tbuckley/cabot-search huggingface dataset:
Up-regulation of p21 Gene Expression by Peroxisome Proliferator-Activated Receptor γ in Human Lung Carcinoma Cells
Authors: Shouwei Han, Neil Sidell, Paul B. Fisher, Jesse Roman
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The peroxisome proliferator-activated receptor γ (PPARγ), a ligand-dependent transcription factor belonging to the family of nuclear receptors, has been implicated in the regulation of cell growth and differentiation although the exact mechanism(s) of this activity has not been elucidated. In this study, we explored the role of PPARγ signaling on the control of gene expression of the cycle-dependent kinase inhibitor p21 in human lung carcinoma cells. Experimental Design: Using several human lung carcinoma cell lines (small and non-small carcinoma cells), we assayed for cell growth inhibition and apoptosis induction. We also assayed for p21 mRNA and protein expression by reverse transcription-PCR, real-time reverse transcription-PCR, and Western blot analysis. Nuclear protein binding activities to three response elements located in the p21 promoter [nuclear factor (NF)-κB, Sp1, and NF-interleukin 6 (IL6) CAAT/enhancer binding protein (C/EBP)] were measured by gel mobility shift assays. We used transient transfection assays with p21 promoter reporter gene constructs to determine the transcriptional regulation by PPARγ ligands. Finally, by using p21 antisense oligonucleotides, we tested the link between PPARγ activation and p21 signaling in cell growth inhibition assays and by Western blot analysis. Results: We showed that the PPARγ ligands PGJ2 and ciglitazone inhibit the growth and induce the apoptosis of several human lung carcinoma cell lines, whereas the PPARα agonist WY14643 has little effect. Treatment of lung carcinoma cells with the PPARγ ligands PGJ2, ciglitazone, troglizaone, and GW1929 elevated p21 mRNA and protein levels and reduced cyclin D1 mRNA levels. These results were supported by transient transfection assays, which indicated that PPARγ ligands increased p21 gene promoter activity in human lung carcinoma cells. In addition, p21 antisense oligonucleotides inhibited PPARγ ligand-induced p21 protein expression and significantly blocked lung carcinoma cell growth inhibition induced by PPARγ ligands. Finally, electrophoresis mobility shift experiments demonstrated that PPARγ ligands increased the nuclear binding activities of Sp1 and NF-IL6 (C/EBP), two transcription factors with regulatory elements in the promoter region of the p21 gene. Conclusion: PPARγ ligands inhibit human lung carcinoma cell growth and induce apoptosis by stimulating the cyclin-dependent kinase inhibitor p21 and by reducing cyclin D1 gene expression. The induction of p21 gene expression by PPARγ ligands may be mediated through increased Sp1- and NF-IL6 (C/EBP)-dependent transcriptional activation. These observations unveil a mechanism for p21 gene regulation in lung carcinoma that represents a potential target for therapy.
Mouse Ly-49A Interrupts Early Signaling Events in Natural Killer Cell Cytotoxicity and Functionally Associates with the SHP-1 Tyrosine Phosphatase
Authors: Mary C. Nakamura, Eréne C. Niemi, Mark J. Fisher, Leonard D. Shultz, William E. Seaman, James C. Ryan
Journal: The Journal of Experimental Medicine (1997)

The lytic activity of natural killer (NK) cells is inhibited by the expression of class I major histocompatibility complex (MHC) antigens on target cells. In murine NK cells, Ly-49A mediates inhibition of cytotoxicity in response to the class I MHC antigen H-2Dd. In this report, we studied the function of mouse Ly-49A in both the rat NK cell tumor line, RNK-16, transfected with Ly-49A cDNA, and in primary NK cells. We show that ligation of Ly-49A by H-2Dd inhibits early signaling events during target cell stimulation, including polyphosphoinositide turnover and tyrosine phosphorylation. We also show that Ly-49A directly associates with the cytoplasmic tyrosine phosphatase SHP-1, and that Ly-49A function is impaired in NK cells from SHP-1 mutant viable motheaten mice and from SHP-1–deficient motheaten mice. Finally, we demonstrate that mutational substitution of the tyrosine within the proposed SHP-1 binding motif in Ly-49A completely abrogates inhibition of NK cell cytotoxicity through this receptor. These results demonstrate that Ly-49A interrupts early activating signals in NK cells, and that SHP-1 is an important mediator of Ly-49A function.
Signal transduction inhibitors in treatment of myelodysplastic syndromes
Authors: Lohith Bachegowda, Oleg Gligich, Ionnis Mantzaris, Carolina Schinke, Dale Wyville, Tatiana Carrillo, Ira Braunschweig, Ulrich Steidl, Amit Verma
Journal: Journal of Hematology & Oncology (2013)

