tbuckley/cabot-search huggingface dataset:
Functional Evidence for a Role of Vascular Chymase in the Production of Angiotensin II in Isolated Human Arteries
Authors: VincentRichard, SoniaHurel-Merle, ElizabethScalbert, GillesFerry, FrançoiseLallemand, Jean-PaulBessou, ChristianThuillez
Journal: Circulation (2001)

Background In human arteries, angiotensin-converting enzyme (ACE) inhibitors incompletely block the production of angiotensin (Ang) II from Ang I. This ACE-independent production of Ang II appears to be caused by serine proteases, one of which presumably is chymase. However, several serine proteases may produce Ang II, and the exact role of chymase in the vascular production of Ang II has never been directly evaluated using selective chymase inhibitors. Methods and Results Rings of human mammary arteries were subjected to either Ang I or the chymase-selective substrate [pro,11 D-Ala12] Ang I in the absence or the presence of the ACE inhibitor captopril, the serine protease inhibitor chymostatin, or the selective chymase inhibitor C41. Captopril only partially inhibited (by 33%) the response to Ang I. In the absence of captopril, C41 markedly reduced (by 44%) the response to Ang I, and this effect was identical to that of chymostatin. C41 also significantly reduced the response to Ang I in the presence of ...
Depletion of Intracellular Ca2+ Stores Sensitizes the Flow-Induced Ca2+ Influx in Rat Endothelial Cells
Authors: Hiu-YeeKwan, Pan-CheungLeung, YuHuang, XiaoqiangYao
Journal: Circulation Research (2003)

Hemodynamic shear stress elicits a rise in endothelial [Ca2+]i, which may serve as a key second messenger to regulate many flow-associated physiological and biochemical processes. In the present study, we used Mn2+ quenching of fluorescent dye Fluo3 as an assay to investigate the Ca2+ influx of rat aortic endothelial cells in response to flow. We found that the Ca2+ signaling in response to flow could be greatly influenced by the status of intracellular Ca2+ stores. Depletion of intracellular Ca2+ stores by thapsigargin (4 μmol/L) or cyclopiazonic acid (10 μmol/L) drastically sensitized the Ca2+ influx in response to flow. Ca2+-mobilizing agonist bradykinin (100 nmol/L) or ATP (100 μmol/L) had similar sensitizing effect. The effect of bradykinin or ATP was blocked by Xestospongin C and U73122, suggesting that the sensitization was related to the IP3-mediated store depletion. On the other hand, the Mn2+ quenching in response to flow was greatly reduced by ochratoxin A (100 nmol/L), an agent that could incr...
Abstract CT098: Phase Ib/II, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)
Authors: Ezra Cohen, Sarwan Bishnoi, Douglas E. Laux, Deborah Wong, Asim Amin, Lisle Nabell, Emmett V. Schmidt, Biao Xing, Abraham C. Leung, Robert Janssen
Journal: Cancer Research (2018)

Abstract Background and Objectives: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembrolizumab is a PD-1 inhibitor that has demonstrated activity in HNSCC with ORR of 14%. Study DV3-MEL-01 (NCT02521870) assesses the safety and preliminary efficacy of SD-101 in combination with pembrolizumab in patients with recurrent or metastatic HNSCC. Methods: In phase 2 expansion cohort for anti-PD-1 treatment naïve HNSCC patients, SD-101 was injected in a single tumor lesion (weekly x 4 doses then every 3 weeks x 7 doses) at 8 mg and pembrolizumab was administered intravenously at 200 mg every 3 weeks. Responses are assessed per investigator using RECIST v1.1/irRECIST. Preliminary Data and Results: 16 anti-PD-1 treatment naïve HNSCC patients are enrolled to date: median age 65 y/o, male 94%, ECOG PS1 63%, median prior lines of therapy 1. SD-101 safety profile consists of flu-like symptoms and injection-site reactions. Grade≥3 treatment-related AEs observed to date included influenza-like symptoms, myalgia, headache, injection site pain and swelling, and fatigue with each of the toxicities occurring in 1 patient (6.7%). No increase in frequency of known pembrolizumab immune-related AEs has been observed to date. ORR in evaluable pts (n=10) was 40% (4 PRs; 1 SD, 5 PDs with 1 still on treatment). The duration of response will be characterized when follow-up data become more mature. Conclusions: In anti-PD-1 treatment naïve HNSCC patients, SD-101 in combination with pembrolizumab showed a promising response rate and has been well tolerated. Full accrual of subjects in this cohort is ongoing. Citation Format: Ezra Cohen, Sarwan Bishnoi, Douglas E. Laux, Deborah Wong, Asim Amin, Lisle Nabell, Emmett V. Schmidt, Biao Xing, Abraham C. Leung, Robert Janssen. Phase Ib/II, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) [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 CT098.
Late Gadolinium Enhancement in Patients With Hypertrophic Cardiomyopathy and Preserved Systolic Function
Authors: Amgad Mentias, Pejman Raeisi-Giglou, Nicholas G. Smedira, Ke Feng, Kimi Sato, Oussama Wazni, Mohamad Kanj, Scott D. Flamm, Maran Thamilarasan, Zoran B. Popovic, Harry M. Lever, Milind Y. Desai
Journal: Journal of the American College of Cardiology (2018)
Alternation in the Coronary Blood Flow Velocity Pattern in Patients With No Reflow and Reperfused Acute Myocardial Infarction
Authors: KatsuomiIwakura, HiroshiIto, ShinTakiuchi, YoshiakiTaniyama, YoshiakiNakatsuchi, ShinjiNegoro, YorihikoHigashino, AtsunoriOkamura, TohruMasuyama, MasatsuguHori, KenshiFujii, TakazoMinamino
Journal: Circulation (1996)

