tel. group , n=12), telmisartan and pioglitazone ( Tel. and Pio. group , n=12), amlodipine ( Aml. group , n=12), or amlodipine and pioglitazone ( Aml. and Pio. group , n=12). We measured flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NID) of brachial artery, and pulse wave velocity (PWV). We also measured high sensitivity C-reactive peptide (hsCRP) and TBARS levels as indexes of inflammation and oxidative stress. Measurements were performed at baseline, and then at every 6 months after the treatments. Results: Blood pressure was significantly decreased in these groups, and there was no difference among four groups at baseline and during the study. FMD was significantly increased, and PWV, hsCRP, and TBARS were significantly decreased in four groups. However, these improvements were much better in the Tel. and Pio. group than the other groups. NID did not change during the study. Conclusion: Combination therapy with ARB and PPAR-γ agonist was much better in the improvement of vascular failure in patients with HT, DM and CKD as compared with the therapy with ARB alone, CCB alone, or CCB and PPAR-γ agonist.
Rethinking governance for trade and health
Authors: Helen Walls, Richard Smith
Journal: BMJ (2015)

Strengthening governance for more "healthy" trade is a recognised public health priority, 1 and increasingly so given recent shifts in the international trade regime. 2 After the second world war increasing trade liberalisation became a focus of international attention, and the General Agreement on Tariffs and Trade (GATT) was set up to coordinate international trade agreements.This was highly successful, and average world tariff rates fell from about 40% in 1948 to 4% in the early 1990s.
Abstract 15909: Pacemaker and Implantable Defibrillator Lead Survival and Malfunction Study: Long-term Follow-up of the Sprint Fidelis Lead
Authors: Todd J Cohen, Wendy Maltempi, Gerard Doorty, Martin Feuerman
Journal: Circulation (2010)

Introduction:  The Sprint Fidelis lead is the largest defibrillator lead ever recalled. Multiple independent studies have suggested that the manufacturer9s lead failure data significantly underestimates actual lead failure rates observed in clinical practice.   Hypothesis:  The purpose of this study was to test the hypothesis that manufacturer reported data underestimates actual lead failure rates observed at a large implanting center.   Methods:  This study was approved by the Winthrop University Hospital9s IRB. All implanted Sprint Fidelis leads were retrospectively analyzed with respect to age, gender, ejection fraction, and implant approach. Lead failure included failure to capture/sense, abnormal impedance, fracture/insulation defect, dislodgement and/or perforation. Each suspected failure was independently confirmed by an individual who was blinded to the operator and patient identifiers. Kaplan-Meier survival curves were computed and a Cox regression was used to determine the relationship between survival and the continuous variable of age. Results were considered significant when p   Results:  A total of 795 leads were implanted by 5 physicians through October 2007 (595 men: 200 women) with a mean age of 70.8±12.7 years. The mean follow-up was 31.1±5.3 months with a total of 24 lead failures (3.02% failure rate). The first year lead survival was 99.9%, second year was 98.7%, third year was 96.1%, fourth year was 94.7% and the fifth year was 94.7%. 63.1% were implanted via cephalic venous and 36.9% via subclavian venous approach. There were no lead failure differences observed in our study based on age, gender, ejection fraction, or implant approach.   Conclusions:  This study used identical lead failure criteria as employed by the manufacturer and came up with more favorable lead survival results when compared to other independent studies. Manufacturer reported Sprint Fidelis lead failure rates do not underestimate real world clinical experience.
Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guérin
Authors: Ashish M. Kamat, Joseph Briggman, Diana L. Urbauer, Robert Svatek, Graciela M. Nogueras González, Roosevelt Anderson, H. Barton Grossman, Ferran Prat, Colin P. Dinney
Journal: European Urology (2015)
Brief Secondhand Smoke Exposure Depresses Endothelial Progenitor Cells Activity and Endothelial Function
Authors: Christian Heiss, Nicolas Amabile, Andrew C. Lee, Wendy May Real, Suzaynn F. Schick, David Lao, Maelene L. Wong, Sarah Jahn, Franca S. Angeli, Petros Minasi, Matthew L. Springer, S. Katharine Hammond, Stanton A. Glantz, William Grossman, John R. Balmes, Yerem Yeghiazarians
Journal: Journal of the American College of Cardiology (2008)
21P Molecular Characterization of Early-Stage Her2-Overexpressing Breast Cancer (Her2+ Bc) Treated with Adjuvant Trastuzumab: Identification of Prognostic Groups
Authors: D. Fumagalli, D. Lambrechts, P. Neven, J. Vanderhaegen, B. Claes, S.K. Singhal, M. Piccart, S. Michiels, C. Sotiriou, S. Loi
Journal: Annals of Oncology (2012)
Incidence of recurrent thromboembolism and chronic thromboembolic pulmonary hypertension after pulmonary embolism
Authors: Eva Serasli, Maria Antoniadou, Nikolaos Moisiadis, Vasilis Michaelidis, Dimitra Siopi, Venetia Tsara
Journal: European Respiratory Journal (2011)

Aim: To assess the incidence of recurrent thromboembolism and chronic thromboembolic pulmonary hypertension (CTPH) and the associated risk factors.

