tbuckley/cabot-search huggingface dataset:
Abstract 13243: Oxidative Stress From Upregulation of Cardiac β3-AR-Activated iNOS Uncoupling Promotes Diabetic Cardiomyopathy in Cynomolgous Monkeys With Naturally-Occurring Type 2 Diabetes
Authors: Heng-Jie Cheng, Qun Shao, Li Zhang, Janice D Wagner, Che Ping Cheng
Journal: Circulation (2013)

Background:  Recent evidence highlights oxidative stress as an important mechanism to cardiac dysfunction in diabetic cardiomyopathy (DM) and altered β 3 -adrenergic receptor (AR)-activated nitric oxide synthase (NOS) pathway contributing to this process. However, the NOS isoforms involved are controversial. The mechanism of how β 3 -AR stimulation impacts ROS, SERCA2a, and cardiac function in diabetes is unclear. We tested the hypothesis that oxidant stress from upregulation of LV β 3 -AR-activated iNOS uncoupling promotes DM.   Methods:  We compared myocyte β 1 - and β 3 -AR, 3 NOS, peroxynitrite (NT), NADPH and SERCA2a expressions and myocyte functional responses to β- and β 3 -AR stimulation with isoproterenol (ISO,10 -8 M) and BRL-37344 (BRL,10 -8  M), respectively, in the absence and presence of iNOS inhibitor, 1400W (10 -5  M), of 10 male monkeys: 5 normal and 5 with naturally-occurring type 2 diabetes. Myocytes were freshly isolated from LV tissue collected during terminal study.   Results:  Compared to normal myocytes, DM myocytes had significantly increased protein levels of β 3 -AR (0.27 vs 0.15) and iNOS (0.46 vs 0.23) accompanied with increased oxidative stress indicated by significantly-elevated NT formation, NADPH (P67 -phox , 33% and p22 -phox , 25%) and decreased GTPCH expression (0.48 vs 0.82) and activity. DM myocytes had significantly-decreased protein levels of β 1 -AR (0.38 vs 0.59) and SERCA2a (0.95 vs 1.15). These changes were associated with reduced basal cell contraction of dL/dt max  (68.4 vs 121.1 μm/s), relaxation (-63.4 vs -110.2 μm/s), and [Ca 2+ ] iT  (0.15 vs 0.27) accompanied by diminished β-AR-stimulated positive inotropic response, but enhanced β 3 -AR-induced negative inotropic response. Only in DM myocytes, pretreatment with 1400W improved basal cell function and augmented ISO-increased dL/dt max  (63.2%) and [Ca 2+ ] iT  (27.8%), but significantly limited BRL-induced decrease in dL/dt max  (-13.8%) and [Ca 2+ ] iT  (-10.9%).   Conclusions:  DM is associated with contrasting changes on myocyte β 1 - and β 3 -AR expression with decreased SERCA2a and increased iNOS. Upregulation of β 3 -AR triggers iNOS uncoupling, leading to oxidative stress, thus promoting intrinsic myocyte dysfunction with impaired [Ca 2+ ] i  regulation and reduced β-AR reserve.
Long-term results of stage III and IV ovarian carcinoma treatment
Authors: C. Brinkmann, J. Hense, S. Seeber
Journal: Journal of Clinical Oncology (2005)

5171 Background: Cisplatin or Carboplatin with or without taxanes represent todays’s standard firstline treatment of advanced ovarian cancer, whereas therapy guidelines for third line chemotherapy in case of relapse of disease are much more inconsistent. Methods: 77 consecutive patients (median age 55 (21–72) years) treated for advanced ovarian cancer (stage III and IV) at the West German Cancer Centre between 01/92 and 11/04 by one physician were retrospectively analysed for epidemiological data, treatment modalities as well as treatment outcome. Results: 88.3% of the ovarian cancers were epithelial tumors of histological grade 2 (38.6%) or grade 3 (47.4%). The mainstay of systemic treatment consisted of cisplatin, taxanes, oxazaphosphorines, camphtotecines, epipodophyllotoxines, anthracyclines, gemcitabine and 5-FU and response was closely monitored by CA12–5. Whenever feasible repeated surgical procedures were aggressively pursued and intraperitoneal chemotherapy as well as radiation therapy to the abdomen were considered as treatment options in selected cases. The median overall survival of the entire cohort was 55 months with a median number of 6 (1–29) lines of chemotherapy (median 3 mono- and 3 polychemotherapies) administered. The 64 patients (83.1%) with stage III had a median overall survival of 63 months, whereas the 13 patients (16.9%) with stage IV of 52 months. With regard to intial debulking prior to chemotherapy patients after optimal debulking (64.9%) had a better median overall survival (65 months) than patients after suboptimal debulking (46 months). A further difference of median overall survival could be found for patients with early (39.7%; 33 months) and late recurrence (cutoff: 1 year) of disease (60.3%; 65 months). Conclusions: The use of multiple lines of chemotherapy and repeated surgical procedures is feasible and leads to prolongend survival rates in this cohort of patients. No significant financial relationships to disclose.
Abstract 17772: Lack of 2-adrenoceptors Accelerates Skeletal Muscle Atrophy in Myocardial Infarcted Mice: Role of Ubiquitin-Proteasome System and Akt/mTOR Pathway
Authors: Vanessa A Voltarelli, Luiz Roberto G Bechara, Katt C Mattos, Aline V Bacurau, Paulo M Dourado, Dulce E Casarini, Patricia C Brum
Journal: Circulation (2012)

