tbuckley/cabot-search huggingface dataset:
Abstract 5448: The role of CLCA2 in cell proliferation and survival of HNSCC—potential biomarker for sensitivity to EGFR inhibitors
Authors: Yufang Yin, Randolph C. Elble
Journal: Cancer Research (2018)

Abstract Head and neck squamous cell carcinoma (HNSCC) develops in mucous membranes that line the mouth, throat and sinuses. Late stage disease has a poor prognosis, with 5 year survival less than 50%. The epidermal growth factor receptor (EGFR) is overexpressed in more than 90% of HNSCC, and the inhibition of EGFR is an established therapeutic strategy for HNSCC. However, sensitivity to EGFR-targeted therapy cannot be predicted from the expression level of EGFR. Only a subset of HNSCC patients benefit from anti-EGFR targeted therapy, suggesting that additional unknown pathways are involved in EGFR activation. We found that chloride channel accessory 2 (CLCA2) is frequently overexpressed in HNSCC and that its expression level predicts sensitivity to EGFR inhibitors in HNSCC cell lines. Knockdown of CLCA2 in HNSCC cancer cell line Fadu inhibited cell proliferation and sensitized cells to anoikis. Mechanistically, CLCA2 knockdown reduced EGFR signaling, which subsequently attenuated extracellular signal-regulated kinase (ERK). In addition, surface localization of cell-cell adhesion molecule E-cadherin was inhibited, corresponding to reduced cell aggregation. CLCA2 has recently been identified as a positive regulator of store operated calcium influx, and both EGFR activation and E-cadherin surface localization are known to depend on intracellular calcium release. We propose that CLCA2 overexpression in HNSCC allows the cell to better exploit EGFR proliferative signaling and protects from anoikis by promoting cell-cell aggregation. Thus, CLCA2 may serve both as a biomarker for sensitivity to EGFR inhibitors and as a target for inhibition itself. Citation Format: Yufang Yin, Randolph C. Elble. The role of CLCA2 in cell proliferation and survival of HNSCC—potential biomarker for sensitivity to EGFR inhibitors [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 5448.
Abstract 14857: Incidence and its Characteristics of Repetition of Reintervention After Drug-Eluting Stent implantation for Femoropopliteal Lesion
Authors: Osamu Iida, Mitsuyoshi Takahara, Yoshimitsu Soga, Keisuke Hirano, Yasutaka Yamauchi, Kan Zen, Hiroyoshi Yokoi, Masaaki Uematsu
Journal: Circulation (2016)

Background: Although clinical trials demonstrated the superiority of Zilver paclitaxel-eluting stent (PTX), a recently developed drug-eluting stent (DES), to conventional therapy for femoropoplitea...
Human peroxidasin 1 promotes angiogenesis through ERK1/2, Akt, and FAK pathways
Authors: Hayfa Medfai, Alia Khalil, Alexandre Rousseau, Vincent Nuyens, Martina Paumann-Page, Benjamin Sevcnikar, Paul G Furtmüller, Christian Obinger, Nicole Moguilevsky, Olivier Peulen, Michael Herfs, Vincent Castronovo, Mohamed Amri, Pierre Van Antwerpen, Luc Vanhamme, Karim Zouaoui Boudjeltia
Journal: Cardiovascular Research (2018)

The term angiogenesis refers to sprouting of new blood vessels from pre-existing ones. The angiogenic process involves cell migration and tubulogenesis requiring interaction between endothelial cells and the extracellular matrix. Human peroxidasin 1 (hsPxd01) is a multidomain heme peroxidase found embedded in the basement membranes. As it promotes the stabilization of extracellular matrix, we investigated its possible role in angiogenesis both in vitro and in vivo. We analysed the effects of peroxidasin 1 gene silencing and supplementation by recombinant hsPxd01 in TeloHAEC endothelial cells on cell migration, tubulogenesis in matrigel, and intracellular signal transduction as assessed by kinase phosphorylation and expression of pro-angiogenic genes as measured by qRT–PCR. We further evaluated the angiogenic potential of recombinant peroxidasin in a chicken chorioallantoic membrane model. RNA silencing of endogenous hsPxd01 significantly reduced tube formation and cell migration, whereas supplementation by the recombinant peroxidase promoted tube formation in vitro and stimulated vascularization in vivo through its catalytic activity. Moreover, recombinant hsPxd01 promoted phosphorylation of Extracellular signal-Regulated Kinases (ERK1/2), Protein kinase B (Akt), and Focal Adhesion Kinase (FAK), and induced the expression of pro-angiogenic downstream genes: Platelet Derived Growth Factor Subunit B (PDGFB), endothelial-derived Heparin Binding EGF-like growth factor (HB-EGF), CXCL-1, Hairy-Related Transcription Factor 1 (HEY-1), DNA-binding protein inhibitor (ID-2), Snail Family Zinc Finger 1 (SNAI-1), as well as endogenous hsPxd01. However, peroxidasin silencing significantly reduced Akt and FAK phosphorylation but induced ERK1/2 activation after supplementation by recombinant hsPxd01. While hsPxd01 silencing significantly reduced expression of HEY-1, ID-2, and PDGFB, it did not affect expression of SNAI-1, HB-EGF, and CXCL-1 after supplementation by recombinant hsPxd01. Our findings suggest a role of enzymatically active peroxidasin 1 as a pro-angiogenic peroxidase and a modulator of ERK1/2, Akt and FAK signalling.
Abstract 18663: Reference Values for Left Ventricular Strain by Velocity Vector Imaging in Normal Individuals: Impact of Technical and Clinical Confounders.
Authors: Nishaki Mehta, Zachry Zichittella, Marcello Chinali, Gerard P Aurigemma, Heera Pokhrel, Jeffrey C Hill, Dennis A Tighe
Journal: Circulation (2010)

