The transcriptional programme of the androgen receptor (AR) in prostate cancer.

The androgen receptor (AR) is essential for normal prostate and prostate cancer cell growth. AR transcriptional activity is almost always maintained even in hormone relapsed prostate cancer (HRPC) in the absence of normal levels of circulating testosterone. Current molecular techniques, such as chromatin-immunoprecipitation sequencing (ChIP-seq), have permitted identification of direct AR-binding sites in cell lines and human tissue with a distinct coordinate network evident in HRPC. The effectiveness of novel agents, such as abiraterone acetate (suppresses adrenal androgens) or enzalutamide (MDV3100, potent AR antagonist), in treating advanced prostate cancer underlines the on-going critical role of the AR throughout all stages of the disease. Persistent AR activity in advanced disease regulates cell cycle activity, steroid biosynthesis and anabolic metabolism in conjunction with regulatory co-factors, such as the E2F family, c-Myc and signal transducer and activator of transcription (STAT) transcription factors. Further treatment approaches must target these other factors.

A Prospective Study of Stereotactic Body Radiotherapy (SBRT) with Concomitant Whole-Pelvic Radiotherapy (WPRT) for High-Risk Localized Prostate Cancer Patients Using 1.5 Tesla Magnetic Resonance Guidance: The Preliminary Clinical Outcome.

Background: Conventionally fractionated whole-pelvic nodal radiotherapy (WPRT) improves clinical outcome compared to prostate-only RT in high-risk prostate cancer (HR-PC). MR-guided stereotactic body radiotherapy (MRgSBRT) with concomitant WPRT represents a novel radiotherapy (RT) paradigm for HR-PC, potentially improving online image guidance and clinical outcomes. This study aims to report the preliminary clinical experiences and treatment outcome of 1.5 Tesla adaptive MRgSBRT with concomitant WPRT in HR-PC patients. Materials and methods: Forty-two consecutive HR-PC patients (72.5 ± 6.8 years) were prospectively enrolled, treated by online adaptive MRgSBRT (8 Gy(prostate)/5 Gy(WPRT) × 5 fractions) combined with androgen deprivation therapy (ADT) and followed up (median: 251 days, range: 20−609 days). Clinical outcomes were measured by gastrointestinal (GI) and genitourinary (GU) toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) Scale v. 5.0, patient-reported quality of life (QoL) with EPIC (Expanded Prostate Cancer Index Composite) questionnaire, and prostate-specific antigen (PSA) responses. Results: All MRgSBRT fractions achieved planning objectives and dose specifications of the targets and organs at risk, and they were successfully delivered. The maximum cumulative acute GI/GU grade 1 and 2 toxicity rates were 19.0%/81.0% and 2.4%/7.1%, respectively. The subacute (>30 days) GI/GU grade 1 and 2 toxicity rates were 21.4%/64.3% and 2.4%/2.4%, respectively. No grade 3 toxicities were reported. QoL showed insignificant changes in urinary, bowel, sexual, and hormonal domain scores during the follow-up period. All patients had early post-MRgSBRT biochemical responses, while biochemical recurrence (PSA nadir + 2 ng/mL) occurred in one patient at month 18. Conclusions: To our knowledge, this is the first prospective study that showed the clinical outcomes of MRgSBRT with concomitant WPRT in HR-PC patients. The early results suggested favorable treatment-related toxicities and encouraging patient-reported QoLs, but long-term follow-up is needed to confirm our early results.

Prognostic Implications of Comprehensive Whole Vessel Plaque Quantification Using Coronary Computed Tomography Angiography.

Background: The prognostic value of whole vessel plaque quantification has not been fully understood. Objectives: We aimed to investigate the clinical relevance of whole vessel plaque quantification on coronary computed tomography angiography. Methods: In a total of 1,013 vessels with fractional flow reserve (FFR) measurement and available coronary computed tomography angiography, high-risk plaque characteristics (HRPC) included minimum lumen area <4 mm2, plaque burden ≥70%, low attenuation plaque, positive remodeling, spotty calcification, and napkin-ring sign; and high-risk vessel characteristics (HRVC) included total plaque volume ≥306.5 mm3, fibrofatty and necrotic core volume ≥4.46 mm3, or percent total atheroma volume ≥32.2% in a target vessel, based on corresponding optimal cutoff values. Survival analysis for vessel-oriented composite outcome (VOCO) (a composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization) at 5 years was performed using marginal Cox proportional hazard models. Results: Whole vessel plaque quantification had incremental predictability in addition to % diameter stenosis and HRPC (P < 0.001) in predicting FFR ≤0.80. Among 517 deferred vessels based on FFR >0.80, the number of HRVC was significantly associated with the risk of VOCO (HR: 2.54; 95% CI: 1.77-3.64) and enhanced the predictability for VOCO of % diameter stenosis and the number of HRPC (P < 0.001). In a landmark analysis at 2 years, the number of HRVC showed sustained prognostic implications beyond 2 years, but the number of HRPC did not. Conclusions: Whole vessel plaque quantification can provide incremental predictability for low FFR and additive prognostic value in deferred vessels with high FFR over anatomical severity and lesion plaque characteristics. (CCTA-FFR Registry for Risk Prediction; NCT04037163).

