tbuckley/cabot-search huggingface dataset:
Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs
Authors: AkikoShiroshita-Takeshita, GernotSchram, JoelLavoie, StanleyNattel
Journal: Circulation (2004)

Background— There is evidence for a role of oxidant stress and inflammation in atrial fibrillation (AF). Statins have both antioxidant and antiinflammatory properties. We compared the effects of simvastatin with those of antioxidant vitamins on AF promotion by atrial tachycardia in dogs. Methods and Results— We studied dogs subjected to atrial tachypacing (ATP) at 400 bpm in the absence and presence of treatment with simvastatin, vitamin C, and combined vitamins C and E. Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. Atrioventricular block was performed to control ventricular rate. Mean duration of induced AF was increased from 42±18 to 1079±341 seconds at terminal open-chest study after tachypacing alone (P<0.01), and atrial effective refractory period (ERP) at a cycle length of 300 ms was decreased from 117±5 to 76±6 ms (P<0.01). Tachypacing-induced ERP shortening and AF promotion were unaffected by vitamin C or vitam...
Short-Term Clinical Outcome of Patients With Acute Pulmonary Embolism, Normal Blood Pressure, and Echocardiographic Right Ventricular Dysfunction
Authors: StefanoGrifoni, IacopoOlivotto, PaoloCecchini, FilippoPieralli, AlbertoCamaiti, GennaroSantoro, AlbertoConti, GiancarloAgnelli, GiancarloBerni
Journal: Circulation (2000)

Background—The role of echocardiographic right ventricular (RV) dysfunction in predicting clinical outcome in clinically stable patients with pulmonary embolism (PE) is undefined. In this study, we assessed the prevalence and clinical outcome of normotensive patients with RV dysfunction among a broad spectrum of PE patients. Methods and Results—This prospective clinical outcome study included cohort of 209 consecutive patients (age, 65±15 years) with documented PE. Acute RV dysfunction was diagnosed in the presence of ≥1 of the following: RV dilatation (without hypertrophy), paradox septal systolic motion, and Doppler evidence of pulmonary hypertension. Four groups were identified: 28 patients presenting with shock or cardiac arrest (13%), 19 hypotensive patients without shock (9%), 65 normotensive patients with echocardiographic RV dysfunction (31%), and 97 normotensive patients without RV dysfunction (47%). Among normotensive patients with RV dysfunction, 6 (10%) developed PE-related shock after admissi...
Studies on the Structure of the Pulmonary Trunk
Authors: Mariosaldaña, Javierarias-Stella
Journal: Circulation (1963)

A study of the elastic configuration of the pulmonary trunk was undertaken in 443 normal autopsy cases, ranging in ages from the second month of intrauterine life to 96 years. It has been shown that during the whole of fetal life the elastic configuration of the pulmonary trunk is similar to that observed in the ascending aorta. The aortic configuration of the pulmonary trunk, which is characterized by a great content of long elastic fibers, was observed in the first trimester of life, especially in the 29 days that follow birth. Two models of the transitional configuration have been distinguished. The transitional-A model is characterized by a marked fragmentation of the elastic fibers. This elastic pattern has been found between 25 days and 3 years. In the transitional-B model most of the fibers are partially disintegrated but not fragmented. Cases with this characteristic were found from 1 month to 9 years. The adult type of pulmonary configuration, which exhibits a poor content in elastic ti...
Abstract 12892: Intracoronary Brachytherapy For Treatment of In-stent Restenosis in Drug Eluting Stents is Safe and Effective
Authors: Jaspreet Singh, Rajkumar P Doshi, Niraj Shah, Guru Srinivas, Rajiv Jauhar, Marisa Kavanaugh-Hogans, Barry Kaplan, Perwaiz Meraj
Journal: Circulation (2015)

