Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC

Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed bipolar androgen therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill defined. Here, we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and were driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pretreatment AR activity predicted downregulation of MYC, improved clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance was overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and resensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.     

A phase II randomized double blinded trial evaluating the efficacy of curcumin with pre-operative chemoradiation for rectal cancer

BackgroundIn vivo studies demonstrate that curcumin increases radioresponse of colorectal cancers. To demonstrate efficacy in humans, we performed a randomized double-blind study of locally advanced rectal cancer (LARC) patients receiving pre-operative chemoradiation therapy (CRT) ± curcumin. We used pathologic complete response (pCR) rate as a surrogate for clinical outcome.MethodsFrom 2008–2010, LARC patients were randomized to placebo/curcumin in a 1:2 ratio. Patients received CRT [50.4 gray in 28 fractions; capecitabine (825 mg/m² twice daily)] followed by surgery. Curcumin (4 grams orally, twice daily) or placebo was given throughout CRT and 6 weeks afterward. Toxicity was monitored weekly. Blood samples taken pre- and 1-hour post-ingestion and tissue biopsies (both collected at CRT week 2) were analyzed for pharmacokinetics. The primary outcome was surgical pCR rate.ResultsOf 22 enrolled patients, 15 received curcumin. Median age was 61 years and the majority were male (n=13; 59%). The median serum curcumin concentrations before (3.04 ng/mL; range, 1.24–18.88 ng/mL) and 1 hour after (3.32 ng/mL; range, 0.84–5.36 ng/mL) curcumin intake did not differ significantly (P=0.33). Serum curcumin concentrations both increased and decreased 1-hour post-administration (range as percentage of baseline: 8.8–258.1%). Twelve curcumin patient tissue biopsies had median curcumin concentration of 33.7 ng/mg tissue (range, 0.1–4,765.7 ng/mg). Two placebo and 1 curcumin patient achieved pCRs (P=0.18). One grade 3 toxicity (infection) was experienced.ConclusionsThe addition of curcumin to CRT did not increase pCR rates for LARC patients. The unpredictable bioavailability of curcumin contributes to continued uncertainties regarding curcumin efficacy.Trial RegistrationClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00745134","term_id":"NCT00745134"}}NCT00745134.     

Metabolic and Blood Pressure Effects of Consuming Two Kiwifruit Daily for 7 Weeks: A Randomised Controlled Trial

Background: Eating two kiwifruit before breakfast by equi-carbohydrate partial exchange of cereal has been associated with lower postprandial glucose and insulin, but it increases the intake of fruit sugar. We assessed the effects of kiwifruit ingestion at breakfast over 7 weeks on metabolic and physiologic factors. Method: Forty-three healthy Asian participants were randomised to ingest 500 mL of carbonated water (control) or 500 mL of carbonated water plus two kiwifruit (intervention), before breakfast. Three-day weighed diet records were taken before and at week 4 during the intervention. Overnight fasting blood samples were taken at baseline and week 7. Forty-two participants completed the study (n = 22 control, n = 20 intervention). Results: The kiwifruit group consumed more fructose, vitamin C, vitamin E, and carbohydrates as a percentage of energy compared with the control group (p < 0.01). There was no evidence of between-group changes in metabolic outcomes at the end of the intervention, with the following mean (95% confidence interval) differences in fasting blood samples: glucose 0.09 (−0.06, 0.24) mmol/L; insulin −1.6 (−3.5, 0.3) μU/mL; uric acid −13 (−30, 4) μmol/L; triglycerides −0.10 (−0.22, 0.03) mmol/L; and total cholesterol −0.05 (−0.24, 0.14) mmol/L. There was a −2.7 (−5.5, 0.0) mmHg difference in systolic blood pressure for the intervention group compared with the control group. Conclusion: Eating two kiwifruit as part of breakfast increased fruit consumption and intake of antioxidant nutrients without a change in fasting insulin. There was a difference in systolic blood pressure and no adverse fructose-associated increases in uric acid, triglycerides, or total cholesterol. This simple intervention may provide health benefits to other demographic groups.     

Improving Access to COVID-19 Vaccines: An Analysis of TRIPS Waiver Discourse among WTO Members,Civil Society Organizations,and Pharmaceutical Industry Stakeholders

Throughout the COVID-19 pandemic, international access to COVID-19 vaccines and other health technologies has remained highly asymmetric. This inequity has had a particularly deleterious impact on low- and middle-income countries, engaging concerns about the human rights to health and to the equal enjoyment of the benefits of scientific progress enshrined under articles 12 and 15 of the International Covenant on Economic, Social and Cultural Rights. In response, the relationship between intellectual property rights and public health has reemerged as a subject of global interest. In October 2020, a wholesale waiver of the copyright, patent, industrial design, and undisclosed information sections of the Agreement on Trade-Related Aspects of Intellectual Property (TRIPS Agreement) was proposed by India and South Africa as a legal mechanism to increase access to affordable COVID-19 medical products. Here, we identify and evaluate the TRIPS waiver positions of World Trade Organization (WTO) members and other key stakeholders throughout the waiver’s 20-month period of negotiation at the WTO. In doing so, we find that most stakeholders declined to explicitly contextualize the TRIPS waiver within the human right to health and that historical stakeholder divisions on the relationship between intellectual property and access to medicines appear largely unchanged since the early 2000s HIV/AIDS crisis. Given the WTO’s consensus-based decision-making process, this illuminates key challenges faced by policy makers seeking to leverage the international trading system to improve equitable access to health technologies.     

Mobile Phone and Social Media Use of Homeless Youth in Denver,Colorado

The purpose of this study was to investigate homeless youth mobile phone and social media use, to plan health promotion efforts. Nearly half (46.7%) of runaway/homeless youth in this sample (n = 181) owned a mobile phone and a majority of those devices were smart phones. Ownership did not vary significantly by shelter location, though regular use of Facebook was more prevalent among those in housing programs or camping, than those living on the streets. Over 90% of youth in the sample reported using Facebook. Such media use might facilitate parent, family, and health provider communications with homeless youth.     

Magnetic resonance imaging accurately tracks kidney pathology and heterogeneity in the transition from acute kidney injury to chronic kidney disease

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