Outcomes after PD-103 versus I-125 for low dose rate prostate brachytherapy monotherapy: An international, multi-institutional study.

BACKGROUND AND PURPOSE: Pd-103 and I-125 are commonly used in low dose rate (LDR) brachytherapy for prostate cancer. Comparisons of outcomes by isotope type are limited, but Pd-103 has distinct radiobiologic advantages over I-125 despite its lesser availability outside the United States. We evaluated oncologic outcomes after Pd-103 vs I-125 LDR monotherapy for prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed databases at 8 institutions for men who received definitive LDR monotherapy with Pd-103 (n = 1,597) or I-125 (n = 7,504) for prostate cancer. Freedom from clinical failure (FFCF) and freedom from biochemical failure (FFBF) stratified by isotope were analyzed by Kaplan-Meier univariate and Cox multivariate analyses. Biochemical cure rates (prostate-specific antigen level ≤ 0.2 ng/mL between 3.5 and 4.5 years of follow-up) by isotype were calculated for men with at least 3.5 years of follow-up and compared by univariate and multivariate logistic regression. RESULTS: Compared with I-125, Pd-103 led to higher 7-year rates of FFBF (96.2% vs 87.6%, P < 0.001) and FFCF (96.5% vs 94.3%, P < 0.001). This difference held after multivariate adjustment for baseline factors (FFBF hazard ratio [HR] = 0.31, FFCF HR = 0.49, both P < 0.001). Pd-103 was also associated with higher cure rates on univariate (odds ratio [OR] = 5.9, P < 0.001) and multivariate (OR = 6.0, P < 0.001) analyses. Results retained significance in sensitivity analyses of data from the 4 institutions that used both isotopes (n = 2,971). CONCLUSIONS: Pd-103 monotherapy was associated with higher FFBF, FFCF, and biochemical cure rates, and suggests that Pd-103 LDR may lead to improved oncologic outcomes compared with I-125.

Chronic nitric oxide exposure induces prostate cell carcinogenesis, involving genetic instability and a pro-tumorigenic secretory phenotype.

Prostate cancer is a leading cause of cancer death in men. Inflammation and overexpression of inducible nitric oxide synthase (NOS2) have been implicated in prostate carcinogenesis. We aimed to explore the hypothesis that nitric oxide NO exerts pro-tumorigenic effects on prostate cells at physiologically relevant levels contributing to carcinogenesis. We investigated the impact of acute exposure of normal immortalised prostate cells (RWPE-1) to NO on cell proliferation and activation of DNA damage repair pathways. Furthermore we investigated the long term effects of chronic NO exposure on RWPE-1 cell migration and invasion potential and hallmarks of transformation. Our results demonstrate that NO induces DNA damage as indicated by γH2AX foci and p53 activation resulting in a G1/S phase block and activation of 53BP1 DNA damage repair protein. Long term adaption to NO results in increased migration and invasion potential, acquisition of anchorage independent growth and increased resistance to chemotherapy. This was recapitulated in PC3 and DU145 prostate cancer cells which upon chronic exposure to NO displayed increased cell migration, colony formation and increased resistance to chemotherapeutics. These findings indicate that NO may play a key role in the development of prostate cancer and the acquisition of an aggressive metastatic phenotype.

Contrast-Specific Spherical Lesion Phantoms and Ancillary Analysis Software for the Objective Evaluation of Transrectal Ultrasound System Contrast Detectability.

Brachytherapy is an efficacious treatment option because of its benefits for patient recovery, dose localization and conformity, but these favorable outcomes can be ensured only if the transrectal ultrasound (TRUS) system is optimized for the specific application of ultrasound-guided prostate brachytherapy. The ability to delineate the prostate from surrounding tissue during TRUS-guided prostate brachytherapy is vital for treatment planning, and consequently, so is the contrast resolution. This study describes the development of task-specific contrast-detail phantoms with clinically relevant contrast and spherical target sizes for contrast-detail performance evaluation of TRUS systems used in the brachytherapy procedure. The procedure for objective assessment of the contrast detectability of the TRUS systems is also described; a program was developed in MATLAB (R2017a, The MathWorks, Natick, MA, USA) to quantitatively analyze image quality in terms of the lesion signal-to-noise ratio (LSNR) and validated with representative control test images. The LSNR of the Hitachi EUB-7500A (2013, Hitachi, Ltd, Tokyo, Japan) TRUS system was measured on sagittal and transverse TRUS images of the contrast-detail phantoms described in this work. Results revealed the efficacy of the device as an image quality evaluation tool and the impact of the size, depth and relative contrast of the targets to the surrounding tissue on the contrast detectability of a TRUS system for both transducer arrays. The MATLAB program objectively measured the contrast detectability of the TRUS system and has the potential to determine optimized imaging parameters that could be designed as part of standardization of the imaging protocol used in TRUS-guided prostate brachytherapy for prostate cancer.

