Comparative analysis of the vaginal microbiome of healthy and polycystic ovary syndrome women: a large cross-sectional study.

RESEARCH QUESTION: What are the different features of the vaginal microbiome (VMB) between patients with polycystic ovary syndrome (PCOS) and healthy women? DESIGN: A cross-sectional study was conducted at a single academic university-affiliated centre. A total of 1446 participants were recruited (PCOS group, n =713, control group, n = 733). Vaginal swabs were analysed using 16S rRNA gene sequencing. The diversity and composition of the microbiome were compared between the PCOS group and the control group. Microbial interaction networks and functional prediction were investigated. RESULTS: The PCOS group had a higher alpha diversity than the control group (Shannon P = 0.03, Simpson P = 0.02), and higher intra-group variability was observed in PCOS group (P < 2.2E-16). At the genus level, the proportion of Lactobacillus decreased (85.1% versus 89.3%, false discovery rate [FDR] = 0.02), whereas the proportion of Gardnerella vaginalis and Ureaplasma increased in the PCOS group (5.1% versus 3.3%, FDR = 0.006; 1.2% versus 0.6%, FDR = 0.002, respectively). Lactobacillus acidophilus, Prevotella buccalis and G. vaginalis were identified as the main differential species. L. acidophilus was positively correlated with serum levels of anti-Müllerian hormone (AMH), and triglyceride (P = 2.01E-05, P = 0.004, respectively). P. buccalis was negatively correlated with serum levels of AMH and testosterone (P = 0.002, P = 0.003, respectively). G. vaginalis was positively correlated with serum levels of AMH, oestradiol and progesterone (P = 0.004, P = 0.005, P = 0.03, respectively). The VMB interaction network indicated that Lactobacillus crispus, Prevotella timonensis, and P. buccalis could be key drivers in the PCOS group. Overall, 55 predicted genes were found to be differentially abundant between PCOS and the control (FDRs < 0.25). CONCLUSIONS: The PCOS group had a higher diversity of vaginal microbiome and showed an enhanced level of heterogeneity. The proportion of Lactobacillus in the PCOS group decreased, whereas the proportions of Gardnerella and Ureaplasma increased. These results warrant further research that can validate the correlation between PCOS and VMB.

JunD Regulates Pancreatic ß-Cells Function by Altering Lipid Accumulation.

The impairment of pancreatic ß-cells function is partly caused by lipotoxicity, which aggravates the development of type 2 diabetes mellitus. Activator Protein 1 member JunD modulates apoptosis and oxidative stress. Recently, it has been found that JunD regulates lipid metabolism in hepatocytes and cardiomyocytes. Here, we studied the role of JunD in pancreatic ß-cells. The lipotoxic effects of palmitic acid on INS-1 cells were measured, and JunD small-interfering RNA was used to assess the effect of JunD in regulating lipid metabolism and insulin secretion. The results showed that palmitic acid stimulation induced the overexpression of JunD, impaired glucose-stimulated insulin secretion, and increased intracellular lipid accumulation of ß-cells. Moreover, the gene expression involved in lipid metabolism (Scd1, Fabp4, Fas, Cd36, Lpl, and Plin5) was upregulated, while gene expression involved in the pancreatic ß-cells function (such as Pdx1, Nkx6.1, Glut2, and Irs-2) was decreased. Gene silencing of JunD reversed the lipotoxic effects induced by PA on ß-cells. These results suggested that JunD regulated the function of pancreatic ß-cells by altering lipid accumulation.

Deciphering biomarkers of endometriosis by proteomic analysis of eutopic endometrium in infertile patients.

