Effect of autologous bone marrow stem cells-scaffold transplantation on the ongoing pregnancy rate in intrauterine adhesion women: a randomized, controlled trial.

Intrauterine adhesion is a major cause of female reproductive disorders. Although we and others uncontrolled pilot studies showed that treatment with autologous bone marrow stem cells made a few patients with severe intrauterine adhesion obtain live birth, no large sample randomized controlled studies on this therapeutic strategy in such patients have been reported so far. To verify if the therapy of autologous bone marrow stem cells-scaffold is superior to traditional treatment in moderate to severe intrauterine adhesion patients in increasing their ongoing pregnancy rate, we conducted this randomized controlled clinical trial. Totally 195 participants with moderate to severe intrauterine adhesion were screened and 152 of them were randomly assigned in a 1:1 ratio to either group with autologous bone marrow stem cells-scaffold plus Foley balloon catheter or group with only Foley balloon catheter (control group) from February 2016 to January 2020. The per-protocol analysis included 140 participants: 72 in bone marrow stem cells-scaffold group and 68 in control group. The ongoing pregnancy occurred in 45/72 (62.5%) participants in the bone marrow stem cells-scaffold group which was significantly higher than that in the control group (28/68, 41.2%) (RR=1.52, 95%CI 1.08-2.12, P=0.012). The situation was similar in live birth rate (bone marrow stem cells-scaffold group 56.9% (41/72) vs. control group 38.2% (26/68), RR=1.49, 95%CI 1.04-2.14, P=0.027). Compared with control group, participants in bone marrow stem cells-scaffold group showed more menstrual blood volume in the 3rd and 6th cycles and maximal endometrial thickness in the 6th cycle after hysteroscopic adhesiolysis. The incidence of mild placenta accrete was increased in bone marrow stem cells-scaffold group and no severe adverse effects were observed. In conclusion, transplantation of bone marrow stem cells-scaffold into uterine cavities of the participants with moderate to severe intrauterine adhesion increased their ongoing pregnancy and live birth rates, and this therapy was relatively safe.

Analytical model for organic contaminant transport in a cut-off wall and aquifer dual-domain system considering barrier arrangements.

This paper presents an analytical study of organic contaminants transport in a cut-off wall and aquifer dual-domain system, considering the effects of the inlet boundary conditions and cut-off structural arrangements. The comprehensive sensitivity analysis of parameters focusing on the breakthrough time, attenuation time and cumulative concentration are presented using the Monte Carlo simulation and Sobol global method. The simplified constant inlet boundary condition can lead to an excessively conservative prediction of the contaminant breakthrough compared to the 'finite mass' and 'decaying source' boundary conditions. The cut-off wall hydraulic performance can be enhanced by reducing the contaminant's head loss, shape factor, half-life and cut-off wall hydraulic conductivity while increasing the retardation factor. The contaminant's half-life can largely influence the maximum contaminant concentration, attenuation time and breakthrough time. For example, the maximum contaminant concentrations for T1/2 = 1.4 years and T1/2 = 100 years are 13 and 123 times greater than that for T1/2 = 0.1 year, respectively. The influence of the variation of shape factor on the breakthrough curve should be taken into consideration. Altering the structural arrangement of the cut-off wall to accommodate a smaller shape factor increases the contaminant breakthrough time. The proposed solution allows the analysis of a cut-off wall and aquifer system with different inlet boundary conditions and structural arrangements of the cut-off wall.

Numerical simulation of different pollutant control measures around an old landfill contaminated site: A field scale study.

The remediation of contaminated soils is a great challenge for global environmental sciences and engineering. The landfill was a kind of infrastructure to deal with waste from different sources while it would also cause the threat to groundwater. Cut-off walls and pumping wells were usually applied in the landfill to prevent the spread of pollutants to wider areas. However, the combination of using both of methods was rarely analyzed, especially using field data for calibrating and fitting groundwater flow and pollutant transport. 7 monitoring wells were arranged in the study area to survey the subsurface seepage. The pollution monitoring was carried out for a period of 50 days, covering 31 types of inorganic and organic pollutants. The concentration of 2,4,6-trichlorophenol (TCP) was 556.7 times greater than the standard concentration. A coupled numerical model of groundwater flow and pollutant transport was developed to assess the effectiveness of various control methods. Three options were tested, including the implementation of a single cut-off wall as well as a combination of a cut-off wall and a pumping well, for preventing the discharge of pollutants from landfills. The combination of a cut-off wall and a pumping well is the best strategy for removal of TCP. The combination approaches lead to a reduction of pollution plumes by a factor of 11 compared to the case without pollution control measures. The research findings may provide a basis and reference for the application of cutoff walls and pumping well in landfill sites or contaminated groundwater.

