Local vaginal bioelectrical impedance can predict preterm delivery in mice.

Preterm birth is a serious pregnancy complication that affects neonatal mortality, morbidity, and long-term neurological prognosis. Predicting spontaneous preterm delivery (PTD) is important for its management. While excluding the risk of PTD is important, identifying women at high risk of PTD is imperative for medical intervention. Currently used PTD prediction parameters in clinical practice have shown high negative predictive values, but low positive predictive values. We focused on sulfated and sialylated glycocalyx changes in the uterus and vagina prior to the onset of parturition and explored the potential of electrophysiological detection of these changes as a PTD prediction parameter with a high positive predictive value. In vivo local vaginal bioelectrical impedance (VZ) was measured using two different mouse PTD models. PTD was induced in ICR mice through the subcutaneous injection of mifepristone or local intrauterine injection of lipopolysaccharide (LPS). The PTD rates were 100% and 60% post-administration of mifepristone (16-20 h, n = 4) and LPS (12-24 h, n = 20), respectively. The local VZ values (15 and 10 h after mifepristone or LPS treatment, respectively) were significantly lower in the PTD group than in the non-PTD group. Receiver operator characteristic (ROC) curve analysis of VZ at 125 kHz as a predictor of PTD showed an area under the ROC curve of 1.00 and 0.77 and positive predictive values of 1.00 and 0.86, for the mifepristone and LPS models, respectively, suggesting that local VZ value can predict PTD. Histological examination of the LPS-treated model 6 h post-treatment revealed increased expression of sulfomucins and/or sulfated proteoglycans and sialomucins in the cervical epithelium, cervical stroma and vaginal stroma. In conclusion, local VZ values can determine sulfated and sialylated glycocalyx alterations within the uterus and vagina and might be a useful PTD prediction parameter.

A Comparative Study and Prediction of the Ex Vivo Permeation of Six Vaginally Administered Drugs across Five Artificial Membranes and Vaginal Tissue.

The theoretical interpretation of the vaginal permeability phenomenon, the evaluation of the suitability of five artificial membranes, and the prediction of the behaviors of vaginal drugs were the main objectives of this study. Franz vertical diffusion cells and different validated HPLC methods were used to measure the permeability of six vaginally administered drugs (econazole, miconazole, metronidazole, clindamycin, lidocaine, and nonoxynol-9). This study was performed (in vitro) on different membranes of polyvinylidene fluoride (PVDF), plain cellulose or cellulose impregnated with isopropyl myristate (IPM), and cellulose combined with PVDF or IPM. The results were compared with those obtained from cow vaginal tissue (ex vivo), where cellulose was proven to be the best simulant. According to the permeability profiles (Papp), the water solubility of the drugs was considered a necessary criterion for their transport in the membranes or in the tissue, while the size was important for their penetration. Furthermore, it was found that polar compounds show clear superiority when penetrating cellulose or tissue, while non-polar ones show superiority when penetrating the lipophilic PVDF membrane. Finally, a successful attempt was made to predict the Papp values (|Papp-predPapp| < 0.005) of the six drugs under study based on a PLS (Partial Least Squares) in silico simulation model.

E-cadherin and NF-κB expression in the vagina after ovarian ischemia and reperfusion.

PURPOSE: To investigate inflammation and cell adhesion molecules in the vagina after ovarian ischemia-reperfusion (IR) injury. METHODS: 20 Wistar albino female rats were divided into two groups: control, and IR groups. In IR group, blood flow was restricted for 2 hours for ovarian ischemia. Then, tissues were re-blood 2 hours for reperfusion. Vagina tissues were excised and processed for histopathological analysis. Histopathological and biochemical follow-ups were performed. RESULTS: Both malondialdehyde and myeloperoxidase values were increased in IR group compared to control group. Glutathione content was decreased in IR group compared to control group. Epithelial degeneration, inflammation, dilatation, and nuclear factor-κB (NF-κB) expression were increased in IR group compared to control group. E-cadherin expression was significantly decreased in IR group. In the IR group, E-cadherin showed a positive reaction in adenomas, gland-like cryptic structures, cellular junctions with clustered inflammatory cells. In the IR group, NF-κB expression was increased in basement membrane, inflammatory cells, in blood vessels. CONCLUSIONS: Ovarian ischemia caused degeneration of epithelial cells in the vaginal region and disruptions in the cell junction complex, which leads to activation of E-cadherin and NF-κB signaling pathway and alterations in reproductive and embryonal development in the vaginal region.

