Sample records for nancy cox alan

  1. Nancy Drew and her Rivals: No Contest.

    ERIC Educational Resources Information Center

    MacLeod, Anne Scott

    1987-01-01

    Continues an examination of the Nancy Drew series, finding in the character of the young female detective Nancy evidence of autonomy and of a profound but covert feminism that is not present in the many imitations of the series that appeared later. (NKA)

  2. Nancy's Story.

    ERIC Educational Resources Information Center

    Sallans, Dennis

    1999-01-01

    Nancy's recent psychotic episode left her an anxious, fearful person. Participating in an adventure therapy program enabled her to connect with peers, regain social skills and physical stamina, adjust to a full-day activity, regain her confidence, reconstruct purpose and meaning in life, and follow through on plans to complete university and get a…

  3. Alan Wright | NREL

    Science.gov Websites

    , Alan is the technical lead and project leader for the Advanced Controls Task. Under Alan's direction , NREL has become a world leader in the development and testing of advanced controls for wind turbine load mitigation and enhanced energy capture and performed the world's first field tests of advanced

  4. Alan Bean Art Exhibit

    NASA Image and Video Library

    2009-07-19

    NASA Apollo 12 Astronaut and Artist Alan Bean gives remarks at the opening of the exhibit "Alan Bean: Painting Apollo, First Artist on Another World" at the National Air and Space Museum, Monday, July 20, 2009 in Washington. The show opening coincided with the 40th anniversary celebration of Apollo. Photo Credit: (NASA/Bill Ingalls)

  5. Alan Bean Art Exhibit

    NASA Image and Video Library

    2009-07-19

    Guest view works of art by NASA Apollo 12 Astronaut and Artist Alan Bean during the opening of the show "Alan Bean: Painting Apollo, First Artist on Another World" at the National Air and Space Museum, Monday, July 20, 2009 in Washington. The show opening coincided with the 40th anniversary celebration of Apollo. Photo Credit: (NASA/Bill Ingalls)

  6. Botanical reconnaissance of Nancy Brook Research Natural Area

    Treesearch

    Joshua L. Royte; Daniel D. Sperduto; John P. Lortie

    1996-01-01

    A survey of the flora and natural communities of Nancy Brook Research Natural Area, Crawford Notch, White Mountain National Forest, New Hampshire, was conducted during the summer and fall of 1992. Nancy Brook Research Natural Area is noted for being the largest virgin mountain spruce forest in New Hampshire, and one of the few remaining large examples in the...

  7. Alan Bean Art Exhibit

    NASA Image and Video Library

    2009-07-19

    NASA Apollo 7 Astronaut Walt Cunningham, left, and NASA STS-125 Mission Specialist Michael Massimino talk with another guest during the opening of "Alan Bean: Painting Apollo, First Artist on Another World" by NASA Apollo 12 Astronaut and Artist Alan Bean at the National Air and Space Museum, Monday, July 20, 2009 in Washington. The show opening coincided with the 40th anniversary celebration of Apollo. Photo Credit: (NASA/Bill Ingalls)

  8. Low-Cost alpha Alane for Hydrogen Storage

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fabian, Tibor; Petrie, Mark; Crouch-Baker, Steven

    This project was directed towards the further development of the Savannah River National Laboratory (SRNL) lab-scale electrochemical synthesis of the hydrogen storage material alpha-alane and Ardica Technologies-SRI International (SRI) chemical downstream processes that are necessary to meet DoE cost metrics and transition alpha-alane synthesis to an industrial scale. Ardica has demonstrated the use of alpha-alane in a fuel-cell system for the U.S. Army WFC20 20W soldier power system that has successfully passed initial field trials with individual soldiers. While alpha-alane has been clearly identified as a desirable hydrogen storage material, cost-effective means for its production and regeneration on a scalemore » of use applicable to the industry have yet to be established. We focused on three, principal development areas: 1. The construction of a comprehensive engineering techno-economic model to establish the production costs of alpha-alane by both electrochemical and chemical routes at scale. 2. The identification of critical, cost-saving design elements of the electrochemical cell and the quantification of the product yields of the primary electrochemical process. A moving particle-bed reactor design was constructed and operated. 3. The experimental quantification of the product yields of candidate downstream chemical processes necessary to produce alpha-alane to complete the most cost-effective overall manufacturing process. Our techno-economic model shows that under key assumptions most 2015 and 2020 DOE hydrogen storage system cost targets for low and medium power can be achieved using the electrochemical alane synthesis process. To meet the most aggressive 2020 storage system cost target, $1/g, our model indicates that 420 metric tons per year (MT/y) production of alpha-alane is required. Laboratory-scale experimental work demonstrated that the yields of two of the three critical component steps within the overall “electrochemical process” were

  9. Schooling and Social Justice through the Lenses of Nancy Fraser

    ERIC Educational Resources Information Center

    Keddie, Amanda

    2012-01-01

    This review essay draws on Nancy Fraser's work as featured in "Adding insult to injury: Nancy Fraser debates her critics" to explore issues of schooling and social justice. The review focuses on the applicability and usefulness of Fraser's three-dimensional model for understanding matters of justice in education. It begins with an overview of the…

  10. Nancy Kassebaum: Education's New Voice.

    ERIC Educational Resources Information Center

    Penning, Nick

    1989-01-01

    U.S. Senator Nancy Kassebaum has become the leading Republican advocate for education. She shares AASA's support for the Head Start program, but is skeptical about financing a federal day care program. She also supports latchkey, intergenerational, and vocational/technical programs, and favors community volunteering over a national youth service…

  11. [Pharmacy students proceeding from Alsace and Moselle to Nancy between 1872 and 1914].

    PubMed

    Labrude, Pierre; Remmel, François-Xavier

    2004-01-01

    Because of the war against Prussia, the school of pharmacy of Strasbourg was transfered to Nancy in 1872 with some of its professor. These professors are generally well known, but it is not the same for students who came from annexed departments to Nancy for studying pharmacy between 1872 and 1914. The archives stored in Nancy show that, during these fourty years, the quarter of pharmacy students in Nancy were native of Alsace or Moselle. We specify their number for each year after annexation. Some situations, illustrated by examples, are possible: young men who came in France before annexation, students who came with their family when they were children, pharmacists with a diploma obtained in Strasbourg having the wish to emigrate in France some years later. Our results lead to questions whose answers are difficult to formulate and would perhaps justify another study: what were the reasons for the obtaining of the french pharmacist diploma ?, what was the professional activity of these pharmacists ?, what was their posture during the First World War, did some of them return to Alsace or Moselle after the war? Whatever the answers, the presence of these < Alsaciens-Lorrains > students was significant and precious for the school of pharmacy of Nancy at this period.

  12. Hydrogen Sorption Properties of Potassium Alanate

    NASA Astrophysics Data System (ADS)

    Matysina, Z. A.; Zaginaichenko, S. Yu.; Schur, D. V.; Zolotarenko, Al. D.; Zolotarenko, An. D.; Gabdulin, M. T.

    2018-06-01

    Molecular kinetic representations were used to develop the statistical theory of phase transformations of thermal decomposition of KAlH4 potassium alanate with formation of a more complex K3AlH6 alanate and KH potassium hydride and subsequent dehydrogenation of the latter accompanied with free hydrogen, pure potassium and aluminum yield. Temperature dependence of the emitted free hydrogen was established. Isotherms and isopleths were built. The possibility of hysteresis effect manifestation was established. The results of calculations were compared to the experimental data.

  13. Nancy McCormick Rambusch: A Reflection

    ERIC Educational Resources Information Center

    Povell, Phyllis

    2005-01-01

    Fall of 2005 marks the 12th anniversary of Nancy McCormick Rambusch's death. As the founder of the American Montessori Society and as its first president, Rambusch reintroduced Maria Montessori to America at a time--1960--when education for the young was floundering, and a second look at the Montessori method, which had changed the early childhood…

  14. Nancy Rivard. The color of love.

    PubMed

    2002-12-01

    Nancy Rivard's personal journey to be a part of something bigger than herself resulted in the founding of Airline Ambassadors International (AAI). As a flight attendant for American Airlines, she enrolled the industry through a large-scale volunteer effort and established Airline Ambassadors, whose programs have delivered school supplies, food, medicine, and medical supplies to upwards of 100,000 children in 25 nations.

  15. Once a physicist: Alan Pierson

    NASA Astrophysics Data System (ADS)

    2016-08-01

    Alan Pierson is artistic director and conductor of the New York-based contemporary-music ensemble Alarm Will Sound, and a professor of conducting at Northwestern University's Bienen School of Music in Illinois

  16. The Enunciation of the Subject: Sharing Jean-Luc Nancy's Singular Plural in the Classroom

    ERIC Educational Resources Information Center

    Collins, Ashok

    2015-01-01

    This article seeks to explore the implications of Jean-Luc Nancy's reading of the subject for educational philosophy by connecting his re-interpretation of Descartes to his later thinking on what he names the ontological singular plural. Nancy's re-imagining of the Cogito coalesces around the figure of the mouth ("la bouche") through…

  17. Wreath Laying Ceremony for Alan Bean

    NASA Image and Video Library

    2018-05-30

    Members of the news media assemble to cover a ceremony on Wednesday, May 30, 2018, during which a memorial wreath is placed in the Apollo-Saturn V Center of the Kennedy Space Center Visitor Complex honoring former NASA astronaut Alan Bean. In the background is a large mural of a painting by Alan Bean who became an accomplished artist after leaving NASA. Bean was the fourth person to walk on the Moon as lunar module pilot on Apollo 12 in November 1969. He went on to command the 59-day Skylab 3 mission in 1973. He died in Houston on May 26, 2018, at the age of 86.

  18. Methods for synthesizing alane without the formation of adducts and free of halides

    DOEpatents

    Zidan, Ragaiy; Knight, Douglas A; Dinh, Long V

    2013-02-19

    A process is provided to synthesize an alane without the formation of alane adducts as a precursor. The resulting product is a crystallized .alpha.-alane and is a highly stable product and is free of halides.

  19. Alan Bean Art Exhibit

    NASA Image and Video Library

    2009-07-19

    Former NASA Astronaut and U.S. Senator John Glenn is seen at the opening of the exhibit "Alan Bean: Painting Apollo, First Artist on Another World" at the National Air and Space Museum, Monday, July 20, 2009 in Washington. The show opening coincided with the 40th anniversary celebration of Apollo. Photo Credit: (NASA/Carla Cioffi)

  20. Comments on Nancy Snow, "Generativity and Flourishing"

    ERIC Educational Resources Information Center

    Kamtekar, Rachana

    2015-01-01

    In her rich and wide-ranging paper, Nancy Snow argues that there is a virtue of generativity--an other-regarding desire to invest one's substance in forms of life and work that will outlive the self (p. 10). By "virtue" Snow means not just a desirable or praiseworthy quality of a person, but more precisely, as Aristotle defined it, a…

  1. Portrait of Astronaut Alan L. Bean

    NASA Technical Reports Server (NTRS)

    1969-01-01

    Portrait of Astronaut Alan L. Bean, Prime Crew Lunar Module Pilot of the Apollo 12 Lunar Landing Mission, in his space suit minus the helmet. He is standing outside beside a mock-up of the Lunar Lander.

  2. Editors' overview for the Alan Turner Memorial volume

    NASA Astrophysics Data System (ADS)

    O'Regan, Hannah J.; Elton, Sarah; Schreve, Danielle

    2014-07-01

    The papers presented here, in this special volume dedicated to the memory of Alan Turner (1947-2012), provide a glimpse of the multi-faceted ways in which the mammalian fossil record can be investigated. The authors of contributions in this Special Issue are by no means an exhaustive list of his international collaborators and colleagues, and indeed, many are not represented here, but the contents cover many of the topics and issues that were of central archaeological and wider Quaternary mammalian interest to Alan. Although the papers are not intended to provide a comprehensive overview of all techniques that can be applied, the set nevertheless reveals a snapshot of the state-of-the-art and of some of the methods that have the potential to bring much more of the past to life. Alan always sought to move beyond the 'stamp-collecting' approach of simply listing which taxa were present at a site, attempting to elucidate what the presence of those animals might mean in terms of palaeoecology. In particular, the span of Alan's career has seen major advances in our understanding of Quaternary mammalian biostratigraphy and palaeobiogeography, the widespread application of novel techniques such as ancient DNA, the development of high-precision geochronology and the discovery of new hominin species. The papers presented here reflect those developments and highlight interdisciplinary approaches, from examination of sediments to careful measurements of the fossils themselves, from modelling the presence of taxa at particular points in the Quaternary to examination of the similarities and differences in fauna within and between sites.

  3. Obituary: Alan D. Fiala (1942-2010)

    NASA Astrophysics Data System (ADS)

    Kaplan, George

    2011-12-01

    Dr. Alan Dale Fiala, astronomer and expert on solar eclipses, died on May 26, 2010 in Arlington, Virginia, of respiratory failure after a brief illness. He was 67. Fiala had been a staff astronomer at the U.S. Naval Observatory in Washington, D.C., for his entire professional career, where he rose from a position as a summer intern to become the Chief of the Nautical Almanac Office, responsible for annual publications for astronomy and navigation that are used the world over. He retired from the observatory in 2000. Although a childhood case of polio affected his mobility for the rest of his life, he seldom let his physical constraints limit his activities, which were many and varied. Alan Fiala was born in Beatrice, Nebraska on November 9, 1942, the middle son of Emil A. ("John") and Lora Marie Fiala. Fiala's father was a postal clerk and Civil Service examiner. Fiala expressed interest in astronomy at a very young age. He contracted polio when he was 9. He graduated from Beatrice High School in 1960 with a straight-A average and went on to study at Carleton College. He received his B.A. summa cum laude after three years, in 1963, with a major in astronomy and minors in physics and mathematics. He was elected to Phi Beta Kappa, Sigma Xi, and Pi Mu Epsilon (mathematics). In 1962, Alan Fiala obtained a job as a summer intern at the Naval Observatory in Washington, working in the Nautical Almanac Office (NAO). He entered the graduate program at Yale University and continued to work summers at the observatory. He received his Ph.D. in 1968, under Gerald Clemence. His dissertation was titled "Determination of the Mass of Jupiter from a Study of the Motion of 57 Mnemosyne." After receiving his doctorate, Fiala became a permanent member of the Naval Observatory staff. Computers were just being introduced there and he participated in the automation of many procedures used to prepare the annual publications of the Nautical Almanac Office. One of his first assignments was

  4. For Dr. Nancy Snyderman's Parents, Staying Close to Family Is Key

    MedlinePlus

    ... Issues Feature: Senior Living For Dr. Nancy Snyderman's Parents, Staying Close to Family Is Key Past Issues / ... home. "Watching my children grow closer to my parents has been a blessing, and having us nearby ...

  5. Nancy Huston's Polyglot Texts: Linguistic Limits and Transgressions

    ERIC Educational Resources Information Center

    Waite, Genevieve

    2015-01-01

    Throughout her career, Nancy Huston has both accepted and transgressed the limits of bilingualism. "Limbes"/"Limbo" (1998), "L'empreinte de l'ange" (1998), "The Mark of the Angel" (2000), "Danse noire" (2013), and "Black Dance" (2014) are five texts that demonstrate Huston's diverse use…

  6. Thermochemistry of Alane Complexes for Hydrogen Storage: A Theoretical and Experimental Investigation

    PubMed Central

    2011-01-01

    Knowledge of the relative stabilities of alane (AlH3) complexes with electron donors is essential for identifying hydrogen storage materials for vehicular applications that can be regenerated by off-board methods; however, almost no thermodynamic data are available to make this assessment. To fill this gap, we employed the G4(MP2) method to determine heats of formation, entropies, and Gibbs free energies of formation for 38 alane complexes with NH3−nRn (R = Me, Et; n = 0−3), pyridine, pyrazine, triethylenediamine (TEDA), quinuclidine, OH2−nRn (R = Me, Et; n = 0−2), dioxane, and tetrahydrofuran (THF). Monomer, bis, and selected dimer complex geometries were considered. Using these data, we computed the thermodynamics of the key formation and dehydrogenation reactions that would occur during hydrogen delivery and alane regeneration, from which trends in complex stability were identified. These predictions were tested by synthesizing six amine−alane complexes involving trimethylamine, triethylamine, dimethylethylamine, TEDA, quinuclidine, and hexamine and obtaining upper limits of ΔG° for their formation from metallic aluminum. Combining these computational and experimental results, we establish a criterion for complex stability relevant to hydrogen storage that can be used to assess potential ligands prior to attempting synthesis of the alane complex. On the basis of this, we conclude that only a subset of the tertiary amine complexes considered and none of the ether complexes can be successfully formed by direct reaction with aluminum and regenerated in an alane-based hydrogen storage system. PMID:22962624

  7. Award for Distinguished Scientific Applications of Psychology: Nancy E. Adler

    ERIC Educational Resources Information Center

    American Psychologist, 2009

    2009-01-01

    Nancy E. Adler, winner of the Award for Distinguished Scientific Applications of Psychology, is cited for her research on reproductive health examining adolescent decision making with regard to contraception, conscious and preconscious motivations for pregnancy, and perception of risk for sexually transmitted diseases, and for her groundbreaking…

  8. Nancy Colburn Retires after 36 Years, Becomes Scientist Emeritus | Poster

    Cancer.gov

    By Ashley DeVine, Staff Writer Although Nancy Colburn, Ph.D., retired in January after 36 years at NCI, she won’t be disappearing from the NCI campus at Frederick anytime soon; she’s been appointed scientist emeritus in the Laboratory of Cancer Prevention (LCP), Center for Cancer Research (CCR).

  9. 77 FR 37074 - License Amendment Request From the Alan J. Blotcky Reactor Facility

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-20

    ... the Alan J. Blotcky Reactor Facility AGENCY: Nuclear Regulatory Commission. ACTION: Notice of... section of this document. FOR FURTHER INFORMATION CONTACT: Theodore Smith, Project Manager, Reactor... provided the first time that a document is referenced. The Alan J. Blotcky Reactor Facility Decommissioning...

  10. Towards direct synthesis of alane: A predicted defect-mediated pathway confirmed experimentally

    DOE PAGES

    Wang, Lin -Lin; Herwadkar, Aditi; Reich, Jason M.; ...

    2016-08-18

    Here, alane (AlH 3) is a unique energetic material that has not found a broad practical use for over 70 years because it is difficult to synthesize directly from its elements. Using density functional theory, we examine the defect-mediated formation of alane monomers on Al(111) in a two-step process: (1) dissociative adsorption of H 2 and (2) alane formation, which are both endothermic on a clean surface. Only with Ti dopant to facilitate H 2 dissociation and vacancies to provide Al adatoms, both processes become exothermic. In agreement, in situ scanning tunneling microscopy showed that during H 2 exposure, alanemore » monomers and clusters form primarily in the vicinity of Al vacancies and Ti atoms. Moreover, ball milling of the Al samples with Ti (providing necessary defects) showed a 10 % conversion of Al into AlH 3 or closely related species at 344 bar H 2, indicating that the predicted pathway may lead to the direct synthesis of alane from elements at pressures much lower than the 104 bar expected from bulk thermodynamics.« less

  11. SHEPARD, ALAN B., JR. ASTRONAUT - WASHINGTON, DC

    NASA Image and Video Library

    1963-05-06

    S63-06268 (8 May 1963) --- Astronaut Alan B. Shepard, Jr., receives his NASA's Distinguished Service Medal from President John F. Kennedy, after his Mercury-Redstone 3 (MR-3) flight, in a Rose Garden ceremony on May 8, 1961 at the White House.

  12. Bilingualism and Emotion in the Autobiographical Works of Nancy Huston

    ERIC Educational Resources Information Center

    Kinginger, Celeste

    2004-01-01

    Research on the links between bilingualism and emotion suggests that when a second language is learned postpuberty or in adulthood, the two languages of an individual may differ in their emotional impact. The works of bilingual writer Nancy Huston offer unique insight into the process of ascribing differential emotional value to first and second…

  13. Astronaut Alan Bean participates in lunar surface simulation

    NASA Technical Reports Server (NTRS)

    1969-01-01

    Astronaut Alan L. Bean, lunar module pilot of the Apollo 12 lunar landing mission, participates in lunar surface simulation training in bldg 29 at the Manned Spacecraft Center. Bean is strapped to a one-sixth gravity simulator.

  14. COX16 promotes COX2 metallation and assembly during respiratory complex IV biogenesis

    PubMed Central

    Aich, Abhishek; Wang, Cong; Chowdhury, Arpita; Ronsör, Christin; Pacheu-Grau, David; Richter-Dennerlein, Ricarda; Dennerlein, Sven

    2018-01-01

    Cytochrome c oxidase of the mitochondrial oxidative phosphorylation system reduces molecular oxygen with redox equivalent-derived electrons. The conserved mitochondrial-encoded COX1- and COX2-subunits are the heme- and copper-center containing core subunits that catalyze water formation. COX1 and COX2 initially follow independent biogenesis pathways creating assembly modules with subunit-specific, chaperone-like assembly factors that assist in redox centers formation. Here, we find that COX16, a protein required for cytochrome c oxidase assembly, interacts specifically with newly synthesized COX2 and its copper center-forming metallochaperones SCO1, SCO2, and COA6. The recruitment of SCO1 to the COX2-module is COX16- dependent and patient-mimicking mutations in SCO1 affect interaction with COX16. These findings implicate COX16 in CuA-site formation. Surprisingly, COX16 is also found in COX1-containing assembly intermediates and COX2 recruitment to COX1. We conclude that COX16 participates in merging the COX1 and COX2 assembly lines. PMID:29381136

  15. Wreath Laying Ceremony for Alan Bean

    NASA Image and Video Library

    2018-05-30

    Associate Kennedy Space Center Director Kelvin Manning joins guests in a ceremony on Wednesday, May 30, 2018, honoring former NASA astronaut Alan Bean. As lunar module pilot on Apollo 12, Bean was the fourth person to walk on the Moon in November 1969. He went on to command the 59-day Skylab 3 mission in 1973. He died in Houston on May 26, 2018, at the age of 86.

  16. Astronaut Alan Bean shaves while aboard Skylab

    NASA Technical Reports Server (NTRS)

    1973-01-01

    Astronaut Alan L. Bean, Skylab 3 commander, uses battery powered shaver while in the crew quarters of the Skylab space station's Orbital Workshop (OWS) crew quarters. This photograph was taken with a 35mm Nikon camera held by one of Bean's fellow crewmen during the 56.5 day second manned Skylab mission in Earth orbit.

  17. STS-70 Mission Specialist Nancy Jane Currie suits up

    NASA Technical Reports Server (NTRS)

    1995-01-01

    STS-70 Mission Specialist Nancy Jane Currie is donning her launch/entry suit in the Operations and Checkout Building with help from a suit technician. Currie has flown in space once before, on STS-57. Currie and four crew mates will depart shortly for Launch Pad 39B, where the Space Shuttle Discovery is undergoing final preparations for a liftoff scheduled during a two and a half hour launch window opening at 9:41 a.m. EDT.

  18. Bringing Ancient History Back To Life: An Interview With Nancy Toff

    ERIC Educational Resources Information Center

    Curriculum Review, 2005

    2005-01-01

    Nancy Toff, editorial director of school and young adult publishing at Oxford University Press, is out to revolutionize the teaching of history in middle schools. In this interview, she discusses how two new Oxford series, the nine-book, The World in Ancient Times and the seven-book, The Medieval & Early Modern World, get away from the notion of…

  19. Astronaut Alan Bean participates in lunar surface simulation

    NASA Image and Video Library

    1969-10-29

    S69-56059 (24 Oct. 1969) --- Astronaut Alan L. Bean, lunar module pilot of the Apollo 12 lunar landing mission, participates in lunar surface simulation training in Building 29 at the Manned Spacecraft Center (MSC). Bean is strapped to a one-sixth gravity simulator.

  20. Wreath Laying Ceremony for Alan Bean

    NASA Image and Video Library

    2018-05-30

    A memorial wreath placed in the Apollo-Saturn V Center of the Kennedy Space Center Visitor Complex on Wednesday, May 30, 2018, honors former NASA astronaut Alan Bean. He was the fourth person to walk on the Moon as lunar module pilot on Apollo 12 in November 1969. He went on to command the 59-day Skylab 3 mission in 1973. He died in Houston on May 26, 2018, at the age of 86.

  1. Catalog of the George Alan Connor Esperanto Collection.

    ERIC Educational Resources Information Center

    Smith, Karin, Comp.; Haake, Susan, Comp.

    This catalog inventories the collection of books, monographs, serials and periodicals, dictionaries, pamphlets, ephemera, and correspondence concerning Esperanto in the collection of George Alan Connor housed at the University of Oregon Library. Overall, the catalog contains approximately 475 serial entries and 3,000 author entries. Connor was a…

  2. Wreath Laying Ceremony for Alan Bean

    NASA Image and Video Library

    2018-05-30

    Therrin Protze, COO at the Kennedy Space Center Visitor Complex, speaks in the Apollo-Saturn V Center during a ceremony on Wednesday, May 30, 2018, honoring former NASA astronaut Alan Bean. As lunar module pilot on Apollo 12, Bean was the fourth person to walk on the Moon in November 1969. He went on to command the 59-day Skylab 3 mission in 1973. He died in Houston on May 26, 2018, at the age of 86.

  3. Astronaut Owen Garriott trims hair of Astronaut Alan Bean

    NASA Technical Reports Server (NTRS)

    1973-01-01

    Scientist-Astronaut Owen K. Garriott, Skylab 3 science pilot, trims the hair of Astronaut Alan L. Bean, commander, in this on-board photograph from the Skylab Orbital Workshop (OWS). Bean holds a vacuum hose to gather in loose hair.

  4. Astronaut Alan Bean works on Modular Equipment Stowage Assembly

    NASA Technical Reports Server (NTRS)

    1969-01-01

    Astronaut Alan L. Bean, lunar module pilot for the Apollo 12 lunar landing mission, works at the Modular Equipment Stowage Assembly (MESA) on the Apollo 12 Lunar Module during the mission's first extravehicular activity, EVA-1, on November 19, 1969.

  5. Wreath Laying Ceremony for Alan Bean

    NASA Image and Video Library

    2018-05-30

    Kennedy Space Center Director Bob Cabana speaks to guests in the Apollo-Saturn V Center at the spaceport's visitor complex on Wednesday, May 30, 2018. The ceremony is honoring the memory of former NASA astronaut Alan Bean. As lunar module pilot on Apollo 12, Bean was the fourth person to walk on the Moon in November 1969. He went on to command the 59-day Skylab 3 mission in 1973. He died in Houston on May 26, 2018, at the age of 86.

  6. STS-88 Crew Interview: Nancy Currie

    NASA Technical Reports Server (NTRS)

    1998-01-01

    Nancy Currie discusses the seven-day mission that will be highlighted by the mating of the U.S.-built Node 1 station element to the Functional Energy Block (FGB) which will already be in orbit, and two spacewalks to connect power and data transmission cables between the Node and the FGB. Node 1 will be the first Space Station hardware delivered by the Space Shuttle. He also disscusses the assembly sequence. The crew will conduct a series of rendezvous maneuvers similar to those conducted on other Shuttle missions to reach the orbiting FGB. Once the two elements are docked, Ross and Newman will conduct two scheduled spacewalks to connect power and data cables between the Node, PMAs and the FGB. The day following the spacewalks, Endeavour will undock from the two components, completing the first Space Station assembly mission.

  7. Astronaut Alan Bean doing acrobatics in OWS dome area

    NASA Technical Reports Server (NTRS)

    1973-01-01

    Astronaut Alan L. Bean, Skylab 3 commander, doing acrobatics in the dome area of the Orbital Workshop (OWS) on the space station cluster in Earth orbit. The dome area is about 22 feet in diameter and 19 feet from top to bottom.

  8. Astronaut Alan Bean holds Special Environmental Sample Container

    NASA Technical Reports Server (NTRS)

    1969-01-01

    Astronaut Alan L. Bean, lunar module pilot for the Apollo 12 lunar landing mission, holds a Special Environmental Sample Container filled with lunar soil collected during the extravehicular activity (EVA) in which Astronauts Charles Conrad Jr., commander, and Bean participated. Connrad, who took this picture, is reflected in the helmet visor of the lunar module pilot.

  9. Wreath Laying Ceremony for Alan Bean

    NASA Image and Video Library

    2018-05-30

    A memorial wreath placed in the Apollo-Saturn V Center of the Kennedy Space Center Visitor Complex on Wednesday, May 30, 2018, honors former NASA astronaut Alan Bean. He was the fourth person to walk on the Moon as lunar module pilot on Apollo 12 in November 1969. He went on to command the 59-day Skylab 3 mission in 1973. In the background is a large mural of a painting by Bean who became an accomplished artist after leaving NASA. He died in Houston on May 26, 2018, at the age of 86.

  10. COX-1 vs. COX-2 as a determinant of basal tone in the internal anal sphincter.

    PubMed

    de Godoy, Márcio A F; Rattan, Neeru; Rattan, Satish

    2009-02-01

    Prostanoids, produced endogenously via cyclooxygenases (COXs), have been implicated in the sustained contraction of different smooth muscles. The two major types of COXs are COX-1 and COX-2. The COX subtype involved in the basal state of the internal anal sphincter (IAS) smooth muscle tone is not known. To identify the COX subtype, we examined the effect of COX-1- and COX-2-selective inhibitors, SC-560 and rofecoxib, respectively, on basal tone in the rat IAS. We also determined the effect of selective deletion of COX-1 and COX-2 genes (COX-1(-/-) and COX-2(-/-) mice) on basal tone in murine IAS. Our data show that SC-560 causes significantly more efficacious and potent concentration-dependent decreases in IAS tone than rofecoxib. In support of these data, significantly higher levels of COX-1 than COX-2 mRNA were found in the IAS. In addition, higher levels of COX-1 mRNA and protein were expressed in rat IAS than rectal smooth muscle. In wild-type mice, IAS tone was decreased 41.4 +/- 3.4% (mean +/- SE) by SC-560 (1 x 10(-5) M) and 5.4 +/- 2.2% by rofecoxib (P < 0.05, n = 5). Basal tone was 0.172 +/- 0.021 mN//mg in the IAS from wild-type mice and significantly less (0.080 +/- 0.015 mN/mg) in the IAS from COX-1(-/-) mice (P < 0.05, n = 5). However, basal tone in COX-2(-/-) mice was not significantly different from that in wild-type mice. We conclude that COX-1-related products contribute significantly to IAS tone.

  11. COX-1 vs. COX-2 as a determinant of basal tone in the internal anal sphincter

    PubMed Central

    de Godoy, Márcio A. F.; Rattan, Neeru; Rattan, Satish

    2009-01-01

    Prostanoids, produced endogenously via cyclooxygenases (COXs), have been implicated in the sustained contraction of different smooth muscles. The two major types of COXs are COX-1 and COX-2. The COX subtype involved in the basal state of the internal anal sphincter (IAS) smooth muscle tone is not known. To identify the COX subtype, we examined the effect of COX-1- and COX-2-selective inhibitors, SC-560 and rofecoxib, respectively, on basal tone in the rat IAS. We also determined the effect of selective deletion of COX-1 and COX-2 genes (COX-1−/− and COX-2−/− mice) on basal tone in murine IAS. Our data show that SC-560 causes significantly more efficacious and potent concentration-dependent decreases in IAS tone than rofecoxib. In support of these data, significantly higher levels of COX-1 than COX-2 mRNA were found in the IAS. In addition, higher levels of COX-1 mRNA and protein were expressed in rat IAS than rectal smooth muscle. In wild-type mice, IAS tone was decreased 41.4 ± 3.4% (mean ± SE) by SC-560 (1 × 10−5 M) and 5.4 ± 2.2% by rofecoxib (P < 0.05, n = 5). Basal tone was 0.172 ± 0.021 mN//mg in the IAS from wild-type mice and significantly less (0.080 ± 0.015 mN/mg) in the IAS from COX-1−/− mice (P < 0.05, n = 5). However, basal tone in COX-2−/− mice was not significantly different from that in wild-type mice. We conclude that COX-1-related products contribute significantly to IAS tone. PMID:19056763

  12. Professor Alan Turner (1947-2012). Specialist in Miocene-Pleistocene Carnivora, particularly Felidae and Hyaenidae and their palaeoecology

    NASA Astrophysics Data System (ADS)

    O'Regan, Hannah; Turner, Adam; Antón, Mauricio

    2014-07-01

    Alan first trained as a telecom engineer, working for the GPO (General Post Office) which later became British Telecom. He never forgot this early training and was fascinated by how things worked - always happy to take something apart and fix it (although his attempt to close a large plate glass window with a geological hammer was not one of his successes). Following a few years as an engineer, he went to Sheffield University to study archaeology as a mature student in 1973. At this time Sheffield was a hotbed of prehistory with Graeme Barker, Robin Dennell and many others contributing to a truly research-led degree (with tutorials in the pub (well, it was the 1970s)) (Fig. 1). Alan's interest in bones developed at this time, and having graduated in 1976 he went on to take a PhD, supervised by Robin Dennell, on "Aspects of the palaeoecology of large predators, including man, during the British Upper Pleistocene, with particular emphasis on predator-prey relationships" which resulted in a life-long interest in the Carnivora and particularly hyaenas. Following his PhD, Alan moved to the Environmental Archaeology Unit at York to undertake a Science Research Council project on the morphometrics of domestic cattle and pigs from Coppergate and other major urban excavations in the city. Faced with a lot of measurements and statistics, Alan retained his interest in the animals themselves. The project also confirmed to Alan that prehistory was his metier, rather than the historic periods. Former York colleagues still fondly recall Alan's dry wit, and the day that he successfully put the irritating lab telephone beyond use with no externally visible trace of damage.

  13. Astronaut Alan B. Shepard has his blood pressure and temperature checked

    NASA Technical Reports Server (NTRS)

    1961-01-01

    Astronaut Alan B. Shepard has his blood pressure and temperate checked prior to his Mercury-Redstone 3 (MR-3) mission, the first American manned space flight. The attending physician is Dr. William K. Douglas.

  14. Astronaut Alan Bean deploys Lunar Surface Magnetometer on lunar surface

    NASA Image and Video Library

    1969-11-19

    Astronaut Alan L. Bean, lunar module pilot, deploys the Lunar Surface Magnetometer (LSM) during the first Apollo 12 extravehicular activity on the Moon. The LSM is a component of the Apollo Lunar Surface Experiments Package (ALSEP). The Lunar Module can be seen in the left background.

  15. Astronaut Alan Bean deploys Lunar Surface Magnetometer on lunar surface

    NASA Technical Reports Server (NTRS)

    1969-01-01

    Astronaut Alan L. Bean, lunar module pilot, deploys the Lunar Surface Magnetometer (LSM) during the first Apollo 12 extravehicular activity on the Moon. The LSM is a component of the Apollo Lunar Surface Experiments Package (ALSEP). The Lunar Module can be seen in the left background.

  16. "There is One Story Worth Telling": An Essay for James Britton and Nancy Martin

    ERIC Educational Resources Information Center

    Lofty, John S.

    2009-01-01

    In 1992, the University of New Hampshire (UNH) held a conference featuring leaders in the field of composition studies, attended by a wish list of luminaries, including Lil Brannon, Ed Corbett, Peter Elbow, Donald Murray, and Ken Macrorie. James Britton and Nancy Martin flew over from England to join the conversation. The prestigious research…

  17. Select Dietary Phytochemicals Function as Inhibitors of COX-1 but Not COX-2

    PubMed Central

    Li, Haitao; Zhu, Feng; Sun, Yanwen; Li, Bing; Oi, Naomi; Chen, Hanyong; Lubet, Ronald A.; Bode, Ann M.; Dong, Zigang

    2013-01-01

    Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors. Many active dietary factors are reported to suppress carcinogenesis by targeting COX-2. A major question was accordingly raised: why has the lifelong use of phytochemicals that likely inhibit COX-2 presumably not been associated with adverse cardiovascular side effects. To answer this question, we selected a library of dietary-derived phytochemicals and evaluated their potential cardiovascular toxicity in human umbilical vein endothelial cells. Our data indicated that the possibility of cardiovascular toxicity of these dietary phytochemicals was low. Further mechanistic studies revealed that the actions of these phytochemicals were similar to aspirin in that they mainly inhibited COX-1 rather than COX-2, especially at low doses. PMID:24098505

  18. Rein and Zheng Elected to American Academy of Microbiology | Poster

    Cancer.gov

    By Nancy Parrish, Staff Writer Earlier this year, Alan Rein, Ph.D., and Zhi-Ming (Thomas) Zheng, M.D., Ph.D., were elected to fellowship in the American Academy of Microbiology, the honorific leadership group within the American Society for Microbiology (ASM). They were among 88 microbiologists who were elected to the academy “through a highly selective, peer-review process,

  19. Astronaut Alan Bean during news conference prior to Skylab 3 mission

    NASA Image and Video Library

    1973-06-29

    S73-30113 (30 June 1973) --- Astronaut Alan L. Bean, Skylab 3 commander, ponders a question from a newsman during the premission press conference on June 30, 1973, in the Building 1 large auditorium at Johnson Space Center. Photo credit: NASA

  20. Astronaut Alan Bean flies the Astronaut Maneuvering Equipment

    NASA Technical Reports Server (NTRS)

    1973-01-01

    Astronaut Alan L. Bean, Skylab 3 commander, flies the M509 Astronaut Maneuvering Equipment in the foreward dome area of the Orbital Workshop (OWS) on the space station cluster in Earth orbit. Bean is strapped in to the back-mounted, hand-controlled Automatically Stabilized Maneuvering Unit (ASMU). This ASMU exerperiment is being done in shirt sleeves. The dome area where the experiment is conducted is about 22 feet in diameter and 19 feet from top to bottom.

  1. Astronaut Alan Bean flies the Astronaut Maneuvering Equipment

    NASA Technical Reports Server (NTRS)

    1973-01-01

    Astronaut Alan L. Bean, Skylab 3 commander, flies the M509 Astronaut Maneuvering Equipment in the forward dome area of the Orbital Workshop (OWS) on the space station cluster in Earth orbit. Bean is strapped in to the back-mounted, hand-controlled Automatically Stabilized Maneuvering Unit (ASMU). This ASMU exerperiment is being done in shirt sleeves. The dome area where the experiment is conducted is about 22 feet in diameter and 19 feet from top to bottom.

  2. Astronaut Alan Shepard receives MASA Distinguished Service award

    NASA Image and Video Library

    1961-05-07

    S88-31387 (8 May 1961) --- President John F. Kennedy (left) congratulates NASA's Distinguished Service Medal Award recipient astronaut Alan B. Shepard Jr. in a Rose Garden ceremony on May 8, 1961, at the White House. Vice-President Lyndon B. Johnson, NASA Administrator James E. Webb and several NASA astronauts are in the background. Three days earlier, Shepard made history with a 15-minute suborbital space mission in the Freedom 7, Mercury-Redstone 3 spacecraft. Photo credit: NASA

  3. 40 Years in Applied Linguistics: An Interview with Alan Davies

    ERIC Educational Resources Information Center

    Kunnan, Antony John

    2005-01-01

    This article presents an interview with Professor Alan Davies who was born in Wales, studied at Oxford University and Birmingham University, and taught in Scotland at the University of Edinburgh, completing 40 years this year. Professor Davies has travelled widely to give invited talks and seminars, participate in applied linguistics conferences,…

  4. Astronaut Alan Bean looks over data acquisition camera on Skylab trainer

    NASA Technical Reports Server (NTRS)

    1972-01-01

    Astronaut Alan L. Bean, commander for Skylab 3, the second manned Skylab mission, looks over the data acquisition camera mounted on the water tank in the upper level of the Orbital Workshop (OWS) one-G trainer at the Manned Spacecraft Center (MSC).

  5. Binding Energy Calculation of Patchouli Alcohol Isomer Cyclooxygenase Complexes Suggested as COX-1/COX-2 Selective Inhibitor

    PubMed Central

    Mahdi, Chanif; Nurdiana, Nurdiana; Kikuchi, Takheshi; Fatchiyah, Fatchiyah

    2014-01-01

    To understand the structural features that dictate the selectivity of the two isoforms of the prostaglandin H2 synthase (PGHS/COX), the three-dimensional (3D) structure of COX-1/COX-2 was assessed by means of binding energy calculation of virtual molecular dynamic with using ligand alpha-Patchouli alcohol isomers. Molecular interaction studies with COX-1 and COX-2 were done using the molecular docking tools by Hex 8.0. Interactions were further visualized by using Discovery Studio Client 3.5 software tool. The binding energy of molecular interaction was calculated by AMBER12 and Virtual Molecular Dynamic 1.9.1 software. The analysis of the alpha-Patchouli alcohol isomer compounds showed that all alpha-Patchouli alcohol isomers were suggested as inhibitor of COX-1 and COX-2. Collectively, the scoring binding energy calculation (with PBSA Model Solvent) of alpha-Patchouli alcohol isomer compounds (CID442384, CID6432585, CID3080622, CID10955174, and CID56928117) was suggested as candidate for a selective COX-1 inhibitor and CID521903 as nonselective COX-1/COX-2. PMID:25484897

  6. Astronaut Alan Bean with subpackages of the ALSEP during EVA

    NASA Technical Reports Server (NTRS)

    1969-01-01

    Astronaut Alan L. Bean, lunar module pilot, traverses with the two subpackages of the Apollo Lunar Surface Experiments Package (ALSEP) during the first Apollo 12 extravehicular activity (EVA). Bean deployed the ALSEP components 300 feet from the Lunar Module (LM). The LM and deployed erectable S-band antenna can be seen in the background.

  7. Astronaut Alan Shepard using MET during geological training in Mexico

    NASA Technical Reports Server (NTRS)

    1970-01-01

    Astronaut Alan B. Shepard Jr., commander of the Apollo 14 lunar landing mission, takes a piece of equipment from the Modular Equipment Transporter (MET) during geological and lunar surface simulation training training in the Pinacate volcanic area of northwestern Sonora, Mexico. The MET has been nicknamed 'Rickshaw' after its shape and method of propulsion.

  8. Astronaut Alan L. Bean - Family - Houston, TX

    NASA Image and Video Library

    1973-07-05

    S73-31104 (17 July 1973) --- The wife and children of astronaut Alan L. Bean are photographed at their home near the Johnson Space Center (JSC), where their husband and father is preparing for NASA?s second manned Skylab mission. Bean is commander of the Skylab 3 Earth-orbital mission and will be joined by scientist-astronaut Owen K. Garriott, science pilot, and astronaut Jack R. Lousma, pilot for the schedule two-month mission. With Mrs. Sue Bean are the couple?s children Clay, 17, and Amy Sue, 10; and the family?s pet dog. Photo credit: NASA

  9. Astronaut Alan B. Shepard has his blood pressure and temperature checked

    NASA Technical Reports Server (NTRS)

    1961-01-01

    Astronaut Alan B. Shepard has a thermometer in his mouth to check his temperature checked prior to his Mercury-Redstone 3 (MR-3) mission, the first American manned suborbital space flight (02739); Shepard has his heart rate checked. The attending physician is Dr. William K. Douglas (02740).

  10. Astronaut Alan Bean flies the Astronaut Maneuvering Equipment

    NASA Image and Video Library

    1973-08-27

    SL3-107-1215 (27 Aug. 1973) --- Astronaut Alan L. Bean, Skylab 3 commander, flies the M509 Astronaut Maneuvering Equipment in the forward dome area of the Orbital Workshop (OWS) on the space station cluster in Earth orbit. One of his fellow crewmen took this photograph with a 35mm Nikon camera. Bean is strapped into the back mounted, hand-controlled Automatically Stabilized Maneuvering Unit (ASMU). The dome area is about 22 feet in diameter and 19 feet from top to bottom. Photo credit: NASA

  11. Astronaut Alan Bean flies the Astronaut Maneuvering Equipment

    NASA Image and Video Library

    1973-08-18

    SL3-108-1304 (July-September 1973) --- Astronaut Alan L. Bean, Skylab 3 commander, flies the M509 Astronaut Maneuvering Equipment in the forward dome area of the Orbital Workshop (OWS) on the space station cluster in Earth orbit. Bean is strapped in to the back-mounted, hand-controlled Automatically Stabilized Maneuvering Unit (ASMU). This ASMU experiment is being done in shirt sleeves. The dome area where the experiment is conducted is about 22 feet in diameter and 19 feet from top to bottom. Photo credit: NASA

  12. Astronaut Alan Bean looks over data acquisition camera on Skylab trainer

    NASA Image and Video Library

    1972-09-01

    S72-39256 (1972) --- Astronaut Alan L. Bean, commander for Skylab 3, the second manned Skylab mission, looks over the data acquisition camera mounted on the water tank in the upper level of the Orbital Workshop (OWS) one-G trainer at the Manned Spacecraft Center (MSC). Photo credit: NASA

  13. Astronaut Alan B. Shepard has his blood pressure and temperature checked

    NASA Image and Video Library

    1961-01-01

    S61-02749 (5 May 1961) --- Astronaut Alan B. Shepard Jr. has his blood pressure and temperature checked prior to his Mercury-Redstone 3 (MR-3) mission, the first American manned spaceflight. The attending physician is Dr. William K. Douglas. Photo credit: NASA or National Aeronautics and Space Administration

  14. Astronaut Alan B. Shepard has his blood pressure and temperature checked

    NASA Image and Video Library

    1961-01-01

    S61-02740 (5 May 1961) --- Astronaut Alan B. Shepard Jr. has his heart rate checked prior to his Mercury-Redstone 3 (MR-3) mission, the first American manned suborbital spaceflight. The attending physician is Dr. William K. Douglas. Photo credit: NASA or National Aeronautics and Space Administration

  15. 77 FR 74518 - Alan T. Waterman Award Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-14

    ... NATIONAL SCIENCE FOUNDATION Alan T. Waterman Award Committee; Notice of Meeting In accordance with the Federal Advisory Committee Act (Pub. L. 92- 463, as amended), the National Science Foundation..., 2013, 8:30a.m.-1:30 p.m. Place: National Science Foundation, Arlington, Virginia 22230. Type of Meeting...

  16. Astronaut Alan Bean with subpackages of the ALSEP during EVA

    NASA Image and Video Library

    1969-11-19

    AS12-46-6807 (19 Nov. 1969) --- Astronaut Alan L. Bean, lunar module pilot, traverses with the two sub packages of the Apollo Lunar Surface Experiments Package (ALSEP) during the first Apollo 12 extravehicular activity (EVA). Bean deployed the ALSEP components 300 feet from the Lunar Module (LM). The LM and deployed erectable S-band antenna can be seen in the background.

  17. Astronaut Alan Bean holds Special Environmental Sample Container

    NASA Image and Video Library

    1969-11-20

    AS12-49-7278 (19-20 Nov. 1969) --- Astronaut Alan L. Bean holds a Special Environmental Sample Container filled with lunar soil collected during the extravehicular activity (EVA) in which astronauts Charles Conrad Jr., commander, and Bean, lunar module pilot, participated. Conrad, who took this picture, is reflected in Bean's helmet visor. Conrad and Bean descended in the Apollo 12 Lunar Module (LM) to explore the lunar surface while astronaut Richard F. Gordon Jr., command module pilot, remained with the Command and Service Modules (CSM) in lunar orbit. Photo credit: NASA

  18. Astronaut Alan Bean flies the Astronaut Maneuvering Equipment

    NASA Technical Reports Server (NTRS)

    1973-01-01

    Astronaut Alan L. Bean, Skylab 3 commander, flies the M509 Astronaut Maneuvering Equipment in the foreward dome area of the Orbital Workshop (OWS) on the space station cluster in Earth orbit. Bean is strapped in to the back-mounted, hand-controlled Automatically Stabilized Maneuvering Unit (ASMU). He is wearing a pressure suit for this run of the M509 experiment, but other ASMU tests are done in shirt sleeves. The dome area where the experiment is conducted is about 22 feet in diameter and 19 feet from top to bottom.

  19. STS-88 Mission Specialist Nancy Currie suits up before launch

    NASA Technical Reports Server (NTRS)

    1998-01-01

    In the Operations and Checkout Building, STS-88 Mission Specialist Nancy J. Currie gets help with her flight suit from suit technician Drew Billingsley before launch. Mission STS-88 is expected to launch at 3:56 a.m. EST with the six-member crew aboard Space Shuttle Endeavour on Dec. 3. Endeavour carries the Unity connecting module, which the crew will be mating with the Russian-built Zarya control module already in orbit. In addition to Unity, two small replacement electronics boxes are on board for possible repairs to Zarya batteries. The mission is expected to last 11 days, 19 hours and 49 minutes, landing at 10:17 p.m. EST on Dec. 14.

  20. Astronaut Alan Bean steps from ladder of Lunar Module for EVA

    NASA Technical Reports Server (NTRS)

    1969-01-01

    Astronaut Alan L. Bean, lunar module pilot for the Apollo 12 lunar landing mission, steps from the ladder of the Lunar Module to join Astronaut Charles Conrad Jr., commander, in extravehicular activity on November 19, 1969. Astronaut Ricard F. Gordon Jr., command module pilot, remained with the Command/Service Modules in lunar orbit.

  1. Astronaut Alan Bean assisted with egressing command module after landing

    NASA Technical Reports Server (NTRS)

    1969-01-01

    Astronaut Alan L. Bean, lunar module pilot, is assisted with egressing the Apollo 12 Command Module by a U.S. Navy underwater demolition team swimmer during recovery operations in the Pacific Ocean. Already in the life raft are Astronauts Charles Conrad Jr., commander; and Richard F. Gordon Jr., command module pilot. The Apollo 12 splashdown occured at 2:58 p.m., November 24, 1969 near American Samoa.

  2. Computational study of pristine and titanium-doped sodium alanates for hydrogen storage applications

    NASA Astrophysics Data System (ADS)

    Dathar, Gopi Krishna Phani

    The emphasis of this research is to study and elucidate the underlying mechanisms of reversible hydrogen storage in pristine and Ti-doped sodium aluminum hydrides using molecular modeling techniques. An early breakthrough in using complex metal hydrides as hydrogen storage materials is from the research on sodium alanates by Bogdanovic et al., in 1997 reporting reversible hydrogen storage is possible at moderate temperatures and pressures in transition metal doped sodium alanates. Anton reported titanium salts as the best catalysts compared to all other transition metal salts from his further research on transition metal doped sodium alanates. However, a few questions remained unanswered regarding the role of Ti in reversible hydrogen storage of sodium alanates with improved thermodynamics and kinetics of hydrogen desorption. The first question is about the position of transition metal dopants in the sodium aluminum hydride lattice. The position is investigated by identifying the possible sites for titanium dopants in NaAlH4 lattice and studying the structure and dynamics of possible compounds resulting from titanium doping in sodium alanates. The second question is the role of titanium dopants in improved thermodynamics of hydrogen desorption in Ti-doped NaAlH4. Though it is accepted in the literature that formation of TiAl alloys (Ti-Al and TiAl3) is favorable, reaction pathways are not clearly established. Furthermore, the source of aluminum for Ti-Al alloy formation is not clearly understood. The third question in this area is the role of titanium dopants in improved kinetics of hydrogen absorption and desorption in Ti-doped sodium alanates. This study is directed towards addressing the three longstanding questions in this area. Thermodynamic and kinetic pathways for hydrogen desorption in pristine NaAlH4 and formation of Ti-Al alloys in Ti-doped NaAlH 4, are elucidated to understand the underlying mechanisms of hydrogen desorption. Density functional theory

  3. STS-88 Mission Specialist Nancy J. Currie suits up for TCDT

    NASA Technical Reports Server (NTRS)

    1998-01-01

    STS-88 Mission Specialist Nancy J. Currie suits up in the Operations and Checkout Building, as part of flight crew equipment fit check, prior to her trip to Launch Pad 39A. She is helped by suit tech Drew Billingsley. The crew are at KSC to participate in the Terminal Countdown Demonstration Test (TCDT) which includes mission familiarization activities, emergency egress training, and the simulated main engine cut-off exercise. This is Currie's third space flight. Mission STS-88 is targeted for launch on Dec. 3, 1998. It is the first U.S. flight for the assembly of the International Space Station and will carry the Unity connecting module.

  4. COX-1 Inhibitors: Beyond Structure Toward Therapy.

    PubMed

    Vitale, Paola; Panella, Andrea; Scilimati, Antonio; Perrone, Maria Grazia

    2016-07-01

    Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed. © 2016 Wiley Periodicals, Inc.

  5. Astronaut Alan Bean works on Modular Equipment Stowage Assembly

    NASA Image and Video Library

    1969-11-19

    AS12-46-6749 (19 Nov. 1969) --- Astronaut Alan L. Bean, lunar module pilot for the Apollo 12 lunar landing mission, works at the Modular Equipment Stowage Assembly (MESA) on the Apollo 12 Lunar Module (LM) during the mission's first extravehicular activity, (EVA) on Nov. 19, 1969. Astronaut Charles Conrad Jr., commander, and Bean descended in the Apollo 12 LM to explore the moon while astronaut Richard F. Gordon Jr., command module pilot, remained with the Command and Service Modules (CSM) in lunar orbit.

  6. Astronaut Alan Bean steps from ladder of Lunar Module for EVA

    NASA Image and Video Library

    1969-11-19

    AS12-46-6729 (19 Nov. 1969) --- Astronaut Alan L. Bean, lunar module pilot for the Apollo 12 lunar landing mission, steps from the ladder of the Lunar Module to join astronaut Charles Conrad Jr., commander, in extravehicular activity on Nov. 19, 1969. Astronaut Richard F. Gordon Jr., command module pilot, remained with the Command and Service Modules in lunar orbit.

  7. MERCURY-ATLAS (MA)-9 - SHEPARD, ALAN B., JR. ASTRONAUT - MERCURY CONTROL CENTER (MCC) - CAPE

    NASA Image and Video Library

    1963-05-16

    S63-07857 (15-16 May 1963) --- Astronaut Alan Shepard (left) and Walter C. Williams monitor progress of the Mercury Atlas 9 (MA-9) mission from Mercury Control Center, Cape Canaveral, Florida. Photo credit: NASA

  8. Remembering Nancy. 25 Members of the Montessori Community Share Their Reflections on the Death of the AMS Founder.

    ERIC Educational Resources Information Center

    Turner, Joy; And Others

    1995-01-01

    Twenty-five members of the Montessori community share their memories of Dr. Nancy McCormick Rambusch, charismatic founder of the American Montessori movement, early childhood professional, and innovative educator, who died of pancreatic cancer on October 27, 1994. Rambusch's work of 40 years now flowers as an institutionalized educational program…

  9. Box-Cox transformation for QTL mapping.

    PubMed

    Yang, Runqing; Yi, Nengjun; Xu, Shizhong

    2006-01-01

    The maximum likelihood method of QTL mapping assumes that the phenotypic values of a quantitative trait follow a normal distribution. If the assumption is violated, some forms of transformation should be taken to make the assumption approximately true. The Box-Cox transformation is a general transformation method which can be applied to many different types of data. The flexibility of the Box-Cox transformation is due to a variable, called transformation factor, appearing in the Box-Cox formula. We developed a maximum likelihood method that treats the transformation factor as an unknown parameter, which is estimated from the data simultaneously along with the QTL parameters. The method makes an objective choice of data transformation and thus can be applied to QTL analysis for many different types of data. Simulation studies show that (1) Box-Cox transformation can substantially increase the power of QTL detection; (2) Box-Cox transformation can replace some specialized transformation methods that are commonly used in QTL mapping; and (3) applying the Box-Cox transformation to data already normally distributed does not harm the result.

  10. Astronaut Owen Garriott trims hair of Astronaut Alan Bean

    NASA Image and Video Library

    1973-08-19

    SL3-108-1292 (19 Aug. 1973) --- Scientist-astronaut Owen K. Garriott, Skylab 3 science pilot, trims the hair of astronaut Alan L. Bean, commander, in this onboard photograph from the Skylab Orbital Workshop (OWS) in Earth orbit. Astronaut Jack R. Lousma, pilot, took this picture with a 35mm Nikon camera. Bean holds a vacuum hose to gather in loose hair. The crew of the second manned Skylab flight went on to successfully complete 59 days aboard the Skylab space station cluster in Earth orbit. Photo credit: NASA

  11. Astronaut Alan Bean reads data from book while holding teleprinter tape

    NASA Technical Reports Server (NTRS)

    1973-01-01

    Astronaut Alan L. Bean, Skylab 3 commander, reads data from book in his right hand while holding teleprinter tape in his left hand, in the ward room of the Skylab space station's Orbital Workshop (OWS) crew quarters. This photograph was taken with a 35mm Nikon camera held by one of Bean's fellow crewmen during the 56.5 day second manned Skylab mission in Earth orbit.

  12. Astronaut Alan Bean deploys ALSEP during first Apollo 12 EVA on moon

    NASA Technical Reports Server (NTRS)

    1969-01-01

    Astronaut Alan L. Bean, Apollo 12 lunar module pilot, deploys components of the Apollo Lunar Surface Experiments Package (ALSEP) during the first Apollo 12 extravehicular activity (EVA) on the moon. The photo was made by Astronaut Charles Conrad Jr., Apollo 12 commander, using a 70mm handheld Haselblad camera modified for lunar surface usage.

  13. Astronaut Alan Bean deploys ALSEP during first Apollo 12 EVA on moon

    NASA Image and Video Library

    1969-11-19

    AS12-47-6919 (19 Nov. 1969) --- Astronaut Alan L. Bean, lunar module pilot, deploys components of the Apollo Lunar Surface Experiments Package (ALSEP) during the first Apollo 12 extravehicular activity (EVA) on the moon. The photo was made by astronaut Charles Conrad Jr., commander, using a 70mm handheld Hasselblad camera modified for lunar surface usage.

  14. 2016 Summer Series - Alan Stern - The Exploration of Pluto by New Horizons

    NASA Image and Video Library

    2016-08-11

    Interplanetary exploration is essential for the long-term survival of our species. Robotic space exploration allows us to advance our knowledge of our solar system and beyond. Dr. Alan Stern will talk about the New Horizons mission to Pluto and the scientific knowledge gained through the exploration of the icy worlds at the edge of our solar system.

  15. Challenging the Status Quo: Alan Pifer and Higher Education Reform in Colonial Nigeria

    ERIC Educational Resources Information Center

    Anyanwu, Ogechi E.

    2013-01-01

    The historiography of higher education in Nigeria has not fully accounted for Alan Pifer's crucial contributions in reforming the elitist British higher education tradition in colonial Nigeria. Through qualitative analysis of mostly primary sources acquired from the Rare Book and Manuscript Library in Columbia University, this article argues that…

  16. A Life of Learning: Nancy Siraisi. Charles Homer Haskins Prize Lecture for 2010. ACLS Occasional Paper, No. 67

    ERIC Educational Resources Information Center

    American Council of Learned Societies, 2010

    2010-01-01

    Nancy Siraisi has been a prolific and leading scholar in the history of medicine and science of the Middle Ages and the Renaissance. This lecture of hers is the twenty-eighth of series of lectures named for Charles Homer Haskins, first chairman of the American Council of Learned Societies (ACLS) and himself a famed medievalist who brought…

  17. Immunohistochemical and morphometric evaluation of COX-1 and COX-2 in the remodeled lung in idiopathic pulmonary fibrosis and systemic sclerosis* ,**

    PubMed Central

    Parra, Edwin Roger; Lin, Flavia; Martins, Vanessa; Rangel, Maristela Peres; Capelozzi, Vera Luiza

    2013-01-01

    OBJECTIVE: To study the expression of COX-1 and COX-2 in the remodeled lung in systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) patients, correlating that expression with patient survival. METHODS: We examined open lung biopsy specimens from 24 SSc patients and 30 IPF patients, using normal lung tissue as a control. The histological patterns included fibrotic nonspecific interstitial pneumonia (NSIP) in SSc patients and usual interstitial pneumonia (UIP) in IPF patients. We used immunohistochemistry and histomorphometry to evaluate the expression of COX-1 and COX-2 in alveolar septa, vessels, and bronchioles. We then correlated that expression with pulmonary function test results and evaluated its impact on patient survival. RESULTS: The expression of COX-1 and COX-2 in alveolar septa was significantly higher in IPF-UIP and SSc-NSIP lung tissue than in the control tissue. No difference was found between IPF-UIP and SSc-NSIP tissue regarding COX-1 and COX-2 expression. Multivariate analysis based on the Cox regression model showed that the factors associated with a low risk of death were younger age, high DLCO/alveolar volume, IPF, and high COX-1 expression in alveolar septa, whereas those associated with a high risk of death were advanced age, low DLCO/alveolar volume, SSc (with NSIP), and low COX-1 expression in alveolar septa. CONCLUSIONS: Our findings suggest that strategies aimed at preventing low COX-1 synthesis will have a greater impact on SSc, whereas those aimed at preventing high COX-2 synthesis will have a greater impact on IPF. However, prospective randomized clinical trials are needed in order to confirm that. PMID:24473763

  18. Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors.

    PubMed

    Lokwani, Deepak; Azad, Rajaram; Sarkate, Aniket; Reddanna, Pallu; Shinde, Devanand

    2015-08-01

    The various scaffolds containing 1,4-dihydropyrimidine ring were designed by considering the environment of the active site of COX-1/COX-2 and 5-LOX enzymes. The structure-based library design approach, including the focused library design (Virtual Combinatorial Library Design) and virtual screening was used to select the 1,4-dihydropyrimidine scaffold for simultaneous inhibition of both enzyme pathways (COX-1/COX-2 and 5-LOX). The virtual library on each 1,4-dihydropyrimidine scaffold was enumerated in two alternative ways. In first way, the chemical reagents at R groups were filtered by docking of scaffold with single position substitution, that is, only at R1, or R2, or R3, … Rn on COX-2 enzyme using Glide XP docking mode. The structures that do not dock well were removed and the library was enumerated with filtered chemical reagents. In second alternative way, the single position docking stage was bypassed, and the entire library was enumerated using all chemical reagents by docking on the COX-2 enzyme. The entire library of approximately 15,629 compounds obtained from both ways after screening for drug like properties, were further screened for their binding affinity against COX-1 and 5-LOX enzymes using Virtual Screening Workflow. Finally, 142 hits were obtained and divided into two groups based on their binding affinity for COX-1/COX-2 and for both enzyme pathways (COX-1/COX-2 and 5-LOX). The ten molecules were selected, synthesized and evaluated for their COX-1, COX-2 and 5-LOX inhibiting activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Sulforaphane suppresses lipopolysaccharide-induced cyclooxygenase-2 (COX-2) expression through the modulation of multiple targets in COX-2 gene promoter.

    PubMed

    Woo, Kyung Jin; Kwon, Taeg Kyu

    2007-12-15

    Sulforaphane is a natural, biologically active compound extracted from cruciferous vegetables such as broccoli and cabbage. It possesses potent anti-inflammation and anti-cancer properties. The mechanism by which sulforaphane suppresses COX-2 expression remains poorly understood. In the present report, we investigated the effect of sulforaphane on the expression of COX-2 in lipopolysaccharide (LPS)-activated Raw 264.7 cells. Sulforaphane significantly suppressed the LPS-induced COX-2 protein and mRNA expression in a dose-dependent manner. The ability of sulforaphane to suppress the expression of the COX-2 was investigated using luciferase reporters controlled by various cis-elements in COX-2 promoter region. Electrophoretic mobility shift assay (EMSA) verified that NF-kappaB, C/EBP, CREB and AP-1 were identified as responsible for the sulforaphane-mediated COX-2 down-regulation. In addition, we demonstrated the signal transduction pathway of mitogen-activated protein kinase (MAP kinase) in LPS-induced COX-2 expression. Taken together, these results demonstrate that sulforaphane effectively suppressed the LPS-induced COX-2 protein via modulation of multiple core promoter elements (NF-kappaB, C/EBP, CREB and AP-1) in the COX-2 transcriptional regulation. These results will provide new insights into the anti-inflammatory and anti-carcinogenic properties of sulforaphane.

  20. COX-2 and Prostate Cancer Angiogenesis

    DTIC Science & Technology

    2001-03-01

    the optimal dosing and timing of a COX-2 inhibitor (NS398) in an animal model of human prostate cancer, (2)and (3) the mechanisms underlying the...cancer tissues (14) and that a COX-2 inhibitor selectively induces apoptosis in a prostate cancer cell line (15). We also demonstrated that treatment of...human prostate tumor-bearing mice with a selective COX-2 inhibitor (NS-398) significantly reduces tumor size, microvessel density and levels of a

  1. ASTRONAUT BEAN, ALAN L - SIMULATION - BLDG. 35 - COMMAND MODULE TRAINER - JSC

    NASA Image and Video Library

    1975-02-20

    S75-21720 (14 Feb. 1975) --- Astronaut Alan L. Bean (foreground) and cosmonaut Aleksey A. Leonov participate in Apollo-Soyuz Test Project joint crew training in Building 35 at NASA's Johnson Space Center. They are in the Apollo Command Module trainer. The training session simulated activities on the first day in Earth orbit. Bean is the commander of the American ASTP backup crew. Leonov is the commander of the Soviet ASTP first (prime) crew.

  2. Anti-inflammatory, cyclooxygenase (COX)-2, COX-1 inhibitory, and free radical scavenging effects of Rumex nepalensis.

    PubMed

    Gautam, Raju; Karkhile, Kailas V; Bhutani, Kamlesh K; Jachak, Sanjay M

    2010-10-01

    Evaluation of the topical anti-inflammatory activity of chloroform and ethyl acetate extracts of RUMEX NEPALENSIS roots in a TPA-induced acute inflammation mouse model demonstrated a significant reduction in ear edema. The extracts were further tested on purified enzymes for COX-1 and COX-2 inhibition to elucidate their mechanism of action, and a strong inhibition was observed. Six anthraquinones and two naphthalene derivatives were isolated from the ethyl acetate extract. Among the isolated compounds, emodin was found to be a potent inhibitor with slight selectivity towards COX-2, and nepodin exhibited selectivity towards COX-1. Emodin, endocrocin, and nepodin also exhibited significant topical anti-inflammatory activity in mice. Interestingly, nepodin showed better radical scavenging activity than trolox and ascorbic acid against DPPH and ABTS radicals. The strong radical scavenging activity of chloroform and ethyl acetate extracts could be explained by the presence of nepodin as well as by the high phenolic content of the ethyl acetate extract. Thus, the anti-inflammatory effect of R. NEPALENSIS roots was assumed to be mediated through COX inhibition by anthraquinones and naphthalene derivatives and through the radical scavenging activities of naphthalene derivatives. © Georg Thieme Verlag KG Stuttgart · New York.

  3. The Moxie of Kathy Cox

    ERIC Educational Resources Information Center

    Johns, Stephanie

    2010-01-01

    Kathy Cox, the superintendent of schools for Georgia, believes "excellence is not an accident". She made a name for herself by winning $1 million proving she was smarter than a fifth-grader on a popular television show. This article presents a profile of Cox, her family, her role as school superintendent, and her accomplishments.…

  4. COX-2 chronology

    PubMed Central

    Hawkey, C J

    2005-01-01

    The role of selective cyclooxygenase (COX)-2 inhibitors in medical practice has become controversial since evidence emerged that their use is associated with an increased risk of myocardial infarction. Selective COX-2 inhibitors were seen as successor to non-selective non-steroidal anti-inflammatory drugs, in turn successors to aspirin. The importance of pain relief means that such drugs have always attracted attention. The fact that they work through inhibition of cyclooxygenase, are widespread, and have multiple effects also means that adverse effects that were unanticipated (even though predictable) have always emerged. In this paper I therefore present an historical perspective so that the lessons of the past may be applied to the present. PMID:16227351

  5. Astronaut Alan Bean reads data from book while holding teleprinter tape

    NASA Image and Video Library

    1973-08-08

    SL3-111-1514 (July-September 1973) --- Astronaut Alan L. Bean, Skylab 3 commander, reads data from book in his right hand while holding teleprinter tape in his left hand, in the ward room of the Skylab space station's Orbital Workshop (OWS) crew quarters. This photograph was taken with a 35mm Nikon camera held by one of Bean's fellow crewmen during the 56.5 day second manned Skylab mission in Earth orbit. Photo credit: NASA

  6. Synthesis, biological evaluation and molecular docking studies of stellatin derivatives as cyclooxygenase (COX-1, COX-2) inhibitors and anti-inflammatory agents.

    PubMed

    Gautam, Raju; Jachak, Sanjay M; Kumar, Vivek; Mohan, C Gopi

    2011-03-15

    Stellatin (4), isolated from Dysophylla stellata is a cyclooxygenase (COX) inhibitor. The present study reports the synthesis and biological evaluation of new stellatin derivatives for COX-1, COX-2 inhibitory and anti-inflammatory activities. Eight derivatives showed more pronounced COX-2 inhibition than stellatin and, 17 and 21 exhibited the highest COX-2 inhibition. They also exhibited the significant anti-inflammatory activity in TPA-induced mouse ear edema assay and their anti-inflammatory effects were more than that of stellatin and indomethacin at 0.5mg/ear. The derivatives were further evaluated for antioxidant activity wherein 16 and 17 showed potent free radical scavenging activity against DPPH and ABTS radicals. Molecular docking study revealed the binding orientations of stellatin and its derivatives into the active sites of COX-1 and COX-2 and thereby helps to design the potent inhibitors. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Total brain death: a reply to Alan Shewmon.

    PubMed

    Lee, Patrick; GriseZ, Germain

    2012-06-01

    D. Alan Shewmon has advanced a well-documented challenge to the widely accepted total brain death criterion for death of the human being. We show that Shewmon’s argument against this criterion is unsound, though he does refute the standard argument for that criterion. We advance a distinct argument for the total brain death criterion and answer likely objections. Since human beings are rational animals--sentient organisms of a specific type--the loss of the radical capacity for sentience (the capacity to sense or to develop the capacity to sense) involves a substantial change, the passing away of the human organism. In human beings total brain death involves the complete loss of the radical capacity for sentience, and so in human beings total brain death is death.

  8. The Mysterious Case of the Detective as Child Hero: Sherlock Holmes, Encyclopedia Brown and Nancy Drew as Role Models?

    ERIC Educational Resources Information Center

    Sugarman, Sally

    In the mystery genre, the one characteristic that the enduring figures of Sherlock Holmes, Nancy Drew, and Encyclopedia Brown have in common is a rational mind. The source of their strength is their ability to think and think well. A study examined some typical examples of the mystery genre in young adult literature and surveyed children and…

  9. Rein and Zheng Elected to American Academy of Microbiology | Poster

    Cancer.gov

    By Nancy Parrish, Staff Writer Earlier this year, Alan Rein, Ph.D., and Zhi-Ming (Thomas) Zheng, M.D., Ph.D., were elected to fellowship in the American Academy of Microbiology, the honorific leadership group within the American Society for Microbiology (ASM). They were among 88 microbiologists who were elected to the academy “through a highly selective, peer-review process, based on their records of scientific achievement and original contributions that have advanced microbiology,” according to the society’s website.

  10. A benign synthesis of alane by the composition-controlled mechanochemical reaction of sodium hydride and aluminum chloride

    DOE PAGES

    Hlova, Ihor; Goldston, Jennifer F.; Gupta, Shalabh; ...

    2017-05-30

    Solid-state mechanochemical synthesis of alane (AlH 3) starting from sodium hydride (NaH) and aluminum chloride (AlCl 3) has been achieved at room temperature. The transformation pathway of this solid-state reaction was controlled by a stepwise addition of AlCl 3 to the initial reaction mixture that contained sodium hydride in excess of stoichiometric amount. As in the case of previously investigated LiH–AlCl 3 system, complete selectivity was achieved whereby formation of unwanted elemental aluminum was fully suppressed, and AlH 3 was obtained in quantitative yield. Reaction progress during each step was investigated by means of solid-state NMR and powder X-ray diffraction,more » which revealed that the overall reaction proceeds through a series of intermediate alanates that may be partially chlorinated. The NaH–AlCl 3 system presents some subtle differences compared to LiH–AlCl 3 system particularly with respect to optimal concentrations needed during one of the reaction stages. Based on the results, we postulate that high local concentrations of NaH may stabilize chlorine-containing derivatives and prevent decomposition into elemental aluminum with hydrogen evolution. As a result, complete conversion with quantitative yield of alane was confirmed by both SSNMR and hydrogen desorption analysis.« less

  11. A benign synthesis of alane by the composition-controlled mechanochemical reaction of sodium hydride and aluminum chloride

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hlova, Ihor; Goldston, Jennifer F.; Gupta, Shalabh

    Solid-state mechanochemical synthesis of alane (AlH 3) starting from sodium hydride (NaH) and aluminum chloride (AlCl 3) has been achieved at room temperature. The transformation pathway of this solid-state reaction was controlled by a stepwise addition of AlCl 3 to the initial reaction mixture that contained sodium hydride in excess of stoichiometric amount. As in the case of previously investigated LiH–AlCl 3 system, complete selectivity was achieved whereby formation of unwanted elemental aluminum was fully suppressed, and AlH 3 was obtained in quantitative yield. Reaction progress during each step was investigated by means of solid-state NMR and powder X-ray diffraction,more » which revealed that the overall reaction proceeds through a series of intermediate alanates that may be partially chlorinated. The NaH–AlCl 3 system presents some subtle differences compared to LiH–AlCl 3 system particularly with respect to optimal concentrations needed during one of the reaction stages. Based on the results, we postulate that high local concentrations of NaH may stabilize chlorine-containing derivatives and prevent decomposition into elemental aluminum with hydrogen evolution. As a result, complete conversion with quantitative yield of alane was confirmed by both SSNMR and hydrogen desorption analysis.« less

  12. The pathophysiological roles of COX-1 and COX-2 in the intestinal smooth muscle contractility under the anaphylactic condition.

