A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis

5′AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63–78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63–78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment

Mediterranean-style diet improves systolic blood pressure and arterial stiffness in older adults: Results of a 1-year European multi-center trial

We aimed to determine the effect of a Mediterranean-style diet, tailored to meet dietary recommendations for older adults, on blood pressure and arterial stiffness. In 12 months, randomized controlled trial (NU-AGE [New Dietary Strategies Addressing the Specific Needs of Elderly Population for Healthy Aging in Europe]), blood pressure was measured in 1294 healthy participants, aged 65 to 79 years, recruited from 5 European centers, and arterial stiffness in a subset of 225 participants. The intervention group received individually tailored standardized dietary advice and commercially available foods to increase adherence to a Mediterranean diet. The control group continued on their habitual diet and was provided with current national dietary guidance. In the 1142 participants who completed the trial (88.2%), after 1 year the intervention resulted in a significant reduction in systolic blood pressure (−5.5 mm Hg; 95% CI, −10.7 to −0.4; P=0.03), which was evident in males (−9.2 mm Hg, P=0.02) but not females (−3.1 mm Hg, P=0.37). The −1.7 mm Hg (95% CI, −4.3 to 0.9) decrease in diastolic pressure after intervention did not reach statistical significance. In a subset (n=225), augmentation index, a measure of arterial stiffness, was improved following intervention (−12.4; 95% CI, −24.4 to −0.5; P=0.04) with no change in pulse wave velocity. The intervention also resulted in an increase in 24-hour urinary potassium (8.8 mmol/L; 95% CI, 0.7–16.9; P=0.03) and in male participants (52%) a reduction in pulse pressure (−6.1 mm Hg; 95% CI, −12.0 to −0.2; P=0.04) and 24-hour urinary sodium (−27.1 mmol/L; 95% CI, −53.3 to −1.0; P=0.04). In conclusion, a Mediterranean-style diet is effective in improving cardiovascular health with clinically relevant reductions in blood pressure and arterial stiffness

Cross-sectional analysis of the correlation between daily nutrient intake assessed by 7-day food records and biomarkers of dietary intake among participants of the NU-AGE study

Methods for measuring diet composition and quantifying nutrient intake with sufficient validity are essential to study the association between nutrition and health outcomes and risk of diseases. 7-day food records provides a quantification of food actually and currently consumed and is interesting for its use in intervention studies to monitor diet in a short-term period and to guide participants toward changing their intakes. The objective of this study is to analyze the correlation/association between the daily intake of selected nutrients (collected by a 7-day food records plus a mineral/vitamin supplementation questionnaire) and estimates of energy expenditure as well as blood and urine biomarkers of dietary intakes in 1,140 healthy elderly subjects (65–79 years) at baseline of the NU-AGE intervention study (NCT01754012, clinicaltrials.gov). The results show that: the daily intake of energy correlated significantly with predicted total energy expenditure (pTEE) (ρ = 0.459, p < 0.001, and q < 0.001); protein intake correlated significantly with the ratio of 24 h urinary urea to creatinine excretion (ρ = 0.143 for total protein intake, ρ = 0.296 for animal protein intake, and ρ = 0.359 for protein intake/body weight, p < 0.001 and q < 0.001 for each correlation); vitamin B12 and folate intakes correlated significantly with their serum concentrations (ρ = 0.151 and ρ = 0.363, respectively; p < 0.001 and q < 0.001 for each correlation); sodium and potassium intakes correlated significantly with their 24 h urinary excretion (ρ = 0.298 and ρ = 0.123, respectively; p < 0.001 and q < 0.001 for each correlation); vitamin B12 and folate intakes were negatively associated with plasma homocysteine measure (p = 0.001 and p = 0.004, respectively); stratifying subjects by gender, the correlations between energy intake and pTEE and between potassium intake and its 24 h urinary excretion lost their significance in women. Even if the plasma and urinary levels of these nutrients depend on several factors, the significant correlations between daily reported intake of nutrients (protein, vitamin B12, folate, and sodium) and their blood/urinary markers confirmed that the 7-day food records (plus a supplementation questionnaire) provides reliable data to evaluate short-term current dietary intake in European elderly subjects and it can be exploited to guide and monitor NU-AGE participants through the shift of their diet according NU-AGE recommendations

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096-111. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047

Dietary Supplement Use in Relation to Socio-Demographic and Lifestyle Factors, including Adherence to Mediterranean-Style Diet in University Students