Background: Intracoronary brachytherapy (ICBT) is an effective treatment for restenosis (ISR) of bare metal stents (BMS) but its utilization has waned due to the advent of drug eluting stents (DES). ISR following DES occurs at a frequency of 10% or greater. The purpose of this study is to report on the results following ICBT for clinical ISR in patients with DES and to determine if there are predictors for its success. Materials/Methods: A retrospective analysis was performed to identify 135 patients treated on an IRB approved protocol using ICBT for DES ISR. All patients received ICBT after balloon angioplasty using Sr-90 with a centering balloon and an automated delivery device (Best Vascular Novoste System, Norcross, GA). A dose of 18.4Gy or 23Gy at 2mm depth was delivered based upon the diameter of the injured vessel. Coronary lesion location, length and diameter were evaluated at enrollment. Major adverse coronary events (MACE) defined by death, myocardial infarction, CVA, and target vessel revascularization (TVR) were the primary outcomes, while angina relief and repeat hospitalization were the secondary outcomes. Results: At 1 year, ICBT restenosis occurred in 27% of treated patients and MACE free survival was 13.6%. When comparing patients in whom restenosis after ICBT occurred, there was a higher association of post ICBT MI which remained significant after multivariate analysis. All other primary and secondary outcomes remained insignificant (Table 1 and 2). Conclusion: ICBT is safe and effective for the treatment of DES ISR. Very few alternatives other than coronary bypass surgery exist to treat DES ISR. Given the success of ICBT in DES ISR, we propose that it should be utilized as the primary therapy. Restenosis after ICBT appears to be associated with post-ICBT MI. Additional data is needed to determine if there are other predictors for ICBT success.
Calmodulin Kinases II and IV and Calcineurin Are Involved in Leukemia Inhibitory Factor–Induced Cardiac Hypertrophy in Rats
Authors: TakahiroKato, MotoakiSano, ShunichiroMiyoshi, ToshihikoSato, DaihikoHakuno, HideyukiIshida, HiroeKinoshita-Nakazawa, KeiichiFukuda, SatoshiOgawa
Journal: Circulation Research (2000)

Abstract—We recently reported that leukemia inhibitory factor (LIF) enhances Ca2+]i through an increase in L-type Ca2+ current (ICa,L) in adult cardiomyocytes. The aim of this study was to investigate whether LIF activates Ca2+-dependent signaling molecules, such as calcineurin and calmodulin kinases II and IV (CaMKII and CaMKIV), and, if so, whether these Ca2+-mediated signaling events contribute to LIF-mediated cardiac hypertrophy. We first confirmed that LIF increased ICa,L and [Ca2+]i in primary cultured rat neonatal cardiomyocytes. Calcineurin, CaMKII, and CaMKIV activities increased at 2 minutes and peaked by 1.6-, 2.2-, and 2.2-fold, respectively, at 15 minutes. Nicardipine or verapamil fully inhibited these activities. Autophosphorylation of CaMKII was also observed to parallel the timing of CaMKII activity, and this phosphorylation was blocked by nicardipine, verapamil, or EGTA. LIF treatment led to a 3-fold increase in nuclear factor of activated T cell–luciferase activity. To confirm that inosi...
Abstract 5893: Expression and role of autophagy-associated p62 (SQSTM1) in multidrug-resistant ovarian cancer
Authors: Jinglu Wang, Cassandra Garbutt, Francis J Hornicek, Zhenfeng Duan
Journal: Cancer Research (2018)

Abstract Multidrug resistance is the major cause of treatment failure in ovarian cancer. p62 (SQSTM1) is a multifunctional protein involved in multiple cellular processes including proliferation, drug sensitivity and autophagy-associated cancer cell growth. p62 is a critical indicator of autophagic flux, which is inversely associated with autophagy activity. However, the role of p62 remains controversial in drug resistance in human ovarian cancer. In this study, we examined p62 expression by immunohistochemistry in a unique ovarian cancer tissue microarray (TMA), which was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. Results showed that both the metastatic and recurrent tumor tissues expressed less p62 than the patient-matched primary tumor. A significant inverse correlation has been found between p62 expression and both the disease free survival and overall survival. In addition, multidrug resistant cancer cell lines expressed lower levels of p62 as compared with their parental drug sensitive cell lines. Importantly, cell viabilities determined by MTT assay after exposure to different concentrations of paclitaxel showed inhibition of autophagy or accumulation of p62 enhances paclitaxel sensitivity in ovarian cancer drug resistant cells. Furthermore, the wound healing assay exhibited that inhibition of autophagy significantly decreased multidrug resistant ovarian cancer cell migration in vitro. Collectively, these data highlight that autophagy pathway may be a promising therapeutic target to prevent metastasis, recurrence and to reverse drug resistance in ovarian cancer. Citation Format: Jinglu Wang, Cassandra Garbutt, Francis J Hornicek, Zhenfeng Duan. Expression and role of autophagy-associated p62 (SQSTM1) in multidrug-resistant ovarian 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 5893.
Abstract 5869: TT-00420, a dual mechanism kinase inhibitor targeting both mitosis and tumor microenvironment, is highly active against TNBC both <i>in vitro</i> and <i>in vivo</i>
Authors: Peng Peng, Xiaoju Yang, Xiaoyan Qiang, Lin Li, Shumao Ni, Xiaofen Sun, Di Wu, Frank Wu
Journal: Cancer Research (2018)

