tbuckley/cabot-search huggingface dataset:
Angiotensin-Converting Enzyme Gene Polymorphism Has No Influence on the Circulating Renin-Angiotensin-Aldosterone System or Blood Pressure in Normotensive Subjects
Authors: M.-L. Lachurié, M. Azizi, T.-T. Guyene, F. Alhenc-Gelas, J. Ménard
Journal: Circulation (1995)

Background Angiotensin-converting enzyme (ACE) is involved in the metabolism of two major vasoactive peptides, converting angiotensin (Ang) I into Ang II and inactivating bradykinin. An insertion/deletion (I/D) polymorphism is present in the 16th intron of the ACE gene and is strongly associated with plasma and cellular ACE levels. Contrasting with the lack of relation between ACE gene polymorphism and blood pressure level, a large case-control study has shown that the deletion marker allele of the ACE gene was associated with an increased risk of myocardial infarction. The pathophysiological link between ACE gene polymorphism and cardiovascular events remains hypothetical. One hypothesis is that this polymorphism influences Ang II and bradykinin concentrations in the peripheral and/or local circulations through its effects on ACE levels in plasma and endothelial cells. The aim of this study was to investigate the effect of the ACE gene I/D polymorphism on blood pressure, plasma active renin, and aldosterone regulation in normal subjects. Methods and Results Twenty-four normotensive male volunteers homozygous for the ACE I/D polymorphism (12 DD and 12 II) received a renin inhibitor infusion (remikiren 0.1 mg · kg −1 · h −1 for 130 minutes) to suppress endogenous Ang I and Ang II production. Forty minutes after initiating the remikiren infusion, an exogenous Ang I infusion was begun and increased gradually every 15 minutes from 1 to 10 ng · kg −1 · min −1 . Median (range) plasma ACE levels (mU/mL) were 39 (32 to 57) and 24 (12 to 30) in the DD and II groups, respectively. Remikiren suppressed plasma Ang I and Ang II, increased plasma active renin (from 23±12 to 154±161 pg/mL), decreased plasma aldosterone (from 106±42 to 82±33 pg/mL), and slightly decreased diastolic blood pressure (from −2.4±2.7 mm Hg). The blood pressure and hormonal responses to Ang I infusion after renin inhibition and the slope of the rise in plasma Ang II with increasing Ang I dose were identical in both groups, as was the plasma Ang I/Ang II ratio before (DD, 2.09±1.04; II, 2.59±0.76) and after (DD, 0.15±0.13; II, 0.09±0.03) combined renin inhibitor and Ang I infusion. Conclusions Despite its association with a major difference in plasma ACE levels, the ACE I/D polymorphism did not influence the Ang II and plasma aldosterone production, plasma active renin decrease, or diastolic blood pressure increase induced by exogenous Ang I infusion, suggesting that ACE has no limiting influence on systemic Ang II generation and effects under these experimental conditions.
Dose Response of Almonds on Coronary Heart Disease Risk Factors: Blood Lipids, Oxidized Low-Density Lipoproteins, Lipoprotein(a), Homocysteine, and Pulmonary Nitric Oxide
Authors: David J.A. Jenkins, Cyril W.C. Kendall, Augustine Marchie, Tina L. Parker, Philip W. Connelly, Wei Qian, James S. Haight, Dorothea Faulkner, Edward Vidgen, Karen G. Lapsley, Gene A. Spiller
Journal: Circulation (2002)

Background— Although recent studies have indicated that nut consumption may improve levels of blood lipids, nuts are not generally recommended as snacks for hyperlipidemic subjects because of their high fat content. Furthermore, the effective dose is still unknown. Methods and Results— The dose-response effects of whole almonds, taken as snacks, were compared with low-saturated fat (&lt;5% energy) whole-wheat muffins (control) in the therapeutic diets of hyperlipidemic subjects. In a randomized crossover study, 27 hyperlipidemic men and women consumed 3 isoenergetic (mean 423 kcal/d) supplements each for 1 month. Supplements provided 22.2% of energy and consisted of full-dose almonds (73±3 g/d), half-dose almonds plus half-dose muffins, and full-dose muffins. Fasting blood, expired air, blood pressure, and body weight measurements were obtained at weeks 0, 2, and 4. Mean body weights differed &lt;300 g between treatments. The full-dose almonds produced the greatest reduction in levels of blood lipids. Significant reductions from baseline were seen on both half- and full-dose almonds for LDL cholesterol (4.4±1.7%, P =0.018, and 9.4±1.9%, P &lt;0.001, respectively) and LDL:HDL cholesterol (7.8±2.2%, P =0.001, and 12.0±2.1%, P &lt;0.001, respectively) and on full-dose almonds alone for lipoprotein(a) (7.8±3.5%, P =0.034) and oxidized LDL concentrations (14.0±3.8%, P &lt;0.001), with no significant reductions on the control diet. No difference was seen in pulmonary nitric oxide between treatments. Conclusions— Almonds used as snacks in the diets of hyperlipidemic subjects significantly reduce coronary heart disease risk factors, probably in part because of the nonfat (protein and fiber) and monounsaturated fatty acid components of the nut.
