tbuckley/cabot-search huggingface dataset:
A Randomized Phase II Trial of Multiepitope Vaccination with Melanoma Peptides for Cytotoxic T Cells and Helper T Cells for Patients with Metastatic Melanoma (E1602)
Authors: Craig L. Slingluff, Sandra Lee, Fengmin Zhao, Kimberly A. Chianese-Bullock, Walter C. Olson, Lisa H. Butterfield, Theresa L. Whiteside, Philip D. Leming, John M. Kirkwood
Journal: Clinical Cancer Research (2013)

Abstract Purpose: This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma. Experimental Design: One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CTL (12MP, group A), plus a tetanus peptide (group B), or a mixture of 6 melanoma helper peptides (6MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6 melanoma helper peptide (6MHP) alone (group D), in incomplete Freund's adjuvant plus granulocyte macrophage colony-stimulating factor. CTL responses were assessed using an in vitro-stimulated IFN-γ ELIspot assay, and HTL responses were assessed using a proliferation assay. Results: In groups A to D, respectively, CTL response rates to 12 melanoma peptides were 43%, 47%, 28%, and 5%, and HTL response rates to 6MHP were in 3%, 0%, 40%, and 41%. Best clinical response was partial response in 7 of 148 evaluable patients (4.7%) without significant difference among study arms. Median overall survival (OS) was 11.8 months. Immune response to 6 MHP was significantly associated with both clinical response (P = 0.036) and OS (P = 0.004). Conclusion: Each vaccine regimen was immunogenic, but MHPs did not augment CTL responses to 12 melanoma peptides. The association of survival and immune response to 6MHP supports further investigation of helper peptide vaccines. For patients with advanced melanoma, multipeptide vaccines should be studied in combination with other potentially synergistic active therapies. Clin Cancer Res; 19(15); 4228–38. ©2013 AACR.
miR-638 regulates gene expression networks associated with emphysematous lung destruction
Authors: Stephanie A Christenson, Corry-Anke Brandsma, Joshua D Campbell, Darryl A Knight, Dmitri V Pechkovsky, James C Hogg, Wim Timens, Dirkje S Postma, Marc Lenburg, Avrum Spira
Journal: Genome Medicine (2013)

Abstract Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how genome-wide microRNA expression is altered with regional emphysema severity and how these microRNAs regulate disease-associated gene expression networks. Methods We profiled microRNAs in different regions of the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified by mean linear intercept. Whole genome microRNA and gene expression data were integrated in the same samples to build co-expression networks. Candidate microRNAs were perturbed in human lung fibroblasts in order to validate these networks. Results The expression levels of 63 microRNAs ( P &lt; 0.05) were altered with regional emphysema. A subset, including miR-638, miR-30c, and miR-181d, had expression levels that were associated with those of their predicted mRNA targets. Genes correlated with these microRNAs were enriched in pathways associated with emphysema pathophysiology (for example, oxidative stress and accelerated aging). Inhibition of miR-638 expression in lung fibroblasts led to modulation of these same emphysema-related pathways. Gene targets of miR-638 in these pathways were amongst those negatively correlated with miR-638 expression in emphysema. Conclusions Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression pathways related to the oxidative stress response and aging in emphysematous lung tissue and lung fibroblasts.
Platelet nitric oxide signalling in heart failure: role of oxidative stress
Authors: Ashish Shah, Gabriella Passacquale, Eugenia Gkaliagkousi, James Ritter, Albert Ferro
Journal: Cardiovascular Research (2011)