Patients-Methods: Prospective study in 126 patients (mean age 54.4±15.8 years) with confirmed acute pulmonary embolism (PE), during the period 2004-2010 (mean time follow up 32±19.7 months). For the evaluation of CTPH, patients underwent transthoracic echocardiography, ventilation-perfusion lung scanning and the diagnosis was established with right heart catheterization.

Results: Recurrent venous thromboembolism was documented in 8, 7% of patients, with an incidence of 4.5% after 12 months (95% CI: 0.6-8.4%) and 11.5% after 24 months (95% CI: 5.0-18%). The mortality was 2.6% at 1 year (95% CI: 0.0-5.5%), 3.7% at 2 years (95% CI: 0.0-7.4%) and 7.7% at 5 years (95% CI: 0.0-16.1%). Older age (p=0.046), SPAP>50mmHg (p=0.009) and thrombolysis (p=0.005) were significantly associated with increased risk for recurrence. CTPH was developed in 7 of 126 patients (5.6%). During the acute episode of PE, 33 patients (26.2%) presented with SPAP>40 mmHg and 54% of them were with SPAP>50mmHg. CTPH developed in 7 of these 33 patients. Severe PH at the time of the acute PE (SPAP>50mmHg) was associated with an increased risk of CTPH (odds ratio: 20.385, SE: 0.88, P<0.05).

Conclusions: The rates of recurrent thromboembolism underscore the need for long term follow up. Risk factors must be considered for the duration of anticoagulant therapy. During the first year after an acute episode of PE, CTPH appears to developed in a substantial number of patients. The severity of PH should increase physicians' awareness for the potential of CTPH.
The Failing Heart of Middle Life
Authors: David Riesman
Journal: Annals of Internal Medicine (1929)

Article1 August 1929The Failing Heart of Middle LifeDAVID RIESMAN, M.D., ScD.DAVID RIESMAN, M.D., ScD.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-3-2-112 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptMany men lead active professional and business lives; they may even live reasonably well according to our present standards, but when they reach the age of 50 or thereabouts something happens that was not foreseen by them or by their medical advisors. In ordinary parlance they go to pieces. Upon analysis the disintegration will usually be found due to some change in the heart or circulation. The man who up to the moment of the appearance of the symptoms was active and in the possession of all the energy of the best years of life suddenly becomes an old man.... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Philadelphia*Read before the American College of Physicians, Boston, April 10, 1929. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 August 1929Volume 3, Issue 2Page: 112-121KeywordsHeart Issue Published: 1 August 1929 PDF downloadLoading ...
Educational experience for trainees is better than in Britain
Authors: C. F MacKenzie
Journal: BMJ (1996)

maintenance organisations and capitation are here to stay, and large drops in clinical earnings are predicted.Partners earning high salaries are reducing their holidays and supervising more certified nurse anaesthetists rather than employing another partner and reducing income.It is rumoured that deans of medical schools are dissuading medical students from entering training in anaesthesia.The staffing crisis in teaching hospitals is only just starting and has yet to be resolved.Academic anaesthesiologists, who are accustomed to
Scheme has to be compulsory for proper evaluation
Authors: G. Houghton
Journal: BMJ (1996)

EDITOR,—Douglas Carnall is correct in pointing out the lack of evidence to show that there has been any improvement in patients' care as a result of summative assessment in general practice.1 This is hardly surprising, given the longstanding difficulties in deciding on reliable measures of practice performance and the achievement of Professor T Murray and his educational team in the west of Scotland in presenting a practical, validated assessment tool in so short a period.