Dose-Dependent Effects of the Renin Inhibitor Zankiren HCl After a Single Oral Dose in Mildly Sodium-Depleted Normotensive Subjects
Authors: Joël Ménard, Robert S. Boger, Denise M. Moyse, Tam T. Guyene, Harriet N. Glassman, Hollis D. Kleinert
Journal: Circulation (1995)

Background Zankiren HCl (A-72517) is a potent renin inhibitor shown to have substantial bioavailability in several animal species and to produce dose-related reductions in blood pressure, plasma renin activity, and angiotensin II (Ang II) in salt-depleted dogs. The present study was designed to evaluate the hemodynamic effects of oral zankiren HCl administration in healthy volunteers and to characterize the response of the renin-angiotensin system (RAS) to specific blockade by this new renin inhibitor. Methods and Results Twenty-four male volunteers participated in a double-blind randomized, placebo-controlled in-hospital study to evaluate the effects of zankiren HCl (10 to 250 mg). All subjects were pretreated with 40 mg furosemide 12 hours before study drug administration. Blood pressure and heart rate were monitored by an automated oscillometric device, and blood samples were obtained for active renin, total renin, plasma renin activity, angiotensin I (Ang I), Ang II, aldosterone, and plasma zankiren concentration. Satisfactory absorption of zankiren HCl was demonstrated by the results of plasma drug concentration determinations, and renin inhibitory activity was confirmed by dose-related suppression of plasma renin activity, Ang I, Ang II, and aldosterone and increases in plasma active renin concentration. Furthermore, hypotensive activity was readily observed in these normotensive subjects, as evidenced by statistically significant dose-related blood pressure reductions ( P &lt;.01). Conclusions Results from this study demonstrate for the first time that oral administration of a renin inhibitor can dose-dependently decrease blood pressure and circulating components of the RAS in normotensive volunteers as a result of documented absorption.
Polymeric Nanoparticle-Encapsulated Hedgehog Pathway Inhibitor HPI-1 (NanoHHI) Inhibits Systemic Metastases in an Orthotopic Model of Human Hepatocellular Carcinoma
Authors: Yang Xu, Venugopal Chenna, Chaoxin Hu, Hai-Xiang Sun, Mehtab Khan, Haibo Bai, Xin-Rong Yang, Qing-Feng Zhu, Yun-Fan Sun, Anirban Maitra, Jia Fan, Robert A. Anders
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To illustrate the prognostic significance of hedgehog (Hh) signaling in patients with hepatocellular carcinoma (HCC) and to evaluate the efficacy of a novel nanoparticle-encapsulated inhibitor of the Hh transcription factor, Gli1 (NanoHHI) using in vitro and in vivo models of human HCCs. Experimental Design: Patched1 (Ptch1) expression was detected in tumor tissue microarrays of 396 patients with HCC who underwent curative surgical resection during February 2000 to December 2002. Prognostic significance was assessed using Kaplan–Meier survival estimates and log-rank tests. The effects of NanoHHI alone and in combination with sorafenib were investigated on HCC cell lines. Primary HCC tumor growth and metastasis were examined in vivo using subcutaneous and orthotopic HCC xenografts in nude mice. Results: Elevated expression of Ptch1 in HCC tissues was significantly related to disease recurrence, as well as a shorter time to recurrence in patients with HCC. In vitro, NanoHHI significantly inhibited the proliferation and invasion of HCC cell lines. NanoHHI potently suppressed in vivo tumor growth of HCC xenografts in both subcutaneous and orthotopic milieus, and in contrast to sorafenib, resulted in significant attenuation of systemic metastases in the orthotopic setting. Furthermore, NanoHHI significantly decreased the population of CD133-expressing HCC cells, which have been implicated in tumor initiation and metastases. Conclusion: Downstream Hh signaling has prognostic significance in patients with HCC as it predicts early recurrence. Gli inhibition through NanoHHI has profound tumor growth inhibition and antimetastatic effects in HCC models, which may provide a new strategy in the treatment of patients with HCC and prevention post-operative recurrence. Clin Cancer Res; 18(5); 1291–302. ©2011 AACR.