Although heart failure (HF) is a syndrome of cardiac origin, it promotes changes in other tissues, such as skeletal muscle, where modifications of muscle phenotype and the loss of skeletal muscle m...
Changes in sexual functioning after germ cell tumor (GCT) therapy estimated by patients and their partners
Authors: M. Hentrich, S. Meiler, M. Fegg, A. Gerl
Journal: Journal of Clinical Oncology (2008)

5086 Background: Only few studies have addressed sexual difficulties and sexual satisfactions as an area of subjective quality- of-life in long-term survivors of GCT. We investigated the sexual functioning and sexual well-being in patients (pts) and their partners after GCT therapy. Methods: 474 pts treated for GCT between 1979 and 2000 were asked to complete a self-report questionnaire on psychosocial dimensions such as sexual functioning and partnership. Female partners were asked to complete a part of the questionnaire. Results: A completed questionnaire was returned by 341 of 474 pts (71.9%) and by 196 female partners of the responding pts (57.5%). The median age of the pts was 41.9 years at the time of the study and 31.2 years at the time of GCT diagnosis (median follow-up 9.6 yrs). Of 327 pts who provided information on their marital status 203 (62%) were married/lived in a partnership, 101 (31%) were single and 24 (7%) divorced. 81 pts (25%) complained of decreased sexual attractivity which was more frequently reported in pts divorced (42%) than in singles (30%) or married pts (19%). Libido loss, arousal loss, decreased erection, decreased ejaculation and decreased orgasm intensity were reported by 66 (19%), 73 (21%), 70 (21%), 110 (32%) and 70 (21%) pts, respectively. All of these complaints more frequently occurred in pts ≥40 yrs at time of the study compared to age <40 (p<0.001). Of responding couples more males than females reported to be sexually unsatisfied (32% vs 23%) after GCT therapy. Sexual satisfaction decreased with the duration of the partnership in females (p=0.005) but not in males (p=0.5). More pts than female partners reported fear of sexually dissatisfying the partner before (10% vs 4%) and after GCT therapy (24% vs 7%). More females (22%) than pts (14%) reported a positive influence of the disease on their partnership with a significant difference observed in partnerships of <1 year duration (67% vs 32%, p=0.007). Conclusions: About 20% of pts are limited in sexual functioning after GCT therapy. Overall, more female partners than pts have a favorable perception of the influence of the disease on the partnership. No significant financial relationships to disclose.
Abstract P004: Association of C-Reactive Protein with Incident Coronary Events in Blacks and Whites: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Neil A Zakai, Mary Cushman, Leslie A McClure, Todd M Brown, Stephen P Glasser, James M Shikany, Monika M Safford
Journal: Circulation (2012)

