tbuckley/cabot-search huggingface dataset:
Abstract 3: Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy
Authors: Frédéric R. Santer, Holger H.H. Erb, Su Jung Oh, Florian Handle, Gertrud E. Feiersinger, Birgit Luef, Huajie Bu, Georg Schäfer, Christian Ploner, Martina Egger, Jayant K. Rane, Norman J. Maitland, Helmut Klocker, Iris E. Eder, Zoran Culig
Journal: Cancer Research (2015)

Abstract The cellular consequences of androgen deprivation therapy (ADT), a first-line therapy for locally advanced and metastatic prostate cancer (PCa), are induction of apoptosis or G1 cell cycle arrest. Inability of PCa cells to induce apoptosis is the starting point of development of castration resistance. Hence, an improved therapy should target the cell cycle-arrested cells in a combinatorial approach together with currently applied ADT. Here we set out to analyze whether MCL1, a pro-survival member of the BCL2 family and known mediator of chemotherapy resistance regulates the cellular response to androgen withdrawal. Analysis of MCL1 protein and mRNA expression in PCa tissue and primary cell culture specimens of luminal and basal origin, respectively, reveals higher expression in cancerous tissue compared to benign origin. Using PCa cellular models in vitro and in vivo we show that MCL1 expression is regulated through the action of androgens and upregulated in androgen-sensitive PCa cells when grown under steroid-deprived conditions. Analysis of the underlying mechanism suggests that regulation of MCL1 through the AR signaling axis is indirectly mediated via a cell cycle-dependent mechanism. Using constructs downregulating or overexpressing MCL1 we demonstrate that expression of MCL1 prevents induction of apoptosis when androgen-sensitive PCa cells are grown under steroid-deprived conditions. The BH3-mimetic Obatoclax induces apoptosis and decreases MCL1 expression in androgen-sensitive PCa cells, while castration-resistant PCa cells are less sensitive and react with an upregulation of MCL1 expression. Synergistic effects of Obatoclax with androgen receptor inactivation can be observed in androgen-sensitive cells. In addition, Obatoclax efficiently inhibits clonogenicity of primary basal PCa cells. Altogether, our results suggest that MCL1 is a key molecule deciding over the fate of PCa cells upon inactivation of androgen receptor signaling and provide a mechanistic rationale for a clinical assessment of a MCL1-targeting therapy adjuvant to ADT. Citation Format: Frédéric R. Santer, Holger H.H. Erb, Su Jung Oh, Florian Handle, Gertrud E. Feiersinger, Birgit Luef, Huajie Bu, Georg Schäfer, Christian Ploner, Martina Egger, Jayant K. Rane, Norman J. Maitland, Helmut Klocker, Iris E. Eder, Zoran Culig. Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3. doi:10.1158/1538-7445.AM2015-3
Abstract 18610: High-sensitivity Cardiac Troponin T Level in the Emergency Department and Long-term Mortality in Patients With and Without Myocardial Infarction
Authors: Nadia Bandstein, Rickard Ljung, Magnus Johansson, Martin Holzmann
Journal: Circulation (2014)

Introduction:  The level of high-sensitivity cardiac troponin T (hs-cTnT) is related to outcome in patients with myocardial infarction (MI). However, the importance of elevated hs-cTnT levels in patients without MI is unknown. We investigated the association between elevation of hs-cTnT and death in patients with and without MI. Also, we compared the risk of death between patients with and without MI at different levels of hs-cTnT.[[Unable to Display Character:  ]]   Methods:  We included all patients > 25 years of age who came to the emergency department (ED), at the Karolinska university hospital in Stockholm, Sweden, during 2011 to 2012, with chest pain and at least one hs-cTnT measured. Cox hazard regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI), for all-cause mortality at different levels of first hs-cTnT (5-14, 15-29, 30-49, 50-100, and >100 ng/l), using    Results:  13 735 patients were included of whom 817 (5.9%) had MI. During 1.7 years of follow-up 99 (12%) patients with, and 729 (5.6%) without MI died. The assocation between hs-cTnT level and death was stronger in patients without MI, than among those with MI in each strata (5-14, 15-29, 30-49, 50-100, and >100 ng/l) of hs-cTnT (HR 95% CI: 2.7 (2.0-3.5) vs 1.9 (0.3-16), 4.7 (3.5-6.3) vs 2.0 (0.3-15), 7.4 (5.3-109) vs 2.2 (0.3-16), 11.2 (7.9-16) vs 2.0 (0.3-16), and 9.3 (6.4-13) vs 3.3 (0.4-24)). MI was associated with a lower risk of death compared with no MI in all strata of hs-cTnT > 14 ng/l. In patients with a hs-cTnT level of 50-100 ng/l the risk of death associated with MI compared with no MI was 0.39 (0.22 to 0.70).[[Unable to Display Character:  ]]   Conclusions:  An elevated first hs-cTnT is a stronger predictor of death in patients without MI than in those with MI. Patients with compared to those without MI have a lower risk of death at each level of elevated hs-cTnT.
Abstract P092: Debunking the Myth of the “Jolly Fat and Fit”: A Longitudinal Cohort Analysis
Authors: Dhananjay Vaidya, Lisa R Yanek, Taryn F Moy, Brian G Kral, Diane M Becker
Journal: Circulation (2014)

