tbuckley/cabot-search huggingface dataset:
Abstract 3768: Targeting of epithelial-to-mesenchyme transition by a novel small molecule inhibitor attenuates prostate and breast cancer invasiveness and bone metastases
Authors: Jan Kroon, Onno van Hooij, Eugenio Zoni, Maaike van der Mark, Geertje van der Horst, Johan Tijhuis, Cindy van Rijt-van de Westerlo, Gerald Verhaegh, Henk Viëtor, Antoine Wellink, Peter Maas, Jack Schalken, Gabri van der Pluijm
Journal: Cancer Research (2016)

Abstract Transformed epithelial cells can activate embryonic programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype also referred to as epithelial-to-mesenchymal transition (EMT). EMT is associated with poor prognosis in patients with osteotropic cancers. E-cadherin (CDH1) is an essential homotypic cell adhesion molecule that is often down regulated during this process. EMT-like processes are increasingly linked to therapy resistance and metastasis-initiating cells, thus providing the rationale for the development of novel small-molecule inhibitors that a) block the acquisition of an invasive phenotype in osteotropic cancer cells via EMT or b) revert their invasive, mesenchymal phenotype into epithelial phenotype (MET) by upregulation of CDH1 expression. High throughput screening of &amp;gt;43,000 LMW compounds, followed by compound design &amp; optimization in vitro led to the identification ten candidate therapeutic compounds. These compounds displayed significant inhibitory effects on cancer cell invasion (&amp;gt;80%) and induced E-cadherin (re)expression, most likely through interference with the binding of transcriptional repressors to the CDH1 E-box elements. We identified a unique compound, OCD155, can effectively and dose-dependently block the acquisition of an invasive phenotype in osteotropic prostate and breast cancer cells (PC-3M-Pro4luc2 and MDA-MB-231/Bluc). When tested in our in vivo models of prostate and breast cancer bone metastasis, treatment of mice with OCD155 strongly and dose-dependently inhibited skeletal metastasis (number of metastases, tumor burden) according to preventive and curative protocols. At the dosages tested, no adverse effects of OCD155 were observed (body weight, liver toxicity parameters). To the best of our knowledge, our studies are the first to demonstrate the efficacy of new small molecule EMT inhibitor in the treatment of experimental skeletal metastasis. Citation Format: Jan Kroon, Onno van Hooij, Eugenio Zoni, Maaike van der Mark, Geertje van der Horst, Johan Tijhuis, Cindy van Rijt-van de Westerlo, Gerald Verhaegh, Henk Viëtor, Antoine Wellink, Peter Maas, Jack Schalken, Gabri van der Pluijm. Targeting of epithelial-to-mesenchyme transition by a novel small molecule inhibitor attenuates prostate and breast cancer invasiveness and bone metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3768.
Analysis of gene expression pathways associated with prostate carcinogenesis after short term testosterone replacement in hypogonadal men
Authors: Elahe A. Mostaghel, Leonard S. Marks, Ilsa M. Coleman, David Hess, Ruth F. Dumpit, Peter S. Nelson
Journal: Cancer Research (2006)

424   Introduction: Despite the increasing popularity of testosterone (T) replacement therapy, there are concerns regarding the potential adverse effects of exogenous T administration on prostatic growth and carcinogenesis. While studies of T supplementation have utilized  macroscopic  indicators of prostatic effect (such as alterations in prostate volume and serum PSA level),  no study has evaluated the effect of androgen replacement on prostatic tissue at the molecular level . We prospectively evaluated whether short term T supplementation of hypogonadal men would alter the expression of genes important in prostate cancer development and progression. Methods: 44 men, ages 50-75, with hypogonadal T levels (T nd  biopsy. Prostate epithelial cells were micro-dissected from pre- and post-treatment samples, followed by RNA isolation, amplification and hybridization of labeled cDNA to a prostate-specific custom cDNA microarray. Expression data were normalized and subject to an unpaired two sample t-test. Results: Despite normalization of serum T levels, global expression profiling did not demonstrate any statistically significant changes in prostate epithelial gene expression in T-treated patients. While median tissue androgen levels did not change in the T-treated group, a subset of patients did have substantial increases in prostate androgen levels compared to baseline. Remarkably, this was not associated with any statistically significant changes in global or androgen-regulated gene expression. Validation of microarray findings by quantitative RT-PCR demonstrated no significant change in the expression of known androgen-regulated genes (including PSA, AR, NKX3.1, PAP2A), or in gene pathways related to cell survival, apoptosis, differentiation or angiogenesis (including clusterin, bcl-2, NDRG1 and VEGF). Conclusions: Normalization of serum androgen levels does not appear to alter prostate gene expression in hypogonadal men treated with short term T replacement. Despite a range of androgen levels, the prostate appears able to buffer intracellular androgens to maintain biological effects within physiological boundaries. Replacement of T to a physiologic range that positively impacts target organs such as bone and muscle, but avoids potential adverse effects such as prostatic growth and carcinogenesis appears feasible. Our study provides molecular evidence that prostatic growth and differentiation pathways implicated in carcinogenesis are not adversely affected by short term T replacement, and awaits confirmation in larger RCT9s of longer duration.
Abstract 17528: Delayed Rocovery in Peripartum Cardiomyopathy: An Indication for Long-Term Follow-Up and Sustained Therapy
Authors: Murat Biteker, Erkan İlhan, Dursun Duman, Mehmet M Can, Ahmet Tekkeşin
Journal: Circulation (2011)