AIM: Endometriosis is associated with infertility. The aim of this study was to examine the overall proteomic changes of eutopic endometrium in infertile women with endometriosis. METHODS: Tandem mass tags combined with multidimensional liquid chromatography and mass spectrometry analyses were used to screen the proteomic profiles of eutopic endometrium from infertile patients with endometriosis (N = 4), compared with that from patients without endometriosis (N = 4). Quantitative proteomic analysis, functional categories and significant pathway analysis were investigated subsequently. RESULTS: In total, 6.698 proteins were identified, among which 5,812 proteins were quantified. Compared with controls, proteomic analysis showed some differentially expressed proteins: 16 up-regulated proteins and 23 down-regulated proteins. Bioinformatics analysis indicated that differentially expressed proteins were involved in humoral immune response pathways, antimicrobial humoral response and regulation of nitric oxide biosynthetic process. Besides, our results showed that alpha-1-acid glycoprotein 2, complement factor B and zinc transporter Zip14 were important resources for investigating potential mechanism of infertility in infertile women with endometriosis. CONCLUSIONS: This study provided a reference proteome map of eutopic endometrium from infertile women with endometriosis. The long-term benefits of using those markers to stratify clinical treatment warrant further investigation.

Administration of metrnl delays the onset of diabetes in non-obese diabetic mice.

Type 1 diabetes is a chronic metabolic disease characterized by hyperglycemia due to progressive destruction of pancreatic beta cells via autoimmune attack. Meteorin-like protein (metrnl) is a secreted protein homologous to the neurotrophin metrn and it is induced after exercise in the skeletal muscle. In our paper published previously, we showed that the serum level of metrnl was significantly correlated with the lipid profile, glucose profile and insulin resistance. In this experiment, we asked whether intravenous administration of metrnl could delay the onset of diabetes in non-obese diabetic (NOD) mice. 4-week-old NOD mice were injected intravenously with metrnl. Blood glucose levels were measured weekly. Insulitis scoring, intraperitoneal glucose tolerance test, adoptive T cell transfer, flow cytometry analysis and real-time PCR were performed to investigate the underlying mechanism. The results showed that intravenous administration of metrnl delayed the onset of diabetes in NOD mice. Histology of pancreas showed a decreased infiltration of leukocytes, which was in association with augmentation of regulatory T cells, suppression of autoreactive T cells and altered cytokine secretion. To sum up, the present study showed that intravenous administration of metrnl ameliorated islet lymphocyte infiltration and modulated immune cell responses, raising the possibility that it might be beneficial in improving islet function clinically.

Reproductive Outcomes of In Vitro Fertilization-Intracytoplasmic Sperm Injection after Transcervical Resection of Adhesions: A Retrospective Cohort Study.

STUDY OBJECTIVE: To investigate pregnancy and obstetric outcomes of patients with intrauterine adhesions (IUAs) after treatment with in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) and fresh embryo transplantation after transcervical resection of adhesions (TCRA). DESIGN: Retrospective cohort study. SETTING: University-based reproductive medical center. PATIENTS: A total of 535 patients with IUAs and with a history of TCRA and 1605 matched patients without a history of IUAs underwent IVF-ICSI and received fresh embryo transfers. INTERVENTIONS: Between January 2014 and December 2018, all patients underwent IVF-ICSI treatment and received fresh embryo transfers. MEASUREMENTS AND MAIN RESULTS: The patients in the TCRA group were matched with the control group according to strict criteria. Pregnancy and obstetric outcomes were compared. There were no significant differences in clinical pregnancies, ectopic pregnancies, live births, preterm births, and obstetric outcomes between the 2 groups (p >.05). However, the TCRA group had a higher risk of miscarriage than the control group (p = .048). CONCLUSION: TCRA improved the reproductive outcomes of patients with IUAs, but the risk of miscarriage was higher than that in the general population. To avoid miscarriage, careful monitoring is critical for pregnant patients with a history of TCRA who undergo embryo transfers during IVF treatment.

Effect of Recurrence of Hydrosalpinx after Tubal Ligation on the Outcome of In vitro Fertilization Treatment: A Retrospective Cohort Study.

