tbuckley/cabot-search huggingface dataset:
Physical Training Improves Endothelial Function in Patients With Chronic Heart Failure
Authors: BurkhardHornig, VolkerMaier, HelmutDrexler
Journal: Circulation (1996)

Background Chronic heart failure is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). Since endothelial function is thought to play an important role in coordinating tissue perfusion and modulating arterial compliance, interventions to improve endothelial dysfunction are imperative. Methods and Results To assess the potential of physical training to restore FDD, 12 patients with chronic heart failure were studied and compared with FDD of 7 age-matched normal subjects. With a recently developed high-resolution ultrasound system, diameters of radial artery were measured at rest, during reactive hyperemia (with increased flow causing endothelium-mediated dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Determination of FDD was repeated after intra-arterial infusion of NG-monomethyl-l-arginine (L-NMMA, 7 μmol/min) to inhibit endothelial synthesis and release of nitric oxide. The protocol was performed at baselin...
EphA4-Mediated Rho Activation via Vsm-RhoGEF Expressed Specifically in Vascular Smooth Muscle Cells
Authors: HisakazuOgita, SatoshiKunimoto, YujiKamioka, HirofumiSawa, MichitakaMasuda, NaokiMochizuki
Journal: Circulation Research (2003)

Rho-kinase, an effector of Rho GTPase, increases the contractility of vascular smooth muscle by phosphorylating myosin light chain (MLC) and by inactivating MLC phosphatase. A wide variety of extracellular stimuli activate RhoA via G protein–coupled receptors. In the present study, we demonstrate a novel cell-cell interaction–mediated Rho activation signaling pathway in vascular smooth muscle cells (VSMCs). Among many receptor tyrosine kinases, the Eph family receptors are unique in that they require cell-cell interaction to engage their ligands, ephrin. We found that a novel VSMC-specific guanine nucleotide exchange factor (GEF) for Rho (Vsm-RhoGEF/KIAA0915) was expressed specifically in VSMCs of several organs including the heart, aorta, liver, kidney, and spleen, as examined by the immunohistochemical analysis using a specific antibody against Vsm-RhoGEF. Based on the association of Vsm-RhoGEF with EphA4 in quiescent cells, we tested whether EphA4 and Vsm-RhoGEF were expressed in the same tissue and fu...
Abstract 12310: Impact of Diastolic Dysfunction on Outcome in Patients With Low-Flow, Low-Gradient and Low Ejection Fraction Aortic Stenosis -Results From the TOPAS Study-
Authors: Abdellaziz Dahou, Marie-annick Clavel, Romain Capoulade, Mario Sénéchal, Kim O’Connor, Jean G Dumesnil, Haïfa Mahjoub, Florent Le Ven, Christophe Thebault, Philippe Pibarot
Journal: Circulation (2013)

Background: Diastolic dysfunction (DD) is very common in patients with low-flow, low-gradient aortic stenosis (LF-LG AS) and low ejection fraction (EF). However, its impact on prognosis remains unknown in this condition. The aim of this study was to examine the impact of DD on all-cause mortality in this population of patients. Methods: 215 patients (73±10 yrs; 77% men) with LF-LG AS and low EF (EF≤40%, mean gradient≤40 mmHg, and an Aortic Valve Area [AVA]≤0.6 cm2/m2) were included. The severity of AS was assessed by the projected AVA (AVAproj) at normal flow rate. Patients were separated in 2 groups according to the severity of DD: group1=patients with no or mild DD (abnormal relaxation pattern); group2=patients with moderate DD (pseudonormal pattern) or severe DD (restrictive pattern). Results: Among the 215 patients, 162(75%) had assessment of diastolic function (DF). Due to atrial fibrillation, the assessment of DF was not available in the other patients. 90(56%) had no/mild DD (14 patients with no DD...
Abstract 2327: Azole antifungal drugs induce cell death by suppressing mTOR through PI3K/Akt inhibition in human breast cancer
Authors: Ju Ho Park, Hyesook Kim, So Hee Kim
Journal: Cancer Research (2018)

