tbuckley/cabot-search huggingface dataset:
Effect of inhibition of heat-shock protein 90 on mutant c-Kit protein as modulated by mRNA expression and protein degradation through both proteasome and autophagy-mediated pathways.
Authors: L. Chen, Y. Hsueh, N. Chiang, C. Yen, N. Shih
Journal: Journal of Clinical Oncology (2011)

54 Background: c-Kit is a known client protein of heat-shock protein 90 (Hsp90). Inhibition of Hsp90 can reduce the expression of c-Kit protein in human mastocytoma and gastrointestinal stromal tumor (GIST) cells, which is conceived through the proteasome degradation pathway. Methods: COS-1 cells transfected with vectors containing CMV promoter-driven various c-Kit mutants (imatinib- sensitive or imatinib-resistant) and human GIST882 cells (with endogenous exon 13 mutant c-Kit) were used to investigate the efficacy NVP-AUY922, a new class of Hsp90 inhibitor, on suppressing the constitutive activation of mutated c-Kit. Detail mechanisms of protein regulation, as RNA transcription, RNA stability, and protein degradation were studied. Results: NVP-AUY922 is more potent than 17-AAG to inhibit the proliferation of imatinib-sensitive GIST882 cells. Further study showed that NVP-AUY922 down-regulated both total and phosphorylated c-Kit proteins in dose- and time-dependent manners in both GIST882 cells and mutant c-Kit (including imatinib-resistant exon11/17 double mutants) expressed in COS-1 cells. Surprisingly, the NVP-AUY922-induced c-Kit degradation in both cell models could be reversed by proteasome-degradation inhibitor and autophagy inhibitor. The involvement of autophagy in NVP-AUY922-induced c-Kit protein degradation was further confirmed by co-localization of c-Kit and autophagosome by immuno-staining. In addition, NVP-AUY922 treatment resulted in a reduction of c-Kit mRNA level in GIST882 cells but not c-Kit expressing COS-1 cells, which could be explained by the use of CMV promoter in artificial COS-1 cell model. Conclusions: Taken together, these findings provide the first evidence that down-regulation of mutant c-Kit protein by Hsp90 inhibitor involved both transcription and post-translation levels. Of the latter, autophagy- as well as proteasome-mediated degradation pathways were involved. These observations highlight the use of NVP-AUY922 either alone or in combination with autophagy modulators in imatinib-refractory, c-Kit-expressing GIST. Supported by 99D1-TC-CADOH03. [Table: see text]
Abstract 1678: Nicotine Upregulates Early Growth Factor-1 Expression in Vascular Smooth Muscle Cell via ERK 1/2-Elk-1 Signaling and Exacerbates Neointimal Formation after Vascular Injury
Authors: Luis Rodriguez-Menocal, Dania Mateu, Yuntao Wei, Si Pham, Roberto I Vazquez-Padron
Journal: Circulation (2008)
Abstract 370: Type 2 Diabetes Is Associated with the Exacerbation of Heart Failure via Increasing Myocardial NAD(P)H Oxidase-Derived Superoxide Production
Authors: Shintaro Kinugawa, Shouji Matsushima, Takashi Yokota, Yukihiro Ohta, Naoki Inoue, Hiroyuki Tsutsuin
Journal: Circulation (2008)

Type 2 diabetes mellitus (DM) adversely affects the outcomes in patients with myocardial infarction (MI), which is associated with the development of left ventricular (LV) remodeling and failure. NAD(P)H oxidase-derived superoxide (O 2 − ) production is increased in DM. However, its pathophysiological significance in advanced post-MI LV failure associated with DM remains unestablished. We thus determined whether an inhibitor of NAD(P)H oxidase activation, apocynin, could attenuate the exacerbated LV remodeling and heart failure after MI in high-fat diet (HFD)-induced obese mice with DM. Male C57BL/6J mice were fed on either HFD or normal diet (ND) for 8 weeks. At 4 weeks of feeding, MI was created in all mice by ligating left coronary artery. MI mice were treated with either apocynin (10 mmol/l in drinking water; n = 10 for ND and n = 11 for HFD) or vehicle (n = 15 for ND and n = 13 for HFD). HFD significantly increased body