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The current state of cancer treatment is still far from being satisfactory considering the strong impairment of patients’ quality of life and the high lethality of malignant diseases. Therefore, it is critical for innovative approaches to be tested in the near future. In view of the crucial role that is played by tumor immunity, the present review provides essential information on the immune-mediated effects potentially generated by the interplay between ionizing radiation and cytotoxic antitumor agents when interacting with target malignant cells. Therefore, the radiation-dependent abscopal effect (i.e., a biological effect of ionizing radiation that occurs outside the irradiated field), the influence of cancer chemotherapy on the antigenic pattern of target neoplastic cells, and the immunogenic cell death (ICD) caused by anticancer agents are the main topics of this presentation. It is widely accepted that tumor immunity plays a fundamental role in generating an abscopal effect and that anticancer drugs can profoundly influence not only the host immune responses, but also the immunogenic pattern of malignant cells. Remarkably, several anticancer drugs impact both the abscopal effect and ICD. In addition, certain classes of anticancer agents are able to amplify already expressed tumor-associated antigens (TAA). More importantly, other drugs, especially triazenes, induce the appearance of new tumor neoantigens (TNA), a phenomenon that we termed drug-induced xenogenization (DIX). The adoption of the abscopal effect is proposed as a potential therapeutic modality when properly applied concomitantly with drug-induced increase in tumor cell immunogenicity and ICD. Although little to no preclinical or clinical studies are presently available on this subject, we discuss this issue in terms of potential mechanisms and therapeutic benefits. Upcoming investigations are aimed at evaluating how chemical anticancer drugs, radiation, and immunotherapies are interacting and cooperate in evoking the abscopal effect, tumor xenogenization and ICD, paving the way for new and possibly successful approaches in cancer therapy.

International audience; Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids conjugated to coenzyme A to esterify cholesterol. Cholesterol esterification is tightly regulated and enables formation of lipid droplets that act as storage organelles for lipid soluble vitamins and minerals, and as cholesterol reservoirs. In cancer, this provides rapid access to cholesterol to maintain continual synthesis of the plasma membrane. In this systematic review and meta-analysis, we summarise the current depth of understanding of the role of this metabolic pathway in pan-cancer development. A systematic search of PubMed, Scopus, Web of Science, and Cochrane Library for preclinical studies identified eight studies where cholesteryl ester concentrations were compared between tumour and adjacent-normal tissue, and 24 studies where cholesterol esterification was blocked by pharmacological or genetic approaches. Tumour tissue had a significantly greater concentration of cholesteryl esters than non-tumour tissue (p < 0.0001). Pharmacological or genetic inhibition of SOAT was associated with significantly smaller tumours of all types (p ≤ 0.002). SOAT inhibition increased tumour apoptosis (p = 0.007), CD8 + lymphocyte infiltration and cytotoxicity (p ≤ 0.05), and reduced proliferation (p = 0.0003) and metastasis (p < 0.0001). Significant risk of publication bias was found and may have contributed to a 32% overestimation of the meta-analysed effect size. Avasimibe, the most frequently used SOAT inhibitor, was effective at doses equivalent to those previously reported to be safe and tolerable in humans. This work indicates that SOAT inhibition should be explored in clinical trials as an adjunct to existing anti-neoplastic agents.

Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases.

Background. Noncommunicable diseases (NCDs) are the first cause of death worldwide. Mediterranean diet may play a crucial role in the prevention of NCDs, and the presence of wine in this diet could play a positive role on health. Methods. 54 healthy volunteers consumed one of the following beverages: red (RW) or white wine (WW), vodka (VDK), and/or Mediterranean meal (MeDM) and high-fat meal (HFM). Results. OxLDL-C changed significantly between baseline versus HFM, MeDM versus HFM, and HFM versus HFM + RW (p<0.05). Significant upregulation of catalase (CAT) was observed only after RW. Conversely, WW, VDK, RW + MeDM, HF + WW, and HF + VDK determined a significant downregulation of CAT gene. Superoxide dismutase 2 (SOD2) gene expression was upregulated in WW, MeDM + VDK, and RW. Contrariwise, HFM + VDK determined a downregulation of its expression. RW, RW + MeDM, and RW + HFM caused the upregulation of glutathione peroxidase-1 (GPX1). Conclusions. Our results suggest that the association of low/moderate intake of alcohol beverages, with nutraceutical-proven effectiveness, and ethanol, in association with a Mediterranean diet, could determine a reduction of atherosclerosis risk onset through a positive modulation of antioxidant gene expression helping in the prevention of inflammatory and oxidative damages.

