tbuckley/cabot-search huggingface dataset:
MDA-7/IL-24 suppresses human ovarian carcinoma growth in vitro and in vivo
Authors: Began Gopalan, Manish Shanker, Sunil Chada, Rajagopal Ramesh
Journal: Molecular Cancer (2007)

Previous studies showed that the human melanoma differentiation-associated gene-7 (mda-7), also known as interleukin-24 (IL-24), has potent antitumor activity against human and murine cancer cells. However, the majority of these studies were limited to in vitro testing. In the present study, we investigated the antitumor activity of mda-7/IL-24 against human ovarian cancer cells both in vitro and in vivo.In vitro, treatment of ovarian cancer cells with an adenoviral vector carrying the mda-7 gene (Ad-mda7) resulted in inhibition of cell proliferation and induction of cell cycle arrest, leading to apoptosis. We did not observe inhibitory activity in Ad-mda7-treated normal cells. In vivo, treatment of subcutaneous tumor xenografts with Ad-mda7 resulted in significant tumor growth inhibition when compared with that in control groups (p < 0.001). Molecular analysis of ovarian tumor tissue lysates treated with Ad-mda7 showed that MDA-7 protein expression was associated with activation of the caspase cascade.Our results show that treatment of ovarian cancer cells with mda-7/IL-24 results in growth suppression both in vitro and in vivo.
Kidney Dysfunction, Inflammation, and Coronary Events
Authors: Eric L. Knight, Eric B. Rimm, Jennifer K. Pai, Kathryn M. Rexrode, Carolyn C. Cannuscio, JoAnn E. Manson, Meir J. Stampfer, Gary C. Curhan
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Kidney dysfunction and high C-reactive protein (CRP) levels are independently associated with coronary events. However, it is unclear whether the risk of coronary events associated with decreased kidney function is at least partially mediated by inflammation and whether the association between inflammatory biomarkers and coronary events is influenced by level of kidney function. With the use of a prospective, nested, case-control study design, the association among kidney function, inflammatory biomarker levels, and coronary events was studied. A total of 244 women who were participants in the Nurses' Health Study and had no history of cardiovascular disease received a diagnosis of an incident coronary event (defined as nonfatal myocardial infarction or death as a result of coronary disease) during the follow-up period from 1990 to 1998 and were matched to 486 control subjects. Serum creatinine and inflammatory biomarker levels were measured in blood samples collected in 1989. Creatinine clearance (CrCl) was estimated using creatinine, age, weight, and height. In multivariate analyses, the odds ratio (OR) for a coronary event in women with an estimated CrCl &lt;60 ml/min was 2.33 (95% confidence interval [CI], 1.01 to 5.38) compared with those with a CrCl ≥90 ml/min. When soluble tumor necrosis factor receptor (sTNFR) I and II levels were added into this model individually, the observed OR for women with CrCl &lt;60 ml/min was attenuated. In analyses stratified by estimated CrCl, higher high-sensitivity CRP (hs-CRP), IL-6, and sTNFR I and II levels each were significantly associated with an increased odds of coronary events in women with an estimated CrCl ≤74 ml/min but not in women with an estimated CrCl ≥75 ml/min. The OR per 5-mg/L unit increase in hs-CRP was 1.68 (95% CI, 1.13 to 2.52) for women with an estimated CrCl ≤74 ml/min, compared with 1.23 (95% CI, 0.86 to 1.76) and 0.99 (95% CI, 0.76 to 1.29) for women with an estimated CrCl 75 to 89 and ≥90 ml/min, respectively (<i>P</i> = 0.004 for interaction). In conclusion, kidney dysfunction is associated with an increased odds of coronary events, and inflammation, as assessed by higher sTNFR I and II levels, may mediate some of this risk. Higher inflammatory biomarkers levels, specifically, hs-CRP, IL-6, and sTNFR I and II, were significantly associated with coronary events only in women with reduced kidney function. These findings warrant further investigation in other populations.
Genetic Inhibition of Na <sup>+</sup> -Ca <sup>2+</sup> Exchanger Current Disables Fight or Flight Sinoatrial Node Activity Without Affecting Resting Heart Rate
Authors: Zhan Gao, Tyler P. Rasmussen, Yue Li, William Kutschke, Olha M. Koval, Yiming Wu, Yuejin Wu, Duane D. Hall, Mei-ling A. Joiner, Xiang-Qiong Wu, Paari D. Swaminathan, Anil Purohit, Kathy Zimmerman, Robert M. Weiss, Kenneth D. Philipson, Long-sheng Song, Thomas J. Hund, Mark E. Anderson
Journal: Circulation Research (2012)

