Androgen supplementation and prostate cancer risk: strategies for pretherapy assessment and monitoring

Since in men androgen levels decrease with age and result in symptoms of hypogonadism, the use of testosterone supplementation to treat symptoms resulting from hypogonadism is increasing. One potential complication of this treatment is the possibility of an increased risk of prostate cancer. Although most authorities agree that androgen is involved in the exacerbation of existing carcinoma of the prostate, the action of androgens on the carcinogenic process is not well understood. Attempts to demonstrate a correlation between hormone levels and prostate cancer have yielded inconsistent results. No clear evidence exists that androgen supplementation to restore physiologic levels produces any deleterious effects on the prostate. It is highly doubtful that when testosterone therapy is administered to middle-aged or older men, any potential prostate cancer promotion effect will be clinically manifested in the absence of already established cancer. It is, however, imperative that existing or developing prostate cancer be ruled out before initiation and during androgen replacement therapy. As with any therapeutic regimen, careful monitoring of the patient receiving treatment is recommended and constitutes good medical care.     

The first step in the development of text mining technology for cancer risk assessment: identifying and organizing scientific evidence in risk assessment literature

Background  

One of the most neglected areas of biomedical Text Mining (TM) is the development of systems based on carefully assessed user needs. We have recently investigated the user needs of an important task yet to be tackled by TM -- Cancer Risk Assessment (CRA). Here we take the first step towards the development of TM technology for the task: identifying and organizing the scientific evidence required for CRA in a taxonomy which is capable of supporting extensive data gathering from biomedical literature.     

Text mining for literature review and knowledge discovery in cancer risk assessment and research

Research in biomedical text mining is starting to produce technology which can make information in biomedical literature more accessible for bio-scientists. One of the current challenges is to integrate and refine this technology to support real-life scientific tasks in biomedicine, and to evaluate its usefulness in the context of such tasks. We describe CRAB - a fully integrated text mining tool designed to support chemical health risk assessment. This task is complex and time-consuming, requiring a thorough review of existing scientific data on a particular chemical. Covering human, animal, cellular and other mechanistic data from various fields of biomedicine, this is highly varied and therefore difficult to harvest from literature databases via manual means. Our tool automates the process by extracting relevant scientific data in published literature and classifying it according to multiple qualitative dimensions. Developed in close collaboration with risk assessors, the tool allows navigating the classified dataset in various ways and sharing the data with other users. We present a direct and user-based evaluation which shows that the technology integrated in the tool is highly accurate, and report a number of case studies which demonstrate how the tool can be used to support scientific discovery in cancer risk assessment and research. Our work demonstrates the usefulness of a text mining pipeline in facilitating complex research tasks in biomedicine. We discuss further development and application of our technology to other types of chemical risk assessment in the future.     

An image analysis method for assessment of prognostic risk in prostate cancer: a pilot study

Fully automated computerized image analysis at medium resolution (1 micron per pixel space) was applied in a study of 17 patients with stage D1 prostate cancer. For this pilot study, patients were selected on the basis of very good or very poor outcome. This selection was made in the hope of identifying morphometric features that are useful in prognostic assessment. Nine patients with good outcome were alive after 7 or more years of follow-up and eight patients with poor prognosis were dead of disease in less than 3 years. All patients were treated with 125I seed implantation to the prostate and pelvic lymph node dissection. Hormone therapy was not administered until the time of distant failure. Routine hematoxylin and eosin tissue sections of lymph nodal tissue bearing metastatic neoplasm were used for this analysis. A minimum of eight scenes per case was analysed. Of 50 measured parameters on each cluster, five (gray level distribution, number of cell clusters per scene, bending energy, average cluster area and cluster polarity) were useful to distinguish patients with good outcome from those with a poor outcome. Thirteen of the 17 patients were correctly classified by image analysis (P = 0.044, Fischer's exact test). By comparison, flow cytometry of the identical tissue samples correctly classified 14 of 17 patients (diploid, good outcome; aneuploid, poor outcome; P = 0.009). Only one patient was incorrectly classified by both image analysis and flow cytometry, implying a complementary prognostic role for the two methods. The encouraging result, successful identification of useful morphometric features, justifies a larger study of unselected patients.     