The study aimed to examine socio-demographic and lifestyle determinants, including diet quality, of dietary supplement (DS) use among 2545 students who attended public universities in Warsaw. The data was collected using a self-administered health and lifestyle questionnaire and a 5-day dietary record method. Diet quality was assessed using a Mediterranean Diet Score. To determine the covariates of DS use, multivariate-adjusted logistic regression models with an estimation of odds ratios (ORs) and 95% confidence intervals (95% CIs) were used. The results showed that 41% of participants were DS users. The following predictors of DS use were identified: gender (male vs. female; OR:0.62, 95% CI:0.50&ndash;0.79), physical activity (high vs. low; OR:1.79, 95% CI:1.45&ndash;2.20), BMI (&ge;25 vs. 18.5&ndash;24.9 kg/m2; OR:0.77, 95% CI:0.61&ndash;0.98), cigarette smoking (yes vs. no; OR:0.67, 95% CI:0.52&ndash;0.86), and presence of chronic diseases (yes vs. no; OR:2.37, 95% CI:1.89&ndash;2.98). Moreover, higher nutritional knowledge, special diet usage, eating more meals/day, and fortified food consumption were determinants of DS use. Adherence to the Mediterranean-style diet was positively associated with DS use, a 1-score increment was associated with a 10% (p-trend = 0.011) higher probability of DS usage. Given that the use of vitamins and/or minerals is common among university students and their users are characterized by eating a higher quality diet, investigating the contribution of DS in overall dietary nutrient intake warrants further study

Adherence to the Mediterranean Diet in Women and Reproductive Health across the Lifespan: A Narrative Review

The Mediterranean diet (MD) has been previously proven to have various health-related benefits; however, its effect on women’s reproductive health over a lifespan is yet to be summarized. This study aimed to summarize the evidence-based knowledge regarding the association between the MD and selected reproductive health outcomes. By searching PubMed, ScienceDirect, and Google Scholar databases, as well as reference lists, 21 studies were included in this narrative review. The available evidence was very limited; however, there is some suggestion that higher adherence to the MD may be positively associated with a lower risk of early age menarche (1 study) and shorter menstrual cycles (1 study), but is unrelated to dysmenorrhea (1 study). Moreover, no study to date has examined the relationship between the MD and the onset age of natural menopause. Considering reproductive health diseases, there was limited evidence that a higher adherence to the MD was associated with a lower risk of premenstrual syndrome (1 study), an improvement in sexual health and a lower prevalence of sexual dysfunction (3 studies), and an improvement in the general condition of with endometriosis and the pain they can experience (1 study). The largest number of studies were found for polycystic ovarian syndrome (PCOS; 7 studies) and infertility (6 studies). Results showed that a higher adherence to the MD was associated with a lower risk of infertility, while results for PCOS were unclear, but mostly indicated a beneficial trend. Further investigations are necessary to establish the role of adherence to the MD in reproductive health maintenance and its possible role in the prevention and treatment of reproductive health diseases in women

Deletion of the p27(Kip1) gene restores normal development in cyclin D1-deficient mice

D-type cyclins (cyclins D1, D2, and D3) are key components of cell cycle machinery in mammalian cells. These proteins are believed to drive cell cycle progression by associating with their kinase partners, cyclin-dependent kinases, and by directing phosphorylation of critical cellular substrates. In addition, D-cyclins play a kinase-independent role by sequestering cell cycle inhibitors p27(Kip1) and p21(Cip1). In the past, we and others generated cyclin D1-deficient mice and have shown that these mice display developmental abnormalities, hypoplastic retinas, and pregnancy-insensitive mammary glands. To test the significance of cyclin D1–p27(Kip1) interaction within a living mouse, we crossed cyclin D1-deficient mice with mice lacking p27(Kip1), and we generated double-mutant cyclin D1(−/−)p27(−/−) animals. Here we report that ablation of p27(Kip1) restores essentially normal development in cyclin D1-deficient mice. Our results provide genetic evidence that p27(Kip1) functions downstream of cyclin D1

Mediterranean-Style Diet and Other Determinants of Well-Being in Omnivorous, Vegetarian, and Vegan Women

Due to the lack of studies comparing the determinants of well-being in omnivores and vegetarians, we examined associations of socio-demographic and lifestyle factors, including adherence to a Mediterranean-style diet, in relation to well-being in omnivorous, vegetarian, and vegan women. Well-being was assessed using a validated WHO-5 Well-Being Index. Adherence to the Mediterranean-style diet was determined using a modified Mediterranean diet score. The study was conducted on 636 women (23.9 &plusmn; 5.7 years), of whom 47.3% were omnivores, 33.2% vegetarians, and 19.5% vegans. The good well-being group (WHO-5 Index &ge; 13 points) comprised 30.9% of the omnivores, 46.0% of the vegetarians, and 57.3% of the vegans. The remaining participants were classified as belonging to the poor well-being group (&lt;13 points). Compared to the omnivores, the vegetarians and vegans had a 1.6-fold (95% CI: 1.04&ndash;2.42) and a 2.4-fold (95% CI: 1.45&ndash;3.99) higher probability of having good well-being, respectively. In omnivores, the predictors of good well-being were adherence to the Mediterranean-style diet (a 1-score increment was associated with a 17% higher probability of good well-being, P-trend = 0.016), higher self-perceived health status, and lower levels of stress. In vegetarians and vegans, it was older age, higher physical activity (&ge;3 h/week), 7&ndash;8 h sleep time, and similarly to omnivores&rsquo; higher self-perceived health status and lower stress level. Our findings indicate that following a Mediterranean-style diet was associated with better well-being in omnivores. Furthermore, we identified that different determinants were associated with well-being in omnivorous and vegetarian and vegan women