Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer.

Ovarian cancer (OC) is most lethal malignancy among all gynecological cancer. Large bodies of evidences suggest that mitochondrial-derived ROS play a critical role in the development and progression of OC. Paraoxonase 2 (PON2) is a membrane-associated lactonase with anti-oxidant properties. PON2 deficiency aggravates mitochondrial ROS formation, systemic inflammation, and atherosclerosis. The role of PON2 in cancer development remains unknown. In this report, in human, we identified that PON2 expression is higher in early stages (but not in late stages) of OC when compared to normal tissue. Using a mouse xenograft model of OC, we demonstrate that overexpression of PON2 prevents tumor formation. Mechanistically, PON2 decreases OC cell proliferation by inhibiting insulin like growth factor-1 (IGF-1) expression and signaling. Intriguingly, PON2 reduces c-Jun-mediated transcriptional activation of IGF-1 gene by decreasing mitochondrial superoxide generation. In addition, PON2 impairs insulin like growth factor-1 receptor (IGF-1R) signaling in OC cells by altering cholesterol homeostasis, which resulted in reduced caveolin-1/IGF-1R interaction and IGF-1R phosphorylation. Taken together, we report for the first time that PON2 acts as a tumor suppressor in the early stage of OC by reducing IGF-1 production and its signaling, indicating PON2 activation might be a fruitful strategy to inhibit early stage ovarian tumor

International Consensus Statement on Obstructive Sleep Apnea

Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy