tbuckley/cabot-search huggingface dataset:
Regulation of Vascular Proteoglycan Synthesis by Angiotensin II Type 1 and Type 2 Receptors
Authors: Ryoko Shimizu-Hirota, Hiroyuki Sasamura, Mizuo Mifune, Hideaki Nakaya, Mari Kuroda, Matsuhiko Hayashi, Takao Saruta
Journal: Journal of the American Society of Nephrology (2001)

ABSTRACT. Recent studies have shown that proteoglycans play an important role in the development of vascular disease and renal failure. In this study, the effects of angiotensin II (AngII) type 1 (AT1) and type 2 (AT2) receptor stimulation on glycosaminoglycan and proteoglycan core protein synthesis in vascular smooth muscle cells (VSMC) were examined. Treatment of AT1 receptor-expressing VSMC with AngII resulted in a dose-dependent and time-dependent increase (2- to 4-fold) in 3H-glucosamine/35S-sulfate incorporation, which was abolished by pretreatment with the AT1 receptor antagonist, losartan. The effects of AngII were inhibited by the epidermal growth factor receptor inhibitor, AG1478, and the mitagen-activated protein kinase kinase inhibitor, PD98059, but not the protein kinase C inhibitors, chelerythrine and staurosporine. AngII treatment also resulted in significant increases in the mRNA of the core proteins, versican, biglycan, and perlecan. The effects of AT2 receptor stimulation were examined by retroviral transfection of VSMC with the AT2 receptor. Stimulation of the AT2 receptor in these VSMC-AT2 cells resulted in a significant (1.3-fold) increase in proteoglycan synthesis, which was abolished by the AT2 receptor antagonist, PD123319, and attenuated by pretreatment with pertussis toxin. These results implicate both AT1 and AT2 receptors in the regulation of proteoglycan synthesis and suggest the involvement of epidermal growth factor receptor-dependent tyrosine kinase pathways and Gαi/o-mediated mechanisms in the effects of the two receptors.
Risks and Benefits of Nutritional Support During Critical Illness
Authors: Yves Debaveye, Greet Van den Berghe
Journal: Annual Review of Nutrition (2006)

Critically ill patients who depend on intensive care for more than a few days reveal profound erosion of lean body mass, which is thought to contribute to high morbidity and mortality. Despite a shortfall of evidence that supplemental feeding actually alters clinical outcome of these life-threatening disease states, this observation evoked an almost universal, albeit often inappropriate, use of nutritional support (NS) in the critically ill, administered via the parenteral or the enteral route. Lack of knowledge and overenthusiasm subsequently resulted in complications associated with both parenteral nutrition (PN) and enteral nutrition (EN), which led to the standing controversy over which should be preferred. With time, however, it became clear that EN and PN are not mutually exclusive and that critically ill patients requiring NS should be fed according to the functional status of the gastrointestinal tract. In addition, tight blood glucose control with insulin is advised in fed critically ill patients because overall metabolic control appears to surpass any outcome benefit attributed to the route of feeding. Recently, various special nutritional formulas have been suggested to prevent or treat multiorgan failure in the critically ill, among other pathways via modulation of immune function. Although special nutritional formulas may be promising in a variety of clinical settings, based on currently available data, these cannot be recommended for routine use in critically ill patients.
Relation between COPD assessment test"CATâ and functional parameters and quality of life in COPD patients
Authors: Selim Erkan Akdemir, Arzu Yorgancioglu, Yavuz Havlucu, Levent Ozdemir, Tugba Goktalay, Aysin Sakar Coskun, Pinar Celik
Journal: European Respiratory Journal (2012)

The aim was to investigate the relation between COPD assessment test(CAT™) and pulmonary function tests(PFT),BODE index,and St.George Respiratory Questionnaire(SGRQ).

100 patients diagnosed by GOLD criteria were included to the study.A questionnaire that include sociodemographic findings as well as CAT,PFT,SGRQ,and BODE index were assessed for each patient.

