Prospective observational study investigating the effectiveness, safety, women's experiences and quality of life at 3 months regarding cervical ripening methods for induction of labor at term-The MATUCOL study protocol.

BACKGROUND: The purposes of successful induction of labor (IOL) are to shorten the time for IOL to delivery, increase the vaginal delivery rate, and reduce the rate of maternal and neonatal morbidity. In cases of unfavorable cervix (Bishop score <6), cervical ripening is advised to improve vaginal delivery rate. It may be initiated by mechanical (double balloon catheter (DBC), synthetic osmotic dilator) or pharmacologic (prostaglandins) methods, and the problem is complex due to the multitude of cervical ripening methods. We are constantly looking for the optimal protocol of cervical ripening for each woman. The present study aims to elucidate whether cervical ripening method is associated with increase rate of vaginal delivery, good women's experience and unaltered long-term quality of life after cervical ripening at term regarding maternal and obstetric characteristics. METHODS AND DESIGN: The MATUCOL study is a monocentric, prospective, observational study of all consecutive women who required cervical ripening (Bishop score <6) using different methods (DBC, vaginal dinoprostone, oral misoprostol) with a live fetus at term (≥37 weeks) between January 2020 and August 2021. The outcomes will be mode of delivery, maternal and neonatal morbidity, discomfort/pain assessments during cervical ripening, women's experience and satisfaction, and the impact of cervical ripening on the health-related quality of life at 3 months. If it reports a significant efficacy/safety/perinatal morbidity/women's satisfaction/quality of life at 3 months post-delivery associated with a method of cervical ripening in a specific situation (gestational and/or fetal disease) using a multivariate analysis, its use should be reconsidered in clinical practice. DISCUSSION: This study will reveal that some cervical ripening methods will be more effectiveness, safe, with good women's experiences and QOL at 3 months compared to others regarding maternal and obstetric characteristics. TRIAL REGISTRATION: This study is being performed at La Roche sur Yon Hospital following registration as GNEDS on January 8, 2020.

Relationship of Notch Signal, Surfactant Protein A, and Indomethacin in Cervix During Preterm Birth: Mast Cell and Jagged-2 May Be Key in Understanding Infection-mediated Preterm Birth.

Although it is thought that there is a close relationship between Notch signal and preterm birth, the functioning of this mechanism in the cervix is unknown. The efficacy of surfactants and prostaglandin inhibitors in preterm labor is also still unclear. In this study, 48 female CD-1 mice were distributed to pregnant control (PC), Sham, PBS, indomethacin (2 mg/kg; intraperitoneally), lipopolysaccharides (LPS) (25 µg/100 µl; intrauterine), LPS + IND, and Surfactant Protein A Block (SP-A Block: SP-A B; the anti-SP-A antibody was applied 20 µg/100µl; intrauterine) groups. Tissues were examined by immunohistochemistry, immunofluorescence, and Western blot analysis. LPS administration increased the expression of N1 Dll-1 and Jagged-2 (Jag-2). Although Toll-like receptor (Tlr)-2 significantly increased in the LPS-treated and SP-A-blocked groups, Tlr-4 significantly increased only in the LPS-exposed groups. It was observed that Jag-2 is specifically expressed by mast cells. Overall, this experimental model shows that some protein responses increase throughout the uterus, starting at a specific point on the cervix epithelium. Surfactant Protein A, which we observed to be significantly reduced by LPS, may be associated with the regulation of the epithelial response, especially during preterm delivery due to infection. On the contrary, prostaglandin inhibitors can be considered an option to delay infection-related preterm labor with their dose-dependent effects. Finally, the link between mast cells and Jag-2 could potentially be a control switch for preterm birth.

Labor induction with randomized comparison of cervical, oral and intravaginal misoprostol.

