tbuckley/cabot-search huggingface dataset:
Review focus on the role of microRNA in cardiovascular biology and disease
Authors: T. Thum, M. Mayr
Journal: Cardiovascular Research (2012)

MicroRNAs (miRNAs; miR) are emerging therapeutic targets in a broad range of diseases, including cardiovascular disease.There are many programmes at the international level currently investigating the suitability of miRNA therapeutics for clinical purposes, and these new developments may potentially result in a novel armada of more powerful and mechanism-oriented therapeutics.It is now well accepted that miRNAs represent critical regulators of cardiovascular function. 1,2Initial reports about the role of miRNAs in cardiovascular development 3 and disease 4 have stimulated tremendous interest, resulting in a substantial gain of knowledge about miRNAs in the cardiovascular system.This almost unprecedented speed of development can probably be explained by the direct translational impact of miRNA research: the suitability of miRNAs to serve as potential prognostic biomarkers 1,5 and as therapeutic targets 6,7 for cardiovascular disease is intriguing and justifies our initial excitement about non-coding RNAs.This review focus issue of Cardiovascular Research summarizes novel and exciting aspects of miRNA-based mechanisms, diagnostics, and therapeutic developments for cardiovascular diseases.To start with, it is important to note that the fast pace of miRNA research has required the development of many new techniques and methods.Thus, the review article by Dangwal et al. 8 mainly focuses on techniques and methods in cardiovascular miRNA research.In essence, the authors describe new methods to screen for miRNA expression and to identify and validate miRNA targets.They also address advances in the manipulation of miRNA expression both in vitro and in vivo, a prerequisite for studies using miRNA-based therapeutics.Surprisingly, miRNAs also exist extracellularly, where they may serve as biomarkers for disease in the circulation and other bodily fluids.This aspect is introduced by Dangwal et al. 8 and in more detail by Zampetaki et al. 9 The latter group points out that
Targeting Toll-like Receptor 9 with CpG Oligodeoxynucleotides Enhances Tumor Response to Fractionated Radiotherapy
Authors: Kathryn A. Mason, Hisanori Ariga, Robert Neal, David Valdecanas, Nancy Hunter, Arthur M. Krieg, John K. Whisnant, Luka Milas
Journal: Clinical Cancer Research (2005)

Abstract Synthetic oligodeoxynucleotides containing unmethylated CpG motifs detected by Toll-like receptor 9 of dendritic cells and B cells have potent immunomodulatory effects. CpG oligodeoxynucleotides induce cytokines, activate natural killer cells, and elicit T-cell responses leading to antitumor effects, including improved efficacy of chemotherapeutic agents and, as we reported recently, synergy between CpG oligodeoxynucleotide 1826 and single-dose radiotherapy of an immunogenic mouse fibrosarcoma. The present study extends this finding to the fractionated radiotherapy of the fibrosarcoma tumor and assesses the ability of CpG oligodeoxynucleotide 1826 to increase the radioresponse of a tumor (nonimmunogenic fibrosarcoma). The experiments used a murine immunogenic fibrosarcoma tumor, fibrosarcoma growing in the leg of mice, and response to radiotherapy was assessed by tumor growth delay and tumor cure rate (TCD50, radiation dose yielding 50% tumor cure). Multiple s.c. peritumoral or i.t. administrations of CpG oligodeoxynucleotide 1826 at a dose of 100 μg per mouse were given when established tumors were 6 mm in diameter. Local tumor irradiation was initiated when tumors grew to 8 mm in diameter; radiation was delivered in 1 to 9 Gy fractions given twice daily separated by 6 to 7 hours for 5 consecutive days to achieve a total dose of 10 to 90 Gy. CpG oligodeoxynucleotide 1826, given as a single agent, had only a small antitumor effect, but it dramatically enhanced fibrosarcoma response to radiotherapy. Although 83.1 (79.2-90.0) Gy total dose were needed to achieve tumor cures in 50% of mice treated with radiotherapy alone, only 23.0 (11.5-32.7) Gy total dose were needed in mice treated with both CpG oligodeoxynucleotide 1826 and radiotherapy. The magnitude of potentiation of tumor radioresponse at the TCD50 level was by a factor of 3.61, a much higher value than that (a factor of 1.93) that we reported for single-dose radiotherapy. Mice cured of their tumors by combined CpG oligodeoxynucleotide 1826 plus radiotherapy were highly resistant to s.c. tumor take or development of tumor nodules in the lung from i.v. injected tumor cells when rechallenged with fibrosarcoma cells 100 to 120 days after the treatment, suggesting the development of a memory response. CpG oligodeoxynucleotide 1826 also increased radioresponse of the nonimmunogenic fibrosarcoma tumor by a factor of 1.41 and 1.73 when CpG oligodeoxynucleotide 1826 was given s.c. and i.t., respectively. These findings show that CpG oligodeoxynucleotides are highly potent enhancers of tumor response to both single-dose and fractionated radiation and as such have potential to improve clinical radiotherapy.
Effect of Aliskiren on Progression of Coronary Disease in Patients With Prehypertension
Authors: Stephen J. Nicholls, George L. Bakris, John J. P. Kastelein, Venu Menon, Bryan Williams, Juergen Armbrecht, Patrick Brunel, Maria Nicolaides, Amy Hsu, Bo Hu, Hui Fang, Rishi Puri, Kiyoko Uno, Yu Kataoka, Dianna Bash, Steven E. Nissen
Journal: JAMA (2013)