Abstract The hallmarks of cancer comprise dysregulated cell cycle and mitosis, active angiogenesis, tumor-promoting inflammation, and immune escape as well as other features. Therapeutic targeting one of the hallmarks has shown promising but short-lived efficacy in cancer therapy. Therefore, combination of two or more mechanisms holds great promise of next generation oncology drug development. Aurora kinase A and B are often over expressed in many malignancies and associated with poor prognosis. Several anti-angiogenesis agents have been approved alone or in combination with other oncology drugs. In addition to its role for tumor growth, recent studies illustrate that angiogenesis also plays critical roles in the complexity and dynamic regulation of tumor microenvironment (TME). With the rapid advancement of immune-oncology, several attractive targets involved in tumor-promoting inflammation and immune escape have emerged. We have focused our efforts on the discovery and development of small molecule kinase inhibitors with novel mechanisms to treat cancer. Kinase profiling showed that TT-00420, one of our leading compounds, inhibited Aurora A/B, RTKs involved in angiogenesis, and a few other targets directly involved in tumor-assocated inflammation and immune escape with low nano molar activities. In a screening of human breast cancer cell lines, TT-00420 was highly efficacious against triple negative breast cancer (TNBC) cells while leaving ER+ cells intact, which is completely complimentary to the activity of CDK4/6 inhibitors. This anti-TNBC activity was confirmed in a patient derived xenograft (PDX) TNBC model in vivo, in which TT-00420 was highly active both as first-line and second-line treatment. TT-00420 demonstrated good oral bioavailability and pharmacokinetic properties in mice, rats and dogs. 2-week repeated dose-range finding studies revealed mechanism-related but manageable toxicities of TT-00420 in the 3 species mentioned above. Its dual mechanism involving anti-mitosis and TME modulation will be discussed in this presentation. TT-00420 is now under active development for IND filings both in the US and China. Citation Format: Peng Peng, Xiaoju Yang, Xiaoyan Qiang, Lin Li, Shumao Ni, Xiaofen Sun, Di Wu, Frank Wu. TT-00420, a dual mechanism kinase inhibitor targeting both mitosis and tumor microenvironment, is highly active against TNBC both in vitro and in vivo [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 5869.
Drug-free microneedles in the treatment of keloids: a single-blinded intraindividual controlled clinical trial
Authors: C. Tan, D. Yeo Chen Long, T. Cao, V. Tan Wei Ding, R. Srivastava, A.P. Yow, W.P. Tan, D. Wong Wing Kee, C. Xu, H.L. Tey
Journal: British Journal of Dermatology (2018)
Generation of Functional Culture–Derived Platelets From CD34+ Progenitor Cells to Study Transgenes in the Platelet Environment
Authors: MartinUngerer, MarioPeluso, AngelikaGillitzer, SteffenMassberg, UlrichHeinzmann, ChristianSchulz, GötzMünch, MeinradGawaz
Journal: Circulation Research (2004)

Abstract:— The possibility of evaluating the function of transgenes in platelets requires the generation of platelets from nucleated progenitor cells in vitro. In this article, we provide effective culture conditions for generating functional culture-derived (CD) human and mouse platelets from CD34+ progenitor cells that allow expression of any foreign protein of interest. We have evolved an effective cytokine cocktail (thrombopoietin, stem cell factor, interleukin [IL]-1β, IL-6) that induces a high yield of CD platelets and optimal shedding from cultivated megakaryocytes generated from CD34+ progenitor cells. CD platelets showed similar functional and morphological characteristics compared with isolated blood platelets, including surface expression of platelet antigens (CD41, CD42, CD62P), aggregation, release of granule constituents (P-selectin, platelet factor 4, serotonin). Moreover, transmission electron microscopy revealed the presence of typical α- and dense granules and dense tubular system in CD ...
Molecular profiling of mucinous epithelial ovarian carcinomas (mEOC): Opportunities for clinical trials.
Authors: Michael Friedlander, Kenneth Russell, Sherri Z. Millis, Zoran Gatalica, Andreas Voss
Journal: Journal of Clinical Oncology (2015)