Background Experimental and clinical evidence indicates that myocardial ischemia often damages the coronary microvasculature (“no-reflow” phenomenon). In this study, we examined the effect of this phenomenon on the coronary blood flow velocity pattern in patients with reperfused acute myocardial infarction. Methods and Results We measured coronary blood flow velocity after coronary angioplasty in 42 patients with acute myocardial infarction using a Doppler guidewire. Myocardial contrast echocardiography (MCE) was also performed before and after angioplasty. Thirty-one patients showed good contrast reperfusion (MCE reflow), whereas the other 11 showed no reflow (MCE no reflow). Peak velocity and duration of systolic coronary flow were significantly less in patients with MCE no reflow than in those with MCE reflow (8±4 versus 17±10 cm/s and 207±79 versus 289±55 ms, respectively; P<.01). Early systolic retrograde flow was frequently observed in patients with MCE no reflow, whereas it was observed in only 1 p...
Integrin-Linked Kinase Regulates Vasomotor Function by Preventing Endothelial Nitric Oxide Synthase Uncoupling
Authors: BeatrizHerranz, SusanaMarquez, BrendaGuijarro, EnriqueAracil, ClaraAicart-Ramos, IgnacioRodriguez-Crespo, IsabelSerrano, ManuelRodríguez-Puyol, CarlosZaragoza, MartaSaura
Journal: Circulation Research (2012)

Rationale:Atherosclerotic lesions develop in regions of disturbed flow, whereas laminar flow protects from atherogenesis; however, the mechanisms involved are not completely elucidated. Integrins are mechanosensors of shear stress in endothelial cells, and integrin-linked kinase (ILK) is important for blood vessel integrity and cardiovascular development. Objectives:To explore the role of ILK in vascular function by studying conditionally ILK-deficient (cKO) mice and human atherosclerotic arteries. Results:ILK expression was detected in the endothelial cell layer of nonatherosclerotic vessels but was absent from the endothelium of atherosclerotic arteries. Live ultrasound imaging revealed that acetylcholine-mediated vasodilatation was impaired in cKO mice. These mice exhibited lowered agonist-induced nitric oxide synthase (NOS) activity and decreased cyclic guanosine monophosphate and nitrite production. ILK deletion caused endothelial NOS (eNOS) uncoupling, reflected in reduced tetrahydrobiopterin (BH4) ...
Abstract 17760: Safety and Reliability of Low Dose Contrast CT Angiography in Preoperative Evaluation of Renal Dysfunction Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Cheng Chu, Vadim Spektor, Michael Sadler, Saman Kiumehr, Varun Malik, Patricia Panfile, Mark Russo, Bruce Haik, Paul Burn, Marc Cohen, Chunguang Chen
Journal: Circulation (2014)

