ANKRD13a controls early cell-death checkpoint by interacting with RIP1 independent of NF-κB.

In TNF signaling, ubiquitination of RIP1 functions as an early cell-death checkpoint, which prevents the spatial transition of the signaling complex from complex-I to death-inducing complex-II. Here, we report that ankyrin repeat domain 13a (ANKRD13a) acts as a novel component of complex-II to set a higher signal threshold for the cytotoxic potential of TNF. ANKRD13a deficiency is sufficient to turn the response to TNF from survival to death by promoting the formation of complex-II without affecting NF-κB activation. ANKRD13a binds to ubiquitinated-RIP1 via its UIM, and subsequently limits the association of FADD and caspase-8 with RIP1. Moreover, high ANKRD13a expression is inversely correlated with apoptotic phenotypes in ovarian cancer tissues and is associated with poor prognosis. Our work identifies ANKRD13a as a novel gatekeeper of the early cell-death checkpoint, which may function as part of an escape mechanism from cell death in some cancers.

Feasibility and efficacy of gonadotropin-releasing hormone agonists for the prevention of chemotherapy-induced ovarian insufficiency in patients with malignant ovarian germ cell tumours (KGOG 3048R).

BACKGROUND: This study assessed the effects of gonadotropin-releasing hormone agonists (GnRHa) on the prevention of chemotherapy-induced ovarian insufficiency among young patients with malignant ovarian germ cell tumour (MOGCT) receiving chemotherapy. METHODS: This multicentre, retrospective study was conducted at 15 sites affiliated with the Korean Gynecologic Oncology Group and enrolled 354 patients between January 1995 and September 2018. Among them, 227 patients were included in this study and divided into two groups according to the use of GnRHa during chemotherapy (GnRHa versus no GnRHa groups). The primary objective was to compare the rates of menstrual resumption between the two groups. We also assessed the clinical determinants affecting menstrual resumption among the study groups. RESULTS: There were no significant differences between the GnRHa (n = 63) and no GnRHa (n = 164) groups regarding age at diagnosis, parity, ethnicity, age at menarche, body mass index, International Federation of Gynecology and Obstetrics stage, mode of surgery and surgery type. The rate of menstrual resumption after chemotherapy was 100% (63 of 63) in the GnRHa group and 90.9% (149 of 164) in the no GnRHa group (p = 0.013). The mean periods from last chemotherapy to menstrual resumption were 7.4 and 7.3 months in the GnRHa and no GnRHa groups, respectively. GnRHa co-administration during chemotherapy reduced the likelihood of amenorrhoea after chemotherapy, although statistical significance was not confirmed in the univariate analysis (odds ratio: 0.276; 95% confidence interval, 0.004-1.317; p = 0.077). CONCLUSION: Temporary ovarian suppression with GnRHa during chemotherapy does not significantly increase the chances of menstrual resumption in young patients with MOGCT.

Suicide in Elderly Patients with Hip Fracture: A South Korean Nationwide Cohort Study.