Background: Persistence of left ventricle systolic dysfunction after 6 months of diagnosis is believed to be a marker of an irreversible cardiomyopathy and worse survival in peripartum cardiomyopathy (PPCM). We sought to determine the length of time required for recovery of left ventricle systolic function (LVSF) in patients with PPCM. Methods: Forty-two consecutive women with PPCM treated at two tertiary hospitals in Turkey were enrolled in this prospective study over a 5-year period. The minimum required time of follow-up for inclusion was 30 months (range 30-65 months). Clinical evaluation, B-type natriuretic peptide (BNP) and C-reactive protein (CRP) concentrations, and transthoracic echocardiography were evaluated at baseline, every 3 months during the first year, and every 6 months thereafter. Rapid recovery is defined as resolution of heart failure symptoms or signs and normalization of LVSF at 6 months post-diagnosis. Delayed recovery is defined if the length of time required for recovery of LVSF was longer than 6 months. Persistent left ventricular dysfunction (PLVD) is defined as an ejection fraction of less than 50 % at the end of follow-up. Results: Twenty patients (47.6%) recovered completely, 10 died (23.8%), and 12 (28.6%) were left with PLVD. Average time to complete recovery was 19.3 months after initial diagnosis (3-42 months). Rapid recovery is observed only in 6 patients (30%) whereas delayed recovery is observed in 14 out of 20 patients (%70) (Figure). Persistent elevation of plasma BNP and CRP above the cut-off values at 3th month is predictive of delayed recovery. Conclusions: Full recovery of LVSF in PPCM patients often requires longer than 6 months. Persistent elevation of plasma CRP and BNP above the cut-off values portends a slower response.
The medical basis of psychiatry
Authors: A M Ludwig, K Othmer
Journal: American Journal of Psychiatry (1977)

The authors state that the medical model represents the most useful and appropriate model available for the practice of psychiatry. They discuss the implications for psychiatry of the three essential features of the medical model: the concept of disease and diagnosis, the concept of etiology and treatment, and the nature of the doctor-patient relationship. They conclude that the adoption of the medical model for psychiatry would have profound implications for residency training, continuing education, delivery of care, standards of ethical and professional practice, dealings with third-party payers, and conflicts with other professions.
In situ facile-forming PEG cross-linked albumin hydrogels loaded with an apoptotic TRAIL protein
Authors: Insoo Kim, Ji Su Choi, Seunghyun Lee, Hyeong Jun Byeon, Eun Seong Lee, Beom Soo Shin, Han-Gon Choi, Kang Choon Lee, Yu Seok Youn
Journal: Journal of Controlled Release (2015)
Proposals do not refer to need for consultant provided service
Authors: J. G Temple
Journal: BMJ (1995)

are shorter and of a finite duration.Our qualifications, both public and private, were that a large increase in the number of consultants was needed, which would require greatly increased resources, and that the scheme should be introduced gradually over 10 years.Fourthly, many of the questions posed in table I of the paper are only tangentially relevant to the
Abstract 40: Is Severe Post-shock Bradyarrhythmia In Patients Using Wearable Defibrillators Common or Serious?
Authors: Gary Freeman, Weilun Quan, Steven Szymkiewicz, Graham Nichol
Journal: Circulation (2007)

