tbuckley/cabot-search huggingface dataset:
Abstract 3720: Augmented loading efficiency of doxorubicin into glioma-derived exosomes by an integrated microfluidic device
Authors: Abhimanyu Thakur, Heng Zou, Mengsu Yang, Youngjin Lee
Journal: Cancer Research (2018)

Abstract Glioma is a lethal brain cancer in the central nervous system (CNS). The therapeutic usage of potent anticancer drugs for glioma is restricted by their poor penetration across the blood-brain barrier (BBB). Current reports have revealed that cell-derived exosomes can cross the BBB, suggesting their prospective use as drug delivery vehicles for targeting glioma as well as neurological disorders. However, conventional isolation of intact, specific, and optimal exosomes for drug delivery from various donor cells is laborious and time-consuming. Particularly, increasing loading efficiency of non-hydrophobic anticancer drugs, such as doxorubicin, into exosomes has been challenged. Therefore, a single integrated microfluidic device has been developed, based on the principles of immunocapture and density-gradient-free centrifugation, using soft lithography for efficient exosome isolation and drug loading consecutively. The isolated glioma-exosomes were characterized by transmission electron microscopy (TEM), immunogold-EM, and nano tracking analyzer. The loading efficiency of doxorubicin into glioma-exosomes was evaluated by UV-visible spectrophotometer as well high performance liquid chromatography (HPLC). Furthermore, the doxorubicin loaded glioma-exosomes were treated to autologous and heterologous glioma cells, followed by evaluation with confocal microscopy. The present study has shown that our integrated microfluidic device isolates pure exosomes from glioma cells, and it dramatically increases loading efficiency of doxorubicin into the exosomes, supporting its usefulness to study the exosome-mediated drug delivery for glioma therapy. Citation Format: Abhimanyu Thakur, Heng Zou, Mengsu Yang, Youngjin Lee. Augmented loading efficiency of doxorubicin into glioma-derived exosomes by an integrated microfluidic device [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 3720.
Abstract 17061: Myocardial Strain in Prediction of the Outcomes After Surgery for Severe Mitral Regurgitation
Authors: Hyue Mee Kim, Goo-Yeong Cho, Hong-Mi Choi, Jun-Bean Park, Yeonyee E Yoon, Hyung-Kwan Kim
Journal: Circulation (2017)

Introduction: Optimal timing for surgery is guided by LV dimension or LVEF, even though normal left ventricular ejection fraction (LVEF) can mask depressed myocardial contractility in severe mitral...
Letter by Ryding et al Regarding Article, “Impact of Pretreatment With Clopidogrel on Initial Patency and Outcome in Patients Treated With Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction: A Systematic Review”
Authors: AlisdairRyding, SaurabhKumar, RavinayBhindi
Journal: Circulation (2009)
Abstract IA18: Integrin-α10 drives metastasis and sarcomagenesis in mxyofibrosarcoma and undifferentiated pleomorphic sarcoma
Authors: Samuel Singer
Journal: Clinical Cancer Research (2018)

Abstract Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are the most common and aggressive types of genetically complex sarcoma. The development of new targeted therapies is vital for improving patients' outcomes; however, the complexity of alterations in these sarcomas has made it difficult to find the true drivers of oncogenesis. To investigate the molecular basis of MFS and UPS oncogenesis and progression, we undertook gene expression and copy number profiling of a well-characterized set of 94 primary untreated high-grade MFS and UPS. Unsupervised clustering identified a subgroup associated with poor clinical outcome. This subgroup had strikingly higher expression of the integrin-α10 gene, ITGA10, and its expression was also independently associated with outcome. We therefore investigated the role of integrin-α10 in MFS and UPS cells, defined the pathways by which it exerts its effects, and tested pharmacologic inhibition of these pathways for antitumor effects both in vitro and in vivo. Silencing of integrin-α10 induces growth suppression through apoptosis in MFS and UPS cells but not in normal mesenchymal cells. Integrin-α10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had antitumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-α10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease. Citation Format: Samuel Singer. Integrin-α10 drives metastasis and sarcomagenesis in mxyofibrosarcoma and undifferentiated pleomorphic sarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA18.
Abstract 4926: Preclinical intratumoral pharmacokinetics (PK) of capecitabine (Cap) given +/- eribulin (Eri)
Authors: Maria Jove Casulleras, Jade Spencer, Paul Loadman, Malcolm Clench, Steve Shnyder, Patricia Cooper, Cristina Russo, Amanda Race, Ramon Salazar, Chris Twelves
Journal: Cancer Research (2018)

