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Background: Safety is a central consideration when choosing between multiple medications with similar efficacy. We aimed to evaluate whether adverse event (AE) profiles of 3 such drugs in advanced prostate cancer could be distinguished based on published literature.Methods: We assessed consistency in AE reporting, AE risk in placebo arms, and methodology used for risk estimates and quantification of statistical uncertainty in randomized placebo-controlled phase III trials of apalutamide, enzalutamide, and darolutamide in advanced prostate cancer.Results: Seven included clinical trials enrolled a total of 9215 participants (range = 1051-1715 per trial) across 3 prostate cancer disease states. Within disease states, baseline patient characteristics appeared similar between trials. Of 54 distinct AE types in total, only 3 (fatigue, hypertension, and seizure) were reported by all 7 trials. Absolute risks of AEs in the placebo arms differed systematically and more than twofold between trials, which was associated with visit frequency and resulted in different degrees of uncertainty in AE profiles between trials. No trial used inferential methodology to quantify statistical uncertainty in AE risks, but 6 of 7 trials drew overall conclusions. Two trials concluded that there was no elevated AE risk because of the intervention, including the trial of darolutamide, which had the greatest statistical uncertainty.Conclusions: Rigorous comparison of drug safety was precluded by heterogeneity in AE reporting, variation in AE risks in the placebo arms, and lack of inferential statistical methodology, underscoring considerable opportunities to improve how AE data are collected, analyzed, and interpreted in oncology trials. [ABSTRACT FROM AUTHOR]

Objective: To assess the use of diet and the use of exercise for prostate cancer (and/or its treatments’ side effects) by long-term survivors and whether such use is associated with selected socio-demographic, clinical, health-related quality-of-life (HRQOL) and psychological factors. Design, setting and participants: Population-based cohort study in New South Wales, Australia of prostate cancer survivors aged <70 years at diagnosis and who returned a 10-year follow-up questionnaire. Methods: Validated instruments assessed patient’s HRQOL and psychological well-being. Poisson regression was used to estimate adjusted relative proportions (RRs) of prostate cancer survivor groups who were currently eating differently (‘using diet’) or exercise differently (‘using exercise’) to help with their prostate cancer. Results: 996 (61.0% of 1634) participants completed the 10-year questionnaire of whom 118 (11.8%; 95%CI[9.8–13.9]) were using diet and 78 (7.8%; 95%CI[6.2–9.5]) were using exercise to help with their prostate cancer. Men were more likely to use diet or use exercise for prostate cancer if they were younger (p-trend = 0.020 for diet, p-trend = 0.045 for exercise), more educated (p-trend<0.001, p-trend = 0.011), support group participants (p-nominal<0.001, p-nominal = 0.005), had higher Gleason score at diagnosis (p-trend<0.001, p-trend = 0.002) and had knowledge of cancer spread (p-nominal = 0.002, p-nominal = 0.001). Use of diet was also associated with receipt of androgen deprivation therapy (RR = 1.59; 95%CI[1.04–2.45]), a greater fear of cancer recurrence (p-trend = 0.010), cognitive avoidance (p-trend = 0.025) and greater perceived control of cancer course (p-trend = 0.014). Use of exercise was also associated with receipt of prostatectomy (RR = 2.02; 95%CI[1.12–3.63]), receipt of androgen deprivation therapy (RR = 2.20; 95%CI[1.34–3.61]) and less satisfaction with medical treatments (p-trend = 0.044). Conclusions: Few long-term prostate cancer survivors use diet or exercise to help with their prostate cancer. Survivors may benefit from counselling on the scientific evidence supporting healthy eating and regular exercise for improving quality-of-life and cancer-related outcomes. [ABSTRACT FROM AUTHOR]

Background: Physical exercise has been shown to be effective in relation to fatigue, aerobic fitness, and lower body strength in men with prostate cancer. However, research into the clinically relevant effects of interventions conducted in heterogeneous patient populations and in real-life clinical practice settings is warranted.Methods and Findings: We conducted a pragmatic, multicentre, parallel randomised controlled trial in 5 Danish urological departments. Recruitment began in May 2015, the first participant was randomised in June 2015, and the last participant was included in February 2017. In total, 214 men with prostate cancer were randomly assigned to either 6 months of free-of-charge football training twice weekly at a local club (football group [FG]) (n = 109) or usual care (usual care group [UG]) (n = 105), including brief information on physical activity recommendations at randomisation. Participants were on average 68.4 (SD 6.2) years old, 157 (73%) were retired, 87 (41%) were on castration-based treatment, 19 (9%) had received chemotherapy, and 41 (19%) had skeletal metastases at baseline. In this 1-year follow-up study, we evaluated the effects of community-based football training on the following outcomes: primary outcome, quality of life; secondary outcomes: continuation of football after 6 months, hip and lumbar spine bone mineral density (BMD), mental health score, fat and lean body mass, and safety outcomes, i.e., fractures, falls, and hospital admissions. Intention to treat (ITT) and per protocol (PP) analyses were conducted. No statistically significant between-group difference was observed in change in prostate-cancer-specific quality of life (ITT: 1.9 points [95% CI -1.9 to 5.8], p = 0.325; PP: 3.6 points [95% CI -0.9 to 8.2], p = 0.119). A statistically significant between-group difference was observed in change in total hip BMD, in favour of FG (0.007 g/cm2 [95% CI 0.004 to 0.013], p = 0.037). No differences were observed in change in lumbar spine BMD or lean body mass. Among patients allocated to football, 59% chose to continue playing football after the end of the 6-month intervention period. At 1-year follow-up in the PP population, FG participants had more improvement on the Mental Component Summary (2.9 [95% CI 0.0 to 5.7], p = 0.048 points higher) than UG participants, as well as a greater loss of fat mass (-0.9 kg [95% CI -1.7 to -0.1], p = 0.029). There were no differences between groups in relation to fractures or falls. Hospital admissions were more frequent in UG compared to FG (33 versus 20; the odds ratio based on PP analysis was 0.34 for FG compared to UG). There were 3 deaths in FG and 4 in UG. Main limitations of the study were the physically active control group and assessment of physical activity by means of self-report.Conclusions: In this trial, participants allocated to football appeared to have improved hip BMD and fewer hospital admissions. Men who played football more than once a week for 1 year lost fat mass and reported improved mental health. Community-based football proved to be acceptable, even when club membership was not subsidised.Trial Registration: ClinicalTrials.gov NCT02430792. [ABSTRACT FROM AUTHOR]

The growth inhibitory efficacy of methylseleninic acid (MSA) in prostate cancer cells has been documented extensively. However, our understanding of the immediate targets that are key to the growth inhibitory effects of MSA remains limited. Here, using multiple preclinical prostate cancer models, we demonstrated in vitro and in vivo that GDF15 is a most highly induced, immediate target of MSA. We further showed that knockdown of GDF15 mitigates MSA inhibition of cell proliferation and induction of apoptosis. Analysis of gene expression data from over 1000 primary and 200 metastatic prostate cancer samples revealed that GDF15 expression is decreased in metastatic prostate cancers compared to primary tumors and that lower GDF15 levels in primary tumors are associated with higher Gleason scores and shorter survival of the patients. Additionally, pathways that are negatively correlated with GDF15 levels in clinical samples are also negatively correlated with MSA treatment in cultured cells. Since most, if not all, of these pathways have been implicated in prostate cancer progression, suppressing their activities by inducing GDF15 is consistent with the anticancer effects of MSA in prostate cancer. Overall, this study provides support for GDF15 as an immediate target of MSA in prostate cancer cells. [ABSTRACT FROM AUTHOR]

