Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network.

Pluripotency and cell fates can be modulated through the regulation of super-enhancers; however, the underlying mechanisms are unclear. Here, we showed a novel mechanism in which Ash2l directly binds to super-enhancers of several stemness genes to regulate pluripotency and self-renewal in pluripotent stem cells. Ash2l recruits Oct4/Sox2/Nanog (OSN) to form Ash2l/OSN complex at the super-enhancers of Jarid2, Nanog, Sox2 and Oct4, and further drives enhancer activation, upregulation of stemness genes, and maintains the pluripotent circuitry. Ash2l knockdown abrogates the OSN recruitment to all super-enhancers and further hinders the enhancer activation. In addition, CRISPRi/dCas9-mediated blocking of Ash2l-binding motifs at these super-enhancers also prevents OSN recruitment and enhancer activation, validating that Ash2l directly binds to super-enhancers and initiates the pluripotency network. Transfection of Ash2l with W118A mutation to disrupt Ash2l-Oct4 interaction fails to rescue Ash2l-driven enhancer activation and pluripotent gene upregulation in Ash2l-depleted pluripotent stem cells. Together, our data demonstrated Ash2l formed an enhancer-bound Ash2l/OSN complex that can drive enhancer activation, govern pluripotency network and stemness circuitry.

Dysregulated immunological and metabolic functions discovered by a polygenic integrative analysis for PCOS.

RESEARCH QUESTION: Polycystic ovary syndrome (PCOS) is a complex disease and its pathophysiology is still unclear. This polygenic study may provide some clues. DESIGN: A polygenic, functionome-based study with the ovarian gene expression profiles downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, including 48 PCOS and 181 normal control samples. These profiles were converted to the gene set regularity (GSR) indices, which were computed by the modified differential rank conversion algorithm and were defined by the gene ontology terms. RESULTS: Machine learning could accurately recognize the patterns of functional regularities between PCOS and normal controls. The significantly aberrant functions in PCOS included transporter activity, catalytic activity, the receptor signalling pathway via signal transducer and activator of transcription (STAT), the cellular metabolic process, and immune response. CONCLUSION: This study provided a comprehensive view of the dysregulated functions and information for further studies on the management of PCOS.

An extremely patient-friendly and efficient stimulation protocol for assisted reproductive technology in normal and high responders.

BACKGROUND: The use of oral progestin has been shown to effectively prevent luteining hormone (LH) surge during ovarian stimulation with daily human menopausal gonadotropin injections. This study was aimed to investigate the efficacy of long-acting follicle stimulating hormone (long-acting FSH; corifollitropin alfa, Elonva®) use in progestin-primed ovarian stimulation for normal and high responders undergoing IVF/ICSI. METHODS: This is a retrospective and proof-of-concept study. We developed an extremely patient-friendly protocol to be applied to forty-five normal or high responders, in which a single injection of corifollitropin alfa (Elonva®) was administered and medroxyprogesterone acetate (MPA) was taken orally every day from the day after Elonva injection to the day of trigger. Seven days after Elonva injection, folliculometry and hormone tests were performed, followed by short-acting daily FSH/LH injections, if needed, until the day before trigger. Duration of stimulation, number of injections and visits before trigger, incidence of premature LH surge, the number of oocytes retrieved, fertilization rate, cleavage rate, the rate of day 2 good embryos available, and cumulative ongoing pregnancy rate per retrieval were assessed. RESULTS: The average age of the population was 34.7 years. Duration of stimulation was 9.4 days in average. Before trigger, only 3.6 injection shots and 1.4 visits were needed on average. There was no case of premature LH surge. Number of oocytes retrieved was 13.7, fertilization rate was 79.04%, cleavage rate was 91.11%, and day 2 good embryo rate was 64.34%, in average respectively. There was no case of ovarian hyperstimulation syndrome. The cumulative ongoing pregnancy rate per oocyte retrieval achieved a satisfactory level as 53.1%. CONCLUSIONS: Our protocol consisting of long-acting FSH injection and oral MPA preventing LH surge reduces the number of injections and visits to an extreme and achieves a satisfactory reproductive outcome, and, therefore, is a really patient-friendly and effective approach to ovarian stimulation.