    PubMed

    Kadowaki, Hiroko; Yamamoto, Takeshi; Kageyama-Yahara, Natsuko; Kurokawa, Nobuo; Kadowaki, Makoto

    2008-04-01

    Various inflammatory mediators released from antigen-activated mast cells are considered to play a key role in the pathogenesis of food allergy. The aim of the present study was to determine the mechanisms underlying the antigen-induced anaphylactic responses in the rat colons. Wistar rats were sensitized by intraperitoneal injection of ovalbumin (OVA). The contractilities of isolated proximal colons of the sensitized rats were studied in the organ bath. OVA challenges of sensitized tissues induced prolonged contractile responses. The antigen-induced contractions were greatly reduced by mast cell stabilizer doxantrazole (10 microM). However, the contractions were resistant to histamine H1 receptor antagonist and prostaglandin D2 receptor antagonist. In contrast, non-selective cyclooxygenase (COX) inhibitor indomethacin (1 microM) significantly reduced the contractions by 61.0%. Furthermore, selective COX-1 inhibitor FR122047 (10 microM) as well as selective COX-2 inhibitor NS-398 (10 microM) significantly inhibited the contractions by 50.1% and 50.3%, respectively. Nevertheless, the transcript levels of COX-2 as well as COX-1 were not upregulated by OVA in the proximal colons of the sensitized rats. The present results indicate that de novo arachidonic acid metabolites synthesis by constitutive COX-1 as well as constitutive COX-2 within mast cells contribute to the altered smooth muscle contractilities in the colons under the anaphylactic condition.

  13. Resveratrol Directly Targets COX-2 to Inhibit Carcinogenesis

    PubMed Central

    Zykova, Tatyana A.; Zhu, Feng; Zhai, Xiuhong; Ma, Wei-ya; Ermakova, Svetlana P.; Lee, Ki Won; Bode, Ann M.; Dong, Zigang

    2008-01-01

    Targeted molecular cancer therapies can potentially deliver treatment directly to a specific protein or gene to optimize efficacy and reduce adverse side effects often associated with traditional chemotherapy. Key oncoprotein and oncogene targets are rapidly being identified based on their expression, pathogenesis and clinical outcome. One such protein target is cyclooxygenase-2 (COX-2), which is highly expressed in various cancers. Research findings suggest that resveratrol (3,5,4'-trihydroxy-trans-stilbene) demonstrates non-selective COX-2 inhibition. We report herein that resveratrol (RSVL) directly binds with COX-2 and this binding is absolutely required for RSVL's inhibition of the ability of human colon adenocarcinoma HT-29 cells to form colonies in soft agar. Binding of COX-2 with RSVL was compared with two RSVL analogues, 3,3’,4’,5’5’-pentahydroxy-trans-stilbene (RSVL-2) or 3,4’,5-trimethoxy-trans-stilbene (RSVL-3). The results indicated that COX-2 binds with RSVL-2 more strongly than with RSVL, but does not bind with RSVL-3. RSVL or RSVL-2, but not RSVL-3, inhibited COX-2-mediated PGE2 production in vitro and ex vivo. HT-29 human colon adenocarcinoma cells express high levels of COX-2 and either RSVL or RSVL-2, but not RSVL-3, suppressed anchorage independent growth of these cells in soft agar. RSVL or RSVL-2 (not RSVL-3) suppressed growth of COX-2+/+ cells by 60 or 80%, respectively. Notably, cells deficient in COX-2 were unresponsive to RSVL or RSVL-2. These data suggest that the anticancer effects of RSVL or RSLV-2 might be mediated directly through COX-2. PMID:18381589

  14. Astronaut Alan Bean flies the Astronaut Maneuvering Equipment in the OWS

    NASA Technical Reports Server (NTRS)

    1973-01-01

    Astronaut Alan L. Bean, Skylab 3 commander, flies the M509 Astronaut Maneuvering Equipment, as seen in this photographic reproduction taken from a television transmission made by a color television camera in the Orbital Workshop (OWS) of the Skylab space station in Earth orbit. Bean is strapped into the back-mounted, hand-controlled Automatically stabilized Maneuvering Unit (ASMU). The M509 exercise was in the forward dome area of the OWS. THe dome area is about 22 feet in diameter and 19 feet form top to bottom.

  15. Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition

    PubMed Central

    Limongelli, Vittorio; Bonomi, Massimiliano; Marinelli, Luciana; Gervasio, Francesco Luigi; Cavalli, Andrea; Novellino, Ettore; Parrinello, Michele

    2010-01-01

    The widely used nonsteroidal anti-inflammatory drugs block the cyclooxygenase enzymes (COXs) and are clinically used for the treatment of inflammation, pain, and cancers. A selective inhibition of the different isoforms, particularly COX-2, is desirable, and consequently a deeper understanding of the molecular basis of selective inhibition is of great demand. Using an advanced computational technique we have simulated the full dissociation process of a highly potent and selective inhibitor, SC-558, in both COX-1 and COX-2. We have found a previously unreported alternative binding mode in COX-2 explaining the time-dependent inhibition exhibited by this class of inhibitors and consequently their long residence time inside this isoform. Our metadynamics-based approach allows us to illuminate the highly dynamical character of the ligand/protein recognition process, thus explaining a wealth of experimental data and paving the way to an innovative strategy for designing new COX inhibitors with tuned selectivity. PMID:20215464

  16. Elusive silane-alane complex [Si-H⋅⋅⋅Al]: isolation, characterization, and multifaceted frustrated Lewis pair type catalysis.

    PubMed

    Chen, Jiawei; Chen, Eugene Y-X

    2015-06-01

    The super acidity of the unsolvated Al(C6F5)3 enabled isolation of the elusive silane-alane complex [Si-H⋅⋅⋅Al], which was structurally characterized by spectroscopic and X-ray diffraction methods. The Janus-like nature of this adduct, coupled with strong silane activation, effects multifaceted frustrated-Lewis-pair-type catalysis. When compared with the silane-borane system, the silane-alane system offers unique features or clear advantages in the four types of catalytic transformations examined in this study, including: ligand redistribution of tertiary silanes into secondary and quaternary silanes, polymerization of conjugated polar alkenes, hydrosilylation of unactivated alkenes, and hydrodefluorination of fluoroalkanes. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. In Silico Analysis of the Potential of the Active Compounds Fucoidan and Alginate Derived from Sargassum Sp. as Inhibitors of COX-1 and COX-2.

    PubMed

    Dewi, Lestari

    2016-06-01

    The enzyme cyclooxygenase (COX) is an enzyme that catalyzes the formation of one of the mediators of inflammation, the prostaglandins. Inhibition of COX allegedly can improve inflammation-induced pathological conditions. The purpose of the present study was to evaluate the potential of Sargassum sp. components, Fucoidan and alginate, as COX inhibitors. The study was conducted by means of a computational (in silico) method. It was performed in two main stages, the docking between COX-1 and COX-2 with Fucoidan, alginate and aspirin (for comparison) and the analysis of the amount of interactions formed and the residues directly involved in the process of interaction. Our results showed that both Fucoidan and alginate had an excellent potential as inhibitors of COX-1 and COX-2. Fucoidan had a better potential as an inhibitor of COX than alginate. COX inhibition was expected to provide a more favorable effect on inflammation-related pathological conditions. The active compounds Fucoidan and alginate derived from Sargassum sp. were suspected to possess a good potential as inhibitors of COX-1 and COX-2.

  18. In Silico Analysis of the Potential of the Active Compounds Fucoidan and Alginate Derived from Sargassum Sp. as Inhibitors of COX-1 and COX-2

    PubMed Central

    Dewi, Lestari

    2016-01-01

    Introduction: The enzyme cyclooxygenase (COX) is an enzyme that catalyzes the formation of one of the mediators of inflammation, the prostaglandins. Inhibition of COX allegedly can improve inflammation-induced pathological conditions. Aim: The purpose of the present study was to evaluate the potential of Sargassum sp. components, Fucoidan and alginate, as COX inhibitors. Material and methods: The study was conducted by means of a computational (in silico) method. It was performed in two main stages, the docking between COX-1 and COX-2 with Fucoidan, alginate and aspirin (for comparison) and the analysis of the amount of interactions formed and the residues directly involved in the process of interaction. Results: Our results showed that both Fucoidan and alginate had an excellent potential as inhibitors of COX-1 and COX-2. Fucoidan had a better potential as an inhibitor of COX than alginate. COX inhibition was expected to provide a more favorable effect on inflammation-related pathological conditions. Conclusion: The active compounds Fucoidan and alginate derived from Sargassum sp. were suspected to possess a good potential as inhibitors of COX-1 and COX-2. PMID:27594740

  19. 75 FR 68598 - Notice of Appointment of Members to the National Agricultural Research, Extension, Education, and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-08

    ... follows: Category F. ``National Food Animal Science Society,'' Nancy M. Cox, Director, Kentucky... and processing, forestry research, crop and animal science, land-grant institutions, non-land grant college or university with a historic commitment to research in the food and agricultural sciences, food...

  20. STS-88 Mission Specialist Nancy Currie arrives at KSC for TCDT

    NASA Technical Reports Server (NTRS)

    1998-01-01

    STS-88 Mission Specialist Nancy J. Currie climbs out of a T-38 jet aircraft in which she arrived after dark at the Shuttle Landing Facility in order to take part in Terminal Countdown Demonstration Test (TCDT) activities. The TCDT provides the crew with simulated countdown exercises, emergency egress training, and opportunities to inspect their mission payloads in the orbiter's payload bay. Mission STS-88 is targeted for launch on Dec. 3, 1998. It is the first U.S. flight for the assembly of the International Space Station and will carry the Unity connecting module. Others in the STS-88 crew are Mission Commander Robert D. Cabana, Pilot Frederick W. 'Rick' Sturckow, Mission Specialists Jerry L. Ross, James H. Newman and Sergei Krikalev, a Russian cosmonaut. Ross and Newman will make three spacewalks to connect power, data and utility lines and install exterior equipment.

  1. Alan Stone and the ethics of forensic psychiatry: an overview.

    PubMed

    Miller, Glenn H

    2008-01-01

    In 1982, Alan Stone presented a keynote speech at the Annual Meeting of the American Academy of Psychiatry and the Law (AAPL) on the ethics of forensic psychiatry. That speech was sharply critical of the prevailing ethics standards and led forensic psychiatrists to study his ideas carefully. A quarter-century later, he returned to the AAPL's Annual Meeting to present his current thinking. This overview outlines the development of Stone's thought over 25 years and the dialectic among Stone and three critics: Paul Appelbaum, Ezra Griffith, and Stephen Morse. Stone is now more optimistic about the possibility of developing an ethic for forensic psychiatry.

  2. Differential effects of selective cyclooxygenase (COX)-1 and COX-2 inhibitors on anorexic response and prostaglandin generation in various tissues induced by zymosan.

    PubMed

    Naoi, Kazuhisa; Kogure, Suguru; Saito, Masataka; Hamazaki, Tomohito; Watanabe, Shiro

    2006-07-01

    We have shown that anorexic response is induced by intraperitoneal injection of zymosan in mice, although the role of prostaglandins in this response is relatively unknown as compared with lipopolysaccharide (LPS)-induced anorexic response. Indomethacin (0.5 and 2.0 mg/kg), a non-selective cyclooxygenase (COX) inhibitor, as well as meloxicam (0.5 mg/kg), a selective COX-2 inhibitor, but not FR122047 (2.0 mg/kg), a selective COX-1 inhibitor, attenuated zymosan-induced anorexia. Zymosan injection elevated COX-2 expression in brain and liver but not in small intestine and colon. Meloxicam (0.5 mg/kg) and FR122047 treatment (2.0 mg/kg) similarly suppressed the generation of brain prostaglandin E(2) (PGE(2)) and peritoneal prostacyclin (PGI(2)) upon zymosan injection. PGE(2) generation in liver upon zymosan injection was suppressed by meloxicam (0.5 mg/kg) but not by FR122047 treatment (2.0 mg/kg). Our observations suggest that COX-2 plays an important role in zymosan-induced anorexia, which is a similar feature in LPS-induced anorexic response. However, non-selective inhibition by selective COX-1 and COX-2 inhibitors of brain PGE(2) generation upon zymosan injection does not support the role of COX-2 expressed in brain in zymosan-induced anorexic response. PGE(2) generation in liver may account for peripheral role of COX-2 in zymosan-induced anorexic response.

  3. Isolation of (S)-(+)-naproxene from Musa acuminata. Inhibitory effect of naproxene and its 7-methoxy isomer on constitutive COX-1 and inducible COX-2.

    PubMed

    Abad, T; McNaughton-Smith, G; Fletcher, W Q; Echeverri, F; Diaz-Peñate, R; Tabraue, C; Ruiz de Galarreta, C M; López-Blanco, F; Luis, J G

    2000-06-01

    The isolation and characterisation of (S)-(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, a well known synthetic non-steroidal anti-inflammatory drug (naproxene), from a natural source is described for the first time. We evaluated the ability of naproxene and its 7-methoxy isomer to abrogate constitutive COX-1 and inducible COX-2 activity in human A549 cells. Naproxene inhibited COX-1 (IC50 = 3.42 microM) and COX-2 (IC50 = 1.53 microM), whereas the 7-methoxy isomer had no appreciable effect on COX-1 (IC50 > 100 microM) but also abrogated the activity of COX-2 enzyme (IC50 = 14.42 microM).

  4. Is the 'Cox effect' good for us?

    NASA Astrophysics Data System (ADS)

    Mellor, Felicity

    2012-10-01

    Some claim that recent increases in the number of students studying physics in the UK are due to the TV appearances of physicist Brian Cox. But as Felicity Mellor warns, the "Cox effect" may not be all good news.

  5. Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase

    PubMed Central

    Bode, Manuela; Woellhaf, Michael W.; Bohnert, Maria; van der Laan, Martin; Sommer, Frederik; Jung, Martin; Zimmermann, Richard; Schroda, Michael; Herrmann, Johannes M.

    2015-01-01

    Members of the twin Cx9C protein family constitute the largest group of proteins in the intermembrane space (IMS) of mitochondria. Despite their conserved nature and their essential role in the biogenesis of the respiratory chain, the molecular function of twin Cx9C proteins is largely unknown. We performed a SILAC-based quantitative proteomic analysis to identify interaction partners of the conserved twin Cx9C protein Cox19. We found that Cox19 interacts in a dynamic manner with Cox11, a copper transfer protein that facilitates metalation of the Cu(B) center of subunit 1 of cytochrome c oxidase. The interaction with Cox11 is critical for the stable accumulation of Cox19 in mitochondria. Cox19 consists of a helical hairpin structure that forms a hydrophobic surface characterized by two highly conserved tyrosine-leucine dipeptides. These residues are essential for Cox19 function and its specific binding to a cysteine-containing sequence in Cox11. Our observations suggest that an oxidative modification of this cysteine residue of Cox11 stimulates Cox19 binding, pointing to a redox-regulated interplay of Cox19 and Cox11 that is critical for copper transfer in the IMS and thus for biogenesis of cytochrome c oxidase. PMID:25926683

  6. COX2 Inhibition Reduces Aortic Valve Calcification In Vivo

    PubMed Central

    Wirrig, Elaine E.; Gomez, M. Victoria; Hinton, Robert B.; Yutzey, Katherine E.

    2016-01-01

    Objective Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality, which affects approximately 1% of the US population and is characterized by calcific nodule formation and stenosis of the valve. Klotho-deficient mice were used to study the molecular mechanisms of CAVD as they develop robust aortic valve (AoV) calcification. Through microarray analysis of AoV tissues from klotho-deficient and wild type mice, increased expression of the gene encoding cyclooxygenase 2/COX2 (Ptgs2) was found. COX2 activity contributes to bone differentiation and homeostasis, thus the contribution of COX2 activity to AoV calcification was assessed. Approach and Results In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells (VICs) prior to calcification formation. Similarly, COX2 expression is increased in human diseased AoVs. Treatment of cultured porcine aortic VICs with osteogenic media induces bone marker gene expression and calcification in vitro, which is blocked by inhibition of COX2 activity. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacologic inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks osteogenic gene expression. Conclusions COX2 expression is upregulated in CAVD and its activity contributes to osteogenic gene induction and valve calcification in vitro and in vivo. PMID:25722432

  7. The cardiac copper chaperone proteins Sco1 and CCS are up-regulated, but Cox 1 and Cox4 are down-regulated, by copper deficiency.

    PubMed

    Getz, Jean; Lin, Dingbo; Medeiros, Denis M

    2011-10-01

    Copper is ferried in a cell complexed to chaperone proteins, and in the heart much copper is required for cytochrome c oxidase (Cox). It is not completely understood how copper status affects the levels of these proteins. Here we determined if dietary copper deficiency could up- or down-regulate select copper chaperone proteins and Cox subunits 1 and 4 in cardiac tissue of rats. Sixteen weanling male Long-Evans rats were randomized into treatment groups, one group receiving a copper-deficient diet (<1 mg Cu/kg diet) and one group receiving a diet containing adequate copper (6 mg Cu/kg diet) for 5 weeks. Hearts were removed, weighed, and non-myofibrillar proteins separated to analyze for levels of CCS, Sco1, Ctr1, Cox17, Cox1, and Cox4 by SDS-PAGE and Western blotting. No changes were observed in the concentrations of CTR1 and Cox17 between copper-adequate and copper-deficient rats. CCS and Sco1 were up-regulated and Cox1 and Cox4 were both down-regulated as a result of copper deficiency. These data suggest that select chaperone proteins and may be up-regulated, and Cox1 and 4 down-regulated, by a dietary copper deficiency, whereas others appear not to be affected by copper status.

  8. Characterization of Free Radicals Formed from COX-Catalyzed DGLA Peroxidation

    PubMed Central

    Xiao, Ying; Gu, Yan; Purwaha, Preeti; Ni, Kunyi; Law, Benedict; Mallik, Sanku; Qian, Steven Y.

    2011-01-01

    Like arachidonic acid (AA), dihomo-γ-linolenic acid (DGLA) is a 20-carbon ω-6 polyunsaturated fatty acid and a substrate of cyclooxygenase (COX). Through free radical reactions, COX metabolizes DGLA and AA to form well-known bioactive metabolites, namely, the 1- and 2-series of prostaglandins (PGs1 and PGs2), respectively. Unlike PGs2, which are viewed as pro-inflammatory, PGs1 possess anti-inflammatory and anticancer activities. However, the mechanisms linking the PGs to their bioactivities are still unclear, and radicals generated in COX-DGLA have not been detected. In order to better understand PGs biology and determine whether different reactions occur in COX-DGLA than in COX-AA, we have used LC/ESR/MS with a spin trap, α-[4-pyridyl-1-oxide]-N-tert-butyl nitrone (POBN), to characterize the carbon-centered radicals formed from COX-DGLA in vitro, including cellular peroxidation. A total of five types of DGLA-derived radicals were characterized as POBN adducts: m/z 266, m/z 296 and m/z 550 (same as and/or similar to COX-AA), and m/z 324 and m/z 354 (exclusively from COX-DGLA). Our results suggested that C-15 oxygenation to form PGGs occurs in both COX-DGLA and COX-AA; however, C-8 oxygenation occurs exclusively in COX-DGLA. This new finding will be further investigated for its association with different bioactivities of PGs, with potential implications for inflammatory diseases. PMID:21310230

  9. Targeted Deletions of COX-2 and Atherogenesis in Mice

    PubMed Central

    Hui, Yiqun; Ricciotti, Emanuela; Crichton, Irene; Yu, Zhou; Wang, Dairong; Stubbe, Jane; Wang, Miao; Puré, Ellen; FitzGerald, Garret A.

    2010-01-01

    Background While the dominant product of vascular cyclooxygenase (COX)-2, prostacyclin (PGI2), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages (Mac) and T cells (TC) to atherogenesis. Methods and Results Deletion of Mac COX-2 (MacKO) was attained using LysMCre mice and suppressed completely lipopolysaccharide (LPS) stimulated Mac prostaglandin (PG) formation and LPS evoked systemic PG biosynthesis by ∼ 30%. LPS stimulated COX-2 expression was suppressed in polymorphonuclear leucocytes (PMN) isolated from MacKOs, but PG formation was not even detected in PMN supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic LdlR KOs. Deletion of Mac COX-2 appeared to remove a restraint on COX-2 expression in lesional non-leukocyte (CD45 and CD11b negative) vascular cells that express vascular cell adhesion molecule and variably, α-smooth muscle actin and vimentin, portending a shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts (TCKOs) depressed its modest upregulation by anti-CD3ε. However, biosynthesis of PGs, TC composition in lymphatic organs and atherogenesis in LDLR KOs were unaltered in TCKOs. Conclusions Mac COX-2, primarily a source of thromboxane A2 and PGE2, promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source of atheroprotective PGI2. TC COX-2 does not influence detectably TC development or function nor atherogenesis in mice. PMID:20530000

  10. Alan Bean and Don Peterson Wreath Laying Ceremony

    NASA Image and Video Library

    2018-05-30

    NASA’s Kennedy Space Center Visitor Complex hosted two remembrance ceremonies Wednesday, May 30 in honor of astronauts Alan Bean and Don Peterson, respectively. Bean, a member of the U.S. Astronaut Hall of Fame was selected to join NASA’s third astronaut class in 1963. He was the fourth person to walk on the Moon during the Apollo 12 mission in 1969. Bean went on to become the commander of the second crewed flight of Skylab in 1973 and an accomplished artist during his retirement. He passed away on May 26 at the age of 86. Peterson became a NASA astronaut in 1969. He flew on the maiden voyage of Space Shuttle Challenger in 1983 and was one of the first astronauts to perform a spacewalk from the shuttle. He passed away on May 27 at the age of 84.WreatWreljklaejlkjawekjwWwewerewrwefdsfdsgdfgsdfggdfsgdfsgdfsfdgdffgddsfgrtWrjelkwjlkrewsadjkl

  11. [From guinea pig to man: Tinea outbreak due to Trichophyton mentagrophytes var. porcellae in pet shops in Nancy (France)].

    PubMed

    Bloch, M; Cavignaux, R; Debourgogne, A; Dorin, J; Machouart, M; Contet-Audonneau, N

    2016-09-01

    Dermatophytes are responsible for widespread superficial fungal infections, currently representing a real public health problem. Some of the fungi involved in these mycoses are transmitted by pets, illustrating great host specificity within this fungal group. Thus, a new variety of zoophilic dermatophyte has been described in recent years by the Mycology Laboratory of the University Hospital of Nancy, within the complex T. mentagrophytes. This variant was named T. mentagrophytes var. porcellae, following the observation of a significant number of patients with dermatomycoses of exposed parts of the body and having had contact with a guinea pig. The current work follows this first description and aims to assess the frequency of T. mentagrophytes var. porcellae in guinea pigs within three pet shops in the region of Nancy (France). In total, almost two thirds of collected guinea pigs were carriers of this new dermatophyte. This study highlights the risks associated with the adaptation of dermatophytes to potential new hosts that may spread to new species. Thus, in this context, sanitary measures could be proposed to the pet shops, usually not informed of the risks facing the growing enthusiasm of the population for new pets, in order to limit contamination. Copyright © 2016. Published by Elsevier Masson SAS.

  12. Inhibition of cyclooxygenase (COX)-2 affects endothelial progenitor cell proliferation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Colleselli, Daniela; Bijuklic, Klaudija; Mosheimer, Birgit A.

    2006-09-10

    Growing evidence indicates that inducible cyclooxygenase-2 (COX-2) is involved in the pathogenesis of inflammatory disorders and various types of cancer. Endothelial progenitor cells recruited from the bone marrow have been shown to be involved in the formation of new vessels in malignancies and discussed for being a key point in tumour progression and metastasis. However, until now, nothing is known about an interaction between COX and endothelial progenitor cells (EPC). Expression of COX-1 and COX-2 was detected by semiquantitative RT-PCR and Western blot. Proliferation kinetics, cell cycle distribution and rate of apoptosis were analysed by MTT test and FACS analysis.more » Further analyses revealed an implication of Akt phosphorylation and caspase-3 activation. Both COX-1 and COX-2 expression can be found in bone-marrow-derived endothelial progenitor cells in vitro. COX-2 inhibition leads to a significant reduction in proliferation of endothelial progenitor cells by an increase in apoptosis and cell cycle arrest. COX-2 inhibition leads further to an increased cleavage of caspase-3 protein and inversely to inhibition of Akt activation. Highly proliferating endothelial progenitor cells can be targeted by selective COX-2 inhibition in vitro. These results indicate that upcoming therapy strategies in cancer patients targeting COX-2 may be effective in inhibiting tumour vasculogenesis as well as angiogenic processes.« less

  13. Astronaut Alan Bean flies the Astronaut Maneuvering Equipment in the OWS

    NASA Image and Video Library

    1973-08-28

    S73-34207 (28 Aug. 1973) --- Astronaut Alan L. Bean, Skylab 3 commander, flies the M509 astronaut Maneuvering Equipment, as seen in this photographic reproduction taken from a television transmission made by a color television camera in the Orbital Workshop (OWS) of the Skylab space station in Earth orbit. Bean is strapped into the back-mounted, hand-controlled Automatically Stabilized Maneuvering Unit (ASMU). The M509 exercise was in the forward dome area of the OWS. The dome area is about 22 feet in diameter and 19 feet from top to bottom. Photo credit: NASA

  14. Vacancy-mediated dehydrogenation of sodium alanate

    PubMed Central

    Gunaydin, Hakan; Houk, Kendall N.; Ozoliņš, Vidvuds

    2008-01-01

    Clarification of the mechanisms of hydrogen release and uptake in transition-metal-doped sodium alanate, NaAlH4, a prototypical high-density complex hydride, has fundamental importance for the development of improved hydrogen-storage materials. In this and most other modern hydrogen-storage materials, H2 release and uptake are accompanied by long-range diffusion of metal species. Using first-principles density-functional theory calculations, we have determined that the activation energy for Al mass transport via AlH3 vacancies is Q = 85 kJ/mol·H2, which is in excellent agreement with experimentally measured activation energies in Ti-catalyzed NaAlH4. The activation energy for an alternate decomposition mechanism via NaH vacancies is found to be significantly higher: Q = 112 kJ/mol·H2. Our results suggest that bulk diffusion of Al species is the rate-limiting step in the dehydrogenation of Ti-doped samples of NaAlH4 and that the much higher activation energies measured for uncatalyzed samples are controlled by other processes, such as breaking up of AlH4− complexes, formation/dissociation of H2 molecules, and/or nucleation of the product phases. PMID:18299582

  15. Cell-type-specific roles for COX-2 in UVB-induced skin cancer

    PubMed Central

    Herschman, Harvey

    2014-01-01

    In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2 flox/flox mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2 flox/flox;K14Cre + mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2 flox/flox;K14Cre + papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2 flox/flox; LysMCre + myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. PMID:24469308

  16. Cell-type-specific roles for COX-2 in UVB-induced skin cancer.

    PubMed

    Jiao, Jing; Mikulec, Carol; Ishikawa, Tomo-o; Magyar, Clara; Dumlao, Darren S; Dennis, Edward A; Fischer, Susan M; Herschman, Harvey

    2014-06-01

    In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2(flox/flox); LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Award for Distinguished Career Contributions to Education and Training in Psychology: Nancy S. Elman.

    PubMed

    2017-12-01

    The Award for Distinguished Career Contributions to Education and Training in Psychology is given in recognition of the efforts of psychologists who have made distinguished contributions to education and training, who have produced imaginative innovations, or who have been involved in the developmental phases of programs in education and training in psychology. The Career designation is added to the award at the discretion of the Education and Training Awards Committee to recognize continuous significant contributions made over a lifelong career in psychology. The 2017 recipient of this award is Nancy S. Elman, whose leadership roles have brought significant advancements for the education and training of psychologists. Her award citation, biography, and a selected bibliography are presented here. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  18. Thrombosis Is Reduced by Inhibition of COX-1, but Unaffected by Inhibition of COX-2, in an Acute Model of Platelet Activation in the Mouse

    PubMed Central

    Armstrong, Paul C.; Kirkby, Nicholas S.; Zain, Zetty N.; Emerson, Michael; Mitchell, Jane A.; Warner, Timothy D.

    2011-01-01

    Background Clinical use of selective inhibitors of cyclooxygenase (COX)-2 appears associated with increased risk of thrombotic events. This is often hypothesised to reflect reduction in anti-thrombotic prostanoids, notably PGI2, formed by COX-2 present within endothelial cells. However, whether COX-2 is actually expressed to any significant extent within endothelial cells is controversial. Here we have tested the effects of acute inhibition of COX on platelet reactivity using a functional in vivo approach in mice. Methodology/Principal Findings A non-lethal model of platelet-driven thromboembolism in the mouse was used to assess the effects of aspirin (7 days orally as control) diclofenac (1 mg.kg−1, i.v.) and parecoxib (0.5 mg.kg−1, i.v.) on thrombus formation induced by collagen or the thromboxane (TX) A2-mimetic, U46619. The COX inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo. Collagen and U46619 caused in vivo thrombus formation with the former, but not latter, sensitive to oral dosing with aspirin. Diclofenac inhibited COX-1 and COX-2 ex vivo and reduced thrombus formation in response to collagen, but not U46619. Parecoxib inhibited only COX-2 and had no effect upon thrombus formation caused by either agonist. Conclusions/Significance Inhibition of COX-1 by diclofenac or aspirin reduced thrombus formation induced by collagen, which is partly dependent upon platelet-derived TXA2, but not that induced by U46619, which is independent of platelet TXA2. These results are consistent with the model demonstrating the effects of COX-1 inhibition in platelets, but provide no support for the hypothesis that acute inhibition of COX-2 in the circulation increases thrombosis. PMID:21629780

  19. Toward the understanding of the molecular basis for the inhibition of COX-1 and COX-2 by phenolic compounds present in Uruguayan propolis and grape pomace.

    PubMed

    Paulino, Margot; Alvareda, Elena; Iribarne, Federico; Miranda, Pablo; Espinosa, Victoria; Aguilera, Sara; Pardo, Helena

    2016-12-01

    Propolis and grape pomace have significant amounts of phenols which can take part in anti-inflammatory mechanisms. As the cyclooxygenases 1 and 2 (COX-1 and COX-2) are involved in said mechanisms, the possibility for a selective inhibition of COX-2 was analyzed in vitro and in silico. Propolis and grape pomace from Uruguayan species were collected, extracted in hydroalcoholic mixture and analyzed. Based on phenols previously identified, and taking as reference the crystallographic structures of COX-1 and COX-2 in complex with the commercial drug Celecoxib, a molecular docking procedure was devised to adjust 123 phenolic molecular models at the enzyme-binding sites. The most important results of this work are that the extracts have an overall inhibition activity very similar in COX-1 and COX-2, i.e. they do not possess selective inhibition activity for COX-2. Nevertheless, 10 compounds of the phenolic database turned out to be more selective and 94 phenols resulted with similar selectivity than Celecoxib, an outcome that accounts for the overall experimental inhibition measures. Binding site environment observations showed increased polarity in COX-2 as compared with COX-1, suggesting that polarity is the key for selectivity. Accordingly, the screening of molecular contacts pointed to the residues: Arg106, Gln178, Leu338, Ser339, Tyr341, Tyr371, Arg499, Ala502, Val509, and Ser516, which would explain, at the atomic level, the anti-inflammatory effect of the phenolic compounds. Among them, Gln178 and Arg499 appear to be essential for the selective inhibition of COX-2.

  20. Astronaut Alan Shepard near Lunar Landing Training Vehicle prior to test

    NASA Image and Video Library

    1970-12-14

    S70-56287 (14 Dec. 1970) --- Astronaut Alan B. Shepard Jr., commander of the Apollo 14 lunar landing mission, stands near a Lunar Landing Training Vehicle (LLTV) prior to a test flight at Ellington Air Force Base, Houston, on Dec. 14, 1970. Shepard will be at the controls of the Apollo 14 Lunar Module (LM) when it lands on the moon in the highlands near Fra Mauro. Astronaut Stuart A. Roosa, command module pilot, will remain with the Command and Service Modules (CSM) in lunar orbit while astronauts Shepard and Edgar D. Mitchell, lunar module pilot, descend in the LM to explore the moon.

  1. From Mercury to Apollo: astronaut Alan Shepard reflects on life support and other space issues [interview by Winston Huff].

    PubMed

    Shepard, A

    1995-01-01

    Alan Shepard was one of the original Mercury astronauts. He became the first American in space on May 5, 1961, in the Freedom 7 capsule, during a 15 minute suborbital trip reaching 115 miles altitude and 302 miles down the Atlantic tracking range. Grounded by an inner ear problem, he served as Chief of the Astronaut Office for several years. After an operation to correct the problem, he commanded the Apollo 14 moon mission in 1971. He retired as a Rear Admiral in 1974. Here, Alan Shepard offers his views on life support comedies and tragedies, going back to the moon, future drivers of the manned space flight program, the benefits of the space program, joint NASA and Russia missions, how his NASA experience affected his personal life, and the profitability of working with NASA.

  2. The Third Turn toward the Social: Nancy Welch's "Living Room," Tony Scott's "Dangerous Writing," and Rhetoric and Composition's Turn toward Grassroots Political Activism

    ERIC Educational Resources Information Center

    Kinney, Kelly; Girshin, Thomas; Bowlin, Barrett

    2013-01-01

    This review essay examines recent texts by Nancy Welch and Tony Scott, both of which use embodied activism as a starting point for their inquiries. Taken together, these works point to a distinct shift in composition studies' turn toward the social, one that calls on workers both within and outside the academy to actively engage in grassroots…

  3. The Great Tunes of the Hough: Music and Song in Alan Garner's "The Stone Book Quartet "

    ERIC Educational Resources Information Center

    Godek, Sarah

    2004-01-01

    Although song and music are often elements in children's books, little critical attention has gone into examining their literary uses. Alan Garner's "The Stone Book Quartet" is an example of four texts for children in which music plays a vital role. The several snatches of traditional songs found throughout the quartet bring to life the culture of…

  4. Overexpression of COX-2 in Rat Oral Cancers and Prevention of Oral Carcinogenesis in Rats by Selective and Non-Selective COX Inhibitors

    PubMed Central

    McCormick, David L.; Phillips, Jonathan M.; Horn, Thomas L.; Johnson, William D.; Steele, Vernon E.; Lubet, Ronald A.

    2009-01-01

    Oral squamous cell carcinomas induced in rats by 4-nitroquinoline-1-oxide (NQO) demonstrate substantial overexpression of cyclooxygenase-2 (COX-2) when compared to adjacent phenotypically normal oral tissues. By contrast, neither 5-lipoxygenase (5-LOX) nor 12-lipoxygenase (12-LOX) is overexpressed in rat oral cancers. Two chemoprevention studies were performed to test the resulting hypothesis that COX-2 is a useful target for oral cancer chemoprevention in the rat. In both studies, male F344 rats received drinking water exposure to NQO (20 ppm) for 10 weeks, followed by administration of chemopreventive agents from week 10 until study termination at week 26. In the first study, groups of rats were fed basal diet (control), or basal diet supplemented with the selective COX-2 inhibitor, celecoxib (500 or 1500 mg/kg diet); the non-selective COX inhibitor, piroxicam (50 or 150 mg/kg diet); or the 5-LOX inhibitor, zileuton (2000 mg/kg diet). In the second study, rats were fed basal diet (control) or basal diet supplemented with NO-Naproxen (180 or 90 mg/kg diet), a non-selective COX inhibitor that demonstrates reduced gastrointestinal toxicity. When compared to dietary controls, celecoxib decreased oral cancer incidence, cancer invasion score, and cancer-related mortality. Piroxicam decreased cancer-related mortality and cancer invasion score, while NO-naproxen decreased oral cancer incidence and cancer invasion score. By contrast, zileuton demonstrated no chemopreventive activity by any parameter assessed. These data demonstrate that both selective and non-selective inhibitors of COX-2 can prevent NQO-induced oral carcinogenesis in rats. The chemopreventive activity of COX inhibitors may be linked to overexpression of their enzymatic target in incipient oral neoplasms. PMID:20051374

  5. An appreciation of Richard Threlkeld Cox

    NASA Astrophysics Data System (ADS)

    Tribus, Myron

    2002-05-01

    Richard T. Cox's contributions to the foundations of probability theory and inductive logic are not generally appreciated or understood. This paper reviews his life and accomplishments, especially those in his book The Algebra of Probable Inference and his final publication Inference and Inquiry which, in this author's opinion, has the potential to influence in a significant way the design and analysis of self organizing systems which learn from experience. A simple application to the simulation of a neuron is presented as an example of the power of Cox's contribution.

  6. Targeting Estrogen-Induced COX-2 Activity in Lymphangioleiomyomatosis (LAM)

    DTIC Science & Technology

    2014-12-01

    production was also increased in TSC2-deficient cells. In preclinical models, both Celecoxib and aspirin reduced tumor development. LAM patients had...increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. In vitro, 15-epi-lipoxin-A4 reduced the proliferation of...inhibit COX-2 pharmacologically, we treated TSC2-deficient cells with aspirin or NS398, and found that both agents reduced COX-2 protein levels and

  7. Astronaut Alan Shepard - U.S.S. Champlain - Post-Recovery Mercury Capsule

    NASA Image and Video Library

    1961-05-05

    S61-02727 (5 May 1961) --- Astronaut Alan B. Shepard is seen on the deck of the USS Lake Champlain after the recovery of his Mercury capsule in the western Atlantic Ocean. Shepard and the Mercury spacecraft designated the ?Freedom 7? were flown to the deck of the recovery ship within 11 minutes of splashdown. MR-3 was the United States? first manned space mission. The spacecraft attained a maximum speed of 5,180 miles per hour, reached an altitude of 116 1/2 statute miles, and landed 302 statute miles downrange from Cape Canaveral, Florida. The suborbital mission lasted 15 minutes and 22 seconds. Photo credit: NASA or National Aeronautics and Space Administration

  8. An Interview with Alan J. Hovestadt: AAMFT Past President and Long-Time Marriage and Family Counselor Educator

    ERIC Educational Resources Information Center

    Juhnke, Gerald A.; Sunich, Michael F.; Coll, Kenneth M.; Lebron-Striker, Maritza

    2009-01-01

    Alan J. Hovestadt, EdD, is the immediate past president of the 24,000 member American Association for Marriage and Family Therapy (AAMFT) and a long-time IAMFC member who served as an IAMFC founding board member when American Counseling Association (ACA) first granted International Association of Marriage and Family Counselors (IAMFC) divisional…

  9. [The beginning of the teaching of chemistry in Lorraine: the Royal College of Medicine and the Faculty of Medicine of Nancy (1752 and 1776)].

    PubMed

    Labrude, Pierre

    2005-01-01

    The faculty of medicine of the university created in Pont-à-Mousson in the second part of the XVIth century, transferred to Nancy in 1768, was not in possession of a chair of chemistry, but, in the middle of the XVIIIth century, it was interested by the development of this science. In Nancy, the Royal College of medicine, created by King Stanislas in 1752, disposed of a professor of chemistry since 1756, and also of a demonstrator who was one of the apothecaries of the town. In Metz, a course of this science occurred between 1756 and 1769 with the apothecary Thyrion. In 1776, the physician Henry Michel du Tennetar and the apothecary Pierre-François Nicolas opened a private course of chemistry, immediately transformed into a chair of the faculty of medicine. This chair will be maintained until Révolution. The personality and work of Michel du Tennetar and Nicolas, the circumstances and conditions of the creation of the chair, the inheritance of Michel, and the appointment of the demonstrator, also an apothecary, are successively described.

  10. COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis

    PubMed Central

    2014-01-01

    Background Overexpression of cyclooxygenase-2 (COX-2) has been implicated in oncogenesis and progression of adenocarcinomas of the pancreatic head. The data on the prognostic importance of COX expression in these tumours is inconsistent and conflicting. We evaluated how COX-2 overexpression affected overall postoperative survival in pancreatic head adenocarcinomas. Methods The study included 230 consecutive pancreatoduodenectomies for pancreatic cancer (PC, n = 92), ampullary cancer (AC, n = 62) and distal bile duct cancer (DBC, n = 76). COX-2 expression was assessed by immunohistochemistry. Associations between COX-2 expression and histopathologic variables including degree of differentiation, histopathologic type of differentiation (pancreatobiliary vs. intestinal) and lymph node ratio (LNR) were evaluated. Unadjusted and adjusted survival analysis was performed. Results COX-2 staining was positive in 71% of PC, 77% in AC and 72% in DBC. Irrespective of tumour origin, overall patient survival was more favourable in patients with COX-2 positive tumours than COX-2 negative (p = 0.043 in PC, p = 0.011 in AC, p = 0.06 in DBC). In tumours of pancreatobiliary type of histopathological differentiation, COX-2 expression did not significantly affect overall patient survival. In AC with intestinal differentiation COX-2 expression significantly predicted favourable survival (p = 0.003). In PC, COX-2 expression was significantly associated with high degree of differentiation (p = 0.002). COX-2 and LNR independently predicted good prognosis in a multivariate model. Conclusions COX-2 is overexpressed in pancreatic cancer, ampullary cancer and distal bile duct cancer and confers a survival benefit in all three cancer types. In pancreatic cancer, COX-2 overexpression is significantly associated with the degree of differentiation and independently predicts a favourable prognosis. PMID:24950702

  11. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases.

    PubMed

    Berkson, Burton M; Rubin, Daniel M; Berkson, Arthur J

    2009-12-01

    The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF(k)B, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.

  12. Cox-2 inhibitory effects of naturally occurring and modified fatty acids.

    PubMed

    Ringbom, T; Huss, U; Stenholm , A; Flock, S; Skattebøl, L; Perera, P; Bohlin, L

    2001-06-01

    In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-7,11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and alpha-LNA were most selective toward COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha-LNA and compound 2 showed selectivity toward COX-2.

  13. Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors.

    PubMed

    Vernieri, Ermelinda; Gomez-Monterrey, Isabel; Milite, Ciro; Grieco, Paolo; Musella, Simona; Bertamino, Alessia; Scognamiglio, Ilaria; Alcaro, Stefano; Artese, Anna; Ortuso, Francesco; Novellino, Ettore; Sala, Marina; Campiglia, Pietro

    2013-01-01

    Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 20(3) possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs.

  14. Transgenic expression of cyclooxygenase-2 (COX2) causes premature aging phenotypes in mice.

    PubMed

    Kim, Joohwee; Vaish, Vivek; Feng, Mingxiao; Field, Kevin; Chatzistamou, Ioulia; Shim, Minsub

    2016-10-07

    Cyclooxygenase (COX) is a key enzyme in the biosynthesis of prostanoids, lipid signaling molecules that regulate various physiological processes. COX2, one of the isoforms of COX, is highly inducible in response to a wide variety of cellular and environmental stresses. Increased COX2 expression is thought to play a role in the pathogenesis of many age-related diseases. COX2 expression is also reported to be increased in the tissues of aged humans and mice, which suggests the involvement of COX2 in the aging process. However, it is not clear whether the increased COX2 expression is causal to or a result of aging. We have now addressed this question by creating an inducible COX2 transgenic mouse model. Here we show that post-natal expression of COX2 led to a panel of aging-related phenotypes. The expression of p16, p53, and phospho-H2AX was increased in the tissues of COX2 transgenic mice. Additionally, adult mouse lung fibroblasts from COX2 transgenic mice exhibited increased expression of the senescence-associated β-galactosidase. Our study reveals that the increased COX2 expression has an impact on the aging process and suggests that modulation of COX2 and its downstream signaling may be an approach for intervention of age-related disorders.

  15. COX-2/EGFR expression and survival among women with adenocarcinoma of the lung

    PubMed Central

    Van Dyke, Alison L.; Cote, Michele L.; Prysak, Geoffrey M.; Claeys, Gina B.; Wenzlaff, Angie S.; Murphy, Valerie C.; Lonardo, Fulvio; Schwartz, Ann G.

    2008-01-01

    Previous studies suggest that cyclooxygenase-2 (COX-2) expression may predict survival among patients with non-small cell lung cancer. COX-2 may interact with epidermal growth factor receptor (EGFR), suggesting that combined COX-2/EGFR expression may provide predictive value. The extent to which their independent or combined expression is associated with prognosis in women with adenocarcinoma of the lung is unknown. In the present study, we examined relationships between COX-2 expression (n = 238), EGFR expression (n = 158) and dual COX-2/EGFR expression (n = 157) and survival among women with adenocarcinoma of the lung. Overall survival was estimated by constructing Cox proportional hazards models adjusting for other significant variables and stratifying by stage at diagnosis and race. Clinical or demographic parameters were not associated with either COX-2 or EGFR expression. Patients with COX-2-positive tumors tended to have poorer prognosis than did patients with COX-2-negative tumors [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.01–2.78]. African-Americans with COX-2-positive tumors had a statistically non-significant higher risk of death than African-Americans with COX-2-negative tumors (HR 5.58, 95% CI 0.64–48.37). No association between COX-2 expression and survival was observed among Caucasians (HR 1.29, 95% CI 0.72–2.30). EGFR expression was associated with a 44% reduction in the risk of death (HR 0.56, 95% CI 0.32–0.98). COX-2−/EGFR+ tumor expression, but not COX-2+/EGFR+ tumor expression, was associated with survival when compared with other combined expression results. In conclusion, COX-2 and EGFR expression, but not combined COX-2+/EGFR+ expression, independently predict survival of women with adenocarcinoma of the lung. PMID:18453539

  16. NASA Remembers Astronaut Alan Bean - Moonwalker, Skylab Commander, Artist

    NASA Image and Video Library

    2018-05-26

    Apollo 12 astronaut Alan Bean has died at the age of 86. Bean walked on the Moon in 1969, commanded the second Skylab crew in 1973 and went on in retirement to paint the remarkable worlds and sights he had seen like no other artist. Born in Wheeler, Texas, Bean got an aeronautical engineering degree from the University of Texas before joining the Navy, where he spent four years with a jet attack squadron. As a Navy test pilot, Bean flew several types of aircraft before he was selected with the third group of NASA astronauts in October 1963. He served as a backup for crewmembers on Gemini 10 and Apollo 9. After his Apollo and Skylab flights, Bean remained with NASA until 1981, when he retired to devote full time to painting. He followed that dream for many years at his home studio in Houston, with considerable success. His paintings were particularly popular among space enthusiasts.

  17. Radiolarians, foraminifers, and biostratigraphy of the Coniacian-Campanian deposits of the Alan-Kyr Section, Crimean Mountains

    NASA Astrophysics Data System (ADS)

    Bragina, L. G.; Beniamovsky, V. N.; Kopaevich, L. F.

    2016-01-01

    Data on the distribution of radiolarians and planktonic and benthic foraminifers are obtained for the first time from the Alan-Kyr Section (Coniacian-Campanian), in the central regions of the Crimean Mountains. Radiolarian biostrata, previously established from Ak-Kaya Mountain (central regions of the Crimean Mountains) were traced: Alievium praegallowayi-Crucella plana (upper Coniacian-lower Santonian), Alievium gallowayi-Crucella espartoensis (upper Santonian without the topmost part), and Dictyocephalus (Dictyocryphalus) (?) legumen-Spongosaturninus parvulus (upper part of the upper Santonian). Radiolarians from the Santonian-Campanian boundary beds of the Crimean Mountains are studied for the first time, and Prunobrachium sp. ex gr. crassum-Diacanthocapsa acanthica Beds (uppermost Santonian-lower Campanian) are recognized. Bolivinoides strigillatus Beds (upper Santonian) and Stensioeina pommerana-Anomalinoides (?) insignis Beds (upper part of the upper Santonian-lower part of the lower Campanian) are recognized. Eouvigerina aspera denticulocarinata Beds (middle and upper parts of the lower Campanian) and Angulogavelinella gracilis Beds (upper part of the upper Campanian are recognized on the basis of benthic foraminifers. These beds correspond to the synchronous biostrata of the East European Platform and Mangyshlak. Marginotruncana coronata- Concavatotruncana concavata Beds (Coniacian-upper Santonian), Globotruncanita elevata Beds (terminal Santonian), and Globotruncana arca Beds (lower Campanian) are recognized on the basis of planktonic foraminifers. Radiolarian and planktonic and benthic foraminiferal data agree with one another. The position of the Santonian-Campanian boundary in the Alan-Kyr Section, which is located stratigraphically above the levels of the latest occurrence of Concavatotruncana concavata and representatives of the genus Marginotruncana, is refined, i.e., at the level of the first appearance of Globotruncana arca. A gap in the Middle

  18. The reactivity of sodium alanates with O[2], H[2]O, and CO[2] : an investigation of complex metal hydride contamination in the context of automotive systems.

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dedrick, Daniel E.; Bradshaw, Robert W.; Behrens, Richard, Jr.

    2007-08-01

    Safe and efficient hydrogen storage is a significant challenge inhibiting the use of hydrogen as a primary energy carrier. Although energy storage performance properties are critical to the success of solid-state hydrogen storage systems, operator and user safety is of highest importance when designing and implementing consumer products. As researchers are now integrating high energy density solid materials into hydrogen storage systems, quantification of the hazards associated with the operation and handling of these materials becomes imperative. The experimental effort presented in this paper focuses on identifying the hazards associated with producing, storing, and handling sodium alanates, and thus allowingmore » for the development and implementation of hazard mitigation procedures. The chemical changes of sodium alanates associated with exposure to oxygen and water vapor have been characterized by thermal decomposition analysis using simultaneous thermogravimetric modulated beam mass spectrometry (STMBMS) and X-ray diffraction methods. Partial oxidation of sodium alanates, an alkali metal complex hydride, results in destabilization of the remaining hydrogen-containing material. At temperatures below 70 C, reaction of sodium alanate with water generates potentially combustible mixtures of H{sub 2} and O{sub 2}. In addition to identifying the reaction hazards associated with the oxidation of alkali-metal containing complex hydrides, potential treatment methods are identified that chemically stabilize the oxidized material and reduce the hazard associated with handling the contaminated metal hydrides.« less

  19. Compensatory Hypertrophy Induced by Ventricular Cardiomyocyte Specific COX-2 Expression in Mice

    PubMed Central

    Streicher, John M.; Kamei, Kenichiro; Ishikawa, Tomo-o; Herschman, Harvey; Wang, Yibin

    2010-01-01

    Cyclooxygenase-2 (COX-2) is an important mediator of inflammation in stress and disease states. Recent attention has focused on the role of COX-2 in human heart failure and diseases, due to the finding that highly specific COX-2 inhibitors (i.e. Vioxx) increased the risk of myocardial infarction and stroke in chronic users. However, the specific impact of COX-2 expression in the intact heart remains to be determined. We report here the development of a transgenic mouse model, using a loxP-Cre approach, that displays robust COX-2 overexpression and subsequent prostaglandin synthesis specifically in ventricular myocytes. Histological, functional and molecular analyses showed that ventricular myocyte specific COX-2 overexpression led to cardiac hypertrophy and fetal gene marker activation, but with preserved cardiac function. Therefore, specific induction of COX-2 and prostaglandin in vivo is sufficient to induce compensated hypertrophy and molecular remodeling. PMID:20170663

  20. Box-Cox transformation of firm size data in statistical analysis

    NASA Astrophysics Data System (ADS)

    Chen, Ting Ting; Takaishi, Tetsuya

    2014-03-01

    Firm size data usually do not show the normality that is often assumed in statistical analysis such as regression analysis. In this study we focus on two firm size data: the number of employees and sale. Those data deviate considerably from a normal distribution. To improve the normality of those data we transform them by the Box-Cox transformation with appropriate parameters. The Box-Cox transformation parameters are determined so that the transformed data best show the kurtosis of a normal distribution. It is found that the two firm size data transformed by the Box-Cox transformation show strong linearity. This indicates that the number of employees and sale have the similar property as a firm size indicator. The Box-Cox parameters obtained for the firm size data are found to be very close to zero. In this case the Box-Cox transformations are approximately a log-transformation. This suggests that the firm size data we used are approximately log-normal distributions.

  1. Predicting a future lifetime through Box-Cox transformation.

    PubMed

    Yang, Z

    1999-09-01

    In predicting a future lifetime based on a sample of past lifetimes, the Box-Cox transformation method provides a simple and unified procedure that is shown in this article to meet or often outperform the corresponding frequentist solution in terms of coverage probability and average length of prediction intervals. Kullback-Leibler information and second-order asymptotic expansion are used to justify the Box-Cox procedure. Extensive Monte Carlo simulations are also performed to evaluate the small sample behavior of the procedure. Certain popular lifetime distributions, such as Weibull, inverse Gaussian and Birnbaum-Saunders are served as illustrative examples. One important advantage of the Box-Cox procedure lies in its easy extension to linear model predictions where the exact frequentist solutions are often not available.

  2. COX-2 Expression Correlates With Survival in Patients With Osteosarcoma Lung Metastases

    PubMed Central

    Rodriguez, Nidra I.; Hoots, William Keith; Koshkina, Nadezhda V.; Morales-Arias, Jaime A.; Arndt, Carola A.; Inwards, Carrie Y.; Hawkins, Douglas S.; Munsell, Mark F.; Kleinerman, Eugenie S.

    2009-01-01

    Summary The purpose of this study was to determine whether a correlation exists between tumor cyclooxygenase (COX)-2 expression and disease-specific survival in patients with osteosarcoma lung metastases. Thirty-six patients diagnosed with osteosarcoma lung metastases between the years 1990 and 2001 were included in this retrospective study. The majority of the patients (72%) presented newly -diagnosed osteosarcoma lung metastases whereas the remaining patients (28%) presented recurrent disease. Clinicopathologic parameters were obtained from patients’ clinical records. Tissue samples were obtained at the time of resection of the lung metastases and stained for COX-2 using immunohistochemistry. Samples were graded according to the intensity of COX-2 staining (grade 0: negative, grade 1: very weak, grade 2: weak, grade 3: moderate, and grade 4: strong). COX-2 staining was correlated with disease-specific survival and clinicopathologic parameters using the Jonckheere-Terpstra and the Kruskal-Wallis tests. All patients with grade 3 or 4 COX-2 expression died of osteosarcoma lung metastases. Ten percent of patients with grade 2 COX-2 expression and 29% of patients with grade 1 expression were alive and free of disease at the last follow-up. By contrast, 60% of the patients with grade 0 COX-2 expression were alive and free of disease at the last follow-up. No association between COX-2 expression and clinicopathologic parameters was found. However, COX-2 expression correlated inversely with disease-specific survival in patients with osteosarcoma lung metastases. Our data indicate that COX-2 expression in metastatic osteosarcoma may have prognostic significance. PMID:18797196

  3. Robots testing robots: ALAN-Arm, a humanoid arm for the testing of robotic rehabilitation systems.

    PubMed

    Brookes, Jack; Kuznecovs, Maksims; Kanakis, Menelaos; Grigals, Arturs; Narvidas, Mazvydas; Gallagher, Justin; Levesley, Martin

    2017-07-01

    Robotics is increasing in popularity as a method of providing rich, personalized and cost-effective physiotherapy to individuals with some degree of upper limb paralysis, such as those who have suffered a stroke. These robotic rehabilitation systems are often high powered, and exoskeletal systems can attach to the person in a restrictive manner. Therefore, ensuring the mechanical safety of these devices before they come in contact with individuals is a priority. Additionally, rehabilitation systems may use novel sensor systems to measure current arm position. Used to capture and assess patient movements, these first need to be verified for accuracy by an external system. We present the ALAN-Arm, a humanoid robotic arm designed to be used for both accuracy benchmarking and safety testing of robotic rehabilitation systems. The system can be attached to a rehabilitation device and then replay generated or human movement trajectories, as well as autonomously play rehabilitation games or activities. Tests of the ALAN-Arm indicated it could recreate the path of a generated slow movement path with a maximum error of 14.2mm (mean = 5.8mm) and perform cyclic movements up to 0.6Hz with low gain (<1.5dB). Replaying human data trajectories showed the ability to largely preserve human movement characteristics with slightly higher path length and lower normalised jerk.

  4. DPPC regulates COX-2 expression in monocytes via phosphorylation of CREB

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Morris, R.H.K.; Tonks, A.J.; Jones, K.P.

    2008-05-23

    The major phospholipid in pulmonary surfactant dipalmitoyl phosphatidylcholine (DPPC) has been shown to modulate inflammatory responses. Using human monocytes, this study demonstrates that DPPC significantly increased PGE{sub 2} (P < 0.05) production by 2.5-fold when compared to untreated monocyte controls. Mechanistically, this effect was concomitant with an increase in COX-2 expression which was abrogated in the presence of a COX-2 inhibitor. The regulation of COX-2 expression was independent of NF-{kappa}B activity. Further, DPPC increased the phosphorylation of the cyclic AMP response element binding protein (CREB; an important nuclear transcription factor important in regulating COX-2 expression). In addition, we also showmore » that changing the fatty acid groups of PC (e.g. using L-{alpha}-phosphatidylcholine {beta}-arachidonoyl-{gamma}-palmitoyl (PAPC)) has a profound effect on the regulation of COX-2 expression and CREB activation. This study provides new evidence for the anti-inflammatory activity of DPPC and that this activity is at least in part mediated via CREB activation of COX-2.« less

  5. Flavocoxid Inhibits Phospholipase A2, Peroxidase Moieties of the Cyclooxygenases (COX), and 5-Lipoxygenase, Modifies COX-2 Gene Expression, and Acts as an Antioxidant

    PubMed Central

    Burnett, Bruce P.; Bitto, Alessandra; Altavilla, Domenica; Squadrito, Francesco; Levy, Robert M.; Pillai, Lakshmi

    2011-01-01

    The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA2) (IC50 = 60 μg/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC50 = 12.3) and COX-2 (IC50 = 11.3 μg/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC50 = 110 μg/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC50 = 38 μg/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS). PMID:21765617

  6. Flavocoxid inhibits phospholipase A2, peroxidase moieties of the cyclooxygenases (COX), and 5-lipoxygenase, modifies COX-2 gene expression, and acts as an antioxidant.

    PubMed

    Burnett, Bruce P; Bitto, Alessandra; Altavilla, Domenica; Squadrito, Francesco; Levy, Robert M; Pillai, Lakshmi

    2011-01-01

    The multiple mechanisms of action for flavocoxid relating to arachidonic acid (AA) formation and metabolism were studied in vitro. Flavocoxid titrated into rat peritoneal macrophage cultures inhibited cellular phospholipase A2 (PLA(2)) (IC(50) = 60 μg/mL). In in vitro enzyme assays, flavocoxid showed little anti-cyclooxygenase (CO) activity on COX-1/-2 enzymes, but inhibited the COX-1 (IC(50) = 12.3) and COX-2 (IC(50) = 11.3 μg/mL) peroxidase (PO) moieties as well as 5-lipoxygenase (5-LOX) (IC(50) = 110 μg/mL). No detectable 5-LOX inhibition was found for multiple traditional and COX-2 selective NSAIDs. Flavocoxid also exhibited strong and varied antioxidant capacities in vitro and decreased nitrite levels (IC(50) = 38 μg/mL) in rat peritoneal macrophages. Finally, in contrast to celecoxib and ibuprofen, which upregulated the cox-2 gene, flavocoxid strongly decreased expression. This work suggests that clinically favourable effects of flavocoxid for management of osteoarthritis (OA) are achieved by simultaneous modification of multiple molecular pathways relating to AA metabolism, oxidative induction of inflammation, and neutralization of reactive oxygen species (ROS).

  7. Exploring selectivity requirements for COX-2 versus COX-1 binding of 2-(5-phenyl-pyrazol-1-yl)-5-methanesulfonylpyridines using topological and physico-chemical parameters.

    PubMed

    Chakraborty, Santanu; Sengupta, Chandana; Roy, Kunal

    2005-04-01

    Considering the current need for development of selective cyclooxygenase-2 (COX-2) inhibitors, an attempt has been made to explore physico-chemical requirements of 2-(5-phenyl-pyrazol-1-yl)-5-methanesulfonylpyridines for binding with COX-1 and COX-2 enzyme subtypes and also to explore the selectivity requirements. In this study, E-states of different common atoms of the molecules (calculated according to Kier & Hall), first order valence connectivity and physicochemical parameters (hydrophobicity pi, Hammett sigma and molar refractivity MR of different ring substituents) were used as independent variables along with suitable dummy parameters in the stepwise regression method. The best equation describing COX-1 binding affinity [n = 25, Q2 = 0.606, R(a)2 = 0.702, R2 = 0.752, R = 0.867, s = 0.447, F = 15.2 (df 4, 20)] suggests that the COX-1 binding affinity increases in the presence of a halogen substituent at R1 position and a p-alkoxy or p-methylthio substituent at R2 position. Furthermore, a difluoromethyl group is preferred over a trifluoromethyl group at R position for the COX-1 binding. The best equation describing COX-2 binding affinity [n = 32, Q2 = 0.622, R(a)2= 0.692, R2 = 0.732, R = 0.856, s = 0.265, F = 18.4 (df 4, 27)] shows that the COX-2 binding affinity increases with the presence of a halogen substituent at R1 position and increase of size of R2 substituents. However, it decreases in case of simultaneous presence of 3-chloro and 4-methoxy groups on the phenyl nucleus and in the presence of highly lipophilic R2 substituents. The best selectivity relation [n = 25, Q2 = 0.455, R(a)2 = 0.605, R2 = 0.670, R = 0.819, s = 0.423, F = 10.2 (df 4, 20)] suggests that the COX-2 selectivity decreases in the presence of p-alkoxy group and electron-withdrawing para substituents at R2 position. Again, a trifluoro group is conductive for the selectivity instead of a difluoromethyl group at R position. Furthermore, branching may also play significant role in

  8. Nucleobindin Co-Localizes and Associates with Cyclooxygenase (COX)-2 in Human Neutrophils

    PubMed Central

    Leclerc, Patrick; Biarc, Jordane; St-Onge, Mireille; Gilbert, Caroline; Dussault, Andrée-Anne; Laflamme, Cynthia; Pouliot, Marc

    2008-01-01

    The inducible cyclooxygenase isoform (COX-2) is associated with inflammation, tumorigenesis, as well as with physiological events. Despite efforts deployed in order to understand the biology of this multi-faceted enzyme, much remains to be understood. Nucleobindin (Nuc), a ubiquitous Ca2+-binding protein, possesses a putative COX-binding domain. In this study, we investigated its expression and subcellular localization in human neutrophils, its affinity for COX-2 as well as its possible impact on PGE2 biosynthesis. Complementary subcellular localization approaches including nitrogen cavitation coupled to Percoll fractionation, immunofluorescence, confocal and electron microscopy collectively placed Nuc, COX-2, and all of the main enzymes involved in prostanoid synthesis, in the Golgi apparatus and endoplasmic reticulum of human neutrophils. Immunoprecipitation experiments indicated a high affinity between Nuc and COX-2. Addition of human recombinant (hr) Nuc to purified hrCOX-2 dose-dependently caused an increase in PGE2 biosynthesis in response to arachidonic acid. Co-incubation of Nuc with COX-2-expressing neutrophil lysates also increased their capacity to produce PGE2. Moreover, neutrophil transfection with hrNuc specifically enhanced PGE2 biosynthesis. Together, these results identify a COX-2-associated protein which may have an impact in prostanoid biosynthesis. PMID:18493301

  9. Tpl-2/Cot and COX-2 in breast cancer.

    PubMed

    Krcova, Zuzana; Ehrmann, Jiri; Krejci, Veronika; Eliopoulos, Aris; Kolar, Zdenek

    2008-06-01

    Breast cancer is the most common cancer in women worldwide and although mortality (129,000/year) stagnates, incidence (370,000/year) is increasing. In addition to histological type, grade, stage, hormonal and c-erbB2 status there is therefore a strong need for new and reliable prognostic and predictive factors. This minireview focuses on two potential prognostic and predictive candidates Tpl2/Cot and COX-2 and summarise information about them. Tumor progression locus 2 (Tpl2/Cot) is a serine/threonine protein kinase belonging to the family of MAP3 kinases. Activated Tpl2/Cot leads to induction of ERK1/2, JNK, NF-kappaB and p38MAPK pathways. The first study on Tpl2/Cot mRNA in breast cancer showed its increase in 40 % of cases of breast cancer but no available data exist on protein expression. Cyclo-oxygenase 2 (COX-2) is inducible by growth and inflammatory factors and contributes to the development of various tumours. Expression of COX-2 in breast cancer varied from 5-100 % in reviewed papers with significantly higher values in poorly differentiated tumours. Tpl2/Cot and COX-2 have their importance in different intracellular pathways and some of these are involved in cancer development. Briefly, the results from recent studies suggest that Tpl2/Cot and COX-2 could be prognostic factors in breast cancer.

  10. Ku80 cooperates with CBP to promote COX-2 expression and tumor growth

    PubMed Central

    Qin, Yu; Xuan, Yang; Jia, Yunlu; Hu, Wenxian; Yu, Wendan; Dai, Meng; Li, Zhenglin; Yi, Canhui; Zhao, Shilei; Li, Mei; Du, Sha; Cheng, Wei; Xiao, Xiangsheng; Chen, Yiming; Wu, Taihua; Meng, Songshu; Yuan, Yuhui; Liu, Quentin; Huang, Wenlin; Guo, Wei; Wang, Shusen; Deng, Wuguo

    2015-01-01

    Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX-2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer. PMID:25797267

  11. Kinetics and docking studies of a COX-2 inhibitor isolated from Terminalia bellerica fruits.

    PubMed

    Reddy, Tamatam Chandramohan; Aparoy, Polamarasetty; Babu, Neela Kishore; Kumar, Kotha Anil; Kalangi, Suresh Kumar; Reddanna, Pallu

    2010-10-01

    Triphala is an Ayurvedic herbal formulation consisting of equal parts of three myrobalans: Terminalia chebula, Terminalia bellerica and Emblica officinalis. We recently reported that chebulagic acid (CA) isolated from Terminalia chebula is a potent COX-2/5-LOX dual inhibitor. In this study, compounds isolated from Terminalia bellerica were tested for inhibition against COX and 5-LOX. One of the fractionated compounds showed potent inhibition against COX enzymes with no inhibition against 5-LOX. It was identified as gallic acid (GA) by LC-MS, NMR and IR analyses. We report here the inhibitory effects of GA, with an IC(50) value of 74 nM against COX-2 and 1500 nM for COX-1, showing ≈20 fold preference towards COX-2. Further docking studies revealed that GA binds in the active site of COX-2 at the non-steroidal anti-inflammatory drug (NSAID) binding site. The carboxylate moiety of GA interacts with Arg120 and Glu524. Based on substrate dependent kinetics, GA was found to be a competitive inhibitor of both COX-1 and COX-2, with more affinity towards COX-2. Taken together, our studies indicate that GA is a selective inhibitor of COX-2. Being a small natural product with selective and reversible inhibition of COX-2, GA would form a lead molecule for developing potent anti-inflammatory drug candidates.

  12. COX-2-derived endocannabinoid metabolites as novel inflammatory mediators.

    PubMed

    Alhouayek, Mireille; Muccioli, Giulio G

    2014-06-01

    Cyclooxygenase-2 (COX-2) is an enzyme that plays a key role in inflammatory processes. Classically, this enzyme is upregulated in inflammatory situations and is responsible for the generation of prostaglandins (PGs) from arachidonic acid (AA). One lesser-known property of COX-2 is its ability to metabolize the endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG). Endocannabinoid metabolism by COX-2 is not merely a means to terminate their actions. On the contrary, it generates PG analogs, namely PG-glycerol esters (PG-G) for 2-AG and PG-ethanolamides (PG-EA or prostamides) for AEA. Although the formation of these COX-2-derived metabolites of the endocannabinoids has been known for a while, their biological effects remain to be fully elucidated. Recently, several studies have focused on the role of these PG-G or PG-EA in vivo. In this review we take a closer look at the literature concerning these novel bioactive lipids and their role in inflammation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. COX-2 expression and outcome in canine nasal carcinomas treated with hypofractionated radiotherapy.

    PubMed

    Belshaw, Z; Constantio-Casas, F; Brearley, M J; Dunning, M D; Holmes, M A; Dobson, J M

    2011-06-01

    The expression of cyclooxygenase isoform 2 (COX-2) in canine nasal carcinomas has been well documented. COX-2 expression has proven to be a prognostic factor in several human tumours. The aims of this study were to assess the correlation between immunohistochemical COX-2 expression and prognosis using rhinoscopic biopsies from 42 dogs with nasal carcinomas treated with hypofractionated radiotherapy, and to establish a replicable COX-2 scoring system. Ninety per cent of sections evaluated were COX-2 positive with a mean score of 6.6 (median 8.0; range 0-12). Neither COX-2 expression nor tumour type had a significant correlation with survival. There are likely to be many as yet unidentified variants which contribute to length of survival in dogs with nasal carcinomas. Immunohistochemical COX-2 expression appears unlikely to be of prognostic significance for canine nasal carcinoma. © 2010 Blackwell Publishing Ltd.

  14. The U.S. Navy in Operation Overlord Under the Command of Rear Admiral Alan G. Kirk

    DTIC Science & Technology

    1994-05-19

    assault on the beaches. 14. SUBJECT TERMS 15. NUMBER OF PAGES Operation Overlord, COSSAC, Admiral Alan G. Kirk, U.S. Navy 16. PRICE CODE 17. SECUriLY ...Allies’ smal2 but growing forces. 5 Although reluctant to confront the German Army in France, Brooke admitted that reasons existed to take the Qamble; the...After Kirk took command of TF122, the pace of American landing craft and personnel arrival into Britain rapidly increased. Kirk told Stark that the

  15. Understanding the role of Ti in reversible hydrogen storage as sodium alanate: a combined experimental and density functional theoretical approach.

    PubMed

    Chaudhuri, Santanu; Graetz, Jason; Ignatov, Alex; Reilly, James J; Muckerman, James T

    2006-09-06

    We report the results of an experimental and theoretical study of hydrogen storage in sodium alanate (NaAlH(4)). Reversible hydrogen storage in this material is dependent on the presence of 2-4% Ti dopant. Our combined study shows that the role of Ti may be linked entirely to Ti-containing active catalytic sites in the metallic Al phase present in the dehydrogenated NaAlH(4). The EXAFS data presented here show that dehydrogenated samples contain a highly disordered distribution of Ti-Al distances with no long-range order beyond the second coordination sphere. We have used density functional theory techniques to calculate the chemical potential of possible Ti arrangements on an Al(001) surface for Ti coverages ranging from 0.125 to 0.5 monolayer (ML) and have identified those that can chemisorb molecular hydrogen via spontaneous or only moderately activated pathways. The chemisorption process exhibits a characteristic nodal symmetry property for the low-barrier sites: the incipient doped surface-H(2) adduct's highest occupied molecular orbital (HOMO) incorporates the sigma antibonding molecular orbital of hydrogen, allowing the transfer of charge density from the surface to dissociate the molecular hydrogen. This work also proposes a plausible mechanism for the transport of an aluminum hydride species back into the NaH lattice that is supported by Car-Parrinello molecular dynamics (CPMD) simulations of the stability and mobility of aluminum clusters (alanes) on Al(001). As an experimental validation of the proposed role of titanium and the subsequent diffusion of alanes, we demonstrate experimentally that AlH(3) reacts with NaH to form NaAlH(4) without any requirement of a catalyst or hydrogen overpressure.

  16. Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair.

    PubMed

    Oak, Nikhil R; Gumucio, Jonathan P; Flood, Michael D; Saripalli, Anjali L; Davis, Max E; Harning, Julie A; Lynch, Evan B; Roche, Stuart M; Bedi, Asheesh; Mendias, Christopher L

    2014-12-01

    The repair and restoration of function after chronic rotator cuff tears are often complicated by muscle atrophy, fibrosis, and fatty degeneration of the diseased muscle. The inflammatory response has been implicated in the development of fatty degeneration after cuff injuries. Licofelone is a novel anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX), as well as cyclooxygenase (COX)-1 and COX-2 enzymes, which play important roles in inducing inflammation after injuries. While previous studies have demonstrated that nonsteroidal anti-inflammatory drugs and selective inhibitors of COX-2 (coxibs) may prevent the proper healing of muscles and tendons, studies about bone and cartilage have demonstrated that drugs that inhibit 5-LOX concurrently with COX-1 and COX-2 may enhance tissue regeneration. After the repair of a chronic rotator cuff tear in rats, licofelone would increase the load to failure of repaired tendons and increase the force production of muscle fibers. Controlled laboratory study. Rats underwent supraspinatus release followed by repair 28 days later. After repair, rats began a treatment regimen of either licofelone or a vehicle for 14 days, at which time animals were euthanized. Supraspinatus muscles and tendons were then subjected to contractile, mechanical, histological, and biochemical analyses. Compared with controls, licofelone-treated rats had a grossly apparent decrease in inflammation and increased fibrocartilage formation at the enthesis, along with a 62% increase in the maximum load to failure and a 51% increase in peak stress to failure. Licofelone resulted in a marked reduction in fibrosis and lipid content in supraspinatus muscles as well as reduced expression of several genes involved in fatty infiltration. Despite the decline in fibrosis and fat accumulation, muscle fiber specific force production was reduced by 23%. The postoperative treatment of cuff repair with licofelone may reduce fatty degeneration and enhance the development

  17. Multi-omics facilitated variable selection in Cox-regression model for cancer prognosis prediction.

    PubMed

    Liu, Cong; Wang, Xujun; Genchev, Georgi Z; Lu, Hui

    2017-07-15

    New developments in high-throughput genomic technologies have enabled the measurement of diverse types of omics biomarkers in a cost-efficient and clinically-feasible manner. Developing computational methods and tools for analysis and translation of such genomic data into clinically-relevant information is an ongoing and active area of investigation. For example, several studies have utilized an unsupervised learning framework to cluster patients by integrating omics data. Despite such recent advances, predicting cancer prognosis using integrated omics biomarkers remains a challenge. There is also a shortage of computational tools for predicting cancer prognosis by using supervised learning methods. The current standard approach is to fit a Cox regression model by concatenating the different types of omics data in a linear manner, while penalty could be added for feature selection. A more powerful approach, however, would be to incorporate data by considering relationships among omics datatypes. Here we developed two methods: a SKI-Cox method and a wLASSO-Cox method to incorporate the association among different types of omics data. Both methods fit the Cox proportional hazards model and predict a risk score based on mRNA expression profiles. SKI-Cox borrows the information generated by these additional types of omics data to guide variable selection, while wLASSO-Cox incorporates this information as a penalty factor during model fitting. We show that SKI-Cox and wLASSO-Cox models select more true variables than a LASSO-Cox model in simulation studies. We assess the performance of SKI-Cox and wLASSO-Cox using TCGA glioblastoma multiforme and lung adenocarcinoma data. In each case, mRNA expression, methylation, and copy number variation data are integrated to predict the overall survival time of cancer patients. Our methods achieve better performance in predicting patients' survival in glioblastoma and lung adenocarcinoma. Copyright © 2017. Published by Elsevier

  18. Constitutively expressed COX-2 in osteoblasts positively regulates Akt signal transduction via suppression of PTEN activity.

