tbuckley/cabot-search huggingface dataset:
A comparison of specific health- related quality of life questionnaires to predict COPD exacerbations
Authors: Angelica Consuegra, Marina Blanco-Aparicio, Isabel Vazquez, Héctor Verea-Hernando
Journal: European Respiratory Journal (2012)

Objectives: Compare the COPD specific health-related quality of life (HRQoL) instruments, St George respiratory Questionnaire (SGRQ), Chronic Respiratory Questionnaire (CRQ), Clinical COPD Questionnaire (CCQ) and Airways Questionnaire 20 (AQ20) to predict COPD exacerbations.  Methods: One hundred COPD patients who completed SGRQ, CRQ, CCQ and AQ20 were followed for 2 years. Emergency visits and hospitalizations were collected.We also assessed sociodemographic, clinical and pulmonary function data. The chi-squared, t test, and Mann-Whitney U were used to compare differences between groups. Multivariate logistic regression was performed for all variables showing statistically significant differences. A p-value  Results: The mean (SD) age was 65.9 (8.4) years and the mean FEV1 was 59.1 (19.5) % of predicted value. In the univariate analysis only CCQ questionnaire showed differences for patients with emergency visits in the first year. Significant differences were seen in the scores of the CCQ, total score SGRQ and all subscales, except SGRQ symptoms, and the scale disease control of CRQ between the group with hospitalization in the first year. In the logistic regression model, the CCQ questionnaire finally proved to be independent predictor of emergency visits during the first year (OR: 1.06; 95% CI, 1.00 to1.11; p=0.036). Other variables significantly associated were BMI (0.87; p=0.04) and prior hospitalizations (OR: 1.79; p=0.01).  Conclusions: Among a wide range of HRQoL questionnaires only the CCQ are independently associated with a higher risk of emergency visits for COPD exacerbations the first year of follow-up.
Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects
Authors: Matthew G. Sampson, Catherine C. Robertson, Sebastian Martini, Laura H. Mariani, Kevin V. Lemley, Christopher E. Gillies, Edgar A. Otto, Jeffrey B. Kopp, Anne Randolph, Virginia Vega-Warner, Felix Eichinger, Viji Nair, Debbie S. Gipson, Daniel C. Cattran, Duncan B. Johnstone, John F. O’Toole, Serena M. Bagnasco, Peter X. Song, Laura Barisoni, Jonathan P. Troost, Matthias Kretzler, John R. Sedor
Journal: Journal of the American Society of Nephrology (2015)

APOL1 variants have been associated with renal phenotypes in blacks. To refine clinical outcomes and discover mechanisms of APOL1-associated kidney injury, we analyzed clinical and genomic datasets derived from 90 black subjects in the Nephrotic Syndrome Study Network (NEPTUNE), stratified by APOL1 risk genotype. Ninety subjects with proteinuria ≥0.5 g/d were enrolled at first biopsy for primary nephrotic syndrome and followed. Clinical outcomes were determined, and renal histomorphometry and sequencing of Mendelian nephrotic syndrome genes were performed. APOL1 variants were genotyped, and glomerular and tubulointerstitial transcriptomes from protocol renal biopsy cores were analyzed for differential and correlative gene expression. Analyses were performed under the recessive model (high-risk genotype defined by two risk alleles). APOL1 high-risk genotype was significantly associated with a 17 ml/min per 1.73 m2 lower eGFR and a 69% reduction in the probability of complete remission at any time, independent of histologic diagnosis. Neither APOL1 risk group was enriched for Mendelian mutations. On renal biopsy, high-risk genotype was associated with increased fractional interstitial area, interstitial fibrosis, and tubular atrophy. Risk genotype was not associated with intrarenal APOL1 mRNA expression levels. Differential expression analysis demonstrated an increased steady-state level of five genes associated with the high-risk genotype (CXCL9, CXCL11, and UBD in glomerulus; SNOR14B and MUC13 in tubulointerstitium). APOL1 tubulointerstitial coexpression analysis showed coexpression of APOL1 mRNA levels with a group of intrarenal transcripts that together were associated with increased interstitial fibrosis and tubular atrophy. These data indicate the high-risk APOL1 genotype confers renal risk across histopathologic diagnoses.
Relation Between Gd-DTPA Contrast Enhancement and Regional Inotropic Response in the Periphery and Center of Myocardial Infarction
Authors: Bernhard L. Gerber, Carlos E. Rochitte, David A. Bluemke, Jacques A. Melin, Pierre Crosille, Lewis C. Becker, João A.C. Lima
Journal: Circulation (2001)

