tbuckley/cabot-search huggingface dataset:
Application of Transcription Factor “Decoy” Strategy as Means of Gene Therapy and Study of Gene Expression in Cardiovascular Disease
Authors: RyuichiMorishita, JitsuoHigaki, NaruyaTomita, ToshioOgihara
Journal: Circulation Research (1998)

Abstract—Recent progress in molecular biology has provided new techniques for inhibiting target gene expression. In particular, the application of DNA technology, such as antisense strategy to regulate the transcription of disease-related genes in vivo, has important therapeutic potential. Recently, transfection of cis-element double-stranded oligodeoxynucleotides (ODNs), referred to as “decoy” ODNs, has been reported to be a powerful tool in a new class of anti-gene strategies for gene therapy and in the study of transcriptional regulation. Transfection of double-stranded ODNs corresponding to the cis sequence will result in the attenuation of authentic cis-trans interaction, leading to the removal of trans factors from the endogenous cis elements with subsequent modulation of gene expression. This “decoy” strategy is not only a novel strategy for gene therapy as an anti-gene strategy but also a powerful tool for the study of endogenous gene regulation in vivo as well as in vitro. In this article, we rev...
Long-Term Survival After Acute Myocardial Infarction Is Lower in More Deprived Neighborhoods
Authors: CathrynTonne, JoelSchwartz, MurrayMittleman, SteveMelly, HelenSuh, RobertGoldberg
Journal: Circulation (2005)

Background— As part of the Worcester Heart Attack Study, a community-wide study examining changes over time in the incidence and long-term case-fatality rates of greater Worcester, Mass, residents hospitalized with confirmed acute myocardial infarction (AMI), we investigated the hypothesis that census tract–level socioeconomic position is an important predictor of survival after hospital discharge for AMI, after adjusting for demographic and clinical characteristics. Methods and Results— Data were available for 3423 confirmed cases of AMI among metropolitan Worcester residents during the 4 study years of 1995, 1997, 1999, and 2001 who were followed up through the end of 2002. The mean age among patients was 69 years, and 58% were men. Using a multilevel Cox proportional hazards regression model, we estimated a 30% higher death rate after AMI for patients living in census tracts with the most residents living below the poverty line compared with patients living in the wealthiest census tracts (relative ris...
Abstract B08: Urinary PGE-M levels and risk of ovarian cancer
Authors: Mollie E. Barnard, A. Heather Eliassen, Bernard A. Rosner, Kathryn L. Terry, Ginger L. Milne, Shelley S. Tworoger
Journal: Clinical Cancer Research (2018)

Abstract Introduction: Prostaglandin E2 (PGE2) is thought to influence ovarian carcinogenesis by increasing cell proliferation, tumor cell invasiveness, and angiogenesis. PGE-M is the major metabolite of PGE2 and a marker of systemic PGE2 production. Prior research has reported positive associations between urinary PGE-M and risk of colorectal, gastric, lung, pancreatic, and breast cancer; however, this is the first study to evaluate the association between urinary PGE-M and risk of ovarian cancer. Methods: We conducted a prospective case-control study nested in the Nurses’ Health Study (NHS) and NHSII cohorts. We included 194 cases of invasive epithelial ovarian cancer and 387 matched controls. All cases were diagnosed between the time of urine specimen collection (1996-97 NHSII; 2000-2002 NHS) and the end of follow-up (2015). Controls were selected using incidence density sampling and matched to cases on year of birth, menopausal status at collection and diagnosis, date and time of day of collection, hormone therapy use at collection, and fasting status. We measured PGE-M levels using LC/MS methods, and used the PGE-M distribution among controls to identify tertile cutpoints. We estimated the association between prediagnosis urinary PGE-M (in tertiles) and risk of ovarian cancer using conditional logistic regression. Results: We observed a suggestively lower risk of ovarian cancer for those with the highest PGE-M levels in NHS (OR=0.66; 95%CI=0.36-1.21; p-trend=0.15; n=123 cases), and no association in NHSII (OR=1.15; 95%CI=0.50-2.67; p-trend=0.75; n=71 cases). When results from the two cohorts were pooled, we observed nonsignificant, lower odds of ovarian cancer among those in the highest tertile of PGE-M compared to the lowest tertile (OR=0.80; 95%CI=0.50-1.27; p-trend=0.34), particularly after restricting our analysis to study participants who provided first morning urine samples (OR=0.68; 95%CI=0.40-1.14; p-trend=0.13). However, when we examined quartiles, no clear association was observed, although power was limited. Conclusions: Overall, our results suggest that higher prediagnosis PGE-M levels are not associated with an increased risk of ovarian cancer. Further analyses are under way to evaluate the potential for effect modification by menopausal status, BMI, and NSAID use. Citation Format: Mollie E. Barnard, A. Heather Eliassen, Bernard A. Rosner, Kathryn L. Terry, Ginger L. Milne, Shelley S. Tworoger. Urinary PGE-M levels and risk of ovarian cancer. [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 B08.
Alzheimer’s disease: researcher behind “new test” paper tried to silence critics
Authors: Nigel Hawkes
Journal: BMJ (2018)