Blood pressure reduction and renin-angiotensin-aldosterone system inhibition are targets for treatment of atherosclerosis. The effect of renin inhibition on coronary disease progression has not been investigated.To determine the effects of renin inhibition with aliskiren on progression of coronary atherosclerosis.A double-blind, randomized, multicenter trial (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) comparing aliskiren with placebo in 613 participants with coronary artery disease, systolic blood pressure between 125 and 139 mm Hg (prehypertension range), and 2 additional cardiovascular risk factors conducted at 103 academic and community hospitals in Europe, Australia, and North and South America (enrollment from March 2009 to February 2011; end of follow-up: January 31, 2013).Participants underwent coronary intravascular ultrasound (IVUS) imaging and were randomized to receive 300 mg of aliskiren (n = 305) or placebo (n = 308) taken orally daily for 104 weeks. Disease progression was measured by repeat IVUS examination after at least 72 weeks of treatment.The primary efficacy parameter was the change in percent atheroma volume (PAV) from baseline to study completion. Secondary efficacy parameters included the change in normalized total atheroma volume (TAV) and the percentage of participants with atheroma regression. Safety and tolerability were also assessed.Evaluable imaging data were available at baseline and follow-up for 458 participants (74.7%). The primary IVUS efficacy parameter, PAV, did not differ between participants treated with aliskiren (-0.33%; 95% CI, -0.68% to 0.02%) and placebo (0.11%; 95% CI, -0.24% to 0.45%) (between-group difference, -0.43% [95% CI, -0.92% to 0.05%]; P = .08). The secondary IVUS efficacy parameter, TAV, did not differ between participants treated with aliskiren (-4.1 mm3; 95% CI, -6.27 to -1.94 mm3) and placebo (-2.1 mm3; 95% CI, -4.21 to 0.07 mm3) (between-group difference, -2.04 mm3 [95% CI, -5.03 to 0.95 mm3]; P = .18). There were no significant differences in the proportion of participants who demonstrated regression of PAV (56.9% vs 48.9%; P = .08) and TAV (64.4% vs 57.5%; P = .13) in the aliskiren and placebo groups, respectively.Among participants with prehypertension and coronary artery disease, the use of aliskiren compared with placebo did not result in improvement or slowing of progression of coronary atherosclerosis. These findings do not support the use of aliskiren for regression or prevention of progression of coronary atherosclerosis.clinicaltrials.gov Identifier: NCT00853827.
The correspondence metaphor: Prescriptive or descriptive?
Authors: Darryl Bruce
Journal: Behavioral and Brain Sciences (1996)

Abstract Koriat &amp; Goldsmith's abstract correspondence metaphor is unlikely to prove useful to memory science. It aims to motivate and inform the investigation of everyday memory, but that movement has prospered without it. The irrelevance of its competitor – the more concrete storehouse metaphor – as a guiding force in memory research presages a similar fate for the correspondence perspective.
Mammography Use Helps To Explain Differences in Breast Cancer Stage at Diagnosis between Older Black and White Women
Authors: Ellen P. McCarthy
Journal: Annals of Internal Medicine (1998)