OBJECTIVE: The objective of the study was to evaluate the effects of recurrent hydrosalpinx after proximal tubal ligation and distal salpingostomy on the outcomes of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. MATERIALS AND METHODS: Seven hundred and twenty-six patients with hydrosalpinx undergoing laparoscopic surgery before IVF were enrolled in the study. Five hundred and sixty-two patients treated with proximal tubal ligation and distal salpingostomy were included in Group A. One hundred and sixty-four cases managed with salpingectomy were grouped into Group B. Group A were further divided into two subgroups. One hundred and forty-six patients in Group A1 had a recurrence of hydrosalpinx. Four hundred and sixteen patients in Group A2 had no repetition of hydrosalpinx. We compared the pregnancy outcomes of their subsequent fresh embryo transfer cycles among the three groups. RESULTS: There were no significant differences among the three groups in terms of age, body mass index (23.56 ± 3.27 vs. 23.13 ± 3.42 vs. 23.63 ± 3.73, P = 0.195), basal hormone level (7.03 ± 1.75 vs. 7.08 ± 2.26 vs. 7.44 ± 2.93, P = 0.195), antral follicle count (12.25 ± 5.92 vs. 12.63 ± 5.71 vs. 11.70 ± 4.98, P = 0.188), duration of gonadotropin (Gn) (11.19 ± 2.1 vs. 10.93 ± 1.84 vs. 10.79 ± 2.03, P = 0.182), consumption of Gn (2136.73 ± 855.65 vs. 1997.15 ± 724.72 vs. 2069.05±765.12 , P = 0.14), endometrial thickness (1.1 ± 0.27 vs. 1.1 ± 0.24 vs. 1.1 ± 0.17, P = 0.352), base follicle-stimulating hormone (6.21 ± 3.43 vs. 6.52 ± 3.20 vs. 5.89 ± 3.10, P = 0.1), number of embryos transferred (1.87 ± 0.36 vs. 1.83 ± 0.42 vs. 1.88 ± 0.37, P = 0.224), and number of high-grade embryos (3.77 ± 2.42 vs. 4.01 ± 2.72 vs. 4.17 ± 2.74, P = 0.41). No differences were detected in clinical pregnancy rate (50% vs. 54.8% vs. 50%, P = 0.439), the live birth rate (86.3% vs. 82.0% vs. 87.8%, P = 0.398), fertilization rate (64.1% vs. 64.4% vs. 64.7%, P = 0.928), and biochemical pregnancy rate (4% vs. 4.5% vs. 7%, P = 0.332) among the three groups. CONCLUSION: The recurrence of hydrosalpinx after tubal ligation does not affect the outcomes of IVF/ICSI. It is not necessary to worry about the effect of recurrent hydrosalpinx on pregnancy outcomes of IVF/ICSI that may due to the spread of inflammation through lymphatic circulation or blood circulation.

Deciphering novel biomarkers of lymph node metastasis of thyroid papillary microcarcinoma using proteomic analysis of ultrasound-guided fine-needle aspiration biopsy samples.

