Ovarian response determines the luteinizing hormone suppression threshold for patients following the gonadotrophin releasing hormone antagonist protocol: A retrospective cohort study.

Background: Ovarian reactivity to gonadotrophin stimulation varies, and individual adjustments to the timing and dose of gonadotrophin-releasing hormone (GnRH) antagonist administration are necessary to prevent excessive increases and decreases in luteinizing hormone (LH) levels in patients with different ovarian response following the GnRH antagonist (GnRH-A) protocol. The present study aims to investigate optimal LH suppression thresholds for patients with normal ovarian response (NOR), high ovarian response (HOR), and poor ovarian response (POR) following the GnRH-A protocol respectively. Methods: A total of 865 in vitro fertilization (IVF) cycles using a flexible or fixed GnRH-A protocol were included. Patients were categorized into the HOR, NOR, or POR group according to their anti-Müllerian hormone (AMH) levels. Then, patients in each group were stratified into one of four subgroups according to the quartile (Q1-Q4) of the basal LH level to LH on triggering day ratio (bLH/hLH). The primary outcomes were the clinical pregnancy and live birth rates, and the secondary outcomes were the number of oocytes retrieved, MII oocytes, two pronucleus (2PN) embryos, and good-quality embryos. Results: There were 526 patients with NOR, 180 with HOR, and 159 with POR. Basal LH level, LH on triggering day and bLH/hLH were identified as independent predictors of clinical pregnancy rate and live birth rate by logistics regression analysis. Compared to those with NOR, patients with POR had the lowest embryo implantation rate (22.6% vs. 32.8%, P < 0.05), clinical pregnancy rate (32.3% vs. 47.3%, P < 0.05) and live birth rate (22.6 vs. 37.8%, P < 0.05) of fresh embryo transfer (ET). The embryo implantation, clinical pregnancy and live birth rates of frozen embryo transfer (FET) were not significantly different among the three groups. In the subgroup analysis, patients with HOR had the highest embryo implantation rate (51.6%, P < 0.05), clinical pregnancy rate (68.4%, P < 0.05) and live birth rate (52.6%, P < 0.05) of ET in Q3, with a bLH/hLH ratio of 2.40-3.69. In the NOR group, the embryo implantation rate (41.9%, P < 0.05), clinical pregnancy rate (61.5%, P < 0.05) and live birth rate (50.8%, P < 0.05) of ET and live birth rate (53.1%, P < 0.05) of FET were highest in Q2, with a bLH/hLH ratio of 1.29-2.05. Patients with POR had the highest clinical pregnancy rate (57.1%, P < 0.05) and live birth rate (42.9%, P < 0.05) of ET in Q2, with a bLH/hLH ratio of 0.86-1.35. Conclusions: In the present study, the bLH/hLH ratio represented the LH suppression threshold. The subgroup analysis of HOR, NOR and POR showed that, the LH suppression threshold varies according to ovarian response. We recommend LH suppression thresholds of 2.40-3.69 for HOR, 1.29-2.05 for NOR, and 0.86-1.35 for POR to obtain the highest clinical pregnancy rate and live birth rate. This study provides comprehensive and precise references for clinicians to monitor LH levels individually during controlled ovarian stimulation (COS) according to the patient's ovarian response following the GnRH-A protocol.

ALKBH5 controls the meiosis-coupled mRNA clearance in oocytes by removing the N 6-methyladenosine methylation.

N6-methyladenosine (m6A) maintains maternal RNA stability in oocytes. One regulator of m6A, ALKBH5, reverses m6A deposition and is essential in RNA metabolism. However, the specific role of ALKBH5 in oocyte maturation remains elusive. Here, we show that Alkbh5 depletion causes a wide range of defects in oocyte meiosis and results in female infertility. Temporal profiling of the maternal transcriptomes revealed striking RNA accumulation in Alkbh5-/- oocytes during meiotic maturation. Analysis of m6A dynamics demonstrated that ALKBH5-mediated m6A demethylation ensures the timely degradation of maternal RNAs, which is severely disrupted following Alkbh5-/- depletion. A distinct subset of transcripts with persistent m6A peaks are recognized by the m6A reader IGF2BP2 and thus remain stabilized, resulting in impaired RNA clearance. Additionally, reducing IGF2BP2 in Alkbh5-depleted oocytes partially rescued these defects. Overall, this work identifies ALKBH5 as a key determinant of oocyte quality and unveil the facilitating role of ALKBH5-mediated m6A removal in maternal RNA decay.