Live implant dosimetry may be an effective replacement for postimplant computed tomography in localized prostate cancer patients receiving low dose rate brachytherapy.

PURPOSE: To determine if Live Implant Dosimetry (LIDO) utilizing intraoperative transrectal ultrasound (TRUS) is equivalent to postimplant CT dosimetry (either day 0 or day 30) in patients with localized prostate cancer (PC) treated with low dose rate (LDR) prostate seed brachytherapy. METHODS AND MATERIALS: The treated population consisted of 628 men with localized (T1-T2) PC. All d'Amico risk categories (low, intermediate, and high) were included, and 437 patients were treated with monotherapy (160 Gy) [low and low tier intermediate], and the remainder (191) [high tier intermediate and high risk] with an implant boost (106 Gy) post external beam radiation, to a volume including the prostate and seminal vesicles (46 Gy). LIDO with intraoperative TRUS, postimplant CT (day 0 and day 30) were performed in all cases. Prostate volumes (V), V100 (prostate) and dose (D) D90 (prostate), D30 (urethra), and Rectum D2cc, were recorded. No urinary catheter was used on Day 30 CT. RESULTS: More than 91.33% of monotherapy patients reached the target D90 according to LIDO while only 82.99% of Day 0 CT and 92.82% of Day 30 CT achieved target D90. When considering V100, monotherapy patients recorded target dosimetry in 90.93%, 82.31%, and 92.02% of cases assessed by LIDO, Day 0 CT and Day 30 CT, respectively. Strong correlations are observed in D90, Rectum D2cc and Urethra D30 across imaging modalities but V100 and V150 were poorly correlated due to the relative quantification of this parameter and high degree of error in measurement. Of all monotherapy patients with satisfactory dosimetry on LIDO, 94.82% reached target D90 at day 30 CT and 94.19% reached target V100. CONCLUSIONS: LIDO and CT are both effective tools for assessing postimplant dosimetry. Patients with satisfactory LIDO dosimetry are highly likely to have equivalent dosimetry on CT at follow-up, indicating that postimplant CT may be eliminated in PC a patients implanted with this technique.

Ocean Acidification and Human Health.

The ocean provides resources key to human health and well-being, including food, oxygen, livelihoods, blue spaces, and medicines. The global threat to these resources posed by accelerating ocean acidification is becoming increasingly evident as the world's oceans absorb carbon dioxide emissions. While ocean acidification was initially perceived as a threat only to the marine realm, here we argue that it is also an emerging human health issue. Specifically, we explore how ocean acidification affects the quantity and quality of resources key to human health and well-being in the context of: (1) malnutrition and poisoning, (2) respiratory issues, (3) mental health impacts, and (4) development of medical resources. We explore mitigation and adaptation management strategies that can be implemented to strengthen the capacity of acidifying oceans to continue providing human health benefits. Importantly, we emphasize that the cost of such actions will be dependent upon the socioeconomic context; specifically, costs will likely be greater for socioeconomically disadvantaged populations, exacerbating the current inequitable distribution of environmental and human health challenges. Given the scale of ocean acidification impacts on human health and well-being, recognizing and researching these complexities may allow the adaptation of management such that not only are the harms to human health reduced but the benefits enhanced.

A prospective feasibility study of MammoSite accelerated partial breast irradiation for early breast Cancer.