Introduction:  Cardiac and peripheral CT Angiography (CTA) is required for pre-operative evaluation of transcatheter aortic valve replacement (TAVR) in high risk patients who often have renal dysfunction. Standard doses of IV contrast may exaggerate renal dysfunction which affects survival in TAVR patients. The purpose of this study is to evaluate safety and diagnostic accuracy of low dose contrast (LDC) for both pre-operative cardiac and peripheral CTA assessment compared to standard dose contrast (SDC).   Methods:  In 130 patients who underwent TAVR at a single institution during 2012 and 2013, SDC (≥60 ml of Omnipaque) was given to 83 patients with eGFR>40 and LDC (   Results:  LDC group received 46.17±7.95 ml and SDC group 65.66 ±10.02 ml of contrast (p   Conclusion:  Low dose contrast for cardiac and peripheral CTA (40-60 ml) in one scan is safe and reliable for pre-TAVR evaluation in patients with significantly impaired renal function.
Abstract LB-188: POH1 knockdown induces cancer cell apoptosis via p53 and Bim
Authors: Shi-Lu Chen
Journal: Cancer Research (2018)

Abstract The ubiquitin-proteasome system is implicated in cell apoptosis that is frequently dysregulated in human cancers. POH1/rpn11/PSMD14, as a part of the 19S proteasomal subunit, contributes to the progression of malignancy, but its role in apoptosis remains unclear. Here, we showed that POH1 expression was increased and associated with poor outcomes in three independent cohorts of patients with hepatocellular carcinoma (HCC), esophageal cancer (EC), and colorectal cancer (CRC). The knockdown of POH1 significantly inhibited tumor cell proliferation and induced apoptosis mediated by the mitochondrial pathway in vitro. Intratumoral injection of POH1 small interfering RNA (siRNA) significantly reduced the progression of tumor growth and induced apoptosis in vivo. Furthermore, p53 or Bim siRNA markedly attenuated the apoptosis induced by POH1 depletion. POH1 depletion resulted in cell apoptosis by increasing the stability of p53 and Bim and inhibiting their ubiquitination. Overall, POH1 knockdown induced cell apoptosis through increased expression of p53 and Bim via enhanced protein stability and attenuated degradation. Thus, POH1 may serve as a potential prognostic marker and therapeutic target in human cancers. Citation Format: Shi-Lu Chen. POH1 knockdown induces cancer cell apoptosis via p53 and Bim [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 LB-188.
A Redox-Based Mechanism for Cardioprotection Induced by Ischemic Preconditioning in Perfused Rat Heart
Authors: WeinaChen, ScottGabel, CharlesSteenbergen, ElizabethMurphy
Journal: Circulation Research (1995)

Abstract Recent studies have suggested that mild redox alterations can regulate cell function. Therefore, we tested the hypothesis that alteration in the thiol redox state might be responsible for the cardioprotective effects conferred by ischemic preconditioning in the perfused rat heart. We find that preconditioning with four 5-minute periods of ischemia, each separated by 5 minutes of reflow, is associated with a significant loss of glutathione (3.98±0.32 μmol/g dry wt, n=8) compared with no preconditioning (6.38±0.24 μmol/g dry wt, n=14). We further find that the addition of N-acetylcysteine (NAC, a glutathione precursor and antioxidant) during the preconditioning protocol not only blocks the loss of glutathione (5.60±0.31 μmol/g dry wt, n=9) but also blocks the protective effects of preconditioning. It is observed that after 20 minutes of ischemia followed by 20 minutes of reflow, untreated hearts recover 38±7% (n=5) of their initial preischemic contractile function, whereas preconditioned hearts rec...
Angiotensin II Type 2 Receptor Mediates Vascular Smooth Muscle Cell Apoptosis in Cystic Medial Degeneration Associated With Marfan’s Syndrome
Authors: Hirotaka Nagashima, Yasunari Sakomura, Yoshikazu Aoka, Kenta Uto, Kin-ichi Kameyama, Motoko Ogawa, Shigeyuki Aomi, Hitoshi Koyanagi, Naoko Ishizuka, Mitsuhide Naruse, Masatoshi Kawana, Hiroshi Kasanuki
Journal: Circulation (2001)

