Methylation in host and viral genes as marker of aggressiveness in cervical lesions: Analysis in 543 unscreened women.

OBJECTIVE: The present study aimed to evaluate the association between altered methylation and histologically confirmed high grade cervical intraepithelial neoplasia (hgCIN). METHODS: Methylation levels in selected host (CADM1, MAL, DAPK1) and HPV (L1_I, L1_II, L2) genes were measured by pyrosequencing in DNA samples obtained from 543 women recruited in Curitiba (Brazil), 249 with hgCIN and 294 without cervical lesions. Association of methylation status with hgCIN was estimated by Odds Ratio (OR) with 95% confidence interval (CI). RESULTS: The mean methylation level increased with severity of the lesion in the host and viral genes (p-trend < 0.05), with the exception of L1_II region (p-trend = 0.075). Positive association was found between methylation levels for host genes and CIN2 and CIN3 lesions respectively [CADM1: OR 4.17 (95%CI 2.03-8.56) and OR 9.54 (95%CI 4.80-18.97); MAL: OR 5.98 (95%CI 2.26-15.78) and OR 22.66 (95%CI 9.21-55.76); DAPK1: OR 3.37 (95%CI 0.93-12.13) and OR 6.74 (95%CI 1.92-23.64)]. Stronger risk estimates were found for viral genes [L1_I: OR 10.74 (95%CI 2.66-43.31) and OR 15.00 (95%CI 3.00-74.98); L1_II: OR 73.18 (95%CI 4.07-1315.94) and OR 32.50 (95%CI 3.86-273.65); L2: OR 4.73 (95%CI 1.55-14.44) and OR 10.62 (95%CI 2.60-43.39)]. The cumulative effect of the increasing number of host and viral methylated genes was associated with the risk of CIN2 and CIN3 lesions (p-trend < 0.001). CONCLUSIONS: Our results, empowered by a wide cervical sample series with a large number of hgCIN, supported the role of methylation as marker of aggressiveness.

Stem Cell-Derived Extracellular Vesicles and Kidney Regeneration.

Extracellular vesicles (EVs) are membranous vesicles containing active proteins, lipids, and different types of genetic material such as miRNAs, mRNAs, and DNAs related to the characteristics of the originating cell. They possess a distinctive capacity to communicate over long distances. EVs have been involved in the modulation of several pathophysiological conditions and, more importantly, stem cell-derived EVs appear as a new promising therapeutic option. In fact, several reports provide convincing evidence of the regenerative potential of EVs released by stem cells and, in particular, mesenchymal stromal cells (MSCs) in different kidney injury models. Described mechanisms involve the reprogramming of injured cells, cell proliferation and angiogenesis, and inhibition of cell apoptosis and inflammation. Besides, the therapeutic use of MSC-EVs in clinical trials is under investigation. This review will focus on MSC-EV applications in preclinical models of acute and chronic renal damage including recent data on their use in kidney transplant conditioning. Moreover, ongoing clinical trials are described. Finally, new strategies to broaden and enhance EV therapeutic efficacy by engineering are discussed.