    PubMed

    Li, Ching-Ju; Chang, Je-Ken; Wang, Gwo-Jaw; Ho, Mei-Ling

    2011-02-01

    Cyclooxygenase-2 (COX-2) is thought to be an inducible enzyme, but increasing reports indicate that COX-2 is constitutively expressed in several organs. The status of COX-2 expression in bone and its physiological role remains undefined. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, which commonly suppress COX-2 activity, were reported to suppress osteoblast proliferation via Akt/FOXO3a/p27(Kip1) signaling, suggesting that COX-2 may be the key factor of the suppressive effects of NSAIDs on proliferation. Although Akt activation correlates with PTEN deficiency and cell viability, the role of COX-2 on PTEN/Akt regulation remains unclear. In this study, we hypothesized that COX-2 may be constitutively expressed in osteoblasts and regulate PTEN/Akt-related proliferation. We examined the localization and co-expression of COX-2 and p-Akt in normal mouse femurs and in cultured mouse (mOBs) and human osteoblasts (hOBs). Our results showed that osteoblasts adjacent to the trabeculae, periosteum and endosteum in mouse femurs constitutively expressed COX-2, while COX-2 co-expressed with p-Akt in osteoblasts sitting adjacent to trabeculae in vivo, and in mOBs and hOBs in vitro. We further used COX-2 siRNA to test the role of COX-2 in Akt signaling in hOBs; COX-2 silencing significantly inhibited PTEN phosphorylation, enhanced PTEN activity, and suppressed p-Akt level and proliferation. However, replenishment of the COX-2 enzymatic product, PGE2, failed to reverse COX-2-dependent Akt phosphorylation. Furthermore, transfection with recombinant human COX-2 (rhCOX-2) significantly reversed COX-2 siRNA-suppressed PTEN phosphorylation, but this effect was reduced when the enzymatic activity of rhCOX-2 was blocked. This finding indicated that the effect of COX-2 on PTEN/Akt signaling is not related to PGE2 but still dependent on COX-2 enzymatic activity. Conversely, COX-1 silencing did not affect PTEN/Akt signaling. Our findings provide

  19. Forecasts of non-Gaussian parameter spaces using Box-Cox transformations

    NASA Astrophysics Data System (ADS)

    Joachimi, B.; Taylor, A. N.

    2011-09-01

    Forecasts of statistical constraints on model parameters using the Fisher matrix abound in many fields of astrophysics. The Fisher matrix formalism involves the assumption of Gaussianity in parameter space and hence fails to predict complex features of posterior probability distributions. Combining the standard Fisher matrix with Box-Cox transformations, we propose a novel method that accurately predicts arbitrary posterior shapes. The Box-Cox transformations are applied to parameter space to render it approximately multivariate Gaussian, performing the Fisher matrix calculation on the transformed parameters. We demonstrate that, after the Box-Cox parameters have been determined from an initial likelihood evaluation, the method correctly predicts changes in the posterior when varying various parameters of the experimental setup and the data analysis, with marginally higher computational cost than a standard Fisher matrix calculation. We apply the Box-Cox-Fisher formalism to forecast cosmological parameter constraints by future weak gravitational lensing surveys. The characteristic non-linear degeneracy between matter density parameter and normalization of matter density fluctuations is reproduced for several cases, and the capabilities of breaking this degeneracy by weak-lensing three-point statistics is investigated. Possible applications of Box-Cox transformations of posterior distributions are discussed, including the prospects for performing statistical data analysis steps in the transformed Gaussianized parameter space.

  20. Houttuynia cordata, a novel and selective COX-2 inhibitor with anti-inflammatory activity.

    PubMed

    Li, Weifeng; Zhou, Ping; Zhang, Yanmin; He, Langchong

    2011-01-27

    Houttuynia cordata Thunb. (Saururaceae; HC) has been long used in traditional oriental medicine for the treatment of inflammation diseases. Modern research has implicated inducible cyclooxygenase-2 (COX-2) as a key regulator of the inflammatory process. In the present study, we aimed to investigate the effect of HC on COX-2. We examined the effects of HC on lipopolysaccharide (LPS)-induced prostaglandin (PG) E(2) production, an indirect indicator of COX-2 activity, and COX-2 gene and protein expression in mouse peritoneal macrophages. LPS-induced mouse peritoneal macrophages were employed as an in vitro model system. LPS-induced PGE(2) production was assessed by enzyme-linked immunosorbant assay and COX-2 protein expression was assessed by Western blot assay. The results showed that HC was able to inhibit the release of LPS-induced PGE(2) from mouse peritoneal macrophages (IC50 value: 44.8 μg/mL). Moreover, the inhibitory activity of HC essential oil elicited a dose-dependent inhibition of COX-2 enzyme activity (IC50 value: 30.9 μg/mL). HC was also found to cause reduction in LPS-induced COX-2 mRNA and protein expression, but did not affect COX-1 expression. The non-steroidal anti-inflammatory drug (NSAID) and specific COX-2 inhibitor NS398 functioned similarly in LPS-induced mouse peritoneal macrophages. Taken together, our data suggest HC mediates inhibition of COX-2 enzyme activity and can affect related gene and protein expression. HC works by a mechanism of action similar to that of NSAIDs. These results add a novel aspect to the biological profile of HC. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  1. Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pachkoria, Ketevan; Zhang Hong; Adell, Gunnar

    2005-11-01

    Purpose: Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. Methods and Materials: Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy.more » Results: Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p {<=} 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. Conclusion: Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors.« less

  2. Myeloid Cell COX-2 deletion reduces mammary tumor growth through enhanced cytotoxic T-lymphocyte function

    PubMed Central

    Chen, Edward P.; Markosyan, Nune; Connolly, Emma; Lawson, John A.; Li, Xuanwen; Grant, Gregory R.; Grosser, Tilo; FitzGerald, Garret A.; Smyth, Emer M.

    2014-01-01

    Cyclooxygenase-2 (COX-2) expression is associated with poor prognosis across a range of human cancers, including breast cancer. The contribution of tumor cell-derived COX-2 to tumorigenesis has been examined in numerous studies; however, the role of stromal-derived COX-2 is ill-defined. Here, we examined how COX-2 in myeloid cells, an immune cell subset that includes macrophages, influences mammary tumor progression. In mice engineered to selectively lack myeloid cell COX-2 [myeloid-COX-2 knockout (KO) mice], spontaneous neu oncogene-induced tumor onset was delayed, tumor burden reduced, and tumor growth slowed compared with wild-type (WT). Similarly, growth of neu-transformed mammary tumor cells as orthotopic tumors in immune competent syngeneic myeloid-COX-2 KO host mice was reduced compared with WT. By flow cytometric analysis, orthotopic myeloid-COX-2 KO tumors had lower tumor-associated macrophage (TAM) infiltration consistent with impaired colony stimulating factor-1-dependent chemotaxis by COX-2 deficient macrophages in vitro. Further, in both spontaneous and orthotopic tumors, COX-2-deficient TAM displayed lower immunosuppressive M2 markers and this was coincident with less suppression of CD8+ cytotoxic T lymphocytes (CTLs) in myeloid-COX-2 KO tumors. These studies suggest that reduced tumor growth in myeloid-COX-2 KO mice resulted from disruption of M2-like TAM function, thereby enhancing T-cell survival and immune surveillance. Antibody-mediated depletion of CD8+, but not CD4+ cells, restored tumor growth in myeloid-COX-2 KO to WT levels, indicating that CD8+ CTLs are dominant antitumor effectors in myeloid-COX-2 KO mice. Our studies suggest that inhibition of myeloid cell COX-2 can potentiate CTL-mediated tumor cytotoxicity and may provide a novel therapeutic approach in breast cancer therapy. PMID:24590894

  3. Use of cyclo-oxygenase 2 inhibitors (COX-2) and prescription non-steroidal anti-inflammatory drugs (NSAIDS) in UK and USA populations. Implications for COX-2 cardiovascular profile.

    PubMed

    Arellano, Félix M; Yood, Marianne Ulcickas; Wentworth, Charles E; Oliveria, Susan A; Rivero, Elena; Verma, Anila; Rothman, Kenneth J

    2006-12-01

    COX-2 and NSAIDS differ in their gastrointestinal (GI) and cardiovascular (CV) toxicity from pharmacological, clinical and epidemiologic point of views. Describe the patterns of use of NSAIDS and COX-2 in The Health Improvement Network (THIN) database in UK and the PharMetrics database in USA. We examined the experience of 10 distinct cohorts of new users of diclofenac, naproxen, ibuprofen, piroxicam, other NSAIDS, meloxicam, celecoxib, etoricoxib, rofecoxib and valdecoxib. The study period was 1 January 1995 through 2004 (31 March in UK and 28 February in USA). We collected information on covariates including history of upper GI disease, CV disease, hepatic disease, dosage, concomitant medication, and visits to a rheumatologist. We identified 486 076 unique patient-drug pairs in UK and 1 533 239 in USA. In UK population 78 201 (16%) were COX-2 users and in PharMetrics 324 206 (21%) were COX-2 users. Diclofenac and ibuprofen (NSAIDS), and celecoxib and rofecoxib (COX-2) were the agents prescribed most frequently. The duration of therapy was longer among celecoxib and rofecoxib users than among other users. More COX-2 users than NSAIDS users received concomitant gastroprotective agents (GPA), corticosteroids and anti-platelet therapy, and had a history of thromboembolic events and hypertension. PharMetrics patients were prescribed higher doses of NSAIDS and COX-2. The use of any single agent for more than 90 days was uncommon, but more frequent in PharMetrics. Switching was uncommon and was generally to a NSAID. Our results confirm some previous findings from other authors such as the presence of both GI and CV channelling to COX-2 agents but refute others, such as the frequency of drug switching between these agents. The typical use of COX-2 agents in practice is for shorter duration, and at lower doses, than was employed in randomized clinical trials. This difference may help clarify the apparent discrepancy with respect to CV toxicity between the results from

  4. Association of COX-2 Promoter Polymorphisms -765G/C and -1195A/G with Migraine.

    PubMed

    Mozaffari, Elahe; Doosti, Abbas; Arshi, Asghar; Faghani, Mostafa

    2016-12-01

    Migraine is a common debilitating primary headache disorder with current head pain attacks, which contributes to physical activity dysfunctions in chronic pain phase. PGE2 and PGI2 are two important prostaglandins synthesised by COX-2 enzymes, involved in migraine pain signals. COX-2 modulation is essential in treatment and pathogenesis of migraine. This study aimed to investigating the association between COX-2 gene polymorphisms with the risk of migraine susceptibility in migraine patients with related and unrelated parents. This case- control study was based on 100 migraine patients and 100 non-migraine subjects in Bushehr province, Iran in 2013. Genomic DNA of blood samples was extracted and genotyping of COX-2-765G>C (rs20417) and COX-2-1195A>G (rs689466) gene variants was investigated by PCR-RFLP method. Statistical analyses were accomplished using the SPSS software package. There was a significant differences in the frequencies of the COX-2-765G>C and COX-2-1195A>G genotypes between migraine patients and controls ( P ≤0.05). COX-2-765CC , COX-2-765CG , COX-2-1195GG and COX-2-1195AG genotypes can increase the risk of migraine significantly. As the first study in Iran, we are hopeful to achieve greater results about the relevancy of COX-2 gene, migraine and pain signals pathway by repeating these experiments on more samples.

  5. Moral absolutism and abortion: Alan Donagan on the hysterectomy and craniotomy cases.

    PubMed

    Reynolds, Terrence

    1985-07-01

    Reynolds argues that the nonconsequentialist moral theory proposed by Alan Donagan in his book The Theory of Morality (University of Chicago Press; 1977) does not resolve the cases in which craniotomy or removal of a cancerous uterus appears necessary to save the life of a pregnant woman. Donagan's absolute prohibition against the murder of the innocent and his rejection of the principle of double effect have led him to view the fetus as a pursuer or assailant or to assert the theory of proleptic agreement--that in risk taking ventures the parties may agree that killing one person to save the lives of the others will be accepted. Reynolds holds these arguments to be inapplicable in therapeutic abortions involving craniotomy or hysterectomy and concludes that Donagan's absolutist theory must be reexamined.

  6. Potential use of COX-2–aromatase inhibitor combinations in breast cancer

    PubMed Central

    Bundred, N J; Barnes, N L P

    2005-01-01

    Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer. PMID:16100520

  7. Apollo 12 Mission image - Alan Bean unloads ALSEP RTG fuel element

    NASA Image and Video Library

    1969-11-19

    AS12-46-6790 (19 Nov. 1969) --- Astronaut Alan L. Bean, lunar module pilot, is photographed at quadrant II of the Lunar Module (LM) during the first Apollo 12 extravehicular activity (EVA) on the moon. This picture was taken by astronaut Charles Conrad Jr., commander. Here, Bean is using a fuel transfer tool to remove the fuel element from the fuel cask mounted on the LM's descent stage. The fuel element was then placed in the Radioisotope Thermoelectric Generator (RTG), the power source for the Apollo Lunar Surface Experiments Package (ALSEP) which was deployed on the moon by the two astronauts. The RTG is next to Bean's right leg. While astronauts Conrad and Bean descended in the LM "Intrepid" to explore the Ocean of Storms region of the moon, astronaut Richard F. Gordon Jr., command module pilot, remained with the Command and Service Modules (CSM) "Yankee Clipper" in lunar orbit.

  8. Astronauts Alan Bean and Charles Conrad on Lunar Surface

    NASA Technical Reports Server (NTRS)

    1969-01-01

    The second manned lunar landing mission, Apollo 12 launched from launch pad 39-A at Kennedy Space Center in Florida on November 14, 1969 via a Saturn Five launch vehicle. The Saturn V vehicle was developed by the Marshall Space Flight Center (MSFC) under the direction of Dr. Wernher von Braun. Aboard Apollo 12 was a crew of three astronauts: Alan L. Bean, pilot of the Lunar Module (LM), Intrepid; Richard Gordon, pilot of the Command Module (CM), Yankee Clipper; and Spacecraft Commander Charles Conrad. The LM, Intrepid, landed astronauts Conrad and Bean on the lunar surface in what's known as the Ocean of Storms while astronaut Richard Gordon piloted the CM, Yankee Clipper, in a parking orbit around the Moon. Their lunar soil activities included the deployment of the Apollo Lunar Surface Experiments Package (ALSEP), finding the unmanned Surveyor 3 that landed on the Moon on April 19, 1967, and collecting 75 pounds (34 kilograms) of rock samples. In this photograph, one of the astronauts on the Moon's surface is holding a container of lunar soil. The other astronaut is seen reflected in his helmet. Apollo 12 safely returned to Earth on November 24, 1969.

  9. Albumin-induced podocyte injury and protection are associated with regulation of COX-2.

    PubMed Central

    Agrawal, Shipra; Guess, Adam J.; Chanley, Melinda A.; Smoyer, and William E.

    2014-01-01

    Albuminuria is both a hallmark and a risk factor for progressive glomerular disease, and results in increased exposure of podocytes to serum albumin with its associated factors. Here in vivo and in vitro models of serum albumin overload were used to test the hypothesis that albumin-induced proteinuria and podocyte injury directly correlate with COX-2 induction. Albumin induced COX-2, MCP-1, CXCL1 and the stress protein HSP25 in both rat glomeruli and cultured podocytes, while B7-1 and HSP70i were also induced in podocytes. Podocyte exposure to albumin induced both mRNA and protein and enhanced the mRNA stability of COX-2, a key regulator of renal hemodynamics and inflammation, which renders podocytes susceptible to injury. Podocyte exposure to albumin also stimulated several kinases (p38 MAPK, MK2, JNK/SAPK and ERK1/2), inhibitors of which (except JNK/SAPK) down-regulated albumin-induced COX-2. Inhibition of AMPK, PKC and NFκB also down-regulated albumin-induced COX-2. Critically, albumin-induced COX-2 was also inhibited by glucocorticoids and thiazolidinediones, both of which directly protect podocytes against injury. Furthermore, specific albumin-associated fatty acids were identified as important contributors to COX-2 induction, podocyte injury and proteinuria. Thus, COX-2 is associated with podocyte injury during albuminuria, as well as with the known podocyte protection imparted by glucocorticoids and thiazolidinediones. Moreover, COX-2 induction, podocyte damage and albuminuria appear mediated largely by serum albumin-associated fatty acids. PMID:24918154

  10. Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity.

    PubMed

    Srivastava, Janmejai K; Pandey, Mitali; Gupta, Sanjay

    2009-11-04

    Inducible cyclooxygenase (COX-2) has been implicated in the process of inflammation and carcinogenesis. Chamomile has long been used in traditional medicine for the treatment of inflammatory diseases. In this study we aimed to investigate whether chamomile interferes with the COX-2 pathway. We used lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as an in vitro model for our studies. Chamomile treatment inhibited the release of LPS-induced prostaglandin E(2) in RAW 264.7 macrophages. This effect was found to be due to inhibition of COX-2 enzyme activity by chamomile. In addition, chamomile caused reduction in LPS-induced COX-2 mRNA and protein expression, without affecting COX-1 expression. The non-steroidal anti-inflammatory drug, sulindac and a specific COX-2 inhibitor, NS398, were shown to act similarly in LPS-activated RAW 264.7 cells. Our data suggest that chamomile works by a mechanism of action similar to that attributed to non-steroidal anti-inflammatory drugs. These findings add a novel aspect to the biological profile of chamomile which might be important for understanding the usefulness of aqueous chamomile extract in the form of tea in preventing inflammation and cancer.

  11. Mutational analysis of the Saccharomyces cerevisiae cytochrome c oxidase assembly protein Cox11p.

    PubMed

    Banting, Graham S; Glerum, D Moira

    2006-03-01

    Cox11p is an integral protein of the inner mitochondrial membrane that is essential for cytochrome c oxidase assembly. The bulk of the protein is located in the intermembrane space and displays high levels of evolutionary conservation. We have analyzed a collection of site-directed and random cox11 mutants in an effort to further define essential portions of the molecule. Of the alleles studied, more than half had no apparent effect on Cox11p function. Among the respiration deficiency-encoding alleles, we identified three distinct phenotypes, which included a set of mutants with a misassembled or partially assembled cytochrome oxidase, as indicated by a blue-shifted cytochrome aa(3) peak. In addition to the shifted spectral signal, these mutants also display a specific reduction in the levels of subunit 1 (Cox1p). Two of these mutations are likely to occlude a surface pocket behind the copper-binding domain in Cox11p, based on analogy with the Sinorhizobium meliloti Cox11 solution structure, thereby suggesting that this pocket is crucial for Cox11p function. Sequential deletions of the matrix portion of Cox11p suggest that this domain is not functional beyond the residues involved in mitochondrial targeting and membrane insertion. In addition, our studies indicate that Deltacox11, like Deltasco1, displays a specific hypersensitivity to hydrogen peroxide. Our studies provide the first evidence at the level of the cytochrome oxidase holoenzyme that Cox1p is the in vivo target for Cox11p and suggest that Cox11p may also have a role in the response to hydrogen peroxide exposure.

  12. [The "conclusions of Pharmacy" in Nancy, at the end of the 18th century: between "synthèses" and "thèses"].

    PubMed

    Julien, P; Martin, J

    1995-01-01

    A special requirement of the law for apothecaries in Nancy in 1764 imposed on the candidates for a master's degree was the written response to four questions following their practical examinations. Two documents heretofore unpublished show the results of this obligation: the Conclusions de Pharmacie by Joseph Pierson (1765) and the Conclusions de Pharmacie et de Chimie by François Mandel (1771). The authors of the present article comment on these documents and make an attempt to place them in the confused history of "synthèses" and "thèses".

  13. Staurosporine synergistically potentiates the deoxycholate-mediated induction of COX-2 expression.

    PubMed

    Saeki, Tohru; Inui, Haruka; Fujioka, Saya; Fukuda, Suguru; Nomura, Ayumi; Nakamura, Yasushi; Park, Eun Young; Sato, Kenji; Kanamoto, Ryuhei

    2014-08-01

    Colorectal cancer is a major cause of cancer-related death in western countries, and thus there is an urgent need to elucidate the mechanism of colorectal tumorigenesis. A diet that is rich in fat increases the risk of colorectal tumorigenesis. Bile acids, which are secreted in response to the ingestion of fat, have been shown to increase the risk of colorectal tumors. The expression of cyclooxygenase (COX)-2, an inducible isozyme of cyclooxygenase, is induced by bile acids and correlates with the incidence and progression of cancers. In this study, we investigated the signal transduction pathways involved in the bile-acid-mediated induction of COX-2 expression. We found that staurosporine (sts), a potent protein kinase C (PKC) inhibitor, synergistically potentiated the deoxycholate-mediated induction of COX-2 expression. Sts did not increase the stabilization of COX-2 mRNA. The sts- and deoxycholate-mediated synergistic induction of COX-2 expression was suppressed by a membrane-permeable Ca(2+) chelator, a phosphoinositide 3-kinase inhibitor, a nuclear factor-κB pathway inhibitor, and inhibitors of canonical and stress-inducible mitogen-activated protein kinase pathways. Inhibition was also observed using PKC inhibitors, suggesting the involvement of certain PKC isozymes (η, θ, ι, ζ, or μ). Our results indicate that sts exerts its potentiating effects via the phosphorylation of p38. However, the effects of anisomycin did not mimic those of sts, indicating that although p38 activation is required, it does not enhance deoxycholate-induced COX-2 expression. We conclude that staurosporine synergistically enhances deoxycholate-induced COX-2 expression in RCM-1 colon cancer cells. © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  14. The effects of the Cox maze procedure on atrial function

    PubMed Central

    Voeller, Rochus K.; Zierer, Andreas; Lall, Shelly C.; Sakamoto, Shun–ichiro; Chang, Nai–Lun; Schuessler, Richard B.; Moon, Marc R.; Damiano, Ralph J.

    2010-01-01

    Objective The effects of the Cox maze procedure on atrial function remain poorly defined. The purpose of this study was to investigate the effects of a modified Cox maze procedure on left and right atrial function in a porcine model. Methods After cardiac magnetic resonance imaging, 6 pigs underwent pericardiotomy (sham group), and 6 pigs underwent a modified Cox maze procedure (maze group) with bipolar radiofrequency ablation. The maze group had preablation and immediate postablation left and right atrial pressure–volume relations measured with conductance catheters. All pigs survived for 30 days. Magnetic resonance imaging was then repeated for both groups, and conductance catheter measurements were repeated for the right atrium in the maze group. Results Both groups had significantly higher left atrial volumes postoperatively. Magnetic resonance imaging–derived reservoir and booster pump functional parameters were reduced postoperatively for both groups, but there was no difference in these parameters between the groups. The maze group had significantly higher reduction in the medial and lateral left atrial wall contraction postoperatively. There was no change in immediate left atrial elastance or in the early and 30-day right atrial elastance after the Cox maze procedure. Although the initial left atrial stiffness increased after ablation, right atrial diastolic stiffness did not change initially or at 30 days. Conclusions Performing a pericardiotomy alone had a significant effect on atrial function that can be quantified by means of magnetic resonance imaging. The effects of the Cox maze procedure on left atrial function could only be detected by analyzing segmental wall motion. Understanding the precise physiologic effects of the Cox maze procedure on atrial function will help in developing less-damaging lesion sets for the surgical treatment of atrial fibrillation. PMID:19026812

  15. [Suppression of COX-2 protein to cell apoptosis in non-small cell lung cancer].

    PubMed

    Sun, Limei; Zhao, Yue; Wang, Lujian; Song, Min; Song, Jiye

    2007-06-20

    One of mechanisms of carcinogenesis is suppression of cell apoptosis which leads to accumulation of aberrant cells. The aim of this study is to investigate cell apoptosis and COX-2 protein expression in non-small cell lung cancer (NSCLC). Cell apoptosis, expression of COX-2 and microvessel density (MVD) were detcted in 111 NSCLC samples by TdT-mediated dUTP nick end labeling (TUNEL) technique and immunohistochemical staining. The positive rate of COX-2 protein expression was 67.6% (75/111), and there were 53 patients with high level cell apoptosis (47.7%). Expression of COX-2 protien was significantly related to TNM stages (P=0.025) and lymph node metastasis (P=0.018). The MVD in NSCLC tissues with positive COX-2 expression was significantly higher than that in negative expression ones (P=0.000). COX model showed that lymph node metastasis (P=0.006) and positive expression of COX-2 protein (P=0.000) were independent prognostic factors of NSCLC. The expression of COX-2 protein may suppress cell apoptosis of tumor, and it may serve as a potential marker of prognosis for NSCLC.

  16. Smad3 mutant mice develop colon cancer with overexpression of COX-2

    PubMed Central

    Zhu, Yu-Ping; Liu, Zhuo; Fu, Zhi-Xuan; Li, De-Chuan

    2017-01-01

    Colon cancer is the second most common cause of cancer-associated mortality in human populations. The aim of the present study was to identify the role of cyclooxygenase-2 (COX-2) in Smad3 mutant mice, which are known to develop colon cancer. Homozygous Smad3 (−/−) mutant mice were generated from inbred and hybrid Smad3 mouse strains by intercrossing the appropriate heterozygotes. Immunohistochemistry with COX-2 antibody was performed throughout this experiment and the data was validated and cross-checked with reverse transcription-polymerase chain reaction (RT-PCR). Homozygous mutant Smad3 mice were generated and the overexpression pattern of COX-2 was identified by immunohistochemistry and validated with RT-PCR. The results of the present study demonstrated a link between the Smad3 mutant mice, colon cancer and COX-2. In addition, the overexpression pattern of COX-2 in Smad3 mutant mice that develop colon cancer was identified. PMID:28454287

  17. Immunohistochemical expression of cyclooxygenase-2 (COX-2) in oral nevi and melanoma.

    PubMed

    de Souza do Nascimento, Juliana; Carlos, Román; Delgado-Azañero, Wilson; Mosqueda Taylor, Adalberto; de Almeida, Oslei Paes; Romañach, Mário José; de Andrade, Bruno Augusto Benevenuto

    2016-07-01

    Cyclooxygenase-2 (COX-2) catalyses the conversion of arachidonic acid to prostaglandin, and its overexpression has been demonstrated in different malignant tumors, including cutaneous melanoma. However, no data about the expression of this protein in oral melanocytic lesions are available to date. The aim of this study was to evaluate the immunohistochemical expression of COX-2 in oral nevi and melanomas, comparing the results with correspondent cutaneous lesions. COX-2 was evaluated by immunohistochemistry in 49 oral melanocytic lesions, including 36 intramucosal nevi and 13 primary oral melanomas, and in four cutaneous nevi and eight melanomas. All cases of oral and cutaneous melanomas were positive for COX-2. On the other hand, all oral and cutaneous melanocytic nevi were negative. COX-2 is highly positive in oral melanomas and negative in oral nevi and might represent a useful marker to distinguish melanocytic lesions of the oral cavity. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

    PubMed

    Ramer, Robert; Heinemann, Katharina; Merkord, Jutta; Rohde, Helga; Salamon, Achim; Linnebacher, Michael; Hinz, Burkhard

    2013-01-01

    The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.

  19. Overexpression of COX-2 and LMP1 are correlated with lymph node in Tunisian NPC patients.

    PubMed

    Fendri, Ali; Khabir, Abdelmajid; Hadhri-Guiga, Boutheina; Sellami-Boudawara, Tahia; Ghorbel, Abdelmoonem; Daoud, Jamel; Frikha, Mounir; Jlidi, Rachid; Gargouri, Ali; Mokdad-Gargouri, Raja

    2008-07-01

    Cyclooxygenase 2 (COX-2) an inducible form of COX is frequently up-regulated in many human tumours. The expression of COX-2 in nasopharyngeal carcinoma (NPC) and its relationship to clinicopathological features were studied in Tunisian patients. COX-2 mRNA was detected in 91% of tumour tissues. Immunohistochemical analysis showed that COX-2 protein was strongly detected in tumour cells and the staining was mainly cytoplasmic. In contrast, COX-2 mRNA and protein were very low or undetectable in normal nasopharyngeal mucosa. Our result showed a significant association of COX-2 overexpression with the lymph node involvement, however, no correlation was observed with age, tumour stage, histological type and distant metastasis. Moreover, we showed that all tumour specimens co-overexpressed COX-2 and the EBV oncoprotein LMP1 corroborating the fact that LPM1 is known to induce COX-2. Altogether, our data suggests that the COX-2 is overexpressed in NPC biopsies and that is linked to the lymph node involvement.

  20. Astronaut Alan Shepard is rescued by helicopter at end of MR-3 flight

    NASA Image and Video Library

    1961-05-05

    S88-31376 (5 May 1961) --- Astronaut Alan B. Shepard Jr., pilot of the Mercury-Redstone 3 (MR-3) suborbital spaceflight, is retrieved by a helicopter from the USS Lake Champlain during recovery operations in the western Atlantic Ocean. Shepard and the Mercury spacecraft designated the ?Freedom 7? (floating in water below) were flown to the deck of the recovery ship within 11 minutes of splashdown. MR-3 was the United States? first manned space mission. The spacecraft attained a maximum speed of 5,180 miles per hour, reached an altitude of 116 1/2 statute miles, and landed 302 statute miles downrange from Cape Canaveral, Florida. The suborbital mission lasted 15 minutes and 22 seconds. Photo credit: NASA or National Aeronautics and Space Administration

  1. COX-2 expression and function in the hyperalgesic response to paw inflammation in mice

    PubMed Central

    Jain, Naveen K.; Ishikawa, Tomo-o; Spigelman, Igor; Herschman, Harvey R.

    2009-01-01

    Peripheral inflammation and edema are often accompanied by primary and secondary hyperalgesia which are mediated by both peripheral and central mechanisms. The role of cyclooxygenase-2 (COX-2)-mediated prostanoid production in hyperalgesia is a topic of substantial current interest. We have established a murine foot-pad inflammation model in which both pharmacologic and genetic tools can be used to characterize the role of COX-2 in hyperalgesia. Zymosan, an extract from yeast, injected into the plantar surface of the hind paw induces an edema response and an increase in COX-2 expression in the hindpaw, spinal cord and brain. Zymosan-induced primary hyperalgesia, measured as a decrease in hindpaw withdrawal latency in response to a thermal stimulus, is long-lasting and is not inhibited by pre-treatment with the systemic COX-2 selective inhibitor, parecoxib (20 mg/kg). In contrast, the central component of hyperalgesia, measured as a reduction in tail flick latency in response to heat, is reduced by parecoxib. Zymosan-induced primary hyperalgesia in Cox-2−/− mice is similar to that of their Cox-2+/+ littermate controls. However, the central component of hyperalgesia is substantially reduced in Cox-2−/− versus Cox-2+/+ mice, and returns to baseline values much more rapidly. Thus pharmacological data suggest, and genetic experiments confirm, (i) that primary hyperalgesia in response to zymosan inflammation in the mouse paw is not mediated by COX-2 function and (ii) that COX-2 function plays a major role in the central component of hyperalgesia in this model of inflammation. PMID:18829279

  2. Novel Fatty Acid Lipoxygenases in the Development of Human and Murine Prostate Cancer

    DTIC Science & Technology

    2000-10-01

    expression of COX-2 mRNA in benign and malignant prostate samples by RNase protection assays in collaboration with Dr. Matthew Breyer at Vanderbilt. COX-2...Shappell,* William E. Boeglin,t prostate adenocarcinomas. (Am J Pathol 1999, Sandy J. Olson,* Susan Kasper,f and 155:235-245) Alan R. Brasht From the...possible role of this novel enzyme in secretory function, 33157-331605. Samuelssor,- B. Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN: Reduced expression in

  3. Genetic deletion of COX-2 diminishes VEGF production in mouse retinal Müller cells.

    PubMed

    Yanni, Susan E; McCollum, Gary W; Penn, John S

    2010-07-01

    Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX activity, reduce the production of retinal VEGF and neovascularization in relevant models of ocular disease. We hypothesized that COX-2 mediates VEGF production in retinal Müller cells, one of its primary sources in retinal neovascular disease. The purpose of this study was to determine the role of COX-2 and its products in VEGF expression and secretion. These studies have more clearly defined the role of COX-2 and COX-2-derived prostanoids in retinal angiogenesis. Müller cells derived from wild-type and COX-2 null mice were exposed to hypoxia for 0-24 h. COX-2 protein and activity were assessed by western blot analysis and GC-MS, respectively. VEGF production was assessed by ELISA. Wild-type mouse Müller cells were treated with vehicle (0.1% DMSO), 10 microM PGE(2), or PGE(2) + 5 microM H-89 (a PKA inhibitor), for 12 h. VEGF production was assessed by ELISA. Hypoxia significantly increased COX-2 protein (p < 0.05) and activity (p < 0.05), and VEGF production (p < 0.0003). COX-2 null Müller cells produced significantly less VEGF in response to hypoxia (p < 0.05). Of the prostanoids, PGE(2) was significantly increased by hypoxia (p < 0.02). Exogenous PGE(2) significantly increased VEGF production by Müller cells (p < 0.0039), and this effect was inhibited by H-89 (p < 0.055). These data demonstrate that hypoxia induces COX-2, prostanoid production, and VEGF synthesis in Müller cells, and that VEGF production is at least partially COX-2-dependent. Our study suggests that PGE(2), signaling through the EP(2) and/or EP(4) receptor and PKA, mediates the VEGF response of Müller cells. Copyright 2010 Elsevier Ltd. All rights reserved.

  4. Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity

    PubMed Central

    Srivastava, Janmejai K; Pandey, Mitali; Gupta, Sanjay

    2009-01-01

    Aims Inducible cyclooxygenase (COX-2) has been implicated in the process of inflammation and carcinogenesis. Chamomile has long been used in traditional medicine for the treatment of inflammatory diseases. In this study we aimed to investigate whether chamomile interferes with the COX-2 pathway. Main Methods We used lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as an in vitro model for our studies. Key Findings Chamomile treatment inhibited the release of LPS-induced prostaglandin E(2) in RAW 264.7 macrophages. This effect was found to be due to inhibition of COX-2 enzyme activity by chamomile. In addition, chamomile caused reduction in LPS-induced COX-2 mRNA and protein expression, without affecting COX-1 expression. The non-steroidal anti-inflammatory drug, sulindac and a specific COX-2 inhibitor, NS398, were shown to act similarly in LPS-activated RAW 264.7 cells. Our data suggest that chamomile works by a mechanism of action similar to that attributed to non-steroidal anti-inflammatory drugs. Significance These findings add a novel aspect to the biological profile of chamomile which might be important for understanding the usefulness of aqueous chamomile extract in the form of tea in preventing inflammation and cancer. PMID:19788894

  5. COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice

    PubMed Central

    Vardeh, Daniel; Wang, Dairong; Costigan, Michael; Lazarus, Michael; Saper, Clifford B.; Woolf, Clifford J.; FitzGerald, Garret A.; Samad, Tarek A.

    2009-01-01

    A cardinal feature of peripheral inflammation is pain. The most common way of managing inflammatory pain is to use nonsteroidal antiinflammatory agents (NSAIDs) that reduce prostanoid production, for example, selective inhibitors of COX2. Prostaglandins produced after induction of COX2 in immune cells in inflamed tissue contribute both to the inflammation itself and to pain hypersensitivity, acting on peripheral terminals of nociceptors. COX2 is also induced after peripheral inflammation in neurons in the CNS, where it aids in developing a central component of inflammatory pain hypersensitivity by increasing neuronal excitation and reducing inhibition. We engineered mice with conditional deletion of Cox2 in neurons and glial cells to determine the relative contribution of peripheral and central COX2 to inflammatory pain hypersensitivity. In these mice, basal nociceptive pain was unchanged, as was the extent of peripheral inflammation, inflammatory thermal pain hypersensitivity, and fever induced by lipopolysaccharide. By contrast, peripheral inflammation–induced COX2 expression in the spinal cord was reduced, and mechanical hypersensitivity after both peripheral soft tissue and periarticular inflammation was abolished. Mechanical pain is a major symptom of most inflammatory conditions, such as postoperative pain and arthritis, and induction of COX2 in neural cells in the CNS seems to contribute to this. PMID:19127021

  6. Use of real time control modelling on the urban sewage system of Nancy.

    PubMed

    Zug, M; Faure, D; De Belly, B; Phan, L

    2001-01-01

    Since 1991, European Legislation on the urban treatment of wastewater requires local authorities to take into account the treatment of polluted water transported by the sewerage system and this during dry and wet weather conditions. In the seventies, the urban Community of Grand Nancy constructed storage tanks in its sewerage system in order to prevent flooding and wish today to use them to reduce and control the pollution discharges into the receiving water. This action is a part of a European LIFE project 1996-2000. The main aim of this project was to assess the effectiveness of reducing pollution of one particular retention basin, the 12,000 m3 Gentilly tank. This one has two operating modes: protection against floods during heavy rain and reduction of pollutant overflows during lighter rain. To assess its effect on the pollutant discharge, the HYDROWORKS DM software and its Real Time Control Module have been used, calibrated and validated. As this study is still in progress, this paper describes the studied site and the modelling results under different weather conditions and shows that the mathematical model can be used to simulate the operation of the catchment area and its associated sewerage system realistically.

  7. Docking studies on NSAID/COX-2 isozyme complexes using Contact Statistics analysis

    NASA Astrophysics Data System (ADS)

    Ermondi, Giuseppe; Caron, Giulia; Lawrence, Raelene; Longo, Dario

    2004-11-01

    The selective inhibition of COX-2 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects; e.g. celecoxib (Celebrex®) and rofecoxib (Vioxx®). To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between COX isozymes and NSAIDs. Although X-ray structures of COX-2 complexed with a small number of ligands are available, experimental data are missing for two well-known selective COX-2 inhibitors (rofecoxib and nimesulide) and docking results reported are controversial. We use a combination of a traditional docking procedure with a new computational tool (Contact Statistics analysis) that identifies the best orientation among a number of solutions to shed some light on this topic.

  8. Potential interaction of natural dietary bioactive compounds with COX-2.

    PubMed

    Maldonado-Rojas, Wilson; Olivero-Verbel, Jesus

    2011-09-01

    Bioactive natural products present in the diet play an important role in several biological processes, and many have been involved in the alleviation and control of inflammation-related diseases. These actions have been linked to both gene expression modulation of pro-inflammatory enzymes, such as cyclooxygenase 2 (COX-2), and to an action involving a direct inhibitory binding on this protein. In this study, several food-related compounds with known gene regulatory action on inflammation have been examined in silico as COX-2 ligands, utilizing AutoDock Vina, GOLD and Surflex-Dock (SYBYL) as docking protocols. Curcumin and all-trans retinoic acid presented the maximum absolute AutoDock Vina-derived binding affinities (9.3 kcal/mol), but genistein, apigenin, cyanidin, kaempferol, and docosahexaenoic acid, were close to this value. AutoDock Vina affinities and GOLD scores for several known COX-2 inhibitors significatively correlated with reported median inhibitory concentrations (R² = 0.462, P < 0.001 and R² = 0.238, P = 0.029, respectively), supporting the computational reliability of the predictions made by our docking simulations. Moreover, docking analysis insinuate the synergistic action of curcumin on celecoxib-induced inhibition of COX-2 may occur allosterically, as this natural compound docks to a place different from the inhibitor binding site. These results suggest that the anti-inflammatory properties of some food-derived molecules could be the result of their direct binding capabilities to COX-2, and this process can be modeled using protein-ligand docking methodologies. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. COX-2 and Prostate Cancer Angiogenesis

    DTIC Science & Technology

    2002-03-01

    papilloma virus -18 ing cell nuclear antigen staining), but induced ap- immortalization of PIN cell areas of radical-pros- optosis (TdT-mediated dUTP...the COX-2 surrounding basal cells (75%).3cA human PIN cell inhibitor had no effect on proliferation (proliferat- line was established by human

  10. Finite size effect on hydrogen bond cooperativity in (Ala)n polypeptides: A DFT study using numeric atom-centered orbitals

    NASA Astrophysics Data System (ADS)

    Blum, Volker; Ireta, Joel; Scheffler, Matthias

    2007-03-01

    An accurate representation of the energetic contribution Ehb of hydrogen bonds to structure formation is paramount to understand the secondary structure stability of proteins, both qualitatively and quantitatively. However, Ehb depends strongly on its environment, and even on the surrounding peptide conformation itself. For instance, a short α-helical polypeptide (Ala)4 can not be stabilized by its single hydrogen bond, whereas an infinite α-helical chain (Ala)∞ is clearly energetically stable over a fully extended conformation. We here use all-electron density functional calculations in the PBE generalized gradient approximation by a recently developed, computationally efficient numeric atom-centered orbital based code^1 to investigate this H-bond cooperativity that is intrinsic to Alanine-based polypeptides (Ala)n (n=1-20,∞). We compare finite and infinite prototypical helical conformations (α, π, 310) on equal footing, with both neutral and ionic termination for finite (Ala)n peptides. Moderately sized NAO basis sets allow to capture Ehb with meV accuracy, revealing a clear jump in Ehb (cooperativity) when two H-bonds first appear in line, followed by slower and more continuous increase of Ehb towards n->∞. ^1 V. Blum, R. Gehrke, P. Havu, V. Havu, M. Scheffler, The FHI Ab Initio Molecular Simulations (aims) Project, Fritz-Haber-Institut, Berlin (2006).

  11. Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage.

    PubMed

    Angoa-Pérez, Mariana; Kreipke, Christian W; Thomas, David M; Van Shura, Kerry E; Lyman, Megan; McDonough, John H; Kuhn, Donald M

    2010-12-01

    Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4h to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity. Published by Elsevier B.V.

  12. Losartan reverses COX-2-dependent vascular dysfunction in offspring of hyperglycaemic rats.

    PubMed

    de Queiroz, Diego Barbosa; Ramos-Alves, Fernanda Elizabethe; Santos-Rocha, Juliana; Duarte, Gloria Pinto; Xavier, Fabiano Elias

    2017-09-01

    This study examined whether chronic treatment with losartan, an angiotensin II type 1 receptor (AT 1 R) antagonist, might reverse COX-2-mediated vascular dysfunction in mesenteric resistance arteries (MRA) from offspring of hyperglycaemic rats. Male 12-month-old offspring of hyperglycaemic (O-DR) and normoglycaemic (O-CR) rats were treated with losartan (15mg·kg·day -1 ) during 2months. Third order MRA of untreated and losartan-treated O-DR and O-CR were mounted in wire myograph for isometric tension measurements. COX-2 expression was analyzed by Western blot; TxA 2 , PGE 2 and PGF 2α release was measured using commercial kits. O-DR showed increased blood pressure, impaired acetylcholine-induced vasodilation and increased noradrenaline-induced vasoconstriction than O-CR. All these parameters were normalized by losartan in O-DR. Pre-incubation of MRA with indomethacin (COX-1/2 inhibitor), NS-398 (COX-2 inhibitor) or tempol (superoxide dismutase mimetic) increased relaxation to acetylcholine and reduced contraction to noradrenaline only in O-DR. COX-2 expression, TxA 2 , PGE 2 and PGF 2α release were increased in O-DR. In losartan-treated O-DR, NS-398, indomethacin or tempol failed to produce any effect on acetylcholine or noradrenaline responses. Losartan treatment reduced COX-2 expression, TxA 2 , PGE 2 and PGF 2α release in O-DR. The present results reveal that chronic losartan administration in O-DR normalizes endothelial function in MRA by correcting the existing COX-2 overexpression and the imbalance between endothelium-derived relaxing and contracting factors. These findings not only support the beneficial effects of AT 1 receptor antagonist in O-DR, but also suggest the implication of angiotensin II as a putative mediator of hyperglycemia-programmed vascular dysfunction in rats. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Early increased density of cyclooxygenase-2 (COX-2) immunoreactive neurons in Down syndrome.

    PubMed

    Mulet, Maria; Blasco-Ibáńez, José Miguel; Crespo, Carlos; Nácher, Juan; Varea, Emilio

    2017-01-01

    Neuroinflammation is one of the hallmarks of Alzheimer's disease. One of the enzymes involved in neuroinflammation, even in early stages of the disease, is COX-2, an inducible cyclooxygenase responsible for the generation of eicosanoids and for the generation of free radicals. Individuals with Down syndrome develop Alzheimer's disease early in life. Previous studies pointed to the possible overexpression of COX-2 and correlated it to brain regions affected by the disease. We analysed the COX-2 expression levels in individuals with Down syndrome and in young, adult and old mice of the Ts65Dn mouse model for Down syndrome. We have observed an overexpression of COX-2 in both, Down syndrome individuals and mice. Importantly, mice already presented an overexpression of COX-2 at postnatal day 30, before neurodegeneration begins; which suggests that neuroinflammation may underlie the posterior neurodegeneration observed in individuals with Down syndrome and in Ts65Dn mice and could be a factor for the premature appearance of Alzheimer's disease..

  14. New Ferrocene Compounds as Selective Cyclooxygenase (COX-2) Inhibitors: Design, Synthesis, Cytotoxicity and Enzyme-inhibitory Activity.

    PubMed

    Farzaneh, Shabnam; Zeinalzadeh, Elnaz; Daraei, Bahram; Shahhosseini, Soraya; Zarghi, Afshin

    2018-01-01

    Due to the astonishing properties of ferrocene and its derivatives, it has a broad application in diverse areas. Numerous ferrocene derivatives demonstrated anti-proliferative activity. Also COX-2, as a key isoenzyme for production of prostaglandins, is frequently overexpressed in various cancers. It is now recognized that COX-2 over expression promotes tumorigenic functions which can be suppressed by COX-2 inhibitors, a phenomenon useful for the preventing of tumor progression. The combination of COX-2 inhibitors with other anti-cancer or cancer prevention drugs may reduce their side effects in future cancer prevention and treatment. Owing to high anticancer potential of ferrocene derivatives and considerable COX-2 inhibitory and cytotoxicity effects of our previously synthesized chalcones, we decided to incorporate the ferrocenyl moiety into appropriate COX-2 inhibitor chalcone based scaffold, to evaluate COX-2 inhibitory activity as well as anticancer activities. Chalcones were synthesized via clasien-schmidt condensation of methylsulfonyl aldehyde and acetyl ferrocene. Further different amines with solvent free and ultra sound condition were reacted with chalcones to have different 1-ferrocenyl-3-amino carbonyl compounds. Docking study was carried out with Auto Dock vina software. All the newly-synthesized compounds were evaluated for their cyclooxygenase-2 (COX-2) inhibitory activity using chemiluminescent enzyme assays as well as cytotoxicity activity against MCF-7 and T47D and fibroblast cell lines by MTT assay. In vitro COX-1/COX-2 inhibition studies demonstrated that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the highly potent 0.05-0.12 µM range, and COX-2 selectivity indexes (SI) in the 148.3-313.7 range. These results indicated that either potency or selectivity of COX-2 inhibitory activity was affected by the nature and size of the substituents on C-3 of propane-1-one. Also anti-proliferative and toxicity

  15. Quantifying parameter uncertainty in stochastic models using the Box Cox transformation

    NASA Astrophysics Data System (ADS)

    Thyer, Mark; Kuczera, George; Wang, Q. J.

    2002-08-01

    The Box-Cox transformation is widely used to transform hydrological data to make it approximately Gaussian. Bayesian evaluation of parameter uncertainty in stochastic models using the Box-Cox transformation is hindered by the fact that there is no analytical solution for the posterior distribution. However, the Markov chain Monte Carlo method known as the Metropolis algorithm can be used to simulate the posterior distribution. This method properly accounts for the nonnegativity constraint implicit in the Box-Cox transformation. Nonetheless, a case study using the AR(1) model uncovered a practical problem with the implementation of the Metropolis algorithm. The use of a multivariate Gaussian jump distribution resulted in unacceptable convergence behaviour. This was rectified by developing suitable parameter transformations for the mean and variance of the AR(1) process to remove the strong nonlinear dependencies with the Box-Cox transformation parameter. Applying this methodology to the Sydney annual rainfall data and the Burdekin River annual runoff data illustrates the efficacy of these parameter transformations and demonstrate the value of quantifying parameter uncertainty.

  16. Co-expression of COX-2 and 5-LO in primary glioblastoma is associated with poor prognosis.

    PubMed

    Wang, Xingfu; Chen, Yupeng; Zhang, Sheng; Zhang, Lifeng; Liu, Xueyong; Zhang, Li; Li, Xiaoling; Chen, Dayang

    2015-11-01

    Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) are important factors in tumorigenesis and malignant progression; however, studies of their roles in glioblastoma have produced conflicting results. To define the frequencies of COX-2 and 5-LO expression and their correlation with clinicopathological features and prognosis, tumor tissues from 76 cases of newly diagnosed primary ordinary glioblastoma were examined for COX-2 and 5-LO expression by immunohistochemistry. The expression levels of COX-2 and 5-LO and the relationships between the co-expression of COX-2/5-LO and patient age and gender, edema index (EI), Karnofsky Performance Scale and overall survival (OS) were analyzed. COX-2 and 5-LO were expressed in 73.7 % (56/76) and 92.1 % (70/76) of the samples, respectively. Among the clinicopathological characteristics, only age (>60 years) exhibited a significant association with the high expression of COX-2. No statistically significant correlations were found in the 5-LO cohort. A significant positive correlation was revealed between the COX-2 and 5-LO scores (r = 0.374; p = 0.001). The elevated co-expression of COX-2 and 5-LO was observed primarily in the patients over the age of 60 years. Patients with a high expression of COX-2 had a significantly shorter OS (p < 0.01), whereas the immunoexpression of 5-LO was not associated with the OS of patients with glioblastoma. Survival analysis indicated that simultaneous high levels of COX-2 and 5-LO expression were significantly correlated with poor OS and, conversely, that a low/low expression pattern of these two proteins was significantly associated with better OS (p < 0.05). Moreover, the Cox multivariable proportional hazard model showed that a high expression of COX-2, high co-expression of COX-2 and 5-LO, and a high Ki-67 index were significant predictors of shorter OS in primary glioblastoma, independent of age, gender, EI, 5-LO expression and p53 status. The hazard ratios for OS were 2.347 (95 % CI 1

  17. Simultaneous confidence bands for Cox regression from semiparametric random censorship.

    PubMed

    Mondal, Shoubhik; Subramanian, Sundarraman

    2016-01-01

    Cox regression is combined with semiparametric random censorship models to construct simultaneous confidence bands (SCBs) for subject-specific survival curves. Simulation results are presented to compare the performance of the proposed SCBs with the SCBs that are based only on standard Cox. The new SCBs provide correct empirical coverage and are more informative. The proposed SCBs are illustrated with two real examples. An extension to handle missing censoring indicators is also outlined.

  18. Design, Synthesis and Biological Evaluation of Novel Peptide-Like Analogues as Selective COX-2 Inhibitors

    PubMed Central

    Ahmaditaba, Mohammad Ali; Houshdar Tehrani, Mohammad Hassan; Zarghi, Afshin; Shahosseini, Sorayya; Daraei, Bahram

    2018-01-01

    A new series of peptide-like derivatives containing different aromatic amino acids and possessing pharmacophores of COX-2 inhibitors as SO2Me or N3 attached to the para position of an end phenyl ring was synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. The synthetic reactions were based on the solid phase peptide synthesis method using Wang resin. One of the analogues, i.e., compound 2d, as the representative of these series was recognized as the most effective and the highest selective COX-2 inhibitor with IC50 value of 0.08 μM and COX-2 selectivity index of 351.2, among the other synthesized compounds. Molecular docking study was operated to determine possible binding models of compound 2d to COX-2 enzyme. The study showed that the p-azido-phenyl fragment of 2d occupied inside the secondary COX-2 binding site (Arg513, and His90). The structure-activity relationships acquired disclosed that compound 2d with 4-(azido phenyl) group as pharmacophore and histidine as amino acid gives the essential geometry to provide inhibition of the COX-2 enzyme with high selectivity. Compound 2d can be a good candidate for the development of new hits of COX-2 inhibitors.

  19. COX-2 in cancer: Gordian knot or Achilles heel?

    PubMed Central

    Stasinopoulos, Ioannis; Shah, Tariq; Penet, Marie-France; Krishnamachary, Balaji; Bhujwalla, Zaver M.

    2013-01-01

    The networks of blood and lymphatic vessels and of the extracellular matrix and their cellular and structural components, that are collectively termed the tumor microenvironment, are frequently co-opted and shaped by cancer cells to survive, invade, and form distant metastasis. With an enviable capacity to adapt to continually changing environments, cancer represents the epitome of functional chaos, a stark contrast to the hierarchical and organized differentiation processes that dictate the development and life of biological organisms. The consequences of changing landscapes such as hypoxia and acidic extracellular pH in and around tumors create a cascade of changes in multiple pathways and networks that become apparent only several years later as recurrence and metastasis. These molecular and phenotypic changes, several of which are mediated by COX-2, approach the complexities of a “Gordian Knot.” We review evidence from our studies and from literature suggesting that cyclooxygenase-2 (COX-2) biology presents a nodal point in cancer biology and an “Achilles heel” of COX-2-dependent tumors. PMID:23579438

  20. Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling

    PubMed Central

    Yang, Hongwei; Tang, Ya-ping; Sun, Hao; Song, Yunping; Chen, Chu

    2013-01-01

    SUMMARY Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2. PMID:24267894

  1. Properties of added variable plots in Cox's regression model.

    PubMed

    Lindkvist, M

    2000-03-01

    The added variable plot is useful for examining the effect of a covariate in regression models. The plot provides information regarding the inclusion of a covariate, and is useful in identifying influential observations on the parameter estimates. Hall et al. (1996) proposed a plot for Cox's proportional hazards model derived by regarding the Cox model as a generalized linear model. This paper proves and discusses properties of this plot. These properties make the plot a valuable tool in model evaluation. Quantities considered include parameter estimates, residuals, leverage, case influence measures and correspondence to previously proposed residuals and diagnostics.

  2. Cox-nnet: An artificial neural network method for prognosis prediction of high-throughput omics data.

    PubMed

    Ching, Travers; Zhu, Xun; Garmire, Lana X

    2018-04-01

    Artificial neural networks (ANN) are computing architectures with many interconnections of simple neural-inspired computing elements, and have been applied to biomedical fields such as imaging analysis and diagnosis. We have developed a new ANN framework called Cox-nnet to predict patient prognosis from high throughput transcriptomics data. In 10 TCGA RNA-Seq data sets, Cox-nnet achieves the same or better predictive accuracy compared to other methods, including Cox-proportional hazards regression (with LASSO, ridge, and mimimax concave penalty), Random Forests Survival and CoxBoost. Cox-nnet also reveals richer biological information, at both the pathway and gene levels. The outputs from the hidden layer node provide an alternative approach for survival-sensitive dimension reduction. In summary, we have developed a new method for accurate and efficient prognosis prediction on high throughput data, with functional biological insights. The source code is freely available at https://github.com/lanagarmire/cox-nnet.

  3. COX-2 verexpression in pretreatment biopsies predicts response of rectal cancers to neoadjuvant radiochemotherapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Smith, Fraser M.; Reynolds, John V.; Kay, Elaine W.

    2006-02-01

    Purpose: To determine the utility of COX-2 expression as a response predictor for patients with rectal cancer who are undergoing neoadjuvant radiochemotherapy (RCT). Methods and Materials: Pretreatment biopsies (PTB) from 49 patients who underwent RCT were included. COX-2 and proliferation in PTB were assessed by immunohistochemistry (IHC) and apoptosis was detected by TUNEL stain. Response to treatment was assessed by a 5-point tumor-regression grade (TRG) based on the ratio of residual tumor to fibrosis. Results: Good response (TRG 1 + 2), moderate response (TRG 3), and poor response (TRG 4 + 5) were seen in 21 patients (42%), 11 patientsmore » (22%), and 17 patients (34%), respectively. Patients with COX-2 overexpression in PTB were more likely to demonstrate moderate or poor response (TRG 3 + 4) to treatment than were those with normal COX-2 expression (p = 0.026, chi-square test). Similarly, poor response was more likely if patients had low levels of spontaneous apoptosis in PTBs (p = 0.0007, chi-square test). Conclusions: COX-2 overexpression and reduced apoptosis in PTB can predict poor response of rectal cancer to RCT. As COX-2 inhibitors are commercially available, their administration to patients who overexpress COX-2 warrants assessment in clinical trials in an attempt to increase overall response rates.« less

  4. Azoxymethane protects intestinal stem cells and reduces crypt epithelial mitosis through a COX-1-dependent mechanism.

    PubMed

    Riehl, Terrence E; George, Robert J; Sturmoski, Mark A; May, Randal; Dieckgraefe, Brian; Anant, Shrikant; Houchen, Courtney W

    2006-12-01

    Azoxymethane (AOM) is a potent DNA-damaging agent and carcinogen that induces intestinal and colonic tumors in rodents. Evaluation of the stem cell population by colony formation assay reveals that, within 8 h after treatment, AOM (10 mg/kg) elicited a prosurvival response. In wild-type (WT) mice, AOM treatment induced a 2.5-fold increase in intestinal crypt stem cell survival. AOM treatment increased stem cell survival in cyclooxygenase (COX)-2(-/-) but not COX-1(-/-) mice, confirming a role of COX-1 in the AOM-induced increase in stem cell survival. COX-1 mRNA and protein expression as well as COX-1-derived PGE(2) synthesis were increased 8 h after AOM treatment. Immunohistochemical staining of COX-1 demonstrated expression of the enzyme in the crypt epithelial cells, especially in the columnar epithelial cells between the Paneth cells adjacent to the stem cell zone. WT mice receiving AOM exhibited increased intestinal apoptosis and a simultaneous reduction in crypt mitotic figures within 8 h of injection. There were no significant differences in baseline or AOM-induced intestinal epithelial apoptosis between WT and COX-1(-/-) mice, but there was a complete reversal of the AOM-mediated reduction in mitosis in COX-1(-/-) mice. This suggests that COX-1-derived PGE(2) may play a key role in the early phase of intestinal tumorigenesis in response to DNA damage and suggests that COX-1 may be a potential therapeutic target in this model of colon cancer.

  5. Specific trans-acting proteins interact with auxiliary RNA polyadenylation elements in the COX-2 3′-UTR

    PubMed Central

    Hall-Pogar, Tyra; Liang, Songchun; Hague, Lisa K.; Lutz, Carol S.

    2007-01-01

    Two cyclooxygenase (COX) enzymes, COX-1 and COX-2, are present in human cells. While COX-1 is constitutively expressed, COX-2 is inducible and up-regulated in response to many signals. Since increased transcriptional activity accounts for only part of COX-2 up-regulation, we chose to explore other RNA processing mechanisms in the regulation of this gene. Previously, we showed that COX-2 is regulated by alternative polyadenylation, and that the COX-2 proximal polyadenylation signal contains auxiliary upstream sequence elements (USEs) that are very important in efficient polyadenylation. To explore trans-acting protein factors interacting with these cis-acting RNA elements, we performed pull-down assays with HeLa nuclear extract and biotinylated RNA oligonucleotides representing COX-2 USEs. We identified PSF, p54nrb, PTB, and U1A as proteins specifically bound to the COX-2 USEs. We further explored their participation in polyadenylation using MS2 phage coat protein-MS2 RNA binding site tethering assays, and found that tethering any of these four proteins to the COX-2 USE mutant RNA can compensate for these cis-acting elements. Finally, we suggest that these proteins (p54nrb, PTB, PSF, and U1A) may interact as a complex since immunoprecipitations of the transfected MS2 fusion proteins coprecipitate the other proteins. PMID:17507659

  6. Allan Cox 1926”1987

    NASA Astrophysics Data System (ADS)

    Coe, Rob; Dalrymple, Brent

    More than 1000 friends, students, and colleagues from all over the country filled Stanford Memorial Chapel (Stanford, Calif.) on February 3, 1987, to join in “A Celebration of the Life of Allan Cox.” Allan died early on the morning of January 27 while bicycling, the sport he had come to love the most. Between pieces of his favorite music by Bach and Mozart, Stanford administrators and colleagues spoke in tribute of Allan's unique qualities as friend, scientist, teacher, and dean of the School of Earth Sciences. James Rosse, Vice President and Provost of Stanford University, struck a particularly resonant chord with his personal remarks: "Allan reached out to each person he knew with the warmth and attention that can only come from deep respect and affection for others. I never heard him speak ill of others, and I do not believe he was capable of doing anything that would harm another being. He cared too much to intrude where he was not wanted, but his curiosity about people and the loving care with which he approached them broke down reserve to create remarkable friendships. His enthusiasm and good humor made him a welcome guest in the hearts of the hundreds of students and colleagues who shared the opportunity of knowing Allan Cox as a person."

  7. Brain-targeted ACE2 overexpression attenuates neurogenic hypertension by inhibiting COX mediated inflammation

    PubMed Central

    Sriramula, Srinivas; Xia, Huijing; Xu, Ping; Lazartigues, Eric

    2014-01-01

    Overactivity of the renin angiotensin system (RAS), oxidative stress, and cyclooxygenases (COX) in the brain are implicated in the pathogenesis of hypertension. We previously reported that Angiotensin-Converting Enzyme 2 (ACE2) overexpression in the brain attenuates the development of DOCA-salt hypertension, a neurogenic hypertension model with enhanced brain RAS and sympathetic activity. To elucidate the mechanisms involved, we investigated whether oxidative stress, mitogen activated protein kinase signaling and cyclooxygenase (COX) activation in the brain are modulated by ACE2 in neurogenic hypertension. DOCA-salt hypertension significantly increased expression of Nox-2 (+61 ±5 %), Nox-4 (+50 ±13 %) and nitrotyrosine (+89 ±32 %) and reduced activity of the antioxidant enzymes, catalase (−29 ±4 %) and SOD (−31 ±7 %), indicating increased oxidative stress in the brain of non-transgenic mice. This increased oxidative stress was attenuated in transgenic mice overexpressing ACE2 in the brain. DOCA-salt-induced reduction of nNOS expression (−26 ±7 %) and phosphorylated eNOS/total eNOS (−30 ±3 %), and enhanced phosphorylation of Akt and ERK1/2 in the paraventricular nucleus (PVN), were reversed by ACE2 overexpression. In addition, ACE2 overexpression blunted the hypertension-mediated increase in gene and protein expression of COX-1 and COX-2 in the PVN. Furthermore, gene silencing of either COX-1 or COX-2 in the brain, reduced microglial activation and accompanied neuro-inflammation, ultimately attenuating DOCA-salt hypertension. Together, these data provide evidence that brain ACE2 overexpression reduces oxidative stress and COX-mediated neuro-inflammation, improves anti-oxidant and nitric oxide signaling, and thereby attenuates the development of neurogenic hypertension. PMID:25489058

  8. Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling.

    PubMed

    Chen, Rongqing; Zhang, Jian; Fan, Ni; Teng, Zhao-Qian; Wu, Yan; Yang, Hongwei; Tang, Ya-Ping; Sun, Hao; Song, Yunping; Chen, Chu

    2013-11-21

    Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in the brain. COX-2 induction by Δ(9)-THC is mediated via CB1 receptor-coupled G protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ(9)-THC exposures. Ablation of COX-2 also eliminates Δ(9)-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ(9)-THC in Alzheimer's disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Cox-nnet: An artificial neural network method for prognosis prediction of high-throughput omics data

    PubMed Central

    Ching, Travers; Zhu, Xun

    2018-01-01

    Artificial neural networks (ANN) are computing architectures with many interconnections of simple neural-inspired computing elements, and have been applied to biomedical fields such as imaging analysis and diagnosis. We have developed a new ANN framework called Cox-nnet to predict patient prognosis from high throughput transcriptomics data. In 10 TCGA RNA-Seq data sets, Cox-nnet achieves the same or better predictive accuracy compared to other methods, including Cox-proportional hazards regression (with LASSO, ridge, and mimimax concave penalty), Random Forests Survival and CoxBoost. Cox-nnet also reveals richer biological information, at both the pathway and gene levels. The outputs from the hidden layer node provide an alternative approach for survival-sensitive dimension reduction. In summary, we have developed a new method for accurate and efficient prognosis prediction on high throughput data, with functional biological insights. The source code is freely available at https://github.com/lanagarmire/cox-nnet. PMID:29634719

  10. Effect of uric acid on inflammatory COX-2 and ROS pathways in vascular smooth muscle cells.

    PubMed

    Oğuz, Nurgül; Kırça, Mustafa; Çetin, Arzu; Yeşilkaya, Akın

    2017-10-01

    Hyperuricemia is thought to play a role in cardiovascular diseases (CVD), including hypertension, coronary artery disease and atherosclerosis. However, exactly how uric acid contributes to these pathologies is unknown. An underlying mechanism of inflammatory diseases, such as atherosclerosis, includes enhanced production of cyclooxygenase-2 (COX-2) and superoxide anion. Here, we aimed to examine the effect of uric acid on inflammatory COX-2 and superoxide anion production and to determine the role of losartan. Primarily cultured vascular smooth muscle cells (VSMCs) were time and dose-dependently induced by uric acid and COX-2 and superoxide anion levels were measured. COX-2 levels were determined by ELISA, and superoxide anion was measured by the superoxide dismutase (SOD)-inhibitable reduction of ferricytochrome c method. Uric acid elevated COX-2 levels in a time-dependent manner. Angiotensin-II receptor blocker, losartan, diminished uric-acid-induced COX-2 elevation. Uric acid also increased superoxide anion level in VSMCs. Uric acid plays an important role in CVD pathogenesis by inducing inflammatory COX-2 and ROS pathways. This is the first study demonstrating losartan's ability to reduce uric-acid-induced COX-2 elevation.

  11. Increased Dietary Sodium Induces COX2 Expression by activating NFκB in Renal Medullary Interstitial Cells

    PubMed Central

    Zhao, Min; Davis, Linda S.; Blackwell, Timothy S.; Yull, Fiona; Breyer, Matthew D.; Hao, Chuan-Ming

    2013-01-01

    High salt diet induces renal medullary COX2 expression. Selective blockade of renal medullary COX2 activity in rats causes salt sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8% NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6J mice. Co-immunofluorescence using a COX2 antibody and antibodies against AQP2, ClC-K, AQP1 and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a 7 fold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of EGFP expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet fed C57Bl/6J mice with selective IκB kinase inhibitor IMD-0354 (8mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary PGE2. These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium. PMID:23900806

  12. A global goodness-of-fit statistic for Cox regression models.

    PubMed

    Parzen, M; Lipsitz, S R

    1999-06-01

    In this paper, a global goodness-of-fit test statistic for a Cox regression model, which has an approximate chi-squared distribution when the model has been correctly specified, is proposed. Our goodness-of-fit statistic is global and has power to detect if interactions or higher order powers of covariates in the model are needed. The proposed statistic is similar to the Hosmer and Lemeshow (1980, Communications in Statistics A10, 1043-1069) goodness-of-fit statistic for binary data as well as Schoenfeld's (1980, Biometrika 67, 145-153) statistic for the Cox model. The methods are illustrated using data from a Mayo Clinic trial in primary billiary cirrhosis of the liver (Fleming and Harrington, 1991, Counting Processes and Survival Analysis), in which the outcome is the time until liver transplantation or death. The are 17 possible covariates. Two Cox proportional hazards models are fit to the data, and the proposed goodness-of-fit statistic is applied to the fitted models.

  13. Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention.

    PubMed

    McCarty, Mark F

    2012-01-01

    A recent meta-analysis examining long-term mortality in subjects who participated in controlled studies evaluating the impact of daily aspirin on vascular risk, has concluded that aspirin confers substantial protection from cancer mortality. Remarkably, low-dose aspirin was as effective as higher-dose regimens; hence this protection may be achievable with minimal risk. There is reason to believe that this protection stems primarily from inhibition of cox-2 in pre-neoplastic lesions. Since safe aspirin regimens can only achieve a partial and transitory inhibition of cox-2, it may be feasible to complement the cancer-protective benefit of aspirin with other measures which decrease cox-2 expression or which limit the bioactivity of cox-2-derived PGE2. Oxidative stress boosts cox-2 expression by up-regulating activation of NF-kappaB and MAP kinases; NADPH oxidase activation may thus promote carcinogenesis by increasing cox-2 expression while also amplifying oxidant-mediated mutagenesis. A prospective cohort study has observed that relatively elevated serum bilirubin levels are associated with a marked reduction in subsequent cancer mortality; this may reflect bilirubin's physiological role as a potent inhibitor of NADPH oxidase. It may be feasible to mimic this protective effect by supplementing with spirulina, a rich source of a phycobilin which shares bilirubin's ability to inhibit NADPH oxidase. Ancillary antioxidant measures - phase 2 inducing phytochemicals, melatonin, N-acetylcysteine, and astaxanthin - may also aid cox-2 down-regulation. The cancer protection often associated with high-normal vitamin D status may be attributable, in part, to the ability of the activated vitamin D receptor to decrease cox-2 expression while promoting PGE2 catabolism and suppressing the expression of PGE2 receptors. Diets with a relatively low ratio of omega-6 to long-chain omega-3 fats may achieve cancer protection by antagonizing the production and bioactivity of PGE2. Growth

  14. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Meng, Zhen; Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081; Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocationmore » and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.« less

  15. Survival analysis of cervical cancer using stratified Cox regression

    NASA Astrophysics Data System (ADS)

    Purnami, S. W.; Inayati, K. D.; Sari, N. W. Wulan; Chosuvivatwong, V.; Sriplung, H.

    2016-04-01

    Cervical cancer is one of the mostly widely cancer cause of the women death in the world including Indonesia. Most cervical cancer patients come to the hospital already in an advanced stadium. As a result, the treatment of cervical cancer becomes more difficult and even can increase the death's risk. One of parameter that can be used to assess successfully of treatment is the probability of survival. This study raises the issue of cervical cancer survival patients at Dr. Soetomo Hospital using stratified Cox regression based on six factors such as age, stadium, treatment initiation, companion disease, complication, and anemia. Stratified Cox model is used because there is one independent variable that does not satisfy the proportional hazards assumption that is stadium. The results of the stratified Cox model show that the complication variable is significant factor which influent survival probability of cervical cancer patient. The obtained hazard ratio is 7.35. It means that cervical cancer patient who has complication is at risk of dying 7.35 times greater than patient who did not has complication. While the adjusted survival curves showed that stadium IV had the lowest probability of survival.

  16. The Society of Brains: How Alan Turing and Marvin Minsky Were Both Right

    NASA Astrophysics Data System (ADS)

    Struzik, Zbigniew R.

    2015-04-01

    In his well-known prediction, Alan Turing stated that computer intelligence would surpass human intelligence by the year 2000. Although the Turing Test, as it became known, was devised to be played by one human against one computer, this is not a fair setup. Every human is a part of a social network, and a fairer comparison would be a contest between one human at the console and a network of computers behind the console. Around the year 2000, the number of web pages on the WWW overtook the number of neurons in the human brain. But these websites would be of little use without the ability to search for knowledge. By the year 2000 Google Inc. had become the search engine of choice, and the WWW became an intelligent entity. This was not without good reason. The basis for the search engine was the analysis of the ’network of knowledge’. The PageRank algorithm, linking information on the web according to the hierarchy of ‘link popularity’, continues to provide the basis for all of Google's web search tools. While PageRank was developed by Larry Page and Sergey Brin in 1996 as part of a research project about a new kind of search engine, PageRank is in its essence the key to representing and using static knowledge in an emergent intelligent system. Here I argue that Alan Turing was right, as hybrid human-computer internet machines have already surpassed our individual intelligence - this was done around the year 2000 by the Internet - the socially-minded, human-computer hybrid Homo computabilis-socialis. Ironically, the Internet's intelligence also emerged to a large extent from ‘exploiting’ humans - the key to the emergence of machine intelligence has been discussed by Marvin Minsky in his work on the foundations of intelligence through interacting agents’ knowledge. As a consequence, a decade and a half decade into the 21st century, we appear to be much better equipped to tackle the problem of the social origins of humanity - in particular thanks to the

  17. Apollo 12 Mission image - Dark view of Astronaut Alan L. Bean climbing down the ladder of the Lunar Module (LM)

    NASA Image and Video Library

    1969-11-19

    AS12-46-6728 (19 Nov. 1969) --- Astronaut Alan L. Bean, lunar module pilot for the Apollo 12 mission, is about to step off the ladder of the Lunar Module to join astronaut Charles Conrad Jr., mission commander, in extravehicular activity (EVA). Conrad and Bean descended in the Apollo 12 LM to explore the moon while astronaut Richard F. Gordon Jr., command module pilot, remained with the Command and Service Modules in lunar orbit.