Background: Positive emotional health has been shown to be protective against coronary artery disease, putatively through pro-health behaviors including exercise and fitness. It has been suggested that this positive emotion trait is prevalent among obese persons (“jolly fat” hypothesis) implying that it may lead to fitness even with higher BMI. We thus examined the longitudinal associations among fatness, fitness and positive emotion using structural equation modeling (SEM). Methods: We examined GeneSTAR (Genetic Study of Atherosclerosis Risk) cohort data (N = 947, 57% women, 50% African American, baseline age 47 ± 7 years, follow-up measures 7 ± 2 years). We fit SEMs to determine the temporal associations between fatness (BMI), fitness (METs achieved on a treadmill test) and positive emotion (General Well Being Schedule, GWBS) adjusting for age, sex, race and follow-up time. Results: The cross-sectional correlations were significant in SEM (BMI-METs -0.42, GWBS-MET -0.14, BMI-GWBS -0.15; all p&lt;0.001). Significant or suggestive temporal paths (standardized r) are shown in the figure. All within-variable correlations were strong (p &lt; 0.001). Baseline BMI was negatively correlated with GWB scores at follow-up but baseline GWBS was not associated with BMI at follow-up (difference between paths, p = 0.007). Thus, adjusting for cross-sectional correlations, lower BMI occurs temporally prior to measures of a greater level of positive emotion. Although the temporal paths between baseline BMI and followup MET and vice versa were jointly significant (p = 0.004), neither was significantly stronger (p = 0.25), suggesting temporal bidirectionality. There was no significant temporal relationship between GWBS and MET. Conclusion: Both cross sectional and longitudinal relationships are contrary to the “jolly fat” hypothesis. Greater BMI is temporally and cross-sectionally associated with worse measures of the positive emotion trait and fitness.
Propagation of Onset and PeakTime of Myocardial Shortening in Time of Myocardial Shortening in Ischemic Versus Nonischemic Cardiomyopathy
Authors: Jaco J.M. Zwanenburg, Marco J.W. Götte, J. Tim Marcus, Joost P.A. Kuijer, Paul Knaapen, Robert M. Heethaar, Albert C. van Rossum
Journal: Journal of the American College of Cardiology (2005)
Cleaning, Disinfection and Sterilization of Heat-Sensitive Endoscopes
Authors: Norman Miner
Journal: Endoscopy (2013)

High level disinfection is a process that kills high numbers of all types of vegetative nonspore forming bacteria (Gram-positive and Gram-negative), fungi, all types of viruses (hy‐ drophylic and lipophylic), and mycobacteria (TB), but not necessarily high numbers of bacterial spores in the relatively brief exposure time for disinfection. Sterilization is a proc‐ ess that kills all types of microbes including highly resistant bacterial spores. Sterilization usually requires a much longer exposure time than disinfection. Gastroscopes, colono‐ scopes, urethroscopes, and cystoscopes normally do not break the barrier between non-ster‐ ile areas of the body and sterile areas, and therefore high level disinfection is the commonly accepted practice for these endoscopes. Bronchoscopes are a possible exception as they may enter into the sterile bronchioles, although they make that entrance through the non-sterile nasal passages where they likely become contaminated with the flora of the oral-nasal body cavities. Endoscopists, and certainly patients, all agree that endoscopes and their accessories such as biopsy forceps should be thoroughly cleaned of all body fluids and any possible mi‐ crobes between patients, even if not technically sterilized.
TKI258 is an effective multi-targeted receptor tyrosine kinase (RTK) inhibitor against xenograft models of human melanoma.
Authors: Katherine Rendahl, Daniel Menezes, Paul Hollenbach, Yan Tang, Helen Ye, Debbie Swinarski, XiaoHong Niu, Tinya Abrams, Michel Faure, Natasha Aziz, Michael Rowe, Pablo Garcia, Jocelyn Holash, Nancy Pryer, Carla Heise
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3258 