Background Cystic medial degeneration (CMD) is a histological abnormality that is common in the aortic diseases associated with Marfan’s syndrome (MFS). Although little known about the mechanism underlying CMD, several recent reports have demonstrated that vascular smooth muscle cell (VSMC) apoptosis could play a substantial role in CMD. On the other hand, angiotensin II (Ang II) has been reported to play an important role in the regulation of VSMC growth and apoptosis via the Ang II type 1 receptor (AT1R) and type 2 receptor (AT2R). Methods and Results To elucidate the role of Ang II signaling via the Ang II receptors in CMD, we investigated AT1R and AT2R mRNA expression and tissue concentration of Ang II in MFS aortas (n=10) and control aortas (n=12). Furthermore, we examined the effects of an ACE inhibitor, an AT1R blocker, and an AT2R blocker on serum deprivation-induced VSMC apoptosis by organ culture system. AT1R expression was significantly decreased ( P &lt;0.01) and AT2R expression was significantly increased ( P &lt;0.001) in MFS aortas compared with control aortas, and tissue Ang II concentration was significantly higher in CMD than in the control condition ( P &lt;0.01). Both the ACE inhibitor and AT2R blocker significantly inhibited serum deprivation-induced VSMC apoptosis ( P &lt;0.05), although the AT1R blocker did not inhibit apoptosis in cultured aortic media from MFS patients. Conclusions Accelerated ACE-dependent Ang II formation and signaling via upregulated AT2R play a pivotal role in VSMC apoptosis in CMD, and the ACE inhibitor could have clinical value in the prevention and treatment of CMD.
Abstract 11304: Depression Predicts Higher Levels of Cardiac Sympathetic Innervation in Patients With Post Acute Coronary Syndrome - PULSE Pilot Study
Authors: JamesPeacock, SabahatBokhari, TomasBorda, AnupamaBhimavarapu, MatthewBurg, KarinaDavidson, WilliamWhang
Journal: Circulation (2013)

BACKGROUND: Depression predicts cardiac mortality after acute coronary syndrome (ACS), and may be mediated by abnormal cardiac sympathetic activity. We hypothesized that depressed post-ACS patients would have dysregulated cardiac sympathetic innervation compared with non-depressed patients quantified by [123I]meta-iodobenzylguanidine (mIBG) imaging. METHODS: Post-ACS patients, recruited between June 2012 and January 2013, underwent planar and single photon emission tomography (SPECT) imaging with mIBG at 25 minutes (early) and 3 hours and 50 minutes (late) after injection, along with (99mTc) sestamibi SPECT myocardial perfusion imaging (MPI). Studies were read by a blinded nuclear cardiologist, using the standard 17-segment/five point model. For identification of mIBG defects resulting from sympathetic denervation (as opposed to hypoperfusion or scar), the summed difference between late mIBG defect score and MPI defect score (mismatch score) was used as the primary outcome variable. Depressed group status...
Abstract 19: Trastuzumab resistance accompanies vasculogenic mimicry in HER2-positive breast cancer cells
Authors: Masafumi Shimoda, Ami Hori, Shinzaburo Noguchi
Journal: Cancer Research (2018)

Abstract Trastuzumab (Tzm) is a drug that targets HER2/ERBB2/Neu, and is essential for the treatment of HER2-positive breast cancer. However, resistance to the drug is a major obstacle in controlling the progression of this devastating disease. We hypothesized that Tzm load might induce a phenotypic change in HER2-positive breast cancer cells, enabling them to escape and survive Tzm activity. We conducted comprehensive immunophenotyping to detect the phenotypic changes in HER2-positive breast cancer cells loaded with Tzm, and compared the immunophenotype of Tzm-loaded cells with that of control cells based on the criteria determined a priori. Out of 242 cell surface antigens, 9 antigens were significantly upregulated and 3 were significantly downregulated. Surprisingly, all the antigens were related to endothelial and stem cell phenotypes, suggesting that Tzm load induced vasculogenic mimicry (VM). Moreover, we found VM markers like COX2, MMP2, MMP14, phospho-SMAD2/3, VEGFA, HIF1A, and TWIST1 to be upregulated in Tzm-loaded cells. However, Tzm-loaded cells did not exhibit tube formation on Matrigel, a hallmark of VM. Since the Tzm-loaded cells were still sensitive to Tzm, we used three Tzm-resistant cell lines to investigate if Tzm resistance accompanied VM. All Tzm-resistant cell lines exhibited tube formation on Matrigel. Importantly, several growth factors including EGF, FGF2, IGF1, and VEGF promoted VM in these cells, suggesting that single molecular-targeted drugs did not effectively inhibit VM as other growth factors could quickly compensate the VM pathways. We then examined if eribulin, a tubulin-binding chemotherapeutic drug that promotes vascular remodeling, inhibited VM in Tzm-resistant cells. Eribulin inhibited tube formation in Tzm-resistant cells at a clinically relevant concentration. In conclusion, Tzm load induces an incomplete vasculogenic phenotype in HER2-positive breast cancer cells. The cells exhibit VM after eventually acquiring Tzm resistance. Since VM drives metastasis, its regulation in Tzm-resistant HER2-positive breast cancer appears to be a promising approach in suppressing the progression of HER2-positive breast cancer. Citation Format: Masafumi Shimoda, Ami Hori, Shinzaburo Noguchi. Trastuzumab resistance accompanies vasculogenic mimicry in HER2-positive breast cancer 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 19.
Abstract 2871: Diosgenin inhibits the proliferation of MCF-7 breast cancer cells through the demethylation of miR-145 gene
Authors: Fengqin Shi, Lingeng Lu, Ya Li, Li Hou, Xinyi Chen, Han Rui, Chong Wang, Ya Yue
Journal: Cancer Research (2018)

