TSLP enhances progestin response in endometrial cancer via androgen receptor signal pathway.

BACKGROUND: The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC). METHODS: The expression of thymic stromal lymphopoietin (TSLP) in EC was evaluated by immunoblot and IHC analysis. Transcriptome sequencing screened out the downstream pathway regulated by TSLP. The role of TSLP, androgen receptor (AR) and KANK1 in regulating the sensitivity of EC to progestin was verified through a series of in vitro and in vivo experiments. RESULTS: TSLP facilitates the formation of a BMP4/BMP7 heterodimer, resulting in activation of Smad5, augmenting AR signalling. AR in turn sensitises EC cells to progestin via KANK1. Downregulation of TSLP, loss of AR and KANK1 in EC patients are associated with tumour malignant progress. Moreover, exogenous TSLP could rescue the anti-tumour effect of progestin on mouse in vivo xenograft tumour. CONCLUSIONS: Our findings suggest that TSLP enhances the sensitivity of EC to progestin through the BMP4/Smad5/AR/KANK1 axis, and provide a link between embryo development and cancer progress, paving the way for the establishment of novel strategy overcoming progestin resistance using embryo original factors.

Progestin Resistance and Corresponding Management of Abnormal Endometrial Hyperplasia and Endometrial Carcinoma.

With a younger tendency in morbidity age, endometrial cancer (EC) incidence has grown year after year. Worse, even more commonly occurring is endometrial hyperplasia (EH), which is a precancerous endometrial proliferation. For young women with early EC and EH who want to preserve fertility, progestin therapy has been utilized as a routine fertility-preserving treatment approach. Nevertheless, progestin medication failure in some patients is mostly due to progestin resistance and side effects. In order to further analyze the potential mechanisms of progestin resistance in EH and EC, to provide theoretical support for effective therapeutic strategies, and to lay the groundwork for searching novel treatment approaches, this article reviews the current therapeutic effects of progestin in EH and EC, as well as the mechanisms and molecular biomarkers of progestin resistance, and systematically expounds on the potential therapeutic methods to overcome progestin resistance.

Androgen Signaling in Uterine Diseases: New Insights and New Targets.

Common uterine diseases include endometriosis, uterine fibroids, endometrial polyps, endometrial hyperplasia, endometrial cancer, and endometrial dysfunction causing infertility. Patients with uterine diseases often suffer from abdominal pain, menorrhagia, infertility and other symptoms, which seriously impair their health and disturb their lives. Androgens play important roles in the normal physiological functions of the uterus and pathological progress of uterine diseases. Androgens in women are synthesized in the ovaries and adrenal glands. The action of androgens in the uterus is mainly mediated by its ligand androgen receptor (AR) that regulates transcription of the target genes. However, much less is known about the signaling pathways through which androgen functions in uterine diseases, and contradictory findings have been reported. This review summarizes and discusses the progress of research on androgens and the involvement of AR in uterine diseases. Future studies should focus on developing new therapeutic strategies that precisely target specific AR and their related signaling pathways in uterine diseases.

GnRH-agonist pretreatment in hormone replacement therapy improves pregnancy outcomes in women with male-factor infertility.

Objective: This study aimed to examine the efficacy of HRT with gonadotropin-releasing hormone agonist (GnRH-a) pre-treatment in women with male-factor infertility who underwent a frozen embryo transfer (FET) programme. Design: Between January 2016 and October 2020, 2733 women with male-factor infertility who underwent the HRT protocol as the endometrial preparation method were enrolled at two Reproductive Medicine Centres. Patients were divided into two groups based on whether they had GnRH-a pre-treatment before HRTs: the GnRHa-HRT group and the HRT group. The inverse probability of treatment weighting (IPTW) method was conducted to balance patient baseline characteristics between treatment cohorts to reduce selection bias. The live birth rate was considered regarded as the primary pregnancy outcome. Results: Multivariate logistic regression adjusted for confounding factors, the GnRHa-HRT group showed a notably higher rate of live birth (OR 2.154, 95% CI 1.636~2.835, P<0.001) when compared to the HRT group. Additionally, the rate of miscarriage was significantly lower in the GnRHa-HRT group. The GnRHa-HRT group had significantly higher rates of biochemical pregnancy, clinical pregnancy, multiple pregnancy, and term birth. Conclusion: The endometrial preparation protocol of HRT with GnRH-a pre-treatment could obviously increase the live birth rate for women with male-factor infertility undergoing the FET programme.