5540 Background: mEOCs are an uncommon subset of epithelial ovarian cancers. Most patients have early stage disease at presentation and a good prognosis. However, patients with advanced stage disease at diagnosis are rare and can be difficult to distinguish from gastrointestinal metastases to the ovary. They have a poor prognosis and a low response to standard platinum /taxane chemotherapy. Rather than assigning chemotherapy according to the tissue of origin, selecting treatment based on the molecular characteristics of mEOC should be explored. Molecular profiling of mEOCs may help identify patients for clinical trials with targeted/novel therapies. Methods: 304 mEOCs referred to Caris Life Sciences (from 2009 - 2014) were evaluated. The diagnosis was based on reported pathology. Specific testing was performed per physician request and included a combination of sequencing (Sanger, NGS or pyrosequencing), protein expression (IHC), gene amplification (CISH or FISH), and/or RNA fragment analysis. Results: Alterations in the MAP Kinase pathway were common in mEOCs with the most frequent mutations observed in KRAS (49%). The mutation rate in BRAF was 3.5%. Alterations in the mTOR pathway occurred at a less frequent rate (PIK3CA 12% and PTEN 6%). PD-1 positivity was observed in 43% of tumor infiltrating lymphocytes and PD-L1 was positive in 14% of mEOCs. cMET overexpression was seen in 33% of cases, but no cMET amplification was seen. HER2 amplification (per ASCO-CAP guidelines) by FISH was observed in 11%. EGFR amplification occurred in 50% of cases and 57% had overexpression of EGFR by IHC.35% of mEOCs tested (37 of 105 cases) had P53 mutations. P53 mutated (n = 37) and wildtype (n = 68) mEOCs differed significantly in ER, PR and HER2 expression and BRAF, PIK3CA and PTEN mutation prevalence. Conclusions: Molecular profiling highlights the genomic heterogeneity and distinct molecular subsets in mEOCS and demonstrates the similarities with mucinous gastrointestinal cancers. There are a number of potential treatment targets and therapeutic options that could be investigated in phase 2 basket trials. Given the rarity of advanced stage mEOCs this will require international collaboration.
Abstract 4032: Pharmacogenomic analysis of acquired resistance can reveal effective drug combination in glioblastoma
Authors: Xiaolong Li, Juan Martinez-Ledesma, Chen Zhang, Feng Gao, W.K. Alfred Yung, Dimpy Koul
Journal: Cancer Research (2018)

Abstract Targeted cancer therapies have produced substantial clinical responses, but glioblastoma multiforme (GBM) has poor response due to developing resistance. The goal is thus to design strategies to overcome resistance to targeted drugs. To address this, we have embarked on a new type of screening for resistant targets, by developing acquired resistant glioma models and using pharmacogenomic platform to identify the resistant targets. We have established several patient-derived in vivo glioma stem cells (GSC) models using a PI3K specific inhibitor BKM-120 by a selective pressure after a chronic drug treatment. The resistant cells were subjected to RNA-seq analysis as well as pharmacologic analysis utilizing high-throughput kinase drug library screening. Analysis of integrated RNA-seq and kinase drug library screening of resistant cells identified multiple effective drug combination. Activation of Aurora kinase A (Aurora A)/Polo-like kinase 1 (Plk1)/cyclin-dependent kinase (CDK) signaling pathway was predominant in resistant GSCs. Concomitant targeting of PI3K together with Aurora A, Plk1 or CDK1 had a synergistic growth inhibitory effect. In addition, the combined inhibition of Plk1 and PI3K resulted in tumor growth suppression and significant delay of acquired resistance in vivo. These observations suggest that cell cycle pathway serves as a major survival signal upon PI3K inhibition and provides a rationale for the combined use of PI3K and cell cycle inhibition to prevent acquired resistance in human GBM. Citation Format: Xiaolong Li, Juan Martinez-Ledesma, Chen Zhang, Feng Gao, W.K. Alfred Yung, Dimpy Koul. Pharmacogenomic analysis of acquired resistance can reveal effective drug combination 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 4032.
Abstract 3086: CPAP enhances diethylnitrosamine-induced hepatocarcinogenesis via STAT3 pathway
Authors: Liang-Yi Hung
Journal: Cancer Research (2018)

