tbuckley/cabot-search huggingface dataset:
Abstract 9483: Oxidative Stress Induced by Acute Sodium Loading is Associated with Diastolic Dysfunction in Prehypertensives
Authors: Scott L Hummel, Theodore J Kolias, Alan B Weder
Journal: Circulation (2011)

Introduction: In 'salt-sensitive’ animals, chronic sodium (Na) loading causes oxidative stress and ventricular diastolic dysfunction. In humans, less is known about how early in the course of hypertension these responses begin, or if they differ following acute Na loading. Hypothesis: Acute Na loading in prehypertensives induces systemic oxidative stress that in turn is associated with post-Na loading ventricular diastolic dysfunction. Methods: We studied 14 prehypertensive humans (10 male, 4 female; age 28 ± 7 years, blood pressure 132 ± 12/ 77 ± 9 mmHg) over 6 days. Subjects ate a low-Na (20 mMol) diet on days 1-4. On day 5, they received 2 liters of 0.9% saline (308 mMol Na) intravenously over 2 hours, then 130 mMol Na over two high-Na meals. Urinary F-2 isoprostanes from overnight collections were used to measure systemic oxidative stress. Transthoracic echocardiograms were done on day 4 and day 6. Since standard diastolic function measures are less sensitive in structurally normal hearts, we used novel speckle tracking software (EchoInsight, Epsilon Imaging) to obtain a newer measure, global early diastolic strain rate (DSR). We used t-testing and linear regression to evaluate the association between ΔF2-isoprostanes and ΔDSR with Na loading. Results: F2-isoprostanes increased post-Na loading (4.1 ± 2.1 to 7.3 ± 7.4 pg/mMol Cr, p = .08), as did DSR (0.89 ± 0.20 to 1.08 ± 0.27 s -1 , p = .06). However, subjects below the median ΔF2-isoprostanes (group A) had significant increase in DSR post-Na loading; while those above the median ΔF2-isoprostanes (group B) did not ( Figure ). On linear regression, adjusted for urinary volume excretion, ΔDSR was inversely related to ΔF2-isoprostanes (β -.03, p &lt; .02; r 2 = 0.53). In contrast to DSR, other diastolic function measures were unrelated to ΔF2-isoprostanes. Conclusions: Oxidative stress generated by acute Na loading is associated with impaired diastolic function in prehypertensive humans with structurally normal hearts.
Detection of tyrosine kinase receptor activation in endothelial cells by proximity ligation assay (PLA) in situ
Authors: Johan Kreuger, Ann-Catrin Andersson, Ulf Landegren, Ola Soederberg
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2818 

Endothelial cells make up the inner lining of both blood and lymphatic vessels. The ability of endothelial cells to divide and migrate to form new vessels is at the heart of many diseases, e.g. tumor progression and dissemination. Tyrosine kinase receptors, including the receptors for vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), strongly influence the development and function of the vascular system during normal development and in disease. The receptors for VEGF and PDGF dimerize and become phosphorylated upon ligand binding to induce activation of several signaling pathways.

We have in the present study employed PLA in situ to monitor global and site specific phosphorylation of tyrosine kinase receptors in endothelial cells. The PLA in situ method can be used to study the kinetics of receptor activation in both cell and tissue samples.
Abstract MP81: Differences in Body Composition Between Metabolically Healthy Obese and Metabolically Abnormal Obese Phenotypes
Authors: Sarah M Camhi, Peter T Katzmarzyk
Journal: Circulation (2013)