  18. COX-2 expression in canine anal sac adenocarcinomas and in non-neoplastic canine anal sacs.

    PubMed

    Knudsen, C S; Williams, A; Brearley, M J; Demetriou, J L

    2013-09-01

    Anal sac adenocarcinoma (ASAC) is a clinically significant canine neoplasm characterized by early lymphatic invasion. Up-regulation of cyclooxygenase isoform 2 (COX-2) has been confirmed in several animal and human neoplastic tissues. The aim of the current study was primarily to evaluate COX-2 expression in canine ASAC and compare it to COX-2 expression in non-neoplastic canine anal sac tissue using immunohistochemistry with scoring for percentage positivity and intensity. Twenty-five ASAC samples and 22 normal anal sacs were available for evaluation. All canine ASAC samples and the normal anal sac tissues stained positively for COX-2. However, while normal anal sac tissue showed strong staining of the ductal epithelial cells, ASAC samples showed staining of the neoplastic glandular epithelial cells, with varying percentage positivity and intensity between ASAC samples. COX-2 immunoreactivity of ASAC samples was of low intensity in 52% and high in 12% of the cases; the remaining samples were of intermediate intensity. Seventy-six per cent of the ASAC had over 50% of the neoplastic glandular cells staining positive. These results confirm that COX-2 is expressed in the neoplastic glandular epithelial cells in canine ASAC and suggest a potential role for COX-2 inhibitors in the management of ASAC. Furthermore, the results indicate that COX-2 is expressed in ductal epithelial cells of the normal anal sac. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Scoring and staging systems using cox linear regression modeling and recursive partitioning.

    PubMed

    Lee, J W; Um, S H; Lee, J B; Mun, J; Cho, H

    2006-01-01

    Scoring and staging systems are used to determine the order and class of data according to predictors. Systems used for medical data, such as the Child-Turcotte-Pugh scoring and staging systems for ordering and classifying patients with liver disease, are often derived strictly from physicians' experience and intuition. We construct objective and data-based scoring/staging systems using statistical methods. We consider Cox linear regression modeling and recursive partitioning techniques for censored survival data. In particular, to obtain a target number of stages we propose cross-validation and amalgamation algorithms. We also propose an algorithm for constructing scoring and staging systems by integrating local Cox linear regression models into recursive partitioning, so that we can retain the merits of both methods such as superior predictive accuracy, ease of use, and detection of interactions between predictors. The staging system construction algorithms are compared by cross-validation evaluation of real data. The data-based cross-validation comparison shows that Cox linear regression modeling is somewhat better than recursive partitioning when there are only continuous predictors, while recursive partitioning is better when there are significant categorical predictors. The proposed local Cox linear recursive partitioning has better predictive accuracy than Cox linear modeling and simple recursive partitioning. This study indicates that integrating local linear modeling into recursive partitioning can significantly improve prediction accuracy in constructing scoring and staging systems.

  20. Cyclooxygenases in human and mouse skin and cultured human keratinocytes: association of COX-2 expression with human keratinocyte differentiation

    NASA Technical Reports Server (NTRS)

    Leong, J.; Hughes-Fulford, M.; Rakhlin, N.; Habib, A.; Maclouf, J.; Goldyne, M. E.

    1996-01-01

    Epidermal expression of the two isoforms of the prostaglandin H-generating cyclooxygenase (COX-1 and COX-2) was evaluated both by immunohistochemistry performed on human and mouse skin biopsy sections and by Western blotting of protein extracts from cultured human neonatal foreskin keratinocytes. In normal human skin, COX-1 immunostaining is observed throughout the epidermis whereas COX-2 immunostaining increases in the more differentiated, suprabasilar keratinocytes. Basal cell carcinomas express little if any COX-1 or COX-2 immunostaining whereas both isozymes are strongly expressed in squamous cell carcinomas deriving from a more differentiated layer of the epidermis. In human keratinocyte cultures, raising the extracellular calcium concentration, a recognized stimulus for keratinocyte differentiation, leads to an increased expression of both COX-2 protein and mRNA; expression of COX-1 protein, however, shows no significant alteration in response to calcium. Because of a recent report that failed to show COX-2 in normal mouse epidermis, we also looked for COX-1 and COX-2 immunostaining in sections of normal and acetone-treated mouse skin. In agreement with a previous report, some COX-1, but no COX-2, immunostaining is seen in normal murine epidermis. However, following acetone treatment, there is a marked increase in COX-1 expression as well as the appearance of significant COX-2 immunostaining in the basal layer. These data suggest that in human epidermis as well as in human keratinocyte cultures, the expression of COX-2 occurs as a part of normal keratinocyte differentiation whereas in murine epidermis, its constitutive expression is absent, but inducible as previously published.

  1. Functional polymorphisms of cyclooxygenase-2 (COX-2) gene and risk for esophageal squmaous cell carcinoma.

    PubMed

    Upadhyay, Rohit; Jain, Meenu; Kumar, Shaleen; Ghoshal, Uday Chand; Mittal, Balraj

    2009-04-26

    Cyclooxygenase-2 (COX-2) influences carcinogenesis through regulation of angiogenesis, apoptosis and cytokine expression. We aimed to evaluate association of COX-2 polymorphisms with predisposition to esophageal squamous cell carcinoma (ESCC), its phenotype variability and modulation of environmental risk in northern Indian population. We genotyped 174 patients with ESCC and 216 controls for COX-2 gene polymorphisms (-765G>C; -1195G>A; -1290A>G; 3'UTR 8473T>C) using PCR-RFLP. Data were statistically analyzed using chi-square test and logistic regression model. COX-2 -765C allele carriers were at increased risk for ESCC (OR=1.66; 95% CI=1.08-2.54; P=0.004). However, -1195G>A; -1290A>G; 3'UTR 8473T>C polymorphisms of COX-2 gene were not significantly associated with ESCC. We observed significantly enhanced risk for ESCC due to interaction between COX-2 -1195GAx-765GC+CC genotypes (OR=4.60; 95% CI=1.63-13.01; P=0.004). High risk to ESCC was also observed with respect to COX-2 haplotypes, A(-1290)G(-1195)C(-765)T(8473) and A(-1290)A(-1195)C(-765)T(8473) [OR=3.35; 95% CI=0.83-13.44; P=0.089; OR=4.28; 95% CI=0.43-42.40; P=0.246] however, it was not statistically significant. Stratification of subjects based on gender showed that females were at higher risk for ESCC due to COX-2 -765C carrier genotypes (OR=2.97; 95% CI=1.23-7.18; P=0.016). In association of genotypes with clinical characteristics, -765C carrier genotype conferred risk of ESCC in middle third of esophagus (OR=1.78; 95% CI=1.08-2.93; P=0.023). In case-only analysis, interaction of environmental risk factors and COX-2 genotypes did not further modulate the risk for ESCC. In summary, COX-2 -765G>C polymorphism confers ESCC susceptibility particularly in females and patients with middle third anatomical location of the tumor. Interaction of COX-2 -1195GA and -765C carrier genotypes also modulates ESCC risk.

  2. Reduced COX-2 expression in aged mice is associated with impaired fracture healing.

    PubMed

    Naik, Amish A; Xie, Chao; Zuscik, Michael J; Kingsley, Paul; Schwarz, Edward M; Awad, Hani; Guldberg, Robert; Drissi, Hicham; Puzas, J Edward; Boyce, Brendan; Zhang, Xinping; O'Keefe, Regis J

    2009-02-01

    The cellular and molecular events responsible for reduced fracture healing with aging are unknown. Cyclooxygenase 2 (COX-2), the inducible regulator of prostaglandin E(2) (PGE(2)) synthesis, is critical for normal bone repair. A femoral fracture repair model was used in mice at either 7-9 or 52-56 wk of age, and healing was evaluated by imaging, histology, and gene expression studies. Aging was associated with a decreased rate of chondrogenesis, decreased bone formation, reduced callus vascularization, delayed remodeling, and altered expression of genes involved in repair and remodeling. COX-2 expression in young mice peaked at 5 days, coinciding with the transition of mesenchymal progenitors to cartilage and the onset of expression of early cartilage markers. In situ hybridization and immunohistochemistry showed that COX-2 is expressed primarily in early cartilage precursors that co-express col-2. COX-2 expression was reduced by 75% and 65% in fractures from aged mice compared with young mice on days 5 and 7, respectively. Local administration of an EP4 agonist to the fracture repair site in aged mice enhanced the rate of chondrogenesis and bone formation to levels observed in young mice, suggesting that the expression of COX-2 during the early inflammatory phase of repair regulates critical subsequent events including chondrogenesis, bone formation, and remodeling. The findings suggest that COX-2/EP4 agonists may compensate for deficient molecular signals that result in the reduced fracture healing associated with aging.

  3. COX-2 expression positively correlates with PD-L1 expression in human melanoma cells.

    PubMed

    Botti, Gerardo; Fratangelo, Federica; Cerrone, Margherita; Liguori, Giuseppina; Cantile, Monica; Anniciello, Anna Maria; Scala, Stefania; D'Alterio, Crescenzo; Trimarco, Chiara; Ianaro, Angela; Cirino, Giuseppe; Caracò, Corrado; Colombino, Maria; Palmieri, Giuseppe; Pepe, Stefano; Ascierto, Paolo Antonio; Sabbatino, Francesco; Scognamiglio, Giosuè

    2017-02-23

    The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma. Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAF V600E A375 and NRAS Q61R SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro. BRAF V600E/V600K and NRAS Q61R/Q61L were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions (P = 0.002). COX-2 expression significantly correlated with PD-L1 expression in both primary (P = 0.001) and not matched metastatic (P = 0.048) lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAF V600E A375 and NRAS Q61R SK-MEL-2 melanoma cell lines. COX-2 expression correlates

  4. The Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition.

    PubMed

    Palermo, Giulia; Favia, Angelo D; Convertino, Marino; De Vivo, Marco

    2016-06-20

    The design of multitarget-directed ligands is a promising strategy for discovering innovative drugs. Here, we report a mechanistic study that clarifies key aspects of the dual inhibition of the fatty acid amide hydrolase (FAAH) and the cyclooxygenase (COX) enzymes by a new multitarget-directed ligand named ARN2508 (2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid). This potent dual inhibitor combines, in a single scaffold, the pharmacophoric elements often needed to block FAAH and COX, that is, a carbamate moiety and the 2-arylpropionic acid functionality, respectively. Molecular modeling and molecular dynamics simulations suggest that ARN2508 uses a noncovalent mechanism of inhibition to block COXs, while inhibiting FAAH via the acetylation of the catalytic Ser241, in line with previous experimental evidence for covalent FAAH inhibition. This study proposes the molecular basis for the dual FAAH/COX inhibition by this novel hybrid scaffold, stimulating further experimental studies and offering new insights for the rational design of novel anti-inflammatory agents that simultaneously act on FAAH and COX. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  5. Forecasting the onset of an allergic risk to poaceae in Nancy and Strasbourg (France) with different methods.

    PubMed

    Cassagne, E; Caillaud, P D; Besancenot, J P; Thibaudon, M

    2007-10-01

    Pollen of Poaceae is among the most allergenic pollen in Europe with pollen of birch. It is therefore useful to elaborate models to help pollen allergy sufferers. The objective of this study was to construct forecast models that could predict the first day characterized by a certain level of allergic risk called here the Starting Date of the Allergic Risk (SDAR). Models result from four forecast methods (three summing and one multiple regression analysis) used in the literature. They were applied on Nancy and Strasbourg from 1988 to 2005 and were tested on 2006. Mean Absolute Error and Actual forecast ability test are the parameters used to choose best models, assess and compare their accuracy. It was found, on the whole, that all the models presented a good forecast accuracy which was equivalent. They were all reliable and were used in order to forecast the SDAR in 2006 with contrasting results in forecasting precision.

  6. Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells.

    PubMed

    He, Wenjuan; Zhang, Min; Zhao, Min; Davis, Linda S; Blackwell, Timothy S; Yull, Fiona; Breyer, Matthew D; Hao, Chuan-Ming

    2014-02-01

    High salt diet induces renal medullary cyclooxygenase 2 (COX2) expression. Selective blockade of renal medullary COX2 activity in rats causes salt-sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8 % NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6 J mice. Co-immunofluorescence using a COX2 antibody and antibodies against aquaporin-2, ClC-K, aquaporin-1, and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a sevenfold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of enhanced green fluorescent protein (EGFP) expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet-fed C57Bl/6 J mice with selective IκB kinase inhibitor IMD-0354 (8 mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary prostaglandin E2 (PGE2). These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium.

  7. Triptolide inhibits COX-2 expression by regulating mRNA stability in TNF-{alpha}-treated A549 cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sun, Lixin; Zhang, Shuang; Jiang, Zhenzhou

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer Triptolide inhibited COX-2 expression and the half-life of COX-2 mRNA is decreased. Black-Right-Pointing-Pointer The HuR protein shuttling from nucleus to cytoplasm is inhibited by triptolide. Black-Right-Pointing-Pointer Triptolide inhibited 3 Prime -UTR fluorescence reporter gene activity. Black-Right-Pointing-Pointer COX-2 mRNA binding to HuR is decreased by triptolide in pull-down experiments. -- Abstract: Cyclooxygenase-2 (COX-2) over-expression is frequently associated with human non-small-cell lung cancer (NSCLC) and involved in tumor proliferation, invasion, angiogenesis and resistance to apoptosis. In the present study, the effects of triptolide on COX-2 expression in A549 cells were investigated and triptolide was found to inhibit TNF-{alpha}-induced COX-2 expression.more » In our further studies, it was found that triptolide decreased the half-life of COX-2 mRNA dramatically and that it inhibited 3 Prime -untranslated region (3 Prime -UTR) fluorescence reporter gene activity. Meanwhile, triptolide inhibited the HuR shuttling from nucleus to cytoplasm. After triptolide treatment, decreased COX-2 mRNA in pull-down experiments with anti-HuR antibodies was observed, indicating that the decreased cytoplasmic HuR is responsible for the decreased COX-2 mRNA. Taken together, our results provided evidence for the first time that triptolide inhibited COX-2 expression by COX-2 mRNA stability modulation and post-transcriptional regulation. These results provide a novel mechanism of action for triptolide which may be important in the treatment of lung cancer.« less

  8. Correlated non-nuclear COX2 and low HER2 expression confers a good prognosis in colorectal cancer.

    PubMed

    Zhou, Fei-Fei; Huang, Rong; Jiang, Jun; Zeng, Xiao-Hong; Zou, Shu-Qian

    2018-06-05

    COX2 and HER2 are shown to be critical in the regulation of cancer progression. However, the prognostic value of nuclear COX2 in colorectal cancer (CRC) and its relationship with HER2 still remains unknown. In this study, the expression and biological significance of COX2 and HER2 were evaluated in CRC at mRNA and protein levels. RNA-Seq data of CRC were downloaded from TCGA, and 229 CRC and 50 non-cancerous subjects were enrolled in this study. Bioinformatics and immunohistochemistry analysis was performed based on the obtained data. Survival analysis was conducted to identify factors associated with overall survival of CRC patients. We showed that mRNA and protein levels of COX2 and HER2 were upregulated in CRC compared with the adjacent tissues. COX2 protein levels and nuclear COX2 expression were correlated with a poor prognosis of CRC patients. In addition, we also revealed that nuclear COX2 expression was positively associated with HER2 expression. Non-nuclear COX2 combined with low HER2 expression, was negatively correlated with Duke's stage and lymph node metastasis, predicting the best outcomes for CRC patients. In addition, our data indicated that non-nuclear COX2 combined with low HER2 expression is an independent prognostic factor for CRC after surgical resection. The study suggests that nuclear COX2 in combination with HER2 can serve as potential biomarkers for the clinical diagnosis and prognosis of CRC, and targeted inhibition of COX2 and HER2 might be an alternative strategy for the management of CRC.

  9. External validation of a Cox prognostic model: principles and methods

    PubMed Central

    2013-01-01

    Background A prognostic model should not enter clinical practice unless it has been demonstrated that it performs a useful role. External validation denotes evaluation of model performance in a sample independent of that used to develop the model. Unlike for logistic regression models, external validation of Cox models is sparsely treated in the literature. Successful validation of a model means achieving satisfactory discrimination and calibration (prediction accuracy) in the validation sample. Validating Cox models is not straightforward because event probabilities are estimated relative to an unspecified baseline function. Methods We describe statistical approaches to external validation of a published Cox model according to the level of published information, specifically (1) the prognostic index only, (2) the prognostic index together with Kaplan-Meier curves for risk groups, and (3) the first two plus the baseline survival curve (the estimated survival function at the mean prognostic index across the sample). The most challenging task, requiring level 3 information, is assessing calibration, for which we suggest a method of approximating the baseline survival function. Results We apply the methods to two comparable datasets in primary breast cancer, treating one as derivation and the other as validation sample. Results are presented for discrimination and calibration. We demonstrate plots of survival probabilities that can assist model evaluation. Conclusions Our validation methods are applicable to a wide range of prognostic studies and provide researchers with a toolkit for external validation of a published Cox model. PMID:23496923

  10. The first characterization of free radicals formed from cellular COX-catalyzed peroxidation.

    PubMed

    Gu, Yan; Xu, Yi; Law, Benedict; Qian, Steven Y

    2013-04-01

    Through free radical-mediated peroxidation, cyclooxygenase (COX) can metabolize dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA) to form well-known bioactive metabolites, namely, the 1-series of prostaglandins (PGs1) and the 2-series of prostaglandins (PGs2), respectively. Unlike PGs2, which are generally viewed as proinflammatory and procarcinogenic PGs, PGs1 may possess anti-inflammatory and anti-cancer activity. Previous studies using ovine COX along with spin trapping and the LC/ESR/MS technique have shown that certain exclusive free radicals are generated from different free radical reactions in DGLA and AA peroxidation. However, it has been unclear whether the differences were associated with the contrasting bioactivity of DGLA vs AA. The aim of this study was to refine the LC/MS and spin trapping technique to make it possible for the association between free radicals and cancer cell growth to be directly tested. Using a colon cancer cell line, HCA-7 colony 29, and LC/MS along with a solid-phase extraction, we were able to characterize the reduced forms of radical adducts (hydroxylamines) as the free radicals generated from cellular COX-catalyzed peroxidation. For the first time, free radicals formed in the COX-catalyzed peroxidation of AA vs DGLA and their association with cancer cell growth were assessed (cell proliferation via MTS and cell cycle distribution via propidium iodide staining) in the same experimental setting. The exclusive free radicals formed from the COX-catalyzed peroxidation of AA and DGLA were shown to be correlated with the cell growth response. Our results indicate that free radicals generated from the distinct radical reactions in COX-catalyzed peroxidation may represent the novel metabolites of AA and DGLA that correspond to their contrasting bioactivity. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. The First Characterization of Free Radicals Formed From Cellular COX-Catalyzed Peroxidation

    PubMed Central

    Gu, Yan; Xu, Yi; Law, Benedict; Qian, Steven Y.

    2014-01-01

    Through free radical-mediated peroxidation, cyclooxygenase (COX) can metabolize dihomo-γ-linolenic acid (DGLA) and arachidonic acid(AA) to form well-known bioactive metabolites, namely, the 1-series of prostaglandins (PGs1) and 2-series of prostaglandins(PGs2), respectively. Unlike PGs2, which are generally viewed as pro-inflammatory and pro-carcinogenic PGs, PGs1 may possess anti-inflammatory and anti-cancer activity. Previous studies using ovine COX along with spin trapping and the LC/ESR/MS technique have shown that certain exclusive free radicals are generated from different free radical reactions in DGLA and AA peroxidation. However, it has been unclear whether the differences were associated with the contrasting bioactivity of DGLA vs. AA. The aim of this study was to refine the LC/MS and spin-trapping technique to make it possible for the association between free radicals and cancer cell growth to be directly tested. Using a colon cancer cell line, HCA-7 colony 29, and LC/MS along with a solid phase extraction, we were able to characterize the reduced forms of radical adducts (hydroxylamines) as the free radicals generated from cellular COX-catalyzed peroxidation. For the first time, free radicals formed in the COX-catalyzed peroxidation of AA vs. DGLA and their association with cancer cell growth was assessed (cell proliferation via MTS and cell cycle distribution via PI staining) in the same experimental setting. The exclusive free radicals formed from the COX-catalyzed peroxidation of AA and DGLA were shown to be correlated with the cell growth response. Our results indicate that free radicals generated from the distinct radical reactions in COX-catalyzed peroxidation may represent the novel metabolites of AA and DGLA that correspond to their contrasting bioactivity. PMID:23261941

  12. Is there still a role for the classical Cox-Maze III?

    PubMed

    Yap, Cheng-Hon; Prior, David; Kenny, James; Zimmet, Adam; Chao, Victor; Mooney, Donald; Yii, Michael

    2006-05-01

    The incidence of surgery for atrial fibrillation (AF) is rising, paralleled by an increase in the types of lesion sets and energy sources used. These alternate energy sources have simplified the surgery at the expense of increased cost of consumables. The classical Cox-Maze III is the gold standard therapy with a proven efficacy in curing AF. Our complete experience with this procedure is presented. All 28 patients undergoing the classical Cox-Maze III procedure at our institution underwent preoperative assessment and were followed prospectively. Twenty-eight patients underwent the Cox-Maze III procedure between January 2001 and May 2003. Their mean age was 65 years (range, 44-80 years). Twenty-five patients had concomitant cardiac procedures. Mean duration of AF was 8.3 years. Permanent AF was present in 82%. Mean follow-up time was 15 +/- 8 months (range, 4-30 months). There were no perioperative or late deaths, or thromboembolic events. Sixty-one per cent had early (<3 months) atrial arrhythmia. Freedom from AF at most recent clinical follow up was 93%. Freedom from late atrial arrhythmia was 82%. Freedom from late AF or atrial flutter by pacemaker interrogation or Holter assessment was 77%. Anti-arrhythmic medication use was reduced. New York Heart Association class improved from an average of 2.8 preoperatively to 1.3 postoperatively. The result of the present study shows the safety and efficacy of the classical Cox-Maze III procedure. With the advantage of proven long-term efficacy, demonstrable safety and avoidance of costly technology, the Cox-Maze III should not be discounted as a treatment option in patients because of its perceived complexity.

  13. Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans

    PubMed Central

    Song, Wen-Liang; Stubbe, Jane; Ricciotti, Emanuela; Alamuddin, Naji; Ibrahim, Salam; Crichton, Irene; Prempeh, Maxwell; Lawson, John A.; Wilensky, Robert L.; Rasmussen, Lars Melholt; Puré, Ellen; FitzGerald, Garret A.

    2012-01-01

    The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1–dependent formation of PGD2 and PGE2 followed by COX-2–dependent production of PGE2. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD2 receptor DP1. NSAID-mediated suppression of COX-2–derived PGI2 has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD2. Here, we show that PGD2 biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1–derived PGD2 biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD2 was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD2, like PGI2, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy. PMID:22406532

  14. [Specific inhibitors of cyclooxygenase-2 (COX-2): current knowledge and perspectives].

    PubMed

    Rioda, W T; Nervetti, A

    2001-01-01

    The Authors summarize the current knowledge on a new class of nonsteroidal anti-inflammatory drugs (NSAIDs), the coxib (celecoxib and rofecoxib), in the treatment of rheumatic diseases. Celecoxib and rofecoxib are selective cyclooxygenase-2 (COX-2) inhibitors which possess the same anti-inflammatory and analgesic activities, but a better gastric tolerability compared to the non-selective COX-1 and COX-2 inhibitors. The Authors also report other possible therapeutic effects of these NSADIs as evidenced by the more recent data of the literature. Celecoxib seems to reduce the incidence of new polyps in patients with familial adenomatous polyposis. It has been suggested the use of celecoxib as a protective drug against the development of colorectal cancer. Other (neoplastic) or pre-neoplastic conditions, such as bladder dysplasia, Barret esophagus, attinic keratosis and Alzheimer's disease seem to have benefit from this class of drugs.

  15. Stromal COX-2 signaling activated by deoxycholic acid mediates proliferation and invasiveness of colorectal epithelial cancer cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhu, Yingting, E-mail: yitizhu@yahoo.com; Tissue Tech Inc., Miami, FL 33173; Zhu, Min

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Human colonic cancer associated fibroblasts are major sources of COX-2 and PGE{sub 2}. Black-Right-Pointing-Pointer The fibroblasts interact with human colonic epithelial cancer cells. Black-Right-Pointing-Pointer Activation of COX-2 signaling in the fibroblasts affects behavior of the epithelia. Black-Right-Pointing-Pointer Protein Kinase C controls the activation of COX-2 signaling. -- Abstract: COX-2 is a major regulator implicated in colonic cancer. However, how COX-2 signaling affects colonic carcinogenesis at cellular level is not clear. In this article, we investigated whether activation of COX-2 signaling by deoxycholic acid (DCA) in primary human normal and cancer associated fibroblasts play a significant role in regulationmore » of proliferation and invasiveness of colonic epithelial cancer cells. Our results demonstrated while COX-2 signaling can be activated by DCA in both normal and cancer associated fibroblasts, the level of activation of COX-2 signaling is significantly greater in cancer associated fibroblasts than that in normal fibroblasts. In addition, we discovered that the proliferative and invasive potential of colonic epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts pre-treated with DCA than with normal fibroblasts pre-treated with DCA. Moreover, COX-2 siRNA attenuated the proliferative and invasive effect of both normal and cancer associate fibroblasts pre-treated with DCA on the colonic cancer cells. Further studies indicated that the activation of COX-2 signaling by DCA is through protein kinase C signaling. We speculate that activation of COX-2 signaling especially in cancer associated fibroblasts promotes progression of colonic cancer.« less

  16. Comparative analysis of COX-2, vascular endothelial growth factor and microvessel density in human renal cell carcinomas.

    PubMed

    Hemmerlein, B; Galuschka, L; Putzer, N; Zischkau, S; Heuser, M

    2004-12-01

    Cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are frequently up-regulated in malignant tumours and play a role in proliferation, apoptosis, angiogenesis and tumour invasion. In the present study, the expression of COX-2 and VEGF in renal cell carcinoma (RCC) was analysed and correlated with the microvessel density (MVD). COX-2 and VEGF were analysed by realtime reverse transcriptase-polymerase chain reaction and immunohistochemistry. The MVD was assessed by CD31 immunohistochemistry. The expression of COX-2 and VEGF was determined in the RCC cell lines A498 and Caki-1 under short-term hypoxia and in multicellular tumour cell aggregates. COX-2 was expressed in RCC by tumour epithelia, endothelia and macrophages in areas of cystic tumour regression and tumour necrosis. COX-2 protein in RCC was not altered in comparison with normal renal tissue. VEGF mRNA was up-regulated in RCC and positively correlated with MVD. RCC with high up-regulation of VEGF mRNA showed weak intracytoplasmic expression of VEGF in tumour cells. Intracytoplasmic VEGF protein expression was negatively correlated with MVD. In RCC with necrosis the MVD was reduced in comparison with RCC without necrosis. A498 RCC cells down-regulated COX-2 and up-regulated VEGF under conditions of hypoxia. In Caki-1 cells COX-2 expression remained stable, whereas VEGF was significantly up-regulated. In multicellular A498 cell aggregates COX-2 and VEGF were up-regulated centrally, whereas no gradient was found in Caki-1 cells. COX-2 and VEGF are potential therapeutic targets because COX-2 and VEGF are expressed in RCC and associated cell populations such as endothelia and monocytes/macrophages.

  17. Carbonic anhydrase inhibition: insight into non-COX-2 pharmacological effect of some coxibs.

    PubMed

    Dogné, Jean-Michel; Thiry, Anne; Supuran, Claudiu T

    2008-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described adverse drug reactions (ADRs) limit their use. These drugs act via the inhibition of cyclooxygenase (COX) enzyme of which at least two isoforms were described: COX-1 which plays important roles in homeostatic processes such as thrombogenesis and homeostasis of the gastrointestinal tract and kidneys and COX-2 expressed in pathological conditions such as inflammation or cancer proliferation. Selective COX-2 inhibitors or "coxibs" were initially developed as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of non specific NSAIDs. However, this class of drug did not fulfill all their promises. Indeed, numerous unexpected side effects have limited their use and some of them have been withdrawn or suspended from the market for different safety reasons including cardiovascular, hepatic and skin adverse reactions. For instance, cardiovascular warnings have been applied to the whole class of coxibs and more recently for all classical NSAIDs as well. However, differences in the chemical structures should be taken into consideration in order to discriminate between coxibs and the development of some ADRs of which renal events and hypertension. The aim of this paper is to focus on the differences in chemical structures of all marketed COX-2 inhibitors and their unexpected effects on carbonic anhydrase in order to provide non-COX-2 mechanistic insights into some of the differences observed between coxibs.

  18. A Box-Cox normal model for response times.

    PubMed

    Klein Entink, R H; van der Linden, W J; Fox, J-P

    2009-11-01

    The log-transform has been a convenient choice in response time modelling on test items. However, motivated by a dataset of the Medical College Admission Test where the lognormal model violated the normality assumption, the possibilities of the broader class of Box-Cox transformations for response time modelling are investigated. After an introduction and an outline of a broader framework for analysing responses and response times simultaneously, the performance of a Box-Cox normal model for describing response times is investigated using simulation studies and a real data example. A transformation-invariant implementation of the deviance information criterium (DIC) is developed that allows for comparing model fit between models with different transformation parameters. Showing an enhanced description of the shape of the response time distributions, its application in an educational measurement context is discussed at length.

  19. Reaction paths of alane dissociation on the Si(0 0 1) surface

    NASA Astrophysics Data System (ADS)

    Smith, Richard; Bowler, David R.

    2018-03-01

    Building on our earlier study, we examine the kinetic barriers to decomposition of alane, AlH3, on the Si(0 0 1) surface, using the nudged elastic band approach within density functional theory. We find that the initial decomposition to AlH with two H atoms on the surface proceeds without a significant barrier. There are several pathways available to lose the final hydrogen, though these present barriers of up to 1 eV. Incorporation is more challenging, with the initial structures less stable in several cases than the starting structures, just as was found for phosphorus. We identify a stable route for Al incorporation following selective surface hydrogen desorption (e.g. by scanning tunneling microscope tip). The overall process parallels PH3, and indicates that atomically precise acceptor doping should be possible.

  20. COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP

    PubMed Central

    Sharma-Walia, N; Patel, K; Chandran, K; Marginean, A; Bottero, V; Kerur, N; Paul, A G

    2012-01-01

    Kaposi's sarcoma herpesvirus (KSHV) latent oncoprotein viral FLICE (FADD-like interferon converting enzyme)-like inhibitory protein (v-FLIP) or K13, a potent activator of NF-κB, has well-established roles in KSHV latency and oncogenesis. KSHV-induced COX-2 represents a novel strategy employed by KSHV to promote latency and inflammation/angiogenesis/invasion. Here, we demonstrate that v-FLIP/K13 promotes tumorigenic effects via the induction of host protein COX-2 and its inflammatory metabolite PGE2 in an NF-κB-dependent manner. In addition to our previous studies demonstrating COX-2/PGE2's role in transcriptional regulation of KSHV latency promoter and latent gene expression, the current study adds to the complexity that though LANA-1 (latency associated nuclear antigen) is utilizing COX-2/PGE2 as critical factors for its transcriptional regulation, it is the v-FLIP/K13 gene in the KSHV latency cluster that maintains continuous COX-2/PGE2 levels in the infected cells. We demonstrate that COX-2 inhibition, via its chemical inhibitors (NS-398 or celecoxib), reduced v-FLIP/K13-mediated NF-κB induction, and extracellular matrix (ECM) interaction-mediated signaling, mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) levels, and subsequently downregulated detachment-induced apoptosis (anoikis) resistance. vFLIP expression mediated the secretion of cytokines, and spindle cell differentiation activated the phosphorylation of p38, RSK, FAK, Src, Akt and Rac1-GTPase. The COX-2 inhibition in v-FLIP/K13-HMVECs reduced inflammation and invasion/metastasis-related genes, along with reduced anchorage-independent colony formation via modulating ‘extrinsic' as well as ‘intrinsic' cell death pathways. COX-2 blockade in v-FLIP/K13-HMVEC cells drastically augmented cell death induced by removal of essential growth/survival factors secreted in the microenvironment. Transformed cells obtained from anchorage-independent colonies of COX-2 inhibitor-treated v

  1. MicroRNA-128 inhibits proliferation and invasion of glioma cells by targeting COX-2.

    PubMed

    Lin, Yihai; Wu, Zhangyi

    2018-06-05

    MicroRNAs (miRNA), a class of small noncoding RNAs, regulates message RNA (mRNA) by targeting the 3'-untranslated region (3'-UTR) resulting in suppression of gene expression. In this study, we identified the expression and function of miR-128, which was found to be downregulated in glioma tissues and glioma cells by real time PCR. Overexpression of miR-128 mimics into LN229 and U251 cells could inhibit proliferation and invasion of glioma cells. However, the inhibitory effects of miR-128 mimics on the invasion and proliferation of glioma cells were reversed by overexpression of cyclooxygenase-2 (COX-2). Our data showed that COX-2 was a candidate target of miR-128. Luciferase activity of 3'-UTR of COX-2 was reduced in the presence of miR-128. Additionally, miR-128 obviously decreased COX-2 mRNA stability determined by real time PCR. Contrarily, we found that miR-128 inhibitor significantly increased the COX-2 mRNA expression, and elevated the protein expression of MMP9 and ki67, and promoted the proliferation of glioma cells. Furthermore, luciferase activity of the 3'-UTR was upregulated by miR-128 inhibitor. All of these results supported that miR-128 was a direct regulator of COX-2. Further studies proved that COX-2 was elevated in glioma tissues and its expression was negatively correlated with the levels of miR-128. These findings may establish miR-128 as a new potential target for the treatment of patients with gliomas. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. COX inhibitors directly alter gene expression: role in cancer prevention?

    PubMed Central

    Wang, Xingya; Baek, Seung Joon; Eling, Thomas

    2016-01-01

    Inflammation is an important contributor to the development and progression of human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs) bind to specific receptors that activate signaling pathways driving the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs) are well documented as agents that inhibit tumor growth and with long-term use prevent tumor development. NSAIDs also alter gene expression independent of COX inhibition and these changes in gene expression also appear to contribute to the anti-tumorigenic activity of these drugs. Many NSAIDs, as illustrated by sulindac sulfide, alter gene expressions by altering the expression or phosphorylation status of the transcription factors specificity protein 1 and early growth response-1 with the balance between these two events resulting in increases or decreases in specific target genes. In this review, we have summarized and discussed the various genes altered by this mechanism after NSAID treatment and how these changes in expression relate to the anti-tumorigenic activity. A major focus of the review is on NSAID-activated gene (NAG-1) or growth differentiation factor 15. This unique member of the TGF-β superfamily is highly induced by NSAIDs and numerous drugs and chemicals with anti-tumorigenic activities. Investigations with a transgenic mouse expressing the human NAG-1 suggest it acts to suppress tumor development in several mouse models of cancer. The biochemistry and biology of NAG-1 were discussed as potential contributor to cancer prevention by COX inhibitors. PMID:22020924

  3. Identification of COX inhibitors in the hexane extract of Japanese horse chestnut (Aesculus turbinata) seeds.

    PubMed

    Sato, Itaru; Kofujita, Hisayoshi; Tsuda, Shuji

    2007-07-01

    Japanese horse chestnut (Aesculus turbinata) seed extract inhibits the activity of cyclooxygenase (COX), but its active constituents have not been identified. In the present study, COX inhibitors were isolated from the hexane extract of this seed by means of 4 steps of liquid chromatography and were identified by gas chromatography/mass spectrometry and nuclear magnetic resonance. The COX inhibitors in the extract of Japanese horse chestnut seeds were identified as linoleic acid, linolenic acid, and oleic acid. Their efficacies were in the following order: linolenic acid = linoleic acid > oleic acid. These active constituents are C18 unsaturated fatty acids; stearic acid, a C18 saturated fatty acid, had no activity. Linolenic acid and linoleic acid had high selectivity toward COX-2 (selectivity index = 10), whereas oleic acid had no selectivity. Considering the efficacy and yield of each fatty acid, linoleic acid may be the principal COX inhibitor in this seed.

  4. Direct-to-consumer advertising of COX-2 inhibitors: effect on appropriateness of prescribing.

    PubMed

    Spence, Michele M; Teleki, Stephanie S; Cheetham, T Craig; Schweitzer, Stuart O; Millares, Mirta

    2005-10-01

    Spending on direct-to-consumer advertising (DTCA) of prescription drugs has increased dramatically in the past several years. An unresolved question is whether such advertising leads to inappropriate prescribing. In this study, the authors use survey and administrative data to determine the association of DTCA with the appropriate prescribing of cyclooxygenase-2 (COX-2) inhibitors for 1,382 patients. Treatment with either a COX-2 or a traditional nonsteroidal anti-inflammatory drug (NSAID) was defined as appropriate or not according to three different definitions of gastrointestinal risk. Patients who saw or heard a COX-2 advertisement and asked their physician about the advertised drug were significantly more likely to be prescribed a COX-2 (versus a NSAID, as recommended by evidence-based guidelines) than all other patients. Findings also suggest that some patients may benefit from DTCA. The authors discuss the need for balanced drug information for consumers, increased physician vigilance in prescribing appropriately, and further study of DTCA.

  5. IL-1β Stimulates COX-2 Dependent PGE2 Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells

    PubMed Central

    Neeb, Lars; Hellen, Peter; Boehnke, Carsten; Hoffmann, Jan; Schuh-Hofer, Sigrid; Dirnagl, Ulrich; Reuter, Uwe

    2011-01-01

    Objective Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. Methods and Results 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE2) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE2 and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. Conclusion We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE2 (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The

  6. Intracellular gene transfer in action: Dual transcription and multiple silencings of nuclear and mitochondrial cox2 genes in legumes

    PubMed Central

    Adams, Keith L.; Song, Keming; Roessler, Philip G.; Nugent, Jacqueline M.; Doyle, Jane L.; Doyle, Jeff J.; Palmer, Jeffrey D.

    1999-01-01

    The respiratory gene cox2, normally present in the mitochondrion, was previously shown to have been functionally transferred to the nucleus during flowering plant evolution, possibly during the diversification of legumes. To search for novel intermediate stages in the process of intracellular gene transfer and to assess the evolutionary timing and frequency of cox2 transfer, activation, and inactivation, we examined nuclear and mitochondrial (mt) cox2 presence and expression in over 25 legume genera and mt cox2 presence in 392 genera. Transfer and activation of cox2 appear to have occurred during recent legume evolution, more recently than previously inferred. Many intermediate stages of the gene transfer process are represented by cox2 genes in the studied legumes. Nine legumes contain intact copies of both nuclear and mt cox2, although transcripts could not be detected for some of these genes. Both cox2 genes are transcribed in seven legumes that are phylogenetically interspersed with species displaying only nuclear or mt cox2 expression. Inactivation of cox2 in each genome has taken place multiple times and in a variety of ways, including loss of detectable transcripts or transcript editing and partial to complete gene loss. Phylogenetic evidence shows about the same number (3–5) of separate inactivations of nuclear and mt cox2, suggesting that there is no selective advantage for a mt vs. nuclear location of cox2 in plants. The current distribution of cox2 presence and expression between the nucleus and mitochondrion in the studied legumes is probably the result of chance mutations silencing either cox2 gene. PMID:10570164

  7. COX-2 contributes to LPS-induced Stat3 activation and IL-6 production in microglial cells

    PubMed Central

    Zhu, Jie; Li, Shuzhen; Zhang, Yue; Ding, Guixia; Zhu, Chunhua; Huang, Songming; Zhang, Aihua; Jia, Zhanjun; Li, Mei

    2018-01-01

    Many stimuli including lipopolysaccharide (LPS) could activate microglial cells to subsequently cause inflammatory nerve injury. However, the mechanism of LPS-induced neuroinflammation in microglial cells is still elusive. Thus, the present study was undertaken to examine the role of COX-2 in mediating the activation of Stat3 and the production of IL-6 in BV2 cells challenged with LPS. After 24 h treatment, LPS dose-dependently enhanced COX-2 expression at both mRNA and protein levels. Meanwhile, IL-6 with other inflammatory cytokines including IL-1β, TNF-α, and MCP-1 were similarly enhanced by LPS. Then a specific COX-2 inhibitor (NS-398) was administered to BV2 before LPS treatment. Significantly, COX-2 inhibition suppressed the upregulation of IL-6 at both mRNA and protein levels in line with the trend blockade on IL-1β, TNF-α, and MCP-1. Stat3 drives proinflammatory signaling pathways and contributes to IL-6 production via a transcriptional mechanism in many diseases. Here we found that inhibition of COX-2 entirely blocked LPS-induced Stat3 phosphorylation, which might contribute to the blockade of IL-6 production to some extent. Meanwhile, COX-2 siRNA approach largely reproduced the phenotypes shown by specific COX-2 inhibitor in LPS-treated BV2 cells. Together, these findings suggested that COX-2 might contribute to LPS-induced IL-6 production possibly through activating Stat3 signaling pathway in microglial cells. PMID:29636886

  8. Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice.

    PubMed

    Praticò, D; Tillmann, C; Zhang, Z B; Li, H; FitzGerald, G A

    2001-03-13

    The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.

  9. Apollo 12 Mission image - Dark view of Astronaut Alan L. Bean climbing down the ladder of the Lunar Module (LM)

    NASA Image and Video Library

    1969-11-19

    AS12-46-6726 (19 Nov. 1969) --- Astronaut Alan L. Bean, lunar module pilot for the Apollo 12 mission, starts down the ladder of the Lunar Module (LM) to join astronaut Charles Conrad Jr., mission commander, in extravehicular activity (EVA). While astronauts Conrad and Bean descended in the LM "Intrepid" to explore the Ocean of Storms region of the moon, astronaut Richard F. Gordon Jr., command module pilot, remained with the Command and Service Modules (CSM) "Yankee Clipper" in lunar orbit.

  10. Histamine, carbachol, and serotonin induce hyperresponsiveness to ATP in guinea pig tracheas: involvement of COX-2 pathway.

    PubMed

    Montaño, Luis M; Carbajal, Verónica; Vargas, Mario H; García-Hernández, Luz M; Díaz-Hernández, Verónica; Checa, Marco; Barajas-López, Carlos

    2013-08-01

    Extracellular ATP promotes an indirect contraction of airway smooth muscle via the secondary release of thromboxane A2 (TXA2) from airway epithelium. Our aim was to evaluate if common contractile agonists modify this response to ATP. Tracheas from sensitized guinea pigs were used to evaluate ATP-induced contractions before and after a transient contraction produced by histamine, carbachol, or serotonin. Epithelial mRNA for COX-1 and COX-2 was measured by RT-PCR and their expression assessed by immunohistochemistry. Compared with the initial response, ATP-induced contraction was potentiated by pretreatment with histamine, carbachol, or serotonin. Either suramin (antagonist of P2X and P2Y receptors) plus RB2 (antagonist of P2Y receptors) or indomethacin (inhibitor of COX-1 and COX-2) annulled the ATP-induced contraction, suggesting that it was mediated by P2Y receptor stimulation and TXA2 production. When COX-2 was inhibited by SC-58125 or thromboxane receptors were antagonized by SQ-29548, just the potentiation was abolished, leaving the basal response intact. Airway epithelial cells showed increased COX-2 mRNA after stimulation with histamine or carbachol, but not serotonin, while COX-1 mRNA was unaffected. Immunochemistry corroborated this upregulation of COX-2. In conclusion, we showed for the first time that histamine and carbachol cause hyperresponsiveness to ATP by upregulating COX-2 in airway epithelium, which likely increases TXA2 production. Serotonin-mediated hyperresponsiveness seems to be independent of COX-2 upregulation, but nonetheless is TXA2 dependent. Because acetylcholine, histamine, and serotonin can be present during asthmatic exacerbations, their potential interactions with ATP might be relevant in its pathophysiology.

  11. HPV16 E6 Promotes Breast Cancer Proliferation via Upregulation of COX-2 Expression

    PubMed Central

    Li, Y. Z.; Zhang, Z. Y.; Wang, J. Q.

    2017-01-01

    Background. Breast cancer remains the leading cause of cancer-related mortality worldwide. It has been indicated that human papillomaviruses 16 (HPV16) might participate in the pathogenesis and development of breast cancer. However, the detected rate of HPV16 varies with region. We will investigate HPV16 E6 expression in North China and explore the effects and mechanism of HPV16 E6 on breast cancer proliferation in this study. Methods. The expressions of HPV16 E6 and COX-2 in paraffin-embedded tissues of the invasive ductal breast cancer were detected by qPCR and IHC. The effects of HPV16 E6 on breast cancer proliferation were determined by function studies. The mechanism of HPV16 E6 in promoting breast cancer proliferation was explored by Western blot and Dual-Luciferase Reporter Assay. Results. HPV16 E6 was positive in 28% invasive ductal breast carcinoma in North China; HPV16 E6 promoted breast cancer proliferation. Inhibition of COX-2 by siCOX-2 or Celecoxib attenuated the proliferation of breast cancer cells with HPV16 E6 expression; and the upregulation of COX-2 could be suppressed by the inhibition of NF-κB activity. Conclusion. HPV16 E6 promotes breast cancer proliferation by activation of NF-κB signaling pathway and increase of COX-2 expression. COX-2 will be a potential target for HPV16 E6-associated breast cancer. PMID:29250535

  12. Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury.

    PubMed

    Shiow, Lawrence R; Favrais, Geraldine; Schirmer, Lucas; Schang, Anne-Laure; Cipriani, Sara; Andres, Christian; Wright, Jaclyn N; Nobuta, Hiroko; Fleiss, Bobbi; Gressens, Pierre; Rowitch, David H

    2017-12-01

    Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro-inflammatory IL-1β to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy (HIE). In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal HIE cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with "A2" reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1β-induced model of NWMI, astrocytes also exhibit "A2" reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop "A2" reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection. © 2017 Wiley Periodicals, Inc.

  13. IL1{beta}-mediated Stromal COX-2 signaling mediates proliferation and invasiveness of colonic epithelial cancer cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhu, Yingting, E-mail: yitizhu@yahoo.com; Tissue Tech Inc, Miami, FL 33173; Zhu, Min

    2012-11-15

    COX-2 is a major inflammatory mediator implicated in colorectal inflammation and cancer. However, the exact origin and role of COX-2 on colorectal inflammation and carcinogenesis are still not well defined. Recently, we reported that COX-2 and iNOS signalings interact in colonic CCD18Co fibroblasts. In this article, we investigated whether activation of COX-2 signaling by IL1{beta} in primary colonic fibroblasts obtained from normal and cancer patients play a critical role in regulation of proliferation and invasiveness of human colonic epithelial cancer cells. Our results demonstrated that COX-2 level was significantly higher in cancer associated fibroblasts than that in normal fibroblasts withmore » or without stimulation of IL-1{beta}, a powerful stimulator of COX-2. Using in vitro assays for estimating proliferative and invasive potential, we discovered that the proliferation and invasiveness of the epithelial cancer cells were much greater when the cells were co-cultured with cancer associated fibroblasts than with normal fibroblasts, with or without stimulation of IL1{beta}. Further analysis indicated that the major COX-2 product, prostaglandin E{sub 2}, directly enhanced proliferation and invasiveness of the epithelial cancer cells in the absence of fibroblasts. Moreover, a selective COX-2 inhibitor, NS-398, blocked the proliferative and invasive effect of both normal and cancer associate fibroblasts on the epithelial cancer cells, with or without stimulation of IL-1{beta}. Those results indicate that activation of COX-2 signaling in the fibroblasts plays a major role in promoting proliferation and invasiveness of the epithelial cancer cells. In this process, PKC is involved in the activation of COX-2 signaling induced by IL-1{beta} in the fibroblasts.« less

  14. Molecular docking analysis of known flavonoids as duel COX-2 inhibitors in the context of cancer

    PubMed Central

    Dash, Raju; Uddin, Mir Muhammad Nasir; Hosen, S.M. Zahid; Rahim, Zahed Bin; Dinar, Abu Mansur; Kabir, Mohammad Shah Hafez; Sultan, Ramiz Ahmed; Islam, Ashekul; Hossain, Md Kamrul

    2015-01-01

    Cyclooxygenase-2 (COX-2) catalyzed synthesis of prostaglandin E2 and it associates with tumor growth, infiltration, and metastasis in preclinical experiments. Known inhibitors against COX-2 exhibit toxicity. Therefore, it is of interest to screen natural compounds like flavanoids against COX-2. Molecular docking using 12 known flavanoids against COX-2 by FlexX and of ArgusLab were performed. All compounds showed a favourable binding energy of >-10 KJ/mol in FlexX and > -8 kcal/mol in ArgusLab. However, this data requires in vitro and in vivo verification for further consideration. PMID:26770028

  15. Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ghezali, Lamia; Leger, David Yannick; Limami, Youness

    2013-04-15

    Erythroleukemia is generally associated with a very poor response and survival to current available therapeutic agents. Cyclooxygenase-2 (COX-2) has been described to play a crucial role in the proliferation and differentiation of leukemia cells, this enzyme seems to play an important role in chemoresistance in different cancer types. Previously, we demonstrated that diosgenin, a plant steroid, induced apoptosis in HEL cells with concomitant COX-2 overexpression. In this study, we investigated the antiproliferative and apoptotic effects of cyclopamine and jervine, two steroidal alkaloids with similar structures, on HEL and TF1a human erythroleukemia cell lines and, for the first time, their effectmore » on COX-2 expression. Cyclopamine, but not jervine, inhibited cell proliferation and induced apoptosis in these cells. Both compounds induced COX-2 overexpression which was responsible for apoptosis resistance. In jervine-treated cells, COX-2 overexpression was NF-κB dependent. Inhibition of NF-κB reduced COX-2 overexpression and induced apoptosis. In addition, cyclopamine induced apoptosis and COX-2 overexpression via PKC activation. Inhibition of the PKC pathway reduced both apoptosis and COX-2 overexpression in both cell lines. Furthermore, we demonstrated that the p38/COX-2 pathway was involved in resistance to cyclopamine-induced apoptosis since p38 inhibition reduced COX-2 overexpression and increased apoptosis in both cell lines. - Highlights: ► Cyclopamine alone but not jervine induces apoptosis in human erythroleukemia cells. ► Cyclopamine and jervine induce COX-2 overexpression. ► COX-2 overexpression is implicated in resistance to cyclopamine-induced apoptosis. ► Apoptotic potential of jervine is restrained by NF-κB pathway activation. ► PKC is involved in cyclopamine-induced apoptosis and COX-2 overexpression.« less

  16. COX-2 expression in papillary thyroid carcinoma (PTC) in cytological material obtained by fine needle aspiration biopsy (FNAB)

    PubMed Central

    2011-01-01

    Background COX-2 is an enzyme isoform that catalyses the formation of prostanoids from arachidonic acid. An increased COX-2 gene expression is believed to participate in carcinogenesis. Recent studies have shown that COX-2 up-regulation is associated with the development of numerous neoplasms, including skin, colorectal, breast, lung, stomach, pancreas and liver cancers. COX-2 products stimulate endothelial cell proliferation and their overexpression has been demonstrated to be involved in the mechanism of decreased resistance to apoptosis. Suppressed angiogenesis was found in experimental animal studies as a consequence of null mutation of COX-2 gene in mice. Despite the role of COX-2 expression remains a subject of numerous studies, its participation in carcinogenesis or the thyroid cancer progression remains unclear. Methods Twenty three (23) patients with cytological diagnosis of PTC were evaluated. After FNAB examination, the needle was washed out with a lysis buffer and the obtained material was used for COX-2 expression estimation. Total RNA was isolated (RNeasy Micro Kit), and RT reactions were performed. β-actin was used as endogenous control. Relative COX-2 expression was assessed in real-time PCR reactions by an ABI PRISM 7500 Sequence Detection System, using the ΔΔCT method. Results COX-2 gene expression was higher in patients with PTC, when compared to specimens from patients with non-toxic nodular goitre (NTG). Conclusions The preliminary results may indicate COX-2 role in thyroid cancer pathogenesis, however the observed variability in results among particular subjects requires additional clinical data and tumor progression analysis. PMID:21214962

  17. COX-2 expression in papillary thyroid carcinoma (PTC) in cytological material obtained by fine needle aspiration biopsy (FNAB).

    PubMed

    Krawczyk-Rusiecka, Kinga; Wojciechowska-Durczyńska, Katarzyna; Cyniak-Magierska, Anna; Adamczewski, Zbigniew; Gałecka, Elżbieta; Lewiński, Andrzej

    2011-01-10

    COX-2 is an enzyme isoform that catalyses the formation of prostanoids from arachidonic acid. An increased COX-2 gene expression is believed to participate in carcinogenesis. Recent studies have shown that COX-2 up-regulation is associated with the development of numerous neoplasms, including skin, colorectal, breast, lung, stomach, pancreas and liver cancers. COX-2 products stimulate endothelial cell proliferation and their overexpression has been demonstrated to be involved in the mechanism of decreased resistance to apoptosis. Suppressed angiogenesis was found in experimental animal studies as a consequence of null mutation of COX-2 gene in mice. Despite the role of COX-2 expression remains a subject of numerous studies, its participation in carcinogenesis or the thyroid cancer progression remains unclear. Twenty three (23) patients with cytological diagnosis of PTC were evaluated. After FNAB examination, the needle was washed out with a lysis buffer and the obtained material was used for COX-2 expression estimation. Total RNA was isolated (RNeasy Micro Kit), and RT reactions were performed. β-actin was used as endogenous control. Relative COX-2 expression was assessed in real-time PCR reactions by an ABI PRISM 7500 Sequence Detection System, using the ΔΔCT method. COX-2 gene expression was higher in patients with PTC, when compared to specimens from patients with non-toxic nodular goitre (NTG). The preliminary results may indicate COX-2 role in thyroid cancer pathogenesis, however the observed variability in results among particular subjects requires additional clinical data and tumor progression analysis.

  18. Targeted deletion and lipidomic analysis identify epithelial cell COX-2 as a major driver of chemically induced skin cancer.

    PubMed

    Jiao, Jing; Ishikawa, Tomo-O; Dumlao, Darren S; Norris, Paul C; Magyar, Clara E; Mikulec, Carol; Catapang, Art; Dennis, Edward A; Fischer, Susan M; Herschman, Harvey R

    2014-11-01

    Pharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX-2) plays a critical role in DMBA/TPA-induced skin tumor induction. Although many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell type-specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell-specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell-specific Cox-2 gene deletion, compared with littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2-expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA-treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2-dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell type-specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biologic responses. Cox-2 gene deletion demonstrates that intrinsic COX-2 expression in initiated keratinocytes is a principal driver of skin carcinogenesis; lipidomic analysis identifies likely prostanoid effectors. ©2014 American Association for Cancer Research.

  19. STIM1 Overexpression Promotes Colorectal Cancer Progression, Cell Motility and COX-2 Expression

    PubMed Central

    Wang, Jaw-Yuan; Sun, Jianwei; Huang, Ming-Yii; Wang, Yu-Shiuan; Hou, Ming-Feng; Sun, Yan; He, Huifang; Krishna, Niveditha; Chiu, Siou-Jin; Lin, Shengchen; Yang, Shengyu; Chang, Wei-Chiao

    2014-01-01

    Tumor metastasis is the major cause of death among cancer patients, with more than 90% of cancer-related death attributable to the spreading of metastatic cells to secondary organs. Store-operated Ca2+ entry (SOCE) is the predominant Ca2+ entry mechanism in most cancer cells, and STIM1 is the endoplasmic reticulum (ER) Ca2+ sensor for store-operated channels (SOC). Here we reported that the STIM1 was overexpressed in colorectal cancer (CRC) patients. STIM1 overexpression in CRC was significantly associated with tumor size, depth of invasion, lymphnode metastasis status and serum levels of carcinoembryonic antigen. Furthermore, ectopic expression of STIM1 promoted CRC cell motility, while depletion of STIM1 with shRNA inhibited CRC cell migration. Our data further suggested that STIM1 promoted CRC cell migration through increasing the expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). Importantly, ectopically expressed COX-2 or exogenous PGE2 were able to rescue migration defect in STIM1 knockdown CRC cells, and inhibition of COX-2 with ibuprofen and indomethacin abrogated STIM1-mediated CRC cell motility. In short, our data provided clinicopathological significance for STIM1 and store-operated Ca2+ entry in CRC progression, and implicated a role for COX-2 in STIM1-mediated CRC metastasis. Our studies also suggested a new approach to inhibit STIM1-mediated metastasis with COX-2 inhibitors. PMID:25381814

  20. Expression of COX-2 and bcl-2 in oral lichen planus lesions and lichenoid reactions

    PubMed Central

    Arreaza, Alven J; Rivera, Helen; Correnti, María

    2014-01-01

    Oral lichen planus and lichenoid reactions are autoimmune type inflammatory conditions of the oral mucosa with similar clinical and histological characteristics. Recent data suggest that oral lichenoid reactions (OLR) present a greater percentage of malignant transformation than oral lichen planus (OLP). Objective To compare the expression of bcl-2 and COX-2 in OLP and OLR. Methods The study population consisted of 65 cases; 34 cases diagnosed as OLR and 31 as OLP. A retrospective study was done, and bcl-2 and COX-2 expression was semiquantitatively analysed. Results Fifty-three per cent (18/34) of the ORL samples tested positive for COX-2, whereas in the OLP group, 81% of the samples (25/31) immunostained positive for COX-2. The Fisher’s exact test for the expression of COX-2 revealed that there are significant differences between the two groups, P = 0.035. With respect to the expression of the bcl-2 protein, 76% (26/34) of the samples were positive in OLR, while 97% (30/31) were positive in the group with OLP. The Fisher’s exact test for the expression of bcl-2 revealed that there are significant statistical differences between the two groups, P = 0.028. Conclusions The expression of bcl-2 and COX-2 was more commonly expressed in OLP when compared with OLR. PMID:24834112

  1. COX-derived prostanoid pathways in gastrointestinal cancer development and progression: novel targets for prevention and intervention.

    PubMed

    Cathcart, Mary-Clare; O'Byrne, Kenneth J; Reynolds, John V; O'Sullivan, Jacintha; Pidgeon, Graham P

    2012-01-01

    Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE(2), which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA(2) in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD(2) and its metabolite 15d-PGJ2, PGF(1α) and PGI(2). Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity. A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will

  2. Actinic cheilitis: epithelial expression of COX-2 and its association with mast cell tryptase and PAR-2.

    PubMed

    Rojas, I Gina; Martínez, Alejandra; Brethauer, Ursula; Grez, Patricia; Yefi, Roger; Luza, Sandra; Marchesani, Francisco J

    2009-03-01

    Cyclooxygenase-2 (COX-2) is overexpressed in various types of human malignancies, including oral cancers. Recent studies have shown that mast cell-derived protease tryptase can induce COX-2 expression by the cleavage of proteinase-activated receptor-2 (PAR-2). Actinic cheilitis (AC) is a premalignant form of lip cancer characterized by an increased density of tryptase-positive mast cells. To investigate the possible contribution of tryptase to COX-2 overexpression during early lip carcinogenesis, normal lip (n=24) and AC (n=45) biopsies were processed for COX-2, PAR-2 and tryptase detection, using RT-PCR and immunohistochemistry. Expression scores were obtained for each marker and tested for statistical significance using Mann-Whitney and Spearmann's correlation tests as well as multivariate logistic regression analysis. Increased epithelial co-expression of COX-2 and PAR-2, as well as, elevated subepithelial density of tryptase-positive mast cells were found in AC as compared to normal lip (P<0.001). COX-2 overexpression was found to be a significant predictor of AC (P<0.034, forward stepwise, Wald), and to be correlated with both tryptase-positive mast cells and PAR-2 expression (P<0.01). The results suggest that epithelial COX-2 overexpression is a key event in AC, which is associated with increased tryptase-positive mast cells and PAR-2. Therefore, tryptase may contribute to COX-2 up-regulation by epithelial PAR-2 activation during early lip carcinogenesis.

  3. A fast identification algorithm for Box-Cox transformation based radial basis function neural network.

    PubMed

    Hong, Xia

    2006-07-01

    In this letter, a Box-Cox transformation-based radial basis function (RBF) neural network is introduced using the RBF neural network to represent the transformed system output. Initially a fixed and moderate sized RBF model base is derived based on a rank revealing orthogonal matrix triangularization (QR decomposition). Then a new fast identification algorithm is introduced using Gauss-Newton algorithm to derive the required Box-Cox transformation, based on a maximum likelihood estimator. The main contribution of this letter is to explore the special structure of the proposed RBF neural network for computational efficiency by utilizing the inverse of matrix block decomposition lemma. Finally, the Box-Cox transformation-based RBF neural network, with good generalization and sparsity, is identified based on the derived optimal Box-Cox transformation and a D-optimality-based orthogonal forward regression algorithm. The proposed algorithm and its efficacy are demonstrated with an illustrative example in comparison with support vector machine regression.

  4. Ubiquitin-proteasomal degradation of COX-2 in TGF-β stimulated human endometrial cells is mediated through endoplasmic reticulum mannosidase I.

    PubMed

    Singh, Mohan; Chaudhry, Parvesh; Parent, Sophie; Asselin, Eric

    2012-01-01

    Cyclooxygenase (COX)-2 is a key regulatory enzyme in the production of prostaglandins (PG) during various physiological processes. Mechanisms of COX-2 regulation in human endometrial stromal cells (human endometrial stromal cells) are not fully understood. In this study, we investigate the role of TGF-β in the regulation of COX-2 in human uterine stromal cells. Each TGF-β isoform decreases COX-2 protein level in human uterine stromal cells in Smad2/3-dependent manner. The decrease in COX-2 is accompanied by a decrease in PG synthesis. Knockdown of Smad4 using specific small interfering RNA prevents the decrease in COX-2 protein, confirming that Smad pathway is implicated in the regulation of COX-2 expression in human endometrial stromal cells. Pretreatment with 26S proteasome inhibitor, MG132, significantly restores COX-2 protein and PG synthesis, indicating that COX-2 undergoes proteasomal degradation in the presence of TGF-β. In addition, each TGF-β isoform up-regulates endoplasmic reticulum (ER)-mannosidase I (ERManI) implying that COX-2 degradation is mediated through ER-associated degradation pathway in these cells. Furthermore, inhibition of ERManI activity using the mannosidase inhibitor (kifunensine), or small interfering RNA-mediated knockdown of ERManI, prevents TGF-β-induced COX-2 degradation. Taken together, these studies suggest that TGF-β promotes COX-2 degradation in a Smad-dependent manner by up-regulating the expression of ERManI and thereby enhancing ER-associated degradation and proteasomal degradation pathways.

  5. Cox's chair: 'a moral and a medical mean in the treatment of maniacs'.

    PubMed

    Wade, Nicholas J; Norrsell, U; Presly, A

    2005-03-01

    Two hundred years ago Joseph Cox published his book on the treatment of insanity. His novel technique was rotating the body in a specially designed chair. Initially modest and later extravagant claims were made for the therapeutic benefit of 'Cox's chair'. It was widely adopted in Europe in the first decades of the nineteenth century, but lost favour thereafter. Its benefits have proved to be scientific rather than medical because it was adopted by students of the senses to investigate vertigo; a century later it re-emerged as the Bárány chair for the clinical assessment of vestibular function. The legacy of Cox's chair, and its related treatment of swinging, are to be found in funfairs throughout the world.

  6. Leigh syndrome associated with a novel mutation in the COX15 gene.

    PubMed

    Miryounesi, Mohammad; Fardaei, Majid; Tabei, Seyed Mohammadbagher; Ghafouri-Fard, Soudeh

    2016-06-01

    Leigh syndrome (LS) is a subacute necrotizing encephalomyelopathy with a diverse range of symptoms, such as psychomotor delay or regression, weakness, hypotonia, truncal ataxia, intention tremor as well as lactic acidosis in the blood, cerebrospinal fluid or urine. Both nuclear gene defects and mutations of the mitochondrial genome have been detected in these patients. Here we report a 7-year-old girl with hypotonia, tremor, developmental delay and psychomotor regression. However, serum lactate level as well as brain magnetic resonance imaging were normal. Mutational analysis has revealed a novel mutation in exon 4 of COX15 gene (c.415C>G) which results in p.Leu139Val. Previous studies have demonstrated that COX15 mutations are associated with typical LS as well as fatal infantile hypertrophic cardiomyopathy. Consequently, clinical manifestations of COX15 mutations may be significantly different in patients. Such information is of practical importance in genetic counseling.

  7. TNF-α stimulates colonic myofibroblast migration via COX-2 and Hsp27.

    PubMed

    Saini, Shyla; Liu, Tiegang; Yoo, James

    2016-07-01

    Crohn's disease (CD) is a chronic inflammatory enteropathy characterized by fibrotic strictures. Myofibroblasts (MFBs) are stromal cells of the gastrointestinal tract found in increased numbers in patients with CD and represent the key effector cells involved in pathologic fibrosis. MFB is a known target of tumor necrosis factor alpha (TNF-α), a proinflammatory cytokine strongly implicated in the pathophysiology of CD. However, the precise mechanisms through which TNF-α contributes to fibrosis remain incompletely understood. Here, we demonstrate for the first time that TNF-α increases MFB migration through the cyclooxygenase 2 (COX-2) and heat-shock protein 27 (Hsp27) pathways. The human colonic MFB cell line 18Co was grown to confluence on 35 × 10 mm cell culture dishes and used from passages 8-14. An in vitro scratch assay assessed the effect of TNF-α (10 ng/mL) on MFB migration over 24 h in the presence or absence of several inhibitors (NS398, SB203580, Hsp27 siRNA). TNF-α significantly increased MFB migration over 24 h. TNF-α also led to the increased expression of COX-2 and stimulated rapid phosphorylation of Hsp27 at serine 82. TNF-α-induced COX-2 expression, Hsp27 phosphorylation, and MFB migration were all significantly inhibited by the P38 MAPK inhibitor SB203580 (P < 0.05). TNF-α-induced MFB migration was also significantly inhibited by NS398 (P < 0.05), a direct inhibitor of COX-2, and by siRNA targeting Hsp27 (P < 0.05). TNF-α stimulates colonic MFB migration through P38 MAPK-mediated activation of COX-2 and Hsp27. Further elucidating these inflammatory signaling pathways may lead to novel therapeutic targets for the treatment of CD-related fibrosis and strictures. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Magnetic structure in Mn1 -xCoxGe compounds

    NASA Astrophysics Data System (ADS)

    Altynbaev, E.; Siegfried, S.-A.; Strauß, P.; Menzel, D.; Heinemann, A.; Fomicheva, L.; Tsvyashchenko, A.; Grigoriev, S.

    2018-04-01

    The magnetic system of the pseudobinary compound Mn1 -xCoxGe has been studied using small-angle neutron scattering and susceptibility measurements. It is found that Mn1 -xCoxGe orders magnetically at low temperatures in the whole concentration range of x ∈[0 /0.9 ] . Four different states of the magnetic structure have been found at low temperatures: the long-range-ordered (LRO) short-period helical magnetic structure at x

  9. New carboxamide derivatives bearing benzenesulphonamide as a selective COX-II inhibitor: Design, synthesis and structure-activity relationship

    PubMed Central

    Okoro, Uchechukwu Chris; Ahmad, Hilal

    2017-01-01

    Sixteen new carboxamide derivatives bearing substituted benzenesulphonamide moiety (7a-p) were synthesized by boric acid mediated amidation of appropriate benzenesulphonamide with 2-amino-4-picoline and tested for anti-inflammatory activity. One compound 7c showed more potent anti-inflammatory activity than celecoxib at 3 h in carrageenan-induced rat paw edema bioassay. Compounds 7g and 7k also showed good anti-inflammatory activity comparable to celecoxib. Compound 7c appeared selectivity index (COX-2/COX-1) better than celecoxib. Compound 7k appeared selectivity index (COX-2/COX-1) a little higher than the half of celecoxib while compound 7g is non-selective for COX-2. The LD50 of compounds 7c, 7g and 7k were comparable to celecoxib. PMID:28922386

  10. Low-dose aspirin, non-steroidal anti-inflammatory drugs, selective COX-2 inhibitors and breast cancer recurrence

    PubMed Central

    Cronin-Fenton, Deirdre P; Heide-Jørgensen, Uffe; Ahern, Thomas P; Lash, Timothy L; Christiansen, Peer; Ejlertsen, Bent; Sørensen, Henrik T

    2017-01-01

    Background Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors may improve outcomes in breast cancer patients. We investigated the association of aspirin, NSAIDs, and use of selective COX-2 inhibitors with breast cancer recurrence. Methods We identified incident stage I–III Danish breast cancer patients in the Danish Breast Cancer Cooperative Group registry, who were diagnosed during 1996–2008. Prescriptions for aspirin (>99% low-dose aspirin), NSAIDs, and selective COX-2 inhibitors were ascertained from the National Prescription Registry (NPR). Follow-up began on the date of breast cancer primary surgery and continued until the first of recurrence, death, emigration, or 01/01/2013. We used Cox regression models to compute hazard ratios (HR) and corresponding 95% confidence intervals (95%CI) associating prescriptions with recurrence, adjusting for confounders. Results We identified 34,188 breast cancer patients with 233,130 person-years of follow-up. Median follow-up was 7.1 years; 5,325 patients developed recurrent disease. Use of aspirin, NSAIDs, or selective COX-2 inhibitors was not associated with the rate of recurrence (HRadjusted aspirin=1.0, 95% CI=0.90, 1.1; NSAIDs=0.99, 95% CI=0.92, 1.1; selective COX-2 inhibitors=1.1, 95% CI=0.98, 1.2), relative to non-use. Pre-diagnostic use of the exposure drugs was associated with reduced recurrence rates (HRaspirin=0.92, 95%CI=0.82, 1.0; HRNSAIDs=0.86, 95%CI=0.81, 0.91; HRsCOX-2inhibitors=0.88, 95%CI=0.83, 0.95). Conclusions This prospective cohort study suggests that post-diagnostic prescriptions for aspirin, NSAIDs, and selective COX-2 inhibitors have little or no association with the rate of breast cancer recurrence. Pre-diagnostic use of the drugs was, however, associated with a reduced rate of breast cancer recurrence. PMID:27007644

  11. The COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates.

    PubMed

    McCann, Nicole C; Lynch, Terrie J; Kim, Soon Ok; Duffy, Diane M

    2013-12-01

    Cyclooxygenase-2 (COX-2) inhibitors reduce prostaglandin synthesis and disrupt essential reproductive processes. Ultrasound studies in women demonstrated that oral COX-2 inhibitors can delay or prevent follicle collapse associated with ovulation. The goal of this study was to determine if oral administration of a COX-2 inhibitor can inhibit reproductive function with sufficient efficacy to prevent pregnancy in primates. The COX-2 inhibitor meloxicam (or vehicle) was administered orally to proven fertile female cynomolgus macaques using one emergency contraceptive model and three monthly contraceptive models. In the emergency contraceptive model, females were bred with a proven fertile male once 2±1 days before ovulation, returned to the females' home cage, and then received 5 days of meloxicam treatment. In the monthly contraceptive models, females were co-caged for breeding with a proven fertile male for a total of 5 days beginning 2±1 days before ovulation. Animals received meloxicam treatment (1) cycle days 5-22, or (2) every day, or (3) each day of the 5-day breeding period. Female were then assessed for pregnancy. The pregnancy rate with meloxicam administration using the emergency contraception model was 6.5%, significantly lower than the pregnancy rate of 33.3% when vehicle without meloxicam was administered. Pregnancy rates with the three monthly contraceptive models (75%-100%) were not consistent with preventing pregnancy. Oral COX-2 inhibitor administration can prevent pregnancy after a single instance of breeding in primates. While meloxicam may be ineffective for regular contraception, pharmacological inhibition of COX-2 may be an effective method of emergency contraception for women. COX-2 inhibitors can interfere with ovulation, but the contraceptive efficacy of drugs of this class has not been directly tested. This study, conducted in nonhuman primates, is the first to suggest that a COX-2 inhibitor may be effective as an emergency contraceptive.

