AI-Based Optimal Treatment Strategy Selection for Female Infertility for First and Subsequent IVF-ET Cycles.

Over the last 20 years, China's infertility rate has risen from 3% to 12.5%-15%. Infertility has become the third largest disease following cancer and cardiovascular disease. Then, the in vitro fertilization and embryo transfer (IVF-ET) becomes more and more important in infertility treatment field. However, the reported success rate for IVT-ET is 30%-40% and costs are gradually rising. Meanwhile, to increase success rates and decrease costs, the optimal selection of the IVF-ET treatment strategy is crucial. In a clinical work, the IVF-ET treatment strategy selection is always based on the experience of the doctor without a uniform standard. To solve this important and complex problem, we proposed an artificial intelligence (AI)-based optimal treatment strategy selection system to extract implicit knowledge from clinical data for new and returning patients, by mimicking the IVF-ET process and analysing a myriad of treatment decisions. We demonstrated that the performance of the model was different in 10 AI classification algorithms. Hence, we need to select the optimal method for predicting patient pregnancy result in different IVF-ET treatment strategies. Moreover, feature ranking is determined in the proposed model to measure the importance of each patient characteristics. Therefore, better advice can be provided for individual patient characteristics, doctors can provide more valid suggestions regarding certain patient characteristics to improve the accuracy of diagnosis and efficiency.

Immunopathogenesis of patients with COVID-19: from the perspective of immune system 'evolution' and 'revolution'.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 is sweeping the world, threatening millions of lives and drastically altering our ways of living. According to current studies, failure to either activate or eliminate inflammatory responses timely and properly at certain stages could result in the progression of the disease. In other words, robust immune responses to coronavirus disease 2019 (COVID-19) are critical. However, they do not theoretically present in some special groups of people, including the young, the aged, patients with autoimmunity or cancer. Differences also do occur between men and women. Our immune system evolves to ensure delicate coordination at different stages of life. The innate immune cells mainly consisted of myeloid lineage cells, including neutrophils, basophils, eosinophils, dendritic cells and mast cells; they possess phagocytic capacity to different degrees at different stages of life. They are firstly recruited upon infection and may activate the adaptive immunity when needed. The adaptive immune cells, on the other way, are comprised mainly of lymphoid lineages. As one grows up, the adaptive immunity matures and expands its memory repertoire, accompanied by an adjustment in quantity and quality. In this review, we would summarise and analyse the immunological characteristics of these groups from the perspective of the immune system 'evolution' as well as 'revolution' that has been studied and speculated so far, which would aid the comprehensive understanding of COVID-19 and personalised-treatment strategy.

The Effects of Negative Elements in Environment and Cancer on Female Reproductive System.

With the development of human society, factors that contribute to the impairment of female fertility is accumulating. Lifestyle-related risk factors, occupational risk factors, and iatrogenic factors, including cancer and anti-cancer treatments, have been recognized with their negative effects on the function of female reproductive system. However, the exact influences and their possible mechanism have not been elucidated yet. It is impossible to accurately estimate the indexes of female fertility, but many researchers have put forward that the general fertility has inclined through the past decades. Thus the demand for fertility preservation has increased more and more dramatically. Here we described some of the factors which may influence female reproductive system and methods for fertility preservation in response to female infertility.

Analysis of endometrial thickness patterns and pregnancy outcomes considering 12,991 fresh IVF cycles.

BACKGROUND: Different endometrial patterns have an important effect on the relationship between endometrial thickness (EMT) and clinical pregnancy rate. There is a significant difference in age, selection of cycle protocols, and clinical pregnancy rates among four groups with diverse endometrial patterns. METHODS: This retrospective study aimed to assess the association between EMT on human chorionic gonadotropin (HCG) administration day and the clinical outcome of fresh in vitro fertilization (IVF). The 5th, 50th, and 95th percentiles for EMT were determined as 8, 11, and 14 mm, respectively. Patients were sub-divided into four groups based on their EMT in different endometrial patterns (Group 1: < 8 mm; Group 2: ≥ 8 and ≤ 11 mm; Group 3: > 11 and ≤ 14 mm; Group 4: > 14 mm). We divided patients into three groups based on their endometrial pattern and evaluated the correlation between EMT and clinical pregnancy rate. RESULTS: We found a positive correlation between pregnancy rates and EMT in all endometrial patterns. Multiple logistic regression analysis proved age, duration of infertility, cycle protocols, number of embryos transferred, progesterone on HCG day, endometrial patterns, and EMT have significant effects on clinical pregnancy rates. Meanwhile, there was a significant difference in age, selection of cycle protocols, and clinical pregnancy rates among four groups with diverse endometrial patterns. CONCLUSIONS: Different endometrial patterns have an important effect on the relationship between EMT and clinical pregnancy rate.