A researcher who made headlines with a paper that claimed to have found a genetic test to measure ageing and diagnose Alzheimer’s disease tried to suppress scientific discussion about his data by threatening legal action.

Jamie Timmons and colleagues published their research in Genome Biology ,1 with widespread pick-up in UK newspapers. The story was also listed by the BBC among its 10 scientific breakthroughs of 2015.

The researchers claimed that they had identified a 150 gene expression signature in blood for healthy ageing, which was also “diagnostic for” Alzheimer’s disease. The claim seemed surprising to some others in the field.

The data presented on healthy ageing were based on muscle samples from 108 men, all aged around 70. But David Melzer, professor of epidemiology and public health at the University of Exeter, said that the blood sample results reported showed limited ability to distinguish Alzheimer’s from healthy control participants and failed to identify mild cognitive impairment samples correctly.

Melzer and his group were part of an international collaboration on gene expression and ageing that studied 15 000 participants from 14 cohorts. That study found 1497 genes in blood associated with age,2 but only 10 overlapped with the 150 gene signature in Timmons’s paper.

Melzer and colleagues posted results for …
Gene expression profiles in HCT116 and HT29 cells exposed to RTA 502 lead to insights into the mechanism of action
Authors: Teresa Kosakowska-Cholody, W Cholody, Humcha Hariprakasha, Colin Meyer, Christopher Michejda
Journal: Cancer Research (2007)

4895  RTA 502 (5-nitro-2-(3-{4-[3-(8-methoxy-6-oxo-6H-2,10b-diaza-aceanthrylen-5-ylamino)propyl]piperazin-1-yl}-propyl)-2-aza-phenalene-1,3-dione) is a synthetic anti-tumor agent with excellent in vitro and in vivo anti-tumor activity, especially against colon, liver and pancreatic cancer. We probed the DNA expression profiles in two colon cancer cell lines, HCT116 (wt p53) and HT29 (mut p53) that had been exposed to RTA 502 in order to provide information on the mechanism of action of the drug. Biophysical and biochemical studies showed that RTA 502 binds reversibly to DNA in the major groove. Our operational hypothesis is that the drug/ DNA complex interferes with proteins involved in DNA repair and transcription by forming ternary complexes with critical proteins. We have previously reported that sensitive wt p53 cancer cell lines such as colon HCT116 and RKO or hepatoma HepG2 are killed through p53-mediated apoptosis. Cancer cell lines with mutated or null p53 (e.g colon HT29, pancreas ASPC1 or 10.05 and hepatoma Hep3B) are also killed by the drug, which indicates induction of a p53-independent cell death pathways. Gene expression profiles were developed from mRNA isolated from HCT116 and HT29 cells exposed to 100 nM RTA 502 for 4, 24, 48 and 72 h using the Affymetrix 2K array, and all genes altered more than +/- 3-fold were subjected to a bioinformatics analysis utilizing DAVID (Database for Annotation, Visualization and Integrated Discovery). Drug treatment of HCT116 cells triggers immediate stabilization of p53 protein (as evidenced by Western blots) and subsequent suppression or activation of a great number of p53-controlled genes involved in DNA damage response (e.g. CHK1, RAD54, H2AFX), DNA replication arrest (e.g. CDC6, CDC7, RRM2, MCM 2-7, CDT1, RFC3, PSF2), cell cycle arrest (e.g. CDKN1A, GADD45, BTG1, CDC2, CDC20) and apoptosis (e.g. TP53, TNF, FAS, BAX, CASP8). The changes in gene transcription are time dependent and coincide with changes in corresponding protein levels. RTA 502 treatment of HT29 cells induces slightly different profiles. Thus, more than 20 stress response genes (e.g. TGFB1, IL1R1, MDK, GPX3, MHC) are upregulated but, in contrast to HCT116, these are not p53-regulated genes. We found 37 cell cycle and replication arrest genes (e.g. PML, ORC, MCM 2, 4, 5 and 7, RRM2, CHK1) that were common to both lines, although the level of dysregulation varied. Finally, we found strong up-regulation of 10 genes in HT29 cells that were involved in TNF-dependent apoptosis. The array data support the mechanistic conclusion that RTA 502 affects the expression of cellular stress response genes and induces replication arrest in tumor cells, which eventually leads to the activation of p53-dependent and p53-independent apoptosis pathways.
Abstract CT081: Tumor treating fields in combination with Bevacizumab in recurrent or progressive meningioma in a phase II study
Authors: Priya Kumthekar, Timothy Kruser, Sean Sachev, Jeffrey Raizer, Sean Grimm, Karan Dixit
Journal: Cancer Research (2018)