Abstract Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.
In defence of the carbon monoxide transfer coefficient<i>K</i><sub>CO</sub>(<i>T</i><sub>L</sub>/<i>V</i><sub>A</sub>)
Authors: J.M.B. Hughes, N.B. Pride
Journal: European Respiratory Journal (2001)

The carbon monoxide transfer factor (TL,co) is the product of the two primary measurements during breath-holding, the CO transfer coefficient (Kco) and the alveolar volume (VA). Kco is essentially the rate constant for alveolar CO uptake (Krogh's kco), and in healthy subjects, increases when VA is reduced by submaximal inflation, or when pulmonary blood flow increases. Recently, new reference values were proposed for clinical use which included the observed VA at full inflation; this was claimed to "eliminate the need for Kco". In this commentary, some mechanisms e.g. respiratory muscle weakness, lung resection, diffuse alveolar damage and airflow obstruction, which decrease or increase total lung capacity (TLC) are reviewed. Even when alveolar structure and function are normal, the change in Kco at a given VA varies according to the underlying pathophysiological mechanism. The advantages and disadvantages of normalizing Kco and TL,co to predisease predicted TLC or to the patient's actual VA (using lack of expansion or loss of alveolar units models) are considered. Examination of carbon monoxide transfer coefficient and alveolar volume separately provides information on disease pathophysiology which cannot be obtained from their product, the carbon monoxide transfer factor.
Unity in Variety--The Pan-Genome of the Chlamydiae
Authors: A. Collingro, P. Tischler, T. Weinmaier, T. Penz, E. Heinz, R. C. Brunham, T. D. Read, P. M. Bavoil, K. Sachse, S. Kahane, M. G. Friedman, T. Rattei, G. S. A. Myers, M. Horn
Journal: Molecular Biology and Evolution (2011)