LncRNA landscape and associated ceRNA network in placental villus of unexplained recurrent spontaneous abortion.

BACKGROUND: Unexplained recurrent spontaneous abortion (URSA) is one of the most challenging conditions frustrates women of childbearing age profoundly. The gene expression patterns and biological characteristics of placental villus in patients with URSA remain largely unknown. The aim of our study was to identify potential lncRNAs as well as their action mechanisms in URSA. METHOD: The ceRNA microarray was used to identify the mRNA and lncRNA expression profiles of URSA patients and normal pregnancy. Functional enrichment analyses for differentially expressed mRNAs in URSA were performed. Protein-protein interaction analysis of differentially expressed mRNAs was performed to identify hub genes and key modules. Subsequently, the co-dysregulated ceRNA network of URSA was established, and the enrichment analyses for the mRNAs in the ceRNA network was implemented. qRT-PCR was performed to validated the expression of key ENST00000429019 and mRNAs in URSA. RESULTS: We found that URSA placental villus have distinct mRNA and lncRNA expression profiles through ceRNA microarray, with a total of 347 mRNAs and 361 lncRNAs differentially expressed compared with controls. The functional enrichment analysis revealed that ncRNA processing, DNA replication, cell cycle, apoptosis, cytokine-mediated signaling pathway, ECM-receptor interaction were the potentially disrupted pathways in URSA patients. Then we constructed a co-dysregulated ceRNA network and found differentially expressed mRNAs were regulated by a small fraction of hub lncRNAs. Finally, we found a key network of ENST00000429019 and three cell proliferation or apoptosis related key mRNAs (CDCA3, KIFC1, NCAPH), and validated their expression and regulation in tissue and cellular levels. CONCLUSIONS: This study identified a key ceRNA network, which might take part in URSA and correlate with cell proliferation and apoptosis. Optimistically, this study may deepen our apprehensions about the underlying molecular and biological causes of URSA and provide an important theoretical basis for future therapeutic strategies for patients with URSA.

Interleukin-1 increases cyclooxygenase-2 expression and prostaglandin E2 production in human granulosa-lutein cell via nuclear factor kappa B/P65 and extracellular signal-regulated kinase 1/2 signaling pathways.

A multitude of cytokines have been reported to participate in the folliculogenesis process in female. Interleukin-1 (IL-1), belonging to interleukin family, is originally identified as an important immune factor involved in inflammation response. Besides the immunity system, IL-1 is also expressed in reproductive system. However, the role of IL-1 in regulating ovarian follicle function remains to be elucidated. In the current study, using the primary human granulosa-lutein (hGL) and immortalized human granulosa-like tumor cell line (KGN) models, we demonstrated that both IL-1α and IL-1ß increased prostaglandin E2 (PGE2) production via upregulating its cyclooxygenase (COX) enzyme COX-2 expression in human granulosa cells. Mechanistically, IL-1α and IL-1ß treatment activated nuclear factor kappa B (NF-κB) signaling pathway. Using the specific siRNA to knock down endogenous gene expression, we found that the inhibition of p65 expression abolished IL-1α and IL-1ß-induced upregulation of COX-2 expression whereas knockdown of p50 and p52 had no effect. Moreover, our results also showed that IL-1α and IL-1ß promoted the nuclear translocation of p65. ChIP assay demonstrated the transcriptional regulation of p65 on COX-2 expression. Additionally, we also found that IL-1α and IL-1ß could activate the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. The inhibition of ERK1/2 signaling pathway activation reversed IL-1α and IL-1ß-induced upregulation of COX-2 expression. Our findings shed light on the cellular and molecular mechanisms by which IL-1 modulates the COX-2 expression through NF-κB/P65 and ERK1/2 signaling pathways in human granulosa cells.