Abstract Meningioma is the most common primary brain tumor with a prevalence of about 170,000 in the United States. For patients with WHO grade II meningioma, the two-year and five-year overall survival was 93% and 73%, respectively. Patients with malignant meningioma (grade III) had significantly worse outcomes, with two-year and five-year overall survival rates of 57% and 42%. The recurrence rate remains high and in the case of grade 3 meningioma overall survival is as low as 3 years after diagnosis. The current treatment for high grade and recurrent meningioma includes maximal safe surgical resection and radiation. Tumor treating fields (TTFields) and Bevacizumab (BEV) have been reported to show activity in recurrent and high-grade meningioma. The combination of TTFields and BEV may provide a viable treatment option for patients with recurrent and high grade meningioma. This Phase 2 Simon two-staged, non-randomized, open-label, phase II, single arm clinical trial [NCT02847559] will investigate the combination of TTFields and BEV in recurrent or progressive meningioma. The primary endpoint will be progression free survival (PFS) at 6 months (PFS-6). Secondary endpoints will include overall survival (OS); Tumor Response Rate (TRR), Objective Response Rate (ORR); and Quality of Life (QOL) using FACT-Br questionnaire. Patients (N=27), including those who have failed prior BEV therapy, will receive BEV IV 10 mg/kg over 30-90 minutes on days 1 and 15 of courses 1-4. Beginning on day 1 of course 5, patients may choose to receive bevacizumab IV 15 mg/kg every 3 weeks or remain on the every 2-week schedule. Patients will receive TTFields 200 KHz (1-3 V/cm) daily via the Optune device for at least 18 hours/day. This study is powered to detect a true PFS-6 rate of 20% with 80% probability (80% power) and to detect a true PFS-6 rate of 5% with 90% probability (alpha=0.10). We planned for 27 patients in total to have 24 evaluable patients. For patients who are unable to obtain commercial BEV, the study has been amended to include a monotherapy arm of TTFields alone to increase the pool of eligible patients. Citation Format: Priya Kumthekar, Timothy Kruser, Sean Sachev, Jeffrey Raizer, Sean Grimm, Karan Dixit. Tumor treating fields in combination with Bevacizumab in recurrent or progressive meningioma in a phase II study [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 CT081.
Circulating Nonesterified Fatty Acid Level as a Predictive Risk Factor for Sudden Death in the Population
Authors: XavierJouven, Marie-AlineCharles, MichelDesnos, PierreDucimetière
Journal: Circulation (2001)