weight (BW), adipose tissue mass, fasting plasma glucose and insulin levels compared to ND after 4 and 8 weeks. HFD + MI had significantly greater LV end-diastolic diameter (LVEDD; 5.7 ± 0.1 vs. 5.3 ± 0.2 mm) by echocardiography, end-diastolic pressure (EDP; 12 ± 2 vs. 8 ± 1 mmHg) and lung weight/tibial length (10.1 ± 0.3 vs. 8.7 ± 0.7 mg/mm) than ND + MI, which was accompanied by an increased interstitial fibrosis of non-infarcted LV. Treatment of HFD + MI with apocynin significantly decreased LVEDD (5.4 ± 0.1 mm), LVEDP (9.7 ± 0.8 mmHg), lung weight/tibial length (9.0 ± 0.3 mg/mm), and concomitantly interstitial fibrosis of non-infarcted LV to ND + MI level without affecting BW, glucose metabolism, infarct size and aortic pressure. On the other hand, treatment of ND + MI with apocynin did not affect LV remodeling and failure. NAD(P)H oxidase activity, O 2 − production measured by lucigenin chemiluminescence, and thiobarbituric acid-reactive substances were increased in non-infarcted LV tissues from HFD + MI, all of which were also attenuated by apocynin to ND + MI level. Type 2 DM was associated with the exacerbation of LV remodeling and failure after MI via increasing NAD(P)H oxidase derived O 2 − production, which may be a novel important therapeutic target in advanced heart failure with DM.
Abstract 3312: Cilostazol Improves Long-term Patency after Percutaneous Transluminal Angioplasty in Hemodialysis Patients with Peripheral Artery Disease
Authors: Yoshitaka Kumada, Hideki Ishii, Toru Aoyama, Miho Tanaka, Takanobu Toriyama, Hiroshi Takahashi, Tetsuji Morishita, Tetsuya Amano, Hideo Izawa, Ryuichiro Murakami, Tatsuaki Matsubara, Toyoaki Murohara
Journal: Circulation (2007)

Background: Percutaneous transluminal angioplasty (PTA) has become common therapeutic standard for peripheral artery disease (PAD). Although initial success rate of PTA is high, higher restenosis rate is a limitation in hemidialysis (HD) patients. Cilostazol is a PDE3 inhibitor with anti-platelet and vasodilatory effects, and also inhibits the proliferation of the smooth muscle cells, and has been reported to reduce target lesion revascularization (TLR) in PAD patients. The aim of this study was to clarify the effects of cilostazol administration for long-term patency after PTA in HD patients. Methods: Consecutive 372 lesions of 193 HD patients undergoing successfully PTA were enrolled. They were divided into two groups; patients administered cilostazol (130 lesions of 71 patients) and those without cilostazol as a control (242 lesions of 122 patients). They were followed-up using Doppler ultrasound and/or angiography for 5 years. To minimize the selection bias for cilostazol administration, a propensity-matched analysis using the model including male, age, diabetes, critical limb ischemia (CLI), TASC C+D type, femoropopoliteal (FPA) lesion and stenting was performed. The propensity score was matched 1:1 with two-digit (AUC=0.69 using ROC analysis). Results: Mean follow-up period was 28±24months. Primary patency rate for 5 years was significantly higher in the cilostazol group than in the control group (53% vs 33%, p = 0.0003). Also, rates for freedom from TLR and for limb salvage were higher in cilostazol group than in control group (67% vs. 50%, p=0.011 and 88% vs. 72%, p =0.031, respectively). In 102 lesions matched after propensity score analysis, the primary patency for 5-year was significantly higher in the cilostazol group (58%) than in the control group (35%) (HR 0.48, 95%CI 0.30 – 0.76, p = 0.0017). Upon multivariate Cox analysis, Cilostazol (HR 0.50, 95%CI 0.26 – 0.87, p = 0.014), age (HR 1.03, 95%CI 1.01–1.07, p = 0.041), FPA lesion (HR 2.62, 95%CI 1.22–5.62, p = 0.013), TASC C+D type (HR 2.85, 95%CI 1.56 –5.20, p = 0.0006) and CLI (HR 4.09, 95%CI 2.10 –7.94, p &lt;0.0001) were independent predictors of restenosis after PTA. Conclusion: These data suggest that cilostazol administration improves long-term patency after PTA in HD Patients with PAD.