Risk of Higher Blood Pressure in 3 to 6 Years Old Singleton Born From OHSS Patients Undergone With Fresh IVF/ICSI.

Background: A large registry-based study found the increasing disorders of cardiovascular and metabolism in IVF children but underlying mechanism is still unknown. Few studies have investigated any association between OHSS and cardiovascular or metabolic function in subsequent children. Objective: To evaluate the effect of ovarian hyperstimulation syndrome (OHSS) on blood pressure of singletons after in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). Study Design: The singlet-center corhort study included 1780 singletons born with IVF/ICSI and 83 spontaneously conceived children from 2003 to 2014. Follow-up has lasted more than 10 years, and is still ongoing. This study analyzed data from follow-up surveys at 3 to 6 years of age. Participants Setting and Methods: We recruited 83 children (Group E) spontaneously conceived (SC) as control group and 1780 children born with IVF/ICSI including 126 children born to OHSS-fresh embryo transfer (ET) women (Group A), 1069 children born to non OHSS-ET women (Group B), 98 children conceived by women who developed into moderate or severe OHSS after oocyte retrieval and selected the frozen-thawed embryo transfer (FET) (Group C), 487 children conceived with non OHSS-FET (Group D). We evaluated cardiometabolic function, assessed BP in mmHg, heart rate, anthropometrics, and metabolic index including glucose, serum lipid (triglyceride, total cholesterol, low density lipoprotein, high density lipoprotein), thyroid function, of those children. The BP and heart rate were measured twice on the same day. We applied several multiple regression analyses to investigate the effect of OHSS in the early pregnancy. Main Findings: By the single factor analysis, the SBP and DBP in the SC group (SBP: 99.84 ± 8.9; DBP: 55.27 ± 8.8) were significantly lower than OHSS-ET group's, while the blood pressure was similar between the SC group and other three ART groups. Children had higher BP in the OHSS-ET group (SBP: 101.93 ± 8.17; DBP: 58.75 ± 8.48) than in the non OHSS-ET (SBP: 99.49 ± 8.91; DBP: 56.55 ± 8.02) or OHSS-FET group (SBP: 99.38 ± 8.17; DBP: 55.72 ± 7.94). After using multiple regression analysis to adjust current, early life, parental and ART characteristics, the differences in the SBP and DBP (B (95% confidence interval)) between OHSS-ET and non OHSS-ET remained significant (SBP: 3.193 (0.549 to 2.301); DBP: 3.440 (0.611 to 2.333)). And the BP showed no significant difference complementarily when compared non OHSS-FET group with non OHSS-ET group. In addition, the anthropometrics, fast glucose, serum lipid, and thyroid index did not differ among the ART groups. Principal Conclusions: OHSS might play an independent key role on offspring's BP even cardiovascular function. Electing frozen-thawed embryo transfer for high risk of OHSS population may reduce the risk of the high BP trend. Wider Implications of the Findings: It is a large sample study to investigate the effect of OHSS on offspring's health. These findings provide a clinic evidence of the impact of early environment (embryo even oocyte stage) on the offspring's cardiovascular health. Our study emphasis the importance of the accuracy of IVF clinic strategy and preventing the OHSS after fresh embryo transfer.

LARS2 Regulates Apoptosis via ROS-Mediated Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Ovarian Granulosa Cells.