Abstract Background: Eri &amp; Cap are active as single agents in metastatic breast cancer, but the combination appears particularly active &amp; well tolerated clinically. We explored the hypothesis that normalisation of tumor vasculature by Eri seen in preclinical models may enhance delivery of Cap to the tumor when given in combination. Methods: Mice bearing MDA-MD-231 xenografts were treated with Cap 540mg/kg p.o. day 1 alone or following Eri 1mg/kg i.v. on day -8 then sacrificed on day 1 at 15min, 30min, 1h, 2h, 4h, 6h or 24h after Cap (n=3/ time point). Concentrations of Cap &amp; its metabolites (5'-deoxy-5-fluorocytidine, 5DFCR; 5-Fluoro-5'-deoxyuridine, 5DFUR; 5-Fluorouracil, 5FU; 5-Fluorouridine, 5FUrd; &amp; 5-Fluoro-2'-deoxyuridine, 5FdUrd) in plasma, tumor, skin &amp; muscle were analysed by LC-MS/MS. Half the tumor was reserved to study Cap distribution using matrix-assisted laser desorption/ionization mass spectrometry imaging with haem imaged as a surrogate marker for tumour vasculature. Results: We found no differences in the plasma, skin, muscle or tumor PK profiles of Cape &amp; its metabolites with the addition of Eri (Table 1). In both treatment arms intratumoral concentrations of 5DFUR, 5FU, 5FUrd &amp; 5FdUrd appeared higher in tumors while those of Cape &amp; 5DFCR appeared higher in normal healthy tissues. To mitigate the variability in tumor Cape concentrations between animals, we also expressed the results as the ratio of drug concentration in tumour:healthy tissue but again found no apparent effect of Eri on intratumoral drug concentrations. Analyses of drug distribution are on-going &amp; will be presented. Conclusion: No clear effect of Eri on intratumoral concentrations of Cape or its metabolites was seen. We are exploring potential differences in tumour drug distribution. Citation Format: Maria Jove Casulleras, Jade Spencer, Paul Loadman, Malcolm Clench, Steve Shnyder, Patricia Cooper, Cristina Russo, Amanda Race, Ramon Salazar, Chris Twelves. Preclinical intratumoral pharmacokinetics (PK) of capecitabine (Cap) given +/- eribulin (Eri) [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 4926.
Abstract 2470: Identification of long noncoding RNAs regulated by ZEB1 and epithelial-mesenchymal transition in lung cancer cells
Authors: Jeong Seon Kim, Young-Ho Ahn
Journal: Cancer Research (2018)

Abstract Long non-coding RNA (lncRNA) are known to have various physiological and pathological functions. Some lncRNAs also show differential expression between cancer and normal tissues and play important roles in cancer development. In this study, we tried to identify novel lncRNAs that regulate epithelial-mesenchymal transition (EMT), invasion, tumorigenesis, and metastasis of lung cancer cells. We performed an NGS-based RNA sequencing analysis in murine lung cancer cells overexpressing ZEB1, an EMT-inducing transcription factor. ZEB1 overexpression changed the expression of total 194 lncRNAs: increased 80 and decreased 114 lncRNAs (fold change≥2, p≤0.01). We then selected 32 lncRNAs with high basal levels and confirmed their differential expression by qRT-PCR. In addition, we measured their expression changes after ZEB1-knockout in mesenchymal-like cells, TGFβ-treatment in epithelial-like cells, and ZEB1-overexpression in human lung cancer cells. Through these experiments, we found several lncRNAs regulated by ZEB1 or EMT in lung cancer cells. Expressions of these lncRNAs showed correlation with that of ZEB1 in human lung adenocarcinoma TCGA data. Further investigation will unveil the effects of these lncRNAs on EMT, cancer development, and metastasis of lung cancer cells. Citation Format: Jeong Seon Kim, Young-Ho Ahn. Identification of long noncoding RNAs regulated by ZEB1 and epithelial-mesenchymal transition in lung 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 2470.
A Missense Mutation in the CHRM2 Gene Is Associated With Familial Dilated Cardiomyopathy
Authors: LinZhang, AihuaHu, HaixinYuan, LiangCui, GuobinMiao, XinchunYang, LefengWang, JinchunLiu, XiulanLiu, ShuyanWang, ZhiyongZhang, LishengLiu, RongruiZhao, YanShen
Journal: Circulation Research (2008)