Background Gd-DTPA contrast-enhanced (CE) MRI identifies patterns of early hypoenhancement and delayed hyperenhancement in acute myocardial infarction, but their clinical significance for the prediction of myocardial viability remains controversial. Therefore, we closely examined the relationship between these CE patterns and regional inotropic response to low-dose dobutamine infusion at a regional level. Methods and Results Thirteen dogs underwent CE and tagged MRI at rest and during 5 μg · kg −1 · min −1 dobutamine 48 hours after MI. CE patterns and 3D regional strains were measured in 96 segments per animal. Segments were categorized as being normofunctional (n=828) if resting circumferential shortening was within the range of remote myocardium, or dysfunctional (n=420) if not. Inotropic response in resting dysfunctional segments was assessed according to CE patterns. Significant improvement of radial thickening (from +12±1% [mean±SEM] to +22±2%, P &lt;0.05) and circumferential shortening (from +1±1% to −5±1%, P &lt;0.05) strains occurred in dysfunctional myocardium with normal CE pattern but not in myocardium with early hypoenhancement. Delayed hyperenhanced myocardium displayed a more complex behavior. Circumferential stretching improved in the peripheral regions (from +4±1% to −2±2%, P &lt;0.05), where the infarct was nontransmural (38±3% transmurality), but not in centrally hyperenhanced regions (from +4±1% to +1±1% P =NS), where the infarct was 66±3% transmural. Conclusions Inotropic reserve was confined to dysfunctional myocardium with normal contrast enhancement but not to myocardium with early hypoenhancement. Inotropic response in delayed hyperenhanced myocardium is influenced by transmurality of necrosis. These observations support the use of CE MRI for the clinical detection of myocardial viability.
Dose–Response Relationship in Phase I Clinical Trials: A European Drug Development Network (EDDN) Collaboration Study
Authors: Victor Moreno García, David Olmos, Carlos Gomez-Roca, Philippe A. Cassier, Rafael Morales-Barrera, Gianluca Del Conte, Elisa Gallerani, Andre T. Brunetto, Patrick Schöffski, Silvia Marsoni, Jan H.M. Schellens, Nicolas Penel, Emile Voest, Jeffrey Evans, Ruth Plummer, Richard H. Wilson, Jean Charles Soria, Josep Tabernero, Jaap Verweij, Stan B. Kaye
Journal: Clinical Cancer Research (2014)

Abstract Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors. Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available. Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003). Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD). Clin Cancer Res; 20(22); 5663–71. ©2014 AACR.
Expression of intracellular adhesion molecule 1 by activated hepatic stellate cells
Authors: C Hellerbrand, S C Wang, H Tsukamoto, D A Brenner, R A Rippe
Journal: Hepatology (1996)

The hepatic stellate cell (HSC), following a fibrogenic stimulus, is transformed from a quiescent to an activated cell. HSC activation results in numerous changes in cellular morphology, cellular metabolism, and in the pattern of gene expression. Many of the changes that are observed in activated HSCs in animal models of hepatic fibrosis are also seen when these cells are activated by culturing on plastic. These changes include morphological changes to a myofibroblast– like cell with the appearance of smooth muscle α–actin, a loss of the retinol stores, an increase in the rough endoplasmic reticulum, and increases in extracellular matrix production, including a dramatic increase in type I collagen. To identify additional genes that are induced or suppressed during HSC activation, we used the differential polymerase chain reaction (PCR) display technique. Using this technique, we isolated a complementary DNA (cDNA) fragment for the intercellular adhesion molecule 1 (ICAM–1). Northern blotting confirmed that the ICAM–1 messenger RNA (mRNA) was expressed in HSCs activated by culture, but not in quiescent, freshly isolated HSCs. The presence of ICAM–1 protein was demonstrated in culture–activated HSCs, but not in quiescent cells by Western blot analysis and immunohistochemical staining. A functional assay was performed, demonstrating that lymphocytes will adhere to activated HSCs and that treatment of these cells with tumor necrosis factor α (TNF–α) increases lymphocyte adherence. Furthermore, ICAM–1 mRNA levels were increased in HSCs activated in rats in vivo after 1 week of bile duct ligation (BDL). Together, these data indicate that ICAM–1 expression is induced following HSC activation and that the HSC may have a direct role in the transmigration of leukocytes from the hepatic sinusoid to sites of tissue damage during the inflammatory response in the liver.
Hemoglobin stability: observations on the denaturation of normal and abnormal hemoglobins by oxidant dyes, heat, and alkali
Authors: Ronald F. Rieder
Journal: Journal of Clinical Investigation (1970)