BACKGROUND: The purpose of the present study was to evaluate the incidence rate (IR) of suicide in elderly patients with hip fracture on the basis of a nationwide cohort and to analyze the change in the hazard ratio for suicide after hip fracture over time in comparison with a control group. METHODS: Patients with hip fracture and their matched controls were selected from the National Health Insurance Service-Senior cohort (NHIS-Senior) of the Republic of Korea. The NHIS-Senior consists of 558,147 people selected by a 10% simple random-sampling method from a total of 5.5 million subjects ≥60 years of age in 2002. Risk-set matching (1:2) on the propensity score was performed with use of a nearest neighbor matching algorithm with a maximum caliper of 0.1 for the hazard components. The IR of suicide and 95% confidence interval (CI) were calculated on the basis of a generalized linear model with a Poisson distribution. The effect size was presented as a hazard ratio (HR) with use of the Cox proportional-hazard model with a robust variance estimator that accounts for clustering within matched pairs. RESULTS: A total of 11,477 patients with hip fracture and 22,954 matched controls were included. The mean duration of follow-up was 4.59 years, generating 158,139 person-years. During follow-up, a total of 170 suicides were identified. Comparisons at up to 180 days and 365 days showed that patients with hip fracture were at higher risk for suicide than matched controls (p = 0.009 and 0.004, respectively; stratified log-rank test). During the first 180 days of follow-up, 14 suicides were identified in patients with hip fracture during 11,152 person-years (IR, 266.1 per 100,000 person-years; 95% CI, 157.6 to 449.4). Patients with hip fracture were 2.97 times more likely to kill themselves than their matched controls during the same period (HR = 2.97; 95% CI, 1.32 to 6.69). CONCLUSIONS: Hip fracture in elderly patients increased suicide risk within a year. A new approach to psychiatric evaluation and management is needed in elderly patients with hip fracture. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Safety of umbilical cord milking in very preterm neonates: a randomized controlled study.

OBJECTIVE: To investigate the safety of umbilical cord milking on both the mother and neonate among very preterm deliveries of less than 33 weeks of gestation. METHODS: Pregnant women who were expected to deliver at between 24 0/7 and 32 6/7 weeks of gestation were randomized to either the umbilical cord milking or immediate cord clamping group. Maternal and neonatal data associated with delivery, in addition to neonatal morbidity and mortality data, were collected and analyzed. RESULTS: Of the 66 preterm deliveries included in the study, 34 were randomized into the milking and 32 into the clamping group. Differences between maternal pre- and post-partum hemoglobin levels were 1.35 g/dL in the milking and 1.58 g/dL in the clamping group (P=0.451). Neonatal Apgar scores at both 1 and 5 minutes, initial blood gas analysis results, body temperature at admission, need for early intubation, and maximum bilirubin levels were all similar between the 2 groups. However, neonatal hemoglobin levels at birth (15.79 vs. 14.69 g/dL; P<0.05) and at 24 hours of age (14.83 vs. 13.29 g/dL; P<0.05) were significantly higher in the milking group. Neonates in the clamping group required more blood transfusion (1.78 vs. 0.93; P=0.049), and a higher percentage of neonates in the clamping group required inotropic drugs (63% vs. 29%; P=0.007). The mortality rate was significantly lower in the milking group (6% vs. 28%; P=0.015). CONCLUSION: Umbilical cord milking can be a safe and beneficial procedure for both the mother and the neonate in deliveries of less than 33 weeks of gestation.

Differential microscopic finding and glucose transporter 3 expression in terminal chorionic villi among birth weight-discordant twin placentas.

OBJECTIVE: To evaluate differences in microscopic findings and glucose transporter 3 (GLUT3) expression in terminal chorionic villi (TV) among birth weight-discordant twin (BWDT) placentas compared with the birth weight-concordant twin (BWCT) placentas. METHODS: We retrospectively studied a cohort of 26 BWDT, 10 BWCT, 10 pre-eclampsia singleton and 10 normal singleton pregnancies. Placentas were scored for the percentage of TV, the percentage of TV with syncytial knots, the presence of capillary branching patterns of TV, the capillary to terminal villous ratios, the membranous expression of GLUT3 and the nuclear expression of HIF-1α in trophoblasts and capillary endothelial cells of TV using immunohistochemistry. The clinical characteristics and microscopic findings were analyzed and compared. RESULTS: BWDT placentas exhibited differential percentages of TV, percentages of TV with syncytial knots, capillary to terminal villous ratios, expression of HIF-1α in capillary endothelial cells and expression of GLUT3 in trophoblasts and capillary endothelial cells of TV among each twin pair compared with BWCT placentas (P=0.003, P=0.022, P=0.037, P=0.007, P=0.046 and P=0.002, respectively). Pre-eclampsia singleton placentas exhibited higher GLUT3 expression in trophoblasts, higher HIF-1α expression in capillary endothelial cells of TV and high capillary to terminal villous ratios compared with normal singleton placentas (P=0.001, P<0.001 and P=0.001, respectively). CONCLUSIONS: We observed a strong relationship between characteristics of adaptive change to hypoxia (GLUT3 expression, TV and syncytial knotting and higher capillary to terminal villous ratios) and BWDT pregnancy but not BWCT pregnancy.

