tbuckley/cabot-search huggingface dataset:
Role of Endothelium-Derived Nitric Oxide in the Modulation of Canine Myocardial Mitochondrial Respiration In Vitro
Authors: Yi-Wu Xie, Weiqun Shen, Gong Zhao, Xiaobin Xu, Michael S. Wolin, Thomas H. Hintze
Journal: Circulation Research (1996)

The mechanism responsible for the regulation of cardiac function by endogenous nitric oxide (NO) remains unclear. In this investigation, O 2 consumption by freshly isolated myocardial muscle segments from the left ventricular free wall of canine hearts was quantified by a Clark-type O 2 electrode at 37°C. S -nitroso- N -acetylpenicillamine (SNAP, 9±3% to 50±8%), bradykinin (BK, 14±3% to 30±5%), or carbachol (CCh, 15±4% to 29±4%) significantly attenuated tissue O 2 consumption at doses of 10 −7 to 10 −4 mol/L (mean±SE, P &lt;.05). The effects of BK and CCh, but not SNAP, were blocked by 10 −4 mol/L N G -nitro- l -arginine, consistent with both BK and CCh stimulating NO biosynthesis and with SNAP decomposing to release NO, respectively. Similar doses of 8-Br-cGMP caused a respiratory inhibition, but to a lesser extent (9±2% to 14±6%). A mitochondrial uncoupler, 2,4-dinitrophenol (at 1 mmol/L), blocked the effects of 8-Br-cGMP, but not those of SNAP, BK, or CCh, suggesting that the major site of action of NO is on mitochondrial electron transport. Myocardial muscle from dogs with pacing-induced heart failure had a basal O 2 consumption rate of 251±21 nmol·min −1 ·g −1 , which was 54% higher than the rate seen in muscle from normal healthy canine hearts. The inhibitory effects of BK and CCh on O 2 consumption were not observed in failing cardiac tissue, but SNAP showed an unaltered inhibitory effect. Therefore, our results indicate that NO released from microvascular endothelium by BK, stimulation of muscarinic receptors, and perhaps flow velocity may play an important physiological role in the control of cardiac mitochondrial respiration, and the loss of this regulatory function may contribute to the development of heart failure.
Depletion of the Ras Association Domain Family 1, Isoform A–Associated Novel Microtubule-Associated Protein, C19ORF5/MAP1S, Causes Mitotic Abnormalities
Authors: Ashraf Dallol, Wendy N. Cooper, Fahd Al-Mulla, Angelo Agathanggelou, Eamonn R. Maher, Farida Latif
Journal: Cancer Research (2007)

Abstract Ras association domain family 1, isoform A (RASSF1A) is a novel tumor suppressor gene that is found to be inactivated in more than 40 types of sporadic cancers. In addition, mouse Rassf1a knockout models have an increased frequency of spontaneous and induced tumors. The mechanisms by which RASSF1A exerts its tumor suppression activities or the pathways it can regulate are not yet fully understood. Using yeast two-hybrid system, we have previously identified C19ORF5/MAP1S as the major RASSF1A-interacting protein. C19ORF5 has two conserved microtubule-associated regions and may function to anchor RASSF1A to the centrosomes. In this study, we have analyzed the cellular functions of C19ORF5. By using small interfering RNA–mediated depletion and time-lapse video microscopy, we show that C19ORF5 knockdown causes mitotic abnormalities that consist of failure to form a stable metaphase plate, premature sister chromatid separation, lagging chromosomes, and multipolar spindles. We also show that a fraction of C19ORF5 localizes to the spindle microtubules. Additionally, we show here that C19ORF5 localizes to the microtubule-organizing centers during microtubule regrowth after nocodazole washout. Knockdown of C19ORF5 disrupts the microtubule-organizing center and results in microtubule nucleation from several sites. Whereas the localization of pericentrin is not affected, α- and γ-tubulin localization and sites of nucleation are greatly altered by C19ORF5 depletion. This may indicate that C19ORF5 plays a role in anchoring the microtubule-organizing center to the centrosomes. In addition, we show that the NH2 terminus of C19ORF5 is essential for this process. This novel role for C19ORF5 could explain the resulting mitotic abnormalities that occur on its depletion and can potentially provide an underlying mechanism for the frequent centrosome and microtubule abnormalities detected in several cancers. [Cancer Res 2007;67(2):492–500]
A New Approach to Weight Loss
Authors: William C. Sessa
Journal: Circulation Research (2012)