Abstract Chronic and persistent inflammation is a well-known carcinogenesis promoter. Hepatocellular carcinoma (HCC) is one of the most common inflammation-associated cancers; most HCC arises in the context of chronic inflammation and hepatic injury. Both NF-κB and STAT3 are important regulators for inflammation. Our previous studies indicated that CPAP (centrosomal P4.1-associated protein), a centrosomal protein that majorly participates in centrosome functions, is overexpressed in HCC and can increase TNFα-mediated NF-κB activation and IL-6-induced STAT3 activation. A hepatocyte-specific CPAP-expressing transgenic mouse was generated to investigate the physiological role of CPAP in hepatocarcinogenesis. An obvious inflammatory cell accumulation and fatty change were shown in the CPAP transgenic (Tg) mouse liver. The ALT level as well as the expression of inflammatory genes, such as IL-6, IL1β and TNF-α in CPAP Tg mouse are higher than in the wild type (WT) mouse. By high-dose and short-term diethylnitrosamine (DEN) treatment, the ALT level, pro-inflammatory genes and STAT3 activation are increased in CPAP Tg mouse; low-dose and long-term DEN treatment induces more severe liver tumor formation in CPAP Tg mouse than in WT mouse. In summary, these results suggest that CPAP may promote hepatocarcinogenesis through enhancing the inflammation pathway via activating the STAT3 pathway. Citation Format: Liang-Yi Hung. CPAP enhances diethylnitrosamine-induced hepatocarcinogenesis via STAT3 pathway [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 3086.
Abstract 516: Long noncoding RNA NEAT1 promotes lung metastasis of soft tissue sarcoma
Authors: Jianguo Huang, Eric Xu, Mohit Sachdeva, Timothy Robinson, Xiaodi Qin, Dadong Zhang, Kouros Owzar, Nalan Gokgoz, Andrew Seto, Irene Andrulis, Jay Wunder, Tomoyo Okada, Samuel Singer, Alexander Lazar, Brian Rubin, David G. Kirsch
Journal: Cancer Research (2018)

Abstract Soft tissue sarcomas (STS) are malignant tumors from diverse mesenchymal tissues. About 40% STS patients develop fatal lung metastasis with a median survival of 15 months. The mechanisms driving the development of lung metastasis in sarcoma patients are poorly understood. Therefore, our lab has developed a genetically engineered mouse model (GEMM) of high-grade primary STS with conditional mutations in Kras and Trp53 (KP) where 40% of mice tumors develop lung metastasis. This KP model recapitulates human patients with Undifferentiated Pleomorphic Sarcoma (UPS), one of the most common subtypes of STS diagnosed in adults. RNA sequencing (RNA-Seq) was performed on paired primary and lung metastases in KP mouse sarcomas and determined that the expression of the long non-coding RNA (lncRNA) Neat1 is increased in lung metastases compared to paired primary tumors. Real time PCR (qPCR) in 22 paired KP mouse primary sarcomas and lung metastases further confirmed that Neat1 is significantly upregulated in lung metastases. In addition, RNA-Seq data from 5 pairs of human primary sarcomas and matched lung metastases also showed that NEAT1 levels are increased in lung metastases. Furthermore, NEAT1 RNA in situ hybridization (ISH) on tissue microarrays (TMAs) of human primary UPS and lung metastases determined that the expression of NEAT1 is upregulated in lung metastases. Next, CRISPR/Cas9 technology was applied to delete Neat1 in primary mouse sarcoma cells and loss of expression of Neat1 was confirmed by qPCR and northern blot in knockout (KO) clones. In addition, loss of Neat1 significantly reduced lung metastasis in vivo following tail vein injection of these modified cells into nude mice. To further test that loss of Neat1 reduces lung metastasis in primary sarcoma mouse model, primary tumors with Neat1 deletion are generated in GEMMs using in vivo CRISPR/Cas9 technology and KrasLSL-G12D/+; Trp53Flox/Flox; Neat1-/- (KPN) mouse model. Finally, RNA-Seq and capture hybridization analysis of RNA targets (CHART) are performed to determine mechanisms by which Neat1 regulates lung metastasis. Overall, these results suggest that upregulation of Neat1 promotes lung metastasis of soft tissue sarcoma and NEAT1 is a potential target to prevent or treat lung metastasis in sarcoma patients. Citation Format: Jianguo Huang, Eric Xu, Mohit Sachdeva, Timothy Robinson, Xiaodi Qin, Dadong Zhang, Kouros Owzar, Nalan Gokgoz, Andrew Seto, Irene Andrulis, Jay Wunder, Tomoyo Okada, Samuel Singer, Alexander Lazar, Brian Rubin, David G. Kirsch. Long noncoding RNA NEAT1 promotes lung metastasis of soft tissue sarcoma [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 516.