Several studies have indicated that mutations of LARS2 are associated with premature ovarian insufficiency (POI). However, the pathogenic mechanism of LARS2 in POI has not been reported yet. In the present study, the expression levels of LARS2 and E2F1 in granulosa cells (GCs) of POI patients were examined. CCK-8 and Edu assay were performed to determine the effect of LARS2 on cell proliferation. Apoptosis rate, mitochondrial membrane potential, reactive oxygen species (ROS), and cytoplasm Ca2+ levels were analyzed by flow cytometry. Western blot was conducted to evaluate the expression level of genes affected by LARS2. Transmission electron microscopy (TEM) was used to observe mitochondrial structure in GCs. Chromatin immunoprecipitation (ChIP) was used to evaluate the regulatory effect of E2F1 on Mfn-2 expression. Our results showed that LARS2 expression was downregulated in GCs of POI patients. Silencing of LARS2 inhibited cell proliferation and promoted the apoptosis of GCs. Meanwhile, LARS2 knockdown could induce mitochondrial dysfunction and accumulation of ROS levels. Moreover, ROS was found to be involved in the antiproliferation, proapoptotic, and endoplasmic reticulum (ER) stress effects of LARS2 knockdown. Furthermore, we also found that the expression level of E2F1 was positively correlated with LARS2. In addition, E2F1 could bind at the -61/-46 region of Mfn-2 promoter and regulated MFN-2 transcription. These findings demonstrated that LARS2 could promote the expression of E2F1. E2F1 mediated the effect of LARS2 on Mfn-2 expression via targeting the promoter region of Mfn-2, in which subsequently regulated cell proliferation and apoptosis, which resulted in the etiology of POI. This study will provide useful information for further investigations on the LARS2 in the occurrence of POI.

circRNA-DURSA regulates trophoblast apoptosis via miR-760-HIST1H2BE axis in unexplained recurrent spontaneous abortion.

Unexplained recurrent spontaneous abortion (URSA) is one of the most intractable clinical challenges in reproduction. As a specific type of endogenous non-coding RNA, circular RNAs (circRNAs) have great pre-clinical diagnostic and therapeutic values in diseases. Recently, thousands of circRNAs were detected in human pre-implantation embryos, indicating that circRNAs potentially have important regulatory functions. However, the roles of circRNAs in URSA remain largely unknown. In this study, we elucidated deregulated circRNA expression and distinct competing endogenous RNA (ceRNA) networks by comparing URSA placental villus with that of patients with normal pregnancy using microarrays. We characterized a distinct circRNA, circRNA-0050703, which is downregulated in URSA placental villus (thus we named it circRNA-DURSA). Silencing of circRNA-DURSA results in trophoblast cell apoptosis in vitro. Furthermore, mechanistic dissection revealed that circRNA-DURSA exerts its effects by competitively binding to miR-760, which post-transcriptionally targets HIST1H2BE. Additionally, after circRNA-DURSA silencing in vivo, the numbers of implanted embryos decreased significantly. These results reveal the regulatory roles of circRNA-DURSA in trophoblasts and identified a distinct circRNA-DURSA/miR-760/HIST1H2BE axis as potentially important diagnostic and therapeutic targets for URSA treatment.

Loss of miR-29a impairs decidualization of endometrial stromal cells by TET3 mediated demethylation of Col1A1 promoter.

A conceptual framework for understanding abnormal endometrial decidualization, with considerable significance for the diagnosis and treatment of abnormal decidualization-related changes in non-receptive endometrium in implantation failure during early pregnancy is very important. Here, we found the expression levels of miR-29a in endometrial tissues were associated with the menstrual phases and pregnancy outcome. Inhibition of miR-29a led to decreased decidualization of endometrial stromal cells (ESCs) in vitro, whereas Tet methylcytosine dioxygenase 3 (TET3) and its potential demethylation target, the collagen type I alpha 1 chain (Col1A1), were restored. The binding capacity of TET3 to the Col1A1 promoter could be enhanced by the inhibition of miR-29a. Finally, deletion of TET3 rescued the inhibitory effect of the miR-29a antagomir on the proliferation of decidualized ESCs in vitro and embryo implantation in vivo. Thus, loss of miR-29a causes implantation failure because of the limitation of ESCs decidualization-related changes in non-receptive endometrium during early pregnancy.

The BMP2 Signaling Axis Promotes Invasive Differentiation of Human Trophoblasts.