BACKGROUND: This study attempts to evaluate the safety and effectiveness of 50µgm intracervical misoprostol in comparison with intravaginal and sublingual for the induction of labor at term pregnant women. METHODS: This study is designed as a parallel clinical trial study. Three hundred and fifteen term pregnancies requiring induction of labor were treated with the maximum used misoprostol intracervical, sublingual, and vaginal doses. Participants were randomly allocated into three groups of 105. The dose was repeated every 4 h until adequate uterine contraction and Bishop Score were achieved. The duration of induction to births, time to the active phase, the rate of births, and the need for caesarean section were compared in three groups. Additionally, labor course and side effects were recorded and analyzed. Data were analyzed using SPSS software. A significance level of p <  0.05 was considered for statistical analyses. FINDINGS: Labor was successfully induced in all cases most (63%) of which required a single dose of misoprostol. Ninety-three (93.0%, p <  0.05) cervical participants proceeded to vaginal births. This figure was also the same in the vaginal and sublingual group of 83 cases (83.0%). The other 41 cases received caesarean section with more indications of failure to progress and meconium-stained liquor. The results indicated that 278 (92.7%) births were achieved in less than 10 h. Time from start of medication to the active phase of labor and childbirth was 3.01 ± 0.86 and 6.1 ± 1.3 h in the Cervical group, 4.2 ± 0.66 and 8.4 ± 0.92 h in the sublingual group, and 5.06 ± 1.1 and 9.2 ± 1.5 h in the vaginal group respectively (p < 0.001). The Caesarean rate was lower in the cervical group than in the two other groups (p = 0.05). No significant differences were observed between the study groups in terms of Apgar score and meconium-stained amniotic fluid. Furthermore, no maternal and neonatal complications were observed. CONCLUSION: In addition to the sublingual and intravaginal routes of administration, intracervical misoprostol at a single dose of 50µgm appears to be an effective method for induction of labor in women with an unfavorable cervix. Like all medical interventions, a discussion of the risks, benefits, and alternatives to induction of labor with this medication in each woman should be undertaken before treatment. TRIAL REGISTRATION: This clinical study was approved by the Iranian Registry of Clinical Trials with IRCT ID: IRCT20190415043278N1 . Registration date was on May 13, 2019 and May 27, 2019 respectively ( http://www.irct.ir ).

Chloroorganic (DDT) and organophosphate (malathion) insecticides impair the motor function of the bovine cervix.

Dichlorodiphenyltrichloroethane (DDT) is a representative organochlorine insecticide and a known endocrine disruptor. Malathion is an organophosphate insecticide and a next-generation pesticide. Previously, it was shown that oxytocin (OT) and prostaglandins (PGs) are involved in the mechanism of the adverse effect of DDT on bovine myometrial contractions. However, disruption of myometrial contractions without disruption of cervical activity may not be sufficient to cause preterm delivery. Hence, the aim of this study was to determine the effects of insecticides on the function of the bovine cervix at preovulation period. Bovine cervical cells or strips were treated with DDT or malathion (0.1-100 ng/ml), and neither DDT nor malathion (each at a dose of 100 ng/ml) affected the viability of cervical cells. Malathion (0.1-10 ng/ml) and the high doses of DDT (10 ng/ml) decreased the force of cervical contractions, in contrast to a low dose of DDT (0.1 ng/ml). Both insecticides also decreased the mRNA expression of the OT receptor and the level of the second messenger (inositol triphosphate, IP3). Moreover, DDT decreased the amount of other second messengers (diacylglycerol, DAG), while malathion decreased the amount of gap junction protein (GAP). Only malathion increased PGE2 and decreased PGF2α secretion, while neither insecticide had an effect on both prostaglandins synthesis. Both DDT and malathion impaired cervical contractions, secretory function and cellular signalling. It is also possible that malathion-mediated induction of locally produced PGE2 can be followed by cervical softening. Admittedly it was shown that DDT and malathion can evoke failures in the regulation of motor function of cervix during oestrus cycle, while their harmful effect on gestation can be also not excluded.

Total Mesometrial Resection With (Neo)Adjuvant Chemotherapy in Locally Advanced Cervical Cancer: A Tumor Response Score.

BACKGROUND/AIM: There is a lack of data concerning the surgical treatment of locally advanced squamous cell carcinoma of the uterine cervix (LACC) with neoadjuvant and adjuvant chemotherapy (NACT, ACT) as well as total mesometrial resection (TMMR). The aim of the study was to present a novel approach for treating LACC using a tumor response score for NACT. PATIENTS AND METHODS: A total of 12 patients with LACC were treated with NACT [cisplatin, ifosfamide, paclitaxel (TIP)], TMMR and ACT containing TIP. To measure the response during NACT, we scored i) the maximum tumor diameter (maxTD) in gynecological examination, ii) the MRI for radiologic maxTD, iii) the tumor volume and iv) the squamous cell carcinoma antigen before and after two applications of TIP. RESULTS: TIP reduced all score-parameters in 10 of 12 patients (p<0.005). We found a possible reduction of lymph node metastasis in 72.7%. The proposed score detected sufficient and insufficient tumor response. CONCLUSION: TIP followed by TMMR with ACT could be a possibility for patients denying radiochemotherapy. The tumor response score can detect patients with inadequate benefit from NACT.