90 of the patients(90%) were male and mean age was 63,25±9.55 years.43% patients had comorbidities.There were 3 patients(3%) in stage 1,40 patients(40%) in stage 2,41 patients(41%) in stage 3,and 16 patients(16%) in stage 4.The correlation between COPD stage and exacerbation number in a year,hospitalization in a year, FEV1, FEV1/FVC,six minute walk test,CAT score,SGRQ scores (impact,activity,symptom,total),BODE score,and MMRC score was observed(p<0,001).When the relation of these parameters between each other was investigated,high degree correlation between each other was observed(Pearson correlation test).The correlation of CAT and SGRQ scores was higher than other.

View this table:

Table 1. Correlation of CAT, functional parameters and SGRQ scores (Pearson correlation test)





Exacerbation number in a year and hospitalization in a year was related with all the parameters above.

High degree correlation between CAT and functional tests and quality of life in COPD patients and also correlation between these parameters and disease stage was observed.CAT can be used as simple,practical test when PFT were unavailable or there was no enough time to apply quality of life questionnaire.
Bronchiectasis in bone marrow transplantation
Authors: R. S. Morehead
Journal: Thorax (1997)

Two patients are described with clinical and radiographic bronchiectasis which occurred after allogeneic bone marrow transplantation for haematological malignancy. Both had evidence of chronic graft versus host disease in other organs. Increased immunosuppression with corticosteroids resulted in clinical response, although both patients persisted with chronic mucopurulent sputum production and one had progressive airflow obstruction. Bronchiectasis may be an under-recognised manifestation of chronic graft versus host disease of the lung.
The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice
Authors: Jinping Zhang, Sang-Myeong Lee, Stephen Shannon, Beixue Gao, Weimin Chen, An Chen, Rohit Divekar, Michael W. McBurney, Helen Braley-Mullen, Habib Zaghouani, Deyu Fang
Journal: Journal of Clinical Investigation (2009)

Although many self-reactive T cells are eliminated by negative selection in the thymus, some of these cells escape into the periphery, where they must be controlled by additional mechanisms. However, the molecular mechanisms underlying peripheral T cell tolerance and its maintenance remain largely undefined. In this study, we report that sirtuin 1 (Sirt1), a type III histone deacetylase, negatively regulates T cell activation and plays a major role in clonal T cell anergy in mice. In vivo, we found that loss of Sirt1 function resulted in abnormally increased T cell activation and a breakdown of CD4+ T cell tolerance. Conversely, upregulation of Sirt1 expression led to T cell anergy, in which the activity of the transcription factor AP-1 was substantially diminished.Furthermore, Sirt1 interacted with and deacetylated c-Jun, yielding an inactive AP-1 factor. In addition, Sirt1-deficient mice were unable to maintain T cell tolerance and developed severe experimental allergic encephalomyelitis as well as spontaneous autoimmunity. These findings provide insight into the molecular mechanisms of T cell activation and anergy, and we suggest that activators of Sirt1 may be useful as therapeutic agents for the treatment and/or prevention of autoimmune diseases.
Discovery and Validation of Novel Expression Signature for Postcystectomy Recurrence in High-Risk Bladder Cancer
Authors: Anirban P. Mitra, Lucia L. Lam, Mercedeh Ghadessi, Nicholas Erho, Ismael A. Vergara, Mohammed Alshalalfa, Christine Buerki, Zaid Haddad, Thomas Sierocinski, Timothy J. Triche, Eila C. Skinner, Elai Davicioni, Siamak Daneshmand, Peter C. Black
Journal: JNCI Journal of the National Cancer Institute (2014)