  12. Modulation of IgE-dependent COX-2 gene expression by reactive oxygen species in human neutrophils.

    PubMed

    Vega, Antonio; Chacón, Pedro; Alba, Gonzalo; El Bekay, Rajaa; Martín-Nieto, José; Sobrino, Francisco

    2006-07-01

    Cyclooxygenase (COX) is a key enzyme in prostaglandin (PG) synthesis. Up-regulation of its COX-2 isoform is responsible for the increased PG release, taking place under inflammatory conditions, and also, is thought to be involved in allergic and inflammatory diseases. In the present work, we demonstrate that COX-2 expression becomes highly induced by anti-immunoglobulin E (IgE) antibodies and by antigens in human neutrophils from allergic patients. This induction was detected at mRNA and protein levels and was accompanied by a concomitant PGE(2) and thromboxane A(2) release. We also show evidence that inhibitors of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, such as 4-(2-aminoethyl)benzenesulphonyl fluoride and 4-hydroxy-3-methoxyaceto-phenone, completely cancelled anti-IgE-induced COX-2 protein up-regulation, suggesting that this process is mediated by reactive oxygen species (ROS) derived from NADPH oxidase activity. Moreover, the mitogen-activated protein kinases (MAPKs), p38 and extracellular signal-regulated kinase, and also, the transcription factor, nuclear factor (NF)-kappaB, are involved in the up-regulation of COX-2 expression, as specific chemical inhibitors of these two kinases, such as SB203580 and PD098059, and of the NF-kappaB pathway, such as N(alpha)-benzyloxycarbonyl-l-leucyl-l-leucyl-l-leucinal, abolished IgE-dependent COX-2 induction. Evidence is also presented, using Fe(2)(+)/Cu(2)(+) ions, that hydroxyl radicals generated from hydrogen peroxide through Fenton reactions could constitute candidate modulators able to directly trigger anti-IgE-elicited COX-2 expression through MAPK and NF-kappaB pathways. Present results underscore a new role for ROS as second messengers in the modulation of COX-2 expression by human neutrophils in allergic conditions.

  13. Anisotropic storage medium development in a full-scale, sodium alanate-based, hydrogen storage system

    DOE PAGES

    Jorgensen, Scott W.; Johnson, Terry A.; Payzant, E. Andrew; ...

    2016-06-11

    Deuterium desorption in an automotive-scale hydrogen storage tube was studied in-situ using neutron diffraction. Gradients in the concentration of the various alanate phases were observed along the length of the tube but no significant radial anisotropy was present. In addition, neutron radiography and computed tomography showed large scale cracks and density fluctuations, confirming the presence of these structures in an undisturbed storage system. These results demonstrate that large scale storage structures are not uniform even after many absorption/desorption cycles and that movement of gaseous hydrogen cannot be properly modeled by a simple porous bed model. In addition, the evidence indicatesmore » that there is slow transformation of species at one end of the tube indicating loss of catalyst functionality. These observations explain the unusually fast movement of hydrogen in a full scale system and shows that loss of capacity is not occurring uniformly in this type of hydrogen-storage system.« less

  14. Targeted Deletion and Lipidomic Analysis Identify Epithelial Cell COX-2 as a Major Driver of Chemically-induced Skin Cancer

    PubMed Central

    Jiao, Jing; Ishikawa, Tomo-o; Dumlao, Darren S.; Norris, Paul C.; Magyar, Clara E.; Mikulec, Carol; Catapang, Art; Dennis, Edward A.; Fischer, Susan M.; Herschman, Harvey R.

    2014-01-01

    Pharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX2) plays a critical role in DMBA/TPA-induced skin tumor induction. While many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell-type specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell-specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell-specific Cox-2 gene deletion, compared to littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2 expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA-treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2-dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell-type specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biological responses. PMID:25063587

  15. Current approaches to prevent NSAID-induced gastropathy – COX selectivity and beyond

    PubMed Central

    Becker, Jan C; Domschke, Wolfram; Pohle, Thorsten

    2004-01-01

    Gastrointestinal (GI) toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) is still an important medical and socio-economic problem – despite recent pharmaceutical advances. To prevent NSAID-induced gastropathy, three strategies are followed in clinical routine: (i) coprescription of a gastroprotective drug, (ii) use of selective COX-2 inhibitors, and (iii) eradication of Helicobacter pylori. Proton pump inhibitors are the comedication of choice as they effectively reduce gastrointestinal adverse events of NSAIDs and are safe even in long-term use. Co-medication with vitamin C has only been little studied in the prevention of NSAID-induced gastropathy. Apart from scavenging free radicals it is able to induce haeme-oxgenase 1 in gastric cells, a protective enzyme with antioxidant and vasodilative properties. Final results of the celecoxib outcome study (CLASS study) attenuated the initial enthusiasm about the GI safety of selective COX-2 inhibitors, especially in patients concomitantly taking aspirin for cardiovascular prophylaxis. Helicobacter pylori increases the risk for ulcers particularly in NSAID-naive patients and therefore eradication is recommended prior to long-term NSAID therapy at least in patients at high risk. New classes of COX-inhibitors are currently evaluated in clinical studies with very promising results: NSAIDs combined with a nitric oxide releasing moiety (NO-NSAID) and dual inhibitors of COX and 5-LOX. These drugs offer extended anti-inflammatory potency while sparing gastric mucosa. PMID:15563357

  16. COX-2 Elevates Oncogenic miR-526b in Breast Cancer by EP4 Activation.

    PubMed

    Majumder, Mousumi; Landman, Erin; Liu, Ling; Hess, David; Lala, Peeyush K

    2015-06-01

    MicroRNAs (miRs) are small regulatory molecules emerging as potential biomarkers in cancer. Previously, it was shown that COX-2 expression promotes breast cancer progression via multiple mechanisms, including induction of stem-like cells (SLC), owing to activation of the prostaglandin E2 receptor EP4 (PTGER4). COX-2 overexpression also upregulated microRNA-526b (miR-526b), in association with aggressive phenotype. Here, the functional roles of miR-526b in breast cancer and the mechanistic role of EP4 signaling in miR-526b upregulation were examined. A positive correlation was noted between miR-526b and COX-2 mRNA expression in COX-2 disparate breast cancer cell lines. Stable overexpression of miR-526b in poorly metastatic MCF7 and SKBR3 cell lines resulted in increased cellular migration, invasion, EMT phenotype and enhanced tumorsphere formation in vitro, and lung colony formation in vivo in immunodeficient mice. Conversely, knockdown of miR-526b in aggressive MCF7-COX-2 and SKBR3-COX-2 cells reduced oncogenic functions and reversed the EMT phenotype, in vitro. Furthermore, it was determined that miR-526b expression is dependent on EP4 receptor activity and downstream PI3K-AKT and cyclic AMP (cAMP) signaling pathways. PI3K-AKT inhibitors blocked EP4 agonist-mediated miR-526b upregulation and tumorsphere formation in MCF7 and SKBR3 cells. NF-κB inhibitor abrogates EP agonist-stimulated miRNA expression in MCF7 and T47D cells, indicating that the NF-κB pathway is also involved in miR-526b regulation. In addition, inhibition of COX-2, EP4, PI3K, and PKA in COX-2-overexpressing cells downregulated miR-526b and its functions in vitro. Finally, miR-526b expression was significantly higher in cancerous than in noncancerous breast tissues and associated with reduced patient survival. In conclusion, miR-526b promotes breast cancer progression, SLC-phenotype through EP4-mediated signaling, and correlates with breast cancer patient survival. This study presents novel

  17. The COX-2 Selective Blocker Etodolac Inhibits TNFα-Induced Apoptosis in Isolated Rabbit Articular Chondrocytes

    PubMed Central

    Kumagai, Kousuke; Kubo, Mitsuhiko; Imai, Shinji; Toyoda, Futoshi; Maeda, Tsutomu; Okumura, Noriaki; Matsuura, Hiroshi; Matsusue, Yoshitaka

    2013-01-01

    Chondrocyte apoptosis contributes to the disruption of cartilage integrity in osteoarthritis (OA). Recently, we reported that activation of volume-sensitive Cl− current (ICl,vol) mediates cell shrinkage, triggering apoptosis in rabbit articular chondrocytes. A cyclooxygenase (COX) blocker is frequently used for the treatment of OA. In the present study, we examined in vitro effects of selective blockers of COX on the TNFα-induced activation of ICl,vol in rabbit chondrocytes using the patch-clamp technique. Exposure of isolated chondrocytes to TNFα resulted in an obvious increase in membrane Cl− conductance. The TNFα-evoked Cl− current exhibited electrophysiological and pharmacological properties similar to those of ICl,vol. Pretreatment of cells with selective COX-2 blocker etodolac markedly inhibited ICl,vol activation by TNFα as well as subsequent apoptotic events such as apoptotic cell volume decrease (AVD) and elevation of caspase-3/7 activity. In contrast, a COX-1 blocker had no effect on the decrease in cell volume or the increase in caspase-3/7 activity induced by TNFα. Thus, the COX-2-selective blocker had an inhibitory effect on TNFα-induced apoptotic events, which suggests that this drug would have efficacy for the treatment of OA. PMID:24084720

  18. Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells.

    PubMed

    Kim, Hyung Gyun; Jin, Sun Woo; Kim, Yong An; Khanal, Tilak; Lee, Gi Ho; Kim, Se Jong; Rhee, Sang Dal; Chung, Young Chul; Hwang, Young Jung; Jeong, Tae Cheon; Jeong, Hye Gwang

    2017-08-01

    Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if leptin-induced aromatase enhances estrogen production and induces tumor cell growth stimulation. To this end, breast cancer cells were incubated with leptin in the absence or presence of inhibitor pretreatment, and changes in aromatase and cyclooxygenase-2 (COX-2) expression were evaluated at the mRNA and protein levels. Transient transfection assays were performed to examine the aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine protein expression. Leptin induced aromatase expression, estradiol production, and promoter activity in breast cancer cells. Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by leptin. Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition, leptin induced COX-2 expression, promoter activity, and increased the production of prostaglandin E 2 . Finally, a COX-2 inhibitor and aromatase inhibitor suppressed leptin-induced cell proliferation in MCF-7 breast cancer cells. Together, our data show that leptin increased aromatase expression in breast cancer cells, which was correlated with COX-2 upregulation, mediated through CRE activation and cooperation among multiple signaling pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. LEDs/ALAN-Working To Be Good Neighbors

    NASA Astrophysics Data System (ADS)

    Adams, Robert

    2015-08-01

    ALAN (Artificial Light At Night) and LEDs have recently become major discussion topics in the areas of astronomy, light pollution, endangered species and human health to mention but a few. In years past, MH, LPS and HPS dominated night lighting with LPS and its associated narrow spectrum as the preferred source around observatories and shorelines. LEDs offer the ability to modify the spectrum, realize substantial energy savings and other associated benefits while meeting the requirements of the astronomy community.The primary concern of the different groups relates to blue light content of the LED. For astronomers, the molecular (Raleigh) scattering related to the blue light interferes with certain portions of the spectrum used for deep space studies. The ecologists studying various endangered species find blue and green light can be related to declining leatherback turtle population in certain areas of the world. Other animals ranging from bats to moths and other insects are now being studied to determine the effect of the blue light spectrum on their behavior. The impact of blue light on the human circadian rhythm and vision, especially in the older population, is being extensively studied today.This presentation will discuss the spectral power distribution (SPD) of various light sources, the performance of new LED solutions and how the SPD of these new LED’s can be adapted to address some of the issues raised by various constituencies. A discussion describing why some of the metrics used to describe standard lighting are not adequate for specifying the new LED solutions with the modified spectra will be included.Today, lighting plans and implementation are all too often based on opinions and limited data. The ensuing problems and repercussions make it imperative to collect accurate and thorough information. Data collection is now ongoing using a variety of techniques analyzing the “before” and “after” lighting results from the C of HI LED streetlight

  20. Reducing the Harms of College Student Drinking: How Alan Marlatt Changed Approaches, Outcomes, and the Field

    PubMed Central

    Kilmer, Jason R.; Palmer, Rebekka S.; Cronce, Jessica M.; Logan, Diane E.

    2015-01-01

    In this article, we discuss Alan Marlatt’s contributions to the prevention and reduction of alcohol-related harms among college students. We consider Alan’s early research that later led to the development and evaluation of college student drinking programs, and examine Alan’s impact, both directly and indirectly through those he mentored and trained, as a scientist-practitioner. We review the recognition of the efficacy of Alan’s programs, including the Alcohol Skills Training Program (ASTP) and Brief Alcohol Screening and Intervention for College Students (BASICS), in addition to extensions of these interventions in more recent studies. Finally, we discuss how Alan’s work influences interventions with college student drinkers today, and how future directions will continue to be informed by his vision and values. PMID:25774117

  1. Identification and characterization of carprofen as a multi-target FAAH/COX inhibitor

    PubMed Central

    Favia, Angelo D.; Habrant, Damien; Scarpelli, Rita; Migliore, Marco; Albani, Clara; Bertozzi, Sine Mandrup; Dionisi, Mauro; Tarozzo, Glauco; Piomelli, Daniele; Cavalli, Andrea; De Vivo, Marco

    2013-01-01

    Pain and inflammation are major therapeutic areas for drug discovery. Current drugs for these pathologies have limited efficacy, however, and often cause a number of unwanted side effects. In the present study, we identify the non-steroid anti-inflammatory drug, carprofen, as a multi-target-directed ligand that simultaneously inhibits cyclooxygenase-1 (COX-1), COX-2 and fatty acid amide hydrolase (FAAH). Additionally, we synthesized and tested several racemic derivatives of carprofen, sharing this multi-target activity. This may result in improved analgesic efficacy and reduced side effects (Naidu, et al (2009) J Pharmacol Exp Ther 329, 48-56; Fowler, C.J. et al. (2012) J Enzym Inhib Med Chem Jan 6; Sasso, et al (2012) Pharmacol Res 65, 553). The new compounds are among the most potent multi-target FAAH/COXs inhibitors reported so far in the literature, and thus may represent promising starting points for the discovery of new analgesic and anti-inflammatory drugs. PMID:23043222

  2. COX-2 Promotes Migration and Invasion by the Side Population of Cancer Stem Cell-Like Hepatocellular Carcinoma Cells

    PubMed Central

    Guo, Zhe; Jiang, Jing-Hang; Zhang, Jun; Yang, Hao-Jie; Yang, Fu-Quan; Qi, Ya-Peng; Zhong, Yan-Ping; Su, Jie; Yang, Ri-Rong; Li, Le-Qun; Xiang, Bang-De

    2015-01-01

    Abstract Cancer stem cells (CSCs) are thought to be responsible for tumor relapse and metastasis due to their abilities to self-renew, differentiate, and give rise to new tumors. Cyclooxygenase-2 (COX-2) is highly expressed in several kinds of CSCs, and it helps promote stem cell renewal, proliferation, and radioresistance. Whether and how COX-2 contributes to CSC migration and invasion is unclear. In this study, COX-2 was overexpressed in the CSC-like side population (SP) of the human hepatocellular carcinoma (HCC) cell line HCCLM3. COX-2 overexpression significantly enhanced migration and invasion of SP cells, while reducing expression of metastasis-related proteins PDCD4 and PTEN. Treating SP cells with the selective COX-2 inhibitor celecoxib down-regulated COX-2 and caused a dose-dependent reduction in cell migration and invasion, which was associated with up-regulation of PDCD4 and PTEN. These results suggest that COX-2 exerts pro-metastatic effects on SP cells, and that these effects are mediated at least partly through regulation of PDCD4 and PTEN expression. These results further suggest that celecoxib may be a promising anti-metastatic agent to reduce migration and invasion by hepatic CSCs. PMID:26554780

  3. 32. SCIENTISTS ALLAN COX (SEATED), RICHARD DOELL, AND BRENT DALRYMPLE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    32. SCIENTISTS ALLAN COX (SEATED), RICHARD DOELL, AND BRENT DALRYMPLE AT CONTROL PANEL, ABOUT 1965. - U.S. Geological Survey, Rock Magnetics Laboratory, 345 Middlefield Road, Menlo Park, San Mateo County, CA

  4. On nonsingular potentials of Cox-Thompson inversion scheme

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Palmai, Tamas; Apagyi, Barnabas

    2010-02-15

    We establish a condition for obtaining nonsingular potentials using the Cox-Thompson inverse scattering method with one phase shift. The anomalous singularities of the potentials are avoided by maintaining unique solutions of the underlying Regge-Newton integral equation for the transformation kernel. As a by-product, new inequality sequences of zeros of Bessel functions are discovered.

  5. Formononetin inhibits enterovirus 71 replication by regulating COX- 2/PGE₂ expression.

    PubMed

    Wang, Huiqiang; Zhang, Dajun; Ge, Miao; Li, Zhuorong; Jiang, Jiandong; Li, Yuhuan

    2015-03-01

    The activation of ERK, p38 and JNK signal cascade in host cells has been demonstrated to up-regulate of enterovirus 71 (EV71)-induced cyclooxygenase-2 (COX-2)/ prostaglandins E2 (PGE₂) expression which is essential for viral replication. So, we want to know whether a compound can inhibit EV71 infection by suppressing COX-2/PGE₂ expression. The antiviral effect of formononetin was determined by cytopathic effect (CPE) assay and the time course assays. The influence of formononetin for EV71 replication was determined by immunofluorescence assay, western blotting assay and qRT-PCR assay. The mechanism of the antiviral activity of formononetin was determined by western blotting assay and ELISA assay. Formononetin could reduce EV71 RNA and protein synthesis in a dose-dependent manner. The time course assays showed that formononetin displayed significant antiviral activity both before (24 or 12 h) and after (0-6 h) EV71 inoculation in SK-N-SH cells. Formononetin was also able to prevent EV71-induced cytopathic effect (CPE) and suppress the activation of ERK, p38 and JNK signal pathways. Furthermore, formononetin could suppress the EV71-induced COX-2/PGE₂ expression. Also, formononetin exhibited similar antiviral activities against other members of Picornaviridae including coxsackievirus B2 (CVB2), coxsackievirus B3 (CVB3) and coxsackievirus B6 (CVB6). Formononetin could inhibit EV71-induced COX-2 expression and PGE₂ production via MAPKs pathway including ERK, p38 and JNK. Formononetin exhibited antiviral activities against some members of Picornaviridae. These findings suggest that formononetin could be a potential lead or supplement for the development of new anti-EV71 agents in the future.

  6. Licochalcones extracted from Glycyrrhiza inflata inhibit platelet aggregation accompanied by inhibition of COX-1 activity

    PubMed Central

    Okuda-Tanino, Asa; Sugawara, Daiki; Tashiro, Takumi; Iwashita, Masaya; Obara, Yutaro; Moriya, Takahiro; Tsushima, Chisato; Saigusa, Daisuke; Tomioka, Yoshihisa; Ishii, Kuniaki; Nakahata, Norimichi

    2017-01-01

    Licochalcones extracted from Glycyrrhiza inflata are known to have a variety of biological properties such as anti-inflammatory, anti-bacterial, and anti-tumor activities, but their action on platelet aggregation has not yet been reported. Therefore, in this study we investigated the effects of licochalcones on platelet aggregation. Collagen and U46619, a thromboxane A2 receptor agonist, caused rabbit platelet aggregation, which was reversed by pretreatment with licochalcones A, C and D in concentration-dependent manners. Among these compounds, licochalcone A caused the most potent inhibitory effect on collagen-induced platelet aggregation. However, the licochalcones showed marginal inhibitory effects on thrombin or ADP-induced platelet aggregation. In addition to rabbit platelets, licochalcone A attenuated collagen-induced aggregation in human platelets. Because licochalcone A also inhibited arachidonic acid-induced platelet aggregation and production of thromboxane A2 induced by collagen in intact platelets, we further examined the direct interaction of licochalcone A with cyclooxygenase (COX)-1. As expected, licochalcone A caused an inhibitory effect on both COX-1 and COX-2 in vitro. Regarding the effect of licochalcone A on COX-1 enzyme reaction kinetics, although licochalcone A showed a stronger inhibition of prostaglandin E2 synthesis induced by lower concentrations of arachidonic acid, Vmax values in the presence or absence of licochalcone A were comparable, suggesting that it competes with arachidonic acid at the same binding site on COX-1. These results suggest that licochalcones inhibit collagen-induced platelet aggregation accompanied by inhibition of COX-1 activity. PMID:28282426

  7. LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sun Haipeng; Xu Beibei; Sheveleva, Elena

    2008-10-01

    Glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT)-induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a structural analogue and a negative control for PI3K inhibitory activity of LY29, also suppressed COX-2 induction. These data suggest PI3K-independent mechanisms in regulating CT-induced COX-2 expression.more » LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), and DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca{sup 2+} concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT-induced COX-2 expression in cardiomyocytes.« less

  8. Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.

    PubMed

    Vannini, Federica; Chattopadhyay, Mitali; Kodela, Ravinder; Rao, Praveen P N; Kashfi, Khosrow

    2015-12-01

    We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential. Copyright © 2015 The Authors. Published by Elsevier B.V. All

  9. [A SAS marco program for batch processing of univariate Cox regression analysis for great database].

    PubMed

    Yang, Rendong; Xiong, Jie; Peng, Yangqin; Peng, Xiaoning; Zeng, Xiaomin

    2015-02-01

    To realize batch processing of univariate Cox regression analysis for great database by SAS marco program. We wrote a SAS macro program, which can filter, integrate, and export P values to Excel by SAS9.2. The program was used for screening survival correlated RNA molecules of ovarian cancer. A SAS marco program could finish the batch processing of univariate Cox regression analysis, the selection and export of the results. The SAS macro program has potential applications in reducing the workload of statistical analysis and providing a basis for batch processing of univariate Cox regression analysis.

  10. Novel Allelic Variants in the Canine Cyclooxgenase-2 (Cox-2) Promoter Are Associated with Renal Dysplasia in Dogs

    PubMed Central

    Whiteley, Mary H.; Bell, Jerold S.; Rothman, Debby A.

    2011-01-01

    Renal dysplasia (RD) in dogs is a complex disease with a highly variable phenotype and mode of inheritance that does not follow a simple Mendelian pattern. Cox-2 (Cyclooxgenase-2) deficient mice have renal abnormalities and a pathology that has striking similarities to RD in dogs suggesting to us that mutations in the Cox-2 gene could be the cause of RD in dogs. Our data supports this hypothesis. Sequencing of the canine Cox-2 gene was done from clinically affected and normal dogs. Although no changes were detected in the Cox-2 coding region, small insertions and deletions of GC boxes just upstream of the ATG translation start site were found. These sequences are putative SP1 transcription factor binding sites that may represent important cis-acting DNA regulatory elements that govern the expression of Cox-2. A pedigree study of a family of Lhasa apsos revealed an important statistical correlation of these mutant alleles with the disease. We examined an additional 22 clinical cases from various breeds. Regardless of the breed or severity of disease, all of these had one or two copies of the Cox-2 allelic variants. We suggest that the unusual inheritance pattern of RD is due to these alleles, either by changing the pattern of expression of Cox-2 or making Cox-2 levels susceptible to influences of other genes or environmental factors that play an unknown but important role in the development of RD in dogs. PMID:21346820

  11. Adjusted variable plots for Cox's proportional hazards regression model.

    PubMed

    Hall, C B; Zeger, S L; Bandeen-Roche, K J

    1996-01-01

    Adjusted variable plots are useful in linear regression for outlier detection and for qualitative evaluation of the fit of a model. In this paper, we extend adjusted variable plots to Cox's proportional hazards model for possibly censored survival data. We propose three different plots: a risk level adjusted variable (RLAV) plot in which each observation in each risk set appears, a subject level adjusted variable (SLAV) plot in which each subject is represented by one point, and an event level adjusted variable (ELAV) plot in which the entire risk set at each failure event is represented by a single point. The latter two plots are derived from the RLAV by combining multiple points. In each point, the regression coefficient and standard error from a Cox proportional hazards regression is obtained by a simple linear regression through the origin fit to the coordinates of the pictured points. The plots are illustrated with a reanalysis of a dataset of 65 patients with multiple myeloma.

  12. Autocrine prostaglandin E2 signaling promotes promonocytic leukemia cell survival via COX-2 expression and MAPK pathway

    PubMed Central

    Lee, Jaetae; Lee, Young Sup

    2015-01-01

    The COX-2/PGE2 pathway has been implicated in the occurrence and progression of cancer. The underlying mechanisms facilitating the production of COX-2 and its mediator, PGE2, in cancer survival remain unknown. Herein, we investigated PGE2-induced COX-2 expression and signaling in HL-60 cells following menadione treatment. Treatment with PGE2 activated anti-apoptotic proteins such as Bcl-2 and Bcl-xL while reducing pro-apoptotic proteins, thereby enhancing cell survival. PGE2 not only induced COX-2 expression, but also prevented casapse-3, PARP, and lamin B cleavage. Silencing and inhibition of COX-2 with siRNA transfection or treatment with indomethacin led to a pronounced reduction of the extracellular levels of PGE2, and restored the menadione-induced cell death. In addition, pretreatment of cells with the MEK inhibitor PD98059 and the PKA inhibitor H89 abrogated the PGE2-induced expression of COX-2, suggesting involvement of the MAPK and PKA pathways. These results demonstrate that PGE2 signaling acts in an autocrine manner, and specific inhibition of PGE2 will provide a novel approach for the treatment of leukemia. [BMB Reports 2015; 48(2): 109-114] PMID:24965577

  13. Biomedical conflicts of interest: a defence of the sequestration thesis-learning from the cases of Nancy Olivieri and David Healy.

    PubMed

    Schafer, A

    2004-02-01

    No discussion of academic freedom, research integrity, and patient safety could begin with a more disquieting pair of case studies than those of Nancy Olivieri and David Healy. The cumulative impact of the Olivieri and Healy affairs has caused serious self examination within the biomedical research community. The first part of the essay analyses these recent academic scandals. The two case studies are then placed in their historical context-that context being the transformation of the norms of science through increasingly close ties between research universities and the corporate world. After a literature survey of the ways in which corporate sponsorship has biased the results of clinical drug trials, two different strategies to mitigate this problem are identified and assessed: a regulatory approach, which focuses on managing risks associated with industry funding of university research, and a more radical approach, the sequestration thesis, which counsels the outright elimination of corporate sponsorship. The reformist approach is criticised and the radical approach defended.

  14. Analysis of the cytochrome c oxidase subunit II (COX2) gene in giant panda, Ailuropoda melanoleuca.

    PubMed

    Ling, S S; Zhu, Y; Lan, D; Li, D S; Pang, H Z; Wang, Y; Li, D Y; Wei, R P; Zhang, H M; Wang, C D; Hu, Y D

    2017-01-23

    The giant panda, Ailuropoda melanoleuca (Ursidae), has a unique bamboo-based diet; however, this low-energy intake has been sufficient to maintain the metabolic processes of this species since the fourth ice age. As mitochondria are the main sites for energy metabolism in animals, the protein-coding genes involved in mitochondrial respiratory chains, particularly cytochrome c oxidase subunit II (COX2), which is the rate-limiting enzyme in electron transfer, could play an important role in giant panda metabolism. Therefore, the present study aimed to isolate, sequence, and analyze the COX2 DNA from individuals kept at the Giant Panda Protection and Research Center, China, and compare these sequences with those of the other Ursidae family members. Multiple sequence alignment showed that the COX2 gene had three point mutations that defined three haplotypes, with 60% of the sequences corresponding to haplotype I. The neutrality tests revealed that the COX2 gene was conserved throughout evolution, and the maximum likelihood phylogenetic analysis, using homologous sequences from other Ursidae species, showed clustering of the COX2 sequences of giant pandas, suggesting that this gene evolved differently in them.

  15. Cox report and the US-China arms control technical exchange program

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Di Capua, M S

    The ACE program furthered the national security interests of the US by promoting technical approaches to the implementation and verification of arms control treaties that the international community embraces. The Cox Committee report suggests that uncontrolled interactions were taking place between US and Chinese nuclear weapons scientists in the course of the ACE program. On the contrary, elaborate controls were in place at the very beginning and remained in place to control the interactions and protect US national security information. The ACE program payoff to national security was just beginning and its suspension, resulting from the Cox reports allegations, ismore » a setback to US-China progress on arms control.« less

  16. COX-2 expression mediated by calcium-TonEBP signaling axis under hyperosmotic conditions serves osmoprotective function in nucleus pulposus cells.

    PubMed

    Choi, Hyowon; Chaiyamongkol, Weera; Doolittle, Alexandra C; Johnson, Zariel I; Gogate, Shilpa S; Schoepflin, Zachary R; Shapiro, Irving M; Risbud, Makarand V

    2018-06-08

    The nucleus pulposus (NP) of intervertebral discs experiences dynamic changes in tissue osmolarity because of diurnal loading of the spine. TonEBP/NFAT5 is a transcription factor that is critical in osmoregulation as well as survival of NP cells in the hyperosmotic milieu. The goal of this study was to investigate whether cyclooxygenase-2 (COX-2) expression is osmoresponsive and dependent on TonEBP, and whether it serves an osmoprotective role. NP cells up-regulated COX-2 expression in hyperosmotic media. The induction of COX-2 depended on elevation of intracellular calcium levels and p38 MAPK pathway, but independent of calcineurin signaling as well as MEK/ERK and JNK pathways. Under hyperosmotic conditions, both COX-2 mRNA stability and its proximal promoter activity were increased. The proximal COX-2 promoter (-1840/+123 bp) contained predicted binding sites for TonEBP, AP-1, NF-κB, and C/EBP-β. While COX-2 promoter activity was positively regulated by both AP-1 and NF-κB, AP-1 had no effect and NF-κB negatively regulated COX-2 protein levels under hyperosmotic conditions. On the other hand, TonEBP was necessary for both COX-2 promoter activity and protein up-regulation in response to hyperosmotic stimuli. Ex vivo disc organ culture studies using hypomorphic TonEBP +/- mice confirmed that TonEBP is required for hyperosmotic induction of COX-2. Importantly, the inhibition of COX-2 activity under hyperosmotic conditions resulted in decreased cell viability, suggesting that COX-2 plays a cytoprotective and homeostatic role in NP cells for their adaptation to dynamically loaded hyperosmotic niches. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. Characterization of prostaglandin E2 generation through the cyclooxygenase (COX)-2 pathway in human neutrophils

    PubMed Central

    St-Onge, Mireille; Flamand, Nicolas; Biarc, Jordane; Picard, Serge; Bouchard, Line; Dussault, Andrée-Anne; Laflamme, Cynthia; James, Michael J.; Caughey, Gillian E.; Cleland, Leslie G.; Borgeat, Pierre; Pouliot, Marc

    2010-01-01

    In the present study, we characterized the generation of prostaglandin (PG)E2 in human neutrophils. We found that the Ca2+-dependent type IV cytosolic phospholipase A2 (cPLA2) was pivotally involved in the COX-2-mediated generation of PGE2 in response to a calcium ionophore, as determined by the use of selected PLA2 inhibitors. PGE2 biosynthesis elicited by bacterial-derived peptides or by phagocytic stimuli acting on cell surface receptors also showed to be dependent on cPLA2 activity. We then assessed metabolism of unesterified arachidonic acid (AA), and observed that PGE2 production becomes favored over that of LTB4 with higher AA concentrations. Withdrawal of calcium prevented the generation of PGE2 in response to a calcium ionophore but did not affect the up-regulation of COX-2 or its capacity to convert AA, thus limiting its implication at the level of cPLA2 activation. Of the main eicosanoids produced by neutrophils, only LTB4 was able to up-regulate COX-2 expression. Finally, the only PGE synthase isoform found in neutrophils is microsomal PGE synthase-1; it co-localized with COX-2 and its expression appeared mainly constitutive. These results highlight key differences in regulatory processes of the 5-LO and COX pathways, and enhance our knowledge at several levels in the PGE2 biosynthesis in neutrophils. PMID:17643350

  18. Vitamin D Inhibits COX-2 Expression and Inflammatory Response by Targeting Thioesterase Superfamily Member 4*

    PubMed Central

    Wang, Qingsong; He, Yuhu; Shen, Yujun; Zhang, Qianqian; Chen, Di; Zuo, Caojian; Qin, Jing; Wang, Hui; Wang, Junwen; Yu, Ying

    2014-01-01

    Inadequate vitamin D status has been linked to increased risk of type 2 diabetes and cardiovascular disease. Inducible cyclooxygenase (COX) isoform COX-2 has been involved in the pathogenesis of such chronic inflammatory diseases. We found that the active form of vitamin D, 1,25(OH)2D produces dose-dependent inhibition of COX-2 expression in murine macrophages under both basal and LPS-stimulated conditions and suppresses proinflammatory mediators induced by LPS. Administration of 1,25(OH)2D significantly alleviated local inflammation in a carrageenan-induced paw edema mouse model. Strikingly, the phosphorylation of both Akt and its downstream target IκBα in macrophages were markedly suppressed by 1,25(OH)2D in the presence and absence of LPS stimulation through up-regulation of THEM4 (thioesterase superfamily member 4), an Akt modulator protein. Knockdown of both vitamin D receptor and THEM4 attenuated the inhibitory effect of 1,25(OH)2D on COX-2 expression in macrophages. A functional vitamin D-responsive element in the THEM4 promoter was identified by chromatin immunoprecipitation and luciferase reporter assay. Our results indicate that vitamin D restrains macrophage-mediated inflammatory processes by suppressing the Akt/NF-κB/COX-2 pathway, suggesting that vitamin D supplementation might be utilized for adjunctive therapy for inflammatory disease. PMID:24619416

  19. Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model

    PubMed Central

    Sones, Jenny L.; Cha, Jeeyeon; Woods, Ashley K.; Bartos, Amanda; Heyward, Christa Y.; Lob, Heinrich E.; Isroff, Catherine E.; Butler, Scott D.; Shapiro, Stephanie E.; Dey, Sudhansu K.; Davisson, Robin L.

    2016-01-01

    Preeclampsia (PE) is a disorder of pregnancy that manifests as late gestational maternal hypertension and proteinuria and can be life-threatening to both the mother and baby. It is believed that abnormal placentation is responsible for the cascade of events leading to the maternal syndrome. Embryo implantation is critical to establishing a healthy pregnancy. Defective implantation can cause adverse “ripple effects,” leading to abnormal decidualization and placentation, retarded fetal development, and poor pregnancy outcomes, such as PE and fetal growth restriction. The precise mechanism(s) of implantation defects that lead to PE remain elusive. BPH/5 mice, which spontaneously develop the cardinal features of PE, show peri-implantation defects including upregulation of Cox2 and IL-15 at the maternal-fetal interface. This was associated with decreased decidual natural killer (dNK) cells, which have important roles in establishing placental perfusion. Interestingly, a single administration of a Cox2 inhibitor (celecoxib) during decidualization restrained Cox2 and IL-15 expression, restored dNK cell numbers, improved fetal growth, and attenuated late gestational hypertension in BPH/5 female mice. This study provides evidence that decidual overexpression of Cox2 and IL-15 may trigger the adverse pregnancy outcomes reflected in the preeclamptic syndrome, underscoring the idea that Cox2 inhibitor treatment is an effective strategy for the prevention of PE-associated fetal and maternal morbidity and mortality. PMID:27159542

  20. Involvement of COX-2 in nickel elution from a wire implanted subcutaneously in mice.

    PubMed

    Sato, Taiki; Kishimoto, Yu; Asakawa, Sanki; Mizuno, Natsumi; Hiratsuka, Masahiro; Hirasawa, Noriyasu

    2016-07-01

    Many types of medical alloys include nickel (Ni), and the elution of Ni ions from these materials causes toxicities and inflammation. We have previously reported that inflammation enhances Ni elution, although the molecular mechanisms underlying this effect remain unclear. In this study, we investigated how inflammatory responses enhanced Ni elution in a wire-implantation mouse model. Subcutaneous implantation of Ni wire induced the expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) mRNA in the surrounding tissues. Immunostaining analysis showed that cells expressing COX-2 were mainly fibroblast-like cells 8h after implantation of a Ni wire, but were mainly infiltrated leukocytes at 24h. NiCl2 induced the expression of COX-2 mRNA in primary fibroblasts, neutrophils, RAW 264 cells, and THP-1 cells, indicating that Ni ions can induce COX-2 expression in various types of cells. The elution of Ni ions from the implanted Ni wire at 8h was reduced by dexamethasone (Dex), indomethacin (Ind), or celecoxib (Cel) treatment. Ni wire implantation induced an increase in mRNA levels for anaerobic glycolytic pathway components glucose transporter 1 (GLUT1), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4); the expression of these genes was also inhibited by Dex, Ind, and Cel. In primary fibroblasts, the expression of these mRNAs and the production of lactate were induced by NiCl2 and further potentiated by PGE2. Furthermore, Ni wire-induced infiltration of inflammatory leukocytes was significantly reduced by Dex, Ind, or Cel. Depletion of neutrophils with a specific antibody caused reduction of both leukocyte infiltration and Ni elution. These results indicate that Ni ions eluted from wire induced COX-2 expression, which further promoted elution of Ni ions by increasing lactate production and leukocyte infiltration. Since COX inhibitors and Dex reduced the elution of Ni ions, these drugs may be

  1. Nucleotide sequence of the COX1 gene in Kluyveromyces lactis mitochondrial DNA: evidence for recent horizontal transfer of a group II intron.

    PubMed

    Hardy, C M; Clark-Walker, G D

    1991-07-01

    The cytochrome oxidase subunit 1 gene (COX1) in K. lactis K8 mtDNA spans 8,826 bp and contains five exons (termed E1-E5) totalling 1,602 bp that show 88% nucleotide base matching and 91% amino acid homology to the equivalent gene in S. cerevisiae. The four introns (termed K1 cox1.1-1.4) contain open reading frames encoding proteins of 786, 333, 319 and 395 amino acids respectively that potentially encode maturase enzymes. The first intron belongs to group II whereas the remaining three are group I type B. Introns K1 cox1.1, 1.3, and 1.4 are found at identical locations to introns Sc cox1.2, 1.5 a, and 1.5 b respectively from S. cerevisiae. Horizontal transfer of an intron between recent progenitors of K. lactis and S. cerevisiae is suggested by the observation that K1 cox1.1 and Sc cox1.2 show 96% base matching. Sequence comparisons between K1 cox1.3/Sc cox1.5 a and K1 cox1.4/Sc cox1.5 b suggest that these introns are likely to have been present in the ancestral COX1 gene of these yeasts. Intron K1 cox1.2 is not found in S. cerevisiae and appears at an unique location in K. lactis. A feature of the DNA sequences of the group I introns K1 cox1.2, 1.3, and 1.4 is the presence of 11 GC-rich clusters inserted into both coding and noncoding regions. Immediately downstream of the COX1 gene is the ATPase subunit 8 gene (A8) that shows 82.6% base matching to its counterpart in S. cerevisiae mtDNA.

  2. Analyzing Student Learning Outcomes: Usefulness of Logistic and Cox Regression Models. IR Applications, Volume 5

    ERIC Educational Resources Information Center

    Chen, Chau-Kuang

    2005-01-01

    Logistic and Cox regression methods are practical tools used to model the relationships between certain student learning outcomes and their relevant explanatory variables. The logistic regression model fits an S-shaped curve into a binary outcome with data points of zero and one. The Cox regression model allows investigators to study the duration…

  3. Cox regression analysis with missing covariates via nonparametric multiple imputation.

    PubMed

    Hsu, Chiu-Hsieh; Yu, Mandi

    2018-01-01

    We consider the situation of estimating Cox regression in which some covariates are subject to missing, and there exists additional information (including observed event time, censoring indicator and fully observed covariates) which may be predictive of the missing covariates. We propose to use two working regression models: one for predicting the missing covariates and the other for predicting the missing probabilities. For each missing covariate observation, these two working models are used to define a nearest neighbor imputing set. This set is then used to non-parametrically impute covariate values for the missing observation. Upon the completion of imputation, Cox regression is performed on the multiply imputed datasets to estimate the regression coefficients. In a simulation study, we compare the nonparametric multiple imputation approach with the augmented inverse probability weighted (AIPW) method, which directly incorporates the two working models into estimation of Cox regression, and the predictive mean matching imputation (PMM) method. We show that all approaches can reduce bias due to non-ignorable missing mechanism. The proposed nonparametric imputation method is robust to mis-specification of either one of the two working models and robust to mis-specification of the link function of the two working models. In contrast, the PMM method is sensitive to misspecification of the covariates included in imputation. The AIPW method is sensitive to the selection probability. We apply the approaches to a breast cancer dataset from Surveillance, Epidemiology and End Results (SEER) Program.

  4. Bootstrap investigation of the stability of a Cox regression model.

    PubMed

    Altman, D G; Andersen, P K

    1989-07-01

    We describe a bootstrap investigation of the stability of a Cox proportional hazards regression model resulting from the analysis of a clinical trial of azathioprine versus placebo in patients with primary biliary cirrhosis. We have considered stability to refer both to the choice of variables included in the model and, more importantly, to the predictive ability of the model. In stepwise Cox regression analyses of 100 bootstrap samples using 17 candidate variables, the most frequently selected variables were those selected in the original analysis, and no other important variable was identified. Thus there was no reason to doubt the model obtained in the original analysis. For each patient in the trial, bootstrap confidence intervals were constructed for the estimated probability of surviving two years. It is shown graphically that these intervals are markedly wider than those obtained from the original model.

  5. Multiple recent horizontal transfers of the cox1 intron in Solanaceae and extended co-conversion of flanking exons

    PubMed Central

    2011-01-01

    Background The most frequent case of horizontal transfer in plants involves a group I intron in the mitochondrial gene cox1, which has been acquired via some 80 separate plant-to-plant transfer events among 833 diverse angiosperms examined. This homing intron encodes an endonuclease thought to promote the intron's promiscuous behavior. A promising experimental approach to study endonuclease activity and intron transmission involves somatic cell hybridization, which in plants leads to mitochondrial fusion and genome recombination. However, the cox1 intron has not yet been found in the ideal group for plant somatic genetics - the Solanaceae. We therefore undertook an extensive survey of this family to find members with the intron and to learn more about the evolutionary history of this exceptionally mobile genetic element. Results Although 409 of the 426 species of Solanaceae examined lack the cox1 intron, it is uniformly present in three phylogenetically disjunct clades. Despite strong overall incongruence of cox1 intron phylogeny with angiosperm phylogeny, two of these clades possess nearly identical intron sequences and are monophyletic in intron phylogeny. These two clades, and possibly the third also, contain a co-conversion tract (CCT) downstream of the intron that is extended relative to all previously recognized CCTs in angiosperm cox1. Re-examination of all published cox1 genes uncovered additional cases of extended co-conversion and identified a rare case of putative intron loss, accompanied by full retention of the CCT. Conclusions We infer that the cox1 intron was separately and recently acquired by at least three different lineages of Solanaceae. The striking identity of the intron and CCT from two of these lineages suggests that one of these three intron captures may have occurred by a within-family transfer event. This is consistent with previous evidence that horizontal transfer in plants is biased towards phylogenetically local events. The discovery

  6. FOXP3 inhibits cancer stem cell self-renewal via transcriptional repression of COX2 in colorectal cancer cells.

    PubMed

    Liu, Shuo; Zhang, Cun; Zhang, Kuo; Gao, Yuan; Wang, Zhaowei; Li, Xiaoju; Cheng, Guang; Wang, Shuning; Xue, Xiaochang; Li, Weina; Zhang, Wei; Zhang, Yingqi; Xing, Xianghui; Li, Meng; Hao, Qiang

    2017-07-04

    Colon cancer stem cell (cCSC) is considered as the seed cell of colon cancer initiation and metastasis. Cyclooxygenase-2 (COX2), a downstream target of NFκB, is found to be essential in promoting cancer stem cell renewal. However, how COX2 is dysregulated in cCSCs is largely unknown. In this study, we found that the expression of transcription factor FOXP3 was much lower in the spheroids than that in the parental tumor cells. Overexpression of FOXP3 significantly decreased the numbers of spheres, reduced the side population. Accordingly, FOXP3 expression decreased the tumor size and weight in the xenograft model. The tumor inhibitory effects of FOXP3 were rarely seen when COX2 was additionally knocked down. Mechanically, FOXP3 transcriptionally repressed COX2 expression via interacting with and thus inhibiting p65 activity on the putative NFκB response elements in COX2 promoter. Taken together, we here revealed possible involvement of FOXP3 in regulating cCSC self-renewal via tuning COX2 expression, and thus providing a new target for the eradication of colon cancer stem cells.

  7. Suppression of IL-1beta-induced COX-2 expression by trichostatin A (TSA) in human endometrial stromal cells.

    PubMed

    Wu, Yan; Guo, Sun-Wei

    2007-11-01

    Over-production of cyclooxygenase-2 (COX-2) plays an important role in the positive feedback loop that leads to proliferation and inflammation in endometriosis. Following our observation that histone deacetylase inhibitors (HDACIs) trichostatin A (TSA) and valproic acid (VPA) can suppress proliferation of endometrial stromal cells, we sought to determine whether TSA suppresses IL-1beta-induced COX-2 expression in endometrial stromal cells. In vitro study using a recently established immortalized endometrial stromal cell line. The stromal cells were pretreated with TSA before stimulation with IL-1beta, and COX-2 gene and protein expression was measured by real-time quantitative RT-PCR and Western blot analysis, respectively. IL-1beta stimulated COX-2 expression in a concentration-dependent manner in endometrial stromal cells. The induced COX-2 gene and protein expression were suppressed by TSA pretreatment. TSA suppresses IL-1beta-induced COX-2 gene and protein expression in endometrial stromal cells. This finding, coupled with the findings that TSA and another HDACI, valproic acid, suppress proliferation and induce cell cycle arrest, suggests that HDACIs are a promising class of compound that has therapeutic potential for endometriosis.

  8. WebDISCO: a web service for distributed cox model learning without patient-level data sharing.

    PubMed

    Lu, Chia-Lun; Wang, Shuang; Ji, Zhanglong; Wu, Yuan; Xiong, Li; Jiang, Xiaoqian; Ohno-Machado, Lucila

    2015-11-01

    The Cox proportional hazards model is a widely used method for analyzing survival data. To achieve sufficient statistical power in a survival analysis, it usually requires a large amount of data. Data sharing across institutions could be a potential workaround for providing this added power. The authors develop a web service for distributed Cox model learning (WebDISCO), which focuses on the proof-of-concept and algorithm development for federated survival analysis. The sensitive patient-level data can be processed locally and only the less-sensitive intermediate statistics are exchanged to build a global Cox model. Mathematical derivation shows that the proposed distributed algorithm is identical to the centralized Cox model. The authors evaluated the proposed framework at the University of California, San Diego (UCSD), Emory, and Duke. The experimental results show that both distributed and centralized models result in near-identical model coefficients with differences in the range [Formula: see text] to [Formula: see text]. The results confirm the mathematical derivation and show that the implementation of the distributed model can achieve the same results as the centralized implementation. The proposed method serves as a proof of concept, in which a publicly available dataset was used to evaluate the performance. The authors do not intend to suggest that this method can resolve policy and engineering issues related to the federated use of institutional data, but they should serve as evidence of the technical feasibility of the proposed approach.Conclusions WebDISCO (Web-based Distributed Cox Regression Model; https://webdisco.ucsd-dbmi.org:8443/cox/) provides a proof-of-concept web service that implements a distributed algorithm to conduct distributed survival analysis without sharing patient level data. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions

  9. Development of Antioxidant COX-2 Inhibitors as Radioprotective Agents for Radiation Therapy—A Hypothesis-Driven Review

    PubMed Central

    Laube, Markus; Kniess, Torsten; Pietzsch, Jens

    2016-01-01

    Radiation therapy (RT) evolved to be a primary treatment modality for cancer patients. Unfortunately, the cure or relief of symptoms is still accompanied by radiation-induced side effects with severe acute and late pathophysiological consequences. Inhibitors of cyclooxygenase-2 (COX-2) are potentially useful in this regard because radioprotection of normal tissue and/or radiosensitizing effects on tumor tissue have been described for several compounds of this structurally diverse class. This review aims to substantiate the hypothesis that antioxidant COX-2 inhibitors are promising radioprotectants because of intercepting radiation-induced oxidative stress and inflammation in normal tissue, especially the vascular system. For this, literature reporting on COX inhibitors exerting radioprotective and/or radiosensitizing action as well as on antioxidant COX inhibitors will be reviewed comprehensively with the aim to find cross-points of both and, by that, stimulate further research in the field of radioprotective agents. PMID:27104573

  10. A comparison between the use of Cox regression and the use of partial least squares-Cox regression to predict the survival of kidney-transplant patients

    NASA Astrophysics Data System (ADS)

    Solimun

    2017-05-01

    The aim of this research is to model survival data from kidney-transplant patients using the partial least squares (PLS)-Cox regression, which can both meet and not meet the no-multicollinearity assumption. The secondary data were obtained from research entitled "Factors affecting the survival of kidney-transplant patients". The research subjects comprised 250 patients. The predictor variables consisted of: age (X1), sex (X2); two categories, prior hemodialysis duration (X3), diabetes (X4); two categories, prior transplantation number (X5), number of blood transfusions (X6), discrepancy score (X7), use of antilymphocyte globulin(ALG) (X8); two categories, while the response variable was patient survival time (in months). Partial least squares regression is a model that connects the predictor variables X and the response variable y and it initially aims to determine the relationship between them. Results of the above analyses suggest that the survival of kidney transplant recipients ranged from 0 to 55 months, with 62% of the patients surviving until they received treatment that lasted for 55 months. The PLS-Cox regression analysis results revealed that patients' age and the use of ALG significantly affected the survival time of patients. The factor of patients' age (X1) in the PLS-Cox regression model merely affected the failure probability by 1.201. This indicates that the probability of dying for elderly patients with a kidney transplant is 1.152 times higher than that for younger patients.

  11. The role of COX-2 and Nrf2/ARE in anti-inflammation and antioxidative stress: Aging and anti-aging.

    PubMed

    Luo, Cheng; Urgard, Egon; Vooder, Tõnu; Metspalu, Andres

    2011-08-01

    Oxidative stress and inflammation are constant features of many chronic diseases and complications, and have been linked to carcinogenesis. Cyclooxygenase 2 (COX-2), a rate-limiting enzyme for the synthesis of prostaglandins, plays important roles in physiology and pathology, but has been a source of controversy within the scientific and clinical community. However, recent work has shown that nuclear factor erythroid-2-related factor-2 (Nrf2) confers protection against oxidative stress. Furthermore, COX-2-dependent electrophile oxo-derivative (EFOX) molecules have been shown to act as anti-inflammatory mediators via activation of the Nrf2-dependent antioxidant response element (ARE). These studies have provided more insight into COX-2-mediated events. The function of all tissues, especially epithelial and endothelial tissues, declines with age, leading to the production of reactive oxygen species (ROS). COX-2 expression increases with aging in most tissues, due in part to ROS, chemical reactions, physical shearing, and dietary molecules. Here we discuss new findings related to COX-2 inflammatory and anti-inflammatory responses. Taken together, we hypothesize that COX-2 levels increase during the aging process because increasing levels of ROSs necessitate the involvement of COX-2-dependent EFOXs for anti-inflammation and Nrf2/ARE signaling for antioxidation. We also propose that COX-2 may act as an intrinsic biological aging clock due to its role in balancing inflammatory and anti-inflammatory responses. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. HCV NS5A Up-Regulates COX-2 Expression via IL-8-Mediated Activation of the ERK/JNK MAPK Pathway

    PubMed Central

    Chen, Wei-Chun; Tseng, Chin-Kai; Chen, Yen-Hsu; Lin, Chun-Kuang; Hsu, Shih-hsien; Wang, Shen-Nien; Lee, Jin-Ching

    2015-01-01

    Chronic hepatitis C virus (HCV) infection leads to intrahepatic inflammation and liver cell injury, which are considered a risk factor for virus-associated hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. Inflammatory cytokines are critical components of the immune system and influence cellular signaling, and genetic imbalances. In this study, we found that cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) were significantly induced by HCV infection and HCV NS5A expression, and induction of COX-2 correlated with HCV-induced IL-8 production. We also found that the ERK and JNK signaling pathways were involved in the regulation of IL-8-mediated COX-2 induction in response to HCV infection. Using a promoter-linked reporter assay, we identified that the C/EBP regulatory element within the COX-2 promoter was the dominant factor responsible for the induction of COX-2 by HCV. Silencing C/EBP attenuated HCV-induced COX-2 expression. Our results revealed that HCV-induced inflammation promotes viral replication, providing new insights into the involvement of IL-8-mediated COX-2 induction in HCV replication. PMID:26231035

  13. Differential effect of DDT, DDE, and DDD on COX-2 expression in the human trophoblast derived HTR-8/SVneo cells.

    PubMed

    Dominguez-Lopez, Pablo; Diaz-Cueto, Laura; Olivares, Aleida; Ulloa-Aguirre, Alfredo; Arechavaleta-Velasco, Fabian

    2012-11-01

    The purpose of this study was to investigate the effect of 1,1,1-trichloro-2,2-bis-(chlorophenyl)ethane (DDT), 1,1-bis-(chlorophenyl)-2,2-dichloroethene (DDE), and 1,1-dichloro-2,2-bis(chlorophenyl)ethane (DDD) isomers on COX-2 expression in a human trophoblast-derived cell line. Cultured HTR-8/SVneo trophoblast cells were exposed to DDT isomers and its metabolites for 24 h, and COX-2 mRNA and protein expression were assessed by RT-PCR, Western blotting, and ELISA. Prostaglandin E₂ production was also measured by ELISA. Both COX-2 mRNA and protein were detected under control (unexposed) conditions in the HTR-8/SVneo cell line. COX-2 protein expression and prostaglandin E₂ production but not COX-2 mRNA levels increased only after DDE and DDD isomers exposure. It is concluded that DDE and DDD exposure induce the expression of COX-2 protein, leading to increased prostaglandin E2 production. Interestingly, the regulation of COX-2 by these organochlorines pesticides appears to be at the translational level. © 2012 Wiley Periodicals, Inc.

  14. MiR-26b Mimic Inhibits Glioma Proliferation In Vitro and In Vivo Suppressing COX-2 Expression.

    PubMed

    Chen, Zheng-Gang; Zheng, Chuan-Yi; Cai, Wang-Qing; Li, Da-Wei; Ye, Fu-Yue; Zhou, Jian; Wu, Ran; Yang, Kun

    2017-08-11

    Glioma is the most common malignant tumor of the nervous system. Studies have shown the microRNA (miR)-26b/cyclooxygenase (COX)-2 axis in the development and progression in many tumor cells. Our study aims to investigate the effect and mechanism of miR-26b/COX-2 axis in glioma. Decreased expression of miR-26b with increased level of COX-2 was found in glioma tissues compared with matched normal tissues. A strong negative correlation was observed between the level of miR-26b and COX-2 in 30 glioma tissues. The miR-26b was then overexpressed by transfecting miR-26b mimic into U-373 cells. The invasive cell number and wounld closing rate were reduced in U-373 cells transfected with miR-26b mimic. Besides, COX2 siRNA enhanced the effect of miR-26b mimic in suppressing the expression of p-ERK1 and p-JNK. Finally, the in vivo experiment revealed that miR-26b mimic transfection strongly reduced the tumor growth, tumor volume and the expression of matrix metalloproteinase (MMP)-2, MMP-9). Taken together, our research indicated a miR-26b/COX-2/ERK/JNK axis in regulating the motility of glioma in vitro and in vivo, providing a new sight for treatment of glioma.

  15. A new semi-supervised learning model combined with Cox and SP-AFT models in cancer survival analysis.

    PubMed

    Chai, Hua; Li, Zi-Na; Meng, De-Yu; Xia, Liang-Yong; Liang, Yong

    2017-10-12

    Gene selection is an attractive and important task in cancer survival analysis. Most existing supervised learning methods can only use the labeled biological data, while the censored data (weakly labeled data) far more than the labeled data are ignored in model building. Trying to utilize such information in the censored data, a semi-supervised learning framework (Cox-AFT model) combined with Cox proportional hazard (Cox) and accelerated failure time (AFT) model was used in cancer research, which has better performance than the single Cox or AFT model. This method, however, is easily affected by noise. To alleviate this problem, in this paper we combine the Cox-AFT model with self-paced learning (SPL) method to more effectively employ the information in the censored data in a self-learning way. SPL is a kind of reliable and stable learning mechanism, which is recently proposed for simulating the human learning process to help the AFT model automatically identify and include samples of high confidence into training, minimizing interference from high noise. Utilizing the SPL method produces two direct advantages: (1) The utilization of censored data is further promoted; (2) the noise delivered to the model is greatly decreased. The experimental results demonstrate the effectiveness of the proposed model compared to the traditional Cox-AFT model.

  16. Analgesic effects of the COX-2 inhibitor parecoxib on surgical pain through suppression of spinal ERK signaling.

    PubMed

    Guo, Ya-Jing; Shi, Xu-Dan; Fu, DI; Yang, Yong; Wang, Ya-Ping; Dai, Ru-Ping

    2013-07-01

    Cyclooxygenase (COX)-2 inhibitors are widely used for postoperative pain control in clinical practice. However, it is unknown whether spinal sensitization is involved in the analgesic effects of COX-2 inhibitors on surgical pain. Extracellular signal-regulated kinase (ERK) in the spinal cord is implicated in various types of pain, including surgical pain. The present study investigated the role of spinal ERK signaling in the analgesic effect of the COX-2 inhibitor parecoxib on surgical pain. Surgical pain was produced in rats by surgical incision of the hind paw. Phosphorylated (p)-ERK1/2 expression was determined by immunohistochemistry. Pain hypersensitivity was evaluated by measuring the paw withdrawal threshold using the von Frey test. The selective COX-2 inhibitor parecoxib was delivered 20 min before or 20 min after the incision by intraperitoneal injection. Pretreatment with parecoxib markedly attenuated the pain hypersensitivity induced by incision. However, post-treatment with parecoxib produced minimal analgesic effects. Parecoxib inhibited the increase in spinal p-ERK expression following surgical incision. The present study thus suggests that the COX-2 inhibitor parecoxib exerts its analgesic effect on surgical pain through the inhibition of neuronal ERK activation in the spinal cord. COX-2 inhibitor delivery prior to surgery has more potent analgesic effects, suggesting the advantage of preventive analgesia for post-operative pain control.

  17. Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-κB and COX-2 signaling.

    PubMed

    Zhuang, Mingzhu; Zhao, Mouming; Qiu, Huijuan; Shi, Dingbo; Wang, Jingshu; Tian, Yun; Lin, Lianzhu; Deng, Wuguo

    2014-01-01

    Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC) cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-κB proteins. Moreover, effusanin E abrogated the binding of NF-κB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-κB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate) had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-κB/COX-2 (lipopolysaccharides) abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-κB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma.

  18. Oxymatrine attenuated isoproterenol-induced heart failure in rats via regulation of COX-2/PGI2 pathway.

    PubMed

    Zhou, Ru; Xu, Qingbin; Xu, Yehua; Xiong, Aiqin; Wang, Yang; Ma, Ping

    2016-12-01

    Oxymatrine (OMT) is an active constituent of traditional Chinese herb Sophora japonica Ait which has been shown to exert potent anti-inflammatory,anti-oxidant and anti-fibrosis properties. Our previous studies have demonstrated that OMT has protective effects on isoproterenol-induced heart failure in rats through regulation of DDAH/ADMA metabolism pathway.In this study,we further investigated whether OMT could attenuate isoproterenol-induced heart failure through the regulation of COX-2/PGI 2 pathway. Heart failure was induced in Sprague-Dawley rats by 5mg/kg isoproterenol subcutaneous injection for 7days. The rats were maintained on normal diet and randomly divided into five groups: control, isoproterenol, isoproterenol with OMT (50, 100mg/kg), and OMT alone groups (n=12 in each group). Serum brain natruretic peptide (BNP, a heart failure biomarker), histopathological variables, expression of Cytosolic phospholipase A 2 (cPLA 2 ), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and Prostacyclin synthase (PGIS) were analysed. Administration of OMT significantly reduced the increased BNP in plasm of isoproterenol-induced rats, attenuated cardiac fibrosis,suppressed overexpression of myocardial COX-1 expression, up-regulated COX-2 and PGIS expression, but had no effects on isoproterenol-induced elevated protein cPLA 2 . And compared with control group, any indexes in sham rats treated with OMT (100mg/kg) alone were unaltered. These results demonstrated that OMT has cardioprotective effects on isoproterenol-induced heart failure in rats by regulating COX-2/PGI 2 pathway. Copyright © 2016. Published by Elsevier Masson SAS.

  19. Effects of the estrous cycle, pregnancy and interferon tau on expression of cyclooxygenase two (COX-2) in ovine endometrium

    PubMed Central

    Kim, Seokwoon; Choi, Youngsok; Spencer, Thomas E; Bazer, Fuller W

    2003-01-01

    In sheep, the uterus produces luteolytic pulses of prostaglandin F2α (PGF) on Days 15 to 16 of estrous cycle to regress the corpus luteum (CL). These PGF pulses are produced by the endometrial lumenal epithelium (LE) and superficial ductal glandular epithelium (sGE) in response to binding of pituitary and/or luteal oxytocin to oxytocin receptors (OTR) and liberation of arachidonic acid, the precursor of PGF. Cyclooxygenase-one (COX-1) and COX-2 are rate-limiting enzymes in PGF synthesis, and COX-2 is the major form expressed in ovine endometrium. During pregnancy recognition, interferon tau (IFNτ), produced by the conceptus trophectoderm, acts in a paracrine manner to suppress development of the endometrial epithelial luteolytic mechanism by inhibiting transcription of estrogen receptor α (ERα) (directly) and OTR (indirectly) genes. Conflicting studies indicate that IFNτ increases, decreases or has no effect on COX-2 expression in bovine and ovine endometrial cells. In Study One, COX-2 mRNA and protein were detected solely in endometrial LE and sGE of both cyclic and pregnant ewes. During the estrous cycle, COX-2 expression increased from Days 10 to 12 and then decreased to Day 16. During early pregnancy, COX-2 expression increased from Days 10 to 12 and remained higher than in cyclic ewes. In Study Two, intrauterine infusion of recombinant ovine IFNτ in cyclic ewes from Days 11 to 16 post-estrus did not affect COX-2 expression in the endometrial epithelium. These results clearly indicate that IFNτ has no effect on expression of the COX-2 gene in the ovine endometrium. Therefore, antiluteolytic effects of IFNτ are to inhibit ERα and OTR gene transcription, thereby preventing endometrial production of luteolytic pulses of PGF. Indeed, expression of COX-2 in the endometrial epithelia as well as conceptus is likely to have a beneficial regulatory role in implantation and development of the conceptus. PMID:12956885

  20. D. Alan Shewmon and the PCBE's White Paper on Brain Death: are brain-dead patients dead?

    PubMed

    Brugger, E Christian

    2013-04-01

    The December 2008 White Paper (WP) on "Brain Death" published by the President's Council on Bioethics (PCBE) reaffirmed its support for the traditional neurological criteria for human death. It spends considerable time explaining and critiquing what it takes to be the most challenging recent argument opposing the neurological criteria formulated by D. Alan Shewmon, a leading critic of the "whole brain death" standard. The purpose of this essay is to evaluate and critique the PCBE's argument. The essay begins with a brief background on the history of the neurological criteria in the United States and on the preparation of the 2008 WP. After introducing the WP's contents, the essay sets forth Shewmon's challenge to the traditional neurological criteria and the PCBE's reply to Shewmon. The essay concludes by critiquing the WP's novel justification for reaffirming the traditional conclusion, a justification the essay finds wanting.

  1. Apollo 12 Mission image - Astronaut Alan L. Bean,lunar module pilot,and two U.S. spacecraft

    NASA Image and Video Library

    1969-11-20

    AS12-48-7134 (20 Nov. 1969) --- This unusual photograph, taken during the second Apollo 12 extravehicular activity (EVA), shows two U.S. spacecraft on the surface of the moon. The Apollo 12 Lunar Module (LM) is in the background. The unmanned Surveyor 3 spacecraft is in the foreground. The Apollo 12 LM, with astronauts Charles Conrad Jr. and Alan L. Bean aboard, landed about 600 feet from Surveyor 3 in the Ocean of Storms. The television camera and several other pieces were taken from Surveyor 3 and brought back to Earth for scientific examination. Here, Conrad examines the Surveyor's TV camera prior to detaching it. Astronaut Richard F. Gordon Jr. remained with the Apollo 12 Command and Service Modules (CSM) in lunar orbit while Conrad and Bean descended in the LM to explore the moon. Surveyor 3 soft-landed on the moon on April 19, 1967.

  2. CRE-Mediated Transcription and COX-2 Expression in the Pilocarpine Model of Status Epilepticus

    PubMed Central

    Lee, Boyoung; Dziema, Heather; Lee, Kyu Hyun; Choi, Yun-Sik; Obrietan, Karl

    2007-01-01

    Status epilepticus (SE) triggers neuronal death, reactive gliosis and remodeling of synaptic circuitry, thus leading to profound pathological alterations in CNS physiology. These processes are, in part, regulated by the rapid upregulation of both cytotoxic and cytoprotective genes. One pathway that may couple SE to transcriptionally-dependent alterations in CNS physiology is the CREB (cAMP response element-binding protein)/CRE (cAMP response element) cascade. Here, we utilized the pilocarpine model of SE on a mouse strain transgenic for a CRE-reporter construct (β-galactosidase) to begin to characterize how seizure activity regulates the activation state of the CREB/CRE pathway in both glia and neurons of the hippocampus. SE triggered a rapid (4–8 hrs post SE) but transient increase in CRE-mediated gene expression in the neuronal sublayers. In contrast to neurons, SE induced a lasting increase (up to 20 days) in CRE-mediated transcription in both reactive astrocytes and microglia. CRE-mediated gene expression correlated with expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2). To examine the role of CREB in SE-induced COX-2 expression, we generated a transgenic mouse strain that expresses A-CREB, a potent repressor of CREB-dependent transcription. In these animals, the capacity of SE to stimulate COX-2 expression was markedly attenuated, indicating that CREB is a key intermediate in SE-induced COX-2 expression. Collectively these data show that SE triggers two waves of CREB-mediated gene expression, a transient wave in neurons and a long-lasting wave in reactive glial cells, and that CREB couples SE to COX-2 expression. PMID:17029965

  3. Synthesis, in vitro and in silico evaluation of novel trans-stilbene analogues as potential COX-2 inhibitors.

    PubMed

    Regulski, Miłosz; Piotrowska-Kempisty, Hanna; Prukała, Wiesław; Dutkiewicz, Zbigniew; Regulska, Katarzyna; Stanisz, Beata; Murias, Marek

    2018-01-01

    25 new trans-stilbene and trans-stilbazole derivatives were investigated using in vitro and in silico techniques. The selectivity and potency of the compounds were assessed using commercial ELISA test. The obtained results were incorporated into 2D QSAR assay. The most promising compound 4-nitro-3',4',5'-trihydroxy-trans-stilbene (N1) was synthetized and its potency and selectivity were confirmed. N1 was classified as preferential COX-2 inhibitor. Its ability to inhibit COX-2 in MCF-7 cell line was established and its cytotoxicity by MTT test was assessed. The compound was more cytotoxic than celecoxib within studied concentration range. Finally, the investigated trans-stilbene was docked into COX-1 and COX-2 active sites using "CDOCKER" protocol. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Some functional limit theorems for compound Cox processes

    NASA Astrophysics Data System (ADS)

    Korolev, Victor Yu.; Chertok, A. V.; Korchagin, A. Yu.; Kossova, E. V.; Zeifman, Alexander I.

    2016-06-01

    An improved version of the functional limit theorem is proved establishing weak convergence of random walks generated by compound doubly stochastic Poisson processes (compound Cox processes) to Lévy processes in the Skorokhod space under more realistic moment conditions. As corollaries, theorems are proved on convergence of random walks with jumps having finite variances to Lévy processes with variance-mean mixed normal distributions, in particular, to stable Lévy processes.

  5. Some functional limit theorems for compound Cox processes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Korolev, Victor Yu.; Institute of Informatics Problems FRC CSC RAS; Chertok, A. V.

    2016-06-08

    An improved version of the functional limit theorem is proved establishing weak convergence of random walks generated by compound doubly stochastic Poisson processes (compound Cox processes) to Lévy processes in the Skorokhod space under more realistic moment conditions. As corollaries, theorems are proved on convergence of random walks with jumps having finite variances to Lévy processes with variance-mean mixed normal distributions, in particular, to stable Lévy processes.

  6. Glucocorticoids suppress hypoxia-induced COX-2 and hypoxia inducible factor-1α expression through the induction of glucocorticoidinduced leucine zipper

    PubMed Central

    Lim, Wonchung; Park, Choa; Shim, Myeong Kuk; Lee, Yong Hee; Lee, You Mie; Lee, YoungJoo

    2014-01-01

    Background and Purpose The COX-2/PGE2 pathway in hypoxic cancer cells has important implications for stimulation of inflammation and tumourigenesis. However, the mechanism by which glucocorticoid receptors (GRs) inhibit COX-2 during hypoxia has not been elucidated. Hence, we explored the mechanisms underlying glucocorticoid-mediated inhibition of hypoxia-induced COX-2 in human distal lung epithelial A549 cells. Experimental Approach The expressions of COX-2 and glucocorticoid-induced leucine zipper (GILZ) in A549 cells were determined by Western blot and/or quantitative real time-PCR respectively. The anti-invasive effect of GILZ on A549 cells was evaluated using the matrigel invasion assay. Key Results The hypoxia-induced increase in COX-2 protein and mRNA levels and promoter activity were suppressed by dexamethasone, and this effect of dexamethasone was antagonized by the GR antagonist RU486. Overexpression of GILZ in A549 cells also inhibited hypoxia-induced COX-2 expression levels and knockdown of GILZ reduced the glucocorticoid-mediated inhibition of hypoxia-induced COX-2 expression, indicating that the inhibitory effects of dexamethasone on hypoxia-induced COX-2 are mediated by GILZ. GILZ suppressed the expression of hypoxia inducible factor (HIF)-1α at the protein level and affected its signalling pathway. Hypoxia-induced cell invasion was also dramatically reduced by GILZ expression. Conclusion and Implications Dexamethasone-induced upregulation of GILZ not only inhibits the hypoxic-evoked induction of COX-2 expression and cell invasion but further blocks the HIF-1 pathway by destabilizing HIF-1α expression. Taken together, these findings suggest that the suppression of hypoxia-induced COX-2 by glucocorticoids is mediated by GILZ. Hence, GILZ is a potential key therapeutic target for suppression of inflammation under hypoxia. PMID:24172143

  7. Non-Asymptotic Oracle Inequalities for the High-Dimensional Cox Regression via Lasso.

    PubMed

    Kong, Shengchun; Nan, Bin

    2014-01-01

    We consider finite sample properties of the regularized high-dimensional Cox regression via lasso. Existing literature focuses on linear models or generalized linear models with Lipschitz loss functions, where the empirical risk functions are the summations of independent and identically distributed (iid) losses. The summands in the negative log partial likelihood function for censored survival data, however, are neither iid nor Lipschitz.We first approximate the negative log partial likelihood function by a sum of iid non-Lipschitz terms, then derive the non-asymptotic oracle inequalities for the lasso penalized Cox regression using pointwise arguments to tackle the difficulties caused by lacking iid Lipschitz losses.

  8. Non-Asymptotic Oracle Inequalities for the High-Dimensional Cox Regression via Lasso

    PubMed Central

    Kong, Shengchun; Nan, Bin

    2013-01-01

    We consider finite sample properties of the regularized high-dimensional Cox regression via lasso. Existing literature focuses on linear models or generalized linear models with Lipschitz loss functions, where the empirical risk functions are the summations of independent and identically distributed (iid) losses. The summands in the negative log partial likelihood function for censored survival data, however, are neither iid nor Lipschitz.We first approximate the negative log partial likelihood function by a sum of iid non-Lipschitz terms, then derive the non-asymptotic oracle inequalities for the lasso penalized Cox regression using pointwise arguments to tackle the difficulties caused by lacking iid Lipschitz losses. PMID:24516328

  9. QSAR analyses of conformationally restricted 1,5-diaryl pyrazoles as selective COX-2 inhibitors: application of connection table representation of ligands.

    PubMed

    Prasanna, S; Manivannan, E; Chaturvedi, S C

    2005-04-15

    As a part of our continuing efforts in discerning the structural and physicochemical requirements for selective COX-2 over COX-1 inhibition among the fused pyrazole ring systems, herein we report the QSAR analyses of the title compounds. The conformational flexibility of the title compounds was examined using a simple connection table representation. The conformational investigation was aided by calculating a connection table parameter called fraction of rotable bonds, b_rotR encompassing the number of rotable bonds and b_count, the number of bonds including implicit hydrogens of each ligand. The hydrophobic and steric correlation of the title compounds towards selective COX-2 inhibition was reported previously in one of our recent publications. In this communication, we attempt to calculate Wang-Ford charges of the non-hydrogen common atoms of AM1 optimized geometries of the title compounds. Owing to the partial conformational flexibility of title compounds, conformationally restricted and unrestricted descriptors were calculated from MOE. Correlation analysis of these 2D, 3D and Wang-Ford charges was accomplished by linear regression analysis. 2D molecular descriptor b_single, 3D molecular descriptors glob, std_dim3 showed significant contribution towards COX-2 inhibitory activity. Balaban J, a connectivity topological index showed a negative and positive contribution towards COX-1 and selective COX-2 over COX-1 inhibition, respectively. Wang-Ford charges calculated on C(7) showed a significant contribution towards COX-1 inhibitory activity whereas charges calculated on C(8) were crucial in governing the selectivity of COX-2 over COX-1 inhibition among these congeners.