Abstract Breast cancer is a major cancer in women and its incidence rate increases every year. So it needs a perfect treatment. Azole drugs structurally have an imidazole [clotrimazole (CTZ) and ketoconazole (KCZ)] or a triazole [fluconazole (FCZ) and itraconazole (ICZ)]. Recently, azole antifungal drugs have shown anticancer efficacy in clinical trial. However, their antitumor mechanism are vague. Here, we evaluated the effects, as apoptosis, cell arrest, and autophagy and tumor growth using human breast cancer cells. Apoptosis assay showed imidazole-induced cell death, pro-apoptosis maker, as cleaved PARP, cleaved caspase-3, Bax, increased and anti-apoptosis maker, as Bcl-2, decreased by CTZ and KCZ in both MCF-7 and MDA-MB-231 cells. We also checked imidazole of azole drugs blocked the cell cycle in G1 phage by downregulating the protein levels of cyclin D1, CDK2, and CDK6 and increased p21 and p27 in breast cancer. Further experiments showed that azole drugs also induced autophagy through the increased accumulation of LC 3B inside the cells by immunoblot analysis and immunofluorescence staining, increased beclin-1 and decreased p62 protein. With azole decreased that though 3-MA. Azole drugs inhibited PI3K/Akt/mTOR signaling pathway. Tumor growth was also inhibited in nude mice bearing MDA-MB-231 xenograft by CTZ, KCZ and ICZ through the accumulation of LC 3B in tumor xenograft. In conclusion, imidazole antifungal drugs induced apoptosis, cell cycle and autophagy by suppressing mTOR through the regulation of PI3K/Akt pathway in human breast cancer cells, suggesting azole antifungal drugs could be new potential therapeutics for breast cancer. Citation Format: Ju Ho Park, Hyesook Kim, So Hee Kim. Azole antifungal drugs induce cell death by suppressing mTOR through PI3K/Akt inhibition in human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2327.
Effect of Different Intensities of Exercise on Endothelium-Dependent Vasodilation in Humans
Authors: ChikaraGoto, YukihitoHigashi, MasashiKimura, KensukeNoma, KeikoHara, KeigoNakagawa, MitsutoshiKawamura, KazuakiChayama, MasaoYoshizumi, IsaoNara
Journal: Circulation (2003)

Background— Aerobic exercise enhances endothelium-dependent vasodilation in hypertensive patients, patients with chronic heart failure, and healthy individuals. However, it is unclear how the intensity of exercise affects endothelial function in humans. The purpose of the present study was to determine the effects of different intensities of exercise on endothelium-dependent vasodilation in humans. Methods and Results— We evaluated the forearm blood flow responses to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate, an endothelium-independent vasodilator, before and after different intensities of exercise (mild, 25% Vo2max; moderate, 50% Vo2max; and high, 75% Vo2max; bicycle ergometers, 30 minutes, 5 to 7 times per week for 12 weeks) in 26 healthy young men. Forearm blood flow was measured using a mercury-filled Silastic strain-gauge plethysmograph. Twelve weeks of moderate-intensity exercise, but not mild- or high-intensity exercise, significantly augmented acetylcholine-i...
Abstract 1399: Passenger deletion vulnerability in glioblastoma
Authors: Nicole Oatman, Kakajan Komurov, Priyanka Arora, Pankaj Desai, Nupur Dasgupta, Kwangmin Choi, Biplab Dasgupta
Journal: Cancer Research (2018)

