Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts.

BACKGROUND: Growing evidence supports the idea that de novo steroidogenesis has an important role in prostate cancer's progression to the castration-resistant state following androgen deprivation therapy. Therefore, reducing the availability of cholesterol for use as a precursor in androgen synthesis may reduce proliferation and disease progression. METHODS: LNCaP xenograft-bearing mice were castrated and administered simvastatin via diet, and tumor volume and PSA concentration were monitored for 8 weeks post castration. Levels of serum and intratumoral androgens along with serum simvastatin and common toxicity markers were measured at end point. RESULTS: Reduced post-castration tumor growth rate in simvastatin-treated mice correlated with delayed time to castration-resistant progression, determined by two serum PSA doublings from post-castration nadir, when compared with xenografts in mice on control diet. At 8 weeks post castration, serum simvastatin levels were comparable to clinically relevant human doses with no evidence of overt muscle or liver toxicity. This suppressed post-castration tumor growth in the simvastatin diet group was correlated with reduced intratumoral testosterone and dihydrotestosterone levels. CONCLUSIONS: Reduced tumor growth and intratumoral androgen levels observed in simvastatin-treated, castrated mice harboring LNCaP xenograft suggests that suppressing de novo steroidogenesis can delay castration-resistant progression of this tumor model.

Identification of a potent anti-IL-15 antibody with opposing mechanisms of action in vitro and in vivo.

BACKGROUND AND PURPOSE: Interleukin-15 (IL-15) is important in the activation and proliferation of lymphocytic cell populations and is implicated in inflammatory disease. We report the characterization of a novel monoclonal antibody DISC0280 which is specific for human IL-15. EXPERIMENTAL APPROACH: DISC0280 was characterized in a direct binding assay of IL-15 with IL-15 receptor α (IL-15Rα) and by its ability to alter IL-15 mediated proliferation of a range of cell lines (cytotoxic T lymphocyte line-2, M-07e, KIT225). A pharmacodynamic model injecting male C57/BL6 mice with IL-15 or IL-15/IL-15Rα, with or without DISC0280, and assessing changes in lymphocytic cell populations and serum cytokines was utilized. KEY RESULTS: DISC0280 inhibited the binding of IL-15 to IL-15Rα and also potently inhibits IL-15 dependent proliferation of cells expressing IL-15Rα, shared interleukin 2/ interleukin 15 receptor ß chain (IL-15Rß) and common gamma chain (γ(c) ). DISC0280 also inhibited the IL-15 dependent proliferation of M-07e cells that only express IL-15Rß/γ(c) subunits. Human IL-15 injected into mice caused an increase in NK1.1(+) and CD3(+) cells in the spleen and peripheral blood and these effects were unexpectedly potentiated by giving DISC0280 with human IL-15. This increase in cells caused by DISC0280/IL-15 co-administration was greater than that observed when IL-15 was administered complexed with soluble IL-15Rα. CONCLUSIONS AND IMPLICATIONS: The ability of DISC0280 to bind to the IL-15Rα-binding site on IL-15 allows trans-presentation of IL-15 by DISC0280 in vivo, similar to the trans-presentation by soluble IL-15Rα. DISC0280 may be therefore suitable as a clinical substitute for IL-15.

Disability and quality of life in schizophrenia and obsessive compulsive disorder: a cross-sectional comparative study.

OBJECTIVE: To assess and compare the quality of life and disability in patients with schizophrenia and obsessive compulsive disorder. METHODS: A cross-sectional study was carried out in the outpatient psychiatry clinics at Jaipur of India. Fifty patients with obsessive compulsive disorder and 47 with schizophrenia (diagnosed as per criteria of the 10th revision of the International Classification of Diseases), and with a minimum duration of 2 years on maintenance treatments, were evaluated. Evaluation was based on the World Health Organization Quality of Life Instrument, the Global Assessment of Functioning scale, and the Indian Disability Evaluation Assessment Scale. The collected data were analysed using descriptive and inferential statistics. RESULTS: Regarding quality of life domains, there was no statistically significant difference between the 2 groups. Obsessive compulsive disorder patients had lower scores on all domains of disability, all such differences being statistically significant. CONCLUSIONS: The deleterious effect of illness on quality of life and functioning occur not only in schizophrenic but also in obsessive compulsive disorder patients. Thus management should be planned with this consideration to yield better outcomes in both conditions.

Correlation of gene and mediator expression with clinical endpoints in an acute interleukin-1beta-driven model of joint pathology.

OBJECTIVE: Interleukin-1beta (IL-1beta) plays a key role in the pathogenesis of chronic joint diseases, including osteoarthritis (OA), and drives a cascade of inflammatory and destructive responses within the synovial joint. Animal models of arthritis support the role of IL-1beta in joint pathology, however, the molecular changes downstream of IL-1beta are poorly understood in vivo. This study aimed to evaluate the intra-articular (i.a.) injection of IL-1beta in the rat joint as an acute model of joint disease and associate gene and mediator expression with clinical endpoints and pathological changes. METHODS: The effects of i.a. administration of a pathologically relevant dose of IL-1beta on joint swelling, mechanical hyperalgesia, histopathology, gene expression and biochemical changes were measured from 2 to 24h. RESULTS: IL-1beta-induced joint swelling and mechanical hyperalgesia. Gene expression analysis of joint tissue and biochemical analysis of joint lavage fluid identified pro-inflammatory and destructive mediators induced by IL-1beta. Histopathology of joint tissues showed evidence of synovitis and connective tissue inflammation, but not cartilage destruction. However, biochemical analysis of glucosaminoglycan levels in joint lavage fluids indicated cartilage breakdown and might be a sensitive marker of cartilage pathology. CONCLUSIONS: Intra-articular injection of IL-1beta is a reproducible acute model of joint pathology that is potentially useful to evaluate IL-1 pathway inhibitors. The correlation of molecular events with clinical and pathological changes in this model has enhanced the understanding of the role of IL-1beta in joint disease. Methods developed for gene expression analysis using multi-gene microfluidics cards and for biochemical analysis of joint lavage fluid might have utility for characterisation of other arthritis models and corresponding human disease.

The need to redefine the practice of health promotion in the United Kingdom.

It is argued that since the late 1970s the practice of health promotion within the UK has become, at least in part, bound up with the ideological bias of Conservative political thinking. The shift in political thought that occurred with the advent of Thatcherism, a shift characterised by individualism as opposed to collectivism and consensus politics of earlier decades, has heralded a belief in the paramount importance of the responsibility of the individual for maintaining a healthy lifestyle. This strategy fails to consider the social, cultural, and economic context within which individuals find themselves over which little or no control can be exercised. A politicisation of the concept of health promotion has thus taken place which has placed the emphasis on the over-riding responsibility of the individual for his or her health. Such a selective approach to health is inefficient. It is further argued that a purely structuralist perspective, one that negates the influence of the individual, is equally inefficient. If the new Labour administration is to promote the population's health to any more effective manner it must be recognised that while the individual does have a distinct role to play in his or her own health, that individual must also be considered within his or her social, cultural and economic context. An holistic approach to promoting the health of the population must be multi-factorial acknowledging the influence of social, cultural, economic and medical factors, as well as the role of the individual.