Purpose: Studies of body composition between metabolically healthy obese (MHO) and metabolically abnormal obese (OA) cardiometabolic profiles have been limited to mostly small sample sizes and postmenopausal women. Thus, the purpose is to determine whether measures of body composition differ between MHO and OA using men and women across a wide age range. Methods: The sample included 395 obese (≥30 kg/m 2 ) adults (66% women; 62% white, 38% African American) from the Pennington Center Longitudinal Study, 18-68 years of age (mean±SD: 40.6±13.2). Adults were classified as OA (≥2 cardiometabolic risk factors: blood pressure ≥130/85 mmHg; triglycerides ≥150 mg/dL, high density lipoprotein cholesterol men &lt;40, women &lt;50 mg/dL; fasting glucose ≥100 mg/dL) or MHO (&lt;2 cardiometabolic risk factors). Whole-body bone mineral density (BMD; g/cm 2 ), bone mineral content (BMC; kg), percent body fat (%), fat mass (kg), lean mass (kg) and trunk adipose tissue mass (kg) were measured with dual-energy x-ray absorptiometry. Visceral (VAT; cm 2 ), subcutaneous (SAT; cm 2 ), and total abdominal adipose tissue (TAT; cm 2 ) were measured with computed tomography. Non-normally distributed variables were log transformed for analysis (lean mass, VAT, BMD and BMC) but means were reverse-transformed for presentation of results. Gender-specific general linear regression models (men: n=136; women: n=259) were used to determine differences in body composition between MHO (men: n=57; women n=153) and OA (men: n=79; women n=106) controlling for age, race, smoking status, and menopause status (in women). Results: In men, OA had greater fat mass (OA vs. MHO mean±SE; p-value for difference: 31.4±1.2 vs. 28.6±1.2 kg; p=0.02) and greater trunk adipose tissue (16.5±0.7 vs. 14.3±0.8 kg; p=0.002) compared with MHO, but no significant differences between MHO and OA profiles for BMD, BMC, % fat, lean mass, VAT, SAT, or TAT. Women with OA profiles had greater lean mass (54.4±1.0 vs. 51.5±1.0 kg; p&lt;0.0001), greater VAT (119.4±1.1 vs. 95.7±1.1 cm 2 ; p&lt;0.0001) and greater trunk adipose tissue (18.0±0.5 vs. 17.1±0.5 kg; p=0.03) when compared with MHO women, with no significant differences between MHO and OA for BMD, BMC, % fat, fat mass, SAT or TAT. Conclusion: OA and MHO cardiometabolic profiles are characterized by differences in body composition that vary by gender. Men have differences in overall and trunk adipose tissue while women have differences in lean mass and centralized fat (VAT and trunk). Future studies should confirm these results in different race and age groups.
The trimeric engineered fusion protein with CD40L peptide mimetic (OmpC-CD154p), induced apoptotic signaling on B-NHL cell lines: Higher effect than the recombinant CD40L or anti-CD40 mAb.
Authors: Bernardo Martinez-Miguel, Melisa Martinez-Paniagua, Sara Huerta-Yepez, Rogelio Hernandez-Pando, Cesar Gonzalez-Bonilla, Benjamin Bonavida, Mario Vega
Journal: Cancer Research (2008)

4071  CD154 (CD40-ligand) is a critical transmembrane molecule with potent immune-stimulatory properties and is clinical applied in gene therapy for leukemia and lymphoma. The interaction between CD40, a member of the tumor necrosis factor superfamily, and its ligand CD154 is essential for the development of humoral and cellular immune responses. Selective inhibition or activation of this pathway forms the basis for the development of new therapeutics against immunologically-based diseases and malignancies. Engagement of CD40-CD154 induces activation and proliferation of B lymphocytes and triggers apoptosis of carcinoma and B lymphoma cells. Several clinical trials have been reported targeting CD40 in cancer patients using recombinant CD154, mAbs and gene therapy, which were well tolerated and resulted in objective tumor responses. In addition to these therapies, CD154 mimetics have been considered with the objective to augment and potentiate the direct cytotoxic anti-tumor activity and for better accessibility to tumor sites. This approach was developed by us and we hypothesized that the genetic engineering of a fusion protein containing a CD154 peptide mimetic additional to be trimeric may be advantageous in that it may have a better affinity to CD40 on B cell malignancies and trigger cell death. The fusion partner may be a carrier targeting other surface molecules expressed on the malignant cells. This hypothesis was tested by the development of a gene fusion of Salmonella typhi OmpC protein expressing the CD154 Trp140-Ser149 amino acid strand (Vega et al., Immunology 2003; 110: 206-216). This OmpC-CD154p fusion protein binds CD40 and triggers the CD40 expressing B cells. In this study, we demonstrate that OmpC-CD154p treatment inhibits cell growth and proliferation more potently when compared with recombinant CD154 or anti-CD40 mAb, on B-NHL cell lines Raji and Ramos. In addition, significant apoptosis was achieved and the extent of apoptosis was a function of the concentration used and time of incubation. The anti-tumor effect was specific as treatment with OmpC alone had no effect. OmpC-CD154p treatment induced inhibition of expression of anti-apoptotic gene Bcl-2/Bcl-XL and inhibition of NF-kB activity. These findings establish the basis for the development of new fusion proteins with dual specificity targeting the tumor cells directly or targeting the tumor cells and immune cells. This work was supported in part by a Fogarty Training Grant (M.V. & S.H.), by IMSS, Mexico (M-M.B., M-PM., M.V. & S.H.), CONACyT and UNAM (M-M.B., M-PM).
Abstract 4882: Factor V Leiden, But Not Prothrombin G20120A, Is Associated With Premature Myocardial Infarction
Authors: Marta Spreafico, Flora Peyvandi, Luisa Foco, Luisa Bernardinelli, Stefano Duga, Rosanna Asselta, Diego Ardissino, Sekar Kathiresan, Piera A Merlini, Pier M Mannucci
Journal: Circulation (2008)
Telomere dysfunction in prostatic carcinogenesis
Authors: A. M. Joshua, B. Vukovic, I. Braude, A. Evans, J. Srigley, J. A. Squire
Journal: Journal of Clinical Oncology (2006)