Background: Velocity Vector Strain Imaging (VVI-e) is an off-line ultrasound technique which measures e at both the endocardial and epicardial level; importantly, it permits e analysis of DICOM ima...
Neuroscientifically Informed Formulation and Treatment Planning for Patients With Obsessive-Compulsive Disorder
Authors: Darin D. Dougherty, Brian P. Brennan, S. Evelyn Stewart, Sabine Wilhelm, Alik S. Widge, Scott L. Rauch
Journal: JAMA Psychiatry (2018)

Obsessive-compulsive disorder (OCD) is a common and often debilitating psychiatric illness. Recent advances in the understanding of the neuroscience of OCD have provided valuable insights that have begun to transform the way we think about the management of this disorder. This educational review provides an integrated neuroscience perspective on formulation and treatment planning for patients with OCD. The article is organized around key neuroscience themes most relevant for OCD.An integrated neuroscience formulation of OCD is predicated on a fundamental understanding of phenomenology and symptom dimensions, fear conditioning and extinction, neurochemistry, genetics and animal models, as well as neurocircuitry and neurotherapeutics. Symptom dimensions provide a means to better understand the phenotypic heterogeneity within OCD with an eye toward more personalized treatments. The concept of abnormal fear extinction is central to OCD and to the underlying therapeutic mechanism of exposure and response prevention. A framework for understanding the neurochemistry of OCD focuses on both traditional monoaminergic systems and more recent evidence of glutamatergic and γ-aminobutyric acid-ergic dysfunction. Obsessive-compulsive disorder is highly heritable, and future work is needed to understand the contribution of genes to underlying pathophysiology. A circuit dysregulation framework focuses on cortico-striato-thalamo-cortical circuit dysfunction and the development of neurotherapeutic approaches targeting this circuit. The impact of these concepts on how we think about OCD diagnosis and treatment is discussed. Suggestions for future investigations that have the potential to further enhance the clinical management of OCD are presented.These key neuroscience themes collectively inform formulation and treatment planning for patients with OCD. The ultimate goal is to increase crosstalk between clinicians and researchers in an effort to facilitate translation of advances in neuroscience research to improved care for patients with OCD.
Significance of Ventricular Myocytes and Nonmyocytes Interaction During Cardiocyte Hypertrophy
Authors: MasakiHarada, HiroshiItoh, OsamuNakagawa, YoshihiroOgawa, YoshihiroMiyamoto, KoichiroKuwahara, EmikoOgawa, ToshioIgaki, JunYamashita, IzuruMasuda, TakaakiYoshimasa, IsseiTanaka, YoshihikoSaito, KazuwaNakao
Journal: Circulation (1997)

Background In cardiac hypertrophy, both excessive enlargement of cardiac myocytes and progressive interstitial fibrosis are well known to occur simultaneously. In the present study, to investigate the interaction between ventricular myocytes (MCs) and cardiac nonmyocytes (NMCs), mostly fibroblasts, during cardiocytes hypertrophy, we examined the change in cell size and gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cultured MCs as markers for hypertrophy in the neonatal rat ventricular cardiac cell culture system. Methods and Results The size of cultured MCs significantly increased in the MC-NMC coculture. Concomitantly, secretions of ANP and BNP into culture media were significantly increased in the MC-NMC coculture compared with in the MC culture (with the possible contamination of NMC <1% of MC). Moreover, in the MC culture, enlargement of MC and an increase in ANP and BNP secretions were induced by treatment with conditioned media of the NMC culture. A consi...
Abstract 30: miR34a Affects the Functional Potential of Human Cardiac Progenitor Cells
Authors: Rachana Mishra, Sudhish Sharma, Wen C Cheng, Tami J Kingsbury, Progyaparamita Saha, Curt I Civin, Sunjay Kaushal
Journal: Circulation Research (2017)