Heart failure is associated with deficient endothelial nitric oxide (NO) production as well as increased oxidative stress and accelerated NO degradation. The aim of this study was to evaluate platelet NO biosynthesis and superoxide anion (O(2)(-)) production in patients with heart failure.In platelets from patients with heart failure due to idiopathic dilated cardiomyopathy (n= 16) and healthy control subjects (n= 23), NO synthase (NOS) activity was evaluated by L-[(3)H]-arginine to l-[(3)H]-citrulline conversion, cGMP was determined by radioimmunoassay, vasodilator-stimulated phosphoprotein (VASP: total and serine-239-phosphorylated) was assessed by western blotting, and O(2)(-) production and O(2)(-) scavenging capacity were measured by pholasin-enhanced chemiluminescence. In platelets from patients with heart failure, basal NOS activity was higher than in those from controls; furthermore, whereas platelet NOS activity increased as expected in response to albuterol or collagen in controls, no increase occurred in platelets from heart failure subjects. Despite this, basal intraplatelet NO-attributable cGMP was lower in heart failure than in control subjects, as was serine-239 phosphorylation of VASP, suggesting a decrease in bioactive NO. Platelets from heart failure subjects exhibited higher basal and collagen-stimulated O(2)(-) production and impaired O(2)(-) scavenging capacity, resulting in higher oxidative stress, consistent with the observed decrease in bioactive NO.In heart failure, despite activation of NOS, platelets produce less bioactive NO, probably as a result of NO scavenging due to increased O(2)(-) production. This functional defect in the platelet l-arginine/NO/guanylyl cyclase pathway could contribute to the platelet activation observed in heart failure.
JC Virus Infection in Colorectal Neoplasia That Develops after Liver Transplantation
Authors: Michael Selgrad, Jan Jacob Koornstra, Lucia Fini, Marloes Blom, Rong Huang, Edward B. DeVol, Wytske Boersma-van Ek, Gerard Dijkstra, Robert C. Verdonk, Steven de Jong, Ajay Goel, Sharenda L. Williams, Richard L. Meyer, Elizabeth B. Haagsma, Luigi Ricciardiello, C. Richard Boland
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Liver transplant recepients (LTRs) have an increased risk of colorectal neoplasia. The mechanism responsible for this is unknown. JCV encodes for TAg and has been implicated in colorectal carcinogenesis. We hypothesized that the use of immunosuppression in LTRs facilitates activation of JCV and is responsible for the increased risk of neoplasia. Experimental Design: JCV TAg DNA and protein expression were determined in normal colonic epithelium (n = 15) and adenomatous polyps (n = 26) from LTRs and compared with tissue samples from control patients (normal colon, n = 21; adenomas, n = 40). Apoptosis and proliferation were determined by M30 and Ki-67 immunoreactivity, respectively. Results: JCV TAg DNA was found in 10 of 15 (67%) of normal colonic mucosa from LTRs compared with 5 of 21 (24%) of control normal mucosa (P = 0.025). JCV TAg DNA was detected in 16 of 26 (62%) of the adenomas from LTRs and in 20 of 40 (50%) of control adenomas. JCV TAg protein was expressed in 13 of 26 (50%) adenomas from LTRs versus 2 of 40 (5%) of adenomas from controls (P &amp;lt; 0.001). In adenomas from LTRs, the mean proliferative activity was higher compared with controls (60.3 ± 3.2% versus 42.7 ± 2.8%, P &amp;lt; 0.001), whereas mean apoptotic indices were lower in LTRs (0.29 ± 0.08% versus 0.39 ± 0.06%, P = 0.05). Conclusions: The presence of JCV in the colorectal mucosa and adenomas from LTRs, in concert with the use of immunosuppressive agents, suggests that JCV may undergo reactivation, and the subsequent TAg protein expression might explain the increased risk of colorectal neoplasia in LTRs.
Achieving food security in vulnerable populations
Authors: Deborah Cohen
Journal: BMJ (2005)

<h3>Introduction</h3> As reported by the literature, chronic diseases are related to the survival time of older populations. <h3>Objective</h3> To study the association of autonomy, depression cognition loss and alcoholism with older persons9 survival in a medium-sized city in São Paulo state (BRAZIL). <h3>Methodology</h3> Systematic population sampling for unknown prevalence was performed. Three hundred and sixty-five people aged 60 years and older were interviewed by means of home enquiries in 2006–2007. The Activities of Daily Living (ADL) Scale (Katz, Downs <i>et al</i>, 1970), Instrumental Activities of Daily Living (IADL) Scale (Lawton and Brody, 1969), Abridged Geriatric Depression Scale (Yesavage JA, Brink TL <i>et al</i>, 1982), Mini-Mental Status Examination (MMSE) (Folstein, Folstein <i>et al</i>, 1975; Bertolucci, Brucki <i>et al</i>, 1994) and the CAGE Alcohol Use Assessment (Ewing, 1984) were applied. As to survival, the log-rank test was performed, and the proportionality of the curves for each one of the evaluations was observed. Next, they were conjointly studied by the Cox model and adjusted by gender and age. <h3>Results</h3> 3 years after the enquiry, the ADL and IADL evaluations generated proportional survival curves. Only ADLs showed to be a predictive factor for mortality (p=0.02), HR=3.2 (1.3 to 7.7), adjusted for the other scales, gender and age (Cox). <h3>Discussion and Conclusions</h3> Of the elders9 morbidity, ADL alterations are the causes for most concern as they are already noted to be predictive for mortality after 3 years of the cohort9s survival.
Infant antibiotic use and wheeze and asthma risk: a systematic review and meta-analysis
Authors: J. Penders, I. Kummeling, C. Thijs
Journal: European Respiratory Journal (2011)

