Increased dietary and circulating lycopene are associated with reduced prostate cancer risk: a systematic review and meta-analysis.

BACKGROUND: Prostate cancer (PCa) is the fifth leading cause of cancer-related deaths worldwide. Many epidemiological studies have investigated the association between prostate cancer and lycopene, however, results have been inconsistent. This study aims to determine the impact of dietary and circulating concentrations of lycopene on PCa risk and to investigate potential dose-response associations. METHODS: We conducted a systematic review and dose-response meta-analysis for the for the association between dietary and circulating lycopene and PCa risk. Eligible studies were published before 1 December 2016 and were identified from PubMed, Web of Science and the Cochrane Library. We estimated pooled relative risk ratios (RR) and 95% confidence intervals (CI) using random and fixed effects models. Linear and nonlinear dose-response relationships were also evaluated for PCa risk. RESULTS: Forty-two studies were included in the analysis, which included 43 851 cases of PCa reported from 692 012 participants. Both dietary intake (RR=0.88, 95% CI: 0.78-0.98, P=0.017) and circulating concentrations (RR=0.88, 95% CI: 0.79-0.98, P=0.019) of lycopene were significantly associated with reduced PCa risk. Sensitivity analyses within the dose-response analysis further revealed a significant linear dose-response for dietary lycopene and PCa risk such that PCa decreased by 1% for every additional 2 mg of lycopene consumed (P=0.026). Additionally, PCa risk decreased by 3.5 to 3.6% for each additional 10 µgdl-1 of circulating lycopene in the linear and nonlinear models respectively (plinear=0.004, pnonlinear=0.006). While there were no associations between lycopene and advanced PCa, there was a trend for protection against PCa aggressiveness (RR=0.74, 95% CI: 0.55-1.00, P=0.052). CONCLUSIONS: Our data demonstrate that higher dietary and circulating lycopene concentrations are inversely associated with PCa risk. This was accompanied by dose-response relationships for dietary and circulating lycopene. However, lycopene was not associated with a reduced risk of advanced PCa. Further studies are required to determine the mechanisms underlying these associations.

Characterization of neutralization epitopes of simian immunodeficiency virus (SIV) recognized by rhesus monoclonal antibodies derived from monkeys infected with an attenuated SIV strain.

A major limitation in the simian immunodeficiency virus (SIV) system has been the lack of reagents with which to identify the antigenic determinants that are responsible for eliciting neutralizing antibody responses in macaques infected with attenuated SIV. Most of our information on SIV neutralization determinants has come from studies with murine monoclonal antibodies (MAbs) produced in response to purified or recombinant SIV envelope proteins or intact SIV-infected cells for relatively short periods of time. While these studies provide some basic information on the potential immunogenic determinants of SIV envelope proteins, it is unclear whether these murine MAbs identify epitopes relevant to antibody responses elicited in monkeys during infection with either wild-type or attenuated SIV strains. To accomplish maximum biological relevance, we developed a reliable method for the production of rhesus monoclonal antibodies. In the present study, we report on the production and characterization of a unique panel of monoclonal antibodies derived from four individual monkeys inoculated with SIV/17E-CL as an attenuated virus strain at a time when protective immunity from pathogenic challenge was evident. Results from these studies identified at least nine binding domains on the surface envelope glycoprotein; these included linear determinants in the V1, V2, cysteine loop (analogous to the V3 loop in human immunodeficiency virus type 1), and C5 regions, as well as conformational epitopes represented by antibodies that bind the C-terminal half of gp120 and those sensitive to defined mutations in the V4 region. More importantly, three groups of antibodies that recognize closely related, conformational epitopes exhibited potent neutralizing activity against the vaccine strain. Identification of the epitopes recognized by these neutralizing antibodies will provide insight into the antigenic determinants responsible for eliciting neutralizing antibodies in vivo that can be used in the design of effective vaccine strategies.

Evolution of envelope-specific antibody responses in monkeys experimentally infected or immunized with simian immunodeficiency virus and its association with the development of protective immunity.

Previous studies of attenuated simian immunodeficiency virus (SIV) vaccines in rhesus macaques have demonstrated the development of broad protection against experimental challenge, indicating the potential for the production of highly effective immune responses to SIV antigens. However, the development of this protective immune status was found to be critically dependent on the length of time postvaccination with the attenuated virus strain, suggesting a necessary maturation of immune responses. In this study, the evolution of SIV envelope-specific antibodies in monkeys experimentally infected with various attenuated strains of SIV was characterized by using a comprehensive panel of serological assays to assess the progression of antibodies in longitudinal serum samples that indicate the development of protective immunity. In parallel studies, we also used the same panel of antibody assays to characterize the properties of SIV envelope-specific antibodies elicited by inactivated whole-virus and envelope subunit vaccines previously reported to be ineffective in producing protective immunity. The results of these studies demonstrate that the evolution of protective immunity in monkeys inoculated with attenuated strains of SIV is associated with a complex and lengthy maturation of antibody responses over the first 6 to 8 months postinoculation, as reflected in progressive changes in antibody conformational dependence and avidity properties. The establishment of long-term protective immunity at this time in general parallels the absence of further detectable changes in antibody responses and a maintenance of relatively constant antibody titer, avidity, conformational dependence, and the presence of neutralizing antibody for at least 2 years postinoculation. In contrast to the mature antibody responses elicited by the attenuated SIV vaccines, the whole-virus and envelope subunit vaccines in general elicited only immature antibody responses characterized by poor reactivity with native envelope proteins, low avidity, low conformational dependence, and the absence of neutralization activity against the challenge strain. Thus, these studies establish for the first time an association between the effectiveness of experimental vaccines and the capacity of the vaccine to produce a mature antibody response to SIV envelope proteins and further indicate that a combination of several antibody parameters (including titer, avidity, conformational dependence, and virus neutralization) are superior to any single antibody parameter as prognostic indicators to evaluate candidate AIDS vaccines.

A model for the maturation of protective antibody responses to SIV envelope proteins in experimentally immunized monkeys.

Studies using live attenuated virus vaccines in the simian immunodeficiency virus (SIV) rhesus macaque model have demonstrated broad protection against experimental challenge. Protection in these studies was found to be critically dependent on the length of time postvaccination, suggesting that protective immunity involves a necessary maturation of immune responses. The current study characterizes the evolution of protective envelope-specific antibody responses from monkeys inoculated with the highly attenuated SIV/17E-Cl virus vaccine. For comparison, the same antibody assays were used to characterize the properties of SIV envelope-specific antibodies elicited by inactivated whole virus and envelope subunit vaccines that failed to provide protection from experimental virus challenge. Results of these studies identify a continuous and complex maturation of envelope-specific antibody responses during the first six to eight months postinfection. Furthermore, the time required for maturation of SIV envelope-specific antibodies parallels the time required for the development of protective immunity against experimental challenge with heterologous strains of SIV. While no single immune correlate of protection has been identified, we suggest that a combination of antibody parameters may serve as prognostic indicators in the development of candidate AIDS vaccines.