Circulating autoantibodies against the M2-muscarinic acetylcholine receptor (CHRM2) have been detected in patients with dilated cardiomyopathy (DCM). However, it has yet to be determined whether the pathogenesis of familial DCM may be linked to the genetic variability of the CHRM2 gene. The coding regions of the CHRM2 gene were examined by direct DNA sequencing. Plasma concentrations of autoantibodies against CHRM2 were determined by ELISA in 7 unrelated DCM families. Linkage analysis demonstrated cosegregation of the microsatellite markers, D7S509 and D7S495 that flank the CHRM2 gene, with the familial form of DCM. A novel missense mutation (C722G) replacing cysteine with tryptophane (Cys176Trp) was identified in the CHRM2 gene in all affected members but was absent in unaffected members. Additionally, 139 sporadic DCM patients and 450 normal volunteers were screened for the same mutation, but none were identified. Among the 12 affected members with familial DCM, 5 patients had died suddenly and 7 experi...
Both β2- and β1-Adrenergic Receptors Mediate Hastened Relaxation and Phosphorylation of Phospholamban and Troponin I in Ventricular Myocardium of Fallot Infants, Consistent With Selective Coupling of β2-Adrenergic Receptors to Gs-Protein
Authors: PeterMolenaar, SabineBartel, AndrewCochrane, DonatheVetter, HomayounJalali, PeterPohlner, KylieBurrell, PeterKarczewski, Ernst-GeorgKrause, AlbertoKaumann
Journal: Circulation (2000)

Background—In adult human heart, both β1- and β2-adrenergic receptors mediate hastening of relaxation; however, it is unknown whether this also occurs in infant heart. We compared the effects of stimulation of β1- and β2-adrenergic receptors on relaxation and phosphorylation of phospholamban and troponin I in ventricle obtained from infants with tetralogy of Fallot. Methods and Results—Myocardium dissected from the right ventricular outflow tract of 27 infants (age range 21/2 to 35 months) with tetralogy of Fallot was set up to contract 60 times per minute. Selective stimulation of β1-adrenergic receptors with (−)-norepinephrine (NE) and β2-adrenergic receptors with (−)-epinephrine (EPI) evoked phosphorylation of phospholamban (at serine-16 and threonine-17) and troponin I and caused concentration-dependent increases in contractile force (−log EC50 [mol/L] NE 5.5±0.1, n=12; EPI 5.6±0.1, n=13 patients), hastening of the time to reach peak force (−log EC50 [mol/L] NE 5.8±0.2; EPI 5.8±0.2) and 50% relaxation...
Abstract A28: Beta-escin inhibits ovarian cancer metastasis by targeting the tumor microenvironment
Authors: Hilary A. Kenny, Madhu Lal, Min Shen, Betul Kara, Chun-Yi Chiang, Karen Watters, Peter Hart, Marc Ferrer, Ernst Lengyel
Journal: Clinical Cancer Research (2018)

