Effects of Large Extracellular Vesicles from Kidney Cancer Patients on the Growth and Environment of Renal Cell Carcinoma Xenografts in a Mouse Model.

Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In this study, we investigated the effects of three types of lEVs on the growth and peritumoral environment of xenograft clear cell renal cell carcinoma in a mouse model. Xenograft cancer cells were derived from patients' nephrectomy specimens. Three types of lEVs were obtained from pre-nephrectomy patient blood (cEV), the supernatant of primary cancer cell culture (sEV) and from blood from individuals with no medical history of cancer (iEV). Xenograft volume was measured after nine weeks of growth. Xenografts were then removed, and the expression of CD31 and Ki67 were evaluated. We also measured the expression of MMP2 and Ca9 in the native mouse kidney. lEVs from kidney cancer patients (cEV and sEV) tend to increase the size of xenografts, a factor that is related to an increase in vascularization and tumor cell proliferation. cEV also altered organs that were distant from the xenograft. These results suggest that lEVs in cancer patients are involved in both tumor growth and cancer progression.

Use of health services among long-term breast cancer survivors in Spain: longitudinal study based on real-world data.

PURPOSE: This study aimed to evaluate health service utilization in Spain among long-term breast cancer survivors and to compare it with that among women with no history of breast cancer. METHODS: Study based on the SURBCAN cohort includes a sample of long-term breast cancer survivors and a sample of women without breast cancer from 5 Spanish regions. Healthcare utilization was assessed through primary care, hospital visits, and tests during the follow-up period (2012 to 2016) by using electronic health records. Annual contact rates to healthcare services were calculated, and crude and multivariate count models were fitted to estimate the adjusted relative risk of healthcare services use. RESULTS: Data were obtained from 19,328 women, including 6512 long-term breast cancer survivors. Healthcare use was higher among breast cancer survivors (20.9 vs 16.6; p < 0.0001) and decreased from >10 years of survival. Breast cancer survivors who underwent a mastectomy were more likely to have a primary care visit (RR = 3.10 95% CI 3.08-3.11). Five to ten years survivors were more likely to have hospital inpatient visits and imaging test compared to women without breast cancer (RRa = 1.35 95% CI 1.30-1.39 and RRa = 1.27 95% CI 1.25-1.29 respectively). CONCLUSION: This study shows higher use of health services in long-term breast cancer survivors than in women without breast cancer regardless of survival time. IMPLICATIONS FOR CANCER SURVIVORS: These results help to estimate the health resources needed for the growing group of breast cancer survivors and to identify risk factors that drive higher use of health services.

Longitudinal associations between stressors and work ability in hospital workers.

This study sought to assess associations between work stressors and work ability in a cohort (2009-2012) of 498 hospital workers. Time-dependent variables associated with the Work Ability Index (WAI) were evaluated using general linear mixed models. Analyses included effects of individual and work characteristics. Except for work demands, the work stressors (job control, social support, effort-reward imbalance, overcommitment and work-related activities that cause pain/injury) were associated with WAI (p < 0.050) at intercept and in the time interaction. Daytime work and morning shift work were associated with decreased WAI (p < 0.010). Work stressors negatively affected work ability over time independently of other variables.

Pro-oxidant effect of ALA is implicated in mitochondrial dysfunction of HepG2 cells.

Heme biosynthesis begins in the mitochondrion with the formation of delta-aminolevulinic acid (ALA). In acute intermittent porphyria, hereditary tyrosinemia type I and lead poisoning patients, ALA is accumulated in plasma and in organs, especially the liver. These diseases are also associated with neuromuscular dysfunction and increased incidence of hepatocellular carcinoma. Many studies suggest that this damage may originate from ALA-induced oxidative stress following its accumulation. Using the MnSOD as an oxidative stress marker, we showed here that ALA treatment of cultured cells induced ROS production, increasing with ALA concentration. The mitochondrial energetic function of ALA-treated HepG2 cells was further explored. Mitochondrial respiration and ATP content were reduced compared to control cells. For the 300 µM treatment, ALA induced a mitochondrial mass decrease and a mitochondrial network imbalance although neither necrosis nor apoptosis were observed. The up regulation of PGC-1, Tfam and ND5 genes was also found; these genes encode mitochondrial proteins involved in mitochondrial biogenesis activation and OXPHOS function. We propose that ALA may constitute an internal bioenergetic signal, which initiates a coordinated upregulation of respiratory genes, which ultimately drives mitochondrial metabolic adaptation within cells. The addition of an antioxidant, Manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), resulted in improvement of maximal respiratory chain capacity with 300 µM ALA. Our results suggest that mitochondria, an ALA-production site, are more sensitive to pro-oxidant effect of ALA, and may be directly involved in pathophysiology of patients with inherited or acquired porphyria.

Internalization and induction of antioxidant messages by microvesicles contribute to the antiapoptotic effects on human endothelial cells.

Microvesicles are plasma membrane-derived fragments released from various cell types during activation and/or apoptosis and posses the ability to deliver biological information between cells. Microvesicles generated from T lymphocytes undergoing activation and apoptosis bear the morphogen Sonic Hedgehog, and exert a beneficial potential effect on the cardiovascular system through their dual capacity to increase nitric oxide and reduce reactive oxygen species production. This study investigated the effect of microvesicles on the apoptosis of human umbilical vein endothelial cells triggered by actinomycin D. Microvesicles prevented apoptosis induced by actinomycin D by modulating reactive oxygen species production: during the early phase of apoptosis, microvesicles might act directly as reactive oxygen species scavengers, owing to their ability to carry active antioxidant enzymes, catalase, and isoforms of the superoxide dismutase. Furthermore, their effects were associated with the ability to increase the expression of manganese-superoxide dismutase in endothelial cells, through the internalization process. Interestingly, microvesicles bearing Sonic Hedgehog induced cytoprotection in endothelial cells through the activation of the Sonic Hedgehog pathway. These findings provide additional evidence that microvesicles from T lymphocytes exert their vasculoprotective effects by promoting internalization and induction of antioxidant messages to the endothelial monolayer.