Thyroid papillary microcarcinoma is now a common clinical problem. Cervical lymph node metastasis is the main metastasis mode of PTMC. However, before operation, it is still difficult to determine exactly whether PTMC patient is suffering with cervical lymph node metastasis. To resolve this dilemma, for better selection of optimum treatment plans, it is necessary to investigate the overall changes in proteomes of PTMC, and evaluate the potential of biomarkers to predict lymph node metastasis. Tandem mass tags combined with multidimensional liquid chromatography and mass spectrometry analyses were used aiming to screen the proteomic profiles of fine-needle aspiration biopsy samples. Quantitative proteomic analysis, significant pathway and functional categories were investigated. In total, 3391 proteins of the 3793 protein groups identified were quantified. Bioinformatics analysis indicated that differentially expressed proteins were involved in multiple biological functions, metastasis-related pathways. Moreover, IFN-stimulated gene 15 proteins were found to be well distinguished between patients with lymph node metastatic and patients with nonmetastatic PTMC. Knocking down ISG15 with shRNA inhibited the xenografted tumor growth. This study provided a reference proteome map for lymph node metastatic PTMC. ISG15 probably is a prognosis marker of thyroid papillary microcarcinoma patients with lymph node metastasis. SIGNIFICANCE: Nowadays, thyroid cancer has become a widespread epidemic. The rate of thyroid cancer incidence has been faster than any other cancers, reported by the American Cancer Society. Papillary thyroid microcarcinoma (PTMC) is a subset of PTC defined as PTC measuring≤1 cm in size, which comprises nearly one-half of all the cases of PTCs. Actually, the rapidly increasing global incidence of PTC is mainly attributed to the corresponding increase in the diagnosis of PTMC. Scholars have figuratively compared the increase of PTMC to the "tsunami". The treatment scheme for PTMC is still not uniform, and the controversy is mainly focused on the necessity of surgery treatment. PTMCs often have an indolent course in the absence of evidence of metastatic cervical lymph nodes, distant metastases and extrathyroidal extension. Therefore, it is important for us to reliably differentiate the small number of PTMC patients developing significant metastases progression from the larger population of patients that harbor indolent PTMCs. The present study aimed to investigate the overall changes in proteomes of PTMC, and evaluate the potential of biomarkers to predict lymph node metastasis. Tandem mass tags (TMT) combined with multidimensional liquid chromatography and mass spectrometry analyses were used aiming to screen the proteomic profiles of fine-needle aspiration biopsy (FNAB) samples. Quantitative proteomic analysis, significant pathway and functional categories were investigated. Our results showed that some differential expression proteins were likely to be important resources for finding new diagnostic biomarkers.

Oral administration of PDX1 confers protection against insulitis in the non-obese diabetic (NOD) mice.

Type 1 diabetes is a T cell-mediated organ-specific autoimmune disease. Antigen-specific immune intervention allows the selective targeting of autoreactive T cell, while leaving the remainder of the immune system intact. However, immune intervention for type 1 diabetes has not yielded perfect results clinically. In our paper published previously, we asked whether pancreatic duodenal home box 1 (PDX1) is a target of anti-islet autoimmunity in type 1 diabetes. In this experiment, we assessed the therapeutic effect of oral administration of PDX1 on diabetes development of 4-week-old non-obese diabetic (NOD) mice. The results indicate that PDX1 immunization is an effective intervention strategy for delaying the onset of diabetes in NOD mice in association with: 1) reduced insulitis; 2) suppression of destructive autoreactive T cells; 3) augmentation of regulatory T cells; 4) a shift in cytokine production. The present observations suggest that immunization with PDX1 modulates immune cell responses in NOD mice, raising the possibility that it is beneficial in ameliorating autoimmune destruction of beta-cells and delaying type 1 diabetes development clinically.

Bone marrow mesenchymal stem cells ameliorate inflammatory factor-induced dysfunction of INS-1 cells on chip.

Using a microfluidic chip, we have investigated whether bone marrow mesenchymal stem cells (BM-MSCs) could ameliorate IL-1ß/IFN-γ-induced dysfunction of INS-1 cells. BM-MSCs were obtained from diabetes mellitus patients and their cell surface antigen expression profiles were analyzed by flow cytometric. INS-1 cells were cocultured with BM-MSCs on a microfluidic chip with persistent perfusion of medium containing 1 ng/mL IL-1ß and 2.5 U/mL IFN-γ for 72 h. BM-MSCs could partially rescue INS-1 cells from cytokine-induced dysfunction and ameliorate the expression of insulin and PDX-1 gene in INS-1 cells. Thus BM-MSCs can be viewed as a promising stem cell source to depress inflammatory factor-induced dysfunction of pancreatic ß cells in diabetic patients.