  10. MAPK/ERK signal pathway involved expression of COX-2 and VEGF by IL-1β induced in human endometriosis stromal cells in vitro

    PubMed Central

    Huang, Fengying; Cao, Jing; Liu, Qiuhong; Zou, Ying; Li, Hongyun; Yin, Tuanfang

    2013-01-01

    Objective: Now there are more and more evidences that Cyclooxygenase-2 (COX-2) plays an important role in angiogenesis of endometriosis (EMs). Vascular endothelial growth factor (VEGF) has a potent angiogenic activity. However, it is worth studying about the regulating mechanism of COX-2/COX-1 and VEGF in the development of human endometriosis in vitro. The current study was designed to investigate the effect of 4 cytokines on COX-2/COX-1 expression and the effect of IL-1β on VEGF release in human endometriosis stromal cells (ESC), and to explore the related signaling pathways involved in vitro. Methods: Isolation, culture and identification of ESC. Cells were treated with 4 cytokines, and the inhibitor mitogen-activated protein-Erk (MEK) and the inhibitor p38 mitogen-activated protein kinase (MAPK) prior to adding cytokine IL-1β. COX-2 protein expression was measured by western blot and VEGF secretion was determined by ELISA. Results: Among four kinds of cytokines, IL-1β treatment increased COX-2 protein expression and VEGF release in three ESC, and TNF-α had the same effect on COX-2 protein level as IL-1β only in ectopic and eutopic ESC, and MCSF had only slight effect on ectopic ESC. In contrast, cytokines had no effect on COX-1 expression. We also demonstrated that MAPK reduced the synthesis of COX-2 by IL-1β induced. COX-2 inhibitor reduced VEGF release by IL-1β induced. Conclusions: i) In human ESC in vitro, IL-1β up-regulated the COX-2 expression through the activation of p38 MAPK pathway, and not to COX-1. ii) Up-regulation of VEGF level by IL-1β treatment was found in human endometriosis stromal cell and COX-2 inhibitor was involved in this process. PMID:24133591

  11. Regulation of COX-2–mediated signaling by α3 type IV noncollagenous domain in tumor angiogenesis

    PubMed Central

    Boosani, Chandra Shekhar; Mannam, Arjuna P.; Cosgrove, Dominic; Silva, Rita; Hodivala-Dilke, Kairbaan M.; Keshamouni, Venkateshwar G.

    2007-01-01

    Human α3 chain, a noncollagenous domain of type IV collagen [α3(IV)NC1], inhibits angiogenesis and tumor growth. These biologic functions are partly attributed to the binding of α3(IV)NC1 to αVβ3 and α3β1 integrins. α3(IV)NC1 binds αVβ3 integrin, leading to translation inhibition by inhibiting focal adhesion kinase/phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathways. In the present study, we evaluated the role of α3β1 and αVβ3 integrins in tube formation and regulation of cyclooxygenase-2 (COX-2) on α3(IV)NC1 stimulation. We found that although both integrins were required for the inhibition of tube formation by α3(IV)NC1 in endothelial cells, only α3β1 integrin was sufficient to regulate COX-2 in hypoxic endothelial cells. We show that binding of α3(IV)NC1 to α3β1 integrin leads to inhibition of COX-2–mediated pro-angiogenic factors, vascular endothelial growth factor, and basic fibroblast growth factor by regulating IκBα/NFκB axis, and is independent of αVβ3 integrin. Furthermore, β3 integrin–null endothelial cells, when treated with α3(IV)NC1, inhibited hypoxia-mediated COX-2 expression, whereas COX-2 inhibition was not observed in α3 integrin–null endothelial cells, indicating that regulation of COX-2 by α3(IV)NC1 is mediated by integrin α3β1. Our in vitro and in vivo findings demonstrate that α3β1 integrin is critical for α3(IV)NC1-mediated inhibition of COX-2–dependent angiogenic signaling and inhibition of tumor progression. PMID:17426256

  12. Dual evaluation of some novel 2-amino-substituted coumarinylthiazoles as anti-inflammatory-antimicrobial agents and their docking studies with COX-1/COX-2 active sites.

    PubMed

    Chandak, Navneet; Kumar, Pawan; Kaushik, Pawan; Varshney, Parul; Sharma, Chetan; Kaushik, Dhirender; Jain, Sudha; Aneja, Kamal R; Sharma, Pawan K

    2014-08-01

    Synthesis of total eighteen 2-amino-substituted 4-coumarinylthiazoles including sixteen new compounds (3a-o and 5b) bearing the benzenesulfonamide moiety is described in the present report. All the synthesized target compounds were examined for their in vivo anti-inflammatory (AI) activity and in vitro antimicrobial activity. Results revealed that six compounds (3 d, 3 f, 3 g, 3 h, 3 j and 3 n) exhibited pronounced anti-inflammatory activity comparable to the standard drug indomethacin. AI results were further confirmed by the docking studies of the most active (3n) and the least active compound (3a) with COX-1 and COX-2 active sites. In addition, most of the compounds exhibited moderate antimicrobial activity against Gram-positive bacteria as well as fungal yeast, S. cervisiae. Comparison between 3 and 5 indicated that incorporation of additional substituted pyrazole nucleus into the scaffold significantly enhanced AI activity.

  13. Bcr-Abl-independent mechanism of resistance to imatinib in K562 cells: Induction of cyclooxygenase-2 (COX-2) by histone deacetylases (HDACs).

    PubMed

    Kalle, Arunasree M; Sachchidanand, Sachchidanand; Pallu, Reddanna

    2010-09-01

    Our previous studies have shown that overexpression of MDR1 and cyclooygenase-2 (COX-2) resulted in resistance development to imatinib in chronic myelogenous leukemia (CML) K562 (IR-K562) cells. In the present study, the regulatory mechanism of MDR1 induction by COX-2 was investigated. A gradual overexpression of MDR1 and COX-2 during the process of development was observed. Furthermore, down regulation of MDR1 upon COX-2 knockdown by siRNA showed a decrease in the PKC levels and activation of PKC by addition of PGE(2) to K562 cells, suggesting a role for PKC in the COX-2 mediated induction of MDR1. The present study demonstrates COX-2 induction by HDACs and MDR1 induction by COX-2 via PGE(2)-cAMP-PKC-mediated pathway. Copyright 2010 Elsevier Ltd. All rights reserved.

  14. Weak and strong publics: drawing on Nancy Fraser to explore parental participation in neonatal networks.

    PubMed

    Gibson, Andrew J; Lewando-Hundt, Gillian; Blaxter, Loraine

    2014-02-01

    We draw on the work of Nancy Fraser, and in particular her concepts of weak and strong publics, to analyze the process of parental involvement in managed neonatal network boards. Public involvement has moved beyond the individual level to include greater involvement of both patients and the public in governance. However, there is relatively little literature that explores the nature and outcomes of long-term patient involvement initiatives or has attempted to theorize, particularly at the level of corporate decision making, the process of patient and public involvement. A repeated survey of all neonatal network managers in England was carried out in 2006-07 to capture developments and changes in parental representation over this time period. This elicited information about the current status of parent representation on neonatal network boards. Four networks were also selected as case studies. This involved interviews with key members of each network board, interviews with parent representatives, observation of meetings and access to board minutes. Data collected show that a wide range of approaches to involving parents has been adopted. These range from decisions not to involve parents at this level to relatively well-developed systems designed to link parent representatives on network boards to parents in neonatal units. Despite these variations, we suggest that parental participation within neonatal services remains an example of a weak public because the parent representatives had limited participation with little influence on decision making. © 2011 John Wiley & Sons Ltd.

  15. COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats.

    PubMed

    Muñoz, Mercedes; Sánchez, Ana; Pilar Martínez, María; Benedito, Sara; López-Oliva, Maria-Elvira; García-Sacristán, Albino; Hernández, Medardo; Prieto, Dolores

    2015-07-01

    Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX-2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Involvement of PLA2, COX and LOX in Rhinella arenarum oocyte maturation.

    PubMed

    Ortiz, Maria Eugenia; Bühler, Marta Inés; Zelarayán, Liliana Isabel

    2014-11-01

    In Rhinella arenarum, progesterone is the physiological nuclear maturation inducer that interacts with the oocyte surface and starts a cascade of events that leads to germinal vesicle breakdown (GVBD). Polyunsaturated fatty acids and their metabolites produced through cyclooxygenase (COX) and lipoxygenase (LOX) pathways play an important role in reproductive processes. In amphibians, to date, the role of arachidonic acid (AA) metabolites in progesterone (P4)-induced oocyte maturation has not been clarified. In this work we studied the participation of three enzymes involved in AA metabolism - phospholipase A2 (PLA2), COX and LOX in Rhinella arenarum oocyte maturation. PLA2 activation induced maturation in Rhinella arenarum oocytes in a dose-dependent manner. Oocytes when treated with 0.08 μM melittin showed the highest response (78 ± 6% GVBD). In follicles, PLA2 activation did not significantly induce maturation at the assayed doses (12 ± 3% GVBD). PLA2 inhibition with quinacrine prevented melittin-induced GVBD in a dose-dependent manner, however PLA2 inactivation did not affect P4-induced maturation. This finding suggests that PLA2 is not the only phospholipase involved in P4-induced maturation in this species. P4-induced oocyte maturation was inhibited by the COX inhibitors indomethacin and rofecoxib (65 ± 3% and 63 ± 3% GVBD, respectively), although COX activity was never blocked by their addition. Follicles showed a similar response following the addition of these inhibitors. Participation of LOX metabolites in maturation seems to be correlated with seasonal variation in ovarian response to P4. During the February to June period (low P4 response), LOX inhibition by nordihydroguaiaretic acid or lysine clonixinate increased maturation by up to 70%. In contrast, during the July to January period (high P4 response), LOX inhibition had no effect on hormone-induced maturation.

  17. Antitumor effect of the selective COX-2 inhibitor celecoxib on endometrial adenocarcinoma in vitro and in vivo

    PubMed Central

    XIAO, YITAO; TENG, YINCHENG; ZHANG, RUI; LUO, LAIMIN

    2012-01-01

    The aim of this study was to investigate the antitumor effect of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib on endometrial adenocarcinoma in mice. Various amounts of celecoxib were added to HEC-1B cells in vitro for different durations. Cell cycle and apoptosis were analyzed using flow cytometry. HEC-1B cytostasis, invasiveness and COX-2 expression were examined by MTT, transwell cabin and western blot assays, respectively. An in vivo human endometrial adenocarcinoma model was established in BALB/c nude mice using HEC-1B cells. For two weeks, the celecoxib groups were treated with celecoxib 2 or 4 mg/day via oral administration and the control group was treated with saline. Tumor volume, growth curves and the inhibition rate (IR) were recorded. COX-2 expression levels and microvessel density (MVD) were investigated using an immunohistochemical technique. In the celecoxib groups, cell proliferation was significantly inhibited in a concentration- and time-dependent manner. The proportion of cells in the G0/G1 phase increased within 24 h after the addition of celecoxib whereas those in the S and G2/M phases decreased with an increasing apoptosis peak (sub-G1) and apoptosis rate. The microporous Matrigel-coated polycarbonate membrane of the Transwell cabin was traversable for the HEC-1B cells. The invasiveness was attenuated when the celecoxib concentration was increased. The tumor growth was also greatly inhibited when the celecoxib concentration was increased. The tumor IRs were 32.4 and 48.6% following treatment with 2 and 4 mg/day celecoxib, respectively. COX-2 was mainly expressed in the cytoplasm of the tumor cells. In the celecoxib groups, the COX-2 expression levels were concentration-dependent. The COX-2 expression level and MVD decreased when the celecoxib concentration was increased. The results of dependability analysis revealed that the COX-2 expression level was positively correlated with MVD (r=0.921; P<0.01). The antitumor effect of

  18. Kaposi's Sarcoma Associated Herpes Virus (KSHV) Induced COX-2: A Key Factor in Latency, Inflammation, Angiogenesis, Cell Survival and Invasion

    PubMed Central

    Sharma-Walia, Neelam; Sadagopan, Sathish; Veettil, Mohanan Valiya; Kerur, Nagaraj; Chandran, Bala

    2010-01-01

    Kaposi's sarcoma (KS), an enigmatic endothelial cell vascular neoplasm, is characterized by the proliferation of spindle shaped endothelial cells, inflammatory cytokines (ICs), growth factors (GFs) and angiogenic factors. KSHV is etiologically linked to KS and expresses its latent genes in KS lesion endothelial cells. Primary infection of human micro vascular endothelial cells (HMVEC-d) results in the establishment of latent infection and reprogramming of host genes, and cyclooxygenase-2 (COX-2) is one of the highly up-regulated genes. Our previous study suggested a role for COX-2 in the establishment and maintenance of KSHV latency. Here, we examined the role of COX-2 in the induction of ICs, GFs, angiogenesis and invasive events occurring during KSHV de novo infection of endothelial cells. A significant amount of COX-2 was detected in KS tissue sections. Telomerase-immortalized human umbilical vein endothelial cells supporting KSHV stable latency (TIVE-LTC) expressed elevated levels of functional COX-2 and microsomal PGE2 synthase (m-PGES), and secreted the predominant eicosanoid inflammatory metabolite PGE2. Infected HMVEC-d and TIVE-LTC cells secreted a variety of ICs, GFs, angiogenic factors and matrix metalloproteinases (MMPs), which were significantly abrogated by COX-2 inhibition either by chemical inhibitors or by siRNA. The ability of these factors to induce tube formation of uninfected endothelial cells was also inhibited. PGE2, secreted early during KSHV infection, profoundly increased the adhesion of uninfected endothelial cells to fibronectin by activating the small G protein Rac1. COX-2 inhibition considerably reduced KSHV latent ORF73 gene expression and survival of TIVE-LTC cells. Collectively, these studies underscore the pivotal role of KSHV induced COX-2/PGE2 in creating KS lesion like microenvironment during de novo infection. Since COX-2 plays multiple roles in KSHV latent gene expression, which themselves are powerful mediators of cytokine

  19. Apollo 12 Mission image - Astronaut Alan L. Bean,lunar module pilot,and two U.S. spacecraft

    NASA Image and Video Library

    1969-11-20

    AS12-48-7136 (20 Nov. 1969) --- Astronaut Charles Conrad Jr., commander, examines the unmanned Surveyor 3 spacecraft during the second Apollo 12 extravehicular activity (EVA). In the background is the lunar module, parked where the crew had landed it in the Ocean of Storms only 600 feet from Surveyor 3. This series of pictures documents the only occasion wherein Apollo astronauts landed near or had hands-on contact with another spacecraft which had arrived on the moon's surface well ahead of them. This picture was taken by astronaut Alan L. Bean, lunar module pilot. The television camera and several other pieces were taken from Surveyor 3 and brought back to Earth for scientific examination. Surveyor 3 soft-landed on the moon on April 19, 1967. Astronaut Richard F. Gordon Jr., command module pilot, remained with the Command and Service Modules (CSM) in lunar orbit while astronauts Conrad and Bean descended in the LM to explore the moon. Photo credit: NASA

  20. Barcoding Tetrahymena: discriminating species and identifying unknowns using the cytochrome c oxidase subunit I (cox-1) barcode.

    PubMed

    Kher, Chandni P; Doerder, F Paul; Cooper, Jason; Ikonomi, Pranvera; Achilles-Day, Undine; Küpper, Frithjof C; Lynn, Denis H

    2011-01-01

    DNA barcoding using the mitochondrial cytochromecoxidase subunit I (cox-1) gene has recently gained popularity as a tool for species identification of a variety of taxa. The primary objective of our research was to explore the efficacy of using cox-1 barcoding for species identification within the genusTetrahymena. We first increased intraspecific sampling forTetrahymena canadensis, Tetrahymena hegewischi, Tetrahymena pyriformis, Tetrahymena rostrata, Tetrahymena thermophila, and Tetrahymena tropicalis. Increased sampling efforts show that intraspecific sequence divergence is typically less than 1%, though it may be more in some species. The barcoding also showed that some strains might be misidentified or mislabeled. We also used cox-1 barcodes to provide species identifications for 51 unidentified environmental isolates, with a success rate of 98%. Thus, cox-1 barcoding is an invaluable tool for protistologists, especially when used in conjunction with morphological studies. 2010 Elsevier GmbH. All rights reserved.

  1. Expression of prostaglandin metabolising enzymes COX-2 and 15-PGDH and VDR in human granulosa cells.

    PubMed

    Thill, Marc; Becker, Steffi; Fischer, Dorothea; Cordes, Tim; Hornemann, Amadeus; Diedrich, Klaus; Salehin, Darius; Friedrich, Michael

    2009-09-01

    Prostaglandins (PGs) within the periovulatory follicle are essential for various female reproductive functions such as follicular development and maturation. In animal models, granulosa cells express the PG synthesizing enzyme cyclooxygenase-2 (COX-2) and the PG inactivating enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). First references suggest a correlation between vitamin D and prostaglandin metabolism through the impact of 1,25(OH)2D3 (calcitriol) on the expression of COX-2 and 15-PGDH. The expression of COX-2, 15-PGDH and the vitamin D receptor (VDR) in human granulosa cells (COV434, hGC and HGL5), which were originally isolated from different stages of follicular maturation, was determined by real-time PCR (RT-PCR) and Western blot analysis. A positive correlation of COX-2 and VDR protein was found in the COV434 and HGL5 cells and an inverse correlation of 15-PGDH and VDR protein levels in all the investigated cell types. There may be a link between VDR, associated target genes and prostaglandin metabolism in human follicular maturation and luteolysis.

  2. A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease

    PubMed Central

    Tamiya, Gen; Makino, Satoshi; Hayashi, Makiko; Abe, Akiko; Numakura, Chikahiko; Ueki, Masao; Tanaka, Atsushi; Ito, Chizuru; Toshimori, Kiyotaka; Ogawa, Nobuhiro; Terashima, Tomoya; Maegawa, Hiroshi; Yanagisawa, Daijiro; Tooyama, Ikuo; Tada, Masayoshi; Onodera, Osamu; Hayasaka, Kiyoshi

    2014-01-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247−10_247−6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT. PMID:25152455

  3. Monitoring of Fasciola Species Contamination in Water Dropwort by cox1 Mitochondrial and ITS-2 rDNA Sequencing Analysis.

    PubMed

    Choi, In-Wook; Kim, Hwang-Yong; Quan, Juan-Hua; Ryu, Jae-Gee; Sun, Rubing; Lee, Young-Ha

    2015-10-01

    Fascioliasis, a food-borne trematode zoonosis, is a disease primarily in cattle and sheep and occasionally in humans. Water dropwort (Oenanthe javanica), an aquatic perennial herb, is a common second intermediate host of Fasciola, and the fresh stems and leaves are widely used as a seasoning in the Korean diet. However, no information regarding Fasciola species contamination in water dropwort is available. Here, we collected 500 samples of water dropwort in 3 areas in Korea during February and March 2015, and the water dropwort contamination of Fasciola species was monitored by DNA sequencing analysis of the Fasciola hepatica and Fasciola gigantica specific mitochondrial cytochrome c oxidase subunit 1 (cox1) and nuclear ribosomal internal transcribed spacer 2 (ITS-2). Among the 500 samples assessed, the presence of F. hepatica cox1 and 1TS-2 markers were detected in 2 samples, and F. hepatica contamination was confirmed by sequencing analysis. The nucleotide sequences of cox1 PCR products from the 2 F. hepatica-contaminated samples were 96.5% identical to the F. hepatica cox1 sequences in GenBank, whereas F. gigantica cox1 sequences were 46.8% similar with the sequence detected from the cox1 positive samples. However, F. gigantica cox1 and ITS-2 markers were not detected by PCR in the 500 samples of water dropwort. Collectively, in this survey of the water dropwort contamination with Fasciola species, very low prevalence of F. hepatica contamination was detected in the samples.

  4. On the fate of laser-produced NH 2 in a constrained pulsed expansion of trimethylamine alane and NH 3

    NASA Astrophysics Data System (ADS)

    Demchuk, Alexander; Cahill, John J.; Simpson, Steven; Koplitz, Brent

    2001-11-01

    The effects of both 193 nm radiation and NH 3 on an expansion of trimethylamine alane (TMAA) have been studied. In neat TMAA, 193 nm radiation induces small but significant clustering. When NH 3 is introduced in the absence of 193 nm photons, no visible reaction occurs. However, when NH 3 is introduced along with 193 nm photons, the H 3Al:N(CH 3) 3 parent molecule is completely replaced by H 3AlNH 2. Moreover, the clustering channels observed with neat TMAA disappear. The apparent stability or inertness of the R 3MNH 2 (R=H, CH 3 or C 2H 5; M=Ga or Al) species in a variety of metal nitride reactive environments is discussed.

  5. Fungal origin by horizontal transfer of a plant mitochondrial group I intron in the chimeric CoxI gene of Peperomia.

    PubMed

    Vaughn, J C; Mason, M T; Sper-Whitis, G L; Kuhlman, P; Palmer, J D

    1995-11-01

    We present phylogenetic evidence that a group I intron in an angiosperm mitochondrial gene arose recently by horizontal transfer from a fungal donor species. A 1,716-bp fragment of the mitochondrial coxI gene from the angiosperm Peperomia polybotrya was amplified via the polymerase chain reaction and sequenced. Comparison to other coxI genes revealed a 966-bp group I intron, which, based on homology with the related yeast coxI intron aI4, potentially encodes a 279-amino-acid site-specific DNA endonuclease. This intron, which is believed to function as a ribozyme during its own splicing, is not present in any of 19 coxI genes examined from other diverse vascular plant species. Phylogenetic analysis of intron origin was carried out using three different tree-generating algorithms, and on a variety of nucleotide and amino acid data sets from the intron and its flanking exon sequences. These analyses show that the Peperomia coxI gene intron and exon sequences are of fundamentally different evolutionary origin. The Peperomia intron is more closely related to several fungal mitochondrial introns, two of which are located at identical positions in coxI, than to identically located coxI introns from the land plant Marchantia and the green alga Prototheca. Conversely, the exon sequence of this gene is, as expected, most closely related to other angiosperm coxI genes. These results, together with evidence suggestive of co-conversion of exonic markers immediately flanking the intron insertion site, lead us to conclude that the Peperomia coxI intron probably arose by horizontal transfer from a fungal donor, using the double-strand-break repair pathway. The donor species may have been one of the symbiotic mycorrhizal fungi that live in close obligate association with most plants.

  6. Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway

    PubMed Central

    Zhen, Yulan; Wu, Qiaomei; Ding, Yiqian; Zhang, Wei; Zhai, Yuansheng; Lin, Xiaoxiong; Weng, Yunxia; Guo, Ruixian; Zhang, Ying; Feng, Jianqiang; Lei, Yiyan; Chen, Jingfu

    2018-01-01

    The effects of hydrogen sulfide (H2S) on cancer are controversial. Our group previously demonstrated that exogenous H2S promotes the development of cancer via amplifying the activation of the nuclear factor-κB signaling pathway in hepatocellular carcinoma (HCC) cells (PLC/PRF/5). The present study aimed to further investigate the hypothesis that exogenous H2S promotes PLC/PRF/5 cell proliferation and migration, and inhibits apoptosis by activating the signal transducer and activator of transcription 3 (STAT3)-cyclooxygenase-2 (COX-2) signaling pathway. PLC/PRF/5 cells were treated with 500 µmol/l NaHS (a donor of H2S) for 24 h. The expression levels of phosphorylated (p)-STAT3, STAT3, cleaved caspase-3 and COX-2 were measured by western blot assay. Cell viability was detected by Cell Counting kit-8 assay. Apoptotic cells were observed by Hoechst 33258 staining. The expression of STAT3 and COX-2 messenger RNA (mRNA) was detected by semiquantitative reverse transcription-polymerase chain reaction. The production of vascular endothelial growth factor (VEGF) was evaluated by ELISA. The results indicated that treatment of PLC/PRF/5 cells with 500 µmol/l NaHS for 24 h markedly increased the expression levels of p-STAT3 and STAT3 mRNA, leading to COX-2 and COX-2 mRNA overexpression, VEGF induction, decreased cleaved caspase-3 production, increased cell viability and migration, and decreased number of apoptotic cells. However, co-treatment of PLC/PRF/5 cells with 500 µmol/l NaHS and 30 µmol/l AG490 (an inhibitor of STAT3) or 20 µmol/l NS-398 (an inhibitor of COX-2) for 24 h significantly reverted the effects induced by NaHS. Furthermore, co-treatment of PLC/PRF/5 cells with 500 µmol/l NaHS and 30 µmol/l AG490 markedly decreased the NaHS-induced increase in the expression level of COX-2. By contrast, co-treatment of PLC/PRF/5 cells with 500 µmol/l NaHS and 20 µmol/l NS-398 inhibited the NaHS-induced increase in the expression level of p-STAT3. In conclusion, the

  7. Prevention of upper aerodigestive tract cancer in zinc-deficient rodents: Inefficacy of genetic or pharmacological disruption of COX-2

    PubMed Central

    Fong, Louise Y.Y.; Jiang, Yubao; Riley, Maurisa; Liu, Xianglan; Smalley, Karl J.; Guttridge, Denis C.; Farber, John L.

    2009-01-01

    Zinc deficiency in humans is associated with an increased risk of upper aerodigestive tract (UADT) cancer. In rodents, zinc deficiency predisposes to carcinogenesis by causing proliferation and alterations in gene expression. We examined whether in zinc-deficient rodents, targeted disruption of the cyclooxygenase (COX)-2 pathway by the COX-2 selective inhibitor celecoxib or by genetic deletion prevent UADT carcinogenesis. Tongue cancer prevention studies were conducted in zinc-deficient rats previously exposed to a tongue carcinogen by celecoxib treatment with or without zinc replenishment, or by zinc replenishment alone. The ability of genetic COX-2 deletion to protect against chemically-induced for-estomach tumorigenesis was examined in mice on zinc-deficient versus zinc-sufficient diet. The expression of 3 predictive bio-markers COX-2, nuclear factor (NF)-κ B p65 and leukotriene A4 hydrolase (LTA4H) was examined by immunohistochemistry. In zinc-deficient rats, celecoxib without zinc replenishment reduced lingual tumor multiplicity but not progression to malignancy. Celecoxib with zinc replenishment or zinc replenishment alone significantly lowered lingual squamous cell carcinoma incidence, as well as tumor multiplicity. Celecoxib alone reduced overexpression of the 3 biomarkers in tumors slightly, compared with intervention with zinc replenishment. Instead of being protected, zinc-deficient COX-2 null mice developed significantly greater tumor multiplicity and forestomach carcinoma incidence than wild-type controls. Additionally, zinc-deficient COX-2−/− forestomachs displayed strong LTA4H immunostaining, indicating activation of an alter-native pathway under zinc deficiency when the COX-2 pathway is blocked. Thus, targeting only the COX-2 pathway in zinc-deficient animals did not prevent UADT carcinogenesis. Our data suggest zinc supplementation should be more thoroughly explored in human prevention clinical trials for UADT cancer. PMID:17985342

  8. A novel, modernized Golgi-Cox stain optimized for CLARITY cleared tissue.

    PubMed

    Kassem, Mustafa S; Fok, Sandra Y Y; Smith, Kristie L; Kuligowski, Michael; Balleine, Bernard W

    2018-01-15

    High resolution neuronal information is extraordinarily useful in understanding the brain's functionality. The development of the Golgi-Cox stain allowed observation of the neuron in its entirety with unrivalled detail. Tissue clearing techniques, e.g., CLARITY and CUBIC, provide the potential to observe entire neuronal circuits intact within tissue and without previous restrictions with regard to section thickness. Here we describe an improved Golgi-Cox stain method, optimised for use with CLARITY and CUBIC that can be used in both fresh and fixed tissue. Using this method, we were able to observe neurons in their entirety within a fraction of the time traditionally taken to clear tissue (48h). We were also able to show for the first-time that Golgi stained tissue is fluorescent when visualized using a multi-photon microscope, allowing us to image synaptic spines with a detail previously unachievable. These novel methods provide cheap and easy to use techniques to investigate the morphology of cellular processes in the brain at a new-found depth, speed, utility and detail, without previous restrictions of time, tissue type and section thickness. This is the first application of a Golgi-Cox stain to cleared brain tissue, it is investigated and discussed in detail, describing different methodologies that may be used, a comparison between the different clearing techniques and lastly the novel interaction of these techniques with this ultra-rapid stain. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. ORACLE INEQUALITIES FOR THE LASSO IN THE COX MODEL

    PubMed Central

    Huang, Jian; Sun, Tingni; Ying, Zhiliang; Yu, Yi; Zhang, Cun-Hui

    2013-01-01

    We study the absolute penalized maximum partial likelihood estimator in sparse, high-dimensional Cox proportional hazards regression models where the number of time-dependent covariates can be larger than the sample size. We establish oracle inequalities based on natural extensions of the compatibility and cone invertibility factors of the Hessian matrix at the true regression coefficients. Similar results based on an extension of the restricted eigenvalue can be also proved by our method. However, the presented oracle inequalities are sharper since the compatibility and cone invertibility factors are always greater than the corresponding restricted eigenvalue. In the Cox regression model, the Hessian matrix is based on time-dependent covariates in censored risk sets, so that the compatibility and cone invertibility factors, and the restricted eigenvalue as well, are random variables even when they are evaluated for the Hessian at the true regression coefficients. Under mild conditions, we prove that these quantities are bounded from below by positive constants for time-dependent covariates, including cases where the number of covariates is of greater order than the sample size. Consequently, the compatibility and cone invertibility factors can be treated as positive constants in our oracle inequalities. PMID:24086091

  10. ORACLE INEQUALITIES FOR THE LASSO IN THE COX MODEL.

    PubMed

    Huang, Jian; Sun, Tingni; Ying, Zhiliang; Yu, Yi; Zhang, Cun-Hui

    2013-06-01

    We study the absolute penalized maximum partial likelihood estimator in sparse, high-dimensional Cox proportional hazards regression models where the number of time-dependent covariates can be larger than the sample size. We establish oracle inequalities based on natural extensions of the compatibility and cone invertibility factors of the Hessian matrix at the true regression coefficients. Similar results based on an extension of the restricted eigenvalue can be also proved by our method. However, the presented oracle inequalities are sharper since the compatibility and cone invertibility factors are always greater than the corresponding restricted eigenvalue. In the Cox regression model, the Hessian matrix is based on time-dependent covariates in censored risk sets, so that the compatibility and cone invertibility factors, and the restricted eigenvalue as well, are random variables even when they are evaluated for the Hessian at the true regression coefficients. Under mild conditions, we prove that these quantities are bounded from below by positive constants for time-dependent covariates, including cases where the number of covariates is of greater order than the sample size. Consequently, the compatibility and cone invertibility factors can be treated as positive constants in our oracle inequalities.

  11. Apigenin inhibits COX-2, PGE2, and EP1 and also initiates terminal differentiation in the epidermis of tumor bearing mice.

    PubMed

    Kiraly, Alex J; Soliman, Eman; Jenkins, Audrey; Van Dross, Rukiyah T

    2016-01-01

    Non-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States. NMSC overexpresses cyclooxygenase-2 (COX-2). COX-2 synthesizes prostaglandins such as PGE2 which promote proliferation and tumorigenesis by engaging G-protein-coupled prostaglandin E receptors (EP). Apigenin is a bioflavonoid that blocks mouse skin tumorigenesis induced by the chemical carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the effect of apigenin on the COX-2 pathway has not been examined in the DMBA/TPA skin tumor model. In the present study, apigenin decreased tumor multiplicity and incidence in DMBA/TPA-treated SKH-1 mice. Analysis of the non-tumor epidermis revealed that apigenin reduced COX-2, PGE2, EP1, and EP2 synthesis and also increased terminal differentiation. In contrast, apigenin did not inhibit the COX-2 pathway or promote terminal differentiation in the tumors. Since fewer tumors developed in apigenin-treated animals which contained reduced epidermal COX-2 levels, our data suggest that apigenin may avert skin tumor development by blocking COX-2. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis.

    PubMed

    Hull, M L; Prentice, A; Wang, D Y; Butt, R P; Phillips, S C; Smith, S K; Charnock-Jones, D S

    2005-02-01

    Women with endometriosis have elevated levels of cyclooxygenase-2 (COX-2) in peritoneal macrophages and endometriotic tissue. Inhibition of COX-2 has been shown to reduce inflammation, angiogenesis and cellular proliferation. It may also downregulate aromatase activity in ectopic endometrial lesions. Ectopic endometrial establishment and growth are therefore likely to be suppressed in the presence of COX-2 inhibitors. We hypothesized that COX-2 inhibition would reduce the size and number of ectopic human endometrial lesions in a nude mouse model of endometriosis. The selective COX-2 inhibitor, nimesulide, was administered to estrogen-supplemented nude mice implanted with human endometrial tissue. Ten days after implantation, the number and size of ectopic endometrial lesions were evaluated and compared with lesions from a control group. Immunohistochemical assessment of vascular development and macrophage and myofibroblast infiltration in control and treated lesions was performed. There was no difference in the number or size of ectopic endometrial lesions in control and nimesulide-treated nude mice. Nimesulide did not induce a visually identifiable difference in blood vessel development or macrophage or myofibroblast infiltration in nude mouse explants. The hypothesized biological properties of COX-2 inhibition did not influence lesion number or size in the nude mouse model of endometriosis.

  13. Analysis of the cytochrome c oxidase subunit 1 (COX1) gene reveals the unique evolution of the giant panda.

    PubMed

    Hu, Yao-Dong; Pang, Hui-Zhong; Li, De-Sheng; Ling, Shan-Shan; Lan, Dan; Wang, Ye; Zhu, Yun; Li, Di-Yan; Wei, Rong-Ping; Zhang, He-Min; Wang, Cheng-Dong

    2016-11-05

    As the rate-limiting enzyme of the mitochondrial respiratory chain, cytochrome c oxidase (COX) plays a crucial role in biological metabolism. "Living fossil" giant panda (Ailuropoda melanoleuca) is well-known for its special bamboo diet. In an effort to explore functional variation of COX1 in the energy metabolism behind giant panda's low-energy bamboo diet, we looked at genetic variation of COX1 gene in giant panda, and tested for its selection effect. In 1545 base pairs of the gene from 15 samples, 9 positions were variable and 1 mutation leaded to an amino acid sequence change. COX1 gene produces six haplotypes, nucleotide (pi), haplotype diversity (Hd). In addition, the average number of nucleotide differences (k) is 0.001629±0.001036, 0.8083±0.0694 and 2.517, respectively. Also, dN/dS ratio is significantly below 1. These results indicated that giant panda had a low population genetic diversity, and an obvious purifying selection of the COX1 gene which reduces synthesis of ATP determines giant panda's low-energy bamboo diet. Phylogenetic trees based on the COX1 gene were constructed to demonstrate that giant panda is the sister group of other Ursidae. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. The Role of COX-2 in the Inflammatory and Fibrotic Response in the Lung Following Exposure to Multi-Walled Carbon Nanotubes

    NASA Astrophysics Data System (ADS)

    Sayers, Brian C.

    Exposure to multiwalled carbon nanotubes (MWCNT) has been demonstrated to exacerbate airway inflammation and fibrosis in allergen-challenged mouse model. These data have led to concern that individuals with asthma could represent a susceptible population to adverse health effects following exposure to MWCNT, and possibly other engineered nanoparticles. Asthma pathogenesis is caused by the interaction of a complex genetic predisposition and environmental exposures. Because chronic airway inflammation is common to all asthma phenotypes, it is logical to investigate genes that are involved in inflammatory pathways in order to understand the genetic basis of asthma. The metabolism of arachidonic acid by cyclooxygenase (COX) enzymes is the rate-determining step in the synthesis of prostanoids, which are biologically active lipids that are important modulators of inflammation. Based on the role of COX enzymes in inflammatory pathways, we sought to investigate how COX enzymes are involved in the inflammatory response following MWCNT exposure in asthmatic airways. We report that MWCNT significantly exacerbated allergen-induced airway inflammation and mucus cell metaplasia in COX-2 deficient mice compared to wild type mice. In addition, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13, IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2 deficient mice but not in WT mice. We conclude that exacerbation of allergen-induced airway inflammation and mucus cell metaplasia by MWCNTs is enhanced by deficiency in COX-2 and associated with activation of a mixed Th1/Th2/Th17 immune response. Based on our observation that COX-2 deficient mice developed a mixed Th immune response following MWCNT exposure, we sought to evaluate how cytokines associated with different Th immune responses alter COX expression following MWCNT exposure. For this study, a mouse macrophage cell line (RAW264.7) was used because MWCNT were largely sequestered

  15. GROWTH FACTORS AND COX2 IN WOUND HEALING: AN EXPERIMENTAL STUDY WITH EHRLICH TUMORS.

    PubMed

    Salgado, Flávio L L; Artigiani-Neto, Ricardo; Lopes-Filho, Gaspar de Jesus

    2016-01-01

    Healing is an innate biological phenomenon, and carcinogenesis acquired, but with common humoral and cellular elements. Carcinogenesis interferes negatively in healing. To evaluate the histological changes in laparotomy scars of healthy Balb/c mice and with an Ehrlich tumor in its various forms of presentation. Fifty-four mice were divided into three groups of 18 animals. First group was the control; the second had Ehrlich tumor with ascites; and the third had the subcutaneous form of this tumor. Seven days after tumor inoculation, all 54 mice were submitted to laparotomy. All of the animals in the experiment were operated on again on 7th day after surgery, with resection of the scar and subsequent euthanasia of the animal. The scars were sent for histological assessment using immunohistochemical techniques to evaluate Cox-2 (cyclooxygenase 2), VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor). Semi-quantitatively analysis was done in the laparotomy scars and in the abdominal walls far away from the site of the operation. Assessing the weight of the animals, the correct inoculation of the tumor and weight gain in the group with tumoral ascites was observed. The histological studies showed that groups with the tumor showed a statistically significant higher presence of Cox-2 compared to the control. In the Cox-2 analysis of the abdominal wall, the ascites group showed the most significant difference. VEGF did not present any significant differences between the three groups, regardless of the site. The FGF showed a significant increase in animals with the tumor. Histological findings in both laparotomy scar and the abdominal wall showed that with Ehrlich's neoplasia there was an exacerbated inflammatory response, translated by more intense expression of Cox-2 and greater fibroblast proliferation, translated by more intense expression of FGF, that is, it stimulated both the immediate inflammatory reactions, observed with Cox-2 reactions, and

  16. Potentially functional COX-2-1195G>A polymorphism increases the risk of digestive system cancers: a meta-analysis.

    PubMed

    Dong, Jing; Dai, Juncheng; Zhang, Mingfeng; Hu, Zhibin; Shen, Hongbing

    2010-06-01

    Three potentially functional polymorphisms: -765G>C, -1195G>A, and 8473T>C in the cyclooxygenase-2 (COX-2) gene were identified and proposed to be associated with cancer susceptibility. The aim of this meta-analysis was to evaluate the association between these three polymorphisms and the risk of cancer in diverse populations. All case-control studies published up to November 2009 on the association between the three polymorphisms of COX-2 and cancer risk were identified by searching PubMed. The cancer risk associated with the three polymorphisms of the COX-2 gene was estimated for each study by OR together with its 95% confidence interval (CI), respectively. A total of 47 case-control studies were included, and variant genotypes GA/AA of -1195G>A were associated with a significantly increased cancer risk (GA/AA vs GG: odds ratio [OR], 1.29; 95% CI, 1.18-1.41; P(heterogeneity) = 0.113), and this significant association was mainly observed within cancers of the digestive system (e.g. colorectal, gastric, esophageal, oral, biliary tract, gallbladder, and pancreatic) without between-study heterogeneity (GA/AA vs GG: OR, 1.36; 95% CI; 1.23-1.51; P(heterogeneity) = 0.149). Furthermore, a stratification analysis showed that the risk of COX-2-1195G>A associated with cancers in the digestive system was more evident among Asians than Caucasians. However, for COX-2-765G>C and 8473T>C, no convincing association between the two polymorphisms and risk of cancer or cancer type was observed. The effect of three potentially functional polymorphisms (-765G>C, -1195G>A, and 8473T>C) in the COX-2 gene on cancer risk provided evidence that the COX-2-1195G>A polymorphism was significantly associated with increased risk of digestive system cancers, especially among Asian populations.

  17. [Analysis of COX1 sequences of Taenia isolates from four areas of Guangxi].

    PubMed

    Yang, Yi-Chao; Ou-Yang, Yi; Su, Ai-Rong; Wan, Xiao-Ling; Li, Shu-Lin

    2012-06-01

    To analyze the COX1 sequences of Taenia isolates from four areas of Guangxi Zhuang Autonomous Region, and to understand the distribution of Taenia asiatica in Guangxi. Patients with taeniasis in Luzhai, Rongshui, Tiandong and Sanjiang in Guangxi were treated by deworming, and the Taenia isolates were collected. Cyclooxygenase-1 (COX1) sequences of these isolates were amplified by PCR, and the PCR products were sequenced by T-A clone sequencing. The homogeneities and genetic distances were calculated and analyzed, and the phylogenic trees were constructed by some softwares. Meanwhile, the COX1 sequences of the isolates from the 4 areas were compared separately with the sequences of Taenia species in GenBank. The COX1 sequence of the 5 Taenia isolates collected had the same length of 444 bp. There were 5 variable positions between the Luzhai isolate and Taenia asiatica, the homogeneity was 98.87% and their genetic distance was 0.011. The phylogenetic tree analysis revealed that the Luzhai isolate and Taenia asiatica locating at the same node had a close relationship. The homogeneity between Rongshui isolate A and Taenia solium was 100%, while the homogeneity of Rongshui isolate B with Taeniasis saginata and Taenia asiatica were 98.20% and 96.17%, respectively. The homogeneities of the Tiandong and Sanjiang isolates with Taenia solium were 99.55% and 96.40%, respectively, and the genetic distances were 0.005 and 0.037, respectively. The homogeneity between the Luzhai isolate and Taeniasis saginate was 96.40%. Taenia asiatica exists in Luzhai and Taenia solium and Taenia saginata coexist in Rongshui, Guangxi Zhuang Autonomous Region.

  18. When Art Meets Gardens: Does It Enhance the Benefits? The Nancy Hypothesis of Care for Persons with Alzheimer's Disease.

    PubMed

    Jonveaux, Thérèse Rivasseau; Fescharek, Reinhard

    2018-01-01

    The creation of healing gardens for persons with Alzheimer's disease and related diseases (ADRD) offers vast potential. They can play a role in the scaffolding of cognitive disorders, emotional stress, sensory processing, sense of harmony, and appeasement. These effects are achieved through a distributed interplay of psychological functions with the immediate environment and local culture on the one hand, and dialogue on the other. The garden, a natural canvas created by man, shares with art the ability to foster an esthetic sense for which the perception can be measured by functional neurological imaging exploration. Art represents a mediator for the collaborative realization of distributed psychological functions between different individuals. Based on the hypothesis of an optimization of the therapeutic potential of a garden by a design adapted to the neuro-psycho-social and cultural specificities of its users combined with the thoughtful introduction of an artistic dimension, the "art, memory and life" healing garden was created at the University Hospital of Nancy as a prototype for persons with ADRD. The design concept was based on two hypotheses that we formulate herein, discuss their theoretical foundation, and suggest enhanced design for therapeutic gardens based upon our experience.

  19. Rottlerin enhances IL-1β-induced COX-2 expression through sustained p38 MAPK activation in MDA-MB-231 human breast cancer cells

    PubMed Central

    Park, Eun Jung

    2011-01-01

    Cyclooxygenase-2 (COX-2) is an important enzyme in inflammation. In this study, we investigated the underlying molecular mechanism of the synergistic effect of rottlerin on interleukin1β (IL-1β)-induced COX-2 expression in MDA-MB-231 human breast cancer cell line. Treatment with rottlerin enhanced IL-1β-induced COX-2 expression at both the protein and mRNA levels. Combined treatment with rottlerin and IL-1β significantly induced COX-2 expression, at least in part, through the enhancement of COX-2 mRNA stability. In addition, rottlerin and IL-1β treatment drove sustained activation of p38 Mitogen-activated protein kinase (MAPK), which is involved in induced COX-2 expression. Also, a pharmacological inhibitor of p38 MAPK (SB 203580) and transient transfection with inactive p38 MAPK inhibited rottlerin and IL-1β-induced COX-2 upregulation. However, suppression of protein kinase C δ (PKC δ) expression by siRNA or overexpression of dominant-negative PKC δ (DN-PKC-δ) did not abrogate the rottlerin plus IL-1β-induced COX-2 expression. Furthermore, rottlerin also enhanced tumor necrosis factor-α (TNF-α), phorbol myristate acetate (PMA), and lipopolysaccharide (LPS)-induced COX-2 expression. Taken together, our results suggest that rottlerin causes IL-1β-induced COX-2 upregulation through sustained p38 MAPK activation in MDA-MB-231 human breast cancer cells. PMID:21971413

  20. Endoplasmic reticulum stress (ER-stress) by 2-deoxy-D-glucose (2DG) reduces cyclooxygenase-2 (COX-2) expression and N-glycosylation and induces a loss of COX-2 activity via a Src kinase-dependent pathway in rabbit articular chondrocytes.

    PubMed

    Yu, Seon-Mi; Kim, Song-Ja

    2010-11-30

    Endoplasmic reticulum (ER) stress regulates a wide range of cellular responses including apoptosis, proliferation, inflammation, and differentiation in mammalian cells. In this study, we observed the role of 2-deoxy-D-glucose (2DG) on inflammation of chondrocytes. 2DG is well known as an inducer of ER stress, via inhibition of glycolysis and glycosylation. Treatment of 2DG in chondrocytes considerably induced ER stress in a dose- and time-dependent manner, which was demonstrated by a reduction of glucose regulated protein of 94 kDa (grp94), an ER stress-inducible protein, as determined by a Western blot analysis. In addition, induction of ER stress by 2DG led to the expression of COX-2 protein with an apparent molecular mass of 66-70kDa as compared with the normally expressed 72-74 kDa protein. The suppression of ER stress with salubrinal (Salub), a selective inhibitor of eif2-alpha dephosphorylation, successfully prevented grp94 induction and efficiently recovered 2DG- modified COX-2 molecular mass and COX-2 activity might be associated with COX-2 N-glycosylation. Also, treatment of 2DG increased phosphorylation of Src in chondrocytes. The inhibition of the Src signaling pathway with PP2 (Src tyrosine kinase inhibitor) suppressed grp94 expression and restored COX-2 expression, N-glycosylation, and PGE2 production, as determined by a Western blot analysis and PGE2 assay. Taken together, our results indicate that the ER stress induced by 2DG results in a decrease of the transcription level, the molecular mass, and the activity of COX-2 in rabbit articular chondrocytes via a Src kinase-dependent pathway.

  1. Cox17 Protein Is an Auxiliary Factor Involved in the Control of the Mitochondrial Contact Site and Cristae Organizing System.

    PubMed

    Chojnacka, Magdalena; Gornicka, Agnieszka; Oeljeklaus, Silke; Warscheid, Bettina; Chacinska, Agnieszka

    2015-06-12

    The mitochondrial contact site and cristae organizing system (MICOS) is a recently discovered protein complex that is crucial for establishing and maintaining the proper inner membrane architecture and contacts with the outer membrane of mitochondria. The ways in which the MICOS complex is assembled and its integrity is regulated remain elusive. Here, we report a direct link between Cox17, a protein involved in the assembly of cytochrome c oxidase, and the MICOS complex. Cox17 interacts with Mic60, thereby modulating MICOS complex integrity. This interaction does not involve Sco1, a partner of Cox17 in transferring copper ions to cytochrome c oxidase. However, the Cox17-MICOS interaction is regulated by copper ions. We propose that Cox17 is a newly identified factor involved in maintaining the architecture of the MICOS complex. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Integrated Cox's model for predicting survival time of glioblastoma multiforme.

    PubMed

    Ai, Zhibing; Li, Longti; Fu, Rui; Lu, Jing-Min; He, Jing-Dong; Li, Sen

    2017-04-01

    Glioblastoma multiforme is the most common primary brain tumor and is highly lethal. This study aims to figure out signatures for predicting the survival time of patients with glioblastoma multiforme. Clinical information, messenger RNA expression, microRNA expression, and single-nucleotide polymorphism array data of patients with glioblastoma multiforme were retrieved from The Cancer Genome Atlas. Patients were separated into two groups by using 1 year as a cutoff, and a logistic regression model was used to figure out any variables that can predict whether the patient was able to live longer than 1 year. Furthermore, Cox's model was used to find out features that were correlated with the survival time. Finally, a Cox model integrated the significant clinical variables, messenger RNA expression, microRNA expression, and single-nucleotide polymorphism was built. Although the classification method failed, signatures of clinical features, messenger RNA expression levels, and microRNA expression levels were figured out by using Cox's model. However, no single-nucleotide polymorphisms related to prognosis were found. The selected clinical features were age at initial diagnosis, Karnofsky score, and race, all of which had been suggested to correlate with survival time. Both of the two significant microRNAs, microRNA-221 and microRNA-222, were targeted to p27 Kip1 protein, which implied the important role of p27 Kip1 on the prognosis of glioblastoma multiforme patients. Our results suggested that survival modeling was more suitable than classification to figure out prognostic biomarkers for patients with glioblastoma multiforme. An integrated model containing clinical features, messenger RNA levels, and microRNA expression levels was built, which has the potential to be used in clinics and thus to improve the survival status of glioblastoma multiforme patients.

  3. Inflammation in gastric cancer: Interplay of the COX-2/prostaglandin E2 and Toll-like receptor/MyD88 pathways.

    PubMed

    Echizen, Kanae; Hirose, Osamu; Maeda, Yusuke; Oshima, Masanobu

    2016-04-01

    Cyclooxygenase-2 (COX-2) and its downstream product prostaglandin E2 (PGE2 ) play a key role in generation of the inflammatory microenvironment in tumor tissues. Gastric cancer is closely associated with Helicobacter pylori infection, which stimulates innate immune responses through Toll-like receptors (TLRs), inducing COX-2/PGE2 pathway through nuclear factor-κB activation. A pathway analysis of human gastric cancer shows that both the COX-2 pathway and Wnt/β-catenin signaling are significantly activated in tubular-type gastric cancer, and basal levels of these pathways are also increased in other types of gastric cancer. Expression of interleukin-11, chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and CXCL5, which play tumor-promoting roles through a variety of mechanisms, is induced in a COX-2/PGE2 pathway-dependent manner in both human and mouse gastric tumors. Moreover, the COX-2/PGE2 pathway plays an important role in the maintenance of stemness with expression of stem cell markers, including CD44, Prom1, and Sox9, which are induced in both gastritis and gastric tumors through a COX-2/PGE2 -dependent mechanism. In contrast, disruption of Myd88 results in suppression of the inflammatory microenvironment in gastric tumors even when the COX-2/PGE2 pathway is activated, indicating that the interplay of the COX-2/PGE2 and TLR/MyD88 pathways is needed for inflammatory response in tumor tissues. Furthermore, TLR2/MyD88 signaling plays a role in maintenance of stemness in normal stem cells as well as gastric tumor cells. Accordingly, these results suggest that targeting the COX-2/PGE2 pathway together with TLR/MyD88 signaling, which would suppress the inflammatory microenvironment and maintenance of stemness, could be an effective preventive or therapeutic strategy for gastric cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  4. COX-2/mPGES-1/PGE2 cascade activation mediates uric acid-induced mesangial cell proliferation.

    PubMed

    Li, Shuzhen; Sun, Zhenzhen; Zhang, Yue; Ruan, Yuan; Chen, Qiuxia; Gong, Wei; Yu, Jing; Xia, Weiwei; He, John Ci-Jiang; Huang, Songming; Zhang, Aihua; Ding, Guixia; Jia, Zhanjun

    2017-02-07

    Hyperuricemia is not only the main feature of gout but also a cause of gout-related organ injuries including glomerular hypertrophy and sclerosis. Uric acid (UA) has been proven to directly cause mesangial cell (MC) proliferation with elusive mechanisms. The present study was undertaken to examined the role of inflammatory cascade of COX-2/mPGES-1/PGE2 in UA-induced MC proliferation. In the dose- and time-dependent experiments, UA increased cell proliferation shown by the increased total cell number, DNA synthesis rate, and the number of cells in S and G2 phases in parallel with the upregulation of cyclin A2 and cyclin D1. Interestingly, UA-induced cell proliferation was accompanied with the upregulation of COX-2 and mPGES-1 at both mRNA and protein levels. Strikingly, inhibition of COX-2 via a specific COX-2 inhibitor NS-398 markedly blocked UA-induced MC proliferation. Meanwhile, UA-induced PGE2 production was almost entirely abolished. Furthermore, inhibiting mPGES-1 by a siRNA approach in MCs also ameliorated UA-induced MC proliferation in line with a significant blockade of PGE2 secretion. More importantly, in gout patients, we observed a significant elevation of urinary PGE2 excretion compared with healthy controls, indicating a translational potential of this study to the clinic. In conclusion, our findings indicated that COX-2/mPGES-1/PGE2 cascade activation mediated UA-induced MC proliferation. This study offered new insights into the understanding and the intervention of UA-related glomerular injury.

  5. A comparison of Cox and logistic regression for use in genome-wide association studies of cohort and case-cohort design.

    PubMed

    Staley, James R; Jones, Edmund; Kaptoge, Stephen; Butterworth, Adam S; Sweeting, Michael J; Wood, Angela M; Howson, Joanna M M

    2017-06-01

    Logistic regression is often used instead of Cox regression to analyse genome-wide association studies (GWAS) of single-nucleotide polymorphisms (SNPs) and disease outcomes with cohort and case-cohort designs, as it is less computationally expensive. Although Cox and logistic regression models have been compared previously in cohort studies, this work does not completely cover the GWAS setting nor extend to the case-cohort study design. Here, we evaluated Cox and logistic regression applied to cohort and case-cohort genetic association studies using simulated data and genetic data from the EPIC-CVD study. In the cohort setting, there was a modest improvement in power to detect SNP-disease associations using Cox regression compared with logistic regression, which increased as the disease incidence increased. In contrast, logistic regression had more power than (Prentice weighted) Cox regression in the case-cohort setting. Logistic regression yielded inflated effect estimates (assuming the hazard ratio is the underlying measure of association) for both study designs, especially for SNPs with greater effect on disease. Given logistic regression is substantially more computationally efficient than Cox regression in both settings, we propose a two-step approach to GWAS in cohort and case-cohort studies. First to analyse all SNPs with logistic regression to identify associated variants below a pre-defined P-value threshold, and second to fit Cox regression (appropriately weighted in case-cohort studies) to those identified SNPs to ensure accurate estimation of association with disease.

  6. Influence of COX-2 and OXTR polymorphisms on treatment outcome in treatment resistant depression.

    PubMed

    Mendlewicz, Julien; Crisafulli, Concetta; Calati, Raffaella; Kocabas, Neslihan Aygun; Massat, Isabelle; Linotte, Sylvie; Kasper, Siegfried; Fink, Martin; Sidoti, Antonina; Scantamburlo, Gabrielle; Ansseau, Marc; Antonijevic, Irina; Forray, Carlos; Snyder, Lenore; Bollen, Joseph; Montgomery, Stuart; Zohar, Joseph; Souery, Daniel; Serretti, Alessandro

    2012-05-10

    Inflammatory pathways play a crucial role in the pathomechanisms of antidepressant efficacy. The aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within cyclooxygenase-2 (COX-2, rs5275 and rs20417) and oxytocin receptor (OXTR, rs53576 and rs2254298) genes was associated with antidepressant treatment resistance, response or remission. Three hundred seventy-two patients were recruited in the context of a multicenter resistant depression study. They were genotyped for COX-2 and OXTR SNPs. Treatment resistance (according to two different definitions), response and remission were recorded. We did not observe any association between the genotypes or alleles of the selected SNPs within COX-2 and OXTR genes and treatment resistance, response and remission in the whole sample. Our results are consistent with those of some studies but not with those of other ones. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, and different definitions of treatment resistance. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  7. Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition.

    PubMed

    Binion, D G; Otterson, M F; Rafiee, P

    2008-11-01

    Angiogenesis, the growth of new blood vessels, is a critical homeostatic mechanism which regulates vascular populations in response to physiological requirements and pathophysiological demand, including chronic inflammation and cancer. The importance of angiogenesis in gastrointestinal chronic inflammation and cancer has been defined, as antiangiogenic therapy has demonstrated benefit in models of inflammatory bowel disease and colon cancer treatment. Curcumin is a natural product undergoing evaluation for the treatment of chronic inflammation, including inflammatory bowel disease (IBD). The effect of curcumin on human intestinal angiogenesis is not defined. The antiangiogenic effect of curcumin on in vitro angiogenesis was examined using primary cultures of human intestinal microvascular endothelial cells (HIMECs), stimulated with vascular endothelial growth factor (VEGF). Curcumin inhibited proliferation, cell migration and tube formation in HIMECs induced by VEGF. Activation of HIMECs by VEGF resulted in enhanced expression of cyclo-oxygenase-2 (COX-2) mRNA, protein and prostaglandin E(2) (PGE(2)) production. Pretreatment of HIMECs with 10 microM curcumin as well as 1 microM NS398, a selective inhibitor of COX-2, resulted in inhibition of COX-2 at the mRNA and protein level and PGE(2) production. Similarly COX-2 expression in HIMECs was significantly inhibited by Jun N-terminal kinase (JNK; SP600125) and p38 mitogen-activated protein kinase (MAPK; SB203580) inhibitors and was reduced by p44/42 MAPK inhibitor (PD098059). Taken together, these data demonstrate an important role for COX-2 in the regulation of angiogenesis in HIMECs via MAPKs. Moreover, curcumin inhibits microvascular endothelial cell angiogenesis through inhibition of COX-2 expression and PGE(2) production, suggesting that this natural product possesses antiangiogenic properties, which warrants further investigation as adjuvant treatment of IBD and cancer.

  8. Flowers of Clerodendrum volubile exacerbate immunomodulation by suppressing phagocytic oxidative burst and modulation of COX-2 activity.

    PubMed

    Erukainure, Ochuko L; Mesaik, Ahmed M; Muhammad, Aliyu; Chukwuma, Chika I; Manhas, Neha; Singh, Parvesh; Aremu, Oluwole S; Islam, Md Shahidul

    2016-10-01

    The immunomodulatory potentials of the crude methanolic extract and fractions [n-hexane (Hex), n-dichloromethane (DCM), ethyl acetate (EtOAc) and n-butanol (BuOH)] of Clerodendrum volubile flowers were investigated on whole blood phagocytic oxidative burst using luminol-amplified chemiluminescence technique. They were also investigated for their free radicals scavenging activities. The DCM fraction showed significant (p<0.05) anti-oxidative burst and free radical scavenging activities indicating high immunomodulatory and antioxidant potencies respectively. Cytotoxicity assay of the DCM fraction revealed a cytotoxic effect on CC-1 normal cell line. GCMS analysis revealed the presence of triacetin; 3,6-dimethyl-3-octanol; 2R - Acetoxymethyl-1,3,3-trimethtyl - 4t - (3-methyl-2-buten-1-yl) - 1c - cyclohexanol and Stigmastan - 3,5-diene in DCM fraction. These compounds were docked with the active sites of cyclooxygenase-2 (COX-2). Triacetin, 3,6-dimethyl-3-Octanol, and 2R-Acetoxymethyl-1,3,3-trimethtyl-4t-(3-methyl-2-buten-1-yl)-1c-cyclohexanol docked comfortably with COX-2 with good scoring function (-CDocker energy) indicating their inhibitory potency against COX-2. 3,6-dimethyl-3-Octanol, displayed the lowest predicted free energy of binding (-21.4kcalmol -1 ) suggesting its stronger interaction with COX-2, this was followed by 2R - Acetoxymethyl-1, 3, 3-trimethtyl-4t-(3-methyl-2-buten-1-yl)-1c-cyclhexanol (BE=-20.5kcalmol -1 ), and triacetin (BE=-10.9kcalmol -1 ). Stigmastan - 3,5-diene failed to dock with COX-2. The observed suppressive effect of the DCM fraction of C. volubile flower methanolic extract on phagocytic oxidative burst indicates an immunomodulatory potential. This is further reflected in its free scavenging activities and synergetic modulation of COX-2 activities by its identified compounds in silico. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Cyclical DNA Methylation and Histone Changes Are Induced by LPS to Activate COX-2 in Human Intestinal Epithelial Cells

    PubMed Central

    Brancaccio, Mariarita; Coretti, Lorena; Florio, Ermanno; Pezone, Antonio; Calabrò, Viola; Falco, Geppino; Keller, Simona; Lembo, Francesca; Avvedimento, Vittorio Enrico; Chiariotti, Lorenzo

    2016-01-01

    Bacterial lipopolysaccharide (LPS) induces release of inflammatory mediators both in immune and epithelial cells. We investigated whether changes of epigenetic marks, including selected histone modification and DNA methylation, may drive or accompany the activation of COX-2 gene in HT-29 human intestinal epithelial cells upon exposure to LPS. Here we describe cyclical histone acetylation (H3), methylation (H3K4, H3K9, H3K27) and DNA methylation changes occurring at COX-2 gene promoter overtime after LPS stimulation. Histone K27 methylation changes are carried out by the H3 demethylase JMJD3 and are essential for COX-2 induction by LPS. The changes of the histone code are associated with cyclical methylation signatures at the promoter and gene body of COX-2 gene. PMID:27253528

  10. Hexavalent Chromium Cr(VI) Up-Regulates COX-2 Expression through an NFκB/c-Jun/AP-1–Dependent Pathway

    PubMed Central

    Zuo, Zhenghong; Cai, Tongjian; Li, Jingxia; Zhang, Dongyun; Yu, Yonghui

    2012-01-01

    Background: Hexavalent chromium [Cr(VI)] is recognized as a human carcinogen via inhalation. However, the molecular mechanisms by which Cr(VI) causes cancers are not well understood. Objectives: We evaluated cyclooxygenase-2 (COX-2) expression and the signaling pathway leading to this induction due to Cr(VI) exposure in cultured cells. Methods: We used the luciferase reporter assay and Western blotting to determine COX-2 induction by Cr(VI). We used dominant negative mutant, genetic knockout, gene knockdown, and chromatin immunoprecipitation approaches to elucidate the signaling pathway leading to COX-2 induction. Results: We found that Cr(VI) exposure induced COX-2 expression in both normal human bronchial epithelial cells and mouse embryonic fibroblasts in a concentration- and time-dependent manner. Deletion of IKKβ [inhibitor of transcription factor NFκB (IκB) kinase β; an upstream kinase responsible for nuclear factor κB (NFκB) activation] or overexpression of TAM67 (a dominant-negative mutant of c-Jun) dramatically inhibited the COX-2 induction due to Cr(VI), suggesting that both NFκB and c-Jun/AP-1 pathways were required for Cr(VI)-induced COX-2 expression. Our results show that p65 and c-Jun are two major components involved in NFκB and AP-1 activation, respectively. Moreover, our studies suggest crosstalk between NFκB and c-Jun/AP-1 pathways in cellular response to Cr(VI) exposure for COX-2 induction. Conclusion: We demonstrate for the first time that Cr(VI) is able to induce COX-2 expression via an NFκB/c-Jun/AP-1–dependent pathway. Our results provide novel insight into the molecular mechanisms linking Cr(VI) exposure to lung inflammation and carcinogenesis. PMID:22472290

  11. Correlation analysis between expression of PCNA, Ki-67 and COX-2 and X-ray features in mammography in breast cancer.

    PubMed

    Qiu, Xiaoming; Mei, Jixin; Yin, Jianjun; Wang, Hong; Wang, Jinqi; Xie, Ming

    2017-09-01

    This study investigated expression of proliferating cell nuclear antigen (PCNA), proliferation-associated nuclear antigen (Ki-67) and cyclooxygenase-2 (COX-2) in tissues of breast invasive ductal carcinoma, and analyzed the correlations between these indexes and X-ray features in mammography. A total of 90 patients who were admitted to Huangshi Central Hospital and diagnosed as breast invasive ductal carcinoma from January 2014 to January 2016 were selected. The expression of PCNA, Ki-67 and COX-2 in cancer tissues and cancer-adjacent normal tissues of patients were detected by immunohistochemical staining, and X-ray features in mammography of patients were observed. By using Spearman correlation analysis, the correlations between expression of PCNA, Ki-67 and COX-2 and X-ray features in mammography in breast cancer were investigated. As a result, the positive expression rates of PCNA, Ki-67 and COX-2 in cancer tissues of the patient groups were respectively 42.2, 45.6 and 51.1%, which were significantly higher than those in cancer-adjacent normal tissues of the control group (p<0.05). PCNA, Ki-67 and COX-2 expression in cancer tissues of the patient group was associated with clinical staging and lymphatic metastasis (p<0.05), but had no correlation with age and tumor size (p>0.05). PCNA, Ki-67 and COX-2 expression in cancer tissues of the patient group had no correlation with the existence of lumps and localized density-increased shadows (p>0.05), but were associated with manifestations of architectural distortion, calcification as well as skin and nipple depression (p<0.05). Spearman correlation analysis revealed that there was a significantly positive correlation between the expression of PCNA and COX-2 in cancer tissues of the patient group (r=0.676, p<0.05); there was a significantly positive correlation between the expression of Ki-67 and COX-2 (r=0.724, p<0.05); PCNA expression had no obvious correlation with the expression of Ki-67 (p>0.05). In conclusion

  12. Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability

    PubMed Central

    Zago, Michela; Sheridan, Jared A.; Traboulsi, Hussein; Hecht, Emelia; Zhang, Yelu; Guerrina, Necola; Matthews, Jason; Nair, Parameswaran; Eidelman, David H.; Hamid, Qutayba

    2017-01-01

    Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients. PMID:28749959

  13. Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability.

    PubMed

    Zago, Michela; Sheridan, Jared A; Traboulsi, Hussein; Hecht, Emelia; Zhang, Yelu; Guerrina, Necola; Matthews, Jason; Nair, Parameswaran; Eidelman, David H; Hamid, Qutayba; Baglole, Carolyn J

    2017-01-01

    Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients.

  14. O-desmethylquinine as a cyclooxygenase-2 (COX-2) inhibitors using AutoDock Vina

    NASA Astrophysics Data System (ADS)

    Damayanti, Sophi; Mahardhika, Andhika Bintang; Ibrahim, Slamet; Chong, Wei Lim; Lee, Vannajan Sanghiran; Tjahjono, Daryono Hadi

    2014-10-01

    Computational approach was employed to evaluate the biological activity of novel cyclooxygenase-2 COX-2 inhibitor, O-desmethylquinine, in comparison to quinine as common inhibitor which can also be used an agent of antipyretic, antimalaria, analgesic and antiinflamation. The molecular models of the compound were constructed and optimized with the density function theory with at the B3LYP/6-31G (d,p) level using Gaussian 09 program. Molecular docking studies of the compounds were done to obtain the COX-2 complex structures and their binding energies were analyzed using the AutoDock Vina. The results of docking of the two ligands were comparable and cannot be differentiated from the energy scoring function with AutoDock Vina.

  15. Higher aluminum concentration in Alzheimer's disease after Box-Cox data transformation.

    PubMed

    Rusina, Robert; Matěj, Radoslav; Kašparová, Lucie; Kukal, Jaromír; Urban, Pavel

    2011-11-01

    Evidence regarding the role of mercury and aluminum in the pathogenesis of Alzheimer's disease (AD) remains controversial. The aims of our project were to investigate the content of the selected metals in brain tissue samples and the use of a specific mathematical transform to eliminate the disadvantage of a strong positive skew in the original data distribution. In this study, we used atomic absorption spectrophotometry to determine mercury and aluminum concentrations in the hippocampus and associative visual cortex of 29 neuropathologically confirmed AD and 27 age-matched controls. The Box-Cox data transformation was used for statistical evaluation. AD brains had higher mean aluminum concentrations in the hippocampus than controls (0.357 vs. 0.090 μg/g; P = 0.039) after data transformation. Results for mercury were not significant. Original data regarding microelement concentrations are heavily skewed and do not pass the normality test in general. A Box-Cox transformation can eliminate this disadvantage and allow parametric testing.

  16. Comparison of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 (COX-2) inhibitors use in Australia and Nova Scotia (Canada)

    PubMed Central

    Barozzi, Nadia; Sketris, Ingrid; Cooke, Charmaine; Tett, Susan

    2009-01-01

    AIMS Cyclooxygenase-2 (COX-2) inhibitors were marketed aggressively and their rapid uptake caused safety concerns and budgetary challenges in Canada and Australia. The objectives of this study were to compare and contrast COX-2 inhibitors and nonselective nonsteroidal anti-inflammatory drug (ns-NSAID) use in Nova Scotia (Canada) and Australia and to identify lessons learned from the two jurisdictions. METHODS Ns-NSAID and COX-2 inhibitor Australian prescription data (concession beneficiaries) were downloaded from the Medicare Australia website (2001–2006). Similar Pharmacare data were obtained for Nova Scotia (seniors and those receiving Community services). Defined daily doses per 1000 beneficiaries day−1 were calculated. COX-2 inhibitors/all NSAIDs ratios were calculated for Australia and Nova Scotia. Ns-NSAIDs were divided into low, moderate and high risk for gastrointestinal side-effects and the proportions of use in each group were determined. Which drugs accounted for 90% of use was also calculated. RESULTS Overall NSAID use was different in Australia and Nova Scotia. However, ns-NSAID use was similar. COX-2 inhibitor dispensing was higher in Australia. The percentage of COX-2 inhibitor prescriptions over the total NSAID use was different in the two countries. High-risk NSAID use was much higher in Australia. Low-risk NSAID prescribing increased in Nova Scotia over time. The low-risk/high-risk ratio was constant throughout over the period in Australia and increased in Nova Scotia. CONCLUSIONS There are significant differences in Australia and Nova Scotia in use of NSAIDs, mainly due to COX-2 prescribing. Nova Scotia has a higher proportion of low-risk NSAID use. Interventions to provide physicians with information on relative benefits and risks of prescribing specific NSAIDs are needed, including determining their impact. PMID:19660008

  17. Persistency of use of COX-2-specific inhibitors and non-specific non-steroidal anti-inflammatory drugs (NSAIDs) in Quebec.

    PubMed

    Moride, Y; Ducruet, T; Rochon, S; Lavoie, F

    2003-11-01

    The effectiveness of pharmacological therapies is dependent in part on patient persistency with the prescribed therapeutic regimen. In the case of non-specific non-steroidal anti-inflammatory drugs (NSAIDs), effectiveness is often compromised by undesirable side-effects, poor compliance or discontinuation of therapy. While patterns of utilization of non-specific NSAIDs have been investigated, few data are available on the patterns of persistency for cyclooxygenase (COX)-2-specific inhibitors. This study used a provincial health-care system database in Quebec, Canada, to determine the duration of treatment in new users of COX-2-specific inhibitors and non-specific NSAIDs over the first 3 months of treatment, and to characterize the factors associated with treatment persistency. Results demonstrate that the median duration of treatment was longer among patients initially prescribed COX-2-specific inhibitors (30 days and 23 days for celecoxib and rofecoxib respectively) than in those prescribed non-selective NSAIDs (10 days). Although the percentage of patients remaining on COX-2-specific drugs declined over the course of treatment, few patients on either celecoxib or rofecoxib switched drugs, either to the other COX-2-specific inhibitor or to non-specific NSAIDs. Factors associated with persistent drug use were: COX-2-specific inhibitors, age, and the use of gastroprotective agents either at treatment initiation or during follow-up. Dosage, chronic disease score and prescriber's specialty were only marginally associated with persistency. Prior use of gastroprotective agents was associated with lower persistency. Although the limitations of this study, which included lack of information on the indication for the prescription and the reason for switch or discontinuation, preclude definite conclusions regarding patterns of use of these drugs, the data suggest that the use of COX-2-specific inhibitors may result in increased persistency with treatment.

  18. Korean Red Ginseng water extract inhibits COX-2 expression by suppressing p38 in acrolein-treated human endothelial cells

    PubMed Central

    Lee, Seung Eun; Park, Yong Seek

    2013-01-01

    Cigarette smoke is considered a major risk factor for vascular diseases. There are many toxic compounds in cigarette smoke, including acrolein and other α,β-unsaturated aldehydes, which are regarded as mediators of inflammation and vascular dysfunction. Furthermore, recent studies have revealed that acrolein, an α,β-unsaturated aldehyde in cigarette smoke, induces inflammatory mediator expression, which is known to be related to vascular diseases. In this study, we investigated whether Korean Red Ginseng (KRG) water extract suppressed acrolein-induced cyclooxygenase (COX)-2 expression in human umbilical vein endothelial cells (HUVECs). Acrolein-induced COX-2 expression was accompanied by increased levels of phosphorylated p38 in HUVECs and KRG inhibited COX-2 expression in HUVECs. These results suggest that KRG suppresses acrolein-induced COX-2 expression via inhibition of the p38 mitogen-activated protein kinase signaling pathway. In addition, KRG exhibited an inhibitory effect on acrolein-induced apoptosis, as demonstrated by annexin V–propidium iodide staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. Consistent with these results, KRG may exert a vasculoprotective effect through inhibition of COX-2 expression in acrolein-stimulated human endothelial cells. PMID:24558308

  19. Angiotensin-(1-7)-Induced Plasticity Changes in the Lateral Amygdala Are Mediated by COX-2 and NO

    ERIC Educational Resources Information Center

    Albrecht, Doris

    2007-01-01

    It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we…

  20. Genomic selection for slaughter age in pigs using the Cox frailty model.

    PubMed

    Santos, V S; Martins Filho, S; Resende, M D V; Azevedo, C F; Lopes, P S; Guimarães, S E F; Glória, L S; Silva, F F

    2015-10-19

    The aim of this study was to compare genomic selection methodologies using a linear mixed model and the Cox survival model. We used data from an F2 population of pigs, in which the response variable was the time in days from birth to the culling of the animal and the covariates were 238 markers [237 single nucleotide polymorphism (SNP) plus the halothane gene]. The data were corrected for fixed effects, and the accuracy of the method was determined based on the correlation of the ranks of predicted genomic breeding values (GBVs) in both models with the corrected phenotypic values. The analysis was repeated with a subset of SNP markers with largest absolute effects. The results were in agreement with the GBV prediction and the estimation of marker effects for both models for uncensored data and for normality. However, when considering censored data, the Cox model with a normal random effect (S1) was more appropriate. Since there was no agreement between the linear mixed model and the imputed data (L2) for the prediction of genomic values and the estimation of marker effects, the model S1 was considered superior as it took into account the latent variable and the censored data. Marker selection increased correlations between the ranks of predicted GBVs by the linear and Cox frailty models and the corrected phenotypic values, and 120 markers were required to increase the predictive ability for the characteristic analyzed.