In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies demonstrated that Transcription Factor-4 (TCF4), a transcription factor implicated in WNT signaling, mediated neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of metastatic CaP were examined, a positive correlation was found between the expression levels of TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide resistance via NED in CaP. [ABSTRACT FROM AUTHOR]

We apply the Google matrix algorithms for analysis of interactions and influence of 37 cancer types, 203 cancer drugs and 195 world countries using the network of 5 416 537 English Wikipedia articles with all their directed hyperlinks. The PageRank algorithm provides a ranking of cancers which has 60% and 70% overlaps with the top 10 deadliest cancers extracted from World Health Organization GLOBOCAN 2018 and Global Burden of Diseases Study 2017, respectively. The recently developed reduced Google matrix algorithm gives networks of interactions between cancers, drugs and countries taking into account all direct and indirect links between these selected 435 entities. These reduced networks allow to obtain sensitivity of countries to specific cancers and drugs. The strongest links between cancers and drugs are in good agreement with the approved medical prescriptions of specific drugs to specific cancers. We argue that this analysis of knowledge accumulated in Wikipedia provides useful complementary global information about interdependencies between cancers, drugs and world countries. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in American men. Androgen deprivation therapy (ADT) has become a standard treatment strategy for advanced PCa. Although a majority of patients initially respond to ADT well, most of them will eventually develop castration-resistant PCa (CRPC). Previous studies suggest that ADT-induced changes in the immune microenvironment (mE) in PCa might be responsible for the failures of various therapies. However, the role of the immune system in CRPC development remains unclear. To systematically understand the immunity leading to CRPC progression and predict the optimal treatment strategy in silico, we developed a 3D Hybrid Multi-scale Model (HMSM), consisting of an ODE system and an agent-based model (ABM), to manipulate the tumor growth in a defined immune system. Based on our analysis, we revealed that the key factors (e.g. WNT5A, TRAIL, CSF1, etc.) mediated the activation of PC-Treg and PC-TAM interaction pathways, which induced the immunosuppression during CRPC progression. Our HMSM model also provided an optimal therapeutic strategy for improving the outcomes of PCa treatment. [ABSTRACT FROM AUTHOR]

LncRNA Prostate cancer non-coding RNA (PRNCR1) is downregulated in many types of cancer. The current case-control study was performed on 144 patients with colorectal cancer and 130 matching controls. Genotyping was performed using TaqMan assays for four Single Nucleotide Polymorphisms (SNPs) in PRNCR1. RNAsnp Web Server was used to detect variations in the secondary structure for each SNP. The genotyping analysis for SNP rs1456315 showed increased association with colorectal cancer with the homozygous CC variant allele (OR: 2.09; χ2 = 4.95; CI: 1.08–4.02; p = 0.02), the minor allele frequency, and additive genotype, respectively (OR: 1.55; χ2 = 6.24; CI: 1.09–2.19; p = 0.01) & (OR: 1.64; χ2 = 4.04; CI: 1.01–2.67; p = 0.04). A risk association was also observed among younger age patients (≤57) and in female patients as well as in patients with tumors of the colon. For the other SNPs tested (rs16901946, rs13252298, rs1016343), no significant association was observed. The secondary structure of the rs1456315 mutant is different from that of the wild-type. Our findings suggest that the upregulation of PRNCR1 and its variants is associated with increased risk of colorectal cancer in Saudi patients, indicating that PRNCR1 might be a unique and valuable signature for predicting the risk of colorectal cancer in a Saudi population. [ABSTRACT FROM AUTHOR]

Background: Risk models (RM) need external validation to assess their value beyond the setting in which they were developed. We validated a RM combining mpMRI and clinical parameters for the probability of harboring significant prostate cancer (sPC, Gleason Score ≥ 3+4) for biopsy-naïve men. Material and methods: The original RM was based on data of 670 biopsy-naïve men from Heidelberg University Hospital who underwent mpMRI with PI-RADS scoring prior to MRI/TRUS-fusion biopsy 2012–2015. Validity was tested by a consecutive cohort of biopsy-naïve men from Heidelberg (n = 160) and externally by a cohort of 133 men from University College London Hospital (UCLH). Assessment of validity was performed at fusion-biopsy by calibration plots, receiver operating characteristics curve and decision curve analyses. The RM`s performance was compared to ERSPC-RC3, ERSPC-RC3+PI-RADSv1.0 and PI-RADSv1.0 alone. Results: SPC was detected in 76 men (48%) at Heidelberg and 38 men (29%) at UCLH. The areas under the curve (AUC) were 0.86 for the RM in both cohorts. For ERSPC-RC3+PI-RADSv1.0 the AUC was 0.84 in Heidelberg and 0.82 at UCLH, for ERSPC-RC3 0.76 at Heidelberg and 0.77 at UCLH and for PI-RADSv1.0 0.79 in Heidelberg and 0.82 at UCLH. Calibration curves suggest that prevalence of sPC needs to be adjusted to local circumstances, as the RM overestimated the risk of harboring sPC in the UCLH cohort. After prevalence-adjustment with respect to the prevalence underlying ERSPC-RC3 to ensure a generalizable comparison, not only between the Heidelberg and die UCLH subgroup, the RM`s Net benefit was superior over the ERSPC`s and the mpMRI`s for threshold probabilities above 0.1 in both cohorts. Conclusions: The RM discriminated well between men with and without sPC at initial MRI-targeted biopsy but overestimated the sPC-risk at UCLH. Taking prevalence into account, the model demonstrated benefit compared with clinical risk calculators and PI-RADSv1.0 in making the decision to biopsy men at suspicion of PC. However, prevalence differences must be taken into account when using or validating the presented risk model. [ABSTRACT FROM AUTHOR]

Novel Magnesium Oxide (MgO) nanoparticles (NPs) modified with the polymer polyethylene glycol (PEG) were synthesized as carrier for the anticancer drug 2-Methoxyestradiol (2ME) to improve its clinical application. The functionalized NPs were characterized by Infrared spectroscopy with Fourier transform to elucidate the vibration modes of this conjugate, indicating the formation of the MgO-PEG-2ME nanocomposite. The studies of absorption and liberation determined that MgO-PEG-2ME NPs incorporated 98.51 % of 2ME while liberation of 2ME was constant during 7 days at pH 2, 5 and 7.35. Finally, the MgO-PEG-2ME NPs decreased the viability of the prostate cancer cell line LNCap suggesting that this nanocomposite is suitable as a drug delivery system for anticancer prostate therapy. [ABSTRACT FROM AUTHOR]