BACKGROUND: Accelerated partial breast irradiation is a potential alternative to standard whole breast irradiation, following breast-conserving surgery, in the management of breast cancer. The MammoSite applicator-based technique allows for the delivery of a higher dose of radiation to the tumour bed and adjacent area, over a shorter treatment period. AIMS: To investigate the long-term feasibility of the MammoSite technique in early stage breast cancer in an Irish cohort. METHODS: Sixty-two patients with early stage breast cancer were enrolled in this prospective study between November 2005 and October 2012 at the University Hospital Galway. A single-entry MammoSite applicator was inserted post-operatively. A CT scan was performed to assess the balloon to skin distance, the conformance of target tissue to balloon surface and balloon symmetry. A total dose of 34 Gy was delivered over 10 fractions twice daily. RESULTS: Median follow-up was 10 years. 91.9% (57/62) completed the full course of MammoSite treatment. Technical issues with the MammoSite balloon precluded three patients from completing the full course of treatment. On last follow-up, 6.4% (4/62) of patients had developed an ipsilateral breast recurrence. Half of these recurrences occurred more than 10 years after the initial breast cancer treatment. The most common toxicities observed were fibrosis (67.7%), pain (61.3%) and skin erythema (35.5%). CONCLUSION: The use of the MammoSite technique, as an alternative to standard whole breast irradiation, is feasible in a typical Irish clinical setting with integrated multidisciplinary team input.

Measuring a new facet of post traumatic growth: Development of a scale of physical post traumatic growth in men with prostate cancer.

PURPOSE: This study developed a measure of physical post traumatic growth (physical post traumatic growth inventory; P-PTGI) in men with prostate cancer. METHODS: A pool of items was created from themes identified in a qualitative study. A quantitative study was then conducted to assess the psychometric properties of the P-PTGI in a sample of 693 prostate cancer survivors. RESULTS: Tests of dimensionality revealed that the 20-item P-PTGI contained two factors: Health Autonomy and Health Awareness. Results demonstrated that scale score reliability for the P-PTGI and its subscales was excellent. In support of the scale's convergent validity, scores on the P-PTGI correlated positively with mindfulness and quality of life, and correlated negatively with depression and anxiety. A statistically significant correlation between the P-PTGI and another robust indicator of post traumatic growth attests to its concurrent validity. CONCLUSIONS: While further investigation of the P-PTGI's psychometric properties is required, preliminary findings are promising.

What predicts emotional response in men awaiting prostate biopsy?

BACKGROUND: Incidence of prostate cancer is increasing as opportunistic screening becomes widespread and life expectancy rises. Despite screening availability, research reveals conflicting results on medical outcomes, for example, disease specific mortality. However the gold standard in early diagnosis of potentially curable organ confined prostate cancer is transrectal ultrasound-guided systematic prostate biopsy (TRUS-BX). While focus has been given to medical sequalae there is a paucity of research on the psychological impact of biopsy. Awaiting biopsy may be inherently stressful but no studies to date, have assessed men's perception of stress and its impact on emotional response. This study, therefore, examines the role of stress and also personal resources namely, self-efficacy and sense of coherence in emotional adjustment in men awaiting a prostate biopsy. METHODS: Men attending a Rapid Access Prostate Cancer Clinic for a transrectal prostate biopsy (N = 114) participated in the study. They completed self report questionnaires on perceived stress (PSS), generalised self-efficacy (GSES), and sense of coherence (SOC). Adjustment was measured by the Profile of Mood States (POMS-B) which assesses tension, depression, anger, fatigue, confusion and vigour. RESULTS: Hierarchical regression analyses demonstrated that the set of predictors accounted for 17%-34% of variance across six mood states and predicted 46% of total mood disturbance. Perceived stress explained variance on all domains (11%-26%) with high stress linked to poor functioning. CONCLUSION: Perceived stress was the strongest and most consistent predictor of emotional adjustment. This is an important finding as stress appraisal has not been examined previously in this context and suggests that stress management is an important target to enhance emotional wellbeing of men attending for a prostate biopsy.

A Model to Predict Psychological- and Health-Related Adjustment in Men with Prostate Cancer: The Role of Post Traumatic Growth, Physical Post Traumatic Growth, Resilience and Mindfulness.

