tbuckley/cabot-search huggingface dataset:
Evidence That Phospholipid Oxidation Products and/or Platelet-Activating Factor Play an Important Role in Early Atherogenesis
Authors: Ganesamoorthy Subbanagounder, Norbert Leitinger, Peggy T. Shih, Kym F. Faull, Judith A. Berliner
Journal: Circulation Research (1999)

Abstract —The goal of the present studies was to determine whether phospholipid oxidation products and/or platelet-activating factor (PAF) are mediators of early atherogenesis in vivo. Monocyte–endothelial cell interactions have been shown to play an important role in early atherogenesis. We and others have demonstrated that PAF and phospholipid oxidation products, present in atherosclerotic lesions, including 1-palmitoyl-2-(5-oxovaleroyl)- sn -glycero-3-phosphocholine (POVPC), 1-palmitoyl-2-glutaroyl- sn -glycero-3-phosphocholine (PGPC), and 1-palmitoyl-2-epoxyisoprostane E 2 - sn -glycero-3-phosphocholine (PEIPC), mediate the activation of monocytes and/or endothelial cells in vitro. Previous studies have shown that the action of PAF and PAF-like ether-containing phospholipids was inhibited by WEB 2086. We now demonstrate that pretreatment of human aortic endothelial cells with WEB 2086 (10 μmol/L) and several other PAF antagonists before treatment with POVPC and PEIPC but not PGPC prevented the activation of the endothelial cells to bind monocytes. We present evidence to suggest that this inhibition is not mediated by the PAF receptor. The role of bioactive oxidized phospholipids in fatty streak formation was tested using C57BL/6J LDL R−/− mice fed a chow or Western diet for 5 weeks with or without WEB 2086 mixed with drinking water. Quantitative electrospray ionization mass spectrometry showed similar concentrations of WEB 2086 in the plasma of mice on both diets (≈4 to 5 μmol/L); this concentration was inhibitory in vitro. Administration of WEB 2086 did not affect the lipid composition of mouse plasma. However, fatty streak formation was reduced by 62% in animals fed a Western diet, whereas no change was observed in the small lesions of mice on a chow diet. These studies provide evidence that PAF and/or PAF-like phospholipid oxidation products are important mediators of atherosclerotic lesion development in vivo and that specific receptor antagonists for these molecules may represent a novel therapeutic modality.
Combinatorial Chemoprevention Reveals a Novel Smoothened-Independent Role of GLI1 in Esophageal Carcinogenesis
Authors: Sumera I. Ilyas, Cathrine J. DeMars, Andrea Comba, Vladimir G. Gainullin, Zaheer Rizvi, Luciana L. Almada, Kenneth Wang, Gwen Lomberk, Martin E. Fernández-Zapico, Navtej S. Buttar
Journal: Cancer Research (2010)

Abstract Reflux-induced injury promotes esophageal adenocarcinoma, one of the most rapidly increasing, highly lethal cancers in Western countries. Here, we investigate the efficacy of a combinatorial chemoprevention strategy for esophageal adenocarcinoma and characterize the underlying molecular mechanisms. Specifically, our approach involves the use of ursodeoxycholic acid (Urso) due to its ability to decrease injury-inducing bile salts in combination with Aspirin to mitigate the consequences of injury. We find that Urso-Aspirin combination reduces the risk of adenocarcinoma in vivo in animals with reflux, decreases the proliferation of esophageal adenocarcinoma cells, and downregulates a key cell cycle regulator, CDK2. Mechanistically, using cell growth, luciferase reporter, expression, and chromatin immunoprecipitation assays, we identify GLI1, a Hedgehog-regulated transcription factor, as a novel target of Urso-Aspirin combination. We show that GLI1 is upregulated during esophageal carcinogenesis, and GLI1 can bind to the CDK2 promoter and activate its expression. Although the Urso-Aspirin combination downregulates GLI1, the GLI1 overexpression not only abrogates the effect of this combination on proliferation but it also restores CDK-2 expression. These findings support that the chemopreventive effect of the Urso-Aspirin combination occurs, at least in part, through a novel GLI1-CDK2–dependent mechanism. To further understand the regulation of CDK2 by GLI1, both pharmacologic and RNAi-mediated approaches show that GLI1 is a transcriptional activator of CDK2, and this regulation occurs independent of Smoothened, the central transducer of the Hedgehog canonical pathway. Collectively, these results identify a novel GLI1-to-CDK2 pathway in esophageal carcinogenesis, which is a bona fide target for effective combinatorial chemoprevention with Urso and Aspirin. Cancer Res; 70(17); 6787–96. ©2010 AACR.
The α/β fold uracil DNA glycosylases: a common origin with diverse fates
Authors: L Aravind, Eugene V Koonin
Journal: Genome biology (2000)