There is a need to investigate and better understand the inherited risk of cancer to ensure that clinical applications provide more accurate assessments and management strategies. Developing research-based next-generation sequencing gene panels that not only target (present-day) clinically actionable susceptibility genes but also genes that currently lack sufficient evidence for risk as well as candidate genes, such as those in DNA repair pathways, can help aid this effort. Therefore, gene panel B.O.P. (reast, varian, and rostate) was developed to evaluate the genetic risk of breast, ovarian and/or prostate cancer, and this manuscript serves as an introduction to B.O.P. and highlights its initial analytical validity assessment. B.O.P targets 87 genes that have been suggested, predicted, or clinically proven to be associated with breast, ovarian, and/or prostate cancer risk using Agilent Technologies Haloplex probes. The probes were designed for 100 base pair reads on an Illumina platform and target both coding and non-coding exons as well as 10 intronic base pairs flanking the intron-exon boundaries. The initial B.O.P screening involved 43 individuals from the Alabama Hereditary Cancer Cohort, and an average sequencing depth of 809X was obtained. Upon variant filtering and validation, true positives had an average sequencing depth of 659X and allele balance of 0.51. The average false positive sequencing depth was 34X and allele balance was 0.33. Although low sequencing depth was not always indicative of a false positive, high sequencing depths (>100X) signified a true positive. Furthermore, sensitivity and specificity of BRCA1/2 were calculated to be 100% and 92.3%, respectively. Overall, this screening enabled the establishment of criteria to alleviate future validation efforts and strongly supports the use of B.O.P. to further elucidate hereditary cancer susceptibility. Ultimately, continued B.O.P. screening will provide insights toward the genetic risk of and overlap between breast, ovarian, and/or prostate cancer. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate methods for the pre-treatment verification of volumetric modulated arc therapy (VMAT) based on the percentage gamma passing rate (%GP) and its correlation and sensitivity with percentage dosimetric errors (%DE). Methods: A total of 25 patients with prostate cancer and 15 with endometrial cancer were analysed. The %GP values of 2D and 3D verifications with different acceptance criteria (1%/1 mm, 2%/2 mm, and 3%/3 mm) were obtained using OmniPro and Compass. The %DE was calculated using a planned dose volume histogram (DVH) created in Monaco’s treatment planning system (TPS), which relates radiation dose to tissue and the patient’s predicted dose volume histogram in Compass. Statistical correlation between %GP and %DE was verified using Pearson’s correlation coefficient. Sensitivity was calculated based on the receiver operating characteristics (ROC) curve. Plans were calculated using Collapsed Cone Convolution and the Monte Carlo algorithm. Results: The t-test results of the planned and estimated DVH showed that the mean values were comparable (P > 0.05). For the 3%/3 mm criterion, the average %GP was acceptable for the prostate and endometrial cancer groups, with average rates of 99.68 ± 0.49% and 99.03 ± 0.59% for 2D and 99.86 ± 0.39% and 99.53 ± 0.44% for 3D, respectively. The number of correlations was poor for all analysed data. The mean Pearson’s R-values for prostate and endometrial cancer were < 0.45 and < 0.43, respectively. The area under the ROC curve for the prostate and endometrial cancer groups, was lower than 0.667. Conclusions: Analysis of the %GP versus %DE values revealed only weak correlations between 2D and 3D verifications. DVH results obtained using the Compass system will be helpful in confirming that the analysed plans respect dosimetric constraints. [ABSTRACT FROM AUTHOR]

Purpose: To develop a magneto-nanosensor (MNS) based multiplex assay to measure protein and autoantibody biomarkers from human serum for prostate cancer (CaP) diagnosis. Materials and methods: A 4-panel MNS autoantibody assay and a MNS protein assay were developed and optimized in our labs. Using these assays, serum concentration of six biomarkers including prostate-specific antigen (PSA) protein, free/total PSA ratio, as well as four autoantibodies against Parkinson disease 7 (PARK7), TAR DNA-binding protein 43 (TARDBP), Talin 1 (TLN1), and Caldesmon 1 (CALD1) and were analyzed. Human serum samples from 99 patients (50 with non-cancer and 49 with clinically localized CaP) were evaluated. Results: The MNS assay showed excellent performance characteristics and no cross-reactivity. All autoantibody assays showed a statistically significant difference between CaP and non-cancer samples except for PARK7. The most significant difference was the combination of the four autoantibodies as a panel in addition to the free/total PSA ratio. This combination had the highest area under the curve (AUC)– 0.916 in ROC analysis. Conclusions: Our results suggest that this autoantibody panel along with PSA and free PSA have potential to segregate patients without cancer from those with prostate cancer with higher sensitivity and specificity than PSA alone. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common cancer among men worldwide. Most PCa cases are not fatal; however, the outlook is poor when PCa spreads to another organ. Bone is the target organ in about 80% of patients who experience metastasis from a primary PCa tumor. In the present study, we characterized the secretome of PC3/nKR cells, which are a new subline of PC3 cells that were originally isolated from nude mice that were implanted with PC3 cells without anti-natural killer (NK) cell treatment. Wound healing and Transwell assays revealed that PC3/nKR cells had increased migratory and invasive activities in addition to a higher resistance to NK cells-induced cytotoxicity as compared to PC3 cells. We quantitatively profiled the secreted proteins of PC3/nKR and PC3 cells by liquid chromatography-tandem mass spectrometry analysis coupled with 2-plex tandem mass tag labeling. In total, 598 secretory proteins were identified, and 561 proteins were quantified, among which 45 proteins were secreted more and 40 proteins were secreted less by PC3/nKR cells than by PC3 cells. For validation, the adapter molecule crk, serpin B3, and cystatin-M were analyzed by western blotting. PC3/nKR cells showed the selective secretion of NKG2D ligand 2, HLA-A, and IL-6, which may contribute to their NK cell-mediated cytotoxicity resistance, and had a high secretion of crk protein, which may contribute to their high migration and invasion properties. Based on our secretome analysis, we propose that PC3/nKR cells represent a new cell system for studying the metastasis and progression of PCa. [ABSTRACT FROM AUTHOR]

Prostate cancer is the second most common cancer diagnosed in men worldwide; however, few patients are affected by clinically significant disease within their lifetime. Unfortunately, the means to discriminate between patients with indolent disease and those who progress to aggressive prostate cancer is currently unavailable, resulting in over-treatment of patients. We therefore aimed to determine biomarkers of prostate cancer that can be used in the clinic to aid the diagnosis and prognosis. Immunohistochemistry analysis was carried out on prostate cancer specimens with a range of Gleason scores. Samples were stained and analysed for intensity of the Seven Transmembrane Epithelial Antigen of the Prostate (STEAP)-1, -2, -3, -4 and the Divalent Metal Transporter 1 (DMT1) proteins to determine suitable biomarkers for classification of patients likely to develop aggressive prostate cancer. Additionally, these proteins were also analysed to determine whether any would be able to predict future relapse using Kaplan Meier analysis. Data generated demonstrated that the protein expression levels of STEAP2 correlated significantly with Gleason score; furthermore, STEAP4 was a significant predictor of relapse. This data indicates that STEAP2 could be potential prognostic candidate for use in combination with the current prostate cancer detection methods and the presence of STEAP4 could be an indicator of possible relapse. [ABSTRACT FROM AUTHOR]

Background: Prostate-specific antigen (PSA) based screening for early detection of prostate cancer is common although it is associated with both benefits and potential harms (e.g., the risk of overdiagnosis). Evidence-based health information could help individuals make informed decisions about whether to undergo PSA testing or not. This evaluation aimed to determine whether the written health information materials available in Germany provide appropriate information for informed decision-making on PSA based screening. Methods: A list of criteria was developed and used to systematically assess the quality of information on the benefits and harms of prostate cancer screening included in written health information materials. Fourteen information materials identified by information requests and online searches were evaluated independently by two of three reviewers. Consensus was achieved with a third reviewer. Results: Of the 14 information materials evaluated, 10 (71%) list the ability to reduce the absolute risk of death from prostate cancer as a benefit of PSA testing, 9 (64%) point out the risks of follow-up diagnostics, 13 (93%) describe the risks of the available prostate cancer treatments, and all 14 specify the risk of overdiagnosis. The minority provide numerical data on benefits and risks. Partially mismatched framing was identified in four cases: two information materials report only the relative frequencies of benefits, and two report only the absolute frequencies of harms. Half of the materials encouraged participation using downplaying or frightening language. Conclusions: The majority of health information materials in Germany describe the benefits and harms of PSA based screening, including overdiagnosis, but often lack adequate balance, neutrality and numbers. [ABSTRACT FROM AUTHOR]