Background: Post traumatic growth (PTG) can be defined as positive change following a traumatic event. The current conceptualization of PTG encompasses five main dimensions, however, there is no dimension which accounts for the distinct effect of a physical trauma on PTG. The purpose of the present research was to test the role of PTG, physical post traumatic growth (PPTG), resilience and mindfulness in predicting psychological and health related adjustment. Method: Ethical approval was obtained from relevant institutional ethics committees. Participants (N = 241), who were at least 1 year post prostate cancer treatment, were invited to complete a battery of questionnaires either through an online survey or a paper and pencil package received in the post The sample ranged in age from 44 to 88 years (M = 64.02, SD = 7.76). Data were analysis using confirmatory factor analysis and structural equation modeling. Results: The physical post traumatic growth inventory (P-PTGI) was used to evaluate the role of PPTG in predicting adjustment using structural equation modeling. P-PTGI predicted lower distress and improvement of quality of life, whereas conversely, the traditional PTG measure was linked with poor adjustment. The relationship between resilience and adjustment was found to be mediated by P-PTGI. Conclusion: Findings suggest the central role of PTG in the prostate cancer survivorship experience is enhanced by the inclusion of PPTG. Adjusting to a physical trauma such as illness (internal transgressor) is unlike a trauma with an external transgressor as the physical trauma creates an entirely different framework for adjustment. The current study demonstrates the impact of PPTG on adjustment. This significantly adds to the theory of the development of PTG by highlighting the interplay of resilience with PTG, PPTG, and adjustment.

Secreted factors from metastatic prostate cancer cells stimulate mesenchymal stem cell transition to a pro-tumourigenic 'activated' state that enhances prostate cancer cell migration.

Mesenchymal stem cells (MSCs) are a heterogeneous population of multipotent cells that are capable of differentiating into osteocytes, chondrocytes and adipocytes. Recently, MSCs have been found to home to the tumour site and engraft in the tumour stroma. However, it is not yet known whether they have a tumour promoting or suppressive function. We investigated the interaction between prostate cancer cell lines 22Rv1, DU145 and PC3, and bone marrow-derived MSCs. MSCs were 'educated' for extended periods in prostate cancer cell conditioned media and PC3-educated MSCs were found to be the most responsive with a secretory profile rich in pro-inflammatory cytokines. PC3-educated MSCs secreted increased osteopontin (OPN), interleukin-8 (IL-8) and fibroblast growth factor-2 (FGF-2) and decreased soluble fms-like tyrosine kinase-1 (sFlt-1) compared to untreated MSCs. PC3-educated MSCs showed a reduced migration and proliferation capacity that was dependent on exposure to PC3-conditioned medium. Vimentin and α-smooth muscle actin (αSMA) expression was decreased in PC3-educated MSCs compared to untreated MSCs. PC3 and DU145 education of healthy donor and prostate cancer patient-derived MSCs led to a reduced proportion of FAP+ αSMA+ cells contrary to characteristics commonly associated with cancer associated fibroblasts (CAFs). The migration of PC3 cells was increased toward both PC3-educated and DU145-educated MSCs compared to untreated MSCs, while DU145 migration was only enhanced toward patient-derived MSCs. In summary, MSCs developed an altered phenotype in response to prostate cancer conditioned medium which resulted in increased secretion of pro-inflammatory cytokines, modified functional activity and the chemoattraction of prostate cancer cells.

Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways.

Inflammation is implicated in triple negative breast cancer (TNBC) progression. TNBC carries a worse prognosis than other breast cancer subtypes, and with the clinical and molecular heterogeneity of TNBC, there is a lack of effective therapeutic targets available. Identification of molecular targets for TNBC subtypes is crucial towards personalized patient stratification. Inducible nitric oxide synthase (iNOS) has been shown to induce p53 mutation accumulation, basal-like gene signature enrichment and transactivation of the epidermal growth factor receptor (EGFR) via s-nitrosylation. Herein we report that iNOS is associated with disease recurrence, distant metastasis and decreased breast cancer specific survival in 209 cases of TNBC. Employing TNBC cell lines representing normal basal breast, and basal-like 1 and basal-like 2 tumors, we demonstrate that nitric oxide (NO) induces EGFR-dependent ERK phosphorylation in basal-like TNBC cell lines. Moreover NO mediated cell migration and cell invasion was found to be dependent on EGFR and ERK activation particularly in basal-like 2 TBNC cells. This occurred in conjunction with NF-κB activation and increased secretion of pro-inflammatory cytokines IL-8, IL-1ß and TNF-α. This provides substantial evidence for EGFR as a therapeutic target to be taken into consideration in the treatment of a specific subset of basal-like TNBC overexpressing iNOS.