Trichonomas vaginalis metalloproteinase induces apoptosis of SiHa cells through disrupting the Mcl-1/Bim and Bcl-xL/Bim complexes.

To elucidate the roles of metalloproteinases and the Bcl-2 family of proteins in Trichovaginalis. vaginalis-induced apoptosis in human cervical cancer cells (SiHa cells) and vaginal epithelial cells (MS74 cells), SiHa cells and MS74 cells were incubated with live T. vaginalis, T. vaginalis excretory and secretory products (ESP), and T. vaginalis lysates, either with or without the specific metalloproteinase inhibitor 1,10-phenanthroline (1,10-PT), and examined apoptotic events and Bcl-2 signaling. The live T. vaginalis and the T. vaginalis ESP induced the release of cytochrome c into the cytosol, the activation of caspase-3 and caspase-9, and the cleavage of PARP. Additionally, the live T. vaginalis, but not the T. vaginalis lysate, induced the cleavage of the proapoptotic Bim protein. The live T. vaginalis and the T. vaginalis ESP, but not the T. vaginalis lysate, induced the dose-dependent cleavage of the antiapoptotic Bcl-xL and Mcl-1 proteins and decreased the association levels of Bcl-xL/Bim and Mcl-1/Bim complexes. We performed gelatin zymography and casein-hydrolysis assays on the live T. vaginalis and the T. vaginalis ESP to identify the apoptosis-inducing factor. Both the live T. vaginalis and the ESP contained high levels of metalloproteinases, of which activities were significantly inhibited by 1,10-PT treatment. Furthermore, the 1,10-PT blocked the cleavage of Bcl-xL, Mcl-1, PARP, caspase-3, and caspase-9, as well as the release of cytochrome c into the cytosol, and it significantly increased the association levels of the Bcl-xL/Bim and Mcl-1/Bim protein complexes, returning them to normal levels. Our results demonstrate that T. vaginalis induces mitochondria-dependent apoptosis in SiHa cells through the dissociation of Bcl-xL/Bim and Mcl-1/Bim complexes and that the apoptosis is blocked by the metalloproteinase inhibitor 1,10-PT. These results expand our understanding of the role of metalloproteinases in T. vaginalis-induced apoptosis and the signaling pathway in trichomoniasis of the cervicovaginal epithelial cells.

Serum HE4 level is an independent prognostic factor in epithelial ovarian cancer.

BACKGROUND: This study was designed to determine whether serum HE4 is an independent prognostic factor in ovarian cancer patients. METHODS: We measured HE4 in pretreatment serum samples from 80 women with epithelial ovarian cancer, using an enzyme-linked immunosorbent assay. The results were correlated with clinical data. RESULTS: The median serum HE4 level in ovarian cancer patients was 98.7 (range, 80.3-222.8) pg/ml. Elevated serum HE4 levels before therapy significantly correlated with a poorer progression free survival (log-rank test, P = 0.017). Multivariate analysis revealed serum HE4 to be an independent prognostic factor for progression-free survival (P = 0.036). In multivariate regression analysis, high serum HE4 levels significantly correlated with high tumor grade and serous histology (P = 0.004 and 0.017). In addition, high serum HE4 levels were significantly associated with residual tumor size and operative time (P = 0.003 and 0.033). CONCLUSIONS: Pretreatment serum HE4 seems to be an additional factor for predicting the outcome of patients with epithelial ovarian cancer. Due to its independence from established prognostic factors, serum HE4 may provide additional prognostic information.