Microorganism-derived extracellular vesicles: emerging contributors to female reproductive health.

Extracellular vesicles (EVs) are cell-derived nanoparticles that carry small molecules, nucleic acids, and proteins long distances in the body facilitating cell-cell communication. Microorganism-derived EVs mediate communication between parent cells and host cells, with recent evidence supporting their role in biofilm formation, horizontal gene transfer, and suppression of the host immune system. As lipid-bound bacterial byproducts, EVs demonstrate improved cellular uptake and distribution in vivo compared to cell-free nucleic acids, proteins, or small molecules, allowing these biological nanoparticles to recapitulate the effects of parent cells and contribute to a range of human health outcomes. Here, we focus on how EVs derived from vaginal microorganisms contribute to gynecologic and obstetric outcomes. As the composition of the vaginal microbiome significantly impacts women's health, we discuss bacterial EVs from both healthy and dysbiotic vaginal microbiota. We also examine recent work done to evaluate the role of EVs from common vaginal bacterial, fungal, and parasitic pathogens in pathogenesis of female reproductive tract disease. We highlight evidence for the role of EVs in women's health, gaps in current knowledge, and opportunities for future work. Finally, we discuss how leveraging the innate interactions between microorganisms and mammalian cells may establish EVs as a novel therapeutic modality for gynecologic and obstetric indications.

Development and verification of mechanistic vaginal absorption and metabolism model to predict systemic exposure after vaginal ring and gel application.

AIMS: The current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations. METHODS: Vaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel. Due to lack of data, the vaginal absorption parameters were calculated based on assumptions or optimized. The model uses release rate/in vitro release profiles with formulation characteristics to predict drug mass transfer across vaginal tissue into the systemic circulation. RESULTS: For lidocaine and tenofovir vaginal gel, the predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits. The average fold error (AFE) and absolute AFE indicating bias and precision of predictions range from 0.62 to 1.61. For dapivirine, the pharmacokinetic parameters are under and overpredicted in some studies due to lack of formulation composition details and relevance of release rate used in ring model. The predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits for etonogestrel and ethinylestradiol vaginal ring (AFEs and absolute AFEs from 0.84 to 1.83). CONCLUSION: The current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future.

MAP3K1 regulates female reproductive tract development.

Mitogen-activated protein 3 kinase 1 (MAP3K1) has a plethora of cell type-specific functions not yet fully understood. Herein, we describe a role for MAP3K1 in female reproductive tract (FRT) development. MAP3K1 kinase domain-deficient female mice exhibited an imperforate vagina, labor failure and infertility. These defects corresponded with shunted Müllerian ducts (MDs), the embryonic precursors of FRT, that manifested as a contorted caudal vagina and abrogated vaginal-urogenital sinus fusion in neonates. The MAP3K1 kinase domain is required for optimal activation of the Jun-N-terminal kinase (JNK) and cell polarity in the MD epithelium, and for upregulation of WNT signaling in the mesenchyme surrounding the caudal MD. The MAP3K1-deficient epithelial cells and MD epithelium had reduced expression of WNT7B ligands. Correspondingly, conditioned media derived from MAP3K1-competent, but not -deficient, epithelial cells activated a TCF/Lef-luciferase reporter in fibroblasts. These observations indicate that MAP3K1 regulates MD caudal elongation and FRT development, in part through the induction of paracrine factors in the epithelium that trans-activate WNT signaling in the mesenchyme.

Two-Year Preclinical Evaluation of Long-Term Absorbable Poly-4-hydroxybutyrate Scaffold for Surgical Correction of Pelvic Organ Prolapse.