Abstract The high mortality rate that results from ovarian cancer (OvCa) is caused by the wide dissemination of cancer cells within the abdominal cavity. OvCa cells metastasize to the peritoneum, which is covered by a single layer of mesothelial cells, and invade into the underlying stroma, composed of extracellular matrices including fibronectin (FN) and stromal cells such as fibroblasts. Using a three-dimensional organotypic quantitative high-throughput screening platform (3D-qHTS) modeling the peritoneum, we discovered that beta-escin inhibited OvCa adhesion and invasion to the peritoneum. Beta-escin is a natural triterpenoid saponin from Chinese horse chestnut seeds and has a variety of known pharmacologic effects. We hypothesize that beta-escin targets both the cancer cells and the stromal cells to inhibit the metastatic niche. The therapeutic effects of beta-escin and horse chestnut seed extract were tested in vivo using xenograft and syngeneic models of OvCa prevention and intervention. The mechanisms of beta-escin action in cancer cells and microenvironmental cells was explored in vitro using OvCa cell lines and primary human mesothelial cells and fibroblasts, and in vivo using different mouse models of metastasis. Moreover, a collection of 160 analogs of beta-escin were gathered and screened using our 3D-qHTS platform for inhibitory activity in OvCa cell adhesion/invasion. Our results reveal that beta-escin and horse chestnut extract taken orally inhibit metastasis in both OvCa prevention and intervention models. In addition, beta-escin mechanistically depresses the pluripotent stem cell population, inflammatory cytokine secretion, HIF-1alpha expression, and fibronectin production, while it increases autophagy in the tumor microenvironment. Furthermore, three distant analogs of beta-escin inhibited OvCa metastasis, and all three are cardiac glycosides. Taken together, we reveal a potential therapeutic value for beta-escin and/or analogs of beta-escin in preventing and treating OvCa dissemination. Citation Format: Hilary A. Kenny, Madhu Lal, Min Shen, Betul Kara, Chun-Yi Chiang, Karen Watters, Peter Hart, Marc Ferrer, Ernst Lengyel. Beta-escin inhibits ovarian cancer metastasis by targeting the tumor microenvironment. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A28.
Rapid Electrical Stimulation of Contraction Reduces the Density of β-Adrenergic Receptors and Responsiveness of Cultured Neonatal Rat Cardiomyocytes
Authors: HidetoshiYonemochi, SeikohYasunaga, YasushiTeshima, NaohikoTakahashi, MikikoNakagawa, MorioIto, TetsunoriSaikawa
Journal: Circulation (2000)

Background—Although tachycardia is commonly present in patients with congestive heart failure, its role in the development of congestive heart failure remains unclear. We studied the effect of rapid electrical stimulation of contraction on β-adrenergic receptor (β-AR) signal pathway in cultured cardiomyocytes of neonatal rats. Methods and Results—Contraction of cardiomyocytes was induced by electrical stimulation at 50 V with twice the threshold pulse width. β-ARs were identified by [3H]CGP-12177 and [3H]dihydroalprenolol. Electrical stimulation reduced cell-surface but not total β-AR density; the effect was dependent on pacing frequency (a reduction of 11%, 28%, and 18% in cells paced at 2.5, 3.0, and 3.3 Hz, respectively). This reduction was apparent at 3 hours, in contrast to reduced β-AR density after exposure to isoproterenol (ISP) for 1 hour. The fraction and inhibition constant of β-AR binding agonist with high affinity were not affected by rapid electrical stimulation. In cardiomyocytes paced at 3...
Abstract 17153: Increased Atherosclerotic Plaque Instability in Advanced Atherosclerosis with Aging: the Role of Calpain 2 in SOD2-deficient ApoE-/- Mice
Authors: Aleksandr E Vendrov, Nageswara R Madamanchi, Mark D Stevenson, Marschall S Runge
Journal: Circulation (2014)