Chlamydiae are evolutionarily well-separated bacteria that live exclusively within eukaryotic host cells. They include important human pathogens such as Chlamydia trachomatis as well as symbionts of protozoa. As these bacteria are experimentally challenging and genetically intractable, our knowledge about them is still limited. In this study, we obtained the genome sequences of Simkania negevensis Z, Waddlia chondrophila 2032/99, and Parachlamydia acanthamoebae UV-7. This enabled us to perform the first comprehensive comparative and phylogenomic analysis of representative members of four major families of the Chlamydiae, including the Chlamydiaceae. We identified a surprisingly large core gene set present in all genomes and a high number of diverse accessory genes in those Chlamydiae that do not primarily infect humans or animals, including a chemosensory system in P. acanthamoebae and a type IV secretion system. In S. negevensis, the type IV secretion system is encoded on a large conjugative plasmid (pSn, 132 kb). Phylogenetic analyses suggested that a plasmid similar to the S. negevensis plasmid was originally acquired by the last common ancestor of all four families and that it was subsequently reduced, integrated into the chromosome, or lost during diversification, ultimately giving rise to the extant virulence-associated plasmid of pathogenic chlamydiae. Other virulence factors, including a type III secretion system, are conserved among the Chlamydiae to variable degrees and together with differences in the composition of the cell wall reflect adaptation to different host cells including convergent evolution among the four chlamydial families. Phylogenomic analysis focusing on chlamydial proteins with homology to plant proteins provided evidence for the acquisition of 53 chlamydial genes by a plant progenitor, lending further support for the hypothesis of an early interaction between a chlamydial ancestor and the primary photosynthetic eukaryote.
Vaccination of Metastatic Melanoma Patients With Autologous Tumor-Derived Heat Shock Protein gp96-Peptide Complexes: Clinical and Immunologic Findings
Authors: Filiberto Belli, Alessandro Testori, Licia Rivoltini, Michele Maio, Giovanna Andreola, Mario Roberto Sertoli, Gianfrancesco Gallino, Adriano Piris, Alessandro Cattelan, Ivano Lazzari, Matteo Carrabba, Giorgio Scita, Cristina Santantonio, Lorenzo Pilla, Gabrina Tragni, Claudia Lombardo, Flavio Arienti, Alfonso Marchianò, Paola Queirolo, Francesco Bertolini, Agata Cova, Elda Lamaj, Lucio Ascani, Roberto Camerini, Marco Corsi, Natale Cascinelli, Jonathan J. Lewis, Pramod Srivastava, Giorgio Parmiani
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine the immunogenicity and antitumor activity of a vaccine consisting of autologous, tumor-derived heat shock protein gp96-peptide complexes (HSPPC-96, Oncophage; Antigenics, Inc, Woburn, MA) in metastatic (American Joint Committee on Cancer stage IV) melanoma patients. PATIENTS AND METHODS: Sixty-four patients had surgical resection of metastatic tissue required for vaccine production, 42 patients were able to receive the vaccine, and 39 were assessable after one cycle of vaccination (four weekly injections). In 21 patients, a second cycle (four biweekly injections) was given because no progression occurred. Antigen-specific antimelanoma T-cell response was assessed by enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Immunohistochemical analyses of tumor tissues were also performed. RESULTS: No treatment-related toxicity was observed. Of 28 patients with measurable disease, two had a complete response (CR) and three had stable disease (SD) at the end of follow-up. Duration of CR was 559+ and 703+ days, whereas SD lasted for 153, 191, and 272 days, respectively. ELISPOT assay with PBMCs of 23 subjects showed a significantly increased number of postvaccination melanoma-specific T-cell spots in 11 patients, with clinical responders displaying a high frequency of increased T-cell activity. Immunohistochemical staining of melanoma tissues from which vaccine was produced revealed high expression of both HLA class I and melanoma antigens in seven of eight clinical responders (two with CR, three with SD, and the three with long-term disease-free survival) and in four of 12 nonresponders. CONCLUSION: Vaccination of metastatic melanoma patients with autologous HSPPC-96 is feasible and devoid of significant toxicity. This vaccine induced clinical and tumor-specific T-cell responses in a significant minority of patients.
The Influence of Constrictor Drugs on the Distensibility of the Splanchnic Venous System, Analyzed on the Basis of an Aortic Model
Authors: ROBERT S. ALEXANDER
Journal: Circulation Research (1954)

The distensibility of the aorta was measured in anesthetized dogs by injecting blood at controlled rates into an isolated segment. Constrictor drugs produce a moderate increase in distensibility of the aorta at low pressure ranges and a more marked increase in distensibility at normal pressures. Studies of the splanchnic venous system of intestinal loops by the same method, and also by a method which does not require interruption in blood flow, gave evidence of the same type of distensibility phenomena as seen in the aorta, although at low pressures the venous distensibility tends to be actually decreased by vasoconstriction. The splanchnic venous system also differs from the aorta in that it is very dependent upon the rate of pressure-volume change. These results are analyzed in terms of the basic mechanisms involved and their physiologic implications.
Selenium, the Thyroid, and the Endocrine System
Authors: J. Köhrle, F. Jakob, B. Contempré, J. E. Dumont
Journal: Endocrine Reviews (2005)