Cervicovaginal Tissue Residence Confers a Distinct Differentiation Program upon Memory CD8 T Cells.

Tissue-resident memory CD8 T cells (CD8 TRM) are critical for maintaining barrier immunity. CD8 TRM have been mainly studied in the skin, lung and gut, with recent studies suggesting that the signals that control tissue residence and phenotype are highly tissue dependent. We examined the T cell compartment in healthy human cervicovaginal tissue (CVT) and found that most CD8 T cells were granzyme B+ and TCF-1- To address if this phenotype is driven by CVT tissue residence, we used a mouse model to control for environmental factors. Using localized and systemic infection models, we found that CD8 TRM in the mouse CVT gradually acquired a granzyme B+, TCF-1- phenotype as seen in human CVT. In contrast to CD8 TRM in the gut, these CD8 TRM were not stably maintained regardless of the initial infection route, which led to reductions in local immunity. Our data show that residence in the CVT is sufficient to progressively shape the size and function of its CD8 TRM compartment.

Progesterone alters human cervical epithelial and stromal cell transition and migration: Implications in cervical remodeling during pregnancy and parturition.

The cervix undergoes extensive remodeling throughout pregnancy and parturition. This process involves both ECM collagen degradation and cellular remodeling, which includes cell proliferation, transition and migration. Progesterone (P4) has been used clinically to delay cervical ripening and prevent preterm birth (PTB). However, the mechanisms by which progesterone affects cell transition and the migration of cervical epithelial and stromal cells are not yet fully known. In this study, we documented the role of a gestational level of P4 in the cellular transition (epithelial-mesenchymal transition [EMT] and mesenchymal-epithelial transition [MET]), cell migration, and inflammatory responses of endocervical epithelial cells (EEC) and cervical stromal cells (CSC). EEC and CSC were treated with LPS and P4 for 6 days. The epithelial:mesenchymal ratio (regular microscopy and cell shape index analysis), shift in intermediate filaments (immunofluorescence microscopy and western blot analyses for cytokeratin [CK]-18 and vimentin), adhesion molecules and transcription factors (western blot analyses for E-cadherin, N-cadherin and SNAIL), were used to determine growth characteristics and EMT and MET changes in EEC and CSC under the indicated conditions. To test cell remodeling, scratch assays followed by cellular analyses as mentioned above were performed. Inflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor α [TNFα]) and matrix metallopeptidase 9 (MMP9) were measured by ELISA. LPS promoted EMT (decreased cell shape index, decreased CK-18 and E-cadherin, increased vimentin, N-cadherin, and SNAIL), and increased IL-6 and MMP9 production by EEC. A gestational level of P4 prevented LPS-induced EMT in EEC and exhibited anti-inflammatory effect in both EEC and CSC. LPS slowed down wound healing in CSC but P4 treatment prevented the negative impact of LPS in CSC wound healing. These results may explain the cellular mechanisms by which P4 helps to stabilize the cervical epithelial barrier and preserve the mechanical and tensile strength of the cervical stromal layer, which are important in normal cervical remodeling processes during pregnancy.

Should the interval between doses of antenatal corticosteroids be shortened in certain cases? Factors predicting preterm delivery < 48 h from presentation.

PURPOSE: Treatment with antenatal corticosteroids (ACS) to women at risk for preterm birth (PTB) is associated with a reduction in adverse neonatal outcomes. Obstetricians occasionally shorten the interval between the doses of steroids if delivery is predicted to occur before ACS are fully administered. In this study, we aimed to investigate predicting factors to identify patients that will deliver prematurely, less than 48 h from presentation. METHODS: The computerized medical files of all PTBs (< 34 weeks) were reviewed. Maternal demographics, pregnancy and delivery characteristics were compared between PTB that occurred < 48 h vs. > 48 h from triage presentation. RESULTS: In total, 494 PTB cases were included: 302 women in the study group (PTB < 48 h) and 192 women in the control group (PTB > 48 h). No significant differences were found in demographic characteristics between the groups. At presentation, the study group had higher rates of uterine contractions (p < 0.001) and cervical length < 25 mm (p < 0.001) as well as a higher rate of non-reassuring fetal (NRFHR) monitor (p < 0.001). In contrast, the control group presented with higher rates of preeclampsia (p = 0.003) and preterm premature rupture of membranes (p = 0.038). In multivariable analysis, all of the above factors remained significant after controlling for background confounders. CONCLUSIONS: Various factors at presentation can predict delivery < 48 h. These factors can be used to predict patients to whom the ACS interval should be shortened. Future prospective studies should investigate the effect of this shortening on neonatal outcomes.