Inflammation and Nitrosative Stress Effects in Ovarian and Prostate Pathology and Carcinogenesis.

SIGNIFICANCE: Prostate and ovarian cancers are major contributors to cancer-related deaths worldwide. Recently, inflammation and nitrosative stress have been implicated in carcinogenesis, with the overexpression of NOS2 and concomitant release of nitric oxide (NO) associated with cancer initiation and progression. Recent Advances: An increasing body of evidence indicates an association between NOS2 expression and aggressive ovarian cancer. Research also indicates a role for NO in prostate disease pathology and prostate cancer. A therapeutic role for NOS2 inhibition and/or NO drugs exists for the treatment of both ovarian and prostate tumors. CRITICAL ISSUES: Herein, we review the key molecular effects associated with NOS2 in ovarian and prostate cancer. NOS2 increases angiogenesis and tumor proliferation and correlates with aggressive type II ovarian tumors. NOS2 expressing tumors are sensitive to cisplatin chemotherapy, and NO may be used to sensitize cisplatin-resistant tumors to chemotherapy. NOS2 is highly expressed in prostate tumors compared to non-neoplastic prostate pathologies. NO may play a role in the development of androgen-independent prostate cancer via s-nitrosylation of the androgen receptor. Moreover, NOS2 inhibitors and NO donor drugs show therapeutic potential in ovarian and prostate cancer as single agents or dual drugs, by either inhibiting the effects of NOS2 or increasing NO levels to induce cytotoxic effects. FUTURE DIRECTIONS: NOS2 and NO present new targets for the treatment of ovarian and prostate tumors. Furthermore, understanding NO-related tumor biology in these cancers presents a new means for improved patient stratification to the appropriate treatment regimen. Antioxid. Redox Signal. 26, 1078-1090.

Mesenchymal stem cells: key players in cancer progression.

Tumour progression is dependent on the interaction between tumour cells and cells of the surrounding microenvironment. The tumour is a dynamic milieu consisting of various cell types such as endothelial cells, fibroblasts, cells of the immune system and mesenchymal stem cells (MSCs). MSCs are multipotent stromal cells that are known to reside in various areas such as the bone marrow, fat and dental pulp. MSCs have been found to migrate towards inflammatory sites and studies have shown that they also migrate towards and incorporate into the tumour. The key question is how they interact there. MSCs may interact with tumour cells through paracrine signalling. On the other hand, MSCs have the capacity to differentiate to various cell types such as osteocytes, chondrocytes and adipocytes and it is possible that MSCs differentiate at the site of the tumour. More recently it has been shown that cross-talk between tumour cells and MSCs has been shown to increase metastatic potential and promote epithelial-to-mesenchymal transition. This review will focus on the role of MSCs in tumour development at various stages of progression from growth of the primary tumour to the establishment of distant metastasis.

Sensitivity Profiles of Human Prostate Cancer Cell Lines to an 80 Kinase Inhibitor Panel.

BACKGROUND: Taxanes and anti-androgen therapies are routinely used for the treatment of metastatic prostate cancer, however the majority of patients eventually develop resistance. MATERIALS AND METHODS: Eighty kinase inhibitors were screened regarding their ability to inhibit cell viability in CWR22, 22Rv1, PC-3 and DU145 prostate cancer cells using automated toxicity assays. Four kinase inhibitors were selected for further investigation. RESULTS: No significant difference in sensitivity patterns was found between the androgen receptor wild-type CWR22 and its androgen receptor mutant variant 22Rv1, indicating that androgen receptor mutation did not impact on kinase inhibitor sensitivity in this model. Metastatic PC-3 and DU145 prostate cancer cell lines were less sensitive to kinase inhibitors than the non-metastatic CWR22 and 22Rv1. All four cell lines responded to GSK-3 inhibitor BIO, and MEK inhibitor PD198306. DU145 cells were resistant to p75NTR/TrkA and CHK4 inhibitors, RO-082750 and Ryuvidine. CONCLUSION: Kinase inhibition may be an appropriate strategy for the treatment of prostate cancer.