Nearly half of muscle-invasive bladder cancer patients succumb to their disease following cystectomy. Selecting candidates for adjuvant therapy is currently based on clinical parameters with limited predictive power. This study aimed to develop and validate genomic-based signatures that can better identify patients at risk for recurrence than clinical models alone. Transcriptome-wide expression profiles were generated using 1.4 million feature-arrays on archival tumors from 225 patients who underwent radical cystectomy and had muscle-invasive and/or node-positive bladder cancer. Genomic (GC) and clinical (CC) classifiers for predicting recurrence were developed on a discovery set (n = 133). Performances of GC, CC, an independent clinical nomogram (IBCNC), and genomic-clinicopathologic classifiers (G-CC, G-IBCNC) were assessed in the discovery and independent validation (n = 66) sets. GC was further validated on four external datasets (n = 341). Discrimination and prognostic abilities of classifiers were compared using area under receiver-operating characteristic curves (AUCs). All statistical tests were two-sided. A 15-feature GC was developed on the discovery set with area under curve (AUC) of 0.77 in the validation set. This was higher than individual clinical variables, IBCNC (AUC = 0.73), and comparable to CC (AUC = 0.78). Performance was improved upon combining GC with clinical nomograms (G-IBCNC, AUC = 0.82; G-CC, AUC = 0.86). G-CC high-risk patients had elevated recurrence probabilities (P < .001), with GC being the best predictor by multivariable analysis (P = .005). Genomic-clinicopathologic classifiers outperformed clinical nomograms by decision curve and reclassification analyses. GC performed the best in validation compared with seven prior signatures. GC markers remained prognostic across four independent datasets. The validated genomic-based classifiers outperform clinical models for predicting postcystectomy bladder cancer recurrence. This may be used to better identify patients who need more aggressive management.
Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice
Authors: Marcel Wüthrich, Benjamin Gern, Chiung Yu Hung, Karen Ersland, Nicole Rocco, John Pick-Jacobs, Kevin Galles, Hanna Filutowicz, Thomas Warner, Michael Evans, Garry Cole, Bruce Klein
Journal: Journal of Clinical Investigation (2011)

Worldwide rates of systemic fungal infections, including three of the major pathogens responsible for such infections in North America (Coccidioides posadasii, Histoplasma capsulatum, and Blastomyces dermatitidis), have soared recently, spurring interest in developing vaccines. The development of Th1 cells is believed to be crucial for protective immunity against pathogenic fungi, whereas the role of Th17 cells is vigorously debated. In models of primary fungal infection, some studies have shown that Th17 cells mediate resistance, while others have shown that they promote disease pathology. Here, we have shown that Th1 immunity is dispensable and that fungus-specific Th17 cells are sufficient for vaccine-induced protection against lethal pulmonary infection with B. dermatitidis in mice. Further, vaccine-induced Th17 cells were necessary and sufficient to protect against the three major systemic mycoses in North America. Mechanistically, Th17 cells engendered protection by recruiting and activating neutrophils and macrophages to the alveolar space, while the induction of Th17 cells and acquisition of vaccine immunity unexpectedly required the adapter molecule Myd88 but not the fungal pathogen recognition receptor Dectin-1. These data suggest that human vaccines against systemic fungal infections should be designed to induce Th17 cells if they are to be effective.
Tunnel Propagation of Postshock Activations as a Hypothesis for Fibrillation Induction and Isoelectric Window
Authors: Takashi Ashihara, Jason Constantino, Natalia A. Trayanova
Journal: Circulation Research (2008)

Comprehensive understanding of the ventricular response to shocks is the approach most likely to succeed in reducing defibrillation threshold. We propose a new theory of shock-induced arrhythmogenesis that unifies all known aspects of the response of the heart to monophasic (MS) and biphasic (BS) shocks. The central hypothesis is that submerged "tunnel" propagation of postshock activations through shock-induced intramural excitable areas underlies fibrillation induction and the existence of isoelectric window. We conducted simulations of fibrillation induction using a realistic bidomain model of rabbit ventricles. Following pacing, MS and BS of various strengths/timings were delivered. The results demonstrated that, during the isoelectric window, an activation originated deep within the ventricular wall, arising from virtual electrodes; it then propagated fully intramurally through an excitable tunnel induced by the shock, until it emerged onto the epicardium, becoming the earliest-propagated postshock activation. Differences in shock outcomes for MS and BS were found to stem from the narrower BS intramural postshock excitable area, often resulting in conduction block, and the difference in the mechanisms of origin of the postshock activations, namely intramural virtual electrode-induced phase singularity for MS and virtual electrode-induced propagated graded response for BS. This study provides a novel analysis of the 3D mechanisms underlying the origin of postshock activations in the process of fibrillation induction by MS and BS and the existence of isoelectric window. The tunnel propagation hypothesis could open a new avenue for interventions exploration to achieve significantly lower defibrillation threshold.
Completion of Therapy by Medicare Patients With Stage III Colon Cancer
Authors: Sharon A. Dobie, Laura-Mae Baldwin, Jason A. Dominitz, Barbara Matthews, Kevin Billingsley, William Barlow
Journal: JNCI Journal of the National Cancer Institute (2006)