10021 Background: Telomeres are composed of tandemly repeated DNA sequences (TTAGGG) and specific binding proteins located at the ends of eukaryotic chromosomes. They stabilize chromosomal ends; telomere shortening is an important mechanism of genomic instability and can lead to end-to-end chromosomal fusion, rearrangements and cell death. Here we evaluate the hypothesis that telomere shortening contributes to the development of prostate cancer (CaP). Methods: We used telomeric, centromeric and chromosome specific peptide-nucleic acid probes with z-stacked quantitative fluorescence in-situ hybridisation analysis to initially analyse 15 radical prostatectomy specimens and then subsequently sextant core biopsies from 80 men obtained in 1998–2001 containing high-grade prostate intraepithelial neoplasia (HPIN) only. The biopsy cohort outcome is blinded to prevent experimental bias and has a minimum follow-up of 2 years with 41 men diagnosed subsequently with CaP and 39 men without CaP on rebiopsy. Regions of interest were identifying with an overlying haematoxylin and eosin slide. Results: We found a significant decrease in telomere length in both HPIN and CaP in comparison to normal prostatic epithelium accompanied by elevated rates of aneusomy. Telomere erosion in HPIN was more common in regions of the prostate-containing CaP. We now have analyzed ∼4000 cells of matching HPIN and surrounding stroma. Preliminary analysis demonstrated that the median telomere length in HPIN is approximately 27% of the surrounding stroma with upper and lower quartiles being 16% and 38% respectively. Logistic regression analysis is in progress to determine whether the length of the shortest telomeres or the average telomeric length in a sample predicts for subsequent diagnosis of CaP. Secondary analyses are examining the effect of telomere length on the interval to the diagnosis of CaP, the effect of age on telomere length and the eventual Gleason score. Conclusions: Analysis of telomere length holds great promise for developing improved prognostic markers in prostatic carcinogenesis. This is a first of its kind study in the field. No significant financial relationships to disclose.
Abstract B16: Contributions of Ras and EZH2 in acinar to ductal metaplasia and ductal carcinoma in transgenic mouse pancreas
Authors: Jayne Ellis, Eric P. Sandgren, Paul J. Grippo, Marxa L. Figueiredo
Journal: Cancer Research (2015)

Abstract Activating mutations of the ras protooncogene is the most frequent and an early genetic alteration associated with pancreatic cancer. To examine the link between mutant ras oncogenes and exocrine pancreatic cancer, and to develop mouse models of PanINs and also of lesions that progress to malignancy, we generated transgenic mice expressing either Kras or Hras in pancreas. The tetracycline transactivator system expression was targeted to the pancreatic acinar cells via the elastase promoter element. The transactivation target ras genes were placed under the control of the tetracycline-response element. Most double transgenic founder mice displayed perinatal pancreatic acinar cell hyperplasia and dysplasia. However, only adult mice expressing Hras displayed preinvasive pancreatic neoplastic lesions with ductal morphology. Therefore, these Kras and Hras models each represent useful models in which either the lesion histotype and agressiveness (Hras) or the initiating genetic alteration overlap with the human disease (Kras). More recently, we have developed and are characterizing the contributions of expressing enhancer of zeste 2 homolog (EZH2), a histone methyl transferase and key regulator of cell differentiation and tissue regeneration, in modifying aggressiveness of mutated ras genes in vivo. Our findings suggest that ras mutations are associated with development of early stage duct-like lesions in pancreas, which vary in severity depending on the mutated ras gene expressed and the stage of development and growth of pancreas tissue. Citation Format: Jayne Ellis, Eric P. Sandgren, Paul J. Grippo, Marxa L. Figueiredo. Contributions of Ras and EZH2 in acinar to ductal metaplasia and ductal carcinoma in transgenic mouse pancreas. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B16.
Abstract 41: The Wnt3a targetome in triple-negative breast cancer cell lines
Authors: Sylvie Maubant, Bruno Tesson, Virginie Maire, Mengliang Ye, Guillem Rigaill, David Gentien, Francisco Cruzalegui, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois
Journal: Cancer Research (2015)

