tbuckley/cabot-search huggingface dataset:
The PPAR-RXR Transcriptional Complex in the Vasculature
Authors: JorgePlutzky
Journal: Circulation Research (2011)

The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs) are ligand-activated transcription factors that coordinately regulate gene expression. This PPAR-RXR transcriptional complex plays a critical role in energy balance, including triglyceride metabolism, fatty acid handling and storage, and glucose homeostasis: processes whose dysregulation characterize obesity, diabetes, and atherosclerosis. PPARs and RXRs are also involved directly in inflammatory and vascular responses in endothelial and vascular smooth muscle cells. New insights into fundamental aspects of PPAR and RXR biology, and their actions in the vasculature, continue to appear. Although RXRs are obligate heterodimeric partners for PPAR action, the part that RXRs, and their endogenous retinoid mediators, exert in the vessel wall is less well understood. Biological insights into PPAR-RXRs may help inform interpretation of clinical trials with synthetic PPAR agonists and prospects for future PPAR therapeutics....
Abstract LB-065: An enzyme-directed pro-immunotherapeutic activated by muliti-drug resistance
Authors: Amy E. Nielsen, Rock J. Mancini
Journal: Cancer Research (2018)

Abstract Synthetic agonists of innate immune cells are of interest to immunologists due to their synthesis from well-defined materials, optimized activity, and monodisperse chemical purity. Recently we have reported the approach of Bystander-Assisted ImmunoTherapy (BAIT) that exploits the phenomenon of drug efflux in multi-drug-resistant cancers to elicit a localized anti-cancer immune response. In this context we examine the imidazoquinoline class of immunostimulants for susceptibility to drug efflux and begin to determine structural characteristics that drive efflux susceptibility for the Toll-Like Receptor agonist family of immmunsotimulants. Citation Format: Amy E. Nielsen, Rock J. Mancini. An enzyme-directed pro-immunotherapeutic activated by muliti-drug resistance [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-065.
Longitudinal Clinical and Electrophysiological Assessment of Patients With Symptomatic Wolff-Parkinson-White Syndrome and Atrioventricular Node Reentrant Tachycardia
Authors: Shih-AnnChen, Chern-EnChiang, Ching-TaiTai, Shih-HuangLee, Chuen-WangChiou, Kwo-ChangUeng, Zu-ChiWen, Chen-ChuenCheng, Mau-SongChang
Journal: Circulation (1996)

Background Functional changes of the accessory AV pathways and dual AV node pathways are very important for patients with Wolff-Parkinson-White syndrome or AV node reentrant tachycardia who refuse to receive long-term medication or radiofrequency catheter ablation. However, no studies of serial clinical and electrophysiological characteristics in these patients have been performed. Methods and Results One hundred thirteen patients with Wolff-Parkinson-White syndrome or AV node reentrant tachycardia were included in this study. The first and second follow-up electrophysiological studies were performed in years 5 and 10 after the baseline study, respectively. Conduction properties of the accessory pathways became poor over time. After a mean follow-up period of 9±1 years, antegrade ventricular preexcitation and retrograde accessory pathway conduction disappeared in 22.5% and 7.8% (P<.01), respectively; dual AV node pathway physiology persisted and retrograde fast pathway disappeared in 10.8% of the patients...
Abstract 1222: Functional single-nucleotide polymorphisms in the TGFb and TGFbRI gene and their association with prostate cancer in Western Mexicans
Authors: Abril Martínez-Rizo, Brenda González-Cordova, Christopher Peña-George, Cuerpo Académico de Investigación Bioquímica (CA-UAN-266), José Navarro-Partida, Martha González-Carrillo, Jackeline Arvizu-Gómez, Adriana Álvarez-Rodríguez
Journal: Cancer Research (2018)