Several unstable mutant hemoglobins have alterations which affect areas of the molecule involved in the attachment of heme to globin. Loss of heme from globin has been demonstrated during the denaturation of some of these unstable mutants. The importance of heme ligands for the stability of hemoglobin was illustrated in the present experiments on the denaturation of several hemoglobins and hemoglobin derivatives by heat, oxidative dyes, and alkali. Heating of normal hemolysates diluted to 4 g of hemoglobin per 100 ml at 50 degrees C for 20 hr in 0.05 M sodium phosphate, pH 7.4, caused precipitation of 23-54% of the hemoglobin. Dialysis against water or dilution of the sample decreased denaturation to 12-20%. Precipitation was decreased to less than 3.5% by the presence of 0.015 M potassium cyanide. Increasing the ionic strength of the medium increased precipitation. Cyanide prevented the formation of inclusion bodies when red cells containing unstable hemoglobin Philly, beta35 tyr --> phe, were incubated with the redox dye new methylene blue. Conversion to methemoglobin increased the rate of alkali denaturation of hemoglobin but the presence of potassium cyanide returned the denaturation rate to that of ferrohemoglobin. The ability of cyanide to decrease heat precipitation of hemoglobin may depend on a dimeric or tetrameric state of the hemoglobin molecule. Purified beta-chains, which exist as tetramers, were stabilized but purified monomeric alpha-chains were not rendered more heat resistant by the ligand. Stabilization of hemoglobin by cyanide required binding of the ligand to only one heme of an alphabeta-dimer. Hemoglobin Gun Hill, an unstable molecule with heme groups present only on the alpha-chains was quite heat stable in the presence of cyanide. The binding of cyanide to the iron atom in methemoglobin is thought to be associated with increased planarity of the heme group and increased stability of the heme-globin complex. The stabilizing effect of cyanide in the above experiments suggests that Heinz body formation, heat precipitation of hemoglobin, and the increased alkali denaturation of methemoglobin depend on changes of heme-globin binding.
Gonadal steroidogenesis in vitro from juvenile alligators obtained from contaminated or control lakes.
Authors: L J Guillette, T S Gross, D A Gross, A A Rooney, H F Percival
Journal: Environmental Health Perspectives (1995)

The ubiquitous distribution of many contaminants and the nonlethal, multigenerational effects of such contaminants on reproductive, endocrine, and immune systems have led to concerns that wildlife worldwide are affected. Although the causal agents and effects are known for some species, the underlying physiological mechanisms associated with contaminant-induced reproductive modifications are still poorly understood and require extensive research. We describe a study examining the steroidogenic activity of gonads removed from juvenile alligators (Alligator mississippiensis) obtained from contaminated or control lakes in central Florida. Synthesis of estradiol-17 beta (E2) was significantly different when ovaries from the contaminated and control lakes were compared in vitro. Additionally, testes from males obtained from the contaminated lake. Lake Apopka, synthesized significantly higher concentrations of E2 when compared to testes obtained from control males. In contrast, testosterone (T) synthesis from all testes examined in this study displayed a normal pattern and produced concentrations greater than that observed from ovaries obtained from either lake. Interestingly, the pattern of gonadal steroidogenesis differs from previously reported plasma concentrations of these hormones obtained from the same individuals. We suggest that the differences between the in vivo and in vitro patterns are due to modifications in the hepatic degradation of plasma sex steroid hormones.
The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma
Authors: N. Erčulj, V. Kovač, J. Hmeljak, V. Dolžan
Journal: Annals of Oncology (2011)