Oxidative stress promotes cellular damages in the cervix: implications for normal and pathologic cervical function in human pregnancy†.

A physiologic increase in reactive oxygen species throughout pregnancy is required to remodel the cervix. Oxidative stress can cause cellular damage that contributes to dysfunctional tissue. This study determined the oxidative stress-induced cell fate of human cervical epithelial and cervical stromal cells. We treated the ectocervical and endocervical epithelial cells and cervical stromal cells with cigarette smoke extract, an oxidative stress inducer, for 48 h. Cell viability (crystal violet assay); cell cycle, apoptosis, and necrosis (flow cytometry); senescence (senescence-associated ß-galactosidase staining); autophagy (staining for autophagosome protein, microtubule-associated protein 1 light chain 3B); stress signaler p38 mitogen-activated protein kinases pathway activation (western blot analyses); and inflammation by measuring interleukin-6 (enzyme-linked immunosorbent assay) were conducted after 48 h of cigarette smoke extract treatment. Oxidative stress induced reactive oxygen species production in cervical cells, which was inhibited by N-acetylcysteine. Oxidative stress promoted cell cycle arrest and induced necrosis in cervical cells. High senescence and low autophagy were observed in cervical stromal cells under oxidative stress. Conversely, senescence was low and autophagy was high in endocervical epithelial cells. Oxidative stress induced p38 mitogen-activated protein kinases (p38MAPK) activation in all cervical cells but only increased interleukin-6 production by the ectocervical epithelial cells. Inhibition of interleukin-6 production by a p38 mitogen-activated protein kinases inhibitor confirmed the activation of an oxidative stress-induced pathway. In conclusion, oxidative stress can promote cell death and sterile inflammation that is mediated by p38 mitogen-activated protein kinases activation in the cellular components of the cervix. These cellular damages may contribute to the normal and premature cervical ripening, which can promote preterm birth.

Human Chorionic Gonadotropin Modulates the Transcriptome of the Myometrium and Cervix in Late Gestation.

Human chorionic gonadotropin (hCG) is a critical hormone for the establishment and maintenance of pregnancy. hCG administration prevents the onset of preterm labor in mice; yet, the transcriptomic changes associated with this tocolytic effect that take place in the myometrium and cervix have not been elucidated. Herein, we implemented both discovery and targeted approaches to investigate the transcriptome of the myometrium and cervix after hCG administration. Pregnant mice were intraperitoneally injected with 10 IU of hCG on 13.0, 15.0, and 17.0 days post coitum, and the myometrium and cervix were collected. RNA sequencing was performed to determine differentially expressed genes, enriched biological processes, and impacted KEGG pathways. Multiplex qRT-PCR was performed to investigate the expression of targeted contractility- and inflammation-associated transcripts. hCG administration caused the differential expression of 720 genes in the myometrium. Among the downregulated genes, enriched biological processes were primarily associated with regulation of transcription. hCG administration downregulated key contractility genes, Gja1 and Oxtr, but upregulated the prostaglandin-related genes Ptgfr and Ptgs2 and altered the expression of inflammation-related genes in the myometrium. In the cervix, hCG administration caused differential expression of 3348 genes that were related to inflammation and host defense, among others. The downregulation of key contractility genes and upregulation of prostaglandin-related genes were also observed in the cervix. Thus, hCG exerts tocolytic and immunomodulatory effects in late gestation by altering biological processes in the myometrium and cervix, which should be taken into account when considering hCG as a potential treatment to prevent the premature onset of labor.

Preformulation Characterization of Griffithsin, a Biopharmaceutical Candidate for HIV Prevention.