Rationale: The sodium–calcium exchanger 1 (NCX1) is predominantly expressed in the heart and is implicated in controlling automaticity in isolated sinoatrial node (SAN) pacemaker cells, but the potential role of NCX1 in determining heart rate in vivo is unknown. Objective: To determine the role of Ncx1 in heart rate. Methods and Results: We used global myocardial and SAN-targeted conditional Ncx1 knockout ( Ncx1 −/− ) mice to measure the effect of the NCX current on pacemaking activity in vivo, ex vivo, and in isolated SAN cells. We induced conditional Ncx1 −/− using a Cre/loxP system. Unexpectedly, in vivo and ex vivo hearts and isolated SAN cells showed that basal rates in Ncx1 −/− (retaining ≈20% of control level NCX current) and control mice were similar, suggesting that physiological NCX1 expression is not required for determining resting heart rate. However, increases in heart rate and SAN cell automaticity in response to isoproterenol or the dihydropyridine Ca 2+ channel agonist BayK8644 were significantly blunted or eliminated in Ncx1 −/− mice, indicating that NCX1 is important for fight or flight heart rate responses. In contrast, the pacemaker current and L-type Ca 2+ currents were equivalent in control and Ncx1 −/− SAN cells under resting and isoproterenol-stimulated conditions. Ivabradine, a pacemaker current antagonist with clinical efficacy, reduced basal SAN cell automaticity similarly in control and Ncx1 −/− mice. However, ivabradine decreased automaticity in SAN cells isolated from Ncx1 −/− mice more effectively than in control SAN cells after isoproterenol, suggesting that the importance of NCX current in fight or flight rate increases is enhanced after pacemaker current inhibition. Conclusions: Physiological Ncx1 expression is required for increasing sinus rates in vivo, ex vivo, and in isolated SAN cells, but not for maintaining resting heart rate.
Characteristics of Prostate Cancer in Families Potentially Linked to the Hereditary Prostate Cancer 1 (HPC1) Locus
Authors: Henrik Grönberg
Journal: JAMA (1997)

<h3>Context.</h3> —Approximately 9% of prostate cancer cases have been estimated to result from inheritance of mutated prostate cancer susceptibility genes. Few data exist as to whether there are clinical differences between prostate cancers that are inherited and those that occur in the general population. <h3>Objective.</h3> —To investigate phenotypic characteristics of families potentially linked to the hereditary prostate cancer 1 (<i>HPC1</i>) locus on chromosome 1q24-25. <h3>Design.</h3> —Retrospective case study in which clinical data were extracted from medical and pathological records. <h3>Families.</h3> —A total of 74 North American families with hereditary prostate cancer. Prostate cancer cases from the National Cancer Data Base were used as a reference population for comparison. <h3>Main Outcome Measures.</h3> —The families were divided into 2 groups: either potentially linked (33 families with 133 men with prostate cancer), and thus likely to be carrying an altered<i>HPC1</i>gene, or potentially unlinked (41 families with 172 men with prostate cancer), on the basis of haplotype analysis in the region of<i>HPC1</i>. The age at diagnosis of prostate cancer, serum prostate-specific antigen levels, digital rectal examination status, stage, grade, primary treatment of prostate cancers, and occurrence of other cancers were compared between the groups. <h3>Rresults.</h3> —The mean age at diagnosis of prostate cancer for men in potentially linked families was significantly lower than for men in potentially unlinked families (63.7 vs 65.9 years, respectively,<i>P</i>=.01; mean age at diagnosis in the reference population was 71.6 years). Higher-grade cancers (grade 3) were more common in potentially linked families, and advanced-stage disease was found in 41% of the case patients in potentially linked families compared with 31% in both the potentially unlinked families and the reference groups (<i>P</i>=.03 for the latter comparison). In the other clinical parameters, we found no significant differences between the groups. A modest excess of breast cancer and colon cancer was found in potentially linked families in comparison with potentially unlinked families, but this difference was not statistically significant. <h3>Conclusions.</h3> —Families that provide evidence for segregation of an altered<i>HPC1</i>gene are characterized by multiple cases of prostate cancer that, in most respects, are indistinguishable from nonhereditary cases. However, 3 characteristics were observed: younger age at diagnosis, higher-grade tumors, and more advanced-stage disease. Our study shows that a significant fraction of hereditary prostate cancers are diagnosed in advanced stages, emphasizing the clinical importance of early detection in men potentially carrying prostate cancer susceptibility genes. These findings support the current recommendations to screen men with a positive family history of prostate cancer beginning at age 40 years.
A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant
Authors: Eric R. Gross, Vanessa O. Zambelli, Bryce A. Small, Julio C.B. Ferreira, Che-Hong Chen, Daria Mochly-Rosen
Journal: The Annual Review of Pharmacology and Toxicology (2014)