  1. Role of spinal p38α and β MAPK in inflammatory hyperalgesia and spinal COX-2 expression

    PubMed Central

    Fitzsimmons, Bethany L.; Zattoni, Michela; Svensson, Camilla I.; Steinauer, Joanne; Hua, Xiao-Ying; Yaksh, Tony L.

    2010-01-01

    Pharmacological studies indicate that spinal p38 MAPK plays a role in the development of hyperalgesia. We investigated whether either the spinal isoform p38α or p38β is involved in peripheral inflammation-evoked pain state and increased expression of spinal COX-2. Using intrathecal antisense oligonucleotides, we show that hyperalgesia is prevented by downregulation of p38β but not p38α, while increases in spinal COX-2 protein expression at eight hours is mediated by both p38α and β isoforms. These data suggest that early activation of spinal p38β isoform may affect acute facilitatory processing, and both p38β and α isforms mediate temporally delayed upregulation of spinal COX-2. PMID:20134354

  2. miR-143 decreases COX-2 mRNA stability and expression in pancreatic cancer cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pham, Hung; Department of Medicine, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA 90073; Ekaterina Rodriguez, C.

    2013-09-13

    Highlights: •Pancreatic cancer cells express low miR-143 levels and elevated p-MEK, p-MAPK and RREB1. •MEK inhibitors U0126 and PD98059 increase miR-143 expression. •miR-143 decreases COX-2 mRNA stability and expression and PGE{sub 2}. •miR-143 decreases p-p38MAPK, p-MEK, p-MAPK and RREB1 expression. -- Abstract: Small non-coding RNAs, microRNAs (miRNA), inhibit the translation or accelerate the degradation of message RNA (mRNA) by targeting the 3′-untranslated region (3′-UTR) in regulating growth and survival through gene suppression. Deregulated miRNA expression contributes to disease progression in several cancers types, including pancreatic cancers (PaCa). PaCa tissues and cells exhibit decreased miRNA, elevated cyclooxygenase (COX)-2 and increased prostaglandinmore » E{sub 2} (PGE{sub 2}) resulting in increased cancer growth and metastases. Human PaCa cell lines were used to demonstrate that restoration of miRNA-143 (miR-143) regulates COX-2 and inhibits cell proliferation. miR-143 were detected at fold levels of 0.41 ± 0.06 in AsPC-1, 0.20 ± 0.05 in Capan-2 and 0.10 ± 0.02 in MIA PaCa-2. miR-143 was not detected in BxPC-3, HPAF-II and Panc-1 which correlated with elevated mitogen-activated kinase (MAPK) and MAPK kinase (MEK) activation. Treatment with 10 μM of MEK inhibitor U0126 or PD98059 increased miR-143, respectively, by 187 ± 18 and 152 ± 26-fold in BxPC-3 and 182 ± 7 and 136 ± 9-fold in HPAF-II. miR-143 transfection diminished COX-2 mRNA stability at 60 min by 2.6 ± 0.3-fold in BxPC-3 and 2.5 ± 0.2-fold in HPAF-II. COX-2 expression and cellular proliferation in BxPC-3 and HPAF-II inversely correlated with increasing miR-143. PGE{sub 2} levels decreased by 39.3 ± 5.0% in BxPC-3 and 48.0 ± 3.0% in HPAF-II transfected with miR-143. Restoration of miR-143 in PaCa cells suppressed of COX-2, PGE{sub 2}, cellular proliferation and MEK/MAPK activation, implicating this pathway in regulating miR-143 expression.« less

  3. MicroRNA-143 suppresses gastric cancer cell growth and induces apoptosis by targeting COX-2

    PubMed Central

    Wu, Xiao-Li; Cheng, Bin; Li, Pei-Yuan; Huang, Huan-Jun; Zhao, Qiu; Dan, Zi-Li; Tian, De-An; Zhang, Peng

    2013-01-01

    AIM: To investigate the function of microRNA-143 (miR-143) in gastric cancer and explore the target genes of miR-143. METHODS: A quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed to evaluate miR-143 expression in gastric cancer cell lines. After transfecting gastric cancer cells with miR-143-5p and miR-143-3p precursors, Alamar blue and apoptosis assays were used to measure the respective proliferation and apoptosis rates. Cyclooxygenase-2 (COX-2) expression was determined by real-time RT-PCR and Western blot assays after miR-143 transfection. Reporter plasmids were constructed, and a luciferase reporter assay was used to identify the miR-143 binding site on COX-2. RESULTS: Both miR-143-5p and miR-143-3p were significantly downregulated in multiple gastric cancer cell lines. Forced miR-143-5p and miR-143-3p expression in gastric cancer cells produced a profound cytotoxic effect. MiR-145-5p transfection into gastric cancer cells resulted in a greater growth inhibitory effect (61.23% ± 3.16% vs 46.58% ± 4.28%, P < 0.05 in the MKN-1 cell line) and a higher apoptosis rate (28.74% ± 1.93% vs 22.13% ± 3.31%, P < 0.05 in the MKN-1 cell line) than miR-143-3p transfection. Further analysis indicated that COX-2 expression was potently suppressed by miR-143-5p but not by miR-143-3p. The activity of a luciferase reporter construct that contained the 3’-untranslated region (UTR) of COX-2 was downregulated by miR-143-5p (43.6% ± 4.86%, P < 0.01) but not by miR-143-3p. A mutation in the miR-145-5p binding site completely ablated the regulatory effect on luciferase activity, which suggests that there is a direct miR-145-5p binding site in the 3’-UTR of COX-2. CONCLUSION: Both miR-143-5p and miR-143-3p function as anti-oncomirs in gastric cancer. However, miR-143-5p alone directly targets COX-2, and it exhibits a stronger tumor suppressive effect than miR-143-3p. PMID:24616567

  4. Nancy B and Nancy F.

    PubMed

    Burkholder, L

    2001-01-01

    In this article I provide a virtuous slippery slope argument which shows that there is no morally significant difference between passive and active euthanasia. At the top of the slope is an example of passive euthanasia; at the bottom, an example of active euthanasia. For each pair of cases down the slope there is nothing that sensibly makes a morally significant difference between the pair of cases. Thus, there is no morally significant difference between passive euthanasia and active euthanasia.

  5. Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors.

    PubMed

    Grover, Jagdeep; Kumar, Vivek; Sobhia, M Elizabeth; Jachak, Sanjay M

    2014-10-01

    As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a-d, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC50's in 1.79-4.35μM range; COX-2 selectivity index (SI)=6.8-16.7 range). Compound 3b emerged as most potent (COX-2 IC50=1.79μM; COX-1 IC50 >30μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5h) in comparison to celecoxib (51.44% inhibition of edema at 5h) in carrageenan-induced rat paw edema assay. Structure-activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy

    PubMed Central

    Voora, Deepak; Ortel, Thomas L.; Lucas, Joseph E.; Chi, Jen-Tsan; Becker, Richard C.; Ginsburg, Geoffrey S.

    2012-01-01

    Objectives To develop an integrated metric of non COX-1 dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. Background NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. Methods We administered 325mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. Results The PFS strongly correlated with each measure of NCDPF in each cohort. After two or four weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, p<0.0001) and was higher (p < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final - Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = −0.45), HV2 (r = −0.54), DM (r = −0.68), p<0.0001 for all. AAA remained suppressed during aspirin therapy. Conclusions The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time. PMID:22294277

  7. New Coumarin Derivatives as Potent Selective COX-2 Inhibitors: Synthesis, Anti-Inflammatory, QSAR, and Molecular Modeling Studies.

    PubMed

    Dawood, Dina H; Batran, Rasha Z; Farghaly, Thoraya A; Khedr, Mohammed A; Abdulla, Mohamed M

    2015-12-01

    Two new series of coumarin derivatives incorporating thiazoline and thiazolidinone moieties were designed, synthesized, and investigated in vivo for their anti-inflammatory activities using the carrageenan-induced rat paw edema model and in vitro for their inhibitory activities against the human cyclooxygenase (COX)-1 and COX-2 isoforms. Most of the synthesized compounds demonstrated exceptionally high in vivo anti-inflammatory activity and displayed superior GI safety profiles (0-7% ulceration) as compared to indomethacin. All the bioactive compounds showed in vitro high affinity and selectivity toward the COX-2 isoenzyme, compared to the reference celecoxib with IC50 values ranging from 0.31 to 0.78 μM. The ethyl thiosemicarbazone 2b, thiazoline derivatives 3a, 3b, 5b, 6a, and 7f, and the thiazolidinone compounds 8b and 9a showed the highest in vivo and in vitro anti-inflammatory activities with remarkable COX-2 selectivity. Quantitative structure-activity relationship study (QSAR) was done and resulted in a highly predictive power R(2) (0.908). A molecular docking study revealed a relationship between the docking affinity and the biological results. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. The Cox proportional Hazard model on duration of birth process

    NASA Astrophysics Data System (ADS)

    Wuryandari, Triastuti; Haryatmi Kartiko, Sri; Danardono

    2018-05-01

    The duration of birth process, which is measured from the birth sign until baby born, is one important factor to the whole outcome of delivery process. There is a method of birth process that given relaxing and gentle treatment to the mother caled as gentlebirth. Gentlebirth is a method of birth process that combines brain science, birth science and technology to empower positive birth without pain. However the effect of method to the duration of birth process is still need empirical investigations. Therefore, the objective of this paper is to analyze the duration of birth process using the appropriate statistical methods for durational data, survival data or time to event data. Since there are many variables or factor that may affect the duration, a regression model is considerated. The flexibility of the Cox Proportional Hazard Model in the sense that there is no distributional assumption required, makes the Cox Model as the appropriate model and method to analyze the duration birth process. It is concluded that the Gentlebirth method affects on duration of birth process, with Hazard Ratio of 2.073, showing that the duration of birth process with gentlebirth method is faster than the other method.

  9. Antioxidative effects of cinnamomi cortex: A potential role of iNOS and COX-II

    PubMed Central

    Chung, Jin-Won; Kim, Jeong-Jun; Kim, Sung-Jin

    2011-01-01

    Background: Cinnamomi cortex has wide varieties of pharmacological actions such as anti-inflammatory action, anti-platelet aggregation, and improving blood circulation. In this study, we tested to determine whether the Cinnamomi cortex extract has antioxidant activities. Materials and Methods: Antioxidative actions were explored by measuring free radical scavenging activity, NO levels, and reducing power. The mechanism of antioxidative action of Cinnamomi cortex was determined by measuring iNOS and COX-II expression in lipopolysaccharide (LPS) stimulated Raw cells. Results: Seventy percent methanolic extract of Cinnamomi cortex exerted significant 1,1-diphenyl--2--picrylhydrazyl (DPPH) free radicals and NO scavenging activities in a dose-dependent manner. More strikingly, the Cinnamomi cortex extract exerted dramatic reducing power activity (13-fold over control). Production of iNOS induced by LPS was significantly inhibited by the Cinnamomi cortex extract, suggesting that it inhibits NO production by suppressing iNOS expression. Additionally, COX-2 induced by LPS was dramatically inhibited by the Cinnamomi cortex extract. Conclusion: These results suggest that 70% methanolic extract of Cinnamomi cortex exerts significant antioxidant activity via inhibiting iNOS and COX-II induction. PMID:22262934

  10. Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis.

    PubMed

    Benish, Marganit; Bartal, Inbal; Goldfarb, Yael; Levi, Ben; Avraham, Roi; Raz, Amiram; Ben-Eliyahu, Shamgar

    2008-07-01

    COX inhibitors and beta-blockers were recently suggested to reduce cancer progression through inhibition of tumor proliferation and growth factor secretion, induction of tumor apoptosis, and prevention of cellular immune suppression during the critical perioperative period. Here we evaluated the perioperative impact of clinically applicable drugs from these categories in the context of surgery, studying natural killer (NK) cell activity and resistance to experimental metastases. F344 rats were treated with COX-1 inhibitors (SC560), COX-2 inhibitors (indomethacin, etodolac, or celecoxib), a beta-blocker (propranolol), or a combination of a COX-2 inhibitor and a beta-blocker (etodolac and propranolol). Rats underwent laparotomy, and were inoculated intravenously with syngeneic MADB106 tumor cells for the assessment of lung tumor retention (LTR). Additionally, the impact of these drug regimens on postoperative levels of NK cytotoxicity was studied in peripheral blood and marginating-pulmonary leukocytes. Surgery increased MADB106 LTR. COX-2 inhibition, but not COX-1 inhibition, reduced postoperative LTR. Etodolac and propranolol both attenuated the deleterious impact of surgery, and their combined use abolished it. Surgery decreased NK cytotoxicity per NK cell in both immune compartments, and only the combination of etodolac and propranolol significantly attenuated these effects. Lastly, the initiation of drug treatment three days prior to surgery yielded the same beneficial effects as a single pre-operative administration, but, as discussed, prolonged treatment may be more advantageous clinically. Excess prostaglandin and catecholamine release contributes to postoperative immune-suppression. Treatment combining perioperative COX-2 inhibition and beta-blockade is practical in operated cancer patients, and our study suggests potential immunological and clinical benefits.

  11. [Identification of Clonorchis sinensis metacercariae based on PCR targeting ribosomal DNA ITS regions and COX1 gene].

    PubMed

    Yang, Qing-Li; Shen, Ji-Qing; Jiang, Zhi-Hua; Yang, Yi-Chao; Li, Hong-Mei; Chen, Ying-Dan; Zhou, Xiao-Nong

    2014-06-01

    To identify Clonorchis sinensis metacercariae using PCR targeting ribosomal DNA ITS region and COX1 gene. Pseudorasbora parva were collected from Hengxian County of Guangxi at the end of May 2013. Single metacercaria of C. sinensis and other trematodes were separated from muscle tissue of P. parva by digestion method. Primers targeting ribosomal DNA ITS region and COX1 gene of C. sinensis were designed for PCR and the universal primers were used as control. The sensitivity and specificity of the PCR detection were analyzed. C. sinensis metacercariae at different stages were identified by PCR. DNA from single C. sinensis metacercaria was detected by PCR targeting ribosomal DNA ITS region and COX1 gene. The specific amplicans have sizes of 437/549, 156/249 and 195/166 bp, respectively. The ratio of the two positive numbers in PCR with universal primers and specific primers targeting C. sinensis ribosomal DNA ITS1 and ITS2 regions was 0.905 and 0.952, respectively. The target gene fragments were amplified by PCR using COX1 gene-specific primers. The PCR with specific primers did not show any non-specific amplification. However, the PCR with universal primers targeting ribosomal DNA ITS regions performed serious non-specific amplification. C. sinensis metacercariae at different stages are identified by morphological observation and PCR method. Species-specific primers targeting ribosomal DNA ITS region show higher sensitivity and specificity than the universal primers. PCR targeting COX1 gene shows similar sensitivity and specificity to PCR with specific primers targeting ribosomal DNA ITS regions.

  12. Adenovirus-mediated suicide gene therapy under the control of Cox-2 promoter for colorectal cancer.

    PubMed

    Wang, Zhao-Xia; Bian, Hai-Bo; Yang, Jing-Song; De, Wei; Ji, Xiao-Hui

    2009-08-01

    Colorectal cancer is a most frequent type of gastrointestinal tract cancers. The prognosis of patients with colorectal cancer remains poor despite intensive interventions. Tumor specific promoter-directed gene therapy and adenoviral technology can be promising strategies for such advanced disease. This study was conducted to explore the possible therapeutic approach of Cox-2 promoter-directed suicide gene therapy with herpes simplex virus thymidine kinase (HSV-tk) in combination with adenoviral technology for advanced colorectal cancer. Firstly, the activity of Cox-2 promoter was assessed by dual luciferase and enhanced green fluorescent protein reporter gene assays in colorectal cancer cell lines and normal human intestinal epithelial cell line. Then, the expression of coxsackievirus and adenovirus receptor (CAR) was detected in colorectal cancer cell lines. The Cox-2 promoter-directed HSV-tk/ganciclovir (GCV) system mediated by adenovirus (Ad-Cp-TK) was developed (Ad-CMVp-TK, Ad-null and no Ad as controls). In vitro cytoxicity, colony formation and apoptosis assays were performed using Ad-Cp-TK. An animal study was carried out in which BALB/C nude mice bearing tumors were treated with Ad-Cp-TK and GCV treatments. Results showed that Cox-2 promoter possessed high transcriptional activity in a tumor-specific manner. All colorectal cancer cells were detected CAR-positive. In vitro cytotoxic and colony formation assays showed that colorectal cancer cells infected with Ad-Cp-TK became more sensitive to GCV but the sensitivity of normal cells infected with Ad-Cp-TK to GCV were not altered. Moreover, the Ad-Cp-TK system combined with GCV treatment could significantly induce apoptosis of colorectal cancer cells but not normal intestinal epithelial cells. Furthermore, this system also significantly inhibited the growth of subcutaneous tumors and prolonged survival of mice. Thus, adenovirus primary receptor was positive in colorectal cancer cells and adenovirus

  13. Global Gene Expression Analysis of Canine Osteosarcoma Stem Cells Reveals a Novel Role for COX-2 in Tumour Initiation

    PubMed Central

    Pang, Lisa Y.; Gatenby, Emma L.; Kamida, Ayako; Whitelaw, Bruce A.; Hupp, Ted R.; Argyle, David J.

    2014-01-01

    Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation. PMID:24416158

  14. Global gene expression analysis of canine osteosarcoma stem cells reveals a novel role for COX-2 in tumour initiation.

    PubMed

    Pang, Lisa Y; Gatenby, Emma L; Kamida, Ayako; Whitelaw, Bruce A; Hupp, Ted R; Argyle, David J

    2014-01-01

    Osteosarcoma is the most common primary bone tumour of both children and dogs. It is an aggressive tumour in both species with a rapid clinical course leading ultimately to metastasis. In dogs and children distant metastasis occurs in >80% of individuals treated by surgery alone. Both canine and human osteosarcoma has been shown to contain a sub-population of cancer stem cells (CSCs), which may drive tumour growth, recurrence and metastasis, suggesting that naturally occurring canine osteosarcoma could act as a preclinical model for the human disease. Here we report the successful isolation of CSCs from primary canine osteosarcoma, as well as established cell lines. We show that these cells can form tumourspheres, and demonstrate relative resistance to chemotherapy. We demonstrate similar results for the human osteosarcma cell lines, U2OS and SAOS2. Utilizing the Affymetrix canine microarray, we are able to definitively show that there are significant differences in global gene expression profiles of isolated osteosarcoma stem cells and the daughter adherent cells. We identified 13,221 significant differences (p = 0.05), and significantly, COX-2 was expressed 141-fold more in CSC spheres than daughter adherent cells. To study the role of COX-2 expression in CSCs we utilized the COX-2 inhibitors meloxicam and mavacoxib. We found that COX-2 inhibition had no effect on CSC growth, or resistance to chemotherapy. However inhibition of COX-2 in daughter cells prevented sphere formation, indicating a potential significant role for COX-2 in tumour initiation.

  15. Regularization Paths for Cox's Proportional Hazards Model via Coordinate Descent.

    PubMed

    Simon, Noah; Friedman, Jerome; Hastie, Trevor; Tibshirani, Rob

    2011-03-01

    We introduce a pathwise algorithm for the Cox proportional hazards model, regularized by convex combinations of ℓ 1 and ℓ 2 penalties (elastic net). Our algorithm fits via cyclical coordinate descent, and employs warm starts to find a solution along a regularization path. We demonstrate the efficacy of our algorithm on real and simulated data sets, and find considerable speedup between our algorithm and competing methods.

  16. The Influence of Glycosylation of Natural and Synthetic Prenylated Flavonoids on Binding to Human Serum Albumin and Inhibition of Cyclooxygenases COX-1 and COX-2.

    PubMed

    Tronina, Tomasz; Strugała, Paulina; Popłoński, Jarosław; Włoch, Aleksandra; Sordon, Sandra; Bartmańska, Agnieszka; Huszcza, Ewa

    2017-07-21

    The synthesis of different classes of prenylated aglycones (α,β-dihydroxanthohumol ( 2 ) and ( Z )-6,4'-dihydroxy-4-methoxy-7-prenylaurone ( 3 )) was performed in one step reactions from xanthohumol ( 1 )-major prenylated chalcone naturally occurring in hops. Obtained flavonoids ( 2 - 3 ) and xanthohumol ( 1 ) were used as substrates for regioselective fungal glycosylation catalyzed by two Absidia species and Beauveria bassiana . As a result six glycosides ( 4 - 9 ) were formed, of which four glycosides ( 6 - 9 ) have not been published so far. The influence of flavonoid skeleton and the presence of glucopyranose and 4- O -methylglucopyranose moiety in flavonoid molecule on binding to main protein in plasma, human serum albumin (HSA), and inhibition of cyclooxygenases COX-1 and COX-2 were investigated. Results showed that chalcone ( 1 ) had the highest binding affinity to HSA (8.624 × 10⁴ M -1 ) of all tested compounds. It has also exhibited the highest inhibition of cyclooxygenases activity, and it was a two-fold stronger inhibitor than α,β-dihydrochalcone ( 2 ) and aurone ( 3 ). The presence of sugar moiety in flavonoid molecule caused the loss of HSA binding activity as well as the decrease in inhibition of cyclooxygenases activity.

  17. Selecting risk factors: a comparison of discriminant analysis, logistic regression and Cox's regression model using data from the Tromsø Heart Study.

    PubMed

    Brenn, T; Arnesen, E

    1985-01-01

    For comparative evaluation, discriminant analysis, logistic regression and Cox's model were used to select risk factors for total and coronary deaths among 6595 men aged 20-49 followed for 9 years. Groups with mortality between 5 and 93 per 1000 were considered. Discriminant analysis selected variable sets only marginally different from the logistic and Cox methods which always selected the same sets. A time-saving option, offered for both the logistic and Cox selection, showed no advantage compared with discriminant analysis. Analysing more than 3800 subjects, the logistic and Cox methods consumed, respectively, 80 and 10 times more computer time than discriminant analysis. When including the same set of variables in non-stepwise analyses, all methods estimated coefficients that in most cases were almost identical. In conclusion, discriminant analysis is advocated for preliminary or stepwise analysis, otherwise Cox's method should be used.

  18. Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia

    PubMed Central

    2010-01-01

    Background Recent studies suggest an important role for neurotransmitters as modulators of inflammation. Neuroinflammatory mediators such as cytokines and molecules of the arachidonic acid pathway are generated and released by microglia. The monoamine norepinephrine reduces the production of cytokines by activated microglia in vitro. However, little is known about the effects of norepinephrine on prostanoid synthesis. In the present study, we investigate the role of norepinephrine on cyclooxygenase- (COX-)2 expression/synthesis and prostaglandin (PG)E2 production in rat primary microglia. Results Interestingly, norepinephrine increased COX-2 mRNA, but not protein expression. Norepinephrine strongly enhanced COX-2 expression and PGE2 production induced by lipopolysaccharide (LPS). This effect is likely to be mediated by β-adrenoreceptors, since β-, but not α-adrenoreceptor agonists produced similar results. Furthermore, β-adrenoreceptor antagonists blocked the enhancement of COX-2 levels induced by norepinephrine and β-adrenoreceptor agonists. Conclusions Considering that PGE2 displays different roles in neuroinflammatory and neurodegenerative disorders, norepinephrine may play an important function in the modulation of these processes in pathophysiological conditions. PMID:20064241

  19. A random effects meta-analysis model with Box-Cox transformation.

    PubMed

    Yamaguchi, Yusuke; Maruo, Kazushi; Partlett, Christopher; Riley, Richard D

    2017-07-19

    In a random effects meta-analysis model, true treatment effects for each study are routinely assumed to follow a normal distribution. However, normality is a restrictive assumption and the misspecification of the random effects distribution may result in a misleading estimate of overall mean for the treatment effect, an inappropriate quantification of heterogeneity across studies and a wrongly symmetric prediction interval. We focus on problems caused by an inappropriate normality assumption of the random effects distribution, and propose a novel random effects meta-analysis model where a Box-Cox transformation is applied to the observed treatment effect estimates. The proposed model aims to normalise an overall distribution of observed treatment effect estimates, which is sum of the within-study sampling distributions and the random effects distribution. When sampling distributions are approximately normal, non-normality in the overall distribution will be mainly due to the random effects distribution, especially when the between-study variation is large relative to the within-study variation. The Box-Cox transformation addresses this flexibly according to the observed departure from normality. We use a Bayesian approach for estimating parameters in the proposed model, and suggest summarising the meta-analysis results by an overall median, an interquartile range and a prediction interval. The model can be applied for any kind of variables once the treatment effect estimate is defined from the variable. A simulation study suggested that when the overall distribution of treatment effect estimates are skewed, the overall mean and conventional I 2 from the normal random effects model could be inappropriate summaries, and the proposed model helped reduce this issue. We illustrated the proposed model using two examples, which revealed some important differences on summary results, heterogeneity measures and prediction intervals from the normal random effects model. The

  20. Extended cox regression model: The choice of timefunction

    NASA Astrophysics Data System (ADS)

    Isik, Hatice; Tutkun, Nihal Ata; Karasoy, Durdu

    2017-07-01

    Cox regression model (CRM), which takes into account the effect of censored observations, is one the most applicative and usedmodels in survival analysis to evaluate the effects of covariates. Proportional hazard (PH), requires a constant hazard ratio over time, is the assumptionofCRM. Using extended CRM provides the test of including a time dependent covariate to assess the PH assumption or an alternative model in case of nonproportional hazards. In this study, the different types of real data sets are used to choose the time function and the differences between time functions are analyzed and discussed.

  1. Bootstrap-based methods for estimating standard errors in Cox's regression analyses of clustered event times.

    PubMed

    Xiao, Yongling; Abrahamowicz, Michal

    2010-03-30

    We propose two bootstrap-based methods to correct the standard errors (SEs) from Cox's model for within-cluster correlation of right-censored event times. The cluster-bootstrap method resamples, with replacement, only the clusters, whereas the two-step bootstrap method resamples (i) the clusters, and (ii) individuals within each selected cluster, with replacement. In simulations, we evaluate both methods and compare them with the existing robust variance estimator and the shared gamma frailty model, which are available in statistical software packages. We simulate clustered event time data, with latent cluster-level random effects, which are ignored in the conventional Cox's model. For cluster-level covariates, both proposed bootstrap methods yield accurate SEs, and type I error rates, and acceptable coverage rates, regardless of the true random effects distribution, and avoid serious variance under-estimation by conventional Cox-based standard errors. However, the two-step bootstrap method over-estimates the variance for individual-level covariates. We also apply the proposed bootstrap methods to obtain confidence bands around flexible estimates of time-dependent effects in a real-life analysis of cluster event times.

  2. Functional anion concept: effect of fluorine anion on hydrogen storage of sodium alanate.

    PubMed

    Yin, Li-Chang; Wang, Ping; Kang, Xiang-Dong; Sun, Cheng-Hua; Cheng, Hui-Ming

    2007-03-28

    Doping NaAlH(4) with Ti-catalyst has produced a promising hydrogen storage system that can be reversibly operated at moderate temperature conditions. Of the various dopant precursors, TiCl(3) was well recognized due to its pronounced catalytic effect on the reversible dehydrogenation processes of sodium aluminium hydrides. Quite recently we experimentally found that TiF(3) was even better than TiCl(3) in terms of the critical hydrogen storage properties of the doped hydrides, in particular the dehydriding performance at Na(3)AlH(6)/NaH + Al step at moderate temperature. We present here the DFT calculation results of the TiF(3) or TiCl(3) doped Na(3)AlH(6). Our computational studies have demonstrated that F(-) and Cl(-) anions differ substantially from each other with regard to the state and function in the doped sodium aluminium hydride. In great contrast to the case of chloride doping where Cl(-) anion constitutes the "dead weight" NaCl, the fluoride doping results in a substitution of H(-) by F(-) anion in the hydride lattice and accordingly, a favorable thermodynamics adjustment. These results well explain the observed dehydriding performance associated with TiF(3)/TiCl(3)-doping. More significantly, the coupled computational and experimental efforts allow us to put forward a "functional anion" concept. This renews the current mechanism understanding in the catalytically enhanced sodium alanate.

  3. Kirit C. Shah, M.D. v. Stan Harris and Nancy Harris. "Construction of Legal Arguments, Statutes of Limitations, and Medical Malpractice." Lesson Plans for Secondary Teachers on How Lawyers Prepare Their Arguments. Courts in the Classroom: Curriculum Concepts and Other Information on Indiana's Courts for the K-12 Educator.

    ERIC Educational Resources Information Center

    Osborn, Elizabeth

    Stan and Nancy Harris filed a complaint against Kirit C. Shah, M.D., for misdiagnosing Mr. Harris's illness, charging Dr. Shah with negligence and asking for damages. A medical malpractice action in Indiana is governed by a two year statute of limitations. Because the Harrises failed to bring their action against Dr. Shah within this two year…

  4. Evidence for a Pro-Proliferative Feedback Loop in Prostate Cancer: The Role of Epac1 and COX-2-Dependent Pathways

    PubMed Central

    Misra, Uma Kant; Pizzo, Salvatore Vincent

    2013-01-01

    Objective In human prostate cancer cells, a selective Epac agonist, 8-CPT-2Me-cAMP, upregulates cell proliferation and survival via activation of Ras-MAPK and PI- 3-kinase-Akt-mTOR signaling cascades. Here we examine the role of inflammatory mediators in Epac1-induced cellular proliferation by determining the expression of the pro-inflammatory markers p-cPLA2, COX-2, and PGE2 in prostate cancer cells treated with 8-CPT-2Me-cAMP. Methods We employed inhibitors of COX-2, mTORC1, and mTORC2 to probe cyclic AMP-dependent pathways in human prostate cancer cells. RNAi targeting Epac1, Raptor, and Rictor was also employed in these studies. Results 8-CPT-2Me-cAMP treatment caused a 2–2.5-fold increase of p-cPLA2S505, COX-2, and PGE2 levels in human prostate cancer cell lines. Pretreatment of cells with the COX-2 inhibitor SC-58125 or the EP4 antagonist AH-23848, or with an inhibitor of mTORC1 and mTORC2, Torin1, significantly reduced the Epac1-dependent increase of p-cPLA2 and COX-2, p-S6-kinaseT389, and p-AKTS473. In addition, Epac1-induced protein and DNA synthesis were greatly reduced upon pretreatment of cells with either COX-2, EP4, or mTOR inhibitors. Transfection of prostate cancer cells with Epac1 dsRNA, Raptor dsRNA, or Rictor dsRNA profoundly reduced Epac1-dependent increases in p-cPLA2 and COX-2. Conclusion We show that Epac1, a downstream effector of cAMP, functions as a pro-inflammatory modulator in prostate cancer cells and promotes cell proliferation and survival by upregulating Ras-MAPK, and PI 3-kinase-Akt-mTOR signaling. PMID:23646189

  5. Synergistic COX2 Induction by IFNγ and TNFα Self-Limits Type-1 Immunity in the Human Tumor Microenvironment.

    PubMed

    Wong, Jeffrey L; Obermajer, Nataša; Odunsi, Kunle; Edwards, Robert P; Kalinski, Pawel

    2016-04-01

    Maintenance of CTL-, Th1-, and NK cell-mediated type-1 immunity is essential for effective antitumor responses. Unexpectedly, we observed that the critical soluble mediators of type-1 immune effector cells, IFNγ and TNFα, synergize in the induction of cyclooxygenase 2 (COX2), the key enzyme in prostaglandin (PG)E2 synthesis, and the subsequent hyperactivation of myeloid-derived suppressor cells (MDSC) within the tumor microenvironment (TME) of ovarian cancer patients. MDSC hyperactivation by type-1 immunity and the resultant overexpression of indoleamine 2,3-dioxygenase (IDO), inducible nitric oxide synthase (iNOS/NOS2), IL10, and additional COX2 result in strong feedback suppression of type-1 immune responses. This paradoxical immune suppression driven by type-1 immune cell activation was found to depend on the synergistic action of IFNγ and TNFα, and could not be reproduced by either of these factors alone. Importantly, from a therapeutic standpoint, these negative feedback limiting type-1 responses could be eliminated by COX2 blockade, allowing amplification of type-1 immunity in the ovarian cancer TME. Our data demonstrate a new mechanism underlying the self-limiting nature of type-1 immunity in the human TME, driven by the synergistic induction of COX2 by IFNγ and TNFα, and provide a rationale for targeting the COX2-PGE2 axis to enhance the effectiveness of cancer immunotherapies. ©2016 American Association for Cancer Research.

  6. A novel sulindac derivative lacking COX-inhibitory activities suppresses carcinogenesis in the transgenic adenocarcinoma of mouse prostate model

    PubMed Central

    Zhang, Yong; Zhang, Jinhui; Wang, Lei; Quealy, Emily; Gary, Bernard D.; Reynolds, Robert C.; Piazza, Gary A.; Lü, Junxuan

    2016-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac are well-documented to be highly effective for cancer chemoprevention. However, their cyclooxygenase (COX) inhibitory activities cause severe gastrointestinal and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of the NSAIDs, and support the potential for development of a novel generation of sulindac derivatives lacking COX inhibition for cancer chemoprevention. A prototypic sulindac derivative with a N,N-dimethylammonium substitution, referred to as sulindac sulfide amide (SSA) was recently identified to be devoid of COX inhibitory activity yet displays much more potent tumor cell growth inhibitory activity in vitro compared to sulindac sulfide. In this study, we investigated the androgen receptor (AR) signaling pathway as a potential target for its COX-independent antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate carcinogenesis using the TRAMP mouse model. The results showed that SSA significantly suppressed the growth of human and mouse prostate cancer cells expressing AR in strong association with G1 arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption from 6 to 24 weeks of age dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression via repressing cell proliferation in the TRAMP mice, whereas it did not significantly impact neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis. PMID:20587701

  7. Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.

    PubMed

    Hallmann, Kerstin; Kudin, Alexei P; Zsurka, Gábor; Kornblum, Cornelia; Reimann, Jens; Stüve, Burkhard; Waltz, Stephan; Hattingen, Elke; Thiele, Holger; Nürnberg, Peter; Rüb, Cornelia; Voos, Wolfgang; Kopatz, Jens; Neumann, Harald; Kunz, Wolfram S

    2016-02-01

    Isolated cytochrome c oxidase (complex IV) deficiency is one of the most frequent respiratory chain defects in humans and is usually caused by mutations in proteins required for assembly of the complex. Mutations in nuclear-encoded structural subunits are very rare. In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy, we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV. The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript. The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts, similar to the frequent c.845_846delCT mutation in the assembly factor SURF1 gene. Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A. Our findings demonstrate that COX8A is indispensable for function of human complex IV and its mutation causes human disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. MicroRNA-144 is regulated by CP2 and decreases COX-2 expression and PGE2 production in mouse ovarian granulosa cells

    PubMed Central

    Zhou, Jiawei; Lei, Bin; Li, Huanan; Zhu, Lihua; Wang, Lei; Tao, Hu; Mei, Shuqi; Li, Fenge

    2017-01-01

    Mammalian folliculogenesis is a complex process in which primordial follicles develop into pre-ovulatory follicles, followed by ovulation to release mature oocytes. In this study, we explored the role of miR-144 in ovulation. miR-144 was one of the differentially expressed microRNAs, which showed 5.59-fold changes, in pre-ovulatory ovarian follicles between Large White and Chinese Taihu sows detected by Solexa deep sequencing. We demonstrated that overexpression of miR-144 significantly decreased the luciferase reporter activity under the control of the cyclooxygenase-2 (COX-2) or mothers against decapentaplegic homologue 4 (Smad4) 3'-untranslated region (3'-UTR) and suppressed COX-2 and Smad4 expression. In contrast, a miR-144 inhibitor increased COX-2 and Smad4 expression in mouse granulosa cells (mGCs). Meanwhile, Smad4 upregulated COX-2 expression, but this effect was abolished when the mGCs were treated with the transforming growth factor beta signalling pathway inhibitor SB431542. Moreover, luciferase reporter, chromatin immunoprecipitation and electrophoretic mobility shift assay results showed that the transcription factor CP2 upregulated miR-144 expression, which partially contributed to the suppression of COX-2 in mGCs. Both CP2 and miR-144 alter prostaglandin E2 (PGE2) production by regulating COX-2 expression. In addition, miR-144 regulated mGC apoptosis and affected follicular atresia, but these activities did not appear to be through COX-2 and Smad4. Taken together, we revealed an important CP2/miR-144/COX-2/PGE2/ovulation pathway in mGCs. PMID:28182010

  9. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression

    PubMed Central

    Liu, Fei; Mih, Justin D.; Shea, Barry S.; Kho, Alvin T.; Sharif, Asma S.; Tager, Andrew M.

    2010-01-01

    Tissue stiffening is a hallmark of fibrotic disorders but has traditionally been regarded as an outcome of fibrosis, not a contributing factor to pathogenesis. In this study, we show that fibrosis induced by bleomycin injury in the murine lung locally increases median tissue stiffness sixfold relative to normal lung parenchyma. Across this pathophysiological stiffness range, cultured lung fibroblasts transition from a surprisingly quiescent state to progressive increases in proliferation and matrix synthesis, accompanied by coordinated decreases in matrix proteolytic gene expression. Increasing matrix stiffness strongly suppresses fibroblast expression of COX-2 (cyclooxygenase-2) and synthesis of prostaglandin E2 (PGE2), an autocrine inhibitor of fibrogenesis. Exogenous PGE2 or an agonist of the prostanoid EP2 receptor completely counteracts the proliferative and matrix synthetic effects caused by increased stiffness. Together, these results demonstrate a dominant role for normal tissue compliance, acting in part through autocrine PGE2, in maintaining fibroblast quiescence and reveal a feedback relationship between matrix stiffening, COX-2 suppression, and fibroblast activation that promotes and amplifies progressive fibrosis. PMID:20733059

  10. ZN2+ INDUCES COX-2 EXPRESSION THROUGH DOWNREGULATION OF LIPID PHOSPHATASE PTEN

    EPA Science Inventory

    Zn2+ Induces COX-2 Expression through Downregulation of Lipid Phosphatase PTEN
    Weidong Wu*, James M. Samet, Philip A. Bromberg*?, Young E. Whang?, and Lee M. Graves* ?
    *CEMALB, ?Department of Medicine, and ?Department of Pharmacology, UNC-Chapel Hill, NC27599; Human Studie...

  11. Systematic revision of the mealybug genus Delottococcus Cox & Ben-Dov (Hemiptera: Pseudococcidae)

    USDA-ARS?s Scientific Manuscript database

    A systematic revision of the mealybug genus Delottococcus Cox & Ben-Dov is presented. Nine species are treated, including D. millari which is described as new. The 8 previously described species are: Delottococcus aberiae (De Lotto), D. confusus (De Lotto), D. elisabethae (Brain), D. euphorbiae (E...

  12. 2,3,5-Substituted tetrahydrofurans: COX-2 inhibitory activities of 5-hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols.

    PubMed

    Singh, Palwinder; Mittal, Anu; Kaur, Satwinderjeet; Kumar, Subodh

    2008-12-01

    5-Hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols have been investigated for their COX-1 and COX-2 inhibitory activities. Compounds 17, 18 and 20 have been identified as showing appreciable COX-2 inhibition and selectivity. The group present at C-5 of tetrahydrofuran and the substituents at the two phenyl rings, through their interactions with active site amino acid residues, significantly affect the activities of these molecules. The quantitative structure-activity relationship studies indicate the role of logP, TPSA, molecular connectivity and valence connectivity towards the activities of these molecules.

  13. Regulatory effect of the AMPK-COX-2 signaling pathway in curcumin-induced apoptosis in HT-29 colon cancer cells.

    PubMed

    Lee, Yun-Kyoung; Park, Song Yi; Kim, Young-Min; Park, Ock Jin

    2009-08-01

    AMP-activated protein kinase (AMPK), a highly conserved protein in eukaryotes, functions as a major metabolic switch to maintain energy homeostasis. It also intrinsically regulates the mammalian cell cycle. Moreover, the AMPK cascade has emerged as an important pathway implicated in cancer control. In this study we investigated the effects of curcumin on apoptosis and the regulatory effect of the AMPK-cyclooxygenase-2 (COX-2) pathway in curcumin-induced apoptosis. Curcumin has shown promise as a chemopreventive agent because of its in vivo regression of various animal-model colon cancers. This study focused on exploiting curcumin to apply antitumorigenic effects through modulation of the AMPK-COX-2 cascade. Curcumin exhibited a potent apoptotic effect on HT-29 colon cancer cells at concentrations of 50 micromol/L and above. These apoptotic effects were correlated with the decrease in pAkt and COX-2, as well as the increase in p-AMPK. Cell cycle analysis showed that curcumin induced G(1)-phase arrest. Further study with AMPK synthetic inhibitor Compound C has shown that increased concentrations of Compound C would abolish AMPK expression, accompanied by a marked increase in COX-2 as well as pAkt expression in curcumin-treated HT-29 cells. By inhibiting AMPK with Compound C, we found that curcumin-treated colon cancer cells were no longer undergoing apoptosis; rather, they were proliferative. These results indicate that AMPK is crucial in apoptosis induced by curcumin and further that the pAkt-AMPK-COX-2 cascade or AMPK-pAkt-COX-2 pathway is important in cell proliferation and apoptosis in colon cancer cells.

  14. Indomethacin-Induced Apoptosis in Esophageal Adenocarcinoma Cells Involves Upregulation of Bax and Translocation of Mitochondrial Cytochrome C Independent of COX-2 Expression1

    PubMed Central

    Aggarwal, Sanjeev; Taneja, Neelam; Lin, Lin; Orringer, Mark B; Rehemtulla, Alnawaz; Beer, David G

    2000-01-01

    Abstract The prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to exert a chemopreventive effect in esophageal and other gastrointestinal tumors. The precise mechanism by which this occurs, however, is unknown. While the inhibition of COX-2 as a potential explanation for this chemopreventive effect has gained a great deal of support, there also exists evidence supporting the presence of cyclooxygenase-independent pathways through which NSAIDs may exert their effects. In this study, immunohistochemical analysis of 29 Barrett's epithelial samples and 60 esophageal adenocarcinomas demonstrated abundant expression of the COX-2 protein in Barrett's epithelium, but marked heterogeneity of expression in esophageal adenocarcinomas. The three esophageal adenocarcinoma cell lines, Flo-1, Bic-1, and Seg-1, also demonstrated varying expression patterns for COX-1 and COX-2. Indomethacin induced apoptosis in all three cell lines, however, in both a time- and dose-dependent manner. In Flo-1 cells, which expressed almost undetectable levels of COX-1 and COX-2, and in Seg-1, which expressed significant levels of COX-1 and COX-2, indomethacin caused upregulation of the pro-apoptotic protein Bax. The upregulation of Bax was accompanied by the translocation of mitochondrial cytochrome c to the cytoplasm, and activation of caspase 9. Pre-treatment of both cell lines with the specific caspase 9 inhibitor, z-LEHD-FMK, as well as the broad-spectrum caspase inhibitor, z-VAD-FMK, blocked the effect of indomethacin-induced apoptosis. These data demonstrate that induction of apoptosis by indomethacin in esophageal adenocarcinoma cells is associated with the upregulation of Bax expression and mitochondrial cytochrome c translocation, and does not correlate with the expression of COX-2. This may have important implications for identifying new therapeutic targets in this deadly disease. PMID:11005569

  15. Aggravation of Alzheimer's disease due to the COX-2-mediated reciprocal regulation of IL-1β and Aβ between glial and neuron cells.

    PubMed

    Wang, Pu; Guan, Pei-Pei; Wang, Tao; Yu, Xin; Guo, Jian-Jun; Wang, Zhan-You

    2014-08-01

    Alzheimer's disease (AD) is the most common form of dementia and displays the characteristics of chronic neurodegenerative disorders; amyloid plaques (AP) that contain amyloid β-protein (Aβ) accumulate in AD, which is also characterized by tau phosphorylation. Epidemiological evidence has demonstrated that long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) markedly reduces the risk of AD by inhibiting the expression of cyclooxygenase 2 (COX-2). Although the levels of COX-2 and its metabolic product prostaglandin (PG)E2 are elevated in the brain of AD patients, the mechanisms for the development of AD remain unknown. Using human- or mouse-derived glioblastoma and neuroblastoma cell lines as model systems, we delineated the signaling pathways by which COX-2 mediates the reciprocal regulation of interleukin-1β (IL-1β) and Aβ between glial and neuron cells. In glioblastoma cells, COX-2 regulates the synthesis of IL-1β in a PGE2 -dependent manner. Moreover, COX-2-derived PGE2 signals the activation of the PI3-K/AKT and PKA/CREB pathways via cyclic AMP; these pathways transactivate the NF-κB p65 subunit via phosphorylation at Ser 536 and Ser 276, leading to IL-1β synthesis. The secretion of IL-1β from glioblastoma cells in turn stimulates the expression of COX-2 in human or mouse neuroblastoma cells. Similar regulatory mechanisms were found for the COX-2 regulation of BACE-1 expression in neuroblastoma cells. More importantly, Aβ deposition mediated the inflammatory response of glial cells via inducing the expression of COX-2 in glioblastoma cells. These findings not only provide new insights into the mechanisms of COX-2-induced AD but also initially define the therapeutic targets of AD. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  16. Fatal hyperkalemia related to combined therapy with a COX-2 inhibitor, ACE inhibitor and potassium rich diet.

    PubMed

    Hay, Emile; Derazon, Hashmonai; Bukish, Natalia; Katz, Leonid; Kruglyakov, Igor; Armoni, Michael

    2002-05-01

    We describe the case of a 77-year old mildly hypertensive woman with no underlying renal disease who was admitted to the Emergency Department (ED) in a comatose state with fever. The patient had been on low dose enalapril and a potassium rich diet. Five days before admission, rofecoxib, a new selective COX-2 inhibitor nonsteroidal anti-inflammatory drug (NSAID), was added for leg pain. She was found to have severe hyperkalemia and died 90 min after her arrival. We cannot absolutely determine whether the COX-2 inhibitor was the dominant contributor to the development of hyperkalemia or the combination itself, with an intercurrent infection and some degree of dehydration. Physicians should be aware of this possible complication and only prescribe NSAIDs, including the new COX-2 drugs, to the elderly under close monitoring of kidney function and electrolyte tests.

  17. Increased COX-2 expression in epithelial and stromal cells of high mammographic density tissues and in a xenograft model of mammographic density.

    PubMed

    Chew, G L; Huo, C W; Huang, D; Hill, P; Cawson, J; Frazer, H; Hopper, J L; Haviv, I; Henderson, M A; Britt, K; Thompson, E W

    2015-08-01

    Mammographic density (MD) adjusted for age and body mass index is one of the strongest known risk factors for breast cancer. Given the high attributable risk of MD for breast cancer, chemoprevention with a safe and available agent that reduces MD and breast cancer risk would be beneficial. Cox-2 has been implicated in MD-related breast cancer risk, and was increased in stromal cells in high MD tissues in one study. Our study assessed differential Cox-2 expression in epithelial and stromal cells in paired samples of high and low MD human breast tissue, and in a validated xenograft biochamber model of MD. We also examined the effects of endocrine treatment upon Cox-2 expression in high and low MD tissues in the MD xenograft model. Paired high and low MD human breast tissue samples were immunostained for Cox-2, then assessed for differential expression and staining intensity in epithelial and stromal cells. High and low MD human breast tissues were separately maintained in biochambers in mice treated with Tamoxifen, oestrogen or placebo implants, then assessed for percentage Cox-2 staining in epithelial and stromal cells. Percentage Cox-2 staining was greater for both epithelial (p = 0.01) and stromal cells (p < 0.0001) of high compared with low MD breast tissues. In high MD biochamber tissues, percentage Cox-2 staining was greater in stromal cells of oestrogen-treated versus placebo-treated tissues (p = 0.05).

  18. Evolution of structure and superconductivity in Ba(Ni 1 -xCox)2As2

    NASA Astrophysics Data System (ADS)

    Eckberg, Chris; Wang, Limin; Hodovanets, Halyna; Kim, Hyunsoo; Campbell, Daniel J.; Zavalij, Peter; Piccoli, Philip; Paglione, Johnpierre

    2018-06-01

    The effects of Co substitution on Ba (Ni1-xCox) 2As2 (0 ≤x ≤0.251 ) single crystals grown out of Pb flux are investigated via transport, magnetic, and thermodynamic measurements. BaNi2As2 exhibits a first-order tetragonal to triclinic structural phase transition at Ts=137 K upon cooling, and enters a superconducting phase below Tc=0.7 K. The structural phase transition is sensitive to cobalt content and is suppressed completely by x ≥0.133 . The superconducting critical temperature, Tc, increases continuously with x , reaching a maximum of Tc=2.3 K at x =0.083 and then decreases monotonically until superconductivity is no longer observable well into the tetragonal phase. In contrast to similar BaNi2As2 substitutional studies, which show an abrupt change in Tc at the triclinic-tetragonal boundary that extends far into the tetragonal phase, Ba (Ni1-xCox) 2As2 exhibits a domelike phase diagram centered around the zero-temperature tetragonal-triclinic boundary. Together with an anomalously large heat capacity jump Δ Ce/γ T ˜2.2 near optimal doping, the smooth evolution of Tc in the Ba (Ni1-xCox) 2As2 system suggests a mechanism for pairing enhancement other than phonon softening.

  19. Relationship between serum levels of triglycerides and vascular inflammation, measured as COX-2, in arteries from diabetic patients: a translational study

    PubMed Central

    2013-01-01

    Background Inflammation is a common feature in the majority of cardiovascular disease, including Diabetes Mellitus (DM). Levels of pro-inflammatory markers have been found in increasing levels in serum from diabetic patients (DP). Moreover, levels of Cyclooxygenase-2 (COX-2) are increased in coronary arteries from DP. Methods Through a cross-sectional design, patients who underwent CABG were recruited. Vascular smooth muscle cells (VSMC) were cultured and COX-2 was measured by western blot. Biochemical and clinical data were collected from the medical record and by blood testing. COX-2 expression was analyzed in internal mammary artery cross-sections by confocal microscopy. Eventually, PGI2 and PGE2 were assessed from VSMC conditioned media by ELISA. Results Only a high glucose concentration, but a physiological concentration of triglycerides exposure of cultured human VSMC derived from non-diabetic patients increased COX-2 expression .Diabetic patients showed increasing serum levels of glucose, Hb1ac and triglycerides. The bivariate analysis of the variables showed that triglycerides was positively correlated with the expression of COX-2 in internal mammary arteries from patients (r2 = 0.214, P < 0.04). Conclusions We conclude that is not the glucose blood levels but the triglicerydes leves what increases the expression of COX-2 in arteries from DP. PMID:23642086

  20. ELASTIC NET FOR COX'S PROPORTIONAL HAZARDS MODEL WITH A SOLUTION PATH ALGORITHM.

    PubMed

    Wu, Yichao

    2012-01-01

    For least squares regression, Efron et al. (2004) proposed an efficient solution path algorithm, the least angle regression (LAR). They showed that a slight modification of the LAR leads to the whole LASSO solution path. Both the LAR and LASSO solution paths are piecewise linear. Recently Wu (2011) extended the LAR to generalized linear models and the quasi-likelihood method. In this work we extend the LAR further to handle Cox's proportional hazards model. The goal is to develop a solution path algorithm for the elastic net penalty (Zou and Hastie (2005)) in Cox's proportional hazards model. This goal is achieved in two steps. First we extend the LAR to optimizing the log partial likelihood plus a fixed small ridge term. Then we define a path modification, which leads to the solution path of the elastic net regularized log partial likelihood. Our solution path is exact and piecewise determined by ordinary differential equation systems.

  1. Optical response of the sodium alanate system: GW0-BSE calculations and thin film measurements

    NASA Astrophysics Data System (ADS)

    van Setten, M. J.; Gremaud, R.; Brocks, G.; Dam, B.; Kresse, G.; de Wijs, G. A.

    2011-01-01

    We calculate from first principles the optical spectra of the hydrides in the sodium alanate hydrogen storage system: NaH, NaAlH4, and Na3AlH6. In particular we study the effects of systematic improvements of the theoretical description. To benchmark the calculations we also measure the optical response of a thin film of NaH. The simplest calculated dielectric functions are based upon independent electrons and holes, whose spectrum is obtained at the G0W0 level. Successive improvements consist of including partial self-consistency (so-called GW0) and account for excitonic effects, using the Bethe-Salpeter equation (BSE). Each improvement gives a sizable blue shift or red shift of the dielectric functions, but conserves the trend in the optical gap among different materials. Whereas these shifts partially cancel at the highest (GW0-BSE) level of approximation, the shape of the dielectric functions is strongly modified by excitonic effects. Calculations at the GW0-BSE level give a good agreement with the dielectric function of NaH extracted from the measurements. It demonstrates that the approach can be used for a quantitative interpretation of spectra in novel hydrogen storage materials obtained via, e.g., hydrogenography.

  2. Combined Analysis of COX-2 and p53 Expressions Reveals Synergistic Inverse Correlations with Microsatellite Instability and CpG Island Methylator Phenotype in Colorectal Cancer1

    PubMed Central

    Ogino, Shuji; Brahmandam, Mohan; Kawasaki, Takako; Kirkner, Gregory J; Loda, Massimo; Fuchs, Charles S

    2006-01-01

    Abstract Cyclooxygenase-2 (COX-2) overexpression and mutations of p53 (a known COX-2 regulator) are inversely associated with microsatellite instability—high (MSI-H) and CpG island methylator phenotype (CIMP), characterized by extensive promoter methylation, is associated with MSI-H. However, no studies have comprehensively examined interrelations between COX-2, p53, MSI, and CIMP. Using MethyLight, we measured DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16/INK4A), CRABP1, MLH1, and NEUROG1] in relatively unbiased samples of 751 colorectal cancer cases obtained from two large prospective cohorts; 115 (15%) tumors were CIMP-high (≥ 4 of 5 methylated promoters), 251 (33%) were CIMP-low (1 to 3 methylated promoters), and the remaining 385 (51%) were CIMP-0 (no methylated promoters). CIMP-high tumors were much less frequent in COX-2+/p53+ tumors (4.6%) than in COX-2+/p53- tumors (19%; P < .0001), COX-2-/p53+ tumors (17%; P= .04), and COX-2-/p53- tumors (28%; P < .0001). In addition, COX-2+/p53+ tumors were significantly less common in MSI-H CIMP-high tumors (9.7%) than in non-MSI-H CIMP-low/CIMP-0 tumors (44–47%; P< .0001). In conclusion, COX-2 and p53 alterations were synergistically inversely correlated with both MSI-H and CIMP-high. Our data suggest that a combined analysis of COX-2 and p53 may be more useful for the molecular classification of colorectal cancer than either COX-2 or p53 analysis alone. PMID:16820091

  3. Trimethylamine alane for low-pressure MOVPE growth of AlGaAs-based materials and device structures

    NASA Astrophysics Data System (ADS)

    Schneider, R. P.; Bryan, R. P.; Jones, E. D.; Biefield, R. M.; Olbright, G. R.

    The use of trimethylamine alane (TMAA1) as an alternative to trimethylaluminum (TMA1) for low-pressure metalorganic vapor-phase epitaxy (MOVPE) of AlGaAs thin films as well as complex optoelectronic device structures has been studied in detail. AlGaAs layers were grown in a horizontal reaction chamber at 20 - 110 mbar with growth temperatures in the range 650 C less than or equal to T(sub G) less than or equal to 750 C. Wafer thickness uniformity is strongly dependent on growth pressure, and is acceptable only for the highest linear flow velocities. The 12 K photoluminescence (PL) spectra of AlGaAs layers grown using TMAA1 and TEGa exhibit uniformly intense and narrow bound-exciton emission throughout the growth temperature range investigated. To assess the viability of this new source for the low-pressure OMVPE growth of advanced optoelectronic devices, several optically-pumped vertical-cavity surface-emitting laser (VCSEL) structures were grown using TMAA1 extensively. Room temperature lasing at 850 nm was reproducibly obtained from the VCSEL structures, with a threshold pumping power comparable to similar structures grown by molecular beam epitaxy in our laboratories.

  4. The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients.

    PubMed

    Morel, Agnieszka; Miller, Elzbieta; Bijak, Michal; Saluk, Joanna

    2016-09-01

    Platelet activation is increasingly postulated as a possible component of the pathogenesis of multiple sclerosis (MS), especially due to the increased risk of cardiovascular events in MS. Arachidonic acid cascade metabolized by cyclooxygenase (COX) is a key pathway of platelet activation. The aim of our study was to investigate the COX-dependent arachidonic acid metabolic pathway in blood platelets from secondary progressive multiple sclerosis (SP MS) patients. The blood samples were obtained from 50 patients (man n = 22; female n = 28), suffering from SP MS, diagnosed according to the revised McDonald criteria. Platelet aggregation was measured in platelet-rich plasma after arachidonic acid stimulation. The level of COX activity and thromboxane B2 concentration were determined by ELISA method. Lipid peroxidation was assessed by measuring the level of malondialdehyde. The results were compared with a control group of healthy volunteers. We found that blood platelets obtained from SP MS patients were more sensitive to arachidonic acid and their response measured as platelet aggregation was stronger (about 14 %) relative to control. We also observed a significantly increased activity of COX (about 40 %) and synthesis of thromboxane B2 (about 113 %). The generation of malondialdehyde as a marker of lipid peroxidation was about 10 % higher in SP MS than in control. Cyclooxygenase-dependent arachidonic acid metabolism is significantly increased in blood platelets of patients with SP MS. Future clinical studies are required to recommend the use of low-dose aspirin, and possibly other COX inhibitors in the prevention of cardiovascular risk in MS.

  5. COxSwAIN: Compressive Sensing for Advanced Imaging and Navigation

    NASA Technical Reports Server (NTRS)

    Kurwitz, Richard; Pulley, Marina; LaFerney, Nathan; Munoz, Carlos

    2015-01-01

    The COxSwAIN project focuses on building an image and video compression scheme that can be implemented in a small or low-power satellite. To do this, we used Compressive Sensing, where the compression is performed by matrix multiplications on the satellite and reconstructed on the ground. Our paper explains our methodology and demonstrates the results of the scheme, being able to achieve high quality image compression that is robust to noise and corruption.

  6. Thymoquinone suppresses migration of LoVo human colon cancer cells by reducing prostaglandin E2 induced COX-2 activation.

    PubMed

    Hsu, Hsi-Hsien; Chen, Ming-Cheng; Day, Cecilia Hsuan; Lin, Yueh-Min; Li, Shin-Yi; Tu, Chuan-Chou; Padma, Viswanadha Vijaya; Shih, Hui-Nung; Kuo, Wei-Wen; Huang, Chih-Yang

    2017-02-21

    To identify potential anti-cancer constituents in natural extracts that inhibit cancer cell growth and migration. Our experiments used high dose thymoquinone (TQ) as an inhibitor to arrest LoVo (a human colon adenocarcinoma cell line) cancer cell growth, which was detected by cell proliferation assay and immunoblotting assay. Low dose TQ did not significantly reduce LoVo cancer cell growth. Cyclooxygenase 2 (COX-2) is an enzyme that is involved in the conversion of arachidonic acid into prostaglandin E2 (PGE2) in humans. PGE2 can promote COX-2 protein expression and tumor cell proliferation and was used as a control. Our results showed that 20 μmol/L TQ significantly reduced human LoVo colon cancer cell proliferation. TQ treatment reduced the levels of p-PI3K, p-Akt, p-GSK3β, and β-catenin and thereby inhibited the downstream COX-2 expression. Results also showed that the reduction in COX-2 expression resulted in a reduction in PGE2 levels and the suppression of EP2 and EP4 activation. Further analysis showed that TG treatment inhibited the nuclear translocation of β-catenin in LoVo cancer cells. The levels of the cofactors LEF-1 and TCF-4 were also decreased in the nucleus following TQ treatment in a dose-dependent manner. Treatment with low dose TQ inhibited the COX-2 expression at the transcriptional level and the regulation of COX-2 expression efficiently reduced LoVo cell migration. The results were further verified in vivo by confirming the effects of TQ and/or PGE2 using tumor xenografts in nude mice. TQ inhibits LoVo cancer cell growth and migration, and this result highlights the therapeutic advantage of using TQ in combination therapy against colorectal cancer.

  7. The SK-N-AS human neuroblastoma cell line develops osteolytic bone metastases with increased angiogenesis and COX-2 expression

    PubMed Central

    Tsutsumimoto, Takahiro; Williams, Paul; Yoneda, Toshiyuki

    2014-01-01

    Neuroblastoma (NB), which arises from embryonic neural crest cells, is the most common extra-cranial solid tumor of childhood. Approximately half of NB patients manifest bone metastasis accompanied with bone pain, fractures and bone marrow failure, leading to disturbed quality of life and poor survival. To study the mechanism of bone metastasis of NB, we established an animal model in which intracardiac inoculation of the SK-N-AS human NB cells in nude mice developed osteolytic bone metastases with increased osteoclastogenesis. SK-N-AS cells induced the expression of receptor activator of NF-κB ligand and osteoclastogenesis in mouse bone marrow cells in the co-culture. SK-N-AS cells expressed COX-2 mRNA and produced substantial amounts of prostaglandin E2 (PGE2). In contrast, the SK-N-DZ and SK-N-FI human NB cells failed to develop bone metastases, induce osteoclastogenesis, express COX-2 mRNA and produce PGE2. Immunohistochemical examination of SK-N-AS bone metastasis and subcutaneous tumor showed strong expression of COX-2. The selective COX-2 inhibitor NS-398 inhibited PGE2 production and suppressed bone metastases with reduced osteoclastogenesis. NS-398 also inhibited subcutaneous SK-N-AS tumor development with decreased angiogenesis and vascular endothelial growth factor-A expression. Of interest, metastasis to the adrenal gland, a preferential site for NB development, was also diminished by NS-398. Our results suggest that COX2/PGE2 axis plays a critical role in the pathophysiology of osteolytic bone metastases and tumor development of the SK-NS-AS human NB. Inhibition of angiogenesis by suppressing COX-2/PGE2 may be an effective therapeutic approach for children with NB. PMID:26909300

  8. Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition

    PubMed Central

    van Helmond, Noud; Steegers, Monique A.; Filippini-de Moor, Gertie P.; Vissers, Kris C.; Wilder-Smith, Oliver H.

    2016-01-01

    Background Persistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia. Methods 138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months. Results 48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively. Conclusions Perioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of

  9. Up-regulated neuronal COX-2 expression after cortical spreading depression is involved in non-REM sleep induction in rats.

    PubMed

    Cui, Yilong; Kataoka, Yosky; Inui, Takashi; Mochizuki, Takatoshi; Onoe, Hirotaka; Matsumura, Kiyoshi; Urade, Yoshihiro; Yamada, Hisao; Watanabe, Yasuyoshi

    2008-03-01

    Cortical spreading depression is an excitatory wave of depolarization spreading throughout cerebral cortex at a rate of 2-5 mm/min and has been implicated in various neurological disorders, such as epilepsy, migraine aura, and trauma. Although sleepiness or sleep is often induced by these neurological disorders, the cellular and molecular mechanism has remained unclear. To investigate whether and how the sleep-wake behavior is altered by such aberrant brain activity, we induced cortical spreading depression in freely moving rats, monitoring REM and non-REM (NREM) sleep and sleep-associated changes in cyclooxygenase (COX)-2 and prostaglandins (PGs). In such a model for aberrant neuronal excitation in the cerebral cortex, the amount of NREM sleep, but not of REM sleep, increased subsequently for several hours, with an up-regulated expression of COX-2 in cortical neurons and considerable production of PGs. A specific inhibitor of COX-2 completely arrested the increase in NREM sleep. These results indicate that up-regulated neuronal COX-2 would be involved in aberrant brain excitation-induced NREM sleep via production of PGs. (c) 2007 Wiley-Liss, Inc.

  10. Assessing household health expenditure with Box-Cox censoring models.

    PubMed

    Chaze, Jean-Paul

    2005-09-01

    In order to assess the combined presence of zero expenditures and a heavily skewed distribution of positive expenditures, the Box-Cox transformation with location parameter is used to define a set of models generalising the standard Tobit, Heckman selection and double-hurdle models. Extended flexibility with respect to previous specifications is introduced, notably regarding negative transformation parameters, which may prove necessary for medical expenditures, and corner-solution outcomes. An illustration is provided by the analysis of household health expenditure in Switzerland. Copyright (c) 2005 John Wiley & Sons, Ltd.

  11. Late Results of Cox Maze III Procedure in Patients with Atrial Fibrillation Associated with Structural Heart Disease

    PubMed Central

    Gomes, Gustavo Gir; Gali, Wagner Luis; Sarabanda, Alvaro Valentim Lima; da Cunha, Claudio Ribeiro; Kessler, Iruena Moraes; Atik, Fernando Antibas

    2017-01-01

    Background Cox-Maze III procedure is one of the surgical techniques used in the surgical treatment of atrial fibrillation (AF). Objectives To determine late results of Cox-Maze III in terms of maintenance of sinus rhythm, and mortality and stroke rates. Methods Between January 2006 and January 2013, 93 patients were submitted to the cut-and-sew Cox-Maze III procedure in combination with structural heart disease repair. Heart rhythm was determined by 24-hour Holter monitoring. Procedural success rates were determined by longitudinal methods and recurrence predictors by multivariate Cox regression models. Results Thirteen patients that obtained hospital discharge alive were excluded due to lost follow-up. The remaining 80 patients were aged 49.9 ± 12 years and 47 (58.7%) of them were female. Involvement of mitral valve and rheumatic heart disease were found in 67 (83.7%) and 63 (78.7%) patients, respectively. Seventy patients (87.5%) had persistent or long-standing persistent AF. Mean follow-up with Holter monitoring was 27.5 months. There were no hospital deaths. Sinus rhythm maintenance rates were 88%, 85.1% and 80.6% at 6 months, 24 months and 36 months, respectively. Predictors of late recurrence of AF were female gender (HR 3.52; 95% CI 1.21-10.25; p = 0.02), coronary artery disease (HR 4.73 95% CI 1.37-16.36; p = 0.01) and greater left atrium diameter (HR 1.05; 95% CI 1.01-1.09; p = 0.02). Actuarial survival was 98.5% at 12, 24 and 48 months and actuarial freedom from stroke was 100%, 100% and 97.5% in the same time frames. Conclusions The Cox-Maze III procedure, in our experience, is efficacious for sinus rhythm maintenance, with very low late mortality and stroke rates. PMID:28678926

  12. The coxBAC Operon Encodes a Cytochrome c Oxidase Required for Heterotrophic Growth in the Cyanobacterium Anabaena variabilis Strain ATCC 29413

    PubMed Central

    Schmetterer, Georg; Valladares, Ana; Pils, Dietmar; Steinbach, Susanne; Pacher, Margit; Muro-Pastor, Alicia M.; Flores, Enrique; Herrero, Antonia

    2001-01-01

    Three genes, coxB, coxA, and coxC, found in a clone from a gene library of the cyanobacterium Anabaena variabilis strain ATCC 29413, were identified by hybridization with an oligonucleotide specific for aa3-type cytochrome c oxidases. Deletion of these genes from the genome of A. variabilis strain ATCC 29413 FD yielded strain CSW1, which displayed no chemoheterotrophic growth and an impaired cytochrome c oxidase activity. Photoautotrophic growth of CSW1, however, was unchanged, even with dinitrogen as the nitrogen source. A higher cytochrome c oxidase activity was detected in membrane preparations from dinitrogen-grown CSW1 than from nitrate-grown CSW1, but comparable activities of respiratory oxygen uptake were found in the wild type and in CSW1. Our data indicate that the identified cox gene cluster is essential for fructose-dependent growth in the dark, but not for growth on dinitrogen, and that other terminal respiratory oxidases are expressed in this cyanobacterium. Transcription analysis showed that coxBAC constitutes an operon which is expressed from two transcriptional start points. The use of one of them was stimulated by fructose. PMID:11591688

  13. Drug repurposing of novel quinoline acetohydrazide derivatives as potent COX-2 inhibitors and anti-cancer agents

    NASA Astrophysics Data System (ADS)

    Manohar, Chelli Sai; Manikandan, A.; Sridhar, P.; Sivakumar, A.; Siva Kumar, B.; Reddy, Sabbasani Rajasekhara

    2018-02-01

    Novel QuinolineAcetohydrazide (QAh) derivatives (9a-n) were firstly evaluated in silico to determine their anti-inflammatory and anti-cancer efficacy via the mechanisms of COX1 and COX2 inhibition, and NF-ĸB, HDAC and Human Topoisomerase I pathways respectively. In the studied set, the trifluoro substituted QAh derivatives: (E)-N'-(4-(trifluoro methyl) benzylidene)-2-(7-fluoro-2-methoxy quinolin-8-yl) acetohydrazid and (E)-N'-(3-(trifluoro methyl) benzylidene)-2-(7-fluoro-2-methoxy quinolin-8-yl) acetohydrazide are determined to be potential leads, indicated from their best docked scores, relative ligand efficiency, and significant structural attributes evaluated by ab initio simulations. The only setback being their partition co-efficient that retrieved a red flag in the evaluation of their Lipinski parameters. The experimental in vitro studies confirmed the significant enhancement as COX-2 inhibitors and appreciable enhancement in MTT assay of breast and skin cancer cell lines. Significantly, trifluoro substituent in the quinoline scaffold can be reasoned to note the excellent binding affinity to all the evaluated drug targets.

  14. Prognostic factors in multiple myeloma: selection using Cox's proportional hazard model.

    PubMed

    Pasqualetti, P; Collacciani, A; Maccarone, C; Casale, R

    1996-01-01

    The pretreatment characteristics of 210 patients with multiple myeloma, observed between 1980 and 1994, were evaluated as potential prognostic factors for survival. Multivariate analysis according to Cox's proportional hazard model identified in the 160 dead patients with myeloma, among 26 different single prognostic variables, the following factors in order of importance: beta 2-microglobulin; bone marrow plasma cell percentage, hemoglobinemia, degree of lytic bone lesions, serum creatinine, and serum albumin. By analysis of these variables a prognostic index (PI), that considers the regression coefficients derived by Cox's model of all significant factors, was obtained. Using this it was possible to separate the whole patient group into three stages: stage I (PI < 1.485, 67 patients), stage II (PI: 1.485-2.090, 76 patients), and stage III (PI > 2.090, 67 patients), with a median survivals of 68, 36 and 13 months (P < 0.0001), respectively. Also the responses to therapy (P < 0.0001) and the survival curves (P < 0.00001) presented significant differences among the three subgroups. Knowledge of these factors could be of value in predicting prognosis and in planning therapy in patients with multiple myeloma.

  15. Scientific familial lessons in ingestive behavior research: 2016 Alan N. Epstein research award.

    PubMed

    Hayes, Matthew R

    2017-07-01

    While energy balance is under the control of the central nervous system (CNS), a major source of neural regulation for the behavioral, physiological and endocrine processes governing energy balance originates in the periphery. Indeed, the organs of the gastrointestinal (GI) tract, supporting organs of the peritoneal cavity and adipose tissue are the source of numerous neurotransmitter and neuroendocrine signals released from non-neuronal peripheral tissue that signal in a paracrine and endocrine fashion to regulate the physiological and behavioral processes that affect energy balance. Given the ever increasing appreciation that chronic hyperphagia of highly-palatable/rewarding food is a major contributing factor to the obesity epidemic, it is not surprising that the field has increased research efforts focusing on understanding what role peripherally-derived neuroendocrine signals play in modulating food reward and motivated behaviors. Research throughout my career has focused on understanding gut-to-brain communication of relevance to energy balance control. Through very fortuitous opportunities and amazing collaborations, my research program has also expanded widely to include analyses of multiple GI-, pancreatic- and adipose tissue-derived anorectic signals involved in food intake and energy balance control, as well as analyses of higher-order determinants of food reward, nausea, aversion and maladaptive motivated behaviors. I am honored to be the recipient of the 2016 Alan N. Epstein Research Award from the Society for the Study of Ingestive Behavior, and express much appreciation for the amazing collaborations I have had with my mentors, colleagues and trainees. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Experiments to Determine Whether Recursive Partitioning (CART) or an Artificial Neural Network Overcomes Theoretical Limitations of Cox Proportional Hazards Regression

    NASA Technical Reports Server (NTRS)

    Kattan, Michael W.; Hess, Kenneth R.; Kattan, Michael W.