Abstract Background: Prostatic carcinogenesis has been linked to chronic inflammation. Several studies demonstrated the duality of TGFβ during carcinogenesis. This pleiotropic cytokine participates in cell proliferation, migration and survival, epithelial-mesenchymal transition, and apoptosis, among other functions. An increase in its expression is associated with antiproliferative effects, tumor angiogenesis and metastasis of cancer cells. Single-nucleotide polymorphisms (SNPs) of the TGFB1 and TGFBR1 genes have been associated with risk and progression of many cancers. Aim: To investigate the synergic role T29C (rs1800470) of the TGFβ gene and TGFBR1 rs334348 polymorphisms in risk, progression and severity of prostate cancer. Materials and Methods: The present cases-control study includes 211 patients with PCa, and as controls 297 patients with benign prostatic hyperplasia (BPH) were obtained. The functional polymorphisms rs1800470 of the TGFβ gene and TGFBR1 rs334348 were detected by real-time PCR using the TaqMan probe system, according to the manufacturer's amplification recommendations. Hardy Weinberg Equilibrium was calculated by chi-square (χ2) test. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were calculated. The haplotypes were analyzed using the Haploview program. Results: The genotype frequencies of the SNPs analyzed in this work were no significant deviation from Hardy-Weinberg Equilibrium. Chi-square analysis established that there was no significant association between prostate cancer risk and TGFβ or TGFBR1 genotypes and alleles. Neither of the polymorphisms was associated with progression or severity of prostate cancer. Furthermore, the GT haplotype revealed protection for development of prostate cancer (OR=0.57, 95% CI (0.36-0.89) p=0.01). Conclusion: To our knowledge, this research is the first genetic association study to show that GT haplotype confers protection in patients from Western Mexico with PCa. Citation Format: Abril Martínez-Rizo, Brenda González-Cordova, Christopher Peña-George, Cuerpo Académico de Investigación Bioquímica (CA-UAN-266), José Navarro-Partida, Martha González-Carrillo, Jackeline Arvizu-Gómez, Adriana Álvarez-Rodríguez. Functional single-nucleotide polymorphisms in the TGFb and TGFbRI gene and their association with prostate cancer in Western Mexicans [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 1222.
Abstract 13844: Microrna-126 and Microrna-132 Abrogates Deleterious Effects of Diabetes-induced Impaired Angiogenesis
Authors: Shruti Rawal, Emani Munasinghe, Patrick Manning, Rajesh Katare
Journal: Circulation (2015)

Background: Diabetes-induced microvascular abnormalities are implicated in altering cardiac function and structure, a condition referred as diabetic microangiopathy in heart (DMAH). Endothelial-enriched microRNAs (angiomiRs) have been recently demonstrated to play a major role in regulating angiogenesis. However, their pathophysiological role in development of DMAH is elusive. Objective: To investigate the modulation of angiomiRs (miR-126, miR-132) with evolution of DMAH and demonstrate if restoration of angiomiRs can improve functional properties of high glucose treated endothelial cells. Methods &amp; Results: Cardiac tissues were collected from type-2 diabetic mice (BKS.Cg-m+/+Leprdb/J) every 4Wks, from 8 to 32Wks of age. qPCR revealed significant downregulation of miR-126 and -132 starting at 12Wks and continued till 32Wks (miR-126: 0.30±0.03; miR-132: 0.22±0.05,p&lt;0.001 vs. age matched non-diabetic). This was associated with concomitant dysfunction of cardiac functions (assessed through echocardiography). Western blotting analysis confirmed marked dysregulation of VEGF and p120RasGap (P&lt;0.05 vs. non-diabetic), the target proteins for miR-126 and -132, respectively. Importantly, immunohistochemical analysis did not show any noticeable changes in capillary density and arterioles until 20Wks in diabetes. To determine if restoration of miR-126 and -132 could reduce the development of DMAH, high glucose (HG)-treated Human Umbilical Vein Endothelial Cells (HUVECs) were transfected with either miR-126 or -132 mimics. Results showed that restoration of both the miRs markedly improved angiogenesis, assessed by tube formation assay (NG-Control- 8824±212; HG-Control: 3570±304; HG-126: 8970±184; HG-132: 7227±228), proliferation (CyQUANT cell proliferation assay) and reduced cell death (caspase-3/7 assay), p&lt;0.05 for all the parameters. Of note, overexpression of miR-126 alone tends to restore the expression of miR-132 and vice versa in HG-treated HUVECs, suggesting an orchestrated role of miRs in regulating angiogenesis. Conclusion: Modulation of miRs occur much earlier before the development of DMAH and restoration of DMAH from early stages in HUVECs exposed to high glucose markedly improved their angiogenic potential.
Application of Current Guidelines to the Management of Unstable Angina and Non-ST-Elevation Myocardial Infarction
Authors: EugeneBraunwald
Journal: Circulation (2003)

Unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) is a common but heterogeneous disorder with patients exhibiting widely varying risks. Early risk stratification is at the center of the management program and can be achieved using clinical criteria and biomarkers, or a combination. In addition to anti-ischemic therapy and aspirin, the thienopyridine clopidogrel is indicated except in patients who are potential candidates for urgent coronary artery bypass grafting (CABG). Platelet glycoprotein (GP) IIb/IIIa antagonists are indicated in high-risk patients likely to undergo percutaneous coronary intervention (PCI) but are not indicated in the management of lower-risk patients who do not undergo PCI. There is a growing body of evidence to support the substitution of the low-molecular-weight heparin (LMWH) enoxaparin for unfractionated heparin (UFH). Three recent trials have demonstrated the benefit of an early invasive strategy with catheterization followed by revascularization in patients at...
The spectrum of confocal endomicroscopy findings in a cystic neuroendocrine tumor of the pancreas
Authors: Anjuli K. Luthra, Christina A. Arnold, Andrei V. Manilchuk, Somashekar G. Krishna
Journal: Endoscopy (2018)

A 60-year-old man was found to have an incidental pancreatic cystic lesion during surveillance magnetic resonance imaging (MRI) for a known left renal lesion. Endoscopic ultrasound (EUS) revealed a cystic lesion (2.6 × 2.0 cm) with a single thick septum in the pancreatic tail ([Video 1]). Needle-based confocal laser endomicroscopy (nCLE) of this lesion was performed with an AQ-Flex-19 miniprobe (Cellvizio; Mauna Kea Technologies Inc., Paris, France). This demonstrated nests of cells surrounded by fibrous septa and vascularity, suggestive of a cystic pancreatic neuroendocrine tumor (PNET) ([Fig. 1]). A pattern of vacuolization was also observed ([Fig. 2 a]; [Video 1]). Fine needle aspiration (FNA) with immunostaining of the sample obtained confirmed the diagnosis of a well-differentiated PNET.
Abstract 18537: Erythrocyte Rich Thrombi Reduce Everolimus Diffusion in Thrombus and Arterial Wall ex vivo
Authors: Anouchska S Autar, Emma Peschier, Yvette den Hartog, Volkert Van Steijn, Dirk J Duncker, Heleen M Van Beusekom
Journal: Circulation (2016)

Introduction: Drug eluting stents (DES) used to treat acute myocardial infarction, are often placed on thrombus. Mathematical modelling indicates that thrombus acts as a barrier for local drug deli...
Abstract MP62: Aortic Root Dilation and Incident Cardiovascular Events in African Americans: The Jackson Heart Study
Authors: Daisuke Kamimura, Takeki Suzuki, Solomon K Musani, Michael E Hall, Adolfo Correa, Ervin R Fox, William C Little
Journal: Circulation (2016)

Introduction: The structure and function of the proximal aorta is thought to be associated with central aortic pressure. Therefore, it might be associated with cardiovascular (CV) events. Hypothesis: Increased aortic root diameter (AoD) is associated with CV events in a large community-based African American cohort in Jackson, MS. Methods: We conducted a longitudinal analysis in the Jackson Heart Study, a study of risk factors for CV disease in African Americans. AoD at the sinuses of Valsalva was measured by echocardiography at visit 1 (2000 - 2004). Participants without relevant information on covariates or with past history of CV diseases at baseline were excluded. CV events were defined as coronary heart disease, stroke, or incident heart failure (HF) identified as the first hospitalization for HF after 2005. Cox proportional hazards models were used to evaluate the association between baseline AoD and CV events. Kaplan-Meier survival curves were constructed for two groups classified by the sex-stratified top quintile of AoD (35.2±2.8 mm) vs. others quintiles as a group (AoD 30.8±2.8 mm). Results: Among 5301 JHS participants, 3386 participants were included in our study (mean age 56.0 years, 64% women). Participants in the top quintile of AoD were more likely to be older, hypertensive, and obese compared with the rest. Over a mean follow-up of 8.3 years, there were 214 CV events (incident rate: 7.6 per 1,000 person-years). After adjustment for traditional risk factors including age, gender, systolic blood pressure, antihypertensive medications, total cholesterol/HDL ratio, diabetes and smoking status, AoD was independently associated with CV events (hazard ratio per 1 mm increase: 1.05; 95% CI: 1.007-1.102, p &lt; 0.05). Participants in the top AoD quintile had a higher incidence of CV events than those not in the top quintile (Figure). Conclusions: An increased AoD was associated with an increased risk of CV events in a community-based African American cohort. AoD measurements may be useful for CV event risk stratification.
Abstract SY24-01: Genomic biomarkers for radiation resistance and targeted radiosensitizers
Authors: Henning Willers
Journal: Cancer Research (2018)