Abstract The canonical Wnt/beta-catenin pathway has been shown to be activated in triple-negative breast cancer (TNBC). The activation of this pathway leads to the expression of specific target genes depending on the cell/tissue context. Here, we analyzed the transcriptome of two different TNBC cell lines to define a comprehensive list of Wnt target genes. The treatment of cells with Wnt3a for 6h up-regulated the expression (fold change &amp;gt; 1.3) of 59 genes in MDA-MB-468 cells and 241 genes in HCC38 cells. Thirty genes were common to both cell lines. Beta-catenin may also be a transcriptional repressor and we found that 18 and 166 genes were down-regulated in response to Wnt3a treatment for 6h in MDA-MB-468 and HCC38 cells, respectively, of which six were common to both cell lines. Only half of the activated and the repressed transcripts have been previously described as Wnt target genes. Therefore, our study reveals 137 novel genes that may be positively regulated by Wnt3a and 104 novel genes that may be negatively regulated by Wnt3a. These genes are involved in the Wnt pathway itself, and also in TGF-beta, p53 and Hedgehog pathways. Thorough characterization of these novel potential Wnt target genes may reveal new regulators of the canonical Wnt pathway. The comparison of our list of Wnt target genes with those published in other cellular contexts confirms the notion that Wnt target genes are tissue-, cell line- and treatment-specific. Genes up-regulated in Wnt3a-stimulated cell lines were more strongly expressed in TNBC than in luminal A breast cancer samples. These genes were also overexpressed, but to a much lesser extent, in HER2+ and luminal B tumors. We identified 72 Wnt target genes higher expressed in TNBCs (17 with a fold change &amp;gt;1.3) which may reflect the chronic activation of the canonical Wnt pathway that occurs in TNBC tumors. Citation Format: Sylvie Maubant, Bruno Tesson, Virginie Maire, Mengliang Ye, Guillem Rigaill, David Gentien, Francisco Cruzalegui, Gordon C. Tucker, Sergio Roman-Roman, Thierry Dubois. The Wnt3a targetome in triple-negative breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 41. doi:10.1158/1538-7445.AM2015-41
Abstract 2520: Drug-Eluting Stents for the Treatment of Chronic Total Occlusion: A Comparison with Sirolimus, Paclitaxel, Zotarolimus, EPC Capture and Everolimus-Eluting Stent: Multicenter Registry in Asia
Authors: Sunao Nakamura, Shotaro Nakamura, Hisao Ogawa, Jang-Ho Bae, Yeo Hans Cahyadi, Wasan Udayachalerm, Damras Tresukosol, Sudaratana Tansuphaswadikul
Journal: Circulation (2008)

The aim of this study is to compare the safety and efficacy of Sirolimus (SES), Paclitaxel (PES), Zotarolimus (ZES), EPC capture (ECS) and Everolimus-eluting stent (EES) on the outcome of patients with chronic total occlusion (CTO). A prospective analysis of 1149 patients with 1183 CTOs (396 SES, 526 PES, 177 ZES, 41 ECS, 43 EES) in five high volume Asian centers after successful recanalization of CTO was performed. The study endpoints were 30 days and 9 months major adverse cardiac events (MACE), 9 months angiographic restenosis and target lesion revascularization (TLR). See table for clinical results. The use of drug-eluting stents in patients with CTO was safe with low acute complication. Patients treated with SES and EES showed lesser rate of restenosis compared with other drug-eluting stents.
Abstract 10148: In-vivo Detection of High Risk Coronary Plaques by Intravascular Ultrasound and 1-year Cardiovascular Outcome in Patients Undergoing Coronary Angiography
Authors: Jin M Cheng, Hector M Garcia-Garcia, Sanneke de Boer, Isabella Kardys, Jung Ho Heo, Martijn Akkerhuis, Rohit Oemrawsingh, Evelyn Regar, Patrick W Serruys, Robert-Jan van Geuns, Eric Boersma
Journal: Circulation (2013)
Abstract 16509: Microrna-126 is Released in Microvesicles From Cd34+ Progenitor Cells and is Critical for Their Pro-Angiogenic Capacity - Down-Regulation in Diabetes
Authors: Pavani Mocharla, Sylvie Briand, Giovanna Giannotti, Thomas Luescher, Ulf Landmesser
Journal: Circulation (2011)