Ovarian stimulation in IVF couples with severe male factor infertility: GnRH antagonist versus long GnRH agonist.

Objective: To examine the efficacy of gonadotropin releasing hormone (GnRH) antagonist (GnRH-ant) protocol and the long GnRH agonist (GnRH-a) protocol during in vitro fertilization (IVF) therapy in patients with severe male infertile factors. Methods: A total of 983 women with severe male factor infertility undergoing IVF therapy from 2017 to 2020 at one center were retrospectively analyzed. Patients were divided into the GnRH-ant group (n=527) and the GnRH-a group (n=456) according to their ovarian stimulation protocols. Patient baseline characteristics, ovarian stimulation characteristics, and clinical pregnancy outcomes were compared between the groups. The live birth rate was considered the main pregnancy outcome. Results: GnRH-a group had a higher live birth rate compared with the GnRH-ant group (41.0% versus 31.3%, p=0.002). Moreover, the implantation (32.8% vs. 28.1%, p=0.033), biochemical pregnancy (52.4% versus 44.8%, p=0.017), clinical pregnancy (49.3% versus 39.7%, p=0.002) and ongoing pregnancy rates (43.2% vs. 34.9%, p=0.008) were higher in GnRH-a group. For patients with one embryo transferred, the GnRH-a group demonstrated higher live birth (37.0% vs. 19.4%, p=0.010) and ongoing pregnancy rate (38.9% vs. 24.5%, p=0.046) than the GnRH-ant group. Among patients with two embryos transferred, the live birth rate was also higher in the GnRH-a group than in the GnRH-ant group, with no statistical difference. No significant differences were observed in the biochemical abortion rate, clinical miscarriage rate, early miscarriage rate, late miscarriage rate, heterotopic pregnancy rate, twin pregnancy rate, and birth sex ratio between the two groups. Conclusion: For individuals with severe male infertility undergoing IVF, the GnRH-a protocol is considered a more efficient and feasible strategy with a higher live birth rate compared to the GnRH-ant protocol, especially in single embryo transfer.

Comparison of different endometrial preparation protocols on frozen embryo transfer pregnancy outcome in patients with normal ovulation.

RESEARCH QUESTION: What is the effect of letrozole use in patients undergoing frozen embryo transfer (FET) with normal ovulation? Although the number of FETs is increasing, an optimal protocol for FET (particularly vitrified-warmed embryo transfer) is yet to be determined. The aim of this study was to evaluate letrozole use on patients with normal menstrual cycles compared with hormone replacement therapy (HRT) cycles and natural cycles. DESIGN: The study involved 2849 patients. Patients were divided into three groups: HRT cycle (n = 2115), letrozole cycle (n = 532) and natural cycle (n = 202). Inverse probability of treatment weighting aimed to equate each group according to measured baseline covariates to achieve a comparison with reduced selection bias and live birth rate as main pregnancy outcome was analysed. RESULTS: In the crude analysis, the letrozole group had a higher live birth rate compared with the HRT cycle (OR 1.18, 95% CI 1.06 to 1.33) and natural cycle (OR 1.24, 95% CI 1.11 to 1.41); after adjusting for confounding factors, live birth rate was consistently higher in the letrozole group. Moreover, the biochemical pregnancy, clinical pregnancy, ongoing pregnancy and full-term delivery rates were higher in the letrozole group. CONCLUSION: For infertile women with normal menstrual cycle undergoing FET, mildly stimulated cycles with letrozole present a relatively large advantage compared with HRT cycle and natural cycle, with higher live birth pregnancy, indicating that letrozole administration could improve pregnancy outcomes in this population.

Global research trends in the field of liver cirrhosis from 2011 to 2020: A visualised and bibliometric study.