Introduction. Inflammation is associated with obesity condition and plays a pivotal role in the onset and progression of many chronic diseases. Among several nutraceutical foods, hazelnuts (Corylus avellana L.) are considered an excellent anti-inflammatory and hypolipidemic food being the second richest source of monounsaturated fatty acids among nuts and because they are rich in vitamins, minerals, and phenolic compounds. Materials and Methods. A prospective pilot clinical trial on 24 healthy volunteers who consumed daily, as a snack, 40 g of hazelnuts (261.99 kcal/1096.17 kJ) for six weeks was conducted. Anthropometric measurements, body composition analysis, and nutrigenomic analysis on 12 anti-inflammatory and antioxidant genes were evaluated at baseline (T0) and after hazelnut intervention (T1). Results. No significant changes were detected on body composition analysis after hazelnut consumption. Conversely, significant upregulation was detected for SOD1 (2−ΔΔCt=2.42), CAT (2−ΔΔCt=2.41), MIF (2−ΔΔCt=4.12), PPARγ (2−ΔΔCt=5.89), VDR (2−ΔΔCt=3.61), MTHFR (2−ΔΔCt=2.40), and ACE (2−ΔΔCt=2.16) at the end of the study. Conclusions. According to emerging evidences, hazelnut consumption does not lead to weight gain probably due to the improvement of the body’s antioxidant capacity by the upregulation of genes implied in oxidant reactions and inflammation.

Fatty Acid Synthase (FASN) is responsible for the de novo synthesis of fatty acids, which are involved in the preservation of biological membrane structure, energy storage and assembly of factors involved in signal transduction. FASN plays a critical role in supporting tumor cell growth, thus representing a potential target for anti-cancer therapies. Moreover, this enzyme has been recently associated with increased PD-L1 expression, suggesting a role for fatty acids in the impairment of the immune response in the tumor microenvironment. Orlistat, a tetrahydrolipstatin used for the treatment of obesity, has been reported to reduce FASN activity, while inducing a sensible reduction of the growth potential in different cancer models. We have analyzed the effect of orlistat on different features involved in the tumor cell biology of the T-ALL Jurkat cell line. In particular, we have observed that orlistat inhibits Jurkat cell growth and induces a perturbation of cell cycle along with a decline of FASN activity and protein levels. Moreover, the drug produces a remarkable impairment of PD-L1 expression. These findings suggest that orlistat interferes with different mechanisms involved in the control of tumor cell growth and can potentially contribute to decrease the tumor-associated immune-pathogenesis.

Background The Mediterranean diet (MeD) plays a key role in the prevention of obesity. Among the genes involved in obesity, the Fat mass and obesity-associated gene (FTO) is one of the most known, but its interaction with MeD remained uncertain so far. Methods We carried out a study on a sample of 188 Italian subjects, analyzing their FTO rs9939609 alleles, and the difference in body composition between the baseline and a 4-weeks nutritional intervention. The sample was divided into two groups: the control group of 49 subjects, and the MeD group of 139 subjects. Results We found significant relations between MeD and both variation of total body fat (ΔTBFat) (p = 0.00) and gynoid body fat (p = 0.04). ∆TBFat (kg) demonstrated to have a significant relation with the interaction diet-gene (p = 0.04), whereas FTO was associated with the variation of total body water (p = 0.02). Conclusions MeD demonstrated to be a good nutritional treatment to reduce the body fat mass, whereas data about FTO remain uncertain. Confirming or rejecting the hypothesis of FTO and its influence on body tissues during nutritional treatments is fundamental to decide whether its effect has to be taken into consideration during both development of dietetic plans and patients monitoring. Trial Registration ClinicalTrials.gov Id: NCT01890070. Registered 01 July 2013, https://clinicaltrials.gov/ct2/show/NCT01890070

