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The Puerto Rican (PR) population is a racially admixed population that has a high prostate cancer (PCa) mortality rate. We hypothesized in this pilot study that West African Ancestry (WAA) was associated with PCa in this heterogeneous (PR) population.A case/case and case/control study was performed. Controls, 207 African American (AA) and 133 PR were defined as men with no PCa, a serum PSA 2.5 ng/mL and a negative rectal examination. Cases were patients with pathological specimens from radical prostatectomies (RP) (291 PR and 200 AA). DNA was extracted from whole blood of controls and from paraffin embedded normal seminal vesicle from the RPs. We assessed the association of PCa and aggressiveness with genetic ancestry using an ancestry informative marker panel (AIMs) and Wilcoxon rank-sum test and the association of PCa and aggressiveness with 15 previously PCa associated SNPs using Chi square test. Gleason Score (GS) and tumor stage (TS) were used to define low risk (GS ≤ 7[3 + 4]), TS ≤ pT2) and high risk (GS≥ 7[4 + 3], TS pT2) PCa. Statistical analyses were done using SAS.No difference in overall percent WAA was found between PR cases and controls. Among PR or AA cases WAA was not associated with disease severity based upon risk group, Gleason score or stage. Among AA controls WAA was significantly higher than in cases. The SNP rs7824364 (chromosome 8q24) PCa risk allele was significantly increased among cases versus controls for both AA (P 0.0001) and PR (P = 0.0001) men. PR men with ≥1 risk allele exhibited a higher percent of WAA (39% vs 29%, P = 0.034).The SNP rs7824364, a local marker of WAA in the 8q24 region was associated with PCa among both AA and PR men and with increased WAA among PR men. This novel relationship of PCA risk loci, WAA with PCa and its phenotype among PR men deserves further study.

Prostate cancer (PCa) mortality in Puerto Rico (PR) is significantly higher (28.3/100,000 men) compared to US mainland Hispanics. Obesity is prevalent in PR and has been associated with PCa mortality and aggressiveness. Polymorphisms rs9939609 and rs9930506 in the FTO gene have been associated with both obesity and PCa in other populations. Previous work in our laboratory has shown that Puerto Rican patients who underwent radical prostatectomy (RP) and also had at least one G allele in the FTO rs9930506 polymorphism exhibited a greater likelihood for low severity PCa. The aim of this work was to ascertain whether the presence of both polymorphisms (rs9930506 and rs9939609) in tandem correlated with PCa severity in this Puerto Rican population. The study population consisted of the pathology specimens of 294 Puerto Rican PCa patients, aged 40-79 years old who underwent RP as definitive treatment for PCa. Genomic DNA was extracted from normal seminal vesicle paraffin-embedded tissue. Polymorphisms were determined by RT-PCR. PCa severity was defined based on RP stage and Gleason Score. Chi-square test and logistic regression models were used to assess the correlation between FTO gene polymorphisms and PCa severity. Other factors such as BMI and age were considered in the model. We found that the A/G SNP in rs9930506 was present in 135 patients (45.9%). Likewise for rs9939609 we found the A/T SNP in 138 patients (46.9%). We found no statistically significant relationship between either polymorphism by itself and PCa severity. In 104 (35.4%) patients both SNPs were heterozygous. Of these, 77 (74%) were overweight or obese. Within this latter group, 55 (71.4%) exhibited low severity PCa. Data showed that those patients with simultaneous heterozygous forms had about 12% lower odds of low severity of PCa (95% CI: 0.52, 1.50), although no statistical significance was found for this relationship (p = 0.640). These results suggest that the presence of both polymorphisms in their heterozygous form may be related to low severity PCa in the obese/overweight group. Further studies are needed to understand the mechanisms that may be involved in this modulation of the development of severity in PCa in this population. This project was supported by RCMI grant G12MD007600 (Center for Collaborative Research in Health Disparities) and grant 8U54MD007587-03 (Puerto Rico Clinical and Translational Research Consortium) from the National Institute on Minority Health and Health Disparities, and by Award Grant Number# CA096297/CA096300 from the National Cancer Institute of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Citation Format: Jeannette Salgado-Montilla, Jorge Rodríguez-Caban, Lorena Gonzalez-Sepulveda, Ricardo Sanchez-Ortiz, Margarita Irizarry-Ramirez. Presence of FTO rs9939609 and rs9930506 and severity of prostate cancer in Puerto Ricans. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4836. doi:10.1158/1538-7445.AM2015-4836

e16033 Background: The mortality from prostate cancer (PCA) is high in Hispanic Puerto Rican males (HPRM) living on the island of Puerto Rico (PR) and in African American (AA) menliving in the cont...

Spinal cord injury (SCI) releases a cascade of events that leads to the onset of an inhibitory milieu for axonal regeneration. Some of these changes result from the presence of repulsive factors that may restrict axonal outgrowth after trauma. The Eph receptor tyrosine kinase (RTK) family has emerged as a key repellent cue known to be involved in neurite outgrowth, synapse formation, and axonal pathfinding during development. Given the nonpermissive environment for axonal regeneration after SCI, we questioned whether re-expression of one of these molecules occurs during regenerative failure. We examined the expression profile of EphA3 at the mRNA and protein levels after SCI, using the NYU contusion model. There is a differential distribution of this molecule in the adult spinal cord and EphA3 showed an increase in expression after several injury models like optic nerve and brain injury. Standardized semi-quantitative RT-PCR analysis demonstrated a time-dependent change in EphA3 mRNA levels, without alterations in beta-actin levels. The basal level of EphA3 mRNA in the adult spinal cord is low and its expression was induced 2 days after trauma (the earliest time point analyzed) and this upregulation persisted for 28 days post-injury (the latest time point examined). These results were corroborated at the protein level by immunohistochemical analysis and the cell phenotype identified by double labeling studies. In control animals, EphA3 immunoreactivity was observed in motor neurons of the ventral horn but not in lesioned animals. In addition, GFAP-positive cells were visualized in the ventral region of injured white matter. These results suggest that upregulation of EphA3 in reactive astrocytes may contribute to the repulsive environment for neurite outgrowth and may be involved in the pathophysiology generated after SCI.

