A ketogenic diet rich in fish oil is superior to other fats in preventing NNK-induced lung cancer in A/J mice.

Given that ketogenic diets (KDs) are extremely high in dietary fat, we compared different fats in KDs to determine which was the best for cancer prevention. Specifically, we compared a Western and a 15% carbohydrate diet to seven different KDs, containing either Western fats or fats enriched in medium chain fatty acids (MCTs), milk fat (MF), palm oil (PO), olive oil (OO), corn oil (CO) or fish oil (FO) for their ability to reduce nicotine-derived nitrosamine ketone (NNK)-induced lung cancer in mice. While all the KDs tested were more effective at reducing lung nodules than the Western or 15% carbohydrate diet, the FO-KD was most effective at reducing lung nodules. Correlating with this, mice on the FO-KD had low blood glucose and the highest ß-hydroxybutyrate level, lowest liver fatty acid synthase/carnitine palmitoyl-1a ratio and a dramatic increase in fecal Akkermansia. We found no liver damage induced by the FO-KD, while the ratio of total cholesterol/HDL was unchanged on the different diets. We conclude that a FO-KD is superior to KDs enriched in other fats in reducing NNK-induced lung cancer, perhaps by being the most effective at skewing whole-body metabolism from a dependence on glucose to fats as an energy source.

Omega 3 supplementation reduces C-reactive protein, prostaglandin E2 and the granulocyte/lymphocyte ratio in heavy smokers: An open-label randomized crossover trial.

Objectives: Given the current controversy concerning the efficacy of omega 3 supplements at reducing inflammation, we evaluated the safety and efficacy of omega 3 on reducing inflammation in people with a 6-year lung cancer risk >1.5% and a C reactive protein (CRP) level >2 mg/L in a phase IIa cross-over study. Materials and methods: Forty-nine healthy participants ages 55 to 80, who were still smoking or had smoked in the past with ≥30 pack-years smoking history, living in British Columbia, Canada, were randomized in an open-label trial to receive 2.4 g eicosapentaenoic acid (EPA) + 1.2 g docosahexaenoic acid (DHA)/day for 6 months followed by observation for 6 months or observation for 6 months first and then active treatment for the next 6 months. Blood samples were collected over 1 year for measurement of plasma CRP, plasma and red blood cell (RBC) membrane levels of EPA, DHA and other fatty acids, Prostaglandin E2 (PGE2), Leukotriene B4 (LTB4) and an inflammatory marker panel. Results: Twenty one participants who began the trial within the active arm completed the trial while 20 participants who started in the control arm completed the study. Taking omega 3 resulted in a significant decrease in plasma CRP and PGE2 but not LTB4 levels. Importantly, the effect size for the primary outcome, CRP values, at the end of the intervention relative to baseline was medium (Cohen's d = 0.56). DHA, but not EPA levels in RBC membranes inversely correlated with PGE2 levels. Omega 3 also led to a significant reduction in granulocytes and an increase in lymphocytes. These high-dose omega 3 supplements were well tolerated, with only minor gastrointestinal symptoms in a subset of participants. Conclusion: Omega 3 fatty acids taken at 3.6 g/day significantly reduce systemic inflammation with negligible adverse health effects in people who smoke or have smoked and are at high risk of lung cancer.ClinicalTrials.gov, NCT number: NCT03936621.

UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells.

Herein we demonstrate that oncolytic herpes simplex virus-1 (HSV-1) potently activates human peripheral blood mononuclear cells (PBMCs) to lyse leukemic cell lines and primary acute myeloid leukemia samples, but not healthy allogeneic lymphocytes. Intriguingly, we found that UV light-inactivated HSV-1 (UV-HSV-1) is equally effective in promoting PBMC cytolysis of leukemic cells and is 1000- to 10 000-fold more potent at stimulating innate antileukemic responses than UV-inactivated cytomegalovirus, vesicular stomatitis virus, reovirus, or adenovirus. Mechanistically, UV-HSV-1 stimulates PBMC cytolysis of leukemic cells, partly via Toll-like receptor-2/protein kinase C/nuclear factor-κB signaling, and potently stimulates expression of CD69, degranulation, migration, and cytokine production in natural killer (NK) cells, suggesting that surface components of UV-HSV-1 directly activate NK cells. Importantly, UV-HSV-1 synergizes with interleukin-15 (IL-15) and IL-2 in inducing activation and cytolytic activity of NK cells. Additionally, UV-HSV-1 stimulates glycolysis and fatty acid oxidation-dependent oxygen consumption in NK cells, but only glycolysis is required for their enhanced antileukemic activity. Last, we demonstrate that T cell-depleted human PBMCs exposed to UV-HSV-1 provide a survival benefit in a murine xenograft model of human acute myeloid leukemia (AML). Taken together, our results support the preclinical development of UV-HSV-1 as an adjuvant, alone or in combination with IL-15, for allogeneic donor mononuclear cell infusions to treat AML.

MyD88-dependent SHIP1 regulates proinflammatory signaling pathways in dendritic cells after monophosphoryl lipid A stimulation of TLR4.

We previously showed that monophosphoryl lipid A (MLA) activates TLR4 in dendritic cells (DCs) in a Toll/IL-1R domain-containing adaptor inducing IFN-ß (TRIF)-biased manner: MLA produced from Salmonella minnesota Re595 induced signaling events and expression of gene products that were primarily TRIF dependent, whereas MyD88-dependent signaling was impaired. Moreover, when tested in TRIF-intact/MyD88-deficient DCs, synthetic MLA of the Escherichia coli chemotype (sMLA) showed the same activity as its diphosphoryl, inflammatory counterpart (synthetic diphosphoryl lipid A), indicating that TRIF-mediated signaling is fully induced by sMLA. Unexpectedly, we found that the transcript level of one proinflammatory cytokine was increased in sMLA-treated cells by MyD88 deficiency to the higher level induced by synthetic diphosphoryl lipid A, which suggested MyD88 may paradoxically help restrain proinflammatory signaling by TRIF-biased sMLA. In this article, we demonstrate that sMLA induces MyD88 recruitment to TLR4 and activates the anti-inflammatory lipid phosphatase SHIP1 in an MyD88-dependent manner. At the same time, MyD88-dependent signaling activity at the level of IL-1R-associated kinase 1 is markedly reduced. Increased SHIP1 activity is associated with reductions in sMLA-induced IκB kinase α/ß and IFN regulatory factor 3 activation and with restrained expression of their downstream targets, endothelin-1 and IFN-ß, respectively. Results of this study identify a pattern that is desirable in the context of vaccine adjuvant design: TRIF-biased sMLA can stimulate partial MyD88 activity, with MyD88-dependent SHIP1 helping to reduce proinflammatory signaling in DCs.