Construction of a Glycolysis-related long noncoding RNA signature for predicting survival in endometrial cancer.

Background: long noncoding RNA (lncRNA) has been widely studied and understood in various cancer types. However, the expression profiles of glycolysis-related lncRNA in endometrial cancer (EC) have poorly been reported. Methods: In this study, we retrieved the "Glycolysis" gene list from Molecular Signatures Database (MSigDB) and screened prognostic glycolysis-related lncRNA using The Cancer Genome Atlas (TCGA) Uterine Corpus Endometrial Carcinoma (UCEC) RNA-seq dataset. Then, TCGA UCEC patients were randomly divided. Lasso algorithm and multivariate cox regression analyses were then performed to further select hub prognostic lncRNA and to develop a prognostic signature. The efficacy of the signature was also evaluated in the TCGA EC cohort. Moreover, we constructed a nomogram to predict EC patient outcomes. Results: Univariate cox analysis identified thirty-six glycolysis-related lncRNA correlated with EC patient prognosis. Among them, five lncRNA were further selected as hub lncRNA that mostly relate to EC patient outcomes, which are AL121906.2, BOLA3-AS1, LINC01833, AC016405.3, and RAB11B-AS1. A prognostic signature was then built based on the expression and coefficiency of five lncRNA. The efficacy of the signature was validated in part of and the entire TCGA EC cohort. In addition, the risk signature could precisely distinguish high- and low-risk EC patients and predict patient outcomes. The nomogram exhibited absolute concordance between the predictions and actual survival observations. Conclusions: The glycolysis-related lncRNA signature model and the nomogram may provide a new perspective for EC patients outcome prediction in clinical use.

MTA1, a Target of Resveratrol, Promotes Epithelial-Mesenchymal Transition of Endometriosis via ZEB2.

Endometriosis is a benign disease that shares some malignant features. Epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of endometriosis. Metastasis-associated protein 1 (MTA1) plays an important role in various cancers by promoting EMT, yet there are no studies on its function in endometriosis. In the present study, we found that MTA1 was highly expressed in the ectopic endometrium of endometriosis patients and that the expression of MTA1 was related to the revised American Fertility Society stage. MTA1 facilitated endometrial stroma cell proliferation, migration, and invasion by inducing EMT, and the promotion function and MTA1 expression were suppressed by resveratrol, a natural polyphenol. Moreover, we revealed that MTA1 induced EMT through interaction with ZEB2. The findings in a mouse endometriosis model further showed that MTA1 and ZEB2 were upregulated in ectopic tissues and that resveratrol inhibited the growth of ectopic lesions and expression of MTA1 and ZEB2. Taken together, we demonstrate that MTA1 is a protein that promotes EMT via interacting with ZEB2 in the pathogenesis of endometriosis, and may be a target of resveratrol.

Metastasis-associated protein 1, modulated by miR-30c, promotes endometrial cancer progression through AKT/mTOR/4E-BP1 pathway.

OBJECTIVE: Though metastasis-associated protein 1 (MTA1) is widely overexpressed in human cancers and is associated with advanced clinicopathological characteristics and survival in related diseases, the association between MTA1 and endometrial cancer (EC) is little known and needs to be studied. METHODS: Western blot and immunohistochemistry were used to analyze protein expression level of cells and tissues, while real-time PCR was used for RNA detection. Bioinformatics tool analysis revealed the relationship between MTA1 and clinicopathological characteristics and survival. CCK-8 assay, colony-formation assay, cell scratch assay, and Transwell assay were performed to determine cell proliferation, migration and invasion abilities, respectively. RESULTS: The expression level of MTA1 was significantly higher in human EC tissues than in normal endometrium. MTA1 expression was correlated positively with lymph nodes metastasis and poor survival rate in EC. Experimentally overexpressed MTA1 could promote cell proliferation, migration and invasion abilities of EC cell lines Ishikawa, HEC-1B, and RL-952, while reduction of MTA1 inhibited these cell biological behaviors. Moreover, MTA1 could also reverse the negative effect of miR-30c, a direct modulator of MTA1, on EC cells. Our research also revealed that overexpression of MTA1 contributed to EC tumor growth, while knockdown of MTA1 resulted in tumor growth inhibition. Additionally, the phosphorylation levels of mTOR (S2448) and 4E-BP1 (T37/46) changed significantly along with AKT (T308) under regulation of MTA1, both in vivo and vitro. CONCLUSION: Our results showed that MTA1, as a downstream target of miR-30c, might promote EC progression via AKT/mTOR/4E-BP1 pathway, which indicated the potential therapy target of MTA1 in EC.

Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: a phase I clinical trial.

BACKGROUND: Intrauterine adhesions (IUA) are the most common cause of uterine infertility and are caused by endometrium fibrotic regeneration following severe damage to the endometrium. Although current stem cell treatment options using different types of autologous stem cells have exhibited some beneficial outcomes in IUA patients, the reported drawbacks include variable therapeutic efficacies, invasiveness and treatment unavailability. Therefore, the development of new therapeutic stem cell treatments is critical to improving clinical outcomes. METHODS: Twenty-six patients who suffered from infertility caused by recurrent IUA were enrolled in this prospective, non-controlled, phase I clinical trial with a 30-month follow-up. During the procedure, 1 × 107 umbilical cord-derived mesenchymal stromal cells (UC-MSCs), loaded onto a collagen scaffold, were transplanted into the uterine cavity following an adhesion separation procedure. Medical history, physical examination, endometrial thickness, intrauterine adhesion score and the biological molecules related to endometrial proliferation and differentiation were assessed both before and 3 months after cell therapy. RESULTS: No treatment-related serious adverse events were found. Three months after the operation, the average maximum endometrial thickness in patients increased, and the intrauterine adhesion score decreased compared to those before the treatment. A histological study showed the upregulation of ERα (estrogen receptor α), vimentin, Ki67 and vWF (von Willebrand factor) expression levels and the downregulation of ΔNP63 expression level, which indicates an improvement in endometrial proliferation, differentiation and neovascularization following treatment. DNA short tandem repeat (STR) analysis showed that the regenerated endometrium contained patient DNA only. By the end of the 30-month follow-up period, ten of the 26 patients had become pregnant, and eight of them had delivered live babies with no obvious birth defects and without placental complications, one patient in the third trimester of pregnancy, and one had a spontaneous abortion at 7 weeks. CONCLUSIONS: Transplanting clinical-grade UC-MSCs loaded onto a degradable collagen scaffold into the uterine cavity of patients with recurrent IUA following adhesiolysis surgery is a safety and effective therapeutic method. TRIAL REGISTRATION: Clinicaltrials.gov . NCT02313415 , Registered December 6, 2014.

Management and obstetric outcomes of 17 heterotopic interstitial pregnancies.

BACKGROUND: Heterotopic interstitial pregnancy is a rare variant of heterotopic pregnancies, and it poses challenges in treating the heterotopic pregnancy and preserving the intrauterine pregnancy. However, there is no clear consensus regarding the optimal management. The aim of this study was to investigate the pregnancy outcomes of women diagnosed with heterotopic interstitial pregnancy. METHODS: A total of 17 women diagnosed with heterotopic interstitial pregnancy between July 2010 and December 2015 were included. General characteristics of each patient, including age, gravidity and parity, history of pelvic inflammatory disease or surgery, and especially the corresponding therapeutic interventions, were retrospectively analyzed. Moreover, pregnancy outcomes were further followed by face-to-face interview. RESULTS: Of the 17 patients, 10 (58.5%) underwent surgical treatment (7 laparoscopic cornual resection, and 3 laparotomy); and 3 cases simultaneously terminated the intrauterine pregnancy by suction evacuation. Compared with laparotomy, laparoscopic cornual section showed shorter operative time (median 40 vs. 70 min), less blood loss (150 vs. 400 ml) and shorter hospital stay (2 vs. 4 days). In addition, 4 (23.5%) patients underwent selective embryo reduction under transvaginal ultrasound guidance. Expectant management was chosen in the remaining 3 patients. In the follow-up study, other than a case of missed miscarriage, the other 13 women who remained committed to their pregnancies all delivered healthy babies either by caesarean section or vaginal birth. No congenital anomalies were reported, and all the infants were in good growth and development. CONCLUSIONS: Laparoscopic cornual resection is a feasible approach with favorable surgical and long-term pregnancy outcomes. Additionally, medical or expectant management may be a viable treatment option for selected symptom-free patient. Although the survival of the intrauterine pregnancy could not always be assured, the prognosis for a woman with heterotopic interstitial pregnancy is generally good.

Transplantation of collagen scaffold with autologous bone marrow mononuclear cells promotes functional endometrium reconstruction via downregulating ΔNp63 expression in Asherman's syndrome.

