Month: February 2019

they indicate activation of residual cancer that is then therapeutically controlled by androgen deprivation. However, disseminated cancer cells often become androgen-independent, leading to another increase in circulating PSA levels and manifesting metastases. From the observation of the latter rise in PSA level to the appearance of symptomatic metastases, the disease does not exert symptoms affecting physical wellbeing. For this reason, no therapy is administered, lest the quality of life be adversely affected by chemotherapy that is currently used in terminal PCa. Thus, the period of asymptomatic PSA level increase has been considered appropriate for studies testing the efficacy of immunotherapy that is usually devoid of major adverse events. PCa immunotherapy has begun to yield encouraging clinical effects, though not a definitive cure. For example, partial responses have been Methoxsalen induced by autologous transfer of ex vivo activated antigen presenting cells, cytokine-secreting tumor vaccines, vaccines containing recombinant proteins or nucleic acids and other cell-based strategies targeting cancer antigens, such as PSA or prostate-specific membrane antigen. Most recently, a treatment employing ex vivo processed autologous antigen presenting cells combined with prostatic acid Ginsenoside-Rb2 phosphatase has received regulatory approval for treatment of metastatic PCa. In a recent phase 2 clinical study, an allogeneic PCa wholecell vaccine stimulated expansion of tumor-specific immune cells in non-metastatic androgen-independent PCa patients. The treatment was safe, and the rate of PSA increase was reduced in 11 out of the 26 studied patients. Yet, the patients demonstrated a significant variability in response to treatment, that could be due to differences in individual immune history and tumor biology. Suppressed immunity in PCa patients could also contribute to the relative lack of efficacy of PCa immunotherapy. Restoring and enhancing immunity should be a major goal of immunotherapy, yet the complexity of immune system defies the attempts to achieve it. For that reason, immunity has been often studied by mathematical modeling. Mathematical modeling has been a valuable tool in describing, quantifying and predicting the behavior of complex systems. In particular, mathematical models have played an important role in providing non-intuitive insights into tumor growth and progression, tumor-associated angiogenesis, and evolution of drug resistance. Mathematical models have been successfully validated and applied for rational design of cancer therapy, for optimizing efficacy while minimizing toxicity, and for streamlining drug discovery and development. More recently, cytokine-based and cellular immunotherapy have been modeled and scrutinized, and some models were validated experimentally and clinically.

However, we found no evidence of FV replication in FDCs which are the spleen cell population infected by prions in vivo. It remains possible that co-infection of FDCs by other viruses could modify prion infection. Retroviral co-infection could also have had Pimozide indirect effects on prion disease. Follicular dendritic cells are reticular networkforming cells in lymphoid follicles that retain antigen for long periods of time for presentation to B cells, but little is known about their ontogeny and whether they simply migrate to follicles or divide there. Lymphotoxin a/b secreted by B lymphocytes activates FDCs and activated FDCs are important sites of prion replication. It has been suggested that lymphotoxin a/b-triggered differentiation of FDCs is a mechanism by which inflammation could cause prions to replicate in tissues not normally associated with prion infection. Thus, it was also possible that FV infection could indirectly influence prion disease progression via lymphotoxin a/b activation of FDCs. This could lead to increased levels of PrPSc in the spleen during both the acute and chronic phases of FV infection potentially decreasing prion disease incubation times. However, we observed neither a change in prion disease incubation time nor an increase in the levels of FDCs or PrPSc in the spleens of infected mice. Our results suggest that, at most, any indirect effect of FV on prion disease in vivo is either too minor or too transient to have an impact on progression to clinical disease. Our data demonstrating that inflammation in the spleen does not alter prion disease incubation times, brain pathology, or PrPSc levels are consistent with other studies showing that inflammation in peripheral organs, while it can affect the tissue distribution of prion infectivity, does not affect the normal progression of prion disease or lead to early death in mice. By contrast, Cinoxacin intracerebral inoculation of mouse adenovirus at various times post-scrapie infection significantly reduced disease incubation times, albeit without apparently altering scrapie pathology. Furthermore, inducing inflammation in the brain early during prion infection led to a rapid and fatal neurological disease even though PrPSc levels were not affected. In this latter instance, the acceleration of neurological disease in scrapie-infected mice was likely due to the host response to acute inflammation in the CNS rather than to an increase in prion replication. When taken together with the current study, the data suggest that prion infected mice are much more susceptible to the detrimental effects of viral co-infection of or damage to prion-infected CNS tissues rather than to prion-infected peripheral tissues. Prostate cancer is the second most common malignancy in men. Primary treatment includes prostatectomy and/or radiation therapy.