tbuckley/cabot-search huggingface dataset:
Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis
Authors: Bo Ding, Jun-ichi Abe, Heng Wei, Qunhua Huang, Richard A. Walsh, Carlos A. Molina, Allan Zhao, Junichi Sadoshima, Burns C. Blaxall, Bradford C. Berk, Chen Yan
Journal: Circulation (2005)

Myocyte apoptosis plays an important role in pathological cardiac remodeling and the progression of heart failure. cAMP signaling is crucial in the regulation of myocyte apoptosis and cardiac remodeling. Multiple cAMP-hydrolyzing phosphodiesterases (PDEs), such as PDE3 and PDE4, coexist in cardiomyocytes and elicit differential temporal/spatial regulation of cAMP signaling. However, the role of PDE3 and PDE4 in the regulation of cardiomyocyte apoptosis remains unclear. Although chronic treatment with PDE3 inhibitors increases mortality in patients with heart failure, the contribution of PDE3 expression/activity in heart failure is not well known.In this study we report that PDE3A expression and activity were significantly reduced in human failing hearts as well as mouse hearts with chronic pressure overload. In primary cultured cardiomyocytes, chronic inhibition of PDE3 but not PDE4 activity by pharmacological agents or adenovirus-delivered antisense PDE3A promoted cardiomyocyte apoptosis. Both angiotensin II (Ang II) and the beta-adrenergic receptor agonist isoproterenol selectively induced a sustained downregulation of PDE3A expression and induced cardiomyocyte apoptosis. Restoring PDE3A via adenovirus-delivered expression of wild-type PDE3A1 completely blocked Ang II- and isoproterenol-induced cardiomyocyte apoptosis, suggesting the critical role of PDE3A reduction in cardiomyocyte apoptosis. Moreover, we defined a crucial role for inducible cAMP early repressor expression in PDE3A reduction-mediated cardiomyocyte apoptosis.Our results suggest that PDE3A reduction and consequent inducible cAMP early repressor induction are critical events in Ang II- and isoproterenol-induced cardiomyocyte apoptosis and may contribute to the development of heart failure. Drugs that maintain PDE3A function may represent an attractive therapeutic approach to treat heart failure.
Effects of formoterol, salmeterol or oxitropium bromide on airway responses to salbutamol in COPD
Authors: M Cazzola, F Di Perna, P Noschese, A Vinciguerra, F Calderaro, G Girbino, MG Matera
Journal: European Respiratory Journal (1998)

We examined whether a pretreatment with formoterol, oxitropium bromide, or salmeterol might modify the dose-response curves to inhaled salbutamol in patients with stable and partially reversible chronic obstructive pulmonary disease (COPD). Sixteen outpatients with partially reversible, stable COPD received 24 microg formoterol, 50 microg salmeterol, 200 microg oxitropium bromide, or placebo on four non-consecutive days. Spirometric testing was performed immediately before inhalation of treatment and after 2 h. A dose-response curve to inhaled salbutamol was then constructed using doses of 100, 100, 200 microg and 400 microg--that is, a total cumulative dose of 800 microg. Dose increments were given at 20 min intervals with measurements being made 15 min after each dose. Formoterol, salmeterol, or oxitropium bromide elicited a significant increase in forced expiratory volume in one second (FEV1) compared with placebo (mean differences (L) = placebo 0.05; formoterol 0.34; salmeterol 0.27; oxitropium bromide 0.23). Dose-dependent increases in FEV1 were seen (mean values (L) before salbutamol and after a cumulative dose of 100, 200, 400, and 800 microg = placebo: 1.06, 1.28, 1.35, 1.39, 1.41; formoterol: 1.33, 1.37, 1.41, 1.44, 1.44; salmeterol: 1.30, 1.33, 1.36, 1.39, 1.42; oxitropium bromide: 1.27, 1.34, 1.37, 1.41, 1.40). Statistical analysis revealed no significant differences in FEV1 and forced vital capacity (FVC) responses to salbutamol after therapy with formoterol, salmeterol, or oxitropium bromide compared with placebo. This study clearly shows that a pretreatment with a conventional dose of formoterol, salmeterol, or oxitropium bromide does not preclude the possibility of inducing a further bronchodilation with salbutamol in patients suffering from partially reversible chronic obstructive pulmonary disease.
Direct Actions of Urotensin II on the Heart
Authors: Alex Tzanidis, Ross D. Hannan, Walter G. Thomas, Döne Onan, Dominic J. Autelitano, Fiona See, Darren J. Kelly, Richard E. Gilbert, Henry Krum
Journal: Circulation Research (2003)