Abstract Preclinical and clinical development of molecular targeted drugs with radiation therapy (RT) +/- chemotherapy is of critical importance to the field. However, a huge body of preclinical drug/RT studies has not translated into an adequate number of successful radiation oncology trials. Major contributing factors likely include poor reproducibility of preclinical data, over-reliance on tumor growth delay but not long-term local tumor control experiments, and insufficient preclinical modeling of genomic heterogeneity that influences the treatment sensitivity of tumors in the clinic. There exists an urgent need to overcome these barriers to successful clinical translation of targeted radiosensitizers. Our efforts to establish high-throughput screening of targeted radiosensitizers and identify genomic biomarkers of radiosensitization will be presented. The key underlying concept is that short-term, nonclonogenic assays are suitable for capturing the relative change in radiation sensitivity that is induced by a targeted drug, and thus can serve as surrogate endpoints for the “gold standard” clonogenic survival assay. Through the use of a large number of annotated cancer cell lines, high-throughput platforms can model clinically relevant genomic heterogeneity across and within different tumor types. Moreover, these platforms facilitate the inclusion of patient-derived organoid tumor model,s which are likely better suited to mimic in vivo growth conditions than historical 2D monolayer cultures. Examples of biomarker-correlated radiosensitization effects in 2D as well as 3D settings will be shown. In particular, novel therapeutic targets associated with mutated KRAS will be highlighted. To this end, our recent in vitro, in vivo, and clinical data have established KRAS mutation as a biomarker of radiation resistance, especially when accompanied by co-mutation in TP53. The radiation resistance of KRAS mutant cancers constitutes an unmet clinical need. Taken together, by leveraging large panels of genomically characterized preclinical tumor models (2D or 3D) for testing the radiosensitizing properties of novel or repurposed agents, we may ultimately identify biomarker-directed combinatorial approaches that have a higher likelihood of leading to successful radiation therapy clinical trials than past studies. Citation Format: Henning Willers. Genomic biomarkers for radiation resistance and targeted radiosensitizers [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 SY24-01.
Randomized Trial of Cutting Balloon Compared With High-Pressure Angioplasty for the Treatment of Resistant Pulmonary Artery Stenosis
Authors: LisaBergersen, KimberleeGauvreau, HenriJustino, AlanNugent, JonathonRome, JacquelineKreutzer, JohnRhodes, DavidNykanen, EvanZahn, LarryLatson, PhillipMoore, JamesLock, KathyJenkins
Journal: Circulation (2011)

Background—We sought to determine the safety and efficacy of Cutting Balloon therapy (CB) compared with conventional high-pressure balloon therapy (HPB) for the treatment of pulmonary artery stenosis. Methods and Results—This prospective, randomized, multicenter, investigational device exemption trial compared CB with HPB. Patient eligibility was determined at the precatheterization assessment; vessel eligibility was determined at catheterization. In all vessels, low-pressure balloon dilation to 8 atm was performed, and if it was not successful, the vessel was randomized to CB or HPB. The primary efficacy outcome was percent change in minimum lumen diameter. A core laboratory performed all vessel measurements and angiographic assessment of vessel damage. The primary safety outcome was any serious adverse event attributable to vessel dilation as assessed by the Data and Safety Monitoring Board. Seventy-three patients from 8 institutions were enrolled between 2004 and 2008. In these patients, 72 vessels res...
Use of gene expression and alternative splicing signatures to discriminate breast cancer stem cells from fibroblasts.
Authors: David T. Weaver, Irina M Shapiro, Alan G Derr, Daniel Paterson, Jonathan A Pachter
Journal: Journal of Clinical Oncology (2012)