Asherman's syndrome (AS) is a common disease that presents endometrial regeneration disorder. However, little is known about its molecular features of this aregenerative endometrium in AS and how to reconstruct the functioning endometrium for the patients with AS. Here, we report that ΔNp63 is significantly upregulated in residual epithelial cells of the impaired endometrium in AS; the upregulated-ΔNp63 induces endometrial quiescence and alteration of stemness. Importantly, we demonstrate that engrafting high density of autologous bone marrow mononuclear cells (BMNCs) loaded in collagen scaffold onto the uterine lining of patients with AS downregulates ΔNp63 expression, reverses ΔNp63-induced pathological changes, normalizes the stemness alterations and restores endometrial regeneration. Finally, five patients achieved successful pregnancies and live births. Therefore, we conclude that ΔNp63 is a crucial therapeutic target for AS. This novel treatment significantly improves the outcome for the patients with severe AS.

[Efficacy of conservative laparoscopic surgery combined with goserelin in treatment of 206 patients with severe ovarian endometriosis at short-term and long-term follow-up].

OBJECTIVE: To evaluate the short-term and long-term efficacy of conservative laparoscopic surgery combine with goserelin in treatment of severe ovarian endometriosis. METHODS: From January 2004 to December 2008, 206 patients with severe ovarian endometriosis underwent laparoscopy surgery in Nanjing Drum Tower Hospital, Affiliated Nanjing University Medical School were enrolled in this retrospective study. According to the revised classification American Fertility Society (r-AFS), 123 (123/206, 59.7%) cases were at stage III and 83 (83/206, 40.3%) patients were at stage IV. Among 138 cases presented pelvic pain. All the patients underwent laparoscopic cystectomy, of which 117 patients with childbearing preserving underwent hysteroscopy and hydrotubation examination, including 7 cases with bilateral salpingectomy, 2 cases with bilateral tubal obstruction and 108 cases with normal reproduction. After surgery, all cases were administered by goserelin treatment at dose of 3.6 mg per 28 days for 3 to 6 months. At 1 to 5 years following up, pelvic pain, pregnancy and recurrence were observed, those factors associated with pregnancy rate and endometriosis recurrence were analyzed. RESULTS: (1) Pelvic pain: complete remission rate of pelvic pain was 76.1% (105/138) at 1 to 5 years after surgery. (2) Pregnancy: total pregnancy rate was 70.4% (76/108), spontaneous pregnancy rate was 68.8% (66/96) and pregnant rate of in vitro fertilization and embryo transfer (IVF-ET) was 10/12. Pregnancy rate at 1 year was 57.3% (55/96) and accounting for 83.3% (55/66) in all pregnant women. Live birth rates of spontaneous pregnant and IVF-ET were 86.4% (57/66) and 9/10, respectively. (3) Recurrence: the total recurrence rate was 8.3% (17/206) at 1 to 5 years. The recurrence rates and the cumulative recurrence rates were 3.9% (8/206) and 3.9% (8/206) at the first year after operation, 2.0% (3/149) and 6.7% (10/149) at the second year, 1.0% (1/99) and 8.0% (8/99) at the third year, 10.9% (5/46) and 17.4% (8/46) at the fourth year, 0 and 2/18 at the fifth year, respectively. CONCLUSION: It was suggested that conservative laparoscopic surgery combined with goserelin in treatment of stage III or IV ovarian endometriosis could reduce the recurrence risk of severe ovarian endometriosis and improve the pregnant rate of endometriosis-associated infertility.

[Two different genetic analyses of spontaneously aborted specimen].

OBJECTIVE: To explore the feasibility of comparative genomic hybridization (CGH) to be used for analysis of spontaneously aborted tissue. METHODS: Thirty eight patients with spontaneous abortion were recruited in this study. The gestational age of these cases was between 49 and 91 days based on ultrasound scan. All specimens of chorionic villi were collected via the cervix. Conventional cytogenetic karyotyping and CGH analysis were carried out to detect chromosomal unbalanced abnormalities in the tissue specimens. RESULTS: CGH analysis was successful in all 38 cases, but cytogenetic karyotying failed in 7 cases. Identical results in both CGH and conventional cytogenetic analysis were obtained in 90% (28/31) cases. Discrepancy in result between cytogenetic and CGH results was shown in 3 cases. One case presented 46XY karyotype by karyotyping, whereas showed chromosome 3q(22)-q(24) aberration in CGH analysis. Two cases showed triploidy by karyotyping, but normal in CGH analysis. In the 7 cases that failed in cytogenetic analysis there were 3 cases showing aneuploidy in CGH analysis. CONCLUSION: CGH analysis is feasible to be used for identification of chromosomal unbalanced abnormalities related to spontaneous abortion.