S ustained consumption of dietary fats induces endothelial dysfunction and insulin resistance in experimental models and humans.Endothelial dysfunction, manifested by reduced endothelium-dependent dilation, is a hallmark of several cardiovascular diseases and obesity.Indeed, exercise training and caloric restriction attenuate endothelial dysfunction and delay the onset or reduce the magnitude of vascular diseases and insulin resistance.
Aging-Induced Phenotypic Changes and Oxidative Stress Impair Coronary Arteriolar Function
Authors: Anna Csiszar, Zoltan Ungvari, John G. Edwards, Pawel Kaminski, Michael S. Wolin, Akos Koller, Gabor Kaley
Journal: Circulation Research (2002)

We aimed to elucidate the possible role of phenotypic alterations and oxidative stress in age-related endothelial dysfunction of coronary arterioles. Arterioles were isolated from the hearts of young adult (Y, 14 weeks) and aged (A, 80 weeks) male Sprague-Dawley rats. For videomicroscopy, pressure-induced tone of Y and A arterioles and their passive diameter did not differ significantly. In A, arterioles L-NAME (a NO synthase blocker)–sensitive flow-induced dilations were significantly impaired (Y: 41±8% versus A: 3±2%), which could be augmented by superoxide dismutase (SOD) or Tiron (but not l -arginine or the TXA 2 receptor antagonist SQ29,548). For lucigenin chemiluminescence, O 2 ·− generation was significantly greater in A than Y vessels and could be inhibited with SOD and diphenyliodonium. NADH-driven O 2 ·− generation was also greater in A vessels. Both endothelial and smooth muscle cells of A vessels produced O 2 ·− (shown with ethidium bromide fluorescence). For Western blotting, expression of eNOS and COX-1 was decreased in A compared with Y arterioles, whereas expressions of COX-2, Cu/Zn-SOD, Mn-SOD, xanthine oxidase, and the NAD(P)H oxidase subunits p47 phox , p67 phox , Mox-1, and p22 phox did not differ. Aged arterioles showed an increased expression of iNOS, confined to the endothelium. Decreased eNOS mRNA and increased iNOS mRNA expression in A vessels was shown by quantitative RT-PCR. In vivo formation of peroxynitrite was evidenced by Western blotting, and immunohistochemistry showing increased 3-nitrotyrosine content in A vessels. Thus, aging induces changes in the phenotype of coronary arterioles that could contribute to the development of oxidative stress, which impairs NO-mediated dilations.
Mast cell-derived tumour necrosis factor is essential for allergic airway disease
Authors: S. Reuter, A. Heinz, M. Sieren, R. Wiewrodt, E. W. Gelfand, M. Stassen, R. Buhl, C. Taube
Journal: European Respiratory Journal (2007)

Mast cells are thought to contribute to allergic airway disease. However, the role of mast cell-produced mediators, such as tumour necrosis factor (TNF), for the development of allergic airway disease is unclear. In order to define the role of mast cells in acute allergic airway disease two strains of mast cell-deficient mice (Kit W/Wv and Kit W-sh/W-sh ) were studied. Compared with their wild-type littermates, Kit W/Wv and Kit W-sh/W-sh mice developed significantly lower airway responsiveness to methacholine and less airway inflammation and goblet cell metaplasia, following sensitisation in the absence of adjuvant and airway challenge. Transfer of bone marrow-derived mast cells (BMMCs) from wild-type mice to Kit W-sh/W-sh mice reconstituted both airway responsiveness and inflammation to levels similar to those in sensitised and challenged wild-type mice. In contrast, sensitised Kit W-sh/W-sh mice reconstituted with BMMCs from TNF-deficient mice were still severely impaired in their ability to develop airway hyperresponsiveness, inflammation or goblet cell metaplasia following allergen challenge. The present results demonstrate the significance of mast cells in the development of airway disease and highlight the importance of mast cell-derived tumour necrosis factor in these responses.
Pseudomonas infection in CF
Authors: R. ROSEBY
Journal: Thorax (2000)