Background: miR-34a expression is increased in adult hearts and promotes age- associated cardiomyocyte cell death. Here we explored the effect of miR-34a on the secretome of cardiac progenitor cells (CPCs) and their potential to recover the myocardial functional and tissue regeneration in response to injury. Hypothesis: We hypothesize that miR-34a/HSF1 pathway is directly involved in controlling the functional activity of CPCs during chronological aging. Methods: Human specimens were obtained during routine cardiac surgical procedures from right atrial appendage tissue discarded from 2 age groups: neonates and adults patients. We developed a reproducible isolation method that generated c-kit + Cd45 - cells using immune-activated magnetic bead selection, regardless of the initial weight or age. Results and Conclusion: Here we are reporting a novel finding that knock down of miR-34a in adult-derived CPCs (aCPCs) significantly increases their cell survival, paracrine secretion that directly correlated with significantly improved LV function in the myocardial infarcted (MI) rodent model in comparison to aCPCs. Previously, we have showed that heat shock factor 1 (HSF1) is the key chaperone pathway that affects CPC’s growth potential and functional activity. Here we are showing that up-regulation of miR-34a in CPCs are attributed towards down regulation of HSF1 and their paracrine secretion. Data showed not only novel insights into the effects of miR34a/heat shock pathway on CPCs survival and controlling their paracrine behavior but it is also paramount to characterize and dissect the mechanism of cell therapy in order to generate the most optimally designed clinical trial in adult heart -failure patients.
Myocardial Mechanical Responses and Ionic Exchange in High-Sodium Perfusate
Authors: J. H. TILLISCH, G. A. LANGER
Journal: Circulation Research (1974)

The effects of an extracellular sodium (Na) concentration of 200 m M on function, ionic exchange, and water movements were examined in the vascularly perfused rabbit intraventricular septum. When the perfusate was switched from 1.42 m M Na to 200 m M Na, dP/dt fell 20.4% over 2 minutes; dP/dt then recovered to the control level. The time course of the functional recovery correlated with the uptake of Na into the slowly exchangeable fraction of the tissue, and the rate of recovery in 200 m M Na depended on the frequency of contraction of the preparation. During perfusion with 200 m M Na, a 41% increase in slow-phase Na content compared with the content during perfusion with 142 m M Na was observed. The hyperosmolar perfusate induced a 21% cellular dehydration within 10 minutes as estimated from measurement of 10-minute 35 SO 4 space and total tissue water. The time course of dehydration was much more rapid than the time course of functional recovery. Calcium (Ca) influx during the period when dP/dt had returned to control levels in 200 m M Na was the same as it was during a control period in 1.42 m M Na. Thus, there appears to be a Na-Ca exchange system which enhances Ca influx and thus causes an inotropic effect in response to an increase in intracellular Na concentration.
Electrical Stimulation Versus Coronary Artery Bypass Surgery in Severe Angina Pectoris
Authors: ClasMannheimer, ToreEliasson, Lars-ErikAugustinsson, ChristianBlomstrand, HåkanEmanuelsson, StureLarsson, HenrikNorrsell, ÅkeHjalmarsson
Journal: Circulation (1998)

Background—Spinal cord stimulation (SCS) has been shown to have antianginal and anti-ischemic effects in severe angina pectoris. The present study was performed to investigate whether SCS can be used as an alternative to coronary artery bypass grafting (CABG) in selected patient groups, ie, patients with no proven prognostic benefit from CABG and with an increased surgical risk. Methods and Results—One hundred four patients were randomized (SCS, 53; CABG, 51). The patients were assessed with respect to symptoms, exercise capacity, ischemic ECG changes during exercise, rate-pressure product, mortality, and cardiovascular morbidity before and 6 months after the operation. Both groups had adequate symptom relief (P<.0001), and there was no difference between SCS and CABG. The CABG group had an increase in exercise capacity (P=.02), less ST-segment depression on maximum (P=.005) and comparable (P=.0009) workloads, and an increase in the rate-pressure product both at maximum (P=.0003) and comparable (P=.03) wo...
Abstract 10199: Right Atrial Fibrillation in Humans - <i>Evidence for A Right Atrial Driver Activated by Right Atrial Ectopies</i>
Authors: Hideyuki Hasebe, Kentaro Yoshida, Masataka Iida, Naoki Hatano, Toshiro Muramatsu, Kazutaka Aonuma
Journal: Circulation (2015)

