Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men

Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men

Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0?ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals

Cytopathic Killing of Peripheral Blood CD4(+) T Lymphocytes by Human Immunodeficiency Virus Type 1 Appears Necrotic rather than Apoptotic and Does Not Require env

An important unresolved issue of AIDS pathogenesis is the mechanism of human immunodeficiency virus (HIV)-induced CD4(+) T-lymphocyte destruction. We show here that HIV type 1 (HIV-1) exerts a profound cytopathic effect upon peripheral blood CD4(+) T lymphocytes that resembles necrosis rather than apoptosis. Necrotic cytopathology was found with both laboratory-adapted strains and primary isolates of HIV-1. We carefully investigated the role of env, which has been previously implicated in HIV cytopathicity. HIV-1 stocks with equivalent infectivity were prepared from constructs with either an intact or mutated env coding region and pseudotyped with the glycoprotein of vesicular stomatitis virus (VSV-G) so that the HIV envelope was not rate-limiting for infection. Infected Jurkat T cells died whether or not env was intact; however, the expression of env accelerated death significantly. The accelerated death was blocked by protease inhibitors, indicating that it was due to reinfection by newly produced virus in env(+) cultures. Accordingly, we found no disparity in kinetics in CD4(lo) Jurkat cells. In highly infected peripheral blood T cells, profound necrosis occurred equivalently with both env(+) and env(−) stocks of HIV-1. We also found that HIV-1 cytopathicity was undiminished by the absence of nef. However, viral stocks made by complementation or packaging of HIV-1 genomes with the natural protein-coding sequences replaced by the green fluorescent protein were highly infectious but not cytopathic. Thus, env can accelerate cell death chiefly as an entry function, but one or more viral functions other than env or nef is essential for necrosis of CD4(+) T cells induced by HIV-1

Abstract P446: Hispanics/Latinos With Prediabetes are Eligible for Diabetes Prevention Intervention: Findings From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Background: Hispanics/Latinos in the US are at high risk of type 2 diabetes mellitus (T2D). The American Diabetes Association (ADA) consensus statement recommends prediabetes screening in persons with body mass index (BMI) ≥ 25 kg/m 2 from at-risk racial/ethnic groups and/or with additional T2D risk factors to identify those who may benefit from lifestyle and/or pharmacological (metformin) therapy to prevent T2D. Little is known about the proportion of diverse Hispanics/Latinos who have prediabetes and may benefit from such preventive measures. Objectives: This study examined prediabetes prevalence in Hispanics/Latinos by BMI categories to estimate the proportion eligible for preventive therapy per ADA guidelines. Methods: The HCHS/SOL is a prospective, multi-center, population-based study that enrolled 16,415 diverse Hispanic/Latino adults aged 18-74 years from four US communities in 2008 – 2011. Prediabetes was defined per ADA criteria as any of the following: fasting plasma glucose 100-125 mg/dL, oral glucose tolerance test 140-199 mg/dL, or hemoglobin A1C 5.7%-6.4%. Prevalence of prediabetes age-standardized to the 2010 US population was examined in persons aged 18-74 years with BMI ≥ 25 kg/m 2 who were free of diabetes and not taking anti-glycemic medication (n=9393) and a sub-sample of those aged 18-60 with BMI ≥ 35 kg/m 2 (n=1528) to determine eligibility for preventive lifestyle and pharmacological therapy, respectively. Overall and heritage specific prevalence estimates (95% confidence intervals) were computed. Analyses were weighted for sampling probability and non-response. Results: Among individuals with BMI ≥ 25 kg/m 2 , 50.9% (49.6 - 52.3) had prediabetes, i.e., could benefit from preventive lifestyle measures. Prevalence was highest in those of Mexican heritage (53.1%; 50.8 – 55.4), followed by Puerto Rican (49.8%; 46.2 – 53.4) and Central American (49.8%; 45.5 – 54.1) heritage. Persons of South American heritage had the lowest prevalence (45.6%; 41.4 – 49.6) (p=0.29 for overall differences across groups). Among persons with BMI ≥ 35 kg/m 2 , 55.7% (52.2 – 59.2) had prediabetes, i.e., could benefit from metformin therapy; prevalence was highest in persons of South American heritage (62.2%; 48.3 – 76.1). Of those who met the criteria for lifestyle measures, about 64% were age 18-44, 69% had at least a high school education, 41% had income <$20,000, and 40% had family history of diabetes. Over 60% of those eligible for preventive metformin therapy were women. Conclusions: Among Hispanics/Latinos who are overweight/obese, over half of those of Mexican heritage and almost half of those of Puerto Rican and Central American heritage need intensive lifestyle measures to prevent progression to diabetes. Among those who are obese, six out of ten individuals of South American heritage met criteria for preventive metformin therapy

The serial interaction of stress and syncope

Many languages respect the generalization that some or all unstressed vowels are deleted. This generalization proves elusive in classic Optimality Theory, however. The source of the problem is classic OT’s parallel evaluation, which requires that the effects of stress assignment and syncope be optimized together. This article argues for a version of OT called Harmonic Serialism, in which the effects of stress assignment and syncope can and must be evaluated sequentially. The results are potentially applicable to other domains where process interaction is best understood in derivational terms