Platinum-based therapy is widely used in the treatment of malignant mesothelioma (MM); however, the efficacy and toxicity of platinum agents vary greatly between patients. The aim of our study was to evaluate the influence of platinum pathway polymorphisms on treatment outcome in patients with MM.In total, 133 patients with MM treated with (n = 97) or without (n = 36) platinum-based therapy were genotyped for common XPD, ERCC1, and GSTP1 polymorphisms, as well as for GSTM1 and GSTT1 gene deletion. Haplotype analysis was carried out to assess the combined effect of nucleotide excision repair (NER) polymorphisms.GST polymorphisms were not associated with treatment outcome in patients with MM. In the group of platinum-treated patients with MM, ERCC1 8092C/C wild-type genotype significantly influenced progression-free survival (PFS) in multivariable analysis accounting for clinical variables (P = 0.034). XPD 312Asp/Asp and ERCC1 8092C/C wild-type genotypes also increased the odds of treatment-related toxic effects in univariable as well as multivariable analysis. The association of wild-type NER genotypes with better PFS and higher susceptibility to treatment-related toxic effects was confirmed in haplotype analysis.Our results suggest that polymorphisms in NER pathway influence platinum-treatment efficacy and toxicity; therefore, these should be further evaluated as potential markers for the prediction of clinical outcome in patients with MM.
Targeting of a Novel Ca+ <sup>2</sup> /Calmodulin-Dependent Protein Kinase II Is Essential for Extracellular Signal-Regulated Kinase–Mediated Signaling in Differentiated Smooth Muscle Cells
Authors: William A. Marganski, Samudra S. Gangopadhyay, Hyun-Dong Je, Cynthia Gallant, Kathleen G. Morgan
Journal: Circulation Research (2005)

Subcellular targeting of kinases controls their activation and access to substrates. Although Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is known to regulate differentiated smooth muscle cell (dSMC) contractility, the importance of targeting in this regulation is not clear. The present study investigated the function in dSMCs of a novel variant of the γ isoform of CaMKII that contains a potential targeting sequence in its association domain (CaMKIIγ G-2). Antisense knockdown of CaMKIIγ G-2 inhibited extracellular signal-related kinase (ERK) activation, myosin phosphorylation, and contractile force in dSMCs. Confocal colocalization analysis revealed that in unstimulated dSMCs CaMKIIγ G-2 is bound to a cytoskeletal scaffold consisting of interconnected vimentin intermediate filaments and cytosolic dense bodies. On activation with a depolarizing stimulus, CaMKIIγ G-2 is released into the cytosol and subsequently targeted to cortical dense plaques. Comparison of phosphorylation and translocation time courses indicates that, after CaMKIIγ G-2 activation, and before CaMKIIγ G-2 translocation, vimentin is phosphorylated at a CaMKII-specific site. Differential centrifugation demonstrated that phosphorylation of vimentin in dSMCs is not sufficient to cause its disassembly, in contrast to results in cultured cells. Loading dSMCs with a decoy peptide containing the polyproline sequence within the association domain of CaMKIIγ G-2 inhibited targeting. Furthermore, prevention of CaMKIIγ G-2 targeting led to significant inhibition of ERK activation as well as contractility. Thus, for the first time, this study demonstrates the importance of CaMKII targeting in dSMC signaling and identifies a novel targeting function for the association domain in addition to its known role in oligomerization.
Protein structure protection commits gene expression patterns
Authors: Jianping Chen, Han Liang, Ariel Fernández
Journal: Genome biology (2008)

Gene co-expressions often determine module-defining spatial and temporal concurrences of proteins. Yet, little effort has been devoted to tracing coordinating signals for expression correlations to the three-dimensional structures of gene products. We performed a global structure-based analysis of the yeast and human proteomes and contrasted this information against their respective transcriptome organizations obtained from comprehensive microarray data. We show that protein vulnerability quantifies dosage sensitivity for metabolic adaptation phases and tissue-specific patterns of mRNA expression, determining the extent of co-expression similarity of binding partners. The role of protein intrinsic disorder in transcriptome organization is also delineated by interrelating vulnerability, disorder propensity and co-expression patterns. Extremely vulnerable human proteins are shown to be subject to severe post-transcriptional regulation of their expression through significant micro-RNA targeting, making mRNA levels poor surrogates for protein-expression levels. By contrast, in yeast the expression of extremely under-wrapped proteins is likely regulated through protein aggregation. Thus, the 85 most vulnerable proteins in yeast include the five confirmed prions, while in human, the genes encoding extremely vulnerable proteins are predicted to be targeted by microRNAs. Hence, in both vastly different organisms protein vulnerability emerges as a structure-encoded signal for post-transcriptional regulation. Vulnerability of protein structure and the concurrent need to maintain structural integrity are shown to quantify dosage sensitivity, compelling gene expression patterns across tissue types and temporal adaptation phases in a quantifiable manner. Extremely vulnerable proteins impose additional constraints on gene expression: They are subject to high levels of regulation at the post-transcriptional level.
Familial and nonfamilial benign recurrent cholestiasis distinguished by plasma disappearance of indocyanine green but not cholylglycine.
Authors: G P van Berge-Henegouwen, D R Ferguson, A F Hofmann, A G De Pagter
Journal: Gut (1978)