TKI258 (formerly CHIR-258) is an oral, multi-targeted RTK inhibitor of FGFR, VEGFR, PDGFRβ, FLT3 and c-KIT. Given that FGFR 1-4 and their FGF ligands are implicated in the pathogenesis of melanoma, we investigated TKI258 efficacy in melanoma models, based on it’s potential activity against both tumor cells via inhibition of FGFR, and against the tumor vasculature by targeting FGFR, VEGFR and PDGFRβ. In vitro activity of TKI258 was tested in clonogenic assays against a panel of melanoma cell lines and limited passage human melanoma cells propagated in mice. All melanoma cell lines were characterized for expression of FGFR1-4 and mutational status of B-Raf or Ras. In the in vitro clonogenic assays on soft agar, TKI258 activity was observed in all melanoma cells regardless of FGFR1-4 expression levels, or wild-type/mutant Ras/B-Raf status. In vivo efficacy was evaluated in two different subcutaneous melanoma xenograft models: CHL-1 (WT K-Ras and WT B-Raf) and A375M (mutant B-Raf) in athymic nude mice. These xenograft models have similar patterns of expression of FGFR1-4, but differ in Ras/Raf pathway status. Daily oral administration of TKI258 at doses that inhibit FGFR signaling in vivo resulted in significant tumor growth inhibition of both CHL-1 and A375M tumor xenograft models. Antitumor activity of TKI258 was also evaluated in vivo in combination with the chemotherapeutic agents carboplatin and paclitaxel, which are used clinically to treat melanoma. Compared to monotherapy, the combination of TKI258 with carboplatin plus paclitaxel resulted in enhanced activity against both CHL-1 and A375M tumors and was well tolerated. In the CHL-1 model, treatment with carboplatin plus paclitaxel at maximum tolerated doses showed no tumor growth inhibition (TGI), whereas TKI258 therapy demonstrated approximately 44% TGI. The combination of all three agents exhibited 70% TGI. In the A375 model, animals dosed with the carboplatin + paclitaxel combination resulted in 35% TGI, TKI258 treatment alone showed 58% TGI and the combination of all three agents resulted in 73% TGI. In conclusion, anti-tumor activity of TKI258 in these models is likely due to multiple mechanisms, including inhibition of FGFR 1-4 and/or additional TKI258 targets expressed by these melanoma cell lines, and it’s anti-angiogenic activity via inhibition of VEGFR and PDGFRβ. These results demonstrate that TKI258 is effective as a single agent and in combination with chemotherapy in preclinical melanoma models, thus providing a basis for TKI258 clinical trials in melanoma.

*equal contributing authors
Abstract 5549: Recipient-donor contradictory genotype with impact on anticancer drug pharmacogenetics after liver transplant: A deadly gift
Authors: Cindy Serdjebi, Raphaelle Fanciullino, Frederic Fina, Arnaud Verschuur, Bertrand Roquelaure, Bruno Lacarelle, L'Houcine Ouafik, Joseph Ciccolini, Nicolas André
Journal: Cancer Research (2014)

Abstract A 5-year old girl with liver transplant was scheduled for a therapy including high-dose cytarabine for her Burkitt lymphoma. Cytarabine pharmacogenetics focus on cytidine deaminase (CDA) , the polymorphic liver enzyme responsible for its detoxification. Preliminary double testing for her CDA status on DNA lymphocytes showed none of the germline polymorphisms usually associated with CDA deficiency (ie, 79A&amp;gt;C (K27Q), 208G&amp;gt;A), but surprisingly with a functional mild deficiency syndrom. Despite 30% reduction in cytarabine dosing, life-threatening toxicities showed quickly and treatment was discontinued. Genetic HRM-based investigations performed in the patient on liver biopsy failed in generating a clear genotype. Further HRM+sequencing retrospective investigations on liver biopsy collected from the donor showed that he was actually bearing the homozygous CDA*2 allelic variant (ie, 79AA), a genotype usually associated with severe CDA deficiency. Based upon the donor liver genotype, and not the recipient genotype, treatement was resumed with further dose reduction, close monitoring and better tolerance eventually. The patient is now in complete remission more than a year after completion of the treatment. This case report illustrates the limits and risks of searching germline polymorphisms in patients with liver transplant when the story plays in the liver. Citation Format: Cindy Serdjebi, Raphaelle Fanciullino, Frederic Fina, Arnaud Verschuur, Bertrand Roquelaure, Bruno Lacarelle, L'Houcine Ouafik, Joseph Ciccolini, Nicolas André. Recipient-donor contradictory genotype with impact on anticancer drug pharmacogenetics after liver transplant: A deadly gift. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5549. doi:10.1158/1538-7445.AM2014-5549
Principles and Practice of Cardiovascular Imaging.
Authors: Gerald M. Pohost, Robert A. O'Rourke, J. Willis Hurst
Journal: Annals of Internal Medicine (1991)