Our aim was to systematically review and meta-analyse longitudinal studies on antibiotic use and subsequent development of wheeze and/or asthma with regards to study quality, outcome measurement, reverse causation (RC; wheezing/asthma symptoms have caused prescription of antibiotics) and confounding by indication (CbI; respiratory tract infections leading to antibiotic use may be the underlying cause triggering asthma symptom development). English-language papers and studies published before November 1, 2010 with longitudinal observational design were included. Study quality was assessed using the Newcastle–Ottawa scale. We identified 21 longitudinal studies. The effect of antibiotic use on wheeze/asthma risk varied between studies. 18 studies were eligible for meta-analysis showing pooled OR 1.27 (95% CI 1.12–1.43) for wheeze/asthma. When we eliminated studies with possible RC and CbI, the pooled risk estimate in the nine remaining studies was attenuated to OR 1.12 (95% CI 0.98–1.26). Definition of wheeze/asthma and age at follow-up differed between studies. Three studies focused on wheeze/asthma beyond 5–6 yrs of age with the presence of active symptoms and/or medication (pooled OR 1.08, 95% CI 0.93–1.23; dominated by one study). RC and CbI lead to overestimation of the association between antibiotic use and subsequent development of wheeze/asthma. Association was weak when fully adjusted for these types of bias. Heterogeneity of disease definition between studies could affect the results.
Portal and gastric mucosal hemodynamics in cirrhotic patients with portal-hypertensive gastropathy
Authors: Masayuki Ohta, Makoto Hashizume Hidefumi Higashi, Kiichiro Ueno, Morimasa Tomikawa, Fumiaki Kishihara, Hirofumi Kawanaka, Kazuo Tanoue, Keizo Sugimachi
Journal: Hepatology (1994)

Controversy exists as to the nature of gastric perfusion in portal-hypertensive gastropathy. To investigate portal hemodynamics and gastric mucosal perfusion in cirrhotic patients with and without portal-hypertensive gastropathy, we subjected 56 cirrhotic patients with portal hypertension to portal vein catheterization, pneumatic pressure sensor technique, duplex sonography and laser Doppler flowmetry. Thirteen patients had portal-hypertensive gastropathy: In 10 it was mild, and in 3 it was severe. The presence of portal-hypertensive gastropathy seemed to be independent of age, sex, cause of cirrhosis or grade of esophageal varices. Portal venous pressure, esophageal variceal pressure, portal venous flow and congestion index in patients with portal-hypertensive gastropathy were not significantly different from the values in those without portal-hypertensive gastropathy. However, portal-variceal pressure gradient (subtracting esophageal variceal pressure from portal venous pressure) (p < 0.01) and the incidence of palisading-type esophageal varices on portography (p < 0.05) was increased in patients with portal-hypertensive gastropathy significantly more than in those without portal-hypertensive gastropathy. In the fundus, gastric mucosal blood flow was significantly higher in patients with portal-hypertensive gastropathy than in those without portal-hypertensive gastropathy, whereas in the corpus and the antrum the values were not significantly different. We suggest that the mucosa of the upper stomach in patients with portal-hypertensive gastropathy is congestive and highly perfused. The pathogenesis of portal-hypertensive gastropathy may be related to both congestion and hyperemia in the upper stomach.
Increasing butyrate concentration in the distal colon by accelerating intestinal transit
Authors: S J Lewis, K W Heaton
Journal: Gut (1997)