YY1-PVT1 affects trophoblast invasion and adhesion by regulating mTOR pathway-mediated autophagy.

Insufficient trophoblast invasion is the key factor for the occurrence of recurrent spontaneous abortions (RSA). Our previous studies identified Yin Yang 1 (YY1) as a transcription factor involved in the regulation of trophoblast invasiveness at the maternal-fetal interface. Long noncoding RNAs (lncRNAs) can regulate gene expression and autophagy in many ways. The purpose of this study was to explore the relationship between YY1 and lncRNAs and the mechanism by which lncRNAs affect the biological behavior of trophoblasts. Bioinformatic analysis predicted that YY1 had three binding sites in the plasmacytoma variant translocation 1 (PVT1) promoter region. Chromatin immunoprecipitation experiments and electrophoretic mobility shift assays verified that YY1 can directly bind to the PVT1 promoter. Compared with its expression levels in human placental villi tissue samples from the normal pregnancy group, the PVT1 expression levels were significantly lower in tissues from the RSA group. PVT1 knockdown significantly reduced adhesion, invasion, autophagy, and mTOR expression in HTR-8/SVneo cells and greatly increased apoptosis in vitro. This study revealed a novel regulatory pathway in which YY1 can act directly on PVT1 promoter to regulate its transcription, which further affects trophoblast invasion and adhesion by regulating autophagy via the mTOR pathway, and these effects might be involved in RSA pathogenesis.

Genetic variability and functional implication of HPV16 from cervical intraepithelial neoplasia in Shanghai women.

Human papillomavirus (HPV)16 gene mutation is usually associated with persistent HPV infection and cervical intraepithelial neoplasia (CIN). However, the functional implications of HPV16 mutations remain poorly understood.145 LCR/E6/E7 of the HPV16 isolates were amplified and sequenced, and HPV16 integration status was detected. In total, 89 SNPs (68 in the LCR, 13 in E6, 8 in E7) were discovered, 11 of which were nonsynonymous mutations (8 in E6, 3 in E7). The H85Y and E120D variants in E6 were significantly reduced in the high-grade squamous intraepithelial lesion (HSIL) group compared to the T," a potential binding site for TATA-binding protein, is the most common in LCR variants. A4 (Asian) was associated with an increased risk of HSIL compared to A1-3(P = .009). The H85/E120 in E6 and N29 in HPV16 E7 might play a critical role in carcinogenesis by disrupting p53 and Rb degradation due to affecting their interaction, respectively. In a word, the findings in this study provide preventative and therapeutic interventions of HPV16 -related cervical lesions/cancer.

[The development of basic research in the field of male reproductive health in China over the past 30 years supported by the National Natural Science Foundation of China].

Reproductive health is a key aim of the population health strategy, and male reproductive health constitutes an important part of reproductive health. This article systematically analyzes the applications to and grants from the National Natural Science Foundation of China (NSFC) and some related scientific problems in the field of male reproductive health in the past 30 years. It also discusses the development of the basic researches on male reproductive health in China and the facilitating role of NSFC in this field.

The miR-27a-3p/USP25 axis participates in the pathogenesis of recurrent miscarriage by inhibiting trophoblast migration and invasion.

