Chemotactic cell migration: the core autophagy protein ATG9A is at the leading edge.

Accumulating data indicate that several components of the macroautophagy/autophagy machinery mediate additional functions, which do not depend on autophagosome biogenesis or lysosomal cargo degradation. In this context, we found that the core autophagy protein ATG9A participates in the chemotactic movement of several cell lines, including highly invasive glioblastoma cells. Accordingly, ATG9A-depleted cells are unable to form large and persistent leading-edge protrusions. By the design of an ATG9A-pHluorin construct and TIRF imaging, we established that ATG9A-positive vesicles are targeted toward the migration front, where their exocytosis is synchronized with protrusive activity. We finally demonstrated that ATG9A, through its interaction with clathrin adaptor complexes, controls the delivery of ITGB1 (integrin subunit beta 1) to the migration front and normal adhesion dynamics. Together, our work indicates that ATG9A protein has a wider role than anticipated and constitutes a critical component of vesicular trafficking allowing the expansion of cell protrusions and their anchorage to the extracellular matrix.

The core autophagy protein ATG9A controls dynamics of cell protrusions and directed migration.

Chemotactic migration is a fundamental cellular behavior relying on the coordinated flux of lipids and cargo proteins toward the leading edge. We found here that the core autophagy protein ATG9A plays a critical role in the chemotactic migration of several human cell lines, including highly invasive glioma cells. Depletion of ATG9A protein altered the formation of large and persistent filamentous actin (F-actin)-rich lamellipodia that normally drive directional migration. Using live-cell TIRF microscopy, we demonstrated that ATG9A-positive vesicles are targeted toward the migration front of polarized cells, where their exocytosis correlates with protrusive activity. Finally, we found that ATG9A was critical for efficient delivery of ß1 integrin to the leading edge and normal adhesion dynamics. Collectively, our data uncover a new function for ATG9A protein and indicate that ATG9A-positive vesicles are mobilized during chemotactic stimulation to facilitate expansion of the lamellipodium and its anchorage to the extracellular matrix.

The impact of asexual trait and porn addiction in a young men healthy cohort.

In the present study, we aimed to evaluate the association between asexual trait, erectile dysfunction (ED) and porn addiction in a community sample of young men. Between August 2019 and October 2019, a total of 559 young male adults were subjected to an online survey sponsored by social networks with the aim of assessing their sexual habits. The following questionnaires were administered: The International Index of Erectile Function (IIEF-5), Masturbation Erection index (MEI), Pornography Craving Questionnaire (PCQ) and Asexuality Identification Scale (AIS). The overall rate of ED according to IIEF-5 was 26.0% (165/478), the rate of ED according to MEI was 16.9% (81/478) and the rate ED in patients with AIS ≥23 indicating asexual trait was 10.0% (48/478). We found that IIEF-5 was positively associated with MEI (b = 0.32; p < .01) and negatively with AIS (b = -0.36; p < .01) and MEI was negatively associated with AIS (b = -0.36; p < .01). We found that MEI (odds ratio [OR]: 0.86; p < .01) and IIEF-5 (OR: 0.89; p < .01) were inversely associated with asexual trait. The presence of asexual trait can hide a greater risk of finding ED both in intercourse or masturbation. These results should be taken into consideration during the general assessment of the patient with sexual problems.

Targeting the Urotensin II/UT G Protein-Coupled Receptor to Counteract Angiogenesis and Mesenchymal Hypoxia/Necrosis in Glioblastoma.