BACKGROUND: Liver cirrhosis is the leading cause of liver-related mortality worldwide. It is currently a global health challenge. AIM: This research intended to explore and analyse research trends and frontiers in this field during the last 10 years, providing new inspiration for clinical decision-making and scientific research. METHODS: Publications on hepatic cirrhosis research were retrieved from the Web of Science Core Collection on April 4, 2021. Bibliometric visualisation was conducted through VOSviewer and CiteSpace. RESULTS: The analytic research was based on original articles and reviews. A total of 7775 records of hepatic cirrhosis published from 2011 to 2020 were retrieved. In the past ten years, the number of related annual publications has increased significantly, especially in the United States and China. All publications were distributed among 109 countries. The United States contributed the most (21.95%) and was consistently the leading driving force, with a solid academic reputation in this area. The University of Barcelona distributed the most related articles (177 articles) and was cited the most frequently. The Journal of Hepatology ranked third in the top 10 journals, which has the highest impact factor (impact factor 2019 = 20.582). Jasmohan S. Bajaj was the most productive author (72 articles). Burst keywords (e.g., sofosbuvir, burden, care, sarcopenia, chronic liver failure, human gut microbiome, and nonalcoholic fatty liver disease) and a succession of reference citation bursts have provided clues about research frontiers in recent years. CONCLUSION: This study identified developing trends in the evolution of liver cirrhosis to provide new inspiration for researchers.

Botanical characteristics, phytochemistry and related biological activities of Rosa roxburghii Tratt fruit, and its potential use in functional foods: a review.

Due to the growing global population, reduction in arable land and effects of climate change, incongruity between food supply and demand has become increasingly severe. Nowadays, with awareness of the elementary nutrients required for human growth, increasing attention is being paid to the health and medical functions of food. Along with increased food production achieved by modern agricultural techniques, underutilised functional foods are an important strategy for solving food security problems and maintaining the nutritional quality of the human diet. Rosa roxburghii Tratt (RRT) is a natural fruit that contains unique functional and nutritional constituents, which are characterised by a high anti-oxidant potential. This review summarises the biological characteristics, chemical composition, health-promoting properties and development status of RRT products to inspire investigations on the use of RRT fruit as a functional food, dietary supplement and pharmaceutical additive. The nutrients and functional ingredients of RRT fruit are described in detail to provide more reference information for nutritionists and pharmacists.

Therapeutic Potential of Apatinib Against Colorectal Cancer by Inhibiting VEGFR2-Mediated Angiogenesis and ß-Catenin Signaling.

PURPOSE: Apatinib is an inhibitor of VEGFR2 (vascular endothelial growth factor receptor 2) that has attracted a great deal of attention due to its promotion of anticancer activity. In the present study, we investigated the therapeutic effects of apatinib against colorectal cancer (CRC) and examined the underlying mechanism. MATERIALS AND METHODS: Both in vivo and in vitro assays were conducted to study the effect of apatinib on CRC. To elucidate the associated mechanism, RNA-seq (transcriptome) analysis was conducted on apatinib-treated HCT116 cells. RESULTS: Apatinib showed antiproliferative and proapoptotic effects, induced G0/G1 arrest and blocked cell migration and invasion in CRC. An analysis of the mechanism associated with apatinib activity demonstrated that by interacting with VEGFR2, apatinib decreased p-Src, p-Akt, and p-GSK3ß levels, which further increased ß-catenin ubiquitination and reduced the nuclear translocation of ß-catenin. Furthermore, apatinib strongly suppressed CT26 cell growth in mouse xenograft models by inhibiting ß-catenin signaling and angiogenesis. CONCLUSION: Overall, the results of the present study here indicated that by inhibiting the VEGFR2-ß-catenin-mediated malignant phenotype, apatinib significantly suppresses the growth of CRC, suggesting that the use of apatinib is a promising therapeutic strategy for CRC.

Differentiation of usual vertebral compression fractures using CT histogram analysis as quantitative biomarkers: A proof-of-principle study.