Griffithsin (GRFT) has shown potent anti-HIV activity, and it is being developed as a drug candidate for HIV prevention. Successful implementation requires thorough understanding of its preformulation characterization. In this work, preformulation assessments were conducted to characterize GRFT and identify its degradation pathways under selected conditions of temperature, light, pH, shear, ionic strength, and oxidation. Compatibility with vaginal fluid simulant, vaginal enzymes, Lactobacillus spp., and human cervicovaginal secretions was assessed. The purity, melting temperature, and HIV gp120-binding affinity of GRFT stored at 4°C and 25°C in phosphate-buffered saline (PBS) were assessed for 2 years. Chemical modifications were evaluated by intact mass analysis and peptide sequencing. Excised human ectocervical tissue permeability and localization of GRFT were evaluated. Our results demonstrated GRFT to be safe and stable under all the preformulation assessment conditions studied except oxidative stress. When GRFT was exposed to hydrogen peroxide or human cervicovaginal secretion, methionine 78 in the protein sequence underwent oxidation. GRFT did not permeate through human cervical tissue but adhered to the superficial epithelial tissue. The 2-year stability study revealed no significant change in GRFT's aggregation, degradation, melting temperature, or gp120-binding affinity despite a slow increase in oxidation over time. These studies elucidated desirable safety and bioactivity profile for GRFT, showing promise as a potential drug candidate for HIV prevention. However, susceptibility to oxidative degradation was identified. Effective protection of GRFT from oxidation is required for further development.

Supplementation of a combination of herbs improves immunity, uterine cleansing and facilitate early resumption of ovarian cyclicity: A study on post-partum dairy buffaloes.

ETHNOPHARMACOLOGICAL RELEVANCE: A combination of Trachyspermum ammi L., Curcuma longa L., Cuminum cyminum L., Trigonella foenum-graecum L., Foeniculum vulgare Mill., Anethum graveolens L and Zingiber officinale Roscoe is used as immunity booster and reproductive efficiency enhancing agents in folklore medicine. AIM OF THE STUDY: The present study aimed to assess the immunomodulatory, uterine cleansing and reproduction enhancing effects of polyherbal mixture in post-partum buffaloes. MATERIALS AND METHODS: Enzyme linked immunosorbent assay (ELISA) was used to investigate the effects of polyherbal mixture feeding on for quantification of neutrophil functions and blood progesterone hormone estimation. Ultrasonography was used to assess the status of uterine involution, fluid in uterus and ovarian follicular status. Quantitative real time PCR (qRT-PCR) was used to measure the expression of chemokine genes CXCR1, CXCR2 AND IL-8. Artificial insemination with cryopreserved semen was used to breed the animals. Reproductive efficiency parameters were assessed using standard calculation methods. RESULTS: Neutrophil functions and transcriptional abundance of chemokine genes were significantly (P < 0.05) higher in buffaloes supplemented with polyherbal mixture compared to buffaloes in control group. The rate of cervical and uterine involution was significantly (P < 0.05) higher in treatment group compared to control group. The service period was shorter, days to first insemination was earlier and the number of services per conception was lower in buffaloes supplemented with polyherbal mixture compared to the buffaloes in control group. The proportion of buffaloes with large ovarian follicles within 28 days of post-partum was also significantly (P < 0.05) higher in treatment group compared to the control group. CONCLUSIONS: The polyherbal mixture used in the study improved the immunity of the buffaloes, facilitated early involution of cervix and uterus, efficient cleansing of lochia and improved subsequent fertility. It has the potential to be used in dairy animals for improving post-partum reproductive efficiency.

Optimisation and evaluation of the random forest model in the efficacy prediction of chemoradiotherapy for advanced cervical cancer based on radiomics signature from high-resolution T2 weighted images.

PURPOSE: Our objective was to establish a random forest model and to evaluate its predictive capability of the treatment effect of neoadjuvant chemotherapy-radiation therapy. METHODS: This retrospective study included 82 patients with locally advanced cervical cancer who underwent scanning from March 2013 to May 2018. The random forest model was established and optimised based on the open source toolkit scikit-learn. Byoptimising of the number of decision trees in the random forest, the criteria for selecting the final partition index and the minimum number of samples partitioned by each node, the performance of random forest in the prediction of the treatment effect of neoadjuvant chemotherapy-radiation therapy on advanced cervical cancer (> IIb) was evaluated. RESULTS: The number of decision trees in the random forests influenced the model performance. When the number of decision trees was set to 10, 25, 40, 55, 70, 85 and 100, the performance of random forest model exhibited an increasing trend first and then a decreasing one. The criteria for the selection of final partition index showed significant effects on the generation of decision trees. The Gini index demonstrated a better effect compared with information gain index. The area under the receiver operating curve for Gini index attained a value of 0.917. CONCLUSION: The random forest model showed potential in predicting the treatment effect of neoadjuvant chemotherapy-radiation therapy based on high-resolution T2WIs for advanced cervical cancer (> IIb).