Key Immunological Functions Involved in the Progression of Epithelial Ovarian Serous Carcinoma Discovered by the Gene Ontology-Based Immunofunctionome Analysis.

Serous carcinoma (SC) is the most common and lethal subtype of epithelial ovarian carcinoma; immunotherapy is a potential treatment for SC, however, the global immunological functions of SC as well as their change during the progression of SC have not been investigated in detail till now. We conducted a genome-wide integrative analysis to investigate the immunofunctionomes of SC at four tumor stages by quantifying the immunological functions defined by the Gene Ontology gene sets. DNA microarray gene expression profiles of 1100 SCs and 136 normal ovarian tissue controls were downloaded from the Gene Expression Omnibus database and converted to the functionome. Then the immunofunctionomes were reconstructed by extracting the offspring from the functionome for the four SC staging groups. The key immunological functions extracted from immunofunctionomes with a series of filters revealed that the immunopathy of SC consisted of a group of deregulated functions with the core members including B cell activation and differentiation, regulation of leukocyte chemotaxis/cellular extravasation, antigen receptor mediated signaling pathway, T helper mediated immunity and macrophage activation; and the auxiliary elements included leukocyte mediated immunity, regulation of inflammatory response, T cell differentiation, mononuclear cell migration, megakaryocyte differentiation, complement activation and cytokine production. These deregulated immunological functions reveal the candidates to target in the immunotherapy.

CHD1L Regulated PARP1-Driven Pluripotency and Chromatin Remodeling During the Early-Stage Cell Reprogramming.

PARP1 and poly(ADP-ribosyl)ation (PARylation) have been shown to be essential for the initial steps of cellular reprogramming. However, the mechanism underlying PARP1/PARylation-regulated activation of pluripotency loci remains undetermined. Here, we demonstrate that CHD1L, a DNA helicase, possesses chromatin remodeling activity and interacts with PARP1/PARylation in regulating pluripotency during reprogramming. We found that this interaction is mediated through the interplay of the CHD1L macro-domain and the PAR moiety of PARylated-PARP1. Chromatin immunoprecipitation assays demonstrated the co-occupancy of CHD1L and PARP1 at Pou5f1, Nanog, and Esrrb pluripotency loci. Knockdown of CHD1L significantly blocked the binding activity of PARP1 at pluripotency loci and inhibited the efficiency of PARP1-driven reprogramming. Notably, we found that CHD1L-promoted reprogramming requires both a PARP1-interacting domain and DNA helicase activity, partly contributing to the chromatin-remodeling states of pluripotency loci. Taken together, these results identify CHD1L as a key chromatin remodeler involved in PARP1/PARylation-regulated early-stage reprogramming and pluripotency in stem cells.

Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation.

BACKGROUND: Iatrogenic parasitic myomas (PMs), caused by intra-corporeal power morcellation during laparoscopy is gradually increasing. However, the pathogenesis and medical treatment of PMs remain largely unelucidated. METHODS: Laparoscopically-induced PM xenografted mouse model was conducted by xenografting human uterine myoma fragments into the abdominal cavity of SCID mice and hormonal manipulation was performed using this mouse model to demonstrate the role of oestrogen in the development of implanted PMs. Immunohistochemistry of oestrogen receptor α (ERα), progesterone receptor (PR), vimentin, vascular endothelial growth factor (VEGF), microvessel density (MVD) and Ki-67 index was performed and compared. RESULTS: In the patient with PMs, ERα, PR, angiogenesis and proliferative property expression were upregulated in PM lesions compared to uterine myomas. In the laparoscopically-induced PM mouse model, implanted myomas had more steroid receptor expressions, angiogenesis and proliferative property compared with pre-xenografted or non-implanted myoma. Depletion of oestrogen in the ovariectomized (OVX) mice decreased laparoscopically-induced PM implantations. In comparison, the implantations of PMs were increased with additional E2 supplement. Hormonal manipulation in the PM mouse model, including AI, GnRHa and SERM groups, were compared and AI significantly decreased the implantations, steroid receptor, angiogenesis, cell density, and proliferative index of PMs compared with control group. Furthermore, GnRHa significantly decreased VEGF and MVD expressions compared with control group. CONCLUSIONS: These data highlight the crucial role of oestrogen in the development of laparoscopically-induced PMs and suggest that hormone manipulation may be a potential therapeutic agent. TRIAL REGISTRATION: This protocol was approved by the Human and Animal Institutional Review Board of Taipei Veterans General Hospital ( VGHIRB No 2014-10-002C on Nov. 17th, 2014; IACUC 2014-119 on Aug. 22nd, 2014).