Abstract Glioblastoma multiforme (GBM) is the most common, aggressive and lethal primary brain tumor in humans. Despite aggressive therapy the median survival of GBM patients is approximately 15 months. Monoallelic loss of PTEN occurs in ~70% of GBM. Through experimental validation studies in patient-derived primary GBM cell lines, we discovered that the lipogenic gene SCD undergoes unintended co-deletion as a passenger to PTEN, resulting in hemizygous loss of SCD in a subset of GBM. Additional in silico, genetic and biochemical analysis lead to the identification of two distinct PTEN-deleted subgroups: one with hemizygous co-deletion of PTEN and SCD (hereafter SCD-expressing), and another with very little or no PTEN/SCD expression due to PTEN mutation/homozygous loss and epigenetic suppression of the remaining SCD allele (hereafter SCD-non-expressing). SCD is an integral membrane protein of the endoplasmic reticulum (ER), involved in mediating the rate-limiting step of unsaturated fatty acid biosynthesis. SCD catalyzes the desaturation of the saturated fatty acids stearic (C18:0) and palmitic acids (C16:0) to the monounsaturated fatty acids oleic (C18:1) and palmitoleic acids (C16:1), respectively. We showed that the SCD-expressing lines are highly sensitive to SCD inhibition in the absence of dietary oleate and that the SCD-non-expressing lines are resistant to SCD inhibition. In vivo, we showed that mice treated with the SCD inhibitor survive longer than mice treated with vehicle. We also showed that SCD-expressing GBM lines acquire inhibitor resistance upon long-term exposure to the inhibitor in vitro. To understand the mechanism of resistance, we performed Reverse Phase Protein Array (RRPA) and RNA-Seq. Results illustrated the up-regulation of SCD among other genes. To identify the gene/s that provide SCD inhibitor resistance, we are currently performing a targeted shRNA screen of the highly expressed genes that we determined through RPPA and RNA-Seq. Citation Format: Nicole Oatman, Kakajan Komurov, Priyanka Arora, Pankaj Desai, Nupur Dasgupta, Kwangmin Choi, Biplab Dasgupta. Passenger deletion vulnerability in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1399.
Abstract 17454: Inhibition of Anti-angiogenic VEGF-A Isoform Activates a Novel VEGFR1 Signaling That Induces Therapeutic Angiogenesis and Perfusion Recovery in Experimental PAD
Authors: Vijay C Ganta, Anna Kutateladze, Min Choi, Brian Annex
Journal: Circulation (2015)

Introduction: Classic VEGF-A induced angiogenesis involves VEGFR2 (VR2)-PI3K-AKT-eNos activation. Ischemia induces VEGF165b (V165b, an anti-angiogenic VEGF-A isoform) levels in Peripheral Arterial Disease (PAD) muscle. Since V165b competes with pro-angiogenic VEGF-A isoforms to bind and block VEGF-A dependent activation of VR2 and angiogenesis, we hypothesized that “V165b inhibition removes the anti-angiogenic brakes on VR2-PI3K-Akt signaling to promote therapeutic angiogenesis and perfusion recovery in PAD”. Methods and Results: Hind limb ischemia (HLI), an experimental PAD model was performed by femoral artery ligation and resection in worse recovery animal strains (Balbc and type 2-Diabetes (T2D), n=10/group). Mice were treated i.m. with isoform specific V165b blocking antibody or IgG immediately post-surgery. V165b inhibition significantly increased perfusion recovery (Balbc: V165b-Ab=75.35±4.7 vs. IgG=50.13±2.4%, T2D: 65.70±5.8 vs. 44.04±6.08%) assessed by laser Doppler. Furthermore, V165b inhibition increased vascular density by ~2 fold in ischemic muscle and significantly decreased necrosis scores in both animal strains compared to IgG. In vitro, HUVECs treated with V165b-Ab showed significantly higher capillary like tube formation on matrigel suggesting that endogenous V165b inhibition is sufficient to promote angiogenesis. In stark contrast to our hypothesis, V165b inhibition significantly induced VR1 activation but not VR2, along with Stat3 activation, decreased Akt, Erk1/2 activation and decreased P53 levels (in d3 post HLI tissue samples) compared to IgG. In vitro, HUVECs treated with V165b-Ab also showed significant increase in VR1 and Stat3 activation compared to IgG. Moreover, ligand-receptor binding experiments showed that V165b inhibition significantly increased the binding of not only VEGF-A but also VEGF-B and PlGF to VR1 in ischemic muscle as well as in HUVECs in vitro (P&lt;0.05 is considered significant). Conclusion: We conclude that V165b not only competes with VEGF-A but also with VEGF-B and PlGF to bind and block VR1 activation in ischemic muscle. Our data point towards a novel VR1 signaling that activates Stat3 and inhibits P53 to promote perfusion recovery in ischemic muscle post V165b inhibition.
Abstract 150: Elucidating the molecular mechanisms of cutaneous melanoma development from melanocyte stem cells
Authors: Hyeongsun Moon, Leanne Donahue, Jerry Zhu, Andrew White
Journal: Cancer Research (2018)