Insufficient invasion ability of trophoblasts might be associated with the development of recurrent miscarriage (RM). Ubiquitin-specific protease 25 (USP25) can regulate the processes of invasion and migration in different types of cancer cells. However, the effect of USP25 on trophoblasts and its roles in the development of RM are unknown. In this study, we first analyzed the USP25 expression in placental villous tissues from RM patients, and then assessed the roles of USP25 in epithelial-to-mesenchymal transition (EMT), invasion and migration of trophoblasts. Furthermore, bioinformatics prediction and luciferase reporter assay were used to explore the mechanism of microRNA on USP25 expression, and regulation of USP25 expression in trophoblasts was assessed following transfection with microRNA mimics or inhibitor. The results showed that the expression of USP25 in the placental villous tissues was downregulated in RM patients. Knockdown of USP25 suppressed the EMT process, the invasion and migration capability of trophoblast cells, while overexpression of USP25 exhibited opposite results. Mechanistically, miR-27a-3p could regulate USP25 expression by binding to the 3'-untranslated region of USP25 in trophoblasts. Quantitative real-time polymerase chain reaction results found the expression of miR-27a-3p were negatively related to USP25 in RM patients. MiR-27a-3p mimics inhibited but miR-27a-3p inhibitor enhanced the migration and invasion capability of trophoblasts. Furthermore, sh-USP25 counteracted the promotion of invasion and migration mediated by the miR-27a-3p inhibitor. Taken together, these data indicate that USP25 downregulation by miR-27a-3p contributes to the EMT process, thereby inhibiting the migration and invasion of trophoblast cells, and these findings might provide potential biomarkers for RM.

Is differences in embryo morphokinetic development significantly associated with human embryo sex?†.

To date, very few studies have reported on the relationship between live birth gender and embryo development kinetics. This study included 1735 women undergoing in vitro fertilization or intracytoplasmic sperm injection by using a time-lapse system. Finally, a total of 228 qualified patients with 100% implantation and known live birth information were included in the analysis. There were 174 male live births and 134 female live births. The time to 3 (t3), 4 (t4), and 5 (t5) cell development of male embryos was significantly shorter/earlier than female embryos (P < 0.05). The duration of the second cell cycle (cc2) in male embryos was significantly shorter than female embryos (P = 0.002). Multivariate logistic regression showed that only t3 had a significant correlation with live birth gender; the odds ratio (OR) was 0.786, 95% confidence interval (CI) was 0.625-0.988 (P < 0.05). When morphokinetic parameters were divided into groups based on quartiles, embryos within the sex ranges were observed to have significantly different proportions of male and female live births (P < 0.05). The results showed that t3 (<14 h) was the most relevant parameter related to live birth gender (OR 2.452, 95% CI 1.071-5.612, P = 0.03). These findings support the idea that embryo morphokinetic parameters were affected by the sex of the embryo. Currently, embryologists use embryo morphokinetics to establish models of development, in order to improve accurate selection of viable embryos. Thus, this factor needs to be considered when embryologists use embryo morphokinetics to select embryos.

Artificial intelligence in reproductive medicine.

Artificial intelligence (AI) has experienced rapid growth over the past few years, moving from the experimental to the implementation phase in various fields, including medicine. Advances in learning algorithms and theories, the availability of large datasets and improvements in computing power have contributed to breakthroughs in current AI applications. Machine learning (ML), a subset of AI, allows computers to detect patterns from large complex datasets automatically and uses these patterns to make predictions. AI is proving to be increasingly applicable to healthcare, and multiple machine learning techniques have been used to improve the performance of assisted reproductive technology (ART). Despite various challenges, the integration of AI and reproductive medicine is bound to give an essential direction to medical development in the future. In this review, we discuss the basic aspects of AI and machine learning, and we address the applications, potential limitations and challenges of AI. We also highlight the prospects and future directions in the context of reproductive medicine.

[Pediatric projects funded by National Natural Science Foundation of China from 2009 to 2018: retrospect and prospects].

OBJECTIVE: To perform a review and data analysis of the pediatric projects funded by National Natural Science Foundation of China from 2009 to 2018, and to investigate the changes in key support areas, research interest, and research hotspots in pediatrics. METHODS: The database of National Natural Science Foundation of China was searched to screen out pediatric research projects in 2009-2018, and the changes in funding intensity and research direction were analyzed. RESULTS: From 2009 to 2018, a total of 1 017 pediatric projects were funded by National Natural Science Foundation of China, with 485 (47.69%) General Projects, 426 (41.89%) Youth Fund Projects, 73 (7.18%) Regional Research Programs, 16 (1.57%) Key Programs, 6 (0.59%) Outstanding Youth Fund Projects, 7 (0.69%) Overseas Programs, and 4 (0.39%) other programs. There was a seven-fold increase in the total amount of subsidies, which increased from 8.42 million yuan in 2009 to 66.25 million yuan in 2018. The projects with the Primary Discipline Code of reproductive system/perinatology/neonatology, nervous system and mental illness, or circulatory system received the highest amount of fund. CONCLUSIONS: The support of pediatric projects by National Natural Science Foundation of China continues to increase in the past ten years, and the main types of projects are General Projects and Youth Fund Projects. Neonatology, nervous system/mental illness, and circulatory diseases are the main directions of funded projects.