Poly(ADP-Ribose) Polymerase 1: Cellular Pluripotency, Reprogramming, and Tumorogenesis.

Poly(ADP-ribos)ylation (PARylation) is the catalytic function of the Poly(ADP-ribose) polymerases (Parps) family for post-translational modification in cellular process. Being a major member of Parps, Parp1 is a crucial nuclear factor with biological significance in modulating DNA repair, DNA replication, transcription, DNA methylation and chromatin remodeling through PARylation of downstream proteins. In addition, high expression level and activity of Parp1 are correlated with pluripotent status, reprogramming, and cancer. Furthermore, epigenetic modulation of Parp1 is explored for regulating wide variety of gene expression. Genetic and pharmaceutical disruption of Parp1 further confirmed the importance of Parp1 in cell growth, DNA repair, and reprogramming efficiency. Taken together, the proximity toward the understanding of the modulation of Parp1 including interaction and modification in different fields will provide new insight for future studies. In this review, the biological significance of Parp1 in transcription and the epigenetic modulation of Parp1 in pluripotent status, reprogramming process and cancer will be summarized.

Oestrogen-induced angiogenesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells.

Adenomyosis is an oestrogen-dependent disease characterized by the invasion of endometrial epithelial cells into the myometrium of uterus, and angiogenesis is thought to be required for the implantation of endometrial glandular tissues during the adenomyotic pathogenesis. In this study, we demonstrate that compared with eutopic endometria, adenomyotic lesions exhibited increased vascularity as detected by sonography. Microscopically, the lesions also exhibited an oestrogen-associated elevation of microvascular density and VEGF expression in endometrial epithelial cells. We previously reported that oestrogen-induced Slug expression was critical for endometrial epithelial-mesenchymal transition and development of adenomyosis. Our present studies demonstrated that estradiol (E2) elicited a Slug-VEGF axis in endometrial epithelial cells, and also induced pro-angiogenic activity in vascular endothelial cells. The antagonizing agents against E2 or VEGF suppressed endothelial cells migration and tubal formation. Animal experiments furthermore confirmed that blockage of E2 or VEGF was efficient to attenuate the implantation of adenomyotic lesions. These results highlight the importance of oestrogen-induced angiogenesis in adenomyosis development and provide a potential strategy for treating adenomyosis through intercepting the E2-Slug-VEGF pathway.

Improvement of carbon tetrachloride-induced acute hepatic failure by transplantation of induced pluripotent stem cells without reprogramming factor c-Myc.

