Over the last two decades, berries and berry bioactives, particularly anthocyanins and their aglycones anthocyanidins (Anthos) have demonstrated excellent anti-oxidant, anti-proliferative, apoptotic and anti-inflammatory properties. However, their physicochemical and pharmacokinetic limitations such as, low permeability, and poor oral bioavailability are considered as unfavorable properties for development as drugs. Therefore there is a need to develop systems for efficient systemic delivery and robust bioavailability. In this study we prepared nano-formulation of bilberry-derived Anthos using exosomes harvested from raw bovine milk. Exosomal formulation of Anthos enhanced antiproliferative and anti-inflammatory effects compared with the free Anthos against various cancer cells in vitro. Our data also showed significantly enhanced therapeutic response of exosomal-Anthos formulation compared with the free Anthos against lung cancer tumor xenograft in nude mice. The Anthos showed no signs of gross or systemic toxicity in wild-type mice. Thus, exosomes provide an effective alternative for oral delivery of Anthos that is efficacious, cost-effective, and safe, and this regimen can be developed as a non-toxic, widely applicable therapeutic agent.

Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1(PVT1) was aberrantly expressed in various cancers and is associated with tumor prognosis. Here, we aim to investigate its function in prostate cancer. Small interfering RNA against PVT1 was transfected into prostate cancer cell lines and cell growth and apoptosis were analyzed. Our results showed that PVT1 was overexpressed in prostate cancer tissues and cells. Higher levels of PVT1 indicated poorer overall survival and disease-free survival. A significant association was found between PVT1 expression and tumor stage. Besides, PVT1 knockdown significantly inhibited prostate cancer growth in vivo and in vitro and promoted cell apoptosis. PVT1 knockdown also significantly upregulated the expression of cleaved caspase-3 and cleaved caspase-9, but downregulated the expression of c-Myc in prostate cancer cell lines. Our results suggest that PVT1 played an oncogenic role in prostate cancer and could be used as a potential biomarker for diagnosis of prostate cancer.

Diets rich in fat, smoking, as well as exposure to environmental pollutants and dysbiosis of gut microbiota, increase the risk of developing colorectal cancer (CRC). Much progress has been made in combating CRC. However, options for chemoprevention from environmental insult and dysbiosis of gut microbiota remains elusive. We investigated the influence of berry-derived anthocyanidins (Anthos), with and without encapsulating them in bovine milk-derived exosomes (ExoAnthos), on the chemoprevention of bacteria-driven colon tumor development. Anthos and ExoAnthos treatment of colon cancer cells showed dose-dependent decreases in cell viability. Calculated selectivity index (SI) values for Anthos and ExoAnthos suggest that both treatments selectively targeted cancer over normal colon cells. Additionally, ExoAnthos treatment yielded higher SI values than Anthos. Anthos and ExoAnthos treatment of Apc Min/+ mice inoculated with ETBF bacteria led to significant decreases in colon tumor numbers over mice receiving vehicle treatments. Western blot analysis of normal colon, colon tumor, and liver tissue lysates showed that mice inoculated with ETBF featured increased expression of phase I enzymes in normal colon tissue and decreased expression of phase II enzymes in liver tissue. Treatment with the Anthos and ExoAnthos reverted the modulation of phase I and phase II enzymes, respectively; no significant changes in phase II enzyme expression occurred in colon tumor tissue. Treatment of HCT-116 cells with the ubiquitous carcinogen, benzo[a]pyrene led to similar modulation of phase I and II enzymes, which was partially mitigated by treatment with Anthos. These results provide a promising outlook on the impact of berry Anthos for prevention and treatment of bacteria-and benzo[a]pyrene-driven colorectal cancer.

periprosthetic joint infection. Probabilistic sensitivity analysis examined the effect of combined uncertainty across model parameters. RESULTS: Comparing DM to LFH, incremental costs over 3 years were £428 vs. £1,447 in the UK, V451 vs. V1,272 in Germany, V540 vs. V1,425 in Italy, and V523 vs. V1,562 in Spain (95% CI). DM implants were cost saving for patients undergoing revision THA at a cost differential of £1,019 in the UK, V820 in Germany, V885 in Italy, and V1,039 in Spain. CONCLUSIONS: A model using clinical data derived from a large-sample registry, healthcare costs using country-specific procedural reimbursement codes and tariffs, and probabilistic sensitivity analysis within a Markov decision-analytic model provided a novel and reproducible analytic method to assess the costs of DM vs. LFH in revision THAs. OBJECTIVES:Many countries have a national Health Technology Assessment (HTA) body that makes decisions/recommendations on publically reimbursing new healthcare technologies. For some, a key criterion is cost-effectiveness based upon their cost per Quality Adjusted Life Year (QALY) in relation to willingness to pay (WTP) thresholds. This research aims to identify, compare and evaluate WTP thresholds across countries. METHODS: Publically-available HTA guidelines were screened for 35 countries across Europe, Asia-Pacific, and the Americas for key criteria for decision-making and WTP thresholds. RESULTS: 20 countries spanning five continents were identified where cost/QALY was a key decision-making criterion encompassing both developed (e.g. England and Sweden) and emerging markets (e.g. Thailand and Colombia). 17/35 (49%) countries had explicit WTP threshold or threshold ranges, with the lowest in Thailand (160,000THB [V4,200]), and the highest in Sweden, where the upper-most threshold range reaches V90,000. Five countries link the WTP threshold to a multiple of GDP/capita (Brazil, Columbia, Czech Republic, Mexico, Poland). 6/35 (17%) countries had ICER thresholds that varied depending on the severity/burden of disease and/or the level of unmet need (Norway, Sweden, Netherlands, England, Australia, Colombia). An additional 4/35 (11%) markets (England, Australia, Netherlands, and Sweden) had specific decision-modifiers enabling eligible therapies to be considered at higher WTP thresholds (e.g. England: HST for ultra-orphan indications [£100,000-£300,000/QALY; V113,900-V341,700/QALY] and End of Life criteria [not stated]). CONCLUSIONS: The WTP for a QALY can vary substantially between as well as within countries. The WHO recommends a WTP of <3 times GDP per capita/QALY, which few countries follow. If other markets adopted this WHO standard it would substantially increase their WTP thresholds. From a utilitarian perspective, WTP should be consistent across diseases. Another perspective is that WTP should reflect the opportunity cost; new interventions with higher budget impacts should have lower WTP thresholds, supporting higher WTP for orphan diseases.

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