mTORC1-dependent translational control plays a key role in several enduring forms of synaptic plasticity such as long term potentiation (LTP) and mGluR-dependent long term depression. Recent evidence demonstrates an additional role in regulating synaptic homeostasis in response to inactivity, where dendritic mTORC1 serves to modulate presynaptic function via retrograde signaling. Presently, it is unclear whether LTP and homeostatic plasticity use a common route to mTORC1-dependent signaling or whether each engage mTORC1 through distinct pathways. Here, we report a unique signaling pathway that specifically couples homeostatic signaling to postsynaptic mTORC1 after loss of excitatory synaptic input. We find that AMPAR blockade, but not LTP-inducing stimulation, induces phospholipase D (PLD)-dependent synthesis of the lipid second messenger phosphatidic acid (PA) in rat cultured hippocampal neurons of either sex. Pharmacological blockade of PLD1/2 or pharmacogenetic disruption of PA interactions with mTOR eliminates mTORC1 signaling and presynaptic compensation driven by AMPAR blockade, but does not alter mTORC1 activation or functional changes during chemical LTP (cLTP). Overexpression of PLD1, but not PLD2, recapitulates both functional synaptic changes as well as signature cellular adaptations associated with homeostatic plasticity. Finally, transient application of exogenous PA is sufficient to drive rapid presynaptic compensation requiring mTORC1-dependent translation of BDNF in the postsynaptic compartment. These results thus define a unique homeostatic signaling pathway coupling mTORC1 activation to changes in excitatory synaptic drive. Our results further imply that more than one canonical mTORC1 activation pathway may be relevant for the design of novel therapeutic approaches against neurodevelopmental disorders associated with mTORC1 dysregulation. Homeostatic and Hebbian forms of synaptic plasticity are thought to play complementary roles in regulating neural circuit function, but we know little about how these forms of plasticity are distinguished at the single neuron level. Here, we define a signaling pathway that uniquely links mTORC1 with homeostatic signaling in neurons.

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Physical examination and diagnostic studies are important part of the diagnostic workup, but since cytological assessment often yields atypical cells, surgical treatment and pathologic evaluation are the only approach for definitive diagnosis to rule out a potential malignancy.

This retrospective analysis aimed to clarify the clinical and pathologic features of ovarian clear cell carcinoma (OCCC), and to determine the factors predictive of survival.Data waereextracted from OCCC patients who underwent primary surgery followed by adjuvant chemotherapy in Obstetrics & Gynecology Hospital of Fudan University between January2007 and December 2014. Kaplan-Meier survival estimates and Cox proportional hazards model were used for survival analyses.Of 130 patients (mean age = 56.2 years), 66.2% had stage I disease when the 5-year overall survival and 5-year disease-free survival were 89.2% and 88.1%, respectively. Patients frequently presented with large pelvic mass (>10 cm) and mild-to-moderate elevation of serological CA125 (≤200U/ mL). 60.7% of the cases at stage III/IV exhibited resistance to platinum-based chemotherapy; 37.69% of the tumors arose from endometriosis. On multivariate analysis, stage and chemoresistance were independent prognostic factors predictive for poorer survival. Survival at stage IC1 (surgical rupture) was comparable to that at stage IA (capsule intact), whereas survival at stage IC2/IC3 (rupture before surgery) was significantly worse than that at stage IA.OCCC shows distinct features compared to other epithelial ovarian cancers. FIGO stage and response to chemotherapy affect prognosis independently. Arising from endometriosis is not associated with better survival. Preoperative rupture rather than intraoperative rupture confers an adverse prognosis in otherwise stage IA disease.

BackgroundConsidered as the precursor lesion of a subset of ovarian clear cell carcinoma (OCCC), the prognostic role of endometriosis in OCCC patients remains controversial. This study aimed to investigate the prognostic role of coexisting endometriosis in the survival of patients with OCCC, and also sought to identify other prognostic factors.ResultsA total of 125 patients were diagnosed with OCCC during the study period. Of these, 55 (44.0%) patients had coexisting endometriosis. Patients with endometriosis were younger (p = 0.030), had smaller tumor diameter (p = 0.005) and lower preoperative CA125 levels (p = 0.005). More patients with endometriosis had International Federation of Gynecology and Obstetrics (FIGO) stage I disease (83.6% vs. 51.4%, p = 0.000) and exhibited sensitivity to platinum-based regimen (89.6% vs. 66.7%, p = 0.003). Univariate and multivariate analysis revealed that coexisting endometriosis was not a predictor of 5-year overall survival (OS) or progression-free survival (PFS) of OCCC patients. For OS, chemosensitivity was the only useful prognostic factor (Hazards ratio (HR) 109.33, 95% Confidence Interval (CI) 23.46–511.51; p = 0.000). For PFS, the useful prognostic factors were ascites (HR 2.78, 95% CI 1.21–6.47; p = 0.016), FIGO stage (HR 1.61, 95% CI 1.04–2.49; p = 0.033), and chemosensitivity (HR 101.60, 95% CI 29.45–350.49; p = 0.000). Moreover, higher FIGO stage was the only risk factor for resistance to platinum-based chemotherapy (Exp (B) = 0.292, 95% CI 0.123–0.693; p = 0.005).ConclusionsIn this study, coexisting endometriosis was not a prognostic factor for the survival of OCCC patients. The most important predictor of both 5-year OS and PFS was chemosensitivity to platinum-based regimen, which decreased significantly with increase in FIGO stage.