Uracil DNA glycosylases (UDGs) are major repair enzymes that protect DNA from mutational damage caused by uracil incorporated as a result of a polymerase error or deamination of cytosine. Four distinct families of UDGs have been identified, which show very limited sequence similarity to each other, although two of them have been shown to possess the same structural fold. The structural and evolutionary relationships between the rest of the UDGs remain uncertain.Using sequence profile searches, multiple alignment analysis and protein structure comparisons, we show here that all known UDGs possess the same fold and must have evolved from a common ancestor. Although all UDGs catalyze essentially the same reaction, significant changes in the configuration of the catalytic residues were detected within their common fold, which probably results in differences in the biochemistry of these enzymes. The extreme sequence divergence of the UDGs, which is unusual for enzymes with the same principal activity, is probably due to the major role of the uracil-flipping caused by the conformational strain enacted by the enzyme on uracil-containing DNA, as compared with the catalytic action of individual polar residues. We predict two previously undetected families of UDGs and delineate a hypothetical scenario for their evolution.UDGs form a single protein superfamily with a distinct structural fold and a common evolutionary origin. Differences in the catalytic mechanism of the different families combined with the construction of the catalytic pocket have, however, resulted in extreme sequence divergence of these enzymes.
Increasing short-term cardiomyocyte progenitor cell (CMPC) survival by necrostatin-1 did not further preserve cardiac function
Authors: Dries Feyen, Roberto Gaetani, Jia Liu, Willy Noort, Anton Martens, Krista den Ouden, Pieter A. Doevendans, Joost P.G. Sluijter
Journal: Cardiovascular Research (2013)

AimsOne of the main limitations for an effective cell therapy for the heart is the poor cell engraftment after implantation, which is partly due to a large percentage of cell death in the hostile myocardium. In the present study, we investigated the utilization of necrostatin-1 (Nec-1) as a possible attenuator of cell death in cardiomyocyte progenitor cells (CMPCs).
Reduction of Health Status 7 Years After Addition of Chemotherapy to Craniospinal Irradiation for Medulloblastoma: A Follow-Up Study in PNET 3 Trial Survivors—on Behalf of the CCLG (formerly UKCCSG)
Authors: Kim S. Bull, Helen A. Spoudeas, Ghasem Yadegarfar, Colin R. Kennedy
Journal: Journal of Clinical Oncology (2007)

Purpose To compare quality of survival after craniospinal irradiation (CSI) alone with survival after CSI plus chemotherapy (CT) for medulloblastoma. Patients and Methods Follow-up study of surviving UK patients with medulloblastoma diagnosed between 1992 and 2000 treated according to one or other treatment arm of the PNET 3 controlled trial. Results Seventy three percent of all 147 eligible patients ages 6.6 to 24.3 years were assessed at a mean of 7.2 years after diagnosis. Health status was significantly poorer in the group treated in the CSI plus CT arm of the trial than in the CSI alone arm, and there were also trends to poorer outcomes for behavior and quality of life scores. The CSI plus CT group were also significantly more restricted physically and needed more therapeutic and educational support. Body mass index, stature, and other endocrine outcomes were similar in the two treatment arms, except for the trend in increased frequency of medical induction of puberty in the CSI plus CT group. Conclusion The addition of CT to CSI for medulloblastoma was associated with a significant decrease in health status. The effect of the addition of other CT regimens to CSI on quality of survival should be evaluated.
Red cell survival after homograft replacement of the aortic valve
Authors: M. H. Yacoub, M. Kothari, D. Keeling, M. Patterson, D. N. Ross
Journal: Thorax (1969)

Red cell survival was studied in 21 patients following homograft replacement of the aortic valve. Autologous cells labelled with <sup>51</sup>Cr were used. The T½ <sup>51</sup>Cr varied between 24 and 34 days, with only one patient below the normal limit of normal variations. The absence of haemolysis was confirmed by other haematological studies, including estimation of reticulocytes, serum lactic dehydrogenase, and urinary haemosiderin. Haptoglobin levels were low in most of the patients studied. In contrast to prosthetic valves there was no haemolysis in patients with regurgitation around or through the homograft valve.
Hormesis: The Dose-Response Revolution
Authors: Edward J. Calabrese, Linda A. Baldwin
Journal: The Annual Review of Pharmacology and Toxicology (2003)