Older black women are less likely to undergo mammography and are more often given a diagnosis of advanced-stage breast cancer than older white women.To investigate the extent to which previous mammography explains observed differences in cancer stage at diagnosis between older black and white women with breast cancer.Retrospective cohort study using the Linked Medicare-Tumor Registry Database.Population-based data from three geographic areas of the United States included in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program (Connecticut; metropolitan Atlanta, Georgia; and Seattle-Puget Sound, Washington).Black and white women 67 years of age and older in whom breast cancer was diagnosed between 1987 and 1989.Medicare claims were used to classify women according to mammography use in the 2 years before diagnosis as nonusers (no previous mammography), regular users (> or =2 mammographies done at least 10 months apart), or peri-diagnosis users (mammography done only within 3 months before diagnosis). Information on mammography use was linked with SEER data to determine cancer stage at diagnosis. Stage was classified as early (in situ or local) or late (regional or distant).Black women were more likely to not undergo mammography (odds ratio [OR], 3.00 [95% CI, 2.41 to 3.75]) and to be given a diagnosis of late-stage disease (OR, 2.49 [CI, 1.59 to 3.92]) than white women. When women were stratified by previous mammography use, the black-white difference in cancer stage occurred only among nonusers (adjusted OR, 2.54 [CI, 1.37 to 4.71]). Among regular users, cancer was diagnosed in black and white women at similar stages (adjusted OR, 1.34 [CI, 0.40 to 4.51]). In logistic modeling, previous mammography alone explained about 30% of the excess late-stage disease in black women. In a separate model, previous mammography explained 12% of the excess late-stage disease among black women after adjustment for sociodemographic and comorbidity information.Differences in breast cancer stage at diagnosis between older black and white women are related to previous mammography use. Increased regular use of mammography may result in a shift toward earlier-stage disease at diagnosis and narrow the observed differences in stage at diagnosis between older black and white women.
Effects of fundic vagotomy and cholinergic replacement on pentagastrin dose responsive gastric acid and pepsin secretion in man.
Authors: B I Hirschowitz, C A Helman
Journal: Gut (1982)

The effects of fundic vagotomy on acid and pepsin secretion in 12 patients (10 males, two females; nine duodenal ulcer, three gastric ulcer) were studied using a pentagastrin dose response before and after Vagotomy. In the intact stage H, Cl, and pepsin output all had the same ED50, 120-127 pmol/kg/h. Vagotomy reduced basal output of acid by 78%, Cl- by 50%, and pepsin by 62%. Postvagotomy basal outputs were not related to preoperative levels, while maximum acid output was reduced by an average of 35%, proportionally to the preoperative output (r = 0.94). Vagotomy uncompetitively (ED50 increase, Vmax decrease) inhibited the pentagastrin dose response of acid, chloride, and pepsin output. Postoperatively, a six-fold greater dose of pentagastrin (450 vs 76 pmol/kg/h) was required to stimulate acid to 50% of its preoperative maximum output. For pepsin secretion the increase was 12-fold (185 vs 15 pmol/kg/h). In five of the nine duodenal ulcer patients pentagastrin dose responses were repeated with a background infusion of urecholine, 20 micrograms/kg/h. Urecholine increased basal and peak acid, pepsin, and chloride outputs, and the ratio of basal: maximal almost to prevagotomy levels; it also restored the sensitivity to pentagastrin. Serum gastrin was not significantly changed by urecholine or by vagotomy. We conclude that the level of basal acid and pepsin secretion in ulcer patients, which is largely eliminated by vagotomy, is dependent on the vagus and not on serum gastrin. The effects of vagotomy are functional, are due to cholinergic withdrawal, and usually can be restored by cholinergic replacement.
THE OCCURRENCE IN THE RABBIT OF AN ACUTE PHASE PROTEIN ANALOGOUS TO HUMAN C-REACTIVE PROTEIN
Authors: H. C. Anderson, Maclyn McCarty
Journal: The Journal of Experimental Medicine (1951)

The occurrence in the rabbit of an acute phase protein analogous to human C-reactive protein has been confirmed. The acute phase protein of the rabbit reacts with a special form of the pneumococcal somatic polysaccharide, designated Cx polysaccharide, in the same manner that the human C-reactive protein reacts with the classical C polysaccharide. The method of preparation and some of the properties of the Cx polysaccharide are described. The rabbit Cx-reactive protein has been shown to be remarkably similar to human C-reactive protein in its general properties and in the conditions which govern its appearance in the blood. It has been obtained in crystalline form, and appears to be antigenically distinct from the proteins of normal rabbit serum.
Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor α therapy in rheumatoid arthritis
Authors: J D Cañete, R Celis, C Moll, E Izquierdo, S Marsal, R Sanmartí, A Palacín, D Lora, J de la Cruz, J L Pablos
Journal: Annals of the Rheumatic Diseases (2008)