Principles and practice of cardiovascular imaging , Principles and practice of cardiovascular imaging , کتابخانه دیجیتالی دانشگاه علوم پزشکی و خدمات درمانی شهید بهشتی
1064. AdPEDF Therapy for Subfoveal Choroidal Neovascularization (CNV): Preliminary Phase I Results
Authors: Timothy Stout, Michael Klein, Eric Holz, Anurag Gupta, David Saperstein, Lisa L. Wei, Angelita Ray, Paul Kessler, Robert N. Frank, Peter A. Campochiaro
Journal: Molecular Therapy (2004)

Neovascular age-related macular degeneration (AMD) is one of the leading causes of blindness, afflicting approximately 200,000 individuals/year in the United States. Pigment Epithelium-Derived Factor (PEDF), a naturally-occurring factor in the eye is a potent antiangiogenic factor. PEDF opposes not only VEGF but also other angiogenic stimuli such as FGF, PDGF and IL-8. In addition, PEDF is neuroprotective and thus may enhance preservation of retinal ganglion cells and photoreceptors that are essential for vision. To evaluate the safety and feasibility of intravitreal PEDF delivery via a second generation adenovector (AdPEDF) in patients with subfoveal CNV due to AMD, we conducted an open label, dose-escalation protocol with 8 dose levels (106-109.5 pu in 1/2 log increments) in patients with active subfoveal CNV and best corrected visual acuity of 20/200 or worse in the study eye. After a single intravitreal injection of AdPEDF, 1 year follow-up consisted of periodic ocular exams, fluorescein angiograms, and laboratory evaluations including adenovirus neutralizing antibody titers and throat and urine cultures for adenovirus. Optical coherence tomography was performed as a substudy at 2 study sites. Six of 8 dose cohorts have been fully enrolled (n=18), and accrual is ongoing. Intravitreal AdPEDF has been well-tolerated and there have been no dose limiting toxicities or related severe adverse events. Three patients (two at 107.5 and one at 108.5 pu) had mild transient inflammation and Grade 1 elevation in intraocular pressure (IOP) thought to be probably or possibly related to the study drug. Neutralizing antibody titers did not increase at 3 months in 11 out of 12 patients and all adenoviral cultures were negative. Intravitreal injection of up to 108.5 pu of AdPEDF is well-tolerated and has not been associated with any serious short-term toxicity.
Abstract 13901: Elevated Cardiovascular Risk Factors among Appalachian Women with a History of Pregnancy Complications
Authors: Rebecca L Dekker, Kristin B Ashford, Terry A Lennie, Misook L Chung, Martha Biddle, Gia Mudd-Martin, Alison L Bailey, Debra K Moser
Journal: Circulation (2014)

Introduction: A growing body of evidence links complications of pregnancy (gestational diabetes, preeclampsia, and pregnancy-induced hypertension) with double the risk of future cardiovascular disease (CVD) related death in affected women. However, little is known about which CVD risk factors are more prominent among women who have experienced pregnancy complications. Purpose: Compare the presence of modifiable CVD risk factors among women with and without a self-reported history of pregnancy complications living in Appalachian Kentucky- an area with the highest rate of CVD mortality in the U.S. Methods: Rural Kentucky Appalachian women (n = 122, 97% Caucasian, 42 ± 12 years) engaged in a comprehensive measurement of CVD risk factors including body mass index (BMI), waist circumference, blood pressure, A1C, lipid profile (total cholesterol, triglycerides, HDL, and LDL), tobacco smoke exposure (objectively measured with urine cotinine), depression (Patient Health Questionnaire-9), and anxiety (Brief Symptom Inventory). We used independent t-tests and chi-square analysis to compare risk factors between women with and without a history of pregnancy complications. Results: One-fourth of the sample had one or more pregnancy complications: gestational diabetes (8.2%), preeclampsia (6.6%) and pregnancy-induced hypertension (15.6%). Women with at least one pregnancy complication had a higher average BMI (33.4 vs. 30.4, p = .014), larger waist circumference (42.8 vs. 39.1 cm, p = .006), and a higher proportion with moderate to severe symptoms of depression (27.6% vs. 15.9%, p = .02) compared to women without a history of pregnancy complications. There were no differences between groups in systolic or diastolic blood pressure, A1C levels, lipid profiles, tobacco smoke exposure, or anxiety. Conclusions: Women with a history of pregnancy complications have several modifiable risk factors- higher BMI, higher waist circumference, and higher levels of depression- that could constitute a link between past pregnancy complications and their risk of future CVD death. Pinpointing which modifiable risk factors are elevated in these women will help us develop self-management interventions to prevent the development of CVD in this high-risk population.
In vitro performance of an improved collapsible holding chamber (CHC) for the delivery of bronchodilators to patients receiving mechanical ventilation
Authors: Mark Nagel, Valentina Avvakoumova, Rubina Ali, Cathy Doyle, Jolyon Mitchell
Journal: European Respiratory Journal (2011)