The only curative treatment for hepatic failure is liver transplantation. Unfortunately, this treatment has several major limitations, as for example donor organ shortage. A previous report demonstrated that transplantation of induced pluripotent stem cells without reprogramming factor c-Myc (3-genes iPSCs) attenuates thioacetamide-induced hepatic failure with minimal incidence of tumorigenicity. In this study, we investigated whether 3-genes iPSC transplantation is capable of rescuing carbon tetrachloride (CCl(4))-induced fulminant hepatic failure and hepatic encephalopathy in mice. Firstly, we demonstrated that 3-genes iPSCs possess the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that exhibit biological functions and express various hepatic specific markers. 3-genes iPSCs also exhibited several antioxidant enzymes that prevented CCl(4)-induced reactive oxygen species production and cell death. Intraperitoneal transplantation of either 3-genes iPSCs or 3-genes iPSC-Heps significantly reduced hepatic necrotic areas, improved hepatic functions, and survival rate in CCl(4)-treated mice. CCl(4)-induced hepatic encephalopathy was also improved by 3-genes iPSC transplantation. Hoechst staining confirmed the successful engraftment of both 3-genes iPSCs and 3-genes iPSC-Heps, indicating the homing properties of these cells. The most pronounced hepatoprotective effect of iPSCs appeared to originate from the highest antioxidant activity of 3-gene iPSCs among all transplanted cells. In summary, our findings demonstrated that 3-genes iPSCs serve as an available cell source for the treatment of an experimental model of acute liver diseases.

MafA promotes the reprogramming of placenta-derived multipotent stem cells into pancreatic islets-like and insulin+ cells.

MafA is a pancreatic transcriptional factor that controls ß-cell-specific transcription of the insulin gene. However, the role of MafA in the regulation of pancreatic transdifferentiation and reprogramming in human stem cells is still unclear. In this study, we investigate the role of MafA in placenta-derived multipotent stem cells (PDMSCs) that constitutively expressed Oct-4 and Nanog. PDMSCs were isolated and transfected with MafA using a lentivector. Our results showed that overexpression of MafA in PDMSCs significantly up-regulated the expression of pancreatic development-related genes (Sox17, Foxa2, Pdx1 and Ngn3). Microarray analysis suggested that the gene expression profile of MafA-overexpressing PDMSCs was similar to that of pancreas and islet tissues. MafA increased the expression levels of the mRNAs of NKx2.2, Glut2, insulin, glucagons and somatostatin, and further facilitated the differentiation of PDMSCs into insulin(+) cells. The glucose-stimulated responses to insulin and c-peptide production in MafA-overexpressing PDMSCs were significantly higher than in PDMSCs with vector control. Our results indicated that MafA-overexpressing PDMSCs were more resistant to oxidative damage and oxidative damage-induced apoptosis than PDMSCs carrying the vector control were. Importantly, the expression of MafA in PDMSCs xenotransplanted into immunocompromised mice improved the restoration of blood insulin levels to control values and greatly prolonged the survival of graft cells in immunocompromised mice with STZ-induced diabetes. In summary, these data suggest that MafA plays a novel role in the reprogramming of stem cells into pancreatic ß-progenitors, promotes the islet-like characteristics of PDMSCs, as well as functionally enhances insulin production to restore the regulation of blood glucose levels in transplanted grafts.

Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis.

Adenomyosis is an oestrogen-dependent disease caused by a downward extension of the endometrium into the uterine myometrium. Epithelial-mesenchymal transition (EMT) endows cells with migratory and invasive properties and can be induced by oestrogen. We hypothesized that oestrogen-induced EMT is critical in the pathogenesis of adenomyosis. We first investigated whether EMT occurred in adenomyotic lesions and whether it correlated with serum 17ß-oestradiol (E2) levels. Immunohistochemistry was performed on adenomyotic lesions and corresponding eutopic endometrium samples from women with adenomyosis. Endometria from women without endometrial disorders were used as a control. In the epithelial component of adenomyotic lesions, vimentin expression was up-regulated and E-cadherin expression was down-regulated compared to the eutopic endometrium, suggesting that EMT occurs in adenomyosis. In adenomyosis, the serum E2 level was negatively correlated with E-cadherin expression in the epithelial components of the eutopic endometrium and adenomyotic lesions, suggesting the involvement of oestrogen-induced EMT in endometrial cells. In oestrogen receptor-positive Ishikawa endometrial epithelial cells, oestrogen induced a morphological change to a fibroblast-like phenotype, a shift from epithelial marker expression to mesenchymal marker expression, increased migration and invasion, and up-regulation of the EMT regulator Slug. Raloxifene, a selective oestrogen receptor modulator, abrogated these effects. To determine the role of oestrogen-induced EMT in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium or adenomyotic lesions from adenomyosis patients into ovariectomized SCID mice. The implantation of endometrium was oestrogen-dependent and was suppressed by raloxifene. Collectively, these data highlight the crucial role of oestrogen-induced EMT in the development of adenomyosis and suggest that raloxifene may be a potential therapeutic agent for adenomyosis patients.