Objectives: Disutility allows to identify how much population values intervention-related harms contributing to knowledge on the benefits/harms ratio of cancer screening programs. This systematic review evaluates disutility related to cancer screening applying a utility theory framework. Methods: Using a predefined protocol, Embase, Medline Ovid, Web of Science, Cochrane, Google scholar and supplementary sources were systematically searched. The framework grouped disutilities associated with breast, cervical, lung, colorectal, and prostate cancer screening programs into the screening, diagnostic work up, and treatment phases. We assessed the quality of included studies according to the relevance to target population, risk of bias, appropriateness of measure and the time frame. Results: Out of 2840 hits, we included 38 studies, of which 27 measured (and others estimated) disutilities. Around 70% of studies had medium to high-level quality. Measured disutilities and Quality Adjusted Life Years loss were 0–0.03 and 0–0.0013 respectively in screening phases. Both disutilities and Quality Adjusted Life Years loss had similar ranges in diagnostic work up (0–0.26), and treatment (0.09–0.27) phases. We found no measured disutilities available for lung cancer screening and—little evidence for disutilities in treatment phase. Almost 40% of the estimated disutility values were above the range of measured ones. Conclusions: Cancer screening programs led to low disutities related to screening phase, and low to moderate disutilities related to diagnostic work up and treatment phases. These disutility values varied by the measurement instrument applied, and were higher in studies with lower quality. The estimated disutility values comparing to the measured ones tended to overestimate the harms. [ABSTRACT FROM AUTHOR]

Metformin, a first-line treatment for type 2 diabetes mellitus (T2DM), has recently been recognized for its pleotropic anti-proliferative, anti-cancer, and anti-aging effects. Contrary to the studies characterizing metformin effects in prostate cancer, little is known about these effects in BPH progression. With the Sample Cohort DB data during 2007 and 2017 from the Health Insurance Review and Assessment Service (HIRA) in South Korea, we investigated the preventative effect of metformin on BPH progression. The study population consisted of 211,648 BPH naïve patients that were diagnosed with BPH in 2009 and a follow-up occurrence of prostatectomy until 2017 that was defined as progression of BPH. These patients were divided into three treatment groups: without T2DM, T2DM without metformin, and T2DM with metformin. The hazard ratio in the T2DM with metformin group was 0.86 for prostatectomy compared to the group without T2DM (CI = 0.77–0.96, P value = 0.007) after adjusting for confounding factors such as age, comorbidity, residential area, level of hospital, and category of BPH medications. The T2DM with high-dose metformin group had a significantly lower risk of prostatectomy with hazard ratio of 0.76 (CI = 0.62–0.92, P value = 0.005) in stratified analysis. Our results suggest that metformin may improve BPH progression based on the reduced risk of prostatectomy, although T2DM effects on BPH were unclear. Future observational studies and prospective trials are needed to confirm the effects of metformin on BPH progression. [ABSTRACT FROM AUTHOR]

Progression of prostate cancer to lethal forms is marked by emergence of hormone-independent proliferation of the cancer cells. Nutritional and epidemiological studies have indicated that prostate cancer progression is correlated with the consumption of polyunsaturated fatty acids (PUFA). To shed additional light on the cell-level mechanisms of the observed correlation, we compared the sensitivity of hormone-dependent and hormone-independent prostate cancer cells to growth medium supplementation with free PUFAs in a cell proliferation and viability assay. Our data show that the hormone-dependent cells are comparatively insensitive to various PUFAs, at the same time as the growth and viability of hormone-independent cells lines are strongly inhibited by most of the tested PUFAs, whether n–3 or n–6. We speculate that this difference may be at least partially responsible for the observed effects of specific dietary lipids in prostate cancer. The new data strengthen the case for dietary intervention as part of potential new therapeutic strategies seeking to impede prostate cancer progression. [ABSTRACT FROM AUTHOR]

Prostate cancer was the most common form and had the second highest death rate of male cancer in the United States in 2015. Current diagnosis techniques, such as prostate-specific antigen tests, transrectal ultrasound scans, and biopsies, are often inconclusive, and in the latter case, invasive. Here, we explore the use of clofazimine hydrochloride nanoparticles (CFZ-HCl NPs), a repurposed formulation from an FDA-approved antimycobacterial agent, as a photoacoustic contrast agent for the evaluation of prostate cancer due to its macrophage-targeting capabilities and high optical absorbance at 495 nm. Using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, our results indicate a preferential accumulation of intravenously injected CFZ-HCl NPs in cancerous prostates over normal prostates. Differences in accumulation of CFZ-HCl NPs between cancerous and normal prostates were determined using a two-wavelength unmixing technique via ex vivo photoacoustic imaging. Thus, intravenous injection of CFZ-HCl NPs leads to differences in the interactions of the particles with cancerous vs normal prostates, while allowing for photoacoustic detection and analysis of prostate cancer. These findings could lead to the development of a new noninvasive technique for the detection and monitoring of prostate cancer progression in an animal model that can potentially be translated to human patients. [ABSTRACT FROM AUTHOR]

Purpose: To develop and validate a classifier system for prediction of prostate cancer (PCa) Gleason score (GS) using radiomics and texture features of T2-weighted imaging (T2w), diffusion weighted imaging (DWI) acquired using high b values, and T2-mapping (T2). Methods: T2w, DWI (12 b values, 0–2000 s/mm2), and T2 data sets of 62 patients with histologically confirmed PCa were acquired at 3T using surface array coils. The DWI data sets were post-processed using monoexponential and kurtosis models, while T2w was standardized to a common scale. Local statistics and 8 different radiomics/texture descriptors were utilized at different configurations to extract a total of 7105 unique per-tumor features. Regularized logistic regression with implicit feature selection and leave pair out cross validation was used to discriminate tumors with 3+3 vs >3+3 GS. Results: In total, 100 PCa lesions were analysed, of those 20 and 80 had GS of 3+3 and >3+3, respectively. The best model performance was obtained by selecting the top 1% features of T2w, ADCm and K with ROC AUC of 0.88 (95% CI of 0.82–0.95). Features from T2 mapping provided little added value. The most useful texture features were based on the gray-level co-occurrence matrix, Gabor transform, and Zernike moments. Conclusion: Texture feature analysis of DWI, post-processed using monoexponential and kurtosis models, and T2w demonstrated good classification performance for GS of PCa. In multisequence setting, the optimal radiomics based texture extraction methods and parameters differed between different image types. [ABSTRACT FROM AUTHOR]