Recent identification of new selenocysteine-containing proteins has revealed relationships between the two trace elements selenium (Se) and iodine and the hormone network. Several selenoproteins participate in the protection of thyrocytes from damage by H2O2 produced for thyroid hormone biosynthesis. Iodothyronine deiodinases are selenoproteins contributing to systemic or local thyroid hormone homeostasis. The Se content in endocrine tissues (thyroid, adrenals, pituitary, testes, ovary) is higher than in many other organs. Nutritional Se depletion results in retention, whereas Se repletion is followed by a rapid accumulation of Se in endocrine tissues, reproductive organs, and the brain. Selenoproteins such as thioredoxin reductases constitute the link between the Se metabolism and the regulation of transcription by redox sensitive ligand-modulated nuclear hormone receptors. Hormones and growth factors regulate the expression of selenoproteins and, conversely, Se supply modulates hormone actions. Selenoproteins are involved in bone metabolism as well as functions of the endocrine pancreas and adrenal glands. Furthermore, spermatogenesis depends on adequate Se supply, whereas Se excess may impair ovarian function. Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins.
Role of simulated repetitive coughing in mucus clearance
Authors: JM Zahm, M King, C Duvivier, D Pierrot, S Girod, E Puchelle
Journal: European Respiratory Journal (1991)

The role of repetitive simulated coughing on the clearance of gel mucus simulant was investigated in vitro, by using a simulated cough machine. The repetition of cough induced a significant increase (p less than 0.01) in mucus simulant clearance (139.3 +/- 78.7 mm) in comparison to a single cough (24.9 +/- 27.5 mm). Moreover, the increase in frequency of the repetitive coughing induced a marked and significant increase in mucus simulant clearance (75.4 +/- 51.1 mm and 139.3 +/- 78.7 mm at 0.1 Hz and 1.6 Hz frequency, respectively). A significant (p less than 0.05) correlation was observed between the percentage increase of clearance and both shear-thinning index (r = 0.62) and the thixotropic index (r = 0.63). These results suggest that the shear-dependent properties of mucus, associated with a repetitive coughing, may increase the efficiency of mucus clearance by air flow mechanisms.
Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging
Authors: Daisuke Nakano, Kent Doi, Hiroaki Kitamura, Takashige Kuwabara, Kiyoshi Mori, Masashi Mukoyama, Akira Nishiyama
Journal: Journal of the American Society of Nephrology (2015)

Urine output is widely used as a criterion for the diagnosis of AKI. Although several potential mechanisms of septic AKI have been identified, regulation of urine flow after glomerular filtration has not been evaluated. This study evaluated changes in urine flow in mice with septic AKI. The intratubular urine flow rate was monitored in real time by intravital imaging using two-photon laser microscopy. The tubular flow rate, as measured by freely filtered dye (FITC-inulin or Lucifer yellow), time-dependently declined after LPS injection. At 2 hours, the tubular flow rate was slower in mice injected with LPS than in mice injected with saline, whereas BP and GFR were similar in the two groups. Importantly, fluorophore-conjugated LPS selectively accumulated in the proximal tubules that showed reduced tubular flow at 2 hours and luminal obstruction with cell swelling at 24 hours. Delipidation of LPS or deletion of Toll-like receptor 4 in mice abolished these effects, whereas neutralization of TNF-α had little effect on LPS-induced tubular flow retention. Rapid intravenous fluid resuscitation within 6 hours improved the tubular flow rate only when accompanied by the dilation of obstructed proximal tubules with accumulated LPS. These findings suggest that LPS reduces the intratubular urine flow rate during early phases of endotoxemia through a Toll-like receptor 4-dependent mechanism, and that the efficacy of fluid resuscitation may depend on the response of tubules with LPS accumulation.
Forward programming of pluripotent stem cells towards distinct cardiovascular cell types
Authors: Robert David, Juliane Stieber, Evelyn Fischer, Stefan Brunner, Christoph Brenner, Susanne Pfeiler, Florian Schwarz, Wolfgang-Michael Franz
Journal: Cardiovascular Research (2009)