Carnall's demand …
Antivenom for Children with Neurotoxicity from Scorpion Stings
Authors: Shaul Sofer, Himmatrao S Bawaskar, Moshe Gueron
Journal: New England Journal of Medicine (2009)

To the Editor: Boyer et al. (May 14 issue)1 report that among children with neurotoxic effects of scorpion envenomation, scorpion-specific F(ab′)2 antivenom resolved the clinical syndrome within 4 hours. In 1999, we published the results of a negative randomized, controlled trial of antivenom in patients with scorpion envenomation in southern Tunisia.2 Although neurotoxic effects are reported in up to 78% of patients with venomous scorpion stings in North Africa, we assessed the efficacy of scorpion antivenom on objective end points such as a change in severity grade.3 The 100% rate of resolution of neurotoxic symptoms with scorpion-specific antivenom in the study by Boyer et al. is ascribed to rapid neutralization of circulating scorpion venom; this finding has been previously reported, and its clinical relevance largely debated.4,5 The distribution range and the standard deviation around the mean of baseline plasma venom levels in the control group suggest that some patients had no detectable levels of venom. Was the outcome for those patients the same as that of the active group or that of the control group? Midazolam infusion, which affected both the primary and secondary end points, was not standardized according to a validated grading system. Therefore, it is difficult to identify the precise moment that resolution of the neurotoxic syndrome occurred, and the decision to stop the midazolam infusion might have been delayed, since it was based on the observation of the patient’s condition by the physician-investigator.
Oncologists' mindfulness, health, well-being, and patient care.
Authors: A. C. Kracen, K. M. Ingram, L. J. Lyckholm, T. J. Smith
Journal: Journal of Clinical Oncology (2010)

e16527 Background: Occupational demands on oncologists continue. Burnout is a serious concern, especially considering the looming shortage of oncologists. There is scant research regarding oncologists, their personal habits and patient care, and strategies that enhance well-being. Mindfulness, the ability to be present in the moment, is increasingly being encouraged among healthcare workers for personal benefits and possible positive effects for patients. This study examined (a) the health, well-being, and patient care practices of oncologists, and (b) the relationship between oncologists' mindfulness and health indicators (general health and sleep problems) with three outcomes (satisfaction with life [SWL], job satisfaction, and suboptimal patient care). Methods: Survey data were collected from ASCO oncologists (n = 114, response rate of 29%). Results: Participants were male (76%), Caucasian (78%), and married (84%), and featured a mean age of 52 years and an average work week of 58 hours. Half (51%) endorsed sleeping 6 or fewer hours/night, whereas 35% reported inadequate sleep and 57% believed lack of sleep interfered with daily functioning. Participants reported good health, high levels of mindfulness, and satisfaction with their lives and jobs. They reported occasional suboptimal patient care practices and attitudes. About 20% endorsed some burnout, but only 12% were considering changing jobs in the next 5 years. Hierarchical multiple regressions indicated that general health statistically predicted greater SWL, greater job satisfaction, and less suboptimal patient care, whereas mindfulness predicted greater SWL and less suboptimal patient care. Sleep problems statistically predicted less SWL, whereas mindfulness predicted less suboptimal patient care. Conclusions: Although participants endorsed long work hours and inadequate sleep, they reported being generally healthy, satisfied, and very mindful. Mindfulness statistically predicted greater satisfaction with life and better patient care. These findings suggest that being healthier and more mindful has benefits for oncologists and their patients. The results may inform the development of interventions to enhance oncologists' well-being and patient care. No significant financial relationships to disclose.
Abstract 2919: Medical And Economic Long-term Effects Of B-type Natriuretic Peptide Testing In Patients With Acute Dyspnea
Authors: Christian Mueller, Tobias Breidthardt, Anne-Henny Strohmeyer, Christian Schindler, Sophie Meier, Michael Fischer, Andre Scholer, Markus Noveanu, Michael Christ, André P Perruchoud
Journal: Circulation (2007)

Background: The objective of this prospective study was to assess the medical and economic long-term effects of using B-type natriuretic peptide (BNP) levels in the management of patients with acute dyspnea. Methods: We performed follow-up analysis of BASEL, a randomized study including 452 patients who presented to the emergency department with acute dyspnea. Participants were randomly assigned to a diagnostic strategy involving the rapid measurement of BNP levels (n=225) or assessment in a standard manner (n=227). Mortality was assessed at 720 days, morbidity and economic data at 360 days. Results: BNP testing induced several important changes in initial patient management including a reduction in the initial hospital admission rate, the use of intensive care, as well as initial time to discharge. At 720 days, 172 deaths had occurred. Cumulative all-cause 720-day mortality was not different between the BNP group (37%) and the control group (36%, P =0.6). Morbidity as reflected by days spent in-hospital at 360 days was significantly lower in the BNP group (median 12 days [IQR 2–28]) as compared to the control group (median 16 days [IQR 7–32], P =0.025). Functional status was similar in both groups. Economic outcome as quantified by total treatment cost at 360 days was significantly improved in the BNP group (mean $10,144 versus $12,748 in the control group, P =0.008). Conclusions: Rapid BNP testing in patients with acute dyspnea has no effect on long-term mortality. However, morbidity as quantified by days spent in-hospital and economic outcome are still improved at 360 days.