PURPOSE: To investigate the utility of CT histogram analysis (CTHA) for discrimination of traumatic, osteoporotic and malignant fractures in patients with vertebral compression fractures (VCFs). To evaluate the feasibility and accuracy of CTHA in differentiating non-malignant (traumatic and osteoporotic) from malignant VCFs. MATERIALS AND METHODS: Totally, 235 patients with VCFs were enrolled in the current experimental study. There were 132 patients with traumatic VCFs, 51 with osteoporotic VCFs and 52 with malignant VCFs, with MRI and histology as the standard references. All the patients underwent unenhanced CT scans. Nineteen histogram-based parameters were derived using Omni-Kinetics software (Omni-Kinetics, GE Healthcare). The reproducibility of those parameters was evaluated using two independent delineations conducted by two observers. These histogram parameters were compared among the three different VCFs using Kruskal-Wallis H test. Traumatic VCFs and osteoporotic VCFs were combined as non-malignant VCFs and compared with malignant VCFs using Mann-Whitney U test Multivariable logistic regression analysis was performed on the significantly different features and built a diagnosis model. Receiver operating characteristic (ROC) curve was carried out to observe the difference of diagnostic performance between the single positive parameter and the combination of parameters. RESULTS: All the 19 parameters presented excellent reproducibility, with intraclass correlation coefficient values from 0.789 to 0.997. At quantitative evaluation, the best predictive histogram parameters in discrimination of the three different types of VCFs were relative min intensity (p = 0.022), relative entropy (p = 0.043), and relative frequency size (p < 0.001). Relative frequency size (p < 0.001) and relative quantile5 (p = 0.012) resulted in statistically significant difference between non-malignant and malignant VCFs. The area under ROC curve indicated that relative frequency size combined with relative quantile5 (0.754; 95 % confidence intervals: 0.661∼0.829; p < 0.001) was of best performance in differentiating malignant from non-malignant VCFs. CONCLUSIONS: Our results are encouraging and suggest that histogram parameters derived from unenhanced CT could be reliable quantitative biomarkers for diff ;erential diagnosis of usual VCFs.

Development of fermented chestnut with Bacillus natto: Functional and sensory properties.

Food fermentation can improve food nutritional value and sensory performance, it is considered as an ecofriendly bioprocessing technology. In this work, a fermented natto chestnut food was firstly developed and its active ingredients and functional properties were systematically studied. Through systematic experimental screening, including a single factor experiment and Box-Behnken design, the fermentation parameters of chestnut were optimized and selected. Under the optimal fermentation conditions, fermentation time 56 h, temperature 38 â„ƒ and 5% inoculum concentration, the fibrinolytic activity of the natto-chestnut reached 6479 IU/g. Meanwhile, higher antioxidant activity of the natto-chestnut was obtained due to the increased contents of total phenolic, total flavonoid and VC. In addition, α-glucosidase inhibition activity was also improved in the natto-chestnut. These results indicated that fermented chestnut could be a new dietary supplement with higher quality and better activities for people's health.

A simple and efficient sample preparation for taxanes in Taxus chinensis needles with natural menthol-based aqueous deep eutectic solvent.

Taxanes are natural anticancer constituents, and the sample preparation from matrix normally depends on organochlorine solvents. In this study, green and natural menthol-based aqueous deep eutectic solvent was synthesized and used for sample preparation for taxanes. Five key parameters were optimized and the optimal preparation conditions were as follows: menthol/1-propanol ratio 1:1 (mol/mol), solid-liquid ratio 1:30 g/mL, extraction time 30 min, ultrasonic power 250 W, and water content 80%. Under the above conditions, the total extraction efficiency of seven main taxanes was 1.25- to 1.44-fold to the conventional methods. In addition, a high-performance liquid chromatography method with C18 column was established for quantitation of seven main taxanes in <25 min, which had excellent linearity (R2  > 0.9986), precision (relative standard deviation < 3.00%), repeatability (relative standard deviation < 3.69%), and recovery (90.26-109.00%). This method performed the extraction, and enrichment processes simultaneously, and it had advantages such as high extraction efficiency, simple operation, low cost, and eco-friendliness. This work indicated that the natural menthol-based deep eutectic solvent aqueous could be an excellent alternative to the sample preparation from Taxus or other plants.