The prevalence of atherosclerosis and incidence of cardiovascular events increase with advancing age. Increased generation and/or decreased scavenging of reactive oxygen species (ROS) in the vascular wall are major determinants of vascular disease progression. We previously showed that SOD2 deficiency in aging increases vascular oxidative stress and reduces aortic compliance, while young ApoE-/-/SOD2+/- mice show increased mitochondrial DNA damage and accelerated atherogenesis. Here we investigated the effects of aging and SOD2 deficiency on atherosclerosis and vascular wall morphology in ApoE-/- mice. Compared with the control ApoE-/-, aged ApoE-/-/SOD2+/- mice had increased total vascular wall (P &lt; 0.001) and mitochondrial ROS levels (P &lt; 0.05) and 70% higher atherosclerotic lesion area (P &lt; 0.001). Pulse wave velocity (P &lt; 0.001) and aortic wall collagen content (P &lt; 0.05) were significantly increased, while atherosclerotic plaque fibrous cap thickness (P &lt; 0.01) and vascular smooth muscle cell (VSMC)-positive area (P &lt; 0.01) were decreased in aged ApoE-/-/SOD2+/- mice. Immunofluorescence analysis of atherosclerotic lesions revealed higher levels of calpain 2, a cysteine protease implicated in apoptosis and cleaved caspase-3 localized in smooth muscle-positive areas of the plaque in aged ApoE-/-/SOD2+/- mice. VSMC isolated from aged SOD2+/- had higher levels of mitochondrial oxidative stress and dysfunction compared with VSMC from wild-type mice, as determined by increased superoxide generation and mitochondrial protein carbonylation and lower complex I and III activity. The calpain 2 protein levels were significantly higher in the SOD2+/- VSMCs compared with the wild-type cells and its expression and activity increased after TNF-α treatment, causing apoptosis. TNF-α increased MMP2 activity in SOD2+/- VSMC in Calpain 2-dependent manner. In conclusion, enhanced mitochondrial oxidative stress in aging increases aortic stiffening, atherosclerotic burden and plaque instability in advanced atherosclerosis, in part, via the activation of calpain 2 and MMP2. Targeting mitochondrial oxidative stress and calpain 2 activity may be a viable strategy to prevent aging-associated atherosclerosis complications.
Regulation of Cardiac L-Type Ca2+ Channel CaV1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway
Authors: SharonWeiss, ShimritOz, AdvaBenmocha, NathanDascal
Journal: Circulation Research (2013)

In the heart, adrenergic stimulation activates the β-adrenergic receptors coupled to the heterotrimeric stimulatory Gs protein, followed by subsequent activation of adenylyl cyclase, elevation of cyclic AMP levels, and protein kinase A (PKA) activation. One of the main targets for PKA modulation is the cardiac L-type Ca2+ channel (CaV1.2) located in the plasma membrane and along the T-tubules, which mediates Ca2+ entry into cardiomyocytes. β-Adrenergic receptor activation increases the Ca2+ current via CaV1.2 channels and is responsible for the positive ionotropic effect of adrenergic stimulation. Despite decades of research, the molecular mechanism underlying this modulation has not been fully resolved. On the contrary, initial reports of identification of key components in this modulation were later refuted using advanced model systems, especially transgenic animals. Some of the cardinal debated issues include details of specific subunits and residues in CaV1.2 phosphorylated by PKA, the nature, extent,...
Abstract 14988: Prehospital Endotracheal Intubation Increases Survival of Patients With Out of Hospital Cardiac Arrest
Authors: Shu-hsien Hsu, Wen-Chu Chiang, Matthew Huei-Ming Ma
Journal: Circulation (2016)

Introduction: Prehospital endotracheal intubation (PETI) is a prominent intervention for out-of-hospital cardiac arrest (OHCA) patients. However, its effect remained controversial. Besides, how par...
Tranilast Inhibits Vascular Smooth Muscle Cell Growth and Intimal Hyperplasia by Induction of p21waf1/cip1/sdi1 and p53
Authors: AkihiroTakahashi, TakahiroTaniguchi, YuichiIshikawa, MitsuhiroYokoyama
Journal: Circulation Research (1999)

Abstract—Tranilast, which is an antiallergic drug, has a potent effect on preventing postangioplasty restenosis. To elucidate this mechanism, we studied the effect of tranilast on the proliferation of vascular smooth muscle cells (SMCs) in vitro and in vivo. Tranilast decreased the growth rate of SMCs stimulated by either 10% FBS or platelet-derived growth factor. The IC50 value, evaluated as cell number, was 100 μmol/L. These inhibitory effects were associated with inhibition of the retinoblastoma gene product (pRb) phosphorylation. Because pRb phosphorylation is regulated by cyclin-dependent kinases (CDK), we investigated CDK2 and CDK4 activities and the expression of CDK inhibitor p21waf1/cip1/sdi1 (p21). When SMCs were stimulated by 10% FBS or platelet-derived growth factor, CDK2 and CDK4 activities reached a maximum near the G1/S transition. Tranilast suppressed their activities by >80% without reduction of CDK2/cyclin E and CDK4/cyclin D1 protein levels. These inhibitory effects were associated with...