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Background Vitamin E has been studied extensively in the prevention of atherosclerosis. Cross-sectional population studies as well as randomized controlled intervention trials have demonstrated conflicting results. A recent meta-analysis of these trials has emphasized the ineffectiveness of vitamin E in atherosclerosis prevention with a possibility of harm at higher dosages. However, vitamin E has several isomers, with the alpha form being available via dietary supplements and the gamma form being available via dietary foodstuffs. The gamma form of vitamin E demonstrates several superior properties (such as trapping reactive nitrogen species and detoxifying nitrogen dioxide) compared with alpha vitamin E. All clinical trials have utilized the alpha isomer with little concern that this isomer of vitamin E may actually suppress the gamma isomer of vitamin E. Objective We undertook a dose response study in type 2 diabetic volunteers to include all the dosages of alpha vitamin E that have been utilized in cardiovascular prevention trials to determine the effect of alpha vitamin E on gamma vitamin E. We also assessed the effect of alpha vitamin E on several traditional markers of atherosclerotic risk. We added vitamin C to the vitamin E because several clinical trials included this vitamin to enhance the antioxidant effects of alpha vitamin E. Design Volunteers received, in randomized order for a two week period, one of the following vitamin dosage arms: 1) no vitamins, 2) low dose supplemental vitamins E plus C, 3) medium dose supplemental vitamins E plus C, and 4) high dose supplemental vitamins E plus C. Blood levels of both alpha and gamma vitamin E were measured as well as surrogate markers of oxidative stress, hypercoagulation, and inflammation during a high fat atherogenic meal (to increase the ambient oxidative stress level during the study). Results The results demonstrate that alpha vitamin E levels increased in proportion to the dose administered. However, at every dose of alpha vitamin E, gamma vitamin E concentration was significantly suppressed. No beneficial changes in surrogate markers of atherosclerosis were observed, consistent with the negative results of prospective clinical trials utilizing alpha vitamin E. Conclusions Our results suggest that all prospective cardiovascular clinical trials that utilized vitamin E supplementation actually suppressed the beneficial antioxidant gamma isomer of vitamin E. No beneficial effects on several potential cardiovascular risk factors were observed, even when the vitamin E was supplemented with vitamin C. If a standardized preparation of gamma vitamin E (without the alpha isomer) becomes available, the effects of gamma vitamin E on atherosclerotic risk will warrant additional studies.

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The intestinal microbiome is by now an undebatable key player in the clinical outcome of ICI therapies. However, no microbiome profiling method to aid therapy decision is yet validated. We conducted a multi-centric study in patients with stage III/IV melanoma, NSCLC, or RCC receiving ICI treatment. The stool microbiome profile of 63 patients was analyzed with BiomeOne®, a microbiome-based algorithm that anticipates whether a patient will achieve clinical benefit with ICIs prior to therapy initiation. Classification of patient samples as Rs and NRs was achieved with a sensitivity of 81% and a specificity of 50% in this validation cohort. An ICI-favorable response was characterized by an intestinal microbiome rich in bacteria such as Oscillospira sp., Clostridia UCG-014, Lachnospiraceae UCG-010 sp., Prevotella copri, and a decrease in Sutterella sp., Lactobacillales, and Streptococcus sp. Patients who developed immune-related adverse events (irAEs) had an overall increased microbial diversity and richness, and a stool microbiome depleted in Agathobacter. When compared with the programmed death-ligand 1 (PD-L1) expression test in the subcohort of NSCLC patients (n = 38), BiomeOne® exhibited a numerically higher sensitivity (78.6%) in identifying responders when compared with the PD-L1 test (67.9%). This study provides an evaluation of BiomeOne®, the first microbiome-based test for prediction of ICI response, to achieve market authorization. Validation with further indications and expansion to other microbiome-based interventions will be essential to bring microbiome-based diagnostics into standard clinical practice.