Background : Previous studies have shown a 40% to 60% incidence of asystole immediately after transthoracic defibrillation of pulseless ventricular tachycardia/ventricular fibrillation (VT/VF). Such post-shock asystole has very poor outcomes. Wearable cardioverter defibrillators (WCD, LifeVest, ZOLL Lifecor) automatically record and treat VT/VF by delivering transthoracic defibrillation without the need for a bystander. Post-shock bradyarrhythmia (PSB) is of clinical concern in patients (pts) using WCD. Objective : Determine the incidence and outcomes of PSB during WCD use. Methods : ECG recordings from consecutive pts who had VT/VF while using WCD between March 2005 and March 2007 were retrospectively analyzed. All VT/VF occurring within 24 hours from the initial shock for VT/VF were defined as a single sudden death event (SDE) while those beyond 24 hours as a SDE recurrence. ECGs contained 30 seconds prior to the VT/VF detection and &gt; 15 seconds following VT/VF termination. Severe PSB was defined as a pause longer than 10 seconds. Survival was defined as conscious at emergency department (ED) arrival or not needing to go to the ED. Pt calls and medical orders were reviewed to determine the indications for WCD use and pt post-shock status. Results : Between March 2005 and March 2007, 3564 pts used WCD for an average of 51 days. 56 pts (51% ICD explants, 28% ischemic cardiomyopathy (ICM), 11% Non-ICM, 8% delayed ICD implant, 2% others) received 142 shocks for 79 SDE. 14 pts had &gt; 1 SDE (max = 5). 15 SDE had &gt;1 VT/VF (max = 47). 79/79 (100%) initial SDE shocks terminated VT/VF. 76/79 (96%) of treated SDE resulted in survival. Severe PSB was found in 4 ECGs from 4 pts. 3/4 (75%) occurred after the initial SDE shock, 1/4 (25%) after VT/VF recurrence; 2/4 (50%) developed ventricular complexes prior to the end of the recording, 2/4 (50%) did not; 3/4 (75%) pts survived, 1/4 (25%) did not. Median time from VT/VF onset to shock was 44 seconds. Conclusions : WCD is an efficacious therapy. The majority of pts with severe PSB after WCD survived. Severe PSB was less frequent and had a better prognosis than that observed in EMS studies. This may be attributed to faster WCD shock therapy (median 44 seconds) compared with EMS (&gt;10 minutes).
Abstract 17003: Post-Operative Expansion of the Red Cell Distribution Width Powerfully Predicts Poor Outcomes After Aortic Valve Surgery
Authors: Alistair Connell, Suneil Aggarwal, Francesco Papalia, Julia Flint, Susanne Weissert, Nay Aung, Toby Richards, Darlington O Okonko
Journal: Circulation (2011)

Red cell distribution width (RDW), an index of the variation in red cell volume, is a surrogate of many aberrations (iron deficiency, inflammation, malnutrition and oxidative stress) that could impair early and late outcomes after aortic valve replacement (AVR). Whilst an increase In RDW powerfully predicts morbidity and mortality in heart failure and PCI patients, its prognostic relevance in AVR cohorts is unknown. Methods: We analysed the relation of changes in RDW over time to outcomes in 1177 AVR patients (mean [±SD] age 68±13 years, RDW 14.1±1.6%, hemoglobin 12.9±1.8g/dL, EuroSCORE 6±3, 63% male, 24% with ejection fractions [EF]&lt;50%, 60% aortic stenosis, 17% aortic regurgitation, 17% mixed aortic disease). Results: Pre-operatively, 19% of patients had an RDW≥15%. This group were more likely to be female (43% vs 36%), non-elective cases (47% vs 26%) with poorer LVEFs (35% vs 21% with LVEF&lt;50%), have greater congestive symptoms (17 vs 7), and spend more days ventilated (1.7 vs 1.2) and hospitalized (17 vs 14) (all P&lt;0.05). Over a median (±IQR) stay of 8±5 days, 906 (77%) patients had an increase in RDW and 39 (3.3%) died in hospital. Early mortality was related to an increase in RDW over time (HR 1.4, CI:1.2-1.5, P1.6% optimally predicting death (HR 4.0, CI:2.0-8.0, P&lt;0.0001, Figure A ). This was independent of age, LVEF, EuroSCORE, Parsonnet score, hemoglobin and creatinine. Of the 1138 patients who survived to discharge, 88(8%) died over a median follow-up of 4 years. Late mortality was also related to a rise in RDW (HR 1.3, CI: 1.2-1.4, P0.9% optimally predicting death (HR 3, CI:2-5, P&lt;0.0001, Figure B ), independently of all covariates. Conclusions: An Increase in the RDW post-AVR is associated with an amplified risk of early and late surgical mortality. Understanding and ameliorating the drivers of RDW expansion in this cohort may increment survival.
The Metabolic Syndrome Is a Risk Indicator of Microvascular and Macrovascular Complications in Diabetes
Journal: Diabetes Care (2006)