A Multicenter Phase I Study of the Humanized Anti-CD19 Monoclonal Antibody, MEDI-551, in Patients with Relapsed or Refractory B-Cell Lymphoma and Multiple Myeloma
Authors: Michinori Ogura, Kiyoshi Ando, Naokuni Uike, Yoshiaki Ogawa, Toshiki Uchida, Yasunobu Abe, Takanobu Morishita, Minoru Kojima, Ilseung Choi, Katsuro Yagawa, Yuki Yokoi, Jun Okamura
Journal: Blood (2014)
Abstract 5105: The Relationship of Inflammation and Thrombosis with Right Ventricular Mass and Function: The MESA-Right Ventricle Study
Authors: Steven M Kawut, R G Barr, Craig Johnson, Harjit Chahal, Harikrishna Tandri, Aditya Jain, Jorge Kizer, Emilia Bagiella, Michael Bristow, Joao Lima, David Bluemke
Journal: Circulation (2008)

Right ventricular (RV) mass reflects response to afterload, whereas RV ejection fraction (RVEF) is an indicator of RV function. Pulmonary vascular disease is characterized by hemostatic abnormalities and inflammation and may affect RV mass and function. We hypothesized that increased levels of inflammatory markers (ICAM-1, TNF-α, E-Selectin, MMP-3, and MMP-9) would be associated with higher RV mass and lower RVEF, and increased levels of hemostatic markers (tissue factor, PAI-1, and CD40L) and decreased levels of TFPI would be associated with higher RV mass and lower RVEF. The Multi-Ethnic Study of Atherosclerosis (MESA) performed interpretable cardiac MRIs on 5,004 participants without clinical cardiovascular disease at six field centers. 785 randomly selected patients had plasma biomarkers measured, 730 of whom had complete interpretation of RV measures. Endocardial margins of the RV were manually contoured on diastolic and systolic images. End-diastolic volume (EDV) and end-systolic volume (ESV) were calculated by using a summation of disks method (“Simpson’s Rule”). RVEF was calculated from (EDV-ESV)/EDV. RV mass was determined from cine images of the heart. Biomarkers were analyzed in quintiles using multivariate linear regression. The 730 participants in the study sample were 59 ± 10 (mean ± SD) years old, 58% female, 45% Caucasian, 21% African-American, 11% Chinese-American, and 23% Hispanic. The RV mass was 22 g ± 5 g and RVEF was 69% ± 7%. Higher PAI-1 levels were associated with lower RV mass, after adjustment for age, gender, race, height, and weight (test for trend, p = 0.036, n = 710). Higher MMP-9 levels were associated with lower RV mass (test for trend, p = 0.006). Neither hemostatic nor inflammatory biomarkers were associated with RVEF. RV mass was inversely associated with PAI-1, a serine protease which inhibits thrombolysis, and MMP-9, which breaks down the extracellular matrix. The mechanism of these determinants of RV structure and function should be investigated.