Background In ischemic conditions, concentration of circulating nonesterified fatty acids (NEFA) is increased and has a proarrhythmic effect that is responsible for ventricular tachyarrhythmias. In nonischemic patients, high NEFA plasma concentration has been shown to be associated with frequent premature ventricular complexes and increased familial risk of cardiovascular disease, but its relation to sudden death has not been studied. We assessed the role of circulating NEFA in sudden death in asymptomatic men in a long-term cohort study. Methods and Results A total of 5250 men employed by the city of Paris, aged 42 to 53 in 1967 to 1972, free of known ischemic cardiac disease, and included in the Paris Prospective Study I, completed a second annual examination and had fasting plasma circulating NEFA measured. Each subject underwent a physical examination and ECG, provided blood for laboratory tests, and answered questionnaires administered by trained interviewers. Vital status was obtained for each subje...
Major Benefit From Antiplatelet Therapy for Patients at High Risk for Adverse Cardiac Events After Coronary Palmaz-Schatz Stent Placement
Authors: HelmutSchühlen, MartinHadamitzky, HannaWalter, KurtUlm, AlbertSchömig
Journal: Circulation (1997)

Background The Intracoronary Stenting and Antithrombotic Regimen (ISAR) Trial is a randomized study in which antiplatelet therapy is compared with anticoagulant therapy after coronary stent placement, showing a significantly lower rate of noncardiac and cardiac events with antiplatelet therapy. The present study is a report of the analysis of a prospective risk stratification protocol in the ISAR Trial and the association with the incidence of adverse cardiac events and stent vessel occlusion. Methods and Results In all 517 patients randomized in the ISAR Trial, risk stratification was done with a list of 18 clinical, procedural, and angiographic variables: 165 patients with two or fewer criteria were classified as low risk, 148 patients with three criteria were classified as intermediate risk, and 204 patients with four or more criteria were classified as high risk. Within a 30-day follow-up, cardiac event rate (death, myocardial infarction, repeat intervention) was 6.4% for high-risk, 3.4% for intermedi...
Local Expression of Interleukin-1 Receptor Antagonist by Plasmid DNA Improves Mortality and Decreases Myocardial Inflammation in Experimental Coxsackieviral Myocarditis
Authors: Byung-KwanLim, Seong-ChoonChoe, Jae-OkShin, Seong-HyunHo, Jong-MookKim, Seung-ShinYu, SunyoungKim, Eun-SeokJeon
Journal: Circulation (2002)

Background— The inflammatory cytokines have an important role in the pathogenesis of viral myocarditis. Inerleukin-1 (IL-1) is one of the major cytokines that modulate the outcome of viral infection. Among the methods for in vivo gene transfer, direct injection of plasmid DNA is one that is simple and feasible. In this study, we expressed human IL-1 receptor antagonist (hIL-1Ra) in the mouse heart by direct injection of a novel plasmid vector and evaluated its effects on coxsackieviral (CVB3) myocarditis. Methods and Results— A plasmid vector expressing hIL-1Ra (total 40 μg/mouse) was injected into the heart apex of 8-week-old inbred female Balb/C mice (day 3). On day 0, mice (IL-1Ra-CVB3, n=35) were infected intraperitoneally with 104 PFU of CVB3; control mice (pCK-CVB3, n=15) were injected with empty vector on day −3 and infected on day 0. hIL-1Ra was expressed in the heart, reached its peak on day 5, and persisted for 2 weeks. The 14-day survival rate of IL-1Ra-CVB3 was higher (77%) than that of contro...
Abstract 4786: WSD0922: A novel, oral bioavailable, brain penetrable and reversible EGFRm+ inhibitor for the treatment of primary and metastatic brain tumors
Authors: Wei Zhong, Jinqiang Zhang, Zhihua Mu, Claire Sun
Journal: Cancer Research (2018)