Kallikarein-related peptidase 3 common genetic variant and the risk of prostate cancer

Kallikarein-related peptidase 3 (KLK3) gene polymorphisms seem to play a role in susceptibility to prostate cancer (PC). The purpose of this study was to investigate the association between rs2735839 polymorphism of KLK3 gene and risk of PC in an Iranian population. In this case-control study, rs2735839 was genotyped in 532 patients with PC and 602 controls with benign prostate hyperplasia (BPH) using polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of GG, AG, and AA genotypes of KLK3 polymorphism was 24.6% and 76.2%, 46.6% and 21.7%, and 28.8% and 2.1%, in patients with BPH and PC, respectively (P < 0.001). The frequency of G allele in patients with BPH and PC was 47.9% and 87%, respectively (odds ratio: 7.31; confidence interval: 5.88-9.10; P < 0.001). Patients with AG and GG genotypes had a higher total serum level of prostate-specific antigen (PSA) compared to those with AA genotype (P < 0.001). Patients with this polymorphism had higher risk of tumor with higher grade (P = 0.23), advanced stage (P = 0.11), perineural invasion (P = 0.07), and vascular invasion (P = 0.07) compared to those without it but this difference was not statistically significant. Based on our results, KLK3 gene polymorphism was associated with the risk of PC. Higher levels of PSA in the presence of KLK3 polymorphism in patients with PC indicated that rs2735839 polymorphism could be a risk factor for increased levels of PSA.     

Feature extraction and classification for rectal bleeding in prostate cancer radiotherapy: A PCA based method

In this work, we studied the efficiency of principal component analysis for feature extraction and classification of prostate cancer patients suffering from rectal bleeding. We fully exploited the three-dimensional planned dose distribution by considering the voxels as observations. We compared different possibilities for selecting the most relevant features (sequential and combinatory). The receiving operator characteristics were used as performance criterion. The obtained results demonstrate the ability of the method to classify two groups of patients, namely rectal bleeding and non-rectal bleeding. They also suggest that local dose/toxicity relationships exist.     

Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3

Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10⁻²⁸). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade <8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.     

Prostate cancer: risk assessment and diagnostic approaches

The successful treatment of prostate cancer relies on detection of the disease at its earliest stages. Although prostate-specific antigen (PSA)-based screening has been a significant advance in the early diagnosis of prostate cancer, identifying specific genetic alterations in a given family or patient will allow more appropriate screening for early disease. Mapping and identification of specific prostate cancer susceptibility genes is slowly becoming a reality. Other prostate cancer risks include a family history, race, and possibly serum markers such as insulin-like growth factor-I (IGF-I). Once a high-risk man is identified, transrectal ultrasound (TRUS)-guided biopsies are the standard to diagnose prostate cancer. Although TRUS is an advance over traditional digitally directed biopsies, it represents a random sampling of the prostate since most lesions cannot be visualized. Newer modalities such as ultrasound contrast agents, pattern recognition, and artificial neural networks (ANNs), applied to TRUS images, may improve diagnostic accuracy. If a man at risk for prostate cancer has undergone a negative TRUS biopsy, the decision for the need for additional biopsies is problematic. Use of PSA derivatives such as free and total PSA and the initial biopsy abnormalities such as atypia or high-grade prostatic intraepithelial neoplasia may define those patients in need of follow-up biopsy.     

