Prevalence and Spectrum of AR Ligand-Binding Domain Mutations Detected in Circulating-Tumor DNA Across Disease States in Men With Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) is typically treated with agents directly or indirectly targeting the androgen receptor (AR) pathway. However, such treatment is limited by resistance mechanisms, including the development of activating mutations in the AR ligand-binding domain (AR-LBD). METHODS: This study evaluated a database of over 15,000 patients with advanced prostate cancer (PC) undergoing comprehensive circulating-tumor DNA analysis (Guardant360, Redwood City, CA) between 2014 and 2021, with associated clinical information from administrative claims (GuardantINFORM database). RESULTS: Of 15,705 patients with PC included, 54% had mCRPC at the time of their blood draw. Of those, 49% had previous treatment with an AR pathway inhibitor (ARPi). AR-LBD mutation prevalence was 15% in patients with mCRPC who were untreated with a next-generation ARPi, 22% in those after one line of ARPi therapy, and 24% in those after two lines of ARPi treatment. Next-generation ARPi treatment yielded an increase in AR L702H and T878A/S mutations after abiraterone, and an increase in AR L702H and F877L mutations after enzalutamide. AR-LBD+ patients demonstrated unique biology, including increased concurrent mutations in the cell-cycle, wingless-related integration site, homologous recombination repair, and phospho-inositide 3-kinase pathways (all P < .0005), and greater low-level (copy number <10) AR amplifications (P = .0041). AR-LBD+ patients exhibited worse overall survival (OS) relative to a matched cohort of AR-LBD- patients (50.1 v 60.7 months, unadjusted log-rank P = .013). CONCLUSION: This large database analysis demonstrates that AR-LBD mutation prevalence increases after next-generation ARPi use. AR-LBD+ tumors demonstrate unique biology (more oncogenic pathway mutations and low-level AR amplification) and reduced OS. These findings inform the development of novel therapies designed to circumvent AR-mediated therapeutic resistance.

Therapies for Clinically Localized Prostate Cancer: A Comparative Effectiveness Review.

PURPOSE: We sought to identify new information evaluating clinically localized prostate cancer therapies. MATERIALS AND METHODS: Bibliographic databases (2013-January 2020), ClinicalTrials.gov and systematic reviews were searched for controlled studies of treatments for clinically localized prostate cancer with duration ≥5 years for mortality and metastases, and ≥1 year for harms. RESULTS: We identified 67 eligible references. Among patients with clinically, rather than prostate specific antigen, detected localized prostate cancer, watchful waiting may increase mortality and metastases but decreases urinary and erectile dysfunction vs radical prostatectomy. Comparative mortality effect may vary by tumor risk and age but not by race, health status, comorbidities or prostate specific antigen. Active monitoring probably results in little to no mortality difference in prostate specific antigen detected localized prostate cancer vs radical prostatectomy or external beam radiation plus androgen deprivation regardless of tumor risk. Metastases were slightly higher with active monitoring. Harms were greater with radical prostatectomy than active monitoring and mixed between external beam radiation plus androgen deprivation vs active monitoring. 3-Dimensional conformal radiation and androgen deprivation plus low dose rate brachytherapy provided small mortality reductions vs 3-dimensional conformal radiation and androgen deprivation but little to no difference on metastases. External beam radiation plus androgen deprivation vs external beam radiation alone may result in small mortality and metastasis reductions in higher risk disease but may increase sexual harms. Few new data exist on other treatments. CONCLUSIONS: Radical prostatectomy reduces mortality vs watchful waiting in clinically detected localized prostate cancer but causes more harms. Effectiveness may be limited to younger men and those with intermediate risk disease. Active monitoring results in little to no mortality difference vs radical prostatectomy or external beam radiation plus androgen deprivation. Few new data exist on other treatments.

Response surface optimisation of extraction of antioxidants from strawberry fruit, and lipid peroxidation inhibitory potential of the fruit extract in cooked chicken patties.

BACKGROUND: Strawberries contain high levels of antioxidants and have beneficial effects against oxidative stress-mediated diseases, such as cancer. They contain multiple phenolic compounds, which contribute to their biological properties. Hence, a study was carried out to optimise the extraction of antioxidants and evaluate the antioxidant potential of strawberry fruit extract (SE) in cooked chicken patties during refrigerated storage. The activity of SE was compared with that of butylhydroxytoluene (BHT). RESULTS: The effect of solvent type (MeOH and EtOH), concentration (0-70%) of EtOH in the system, temperature (30-60 °C), and time (30-150 min) on DPPH•-scavenging activity of SE was investigated. Response surface methodology was used to estimate the optimum extraction conditions for each parameter. The maximum predicted DPPH• scavenging under the optimised conditions (100% MeOH, 30 °C, 150 min) was 43% at 1 mg SE mL⁻¹. Freshly prepared chicken patties were treated with 5% and 10% SE and 2% BHT, and stored aerobically at 4 °C for 6 days. SE had no influence (P < 0.05) on any of the sensory attributes of the patties. The values of thiobarbituric acid reactive substances reduced significantly (P < 0.05) from 2.47 mg in control patties to 0.312 mg and 0.432 mg malonaldehyde kg⁻¹ sample in 5-SE and 10-SE patties, respectively, on the day 6 of storage. CONCLUSION: The optimised model depicted MeOH at 30 °C with an extended time of 150 min as the optimum settings for extraction of compounds from strawberry that had the scavenging activity. The study shows that the extraction of natural antioxidants from strawberry can be improved by optimising several key extraction parameters. SE also acted as an effective antioxidant and suppressed lipid peroxidation in cooked chicken patties.

Response surface optimisation of antioxidant extraction from kinema, a Bacillus-fermented soybean food.

The objective of this work was to optimise different parameters (solvent concentration, time and temperature) for antioxidant extraction from kinema, demonstrated by total phenol content (TPC) and DPPH-scavenging activity (DSA), using response surface methodology. A central composite design was performed to determine the effect of solvent concentration (methanol, 30-100%), temperature (30-60°C) and time (30-150min) on the TPC and DSA of the extract. The solvent concentration and temperature had the most significant (p<0.05) effect. The optimum conditions for the TPC extraction and DSA were 100% methanol, 50°C and 30min, in which 140mg of gallic acid equivalent (GAE) g-1 lyophilised extract and 52% DSA were predicted, while 135mg GAE g-1 lyophilised extract and 56% DSA were experimentally obtained. No significant difference (p<0.05) was found between the experimental and predicted values of the response variables.

Comparative nuclease and anti-cancer properties of the naturally occurring malabaricones.

The nuclease activities of the malabaricones have been studied so as to establish a structure-activity correlation and deduce the mechanistic pathway of the process. The inactivity of malabaricone A and malabaricone D revealed that the resorcinol moiety, present in the malabaricones did not contribute to the nuclease activity. Amongst the test compounds, malabaricone C (mal C) containing a B-ring catechol moiety showed significantly better Cu(II)-dependent nuclease activity than the partially methylated catechol derivative, mal B and curcumin. Mal C was found to bind efficiently with Cu(II) and DNA to facilitate the DNA nicking via a site-specifically generated Cu(I)-peroxo complex. Consistent with its Cu(II)-dependent nuclease property, mal C showed better cytotoxicity (IC(50)=5.26±1.20 µM) than curcumin (IC(50)=24.46±3.32 µM) against the MCF-7 human breast cancer cell line. The mal C-induced killing of the MCF-7 cells followed an apoptotic pathway involving oxidative damage to the cellular DNA.