Embryo implantation and trophoblast invasion are principal limiting factors of pregnancy establishment. Aberrant embryo development or improper trophoblast differentiation and invasion may lead to various unfavorable pregnancy-related outcomes, including early pregnancy loss (EPL). Our clinical data show that the serum BMP2 levels were significantly increased during the first trimester of pregnancy and that the serum and BMP2 expression levels were lower in women with EPL than in women with normal early pregnancies. Moreover, we observed that BMP2 was expressed in oocytes and trophoblast cells of cleaved embryos and blastocysts prior to implantation in both humans and mice. Exogenous BMP2 promoted embryonic development by enhancing blastocyst formation and hatching in mice. LncRNA NR026833.1 was upregulated by BMP2 and promoted SNAIL expression by competitively binding to miR-502-5p. SNAIL induced MMP2 expression and promoted cell invasion in primary extravillous trophoblast cells. BMP2 promotes the invasive differentiation of mouse trophoblast stem cells by downregulating the expression of TS cell marker and upregulating the expression of trophoblast giant cell marker and labyrinthine/spongiotrophoblast marker. Our findings provide significant insights into the regulatory roles of BMP2 in the development of the placenta, which may give us a framework to explore new therapeutic strategies to pregnancy-related complications.

N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating ß-catenin signaling.

BACKGROUND AND AIMS: Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy. METHODS: In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation. RESULTS: In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/ß-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N6-methyladenosine (m6A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models. CONCLUSIONS: This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.

Impact of maternal prepregnancy body mass index on cognitive and metabolic profiles of singletons born after in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the effect of elevated maternal prepregnancy body mass index (BMI) on intelligence and growth of singletons after in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). DESIGN: Cohort study. SETTING: University hospital. PATIENT(S): Singletons born to infertile couples who underwent an autologous IVF/ICSI cycle from 2002 to 2012 and were followed up with at the age of 3-6 years from 2009 to 2017. INTERVENTIONS(S): We compared the health of offspring born to overweight/obese women and normal weight women through assisted reproductive technology (ART). MAIN OUTCOME MEASURE(S): Age- and sex-specific BMI z-scores, verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ), and full intelligence quotient (FIQ). RESULT(S): After adjusting for confounders, obese women were more likely than normal-BMI women to have obese children (20.0% vs. 5.1%), and overweight women had increased risks of having overweight children (13.6% vs. 8.2%) or obese children (10.1% vs. 5.1%) compared with normal-BMI women. Maternal prepregnancy BMI had a weakly negative effect on estimated IQ of children, but after adjusting for parental educational level, the IQ scores of offspring were similar between groups. However, after adjusting for confounders, offspring of obese women showed increased prevalence of intellectual disability (IQ <80) in VIQ (16.9% vs. 8.5%) and FIQ (10.8% vs. 3.9%) compared with normal-BMI women. CONCLUSION(S): Maternal prepregnancy obesity is associated with increased risks for obesity and overweight at early ages in offspring conceived through IVF/ICSI and may also affect the risk of intellectual disability of offspring. Overall, we suggest that weight management is essential for women before entering an IVF/ICSI cycle for ensuring long-term child health.

Non-starch constituents influence the in vitro digestibility of naked oat (Avena nuda L.) starch.

The present study investigated the effects of proteins, lipids and ß-glucan in naked oat flour (NOF) on the in vitro digestibility of starch. The content of rapidly digested starch (RDS) increased, and the content of resistant starch (RS) decreased in NOF after removing the non-starch constituents. The estimated glycemic index (eGI) of starch in NOF increased after the removal of the non-starch constituents, with a decreasing order of naked oat starch (NOS) > de-ß-glucan flour > de-proteins flour > de-lipids flour > NOF. NOS was found to have an A-type crystalline pattern, but the removal of proteins or ß-glucan rendered NOS a V-type crystalline pattern. The relative crystallinity decreased after removing non-starch constituents. The in vitro digestibility was positively correlated with the short-range molecular order and negatively correlated with the relative crystallinity. These results clearly illustrate the effects of non-starch constituents on the low digestibility of naked oat.