生态风险评价方法述评

生态风险是由环境的自然变化或人类活动引起的生态系统组成、结构的改变而导致系统功能损失的可能性。生态风险评价是定量预测各种风险源对生态系统产生风险的或然性以及评估该风险可接受程度的方法体系,因而是生态环境风险管理与决策的定量依据。在介绍了生态风险概念的基础上,按照风险源性质的分类标准将生态风险划分为化学污染类风险源、生态事件类风险源、复合类风险源3类,并分别论述了3类生态风险对应评价方法的特点与发展的方向。另外,针对生态风险评价研究的现状,讨论了我国生态风险研究的优先领域,包括建立急性、慢性毒理数据库,构建外来生物入侵风险评价标准等,同时,建议将综合概率统计学、复杂系统理论与遥感技术等手段引入生态风险评价方法中,以进一步提高风险评价结果在生态风险管理中的有效性。     

Using graded response model for the prediction of prostate cancer risk

Disease risk-associated single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) have the potential to be used for disease risk prediction. An important feature of these risk-associated SNPs is their weak individual effect but stronger cumulative effect on disease risk. To date, a stable summary estimate of the joint effect of genetic variants on disease risk prediction is not available. In this study, we propose to use the graded response model (GRM), which is based on the item response theory, for estimating the individual risk that is associated with a set of SNPs. We compare the GRM with a recently proposed risk prediction model called cumulative relative risk (CRR). Thirty-three prostate cancer risk-associated SNPs were originally discovered in GWAS by December 2009. These SNPs were used to evaluate the performance of GRM and CRR for predicting prostate cancer risk in three GWAS populations, including populations from Sweden, Johns Hopkins Hospital, and the National Cancer Institute Cancer Genetic Markers of Susceptibility study. Computational results show that the risk prediction estimates of GRM, compared to CRR, are less biased and more stable.     

DNA damage phenotype and prostate cancer risk

The capacity of an individual to process DNA damage is considered a crucial factor in carcinogenesis. The comet assay is a phenotypic measure of the combined effects of sensitivity to a mutagen exposure and repair capacity. In this paper, we evaluate the association of the DNA repair kinetics, as measured by the comet assay, with prostate cancer risk. In a pilot study of 55 men with prostate cancer, 53 men without the disease, and 71 men free of cancer at biopsy, we investigated the association of DNA damage with prostate cancer risk at early (0-15 min) and later (15-45 min) stages following gamma-radiation exposure. Although residual damage within 45 min was the same for all groups (65% of DNA in comet tail disappeared), prostate cancer cases had a slower first phase (38% vs. 41%) and faster second phase (27% vs. 22%) of the repair response compared to controls. When subjects were categorized into quartiles, according to efficiency of repairing DNA damage, high repair-efficiency within the first 15 min after exposure was not associated with prostate cancer risk while higher at the 15-45 min period was associated with increased risk (OR for highest-to-lowest quartiles=3.24, 95% CI=0.98-10.66, p-trend=0.04). Despite limited sample size, our data suggest that DNA repair kinetics marginally differ between prostate cancer cases and controls. This small difference could be associated with differential responses to DNA damage among susceptible individuals.     

Psychological adjustment of men with prostate cancer: a review of the literature

Objective  

Prostate cancer (PCA) is the most common malignancy and a major cause of death in men but, importantly, a substantial proportion will live for several years following diagnosis. However, they face the prospect of experiencing symptoms, side-effects of treatment and diminished quality of life. The patient's psychological adjustment is particularly complex, given the potential trajectory of the disease, from the point of diagnosis, with its immediate impact, to the phase of palliative care, with its attendant issue of facing mortality. Since a comprehensive review of the literature on psychological adjustment of men with PCA has not yet been done, we have documented relevant research, integrated findings and drawn conclusions, where possible, in order to map out clinical and research implications.     

Epigenetic processes and cancer risk assessment

The U.S. Environmental Protection Agency's Guidelines for Carcinogen Risk Assessment encourages the use of mechanistic data in the assessment of human cancer risk at low (environmental) exposure levels. The key events that define a particular mode of action for tumor formation have been concentrated to date more on mutational responses that are broadly the result of induced DNA damage and enhanced cell proliferation. While it is clear that these processes are important in terms of tumor induction, other modes that fall under the umbrella of epigenetic responses are increasingly being considered to play an important role in susceptibility to tumor induction by environmental chemicals and as significant modifiers of tumor responses. Alterations in gene expression, DNA repair, cell cycle control, genome stability and genome reprogramming could be the result of modification of DNA methylation and chromatin remodeling patterns as a consequence of exposure to environmental chemicals. These concepts are described and discussed.