INTRODUCTION AND HYPOTHESIS: Fully absorbable implants may be an alternative to permanent meshes in the correction pf pelvic organ prolapse (POP) as they may reduce adverse events by promoting tissue regeneration and collagen metabolism. This study was aimed at evaluating the long-term host and biomechanical response to a fully absorbable poly-4-hydroxybutyrate (P4HB) scaffold in comparison with polypropylene (PP) mesh. METHODS: Poly-4-hydroxybutyrate scaffold (n = 16) and PP mesh (n = 16) were surgically implanted in the posterior vaginal wall of parous female Dohne Merino sheep. Vaginal explants were evaluated in terms of gross necropsy, host response (immune response, collagen deposition, tissue regeneration), biomechanics, and degradation of P4HB at 12 and 24 months post-implantation. RESULTS: Gross necropsy revealed no infection or fluid collection using P4HB or PP. At 12 months, exposures were observed with both P4HB (3 out of 8) and PP (4 out of 8), whereas at 24 months, exposures were observed only with PP (4 out of 8). The tensile stiffness of the P4HB explants was maintained over time despite complete absorption of P4HB. The collagen amount of the vaginal tissue after P4HB implantation increased over time and was significantly higher than PP at 24 months. P4HB scaffolds exhibited significantly lower myofibroblast differentiation than PP meshes at 24 months. CONCLUSIONS: The P4HB scaffold allowed for gradual load transfer to the vaginal wall and resulted in mechanically self-sufficient tissue. P4HB scaffold had a more favorable host response than PP mesh, with higher collagen content, lower myofibroblastic differentiation, and no exposures at 24 months. P4HB scaffolds have potential as an alternative to permanent implants in treating POP.

The difference in extracellular matrix metabolism in women with and without pelvic organ prolapse: A systematic review and meta-analysis.

BACKGROUND: Studies on the changes of extracellular matrix (ECM) in pelvic organ prolapse (POP) are still controversial. OBJECTIVE: To identify the changes in the ECM in POP patients. SEARCH STRATEGY: Comprehensive searching in Embase, PubMed, Web of Science and the Cochrane Library was carried out until 23 February 2023. SELECTION CRITERIA: Studies comparing the protein levels of ECM-related components between women with and without POP. DATA COLLECTION AND ANALYSIS: Quality and risk of bias were assessed using the Agency for Healthcare Research and Quality assessment. Indicators were pooled with random or fixed effect meta-analysis based on heterogeneity and sub-grouped analysed by the biopsy site. MAIN RESULTS: Thirty cross-sectional studies were included, comprising 840 POP cases and 755 controls. Overall results showed that the expression of type III collagen (COLIII) and several matrix metalloproteinases (MMP-1, -2 and -9) were increased, whereas those of type I collagen (COLI), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were decreased in patients with POP. Subgroup analysis showed that the expression of COLIII in the anterior vaginal wall (AVW) and COLIII, MMP-2 and -9 in the uterosacral ligament (USL) were consistent with the overall results. However, the expression of COLI and MMP-1 in the AVW showed no difference and the expression of COLI and MMP-1 in the USL is still controversial based on current studies. CONCLUSIONS: Patients with POP have lower expression of COLI and TIMP-1 and higher expression of COLIII and MMPs compared with non-POP cases, but further studies are required to investigate in specified anatomical sites.

Bacteria-derived L-lactate fuels cervical cancer chemoradiotherapy resistance.

Accumulating studies have demonstrated the presence of viable and metabolically active bacterial communities within a range of solid tumor types. However, the precise mechanisms by which these microbes modulate their infected tumor niches or impact patient responses to cancer treatments remain to be elucidated. Recently, Colbert et al. revealed that L-lactate produced by intratumoral Lactobacillus iners reprograms metabolic capabilities of cervical tumors to support chemoradiotherapy resistance. This finding has implications for many solid cancer types.

Cotton Fibers with a Lactic Acid-Like Surface for Re-establishment of Protective Lactobacillus Microbiota by Selectively Inhibiting Vaginal Pathogens.