Abstract Cutaneous melanoma is the most lethal form among all skin cancers. Multiple genetic etiologies have been identified in primary and metastatic tumors, however, the cellular origin for cutaneous melanoma and their related molecular mechanisms required for early steps of melanoma initiation have not been well defined. Although great progress has been made in the development of targeted therapies for malignant melanoma, knowledge on the factors that can cause tumor formation would provide valuable insight for melanoma prevention and control. Here, our study aims to determine potential means of prevention by identifying the extrinsic environmental factors and cellular conditions responsible for melanoma initiation particularly from tumor-competent melanocyte stem cells. In the study, adult stem cells have been discovered as a compelling candidate for melanoma formation. We also found that quiescent stem cells are relatively unable to develop melanocytic tumors. On the other hand, environmental and physiological stresses can significantly alter the status of melanocyte stem cells which in turn causes melanoma development. Screening the genetic changes that occur in the melanoma-competent stem cells in tumor initiation stages can help to elucidate which molecular pathways may cause the formation of cutaneous melanoma. Our data will provide a new framework for the early initiation steps of cutaneous melanoma from quiescent but tumor-prone stem cells, with the ultimate goal to find better preventative measurements and targeted therapy for cutaneous melanoma. Citation Format: Hyeongsun Moon, Leanne Donahue, Jerry Zhu, Andrew White. Elucidating the molecular mechanisms of cutaneous melanoma development from melanocyte stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 150.
Abstract 13760: Dipeptidyl-Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin, Prevented the Progression of Established Atheromatous Plaques in ApoE Deficient Mice - Possible Involvement of AMP-Activated Protein Kinase Pathway -
Authors: HirofumiKurokawa, SeigoSugiyama, KoichiSugamura, JunichiMatsubara, KoichiroFujisue, KeisukeOhba, HirofumiMaeda, EiichirouYamamoto, KenichiTsujita, KoichiKaikita, SeijiHokimoto, HisaoOgawa
Journal: Circulation (2014)

Background: We demonstrated that dipeptidyl-peptidase-4 inhibitor (DPP4i) Des-Fluoro-Sitagliptin (DFS) exhibited anti-atherosclerotic effects on the newly development process of atherosclerosis, however it is unknown whether DPP4i also have anti-atherosclerotic effects on the established atheroma (preventing progression or regression). In the practical situation, it is clinically important to investigate whether DPP4i have beneficial effects on the established atherosclerosis. Methods and Results: 8 weeks old ApoE deficient mice were fed by high fat diet (HFD) for 12 weeks lead to development of the established atherosclerotic plaques, followed by randomized into 4 groups; continued HFD arm [HFD alone, HFD+DFS (200mg/kg/day)] and lipid-lowering arm [low fat diet (LFD) alone, LFD+DFS], for additional 8 weeks. DFS significantly reduced the progression of established plaque compared to HFD alone [plaque area per aorta; HFD (n=11): 53.3±4.9% vs. HFD+DFS (n=15): 43.8±9.0%, p<0.05]. During the lipid-lowering th...
Abstract 1168: The “humanized” chicken embryo chorioallantoic membrane (CAM) as a personalized platform for high-throughput (HTP) screening of cancer therapeutics
Authors: Shiran Shapira, Oren Bogin, Nadir Arber
Journal: Cancer Research (2018)