Background: A left-to-right dominant frequency (DF) gradient exists in acute atrial fibrillation (AF) in animals and in paroxysmal AF (PAF) in humans. PAF initiated by right atrial ectopy (PAF-RAE) is rare. Adenosine triphosphate (ATP) can be effective to unmask such a rare non-pulmonary vein (PV) ectopy and accelerate the frequency of a reentrant source of AF (driver). Objective: This study aimed to investigate characteristics of patients with PAF-RAE using pharmacological maneuvers and spectral analysis. Methods: Enrolled were 111 consecutive patients referred for catheter ablation of lone PAF. Infusions of isoproterenol and ATP were used to induce AF. Patients with PAF initiated only by PV ectopies and with PAF-RAE were classified into the PV-ectopy group (N=32) and RA-ectopy group (N=6), respectively. ATP was also injected during ongoing AF to unmask the AF driver. High RA, coronary sinus (CS), and PV-left atrial junction (PV-LAJ) electrograms underwent spectral analyses. Results: RA-ectopy group patients were younger (49±13 vs. 63±7 years, p&lt;0.001), more commonly had a family history of AF (67% vs. 9%, p&lt;0.001), and had a higher RA appendage/RA volume ratio (0.22±0.022 vs. 0.15±0.055, p=0.002) than PV-ectopygroup patients. The most common origin of RA ectopy was the base of the RA appendage (67%). There was a baseline right-to-left DF gradient in the RA-ectopy group (PV-LAJ: 6.0±0.4, CS: 5.7±0.7, RA: 7.4±0.8 Hz, p&lt;0.05), in contrast to a left-to-right DF gradient in the PV-ectopy group (PV-LAJ: 5.9±0.8, CS: 5.3±0.7, RA: 5.2±0.8 Hz, p&lt;0.01). ATP injection mainly increased the DF of the high RA, augmenting a right-to-left DF gradient in the RA ectopy group (PV-LAJ: 8.0±2.0, CS: 7.8±1.0, RA: 10.7±0.7 Hz, p&lt;0.05), whereas it augmented a left-to-right DF gradient in the PV-ectopy group (PV-LAJ: 7.9±1.0, CS: 6.4±0.5, RA: 6.6±1.2 Hz, p&lt;0.05). Conclusions: PAF-RAE may be maintained by a reentrant driver localized in the RA (so-called right atrial fibrillation).
Role of Bradykinin in Mediating Vascular Effects of Angiotensin-Converting Enzyme Inhibitors in Humans
Authors: BurkhardHornig, ChristophKohler, HelmutDrexler
Journal: Circulation (1997)

Background The angiotensin-converting enzyme (ACE) not only generates angiotensin II but is also the main enzyme that destroys bradykinin. It has been hypothesized, therefore, that bradykinin is involved in the vascular effects of ACE inhibitors. However, its contribution has never been demonstrated in humans because of the lack of specific bradykinin receptor antagonists. Methods and Results High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow in 10 healthy volunteers. The vascular effects of the ACE inhibitor quinaprilat, the selective bradykinin B2-receptor antagonist icatibant, and their combination were determined at rest, during reactive hyperemia (with increased flow causing endothelium-mediated, flow-dependent dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Neither icatibant nor quinaprilat affected arterial diameter or blood flow at rest. However, icatibant reduced flow-dependent dilation by 33%, and quinaprilat in...
Autoimmunity Against the Second Extracellular Loop of β1-Adrenergic Receptors Induces β-Adrenergic Receptor Desensitization and Myocardial Hypertrophy In Vivo
Authors: MichikadoIwata, TsutomuYoshikawa, AkiyasuBaba, ToshihisaAnzai, IwaoNakamura, YumikoWainai, ToshiyukiTakahashi, SatoshiOgawa
Journal: Circulation Research (2001)