Background —Populations at low risk of colonic cancer consume large amounts of fibre and starch and pass acid, bulky stools. One short chain fatty acid (SCFA), butyrate, is the colon’s main energy source and inhibits malignant transformation in vitro. Aim —To test the hypothesis that altering colonic transit rate alters colonic pH and the SCFA content of the stools. Patients —Thirteen healthy adults recruited by advertisement. Methods —Volunteers consumed, in turn, wheat bran, senna and loperamide, each for nine days with a two week washout period between study periods, dietary intake being unchanged. Before, and in the last four days of each intervention, whole gut transit time (WGTT), defaecation frequency, stool form, stool β-glucuronidase activity, stool pH, stool SCFA concentrations and intracolonic pH (using a radiotelemetry capsule for continuous monitoring) were assessed. Results —WGTT decreased, stool output and frequency increased with wheat bran and senna, vice versa with loperamide. The pH was similar in the distal colon and stool. Distal colonic pH fell with wheat bran and senna and tended to increase with loperamide. Faecal SCFA concentrations, including butyrate, increased with senna and fell with loperamide. With wheat bran the changes were non-significant, possibly because of the short duration of the study. Baseline WGTT correlated with faecal SCFA concentration ( r =−0.511, p=0.001), with faecal butyrate ( r =−0.577, p&lt;0.001) and with distal colonic pH ( r =0.359, p=0.029). Conclusion —Bowel transit rate is a determinant of stool SCFA concentration including butyrate and distal colonic pH. This may explain the inter-relations between colonic cancer, dietary fibre intake, stool output, and stool pH.
Ca<sup>2+</sup>/calmodulin-dependent protein kinase: A key component in the contractile recovery from acidosis
Authors: Alicia Mattiazzi, Leticia Vittone, Cecilia Mundiña-Weilenmann
Journal: Cardiovascular Research (2006)

Intracellular acidosis exerts substantial effects on the contractile performance of the heart. Soon after the onset of acidosis, contractility diminishes, largely due to a decrease in myofilament Ca(2+) responsiveness. This decrease in contractility is followed by a progressive recovery that occurs despite the persistent acidosis. This recovery is the result of different mechanisms that converge to increase diastolic Ca(2+) levels and Ca(2+) transient amplitude. Recent experimental evidence indicates that activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is an essential step in the sequence of events that increases the Ca(2+) transient amplitude and produces contractile recovery. CaMKII may act as an amplifier, providing compensatory pathways to offset the inhibitory effects of acidosis on many of the Ca(2+) handling proteins. CaMKII-induced phosphorylation of the SERCA2a regulatory protein phospholamban (PLN) has the potential to promote an increase in sarcoplasmic reticulum (SR) Ca(2+) uptake and SR Ca(2+) load, and is a likely candidate to mediate the mechanical recovery from acidosis. In addition, CaMKII-dependent phosphorylation of proteins other than PLN may also contribute to this recovery.
Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells
Authors: D Makrygiannakis, M Hermansson, A-K Ulfgren, A P Nicholas, A J W Zendman, A Eklund, J Grunewald, C M Skold, L Klareskog, A I Catrina
Journal: Annals of the Rheumatic Diseases (2008)

A gene-environment interaction between HLA-DR shared epitope genes and smoking in anti-cyclic citrullinated peptide antibody-positive rheumatoid arthritis (RA) has been reported. Identification of citrullinated proteins in bronchoalveolar lavage (BAL) cells from smokers has led to the suggestion that citrullination induced by smoking might be the first step in the pathogenic chain of RA.To confirm and extend these findings.Immunohistochemistry was performed on BAL cells and bronchial mucosal biopsy sections obtained through bronchoscopy from 14 healthy smokers and 16 healthy non-smokers. Two antibodies recognising citrullinated proteins, two antibodies recognising peptidylarginine deiminase (PAD)2 enzyme and one recognising PAD4 enzyme were used.Citrullinated proteins are upregulated in BAL cells of healthy smokers compared with healthy non-smokers. This was associated with higher expression of the PAD2 enzyme. The same level of citrullinated proteins was present in bronchial mucosal biopsy specimens of healthy smokers and non-smokers, despite higher expression of PAD2 in smokers.This study provides evidence that smoking enhances PAD2 expression in the bronchial mucosal and alveolar compartment, with consequent generation of citrullinated proteins in the latter. Smoking is an environmental factor that may lead to citrulline autoimmunity in genetically susceptible subjects.
Evolution of tubulointerstitial fibrosis in experimental renal infection and scarring.
Authors: T D Hewitson, I A Darby, T Bisucci, C L Jones, G J Becker
Journal: Journal of the American Society of Nephrology (1998)