Objective: To investigate the clinical significance of lymphoid neogenesis (LN) in rheumatoid arthritis (RA), the clinicopathological correlates of this process and its evolution after anti-tumour necrosis factor (TNF)α therapy in a large series of synovial tissues were analysed. Methods: Arthroscopic synovial biopsies from 86 patients with RA were analysed by immunohistochemistry. LN was defined as the presence of large aggregates of lymphocytes with T/B cell compartmentalisation and peripheral node addressin (PNAd) positive high endothelial venules. Clinical variables at baseline and after prospective follow-up were compared in LN positive and negative RA subsets. The evolution of LN and its correlation with the clinical course in a subgroup of 24 patients that underwent a second arthroscopic biopsy after anti-TNFα therapy was also analysed. Results: LN was present in 49% of RA synovial tissues. Patients with LN had a significantly higher disease duration and a higher previous use of anti-TNFα agents. During prospective follow-up, the proportion of patients achieving good or moderate European League Against Rheumatism (EULAR) 28-joint Disease Activity Score (DAS28) responses was significantly lower in patients who were LN positive despite a significantly higher use of anti-TNFα agents. By multivariate logistic regression analysis, LN remained as an independent negative predictor of response to therapy. In the subgroup of patients rebiopsied after anti-TNFα therapy, reversal of LN features occurred in 56% of the patients and correlated with good clinical responses. Conclusions: Synovial LN in RA predicts a lower response to therapy. LN features can be reversed after a short period of anti-TNFα therapy in parallel to good clinical responses.
Validation of the Leicester Cough Questionnaire in non-cystic fibrosis bronchiectasis
Authors: M. P. Murray, K. Turnbull, S. MacQuarrie, J. L. Pentland, A. T. Hill
Journal: European Respiratory Journal (2009)

Health-related quality of life is a potentially important marker for evaluating existing and new therapies in bronchiectasis. The Leicester Cough Questionnaire (LCQ) is a symptom specific questionnaire designed to assess the impact of cough severity, a major symptom of bronchiectasis. This study aimed to validate the LCQ in bronchiectasis. The validity, responsiveness and reliability of the LCQ were assessed as follows: ability to discriminate severe and mild disease; change in score following antibiotic treatment for exacerbations; repeatability over a 6-month period in stable disease; and comparison with the St George's Respiratory Questionnaire (SGRQ). In total, 120 patients (51 with severe disease, 29 with moderate disease and 40 with mild disease) completed the LCQ and SGRQ. The area under the receiver-operator curve was good for both severe and mild disease (0.84 and 0.80 respectively, p<0.0001). Following 2 weeks' antibiotic treatment, the median LCQ score (interquartile range) improved from 11.3 (9.3-13.7) to 17.8 (15-18.8) (p<0.0001). The LCQ score was repeatable over 6 months in stable disease (intraclass correlation coefficient of 0.96 (95%CI 0.93-0.97), p<0.0001). Correlation between the LCQ and SGRQ scores was -0.7 in both stable disease and exacerbations (p<0.0001). The LCQ can discriminate disease severity, is responsive to change and is reliable for use in non-cystic fibrosis bronchiectasis.
Prognostic Implications of <i>NOTCH1</i> and <i>FBXW7</i> Mutations in Adults With T-Cell Acute Lymphoblastic Leukemia Treated on the MRC UKALLXII/ECOG E2993 Protocol
Authors: Marc R. Mansour, Maria L. Sulis, Veronique Duke, Letizia Foroni, Sarah Jenkinson, Kenneth Koo, Christopher G. Allen, Rosemary E. Gale, Georgina Buck, Sue Richards, Elisabeth Paietta, Jacob M. Rowe, Martin S. Tallman, Anthony H. Goldstone, Adolfo A. Ferrando, David C. Linch
Journal: Journal of Clinical Oncology (2009)

Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol.NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome.NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS; MUT v WT, 51% v 27%, P = .10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72).NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.
Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas
Authors: E. Tamborini, E. Virdis, T. Negri, M. Orsenigo, S. Brich, E. Conca, A. Gronchi, S. Stacchiotti, G. Manenti, P. G. Casali, M. A. Pierotti, S. Pilotti
Journal: Neuro-Oncology (2010)