Abstract Background: Altered DNA methylation in microRNA (miRNA) host genes has been frequently associated with abnormal miRNA expression during the pathogenesis of cancer. miR-145 was identified as a tumor-suppressive miRNA that was down-regulated in several cancer types. Accumulating evidence has clearly demonstrated that a low expression of miR-145 in breast cancer was correlated with an aberrant hypermethylation in its host gene. Diosgenin is a steriod saponin, which is extracted from the tubers of Dioscorea wild yam. The anti-tumor mechanisms of diosgenin have been demonstrated via the modulation of multiple cell signaling pathways, which are associated with growth, differentiation, apoptosis and oncogenesis. However, there is little information regarding the epigenetic-based effects of Diosgenin in breast cancer. In our study, we hypothesize that Diosgenin has anti-proliferative effects on breast cancer cells through the demethylation of miR-145. Material and Methods: MCF-10A breast epithelial cells and MCF-7 breast cancer cells were used to investigate the effects of Diosgenin on the expression and methylation of miR-145 using real time-PCR (RT-PCR) and methylation-specific PCR (MSP), respectively. An MTS proliferation assay was performed to assess the effect of Diosgenin on the proliferation of MCF-7 breast cancer cell. Result: In comparison with MCF-10A breast epithelial cells, MCF-7 breast cancer cells showed the hypermethylation of miR-145, and significantly down-regulated miR-145 expression. Diosgenin treatment led to proliferation inhibition of MCF-7 breast cancer cells. In MCF-7 breast cancer cells, the Diosgenin treatment led to significantly up-regulated miR-145, whereas the methylation level of miR-145 significantly decreased. Conclusion: Diosgenin, a natural compound, exhibits an anti-proliferative effect on breast cancer cells, and affects the methylation and expression of miR-145. These findings indicate that the demethylation of miR-145 may be a molecular mechanism underlying the anti-tumor of Diosgenin in breast cancer. Citation Format: Fengqin Shi, Lingeng Lu, Ya Li, Li Hou, Xinyi Chen, Han Rui, Chong Wang, Ya Yue. Diosgenin inhibits the proliferation of MCF-7 breast cancer cells through the demethylation of miR-145 gene [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 2871.
Photoelastic Stress Analysis of Silastic Poppets in Prosthetic Heart Valves
Authors: Harveygreenfield, Thomashampton, Haroldgascoigne, Willemkolff
Journal: Circulation Research (1973)

Some prosthetic heart valves with Silastic ball poppets undergo degeneration and variance. The problem is avoided with metal poppets; however, their impact can damage the cloth coverings on the struts, resulting in distorted blood flow paths. Consequently, renewed interest in mild-cured Silastic poppets and inserts is developing. With photostress equipment, we analyzed two spherical poppet models to study poppet degeneration. The first analysis simulated the ring type of loading transmitted from the valve seat to the poppet, and the second analysis involved hydrostatic pressure loading and a detailed stress analysis to simulate cage confrontation. Results showed that regions of the poppet were susceptible to stress cycling with relatively large tensions below the upper surface but above the ring support. This same location could experience large compressive stress, depending on how the poppet was positioned during a seating stroke. Shear stresses near the valve support ring were at least four times the hy...