Background: The identification of patients with high-risk prostate cancer (PC) is a major challenge for clinicians, and the improvement of current prognostic parameters is an unmet clinical need. We and others have identified an association between the nuclear localization of NF-κB p65 and biochemical recurrence (BCR) in PC in small and/or single-centre cohorts of patients.Methods and Findings: In this study, we accessed 2 different multi-centre tissue microarrays (TMAs) representing cohorts of patients (Test-TMA and Validation-TMA series) of the Canadian Prostate Cancer Biomarker Network (CPCBN) to validate the association between p65 nuclear frequency and PC outcomes. Immunohistochemical staining of p65 was performed on the Test-TMA and Validation-TMA series, which include PC tissues from patients treated by first-line radical prostatectomy (n = 250 and n = 1,262, respectively). Two independent observers evaluated the p65 nuclear frequency in digital images of cancer tissue and benign adjacent gland tissue. Kaplan-Meier curves coupled with a log-rank test and univariate and multivariate Cox regression models were used for statistical analyses of continuous values and dichotomized data (cutoff of 3%). Multivariate analysis of the Validation-TMA cohort showed that p65 nuclear frequency in cancer cells was an independent predictor of BCR using continuous (hazard ratio [HR] 1.02 [95% CI 1.00-1.03], p = 0.004) and dichotomized data (HR 1.33 [95% CI 1.09-1.62], p = 0.005). Using a cutoff of 3%, we found that this biomarker was also associated with the development of bone metastases (HR 1.82 [95% CI 1.05-3.16], p = 0.033) and PC-specific mortality (HR 2.63 [95% CI 1.30-5.31], p = 0.004), independent of clinical parameters. BCR-free survival, bone-metastasis-free survival, and PC-specific survival were shorter for patients with higher p65 nuclear frequency (p < 0.005). As the small cores on TMAs are a limitation of the study, a backward validation of whole PC tissue section will be necessary for the implementation of p65 nuclear frequency as a PC biomarker in the clinical workflow.Conclusions: We report the first study using the pan-Canadian multi-centre cohorts of CPCBN and validate the association between increased frequency of nuclear p65 frequency and a risk of disease progression. [ABSTRACT FROM AUTHOR]

Ectonucleoside Triphosphate Diphosphohydrolase 5 (ENTPD5) has been shown to be important in maintaining cellular function in cancer, and its expression is upregulated through multiple, unique pathways in certain cancers, including laryngeal, glioblastoma multiforme, breast, testicular, and prostate. ENTPD5 supports cancer growth by promoting the import of UDP-glucose, a metabolite used for protein glycosylation and hence proper glycoprotein folding, into the ER by providing the counter molecule, UMP, to the ER antiporter. Despite its cancer-supporting function, no small molecule inhibitors of ENTPD5 are commercially available, and few studies have been performed in tissue culture to understand the effects of chemical inhibition of ENTPD5. We performed a high-throughput screen (HTS) of 21,120 compounds to identify small molecule inhibitors of ENPTD5 activity. Two hits were identified, and we performed a structure activity relationship (SAR) screen around these hits. Further validation of these probes were done in an orthogonal assay and then assayed in cell culture to assess their effect on prostate cancer cell lines. Notably, treatment with the novel ENTPD5 inhibitor reduced the amount of glycoprotein produced in treated cells, consistent with the hypothesis that ENTPD5 is important for glycoprotein folding. This work serves as an important step in designing new molecular probes for ENTPD5 as well as further probing the utility of targeting ENTPD5 to combat cancer cell proliferation. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PC) is a multifocal disease. DNA methylation alterations are not restricted to the immediate peritumor environment, but spatially widespread in the adjacent and distant histologically normal prostate tissues. In the current study, we utilized high-throughput methylation arrays to identify epigenetic changes in the urine from men with and without cancer. Design, setting, and participants: DNA urine samples were enriched for methylated fragments using MBD methyl-binding antibodies and applied to high density CytoScanHD arrays. Significant loci were validated using quantitative pyrosequencing and binary logistic regression modeling applied to urine sample analyses in a training (n = 83) and validation approach (n = 84). Methylation alterations in prostate tissues using pyrosequencing at the PLA2G16 locus were examined in 38 histologically normal specimens from men with (TA, n = 26) and without (NTA, n = 12) cancer and correlated to gene expression. Results: Methylation microarrays identified 3,986 loci showing significantly altered methylation in the urine samples from patients with PC compared to those without (TA vs NTA; p<0.01). These loci were then compared against subjects with their prostates removed to exclude non-prostate cell markers yielding 196 significant regions. Multiple CpGs adjacent to PLA2G16 CpG island showed increased methylation in TA compared to NTA (p<0.01) in a large validation study of urine samples. The predictive accuracy of PLA2G16 methylation at CG2 showed the highest predictive value at 0.8 (odds ratio, 1.37; 95% confidence interval, 1.16–1.62; p<0.001). Using a probability cutoff of 0.065, the sensitivity and specificity of the multivariate model was 92% and 35%. When histologically normal prostate tissues/biopsies from patients with PC (TA) were compared to subjects without cancer, significant hypermethylation of PLA2G16 was noted (odds ratio, 1.35; 95% confidence interval, 1.07–1.71; p = 0.01). Conclusion: PLA2G16 methylation defines an extensive field defect in histologically normal prostate tissue associated with PC. PLA2G16 methylation in urine and prostate tissues can detect the presence of PC. [ABSTRACT FROM AUTHOR]

Background: Area-level indices are widely used to assess the impact of socio-environmental characteristics on cancer outcomes. While area-level measures of socioeconomic status (SES) have been previously used in cancer settings, fewer studies have focused on evaluating the impact of area-level health services supply (HSS) characteristics on cancer outcomes. Moreover, there is significant variation in the methods and constructs used to create area-level indices. Methods: In this study, we introduced a psychometrically-induced, reproducible approach to develop area-level HSS and SES indices. We assessed the utility of these indices in detecting the effects of area-level characteristics on prostate, breast, and lung cancer incidence and stage at diagnosis in the US. The information on county-level SES and HSS characteristics were extracted from US Census, County Business Patterns data and Area Health Resource Files. The Surveillance, Epidemiology, and End Results database was used to identify individuals diagnosed with cancer from 2010 to 2012. SES and HSS indices were developed and linked to 3-year age-adjusted cancer incidence rates. SES and HSS indices empirically summarized the level of employment, education, poverty and income, and the availability of health care facilities and health professionals within counties. Results: SES and HSS models demonstrated good fit (TLI = 0.98 and 0.96, respectively) and internal consistency (alpha = 0.85 and 0.95, respectively). Increasing SES and HSS were associated with increasing prostate and breast cancer and decreasing lung cancer incidence rates. The results varied by stage at diagnosis and race. Conclusion: Composite county-level measures of SES and HSS were effective in ranking counties and detecting gradients in cancer incidence and stage at diagnosis. Thus, these measures provide valuable tools for monitoring geographic disparities in cancer outcomes. [ABSTRACT FROM AUTHOR]

Sequencing data have been instrumental in identifying oncogenic drivers in prostatic carcinoma and highlighting biomarkers that define aggressive disease. A review of a series of 30 primary and metastatic prostatic carcinomas clinically sequenced at our cancer genomics laboratory utilizing a targeted gene panel identified recurrent structural variants in the TP53 gene. These structural variants were found in 27% of all sequenced cases and represented 36% of the cases with metastatic disease. TP53 structural rearrangements have been previously reported in a significant subset of osteosarcomas, where they result in loss of p53 protein expression by immunohistochemistry. Similarly, in our prostate cases with TP53 structural rearrangements for which tissue was available for testing, we find loss of p53 protein expression by immunohistochemistry. In the eight TP53-rearranged cases, concurrent PTEN loss was identified in 4 cases, TMPRSS2-ERG fusion in 5 cases, and AR and FOXA1 amplification in 1 case each. Our results from this small case series suggest that TP53 rearrangements with loss of expression represent a frequent alternative mechanism of inactivation of this key tumor suppressor gene with potential utility as a marker of aggressive disease. Recognition of this TP53 rearrangement pathway is essential to accurately identify prostatic carcinomas with loss of TP53 function. [ABSTRACT FROM AUTHOR]