Bronchodilator delivery by pressurized metered-dose inhaler (pMDI) to patients on mechanical ventilation is best achieved without breaking the breathing circuit. We describe an evaluation of an improved CHC (AeroVent Plus*, Trudell Medical International, London, Canada (n=5 devices, 1 measurement/device)), in which the pMDI canister receptacle is offset from the CHC axis to reduce internal impaction, and can also accept GSK pMDI canisters having a dose counter. Delivery of 3-actuations of salbutamol (HFA-Ventolin*, GSK (Canada); 100-μg/actuation) was assessed with the expanded CHC inserted in the inspiratory limb of an adult breathing circuit equipped with a 7-mm diameter endotracheal tube (ETT). An adult test lung (Michigan Instruments) was used to simulate the patient. The circuit was humidified near to body conditions (T = 36°C, 100%RH), and tidal breathing (600-mL, duty cycle = 33%, 10 breaths/min) was simulated by a servo ventilator (Siemens, model 900C). A filter was located between the distal end of the ETT and test lung to collect the aerosol. Total mass (TM) of salbutamol after 6 respiratory cycles was determined by HPLC-UV spectrophotometry. Similar measurements were undertaken with a Spirale* CHC (Armstrong Medical), providing benchmark data from a European marketed CHC having the pMDI receptacle in-line with the axis of the device. TM (mean ± S.D.) from the AeroVent Plus and Spirale CHCs was 22.7±3.1 and 4.7±0.7 μg/actuation respectively. Clinicians using these devices should be aware of the implications of the difference in drug output between these apparently similar devices.
Lessons from the financial scandals in Wessex and the West Midlands Health authority members found wanting
Authors: R Klein
Journal: BMJ (1994)

Lessons from the financial scandals in Wessex and the West Midlands Health authority membersfound wantingThe management of the NHS has been characterised by two trends in recent years.Firstly, there has been the increasing dominance and assertiveness of the NHS Manage- ment Executive, with ever tighter control from the centre.Secondly, there has been soaring spending on managerial staff
Abstract 18267: Effect of the Stress by Supercooling on Cell Proliferation and Immunogenicity of Transplanted Human Induced Pluripotent Stem (iPS) Derived Cardiomyoctes
Authors: Hisashi Moriguchi
Journal: Circulation (2014)

BACKGROUND: Cell preservation is essential for cell transplantation. I examined the effects of the stress by supercooling on the transplantation of human induced pluripotent stem (iPS) derived cardiomyoctes. METHODS: Human iPS derived cardiomyoctes were cultured for 20 days (control group), cryopreserved by supercooling macine for 1 week, and rapidly thawed and cultured for 20 days. Proliferation was compared among control and cryopreserved human iPS derived cardiomyoctes by constructing growth curves. Growth factors, cytokines, biochemical features, and cell cycle phase were measured immediately before and after cryopreservation by supercooling, and immunogenicity was evaluated from growth curves generated from human iPS derived cardiomyoctes after 7 days in mixed-lymphocyte culture. Control or cryopreserved human iPS derived cardiomyoctes were transplanted into pig connective tissues and evaluated histologically 2 weeks later. RESULTS: Cryopreserved human iPS derived cardiomyoctes proliferated more effectively than control cells (P&lt;0.001). Levels of basic fibroblast growth factor and transforming growth factor-β1 were significantly higher (P&lt;0.001), and those of interleukin (IL)-6 and IL-8 were significantly lower after cryopreservation (P&lt;0.001). Fewer peripheral blood lymphocytes were produced in cryopreserved cells than in noncryopreserved cells (P=0.01), and the cell cycle phase of cryopreserved human iPS derived cardiomyoctes shifted primarily to G2 + M from G1 + G0. Noncryopreserved and cryopreserved human iPS derived cardiomyoctes both survived in connective tissue. CONCLUSION: The stress by supercooling can increase the proliferation of human iPS derived cardiomyoctes and also reduce the immunogenicity of the human heart cells.