Effects of progesterone on the lipolysis of lipid droplets and prostaglandin E2 synthesis in murine cervical epithelial cells.

Previous studies demonstrated that progesterone (P4) can promote prostaglandin (PG) E2 production; however, how P4 mediates the synthesis of PGE2 remains unclear. In this study, cervical epithelial cells from mice during the follicular phase were cultured invitro and treated with different concentrations of P4 (5, 10, and 20nM). The results of the present study suggest that treatment of murine cervical epithelial cells with 10nM P4 for 24h contributed to: (1) significantly increased expression of protein kinase A (PKA), cytosolic phospholipase A2 (cPLA2) and PGE synthase (PGES)-1; (2) higher phosphorylated (p-) to total extracellular signal-regulated kinase (ERK) 1/2 and hormone-sensitive lipase (HSL) ratios; (3) a significant decrease in the number of lipid droplets (LDs) and fatty acid content within LDs in epithelial cells; and (4) enhanced arachidonic acid and PGE2 levels in cells compared with the control (0nM P4) group (P<0.01 for all findings). In contrast, the PKA inhibitor H89 contributed to significantly decreased cPLA2, PGES-1 and HSL expression, ERK1/2 phosphorylation and arachidonic acid and PGE2 levels, even in the presence of P4. These data show that P4 can act via the PKA/ERK1/2 pathway to stimulate lipolysis of triacylglycerol in the LD core and degradation of phospholipid in the LD membrane to promote PGE2 synthesis in murine cervical epithelial cells.

Heparin fragments induce cervical inflammation by recruiting immune cells through Toll-like receptor 4 in nonpregnant mice.

Inflammation is a hallmark in the human cervix remodelling. A possible candidate inducing the inflammatory driven ripening of the cervix is the matrix component heparan sulphate, which has been shown to be elevated in late pregnancy in the cervix and uterus. Heparin and a glycol-split low molecular weight heparin (gsHep) with low anticoagulant potency has been shown to enhance myometrial contraction and interleukin (IL)-8 production by cervical fibroblasts. The aim of this study was to investigate the mechanism by which heparin promotes cervical inflammation. Wild-type, Toll-like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88) and Interferon regulatory factor 3 (IRF3)-deficient mice were treated by deposition of gsHep into the vaginas of nonpregnant mice. To identify which cells that responded to the heparin fragments, a rhodamine fluorescent construct of gsHep was used, which initially did bind to the epithelial cells and were at later time points located in the sub-mucosa. The heparin fragments induced a strong local inflammatory response in wild-type mice shown by a rapid infiltration of neutrophils and to a lesser extent macrophages into the epithelium and the underlying extracellular matrix of the cervix. Further, a marked migration into the cervical and vaginal lumen was seen by both neutrophils and macrophages. The induced mucosal inflammation was strongly reduced in TLR4- and IRF3-deficient mice. In conclusion, our findings suggest that a TLR4/IRF3-mediated innate immune response in the cervical mucosa is induced by gsHep. This low anticoagulant heparin version, a novel TLR4 agonist, could contribute to human cervical ripening during the initiation of labour.

The intervention effect of nicotine on cervical fibroblast-myofibroblast differentiation in lipopolysaccharide-induced preterm birth model through activating the TGF-ß1/Smad3 pathway.