Background: Knowledge about the relationship between PSA, age and ISUP grade group (ISUP) 1 prostate cancer can improve clinical and biological understanding of prostate cancer. We aimed to investigate the associations between PSA and age and the risk of ISUP 1 and ISUP ≥ 2 prostate cancer, respectively. Methods: We included 6 083 men aged 50–69 biopsied with a total of 72 996 individual biopsy cores from the prospective and population based Stockholm3 diagnostic study. We computed the risk of ISUP 1 and ISUP ≥ 2 prostate cancer and their respective associations with PSA and age. Since lower Gleason grades often are masked by higher grades in the overall Gleason score, we compared associations both for overall Gleason score and for Gleason on individual biopsy cores. Results: ISUP 1 prostate cancer was not significantly associated with PSA at diagnosis: odds ratios ranged from 0.82 (95%CI: 0.68–1.00) for PSA 3–4 ng/mL, 0.96 (95%CI: 0.79–1.16) for PSA 4–6 ng/mL, 0.95 (95%CI: 0.75–1.21) for PSA 6–10 ng/mL, and 0.92 (95%CI: 0.58–1.45) for PSA 10–15 ng/mL compared with PSA 2–3 ng/mL. Age was not significantly associated with risk of ISUP 1 cancer. This contrasts to the strong relationship between ISUP ≥ 2 prostate cancer and its respective associations with PSA and age. Conclusions: We find no significant association between the risk of ISUP 1 prostate cancer and PSA and age at diagnosis indicating that PSA contribution from ISUP 1 prostate cancer is closer to that of benign prostate tissue than to that of ISUP ≥ 2 prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: Following years of controversy regarding screening for prostate cancer using prostate-specific antigen, evidence evolves towards a more restrained and preference-based use. This study reports the impact of landmark trials and updated recommendations on the incidence rate of prostate cancer screening by Swiss general practitioners. Methods: We performed a retrospective analysis of primary care data, separated in 3 time periods based on dates of publications of important prostate-specific antigen screening recommendations. 1: 2010-mid 2012 including 2 updates; 2: mid 2012-mid 2014 including a Smarter Medicine recommendation; 3: mid-2014—mid-2017 maintenance period. Period 2 including the Smarter Medicine recommendation was defined as reference period. We further assessed the influence of patient’s age and the number of prostate-specific-antigen (PSA) tests, by the patient and within each time period, on the mean PSA concentration. Uni- and multivariable analyses were used as needed. Results: 36,800 men aged 55 to 75 years were included. 14.6% had ≥ 2 chronic conditions, 11.7% had ≥ 1 prostate-specific antigen test, (mean 2.60 ng/ml [SD 12.3]). 113,921 patient-years were covered. Data derived from 221 general practitioners, 33.5% of GP were women, mean age was 49.4 years (SD 10.0), 67.9% used prostate-specific antigen testing. Adjusted incidence rate-ratio (95%-CI) dropped significantly over time periods: Reference Period 2: incidence rate-ratio 1.00; Period 1: incidence rate-ratio 1.74 (1.59–1.90); Period 3: incidence rate-ratio 0.61 (0.56–0.67). A higher number of chronic conditions and a patient age between 60–69 years were significantly associated with higher screening rate. Increasing numbers of PSA testing per patient, as well as increasing age, were independently and significantly associated with an increase in the PSA value. Conclusion: Swiss general practitioners adapted screening behavior as early as evidence of a limited health benefit evolved, while using a risk-adapted approach whenever performing multiple testing. Updated recommendations might have helped to maintain this decrease. Further recommendations and campaigns should aimed at older patients with multimorbidity, to sustain a further decline in prostate-specific antigen screening practices. [ABSTRACT FROM AUTHOR]

One common reason for cancer chemotherapy failure is increased drug efflux catalyzed by membrane transporters with broad pump substrate specificities, which leads to resistances to a wide range of chemically unrelated drugs. This multidrug resistance (MDR) phenomenon results in failed therapies and poor patient prognoses. A common cause of MDR is over-expression of the P-glycoprotein (ABCB1/P-gp) transporter. We report here on an MDR modulator that is a small molecule inhibitor of P-glycoprotein, but is not a pump substrate for P-gp and we show for the first time that extended exposure of an MDR prostate cancer cell line to the inhibitor following treatment with chemotherapeutics and inhibitor resulted in trapping of the chemotherapeutics within the cancerous cells. This trapping led to decreased cell viability, survival, and motility, and increased indicators of apoptosis in the cancerous cells. In contrast, extended exposure of non-Pgp-overexpressing cells to the inhibitor during and after similar chemotherapy treatments did not lead to decreased cell viability and survival, indicating that toxicity of the chemotherapeutic was not increased by the inhibitor. Increases in efficacy in treating MDR cancer cells without increasing toxicity to normal cells by such extended inhibitor treatment might translate to increased clinical efficacy of chemotherapies if suitable inhibitors can be developed. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance imaging (MRI) combined with targeted biopsy (TB) is increasingly used in men with clinically suspected prostate cancer (PCa), but the long acquisition times, high costs, and inter-center/reader variability of routine multiparametric prostate MRI limit its wider adoption.Methods and Findings: The aim was to validate a previously developed unique MRI acquisition and reporting protocol, IMPROD biparametric MRI (bpMRI) (NCT01864135), in men with a clinical suspicion of PCa in a multi-institutional trial (NCT02241122). IMPROD bpMRI has average acquisition time of 15 minutes (no endorectal coil, no intravenous contrast use) and consists of T2-weighted imaging and 3 separate diffusion-weighed imaging acquisitions. Between February 1, 2015, and March 31, 2017, 364 men with a clinical suspicion of PCa were enrolled at 4 institutions in Finland. Men with an equivocal to high suspicion (IMPROD bpMRI Likert score 3-5) of PCa had 2 TBs of up to 2 lesions followed by a systematic biopsy (SB). Men with a low to very low suspicion (IMPROD bpMRI Likert score 1-2) had only SB. All data and protocols are freely available. The primary outcome of the trial was diagnostic accuracy-including overall accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value-of IMPROD bpMRI for clinically significant PCa (SPCa), which was defined as a Gleason score ≥ 3 + 4 (Gleason grade group 2 or higher). In total, 338 (338/364, 93%) prospectively enrolled men completed the trial. The accuracy and NPV of IMPROD bpMRI for SPCa were 70% (113/161) and 95% (71/75) (95% CI 87%-98%), respectively. Restricting the biopsy to men with equivocal to highly suspicious IMPROD bpMRI findings would have resulted in a 22% (75/338) reduction in the number of men undergoing biopsy while missing 4 (3%, 4/146) men with SPCa. The main limitation is uncertainty about the true PCa prevalence in the study cohort, since some of the men may have PCa despite having negative biopsy findings.Conclusions: IMPROD bpMRI demonstrated a high NPV for SPCa in men with a clinical suspicion of PCa in this prospective multi-institutional clinical trial.Trial Registration: ClinicalTrials.gov NCT02241122. [ABSTRACT FROM AUTHOR]