Induction of insulin-producing cells derived from endometrial mesenchymal stem-like cells.

Studies have demonstrated that mesenchymal stem-like cells can be isolated from endometrium. However, the potential of endometrial-derived stem cells to differentiate into insulin-positive cells and functionally secrete insulin remains undetermined. We isolated endometrial mesenchymal stem-like cells (EMSCs) from human endometrial tissue from six donors. The insulin-secreting function of EMSCs was further analyzed in vitro and in transplanted grafts in vivo. We successfully isolated EMSCs from human endometrium, and our results showed that EMSCs expressed high levels of stemness genes (Nanog, Oct-4, Nestin). Under specific induction conditions for 2 weeks, EMSCs formed three-dimensional spheroid bodies (SBs) and secreted C-peptide. The high insulin content of SB-EMSCs was confirmed by enzyme-linked immunosorbent assay, and glucose responsiveness was demonstrated by measuring glucose-dependent insulin secretion. Using cDNA microarrays, we found that the expression profiles of SB-EMSCs are related to those of islet tissues. Insulin and C-peptide production in response to glucose was significantly higher in SB-EMSCs than in undifferentiated EMSC controls. Furthermore, upon differentiation, SB-EMSCs displayed increased mRNA expression levels of NKx2.2, Glut2, insulin, glucagon, and somatostatin. Our results also showed that SB-EMSCs were more resistant to oxidative damage and oxidative damage-induced apoptosis than fibroblasts from the same patient. It is noteworthy that SB-EMSCs xenotransplanted into immunocompromised mice with streptozotocin-induced diabetes restored blood insulin levels to control values and greatly prolonged the survival of graft cells. These data suggest that EMSCs not only play a novel role in the differentiation of pancreatic progenitors, but also can functionally enhance insulin production to restore the regulation of blood glucose levels in an in vivo transplantation model.

Validating the Use of Corifollitropin Alfa in Progestin-Primed Ovarian Stimulation Protocol on Normal and High Responders by Comparing with Conventional Antagonist Protocol: A Retrospective Study.

Our previous study showed a satisfactory reproductive outcome resulting from the patient-friendly ovarian stimulation protocol using long-acting follicle stimulation hormone (FSH) plus oral medroxyprogesterone acetate (MPA). The present retrospective study aims to compare the efficacy of the patient-friendly ovarian stimulation protocol with that of the antagonist protocol on normal and high responders aged between 24 and 39 years in a tertiary fertility center in Taiwan. To prevent premature luteinizing hormone (LH) surge, oral MPA was given to patients in group 1 (n = 57), whereas antagonist protocol was applied to group 2 (n = 53). Duration and dosage of stimulation, number of injections and visits before trigger, incidence of premature LH surge, number of oocytes retrieved, fertilization rate, cleavage rate, rate of good embryos available, incidence of ovarian hyperstimulation syndrome, cumulative clinical pregnancy rate and live birth rate per retrieval were compared between groups. We conclude that our patient-friendly ovarian stimulation protocol with MPA demonstrates satisfactory stimulation and reproductive outcomes that are comparable to those of an antagonist protocol.

Roles of estrogen and progesterone in endometrial hemodynamics and vascular endothelial growth factor production.