Urotensin II (UII) is a somatostatin-like peptide recently identified as a potent vasoconstrictor. In this study, we examined whether UII promotes cardiac remodeling through nonhemodynamic effects on the myocardium. In a rat model of heart failure after myocardial infarction (MI), increased UII peptide and UII receptor protein expression was observed in both infarct and noninfarct regions of the left ventricle compared with sham. Moreover, post-MI remodeling was associated with a significant 75% increase in UII receptor gene expression in the heart (P<0.05 versus sham controls), with this increase noted in both regions of the left ventricle. In vitro, UII (10-7 mol/L) stimulation of neonatal cardiac fibroblasts increased the level of mRNA transcripts for procollagens alpha1(I), alpha1(III), and fibronectin by 139+/-15% (P<0.01), 59+/-5% (P<0.05), and 141+/-14% (P<0.01), respectively, with a concomitant 23+/-2% increase in collagen peptide synthesis as determined by 3H-proline incorporation (P<0.01). UII had no effect on cellular hypertrophy, as determined by changes in total protein content in isolated neonatal cardiomyocytes. However, expression of recombinant rat UII receptor in neonatal cardiomyocytes resulted in significant UII-dependent activation of hypertrophic signaling as demonstrated by increased total protein content (unstimulated, 122.4+/-4.0 microg/well; rat UII, 147.6+/-7.0 microg/well; P<0.01) and activation of the hypertrophic phenotype through Galpha(q)- and Ras-dependent pathways. These results indicate that, in addition to potent hemodynamic effects, UII may be implicated in myocardial fibrogenesis through increased collagen synthesis by cardiac fibroblasts and may also be an important determinant of pathological cardiac hypertrophy in conditions characterized by UII receptor upregulation.
Tenofovir DF, Emtricitabine, and Efavirenz vs. Zidovudine, Lamivudine, and Efavirenz for HIV
Authors: Joel E. Gallant, Edwin DeJesus, José R. Arribas, Anton L. Pozniak, Brian Gazzard, Rafael E. Campo, Biao Lu, Damian McColl, Steven Chuck, Jeffrey Enejosa, John J. Toole, Andrew K. Cheng
Journal: New England Journal of Medicine (2006)

Durable suppression of replication of the human immunodeficiency virus (HIV) depends on the use of potent, well-tolerated antiretroviral regimens to which patients can easily adhere.
Regulation of FANCD2 by the mTOR Pathway Contributes to the Resistance of Cancer Cells to DNA Double-Strand Breaks
Authors: Changxian Shen, Duane Oswald, Doris Phelps, Hakan Cam, Christopher E. Pelloski, Qishen Pang, Peter J. Houghton
Journal: Cancer Research (2013)

Abstract Deregulation of the mTOR pathway is closely associated with tumorigenesis. Accordingly, mTOR inhibitors such as rapamycin and mTOR-selective kinase inhibitors have been tested as cancer therapeutic agents. Inhibition of mTOR results in sensitization to DNA-damaging agents; however, the molecular mechanism is not well understood. We found that an mTOR-selective kinase inhibitor, AZD8055, significantly enhanced sensitivity of a pediatric rhabdomyosarcoma xenograft to radiotherapy and sensitized rhabdomyosarcoma cells to the DNA interstrand cross-linker (ICL) melphalan. Sensitization correlated with drug-induced downregulation of a key component of the Fanconi anemia pathway, FANCD2 through mTOR regulation of FANCD2 gene transcripts via mTORC1-S6K1. Importantly, we show that FANCD2 is required for the proper activation of ATM-Chk2 checkpoint in response to ICL and that mTOR signaling promotes ICL-induced ATM-Chk2 checkpoint activation by sustaining FANCD2. In FANCD2-deficient lymphoblasts, FANCD2 is essential to suppress endogenous and induced DNA damage, and FANCD2-deficient cells showed impaired ATM-Chk2 and ATR-Chk1 activation, which was rescued by reintroduction of wild-type FANCD2. Pharmacologic inhibition of PI3K–mTOR–AKT pathway in Rh30 rhabdomyosarcoma cells attenuated ICL-induced activation of ATM, accompanied with the decrease of FANCD2. These data suggest that the mTOR pathway may promote the repair of DNA double-strand breaks by sustaining FANCD2 and provide a novel mechanism of how the Fanconi anemia pathway modulates DNA damage response and repair. Cancer Res; 73(11); 3393–401. ©2013 AACR.
Epigenetic Regulation of Endothelial Lineage Committed Genes in Pro-Angiogenic Hematopoietic and Endothelial Progenitor Cells
Authors: Kisho Ohtani, Georgios J. Vlachojannis, Masamichi Koyanagi, Jes-Niels Boeckel, Carmen Urbich, Ruxandra Farcas, Halvard Bonig, Victor E. Marquez, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation Research (2011)