Failure to reconstruct the Lactobacillus microbiota is the major reason for the recurrence of vaginal infection. However, most empiric therapies focus on the efficacy of pathogen elimination but do not sufficiently consider the viability of Lactobacillus. Herein, cotton fibers with a lactic acid-like surface (LC) are fabricated by NaIO4 oxidation and L-isoserine grafting. The lactic acid analog chain ends and imine structure of LC can penetrate cell walls to cause protein cleavage in Escherichia coli and Candida albicans and inhibit vaginal pathogens. Meanwhile, the viability of Lactobacillus acidophilus is unaffected by the LC treatment, thus revealing a selective way to suppress pathogens as well as provide a positive route to re-establish protective microbiota in the vaginal tract. Moreover, LC has excellent properties such as good biosafety, antiadhesion, water absorption, and weight retention. The strategy proposed here not only is practical, but also provides insights into the treatment of vaginal infections.

Early growth response 2, a novel target of pelvic organ prolapse, is highly expressed in anterior vaginal wall tissues with pelvic organ prolapse.

Pelvic organ prolapse (POP) is a common disorder among women that negatively affects women's quality of life. Early growth response 2 (EGR2) is a transcription factor that regulates cell growth. The present study aimed to explore the role of EGR2 in POP progression and provided a new target for the treatment and prevention of POP. Firstly, we extracted primary vaginal anterior wall fibroblasts from POP tissues and non-POP tissues and then constructed an EGR2-silencing lentivirus for further study. Immunoblotting, qPCR, TUNEL assay, CCK-8 assay, dual luciferase assay, and ELISA assay were carried out. EGR2 expression was much higher in POP tissues than in control tissues, and EGR2 expression positively correlated with cytokine signaling 3 (SOCS3) expression. Knockdown of EGR2 increased cell proliferation, upregulated PCNA expression, and reduced apoptosis in POP fibroblasts. Moreover, we found that the knockdown of EGR2 increased COL1A1, COL3A1, and Elastin expression and decreased MMP2 and MMP9 activities, and knockdown of EGR2 increased TGF-ß/Smad pathway activity in POP fibroblasts. Interestingly, the results of dual luciferase assay demonstrated that EGR2 was able to increase SOCS3 transcriptional activity. EGR2 knockdown alleviated the apoptosis of POP fibroblasts by reducing SOCS3 expression and improving the proliferation and collagen synthesis of POP fibroblasts. Overall, our study illustrated that EGR2 was highly expressed in POP tissues, and knockdown of EGR2 alleviated apoptosis and reduced matrix degradation in POP fibroblasts. This study might provide a new insight into the pathogenesis of POP.

Lactic acid enhances vaginal epithelial barrier integrity and ameliorates inflammatory effects of dysbiotic short chain fatty acids and HIV-1.

The vaginal microenvironment is key in mediating susceptibility to sexually transmitted infections. A polymicrobial environment with reduced Lactobacilllus spp. is characteristic of vaginal dysbiosis, associated with increased production of several short chain fatty acids (SCFAs), vaginal inflammation and an increased risk of HIV-1 acquisition. In contrast, a eubiotic vaginal microbiome (VMB), dominated by Lactobacillus spp. correlates with increased production of lactic acid (LA), an acidic milieu and protection against HIV-1. Vaginal metabolites, specifically LA and SCFAs including butyric, succinic and acetic acids are associated with modulation of HIV-1 risk. We assessed the impact of combined and individual SCFAs and LA on vaginal epithelial cells (VK2) grown in air-liquid interface cultures. Treatment of VK2 cells with eubiotic SCFA + LA mixture showed increased epithelial barrier integrity, reduced FITC dextran leakage and enhanced expression of cell-cell adhesion proteins. Treatment with dysbiotic SCFA + LA mixture diminished epithelial barrier integrity, increased NFκB activation and inflammatory mediators: TNF-α, IL-6, IL-8 and RANTES. LA was found to be the primary contributor of the beneficial effects. Eubiotic SCFA + LA mixture ameliorated HIV-1 mediated barrier disruption and HIV-1 leakage, whereas dysbiotic SCFA + LA treatment exacerbated HIV-1 effects. These findings indicate a key role for LA in future prophylactic strategies.

