Role Of Nitric Oxide In Interleukin-2 Therapy-induced Capillary Leak Syndrome

Systemic interleukin-2 (IL-2) therapy has been limited by a major side effect known as capillary leak syndrome , characterized by retention of extravascular fluid, severe hypotension, and multiple organ system dysfunction. The present study tested the hypothesis that an overproduction of nitric oxide (NO) induced by IL-2 therapy was, at least in part, responsible for this syndrome. Studies were undertaken in healthy or C3-L5 mammary adenocarcinoma bearing C3H/HeJ mice to evaluate whether treatment with inhibitors of NO synthesis (N{dollar}\rm\sp{lcub}G{rcub}{dollar}-Methyl-L-Arginine, NMMA and N{dollar}\rm\sp{lcub}G{rcub}{dollar}-Nitro-L-Arginine methyl ester, L-NAME) can prevent IL-2 induced capillary leakage without compromising the therapeutic benefit of IL-2. Intraperitoneal IL-2 therapy in both groups of mice caused substantial capiliary leakage, and a substantial rise in NO production in vivo. Addition of subcutaneous NMMA failed to ameliorate IL-2 induced capillary leakage, or NO overproduction, and did not compromise antitumor effects of IL-2. Subcutaneous NMMA alone reduced primary tumor growth, spontaneous pulmonary metastasis and tumor-induced pulmonary edema. Chronic administration of NMMA by the oral route, however, succeeded in abrogating IL-2 induced NO overproduction as well as capillary leakage in healthy mice.;L-NAME given chronically in the drinking water led to a parallel reduction in the IL-2 therapy-induced NO overproduction and capillary leakage in healthy mice. IL-2 therapy (1) caused structural damage to the lungs and its capillaries; (2) induced inducible type NO synthase (iNOS) expression in numerous tissues, including the endothelium, muscles of the anterior thoracic wall and splenic macrophages; (3) induced a high NOS activity in the lungs and the anterior thoracic wall of animals exhibiting pulmonary edema and pleural effusion. Addition of L-NAME therapy totally abolished NOS activity, but not necessarily iNOS expression, and significantly restored structural integrity of the lungs in conjunction with an amelioration of pulmonary edema and pleural effusion. These results strongly suggested that local NO overproduction, resulting from an induction of iNOS enzyme by IL-2 therapy, was responsible for the structural damage and consequent fluid leakage from the capillaries.;In mammary adenocarcinoma bearing mice, oral L-NAME alone produced significant antitumor as well as antimetastatic effects. L-NAME in combination with IL-2 therapy in these mice succeeded in ameliorating IL-2 induced as well as tumor-induced capillary leakage and potentiated tumor reductive function of IL-2. An abrogation of IL-2 induced NO production by L-NAME treatment in vivo as well as in vitro markedly stimulated IL-2 induced generation of antitumor cytotoxicity of splenocytes of healthy as well as tumor-bearing mice. IL-2 induced increase in NO production interfered with optimal lymphokine activated killer (LAK) cell activation which can be overcome by NO inhibition with L-NAME therapy.;NO apparetnly promoted tumor progression in the C3-L5 mammary tumor model. Tumor cells as well as endothelium of the tumor vasculature were identified as the source of NO within the tumor. Immunoreactive endothelial type NOS (eNOS) was detected in both cell classes within the primary as well as metastatic tumors. Furthermore, C3-L5 cells in vitro were positive for eNOS and expressed iNOS when incubated with LPS+IFN{dollar}\tau.{dollar} Treatment with NO inhibitors NMMA or L-NAME, reduced in vitro invasive ability of C3-L5 tumor cells, which was restored by addition of excess L-arginine. Treatment with IFN{dollar}\tau{dollar}+LPS stimulated NO production by these cells and also stimulated their invasiveness. Thus, NO production by the tumor cells promoted tumor cell invasiveness. (Abstract shortened by UMI.

Using Noerr-Pennington Doctrine’s Sham Exception to Challenge Abusive Patent Tactics by Pharmaceutical Companies

Outrageous drug prices have dominated news coverage of the American healthcare system for years. Yet despite widespread condemnation of skyrocketing drug prices, nothing seems to change. Pharmaceutical companies can raise drug prices with impunity because they hold patents on their drugs, which give them monopolies. These monopolies are only supposed to last twenty years, and then competing lower-cost drugs like generics can enter the market, driving down the costs of pharmaceuticals for all. But pharmaceutical companies have created “patent thickets,” dense webs of overlapping patents surrounding one drug, which have artificially extended the companies’ monopolies for years or even decades after a drug’s initial patent expires. These problems will only be exacerbated as the pharmaceutical industry increasingly focuses on biologic drugs, which already provide more opportunities to acquire multiple patents on one drug than traditional small-molecule drugs. Patent law’s weapons in the fight against patent thickets, namely litigation and inter partes reviews (an abbreviated process for challenging patent validity), have proven to be inadequate-—a scalpel when the public needs a machete. Antitrust law, which polices anticompetitive behavior and corrects market failures, is the ideal weapon to fight the pharmaceutical industry’s exploitation of patent law. The Noerr-Pennington doctrine, which immunizes parties from antitrust liability when a party “petitions” the government, currently stands in the way of an antitrust solution to the patent-thicket problem. “Petitions” eligible for Noerr-Pennington antitrust immunity include patent applications and patent-infringement lawsuits, so the pharmaceutical industry can wield the Noerr-Pennington doctrine as a sword against potential antitrust challenges. The Noerr-Pennington doctrine has a narrow “sham exception,” where Noerr-Pennington antitrust immunity is pierced when a party’s petitions are “mere shams” to interfere with the operations of a competitor. Unfortunately, after two Supreme Court decisions about the sham exception, the circuit courts have disagreed on the sham exception’s operation, leaving potential antitrust plaintiffs, such as consumers and government regulators, with uncertain prospects for challenging patent thickets under antitrust law. This Note proposes that courts adopt an approach to reconcile the Supreme Court decisions wherein courts apply a stricter standard for invoking the sham exception when an antitrust plaintiff challenges a single sham petition and a looser standard when an antitrust plaintiff challenges a pattern of sham petitions. Further, this Note proposes a general framework for analyzing patent proceedings under the looser pattern standard. This solution strikes a balance between protecting parties First Amendment petitioning right and discouraging abuse of the patent law system for anticompetitive effect. If successful, antitrust challenges can lead to quicker market entry for lower-cost drugs and allow more people to benefit from innovative and life-altering drugs