Proangiogenic hematopoietic and endothelial progenitor cells (EPCs) contribute to postnatal neovascularization, but the mechanisms regulating differentiation to the endothelial lineage are unclear.To elucidate the epigenetic control of endothelial gene expression in proangiogenic cells and EPCs.Here we demonstrate that the endothelial nitric oxide synthase (eNOS) promoter is epigenetically silenced in proangiogenic cells (early EPCs), CD34(+) cells, and mesoangioblasts by DNA methylation and prominent repressive histone H3K27me3 marks. In order to reverse epigenetic silencing to facilitate endothelial commitment, we used 3-deazaneplanocin A, which inhibits the histone methyltransferase enhancer of zest homolog 2 and, thereby, reduces H3K27me3. 3-Deazaneplanocin A was not sufficient to increase eNOS expression, but the combination of 3-deazaneplanocin A and the histone deacetylase inhibitor Trichostatin A augmented eNOS expression, indicating that the concomitant inhibition of silencing histone modification and enhancement of activating histone modification facilitates eNOS expression. In ischemic tissue, hypoxia plays a role in recruiting progenitor cells. Therefore, we examined the effect of hypoxia on epigenetic modifications. Hypoxia modulated the balance of repressive to active histone marks and increased eNOS mRNA expression. The reduction of repressive H3K27me3 was associated with an increase of the histone demethylase Jmjd3. Silencing of Jmjd3 induced apoptosis and senescence in proangiogenic cells and inhibited hypoxia-mediated up-regulation of eNOS expression in mesoangioblasts.These findings provide evidence that histone modifications epigenetically control the eNOS promoter in proangiogenic cells.
Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections
Authors: Ming Zeng, Anthony J. Smith, Stephen W. Wietgrefe, Peter J. Southern, Timothy W. Schacker, Cavan S. Reilly, Jacob D. Estes, Gregory F. Burton, Guido Silvestri, Jeffrey D. Lifson, John V. Carlis, Ashley T. Haase
Journal: Journal of Clinical Investigation (2011)

The hallmark of HIV-1 and SIV infections is CD4+ T cell depletion. Both direct cell killing and indirect mechanisms related to immune activation have been suggested to cause the depletion of T cells. We have now identified a mechanism by which immune activation-induced fibrosis of lymphoid tissues leads to depletion of naive T cells in HIV-1 infected patients and SIV-infected rhesus macaques. The T regulatory cell response to immune activation increased procollagen production and subsequent deposition as fibrils via the TGF-β1 signaling pathway and chitinase 3-like-1 activity in fibroblasts in lymphoid tissues from patients infected with HIV-1. Collagen deposition restricted T cell access to the survival factor IL-7 on the fibroblastic reticular cell (FRC) network, resulting in apoptosis and depletion of T cells, which, in turn, removed a major source of lymphotoxin-β, a survival factor for FRCs during SIV infection in rhesus macaques. The resulting loss of FRCs and the loss of IL-7 produced by FRCs may thus perpetuate a vicious cycle of depletion of T cells and the FRC network. Because this process is cumulative, early treatment and antifibrotic therapies may offer approaches to moderate T cell depletion and improve immune reconstitution during HIV-1 infection.
Triggered activity in cardiac muscle fibers of the simian mitral valve.
Authors: A L Wit, P F Cranefield
Journal: Circulation Research (1976)

The action potential of cardiac fibers in the anterior mitral valve leaflet of the monkey heart is followed by an after-hyperpolarization. The addition of catecholamines causes a delayed after-depolarization to follow the after-hyperpolarization. The amplitude of the after-depolarization increases as the stimulus cycle length is decreased, or after premature stimulation, and as a result can reach threshold to yield nondriven, sustained rhythmic activity which we term triggered activity. This sustained rhythmic activity can be terminated by a single, appropriately timed, premature stimulus. The amplitude of the action potentials of mitral valve fibers is increased by catecholamines; the amplitude and rate of depolarization are depressed by verapamil. The amplitude of the action potentials is little affected by tetrodotoxin (TTX) but the maximum rate of depolarization is reduced by TTX. The delayed after-depolarization induced by catecholamines is abolished by verapamil, as is triggered activity. These observations suggest that mitral valve fibers generate slow response action potentials, that triggerable sustained rhythmic activity may be a property of the slow response and that such activity may cause the types of cardiac arrhythmias that usually are attributed to reentry.
Incidence of Breast Cancer in the United States: Current and Future Trends
Authors: W. F. Anderson, H. A. Katki, P. S. Rosenberg
Journal: JNCI Journal of the National Cancer Institute (2011)