We aimed at assessing the degree of association and the predictive power of the metabolic syndrome with regard to clinically detectable complications in patients with diabetes.Metascreen is a cross-sectional survey of metabolic syndrome and clinically detected diabetes complications performed in 8,497 patients (7,859 with type 2 diabetes and 638 with type 1 diabetes) randomly chosen in 176 diabetes outpatient clinics throughout Italy. The metabolic syndrome was defined according to either the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) or the International Diabetes Federation (IDF) diagnostic criteria. Multivariate analyses of the association(s) between either AHA/NHLBI or IDF metabolic syndrome and clinical complications were performed. Receiver-operator characteristic (ROC) curves were constructed to compare the predictive power of the two sets of diagnostic criteria of the metabolic syndrome.Either definition of the metabolic syndrome was an independent statistical indicator of the presence of nephropathy and neuropathy (P < 0.02-0.01) in type 1 diabetes and of all complications (P < 0.0001), including cardiovascular disease and retinopathy, in type 2 diabetes. For each complication, the ROC curves based on either AHA/NHLBI or IDF metabolic syndrome were similar to each other and to the ROC curves constructed with all continuous traits compounding the metabolic syndrome.The metabolic syndrome, defined according to AHA/NHLBI or IDF diagnostic criteria, is an independent clinical indicator and may be involved in the pathogenesis of both macro- and microvascular complications of diabetes.
Abstract 246: Incidence and Outcomes of Rearrest Following Out-of-Hospital Cardiac Arrest
Authors: David D Salcido, Matthew L Sundermann, Allison C Koller, James J Menegazzi
Journal: Circulation (2013)

Background: Rearrest (RA) occurs when a patient experiences cardiac arrest after successfully achieving return of spontaneous circulation (ROSC). The incidence and outcomes of RA following out-of-hospital cardiac arrest (OHCA) have been estimated in limited local studies. We sought to investigate the incidence and outcomes of RA over a broad geographic area. Methods: This retrospective study was approved by the University of Pittsburgh Institutional Review Board. We obtained case data from EMS-treated, non-traumatic OHCA from the Resuscitation Outcomes Consortium, a multi-site clinical research network conducting population level surveillance of OHCA in 11 cities in the US and Canada. The study cohort comprised all OHCA cases surveilled between 2006 and 2008 at ROC sites and having prehospital ROSC. We used three methods to ascertain RA incidence among these cases: direct signal analysis, indirect cardiopulmonary resuscitation (CPR) process analysis, and emergency department arrival vital status. RA incidence was estimated as the proportion of cases with ROSC that experience RA. Regional RA estimates were compared with the Chi-Squared test. Multivariable logistic regression was used to assess the relationship between RA and survival to hospital discharge. Results: Out of 18,937 cases of EMS-assessed OHCA captured between 2006 and 2008, 11,456 (60.5%) cases were treated by EMS and 4,396 (38.4%) had prehospital ROSC. Of these, sufficient data were available for RA ascertainment in 3,253 cases, with 568 (17.5%) experiencing RA. Regional RA incidence varied significantly from 10.2% to 21.2% (p &lt; 0.001). RA was significantly inversely associated with survival (OR: 0.19, 95%CI: 0.14 - 0.26). Conclusions: In this geographically broad and inferentially conservative analysis, RA occurred on average in 1 of every 6 successfully resuscitated patients, though incidence varied significantly across 10 sites in North America. RA was found to be inversely associated with survival to hospital discharge.
Prolonged Survival and Improved Response Rates With ARRY-520 In Relapsed/Refractory Multiple Myeloma (RRMM) Patients With Low α-1 Acid Glycoprotein (AAG) Levels: Results From a Phase 2 Study
Authors: Sagar Lonial, Jatin J. Shah, Jeffrey Zonder, William I. Bensinger, Adam D. Cohen, Jonathan L. Kaufman, Ajay K. Nooka, Donna M. Weber, Brandi Hilder, Selena A Rush, Ann Ptaszynski, Duncan Walker, Robert Z. Orlowski
Journal: Blood (2013)
Abstract 9375: Sum Absolute QRST Integral Predicts Low Risk of Ventricular Tachyarrhythmias and Sudden Cardiac Death In MADIT II Study
Authors: Larisa G Tereshchenko, Scott McNitt, Lichy Han, Wojciech Zareba
Journal: Circulation (2011)