Currently, the clinical treatment of preterm birth, mainly using uterine contraction inhibitors, does not fundamentally reduce the incidence of premature birth (PTB). Premature cervical ripening is an important factor in PTB. We previously found that nicotine-treated pregnant murine had significant cervical resistance to stretch and higher collagen cross-links compared to the control animals, and nicotine prolonged gestation and inhibited cervical ripening. However, the regulatory effects of nicotine on premature cervical ripening and its role in PTB remain unclear. To investigate the effects of nicotine on cervical TGF-ß1/Smad3 pathway and fibroblast-myofibroblast differentiation regulated by this pathway in PTB-like models. Intraperitoneal injection with 15 µg lipopolysaccharide (LPS) in 200 µl PBS into pregnant mice was used to induce the PTB-like model. Mice were randomly divided into four groups: control group, LPS-treated group, LPS + Nicotine co-treated group and LPS + Nicotine+α-BGT co-treated group. Pregnancy outcomes were monitored. The collagen content was assessed by Picrosirius red staining. Expressions of genes and proteins in the TGF-ß/Smad3 pathway were detected by double immunofluorescence staining and quantitative Real-time PCR (qRT-PCR). myofibroblast differentiation were investigated by double immunofluorescence staining and qRT-PCR. Ultrastructures were analyzed by conventional transmission electron microscopy. The rate of PTB and neonatal mortality at birth was significantly higher in the LPS-treated group than in the control group; collagen content also decreased remarkably; the expression of TGF-ß1 in macrophages and p-Smad3 in fibroblasts were reduced; the expression of α-smooth muscle actin (α-SMA, markers for activated fibroblasts) was down-regulated while the expression of calponin and smoothelin (markers for fibroblasts at rest) was up-regulated. Nicotine improved pregnancy outcomes and inhibited collagen degradation, activated the TGF-ß1/Smad3 pathway and promoted cervical fibroblast-myofibroblast differentiation in PTB-like mice; such effects could be reversed by α-bungarotoxin (α-BGT). Nicotine inhibited premature cervical ripening in PTB-like models in relation with up-regulating the TGF-ß/Smad3 pathway and promoting fibroblast to differentiate into myofibroblasts.

Volume computed tomography perfusion as a predictive marker for treatment response to concurrent chemoradiotherapy in cervical cancer: a prospective study.

BACKGROUND: Computed tomography perfusion (CTP) can provide information on blood perfusion as a reliable marker of tumor response to therapy. PURPOSE: To assess the role of volume CTP (vCTP) parameters in predicting treatment response to concurrent chemoradiotherapy (CCRT) for cervical cancer. MATERIAL AND METHODS: Thirty-three patients with cervical cancer underwent vCTP. Three CTP parameters of cervical cancer-including arterial flow (AF), blood volume (BV), and permeability surface (PS)-were measured in two different ways: the region of interest incorporating the "local hot" with the highest enhancement and "cold spot" with the lowest enhancement; and "whole-tumor" measurements. The patients were divided into non-residual and residual tumor groups according to the short-term response to treatment. The clinical and perfusion parameters were compared between the two groups. RESULTS: There was no significant difference in age, body mass index, FIGO stage, pathological grade, or pretreatment tumor size between the two groups (P > 0.05). The non-residual tumor group had higher pretreatment AF in high-perfusion and low-perfusion subregions than the residual tumor group (P <0.05), but the AF in whole-tumor regions was not different between the two groups (P > 0.05). There were no differences in BV and PS between the two groups (P > 0.05). The diagnostic potency of AF in the low-perfusion subregion was higher than that in the high-perfusion subregion. CONCLUSION: vCTP parameters are valuable for the prediction of short-term effects. The AF in the low-perfusion subregion was a more effective index for predicting treatment response to CCRT of cervical cancer.

Local α1-adrenergic blockers: An alternative for sheep cervix dilation?

To facilitate transcervical artificial insemination in sheep, the effects of local treatment with α1-adrenergic receptor antagonists on cervix dilation and hemodynamics were evaluated. Ewes (n = 7) were subjected to oestrous synchronisation every 40 days and assigned to treatments in a Latin square experimental design (seven animals × seven periods) with a factorial treatment arrangement (A × B), Factors A (prazosin or tamsulosin) and B (1, 2, or 4 mg/animal). Ewes of the six treatment groups (P1, P2, P4, T1, T2, and T4) were administered α1-adrenergic receptor antagonists while those of the control group (CG) were administered only α1-adrenergic antagonist carrier agent. Distance that the transcervical catheter penetrated without cervical resistance, mean arterial pressure, and uterine artery dopplerfluxometry were evaluated before and after 30 min, 1, 2, 4, 8, and 10 h of treatment. Catheter penetration distance was greater in ewes of the T4 and P4 groups (P < 0.01), with there being a positive correlation between dose and distance (r = 0.243). The penetration distance was similar (P = 0.84) for treated groups, with the greatest penetration occurring 2, 4, and 6 h after treatment (P < 0.01). The passage into the uterine lumen was greater (P = 0.013) in ewes of the P4 (17.9 %) and T4 (19.6 %) groups. There were no effects on blood pressure or uterine blood flow (P> 0.05). These preliminary results indicate there are benefits of treatment with 4 mg/animal of tamsulosin or prazosin in catheter passage through the sheep cervix 2-6 h after administration without hemodynamic effects.