We have previously demonstrated that chordomas express activated platelet-derived growth factor receptor (PDGFRB) and that treatment with imatinib, which is capable of switching off the activation of various receptor tyrosine kinases (RTKs) including PDGFRB, benefits a number of patients. The aim of this study was to identify the possible presence of other activated RTKs and their downstream signaling effectors. Cryopreserved material from 22 naïve sporadic chordomas was investigated for the presence of activated RTKs and their cognate ligands and downstream signaling effectors by means of human phospho-RTK antibody arrays, Western blotting, and molecular analysis; immunohistochemistry and fluorescence in situ hybridization were used to analyze the corresponding formalin-fixed and paraffin-embedded samples. We detected activated PDGFRB, FLT3, and colony stimulating factor 1 receptor (CSF1R) of the PDGFR family and highly phosphorylated EGFR, HER2/neu, and (to a lesser extent) HER4 of the EGFR family. The detection of PDGFRB/PDGFB confirmed our previous data. The presence of activated EGFR was paralleled by the finding of high levels of epidermal growth factor (EGF) and transforming growth factor α (TGFα) and PDGFB co-expression and PDGFRB co-immunoprecipitation. Of the downstream effectors, the PI3K/AKT and RAS/MAPK pathways were both activated, thus leading to the phosphorylation of mammalian target of rapamycin (mTOR) and 4E-BP1 among the regulators involved in translational control. Taken together, our results (i) provide a rationale for tailored treatments targeting upstream activated receptors, including the PDGFR and EGFR families; (ii) support the idea that a combination of upstream antagonists and mTOR inhibitors enhances the control of tumor growth; and (iii) indicate that the 4E-BP1/eIF4E pathway is a major regulator of protein synthesis in chordoma.
Do atrial tachyarrhythmias beget ventricular tachyarrhythmias in defibrillator recipients?
Authors: Kenneth M Stein, David E Euler, Rahul Mehra, Karlheinz Seidl, David J Slotwiner, Suneet Mittal, Steven M Markowitz, Bruce B Lerman
Journal: Journal of the American College of Cardiology (2002)
Selective In Vivo and In Vitro Effects of a Small Molecule Inhibitor of Cyclin-Dependent Kinase 4
Authors: R. Soni, T. O'Reilly, P. Furet, L. Muller, C. Stephan, S. Zumstein-Mecker, H. Fretz, D. Fabbro, B. Chaudhuri
Journal: JNCI Journal of the National Cancer Institute (2001)

Cyclin-dependent kinase 4 (Cdk4) represents a prime target for the treatment of cancer because most human cancers are characterized by overexpression of its activating partner cyclin D1, loss of the natural Cdk4-specific inhibitor p16, or mutation(s) in Cdk4's catalytic subunit. All of these can cause deregulated cell growth, resulting in tumor formation. We sought to identify a small molecule that could inhibit the kinase activity of Cdk4 in vitro and to then ascertain the effects of that inhibitor on cell growth and tumor volume in vivo.A triaminopyrimidine derivative, CINK4 (a chemical inhibitor of Cdk4), was identified by screening for compounds that could inhibit Cdk4 enzyme activity in vitro. Kinase assays were performed on diverse human Cdks and on other kinases that were expressed in and purified from insect cells to determine the specificity of CINK4. Cell cycle effects of CINK4 on tumor and normal cells were studied by flow cytometry, and changes in phosphorylation of the retinoblastoma protein (pRb), a substrate of Cdk4, were determined by western blotting. The effect of the inhibitor on tumor growth in vivo was studied by use of tumors established through xenografts of HCT116 colon carcinoma cells in mice. Statistical tests were two-sided.CINK4 specifically inhibited Cdk4/cyclin D1 in vitro. It caused growth arrest in tumor cells and in normal cells and prevented pRb phosphorylation. CINK4 treatment resulted in statistically significantly (P: =.031) smaller mean tumor volumes in a mouse xenograft model.Like p16, the natural inhibitor of Cdk4, CINK4 inhibits Cdk4 activity in vitro and slows tumor growth in vivo. The specificity of CINK4 for Cdk4 raises the possibility that this small molecule or one with a similar structure could have therapeutic value.