tbuckley/cabot-search huggingface dataset:
Developmental Changes in Transient Outward Current in Mouse Ventricle
Authors: Li Wang, Henry J. Duff
Journal: Circulation Research (1997)

Abstract Developmental changes in the transient outward K + current ( I to ) in mouse ventricular myocytes were assessed by the whole-cell patch-clamp technique. The density of I to in mouse ventricular myocytes was significantly increased from the day-1 neonate to the adult. At +50 mV, the density of I to was 3±1 pA/pF in the day-1 neonate, 15±3 pA/pF in the day-14 neonate, and 19±4 pA/pF in the adult ( P &lt;.01). Unlike other species, the rate of I to inactivation significantly slowed in mouse ventricular cells during development. Moreover, the time courses of inactivation and recovery from inactivation of I to were well described by a monoexponential function in day-1 neonatal cells, whereas they were best fitted by a biexponential function in day-14 neonatal and adult cells. The characteristics of steady state inactivation were also significantly different in day-1 neonatal cells (half-inactivation potential [V h ]=−66±4 mV, slope factor [k]=12±2 mV), in day-14 neonatal cells (V h =−40±3 mV, k=13±1 mV), and in adult cells (V h =−34±4 mV, k=6±1 mV). Microelectrode studies revealed that action potential duration progressively decreased in mouse ventricles during normal postnatal development. In addition, 4-aminopyridine (1 mmol/L) prolonged action potential duration more in adult than in neonatal mouse ventricles, suggesting that the developmental increase in the density of I to contributes to the age-related shortening of action potential duration in mouse ventricles. In conclusion, I to in adult mouse ventricular myocytes exhibits a higher density, slower inactivation kinetics, and a relatively more positive half-inactivation potential. All these characteristics result in I to being a physiologically more important repolarizing K + current in adult than in neonatal mouse hearts.
Increased Collagen Deposition and Elevated Expression of Connective Tissue Growth Factor in Human Thoracic Aortic Dissection
Authors: Xinwen Wang, Scott A. LeMaire, Li Chen, Ying H. Shen, Yehua Gan, Heather Bartsch, Stacey A. Carter, Budi Utama, Hesheng Ou, Joseph S. Coselli, Xing Li Wang
Journal: Circulation (2006)

Thoracic aortic dissection (TAD) is characterized by dysregulated extracellular matrix. Little is known about the alterations of collagen and stimulators of collagen synthesis, eg, connective tissue growth factor (CTGF), in patients with TAD. In this study, we examined their roles in TAD.Surgical specimens of the aortic wall of TAD patients (n=10) and controls (n=10) were tested for collagen types I and III and CTGF expression. When compared with controls, protein levels of type I and III collagen and CTGF were significantly increased by 3.2-, 3.7-, and 5.3-fold, respectively (P<0.05 for all). Similar patterns were shown in mRNA levels of type Ialpha and Ialpha2 collagen and CTGF. Using immunohistochemistry and trichrome staining, we also observed elevated levels of collagen in the aortic media and adventitia. Treatment with recombinant human CTGF increased collagen synthesis in cultured aortic smooth muscle cells in a dose- and time-dependent fashion, in which expression of collagens increased from 506+/-108 counts per minute to 2764+/-240 cpm by 50 ng/mL CTGF, and from 30+/-43 cpm to 429+/-102 cpm at 48 hours.TAD patients exhibited significantly increased expression of aortic collagen types I and III as well as CTGF, which is likely to be responsible for the compromised aortic distensibility and systemic compliance. Because CTGF can increase collagen expression, CTGF may be a new target molecule in the pathogenesis and progression of TAD.
Alpha-Tocopherol Supplementation in Healthy Individuals Reduces Low-Density Lipoprotein Oxidation but Not Atherosclerosis
Authors: Howard N. Hodis, Wendy J. Mack, Laurie LaBree, Peter R. Mahrer, Alex Sevanian, Chao-ran Liu, Ci-hua Liu, Juliana Hwang, Robert H. Selzer, Stanley P. Azen
Journal: Circulation (2002)

