PGC-1α signaling coordinates susceptibility to metabolic and oxidative injury in the inner retina.

Retinal ganglion cells (RGCs), used as a common model of central nervous system injury, are particularly vulnerable to metabolic and oxidative damage. However, molecular mechanisms underlying this sensitivity have not been determined in vivo. PGC-1α (encoded by PPARGC1A) regulates adaptive metabolism and oxidative stress responses in a tissue- and cell-specific manner. Aberrant PGC-1α signaling is implicated in neurodegeneration, but the mechanism underlying its role in central nervous system injury remains unclear. We provide evidence from a mouse model that PGC-1α expression and activity are induced in adult retina in response to metabolic and oxidative challenge. Deletion of Ppargc1a dramatically increased RGC loss, in association with dysregulated expression of PGC-1α target metabolic and oxidative stress response genes, including Hmox1 (encoding HO-1), Tfam, and Vegfa. Vehicle-treated and naive Ppargc1a(-/-) mice also showed mild RGC loss, and surprisingly prominent and consistent retinal astrocyte reactivity. These cells critically regulate metabolic homeostasis in the inner retina. We show that PGC-1α signaling (not previously studied in glia) regulates detoxifying astrocyte responses to hypoxic and oxidative stresses. Finally, PGC-1α expression was modulated in the inner retina with age and in a model of chronic optic neuropathy. These data implicate PGC-1α signaling as an important regulator of astrocyte reactivity and RGC homeostasis to coordinate pathogenic susceptibility to metabolic and oxidative injury in the inner retina.

Comparison of three surgical approaches for staging lymphadenectomy in high-risk endometrial cancer.

OBJECTIVE: To compare laparotomy, laparoscopy, and robotic surgical approaches to lymphadenectomy for high-risk endometrial cancer staging. METHODS: A retrospective cohort study enrolled patients who underwent surgery for pathologic high-risk endometrial carcinoma at the University Health Network, Toronto, Canada, between January 1, 2005 and December 31, 2013. The primary outcome, the median number of nodes retrieved, was compared based on surgical technique. The secondary outcome was the detection of metastatic nodes. RESULTS: A total of 176 patients who underwent surgery for high-risk endometrial cancer were included, of whom 147 (83.5%) had pelvic and 78 (44.3%) had para-aortic lymphadenectomy. Laparotomy, laparoscopy, and robotic approaches were applied for 69 (39.2%), 44 (25.0%), and 63 (35.8%) patients, respectively. Minimally-invasive staging was associated with an increased proportion of patients undergoing pelvic lymphadenectomy compared with laparotomy (P=0.005). The median number of nodes removed in the pelvis and para-aortic regions did not differ between surgical approaches. The detection of metastatic nodes was also similar between the groups. Increased blood loss (P<0.001) and longer hospital admission (P<0.001) were observed with laparotomy procedures. CONCLUSION: All three techniques demonstrated adequate staging of high-risk endometrial carcinoma. Based on improved peri-operative outcomes, the use of minimally-invasive techniques is advocated where appropriate.