Elborn et al 1 have attempted to address the important question of whether it is better to treat patients with cystic fibrosis (CF) who have chronic Pseudomonas aeruginosa infection with intravenous antibiotics on the basis of symptoms or to treat them electively, and found no significant difference between their groups. They chose a particularly unwell subgroup of the CF population to study, and one might expect a policy of increasing from three symptomatic to four elective courses of intravenous antibiotics to make the least difference in such patients. We believe that patients who require 2–4 courses of intravenous antibiotics per year anyway are not those for whom this question of treatment is most pressing …
Developing a Sustainable Nutrition Research Agenda in Sub-Saharan Africa—Findings from the SUNRAY Project
Authors: Carl Lachat, Eunice Nago, Dominique Roberfroid, Michelle Holdsworth, Karlien Smit, Joyce Kinabo, Wim Pinxten, Annamarie Kruger, Patrick Kolsteren
Journal: PLoS Medicine (2014)

N Here we present the findings of a collaborative effort by stakeholders in sub-Saharan Africa (SSA) to identify priorities for nutrition research and actions to create an enabling research environment.N 117 stakeholders from 40 countries in SSA defined priorities using participatory approaches.N The priority areas for nutrition research were (i) community interventions to improve nutritional status, (ii) behavioral strategies to improve nutritional status, and (iii) food security interventions to improve nutrition.N The priority actions for creating an enabling nutrition research environment were (i) better governance of nutrition research, (ii) alignment of nutrition research funding with priorities identified within SSA, (iii) increased capacity development for nutrition research competencies, and (iv) enhanced information sharing and communication of nutrition research findings.N We propose a new approach for nutrition research in SSA that stimulates a demand from SSA policy makers for research in SSA and holds them accountable for incorporating research into policy and practice.
Pulmonary tuberculosis due to Mycobacterium bovis.
Authors: E G Wilkins, R J Griffiths, C Roberts
Journal: Thorax (1986)

During 1969-84 Mycobacterium bovis was isolated from 20 patients with pulmonary tuberculosis. This represented less than 1% of the total cases of respiratory tuberculosis confirmed bacteriologically at the Liverpool Public Health Laboratory during this period. All 20 patients were considered to have reactivated disease and all presented with the typical features of respiratory tuberculosis. During the same period four cases of pulmonary infection by Mycobacterium africanum were recognised. This organism is difficult to differentiate from M bovis and failure to distinguish the two mycobacteria could lead to a misleading epidemiological picture of bovine tuberculosis in man.
Cloning and Characterization of a p53 and DNA Damage Down-regulated Gene <i>PIQ</i> that Codes for a Novel Calmodulin-Binding IQ Motif Protein and Is Up-regulated in Gastrointestinal Cancers
Authors: Xiuquan Luo, Qin He, Ying Huang, M. Saeed Sheikh
Journal: Cancer Research (2005)

Abstract We have identified a p53 and DNA damage–regulated gene that encodes a novel IQ motif protein, which we have named p53 and DNA damage–regulated IQ motif protein (PIQ). PIQ has two isoforms, long (PIQ-L) and short (PIQ-S), and both bind to calmodulin in the presence and absence of calcium. PIQ expression is down-regulated by p53 and DNA damage–inducing agents, whereas PIQ itself represses the expression of p53 up-regulated modulator of apoptosis that is a key mediator of p53-induced apoptosis. Thus, PIQ is a novel protein that may function to bridge a crosstalk between p53 and calmodulin-regulated cellular processes. We further show that PIQ expression is up-regulated in a number of primary colorectal and gastric tumors when compared with matching normal tissues, suggesting that PIQ may be involved in tumorigenesis and could serve as a valuable diagnostic/prognostic marker for gastrointestinal tumors.
Improvement of rAAV5 transduction efficiency in fibroblast-like synoviocytes by doxorubicin
Authors: C. J. Aalbers, S. A. Loiler, I. de Vries, F. Mingozzi, M. J. Vervoordeldonk, P. P. Tak
Journal: Annals of the Rheumatic Diseases (2010)

We are currently developing local gene therapy for the treatment of rheumatoid arthritis (RA) using interferon β (IFNβ) as therapeutic gene and rAAV5 as vector. We generated a rAAV5 vector that expresses hIFNβ under control of an inflammation inducible promoter (rAAV5.NFkB.hIFNβ). To support development of our clinical gene therapy programme a robust assay is needed to transduce different cell lines with rAAV5.NFkB.hIFNβ. In vitro, rAAV5 does not transduce cells efficiently, including fibroblast-like synoviocytes (FLS), the main target cell …
Long-Term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy
Authors: Pietro Lampertico, Ersilio Del Ninno, Mauro Viganò, Raffaella Romeo, Maria Francesca Donato, Erwin Sablon, Alberto Morabito, Massimo Colombo
Journal: Hepatology (2003)