The Correlation Between Online Marketing Strategies and Fundraising Performance of Nonprofit Organizations

Through primary and secondary data collection, this research explores the correlation between online marketing strategies and fundraising performance of small nonprofits. The purpose of this research was to identify the needs and challenges of small nonprofit organizations\u27 marketing departments, in order to create a new marketing strategy that would help them reach their goals. The study identified several problems which small nonprofits commonly face. As a result, a new Influencer Marketing Platform has been designed, with an intent to solve the issues of volunteer based or part-time marketing staff, the lack of budgets for promotional campaigns, and the inability to create appropriate social media content

Transmittance and near-field characterization of sub-wavelength tapered optical fibers

We have produced high transmission sub-wavelength tapered optical fibers for the purpose of whispering gallery mode coupling in fused silica microcavities at 780 nm. A detailed analysis of the fiber transmittance evolution during tapering is demonstrated to reflect precisely the mode coupling and cutoff in the fiber. This allows to control the final size, the number of guided modes and their effective index. These results are checked by evanescent wave mapping measurements on the resulting taper

Quality definitions and measurements in software engineering experiments on pair programming

Oppgaven analyserer 15 forskningsartikler og presenterer en oversikt over hvordan kvalitet er definert og målt i disse artiklene. Alle artiklene omhandler par programmering. Stikkord: Par programmering, programvareutvikling, kvalitetsdefinisjon, kvalitetsmål, produktkvalitetesmål, prosesskvalitetsmål, subjektive og objektive mål

Bruk av målsetting i byggeprosjekter

Masteroppgave i industriell økonomi og teknologiledelse IND590 2013 – Universitetet i Agder, GrimstadBakgrunnen for tema er prosjektledelse og styring i bygg- og anleggsbransjen, med fokus på mål og målsetting. Interessen for dette kom fra arbeid med temaet i studiet og generell interesse for næringen. Teorien sier at det er viktig å etablere klare mål i en tidlig fase av prosjektet. S.M.A.R.T.e mål er en fremgangsmåte for å danne helhetlige mål som er rele-vante. Dette gir et godt styringsgrunnlag som skaper gode forutsetninger for suksess. For å komme nærmere innpå suksessoppnåelse, beskriver teorien suksessfaktorer og –kriterier som viktige fokusområder. Prosjektledelsen må drive med oppfølgning og styring, samt være bevisste på bruken av korrektive tiltak for å kunne rettlede prosjektet mot de planlagte målene. Det er ofte kostnadsoverskridelser og mangler i byggeprosjekter, og dette førte til følgende problemstilling: Hvordan er bruken av mål i byggprosjekter, og hvor klare (S.M.A.R.T.e) er disse målene? For å finne ut hva som er kjent rundt den problemstillingen, ble det foretatt en litteraturstu-die. Erfaringene fra dette ble grunnlaget for spørreundersøkelsen og intervjuet. Bruken av disse to illustrerer hvordan det er brukt både kvantitative og kvalitative metode, noe som gir muligheten for metodetriangulering. Fokuset for undersøkelsen var å få spredning i respondentenes funksjoner i prosjekter, for å sikre empirien god kvalitet. Resultatet av den kvantitative datainnsamlingen ble samlet i et dataanalyseringsprogram (SPSS), og sortert etter prosjektfunksjoner, bransjeerfaring og lignende. Den kvalitative delen, som består av åpne spørsmål og intervju, ble kategorisert og analysert. Analysen av empirien resulterte i flere overraskende funn. I byggeprosjekter er det en varierende forstå-else av hva mål innebærer, og det blandes ofte med krav og rammebetingelser. Det er også antydninger til mangel på klare prioriteringer rundt mål og målsetting, noe som er bekym-ringsverdig. Funn gjort i analysen tyder på at brukernes forventninger ikke blir tatt nok hensyn til i henhold til hva teorien beskriver

Analysis of IPTV Channels Watching Preferences in Bosnia and Herzegovina

IPTV service is a new service which is today offered from almost every Telecom operator. One of the advantages of IPTV service stemming from its architecture is certainly the fact that it is very easy to measure what TV channels are the ones mostly watched. This papers desribes this measurement and analysis results in one Telecom operator in Bosnia and Herzegovina. They describe what TV channels are mostly watched in different time periods. We developed a simple weighting algorithm to order the channels by watching rate. Based on it we are providing extensive tables. This paper forms an industrial contribution with results important for marketing but also is scientific contribution because it introduces one new method of scoring TV channels based on previous measurements in their audience. We also developed IPTV Statistics model and described results from this research for a new statistics model. This paper is the continuous of previously published contributions from this area