AU-1 from Agavaceae plants causes transient increase in p21/Cip1 expression in renal adenocarcinoma ACHN cells in an miR-34-dependent manner

Here, we show that AU-1, spirostanol saponin isolated from Agavaceae plants, causes a transient increase in cyclin-dependent kinase inhibitor (CDKI) p21/Cip1 through the upregulation of miRNAs, miR-34 and miR-21. AU-1 stimulated p21/Cip1 expression without exerting cytotoxicity against different types of carcinoma cell lines. In renal adenocarcinoma ACHN cells, AU-1 transiently elevated the expression level of p21/Cip1 protein without marked increases in p21/Cip1 mRNA levels. Rapid and transient increases in miR-34 and miR-21, both of which are known to upregulate p21/Cip1, were observed in AU-1-treated cells. Inhibitor for miR-34 and for miR-21 significantly blocked the AU-1-caused increase in p21/Cip1, indicating that elevation of p21/Cip1 protein by AU-1 is dependent on these microRNAs. We further clarified that NAD-dependent deacetylase SIRT1, a direct target of miR-34, is decreased by the treatment with AU-1. Furthermore, we found that SIRT1-knockdown increases p21/Cip1 protein levels in an miR-21-dependent manner. On the other hand, ectopic expression of p21/Cip1 resulted in the lowered expression of miR-34 and miR-21, suggesting that reciprocal regulation exists between p21/Cip1 and these miRNAs. We propose that the following feedback network composed of miR-34/SIRT1/miR-21/p21 is triggered by the treatment with AU-1: in cells treated with AU-1, transient elevation of miR-34 leads to the downregulation of SIRT1, thereby miR-21 is freed from SIRT1-dependent suppression. Then, elevated miR-21 upregulates p21/Cip1 protein, followed by the suppression of miR-34 expression.     

Determinants of Postoperative Outcomes of Female Genital Fistula Repair Surgery

OBJECTIVE:: To determine predictors of fistula repair outcomes 3 months postsurgery. METHODS:: We conducted a multicountry prospective cohort study between 2007 and 2010. Outcomes, measured 3 months postsurgery, included fistula closure and residual incontinence in women with a closed fistula. Potential predictors included patient and fistula characteristics and context of repair. Multivariable generalized estimating equation models were used to generate adjusted risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS:: Women who returned for follow-up 3-month postsurgery were included in predictors of closure analyses (n=1,274). Small bladder size (adjusted RR 1.57, 95% CI 1.39-1.79), prior repair (adjusted RR 1.40, 95% CI 1.11-1.76), severe vaginal scarring (adjusted RR 1.56, 95% CI 1.20-2.04), partial urethral involvement (adjusted RR 1.36, 95% CI 1.11-1.66), and complete urethral destruction or circumferential defect (adjusted RR 1.72, 95% CI 1.33-2.23) predicted failed fistula closure. Women with a closed fistula at 3-month follow-up were included in predictors of residual incontinence analyses (n=1,041). Prior repair (adjusted RR 1.37, 95% CI 1.13-1.65), severe vaginal scarring (adjusted RR 1.35, 95% CI 1.10-1.67), partial urethral involvement (adjusted RR 1.78, 95% CI 1.27-2.48), and complete urethral destruction or circumferential defect (adjusted RR 2.06, 95% CI 1.51-2.81) were significantly associated with residual incontinence. CONCLUSION:: The prognosis for genital fistula closure is related to preoperative bladder size, previous repair, vaginal scarring, and urethral involvement. LEVEL OF EVIDENCE:: II.     

Clinical Efficacy of Cervical Length and Volume for Prediction of Labor Onset in VBAC Candidates

Background: The purpose of this research is to discover whether measurement of cervical length and cervical volume at term is helpful in predicting the onset of labor in VBAC candidates.Methods: Transvaginal sonographic evaluations of the cervixes of pregnant women who desired to undergo VBAC were performed between 36 - 40 weeks gestation. Clinical information such as labor onset time, gestational age at delivery and delivery mode was gathered from medical records.Results: A total of 514 pregnant women participated in this study. Cervical length was significantly longer in the group that delivered 7 days or more after measurement than in the group that delivered within 7 days of measurement (43±0.77 cm vs. 2.99±0.72 cm, p< 0.001). Cervical volume was significantly larger in the group that delivered at and after 7 days than in the group that delivered within 7 days (29.21±11.62 cm³ vs. 34.07±13.41 cm³, p=0.014). The cervical length ROC curve was significantly more predictive than the cervical volume ROC curve (AUC: 0.711 vs 0.594, p= 0.001). There were no significant differences between the combined cervical length/volume ROC curve and the cervical length ROC curve alone (p= 0.565). The AUC of the cervical length ROC curve to predict postterm pregnancy was 0.729.Conclusion: Measuring cervical length is helpful in predicting the onset of spontaneous labor within 7 days and posterm delivery in VBAC candidates.     

New insights into the morphogenesis of the gubernaculum testis and the inguinal canal

There is no consensus about the role of the gubernaculum testis (GT). Nineteen human embryos (Carnegie stages 15–23), 36 fetuses (9 weeks to term), and eight neonates were examined. All the embryos and 25 fetuses (from weeks 9–16) were processed for paraffin wax histology and serially sectioned at 10 µm thickness. The remaining 11 fetuses and the eight neonates were fresh specimens that were dissected under a surgical microscope. The GT appeared during the embryonic period (stages 17–23) with a horseshoe‐shaped mesenchyme condensation of the superior concavity, which was observed in four different topographical regions sequentially through development. The GT was not attached at either of its ends in any of the specimens, not to the gonad or in the scrotal sac. The inguinal canal differentiates around the inguinal portion of the GT during the late embryonic period. After stage 21, the GT appears enveloped by an evagination of the peritoneal cavity. It has few striate muscular fibers and vessels. Although the GT does not appear to have the role traditionally attributed to it, it is still an essential structure and indirectly facilitates the descent of the testes. It contributes to the formation of the inguinal canal and then forges the pathway that the testes will subsequently take through the inguinal canal as they migrate from the abdominal cavity into the scrotal sac. Clin. Anat. 30:599–607, 2017. © 2017 Wiley Periodicals, Inc.