Under conditions closely mimicking vaginal fluid, Lactobacillus jensenii strain 62B produces a bacteriocin-like inhibitory substance that targets and eliminates Gardnerella species.

Within the vaginal ecosystem, lactobacilli and Gardnerella spp. likely interact and influence each other's growth, yet the details of this interaction are not clearly defined. Using medium simulating vaginal fluid and a two-chamber co-culturing system to prevent cell-to-cell contact between the bacteria, we examined the possibility that Lactobacillus jensenii 62B (Lj 62B) and/or G. piotii (Gp) JCP8151B produce extracellular factors through which they influence each other's viability. By 24 h post-inoculation (hpi) in the co-culture system and under conditions similar to the vaginal environment - pH 5.0, 37 °C, and 5% CO2, Lj 62B viability was not affected but Gp JCP8151B had been eliminated. Cell-free supernatant harvested from Lj 62B cultures (Lj-CFS) at 20 hpi, but not 16 hpi, also eliminated Gp JCP8151B growth. Neither lactic acid nor H2O2 production by Lj 62B was responsible for this effect. The Lj-CFS did not affect viability of three species of lactobacilli or eight species of Gram-positive and Gram-negative uropathogens but eliminated viability of eight different strains of Gardnerella spp. Activity of the inhibitory factor within Lj-CFS was abolished by protease treatment and reduced by heat treatment suggesting it is most likely a bacteriocin-like protein; fractionation revealed that the factor has a molecular weight within the 10-30 kDa range. These results suggest that, in medium mimicking vaginal fluid and growth conditions similar to the vaginal environment, Lj 62B produces a potential bacteriocin-like inhibitory substance (Lj-BLIS) that clearly targets Gardnerella spp. strains. Once fully characterized, Lj-BLIS may be a potential treatment for Gardnerella-related BV that does not alter the vaginal microflora.

Injectable polyisocyanide hydrogel as healing supplement for connective tissue regeneration in an abdominal wound model.

In pelvic organ prolapse (POP) patients, the uterus, bladder and/or rectum descends into vagina due to weakened support tissues. High recurrence rates after POP surgery suggest an urgent need for improved surgical outcomes. Our aim is to promote connective tissue healing that results in stimulated tissue support functions by surgically applying a hydrogel functionalized with biological cues. We used known vaginal wound healing promoting factors (basic fibroblast growth factor, ß-estradiol, adipose-derived stem cells) in the biomimetic and injectable polyisocyanide (PIC) hydrogel, which in itself induces regenerative vaginal fibroblast behavior. The regenerative capacity of injected PIC hydrogel, and the additional pro-regenerative effects of these bioactive factors was evaluated in abdominal wounds in rabbits. Assessment of connective tissue healing (tensile testing, histology, immunohistochemistry) revealed that injection with all PIC formulations resulted in a statistically significant stiffness and collagen increase over time, in contrast to sham. Histological evaluation indicated new tissue growth with moderate to mild immune activity at the hydrogel - tissue interface. The results suggest that PIC injection in an abdominal wound improves healing towards regaining load-bearing capacity, which encourages us to investigate application of the hydrogel in a more translational vaginal model for POP surgery in sheep.

Cellular and extracellular vaginal changes following murine ovarian removal.