Certain factors, such as race or age, are known to be associated with variation in initiation of adjuvant chemotherapy for stage III colon cancer, but little is known about what factors are associated with completion of adjuvant therapy. To determine whether predictors of initiation also predict completion, we analyzed Surveillance, Epidemiology, and End Results (SEER) program data linked to Medicare claims. We investigated mortality as a means to testing the validity of the completion measure that we created.We studied 3193 stage III colon cancer patients whose diagnosis was recorded in 1992-1996 SEER program data linked to 1991-1998 Medicare claims and who initiated adjuvant chemotherapy after colon cancer resection. We defined a measure of adjuvant chemotherapy completion as one chemotherapy administration claim in a month. We tested the validity of the created measure and its relation to 3-year cancer mortality adjusted for demographic, clinical, and environmental variables. We explored the association of patient characteristics and treating physician characteristics with chemotherapy completion by use of multivariable logistic regression modeling.Of the 3193 patients, 2497 (78.2%) completed the course. Risk of cancer-related mortality was statistically significantly lower among those completing chemotherapy (relative risk = 0.79, 95% confidence interval = 0.69 to 0.89) than those with no adjuvant therapy. Patients who were female, widowed, increasingly elderly, rehospitalized, and living in certain regions were less likely to complete adjuvant chemotherapy than other patients. Race and other clinical, environmental, and physician characteristics were not associated with completion of therapy.Factors associated with incomplete adjuvant chemotherapy may represent physical frailty, treatment complications, and lack of social and psychological support. Interventions to mitigate these influences are a logical next step toward increasing chemotherapy completion rates.
The TAL1 complex targets the <i>FBXW7</i> tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia
Authors: Marc R. Mansour, Takaomi Sanda, Lee N. Lawton, Xiaoyu Li, Taras Kreslavsky, Carl D. Novina, Marjorie Brand, Alejandro Gutierrez, Michelle A. Kelliher, Catriona H.M. Jamieson, Harald von Boehmer, Richard A. Young, A. Thomas Look
Journal: The Journal of Experimental Medicine (2013)

The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor.
Metabolomics Reveals Signature of Mitochondrial Dysfunction in Diabetic Kidney Disease
Authors: Kumar Sharma, Bethany Karl, Anna V. Mathew, Jon A. Gangoiti, Christina L. Wassel, Rintaro Saito, Minya Pu, Shoba Sharma, Young-Hyun You, Lin Wang, Maggie Diamond-Stanic, Maja T. Lindenmeyer, Carol Forsblom, Wei Wu, Joachim H. Ix, Trey Ideker, Jeffrey B. Kopp, Sanjay K. Nigam, Clemens D. Cohen, Per-Henrik Groop, Bruce A. Barshop, Loki Natarajan, William L. Nyhan, Robert K. Naviaux
Journal: Journal of the American Society of Nephrology (2013)

Diabetic kidney disease is the leading cause of ESRD, but few biomarkers of diabetic kidney disease are available. This study used gas chromatography-mass spectrometry to quantify 94 urine metabolites in screening and validation cohorts of patients with diabetes mellitus (DM) and CKD(DM+CKD), in patients with DM without CKD (DM–CKD), and in healthy controls. Compared with levels in healthy controls, 13 metabolites were significantly reduced in the DM+CKD cohorts (P≤0.001), and 12 of the 13 remained significant when compared with the DM–CKD cohort. Many of the differentially expressed metabolites were water-soluble organic anions. Notably, organic anion transporter-1 (OAT1) knockout mice expressed a similar pattern of reduced levels of urinary organic acids, and human kidney tissue from patients with diabetic nephropathy demonstrated lower gene expression of OAT1 and OAT3. Analysis of bioinformatics data indicated that 12 of the 13 differentially expressed metabolites are linked to mitochondrial metabolism and suggested global suppression of mitochondrial activity in diabetic kidney disease. Supporting this analysis, human diabetic kidney sections expressed less mitochondrial protein, urine exosomes from patients with diabetes and CKD had less mitochondrial DNA, and kidney tissues from patients with diabetic kidney disease had lower gene expression of PGC1α (a master regulator of mitochondrial biogenesis). We conclude that urine metabolomics is a reliable source for biomarkers of diabetic complications, and our data suggest that renal organic ion transport and mitochondrial function are dysregulated in diabetic kidney disease.
Subcutaneous inflammation mimicking metastatic malignancy induced by injection of mistletoe extract
Authors: A I Finall, S A McIntosh, W D Thompson
Journal: BMJ (2006)