BACKGROUND: The endometrium becomes receptive to the embryo after sequential actions of estrogen and progesterone. The purpose of this study was to examine the effects of estrogen and progesterone on endometrial hemodynamics and on secretion of vascular endothelial growth factor (VEGF) from endometrial epithelial cells (EEC). METHODS: Six early postmenopausal women taking sequential estrogen and progestin [days 1-11: estradiol valerate (estrogen) 2 mg daily; days 12-21: estradiol valerate 2 mg plus norethisterone acetate (progestin) 1 mg daily] were recruited. Three-dimensional power Doppler angiography (3D-PDA) was performed before hormone treatment (phase 0), on days 10-11 of hormone treatment (phase E), and on days 18-20 of hormone treatment (phase E + P). Ishikawa EEC were treated with or without 17-beta-estradiol and progesterone for 24 hours, followed by determination of VEGF concentrations in the supernatants. RESULTS: The endometrial volume was significantly increased in phase E and phase E + P as compared with that in phase 0. The vascularization index, flow index, and vascularization flow index in the subendometrial region, as measured by 3D-PDA, were significantly higher in phase E + P than in phase 0, but there were no significant differences in these indices between phase 0 and phase E. While treatment of EEC with 17-beta-estradiol had little enhancing effect on VEGF production, progesterone alone or in combination with 17-beta-estradiol significantly increased VEGF secretion from EEC. CONCLUSION: Our data suggested that progesterone could stimulate VEGF secretion from EEC and subsequently increase subendometrial vascularity and blood flow.

Effects of delayed pushing during the second stage of labor on postpartum fatigue and birth outcomes in nulliparous women.

This article studied differences in postpartum fatigue and birth outcomes between women who pushed immediately and those who delayed pushing during the second stage of labor. Data were collected from primiparous women in their 38th to 42nd gestational week who did not receive epidural analgesia during labor and were free of complications during pregnancy. Using a quasi-experimental design, 72 participants selected by convenient sampling were assigned based on individual participant's preference to either an experimental or control group. For the experimental group, pushing was delayed until the point after full cervical dilation at which (a) the mother felt a strong physical pushing reflex, (b) the fetal head had both descended to at least the +1 level in the pelvis and turned to the occiput anterior position, and (c) uterine contractions were at least 30 mmHg. For the control group, the physician instructed mothers to begin pushing after full cervical dilation at the point when the fetal head was in the occiput anterior position and uterine contractions were at least 30 mmHg. The authors administered the Modified Fatigue Symptom Checklist at 1 and 24 hr after delivery to measure participant's fatigue levels. Birth outcomes were assessed based on medical chart data. Findings showed a significant difference between the two groups in terms of 1- and 24-hr postpartum fatigue scores. The duration of the second labor stage (experimental group, 70.31 +/- 37.17 min; control group, 129.06 +/- 75.69 min) also differed significantly. The group that pushed immediately recorded higher cesarean and instrument-assisted birth rates. No significant differences were observed in terms of perineal tears, maternal/neonatal complications, or neonatal Apgar scores. Results of this study provide important insights for caregivers working in the delivery room and suggest that current care procedures change to include the delayed pushing during the second stage of labor. By delaying pushing exertions until the mother feels a reflexive urge to do so, mothers' feelings of fatigue are significantly reduced.

Successful prevention of follicular rupture at 45 h after hCG and GnRHa triggering by emergent administration of indomethacin: A case report.

OBJECTIVE: To report the management and prevention of pre-operative ovulation before oocyte retrieval with emergent administration of indomethacin. CASE REPORT: During in vitro fertilization (IVF) treatment, the patient described here mistakenly administered 6500 IU of hCG and 0.2 mg of triptorelin (GnRHa) 9 h earlier than scheduled triggering. To avoid emergent oocyte retrieval in the midnight, indomethacin was given (150 mg/day, there times a day) from 2 h after incorrect hCG and GnRHa injection to the night before ovum pickup. The oocyte retrieval was performed at originally scheduled time. The result showed that pre-operative ovulation was effectively prevented and we successfully collected the expected number Andersen et al., 1995 of oocytes at 45 h after triggering. CONCLUSION: The presented case demonstrates that indomethacin can be used safely and effectively as an emergent prescription to prevent and postpone ovulation till up to 45 h after hCG and GnRHa triggering.