Abstract Background Every day, millions of people are taking medications that will not help them. “Personalized medicine,” is the tailoring of medical treatment to a single person, shape his response to a particular treatment and aims to better target intervention, maximize benefit and minimize harm. Several techniques are available to grow primary cell cultures from tumors; however, very few have been found to be promising. Novel, cost-effective model that similarly mimic tumor biology and provide faster information on the activity of anticancer therapies could therefore make an important contribution to the advancement of personalized medicine. Chick Chorioallantoic Membrane (CAM) assays have been used to study the process and therapeutics involving angiogenesis, tumor cell invasion and metastasis. The CAM is naturally immuno-deficient and rich in vascularity therefore an ideal system, allowing to generate 3D cancerous “organoids” in a very efficient, reproducible and cost-effective manner and translates basic research to the clinic. Aim 1) Generate a “personalized medicine” HTP system for a quick and reliable evaluation of the effectiveness of different therapeutic options on of 3D "organoid" tumors; 2) Using the "humanized egg" as a low-cost and highly efficient mimetic of the mouse PDX model ". Methods Fertilized eggs were incubated until day 3 (37°C, 75-90% humidity). 2ml of albumin was pulled from the egg to separate the CAM membrane from the egg shell. Then, a small window in the egg shell has been made, and resealed with adhesive tape. On day 7, 3-5x106 tumor cells were transplanted onto the CAM membrane. The cancer cells become a visible tumor after 3 days. Different therapeutics (such as Erbitux, anti-CD24 mAb) were tested. Tumor growth was monitored by "live imaging" device. Results The efficiency and reproducibility of human cancer cell lines engraftment has been demonstrated. LV-GFP-Puro plasmid was constructed and used to generate GFP-encoded lentiviruses which then were used to generate a stable colorectal cancer cell line expressing GFP. The CAM tumors were evaluated histopathologicaly and IVIS fluorescent imaging. Anti-CD24 mAb inhibited tumor growth by ~70%.The presence of the humanized mAb in the engrafted tissue was confirmed by western blot analysis and IHC. Conclusions The ability to evaluate ex-vivo cancer tissue response to potential therapeutics in “humanized” settings within days is a very powerful tool. Citation Format: Shiran Shapira, Oren Bogin, Nadir Arber. The “humanized” chicken embryo chorioallantoic membrane (CAM) as a personalized platform for high-throughput (HTP) screening of cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1168.
Preferential Impairment of Nitric Oxide–Mediated Endothelium-Dependent Relaxation in Human Cervical Arteries After Irradiation
Authors: TsunekiSugihara, YuichiHattori, YuheiYamamoto, FazhiQi, RyoichiIchikawa, AtsushiSato, Ming-YueLiu, KazuhiroAbe, MorioKanno
Journal: Circulation (1999)

Background—Vascular abnormalities are a major cause of postoperative complications in irradiated tissues. Endothelial cell dysfunction characterized by diminished endothelium-dependent relaxation may be involved. We examined the endothelium-dependent relaxation and morphology of the endothelium in irradiated human cervical arteries. Methods and Results—Irradiated arteries were taken from the neck region of patients who had radiation therapy. Arteries from patients who did not receive radiation therapy were used as controls. Endothelium-dependent relaxation to acetylcholine and A23187 was impaired in irradiated arteries. Norepinephrine-induced contraction and sodium nitroprusside–induced relaxation were unchanged. In control arteries, Nω-nitro-l-arginine and indomethacin each caused a partial inhibition of endothelium-dependent relaxation. In irradiated arteries, the impaired endothelium-dependent relaxation was unaffected by these agents, but it was abolished by high K+. Acetylcholine produced similar deg...
Estrogen-Mediated Endothelial Progenitor Cell Biology and Kinetics For Physiological Postnatal Vasculogenesis
Authors: HaruchikaMasuda, ChristophKalka, TomonoTakahashi, MiyokoYoshida, MikaWada, MichiruKobori, RieItoh, HidekiIwaguro, MasamichiEguchi, YoIwami, RicaTanaka, YoshihiroNakagawa, AtsuhikoSugimoto, SayakaNinomiya, ShinichiroHayashi, ShunichiKato, TakayukiAsahara
Journal: Circulation Research (2007)

Estrogen has been demonstrated to promote therapeutic reendothelialization after vascular injury by bone marrow (BM)–derived endothelial progenitor cell (EPC) mobilization and phenotypic modulation. We investigated the primary hypothesis that estrogen regulates physiological postnatal vasculogenesis by modulating bioactivity of BM-derived EPCs through the estrogen receptor (ER), in cyclic hormonally regulated endometrial neovascularization. Cultured human EPCs from peripheral blood mononuclear cells (PB-MNCs) disclosed consistent gene expression of ER α as well as downregulated gene expressions of ER β. Under the physiological concentrations of estrogen (17β-estradiol, E2), proliferation and migration were stimulated, whereas apoptosis was inhibited on day 7 cultured EPCs. These estrogen-induced activities were blocked by the receptor antagonist, ICI182,780 (ICI). In BM transplanted (BMT) mice with ovariectomy (OVX) from transgenic mice overexpressing β-galactosidase (lacZ) regulated by an endothelial spe...