Patient Time Costs Associated With Cancer Care
Authors: K. Robin Yabroff, William W. Davis, Elizabeth B. Lamont, Angela Fahey, Marie Topor, Martin L. Brown, Joan L. Warren
Journal: JNCI Journal of the National Cancer Institute (2007)

Although costs of medical care for cancer have been investigated extensively, patient time costs associated with cancer care have rarely been estimated systematically. In this study, we estimated patient time costs associated with cancer care in patients aged 65 years and older in the United States.We identified 763,527 patients with breast, colorectal, corpus uteri, gastric, head and neck, lung, melanoma of the skin, ovary, prostate, renal, and urinary bladder cancers from linked Surveillance, Epidemiology, and End Results-Medicare files and 1,145,159 noncancer control subjects among Medicare enrollees who were matched by sex, age-group, and geographic location. Frequency of service use was calculated by category for patients and control subjects using Medicare claims data from 1995 to 2001. For each service category, time estimates were combined with service frequency and an hourly value of patient time. Net patient time costs were summed in the initial, continuing, and last-year-of-life phases of care for each tumor site. Net time cost estimates for the initial phase of care were applied to national estimates of numbers of new cancers in 2005 to obtain national time costs for the initial phase of care.Net patient time costs during the initial phase of care ranged from 271 dollars (95% confidence interval [CI] = 213 dollars to 329 dollars) and 842 dollars (95% CI = 806 dollars to 878 dollars) for melanoma of the skin and prostate cancer, respectively, to 5348 dollars (95% CI = 4978 dollars to 5718 dollars) and 5605 dollars (95% CI = 5273 dollars to 5937 dollars) for gastric and ovarian cancers, respectively. Net patient time costs for care during the last year of life ranged from 1509 dollars (95% CI = 1343 dollars to 1675 dollars) for melanoma of the skin to 7799 dollars (95% CI = 7433 dollars to 8165 dollars), 7435 dollars (95% CI = 7207 dollars to 7663 dollars), and 7388 dollars (95% CI = 7018 dollars to 7758 dollars) for gastric, lung, and ovarian cancers, respectively. In 2005, patient time costs for the initial phase of care were 2.3 billion dollars.Patient time costs for cancer care in the United States are substantial and vary by tumor site and phase of care, likely reflecting differences in stage at diagnosis and availability and intensity of treatment.
Efficacy of Sildenafil Citrate for the Treatment of Erectile Dysfunction in Men Taking Serotonin Reuptake Inhibitors
Authors: H G Nurnberg, A Gelenberg, T B Hargreave, W M Harrison, R L Siegel, M D Smith
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: This study was an evaluation of whether sildenafil citrate is effective for the treatment of erectile dysfunction in men taking concomitant serotonin-reuptake-inhibiting antidepressants. METHOD: A retrospective subanalysis of combined data from 10 phase II/III double-blind, placebo-controlled, fixed- and flexible-dose trials (12–26 weeks) identified a group of men with erectile dysfunction receiving 5 to 200 mg/day of sildenafil (N=65) or placebo (N=33) and concomitant serotonin-reuptake-inhibiting antidepressants. Efficacy was measured by responses to questions from the International Index of Erectile Function on ability to achieve erection, ability to maintain erection, ejaculation frequency, orgasm frequency, and sexual desire. RESULTS: Patients with erectile dysfunction receiving sildenafil and concomitant serotonergic antidepressants had significantly greater improvements in ability to achieve and maintain an erection, frequency of ejaculation, and orgasm frequency than did patients receiving placebo, without increased sexual desire. CONCLUSIONS: Sildenafil significantly improved erectile dysfunction in patients taking concomitant serotonergic antidepressants.