Mesenchymal stem cells and their conditioned medium can enhance the repair of uterine defects in a rat model.

BACKGROUND: Our aim was to examine the roles of mesenchymal stem cell (MSC) transplantation in the repair of large uterine defects. METHODS: Uterine defects were created in both uterine horns of female rats by a punch instrument, and bone marrow-derived MSCs, MSC-conditioned medium (MSC-CM) or vehicle were injected into the myometrium around the defect. The rate of uterine defect repair was monitored on day 2 and 4 after operation. Cytokine array of MSC-CM was performed, followed by neutralizing antibody experiments to clarify the exact cytokine participating in the MSC-CM-enhanced wound repair. RESULTS: Transplantation of MSCs, but not myometrial cells, significantly enhanced uterine defect repair. The transplanted MSCs were detected in the uterine horn with no signs of rejection on day 4 after transplantation, when the MSC-transplanted uterine wound was nearly healed. Moreover, uterine defect repair was also accelerated by injection of MSC-CM, indicating the paracrine effects of MSCs on uterine wound healing. Cytokine array analysis further revealed that MSC-CM contained abundant cytokines and chemokines, among which high levels of interleukin-6 (IL-6) were found. Additionally, antibodies against IL-6 were shown to block MSC-CM-enhanced uterine defect repair. CONCLUSION: This study demonstrated that transplantation of MSCs could enhance uterine defect repair by paracrine effects involving IL-6, which are findings that may be applied to facilitate uterine wound healing in the removal of huge intramural masses.

Promoting Induced Pluripotent Stem Cell-driven Biomineralization and Periodontal Regeneration in Rats with Maxillary-Molar Defects using Injectable BMP-6 Hydrogel.

Periodontal disease may cause considerable destruction of alveolar bone, periodontal ligaments (PDLs) and cementum and even lead to progressive oral dysfunction. Periodontal tissue regeneration is the ultimate goal of periodontal disease treatment to reconstruct both structures and functions. However, the regenerative efficiency is low, possibly due to the lack of a proper periodontal microenvironment. In this study, we applied an injectable and thermosensitive chitosan/gelatin/glycerol phosphate hydrogel to provide a 3D environment for transplanted stem cells and to enhance stem cell delivery and engraftment. The iPSCs-BMP-6-hydrogel complex promoted osteogenesis and the differentiation of new connective tissue and PDL formation. In animal models of maxillary-molar defects, the iPSCs-BMP-6-hydrogel-treated group showed significant mineralization with increased bone volume, trabecular number and trabecular thickness. Synergistic effects of iPSCs and BMP-6 increased both bone and cementum formation. IPSCs-BMP-6-hydrogel-treated animals showed new bone synthesis (increased ALP- and TRAP-positive cells), new PDL regeneration (shown through Masson's trichrome staining and a qualification assay), and reduced levels of inflammatory cytokines. These findings suggest that hydrogel-encapsulated iPSCs combined with BMP-6 provide a new strategy to enhance periodontal regeneration. This combination not only promoted stem cell-derived graft engraftment but also minimized the progress of inflammation, which resulted in highly possible periodontal regeneration.

Acute kidney injury and risk of deep vein thrombosis and pulmonary embolism in Taiwan: A nationwide retrospective cohort study.