    1998-01-01

    New computationally intensive tools for medical survival analyses include recursive partitioning (also called CART) and artificial neural networks. A challenge that remains is to better understand the behavior of these techniques in effort to know when they will be effective tools. Theoretically they may overcome limitations of the traditional multivariable survival technique, the Cox proportional hazards regression model. Experiments were designed to test whether the new tools would, in practice, overcome these limitations. Two datasets in which theory suggests CART and the neural network should outperform the Cox model were selected. The first was a published leukemia dataset manipulated to have a strong interaction that CART should detect. The second was a published cirrhosis dataset with pronounced nonlinear effects that a neural network should fit. Repeated sampling of 50 training and testing subsets was applied to each technique. The concordance index C was calculated as a measure of predictive accuracy by each technique on the testing dataset. In the interaction dataset, CART outperformed Cox (P less than 0.05) with a C improvement of 0.1 (95% Cl, 0.08 to 0.12). In the nonlinear dataset, the neural network outperformed the Cox model (P less than 0.05), but by a very slight amount (0.015). As predicted by theory, CART and the neural network were able to overcome limitations of the Cox model. Experiments like these are important to increase our understanding of when one of these new techniques will outperform the standard Cox model. Further research is necessary to predict which technique will do best a priori and to assess the magnitude of superiority.

  17. Innovative application of Cox Flexion Distraction Decompression to the knee: a retrospective case series

    PubMed Central

    Albano, Luigi

    2017-01-01

    Objective The purpose of this study is to introduce the application of Cox flexion distraction decompression as an innovative approach to treating knee pain and osteoarthritis. Methods Six months of clinical files from one chiropractic practice were retrospectively screened for patients who had been treated for knee pain. Twenty-five patients met the criteria for inclusion. The treatment provided was Cox flexion distraction decompression. Pre-treatment and post-treatment visual analog pain scales (VAS) were used to measure the results. In total, eight patients presented with acute knee pain (less than three months’ duration) and 18 patients presented with chronic knee pain (greater than three months) including two patients with continued knee pain after prosthetic replacement surgery. Results For all 25 patients, a change was observed in the mean VAS scores from 7.7 to 1.8. The mean number of treatments was 5.3 over an average of 3.0 weeks. Acute patient mean VAS scores dropped from 8.1 to 1.1 within 4.8 treatments over 2.4 weeks. Chronic patient mean VAS scores dropped from 7.5 to 2.2 within 5.4 treatments over 3.3 weeks. No adverse events were reported. Conclusion This study showed clinical improvement in patients with knee pain who were managed with Cox flexion distraction decompression applied to the knee. PMID:28928498

  18. Relationship of clinical factors to the use of Cox-2 selective NSAIDs within an arthritis population in a large HMO.

    PubMed

    Bull, Scott A; Conell, Carol; Campen, David H

    2002-01-01

    To investigate the degree to which physicians use clinical factors to focus use of Cox-2 selective NSAIDs within an arthritis population. Diagnostic codes in the medical records of a large group-model HMO in northern California with approximately 3 million members were examined to identify patients with either rheumatoid arthritis (RA) or non-RA (osteoarthritis or degenerative joint disease). RA and non-RA patients were stratified in deciles of relative risk for gastrointestinal (GI) complications according to patient characteristics identified on the Standardized Calculator of Risk for Events (SCORE) that were associated with use of Cox-2 selective NSAIDs. (The SCORE tool stratifies patients by risk of serious GI complications using patient characteristics that are assigned points during an office visit, including age, health status, diagnosis of rheumatoid arthritis, corticosteroid use, and history of GI ulcer or bleed.) The second stage of analysis examined the percentage of arthritis patients in each SCORE-risk decile who received a Cox-2 selective NSAID, lower-risk NSAID, or traditional NSAID during calendar year 1999. The study population consisted of 144,360 members with an arthritis diagnosis, approximately 4.8% of members in this HMO. The mean age was 62.8 years (SD = 14.1), 61% were female, 10,449 (7%) had rheumatoid arthritis (RA), and 133,911 (93%) had non-rheumatoid arthritis. A diagnosis of RA was the most significant predictor of Cox-2 NSAID use (OR=2.4; 95% CI=1.6-3.5), followed by a history of GI problems (OR=1.5; 95% CI=1.4- 1.6). Female gender, chronic steroid use, and age each increased the odds of receiving a Cox-2 selective NSAID by about 35% (P<0.001 for all). Approximately 8.3% of patients in the highest decile of risk and 1.5% of patients in the lowest decile of risk received a Cox-2 selective NSAID. Clinical characteristics of patients identified on the SCORE (GI-risk) tool were strongly associated with use of Cox-2-selective NSAIDs in

  19. Comparative Proteomic Study of Fatty Acid-treated Myoblasts Reveals Role of Cox-2 in Palmitate-induced Insulin Resistance

    PubMed Central

    Chen, Xiulan; Xu, Shimeng; Wei, Shasha; Deng, Yaqin; Li, Yiran; Yang, Fuquan; Liu, Pingsheng

    2016-01-01

    Accumulated studies demonstrate that saturated fatty acids (FAs) such as palmitic acid (PA) inhibit insulin signaling in skeletal muscle cells and monounsaturated fatty acids such as oleic acid (OA) reverse the effect of PA on insulin signaling. The detailed molecular mechanism of these opposite effects remains elusive. Here we provide a comparative proteomic study of skeletal myoblast cell line C2C12 that were untreated or treated with PA, and PA plus OA. A total of 3437 proteins were quantified using SILAC in this study and 29 proteins fall into the pattern that OA reverses PA effect. Expression of some these proteins were verified using qRT-PCR and Western blot. The most significant change was cyclooxygenase-2 (Cox-2). In addition to whole cell comparative proteomic study, we also compared lipid droplet (LD)-associated proteins and identified that Cox-2 was one of three major altered proteins under the FA treatment. This finding was then confirmed using immunofluorescence. Finally, Cox-2 selective inhibitor, celecoxib protected cells from PA-reduced insulin signaling Akt phosphorylation. Together, these results not only provide a dataset of protein expression change in FA treatment but also suggest that Cox-2 and lipid droplets (LDs) are potential players in PA- and OA-mediated cellular processes. PMID:26899878

  20. DNA damage, p53, Ki-67 and COX-2 expression in rat tongue cells exposed to nandrolone decanoate.

    PubMed

    Pozzi, Renan; Fernandes, Kelly Rosseti; Foot Gomes de Moura, Carolina; Ferrari, Raquel Agnelli Mesquita; Fernandes, Kristianne Porta Santos; Chaves, Marcelo Donizeti; Renno, Ana Claudia Muniz; Ribeiro, Daniel Araki

    2013-05-01

    The objective of this article was to evaluate the impact potential of nandrolone decanoate on DNA damage, cellular regulatory proteins and cyclooxygenase (COX)-2 in oral mucosa cells of Wistar rats. A total of 40 rats were distributed into four groups. Two experimental groups were treated with nandrolone decanoate, at 5 mg/kg doses, subcutaneously, three times a week in two periods: 15 and 30 days. The remaining groups received only 0.9% saline subcutaneously, three times a week. To evaluate genetic damage, nandrolone decanoate at 15 mg/kg dose was exposed to 24 h. In the histopathological analysis, no remarkable morphological changes were observed in tongue tissue in all groups. Significant increase in immunoexpression of Ki-67, p53, COX-2 proteins was detected in the groups treated with nandrolone decanoate during 15 and 30 days, when compared to their respective controls. A positive correlation between immunoexpression of p53 and COX-2 protein was detected following nandrolone decanoate exposure. DNA damage was induced by nandrolone decanoate in oral mucosa cells at 15 mg/kg dose. Our results suggest that nandrolone decanoate was able to alter the expression of cell cycle-related proteins, as well as to induce genetic damage and COX-2 immunoexpression in tongue cells of Wistar rats.

  1. A Cross-Talk Between NFAT and NF-κB Pathways is Crucial for Nickel-Induced COX-2 Expression in Beas-2B Cells

    PubMed Central

    Cai, T.; Li, X.; Ding, J.; Luo, W.; Li, J.; Huang, C.

    2013-01-01

    Cyclooxygenase-2 (COX-2) is a critical enzyme implicated in chronic inflammation-associated cancer development. Our studies have shown that the exposure of Beas-2B cells, a human bronchial epithelial cell line, to lung carcinogenic nickel compounds results in increased COX-2 expression. However, the signaling pathways leading to nickel-induced COX-2 expression are not well understood. In the current study, we found that the exposure of Beas-2B cells to nickel compounds resulted in the activation of both nuclear factor of activated T cell (NFAT) and nuclear factor-κB (NF-κB). The expression of COX-2 induced upon nickel exposure was inhibited by either a NFAT pharmacological inhibitor or the knockdown of NFAT3 by specific siRNA. We further found that the activation of NFAT and NF-κB was dependent on each other. Since our previous studies have shown that NF-κB activation is critical for nickel-induced COX-2 expression in Beas-2B cells exposed to nickel compounds under same experimental condition, we anticipate that there might be a cross-talk between the activation of NFAT and NF-κB for the COX-2 induction due to nickel exposure in Beas-2B cells. Furthermore, we showed that the scavenging of reactive oxygen species (ROS) by introduction of mitochondrial catalase inhibited the activation of both NFAT and NF-κB, and the induction of COX-2 due to nickel exposure. Taken together, our results defining the evidence showing a key role of the cross-talk between NFAT and NF-κB pathways in regulating nickel-induced COX-2 expression, further provide insight into the understanding of the molecular mechanisms linking nickel exposure to its lung carcinogenic effects. PMID:21486220

  2. Growth Factors and COX2 Expression in Canine Perivascular Wall Tumors.

    PubMed

    Avallone, G; Stefanello, D; Boracchi, P; Ferrari, R; Gelain, M E; Turin, L; Tresoldi, E; Roccabianca, P

    2015-11-01

    Canine perivascular wall tumors (PWTs) are a group of subcutaneous soft tissue sarcomas developing from vascular mural cells. Mural cells are involved in angiogenesis through a complex crosstalk with endothelial cells mediated by several growth factors and their receptors. The evaluation of their expression may have relevance since they may represent a therapeutic target in the control of canine PWTs. The expression of vascular endothelial growth factor (VEGF) and receptors VEGFR-I/II, basic fibroblast growth factor (bFGF) and receptor Flg, platelet-derived growth factor B (PDGFB) and receptor PDGFRβ, transforming growth factor β1 (TGFβ1) and receptors TGFβR-I/II, and cyclooxygenase 2 (COX2) was evaluated on frozen sections of 40 PWTs by immunohistochemistry and semiquantitatively scored to identify their potential role in PWT development. Statistical analysis was performed to analyze possible correlations between Ki67 labeling index and the expression of each molecule. Proteins of the VEGF-, PDGFB-, and bFGF-mediated pathways were highly expressed in 27 (67.5%), 30 (75%), and 19 (47.5%) of 40 PWTs, respectively. Proteins of the TGFβ1- and COX2-mediated pathways were highly expressed in 4 (10%) and 14 (35%) of 40 cases. Statistical analysis identified an association between VEGF and VEGFR-I/II (P = .015 and .003, respectively), bFGF and Flg (P = .038), bFGF and PDGFRβ (P = .003), and between TGFβ1 and COX2 (P = .006). These findings were consistent with the mechanisms that have been reported to play a role in angiogenesis and in tumor development. No association with Ki67 labeling index was found. VEGF-, PDGFB-, and bFGF-mediated pathways seem to have a key role in PWT development and growth. Blockade of tyrosine kinase receptors after surgery could represent a promising therapy with the aim to reduce the PWT relapse rate and prolong the time to relapse. © The Author(s) 2015.

  3. Apoptosis Inducing Effect of Plumbagin on Colonic Cancer Cells Depends on Expression of COX-2

    PubMed Central

    Subramaniya, Bharathi Raja; Srinivasan, Gayathri; Mohammed Sadullah, Sakeena Sadullah; Davis, Nimitha; Baddi Reddi Subhadara, Lakshmi; Halagowder, Devaraj; Sivasitambaram, Niranjali Devaraj

    2011-01-01

    Plumbagin, a quinonoid found in the plants of the Plumbaginaceae, possesses medicinal properties. In this study we investigated the anti-proliferative and apoptotic activity of plumbagin by using two human colonic cancer cell lines, HT29 and HCT15. IC50 of Plumbagin for HCT15 and HT29 cells (22.5 µM and 62.5 µM, respectively) were significantly different. To study the response of cancer cells during treatment strategies, cells were treated with two different concentrations, 15 µM, 30 µM for HCT15 and 50 µM, 75 µM for HT29 cells. Though activation of NFκB, Caspases-3, elevated levels of TNF-α, cytosolic Cytochrome C were seen in both HCT15 cells HT29 treated with plumbagin, aberrant apoptosis with decreased level of pEGFR, pAkt, pGsk-3β, PCNA and Cyclin D1was observed only in 15 µM and 30 µM plumbagin treated HCT15 and 75 µM plumbagin treated HT29 cells. This suggests that plumbagin induces apoptosis in both HCT15 cells and HT29 treated, whereas, proliferation was inhibited only in 15 µM and 30 µM plumbagin treated HCT15 and 75 µM plumbagin treated HT29 cells, but not in 50 µM plumbagin treated HT29 cells. Expression of COX-2 was decreased in 75 µM plumbagin treated HT29 cells when compared to 50 µM plumbagin treated HT29 cells, whereas HCT15 cells lack COX. Hence the observed resistance to induction of apoptosis in 50 µM plumbagin treated HT29 cells are attributed to the expression of COX-2. In conclusion, plumbagin induces apoptosis in colonic cancer cells through TNF-α mediated pathway depending on expression of COX-2 expression. PMID:21559086

  4. The NF-κB family member RelB regulates microRNA miR-146a to suppress cigarette smoke-induced COX-2 protein expression in lung fibroblasts.

    PubMed

    Zago, Michela; Rico de Souza, Angela; Hecht, Emelia; Rousseau, Simon; Hamid, Qutayba; Eidelman, David H; Baglole, Carolyn J

    2014-04-21

    Diseases due to cigarette smoke exposure, including chronic obstructive pulmonary disease (COPD) and lung cancer, are associated with chronic inflammation typified by the increased expression of cyclooxygenase-2 (COX-2) protein. RelB is an NF-κB family member that suppresses cigarette smoke induction of COX-2 through an unknown mechanism. The ability of RelB to regulate COX-2 expression may be via miR-146a, a miRNA that attenuates COX-2 in lung fibroblasts. In this study we tested whether RelB attenuation of cigarette smoke-induced COX-2 protein is due to miR-146a. Utilizing pulmonary fibroblasts deficient in RelB expression, together with siRNA knock-down of RelB, we show the essential role of RelB in diminishing smoke-induced COX-2 protein expression despite robust activation of the canonical NF-κB pathway and subsequent induction of Cox-2 mRNA. RelB did not regulate COX-2 protein expression at the level of mRNA stability. Basal levels of miR-146a were significantly lower in Relb-deficient cells and cigarette smoke increased miR-146a expression only in Relb-expressing cells. Inhibition of miR-146a had no effects on Relb expression or induction of Cox-2 mRNA by cigarette smoke but significantly increased COX-2 protein. These data highlight the potential of a RelB-miR-146a axis as a novel regulatory pathway that attenuates inflammation in response to respiratory toxicants. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. Late Results of Cox Maze III Procedure in Patients with Atrial Fibrillation Associated with Structural Heart Disease.

    PubMed

    Gomes, Gustavo Gir; Gali, Wagner Luis; Sarabanda, Alvaro Valentim Lima; Cunha, Claudio Ribeiro da; Kessler, Iruena Moraes; Atik, Fernando Antibas

    2017-07-01

    Cox-Maze III procedure is one of the surgical techniques used in the surgical treatment of atrial fibrillation (AF). To determine late results of Cox-Maze III in terms of maintenance of sinus rhythm, and mortality and stroke rates. Between January 2006 and January 2013, 93 patients were submitted to the cut-and-sew Cox-Maze III procedure in combination with structural heart disease repair. Heart rhythm was determined by 24-hour Holter monitoring. Procedural success rates were determined by longitudinal methods and recurrence predictors by multivariate Cox regression models. Thirteen patients that obtained hospital discharge alive were excluded due to lost follow-up. The remaining 80 patients were aged 49.9 ± 12 years and 47 (58.7%) of them were female. Involvement of mitral valve and rheumatic heart disease were found in 67 (83.7%) and 63 (78.7%) patients, respectively. Seventy patients (87.5%) had persistent or long-standing persistent AF. Mean follow-up with Holter monitoring was 27.5 months. There were no hospital deaths. Sinus rhythm maintenance rates were 88%, 85.1% and 80.6% at 6 months, 24 months and 36 months, respectively. Predictors of late recurrence of AF were female gender (HR 3.52; 95% CI 1.21-10.25; p = 0.02), coronary artery disease (HR 4.73 95% CI 1.37-16.36; p = 0.01) and greater left atrium diameter (HR 1.05; 95% CI 1.01-1.09; p = 0.02). Actuarial survival was 98.5% at 12, 24 and 48 months and actuarial freedom from stroke was 100%, 100% and 97.5% in the same time frames. The Cox-Maze III procedure, in our experience, is efficacious for sinus rhythm maintenance, with very low late mortality and stroke rates. A operação de Cox-Maze III é uma das variantes técnicas no tratamento cirúrgico da fibrilação atrial (FA). Estudar os resultados tardios da operação de Cox-Maze III, quanto à eficácia na manutenção de ritmo sinusal e taxas de mortalidade e acidente vascular cerebral (AVC). Entre janeiro de 2006 a janeiro de 2013, 93 pacientes

  6. Injured nerve-derived COX2/PGE2 contributes to the maintenance of neuropathic pain in aged rats.

    PubMed

    Ma, Weiya; Chabot, Jean-Guy; Vercauteren, Freya; Quirion, Remi

    2010-07-01

    Neuropathic pain (NeP) is a debilitating disease afflicting mostly the aged population. Inflammatory responses in injured nerves play a pivotal role in the pathogenesis of NeP. Injured nerve derived cyclooxygenase 2/prostaglandin E2 (COX2/PGE2) contributes to the genesis of NeP at the early stage in young rats. Here we show that COX2/PGE2 is involved in the maintenance of NeP at a chronic stage in aged rats. Eighteen months after partial sciatic nerve ligation (PSNL), NeP remained prominent in aged rats. COX2 expressing macrophages and PGE2 levels were increased in injured nerves. PGE2 receptors (EP1 and EP4) and pain-related ion channel transient receptor potential vanilloid-1 (TRPV1) were increased in the ipsilateral dorsal root ganglion (DRG) neurons of aged PSNL rats. Perineural injection of a selective COX2 inhibitor NS-398 relieved NeP, reversed PSNL increased expression of EP1, EP4 and TRPV1 and suppressed the levels of pain-related peptide substance P and calcitonin gene-related peptide in DRG neurons. These data suggest that injured nerve-derived PGE2 contributes to the maintenance of NeP at the chronic stage in aged rats. Chronically facilitating the synthesis of pain-related molecules in nociceptive DRG neurons is a novel mechanism underpinning the contribution of PGE2. Copyright 2008 Elsevier Inc. All rights reserved.

  7. Celecoxib Induced Tumor Cell Radiosensitization by Inhibiting Radiation Induced Nuclear EGFR Transport and DNA-Repair: A COX-2 Independent Mechanism

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dittmann, Klaus H.; Mayer, Claus; Ohneseit, Petra A.

    2008-01-01

    Purpose: The purpose of the study was to elucidate the molecular mechanisms mediating radiosensitization of human tumor cells by the selective cyclooxygenase (COX)-2 inhibitor celecoxib. Methods and Materials: Experiments were performed using bronchial carcinoma cells A549, transformed fibroblasts HH4dd, the FaDu head-and-neck tumor cells, the colon carcinoma cells HCT116, and normal fibroblasts HSF7. Effects of celecoxib treatment were assessed by clonogenic cell survival, Western analysis, and quantification of residual DNA damage by {gamma}H{sub 2}AX foci assay. Results: Celecoxib treatment resulted in a pronounced radiosensitization of A549, HCT116, and HSF7 cells, whereas FaDu and HH4dd cells were not radiosensitized. The observedmore » radiosensitization could neither be correlated with basal COX-2 expression pattern nor with basal production of prostaglandin E2, but was depended on the ability of celecoxib to inhibit basal and radiation-induced nuclear transport of epidermal growth factor receptor (EGFR). The nuclear EGFR transport was strongly inhibited in A549-, HSF7-, and COX-2-deficient HCT116 cells, which were radiosensitized, but not in FaDu and HH4dd cells, which resisted celecoxib-induced radiosensitization. Celecoxib inhibited radiation-induced DNA-PK activation in A549, HSF7, and HCT116 cells, but not in FaDu and HH4dd cells. Consequentially, celecoxib increased residual {gamma}H2AX foci after irradiation, demonstrating that inhibition of DNA repair has occurred in responsive A549, HCT116, and HSF7 cells only. Conclusions: Celecoxib enhanced radiosensitivity by inhibition of EGFR-mediated mechanisms of radioresistance, a signaling that was independent of COX-2 activity. This novel observation may have therapeutic implications such that COX-2 inhibitors may improve therapeutic efficacy of radiation even in patients whose tumor radioresistance is not dependent on COX-2.« less

  8. Design, Synthesis and Biological Evaluation of4-(Imidazolylmethyl)-2-(4-methylsulfonyl phenyl)-Quinoline Derivatives as Selective COX-2 Inhibitors and In-vitro Anti-breast Cancer Agents

    PubMed Central

    Ghodsi, Razieh; Azizi, Ebrahim; Zarghi, Afshin

    2016-01-01

    A new group of 4-(Imidazolylmethyl)quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors and in-vitroanti breast cancer agents. In-vitro COX-1 and COX-2 inhibition studies showed that all the compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in the potent range 0.063-0.090 µM, and COX-2 selectivity indexes in the 179.9 to 547.6 range. Molecular modeling studies indicated that the methylsulfonyl substituent can be inserted into the secondary pocket of COX-2 active site for interactions with Arg513. Cytotoxicity of quinolines 9a-e against human breast cancer MCF-7 and T47D cell lines were also evaluated. All the compounds 9a-e were more cytotoxic against MCF-7 cells in comparison with those of T47D which express aromatase mRNA less than MCF-7 cells.The data showed that the increase of lipophilic properties of substituents on the C-7 and C-8 quinoline ring increased their cytotoxicity on MCF-7cells andCOX-2 inhibitory activity. Among the quinolines 9a-e, 4-((1H-Imidazol-1-yl)methyl) 7,8,9,10-tetrahydro-2-(4-methylsulfonylphenyl)-benzo[h]quinoline (9d)was identified as the most potent andselective COX-2inhibitor as well as the most cytotoxic agent against MCF-7 cells. PMID:27610157

  9. ERK1/2/COX-2/PGE2 signaling pathway mediates GPR91-dependent VEGF release in streptozotocin-induced diabetes

    PubMed Central

    Li, Tingting; Hu, Jianyan; Du, Shanshan; Chen, Yongdong; Wang, Shuai

    2014-01-01

    Purpose Retinal vascular dysfunction caused by vascular endothelial growth factor (VEGF) is the major pathological change that occurs in diabetic retinopathy (DR). It has recently been demonstrated that G protein-coupled receptor 91 (GPR91) plays a major role in both vasculature development and retinal angiogenesis. In this study, we examined the signaling pathways involved in GPR91-dependent VEGF release during the early stages of retinal vascular change in streptozotocin-induced diabetes. Methods Diabetic rats were assigned randomly to receive intravitreal injections of shRNA lentiviral particles targeting GPR91 (LV.shGPR91) or control particles (LV.shScrambled). Accumulation of succinate was assessed by gas chromatography-mass spectrometry (GC-MS). At 14 weeks, the ultrastructure and function of the retinal vessels of diabetic retinas with or without shRNA treatment were assessed using hematoxylin and eosin (HE) staining, transmission electron microscopy (TEM), and Evans blue dye permeability. The expression of GPR91, extracellular signal-regulated kinases 1 and 2 (ERK1/2) and cyclooxygenase-2 (COX-2) were measured using immunofluorescence and western blotting. COX-2 and VEGF mRNA were determined by quantitative RT–PCR. Prostaglandin E2 (PGE2) and VEGF secretion were detected using an enzyme-linked immunosorbent assay. Results Succinate exhibited abundant accumulation in diabetic rat retinas. The retinal telangiectatic vessels, basement membrane thickness, and Evans blue dye permeability were attenuated by treatment with GPR91 shRNA. In diabetic rats, knockdown of GPR91 inhibited the activities of ERK1/2 and COX-2 as well as the expression of PGE2 and VEGF. Meanwhile, COX-2, PGE2, and VEGF expression was inhibited by ERK1/2 inhibitor U0126 and COX-2 inhibitor NS-398. Conclusions Our data suggest that hyperglycemia causes succinate accumulation and GPR91 activity in retinal ganglion cells, which mediate VEGF-induced retinal vascular change via the ERK1/2/COX-2

  10. Cancer survival analysis using semi-supervised learning method based on Cox and AFT models with L1/2 regularization.

    PubMed

    Liang, Yong; Chai, Hua; Liu, Xiao-Ying; Xu, Zong-Ben; Zhang, Hai; Leung, Kwong-Sak

    2016-03-01

    One of the most important objectives of the clinical cancer research is to diagnose cancer more accurately based on the patients' gene expression profiles. Both Cox proportional hazards model (Cox) and accelerated failure time model (AFT) have been widely adopted to the high risk and low risk classification or survival time prediction for the patients' clinical treatment. Nevertheless, two main dilemmas limit the accuracy of these prediction methods. One is that the small sample size and censored data remain a bottleneck for training robust and accurate Cox classification model. In addition to that, similar phenotype tumours and prognoses are actually completely different diseases at the genotype and molecular level. Thus, the utility of the AFT model for the survival time prediction is limited when such biological differences of the diseases have not been previously identified. To try to overcome these two main dilemmas, we proposed a novel semi-supervised learning method based on the Cox and AFT models to accurately predict the treatment risk and the survival time of the patients. Moreover, we adopted the efficient L1/2 regularization approach in the semi-supervised learning method to select the relevant genes, which are significantly associated with the disease. The results of the simulation experiments show that the semi-supervised learning model can significant improve the predictive performance of Cox and AFT models in survival analysis. The proposed procedures have been successfully applied to four real microarray gene expression and artificial evaluation datasets. The advantages of our proposed semi-supervised learning method include: 1) significantly increase the available training samples from censored data; 2) high capability for identifying the survival risk classes of patient in Cox model; 3) high predictive accuracy for patients' survival time in AFT model; 4) strong capability of the relevant biomarker selection. Consequently, our proposed semi

  11. Expression of Mitochondrial Cytochrome C Oxidase Chaperone Gene (COX20) Improves Tolerance to Weak Acid and Oxidative Stress during Yeast Fermentation

    PubMed Central

    Kumar, Vinod; Hart, Andrew J.; Keerthiraju, Ethiraju R.; Waldron, Paul R.; Tucker, Gregory A.; Greetham, Darren

    2015-01-01

    Introduction Saccharomyces cerevisiae is the micro-organism of choice for the conversion of fermentable sugars released by the pre-treatment of lignocellulosic material into bioethanol. Pre-treatment of lignocellulosic material releases acetic acid and previous work identified a cytochrome oxidase chaperone gene (COX20) which was significantly up-regulated in yeast cells in the presence of acetic acid. Results A Δcox20 strain was sensitive to the presence of acetic acid compared with the background strain. Overexpressing COX20 using a tetracycline-regulatable expression vector system in a Δcox20 strain, resulted in tolerance to the presence of acetic acid and tolerance could be ablated with addition of tetracycline. Assays also revealed that overexpression improved tolerance to the presence of hydrogen peroxide-induced oxidative stress. Conclusion This is a study which has utilised tetracycline-regulated protein expression in a fermentation system, which was characterised by improved (or enhanced) tolerance to acetic acid and oxidative stress. PMID:26427054

  12. γ-Oryzanol suppresses COX-2 expression by inhibiting reactive oxygen species-mediated Erk1/2 and Egr-1 signaling in LPS-stimulated RAW264.7 macrophages.

    PubMed

    Shin, Soon Young; Kim, Heon-Woong; Jang, Hwan-Hee; Hwang, Yu-Jin; Choe, Jeong-Sook; Kim, Jung-Bong; Lim, Yoongho; Lee, Young Han

    2017-09-16

    Cyclooxygenase (COX)-2 produces prostanoids, which contribute to inflammatory responses. Nuclear factor (NF)-κB is a key transcription factor mediating COX-2 expression. γ-Oryzanol is an active component in rice bran oil, which inhibits lipopolysaccharide (LPS)-mediated COX-2 expression by inhibiting NF-κB. However, the inhibition of COX-2 expression by γ-oryzanol independently of NF-κB is poorly understood. We found that LPS upregulated Egr-1 expression at the transcriptional level. Forced expression of Egr-1 trans-activated the Cox-2 promoter independently of NF-κB. In contrast, silencing of Egr-1 abrogated LPS-mediated COX-2 expression. LPS produced reactive oxygen species (ROS), which, in turn, induced Egr-1 expression via the Erk1/2 MAPK pathway. ROS scavenging activity of γ-oryzanol suppressed Egr-1 expression by inhibiting the Erk1/2 MAPK pathway. Our results suggest that γ-oryzanol inhibits LPS-mediated COX-2 expression by suppressing Erk1/2-mediated Egr-1 expression. This study supports that γ-oryzanol may be useful for ameliorating LPS-mediated inflammatory responses. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Caffeic acid, a phenolic phytochemical in coffee, directly inhibits Fyn kinase activity and UVB-induced COX-2 expression

    PubMed Central

    Kang, Nam Joo; Lee, Ki Won; Shin, Bong Jik; Jung, Sung Keun; Hwang, Mun Kyung; Bode, Ann M.; Heo, Yong-Seok; Dong, Zigang

    2009-01-01

    Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical present in many foods, including coffee. Recent studies suggested that caffeic acid exerts anticarcinogenic effects, but little is known about the underlying molecular mechanisms and specific target proteins. In this study, we found that Fyn, one of the members of the non-receptor protein tyrosine kinase family, was required for ultraviolet (UV) B-induced cyclooxygenase-2 (COX-2) expression, and caffeic acid suppressed UVB-induced skin carcinogenesis by directly inhibiting Fyn kinase activity. Caffeic acid more effectively suppressed UVB-induced COX-2 expression and subsequent prostaglandin E2 production in JB6 P+ mouse skin epidermal (JB6 P+) cells compared with chlorogenic acid (5-O-caffeoylquinic acid), an ester of caffeic acid with quinic acid. Data also revealed that caffeic acid more effectively induced the downregulation of COX-2 expression at the transcriptional level mediated through the inhibition of activator protein-1 (AP-1) and nuclear factor-κB transcription activity compared with chlorogenic acid. Fyn kinase activity was suppressed more effectively by caffeic acid than by chlorogenic acid, and downstream mitogen-activated protein kinases (MAPKs) were subsequently blocked. Pharmacological Fyn kinase inhibitor (3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and leflunomide) data also revealed that Fyn is involved in UVB-induced COX-2 expression mediated through the phosphorylation of MAPKs in JB6 P+ cells. Pull-down assays revealed that caffeic acid directly bound with Fyn and non-competitively with adenosine triphosphate. In vivo data from mouse skin also supported the idea that caffeic acid suppressed UVB-induced COX-2 expression by blocking Fyn kinase activity. These results suggested that this compound could act as a potent chemopreventive agent against skin cancer. PMID:19073879

  14. Hormophysa triquerta polyphenol, an elixir that deters CXCR4- and COX2-dependent dissemination destiny of treatment-resistant pancreatic cancer cells

    PubMed Central

    Aravindan, Sheeja; Ramraj, Satishkumar; Kandasamy, Kathiresan; Thirugnanasambandan, Somasundaram S.; Somasundaram, Dinesh Babu; Herman, Terence S.; Aravindan, Natarajan

    2017-01-01

    Therapy-resistant pancreatic cancer (PC) cells play a crucial role in tumor relapse, recurrence, and metastasis. Recently, we showed the anti-PC potential of an array of seaweed polyphenols and identified efficient drug deliverables. Herein, we investigated the benefit of one such deliverable, Hormophysa triquerta polyphenol (HT-EA), in regulating the dissemination physiognomy of therapy-resistant PC cells in vitro,and residual PC in vivo. Human PC cells exposed to ionizing radiation (IR), with/without HT-EA pre-treatment were examined for the alterations in the tumor invasion/metastasis (TIM) transcriptome (93 genes, QPCR-profiling). Utilizing a mouse model of residual PC, we investigated the benefit of HT-EA in the translation regulation of crucial TIM targets (TMA-IHC). Radiation activated 30, 50, 15, and 38 TIM molecules in surviving Panc-1, Panc-3.27, BxPC3, and MiaPaCa-2 cells. Of these, 15, 44, 12, and 26 molecules were suppressed with HT-EA pre-treatment. CXCR4 and COX2 exhibited cell-line-independent increases after IR, and was completely suppressed with HT-EA, across all PC cells. HT-EA treatment resulted in translational repression of IR-induced CXCR4, COX2, β-catenin, MMP9, Ki-67, BAPX, PhPT-1, MEGF10, and GRB10 in residual PC. Muting CXCR4 or COX2 regulated the migration/invasion potential of IR-surviving cells, while forced expression of CXCR4 or COX2 significantly increased migration/invasion capabilities of PC cells. Further, treatment with HT-EA significantly inhibited IR-induced and CXCR4/COX2 forced expression-induced PC cell migration/invasion. This study (i) documents the TIM blueprint in therapy-resistant PC cells, (ii) defines the role of CXCR4 and COX2 in induced metastatic potential, and (iii) recognizes the potential of HT-EA in deterring the CXCR4/COX2-dependent dissemination destiny of therapy-resistant residual PC cells. PMID:27974694

  15. Hormophysa triquerta polyphenol, an elixir that deters CXCR4- and COX2-dependent dissemination destiny of treatment-resistant pancreatic cancer cells.

    PubMed

    Aravindan, Sheeja; Ramraj, Satishkumar; Kandasamy, Kathiresan; Thirugnanasambandan, Somasundaram S; Somasundaram, Dinesh Babu; Herman, Terence S; Aravindan, Natarajan

    2017-01-24

    Therapy-resistant pancreatic cancer (PC) cells play a crucial role in tumor relapse, recurrence, and metastasis. Recently, we showed the anti-PC potential of an array of seaweed polyphenols and identified efficient drug deliverables. Herein, we investigated the benefit of one such deliverable, Hormophysa triquerta polyphenol (HT-EA), in regulating the dissemination physiognomy of therapy-resistant PC cells in vitro,and residual PC in vivo. Human PC cells exposed to ionizing radiation (IR), with/without HT-EA pre-treatment were examined for the alterations in the tumor invasion/metastasis (TIM) transcriptome (93 genes, QPCR-profiling). Utilizing a mouse model of residual PC, we investigated the benefit of HT-EA in the translation regulation of crucial TIM targets (TMA-IHC). Radiation activated 30, 50, 15, and 38 TIM molecules in surviving Panc-1, Panc-3.27, BxPC3, and MiaPaCa-2 cells. Of these, 15, 44, 12, and 26 molecules were suppressed with HT-EA pre-treatment. CXCR4 and COX2 exhibited cell-line-independent increases after IR, and was completely suppressed with HT-EA, across all PC cells. HT-EA treatment resulted in translational repression of IR-induced CXCR4, COX2, β-catenin, MMP9, Ki-67, BAPX, PhPT-1, MEGF10, and GRB10 in residual PC. Muting CXCR4 or COX2 regulated the migration/invasion potential of IR-surviving cells, while forced expression of CXCR4 or COX2 significantly increased migration/invasion capabilities of PC cells. Further, treatment with HT-EA significantly inhibited IR-induced and CXCR4/COX2 forced expression-induced PC cell migration/invasion. This study (i) documents the TIM blueprint in therapy-resistant PC cells, (ii) defines the role of CXCR4 and COX2 in induced metastatic potential, and (iii) recognizes the potential of HT-EA in deterring the CXCR4/COX2-dependent dissemination destiny of therapy-resistant residual PC cells.

  16. Role of IL-1 beta and COX2 in silica-induced IL-6 release and loss of pneumocytes in co-cultures.

    PubMed

    Herseth, Jan I; Refsnes, Magne; Låg, Marit; Schwarze, Per E

    2009-10-01

    The pro-inflammatory cytokines IL-1 beta, TNF-alpha and IL-6 are of great importance in the development of silica-induced lung damage and repair. In this study we investigated the role of IL-1 beta, TNF-alpha and COX2 in silica-induced regulation of IL-6 release and pneumocyte loss in various mono- and co-cultures of monocytes, pneumocytes and endothelial cells. All co-cultures with monocytes, and especially cultures including endothelial cells, showed an increase of silica-induced release of IL-6 compared to the respective monocultures. Treatment with the antagonist IL-1 ra strongly decreased IL-1 beta and IL-6 release in contact co-cultures of monocytes and pneumocytes. COX2 up-regulation by silica and IL-1 beta was eliminated by IL-1 ra. Inhibition of COX2 markedly reduced both IL-1 beta and IL-6 release. IL-1 ra was more effective than COX2-inhibition in reduction of IL-6, but not of IL-1 beta. Silica-induced pneumocyte loss was reduced by IL-1 beta, but this effect was not counteracted by the IL-1 receptor antagonist. Our findings suggest that silica-induced IL-6 release from pneumocytes is mainly mediated via IL-1 beta release from the monocytes, via both COX2-dependent and -independent pathways. Notably, COX2-derived mediators seem crucial for a positive feed-back regulation of IL-1 beta release from the monocytes. In contrast to silica-induced IL-6, the reduction in pneumocyte loss by IL-1 beta does not seem to be regulated through an IL-1R1-dependent mechanism.

  17. Automated Box-Cox Transformations for Improved Visual Encoding.

    PubMed

    Maciejewski, Ross; Pattath, Avin; Ko, Sungahn; Hafen, Ryan; Cleveland, William S; Ebert, David S

    2013-01-01

    The concept of preconditioning data (utilizing a power transformation as an initial step) for analysis and visualization is well established within the statistical community and is employed as part of statistical modeling and analysis. Such transformations condition the data to various inherent assumptions of statistical inference procedures, as well as making the data more symmetric and easier to visualize and interpret. In this paper, we explore the use of the Box-Cox family of power transformations to semiautomatically adjust visual parameters. We focus on time-series scaling, axis transformations, and color binning for choropleth maps. We illustrate the usage of this transformation through various examples, and discuss the value and some issues in semiautomatically using these transformations for more effective data visualization.

  18. The Application of Extended Cox Proportional Hazard Method for Estimating Survival Time of Breast Cancer

    NASA Astrophysics Data System (ADS)

    Husain, Hartina; Astuti Thamrin, Sri; Tahir, Sulaiha; Mukhlisin, Ahmad; Mirna Apriani, M.

    2018-03-01

    Breast cancer is one type of cancer that is the leading cause of death worldwide. This study aims to model the factors that affect the survival time and rate of cure of breast cancer patients. The extended cox model, which is a modification of the proportional hazard cox model in which the proportional hazard assumptions are not met, is used in this study. The maximum likelihood estimation approach is used to estimate the parameters of the model. This method is then applied to medical record data of breast cancer patient in 2011-2016, which is taken from Hasanuddin University Education Hospital. The results obtained indicate that the factors that affect the survival time of breast cancer patients are malignancy and leukocyte levels.

  19. Utility of COX1 phylogenetics to differentiate between locally acquired and imported Plasmodium knowlesi infections in Singapore

    PubMed Central

    Loh, Jin Phang; Gao, Qiu Han Christine; Lee, Vernon J; Tetteh, Kevin; Drakeley, Chris

    2016-01-01

    INTRODUCTION Although there have been several phylogenetic studies on Plasmodium knowlesi (P. knowlesi), only cytochrome c oxidase subunit 1 (COX1) gene analysis has shown some geographical differentiation between the isolates of different countries. METHODS Phylogenetic analysis of locally acquired P. knowlesi infections, based on circumsporozoite, small subunit ribosomal ribonucleic acid (SSU rRNA), merozoite surface protein 1 and COX1 gene targets, was performed. The results were compared with the published sequences of regional isolates from Malaysia and Thailand. RESULTS Phylogenetic analysis of the circumsporozoite, SSU rRNA and merozoite surface protein 1 gene sequences for regional P. knowlesi isolates showed no obvious differentiation that could be attributed to their geographical origin. However, COX1 gene analysis showed that it was possible to differentiate between Singapore-acquired P. knowlesi infections and P. knowlesi infections from Peninsular Malaysia and Sarawak, Borneo, Malaysia. CONCLUSION The ability to differentiate between locally acquired P. knowlesi infections and imported P. knowlesi infections has important utility for the monitoring of P. knowlesi malaria control programmes in Singapore. PMID:26805667

  20. Utility of COX1 phylogenetics to differentiate between locally acquired and imported Plasmodium knowlesi infections in Singapore.

    PubMed

    Loh, Jin Phang; Gao, Qiu Han Christine; Lee, Vernon J; Tetteh, Kevin; Drakeley, Chris

    2016-12-01

    Although there have been several phylogenetic studies on Plasmodium knowlesi (P. knowlesi), only cytochrome c oxidase subunit 1 (COX1) gene analysis has shown some geographical differentiation between the isolates of different countries. Phylogenetic analysis of locally acquired P. knowlesi infections, based on circumsporozoite, small subunit ribosomal ribonucleic acid (SSU rRNA), merozoite surface protein 1 and COX1 gene targets, was performed. The results were compared with the published sequences of regional isolates from Malaysia and Thailand. Phylogenetic analysis of the circumsporozoite, SSU rRNA and merozoite surface protein 1 gene sequences for regional P. knowlesi isolates showed no obvious differentiation that could be attributed to their geographical origin. However, COX1 gene analysis showed that it was possible to differentiate between Singapore-acquired P. knowlesi infections and P. knowlesi infections from Peninsular Malaysia and Sarawak, Borneo, Malaysia. The ability to differentiate between locally acquired P. knowlesi infections and imported P. knowlesi infections has important utility for the monitoring of P. knowlesi malaria control programmes in Singapore. Copyright: © Singapore Medical Association

  1. Gastrointestinal toxicity among patients taking selective COX-2 inhibitors or conventional NSAIDs, alone or combined with proton pump inhibitors: a case-control study.

    PubMed

    Bakhriansyah, Mohammad; Souverein, Patrick C; de Boer, Anthonius; Klungel, Olaf H

    2017-10-01

    To assess the risk of gastrointestinal perforation, ulcers, or bleeding (PUB) associated with the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) with proton pump inhibitors (PPIs) and selective COX-2 inhibitors, with or without PPIs compared with conventional NSAIDs. A case-control study was performed within conventional NSAIDs and/or selective COX-2 inhibitors users identified from the Dutch PHARMO Record Linkage System in the period 1998-2012. Cases were patients aged ≥18 years with a first hospital admission for PUB. For each case, up to four controls were matched for age and sex at the date a case was hospitalized (index date). Logistic regression analysis was used to calculate odds ratios (ORs). At the index date, 2634 cases and 5074 controls were current users of conventional NSAIDs or selective COX-2 inhibitors. Compared with conventional NSAIDs, selective COX-2 inhibitors with PPIs had the lowest risk of PUB (adjusted OR 0.51, 95% confidence interval [CI]: 0.35-0.73) followed by selective COX-2 inhibitors (adjusted OR 0.66, 95%CI: 0.48-0.89) and conventional NSAIDs with PPIs (adjusted OR 0.79, 95%CI: 0.68-0.92). Compared with conventional NSAIDs, the risk of PUB was lower for those aged ≥75 years taking conventional NSAIDs with PPIs compared with younger patients (adjusted interaction OR 0.79, 95%CI: 0.64-0.99). However, those aged ≥75 years taking selective COX-2 inhibitors, the risk was higher compared with younger patients (adjusted interaction OR 1.22, 95%CI: 1.01-1.47). Selective COX-2 inhibitors with PPIs, selective COX-2 inhibitors, and conventional NSAIDs with PPIs were associated with lower risks of PUB compared with conventional NSAIDs. These effects were modified by age. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

  2. Molecular docking, molecular modeling, and molecular dynamics studies of azaisoflavone as dual COX-2 inhibitors and TP receptor antagonists.

    PubMed

    Hadianawala, Murtuza; Mahapatra, Amarjyoti Das; Yadav, Jitender K; Datta, Bhaskar

    2018-02-26

    Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes. Graphical abstract ᅟ.

  3. Inhibitory Effects of Culinary Herbs and Spices on the Growth of HCA-7 Colorectal Cancer Cells and Their COX-2 Expression.

    PubMed

    Jaksevicius, Andrius; Carew, Mark; Mistry, Calli; Modjtahedi, Helmout; Opara, Elizabeth I

    2017-09-21

    It is unclear if the anti-inflammatory properties of culinary herbs and spices (CHS) are linked to their ability to inhibit Colorectal cancer cell (CRC) growth. Furthermore, their therapeutic potential with regards to CRC is unknown. The aim of this study was to establish if the inhibition of HCA-7 CRC cell growth by a selection of culinary herbs and spices (CHS) is linked to the inhibition of the cells' cyclooxygenase-2 (COX-2 )expression, and to investigate their therapeutic potential. CHS inhibited the growth of Human colon adenocarcinoma-7 (HCA-7) cells; the order of potency was turmeric, bay leaf, ginger, sage, and rosemary; their combinations had a synergistic or additive effect on cell growth inhibition. CHS also inhibited COX-2 expression and activity; this action was comparable to that of the specific COX-2 inhibitor Celecoxib. Coincident with COX-2 inhibition was the accumulation of cells in the sub G1 phase of the HCA-7's cell cycle and, using bay leaf and turmeric, the cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP). This latter effect showed that the effect of these CHS on growth arrest was irreversible, and was comparable to that of the caspase activator Etoposide. This study provides evidence of a link between the inhibition of HCA-7 growth, and its COX-2 expression, by CHS, and their therapeutic potential.

  4. Inhibitory Effects of Culinary Herbs and Spices on the Growth of HCA-7 Colorectal Cancer Cells and Their COX-2 Expression

    PubMed Central

    Jaksevicius, Andrius; Carew, Mark; Mistry, Calli

    2017-01-01

    It is unclear if the anti-inflammatory properties of culinary herbs and spices (CHS) are linked to their ability to inhibit Colorectal cancer cell (CRC) growth. Furthermore, their therapeutic potential with regards to CRC is unknown. The aim of this study was to establish if the inhibition of HCA-7 CRC cell growth by a selection of culinary herbs and spices (CHS) is linked to the inhibition of the cells’ cyclooxygenase-2 (COX-2 )expression, and to investigate their therapeutic potential. CHS inhibited the growth of Human colon adenocarcinoma-7 (HCA-7) cells; the order of potency was turmeric, bay leaf, ginger, sage, and rosemary; their combinations had a synergistic or additive effect on cell growth inhibition. CHS also inhibited COX-2 expression and activity; this action was comparable to that of the specific COX-2 inhibitor Celecoxib. Coincident with COX-2 inhibition was the accumulation of cells in the sub G1 phase of the HCA-7’s cell cycle and, using bay leaf and turmeric, the cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP). This latter effect showed that the effect of these CHS on growth arrest was irreversible, and was comparable to that of the caspase activator Etoposide. This study provides evidence of a link between the inhibition of HCA-7 growth, and its COX-2 expression, by CHS, and their therapeutic potential. PMID:28934138

  5. Big Bang Day : Physics Rocks

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    None

    2009-10-07

    Is particle physics the new rock 'n' roll? The fundamental questions about the nature of the universe that particle physics hopes to answer have attracted the attention of some very high profile and unusual fans. Alan Alda, Ben Miller, Eddie Izzard, Dara O'Briain and John Barrowman all have interests in this branch of physics. Brian Cox - CERN physicist, and former member of 90's band D:Ream, tracks down some very well known celebrity enthusiasts and takes a light-hearted look at why this subject can appeal to all of us.

  6. Big Bang Day : Physics Rocks

    ScienceCinema

    None

    2017-12-09

    Is particle physics the new rock 'n' roll? The fundamental questions about the nature of the universe that particle physics hopes to answer have attracted the attention of some very high profile and unusual fans. Alan Alda, Ben Miller, Eddie Izzard, Dara O'Briain and John Barrowman all have interests in this branch of physics. Brian Cox - CERN physicist, and former member of 90's band D:Ream, tracks down some very well known celebrity enthusiasts and takes a light-hearted look at why this subject can appeal to all of us.

  7. Simulation program for estimating statistical power of Cox's proportional hazards model assuming no specific distribution for the survival time.

    PubMed

    Akazawa, K; Nakamura, T; Moriguchi, S; Shimada, M; Nose, Y

    1991-07-01

    Small sample properties of the maximum partial likelihood estimates for Cox's proportional hazards model depend on the sample size, the true values of regression coefficients, covariate structure, censoring pattern and possibly baseline hazard functions. Therefore, it would be difficult to construct a formula or table to calculate the exact power of a statistical test for the treatment effect in any specific clinical trial. The simulation program, written in SAS/IML, described in this paper uses Monte-Carlo methods to provide estimates of the exact power for Cox's proportional hazards model. For illustrative purposes, the program was applied to real data obtained from a clinical trial performed in Japan. Since the program does not assume any specific function for the baseline hazard, it is, in principle, applicable to any censored survival data as long as they follow Cox's proportional hazards model.

  8. Microwave absorption enhancement, magnetic coupling and ab initio electronic structure of monodispersed (Mn1-xCox)3O4 nanoparticles

    NASA Astrophysics Data System (ADS)

    Zhao, Pengfei; Liang, Chongyun; Gong, Xiwen; Gao, Ran; Liu, Jiwei; Wang, Min; Che, Renchao

    2013-08-01

    Monodispersed manganese oxide (Mn1-xCox)3O4 (0 <= x <= 0.5) nanoparticles, less than 10 nm size, are respectively synthesized via a facile thermolysis method at a rather low temperature, ranging from 90 to 100 °C, without any inertia gas for protection. The influences of the Co dopant content on the critical reaction temperature required for the nanoparticle formation, electronic band structures, magnetic properties, and the microwave absorption capability of (Mn1-xCox)3O4 are comprehensively investigated by means of both experimental and theoretical approaches including powder X-ray diffraction (XRD), electron energy loss spectroscopy (EELS), super conductivity quantum interference device (SQUID) examination, and first-principle simulations. Co is successfully doped into the Mn atomic sites of the (Mn1-xCox)3O4 lattice, which is further confirmed by EELS data acquired from one individual nanoparticle. Therefore, continuous solid solutions of well-crystallized (Mn1-xCox)3O4 products are achieved without any impurity phase or phase separation. With increases in the Co dopant concentration x from 0 to 0.5, the lattice parameters change systemically, where the overall saturation magnetization at 30 K increases due to the more intense coupling of the 3d electrons between Mn and Co, as revealed by simulations. The microwave absorption properties of the (Mn1-xCox)3O4 nanoparticles are examined between 2 and 18 GHz. The maximum absorption peak -11.0 dB of the x = 0 sample is enhanced to -11.5 dB for x = 0.2, -12.7 dB for x = 0.25, -15.6 dB for x = 0.33, and -24.0 dB for x = 0.5 respectively, suggesting the Co doping effects. Our results might provide novel insights into the understanding of the influences of metallic ion doping on the electromagnetic properties of metallic oxide nanomaterials.Monodispersed manganese oxide (Mn1-xCox)3O4 (0 <= x <= 0.5) nanoparticles, less than 10 nm size, are respectively synthesized via a facile thermolysis method at a rather low

  9. MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells*

    PubMed Central

    Kwon, Yoojung; Kim, Youngmi; Eom, Sangkyung; Kim, Misun; Park, Deokbum; Kim, Hyuna; Noh, Kyeonga; Lee, Hansoo; Lee, Yun Sil; Choe, Jongseon; Kim, Young Myeong; Jeoung, Dooil

    2015-01-01

    Cyclooxgenase-2 (COX-2) knock-out mouse experiments showed that COX-2 was necessary for in vivo allergic inflammation, such as passive cutaneous anaphylaxis, passive systemic anaphylaxis, and triphasic cutaneous allergic reaction. TargetScan analysis predicted COX-2 as a target of miR-26a and miR-26b. miR-26a/-26b decreased luciferase activity associated with COX-2–3′-UTR. miR-26a/-26b exerted negative effects on the features of in vitro and in vivo allergic inflammation by targeting COX-2. ChIP assays showed the binding of HDAC3 and SNAIL, but not COX-2, to the promoter sequences of miR-26a and miR-26b. Cytokine array analysis showed that the induction of chemokines, such as MIP-2, in the mouse passive systemic anaphylaxis model occurred in a COX-2-dependent manner. ChIP assays showed the binding of HDAC3 and COX-2 to the promoter sequences of MIP-2. In vitro and in vivo allergic inflammation was accompanied by the increased expression of MIP-2. miR-26a/-26b negatively regulated the expression of MIP-2. Allergic inflammation enhanced the tumorigenic and metastatic potential of cancer cells and induced positive feedback involving cancer cells and stromal cells, such as mast cells, macrophages, and endothelial cells. miR-26a mimic and miR-26b mimic negatively regulated the positive feedback between cancer cells and stromal cells and the positive feedback among stromal cells. miR-26a/-26b negatively regulated the enhanced tumorigenic potential by allergic inflammation. COX-2 was necessary for the enhanced metastatic potential of cancer cells by allergic inflammation. Taken together, our results indicate that the miR26a/-26b-COX-2-MIP-2 loop regulates allergic inflammation and the feedback relationship between allergic inflammation and the enhanced tumorigenic and metastatic potential. PMID:25907560

  10. Indomethacin treatment prior to pentylenetetrazole-induced seizures downregulates the expression of il1b and cox2 and decreases seizure-like behavior in zebrafish larvae.

    PubMed

    Barbalho, Patrícia Gonçalves; Lopes-Cendes, Iscia; Maurer-Morelli, Claudia Vianna

    2016-03-09

    It has been demonstrated that the zebrafish model of pentylenetetrazole (PTZ)-evoked seizures and the well-established rodent models of epilepsy are similar pertaining to behavior, electrographic features, and c-fos expression. Although this zebrafish model is suitable for studying seizures, to date, inflammatory response after seizures has not been investigated using this model. Because a relationship between epilepsy and inflammation has been established, in the present study we investigated the transcript levels of the proinflammatory cytokines interleukin-1 beta (il1b) and cyclooxygenase-2 (cox2a and cox2b) after PTZ-induced seizures in the brain of zebrafish 7 days post fertilization. Furthermore, we exposed the fish to the nonsteroidal anti-inflammatory drug indomethacin prior to PTZ, and we measured its effect on seizure latency, number of seizure behaviors, and mRNA expression of il1b, cox2b, and c-fos. We used quantitative real-time PCR to assess the mRNA expression of il1b, cox2a, cox2b, and c-fos, and visual inspection was used to monitor seizure latency and the number of seizure-like behaviors. We found a short-term upregulation of il1b, and we revealed that cox2b, but not cox2a, was induced after seizures. Indomethacin treatment prior to PTZ-induced seizures downregulated the mRNA expression of il1b, cox2b, and c-fos. Moreover, we observed that in larvae exposed to indomethacin, seizure latency increased and the number of seizure-like behaviors decreased. This is the first study showing that il1b and cox-2 transcripts are upregulated following PTZ-induced seizures in zebrafish. In addition, we demonstrated the anticonvulsant effect of indomethacin based on (1) the inhibition of PTZ-induced c-fos transcription, (2) increase in seizure latency, and (3) decrease in the number of seizure-like behaviors. Furthermore, anti-inflammatory effect of indomethacin is clearly demonstrated by the downregulation of the mRNA expression of il1b and cox2b. Our results

  11. Low-level laser therapy (LLLT) reduces the COX-2 mRNA expression in both subplantar and total brain tissues in the model of peripheral inflammation induced by administration of carrageenan.

    PubMed

    Prianti, Antonio Carlos Guimarães; Silva, José Antonio; Dos Santos, Regiane Feliciano; Rosseti, Isabela Bueno; Costa, Maricilia Silva

    2014-07-01

    In the classical model of edema formation and hyperalgesia induced by carrageenan administration in rat paw, the increase in prostaglandin E2 (PGE2) production in the central nervous system (CNS) contributes to the severity of the inflammatory and pain responses. Prostaglandins are generated by the cyclooxygenase (COX). There are two distinct COX isoforms, COX-1 and COX-2. In inflammatory tissues, COX-2 is greatly expressed producing proinflammatory prostaglandins (PGs). Low-level laser therapy (LLLT) has been used in the treatment of inflammatory pathologies, reducing both pain and acute inflammatory process. Herein we studied the effect of LLLT on both COX-2 and COX-1 messenger RNA (mRNA) expression in either subplantar or brain tissues taken from rats treated with carrageenan. The experiment was designed as follows: A1 (saline), A2 (carrageenan-0.5 mg/paw), A3 (carrageenan-0.5 mg/paw + LLLT), A4 (carrageenan-1.0 mg/paw), and A5 (carrageenan-1.0 mg/paw + LLLT). Animals from the A3 and A5 groups were irradiated at 1 h after carrageenan administration, using a diode laser with an output power of 30 mW and a wavelength of 660 nm. The laser beam covered an area of 0.785 cm(2), resulting in an energy dosage of 7.5 J/cm(2). Both COX-2 and COX-1 mRNAs were measured by RT-PCR. Six hours after carrageenan administration, COX-2 mRNA expression was significantly increased both in the subplantar (2.2-4.1-fold) and total brain (8.65-13.79-fold) tissues. COX-1 mRNA expression was not changed. LLLT (7.5 J/cm(2)) reduced significantly the COX-2 mRNA expression both in the subplantar (~2.5-fold) and brain (4.84-9.67-fold) tissues. The results show that LLLT is able to reduce COX-2 mRNA expression. It is possible that the mechanism of LLLT decreasing hyperalgesia is also related to its effect in reducing the COX-2 expression in the CNS.

  12. Using Cox's proportional hazards model for prognostication in carcinoma of the upper aero-digestive tract.

    PubMed

    Wolfensberger, M

    1992-01-01

    One of the major short comings of the traditional TNM system is its limited potential for prognostication. With the development of multifactorial analysis techniques, such as Cox's proportional hazards model, it has become possible to simultaneously evaluate a large number of prognostic variables. Cox's model allows both the identification of prognostically relevant variables and the quantification of their prognostic influence. These characteristics make it a helpful tool for analysis as well as for prognostication. The goal of the present study was to develop a prognostic index for patients with carcinoma of the upper aero-digestive tract which makes use of all prognostically relevant variables. To accomplish this, the survival data of 800 patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx were analyzed. Sixty-one variables were screened for prognostic significance; of these only 19 variables (including age, tumor location, T, N and M stages, resection margins, capsular invasion of nodal metastases, and treatment modality) were found to significantly correlate with prognosis. With the help of Cox's equation, a prognostic index (PI) was computed for every combination of prognostic factors. To test the proposed model, the prognostic index was applied to 120 patients with carcinoma of the oral cavity or oropharynx. A comparison of predicted and observed survival showed good overall correlation, although actual survival tended to be better than predicted.

  13. Visualizing the Effects of a Positive Early Experience, Tactile Stimulation, on Dendritic Morphology and Synaptic Connectivity with Golgi-Cox Staining

    PubMed Central

    Mychasiuk, Richelle; Gibb, Robbin; Kolb, Bryan

    2013-01-01

    To generate longer-term changes in behavior, experiences must be producing stable changes in neuronal morphology and synaptic connectivity. Tactile stimulation is a positive early experience that mimics maternal licking and grooming in the rat. Exposing rat pups to this positive experience can be completed easily and cost-effectively by using highly accessible materials such as a household duster. Using a cross-litter design, pups are either stroked or left undisturbed, for 15 min, three times per day throughout the perinatal period. To measure the neuroplastic changes related to this positive early experience, Golgi-Cox staining of brain tissue is utilized. Owing to the fact that Golgi-Cox impregnation stains a discrete number of neurons rather than all of the cells, staining of the rodent brain with Golgi-Cox solution permits the visualization of entire neuronal elements, including the cell body, dendrites, axons, and dendritic spines. The staining procedure is carried out over several days and requires that the researcher pay close attention to detail. However, once staining is completed, the entire brain has been impregnated and can be preserved indefinitely for ongoing analysis. Therefore, Golgi-Cox staining is a valuable resource for studying experience-dependent plasticity. PMID:24121525

  14. A novel atrial volume reduction technique to enhance the Cox maze procedure: initial results.

    PubMed

    Marui, Akira; Nishina, Takeshi; Tambara, Keiichi; Saji, Yoshiaki; Shimamoto, Takeshi; Nishioka, Masahiko; Ikeda, Tadashi; Komeda, Masashi

    2006-11-01

    Large left atrial diameter is reported to be a predictor for recurrent atrial fibrillation after the Cox maze procedure, and left atrial diameter by itself influences the chance of sinus rhythm recovery, as well as maintenance of sinus rhythm. However, additional cut-and-sew procedures to decrease left atrial diameter extend operative time and can cause bleeding. Thus we developed a no-bleeding, faster, and therefore less invasive left atrial volume reduction technique to enhance the Cox maze procedure. The modified Cox maze III procedure with cryoablation or the left atrial maze procedure in association with mitral valve surgery was performed in 80 patients with atrial fibrillation and enlarged left atria (> or =60 mm). Among them, 44 patients had the concomitant volume reduction technique (VR group); continuous horizontal mattress sutures for left atrial plication were placed on the left atrial wall along the pulmonary vein isolation line. Cryoablation was applied to the suture line so that the plicated left atrium is anatomically and electrically isolated. Another 36 patients did not have the volume reduction technique (control group). The VR group had preoperative left atrial diameters similar to those of the control group (67.1 +/- 7.8 vs 64.5 +/- 6.7 mm) and a longer preoperative duration of atrial fibrillation (14.1 +/- 5.4 vs 9.5 +/- 5.1 years, P < .05) but had smaller postoperative left atrial diameters (47.6 +/- 6.3 vs 62.1 +/- 7.9 mm, P < .01). There were no differences in mean crossclamp/bypass time and chest tube drainage for 12 hours between the groups. Twelve months after surgical intervention, the sinus rhythm recovery rate of the VR group was better than that of the control group (90% vs 69%, P < .05). Even in patients with long-standing atrial fibrillation and an enlarged left atrium, maze procedures concomitant with the novel left atrial volume reduction technique improved the sinus rhythm recovery rate without increasing complications. Although

  15. Network regularised Cox regression and multiplex network models to predict disease comorbidities and survival of cancer.

    PubMed

    Xu, Haoming; Moni, Mohammad Ali; Liò, Pietro

    2015-12-01

    In cancer genomics, gene expression levels provide important molecular signatures for all types of cancer, and this could be very useful for predicting the survival of cancer patients. However, the main challenge of gene expression data analysis is high dimensionality, and microarray is characterised by few number of samples with large number of genes. To overcome this problem, a variety of penalised Cox proportional hazard models have been proposed. We introduce a novel network regularised Cox proportional hazard model and a novel multiplex network model to measure the disease comorbidities and to predict survival of the cancer patient. Our methods are applied to analyse seven microarray cancer gene expression datasets: breast cancer, ovarian cancer, lung cancer, liver cancer, renal cancer and osteosarcoma. Firstly, we applied a principal component analysis to reduce the dimensionality of original gene expression data. Secondly, we applied a network regularised Cox regression model on the reduced gene expression datasets. By using normalised mutual information method and multiplex network model, we predict the comorbidities for the liver cancer based on the integration of diverse set of omics and clinical data, and we find the diseasome associations (disease-gene association) among different cancers based on the identified common significant genes. Finally, we evaluated the precision of the approach with respect to the accuracy of survival prediction using ROC curves. We report that colon cancer, liver cancer and renal cancer share the CXCL5 gene, and breast cancer, ovarian cancer and renal cancer share the CCND2 gene. Our methods are useful to predict survival of the patient and disease comorbidities more accurately and helpful for improvement of the care of patients with comorbidity. Software in Matlab and R is available on our GitHub page: https://github.com/ssnhcom/NetworkRegularisedCox.git. Copyright © 2015. Published by Elsevier Ltd.

  16. Effects of flavocoxid, a dual inhibitor of COX and 5-lipoxygenase enzymes, on benign prostatic hyperplasia

    PubMed Central

    Altavilla, D; Minutoli, L; Polito, F; Irrera, N; Arena, S; Magno, C; Rinaldi, M; Burnett, BP; Squadrito, F; Bitto, A

    2012-01-01

    BACKGROUND AND PURPOSE Inflammation plays a key role in the development of benign prostatic hyperplasia (BPH). Eicosanoids derived from the COX and 5-lipoxygenase (5-LOX) pathways are elevated in the enlarging prostate. Flavocoxid is a novel flavonoid–based ‘dual inhibitor’ of the COX and 5-LOX enzymes. This study evaluated the effects of flavocoxid in experimental BPH. EXPERIMENTAL APPROACH Rats were treated daily with testosterone propionate (3 mg·kg−1 s.c.) or its vehicle for 14 days to induce BPH. Animals receiving testosterone were randomized to receive vehicle (1 mL·kg−1, i.p.) or flavocoxid (20 mg·kg−1, i.p.) for 14 days. Histological changes, eicosanoid content and mRNA and protein levels for apoptosis-related proteins and growth factors were assayed in prostate tissue. The effects of flavocoxid were also tested on human prostate carcinoma PC3 cells. KEY RESULTS Flavocoxid reduced prostate weight and hyperplasia, blunted inducible expression of COX-2 and 5-LOX as well as the increased production of PGE2 and leukotriene B4 (LTB4), enhanced pro-apoptotic Bax and caspase-9 and decreased the anti-apoptotic Bcl-2 mRNA. Flavocoxid also reduced EGF and VEGF expression. In PC3 cells, flavocoxid stimulated apoptosis and inhibited growth factor expression. Flavocoxid-mediated induction of apoptosis was inhibited by the pan-caspase inhibitor, Z-VAD-FMK, in PC3 cells, suggesting an essential role of caspases in flavocoxid-mediated apoptosis during prostatic growth. CONCLUSION AND IMPLICATIONS Our results show that a ‘dual inhibitor’ of the COX and 5-LOX enzymes, such as flavocoxid, might represent a rational approach to reduce BPH through modulation of eicosanoid production and a caspase-induced apoptotic mechanism. PMID:22471974

  17. Effects of flavocoxid, a dual inhibitor of COX and 5-lipoxygenase enzymes, on benign prostatic hyperplasia.

    PubMed

    Altavilla, D; Minutoli, L; Polito, F; Irrera, N; Arena, S; Magno, C; Rinaldi, M; Burnett, B P; Squadrito, F; Bitto, A

    2012-09-01

    Inflammation plays a key role in the development of benign prostatic hyperplasia (BPH). Eicosanoids derived from the COX and 5-lipoxygenase (5-LOX) pathways are elevated in the enlarging prostate. Flavocoxid is a novel flavonoid-based 'dual inhibitor' of the COX and 5-LOX enzymes. This study evaluated the effects of flavocoxid in experimental BPH. Rats were treated daily with testosterone propionate (3 mg·kg(-1)  s.c.) or its vehicle for 14 days to induce BPH. Animals receiving testosterone were randomized to receive vehicle (1 mL·kg(-1) , i.p.) or flavocoxid (20 mg·kg(-1) , i.p.) for 14 days. Histological changes, eicosanoid content and mRNA and protein levels for apoptosis-related proteins and growth factors were assayed in prostate tissue. The effects of flavocoxid were also tested on human prostate carcinoma PC3 cells. Flavocoxid reduced prostate weight and hyperplasia, blunted inducible expression of COX-2 and 5-LOX as well as the increased production of PGE(2) and leukotriene B(4) (LTB(4) ), enhanced pro-apoptotic Bax and caspase-9 and decreased the anti-apoptotic Bcl-2 mRNA. Flavocoxid also reduced EGF and VEGF expression. In PC3 cells, flavocoxid stimulated apoptosis and inhibited growth factor expression. Flavocoxid-mediated induction of apoptosis was inhibited by the pan-caspase inhibitor, Z-VAD-FMK, in PC3 cells, suggesting an essential role of caspases in flavocoxid-mediated apoptosis during prostatic growth. Our results show that a 'dual inhibitor' of the COX and 5-LOX enzymes, such as flavocoxid, might represent a rational approach to reduce BPH through modulation of eicosanoid production and a caspase-induced apoptotic mechanism. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  18. 6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages.

    PubMed

    Pan, Min-Hsiung; Hsieh, Min-Chi; Hsu, Ping-Chi; Ho, Sheng-Yow; Lai, Ching-Shu; Wu, Hou; Sang, Shengmin; Ho, Chi-Tang

    2008-12-01

    Ginger, the rhizome of Zingiber officinale, is a traditional medicine with carminative effect, antinausea, anti-inflammatory, and anticarcinogenic properties. In this study, we investigated the inhibitory effects of 6-shogaol and a related compound, 6-gingerol, on the induction of nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with LPS. Western blotting and reverse transcription-PCR analyses demonstrated that 6-shogaol significantly blocked protein and mRNA expression of inducible NOS (iNOS) and COX-2 in LPS-induced macrophages. The in vivo anti-inflammatory activity was evaluated by a topical 12-O-tetradecanoylphorbol 13-acetate (TPA) application to mouse skin. When applied topically onto the shaven backs of mice prior to TPA, 6-shogaol markedly inhibited the expression of iNOS and COX-2 proteins. Treatment with 6-shogaol resulted in the reduction of LPS-induced nuclear translocation of nuclear factor-kappaB (NF kappaB) subunit and the dependent transcriptional activity of NF kappaB by blocking phosphorylation of inhibitor kappaB (I kappaB)alpha and p65 and subsequent degradation of I kappaB alpha. Transient transfection experiments using NF kappaB reporter constructs indicated that 6-shogaol inhibits the transcriptional activity of NF kappaB in LPS-stimulated mouse macrophages. We found that 6-shogaol also inhibited LPS-induced activation of PI3K/Akt and extracellular signal-regulated kinase 1/2, but not p38 mitogen-activated protein kinase (MAPK). Taken together, these results show that 6-shogaol downregulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NF kappaB by interfering with the activation PI3K/Akt/I kappaB kinases IKK and MAPK.

  19. A simple approach to power and sample size calculations in logistic regression and Cox regression models.

    PubMed

    Vaeth, Michael; Skovlund, Eva

    2004-06-15

    For a given regression problem it is possible to identify a suitably defined equivalent two-sample problem such that the power or sample size obtained for the two-sample problem also applies to the regression problem. For a standard linear regression model the equivalent two-sample problem is easily identified, but for generalized linear models and for Cox regression models the situation is more complicated. An approximately equivalent two-sample problem may, however, also be identified here. In particular, we show that for logistic regression and Cox regression models the equivalent two-sample problem is obtained by selecting two equally sized samples for which the parameters differ by a value equal to the slope times twice the standard deviation of the independent variable and further requiring that the overall expected number of events is unchanged. In a simulation study we examine the validity of this approach to power calculations in logistic regression and Cox regression models. Several different covariate distributions are considered for selected values of the overall response probability and a range of alternatives. For the Cox regression model we consider both constant and non-constant hazard rates. The results show that in general the approach is remarkably accurate even in relatively small samples. Some discrepancies are, however, found in small samples with few events and a highly skewed covariate distribution. Comparison with results based on alternative methods for logistic regression models with a single continuous covariate indicates that the proposed method is at least as good as its competitors. The method is easy to implement and therefore provides a simple way to extend the range of problems that can be covered by the usual formulas for power and sample size determination. Copyright 2004 John Wiley & Sons, Ltd.

  20. [Effect of M8046 on expression of COX-2/PGE2 in spinal cord and DRG in rats with neuropathic pain].

    PubMed

    Ou, Guo-Kun; Wang, Rui-Xian; Li, Jia-Jia; Cao, Hong; Lian, Qing-Quan; Li, Jun

    2013-03-01

    To investigate the effects of glucocorticoid receptor antagonist-M8046 on the behavior and the cyclooxygenase-2/prostaglandin E2( COX-2/PGE2) expression in spinal cord dorsal horn and dorsal root ganglia (DRG) in chronic constrictive injury (CCI) rats. One hundred and forty-four male SD rats were randomly divided into 4 groups, 36 rats in each group: Sham operation group (Sham), chronic constrictive group (CCI), M8046 treated group (M8046) and solvent controlled group (Sc). M8046 3 mg/(kg x d) intraperitoneal injection was given after operation in group M8046. Paw thennal withdrawal (PTWL) and paw mechanical withdrawal threshold (PMWT) of rats were measured on 2 pre-operative and 1, 3, 7, 10, 14 post-operative days. The spinal cord and L15 DRG of the operated side was removed at 3, 7, 14 days after surgery. The change of COX-2 and PGE2 expression was determined by immunohistochemical staining and ELISA separately. PTWL and PMWT in CCI group were significantly lower than those in Sham group on every post-operative day (P < 0.05). PTWL and PMWT in M8046 group were significantly higher than those in CCI group on 7, 10, 14 post-operative day (P < 0.05). In spinal dorsal horn, the level of COX-2 and PGE2 expression in CCI group was significantly higher than that in Sham group (P < 0.05). M8046 could significantly attenuate the activation of COX-2 and PGE2 induced by CCI (P < 0.05). The expression of COX-2 and PGE2 in DRG was similar to that in spinal dorsal horn. The effects of M8046 ameliorate the CCI-induced neuropathic pain may be related to attenuate the expression of COX-2 and PGE2 in spinal cord and DRG.