Abstract Epidermal growth factor receptor (EGFR) is a cell surface protein that regulates normal cellular growth in tissues of epithelial origin. Des-regulated EGFR signaling (caused by mechanisms of overexpression, mutation, autocrine activation) contributes for oncogenesis by inducing cells proliferation and resisting apoptosis. In patients with NSCLC, activating mutants (EGFRm+) occur within exon 18-21 with increased EGFR activity. About 90% of these mutations (G719x, exon 19 deletions and exon 21 mutation) are sensitizing EGFRm+. EGFR TKIs have shown good performance in clinic for systemic NSCLC anchoring EGFRm+. However, up to 65% of NSCLC patients will develop brain metastasis (BM) ultimately. Current approved EGFR TKIs are not so effective for BM due to limited brain penetration as they are substrates of P-gp or BCRP, two main efflux transporters expressed on human BBB. In patients with GBM, the most common mutation is EGFRvIII (exon2-7 deletion) with an overall frequency of 25–64%. Current EGFR TKIs are ineffective in GBM treatment probably due to resistance caused by EGFRvIII as well as limited brain penetration. One-year survival of GBM patients is approximate 43%. Herein, we report a discovery of brain penetrable EGFR inhibitor WSD0922 for NSCLC BM and GBM with IC50 against EGFRm is &amp;lt;10nM. The ex-vivo antiproliferative GI50 in GBM tissues with EGFRvIII amplification is &amp;lt;100nM. WSD0922 is highly selective over other kinases. In-vitro MDCKII transfected cells and Caco-2 assays showed that WSD0922 is highly permeable and not a substrate of P-gp or BCRP. Preclinical CNS PK studies confirmed good brain penetration of WSD0922 with Kp,uu,brain close to unity. Treatment of mice bearing PC-9 (exon 19 del of NSCLC) in both subcutaneous (SC) and intracranial models with WSD0922 at 1-10mpk BID via PO resulted in dose dependent tumor growth inhibition (TGI) or regression with statistically significant survival benefit. Moreover, significant TGI for mice bearing GBM PDX model was achieved by treatment with WSD0922. No toxicity was observed in the animals during the treatment. Predicted human PK properties are very promising to offer sufficient target engagement in clinic. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with BM of NSCLC or GBM harboring EGFRm+. Citation Format: Wei Zhong, Jinqiang Zhang, Zhihua Mu, Claire Sun. WSD0922: A novel, oral bioavailable, brain penetrable and reversible EGFRm+ inhibitor for the treatment of primary and metastatic brain tumors [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 4786.
Activated Protein C Induces Endothelial Cell Proliferation by Mitogen-Activated Protein Kinase Activation In Vitro and Angiogenesis In Vivo
Authors: MitsuhiroUchiba, KenjiOkajima, YuichiOike, YasuhiroIto, KenjiFukudome, HirotakaIsobe, ToshioSuda
Journal: Circulation Research (2004)

Activated protein C (APC), a natural anticoagulant, has recently been demonstrated to activate the mitogen-activated protein kinase (MAPK) pathway in endothelial cells in vitro. Because the MAPK pathway is implicated in endothelial cell proliferation, it is possible that APC induces endothelial cell proliferation, thereby causing angiogenesis. We examined this possibility in the present study. APC activated the MAPK pathway, increased DNA synthesis, and induced proliferation in cultured human umbilical vein endothelial cells dependent on its serine protease activity. Antibody against the endothelial protein C receptor (EPCR) inhibited these events. Early activation of the MAPK pathway was inhibited by an antibody against protease-activated receptor-1, whereas neither late and complete activation of the MAPK pathway nor endothelial cell proliferation were inhibited by this antibody. APC activated endothelial nitric oxide synthase (eNOS) via phosphatidylinositol 3-kinase–dependent phosphorylation, followed ...
Abstract 17712: Association of Bone Mineral Density With Cardiac Valvular and Annular Calcification in Community-dwelling Older Adults - The Cardiovascular Health Study
Authors: Daniele Massera, Shuo Xu, Traci M Bartz, Anna E Bortnick, Joachim H Ix, Michel Chonchol, David S Owens, Eddy Barasch, Julius M Gardin, John S Gottdiener, John A Robbins, David S Siscovick, Jorge R Kizer
Journal: Circulation (2016)

Introduction: The process of cardiac calcification bears a resemblance to bone metabolism and its regulation. Experimental studies suggest that bone mineral density (BMD) and valvular calcification may be reciprocally related, but available epidemiologic data are sparse. Methods: We tested the hypothesis that BMD of total hip and femoral neck measured by dual-energy X-ray absorptiometry (DXA) are inversely associated with prevalence of 3 echocardiographic (echo) measures of cardiac calcification (mitral annular [MAC], aortic annular [AAC] and aortic valve calcification [AVC]) in 1,497 older adults from the population-based Cardiovascular Health Study. Analyses were stratified by sex. Relative risk (RR) regression was used to evaluate the adjusted risks of MAC, AAC and AVC individually with continuous BMD. Dose-response associations were assessed for MAC and AVC. Fully adjusted models included age, race, BMI, SBP, hypertensive therapy, diabetes, smoking, alcohol, physical activity, estrogen therapy, LDL, H...