Background: Elevated C-reactive protein (CRP) is associated with coronary heart disease (CHD) risk independent of traditional CHD risk factors. Few studies include many non-white participants despite known racial differences in CRP. We assessed whether there were racial differences in the association between CRP and incident CHD in a large cohort of AA and white Americans. Methods: 30,239 AAs and whites were enrolled and examined in their homes across the US from 2003-07. CHD, defined as myocardial infarction or acute CHD death, was captured by participant report and physician medical record review. We used Cox models in those free of CHD at baseline to assess the association of CRP with incident CHD. Results: Over a median 3.7 years follow-up (maximum 5.9 years), 505 CHD events occurred in 24,297 individuals without baseline CHD (223 in 10,337 AA). AA had higher levels of many traditional CHD risk factors, including hypertension (69% vs 47%), diabetes (28% vs 13%), current smoking (17% vs 12%, all &lt;0.01), but higher high-density lipoprotein cholesterol (54 vs 52 mg/dL, p&lt;0.01) and similar total cholesterol (195 vs 192 mg/dL, p=0.16). Median CRP was higher in AA than whites (2.85 vs 1.82 mg/L, p&lt;0.01), with 4,615/9,558 (48%) of blacks vs. 4,548/13,217 (34%) of whites having a CRP ≥3 mg/L (p&lt;0.01) . The table presents the HR of CHD for CRP ≥3 mg/L and per 1 unit increase in log CRP stratified by race. AA did not have a higher hazard of CHD than whites in any model (data not shown). Discussion: Despite higher levels of CRP in AA, CRP was not differentially associated with CHD between AA and whites. Though the HR for CRP ≥3 mg/L appeared weaker in AA vs. whites this was not supported by a significant p-interaction. The paradox of an adverse CHD risk factor profile but similar risk of CHD was not explained by differential associations of CRP with CHD in AA vs. whites. Further analyses of fatal and non-fatal MI as well as the performance of traditional and non traditional CHD risk factors in AA vs. whites are warranted. Table Association of CRP with Incident CHD in African-Americans and Whites All HR (95% CI) Blacks HR (95% CI) Whites HR (95% CI) P-interaction between race and CRP CRP ≥3 mg/L Model 1 1.63 (1.35, 1.96) 1.46 (1.11, 1.93) 1.75 (1.37, 2.24) 0.57 Model 2 1.37 (1.14, 1.66) 1.26 (0.95, 1.67) 1.46 (1.13, 1.88) 0.52 Model 3 1.33 (1.10, 1.61) 1.20 (0.90, 1.61) 1.41 (1.10, 1.82) 0.58 Per 1 unit increase in log CRP Model 1 1.32 (1.22, 1.43) 1.29 (1.15, 1.45) 1.34 (1.20, 1.49) 0.95 Model 2 1.23 (1.13, 1.33) 1.23 (1.09, 1.39) 1.22 (1.09, 1.36) 0.81 Model 3 1.21 (1.12, 1.31) 1.21 (1.07, 1.37) 1.20 (1.07, 1.34) 0.73 Model 1: Age, Sex, and Region Model 2: Model 1 + Hypertension, Diabetes, Smoking, Total Cholesterol, HDL Cholesterol, Taking Dyslipidemia Meds Model 3: Model 2 + Income, Education
Phase I Clinical and Pharmacogenetic Study of Weekly TAS-103 in Patients With Advanced Cancer
Authors: Reginald B. Ewesuedo, Lalitha Iyer, Soma Das, Annette Koenig, Sridhar Mani, Nicholas J. Vogelzang, Richard L. Schilsky, Wayne Brenckman, Mark J. Ratain
Journal: Journal of Clinical Oncology (2001)

PURPOSE: TAS-103 is an inhibitor of both topoiso-merase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103. PATIENTS AND METHODS: Thirty-two patients were treated with escalating doses (50 to 200 mg/m 2 ) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m 2 dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques. RESULTS: DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m 2 and in 3 of 6 patients at 200 mg/m 2 . At 160 mg/m 2 , there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P &lt; .05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = −0.63, P &lt; .05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103. CONCLUSION: We recommend a dose of 130 to 160 mg/m 2 , or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted.
Abstract 17439: Prognostic Impact of Body Weight Change in Patients With Chronic Heart Failure: Data From Gissi-Hf Trial
Authors: Gianluigi Savarese, Pasquale Perrone-Filardi, Marco Scarano, Riccardo Cavazzina, Sergio Minneci, Bruno Trimarco, Aldo Pietro Maggioni, Luigi Tavazzi, Gianni Tognoni, Roberto Marchioli
Journal: Circulation (2013)
Cediranib targeting of circulating VEGFR-1+ monocyte subpopulations
Authors: H. Wu, A. J. Zurita, J. Drevs, U. Zirrgiebel, J. M. Jürgensmeier, J. Robertson, T. A. Puchalski, K. S. McKee, J. V. Heymach
Journal: Journal of Clinical Oncology (2008)