Fas and Fas ligand expression in cystic fibrosis airway epithelium
Authors: I. Durieu, C. Amsellem, C. Paulin, M.-T. Chambe, J. Bienvenu, G. Bellon, Y Pacheco
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and defective expression of CFTR protein in epithelial cells. The main cause of mortality in CF is linked to chronic inflammatory and infectious airway processes. Recent studies have suggested perturbations in the apoptotic process in CF cell lines and enterocytes. A study was undertaken to investigate the expression of Fas and Fas ligand (FasL) in CF bronchial epithelium and CF tracheal cell lines. <h3>METHODS</h3> Immunohistochemical staining for Fas (alkaline phosphatase anti-alkaline phosphatase) and FasL (immunoperoxidase) was performed in eight CF bronchial epithelial samples and four controls and immunohistochemical DNA fragmentation (TUNEL) was carried out in four CF patients and four controls. Immunofluorescence staining and flow cytometric analysis of Fas and FasL expression was performed in two human tracheal epithelial cell lines (HTEC) with normal and CF genotype. The dosage of serum soluble FasL was examined in 21 patients with CF and 14 healthy volunteers. <h3>RESULTS</h3> FasL expression was markedly increased in patients with CF in both the ciliated and submucosal glandular bronchial epithelium compared with controls; Fas was similarly expressed in bronchial samples from controls and CF patients in both the ciliated epithelium and submucosal glands. High levels of DNA fragmentation were observed in CF but with some epithelial cell alterations. Serum concentrations of soluble FasL were frequently undetectable in patients with CF. In vitro, HTEC expressed Fas and FasL in both genotypes. A higher mean fluorescence intensity for FasL expression was noted in CF genotype HTEC with median (range) for six experiments of 74 (25–101) for CF cells and 42 (21–70) for non-CF cells. <h3>CONCLUSION</h3> Fas/FasL interaction is probably implicated in the human CF airway apoptotic pathway. The mechanisms of induction of FasL expression and its role in inducing tissue damage or remodelling or in controlling local inflammatory cell apoptosis remain to be determined.
A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease
Authors: R. Casaburi, D.A. Mahler, P.W. Jones, A. Wanner, G. San Pedro, R.L. ZuWallack, S.S. Menjoge, C.W. Serby, T. Witek
Journal: European Respiratory Journal (2002)

Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2±8.7 yrs (mean±sd), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 µg or placebo (mean screening forced expiratory volume in one second (FEV 1 ) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV 1 ( i.e. FEV 1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV 1 response (∼12% over baseline) (p&lt;0.01) and mean response during the 3 h following dosing (∼22% over baseline) (p&lt;0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p&lt;0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p&lt;0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p&lt;0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy.
Wnt Antagonist Family Genes as Biomarkers for Diagnosis, Staging, and Prognosis of Renal Cell Carcinoma Using Tumor and Serum DNA
Authors: Shinji Urakami, Hiroaki Shiina, Hideki Enokida, Hiroshi Hirata, Ken Kawamoto, Toshifumi Kawakami, Nobuyuki Kikuno, Yuichiro Tanaka, Shahana Majid, Masayuki Nakagawa, Mikio Igawa, Rajvir Dahiya
Journal: Clinical Cancer Research (2006)

Abstract Purpose: We hypothesized that combined methylation analysis of Wnt antagonist genes could serve as a panel of biomarkers for diagnosis, staging, and prognosis in renal cell carcinoma (RCC). Experimental Design: Samples (n = 62) of RCC and corresponding normal renal tissue (NRT) were analyzed using methylation-specific PCR for methylation of six Wnt antagonist genes (sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wif-1, and Dkk-3). To increase the sensitivity/specificity of RCC detection, the methylation score (M score) for multigene methylation analysis was developed. Receiver operator characteristic curve analysis was used to determine the optimal sensitivity/specificity of the M score. In addition, the M score was compared with the clinicopathologic outcome. Thirty-three serum DNA samples were also used to investigate the methylation status of Wnt antagonist genes. Results: The methylation levels of all Wnt antagonists were significantly higher in RCC than in NRT. In multivariate regression analysis, the methylation level of sFRP-1 was a significant independent predictor of RCC, whereas for sFRP-2 and sFRP-4 there was a trend toward significance as independent predictors. The M score of Wnt antagonist genes was significantly higher in RCC than in NRT. Overall, the M score had a sensitivity of 79.0% and a specificity of 75.8% (area under the curve, 0.808) as a diagnostic biomarker. In addition, the M score could significantly distinguish grade, pT category, M category, and overall survival of RCC patients. The M score was independent of age and gender in predicting overall survival by the Cox proportional hazards model. In RCC patients, 72.7% of the methylation-specific PCR results had identical methylation in samples of tumor and serum DNA. No serum DNA in normal controls showed aberrant methylation of the Wnt antagonist genes. In addition, the methylation status of Wnt antagonist genes in serum DNA was significantly correlated with tumor grade and stage. Conclusions: This is the first report showing that M score analysis of Wnt antagonist genes can serve as an excellent epigenetic biomarker panel for detection, staging, and prognosis of RCC using serum DNA.