Abstract 2887: Peri-Operative Beta-Blockers in Patients Undergoing Non-cardiac Surgery: A Meta-Analysis of 12,306 Patients from Randomized Trials
Authors: Sripal Bangalore, Shruthi Chandrashekhar, Sandeep Pulimi, Franz H Messerli
Journal: Circulation (2008)

Background: The 2007 ACC/AHA guideline on perioperative evaluation recommends perioperative β-blockers for non-cardiac surgery. However, some clinical trials seem to be at odds with these recommendations. Methods: PUBMED/EMBASE/CENTRAL search for randomized trials (RCTs) evaluating β-blockers for non-cardiac surgery. Efficacy outcomes of all-cause mortality, cardiovascular (CV) mortality, nonfatal MI, nonfatal stroke, heart failure, and myocardial ischemia (30 days), and safety outcomes of perioperative bradycardia, hypotension, and bronchospasm. Results: Among 33 RCTs which evaluated 12,306 patients, β-blockers were not associated with any significant reduction in the risk of all-cause mortality, CV mortality, or heart failure, but were associated with a 35% decrease in nonfatal MI, 64% decrease in myocardial ischemia at the expense of a 101% increase (Figure ) in nonfatal strokes. The beneficial effects were driven mainly by trials with high-bias risk, while analyses of low-biased trials showed a 28% and 101% increase in all-cause mortality and stroke with only a 29% and 59% reduction in nonfatal MI and 59%myocardial ischemia. For the safety outcomes, β-blockers were associated with a significantly increased risk of peri-op bradycardia and peri-op hypotension. Conclusions: In patients undergoing non-cardiac surgery, we estimate that treatment of 1000 patients with β-blockers results in 16 fewer nonfatal MI, but at the expense of 3 disabling strokes and 45 and 59 patients with clinically significant perioperative bradycardia and hypotension respectively, and suggests an increase in all-cause mortality.
Abstract 6023: The Need for Blood Transfusion Is an Independent Predictor of Incident Cardiovascular Events and All-Cause Mortality among Patients Undergoing Percutaneous Coronary Intervention
Authors: Jasper Jan Brugts, Nestor Mercado, Joachim Ix, Michael G Shlipak, Simon R Dixon, Bernard J Gersh, Pedro Lamos, Mimi Guarneri, Paul Terstein, Williom Wijns, William W O’Neill, Eric Boersma
Journal: Circulation (2008)

Periprocedural bleeding is one of the most frequent complications of percutaneours coronary interventions. We assessed the relation between blood transfusion and all-cause mortality or incident cardiovascular events (death, MI, stroke) among 6103 patients of the Evaluation of Oral Xemilofiban in Controlling Thrombotic Events (EXCITE)-trial. Subjects were followed for 7 months after enrollment for the occurrence of events. Multivariate Cox-regression analysis evaluated the independent association of blood transfusion with each outcome adjusted for age, gender, race, diabetes mellitus, hypertension, hypercholesterolemia, history of MI, PCI, CABG, heart failure, LVEF&lt;30%, use of beta-blockers, statins, ACE-inhibitors, platelet inhibitors and allocation to treatment with xemolifiban. In addition, propensity score analyses were performed (ROC 0.80). Mean age was 59.2 years, 21.7% were female, and 18.9% had diabetes mellitus. Of the169 patients who received blood transfusion, 14 (8.3%) died and 42 (24.9%) experienced a CVD event. Of the 5934 patients without transfusion, 65 (1.1%) died (p-value: &lt;0.001) and 555 (9,4%) experienced a CVD event (p-value: &lt;0.001) In multivariate analysis, blood transfusion was associated with a 5.3 fold increased risk of mortality (HR 5.3; 95% CI 2.8 –10.2), and a 2.5 fold increased risk of incident CVD (HR 2.5; 95% CI 1.7–3.4.) Noteworthy, patients who were US citizens had a higher transfusion rate then non-US citizens (OR 1.45, 95%CI 1.02–2.06) The need of blood transfusion is a strong and independent predictor of all-cause mortality and incident CVD events among patients undergoing PCI.