Purification, characterization and tyrosinase inhibition activity of polysaccharides from chestnut (Castanea mollissima Bl.) kernel.

The present paper aimed to obtain the polysaccharides with potent tyrosinase inhibitory activity from chestnut kernel. The ultrasound extracted polysaccharide fractions 1-1 (UEP1-1) and UEP2-1 were obtained by successive ultrasound-assisted-extraction, DEAE-52 and Sephadex G-100 chromatography. The Fourier transform infrared spectrum revealed that both UEP1-1 and UEP2-1 had the characteristic absorption peaks of polysaccharides. The degree of esterification of UEP1-1 (52.4%) and UEP2-1 (49.0%) was higher than that of the crude UEP (33.0%), indicating that the gel properties of the polysaccharides changed after purification. The x-ray diffraction patterns of UEP1-1 and UEP2-1 suggested that they were semi-crystalline polymers with a degree of crystallinity of 23.9 and 35.8%, respectively. The weight-average molecular weight (Mw) of UEP1-1 and UEP2-1 was 75.4 and 59.9 kDA, respectively. The monosaccharide composition of UEP1-1 and UEP2-1 was glucose, galactose, arabinose, mannose, xylose, rhamnose and fructose with different proportions. UEP1-1 displayed a dose-dependent inhibitory effect on tyrosinase activity, and the inhibition mode was found to be competitive.

Impact of Galectin-1 on Trophoblast Stem Cell Differentiation and Invasion in In Vitro Implantation Model.

Trophoblast stem cells (TSCs) differentiate in an orderly manner, which plays an important role in the process of embryo implantation, placentation, and early pregnancy maintenance. At the maternal-fetal interface, the dialogue is crucial between trophoblast cells and endometrial epithelial cells. Previous studies suggested that galectin-1 (Gal-1) may play an important role in placental development. In this study, we used Ishikawa (IK) cells-TSC coculture model to simulate the maternal-fetal interface and induce the differentiation of TSCs by differentiation media. The messenger RNA level of each cell type markers, fusion markers, and Gal-1 was detected by quantitative reverse transcription polymerase chain reaction during the differentiation of TSCs. Wound healing and transwell invasion assays were used to detect the migration and invasion ability in each group. We found that coculture with IK cells or conditioned media from IK cells could promote the differentiation and invasion of TSCs and increase Gal-1 expression in TSCs. Furthermore, recombinant Gal-1 could also promote the differentiation and invasion of TSCs, suggesting that some of IK cells secretion increase the expression of Gal-1 in TSCs during implantation, which then induced trophoblast differentiation and invasion in vitro. These findings provide significant insights into the biology of embryo-maternal interactions with the importance of Gal-1 in TSCs for the successful establishment and maintenance of pregnancy.

A potential role of galectin-1 in promoting mouse trophoblast stem cell differentiation.

Galectin-1 is highly expressed in blastocysts and trophoblast giant cells during implantation, and dysregulated galectin-1 is associated with many pregnancy-related abnormalities. Elevated galectin-1 contributes to cancer cells invasion. Here, we found that galectin-1 is expressed in mouse oocytes, preimplantation embryos (all stages), and trophoblast stem (TS) cells. Peak levels of galectin-1 mRNA and protein were detected on day 4 and day 5 after the induction of TS cells differentiation. Overexpression of galectin-1 increased TS cells migration and invasion, whereas knockdown of galectin-1 attenuated these effects. Additionally, knockdown of galectin-1 in TS cells decreased the expression of matrix metalloproteinase (MMP) 2/9, ZEB-1, Snail, N-cadherin, TGF-ß, Nodal, and phospho-Smad2/3, whereas the expression of E-cadherin was increased. In contrast, overexpression of galectin-1 in TS cells increased the expression of MMP2/9, ZEB-1, and N-cadherin, whereas the expression of E-cadherin was decreased. These findings suggest a potential role of galectin-1 in the differentiation of mouse TS cells.

Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals.

Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2α, increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.

[The involvement of galectin-1 in implantation and pregnancy maintenance at the maternal-fetal interface].

As a member of galectins family, galectin-1(Gal-1)is widely expressed in tissues and cells, and participates in a variety of physiological and pathological processes, such as cell adhesion, proliferation, apoptosis and inflammatory reaction. Recently, it has been found that Gal-1 is highly expressed at the maternal-fetal interface and plays important roles in trophoblast cell proliferation, differentiation and invasion, endometrial receptivity, placental angiogenesis and maternal-fetal immune tolerance. In this review, we outline the expression of Gal-1 at the maternal-fetal interface and the involvement of Gal-1 in embryo implantation and pregnancy maintenance, to provide novel insights for the early diagnosis, prognostic assessment and treatment of early pregnancy loss and pregnancy-related diseases.

Different therapeutic approaches on quality of life in patients with inflammatory bowel disease.

BACKGROUND: The chronic nature of inflammatory bowel disease leads to considerable impairment on the health related quality of life (HRQOL). The aims of the present study are to validate the mainland Chinese translation of the Inflammatory Bowel Disease Questionnaire (MCIBDQ), and to evaluate the impact of infliximab treatment on HRQOL in patients with IBD for the first time in China, as compared with other therapies of different levels. Furthermore, the impact of different medical therapies on marriage, employment and economic burden in IBD patients were also evaluated. METHODS: Consecutive patients who met inclusion/exclusion criteria were investigated with MCIBDQ, SF-36, disease activity index (DAI), marriage, employment and economic burden questionnaires before and after treatment. RESULTS: MCIBDQ showed significant reliability and validity both in CD and UC patients. The scores of total SF-36, total MCIBDQ and all domains were found significantly increased, while both DAI and health transition on general health scores were found significantly decreased after infliximab treatment (all P < 0.001). Scores of SF-36 and MCIBDQ increased significantly more in infliximab group than non-infliximab group (all P < 0.05). Infliximab treatment was suggested to significantly reduce the negative impact on love (P = 0.037), increase work time (P = 0.016) and ease economic burden (P = 0.048). CONCLUSIONS: MCIBDQ was demonstrated to be a reliable and valid scale applied in Chinese IBD patients. Infliximab treatment was found to significantly improve HRQOL in IBD patients in comparison with conventional treatments. Negative impact on marriage, employment, and economic status was found in patients with IBD.

Trends and Factors Affecting Hospitalization Costs in Patients with Inflammatory Bowel Disease: A Two-Center Study over the Past Decade.

With the growing number of patients with inflammatory bowel disease (IBD) and hospitalization cases, the overall medical care cost elevates significantly in consequence. A total of 2458 hospitalizations, involving 1401 patients with IBD, were included from two large medical centers. Hospitalization costs and factors impacting cost changes were determined. Patients with IBD and frequency of hospitalizations increased significantly from 2003 to 2011 (P < 0.001). The annual hospitalization cost per patient, cost per hospitalization, and daily cost during hospitalization increased significantly in the past decade (all P < 0.001). However, length of stay decreased significantly (P < 0.001). Infliximab was the most significant factor associated with higher hospitalization cost (OR = 44380.09, P < 0.001). Length of stay (OR = 1.29, P < 0.001), no medical insurance (OR = 1.31, P = 0.017), CD (OR = 3.55, P < 0.001), inflammatory bowel disease unclassified (IBDU) (OR = 4.30, P < 0.0001), poor prognosis (OR = 6.78, P < 0.001), surgery (OR = 3.16, P < 0.001), and endoscopy (OR = 2.44, P < 0.001) were found to be predictors of higher hospitalization costs. Patients with IBD and frequency of hospitalizations increased over the past decade. CD patients displayed a special one peak for age at diagnosis, which was different from UC patients. The increased hospitalization costs of IBD patients may be associated with infliximab, length of stay, medical insurance, subtypes of IBD, prognosis, surgery, and endoscopy.