Design of Rapid Bacterial Identification System Based on Scattering of Laser Light and Classification of Binned Plots.

The rapid detection and classification of bacterial pathogens have great medical utility, and widespread applications in clinical labs, intensive care units, and infectious disease departments. The Rapid Bacterial Identification System (RBIS) is based on the principle of variation in light scattering when the laser beam passes through bacterial microbes. The use of laser light scattering and classification of binned plots algorithm gives a new dimension for real-time identification of different pathogens without any biochemical processing. Bacterium identification device consists of an assembly of photodetectors surrounded by the bacterial sample at different angles. The photodetectors acquire the scattered light in form of peaks when the laser beam passes by the sample. The acquired peak values were used to create 3D histograms to evaluate the frequency of occurrence. However, the identification is based on creating two dimensional binned plots with the help of the frequency of occurrence of peak values across two photodetectors. The algorithm of the system consists of two parts: Library files and the Comparator. Library files contain data of bacterial species in form of binned plots, while comparator compares the data of test sample with library files. The classification of sample depends on the maximum resemblance of the number of binned plots with library files. The classification of Enterococcus faecalis, Staphylococcus aureus, and Escherichia coli gives mean accuracies of 81.8%, 70.9%, and 71.4 %, respectively. The proposed system can be applied to future real-time intelligent theranostic systems for diagnosis and treatment of pathogenic diseases.

Pharmacological effects of different ginger juices on the concurrent symptoms in animal models of functional dyspepsia: A comparative study.

OBJECTIVE: Patients with gastrointestinal disorders commonly suffer from poor treatment outcomes and adverse effects of traditional pharmacological therapy. Herbal medicine is a favorable alternative due to the low risk of side effects. This study was performed to explore the antiemetic effects and the improvement effect on gastrointestinal function of components of three ginger juice excipients. METHODS: The compositions were analyzed by liquid chromatograph mass spectrometer (LC-MS), especially the gingerols of dried ginger juice (DGJ), fresh ginger juice (FGJ), and fresh ginger boiled juice (FGBJ). Furthermore, the respective gastrointestinal effects on rat models with functional dyspepsia (FD) were compared. RESULTS: The 6-keto-PGF1α levels in the serum of the treated groups were significantly reduced (p < 0.05), as compared with the control group. Compared with the cisplatin group, there was an apparent reduction in kaolin intake for DGJ, FGJ, and FGBJ (p < 0.01; p < 0.01; p < 0.05). The intestinal propulsive rate of the rats in the treated group was significantly higher than that in the control group (p < 0.05). Ginger juices significantly improved gastrointestinal function in rats. Eight common components were found in DGJ, FGJ, and FGBJ, among which 6-paradol, 10-gingerol, and 12-shogaol led to inhibited gastric mucosal damage function effect according to the Pearson correlation analysis. Only 6-shogaol was found to have a positive correlation with gastrointestinal function effect through Pearson correlation analysis. CONCLUSION: Ginger juice should be recommended for the medicinal materials used in the treatment of concurrent symptoms of FD.

Theranostics Applications of Nanoparticles in Cancer Immunotherapy.

With the advancement in the mechanism of immune surveillance and immune evasion in cancer cells, cancer immunotherapy shows promising results for treating cancer with established efficacy and less toxicity. As a result of the off-target effect, the approach for delivering vaccines, adjuvants, or antibodies directly to tumor sites is gaining widespread attention. An effective alternative is to utilize nanoengineered particles, functioning as drug-delivery systems or as antigens themselves. This article reviews the practical implementation of nanotechnology in cancer immunotherapy.

Effect of fermented biogas residue on growth performance, serum biochemical parameters, and meat quality in pigs.