Abstract 5864: In Vivo Aortic Valve Thermal Heterogeneity In Patients With Non-rheumatic Aortic Valve Stenosis: First In Vivo Experience In Humans
Authors: Konstantinos Toutouzas, Maria Drakopoulou, Andreas Synetos, Eleftherios Tsiamis, George Agorogiannis, Nikolaos Kavantzas Nikolaos Kavantzas, Eustratios Patsouris, Dimitris Iliopoulos, Stergios Theodoropoulos, Magdi Yacoub, Christodoulos Stefanadis
Journal: Circulation (2008)

Background: Histological studies have demonstrated a potential role of inflammation and neoangiogenesis in aortic valve stenosis (AVS). Inflammatory activation may generate heat. We investigated in vivo in patients with AVS whether there is: thermal heterogeneity within the valve leaflets, temperature difference between the leaflets and the ascending aortic wall and a possible correlation between heat production, inflammation and neoangiogenesis. Methods: We examined 96 leaflets from 32 patients scheduled for aortic valve replacement. Seventy-five leaflets were from 25 patients with AVS and 21 from 7 patients with aortic valve insufficiency (AVI) (control group). Temperature measurements were performed right before the hypothermic cardioplegia. Temperature difference (ΔT) was assigned as the mean temperature of each aortic leaflet minus the temperature of the aortic wall. Results: Histological, immunohistological analysis for inflammatory cells and vascular endothelial growth factor (VEGF) immunoreactivity was performed. Significant thermal heterogeneity was recorded within the leaflets of AVS, compared AVI (1.52±1.35°C vs 0.13±0.11°C, p&lt;0.01). In AVS ΔT was 1.09±1.16°C for the non-coronary (NC), 1.24±1.03°C for the right and 1.53±1.23°C, for the left leaflet. ΔT was lower in AVI (0.10±0.10°C for the NC, 0.02±0.19°C for the right and 0.05±0.19°C, for the left leaflet, p&lt;0.01 for all comparisons). Leaflets of AVS had increased inflammatory cell infiltration, calcium deposit, and anti-VEGF expression compared to AVI (p&lt;0.01). Conclusions: Thermal heterogeneity is increased in AVS and correlates with inflammatory mononuclear cell infiltration, expression of pro-inflammatory cytokines and neoangiogenic factors. Future studies need to be performed to investigate possible prognostic and therapeutic implications.
Abstract 14771: Iron Plays a Role in the Thrombus Formation of a Rat Model of Deep Vein Thrombosis
Authors: Makiko Oboshi, Yoshiro Naito, Hisashi Sawada, Toshihiro Iwasaku, Yoshitaka Okuhara, Daisuke Morisawa, Akiyo Eguchi, Shinichi Hirotani, Toshiaki Mano, Takeshi Tsujino, Tohru Masuyama
Journal: Circulation (2014)

Introduction: Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism. On the other hand, iron is an essential element for maintaining physiological homeostasis in the body, whereas excess iron leads to toxicity and free radical damage. Hence, iron accumulation is associated with the pathogenesis of several cardiovascular diseases. We have previously reported that dietary iron restriction (IR) prevents the development of hypertension and chronic kidney disease (CKD) in animal models of several cardiovascular diseases. In addition, we have shown that intracellular iron transport protein, transferrin receptor 1 (TfR1), is involved in the mechanism of several cardiovascular diseases. In this study, we hypothesized that iron and TfR1 play roles in the pathogenesis of DVT. We investigate the effects of dietary IR on the thrombus formation and resolution in a rat model of DVT. Methods: We performed the ligation of inferior vena cava to induce DVT in 8-week-old male Sprague-Dawley rats. After the ligation, rats were given either a normal diet (DVT group) or iron-restricted diet (DVT+IR group). The thrombus was harvested at 5days after the ligation. Results: At first, TfR1 expression was increased in the thrombus of a rat model of DVT, suggesting that iron and TfR1 play roles in the pathogenesis of DVT. Interestingly, dietary iron restriction reduced the thrombus size compared with the DVT group (180±17 mg/cm vs 135±13 mg/cm, DVT vs DVT+IR ; p &lt; 0.05). Intrathrombotic collagen content was diminished in the DVT+IR group compared with the DVT group. Intrathrombotic gene expression and activity of matrix metalloproteinase (MMP)-9 were increased in the DVT+IR group compared with the DVT group. In addition, the numbers of CD68 positive cells in the thrombus were fewer in the DVT+IR group than in the DVT group. Furthermore, intrathrombotic gene expression of urokinase-type plasminogen activator and tissue-type plasminogen activator was higher in the DVT+IR group than in the DVT group. Conclusions: These results suggest that iron plays a role in the pathogenesis of DVT.