Bone-marrow derived, circulating CD34+ progenitor cells have been observed to promote cardiac neovascularisation and vascular repair. Recently, microRNAs (miR) have emerged as key regulators of the...
Abstract #1503: The differentiated role of STAT5A and STAT5B in mammary carcinoma cell behavior
Authors: Jian zhong Tang, Dong xu Liu, Peter Lobie
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Signal transducer and activator of transcription factor 5 (STAT5) has two isoforms, STAT5A and STAT5B, encoded by two separate genes. They play a pivotal role in the development and differentiation of the mammary gland. Studies with mouse models of breast cancer have suggested that STAT5A/B may promote malignant transformation and enhance growth of the early tumour. Constitutive activation of STAT5 has also been observed in human mammary carcinoma along with various other types of malignancies. Distinctive roles for STAT5A and STAT5B in neoplasia have been implied in recent studies. In the present study, the functions of STAT5A and STAT5B have been systematically delineated in human mammary carcinoma cells. We demonstrated that forced expression of constitutively-active (CA) STAT5, i.e. CA-STAT5A or CA-STAT5B, in MCF-7 mammary carcinoma cell line, minimally affected cell cycle progression and proliferation in monolayer. However, forced expression of either CA-STAT5A or CA-STAT5B in MCF-7 mammary carcinoma cell line significantly decreased apoptosis and enhanced colony formation in soft agar with the effects of CA-STAT5A being greater than CA-STAT5B. In addition, forced expression of CA-STAT5A in MCF-7 cells, but not CA-STAT5B, significantly attenuated colony scattering, migration and invasion via strengthening cell homotypic adhesion. Reciprocally, depletion of endogenous STAT5A by siRNA in MCF-7 cells significantly enhanced colony scattering, migration and invasion, while depletion of endogenous STAT5B by siRNA exhibited little effect. Depletion of STAT5A also very significantly impaired colony formation of MCF-7 cells in soft agar, whereas a smaller reduction was observed upon siRNA-mediated depletion of STAT5B. Therefore, we have demonstrated that STAT5A and STAT5B function differentially in regulating the cellular behaviour of mammary carcinoma cells.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1503.
Inhibition of fatty acid synthase promotes apoptosis in breast cancer cells via redox and energy stress
Authors: Binghui Li, Hong Liu, Ingrid Espinoza, Ruth Lupu
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

4364 

Fatty acid synthase (FASN) is a NADPH-dependent metabolic enzyme, and thereby it might play an important role in maintaining the NADPH/NADP+ couple redox balance, in addition to its function of fatty acid synthesis. FASN recently emerges as a potential therapeutic target for the treatment of cancer, including breast cancer. There are several hypotheses for the anti-tumorigenic effects mediated by FASN inhibition. Pharmacological inhibition of FASN activity as well as RNA interference of FASN gene expression result in apoptosis of cancer cells. Here we investigated the mechanism by which inhibition of FASN leads to apoptotic cell dead of breast cancer cells expressing FASN. Interestingly, inhibition of FASN in breast cancer cells overexpressing FASN, using a naturally occurring inhibitor Cerulenin, significantly increases the ratio of NADPH/NADP+ and induces the generation of H2O2. Concomitantly, with these results we demonstrated an increase in redox stress, and increases in activated stress-associated kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK). Additionally, we observed that cerulenin-induced H2O2 stimulates glutathione redox to attempt to escape cell dead. Independent of H2O2, the cerulenin-induced imbalance of NADPH/NADP+ damages mitochondrial membrane to release cytochrome c and leads to the apoptosis. We also demonstrated that the 5'AMP-activated protein kinase (AMPK) is activated by H2O2, but it exhibits an antiapoptotic effect. In conclusion, FASN inhibition induces apoptosis in breast cancer cells via the induction of redox stress and/or energy stress.