1057 Background: Tumors frequently contain cancer stem cells (CSCs) or tumor-initiating subpopulations, with an ability to self-renew and regenerate all cell types within the tumor. Basal-like breast cancers exhibit features of CSCs, including expression of surface markers, even though these cells are rare. Given the role of CSCs in the recurrence and spread of cancer, there is an urgent need to develop new therapeutic agents that target CSCs. Development of CSC-targeted drugs will be greatly facilitated by biomarkers that can identify CSCs to aid in patient selection and determination of drug response. Defining the CSCs in tumors is complicated by the high mesenchymal nature of fibroblasts. Analysis of gene expression and alternative splicing patterns in CSCs that are not observed in fibroblasts may provide valuable new CSC-specific markers. Methods: Alternative splicing and gene expression microarray strategies were used to identify selected exons and differentially expressed genes between 10 Basal human breast cancer cell lines and a combination of 12 Luminal and 3 fibroblast cell lines. Q-PCR analysis was conducted to determine candidate CSC gene differential expression between Basal, Luminal, and Fibroblast cells lines. Results: Expression levels of 11 genes were higher and 24 genes were lower in the Basal cell lines versus Luminal or fibroblastic cell lines. Comparison of Basal cell lines to the Luminal/Fibroblast cell lines identified 36 cassette exons that were included, and 26 that were excluded in Basal cell lines. Also, 19 genes were upregulated in Basal cell lines compared to the other groups as detected by Q-PCR. Interestingly, the 19-multigene model defined the Triple Negative Breast Cancer patients that were Likely to Recur under standard chemotherapy with a p = 1.90e-03 and AUC 0.723. Conclusions: Gene and exon marker sets distinguish CSC versus fibroblasts and may be instructive in identifying patients that recur early in Triple Negative Breast Cancer. The CSC-associated RNA signatures identified here will be further refined to develop new CSC-specific diagnostic markers to stratify breast cancer patients and monitor response to novel CSC-targeted therapies.
Nature of Species Differences in the Medial Distribution of Aortic Vasa Vasorum in Mammals
Authors: Harveywolinsky, Seymourglagov
Journal: Circulation Research (1967)

Thoracic aortic segments of 12 mammalian species were fixed while distended at normal physiological pressures after the vasa vasorum were filled by a perfusion mixture containing gelatin and carbon. Mammals whose aortas had 29 or fewer medial lamellar units had no demonstrable intramural vascular channels; those whose aortas had more than 29 medial lamellar units, had medial vasa. Aortas with medial vasa vasorum always had a subintimal medial zone devoid of vasa vasorum. In growing animals the width of this avascular zone increased with age; in adults, the width increased slightly with increasing species body weight. However, the number of lamellar units in the avascular zone was independent of both age and species and equal to 29.0 ± 2.5. All of the species with intramural aortic vasa vasorum as adults had 29 or more aortic medial lamellar units at birth; none of the species which had 29 or fewer lamellar units at birth had more than 29 lamellar units at maturity. In aortas with medial vasa vasorum, wide...
Abstract LB-183: Investigating the role of polarity protein, SCRIB, in hematopoiesis
Authors: Novita Novita, Alysha Dew, Chad Johnson, Carl R. Walkley, Louise E. Purton, Patrick O. Humbert, Phillip K. Darcy, Sarah L. Ellis
Journal: Cancer Research (2018)

Abstract Acting as both a polarity regulator and a scaffolding protein, Scribble (SCRIB), coordinates intracellular signalling pathways that regulate cell proliferation, migration and apoptosis. Deregulation of SCRIB has been linked to multiple epithelial cancers but the role of SCRIB in hematopoiesis and hematopoietic malignancies remains relatively unexplored. Using different approaches, we show that SCRIB is expressed in hematopoietic stem and progenitor cells and in their differentiated progenies, implying a role for SCRIB in blood production. We investigated the effect of SCRIB loss in hematopoiesis using two conditional knockout mouse models in conjunction with an extensive phenotypic labelling regime and multi-color flow cytometry. We reveal a role for SCRIB in T cell development although subtle differences between the two mouse models were noted. Compensatory mechanisms often mask the effects of single protein deletion during steady-state so stress hematopoiesis was induced through a transplant assay to minimise these effects. Lethally irradiated recipient mice receiving a transplant of SCRIB knockout bone marrow revealed a more striking phenotype with significantly altered populations of granulocyte, macrophage, erythroid, T and B cell progenitors, and mature macrophage fractions compared to controls. Collectively, our data shows SCRIB is required for the development of multiple hematopoietic fractions and studies are currently underway to identify the underlying mechanism/s and elucidate how deregulation of SCRIB impacts on hematopoietic malignancies. Citation Format: Novita Novita, Alysha Dew, Chad Johnson, Carl R. Walkley, Louise E. Purton, Patrick O. Humbert, Phillip K. Darcy, Sarah L. Ellis. Investigating the role of polarity protein, SCRIB, in hematopoiesis [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-183.