14687 Background: Recent studies suggest that specific subpopulations of monocytes and myeloid progenitors, particularly those expressing VEGFR-1, play a key role in promoting tumor angiogenesis and resistance to VEGF inhibitors. We hypothesized that cediranib (AZD2171) an oral, highly potent and selective VEGF signaling inhibitor, with activity against VEGFR-1, -2 and -3, would specifically target VEGFR-expressing circulating monocytes. We investigated novel subsets of circulating monocytes and other peripheral blood mononuclear cells (PBMCs) as potential biomarkers for cediranib. Methods: In a previously reported Phase I clinical trial, patients (n=36) with advanced solid tumors were treated with cediranib 20, 30 or 45 mg on a continuous once-daily schedule (Drevs et al. J Clin Oncol 2007;25:3045). We assessed cellular populations in 34 patients (2 were considered outliers) expressing VEGFR-1, markers for monocytes (CD14), progenitor cells (CD34) and proangiogenic subpopulations (Tie-2) by 8-color flow cytometry at baseline and day 28. Viable PBMCs were identified using the nuclear stain Syto16. Results: There was no evidence of significant changes in total white blood cell, monocyte or lymphocyte counts as assessed by routine hematological sampling. Of any subpopulation VEGFR-1+ cells demonstrated the largest dose-dependent decreases (to 63% of baseline value at day 28 [BLV28] overall [P=0.033]; 105%, 20 mg; 71%, 30 mg; 53%, 45 mg); VEGFR-1− cells demonstrated no significant change, indicating that cediranib may preferentially target VEGFR-1+ PBMCs. PBMCs bearing Tie-2+ decreased to a lesser extent (to 78% of BLV28 overall; 84%, 20 mg; 83%, 30 mg, 64%, 45 mg) Analysis of multiple markers revealed decreases during treatment in Tie-2-expressing CD14+ monocytes (to 75% of BLV28 overall; 81% 20 mg; 80%, 30 mg; 61%, 45 mg), and CD14+ VEGFR-1+ monocytes (to 80% BLV28 overall; 97%, 20 mg; 79%, 30 mg; 68%, 45 mg), while CD34+ stem cells increased slightly. Conclusions: These results suggest that VEGFR-1+ PBMCs may be novel biomarkers for cediranib activity. Furthermore, reductions in subpopulations of proangiogenic monocytic cells during treatment could potentially contribute to the antitumor activity of cediranib. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology AstraZeneca Oncology
Randomized Phase III trial: Topotecan vs. topotecan/etoposide vs topotecan/gemcitabine as second-line treatment for patients with relapsed ovarian cancer
Authors: G. Oskay-Özcelik, J. Sehouli, H. Sommer, P. Klare, M. Stauch, A. Zeimet, A. Paulenz, K. Renziehausen, E. Keil, W. Lichtenegger
Journal: Journal of Clinical Oncology (2004)

5139 Background: Topotecan (Hycamtin), a topoisomerase-I-inhibitor is established in the therapy of relapsed OC. Ganem et al (ASCO 1998, abstr.1371) reported good tolerability and a remission rate of 22% for a topotecan/etoposide (T/E) combination in 80 heavily pretreated patients (pts). Gemcitabine has also demonstrated activity in resistant OC. In our recent published study (Ann Onc 2003) we describe a highly active combination of topotecan/gemcitabine (T/G) with a median TTP of 9.8 months for relapsed OC pts. Based on promising phase II results, a phase III study has been conducted to compare topotecan monotherapy (T) with T/E and T/G. The primary endpoint is median survival. Safety results from the planned interim analysis are reported for the first time. Methods: Pts with relapsed ovarian cancer after primary therapy have been stratified according to treatment-free interval of less or more than 12 months respectively. Arm A consisted of T 1.25mg/m2/d, d1–5; arm B of T 1.0mg/m2/d, d1–5 and E 50mg/d oral, d6–12; and arm C of T 0.5mg/m2/d, d1–5 and G 800mg/m2 d1 and 600mg/m2 d8. Results: In December 2003 435 pts were randomized. Safety data for 374 pts (mean age 60.5 years, ECOG 0–2, relapse <12 mo 219 pts and >12 mo 152 pts) with 143/142/89 pts in arm A/B/C respectively are available. According to study design pts were randomized to arms A or B. After recruiting 139 pts, arm C opened and randomization continued in the relation 1:1:2. Pts received a median of 6 cycles in arm A and B and 4 in arm C. Grade 4 events per pt are 0.21% (99% CI: 0.54–1.32) in arm A, 0.34% (99% CI: 0.17–0.5) in arm B and 0.29% (99% CI: 0.09–0.49)in arm C; p=.31. Main tox was leukopenia and thrombopenia. Leukopenia seems to be slightly higher in arm B but was below 1% of all events. Nonhematologic tox included nausea, emesis, diarrhea and alopecia were seldom and in the treatment arms similar. Conclusions: The three treatment arms are safe and well tolerated. Recruitment is ongoing until the target of 133 evaluable pts has been achieved for each arm. We expect close of recruitment by ASCO 2004. No significant financial relationships to disclose.
Abstract 15452: Usefulness of Combination of FDG-PET and Speckle-Tracking Echocardiography to Predict Steroid Responders in Cardiac Sarcoidosis
Authors: Makoto Orii, Kumiko Hirata, Ikuko Teraguchi, Yasutsugu Shiono, Kunihiro Shimamura, Takashi Yamano, Takashi Tanimoto, Yasushi Ino, Tomoyuki Yamaguchi, Takashi Kubo, Toshio Imanishi, Takashi Akasaka
Journal: Circulation (2013)