Glioblastomas (GBMs) are the most common primary brain tumors characterized by strong invasiveness and angiogenesis. GBM cells and microenvironment secrete angiogenic factors and also express chemoattractant G protein-coupled receptors (GPCRs) to their advantage. We investigated the role of the vasoactive peptide urotensin II (UII) and its receptor UT on GBM angiogenesis and tested potential ligand/therapeutic options based on this system. On glioma patient samples, the expression of UII and UT increased with the grade with marked expression in the vascular and peri-necrotic mesenchymal hypoxic areas being correlated with vascular density. In vitro human UII stimulated human endothelial HUV-EC-C and hCMEC/D3 cell motility and tubulogenesis. In mouse-transplanted Matrigel sponges, mouse (mUII) and human UII markedly stimulated invasion by macrophages, endothelial, and smooth muscle cells. In U87 GBM xenografts expressing UII and UT in the glial and vascular compartments, UII accelerated tumor development, favored hypoxia and necrosis associated with increased proliferation (Ki67), and induced metalloproteinase (MMP)-2 and -9 expression in Nude mice. UII also promoted a "tortuous" vascular collagen-IV expressing network and integrin expression mainly in the vascular compartment. GBM angiogenesis and integrin αvß3 were confirmed by in vivo 99mTc-RGD tracer imaging and tumoral capture in the non-necrotic area of U87 xenografts in Nude mice. Peptide analogs of UII and UT antagonist were also tested as potential tumor repressor. Urotensin II-related peptide URP inhibited angiogenesis in vitro and failed to attract vascular and inflammatory components in Matrigel in vivo. Interestingly, the UT antagonist/biased ligand urantide and the non-peptide UT antagonist palosuran prevented UII-induced tubulogenesis in vitro and significantly delayed tumor growth in vivo. Urantide drastically prevented endogenous and UII-induced GBM angiogenesis, MMP, and integrin activations, associated with GBM tumoral growth. These findings show that UII induces GBM aggressiveness with necrosis and angiogenesis through integrin activation, a mesenchymal behavior that can be targeted by UT biased ligands/antagonists.

Adherence to Mediterranean diet and prostate cancer risk in Sicily: population-based case-control study.

Prostate cancer (PCa) is the second most frequently diagnosed cancer and the sixth leading cause of death from cancer worldwide. Countries following a Mediterranean-type dietary pattern, has been reported to have lower PCa incidence and mortality compared with other European regions. A population-based case-control study has been conducted from January 2015 to December 2016 in a single institution of the municipality of Catania, southern Italy. A total of 118 PCa and 238 population-based controls were collected. Controls had significantly higher adherence to the Mediterranean diet, which was evident for several subgroups (including age groups, overweight and obese men, current smokers, alcohol intake, low and medium physical activity levels). PCa cases were found to consume lower amount of vegetables (223 g/d vs. 261 g/d; p = 0.001), legumes (34.26 g/d vs. 53.55 g/d; p = 0.003), and fish (47.75 g/d vs. 58.3 g/d) than controls; other differences emerged were related to alcohol intake (12.37 g/d vs 5.07 g/d; p < 0.01), cereals (254.06 g/d vs.235.94 g/d; p < 0.001), dairy (196 g/d vs. 166 g/d; p < 0.001), and meat consumption (98.09 g/d vs. 70.15 g/d; p < 0.001). However, no statistically significant differences between cases and controls were found regarding fruit, legumes, and olive oil consumption. The Mediterranean diet score was inversely associated with lower likelihood of having PCa in a linear manner (odds ratio [OR]: 0.86 [95% CI 0.77-0.96]). Specifically, individuals in the highest group of adherence had 78% less likelihood of have PCa and 14% less likelihood for each point increase of the score. The model adjusted for total polyphenol intake showed still a significant inverse association between adherence to the Mediterranean diet and PCa, but the relation was no more linear and not significant for one-point increase of the score (OR: 0.88 [95% CI 0.77-1.01]). In our cohorts of Italian men, we observed that high adherence to the Mediterranean diet was inversely associated with likelihood of having PCa cancer.

Association between dietary flavonoids intake and prostate cancer risk: A case-control study in Sicily.