Thanks to all participants in our study who provided a breath of fresh air and a touch of humour.Thanks also to the members of the evaluating committee for taking the risk and having some fun together.Finally, thanks to Sarah Lafuente and Beatriz Serrano
Deaths among Patients with Screen-Detected Lung Cancer
Authors: Gerard A. Silvestri
Journal: Clinical Cancer Research (2008)

To the Editor: I write to seek clarification on information presented by Henschke (1) in her recent editorial specifically with regard to one of the findings in a recent case series published from the International Early Lung Cancer Action Project (2). In her editorial, Henschke reports that “all [the] patients [in the study] with clinical stage I NSCLC who were not treated died within 5 years of their lung cancer.” This comment echoed that provided by Henschke (3) in another recently published editorial, in which she reported that “We had only 8 such patients, and all died of lung cancer within 5 years of diagnosis”. In the original report, however, which was published in 2006 in the New England Journal of Medicine, the investigators did not report that these eight subjects died of lung cancer but instead reported only that the subjects had died, without specifying the cause of death (2). Yee and Lynch (4) pursued the cause of death question in a letter to the editor of that journal asking for clarification on this matter but Henschke et al. (5) did not address Yee and Lynch's question in their response. As Aisner (6) recently noted, whether these subjects died of lung cancer or another cause is a matter of critical importance to the interpretation of the International Early Lung Cancer Action Project findings. Now that Henschke has reported that all eight died of lung cancer, I am writing to ask for some further information about the eight subjects. How was the cause of death ascertained in these subjects? How many of these eight subjects had metastatic or locally advanced disease at the time of their death, and what was the timing of their development of disease progression, relative to the timing of their diagnosis and death? Additionally, did these patients have other competing comorbidities (such as chronic obstructive pulmonary disease) that may have precluded them from undergoing curative surgery at the time of diagnosis?
Molecular Composition of 4-Aminopyridine-Sensitive Voltage-Gated K <sup>+</sup> Channels of Vascular Smooth Muscle
Authors: Kevin S. Thorneloe, Tim T. Chen, Paul M. Kerr, Elizabeth F. Grier, Burton Horowitz, William C. Cole, Michael P. Walsh
Journal: Circulation Research (2001)

Voltage-gated K + channels (Kv) play a critical role in regulating arterial tone by modulating the membrane potential of vascular smooth muscle cells. Our previous work demonstrated that the dominant 4-aminopyridine (4-AP)-sensitive, delayed rectifier Kv current of rabbit portal vein (RPV) myocytes demonstrates similar 4-AP sensitivity and biophysical properties to Kv1α-containing channels. To identify the molecular constituents underlying the 4-AP-sensitive Kv current of vascular myocytes, we characterized the expression pattern of Kv1α subunits and their modulatory Kvβ subunits in RPV. The mRNAs encoding pore-forming subunits Kv1.2, Kv1.4, and Kv1.5 were detected by reverse transcriptase-polymerase chain reaction (RT-PCR), whereas Kv1.1, Kv1.3, and Kv1.6 transcripts were undetectable. Kvβ1.1, β1.2, β1.3, β2.1, and β2.2 messages were expressed, whereas Kvβ3.1 and β4 mRNAs were undetected by RT-PCR. Kv1.2, Kv1.4, Kv1.5, Kvβ1.2, β1.3, and β2.1 proteins were detected in RPV by Western blotting and/or immunocytochemistry of freshly isolated myocytes. We provide the first evidence, from coimmunoprecipitation studies, for the formation of heteromultimeric Kv channel complexes composed of Kv1.2, Kv1.5, and Kvβ1.2 subunits in vascular smooth muscle.