Asian Americans are one of the fastest-growing populations in the United States. A relatively large subset of this population carries a unique loss-of-function point mutation in aldehyde dehydrogenase 2 (ALDH2), ALDH2*2. Found in approximately 560 million people of East Asian descent, ALDH2*2 reduces enzymatic activity by approximately 60% to 80% in heterozygotes. Furthermore, this variant is associated with a higher risk for several diseases affecting many organ systems, including a particularly high incidence relative to the general population of esophageal cancer, myocardial infarction, and osteoporosis. In this review, we discuss the pathophysiology associated with the ALDH2*2 variant, describe why this variant needs to be considered when selecting drug treatments, and suggest a personalized medicine approach for Asian American carriers of this variant. We also discuss future clinical and translational perspectives regarding ALDH2*2 research.
Anaphylaxis caused by Hymenoptera stings: from epidemiology to treatment
Authors: M. B. Bilò
Journal: Allergy (2011)

Hymenoptera venom allergy occasionally causes fatal reactions. The prevalence of systemic reactions (SRs) is 0.3-8.9%, with anaphylaxis in 0.3-42.8% of cases. Factors contributing to reaction severity include older age, insect type, a previous less severe SR, preexisting diseases, concomitant treatments, mast cell diseases and elevated baseline tryptase serum concentration. Venom immunotherapy (VIT) is highly effective, as shown by sting challenge and spontaneous field stings. Indications for VIT are based on history of an SR, positive diagnostic tests, natural history and established risk factors for a severe outcome. Current strategies for reducing adverse reactions include anti-IgE monoclonal antibody pretreatment, and purified aqueous and purified aluminium hydroxide adsorbed preparations. New strategies for VIT, mostly using recombinant allergen, are in development. Further improvements will increase the safety and efficacy of VIT.
AKT Participates in Endothelial Dysfunction in Hypertension
Authors: Guido Iaccarino, Michele Ciccarelli, Daniela Sorriento, Ersilia Cipolletta, Vincenzo Cerullo, Gianni Luigi Iovino, Alessandro Paudice, Andrea Elia, Gaetano Santulli, Alfonso Campanile, Oreste Arcucci, Lucio Pastore, Francesco Salvatore, Gianluigi Condorelli, Bruno Trimarco
Journal: Circulation (2004)

In hypertension, reduced nitric oxide production and blunted endothelial vasorelaxation are observed. It was recently reported that AKT phosphorylates and activates endothelial nitric oxide synthase and that impaired kinase activity may be involved in endothelial dysfunction.To identify the physiological role of the kinase in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), we used adenoviral vectors to transfer the human AKT1 gene selectively to the common carotid endothelium. In vitro, endothelial vasorelaxations to acetylcholine, isoproterenol, and insulin were blunted in control carotids from SHR compared with WKY rats, and human AKT1 overexpression corrected these responses. Similarly, blood flow assessed in vivo by Doppler ultrasound was reduced in SHR compared with WKY carotids and normalized after AKT1 gene transfer. In primary cultured endothelial cells, we evaluated AKT phosphorylation, activity, and compartmentalization and observed a mislocalization of the kinase in SHR.We conclude that AKT participates in the settings of endothelial dysfunction in SHR rats by impaired membrane localization. Our data suggest that AKT is involved in endothelium dysfunction in hypertension.
Systemic medication and the inflammatory cascade
Authors: Aws Alani, Robin Seymour
Journal: Periodontology 2000 (2013)