Epidemiological studies have demonstrated an inverse relationship between vitamin E intake and cardiovascular disease (CVD) risk. In contrast, randomized controlled trials have reported conflicting results as to whether vitamin E supplementation reduces atherosclerosis progression and CVD events.The study population consisted of men and women > or =40 years old with an LDL cholesterol level > or =3.37 mmol/L (130 mg/dL) and no clinical signs or symptoms of CVD. Eligible participants were randomized to DL-alpha-tocopherol 400 IU per day or placebo and followed every 3 months for an average of 3 years. The primary trial end point was the rate of change in the common carotid artery far-wall intima-media thickness (IMT) assessed by computer image-processed B-mode ultrasonograms. A mixed effects model using all determinations of IMT was used to test the hypothesis of treatment differences in IMT change rates. Compared with placebo, alpha-tocopherol supplementation significantly raised plasma vitamin E levels (P<0.0001), reduced circulating oxidized LDL (P=0.03), and reduced LDL oxidative susceptibility (P<0.01). However, vitamin E supplementation did not reduce the progression of IMT over a 3-year period compared with subjects randomized to placebo.The results are consistent with previous randomized controlled trials and extend the null results of vitamin E supplementation to the progression of IMT in healthy men and women at low risk for CVD.
Lymphocyte and lymphocyte subset numbers in blood and in bronchoalveolar lavage and pleural fluid in various forms of human pulmonary tuberculosis at presentation and during recovery.
Authors: G M Ainslie, J A Solomon, E D Bateman
Journal: Thorax (1992)

BACKGROUND: Lymphocytes have a central role in human defences against mycobacteria. A study was designed to assess the relation between lymphocyte responses and clinical pattern of disease, nutrition and recovery during treatment in patients with tuberculosis. METHODS: Lymphocyte numbers and subsets (on the basis of CD3, CD4, and CD8 monoclonal antibodies) were measured in peripheral blood and, where appropriate, bronchoalveolar lavage or pleural fluid of patients with different forms of pulmonary tuberculosis. Eleven had localised pulmonary tuberculosis, 18 miliary tuberculosis and seven a tuberculous pleural effusion. RESULTS: CD4 lymphocytes were found in greatly increased numbers in pleural fluid and were relatively depleted in the blood. Lymphocyte numbers in bronchoalveolar lavage fluid varied widely in localised pulmonary and miliary tuberculosis but were highest in lavage fluid from patients with miliary tuberculosis. This was due to an increase in CD8 lymphocytes, which were also increased in the blood. Lymphocyte numbers bore no relation to nutrition, symptom duration, or radiographic profusion scores. In miliary tuberculosis the time taken for the chest radiograph to clear (mean (SD) 17.6 (7.8) weeks) correlated with lymphocyte numbers in lavage fluid, especially CD8 cells (r = 0.74), but not with the patients9 age or nutrition. After 8 weeks9 treatment, total and CD4 lymphocyte numbers in lavage fluid showed a substantial increase. CONCLUSION: The association of CD8 cells with delayed recovery is compatible with suppression of the antimycobacterial action of macrophages. The switch to predominance of CD4 cells in lavage fluid during successful treatment supports the view that they may have a role in eliminating mycobacteria.
Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells
Authors: Mengqian Chen, Michael A. Feuerstein, Elina Levina, Prateek S. Baghel, Richard D. Carkner, Matthew J. Tanner, Michael Shtutman, Francis Vacherot, Stéphane Terry, Alexandre de la Taille, Ralph Buttyan
Journal: Molecular Cancer (2010)

Abstract Background Castration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells. Results Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates. Conclusions Collectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.
The Impact of Insulin Resistance on Proinsulin Secretion in Pregnancy
Authors: Ravi Retnakaran, Anthony J.G. Hanley, Mathew Sermer, Bernard Zinman
Journal: Diabetes Care (2005)

OBJECTIVE—Excessive secretion of the insulin precursor proinsulin, as manifested by an increased serum proinsulin-to-insulin ratio, has been associated with β-cell dysfunction. In women with gestational diabetes mellitus (GDM), previous studies of the proinsulin-to-insulin ratio have yielded conflicting results, despite the presence of β-cell dysfunction. The interpretation of the proinsulin-to-insulin ratio, however, may be confounded by the variable effects of hepatic insulin extraction. Thus, we sought to determine whether GDM is characterized by relative hyperproinsulinemia as measured by the proinsulin–to–C-peptide ratio, an alternate measure of proinsulin secretion that is not affected by hepatic insulin extraction. RESEARCH DESIGN AND METHODS—Serum proinsulin, C-peptide, and insulin were measured in a cross-sectional study of 180 women undergoing oral glucose tolerance tests (OGTTs) in the late second or early third trimester. Based on the OGTT, participants were stratified into three groups: 1) normal glucose tolerance (NGT; n = 93), 2) impaired glucose tolerance (IGT; n = 39), and 3) GDM (n = 48). Insulin sensitivity (IS) was measured using the ISOGTT index of Matsuda and DeFronzo, which has been previously validated in pregnant women. RESULTS—There were no significant differences in mean fasting proinsulin–to–C-peptide ratio between the three glucose tolerance groups (NGT, 0.024; IGT, 0.022; GDM, 0.019; P = 0.4). Furthermore, adjustment for age, weeks’ gestation, prepregnancy BMI, ethnicity, previous GDM, and family history of diabetes did not reveal any association between the proinsulin–to–C-peptide ratio and glucose tolerance status. Using Spearman univariate correlation analysis, fasting proinsulin–to–C-peptide ratio was significantly correlated with ISOGTT (r = 0.29, P &amp;lt; 0.0001) and inversely related to the homeostasis model assessment of insulin resistance (r = −0.36, P &amp;lt; 0.0001) and prepregnancy BMI (r = −0.23, P &amp;lt; 0.005). On multiple linear regression analysis, ISOGTT emerged as the strongest independent correlate of the dependent variable proinsulin–to–C-peptide ratio. Furthermore, after adjustment for potential covariates, a stepwise decrease in proinsulin–to–C-peptide ratio was observed per decreasing tertile of ISOGTT (trend P = 0.0019), consistent with enhanced efficiency of proinsulin processing (i.e., reduced proinsulin–to–C-peptide ratio) as insulin resistance increases. CONCLUSIONS—GDM is not independently associated with hyperproinsulinemia as measured by the proinsulin–to–C-peptide ratio. Instead, in pregnant women, increased insulin resistance is associated with decreased proinsulin–to–C-peptide ratio, independently of glucose tolerance status. These data suggest that relative proinsulin secretion in late pregnancy is primarily related to insulin resistance and does not necessarily reflect β-cell function.
Revisiting the Insect Mitochondrial Molecular Clock: The Mid-Aegean Trench Calibration
Authors: A. Papadopoulou, I. Anastasiou, A. P. Vogler
Journal: Molecular Biology and Evolution (2010)