Bacterial cell surface hydrophobicity properties in the mediation of in vitro adhesion by the rabbit enteric pathogen Escherichia coli strain RDEC-1.
Authors: B Drumm, A W Neumann, Z Policova, P M Sherman
Journal: Journal of Clinical Investigation (1989)

The role of hydrophobicity in the attachment of enteropathogens to gastrointestinal mucosa is controversial. In vitro binding of Escherichia coli RDEC-1 to rabbit intestine is dependent on the expression of pili. We examined in vitro adherence of piliated RDEC-1 after altering either the hydrophobicity of the organisms, the hydrophobicity of the substrate for attachment, or the surface tension of the suspending liquid. Hydrophobicity of RDEC-1 was determined using four complementary methods. In each assay piliated RDEC-1 demonstrated relatively more hydrophobic properties compared with both organisms grown to suppress pilus expression and a mutant that cannot express mannose-resistant pili. When piliated RDEC-1 were pretreated with tetramethyl urea to disrupt hydrophobic bonds surface hydrophobicity decreased. Concurrently, bacterial adherence to rabbit ileal microvillus membranes, mucus and mucin was reduced. Binding of piliated organisms to hydrophobic surfaces was significantly higher compared to both nonpiliated bacteria and the adherence of piliated RDEC-1 to relatively hydrophilic surfaces. Addition of propanol reduced the surface tension of the suspending liquid, and decreased adhesion of piliated RDEC-1 to polystyrene by 80%. Conversely, adherence of piliated organisms to a hydrophilic surface increased 12-fold after lowering the surface tension of the suspending liquid. We conclude that hydrophobic properties have a role in mediating in vitro adherence of this E. coli enteric pathogen.
HNF-1β Regulates Transcription of the PKD Modifier Gene Kif12
Authors: Yimei Gong, Zhendong Ma, Vishal Patel, Evelyne Fischer, Thomas Hiesberger, Marco Pontoglio, Peter Igarashi
Journal: Journal of the American Society of Nephrology (2008)

Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor that regulates gene expression in the kidney, liver, pancreas, and other epithelial organs. Mutations of HNF-1beta lead to a syndrome of inherited renal cysts and diabetes and are also a common cause of sporadic renal dysplasia. The full complement of target genes responsible for the functions of HNF-1beta, however, is incompletely defined. Using a functional genomics approach involving chromatin immunoprecipitation and promoter arrays, combined with gene expression profiling, we found that an HNF-1beta target gene in the kidney is kinesin family member 12 (Kif12), a gene previously identified as a candidate modifier gene in the cpk mouse model of polycystic kidney disease. Mutations of HNF-1beta inhibited Kif12 transcription in both cultured cells and knockout mice by altering co-factor recruitment and histone modification. Because kinesin-12 family members participate in orienting cell division, downregulation of Kif12 may underlie the abnormal planar cell polarity observed in cystic kidney diseases.
Pulmonary Function Abnormalities in HIV-Infected Patients during the Current Antiretroviral Therapy Era
Authors: Matthew R. Gingo, M. Patricia George, Cathy J. Kessinger, Lorrie Lucht, Barbara Rissler, Renee Weinman, William A. Slivka, Deborah K. McMahon, Sally E. Wenzel, Frank C. Sciurba, Alison Morris
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Before the introduction of combination antiretroviral (ARV) therapy, patients infected with HIV had an increased prevalence of respiratory symptoms and lung function abnormalities. The prevalence and exact phenotype of pulmonary abnormalities in the current era are unknown. In addition, these abnormalities may be underdiagnosed.