Foley Bulb Added to an Oral Misoprostol Induction Protocol: A Cluster Randomized Trial.

OBJECTIVE: To evaluate whether the induction of labor in term gravid women with cervical dilation 2 cm or less and intact membranes by using oral misoprostol preceded by transcervical Foley bulb placement results in a significantly increased vaginal delivery rate compared with the use of oral misoprostol alone. METHODS: We randomized the induction method by week of admission to labor and delivery, with each week group described as a cluster in a block randomized design. Women with gestational age of 37 weeks or greater, cervical dilation 2 cm or less, intact membranes, and indication for labor induction were included. Study arms were either 100 micrograms of oral misoprostol after transcervical Foley bulb placement or 100 micrograms of oral misoprostol alone. The primary outcome was vaginal delivery with the first induction attempt. Secondary outcomes included time to delivery, clinical chorioamnionitis (maternal temperature of 38°C or greater during labor with or without fundal tenderness, without other identified cause), cesarean delivery indication, and adverse outcomes. We estimated that a sample size of 1,077 per arm was needed to detect a 5% increase in vaginal delivery rate with a type I error of 5% and power of 80%, accounting for interim analysis and cluster size of 30 inductions per week. This was a pragmatic trial, and analysis was by intention-to-treat. RESULTS: From January 1, 2018, to May 13, 2019, 1,117 women (34 clusters) were assigned to oral misoprostol plus Foley and 1,110 women (34 clusters) to oral misoprostol alone. Demographic characteristics were similar. Vaginal delivery at the first induction occurred in 78% of the misoprostol plus Foley arm and in 77% of the misoprostol arm (relative risk [RR] 1.00; 95% CI 0.96-1.05; adjusted relative risk [aRR], 1.00; 95% CI 0.95-1.05). Clinical chorioamnionitis occurred in 18% of the misoprostol plus Foley arm and in 14% of the misoprostol arm (RR 1.30; 95% CI 1.07-1.58; aRR 1.30; 95% CI 1.08-1.56). There were no differences in neonatal outcomes. CONCLUSION: Induction of labor in gravid women at term with intact membranes by using oral misoprostol plus Foley bulb did not result in a higher vaginal delivery rate, but it did result in more clinical chorioamnionitis compared with the use of oral misoprostol alone. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03407625.

Cervico-Vaginal Inflammatory Cytokine and Chemokine Responses to Two Different SIV Immunogens.

Studies have shown that vaccine vectors and route of immunization can differentially activate different arms of the immune system. However, the effects of different HIV vaccine immunogens on mucosal inflammation have not yet been studied. Because mucosal sites are the primary route of HIV infection, we evaluated the cervico-vaginal inflammatory cytokine and chemokine levels of Mauritian cynomolgus macaques following immunization and boost using two different SIV vaccine immunogens. The PCS vaccine delivers 12 20-amino acid peptides overlapping the 12 protease cleavage sites, and the Gag/Env vaccine delivers the full Gag and full Env proteins of simian immunodeficiency virus. We showed that the PCS vaccine prime and boosts induced short-lived, lower level increases of a few pro-inflammatory/chemotactic cytokines. In the PCS-vaccine group only the levels of MCP-1 were significantly increased above the baseline (P = 0.0078, Week 6; P = 0.0078, Week 17; P = 0.0234; Week 51) following multiple boosts. In contrast, immunizations with the Gag/Env vaccine persistently increased the levels of multiple cytokines/chemokines. In the Gag/Env group, higher than baseline levels were consistently observed for IL-8 (P = 0.0078, Week 16; P = 0.0078, Week 17; P = 0.0156, Week 52), IL-1ß (P = 0.0234, Week 16; P = 0.0156, Week 17; P = 0.0156, Week 52), and MIP-1α (P = 0.0313, Week 16; P = 0.0156, Week 17; P = 0.0313, Week 52). Over time, repeated boosts altered the relative levels of these cytokines between the Gag/Env and PCS vaccine group. 18 weeks after final boost with a higher dosage, IP-10 levels (P = 0.0313) in the Gag/Env group remained higher than baseline. Thus, the influence of vaccine immunogens on mucosal inflammation needs to be considered when developing and evaluating candidate HIV vaccines.