Phylogenetic trees in insects are frequently dated by applying a "standard" mitochondrial DNA (mtDNA) clock estimated at 2.3% My−1, but despite its wide use reliable calibration points have been lacking. Here, we used a well-established biogeographic barrier, the mid-Aegean trench separating the western and eastern Aegean archipelago, to estimate substitution rates in tenebrionid beetles. Cytochrome oxidase I (cox1) for six codistributed genera across 28 islands (444 individuals) on both sides of the mid-Aegean trench revealed 60 independently coalescing entities delimited with a mixed Yule-coalescent model. One representative per entity was used for phylogenetic analysis of mitochondrial (cox1, 16S rRNA) and nuclear (Mp20, 28S rRNA) genes. Six nodes marked geographically congruent east–west splits whose separation was largely contemporaneous and likely to reflect the formation of the mid-Aegean trench at 9–12 Mya. Based on these "known" dates, a divergence rate of 3.54% My−1 for the cox1 gene (2.69% when combined with the 16S rRNA gene) was obtained under the preferred partitioning scheme and substitution model selected using Bayes factors. An extensive survey suggests that discrepancies in mtDNA substitution rates in the entomological literature can be attributed to the use of different substitution models, the use of different mitochondrial gene regions, mixing of intraspecific with interspecific data, and not accounting for variance in coalescent times or postseparation gene flow. Different treatments of these factors in the literature confound estimates of mtDNA substitution rates in opposing directions and obscure lineage-specific differences in rates when comparing data from various sources.
Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell Leukemia
Authors: Robert J. Kreitman, Martin S. Tallman, Tadeusz Robak, Steven Coutre, Wyndham H. Wilson, Maryalice Stetler-Stevenson, David J. FitzGerald, Robert Lechleider, Ira Pastan
Journal: Journal of Clinical Oncology (2012)

To conduct a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL).
‘Progressive diabetic nephropathy. How useful is microalbuminuria?: contra’
Authors: Richard J. MacIsaac, Elif I. Ekinci, G. Jerums
Journal: Kidney International (2014)

The concept of microalbuminuria has been central to the development of clinical practice and research in the area of diabetic kidney disease (DKD). However, in recent times, the value of a paradigm of DKD based solely on microalbuminuria has been questioned. Although both the absolute level and rate of change of microalbuminuria are linked to the development and progression of DKD, microalbuminuria on its own lacks the necessary sensitivity or specificity to accurately predict kidney outcomes for people with diabetes. The development of microalbumiuria can no longer be viewed as a committed and irreversible stage of DKD, as spontaneous remission is now reported as a common occurrence. In addition, the absence of microalbuminuria or its progression to proteinuria does not signify that an individual patient is safe from a progressive decline in glomerular filtration rate (GFR). Furthermore, although reductions in albuminuria within the microalbuminuric range can be linked to a slower GFR decline in observational studies, this relationship has not been robustly demonstrated in intervention studies. Conclusions regarding the kidney health of individuals with diabetes will continue to be flawed if an inappropriate emphasis is placed on the presence or absence of albuminuria or changes in albuminuria within the microalbuminuric range. This has important implications in terms of undermining the value of microalbuminuria as a surrogate renal end point for intervention trials. There is a need to develop broader models of progressive DKD that include novel pathways and risk markers apart from those related to the traditional 'albuminuric pathway' to renal impairment.
Frequent sensitization to <i><scp>C</scp>andida albicans</i> and profilins in adult eosinophilic esophagitis
Authors: D. Simon, A. Straumann, C. Dahinden, H.‐U. Simon
Journal: Allergy (2013)

