O7 BIOLOGICAL ACTIVITIES OF CHEMOKINES AND THEIR RECEPTORS IN THYROID CANCER Melillo RM 1 ; , Guarino V 1 ; , De Falco V 1 ; , Avilla E 1 ; , Basolo F 2 ; , Faviana P 2 ; , Giannini R 2 ; , Salvatore G 1 ; , Salerno P 1 ; , Santoro M 1 ; Istituto di Endocrinologia ed Oncologia Sperimentale del CNR "G. Salvatore", Dipartimento di Biologia e Patologia Cellulare e Molecolare, University "Federico II", Naples 1 Dipartimento di Oncologia, Pisa 2 ; , Italy Human papillary thyroid carcinomas PTCs ; are characterized either by rearrangements of the RET receptor RET PTC ; , or by activating mutations in the BRAF or RAS oncogenes. These genes are part of the same signalling pathway and these gene mutations are mutually exclusive in PTCs. We previously showed that the activation of the RET PTC-RAS-BRAF-ERK pathway in PTC cells induces the expression of a complex transcriptional programme which includes genes encoding for chemokine and chemokine receptors. In particular, we found up-regulation of CXCR2 and CXCR4. CXCR2 is the receptor for several chemokines, among which CXCL1, 2, 3 and is the low affinity receptor for IL-8. PTC cells also overexpress CXCL1 and IL-8, that, with CXCR2, generate autocrine loops. CXCR4 is the receptor for one chemokine, SDF1, that is not expressed by PTC cells, but is generally expressed by stromal cancer cells. Furthermore, we showed that these chemokines n induce proliferation, survival and motility of both rat and human PTC-derived cancer cells. To investigate whether the expression of these molecules is maintained in the progression from PTC to anaplastic thyroid cancer ATC ; , we screened human ATCderived cells for the expression of these molecules and found expression of CXCR2 and CXCR4. Most of the ATC-derived cell lines also secreted the chemokines CXCL1 and IL-8, but not SDF-1. We also found that 30-40% of human ATC tumor samples expressed CXCR4. Moreover, treatment of ATC cells with CXCL1, Il-8 or SDF1 mediated cell proliferation, survival and chemoinvasive ability, and these effects could be reverted by several blocking reagents. These results suggest a possible use of small compounds with inhibitory activity toward CXCR2 and CXCR4 as novel anti-cancer therapies for ATC. O8 MENSTRUAL AND REPRODUCTIVE FACTORS IN THE RISK OF THYROID CARCINOMA IN FRENCH POLYNESIA: A POPULATION-BASED CASE-CONTROL STUDY Brindel P. 1 ; , Doyon F. 1 ; , Rachedi F. 2 ; , Boissin J.L., Sebbag J. 3 ; , Shan L., Yen Kai Sun L. 4 ; , Bost-Bezeaud F. 2 ; , Petitdidier P. 5 ; , Morales P. 1 ; , Schlumberger M. 6 ; , Caillou B. 6 ; , Paoaafaite J. 7 ; , Teuri J. 7 ; , de Vathaire F. 1 ; Unit 605 INSERM, Institut Gustave Roussy, Villejuif, France 1 Centre Hospitalier Territorial de Mamao, Tahiti, Polynsie Franaise 2 Clinique Paofai, Papeete, Tahiti, Polynsie Franaise 3 Registre des Cancers de Polynsie Franaise, Bureau de la Veille Sanitaire, Papeete, Tahiti, Polynsie Franaise 4 Laboratoire Boz, Papeete, Tahiti, Polynsie Franaise 5 Institut Gustave Roussy, Villejuif, France 6 Institut de Recherche pour le Dveloppement, Papeete, Tahiti, Polynsie Franaise 7 ; A case-control study on thyroid cancer conducted in French Polynesia FP ; , where thyroid cancer incidence is very high, included 529 women born and residing in FP: 203 cases of differentiated thyroid carcinoma diagnosed between 1979 and 2004 and aged less than 55 at diagnosis, matched on birth date to 326 controls randomly selected from FP registry of births. Face to face interviews conducted from 2002 to 2004 collected ethnic group, lifetime weight evolution and menstrual and reproductive factors. Odds ratios OR ; adjusted for ethnic group, educational level, height, body mass index BMI ; and interviewer were calculated using conditional logistic regression. Papillary carcinoma represented 78% of cases. Cases had a lower educational level and a higher weight, height and BMI than controls, but no difference in ethnic group was observed, with 54% of Polynesians in both groups. Risk of thyroid cancer increased with age at menarche p 0.09 ; , natural