Abstract P211: Test Characteristics of the ABI and Ankle Brachial Difference for Medial Calcification on X-ray in Type 1 Diabetes: the Pittsburgh EDC Study
Authors: Joachim H Ix, Rachel Miller, Michael Criqui, Trevor Orchard
Journal: Circulation (2012)

Background: Medial arterial calcification (MAC) is common in diabetes, has a characteristic “tram-track” appearance on x-ray and has been linked with peripheral arterial stiffness, CVD events, and all-cause mortality. While the ankle brachial index (ABI) is often available in epidemiologic studies, few studies have measured MAC by x-ray. It has been suggested that an ABI &gt; 1.30 or ankle brachial difference (ABD) &gt; 75mmHg may identify individuals with MAC, but the test characteristics of the ABI and ABD for MAC are uncertain. Methods: Among 185 individuals with type 1 diabetes, we measured ankle and brachial SBP and calculated the ABI and ABD. Lower limb x-rays where read for MAC by two physician investigators and independently reviewed by investigators in the Netherlands. Only linear calcification was considered diagnostic of MAC. The Kappa statistic for any versus none was 0.89 for the two sets of scores. We determined the area under the receiver operator curve (ROC) of the ABI and ABD for MAC on x-ray. and also evaluated the test characteristics at various ABI and ABD cut-points. Results: The mean age was 32±6 years and mean diabetes duration was 23±7 years. 97 individuals (57%) had MAC, 15 (8%) had ABI &gt; 1.30, and 14 (8%) had ABD &gt; 75mmHg. The area under the ROC of the ABI for MAC was modest (0.65) and was slightly higher for the ABD (0.75). Table 1 shows the test characteristics of different ABI and ABD cut-points. Both ABI &gt; 1.30 and ABD &gt; 75mmHg were highly specific for MAC, but with poor sensitivity. Conclusions: Individuals with type 1 diabetes who have an ABI &gt; 1.30 or ABD &gt; 75mmHg are very likely to have MAC on x-ray, however many individuals with MAC will not have ABI or ABD above these thresholds. Given high specificity, in studies without x-rays, evaluating high ABI or ABD as surrogates of MAC may prove useful to identify MAC risk factors, but may underestimate the prevalence of MAC. Table 1. Test Characteristics of the ABI and ABD for X-ray Medial Arterial Calcification in Type 1 Diabetes Ankle Brachial Index ABI n (%) Sensitivity Specificity PPV NPV Accuracy &gt; 1.05 125 (68%) 70% 35% 54% 52% 54% &gt; 1.10 84 (45%) 57% 67% 65% 58% 62% &gt; 1.20 38 (21%) 32% 92% 82% 55% 61% &gt; 1.30 15 (8%) 14% 99% 93% 51% 55% &gt; 1.40 7 (4%) 7% 100% 100% 49% 51% Ankle Brachial Difference ABD (mmHg) n (%) Sensitivity Specificity PPV NPV Accuracy &gt; 15 133 (72%) 83% 49% 60^ 67% 62% &gt; 20 115 (62%) 78% 56% 66% 70% 68% &gt; 25 84 (46%) 66% 77% 76% 67% 71% &gt; 50 31 (17%) 30% 98% 94% 56% 62% &gt; 75 14 (8%) 14% 100% 100% 52% 55%