Tetrahydrolipstatin (orlistat), an inhibitor of lipases and fatty acid synthase, is used orally for long-term treatment of obesity. Although the drug possesses striking antitumor activities in vitro against human cancer cells and in vitro and in vivo against animal tumors, it also induces precancerous lesions in rat colon. Therefore, we tested the in vitro effect of orlistat on the expression of O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme that plays an essential role in the control of mutagenesis and carcinogenesis. Western blot analysis demonstrated that 2-day continuous exposure to 40 mu M orlistat did not affect MGMT levels in a human melanoma cell line, but downregulated the repair protein by 30-70% in human peripheral blood mononuclear cells, in two leukemia and two colon cancer cell lines. On the other hand, orlistat did not alter noticeably MGMT mRNA expression. Differently from lomeguatrib (a false substrate, strong inhibitor of MGMT) orlistat did not reduce substantially MGMT function after 2-h exposure of target cells to the agent, suggesting that this drug is not a competitive inhibitor of the repair protein. Combined treatment with orlistat and lomeguatrib showed additive reduction of MGMT levels. More importantly, orlistat-mediated downregulation of MGMT protein expression was markedly amplified when the drug was combined with a DNA methylating agent endowed with carcinogenic properties such as temozolomide. In conclusion, even if orlistat is scarcely absorbed by oral route, it is possible that this drug could reduce local MGMT-mediated protection against DNA damage provoked by DNA methylating compounds on gastrointestinal tract epithelial cells, thus favoring chemical carcinogenesis.

Hydroxytyrosol (HT) plays a significant role in cardiovascular disease (CVD) protection, and its metabolites are able to protect from the endothelial dysfunction commonly present in atherosclerosis. This randomized double-blinded, placebo-controlled crossover trial determined the effect in healthy volunteers of two gastroresistant capsules containing 15 mg/day of HT, for a 3-week period (HTT). Evaluation of nutritional status, serum metabolites, oxidative stress biomarkers, and gene expression of 9 genes related to oxidative stress, inflammation, and CVDs was performed. Oxidation biomarkers like thiol group (p=0.001), total antioxidant status (TAS) (p=0.001), superoxide dismutase 1 (SOD1) (2−ΔΔCt = 3.7), and plasma concentration of HT (2.83μg·mL−1) were significantly increased, while nitrite (p=0.001), nitrate (p=0.001), and malondialdehyde (MDA) (p=0.02) were drastically reduced after HTT. A significant reduction of body fat mass percentage (p=0.01), suprailiac skinfold (p=0.01), and weight (p=0.04; Δ% = −0.46%) was observed after HTT. This study shows that regular intake of 15 mg/day of HT changed body composition parameters and modulated the antioxidant profile and the expression of inflammation and oxidative stress-related genes. However, it is advisable to personalize HT doses in order to exert its health benefits in CVD prevention and protection of LDL-C particles from oxidative damage. This trial is registered with ClinicalTrials.govNCT01890070.

Background Evidence of probiotics effects on gut function, brain activity and emotional behaviour were provided. Probiotics can have dramatic effects on behaviour through the microbiome–gut–brain axis, through vagus nerve. We investigated whether chronic probiotic intake could modulate psychological state, eating behaviour and body composition of normal weight obese (NWO) and preobese–obese (PreOB/OB) compared to normal weight lean women (NWL). Methods 60 women were enrolled. At baseline and after a 3-week probiotic oral suspension (POS) intake, all subjects underwent evaluation of body composition by anthropometry and dual X-ray absorptiometry, and psychological profile assessment by self-report questionnaires (i.e. EDI-2, SCL90R and BUT). Statistical analysis was carried out using paired t test or a non-parametric Wilcoxon test to evaluate differences between baseline and after POS intake, one-way ANOVA to compare all three groups and, where applicable, Chi square or t test were used to assess symptoms. Results Of the 48 women that concluded the study, 24% were NWO, 26% were NWL and 50% were PreOB/OB. Significant differences in body composition were highlighted among groups both at baseline and after a POS (p Conclusions A 3-week intake of selected psychobiotics modulated body composition, bacterial contamination, psychopathological scores of NWO and PreOB/OB women. Further research is needed on a larger population and for a longer period of treatment before definitive conclusions can be made. Trial registration ClinicalTrials.gov Id: NCT01890070