Introduction. The need to extend risk stratification beyond use of ejection fraction is well recognized. New ECG risk marker, sum absolute QRST integral (SAI QRST) was recently proposed and was shown to be associated with low risk of sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) in patients with structural heart disease and primary prevention implantable cardioverter-defibrillators (ICDs). The objective of this study was to validate predictive value of SAI QRST in analysis of landmark ICD trial MADIT II. Methods. Baseline orthogonal ECGs were recorded at rest during sinus rhythm in 750 MADIT II study participants and analyzed by customized Matlab software. Absolute QRST integral was measured as the arithmetic sum of areas under the QRST curve, averaged during a 5-minute epoch. Then the sum magnitude of three orthogonal leads absolute QRST integral (SAI QRST) was calculated. Primary end-point for analysis was sustained VT/VF with appropriate ICD therapies (shock or antitachycardia pacing), or sudden cardiac death. Results. During 3.5 years of follow-up, 143 patients experienced sustained VT/VF with appropriate ICD therapies, or died suddenly. In univariate analysis lowest quartile of SAI QRST (&lt; 116 mV*ms) was associated with decreased risk of sustained VT/VF with appropriate ICD therapies or sudden cardiac death (Figure 1). In multivariate analysis after adjustment for blood urea nitrogen and New York Heart Association functional class, low quartile SAI QRST was associated with decreased risk of VT/VF or sudden cardiac death as compared to three higher SAI QRST quartiles (Hazard Ratio 0.64 ; 95% CI 0.42 - 0.99 ; p=0.045). Conclusion . In post-myocardial infarction patients with depressed ejection fraction the lowest quartile of SAI QRST is associated with lower risk of sustained ventricular tachyarrhythmias and sudden cardiac death than it is observed in patients with higher SAI QRST values. Further study of SAI QRST is warranted.
Heterogeneity in expression of interleukin-4/13 receptors in human bladder carcinoma in situ
Authors: Bharat H. Joshi, Pamela Leland, Frederick Varricchio, Syed R. Husain, Raj K. Puri
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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Despite advances in diagnosis and treatment, bladder cancer is still one of the aggressive human cancers. To develop novel targeting approaches, we have reported that a variety of murine and human carcinoma cell lines express high levels of receptors for interleukin-4 (IL-4) and interleukin-13 (IL-13) in vitro and in vivo . We have also reported human bladder carcinoma cell lines express high levels of IL-4 receptors α (IL-4Rα) chain, which sensitized these cells to a chimeric protein comprised of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin [IL-4(38-37)-PE38KDEL]. Here, we report that these receptors are expressed in vivo . These conclusions were made based on the expression of IL-4 and IL-13R mRNA and protein as determined by RT-PCR and IHC analyses, respectively. Highly specific antibodies to IL-4Rα, IL-13Rα2, IL-13Rα1 and IL-2Rγc chain were used for IHC in 15 biopsy samples of bladder carcinoma and 16 normal bladder specimens. Our results indicate that 11 of 15 bladder carcinoma specimens are intensely positive (++ to +++) for IL-4Rα and 3 of 15 samples are positive (+ to ++) for IL-13Rα2 chain. In contrast, normal specimens showed weak positive expression (+/-) in 13 samples for IL-4Rα and 6 samples for IL-13Rα2 chain. The expression of IL-13Rα1 chain was ubiquitous in most cancer and normal samples studied; while IL-2Rγc chain was absent in cancer as well as normal bladder specimens. There was no correlation between receptor expression and the age of the patients or histologic sub type of the disease. Taken together, human bladder carcinoma cells over express type II IL-4R in situ more frequently than IL-13Rα2 chain compared to normal bladder and these receptors may provide targets for bladder cancer therapy.
Distinct transcriptome profiles differentiate nonsteroidal anti-inflammatory drug–dependent from nonsteroidal anti-inflammatory drug–independent food-induced anaphylaxis
Authors: Rosa Muñoz-Cano, Mariona Pascal, Joan Bartra, Cesar Picado, Antonio Valero, Do-Kyun Kim, Stephen Brooks, Michael Ombrello, Dean D. Metcalfe, Juan Rivera, Ana Olivera
Journal: Journal of Allergy and Clinical Immunology (2015)