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As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the inhibition of the NF-κB inducing kinase (NIK), a key enzyme of the NF-κB alternative pathway activation, represents a potential interesting approach. In fact, NIK is involved downstream of many tumor necrosis factor receptors (TNFR) like CD40, RANK or LTβR, implicated in the pathogenesis of RA. But, up to now, the number of reported putative NIK inhibitors is extremely limited. In this work, we report a virtual screening (VS) study combining various filters including high-throughput docking using a 3D-homology model and ranking by using different scoring functions. This work led to the identification of two molecular fragments, 4H-isoquinoline-1,3-dione (5) and 2,7-naphthydrine-1,3,6,8-tetrone (6) which inhibit NIK with an IC50 value of 51 and 90 μM, respectively. This study opens new perspectives in the field of the NF-κB alternative pathway inhibition. © 2010 Elsevier Ltd. All rights reserved.

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Background and purposes: The, appropriate application of 3-D conformal radiotherapy, intensity modulated radiotherapy or image guided radiotherapy for patients undergoing radiotherapy for prostate cancer requires a standardisation of target delineation as well as clinical quality assurance procedures. Patients and methods: Pathological and imaging studies provide valuable information on tumour extension. In addition, clinical investigations on patient positioning and immobilisation as well as treatment verification data offer an abundance of information. Results: Target volume definitions for different risk groups of prostate cancer patients based on pathological and imaging studies are provided. Available imaging modalities, patient positioning and treatment preparation studies as well as verification procedures are collected from literature studies. These studies are summarised and recommendations are given where appropriate. Conclusions: On behalf of the European Organisation for Research and Treatment of Cancer (EORTC) Radiation Oncology Group this article presents a common set of recommendations for external beam radiotherapy of patients with prostate cancer. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

PURPOSE: Between 1978 and 1998, 533 prostate adenocarcinoma patients were treated with mixed photon-neutron radiotherapy. We report on a retrospective series of patients for whom the side effects of the treatment and their impact on quality of life were assessed by a mailed questionnaire. METHODS AND MATERIALS: The European Organization for Research and Treatment of Cancer quality-of-life core questionnaire and a prostate-specific questionnaire were used. Between 1990 and 1996, 308 consecutive patients were treated. Two protocols were used: pelvic fields (50 Gy equivalent photons, 2 Gy/fraction) followed by a prostate boost (66 Gy) or prostate alone. The neutron/photon ratio varied. The questionnaire was mailed to 262 patients presumed to be alive. RESULTS: Of the 262 patients, 230 replied. Of the 230 patients, 73% had no trouble doing strenuous activities and 4% had trouble with taking a short walk. The overall physical condition and quality-of-life questions received a mean score of 5.2 and 5.3 on a 7-point scale, respectively. Twenty-two percent had bowel movements at least four times daily, and 6% did so six times or more. Retaining stool was a problem in 26%, and only 38% reported full continence; 17% urinated four times or more nightly. Urinary incontinence was scored as "quite a bit" or "very much" in 11% and 5%, respectively. Hematuria and dysuria (pain) were reported by 7% and 16%, respectively, mainly as moderate. Only 28% reported easy erections, but 75% judged the sexual change acceptable. A greater neutron/photon ratio was significantly associated with more bowel problems (p = 0.003). CONCLUSION: Mixed photon-neutron therapy for prostate cancer was associated with significant patient-reported side effects. Their significant effect on patients' quality of life is described.

Though lots of numerical methods have been proposed in the literature to optimize me-chanical structures at the final stage of the design process, few designers use these tools since the first stage. However, a minor modification at the first step can bring significant change to the global performances of the structure. Usually, during the initial stage, models are based on theoretical and empirical equations, which are often characterized by mixed variables: continuous (e.g. geometrical dimensions), discrete (e.g. the cross section of a beam available in a catalogue) and/or integer (e.g. the number of layers in a composite material). Furthermore, the functions involved may be non differentiable, or even discontinuous. Therefore, classical algorithms based on the computation of sensi-tivities are no more applicable. Consequently, to solve these problems, the most wide-spread meta-heuristic methods are evolutionary algorithms (EAs), which work as follows: the best individuals among an initial population of randomly generated potential solutions are favoured and com-bined (by specific operators like crossover and mutation) in order to create potentially better individuals at the next generation. The creation of new generations is repeated till the convergence is reached. The ability of EAs to explore widely the design space is useful to solve single-objective unconstrained optimization problems, because it gener-ally prevents from getting trapped into a local optimum, but it is also well known that they do not perform very efficiently in the presence of constraints. Furthermore, in many industrial applications, multiple objectives are pursued together. Therefore, to take into account the constrained and multicriteria aspects of optimization problems in EAs, a new method called PAMUC (Preferences Applied to MUltiobjectiv-ity and Constraints) has been proposed in this dissertation. First the user has to assign weights to the m objectives. Then, an additional, Doctorat en sciences appliquées, info:eu-repo/semantics/nonPublished

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PURPOSE: To retrospectively evaluate survival, progression-free survival (PFS) and biological response in a series of patients irradiated with mixed neutron/photon beams for locally advanced prostate cancer in our institution. PATIENTS AND METHODS: Three hundred and eight patients were treated between January 1990 and December 1996. Fifty-five of these were recruited for pT3 or pN1 tumors after radical prostatectomy. Neoadjuvant androgen deprivation was given in 106 patients. The treatment protocol consisted of a mixed photon/neutron irradiation in a two-to-three proportion, up to a total equivalent dose of 66 Gy (assuming a clinical RBE value of 2.8). Pre- and post-treatment PSA determinations were available in practically all cases. Study endpoints were overall survival (OAS) and progression-free survival (PFS). The Cox proportional hazard regression model was used to investigate the prognostic value of baseline characteristics on survival and progression-free survival were a progression was defined as local, regional, metastatic or biological progression. Mean age was 69 years (49-86); mean pretreatment PSA was 15 (0.5-330) in all patients and 14 (0.5-160) in those receiving neoadjuvant hormonotherapy; seven patients only had an initial PSA < or = 4 ng/mL; 15% were T1, 46% were T2, 28% were T3 or pT3 and 4% were T4 (7% unspecified); WHO grade of differentiation was I in 38%, II in 38% and III in 14% (5% unspecified). RESULTS: The median follow-up was 2.8 years (0-7.8). Five-year overall survival (OAS) was 79% (95% CI: 71-87%) and 5-year progression-free survival (PFS) was 64% (95% CI: 54-74%) for the entire series. PFS in patients with an initial PSA > or = 20 ng/mL was the same. PFS could be predicted by two optimal Cox regression models, one including histological grade (p = 0.003) and initial PSA (p = 0.0009) as cofactors, the other including histological grade (p = 0.003) and T stage (p = 0.02). The main prognostic factors for overall survival were PSA and ag