Abstract—Although immunoapheresis removing autoantibodies against the second extracellular domain of β1-adrenergic receptors (ARs) improves cardiac function in patients with cardiomyopathy, the underlying mechanisms have not been defined. We examined the role of autoimmunity against the domain in the development of cardiac dysfunction in vivo. Japanese white rabbits were immunized with a synthetic peptide corresponding to the second extracellular loop of β1-AR once a month with (β+biso rabbits, n=10) or without (β rabbits, n=13) bisoprolol treatment (2 mg/kg per day). Control rabbits received vehicle without bisoprolol treatment (n=13). Autoantibodies of IgG isotype against the domain were persistently detected in β and β+biso rabbits. Purified IgG from sera of β and β+biso rabbits increased cAMP production in a rabbit cardiac membrane preparation, which was blocked by bisoprolol. At 3 months, β-AR uncoupling with increased G protein–coupled receptor kinase 5 (GRK5) expression was found in β rabbits. At 6...
Abstract 1918: Patient-derived hormone-naive prostate cancer xenograft models reveal <i>GRB10</i> as an AR-repressed gene driving the development of castration-resistant prostate cancer
Authors: Jun Hao, Xinpei Ci, Hui Xue, Rebecca Wu, Xin Dong, Fang Zhang, Sifeng Qu, Fan Zhang, Anne M. Haegert, Peter W. Gout, Colin Collins, Martin E. Gleave, Dong Lin, Yuzhuo Wang
Journal: Cancer Research (2018)

Abstract Prostate cancer is the most commonly diagnosed noncutaneous cancer and the leading cause of cancer-related death in North American men. Although androgen-deprivation therapy is initially effective in controlling the growth of hormone-naive prostate cancers (HNPC) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. Thus, we aim to identify CRPC driver genes that may provide new targets to enhance CRPC therapy. In this study, patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. Eighty genes were found to be significantly upregulated at the CRPC stage while 7 of them also showed elevated expression prior to CRPC development. Among the latter, Growth Factor Receptor Bound Protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, we found GRB10 expression was elevated in clinical CRPC compared to HNPC in several clinical cohorts. Further investigation suggests that GRB10 is transcriptionally regulated by androgen receptor through an androgen-responsive element located in GRB10's intron. Functionally, we found that GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. Also, a positive correlation between AKT activity and GRB10 expression was found in clinical cohorts. In conclusion, GRB10 acts as a driver of CRPC and sensitizes AR pathway inhibitors, and hence GRB10-targeting provides a novel therapeutic strategy for the disease. Citation Format: Jun Hao, Xinpei Ci, Hui Xue, Rebecca Wu, Xin Dong, Fang Zhang, Sifeng Qu, Fan Zhang, Anne M. Haegert, Peter W. Gout, Colin Collins, Martin E. Gleave, Dong Lin, Yuzhuo Wang. Patient-derived hormone-naive prostate cancer xenograft models reveal GRB10 as an AR-repressed gene driving the development of castration-resistant prostate 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 1918.
Abstract 21141: Cystathionine Gamma-Lyase Regulates Autophagy in Ischemic Endothelial Cells
Authors: Saranya Rajendran, Christopher G Kevil
Journal: Circulation (2017)

Introduction: Peripheral arterial disease (PAD) is a chronic arterial occlusive disease leading to lower limb ischemia. Autophagy is a cell adaptive response associated with ischemic stress that may act as a double edged sword. It is essential during tissue ischemia, but may also phagocytize more organelles promoting cell death. Hydrogen sulfide (H 2 S), a gasotransmitter predominantly produced in the vasculature via cystathionine-γ-lyase (CSE), play a key regulatory role in the cardiovascular functions. However, role of H 2 S/CSE in autophagy, and its associated impact on ischemic injury is poorly understood. Objective: To investigate the role of CSE/H2S in the regulation of autophagy under ischemia using murine hind limb ischemia model and in vitro studies. Methods: Unilateral femoral artery ligation (FAL) was performed on C57BL/6J(WT) mice and tissue blood perfusion was measured using laser Doppler flowmetry. LC3B expression was measured in the skeletal muscle tissues by immunohistochemistry. We utilized mouse aortic endothelial cells (MAECs) isolated from WT and CSE deficient (CSEKO) mice respectively and immortalized them. We treated WT and CSE KO MAECs were subjected to normoxia and hypoxia with and without autophagy inhibitor bafilomycin and evaluated for LC3B. ROS levels were evaluated by DCFDH. Apoptosis was measured by LDH assay and cleaved caspase-3. Results: Compared to WT, CSEKO MAECs showed significant reduction in LC3B protein expression. Reduced LC3B and p62 mRNA expressions were also observed in CSEKO cells. In the WT mice subjected to FAL, blood perfusion was significantly reduced in the ligated limbs compared to non-ligated. Interestingly, LC3B was significantly higher in ischemic muscle compared to non-ischemic tissues. Additionally, CSE genetic deletion significantly increased ROS levels that lead to increased apoptosis. CSEKO MAECs showed increased LDH activity and elevated cleaved caspase-3 expression under hypoxia. Conclusions: Our study reveals for the first time that CSE/H 2 S regulates autophagy in ischemic endothelial cells. CSE/H 2 S may be used as a therapeutic agent to protect against ischemia injury by inhibiting autophagy during PAD.