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Background Dexanabinol is a synthetic analogue of tetrahydrocannabinol identified as a potential anti-cancer therapeutic by e-Therapeutics PLC. Dexanabinol was selected for further investigation based on its preclinical tumoricidal activity. This phase I dose-escalation trial examined the safety, drug penetration into the central nervous system (CNS), preliminary antitumor activity, and recommended phase II dose. Methods Dexanabinol formulated in cremophor/ethanol was administered once weekly via 3-hour intravenous infusion to patients with brain cancer. Results A total of 26 patients were dosed once weekly at 2, 4, 8, 16, 24, 28, and 36 mg/kg. Two patients at 36 mg/kg were nonevaluable for dose level confirmation, having withdrawn early for reasons unrelated to study treatment. A recommended phase II dose of dexanabinol was established at 28 mg/kg due to related, reversible adverse events at higher dose levels that required medications for symptomatic relief. The most common drug-related toxicities were the depressed level of consciousness and lightheadedness, diarrhea, itching, fatigue, chest discomfort, and tingling in the mouth. Systemic exposure to dexanabinol (AUC0-t and Cmax) increased from 2 to 36 mg/kg, with dose nonproportionality apparent at the highest dose; dexanabinol was present in appreciable levels in the cerebrospinal fluid (CSF), which implies the possibility of exposure of intracranial tumors to drug. Five of 24 efficacy-evaluable patients (21%) experienced stable disease with a median duration of 2 cycles (28-day cycle) as the best response. Conclusions Dexanabinol administered weekly by intravenous infusion was safe and well-tolerated up to 28 mg/kg in brain cancer patients, but has limited antitumor activity in patients with brain cancer.

Dietary flavonoid intake, especially berry flavonoids, has been associated with reduced risks of cardiovascular disease (CVD) in large prospective cohorts. Few clinical studies have examined the effects of dietary berries on CVD risk factors. We examined the hypothesis that freeze-dried strawberries (FDS) improve lipid and lipoprotein profiles and lower biomarkers of inflammation and lipid oxidation in adults with abdominal adiposity and elevated serum lipids. In a randomized dose-response controlled trial, 60 volunteers [5 men and 55 women; aged 49 ± 10 y; BMI: 36 ± 5 kg/m(2) (means ± SDs)] were assigned to consume 1 of the following 4 beverages for 12 wk: 1) low-dose FDS (LD-FDS; 25 g/d); 2) low-dose control (LD-C); 3) high-dose FDS (HD-FDS; 50 g/d); and 4) high-dose control (HD-C). Control beverages were matched for calories and total fiber. Blood draws, anthropometrics, blood pressure, and dietary data were collected at screening (0 wk) and after 12-wk intervention. Dose-response analyses revealed significantly greater decreases in serum total and LDL cholesterol and nuclear magnetic resonance (NMR)-derived small LDL particle concentration in HD-FDS [33 ± 6 mg/dL, 28 ± 7 mg/dL, and 301 ± 78 nmol/L, respectively (means ± SEMs)] vs. LD-FDS (-3 ± 11 mg/dL, -3 ± 9 mg/dL, and -28 ± 124 nmol/L, respectively) over 12 wk (0-12 wk; all P < 0.05). Compared with controls, only the decreases in total and LDL cholesterol in HD-FDS remained significant vs. HD-C (0.7 ± 12 and 1.4 ± 9 mg/dL, respectively) over 12 wk (0-12 wk; all P < 0.05). Both doses of strawberries showed a similar decrease in serum malondialdehyde at 12 wk (LD-FDS: 1.3 ± 0.2 μmol/L; HD-FDS: 1.2 ± 0.1 μmol/L) vs. controls (LD-C: 2.1 ± 0.2 μmol/L; HD-C: 2.3 ± 0.2 μmol/L) (P < 0.05). In general, strawberry intervention did not affect any measures of adiposity, blood pressure, glycemia, and serum concentrations of HDL cholesterol and triglycerides, C-reactive protein, and adhesion molecules. Thus, HD-FDS exerted greater effects in lowering serum total and LDL cholesterol and NMR-derived small LDL particles vs. LD-FDS in the 12-wk study. These findings warrant additional investigation in larger trials. This trial was registered at clinicaltrials.gov as NCT01883401.