Defining a standard set of patient-centered outcomes for men with localized prostate cancer.

BACKGROUND: Value-based health care has been proposed as a unifying force to drive improved outcomes and cost containment. OBJECTIVE: To develop a standard set of multidimensional patient-centered health outcomes for tracking, comparing, and improving localized prostate cancer (PCa) treatment value. DESIGN, SETTING, AND PARTICIPANTS: We convened an international working group of patients, registry experts, urologists, and radiation oncologists to review existing data and practices. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The group defined a recommended standard set representing who should be tracked, what should be measured and at what time points, and what data are necessary to make meaningful comparisons. Using a modified Delphi method over a series of teleconferences, the group reached consensus for the Standard Set. RESULTS AND LIMITATIONS: We recommend that the Standard Set apply to men with newly diagnosed localized PCa treated with active surveillance, surgery, radiation, or other methods. The Standard Set includes acute toxicities occurring within 6 mo of treatment as well as patient-reported outcomes tracked regularly out to 10 yr. Patient-reported domains of urinary incontinence and irritation, bowel symptoms, sexual symptoms, and hormonal symptoms are included, and the recommended measurement tool is the Expanded Prostate Cancer Index Composite Short Form. Disease control outcomes include overall, cause-specific, metastasis-free, and biochemical relapse-free survival. Baseline clinical, pathologic, and comorbidity information is included to improve the interpretability of comparisons. CONCLUSIONS: We have defined a simple, easily implemented set of outcomes that we believe should be measured in all men with localized PCa as a crucial first step in improving the value of care. PATIENT SUMMARY: Measuring, reporting, and comparing identical outcomes across treatments and treatment centers will provide patients and providers with information to make informed treatment decisions. We defined a set of outcomes that we recommend being tracked for every man being treated for localized prostate cancer.

Human endogenous retrovirus K and cancer: Innocent bystander or tumorigenic accomplice?

Harbored as relics of ancient germline infections, human endogenous retroviruses (HERVs) now constitute up to 8% of our genome. A proportion of this sequence has been co-opted for molecular and cellular processes, beneficial to human physiology, such as the fusogenic activity of the envelope protein, a vital component of placentogenesis. However, the discovery of high levels of HERV-K mRNA and protein and even virions in a wide array of cancers has revealed that HERV-K may be playing a more sinister role-a role as an etiological agent in cancer itself. Whether the presence of this retroviral material is simply an epiphenomenon, or an actual causative factor, is a hotly debated topic. This review will summarize the current state of knowledge regarding HERV-K and cancer and attempt to outline the potential mechanisms by which HERV-K could be involved in the onset and promotion of carcinogenesis.

Factors driving inequality in prostate cancer survival: a population based study.

PURPOSE: As cancer control strategies have become more successful, issues around survival have become increasingly important to researchers and policy makers. The aim of this study was to examine the role of a range of clinical and socio-demographic variables in explaining variations in survival after a prostate cancer diagnosis, paying particular attention to the role of healthcare provider(s) i.e. private versus public status. METHODS: Data were extracted from the National Cancer Registry Ireland, for patients diagnosed with prostate cancer from 1998-2009 (N = 26,183). A series of multivariate Cox and logistic regression models were used to examine the role of healthcare provider and socio-economic status (area-based deprivation) on survival, controlling for age, stage, Gleason grade, marital status and region of residence. Survival was based on all-cause mortality. RESULTS: Older individuals who were treated in a private care setting were more likely to have survived than those who had not, when other factors were controlled for. Differences were evident with respect to marital status, region of residence, clinical stage and Gleason grade. The effect of socio-economic status was modified by healthcare provider, such that risk of death was higher in those men of lower socio-economic status treated by public, but not private providers in the Cox models. The logistic models revealed a socio-economic gradient in risk of death overall; the gradient was larger for those treated by public providers compared to those treated by private providers when controlling for a range of other confounding factors. CONCLUSION: The role of healthcare provider and socio-economic status in survival of men with prostate cancer may give rise to concerns that warrant further investigation.