Abstract Periodontal disease is caused by inflammatory processes initiated by the presence of a biofilm. The management of this disease process is largely achieved by disrupting the biofilm to allow regression of inflammation and healing. As our patients are living for longer they are likely to have been exposed to systemic medications that aim to reduce inflammation. These drugs have been shown to decrease inflammation within the periodontal tissues despite not being a primary function of their use. This paper aims to review the relative effects of common systemic medications on the periodontal tissues by analyzing their modes of action and discussing current research and the implications for periodontal treatment.
Improved Prediction of Disease Relapse after Radical Prostatectomy through a Panel of Preoperative Blood-Based Biomarkers
Authors: Shahrokh F. Shariat, Jose A. Karam, Jochen Walz, Claus G. Roehrborn, Francesco Montorsi, Vitaly Margulis, Fred Saad, Kevin M. Slawin, Pierre I. Karakiewicz
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The preoperative blood levels of biomarkers may allow accurate identification of patients who are likely to fail radical prostatectomy as a first-line therapy for localized prostate cancer, thereby allowing more efficient delivery of neoadjuvant and adjuvant therapy. The aim of this study was to determine the added value of biomarkers relative to established predictors of biochemical recurrence, such as clinical stage, biopsy Gleason sum, and preoperative prostate-specific antigen. Experimental Design: The preoperative plasma levels of transforming growth factor-β1 (TGF-β1), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), vascular endothelial growth factor (VEGF), vascular cell adhesion molecule-1 (VCAM-1), endoglin, urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1, and uPA receptor were measured with the use of commercially available enzyme immunoassays in 423 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostate cancer. Multivariable models were used to explore the gain in the predictive accuracy of the models. This predictive accuracy was quantified by the concordance index statistic and was validated with 200 bootstrap resamples. Results: In standard multivariable analyses, TGF-β1 (P &amp;lt; 0.001), sIL-6R (P &amp;lt; 0.001), IL-6 (P &amp;lt; 0.001), VCAM-1 (P &amp;lt; 0.001), VEGF (P = 0.008), endoglin (P = 0.002), and uPA (P &amp;lt; 0.001) were associated with biochemical recurrence. The multivariable model containing standard clinical variables alone had an accuracy of 71.6%. The addition of TGF-β1, sIL-6R, IL-6, VCAM-1, VEGF, endoglin, and uPA increased the predictive accuracy by 15% to 86.6% (P &amp;lt; 0.001) and showed excellent calibration. Conclusions: A nomogram based on these biomarkers improves the accuracy of standard predictive models and could help counsel patients about their risk of biochemical recurrence following radical prostatectomy.
Diagnosing Gestational Diabetes Mellitus: Is the Gold Standard Valid?
Authors: C David Naylor
Journal: Diabetes Care (1989)

In North America, gestational diabetes mellitus (GDM) is diagnosed from a 100-g oral glucose tolerance test (OGTT) with criteria proposed by the National Diabetes Data Group (NDDG). These criteria were derived in the 1950s from an unrepresentative sample of women tested predominantly in the latter stages of pregnancy. The original studies did not check for reproducibility of OGTT results. Measurements were made with the Somogyi-Nelson whole-blood glucose technique, and test translation errors are present in the threshold values proposed for modern plasma glucose oxidase methods. Whereas GDM is now diagnosed with a view to adverse m ternal-fetal outcomes, the criteria were chosen to reflect maternal risk of developing glucose intolerance as shown by a 75-g OGTT in the nonpregnant state over the ensuing 8 yr. For that outcome, the positive predictive value of the criteria was only 36.1%, and this is a marked overestimate, because the study cohort was a highly selected group with an increased incidence of glucose intolerance both during and after pregnancy. The criteria are also conceptually flawed in that they impose a dichotomous definition of normal and abnormal on gestational glucose tolerance, when the risk of adverse maternal-fetal outcomes and later diabetes mellitus should logically be graded upward with higher values on the gestational OGTT and with the degree of fasting hyperglycemia. Although NDDG criteria merit continued use for lack of a better alternative, new diagnostic criteria for GDM should be derived and validated.
Changing Activation Sequence in the Embryonic Chick Heart
Authors: Emil T. Chuck, David M. Freeman, Michiko Watanabe, David S. Rosenbaum
Journal: Circulation Research (1997)