Quantitative characterizations of horizontal gene transfer are needed to accurately describe gene transfer processes in natural and engineered systems. A number of approaches to the quantitative description of plasmid conjugation have appeared in the literature. In this study, we seek to extend that work, motivated by the question of whether a mathematical model can accurately predict growth and conjugation dynamics in a batch process. We used flow cytometry to make time-point observations of a filter-associated mating between two {\em E. coli} strains, and fit ordinary differential equation models to the data. A model comparison analysis identified the model formulation that is best supported by the data. Identifiability analysis revealed that the parameters were estimated with acceptable accuracy. The predictive power of the model was assessed by comparison with test data that demanded extrapolation from the training experiments. This study represents the first attempt to assess the quality of model predictions for plasmid conjugation. Our successful application of this approach lays a foundation for predictive modelling that can be used both in the study of natural plasmid transmission and in model-based design of engineering approaches that employ conjugation, such as plasmid-mediated bioaugmentation.

Berries have shown several cardiovascular health benefits and have been associated with antioxidant functions in experimental models. Clinical studies are limited. We examined the antioxidant effects of freeze-dried strawberries (FDS) in adults [n=60; age:49±10years; BMI:36±5 kg/m2(mean ± SD)] with abdominal adiposity and elevated serum lipids. Participants were randomized to one of the following arms: low dose strawberry (25 g/day FDS), low dose control beverage (LD-C), high dose strawberry (50 g/d FDS), and high dose control beverage (HD-C) for 12 weeks. Control beverages were matched for calories and total fiber. Plasma antioxidant capacity, trace elements (copper, iron, selenium, and zinc), whole blood glutathione (GSH), and enzyme activity (catalase, glutathione peroxidase, and glutathione reductase) were examined at screening (0 week) and after 12 weeks’ intervention. At 12 weeks, plasma antioxidant capacity and glutathione levels were higher in the strawberry versus control groups (low and high dose FDS: 45% and 42% for plasma antioxidant capacity and 28% and 36% for glutathione, resp.); glutathione was higher in the high versus low dose strawberry group (allp<0.05). Serum catalase activity was higher in the low dose strawberry (43%) versus control group (p<0.01). No differences were noted in plasma trace elements and glutathione enzyme activity. Dietary strawberries may selectively increase plasma antioxidant biomarkers in obese adults with elevated lipids.

BACKGROUND: Dexanabinol is a synthetic analogue of tetrahydrocannabinol previously developed as a neuroprotector and subsequently identified through a network pharmacology platform as a potential anti-cancer therapeutic by e-Therapeutics PLC. Dexanabinol was selected for further investigation based on its tumoricidal activity observed in vitro and in vivo, presumably due to inhibitory activity against NFκB, COX-2, and TNFα. This phase I dose-escalation trial examines the safety of multiple dosing of dexanabinol and drug penetration into the central nervous system in patients with brain cancer. METHODS: Patients having failed prior therapy or having no further available standard therapies and Karnofsky Performance Score of ≥ 60% were included. Dose escalation was performed using a‘3 + 3’ design. Patients received weekly dexanabinol via an intravenous infusion. The objectives were to determine the safety, tolerability, recommended phase 2 dose, pharmacokinetics, and antitumor activity. RESULTS: 26 patients have been enrolled at escalating doses of dexanabinol (range 2 to 36 mg/kg). Two patients at the highest dose level were non-evaluable for dose tolerability and no dose limiting toxicities occurred in this study. Dose escalation was stopped due to emerging data in another clinical study (ETS2101-001). To date, adverse events attributed to dexanabinol were grades 1 or 2 and consisted of a depressed level of consciousness and lightheadedness in 3/26 pts; diarrhea and itching in 2/26 pts; fatigue, chest discomfort and tingling in mouth in 1/26 pts. From 2 to 36 mg/kg, systemic exposure to dexanabinol (AUC0-∞ and Cmax) increased greater than dose proportionately; dexanabinol was present in appreciable levels in the CSF, which implies the possibility of exposure of intracranial tumors to drug. Four of 24 efficacy-evaluable patients (17%) experienced stable disease with median duration of two cycles (28-day cycle) as best response. CONCLUSIONS: Dexanabinol was safe and well-tolerated warranting continued investigation. A Phase 1b program with dexanabinol is planned.