INTRODUCTION: Chronic kidney disease (CKD) increases risk for deep vein thrombosis (DVT) and pulmonary embolism (PE). However, few studies have investigated the relationship between acute kidney injury (AKI) and risk of DVT and PE. Therefore, we conducted a nationwide longitudinal cohort study to determine whether patients with AKI are associated with increased risk of developing DVT and PE. METHODS: We included >30years-old inpatients (n=4734) receiving the diagnosis of AKI from 2000 to 2006 and their age-and sex-matched non-AKI inpatients using medical service in the same year (n=47.340). Diagnosis of DVT and PE was recorded within 5-year after the AKI event or index use of medical service. The hazard ratios were analyzed using Cox regression model and adjustments were made for demographic factors, selected comorbidities and treatments. A time-dependent covariate survival analysis was performed for variations of some comorbidities, treatments and hospitalization. Competing risk regression (CRR) model was also used to adjust the risk for death. Propensity score matching was used to minimize potential selection bias. We also performed sensitivity analysis to examine the effect of other possible residual confounding factors. RESULTS: After adjusting for demographic characteristics, selected comorbidities and treatment, AKI remained a predisposing factor with a 1.44-fold (95% CI, 1.04-2.01) and 1.49-fold (95% CI, 1.12-1.97) increase in patients who were at a risk for developing DVT within 3 and 5years. AKI also remained a significant predisposing factor with a 2.66-fold (95% CI, 1.49-3.20) increase in patients who were at a risk for developing PE within 3years. However, there were no significant results for PE within 5years. The hazard ratios of time-dependent covariate survival analysis and CRR model showed the similar results. CONCLUSIONS: Risk of DVT and PE is higher in patients with AKI than in the general population.

Impact of hysterosalpingography after operative treatment for ectopic pregnancy in Taiwan: A 16-year Nationwide Population-Based Analysis.

By retrieving records from Taiwan's National Health Insurance (NHI) system's database, the current study aimed to investigate the impacts of hysterosalpingography (HSG) to patients after ectopic pregnancy (EP) operations in Taiwan.In this retrospective cohort study, insurance claims data from 1997 to 2013, derived from a cohort of 1 million people randomly sampled to represent all NHI beneficiaries, were analyzed. Patients after ectopic pregnancy (EP) operations were identified via the inclusion of the corresponding NHI procedure codes. We further divided the patients into 2 groups by whether received subsequent HSG, EP-HSG, and EP-no-HSG. Patients with history of previous pregnancies (PP) and subsequent HSG were grouped as PP-HSG. We sought to evaluate the following pregnancies (FP) rate, interval to FP in EP-HSG compared with that in EP-no-HSG, and PP-HSG.EP-HSG had significantly higher FP rate odds ratio than EP-no-HSG (OR, 1.64; 95% CI, 1.24-2.16, P < .001). EP-HSG had lower FP rate odds ratio than that in PP-HSG, but no significant difference (33.1% vs 34.6%, P  =  .654). The INTERVAL(HSG-FP) in EP-HSG was no significantly different from that in PP-HSG (843.34 ±â€Š82 days vs 644.72 ±â€Š24.30 days, P  =  .077). There was significant positive correlation between FP after EP and number of HSG (r  =  0.070, P < .001). There were significant negative correlation between FP and EP age (r  =  -0.270, P < .001), FP and INTERVAL(EP-HSG) (r  =  -0.212, P  =  .001). The multivariate analysis showed that INTERVAL(EP-HSG) less than 1 year is the predictor factor of INTERVAL(EP-FP) (hazard ratio: 1.422; 95% CI: 1.130-1.788; P = .003). It was evident that the longer the INTERVAL(EP-HSG), the lower the FP rate odds ratio; and the older the EP age, the lower the FP rate odds ratio. (OR, 95% CI; >1 year: 0.59, 0.41-0.86; >2 year: 0.42, 0.32-0.55; >25 years old: 0.47, 0.38-0.57; >30 years old: 0.29, 0.24-0.35; >35 years old: 0.12, 0.08-0.18, all P < .001).Receiving HSG after EP, short INTERVAL(EP-HSG), EP age less than 30 years old, had significant positive impacts on the FP. We encourage shortening the INTERVAL(EP-HSG), and the counseling of women on the most appropriate way to conceive thereafter.