OBJECTIVE: This study investigated the effect of fermented biogas residue (FBR) of wheat on the performance, serum biochemical parameters, and meat quality in pigs. METHODS: We selected 128 pigs (the mean initial body weight was 40.24±3.08 kg) and randomly allocated them to 4 groups (1 control group and 3 treatment groups) with 4 replicates per group and 8 pigs per pen in a randomized complete block design based on initial body weight and sex. The control group received a corn-soybean meal-based diet, the treatment group fed diets containing 5%, 10%, and 15% FBR, respectively (abbreviated as FBR5, FBR10, and FBR15, respectively). Every group received equivalent-energy and nitrogen diets. The test lasted 60 days and was divided into early and late stages. Blood and carcass samples were obtained on 60 d. Meat quality was collected from two pigs per pen. RESULTS: During the late stage, the average daily feed intake and average daily gain of the treatment groups was greater than that of the control group (p<0.05). During the entire experiment, the average daily gain of the treatment groups was higher than that of the control group (p<0.05). Fermented biomass residue did not significantly affect serum biochemical parameters or meat quality, but did affect amino acid profiles in pork. The contents of Asp, Arg, Tyr, Phe, Leu, Thr, Ser, Lys, Pro, Ala, essential amino acids, non-essential amino acids, and total amino acids in pork of FBR5 and FBR10 were greater than those of the control group (p<0.05). CONCLUSION: These combined results suggest that feeding FBR could increase the average daily gain and average daily feed intake in pigs and the content of several flavor-promoting amino acids.

Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway.

Breast cancer stem cells (BCSCs) are believed to be responsible for tumor chemoresistance, recurrence, and metastasis formation. Salinomycin (SAL), a carboxylic polyether ionophore, has been reported to act as a selective breast CSC inhibitor. However, the molecular mechanisms underlying SAL-induced cytotoxicity on BCSCs remain unclear. The Hedgehog (Hh) signaling pathway plays an important role in CSC maintenance and carcinogenesis. Here, we investigated whether SAL induces cytotoxicity on BCSCs through targeting Hh pathway. In the present study, we cultured breast cancer MCF-7 cells in suspension in serum-free medium to obtain breast CSC-enriched MCF-7 mammospheres (MCF-7 MS). MCF-7 MS cells possessed typical BCSC properties, such as CD44+CD24-/low phenotype, high expression of OCT4 (a stem cell marker), increased colony-forming ability, strong migration and invasion capabilities, differentiation potential, and strong tumorigenicity in xenografted mice. SAL exhibited selective cytotoxicity to MCF-7 MS cells relative to MCF-7 cells. The Hh pathway was highly activated in BCSC-enriched MCF-7 MS cells and SAL inhibited Hh signaling activation by downregulating the expression of critical components of the Hh pathway such as PTCH, SMO, Gli1, and Gli2, and subsequently repressing the expression of their essential downstream targets including C-myc, Bcl-2, and Snail (but not cyclin D1). Conversely, Shh-induced Hh signaling activation could largely reverse SAL-mediated inhibitory effects. These findings suggest that SAL-induced selective cytotoxicity against MCF-7 MS cells is associated with the inhibition of Hh signaling activation and the expression of downstream targets and the Hh pathway is an important player and a possible drug target in the pathogenesis of BCSCs.

MiR-26a regulates cell cycle and anoikis of human esophageal adenocarcinoma cells through Rb1-E2F1 signaling pathway.

Resistance to anoikis, the subtype of apoptosis induced by lack of matrix adhesion, contributes to malignant transformation and development of metastasis. MicroRNAs play key regulatory roles in tumorigenesis and metastasis. In this study, we described that miR-26a, which is usually downregulated in tumor cells, is involved in the acquisition of anoikis-resistance of human esophageal adenocarcinoma (EA) cells. Results of qRT-PCR in clinical samples showed that downregulated miR-26a expression is related to tumorigenesis and metastasis of EA. In vitro experiments determined that miR-26a directly participates in the regulation of cell cycle and anoikis of human EA OE33 cells. Further, we identified that Rb1 is the direct functional target of miR-26a, and revealed that the reduction of miR-26a expression leads to increased Rb1 protein level and thus inhibits the function of E2F1, by which it influences the phenotypes of cell cycle and anoikis. The findings we reported here presented the evidence that miR-26a may be involved in regulation of anoikis-resistance of EA cells. Targeting miR-26a may provide a novel strategy to inhibit metastasis.