Renal tubulointerstitial fibrosis may result from a loss of tubulointerstitial volume, which produces a disproportionate increase in the density of matrix. This study examines the relationship between fibrogenesis and collapse in scar formation after experimental renal infection. Escherichia coli were inoculated into the renal cortex of Sprague Dawley rats, with saline substituted in a control group. Glomerular, tubular, and interstitial profile areas were determined. Density of glomerular profiles was used as a measure of tubulointerstitial collapse. Collagen type I, III, and IV expression was examined by in situ hybridization and immunohistochemistry. Myofibroblasts were identified by alpha smooth muscle actin immunohistochemistry, and matrix metalloproteinase-1 (MMP-1) and MMP-2 were localized with appropriate antisera. Acute interstitial edema was followed by increasing density of glomerular profiles, paralleled by loss of interstitial volume and progressive tubular atrophy. Glomerular profile area remained unchanged. Density of glomerular profiles was not temporally related to myofibroblast accumulation. Procollagen alpha 1(I), alpha 1(III), and alpha 1(IV) transcription was focal, spatially related but temporally ordered. Collagen I, III, and IV immunostaining was increased from days 3, 24, and 100, respectively (P < 0.05 versus day 0 and day 100 saline). However, when corrected for glomerular density, collagen I immunostaining decreased between days 24 and 100, whereas collagen III and IV no longer differed from day 0. MMP staining within the lesion was confined to occasional interstitial and epithelial cells throughout. It is concluded that in this model, contraction and collapse of the tubulointerstitial parenchyma has a greater influence than new collagen production on final fibrotic density.
Roles of Angiopoietins in Kidney Development and Disease
Authors: Adrian S. Woolf, Luigi Gnudi, David A. Long
Journal: Journal of the American Society of Nephrology (2008)

Angiopoietins are a family of growth factors, the best studied being angiopoietin 1 (Ang-1), which binds to and tyrosine-phosphorylates endothelial Tie-2, causing enhanced survival and cell-cell stabilization. Ang-2 and Tie-1 downregulate Ang-1-induced Tie-2 signaling, and angiopoietin actions are further modified by vascular endothelial growth factor A and integrins. Metanephric capillaries express Tie genes, whereas metanephric mesenchyme, maturing tubules, and mature podocytes express Ang-1. Ang-1 null embryos begin to form blood vessels, but subsequent vascular remodeling fails, and analyses of chimeric wild-type/Tie null mutant embryos show that Tie genes are needed for renal endothelial survival. Ang-2 is transiently expressed in renal arterial smooth muscle and mesangial cells, and tubules around adult vasa rectae express Ang-2. Ang-2 null mice have increased pericytes around kidney cortical peritubular capillaries, perhaps an indirect consequence of upregulated Tie-2 signaling. Ang-1 therapies attenuate peritubular capillary loss in adult models of tubulointerstitial disease, although, in one study, this was accompanied by enhanced inflammation and fibrosis. Podocyte-directed Ang-2 transgenic overexpression causes glomerular endothelial apoptosis, downregulated nephrin expression, and increased albuminuria, and glomerular Ang-2 is upregulated in hyperglycemic and immune-mediated glomerulopathies. Thus, angiopoietins affect podocyte as well as glomerular endothelial biology, and imbalanced angiopoietin signaling contributes to glomerular pathobiology.
Stage I Non-small Cell Lung Cancer (NSCLC) in Patients Aged 75 Years and Older: Does Age Determine Survival After Radical Treatment?
Authors: David A. Palma, Scott Tyldesley, Finbarr Sheehan, Islam G. Mohamed, Sally Smith, Elaine Wai, Nevin Murray, Suresh Senan
Journal: Journal of Thoracic Oncology (2010)
Does Mitral Stenosis Recur after Commissurotomy?
Authors: ROBERT P. GLOVER, JULIO C. DAVILA, THOMAS J. E. O'NEILL, O. HENRY JANTON
Journal: Circulation (1955)

The ultimate fate of the incised commissure following surgery for mitral stenosis will remain unknown for years to come. A clinical appraisal of patients living five years after commissurotomy and a review of available autopsy material from patients surviving surgery for periods up to four years indicates that valvular restenosis does not occur within the first half decade provided the commissurotomy has been properly performed.