To assess whether extended treatment with interferon improves the outcome of hepatitis B e antigen (HBeAg)–negative chronic hepatitis B, 101 consecutive patients were treated with 6 MU of interferon alfa 2b 3 times weekly for 24 months. During the 68–month study, 30 patients (30%) had a sustained response ( i.e. , normal serum transaminase levels and undetectable hepatitis B virus DNA by non–polymerase chain reaction [PCR] assays), and 15 cleared serum surface antigen. Twenty–five nonresponders, 16 relapsers, and 30 who discontinued treatment were considered treatment failures. Multivariate analysis predicted a sustained response for young age (odds ratio, 0.94; 95% confidence interval, 0.89–0.99; P = .041) and high pretreatment serum levels of immunoglobulin M (IgM) anti–hepatitis B core antigen (HBc) (odds ratio, 4.52; 95% confidence interval, 1.63–12.5; P = .004). Liver disease progressed in none of the sustained responders but in 16 with treatment failure (0% vs. 22%, P = .002); hepatocellular carcinoma (HCC) developed with similar frequency in both groups (7%). Overall, estimated 8–year complication–free survival was longer for the 30 sustained responders than the 71 patients with treatment failure (90% vs. 60%, P &lt; .001), but 8–year patient survival was similar in the 2 groups (100% and 90%). Short complication–free survival was predicted by failure to respond to interferon (hazard ratio, 7.8; 95% confidence interval, 1.8–34.0; P = .006) and high scores for liver fibrosis (hazard ratio, 1.71; 95% confidence interval, 1.17–2.50; P = .005). In conclusion, 24 months of treatment with interferon alfa 2b led to sustained disease suppression in a significant proportion of patients with HBeAg–negative chronic hepatitis B. (Hepatology 2003;37:756–763.)
Extensive Divergence in Alternative Splicing Patterns after Gene and Genome Duplication During the Evolutionary History of Arabidopsis
Authors: P. G. Zhang, S. Z. Huang, A.-L. Pin, K. L. Adams
Journal: Molecular Biology and Evolution (2010)

Gene duplication at various scales, from single gene duplication to whole-genome (WG) duplication, has occurred throughout eukaryotic evolution and contributed greatly to the large number of duplicated genes in the genomes of many eukaryotes. Previous studies have shown divergence in expression patterns of many duplicated genes at various evolutionary time scales and cases of gain of a new function or expression pattern by one duplicate or partitioning of functions or expression patterns between duplicates. Alternative splicing (AS) is a fundamental aspect of the expression of many genes that can increase gene product diversity and affect gene regulation. However, the evolution of AS patterns of genes duplicated by polyploidy, as well as in a sizable number of duplicated gene pairs in plants, has not been examined. Here, we have characterized conservation and divergence in AS patterns in genes duplicated by a polyploidy event during the evolutionary history of Arabidopsis thaliana. We used reverse transcription–polymerase chain reaction to assay 104 WG duplicates in six organ types and in plants grown under three abiotic stress treatments to detect organ- and stress-specific patterns of AS. Differences in splicing patterns in one or more organs, or under stress conditions, were found between the genes in a large majority of the duplicated pairs. In a few cases, AS patterns were the same between duplicates only under one or more abiotic stress treatments and not under normal growing conditions or vice versa. We also examined AS in 42 tandem duplicates and we found patterns of AS roughly comparable with the genes duplicated by polyploidy. The alternatively spliced forms in some of the genes created premature stop codons that would result in missing or partial functional domains if the transcripts are translated, which could affect gene function and cause functional divergence between duplicates. Our results indicate that AS patterns have diverged considerably after gene and genome duplication during the evolutionary history of the Arabidopsis lineage, sometimes in an organ- or stress-specific manner. AS divergence between duplicated genes may have contributed to gene functional evolution and led to preservation of some duplicated genes.
Lymphokine regulation of CD45R expression on human T cell clones.
Authors: S A Brod, C E Rudd, M Purvee, D A Hafler
Journal: The Journal of Experimental Medicine (1989)