The incidence of breast cancer increased in the United States until circa 2000 then decreased, mostly among women with estrogen receptor (ER)–positive cancers. Time trends provide important clues for cancer etiology and prevention; however, the observed trends of ER-positive and ER-negative breast cancers can be biased by missing ER data. We developed a simple imputation method to correct invasive female breast cancer incidence for missing or unknown ER expression, using nationally representative data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program during 1980–2008, including 588 720 invasive female breast cancer patients with 471 336 233 woman-years of follow-up. Corrected rates of ER-positive and ER-negative breast cancers were used to calculate age-standardized incidence rates, estimated annual percentage changes, and projections derived from age–period–cohort models. The recent decrease in the incidence of breast cancer overall stabilized near 200 per 100 000 woman-years by 2007–2008, reflecting a transient decrease in ER-positive cancers and a steady decrease in ER-negative cancers. The projected incidence rate for breast cancer overall through the year 2016 was similar to the incidence rate during 2007–2008. In contrast, rates of ER-positive breast cancers were projected to increase 5.3% (95% confidence interval = 5.2% to 5.4%), whereas rates of ER-negative breast cancers were projected to decrease 11.4% (95% confidence interval = 11.3% to 11.6%) during 2009–2016. Recent changes in breast cancer incidence overall reflect the superimposition of divergent trends in ER-positive and ER-negative cancers. If current trends continue, the incidence of ER-positive breast cancers will increase, the incidence of ER-negative breast cancers will continue to decrease, and the incidence of breast cancer overall will remain similar to its current level.
Evaluation of Competence to Consent to Assisted Suicide:Views of Forensic Psychiatrists
Authors: Linda Ganzini, Gregory B. Leong, Darien S. Fenn, J. Arturo Silva, Robert Weinstock
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Mental health evaluation of competence to consent has been proposed as an important safeguard for patients requesting assisted suicide, yet mental health professionals have not developed guidelines or standards to aid in such evaluations. The authors surveyed a national sample of forensic psychiatrists in the United States regarding the process, thresholds, and standards that should be used to determine competence to consent to assisted suicide. METHOD: An anonymous questionnaire was sent to board-certified forensic psychiatrists between August and October 1997. RESULTS: Of the 456 forensic psychiatrists who were sent the questionnaire, 290 (64%) responded. Sixty-six percent believed that assisted suicide was ethical in at least some circumstances, and 63% thought that it should be legalized for some competent persons. Twenty-four percent indicated that it was unethical for psychiatrists to determine competence; however, 61% thought such an evaluation should be required in some or all cases. Seventy-eight percent recommended a very stringent standard of competence. Seventy-three percent believed that at least two independent examiners were needed to determine competence, and 44% favored requiring judicial review of a decision. Fifty-eight percent believed that the presence of major depressive disorder should result in an automatic finding of incompetence. Psychiatrists with ethical objections to assisted suicide advocated a higher threshold for competence and more extensive review of a decision. CONCLUSIONS: The ethical views of psychiatrists may influence their clinical opinions regarding patient competence to consent to assisted suicide. The extensive evaluation recommended by forensic psychiatrists would likely both minimize this bias and assure that only competent patients have access to assisted suicide, but the process might burden terminally ill patients.
On distinguishing phenomenal consciousness from the representational functions of mind
Authors: Leonard D. Katz
Journal: Behavioral and Brain Sciences (1995)

Abstract One can share Block's aim of distinguishing “phenomenal” experience from cognitive function and agree with much in his views, yet hold that the inclusion of representational content within phenomenal content, if only in certain spatial cases, obscures this distinction. It may also exclude some modular theories, although it is interestingly suggestive of what may be the limits of the phenomenal penetration of the representational mind.
Is There an Association Between Meningioma and Hormone Replacement Therapy?
Authors: Svetlana Blitshteyn, Julia E. Crook, Kurt A. Jaeckle
Journal: Journal of Clinical Oncology (2008)