Loss of estrogen as a result of aging, pelvic cancer therapy, genetics, or eating disorders affects numerous body systems including the reproductive tract. Specifically, a chronic hypoestrogenic state fosters debilitating vaginal symptoms like atrophy, dryness, and dyspareunia. Current treatment options, including vaginal estrogen and hyaluronan (HA), anecdotally improve symptoms, but rectifying mechanisms are largely understudied. In order to study the hypoestrogenic vaginal environment, in particular the extracellular matrix (ECM), as well as understand the mechanisms behind current treatments and develop new therapies, we characterized a reliable and reproducible animal model. Bilateral ovariectomies (OVX) were performed on 9-week-old CD1 mice. After 1 month of estrogen loss due to ovarian removal, a phenotype that is similar to human vaginal tissue in an estrogen reduced state was noted in mice compared to sham-operated controls. The uterine to body weight ratio decreased by 80% and vaginal epithelium was significantly thinner in OVX compared to sham mice. Estrogen signaling was altered in OVX, but submucosal ERα localization did not reach statistical differences. HA localization in the submucosal area was altered and CD44 expression decreased in OVX mice. Collagen turn-over was altered following OVX. The inflammation profile was also disrupted, and submucosal vaginal CD45+ and F4/80+ cell populations were significantly reduced in the OVX mice. These results show altered cellular and molecular changes due to reduced estrogen levels. Developing new treatments for hypoestrogenic vaginal symptoms rely on better understanding of not only the cellular changes, but also the altered vaginal ECM environment. Further studies using this mouse model has the potential to advance women's vaginal health treatments and aid in understanding the interplay between organ systems in both healthy, aged, and diseased states.

Advances in mass spectrometry technologies to characterize cervicovaginal microbiome functions that impact spontaneous preterm birth.

Preterm birth (PTB) is a leading cause of morbidity and mortality in young children. Infection is a major cause of this adverse outcome, particularly in PTBs characterised by spontaneous rupture of membranes, referred to as spontaneous (s)PTB. However, the aetiology of sPTB is not well defined and specific bacteria associated with sPTB differ between studies and at the individual level. This may be due to many factors including a lack of understanding of strain-level differences in bacteria that influence how they function and interact with each other and the host. Metaproteomics and metabolomics are mass spectrometry-based methods that enable the collection of detailed microbial and host functional information. Technological advances in this field have dramatically increased the resolution of these approaches, enabling the simultaneous detection of thousands of proteins or metabolites. These data can be used for taxonomic analysis of vaginal bacteria and other microbes, to understand microbiome-host interactions, and identify diagnostic biomarkers or therapeutic targets. Although these methods have been used to assess host proteins and metabolites, few have characterized the microbial compartment in the context of pregnancy. The utilisation of metaproteomic and metabolomic-based approaches has the potential to vastly improve our understanding of the mechanisms leading to sPTB.

Heterogeneity of the group B streptococcal type VII secretion system and influence on colonization of the female genital tract.

Type VIIb secretion systems (T7SSb) in Gram-positive bacteria facilitate physiology, interbacterial competition, and/or virulence via EssC ATPase-driven secretion of small ɑ-helical proteins and toxins. Recently, we characterized T7SSb in group B Streptococcus (GBS), a leading cause of infection in newborns and immunocompromised adults. GBS T7SS comprises four subtypes based on variation in the C-terminus of EssC and the repertoire of downstream effectors; however, the intraspecies diversity of GBS T7SS and impact on GBS-host interactions remains unknown. Bioinformatic analysis indicates that GBS T7SS loci encode subtype-specific putative effectors, which have low interspecies and inter-subtype homology but contain similar domains/motifs and therefore may serve similar functions. We further identify orphaned GBS WXG100 proteins. Functionally, we show that GBS T7SS subtype I and III strains secrete EsxA in vitro and that in subtype I strain CJB111, esxA1 appears to be differentially transcribed from the T7SS operon. Furthermore, we observe subtype-specific effects of GBS T7SS on host colonization, as CJB111 subtype I but not CNCTC 10/84 subtype III T7SS promotes GBS vaginal colonization. Finally, we observe that T7SS subtypes I and II are the predominant subtypes in clinical GBS isolates. This study highlights the potential impact of T7SS heterogeneity on host-GBS interactions.

Quantitative cervicovaginal fetal fibronectin as a predictor of cervical ripening and induced labour duration in late-term pregnancy.