Whether the expression of higher molecular weight isoforms of the T-200 complex represents different lineages of T cells and/or a sequential stage of the differential pathway of T cells has been unclear. Understanding T cell expression of higher molecular weight isoforms of the T-200 complex (CD45R) may be important because of their association with regulation of immune responses. By direct single cell cloning, we observed a number of long-term T cell clones that expressed CD45RA (2H4). CD45RA expression could be further regulated by ionomycin or the cytokines IL-1 and IL-6, but not IL-2, IL-4, or IFN-gamma. These results indicate that CD45RA expression may define T cell lineages of activated T cells partially controlled by the cytokines IL-1 and IL-6. Further, these results may associate regulatory actions of IL-1 and IL-6 with their ability to increase CD45RA expression in subpopulations of human T cells.
Histological categorisation of fibrotic cancer stroma in advanced rectal cancer
Authors: H Ueno
Journal: Gut (2004)

<b>Background and aims:</b> Based on conflicting reports regarding the role of the fibrotic stromal response in cancer development—namely, that a desmoplastic reaction can favour either the host or the tumour—it is clear that the role of the stromal response is varied. We have classified the fibrotic stroma of rectal adenocarcinoma penetrating the muscularis propria, based on histologically identified stromal components. <b>Methods:</b> Three categories of stroma were used: mature—when the stroma was composed of mature collagen fibres (fine and elongated fibres into multiple layers); intermediate—when keloid-like collagen was intermingled with mature fibres; and immature—consisting of a myxoid stroma in which no mature fibres were included. <b>Results:</b> In a data set of 862 patients, 53% of patients had mature fibrotic cancer stroma, 33% had intermediate stroma, and 15% had immature stroma. Five year survival rates decreased as follows: mature stroma (80%), intermediate stroma (55%), and immature stroma (27%). The adverse tumour phenotype, tumour cell budding (conspicuous isolated cells or small clusters of cancer cells), was observed in the cancer fronts in tumours with unfavourable fibrotic stroma (p&lt;0.0001). Based on multivariate analysis, categorised fibrotic stroma was selected as an independent prognostic parameter (hazard ratio 1.39; 95% confidence interval 1.17–1.64) together with tumour differentiation. By immunohistochemical examination, as maturation of the fibrotic stroma decreased, stromal T cells became significantly sparser. Furthermore, myofibroblasts were distributed extensively in immature fibrotic stroma compared with mature and intermediate fibrotic stroma. <b>Conclusion:</b> The morphological categorisation of fibrotic cancer stroma highlights the role of the stromal response in relation to the behaviour and host immune reactions of rectal adenocarcinoma and would be a useful tool for predicting patient prognostic outcome.
Epithelial-Cadherin and β-Catenin Expression Changes in Pancreatic Intraepithelial Neoplasia
Authors: Maamoun M. Al-Aynati, Nikolina Radulovich, Robert H. Riddell, Ming-Sound Tsao
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Cadherins and associated catenins are important mediators of epithelial cell-cell adhesion, as well as the Wnt-signaling pathway. Significant changes in their expression or structure have been implicated in malignancy. This study aimed to investigate the epithelial-cadherin (E-cadherin) and β-catenin expression changes during multistage, pancreatic ductal carcinogenesis. Experimental Design: Ninety-four Whipple resection specimens were retrieved from the surgical pathology files of the University Health Network (Toronto, Canada), from which tissue microarray blocks containing 36 pancreatic ductal adenocarcinomas, 34 PanIN-1A lesions, 28 PanIN-1B lesions, 27 PanIN-2 lesions, 16 PanIN-3 lesions, and 32 normal ducts were constructed. The E-cadherin, β-catenin, and the phosphorylated glycogen synthase kinase-3β of the Wnt/β-catenin pathway were immunohistochemically evaluated in these duct/PanIN lesions. Results: There was marked increase in the cytoplasmic E-cadherin expression in PanIN lesions (P &amp;lt; 0.0001) and adenocarcinoma (P = 0.005) compared with normal pancreatic ducts. In contrast, reduced/loss of E-cadherin membranous expression was also significant in ductal adenocarcinoma compared with both the PanIN lesions (P &amp;lt; 0.0001) and normal ducts (P = 0.05). The β-catenin expression showed significantly more frequent aberrant nuclear localization in high-grade PanIN lesions, particularly PanIN2 and in adenocarcinoma compared with normal ducts or low grade PanIN lesions (P &amp;lt; 0.0001). However, there was a lack of correlation between phosphoSer9-glycogen synthase kinase-3β cytoplasmic expression and β-catenin aberrant nuclear expression (P = 0.07). Conclusions: Aberration in the expression of E-cadherin and its associated β-catenin is evident in pre-invasive (PanIN) neoplastic pancreatic duct cells, suggesting involvement of pathways leading to β-catenin stabilization during pancreatic duct cell carcinogenesis.