Hormesis, a dose-response relationship phenomenon characterized by low-dose stimulation and high-dose inhibition, has been frequently observed in properly designed studies and is broadly generalizable as being independent of chemical/physical agent, biological model, and endpoint measured. This under-recognized and -appreciated concept has the potential to profoundly change toxicology and its related disciplines with respect to study design, animal model selection, endpoint selection, risk assessment methods, and numerous other aspects, including chemotherapeutics. This article indicates that as a result of hormesis, fundamental changes in the concept and conduct of toxicology and risk assessment should be made, including (a) the definition of toxicology, (b) the process of hazard (e.g., including study design, selection of biological model, dose number and distribution, endpoint measured, and temporal sequence) and risk assessment [e.g., concept of NOAEL (no observed adverse effect level), low dose modeling, recognition of beneficial as well as harmful responses] for all agents, and (c) the harmonization of cancer and noncancer risk assessment.
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response
Authors: Evandro de Azambuja, Andrew P Holmes, Martine Piccart-Gebhart, Eileen Holmes, Serena Di Cosimo, Ramona F Swaby, Michael Untch, Christian Jackisch, Istvan Lang, Ian Smith, Frances Boyle, Binghe Xu, Carlos H Barrios, Edith A Perez, Hatem A Azim, Sung-Bae Kim, Sherko Kuemmel, Chiun-Sheng Huang, Peter Vuylsteke, Ruey-Kuen Hsieh, Vera Gorbunova, Alexandru Eniu, Lydia Dreosti, Natalia Tavartkiladze, Richard D Gelber, Holger Eidtmann, José Baselga
Journal: The Lancet Oncology (2014)
Platelet-Derived Stromal Cell–Derived Factor-1 Regulates Adhesion and Promotes Differentiation of Human CD34 <sup>+</sup> Cells to Endothelial Progenitor Cells
Authors: Konstantinos Stellos, Harald Langer, Karin Daub, Tanja Schoenberger, Alexandra Gauss, Tobias Geisler, Boris Bigalke, Iris Mueller, Michael Schumm, Iris Schaefer, Peter Seizer, Bjoern F. Kraemer, Dorothea Siegel-Axel, Andreas E. May, Stephan Lindemann, Meinrad Gawaz
Journal: Circulation (2007)

Background— Peripheral homing of progenitor cells in areas of diseased organs is critical for tissue regeneration. The chemokine stromal cell–derived factor-1 (SDF-1) regulates homing of CD34 + stem cells. We evaluated the role of platelet-derived SDF-1 in adhesion and differentiation of human CD34 + cells into endothelial progenitor cells. Methods and Results— Adherent platelets express substantial amounts of SDF-1 and recruit CD34 + cells in vitro and in vivo. A monoclonal antibody to SDF-1 or to its counterreceptor, CXCR4, inhibits stem cell adhesion on adherent platelets under high arterial shear in vitro and after carotid ligation in mice, as determined by intravital fluorescence microscopy. Platelets that adhere to human arterial endothelial cells enhance the adhesion of CD34 + cells on endothelium under flow conditions, a process that is inhibited by anti-SDF-1. During intestinal ischemia/reperfusion in mice, anti-SDF-1 and anti-CXCR4, but not isotype control antibodies, abolish the recruitment of CD34 + cells in microcirculation. Moreover, platelet-derived SDF-1 binding to CXCR4 receptor promotes platelet-induced differentiation of CD34 + cells into endothelial progenitor cells, as verified by colony-forming assays in vitro. Conclusions— These findings imply that platelet-derived SDF-1 regulates adhesion of stem cells in vitro and in vivo and promotes differentiation of CD34 + cells to endothelial progenitor cells. Because tissue regeneration depends on recruitment of progenitor cells to peripheral vasculature and their subsequent differentiation, platelet-derived SDF-1 may contribute to vascular and myocardial regeneration.
Elevated Levels of the Angiogenic Peptide Basic Fibroblast Growth Factor in Urine of Bladder Cancer Patients
Authors: M. Nguyen, H. Watanabe, A. E. Budson, J. P. Richie, J. Folkman
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Elevated Levels of the Angiogenic Peptide Basic Fibroblast Growth Factor in Urine of Bladder Cancer Patients Get access Mai Nguyen, Mai Nguyen Department of Surgery, Children's Hospital, and Brigham and Women's Hospital, Harvard Medical SchoolBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Hiroyuki Watanabe, Hiroyuki Watanabe Department of Surgery, Children's Hospital, Boston, and Takeda Chemical Industries, Ltd.Osaka, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Andrew E. Budson, Andrew E. Budson Department of Surgery, Children's Hospital Search for other works by this author on: Oxford Academic PubMed Google Scholar Jerome P. Richie, Jerome P. Richie Department of Surgery, Brigham and Women's Hospital, and Department of Urology, Harvard Medical School Search for other works by this author on: Oxford Academic PubMed Google Scholar Judah Folkman Judah Folkman Department of Surgery, Children's Hospital, and Departments of Surgery and Anatomy and Cellular Biology, Harvard Medical School Correspondence to : Judah Folkman, M.D., Children's Hospital, Hunnewell 103, 300 Longwood Ave., Boston, MA 02115. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 3, 3 February 1993, Pages 241–242, https://doi.org/10.1093/jnci/85.3.241 Published: 03 February 1993 Article history Received: 20 October 1991 Revision received: 13 November 1992 Accepted: 18 November 1992 Published: 03 February 1993
The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects
Authors: M A Hurchla, A Garcia-Gomez, M C Hornick, E M Ocio, A Li, J F Blanco, L Collins, C J Kirk, D Piwnica-Worms, R Vij, M H Tomasson, A Pandiella, J F San Miguel, M Garayoa, K N Weilbaecher
Journal: Leukemia (2012)
Human β-myosin heavy chain mRNA prevalence is inversely related to the degree of methylation of regulatory elements
Authors: C Clifford
Journal: Cardiovascular Research (1998)