Feature screening has become a real prerequisite for the analysis of high-dimensional genomic data, as it is effective in reducing dimensionality and removing redundant features. However, existing methods for feature screening have been mostly relying on the assumptions of linear effects and independence (or weak dependence) between features, which might be inappropriate in real practice. In this paper, we consider the problem of selecting continuous features for a categorical outcome from high-dimensional data. We propose a powerful statistical procedure that consists of two steps, a nonparametric significance test based on edge count and a multiple testing procedure with dependence adjustment for false discovery rate control. The new method presents two novelties. First, the edge-count test directly targets distributional difference between groups, therefore it is sensitive to nonlinear effects. Second, we relax the independence assumption and adapt Efron’s procedure to adjust for the dependence between features. The performance of the proposed procedure, in terms of statistical power and false discovery rate, is illustrated by simulated data. We apply the new method to three genomic datasets to identify genes associated with colon, cervical and prostate cancers. [ABSTRACT FROM AUTHOR]

Background: Radium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. Methods: We conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues. Results: We enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC. Conclusions: Osteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Aldo-keto reductase 1C3 (AKR1C3) is known for multiple functions including its catalytic activity towards producing extra-testicular androgen. The present study is towards understanding interaction between biological, lifestyle and genetic impacts of AKR1C3 and their influence on clinical factors in a prostate cancer (PC) cohort from New Zealand (NZ). Method: Characteristics of 516 PC patients were collected from the Auckland Regional Urology Facility, NZ. These men were genotyped for the AKR1C3 rs12529 single nucleotide polymorphism (SNP). The leukocyte AKR1C3 activity was measured in a sub-cohort. Variability of leukocyte AKR1C3 activity between biological, lifestyle and clinical features as well as correlation between biological and clinical features were assessed with and without genetic stratification. Results: The leukocyte AKR1C3 activity was associated with age at diagnosis (0.51 vs 0.34 μM coumberol units for >69y vs ≤69y, P = 0.03); and with anatomic stage/prognostic grouping among the AKR1C3 rs12529 CC genotype carriers (0.50 vs 28 μM coumberol units among low- and high-risk groups respectively, P = 0.02). Significant correlation between leukocyte AKR1C3 activity and age at PC diagnosis was also observed (correlation coefficient 0.20 and P = 0.02). Ever- smoking impacted both age and PSA at PC diagnosis among AKR1C3 rs12529 GG and CG genotype carriers respectively. Age at diagnosis significantly correlated with PSA at diagnosis in the main (correlation coefficient 0.29, and P<0.001) and sub-cohorts (correlation coefficient 0.24, and P = 0.01); and those carrying the AKR1C3 rs12529 CG and GG genotypes in both the main (correlation coefficient 0.30, and P<0.001 and correlation coefficient 0.35, and P<0.001 respectively) and sub-cohorts (correlation coefficient 0.43, and P<0.001 and correlation coefficient 0.39, and P = 0.06 respectively); but not with those carrying the CC genotype. Conclusions: Age dependent PSA thresholds in PC screening could have been valid only in men carrying the AKR1C3 rs12529 CG and GG genotypes in this NZ cohort. [ABSTRACT FROM AUTHOR]

Chemicals interact with genes in the process of disease development and treatment. Although much biomedical research has been performed to understand relationships among genes, chemicals, and diseases, which have been reported in biomedical articles in Medline, there are few studies that extract disease–gene–chemical relationships from biomedical literature at a PubMed scale. In this study, we propose a deep learning model based on bidirectional long short-term memory to identify the evidence sentences of relationships among genes, chemicals, and diseases from Medline abstracts. Then, we develop the search engine DigChem to enable disease–gene–chemical relationship searches for 35,124 genes, 56,382 chemicals, and 5,675 diseases. We show that the identified relationships are reliable by comparing them with manual curation and existing databases. DigChem is available at . [ABSTRACT FROM AUTHOR]

Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant. [ABSTRACT FROM AUTHOR]

A recent study showed that the Prostate Health Index may avoid unnecessary biopsies in men with prostate specific antigen 4-10ng/ml and normal digital rectal examination in the diagnosis of prostate cancer in Hong Kong. This study aimed to conduct an economic evaluation of the impact of adopting this commercially-available test in the Hong Kong public health service to determine whether further research is justified. A cost-consequence analysis was undertaken comparing the current diagnostic pathway with a proposed diagnostic pathway using the Prostate Health Index. Data for the model was taken from a prospective cohort study recruited at a single-institution and micro-costing studies. Using a cut off PHI score of 35 to avoid biopsy would cost HK$3,000 and save HK$7,988 per patient in biopsy costs and HK$511 from a reduction in biopsy-related adverse events. The net cost impact of the change was estimated to be HK$5,500 under base case assumptions. At the base case sensitivity and specificity for all grades of cancer (61.3% and 77.5% respectively) all grade cancer could be missed in 4.22% of the population and high grade cancer in 0.53%. The introduction of the prostate health index into the diagnostic pathway for prostate cancer in Hong Kong has the potential to reduce biopsies, biopsy costs and biopsy-related adverse events. Policy makers should consider the clinical and economic impact of this proposal. [ABSTRACT FROM AUTHOR]

Production of steroid hormones is complex and dependent upon steroidogenic enzymes, cofactors, receptors, and transporters expressed within a tissue. Collectively, these factors create an environment for tissue-specific steroid hormone profiles and potentially tissue-specific responses to drug administration. Our objective was to assess steroid production, including sulfated steroid metabolites in the boar testis, prostate, and liver following inhibition of aromatase, the enzyme that converts androgen precursors to estrogens. Boars were treated with the aromatase inhibitor, letrozole from 11 to 16 weeks of age and littermate boars received the canola oil vehicle. Steroid profiles were evaluated in testes, prostate, and livers of 16, 20, and 40 week old boars using liquid chromatography/mass spectrometry. Testis, prostate, and liver had unique steroid profiles in vehicle-treated animals. Only C18 steroid hormones were altered by treatment with the aromatase inhibitor, letrozole; no significant differences were detected in any of the C19 or C21 steroids evaluated. Testis was the only tissue with significantly decreased free estrogens following treatment with the aromatase inhibitor; estrone and estradiol concentrations were lower (p < 0.05) in testes from 16, 20, and 40 week letrozole-treated boars. However, concentrations of the sulfated conjugates, estrone-sulfate and estradiol-sulfate, were significantly decreased (p<0.05) in 16 and 20 week boar testes, prostates, and livers from letrozole-treated boars. Hence, the distribution of estrogens between the free and conjugated forms was altered in a tissue-specific manner following inhibition of aromatase. The results suggest sulfated testicular estrogens are important estrogen precursors for the prostate, potentially enabling peripheral target tissues to synthesize free estrogens in the male pig. [ABSTRACT FROM AUTHOR]