The use of Trametes versicolor laccase for the polymerization of aniline in the presence of vesicles as templates.

The enzymatic polymerization of aniline to polyaniline (PANI) with Trametes versicolor laccase (TvL) as catalyst and dioxygen (O2) as oxidant was investigated in an aqueous medium containing unilamellar vesicles with an average diameter of about 80 nm formed from AOT (=sodium bis(2-ethylhexyl) sulfosuccinate). Compared to the same reaction carried out with horseradish peroxidase isoenzyme C (HRPC) as catalyst and hydrogen peroxide (H2O2) as oxidant, notable differences were found in the kinetics of the reaction, as well as in the characteristics of the PANI obtained. Under comparable optimal conditions, which are pH 3.5 for TvL/O2 and pH 4.3 for HRPC/H2O2, the reaction with TvL/O2 was much slower than with HRPC/H2O2, i.e. ≈27 days vs. 1 day reaction time to reach equilibrium with >90% yield at 25 °C. Although in both cases, aniline monomer coupling occurred mainly via the carbon atom in para position of aniline, UV-vis-NIR absorption and EPR measurements indicate that the reaction with TvL/O2 yielded mainly overoxidized products (with λ(max)=730 nm). These products had a lower amount of unpaired electrons if compared with the products obtained with HRPC/H2O2 (with λ(max)≈1000 nm, which is characteristic for the polaron state of PANI-ES, the emeraldine salt form of PANI). Similarly to previous findings with HRPC/H2O2, enzyme inactivation occurred during the polymerization also in the case of TvL/O2. Since the aqueous PANI-vesicle suspensions obtained are of high colloidal stability, they can be used directly as ink in a conventional thermal inkjet printer for printing on paper or on surface treated polyimide films. Printed PANI-ES patterns on paper changed colour from green (emeraldine salt) to blue (emeraldine base) upon exposure to ammonia gas, demonstrating the expected ammonia sensing properties.

TroVax in colorectal cancer.

Currently, the backbone of therapy for metastatic disease is cytotoxic chemotherapy, along with the recent addition of targeted therapy based on molecular markers with KRAS testing. Despite the improvement in survival for metastatic colon cancer, newer agents are still needed. The clinical activity of TroVax in metastatic colon cancer has been studied in a small number of clinical trials. There is evidence that supports the vaccine's ability to induce humoral and cellular responses, as demonstrated by positive 5T4 and MVA-specific antibody titers and cellular proliferation assays. Future strategies should focus on investigating the immunomodulatory effects of chemotherapy in conjunction with TroVax, understanding the optimal dosing and schedule of the combination, and examining potential predictive biomarkers to determine which patients may benefit from immunotherapy from those who do not.

Combination of docetaxel and vandetanib in docetaxel-sensitive or resistant PC3 cell line.

OBJECTIVE: To examine the anti-proliferative effect of the combination of docetaxel, the cornerstone of modern chemotherapy for prostate cancer, and vandetanib, a potent inhibitor of VEGFR-2 tyrosine kinase, applied to the representative hormone-refractory human prostate cancer cell line PC3. The aim is to analyze if a supra-additive/synergic effect of the combined treatment on cell viability exists and to understand the molecular key-factors involved. We first hypothesized an effect of vandetanib in modulation the function of MDR1, leading to a longer retention of docetaxel inside the cell. It may also be possible that vandetanib could modulate the docetaxel-induced changes in expression of prosurvival and proapoptotic proteins, leading to a positive balance forward cell death. MATERIALS AND METHODS: We used PC3 cells either wild type (PC3wt) or with acquired resistance to docetaxel (PC3R), characterized by a higher expression of MDR1. We studied both mRNA and protein, the expression of EGF and VEGF receptors at a basal level and after each treatment, as well as the expression of cell cycle and apoptosis related genes. RESULTS: Cell proliferation data suggested a supra-additive cytotoxic effect of the combination of docetaxel plus vandetanib, when given together or with the sequence vandetanib followed by docetaxel. We did not observe any effect of vandetanib on MDR1, in the PC3R cell lines, characterized by a higher pump expression than PC3wt. On the other side, we defined a number of key factors involved in the pro- and anti-survival balance, which regulation, by single drugs and/or by combined treatment, could explain the effect on cell cytotoxicity; also where there are apparently contradictory results. CONCLUSIONS: Our data suggest that combined treatment with vandetanib and docetaxel alters the balance of proapoptotic and prosurvival proteins, ultimately leading to potentiation of docetaxel-induced apoptosis in human prostate cancer cells in vitro, irrespective of cells being sensitive or resistant to docetaxel.