Molecular and clinical observations suggest a role of sex steroid hormones in the occurrence of meningioma. However, there is limited and often conflicting data on the use of hormone replacement therapy (HRT) as a possible risk factor for meningioma. The goal of this study was to investigate whether there is an association between a diagnosis of meningioma and either current or past HRT use in women.We retrospectively reviewed records in the Mayo Clinic Jacksonville electronic patient database between 1993 and 2003 to identify women with a diagnosis of either symptomatic or incidentally discovered, clinically silent meningioma. Records were also searched to identify women with a documented history of either current or past HRT use.Of the 355,318 women, ages 26 to 86, evaluated for any medical issue, 18,037 (5%) were documented as current or past HRT users. A total of 1,390 women with a history of symptomatic or incidentally discovered meningiomas were identified, 156 (11%) of whom were either current or past HRT users. A logistic regression analysis, adjusted for age, demonstrated a positive association between a diagnosis of meningioma and HRT use, with an odds ratio of 2.2 (95% CI, 1.9 to 2.6; P < .0001). The frequency of meningioma in women with either current or past HRT use was 865 in 100,000, whereas the frequency of meningioma in women without the history of HRT use was 366 in 100,000.The study provides evidence of a positive association between HRT use and diagnosis of meningioma, and therefore, HRT use may be a risk factor for meningioma.
Cost-Effectiveness of Lifestyle Modification in Diabetic Patients
Authors: Monique A.M. Jacobs-van der Bruggen, Pieter H. van Baal, Rudolf T. Hoogenveen, Talitha L. Feenstra, Andrew H. Briggs, Kenny Lawson, Edith J.M. Feskens, Caroline A. Baan
Journal: Diabetes Care (2009)

OBJECTIVE To explore the potential long-term health and economic consequences of lifestyle interventions for diabetic patients. RESEARCH DESIGN AND METHODS A literature search was performed to identify interventions for diabetic patients in which lifestyle issues were addressed. We selected recent (2003-2008), randomized controlled trials with a minimum follow-up of 12 months. The long-term outcomes for these interventions, if implemented in the Dutch diabetic population, were simulated with a computer-based model. Costs and effects were discounted at, respectively, 4 and 1.5% annually. A lifelong time horizon was applied. Probabilistic sensitivity analyses were performed, taking account of variability in intervention costs and (long-term) treatment effects. RESULTS Seven trials with 147-5,145 participants met our predefined criteria. All interventions improved cardiovascular risk factors at > or =1 year follow-up and were projected to reduce cardiovascular morbidity over lifetime. The interventions resulted in an average gain of 0.01-0.14 quality-adjusted life-years (QALYs) per participant. Health benefits were generally achieved at reasonable costs (< or =euro50,000/QALY). A self-management education program (X-PERT) and physical activity counseling achieved the best results with > or =0.10 QALYs gained and > or =99% probability to be very cost-effective (< or =euro20,000/QALY). CONCLUSIONS Implementation of lifestyle interventions would probably yield important health benefits at reasonable costs. However, essential evidence for long-term maintenance of health benefits was limited. Future research should be focused on long-term effectiveness and multiple treatment strategies should be compared to determine incremental costs and benefits of one over the other.
Angiotensin II type 1 receptor blocker inhibits arterial calcification in a pre-clinical model
Authors: Z. B. Armstrong, D. R. Boughner, M. Drangova, K. A. Rogers
Journal: Cardiovascular Research (2010)

Arterial calcification is a common complication of several disorders and is a strong predictor of mortality. The mechanism underlying arterial calcification is not fully understood and as such, no pharmaceutical therapies are currently available which impede its progression. The aim of this study was to investigate the effects of an angiotensin II (AngII) type 1 receptor blocker (ARB) on arterial calcification. Male New Zealand White rabbits were fed an atherogenic diet to induce atherosclerosis and arterial calcification over a period of 12 weeks, with an ARB administered in the final 4 weeks. Using clinically relevant micro-computed tomography, we found that animals fed the atherogenic diet displayed extensive arterial calcification when compared with control. In contrast, administration of the ARB completely inhibited calcification (2.80 ± 1.17 vs. 0.01 ± 0.01% calcified tissue in cholesterol and ARB-treated, respectively; n = 6 and 5; P < 0.05). Calcified regions were characterized by up-regulation of bone morphogenetic protein 2, osteocalcin, and the AngII type 1 receptor and concomitant down-regulation of α-smooth muscle actin, consistent with a phenotypic switch from vascular to osteoblast-like cells. These data provide the first evidence that angiotensin receptor blockade can inhibit arterial calcification by disrupting vascular osteogenesis and suggest that ARBs may be a novel treatment option for patients suffering from vascular calcification.