Methylation of cytosine in CG dinucleotides within regulatory elements is believed to silence gene expression. These dinucleotides occur in certain important regulatory elements in the promoter region of the human beta-myosin heavy chain (beta-MHC) gene. We therefore investigated whether methylation of these elements correlates with beta-MHC gene transcription in human 'expressing' (right atrial) and 'non-expressing' (peripheral blood leucocytes) cells.We employed 2 techniques to assess promoter methylation: (i) analysis of the susceptibility to digestion of a particular CCGG restriction site in the promoter region when genomic DNA is cleaved with the restriction endonucleases MspI (methylation-insensitive) and HpaII (methylation-sensitive), and (ii) the bisulphite-PCR method to examine in detail the methylation patterns of 3 important regulatory elements that contain CG dinucleotides. beta-MHC mRNA expression in right atrium and leucocytes was assessed using reverse-transcription-PCR with specific primers that do not detect alpha-MHC cDNA.The digestion pattern observed with MspI or HpaII indicated that the CCGG site was almost completely methylated in leucocytes, but relatively unmethylated in atrial myocardium from the same patients. When methylation was examined with the bisulphite-PCR method we found a reciprocal relationship between the level of beta-MHC mRNA expression in leucocytes and atrial myocardium and the degree of methylation of CG dinucleotides in the 5' regulatory elements of the gene.Tissue-specific methylation of the human beta-MHC gene promoter may play a role in determining the pattern of expression of this gene. Furthermore, alteration of the level of methylation may underlie the changes in transcription of this gene that occur, for example, when atrial or ventricular myocardium hypertrophies.
Vaccine-Type Pneumococcal Pneumonia
Authors: G. Scott Giebink
Journal: JAMA (1979)

SPLENECTOMIZED individuals are at high risk for development of life-threatening pneumococcal bacteremia,<sup>1</sup>and pneumococcal polysaccharide vaccine has been recommended for these patients. While splenectomized patients have shown normal antibody responses to the polyvalent vaccines,<sup>2,3</sup>defined by at least twofold rises in type-specific antibody level, protective levels of these antibodies are not known. This report describes a splenectomized patient in whom vaccine-type pneumococcal pneumonia developed 20 months after polyvalent pneumococcal vaccination. <h3>Report of a Case</h3> A 26-year-old woman was hospitalized on June 24,1978, with a 12-hour history of left pleuritic chest pain and dyspnea preceded by ten days of mild chest pain associated with a nonproductive cough and sore throat. Twenty-two years previously, she had had a splenectomy for familial nonimmune hemolytic anemia, which also affected her mother, all three of her natural siblings, one of three half-siblings, and three of her four nephews. Twenty-one and again 16 years
Colonic short chain fatty acids mediate jejunal growth by increasing gastrin.
Authors: K J Reilly, W L Frankel, A M Bain, J L Rombeau
Journal: Gut (1995)