OBJECTIVES: The aim of this study is to test the association between dietary flavonoids intake and prostate cancer (PCa) in a sample of southern Italian individuals. DESIGN: A population-based case-control study on the association between PCa and dietary factors was conducted from January 2015 to December 2016, in a single institution. SETTING: Patients with elevated PSA (Prostate Specific Antigen) and/or suspicion of PCa underwent transperineal prostate biopsy (≥12 cores). A total of 118 histopathological-verified PCa cases were collected and matched with controls, which were selected from a sample of 2044 individuals randomly recruited among the same reference population. Finally, a total of 222 controls were selected. MAIN OUTCOME MEASURES: Prevalence of PCa. RESULTS: Consumption of certain groups of flavonoids significantly differed between controls and cases, in particular: flavonols (63.36 vs 37.14 mg/d, P < 0.001), flavanols (107.61 vs. 74.24 mg/d, P = .016), flavanones (40.92 vs. 81.32 mg/d, P < 0.001), catechins (63.36 vs. 36.18 mg/d, P = .006). In the multivariate model, flavanols and flavones were associated with reduced risk of PCa, despite not in the highest quartile of intake. Higher flavonol and catechin intake was consistently associated with reduced risk of PCa (Odds Ratio (OR) = 0.19, 95% CI: 0.06-0.56 and OR = 0.12, 95% CI: 0.04-0.36). In contrast, the highest intake of flavanones was positively associated with PCa. CONCLUSION: Flavonols and catechins have proved to be the most promising molecules for a potential protective role against PCa. Nevertheless, further research on flavanones is needed to better establish whether they are associated with PCa.

Association between dietary phytoestrogens intakes and prostate cancer risk in Sicily.

OBJECTIVE: In this study we aimed to investigate the association between dietary phytoestrogen consumption and prostate cancer in a sample of southern Italian individuals. METHODS: A population-based case-control study on the association between prostate cancer and dietary factors was conducted from January 2015 to December 2016 in a single institution of the municipality of Catania, southern Italy (Registration number: 41/2015). A total of 118 histopathological-verified prostate cancer (PCa) cases and a total of 222 controls were collected. Dietary data was collected by using two food frequency questionnaires. RESULTS: Patients with PCa consumed significantly higher levels of phytoestrogens. Multivariate logistic regression showed that lignans (Q[quartile]4 vs. Q1, OR [odds ratio] = 4.72; p < .05) and specifically, lariciresinol (Q4 vs. Q1, OR = 4.60; p < .05), pinoresinol (Q4 vs. Q1, OR = 5.62; p < .05), matairesinol (Q4 vs. Q1, OR = 3.63; p < .05), secoisolariciresinol (Q4 vs. Q1, OR = 4.10; p < .05) were associated with increased risk of PCa. Furthermore, we found that isoflavones (Q3 vs. Q1, OR = 0.28; p < .05) and specifically, genistein (Q4 vs. Q1, OR = 0.40; p < .05) were associated with reduced risk of PCa. CONCLUSION: We found of an inverse association between dietary isoflavone intake and PCa, while a positive association was found with lignans intake.

Dietary Consumption of Phenolic Acids and Prostate Cancer: A Case-Control Study in Sicily, Southern Italy.

Dietary polyphenols gained the interest of the scientific community due to their wide content in a variety of plant-derived foods and beverages commonly consumed, such as fruits, vegetables, coffee, tea, and cocoa. We aimed to investigate whether there was an association between dietary phenolic acid consumption and prostate cancer (PCa) in South Italy. We conducted a population-based case-control study from January 2015 to December 2016 in a single institution of the municipality of Catania, southern Italy (Registration number: 41/2015). Patients with elevated PSA and/or suspicious PCa underwent transperineal prostate biopsy. A total of 118 histopathological-verified PCa cases were collected and a total of 222 controls were selected from a sample of 2044 individuals. Dietary data were collected by using two food frequency questionnaires and data on the phenolic acids content in foods was obtained from the Phenol-Explorer database (www.phenol-explorer.eu). Association between dietary intake of phenolic acids and PCa was calculated through logistic regression analysis. We found lower levels of caffeic acid (2.28 mg/day vs. 2.76 mg/day; p < 0.05) and ferulic acid (2.80 mg/day vs. 4.04 mg/day; p < 0.01) in PCa when compared to controls. The multivariate logistic regression showed that both caffeic acid (OR = 0.32; p < 0.05) and ferulic acid (OR = 0.30; p < 0.05) were associated with reduced risk of PCa. Higher intake of hydroxybenzoic acids and caffeic acids were associated with lower risk of advanced PCa. High intake of caffeic acid and ferulic acid may be associated with reduced risk of PCa.