menopause OR 4, 2 ; or artificial menopause OR 6.8 ; as compared to still menstruating women, but was not related to irregular menstrual cycles or age at menopause. Risk of thyroid cancer increased with number of births p 0.003 ; : risks associated to 1, 2, 3, or 5, and 8 or more births being, respectively, 0.90, 1.7, 2.3, and 1.7, compared to nulliparous women. Similar results were observed in Polynesian women. No association was observed with history of miscarriage or induced abortion, time since last birth, age and outcome at first pregnancy, and lactation. This study confirms the role of menstrual and reproductive factors in the risk of differentiated thyroid cancer in Pacific islands populations. Work supported by ARC Association pour la Recherche sur le Cancer ; , DGS Direction Gnrale de la Sant ; , Committee of Radioprotection of EDF Electricit de France ; , AFSSE Agence Franaise de Scurit Sanitaire Environnementale ; , and CHILD-THYR EEC programme.
That the only surprising thing about the Healy affair was that the University had sought to hire me in the first instance. That the research design of my healthy volunteer study was flawed. That I had not declared conflicts of interest. Coyne claimed the Globe and Mail approached him when the affair first surfaced but then accused him of maintaining his views only because he was in receipt of pharmaceutical company funds. This he denied. It later transpired that Coyne was a member of advisory boards for both Lilly and SolvayDuphar. He also had links to Chamberlain Communications. Apparently senior figures in CAMH or the University of Toronto suggested to the Globe and Mail that Coyne be approached to get another side on the Healy affair. The position taken by the University and CAMH at this point was that the clinical domain produced its own set of particular issues when it came to academic freedom. The usual rules, it was suggested, couldn't apply when vulnerable patients were likely to be affected by what was said. To allow a critic like me to denigrate a treatment like the SSRIs would be like letting a fool cry "Fire!" in a crowded theatre. The need for extra caution in the clinical domain has long been recognized. This is precisely why regulations have been put in place--to limit the abilities of quacks to sell worthless treatments to vulnerable people. But speaking out about the hazards of treatment was exactly why drug treatments were made prescription-only. Keeping quiet about a known hazard de facto breaks the spirit of the law, whatever the letter of the law may be. By this time, the Canadian Association for University Teachers CAUT ; had lobbied the University and others on my behalf. They got no more response than I. In September a letter signed by 29 senior figures in the field-- including two Nobel Prize winners, former presidents of the American Psychiatric Association, the American College of Neuropsychopharmacology, and a range of other psychiatric and psychopharmacological organizations worldwide--was sent to U of President Robert Birgenau, protesting the violation of academic freedom involved in "the Healy case." There was input from Europe, North and South America, Japan, China, and Australia, for example, imdur 120.
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Neurotransmitter, but is also utilized for muscle tone regulation. The third NOS isoform, iNOS, is inducible in virtually all mammalian cells by a variety of proinflammatory stimuli. All three purified isoforms of NOS can generate O2- in the absence of the essential co-factor, tetrahydrobiopterin BH4 ; 48-51 ; . Also, NOS enzymes are "NADPH oxidases" that are inhibitable by DPI 52 ; . Recently, evidence has emerged that BH4 depletion may cause NOS-dependent O2generation in cultured cells and in vivo under certain conditions 53-55 ; . For example, in smokers but not healthy subjects, infusion of BH 4 improves forearm blood flow 53 ; . This suggests that NOS may be a source of O2- in vascular disease.

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