AimsThe proliferative potential of pluripotent stem cell-derived cardiomyocytes is limited, and reasonable yields for novel therapeutic options have yet to be achieved. In addition, various clinical applications will require the generation of specific cardiac cell types. Whereas early cardiovascular precursors appear to be important for novel approaches such as reseeding decellularized hearts, direct cell transplantation may require ventricular cells. Our recent work demonstrated that MesP1 represents a master regulator sufficient to induce cardiovasculogenesis in pluripotent cells. This led to our hypothesis that 'forward programming' towards specific subtypes may be feasible via overexpression of distinct early cardiovascular transcription factors.
Effects of airborne pollen levels on drug consumption for seasonal allergic rhinoconjunctivitis: A ten-year French study
Authors: Denis Caillaud, Sylvie Martin, Clarie Segala, Patricia Vidal, Jérome Lecadet, Paul Rouzaire, Arlette Tridon, Jean-Pierre Besancenot, Michel Thibaudon, Bertrand Evrard
Journal: European Respiratory Journal (2014)

Background : The aim of this study was to analyze the short-term relationship between pollen exposure and seasonal allergic rhinitis (SAR) using drug deliveries in Clermont-Ferrand (260,000 inhabitants).

Methods : A SAR case was defined as the association of an oral antihistamine and a local antiallergic drug on the same prescription. The relationship between daily changes in pollen concentrations and daily changes in the number of treated SAR cases was analyzed using generalized additive models, taking into account confounding factors.

Results : Between 2003-2012, the total yearly number and the yearly median number per day of treated SAR rose, from 7,265 to 11,315 and from 26 to 42. Relative risk of treated SAR (RR [95 CI]) associated with an interquartile increase in pollen concentration increased significantly for Fraxinus 1.01 [1.003-1.03], Betula 1.03 [1.01-1.05], Carpinus 1.02 [1.01-1.03], Platanus 1.04 [1.01-1.09], Poaceae 1.04 [1.038-1.05], Urticaceae whole season 1.02 [1.002-1.04] and Urticaceae first semester 1.17 [1.12-1.23]. Total Platanus and Carpinus pollen counts were low, < 1% of total airborne pollen concentration.

Conclusions : The prevalence of treated SAR rose around 55% in 10 years. While confirming the significant increase in treated SAR related to Fraxinus , Betula and Poaceae pollens, this study showed new association between treated SAR and Carpinus and Platanus pollens, although their total pollen counts were< 1% of total pollen counts; it also showed robust correlations with Urticaceae pollens, especially during first semester, suggesting potential allergenic role of Parietaria pollination in this urban mountainous area of central France.
Analysis of the TLR2 Signaling Pathway in Nasal Epithelial Cells from Patients with Chronic Rhinosinusitis (CRS)
Authors: L.C. Grammer, B. Tancowny, Q. Truong-Tran, J. Lee, A. Peters, K. Harris, D. Conley, R. Kern, R. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2007)
Syndrome of Ruptured Chordae Tendineae.
Authors: J. F. Uricchio
Journal: Annals of Internal Medicine (1961)

s1 May 1961Syndrome of Ruptured Chordae Tendineae.J. F. Uricchio, M.D., (Assoc.), H. T. Nichols, M.D.J. F. Uricchio, M.D., (Assoc.)Search for more papers by this author, H. T. Nichols, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-54-5-1041_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptRupture of the chordae tendineae is generally associated with previous bacterial endocarditis, myocardial infarction, and in rare instances trauma. The present report deals with a group of eight patients, five of whom presented a history of previous rheumatic fever. The unusual pathology was discovered during open heart surgery for correction of mitral regurgitation. The heavier cords which run from the ventricular surface of the cusps at varying distances from the free margins were those involved. In five cases, the chordae arising from the posterior papillary muscles and attached to the posterolateral half of the anterior septal leaflet were torn. "Flail"... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Philadelphia, Pa. (CS) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1961Volume 54, Issue 5Page: 1041-1041KeywordsEndocarditisMitral insufficiencyMyocardial infarctionOpen heart surgeryPapillary musclesRheumatic fever ePublished: 1 December 2008 Issue Published: 1 May 1961 PDF downloadLoading ...