Eosinophilic esophagitis (EoE) is often associated with atopic airway and skin diseases. More than 80% of EoE patients are sensitized to aero- and/or food allergens. Immunoglobulin (Ig)E-mediated immune responses to microbes have been reported to be deleterious in connection with atopic diseases.The aim of this study was to obtain a comprehensive overview about the sensitization spectrum of adult EoE patients.IgE in sera of 35 patients with active EoE were analyzed for reactivity to Candida albicans, as well as to a panel of recombinant and purified natural allergen components, using a microarray.IgE sensitization to Candida albicans was found in 43% of EoE patients. More than 80% of EoE patients were sensitized to aeroallergens and 22% to food-specific allergen components, whereas 69% of the patients exhibited specific IgE to cross-reactive allergens. Among the latter, profilins were identified as most frequent IgE cross-reactive allergen components. Interestingly, dysphagia, the main symptom of adult EoE patients following rice and/or bread ingestion, was associated with sensitization to cross-reactive allergens such as profilins, pathogenesis-related (PR) 10 and lipid transfer proteins (LTP). Intolerance toward meat rarely correlated with sensitization to animal food allergens.Candida albicans and cross-reactive plant allergen components, in particular profilins, were identified as frequent sensitizers in adult EoE patients. Specific elimination therapies are suggested to reveal their actual roles in the pathogenesis of EoE.
Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy
Authors: Blanche Schroen, Joost J. Leenders, Arie van Erk, Anne T. Bertrand, Mirjam van Loon, Rick E. van Leeuwen, Nard Kubben, Rudy F. Duisters, Mark W. Schellings, Ben J. Janssen, Jacques J. Debets, Michael Schwake, Morten A. Høydal, Stephane Heymans, Paul Saftig, Yigal M. Pinto
Journal: The Journal of Experimental Medicine (2007)

The intercalated disc (ID) of cardiac myocytes is emerging as a crucial structure in the heart. Loss of ID proteins like N-cadherin causes lethal cardiac abnormalities, and mutations in ID proteins cause human cardiomyopathy. A comprehensive screen for novel mechanisms in failing hearts demonstrated that expression of the lysosomal integral membrane protein 2 (LIMP-2) is increased in cardiac hypertrophy and heart failure in both rat and human myocardium. Complete loss of LIMP-2 in genetically engineered mice did not affect cardiac development; however, these LIMP-2 null mice failed to mount a hypertrophic response to increased blood pressure but developed cardiomyopathy. Disturbed cadherin localization in these hearts suggested that LIMP-2 has important functions outside lysosomes. Indeed, we also find LIMP-2 in the ID, where it associates with cadherin. RNAi-mediated knockdown of LIMP-2 decreases the binding of phosphorylated β-catenin to cadherin, whereas overexpression of LIMP-2 has the opposite effect. Collectively, our data show that LIMP-2 is crucial to mount the adaptive hypertrophic response to cardiac loading. We demonstrate a novel role for LIMP-2 as an important mediator of the ID.
Heterogeneity and Power in Clinical Biomarker Studies
Authors: Melania Pintilie, Vladimir Iakovlev, Anthony Fyles, David Hedley, Michael Milosevic, Richard P. Hill
Journal: Journal of Clinical Oncology (2009)

Many recent studies have suggested the possibility that a variety of different biomarkers may be associated with treatment outcome. However, it is also apparent that some of these biomarkers are heterogeneously distributed within a tumor. Due to this heterogeneous distribution of the biomarker, the association sought may appear weak or nonexistent. Thus, there is a wide range of conclusions in the literature on the association between a biomarker and an outcome.This article presents how to quantify the heterogeneity and how it influences the observed effect size and the ability to detect it (power of the study). It can be shown that the estimated effect size and the power of the study are diminished when the biomarker is measured with error. The estimated effect of the association with outcome of the average of several replicates per patient is closer to the true effect size when the number of replicates increases.The first step in designing a study of association between a biomarker and outcome is to conduct a pilot study in which several measurements per patient are taken. Based on these data, the heterogeneity of the marker within and between individuals can be estimated and used in the process of designing an appropriate study of the association between the biomarker and outcome.
Stent implantation versus balloon angioplasty in chronic coronary occlusions: results from the GISSOC trial
Authors: Paolo Rubartelli, Luigi Niccoli, Edoardo Verna, Corinna Giachero, Marco Zimarino, Alessandro Fontanelli, Corrado Vassanelli, Luigi Campolo, Eugenio Martuscelli, Giorgio Tommasini
Journal: Journal of the American College of Cardiology (1998)