We evaluated quantitative cervicovaginal foetal-fibronectin as a predictor of cervical ripening and labour duration in late-term pregnant women with an unfavourable cervix. This was an analytical cross-sectional study wherein 152 women, with late-term pregnancy and unfavourable cervix, at 41weeks3days gestational age, had pre-induction quantitative cervicovaginal foetal-fibronectin determined using ELISA. Data were compared in nulliparas and multiparas at a significance level < 0.05. The mean age of late-term pregnant women was 30.4 ± 4.3 years. Median cervicovaginal foetal-fibronectin levels in nulliparous and multiparous women were 45.35 ng/ml and 46.93 ng/ml respectively(p = 0.289). The correlation between foetal-fibronectin levels and cervical ripening duration was poor in nulliparous(r = 0.014) and multiparous(r = 0.024) women. The Youden's foetal-fibronectin cut-off level had a sensitivity of 53.5% and specificity of 71.6% in predicting cervical ripening duration of > 12 hours in late-term pregnancy with an area under the ROC curve of 0.634. Quantitative cervicovaginal foetal-fibronectin is a poor correlate and predictor of cervical ripening and induced labour duration in late-term pregnancy.IMPACT STATEMENTWhat is already known on this subject? Cervicovaginal foetal fibronectin is useful in the prediction of preterm delivery but its role in prolonged pregnancy is unclear.What the results of this study add? Cervicovaginal foetal fibronectin is a poor correlate and predictor of cervical ripening and induced labour duration in late-term pregnancyWhat the implications are of these findings for clinical practice and/or further research? Cervicovaginal fibronectin should not be used to predict ease and success of cervical ripening and induction of labour in women with late-term pregnancy.

Molecular Landscape of Pelvic Organ Prolapse Provides Insights into Disease Etiology.

Pelvic organ prolapse (POP) represents a major health care burden in women, but its underlying pathophysiological mechanisms have not been elucidated. We first used a case-control design to perform an exome chip study in 526 women with POP and 960 control women to identify single nucleotide variants (SNVs) associated with the disease. We then integrated the functional interactions between the POP candidate proteins derived from the exome chip study and other POP candidate molecules into a molecular landscape. We found significant associations between POP and SNVs in 54 genes. The proteins encoded by 26 of these genes fit into the molecular landscape, together with 43 other POP candidate molecules. The POP landscape is located in and around epithelial cells and fibroblasts of the urogenital tract and harbors four interacting biological processes-epithelial-mesenchymal transition, immune response, modulation of the extracellular matrix, and fibroblast function-that are regulated by sex hormones and TGFB1. Our findings were corroborated by enrichment analyses of differential gene expression data from an independent POP cohort. Lastly, based on the landscape and using vaginal fibroblasts from women with POP, we predicted and showed that metformin alters gene expression in these fibroblasts in a beneficial direction. In conclusion, our integrated molecular landscape of POP provides insights into the biological processes underlying the disease and clues towards novel treatments.

Neonatal administration of synthetic estrogen, diethylstilbestrol to mice up-regulates inflammatory Cxclchemokines located in the 5qE1 region in the vaginal epithelium.

A synthetic estrogen, diethylstilbestrol (DES), is known to cause adult vaginal carcinoma by neonatal administration of DES to mice. However, the carcinogenic process remains unclear. By Cap Analysis of Gene Expression method, we found that neonatal DES exposure up-regulated inflammatory Cxcl chemokines 2, 3, 5, and 7 located in the 5qE1 region in the vaginal epithelium of mice 70 days after birth. When we examined the gene expressions of these genes much earlier stages, we found that neonatal DES exposure increased these Cxcl chemokine genes expression even after 17 days after birth. It implies the DES-mediated persistent activation of inflammatory genes. Intriguingly, we also detected DES-induced non-coding RNAs from a region approximately 100 kb far from the Cxcl5 gene. The non-coding RNA up-regulation by DES exposure was confirmed on the 17-day vagina and continued throughout life, which may responsible for the activation of Cxcl chemokines located in the same region, 5qE1. This study shows that neonatal administration of DES to mice causes long-lasting up-regulation of inflammatory Cxcl chemokines in the vaginal epithelium. DES-mediated inflammation may be associated with the carcinogenic process.