A novel in vivo lecithin-cholesterol acyltransferase (LCAT)-deficient mouse expressing predominantly LpX is associated with spontaneous glomerulopathy.

Complete lecithin cholesterol acyltransferase (LCAT) deficiency is a rare genetic cause of extreme reduction in high density lipoproteins and there is a high prevalence of chronic renal dysfunction that may progress to renal failure. Previous in vitro studies suggest the vesicular lipoprotein X (LpX) particles commonly seen in LCAT-deficient plasmas may be causative. To test this hypothesis, we have generated a novel murine model that selectively accumulate LpX in the circulation by cross breeding the sterol regulatory element binding protein (SREBP) 1a transgenic mice (S+) with the LCAT knockout (lcat-/-) mice. Fast protein liquid chromatography fractionation of pooled plasma lipids revealed that virtually all cholesterol is concentrated in the very low density lipoprotein (VLDL)-sized fractions. These fractions are enriched in free cholesterol and phospholipid but extremely poor in triglyceride. Electron microscopy of the d <1.063 g/ml fraction of the S+lcat-/- mice revealed abnormal large vesicular particles, suggestive of LpX. The S+lcat-/- mice developed glomerular lesions spontaneously evident at 6 months with glomerular and tubulointerstitial lipid-deposits. Immunohistochemical staining with RhoA showed marked positive focal staining in glomeruli in the S+lcat-/- mice and undetectable in the S+/lcat+/+ control. By 10 months of age, the kidneys showed progressive glomerular injury including segmental foam cell infiltrates, mesangial expansion, and hyalinosis. Renal abnormalities are very similar to those seen in human LCAT deficiency. We conclude that the selective high-level accumulation of plasma LpX in the S+lcat-/- mice is strongly associated with a spontaneous glomerulopathy, providing in vivo evidence that LpX contributes to the LCAT deficiency-related nephropathy.

[Effects of high concentrations insulin on VEGF expression in cultured Müller cells].

OBJECTIVE: To investigate the effects of high concentrations of insulin on the expression of vascular endothelial growth factor (VEGF) in cultured rabbit retinal Müller cells. METHODS: Immunocytochemistry, in situ hybridization and the ELISA method were used to study the effects of different concentrations of insulin on the expression of vascular endothelial growth factor (VEGF) in cultured rabbit retinal Müller cells qualitatively and quantitatively. RESULTS: VEGF expression was enhanced obviously by the insulin, which regulated the expression of VEGF at the transcription level. CONCLUSIONS: VEGF expression in cultured Müller cells can be enhanced by high concentrations of insulin. Müller cells play a potential role in the development of neovascularization of diabetic retinopathy.

Hypertriglyceridemia in lecithin-cholesterol acyltransferase-deficient mice is associated with hepatic overproduction of triglycerides, increased lipogenesis, and improved glucose tolerance.

Lecithin-cholesterol acyltransferase deficiency is frequently associated with hypertriglyceridemia (HTG) in animal models and humans. We investigated the mechanism of HTG in the ldlr-/- x lcat-/- (double knockout (dko)) mice using the ldlr-/- x lcat+/+ (knock-out (ko)) littermates as control. Mean fasting triglyceride (TG) levels in the dko mice were elevated 1.75-fold compared with their controls (p < 0.002). Both the very low density lipoprotein and the low density lipoprotein/intermediate density lipoprotein fractions separated by fast protein liquid chromatography were TG-enriched in the dko mice. In vitro lipolysis assay revealed that the dko mouse very low density lipoprotein (d < 1.019 g/ml) fraction separated by ultracentrifugation was a more efficient substrate for lipolysis by exogenous bovine lipoprotein lipase. Post-heparin lipoprotein lipase activity was reduced by 61% in the dko mice. Hepatic TG production rate, determined after intravenous Triton WR1339 injection, was increased 8-fold in the dko mice. Hepatic mRNA levels of sterol regulatory element binding protein-1 (srebp-1) and its target genes acetyl-CoA carboxylase-1 (acc-1), fatty acid synthase (fas), and stearoyl-CoA desaturase-1 (scd-1) were significantly elevated in the dko mice compared with the ko control. The hepatic mRNA levels of LXRalpha (lxralpha) and its target genes including angiopoietin-like protein 3 (angptl-3) in the dko mice were unchanged. Fasting glucose and insulin levels were reduced by 31 and 42%, respectively in the dko mice, in conjunction with a 49% reduction in hepatic pepck-1 mRNA (p = 0.014). Both the HTG and the improved fasting glucose phenotype seen in the dko mice are at least in part attributable to an up-regulation of the hepatic srebp-1c gene.