Abstract In the mature heart, impulse propagation through the His-Purkinje system (HPS) is required for efficient ventricular contraction in an apex-to-base direction. However, the embryonic heart begins to contract as a myocardial tube without a specialized conduction system. To identify the developmental stage when the HPS begins to function, we mapped the ventricular depolarization sequence from microvolt-level electrograms recorded from embryonic myocardium using 50-μm extracellular electrodes, high-gain amplification, and signal-processing techniques. Analysis of left ventricular activation in 99 embryonic hearts revealed a transition in the activation sequence that was dependent on developmental stage. As the heart develops, a transition in the activation sequence occurred from the primitive base-to-apex pattern (in 20 of 33 hearts) at early stages (Hamburger-Hamilton stages 25 to 28) to the HPS-like apex-to-base pattern (12 of 17 hearts) late in development (stages 33 to 36). Immunohistological experiments (n=10) also confirm that the expression pattern of two biochemical HPS markers changes in parallel with the change to the mature ventricular activation pattern. These data indicate that the ventricular activation sequence in the chick heart develops to a mature pattern at stages 29 to 31, suggesting that preferential conduction through the HPS begins shortly after ventricular septation is complete.
Is conservation triage just smart decision making?
Authors: Madeleine C. Bottrill, Liana N. Joseph, Josie Carwardine, Michael Bode, Carly Cook, Edward T. Game, Hedley Grantham, Salit Kark, Simon Linke, Eve McDonald-Madden, Robert L. Pressey, Susan Walker, Kerrie A. Wilson, Hugh P. Possingham
Journal: Trends in Ecology & Evolution (2008)
Allopurinol Benefits Left Ventricular Mass and Endothelial Dysfunction in Chronic Kidney Disease
Authors: Michelle P. Kao, Donald S. Ang, Stephen J. Gandy, M. Adnan Nadir, J. Graeme Houston, Chim C. Lang, Allan D. Struthers
Journal: Journal of the American Society of Nephrology (2011)

Allopurinol ameliorates endothelial dysfunction and arterial stiffness among patients without chronic kidney disease (CKD), but it is unknown if it has similar effects among patients with CKD. Furthermore, because arterial stiffness increases left ventricular afterload, any allopurinol-induced improvement in arterial compliance might also regress left ventricular hypertrophy (LVH). We conducted a randomized, double-blind, placebo-controlled, parallel-group study in patients with stage 3 CKD and LVH. We randomly assigned 67 subjects to allopurinol at 300 mg/d or placebo for 9 months; 53 patients completed the study. We measured left ventricular mass index (LVMI) with cardiac magnetic resonance imaging (MRI), assessed endothelial function by flow-mediated dilation (FMD) of the brachial artery, and evaluated central arterial stiffness by pulse-wave analysis. Allopurinol significantly reduced LVH (P = 0.036), improved endothelial function (P = 0.009), and improved the central augmentation index (P = 0.015). This study demonstrates that allopurinol can regress left ventricular mass and improve endothelial function among patients with CKD. Because LVH and endothelial dysfunction associate with prognosis, these results call for further trials to examine whether allopurinol reduces cardiovascular events in patients with CKD and LVH.
Press Release: Study Examines Effects of State-Mandated Reimbursement for Clinical Trials
Authors: S. L. Zielinski
Journal: JNCI Journal of the National Cancer Institute (2004)

An often-cited barrier to enrollment in cancer clinical trials is payer reimbursement.Gross et al. (p.1063) examined if state mandates ensuring coverage of routine medical care costs of cancer trial participants increased patient enrollment rates for National Cancer Institute-sponsored phase II and cooperative group phase III trials between 1996 and 2001.They compared enrollment of participants in four states that had enacted coverage policies in 1999 with enrollment in states without policies.After the state mandates were enacted in 1999, the authors found that phase II trial enrollment increased at a greater rate in states with coverage policies compared with states without policies.However, phase III trial enrollment increased at a similar rate in all states, suggesting that coverage mandates were not associated with an increase in phase III trial enrollment.In an editorial, Hillner (p.1048) addresses the effect of state mandates that cover patient care costs of clinical trial participation on trial enrollment.He discusses the issue of cost as a barrier to enrollment as well as other potential enrollment barriers.
AN IMMUNIZING STRAIN OF THE VIRUS OF POLIOMYELITIS
Authors: Simon Flexner, Harold L. Amoss
Journal: The Journal of Experimental Medicine (1924)

In this communication we have described a strain of the virus of poliomyelitis derived from a rapidly fatal human case, which exhibits mild degrees of infective power and marked degrees of protective effect for the monkey. While Macacus rhesus displays perceptible differences in suceptibility to the attenuated virus, nearly all individuals respond to the inoculation and none succumbs to the infection induced. As compared with previously described examples of experimental poliomyelitis, the modified disease described in this paper is distinguished by its relatively benign nature and its tendency to end in recovery rather than, as with the earlier observed instances, in death.