Colonic infusion of short chain fatty acids (SCFAs) is trophic to rat jejunum and is associated with raised jejunal gastrin concentration. This study examined the hypothesis that the jejunal trophic effects of colonic SCFAs are mediated in part by gastrin. Forty six adult rats underwent caecectomy to reduce endogenous production of SCFA, ileocolonic anastomosis, and placement of a colonic infusion catheter. SCFA (70 mM acetate, 35 mM propionate, 20 mM butyrate) or saline were continuously infused into the colon for seven days. Rats received either a gastrin receptor blocker (L-365,260) or a control solution and animals were killed on day 8. SCFA infused into the colon acted systemically to significantly improve jejunal structure and increase jejunal gastrin concentrations. Gastrin receptor blockade abolished effects of SCFA on jejunal DNA, protein, crypt cell proliferation, and gastrin. Gastrin blockade did not reduce SCFA induced augmentation of villous height or crypt depth. It is concluded that the jejunal trophic effects of colonically infused SCFA are mediated in part by gastrin.
Targeted Cytosine Deaminase-Uracil Phosphoribosyl Transferase Suicide Gene Therapy Induces Small Cell Lung Cancer–Specific Cytotoxicity and Tumor Growth Delay
Authors: Camilla L. Christensen, Torben Gjetting, Thomas T. Poulsen, Frederik Cramer, Jack A. Roth, Hans S. Poulsen
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug. Experimental design: The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1). Therapeutic effect was evaluated in vitro in SCLC cell lines and in vivo in SCLC xenografted nude mice using the nonviral nanoparticle DOTAP/cholesterol for transgene delivery. Results: INSM1-YCD/5-FC and INSM1-YCD-YUPRT/5-FC therapy induced high cytotoxicity in a range of SCLC cell lines. The highest therapeutic effect was obtained from the YCD-YUPRT fusion gene strategy. No cytotoxicity was induced after treatment of cell lines of other origin than SCLC. In addition the INSM1-YCD-YUPRT/5-FC therapy was superior to an established suicide gene system consisting of the herpes simplex virus thymidine kinase (HSVTK) gene and the prodrug ganciclovir. The superior effect was in part due to massive bystander cytotoxicity of YCD-YUPRT-produced toxins. Finally, INSM1-YCD-YUPRT/5-FC therapy induced significant tumor growth delay in SCLC xenografts compared with control-treated xenografts. Conclusions: The current study is the first to test cytosine deaminase-based suicide gene therapy for SCLC and the first to show an antitumor effect from the delivery of suicide gene therapeutics for SCLC in vivo. Clin Cancer Res; 16(8); 2308–19. ©2010 AACR.
ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo
Authors: Hiromi Abe, Michio Imamura, Nobuhiko Hiraga, Masataka Tsuge, Fukiko Mitsui, Tomokazu Kawaoka, Shoichi Takahashi, Hidenori Ochi, Toshiro Maekawa, C. Nelson Hayes, Chise Tateno, Katsutoshi Yoshizato, Shoichi Murakami, Nobuyuki Yamashita, Takashi Matsuhira, Kenji Asai, Kazuaki Chayama
Journal: Journal of Hepatology (2010)
Heterogeneity of small airways flow and hyperinflation are markers of a persistent obstruction phenotype in severe non-controlled asthmatics
Authors: Regina Maria Carvalho-Pinto, Alberto Cukier, Luciene Angelini, Frederico Leon Arrabal Fernandes, João Marcos Salge, Rafael Stelmach
Journal: European Respiratory Journal (2012)

Persistent functional impairment in some severe asthmatics,even after maximal treatment, is usually linked to inflammation, which does not explain all asthma limitations and seems to be determined by small airways structural changes too.

Objective: Evaluate functional mechanisms related to persistent airflow obstruction (PAO) after an intensive therapeutic regimen in severe asthmatics.

Methods: Non-controlled severe asthmatics received high inhaled corticosteroid dose (ICs) plus LABA for 12 weeks and oral corticosteroid (OC) in the first two weeks, after which they were classified into PAO by an FEV1 after BD 10 pack-years were excluded.

Results: At baseline, FEF2575, RV/TLC and resistance (Raw) were significant different between NPAO and PAO.

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All PAO values, including Slope of phase III of the single breath nitrogen washout test (dN2), became different after OC and did not return to normal. ACQ in NPAO decreased to near normal values (1.75±0.94).

Conclusion: Persistent obstruction phenotype in severe asthmatics showed a high heterogeneity of airflow measured by dN2 and early airway closure due to high RV/TLC suggesting a fixed impairment in small airways. VEF1 changes in these patients seem to be influenced by small airway disease. PAO also impairs improvement in asthma control scores.