Background:  We hypothesized that preserved contractility as well as inflammation would be needed for achievement wall motion recovery after steroid therapy in patients with cardiac sarcoidosis (CS).   Purpose:  To assess whether fluorodeoxyglucose (FDG)-PET and two-dimensional speckle-tracking echocardiography (2DSTE) can predict the steroid responder in CS patients.   Methods:  Fourteen CS patients who were diagnosed by consensus criteria of CS were studied. FDG-PET and comprehensive echocardiography were performed before steroid therapy, and consecutively peak circumferential, longitudinal and radial strains were assessed by 2DSTE software in LV 16-segment model. A segment was considered to demonstrate functional improvement after steroid therapy if it improved at least 1 grade in wall motion score.   Results:  Out of 93 segments with impaired wall motion, 29 segments showed regional recovery after steroid therapy. In segments with functional recovery, focal FDG uptake was observed in 27 of 29 segments, while it was observed in 40 of 64 segments of segments without functional recovery (p = 0.002). Compared with segments showing functional improvement, those that failed to recover had lower peak radial (16 ± 11 % vs. 24 ± 12 %; p = 0.004), circumferential (-10 ± 6 % vs. -18 ± 5 %; p    Conclusions:  Combination of FDG-PET and 2DSTE can be useful to predict the reversible myocardial segments after steroid therapy in CS.
L-type Ca<sub>v</sub>1.3 channels regulate ryanodine receptor-dependent Ca<sup>2+</sup>release during sino-atrial node pacemaker activity
Authors: Angelo Giovanni Torrente, Pietro Mesirca, Patricia Neco, Riccardo Rizzetto, Stefan Dubel, Christian Barrere, Martina Sinegger-Brauns, Joerg Striessnig, Sylvain Richard, Joël Nargeot, Ana Maria Gomez, Matteo Elia Mangoni
Journal: Cardiovascular Research (2016)

Sino-atrial node (SAN) automaticity is an essential mechanism of heart rate generation that is still not completely understood. Recent studies highlighted the importance of intracellular Ca2+ ([Ca2+]i) dynamics during SAN pacemaker activity. Nevertheless, the functional role of voltage-dependent L-type Ca2+ channels in controlling SAN [Ca2+]i release is largely unexplored. Since Cav1.3 is the predominant L-type Ca2+ channel isoform in SAN cells, we studied [Ca2+]i dynamics in isolated cells and ex vivo SAN preparations explanted from wild-type (WT) and Cav1.3 knockout (KO) mice (Cav1.3−/−). We found that Cav1.3 deficiency strongly impaired [Ca2+]i dynamics, reducing the frequency of local [Ca2+]i release events and preventing their synchronization. This impairment inhibited the generation of Ca2+ transients and delayed spontaneous activity. We also used action potentials recorded in WT SAN cells as voltage-clamp commands for Cav1.3−/− cells. Although these experiments showed abolished Ca2+ entry through L-type Ca2+ channels in the diastolic depolarization range of KO SAN cells, their sarcoplasmic reticulum Ca2+ load remained normal. β-Adrenergic stimulation enhanced pacemaking of both genotypes, though, Cav1.3−/− SAN cells remained slower than WT. Conversely, we rescued pacemaker activity in Cav1.3−/− SAN cells and intact tissues through caffeine-mediated stimulation of Ca2+-induced Ca2+ release. Cav1.3 channels play a critical role in the regulation of [Ca2+]i dynamics, providing an unanticipated mechanism for triggering local [Ca2+]i releases and thereby controlling pacemaker activity. Our study also provides an additional pathophysiological mechanism for congenital SAN dysfunction and heart block linked to Cav1.3 loss of function in humans.