To determine whether a defect in uptake of organic anions is present in patients with benign recurrent cholestasis, the plasma disappearance of simultaneously injected indocyanine green and cholyglycine-1-14C was measured in eight patients with asymptomatic benign recurrent cholestasis, four with the familial type, as well as 22 healthy control subjects. Evans blue was also simultaneously injected to permit correction for variation in blood volume and speed of mixing. Uptake of indocyanine green was decreased in all three patients with nonfamilial benign recurrent cholestatsis, but normal or increased in the four patients uith the familial form of the disorder. By contrast, cholyglycine-1-14C uptake was abnormal in one patient with each type of the disorder. Thus, patients with nonfamilial benign recurrent cholestasis have a defect in indocyanine green uptake, and patients with benign recurrent cholestasis are heterogeneous with respect to organic anion uptake.
AKT Regulation of Estrogen Receptor β Transcriptional Activity in Breast Cancer
Authors: Bich N. Duong, Steven Elliott, Daniel E. Frigo, Lilia I. Melnik, Lyndsay Vanhoy, Suzanne Tomchuck, Helena P. Lebeau, Odile David, Barbara S. Beckman, Jawed Alam, Melyssa R. Bratton, John A. McLachlan, Matthew E. Burow
Journal: Cancer Research (2006)

Growth factor activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway has been shown to activate the estrogen receptor (ER) alpha and to mediate tamoxifen resistance in breast cancer. Here, we investigated the regulation of the transcriptional activity of the newer ER beta by PI3K-AKT signaling. Tissue arrays of breast cancer specimens showed a positive association between the expressions of AKT and ER beta in the clinical setting. Reporter gene assays using pharmacologic and molecular inhibitors of AKT and constitutively active AKT revealed for the first time the ability of AKT to (a) potentiate ER beta activity and (b) target predominantly the activation function-2 (AF2) domain of the receptor, with a requirement for residue K269. Given the importance of coactivators in ER transcriptional activity, we further investigated the possible involvement of steroid receptor coactivator 1 (SRC1) and glucocorticoid receptor-interacting protein 1 (GRIP1) in AKT regulation of ER beta. Mammalian two-hybrid assays revealed that AKT enhanced both SRC1 and GRIP1 recruitment to the ER beta-AF2 domain, and reporter gene analyses revealed that AKT and GRIP1 cooperatively potentiated ER beta-mediated transcription to a level much greater than either factor alone. Investigations into AKT regulation of GRIP with mammalian one-hybrid assays showed that AKT potentiated the activation domains of GRIP1 itself, and in vitro kinase assays revealed that AKT directly phosphorylated GRIP1. The cross-talk between the PI3K-AKT and ER beta pathways, as revealed by the ability of AKT to regulate several components of ER beta-mediated transcription, may represent an important aspect that may influence breast cancer response to endocrine therapy.
Mesalamine Once Daily Is More Effective Than Twice Daily in Patients With Quiescent Ulcerative Colitis
Authors: Axel U. Dignass, Bernd Bokemeyer, Henning Adamek, Michael Mross, Lars Vinter-Jensen, Norbert Börner, Jouni Silvennoinen, Gie Tan, Marco Oudkerk Pool, Theo Stijnen, Peter Dietel, Tobias Klugmann, Severine Vermeire, Aomesh Bhatt, Henri Veerman
Journal: Clinical Gastroenterology and Hepatology (2009)