Elevated HERV-K mRNA expression in PBMC is associated with a prostate cancer diagnosis particularly in older men and smokers.

Aberrant expression of subgroup k human endogenous retroviruses (HERV-K) has been observed in prostate cancer. This subgroup is unique because it encodes sequences in the human genome containing open reading frames for near intact retroviruses. We hypothesized that HERV-K reactivation could serve as a non-invasive early disease detection marker for prostate cancer. We evaluated HERV-K gag messenger RNA (mRNA) expression in blood samples of African-American and European-American men using a case-control design via quantitative real-time PCR. Additionally, we examined HERV-K envelope protein expression in prostate tumors by immunohistochemistry. HERV-K envelope protein was commonly upregulated in prostate tumors, but more so in tumors of African-American than European-American patients (61% versus 40%, P < 0.01). Examining HERV-K gag expression in peripheral blood mononuclear cells (PBMC) from 294 cases and 135 healthy men, we found that the abundance of HERV-K gag message was significantly higher in cases than controls and was associated with increased plasma interferon-γ. Men with gag expression in the highest quartile had >12-fold increased odds {odds ratio = 12.87 [95% confidence interval 6.3-26.25]} of being diagnosed with prostate cancer than those in the lowest quartile. Moreover, our results showed that HERV-K expression may perform better as a disease biomarker in older than younger men (whereas the sensitivity of prostate-specific antigen (PSA) testing decreases with age) and in men with a smoking history compared with never smokers. Combining non-invasive HERV-K testing with PSA testing may improve the efficacy of prostate cancer detection specifically among older men and smokers who tend to develop a more aggressive disease.

The yin and yang of nitric oxide in cancer progression.

Nitric oxide (NO) is a short-lived, pleiotropic molecule that affects numerous critical functions in the body. Presently, there are markedly conflicting findings in the literature regarding NO and its role in carcinogenesis and tumor progression. NO has been shown to have dichotomous effects on cellular proliferation, apoptosis, migration, invasion, angiogenesis and many other important processes in cancer biology. It has been shown to be both pro- and antitumorigenic, depending on the concentration and the tumor microenvironment in question. NO is generated by three isoforms of NO synthase (NOS) that are widely expressed and sometimes upregulated in human tumors. Due to its vast array of physiological functions, it presents a huge challenge to researchers to discover its true potential in cancer biology and consequently, its use in anticancer therapies. In this study, we review the current knowledge in this area, with an emphasis placed on NO modulation as an anticancer therapy, focusing on NO-donating drugs and NOS inhibitors.

Development and progress of Ireland's biobank network: Ethical, legal, and social implications (ELSI), standardized documentation, sample and data release, and international perspective.

Biobank Ireland Trust (BIT) was established in 2004 to promote and develop an Irish biobank network to benefit patients, researchers, industry, and the economy. The network commenced in 2008 with two hospital biobanks and currently consists of biobanks in the four main cancer hospitals in Ireland. The St. James's Hospital (SJH) Biobank coordinates the network. Procedures, based on ISBER and NCI guidelines, are standardized across the network. Policies and documents-Patient Consent Policy, Patient Information Sheet, Biobank Consent Form, Sample and Data Access Policy (SAP), and Sample Application Form have been agreed upon (after robust discussion) for use in each hospital. An optimum sequence for document preparation and submission for review is outlined. Once consensus is reached among the participating biobanks, the SJH biobank liaises with the Research and Ethics Committees, the Office of the Data Protection Commissioner, The National Cancer Registry (NCR), patient advocate groups, researchers, and other stakeholders. The NCR provides de-identified data from its database for researchers via unique biobank codes. ELSI issues discussed include the introduction of prospective consent across the network and the return of significant research results to patients. Only 4 of 363 patients opted to be re-contacted and re-consented on each occasion that their samples are included in a new project. It was decided, after multidisciplinary discussion, that results will not be returned to patients. The SAP is modeled on those of several international networks. Biobank Ireland is affiliated with international biobanking groups-Marble Arch International Working Group, ISBER, and ESBB. The Irish government continues to deliberate on how to fund and implement biobanking nationally. Meanwhile BIT uses every opportunity to promote awareness of the benefits of biobanking in events and in the media.