Background: Irreversible Electroporation (IRE) is a novel image-guided tissue ablation technology that induces cell death via very short but strong pulsed electric fields. IRE has been shown to have preserving properties towards vessels and nerves and the extracellular matrix. This makes IRE an ideal candidate to treat prostate cancer (PCa) where other treatment modalities frequently unselectively destroy surrounding structures inducing severe side effects like incontinence or impotence. We report the retrospective assessment of 471 IRE treatments in 429 patients of all grades and stages of PCa with 6-year maximum follow-up time. Material and findings: The patient cohort consisted of low (25), intermediate (88) and high-risk cancers (312). All had multi-parametric magnetic resonance imaging, and 199 men had additional 3D-mapping biopsy for diagnostic work-up prior to IRE. Patients were treated either focally (123), sub-whole-gland (154), whole-gland (134) or for recurrent disease (63) after previous radical prostatectomy, radiation therapy, etc. Adverse effects were mild (19.7%), moderate (3.7%) and severe (1.4%), never life-threatening. Urinary continence was preserved in all cases. IRE-induced erectile dysfunction persisted in 3% of the evaluated cases 12 months post treatment. Mean transient IIEF-5-Score reduction was 33% within 12-month post IRE follow-up and 15% after 12 months. Recurrences within the follow-up period occurred in 10% of the treated men, 23 in or adjacent to the treatment field and 18 outside the treatment field (residuals). Including residuals for worst case analysis, Kaplan Maier estimation on recurrence rate at 5 years resulted in 5.6% (CI95: 1.8–16.93) for Gleason 6, 14.6% (CI95: 8.8–23.7) for Gleason 7 and 39.5% (CI95: 23.5–61.4) for Gleason 8–10. Conclusion: The results indicate comparable efficacy of IRE to standard radical prostatectomy in terms of 5-year recurrence rates and better preservation of urogenital function, proving the safety and suitability of IRE for PCa treatment. The data also shows that IRE, besides focal therapy of early PCa, can also be used for whole-gland ablations, in patients with recurrent PCa, and as a problem-solver for local tumor control in T4-cancers not amenable to surgery and radiation therapy anymore. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether whole pelvic radiotherapy (WPRT) improves biochemical relapse-free survival (bRFS) vs. prostate bed radiotherapy (PBRT) in prostate cancer patients receiving salvage radiotherapy (SRT) after radical prostatectomy. Methods: Data from patients with prostate cancer who underwent SRT for biochemical recurrence between 2005 and 2012 in two academic institutions were retrospectively reviewed. Patients treated with WPRT in one hospital were compared with patients treated with PBRT in the other. Propensity scoring was performed to balance the characteristics of the different treatment groups, and bRFS was compared. Results: Data from a total of 191 patients were included in the analysis (WPRT, n = 108; PBRT, n = 83). The median follow-up period was 66 months. Prior to matching, patients who received WPRT had higher pathologic Gleason scores as well as a higher incidence of pre-SRT PSA levels >0.5 ng/mL and lower rates of concurrent androgen-deprivation therapy. Propensity score matching balanced these characteristics and generated a cohort comprising 56 patients from each group. In the matched cohort, the 5 year bRFS of the WPRT group was significantly higher than that of the PBRT group (65.9 vs. 42.2%, p = 0.017). Multivariate analysis revealed that WPRT was an independent prognostic factor for bRFS (hazard ratio: 0.45, 95% confidence interval: 0.26–0.75, p = 0.002). This benefit of WPRT on bRFS was maintained in subgroup analyses, especially in patients with preoperative PSA level ≤20 ng/mL or pre-SRT PSA level ≥0.4 ng/mL. Conclusions: These data suggest that, following radical prostatectomy, elective WPRT during SRT may improve bRFS compared with PBRT in selected patients. Patients with preoperative PSA level ≤20 ng/mL or pre-SRT PSA level ≥0.4 ng/mL represent a potential subgroup who benefit most from receiving WPRT. Results of prospective randomized trials are awaited to confirm this finding. [ABSTRACT FROM AUTHOR]

Urine of prostate cancer (PCa) carries miRNAs originated from prostate cancer cells as a part of both nucleoprotein complexes and cell-secreted extracellular vesicles. The analysis of such miRNA-markers in urine can be a convenient option for PCa screening. The aims of this study were to reveal miRNA–markers of PCa in urine and design a robust and precise diagnostic test, based on miRNA expression analysis. The expression analysis of the 84 miRNAs in paired urine extracellular vesicles (EVs) and cell free urine supernatant samples from healthy donors, patients with benign and malignant prostate tumours was done using miRCURY LNA miRNA qPCR Panels (Exiqon, Denmark). Sets of miRNAs differentially expressed between the donor groups were found in urine EVs and urine supernatant. Diagnostically significant miRNAs were selected and algorithm of data analysis, based on expression data on 24-miRNA in urine and obtained using 17 analytical systems, was designed. The developed algorithm of data analysis describes a series of steps necessary to define cut-off values and sequentially analyze miRNA expression data according to the cut-offs to facilitate classification of subjects in case/control groups and allows to detect PCa patients with 97.5% accuracy. [ABSTRACT FROM AUTHOR]

Triple-Negative Breast Cancers (TNBCs) are the most difficult to treat subtype of breast cancer and are often associated with high nuclear expression of Snail and Cathepsin L (Cat L) protease. We have previously shown that Snail can increase Cat L expression/activity in prostate and breast cancer cells. This study investigated the role of CUX1 (a downstream substrate of Cat L) in TNBC. We showed that Cat L and CUX1 were highly expressed in TNBC patient tissue/cell lines, as compared to ER-positive samples, using cBioportal data and western blot/zymography analyses. Additionally, luciferase reporter and chromatin immunoprecipitation assays showed that CUX1 directly bound to estrogen receptor-alpha (ER-α) promoter in MDA-MB-468, a representative TNBC cell line, and that CUX1 siRNA could restore ER-α transcription and protein expression. Furthermore, Snail and CUX1 expression in various TNBC cell lines was inhibited by muscadine grape skin extract (MSKE, a natural grape product rich in anthocyanins) or Cat L inhibitor (Z-FY-CHO) leading to decreased cell invasion and migration. MSKE decreased cell viability and increased expression of apoptotic markers in MDA-MB-468 cells, with no effect on non-tumorigenic MCF10A cells. MSKE also decreased CUX1 binding to ER-α promoter and restored ER-α expression in TNBC cells, while both MSKE and CUX1 siRNA restored sensitivity to estradiol and 4-hydoxytamoxifen as shown by increased cell viability. Therefore, CUX1 activated by Snail-Cat L signaling may contribute to TNBC via ER-α repression, and may be a viable target for TNBC using natural products such as MSKE that targets cancer and not normal cells. [ABSTRACT FROM AUTHOR]

Prostate cancer (PrCa) is highly heritable; 284 variants have been identified to date that are associated with increased prostate cancer risk, yet few genes contributing to its development are known. Expression quantitative trait loci (eQTL) studies link variants with affected genes, helping to determine how these variants might regulate gene expression and may influence prostate cancer risk. In the current study, we performed eQTL analysis on 471 normal prostate epithelium samples and 249 PrCa-risk variants in 196 risk loci, utilizing RNA sequencing transcriptome data based on ENSEMBL gene definition and genome-wide variant data. We identified a total of 213 genes associated with known PrCa-risk variants, including 141 protein-coding genes, 16 lncRNAs, and 56 other non-coding RNA species with differential expression. Compared to our previous analysis, where RefSeq was used for gene annotation, we identified an additional 130 expressed genes associated with known PrCa-risk variants. We detected an eQTL signal for more than half (n = 102, 52%) of the 196 loci tested; 52 (51%) of which were a Group 1 signal, indicating high linkage disequilibrium (LD) between the peak eQTL variant and the PrCa-risk variant (r2>0.5) and may help explain how risk variants influence the development of prostate cancer. [ABSTRACT FROM AUTHOR]