Narita target heart rate equation underestimates the predicted adequate exercise level in sedentary young boys.

PURPOSE: Optimal training intensity and the adequate exercise level for physical fitness is one of the most important interests of coaches and sports physiologists. The aim of this study was to investigate the validity of the Narita et al target heart rate equation for the adequate exercise training level in sedentary young boys. METHODS: Forty two sedentary young boys (19.07±1.16 years) undertook a blood lactate transition threshold maximal treadmill test to volitional exhaustion with continuous respiratory gas measurements according to the Craig method. The anaerobic threshold (AT) of the participants then was calculated using the Narita target heart rate equation. RESULTS: Hopkin's spreadsheet to obtain confidence limit and the chance of the true difference between gas measurements and Narita target heart rate equation revealed that the Narita equation most likely underestimates the measured anaerobic threshold in sedentary young boys (168.76±15 vs. 130.08±14.36) (Difference ±90% confidence limit: 38.1±18). Intraclass correlation coefficient (ICC) showed a poor agreement between the criterion method and Narita equation (ICC= 0.03). CONCLUSION: According to the results, the Narita equation underestimates the measured AT. It seems that the Narita equation is a good predictor of aerobic not AT which can be investigated in the future studies.

Green tea polyphenol epigallocatechin-3-gallate (EGCG) as adjuvant in cancer therapy.

BACKGROUND & AIMS: Green tea catechins, especially epigallocatechin-3-gallate (EGCG), have been associated with cancer prevention and treatment. This has resulted in an increased number of studies evaluating the effects derived from the use of this compound in combination with chemo/radiotherapy. This review aims at compiling latest literature on this subject. METHODS: Keywords including EGCG, cancer, chemotherapy, radiotherapy and side effects, were searched using PubMed and ScienceDirect databases to identify, analyze, and summarize the research literature on this topic. Most of the studies on this subject up to date are preclinical. Relevance of the findings, impact factor, and date of publication were critical parameters for the studies to be included in the review. RESULTS: Additive and synergistic effects of EGCG when combined with conventional cancer therapies have been proposed, and its anti-inflammatory and antioxidant activities have been related to amelioration of cancer therapy side effects. However, antagonistic interactions with certain anticancer drugs might limit its clinical use. CONCLUSIONS: The use of EGCG could enhance the effect of conventional cancer therapies through additive or synergistic effects as well as through amelioration of deleterious side effects. Further research, especially at the clinical level, is needed to ascertain the potential role of EGCG as adjuvant in cancer therapy.

Health-related quality of life in pain-free or mildly symptomatic patients with metastatic hormone-resistant prostate cancer following treatment with the specific endothelin A receptor antagonist zibotentan (ZD4054).

PURPOSE: Zibotentan (ZD4054) is a specific endothelin A receptor antagonist in clinical development for the treatment of hormone-resistant prostate cancer (HRPC). In a Phase II trial in patients with pain-free or mildly symptomatic metastatic HRPC, zibotentan was well tolerated with a promising signal for prolonged overall survival compared with placebo. As part of this trial, the impact of zibotentan compared with placebo on health-related quality of life (HRQoL) was assessed. METHODS: Patients were randomized to receive once-daily oral zibotentan 10 or 15 mg, or matching placebo. Patients were allocated to one of two questionnaires; the Functional Assessment of Cancer Therapy-Prostate (FACT-P) or the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), supplemented by PR25, specific for prostate cancer. Questionnaires were completed at baseline and every 4 weeks until disease progression when study treatment was discontinued. RESULTS: Compliance with questionnaire completion was >90% (286 of 312 patients) of the intention-to-treat population at baseline. Of baseline completers who were available for assessment (i.e., had not clinically progressed), 89% (164 of 184) and 83% (73 of 88) completed questionnaires at 12 and 24 weeks, respectively. HRQoL scores from both questionnaires were high at baseline and remained high throughout the study, with scores being similar in the zibotentan and placebo groups. However, some floor and ceiling effects were seen in the EORTC QLQ-C30 questionnaire. CONCLUSIONS: High-baseline HRQoL scores were maintained throughout treatment with zibotentan. The FACT-P instrument was selected to further assess the impact of zibotentan on HRQoL in the Phase III clinical trial program.