After spinal cord injury (SCI), the inability of supraspinal neurons to regenerate or reform functional connections is likely due to proteins in the surrounding microenvironment restricting regeneration. EphAs are a family of receptor tyrosine kinases that are involved in axonal guidance during development. These receptors and their ligands, the Ephrins, act via repulsive mechanisms to guide growing axons towards their appropriate targets and allow for the correct developmental connections to be made. In the present study, we investigated whether EphA receptor expression changed after a thoracic contusion SCI. Our results indicate that several EphA molecules are upregulated after SCI. Using semiquantitative RT-PCR to investigate mRNA expression after SCI, we found that EphA3, A4, and A7 mRNAs were upregulated. EphA3, A4, A6, and A8 receptor immunoreactivity increased in the ventrolateral white matter (VWM) at the injury epicenter. EphA7 had the highest level of immunoreactivity in both control and injured rat spinal cord. EphA receptor expression in the white matter originated from glial cells as coexpression in both astrocytes and oligodendrocytes was observed. In contrast, gray matter expression was localized to neurons of the ventral gray matter (motor neurons) and dorsal horn. After SCI, specific EphA receptor subtypes are upregulated and these increases may create an environment that is unfavorable for neurite outgrowth and functional regeneration.

Abstract: Introduction and Objective: Prostate Cancer (PC) mortality is higher in Puerto Rico (PR) versus either US Hispanics or Caucasians, despite lower incidence. Also, PR has the highest self- reported prevalence of diabetes mellitus type 2 (DM) among all states and territories. Data on the association between DM and PC is mixed, but a prior study by our group suggested it may affect PC differentially by White vs. Black race. This has not been studied in Hispanic men. Methods: We conducted a retrospective analysis of men treated with RP between 2000-2010 at the San Juan, PR VA Hospital. Data collection is ongoing with 99 men identified to date treated between 2000 and 2003. The association between DM and PSA recurrence was tested using a Cox proportional hazards model. Results: Of the 99 abstracted to date, 21 had DM (21%). There were no differences in pre-operative features between men with and without DM (all p>0.14). Similarly, pathological features were similar between men with and without DM at surgery (all p>0.13). On unadjusted analyses, DM was significantly associated with increased risk of PSA recurrence (HR 2.81, 95% CI 1.31-6.07, p=0.008). These results did not vary significantly after adjusting for age, BMI, Gleason score, and PSA (HR 2.61, 95% CI 1.16-5.89, p=0.021). Updated data will be presented. Conclusion: In a radical prostatectomy cohort of Hispanic men from PR, our preliminary data showed that men with DM at the time of surgery had significantly higher rates of PSA recurrence. As this is the first study of DM and RP outcomes in Hispanic men, these results require validation both in our full cohort and in other datasets. If confirmed, further research is needed to better understand why DM is linked with aggressive PC in Hispanics and whether this information can be used to identify better prevention and treatment strategies for PC, especially for Hispanic men. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 672. doi:1538-7445.AM2012-672

Background While obesity and fat intake have been associated with an increased risk of prostate cancer (PCa) aggressiveness and mortality, the association between lipid levels and PCa phenotype remains unclear. Previous reports evaluating this association are inconsistent and highly variable when considering different racial/ethnic groups. There are scarce data regarding this association among Hispanics, and specifically Puerto Rico’s Hispanic men, a population with a higher burden of PCa, metabolic syndrome and overweight. This population has a different ancestry profile than other Hispanics from Central and South America. Due to the above the researchers inquired if there is a relationship between serum lipid levels and PCa phenotype in this understudied population using a cohort of patients treated with radical prostatectomy as their first treatment. Methods We performed an exploratory retrospective medical record review study of 199 PCa patients who underwent radical prostatectomy between 2005 and 2012. Variables analyzed included age at PCa diagnosis, Body Mass Index (BMI), preoperative serum prostate-specific antigen (PSA), lipid levels, and clinical parameters such as prostatectomy pathologic stage and Gleason Score (GS). PCa severity was defined using pathologic stage and GS. Unadjusted and adjusted logistic regression models were fitted to estimate the odds ratios (ORs) with 95 % confidence intervals (CI) to define the relationship among clinical characteristics and PCa severity. Results Mean age for the cohort was 58.8 years (range: 40–75), 78.9 % were overweight or obese, 36.7 % had hypertriglyceridemia, and 35.2 % had low HDL levels. In the unadjusted logistic regression model, hypertriglyceridemia (OR: 2.11, 95 % CI = 1.13–3.93), low HDL (OR: 1.90, 95 % CI = 1.02–3.56-), and age (OR: 2.34, 95 % CI 1.25–4.40) were significantly associated with a diagnosis of high severity of PCa. Conclusions In Puerto Rican men with PCa, elevated hypertriglyceridemia, low HDL levels, and age were statistically associated with high grade PCa on bivariate analysis. Total cholesterol level was not associated with severity of disease. Associations lost significance upon multivariate adjustment. These data generate important hypotheses regarding the potential relationship between lipid pathways and PCa development and underscore the need to perform larger scale and longitudinal studies to sort out whether, hypertriglyceridemia is associated with PCa phenotype and development.