A Promising New Model: Establishment of Patient-Derived Organoid Models Covering HPV-Related Cervical Pre-Cancerous Lesions and Their Cancers.

The lack of human-derived in vitro models that recapitulate cervical pre-cancerous lesions has been the bottleneck in researching human papillomavirus (HPV) infection-associated pre-cancerous lesions and cancers for a long time. Here, a long-term 3D organoid culture protocol for high-grade squamous intraepithelial lesions and cervical squamous cell carcinoma that stably recapitulates the two tissues of origin is described. Originating from human-derived samples, a small biobank of cervical pre-tumoroids and tumoroids that faithfully retains genomic and transcriptomic characteristics as well as the causative HPV genome is established. Cervical pre-tumoroids and tumoroids show differential responses to common chemotherapeutic agents and grow differently as xenografts in mice. By coculture organoid models with peripheral blood immune cells (PBMCs) stimulated by HPV antigenic peptides, it is illustrated that both organoid models respond differently to immunized PBMCs, supporting organoids as reliable and powerful tools for studying virus-specific T-cell responses and screening therapeutic HPV vaccines. In this study, a model of cervical pre-cancerous lesions containing HPV is established for the first time, overcoming the bottleneck of the current model of human cervical pre-cancerous lesions. This study establishes an experimental platform and biobanks for in vitro mechanistic research, therapeutic vaccine screening, and personalized treatment for HPV-related cervical diseases.

Silencing of the STAT3 signaling pathway reverses the inherent and induced chemoresistance of human ovarian cancer cells.

Ovarian cancer is the leading cause of gynecologic cancer deaths among women. Although platinum-based chemotherapy is the first-line treatment for human ovarian cancer, chemoresistance remains a major obstacle to successful treatment, and there are currently no approved molecularly targeted therapies. Recent evidence indicates that signal transducer and activator of transcription-3 (STAT3) is a determinant of chemoresistance and is related to tumor recurrence in a large number of solid malignancies. In this study, we demonstrated that high levels of pSTAT3 were associated with chemoresistance in human ovarian cancer cells. Targeting STAT3 by siRNA technology markedly enhanced cisplatin-induced apoptosis in cisplatin-resistant ovarian cancer cells that expressed a high level of pSTAT3. Interleukin-6 (IL-6) could induce STAT3 activation in cisplatin-sensitive ovarian cancer cells and led to protection against cisplatin. The STAT3 siRNA treatment also blocked IL-6-induced STAT3 phosphorylation, resulting in the attenuation of the anti-apoptotic activity of IL-6. We found that the combination of cisplatin and STAT3 siRNA resulted in the collapse of the mitochondrial membrane potential, attenuated the expression of Bcl-xL and Bcl-2, and increased the release of cytochrome C and expression of Bax. Taken together, these results suggest that the pharmacological inhibition of STAT3 may be a promising therapeutic strategy for the management of chemoresistance in ovarian cancer.

HPV16 E5 peptide vaccine in treatment of cervical cancer in vitro and in vivo.

Human papillomavirus (HPV)-induced cervical cancer is the second most common cancer among women worldwide. Despite the encouraging development of the preventive vaccine for HPV, a vaccine for both prevention and therapy or pre-cancerous lesions remains in high priority. Thus far, most of the HPV therapeutic vaccines are focused on HPV E6 and E7 oncogene. However these vaccines could not completely eradicate the lesions. Recently, HPV E5, which is considered as an oncogene, is getting more and more attention. In this study, we predicted the epitopes of HPV16 E5 by bioinformatics as candidate peptide, then, evaluated the efficacy and chose an effective one to do the further test. To evaluate the effect of vaccine, rTC-1 (TC-1 cells infected by rAAV-HPV16E5) served as cell tumor model and rTC-1 loading mice as an ectopic tumor model. We prepared vaccine by muscle injection. The vaccine effects were determined by evaluating the function of tumor-specific T cells by cell proliferation assay and ELISPOT, calculating the tumor volume in mice and estimating the survival time of mice. Our in vitro and in vivo studies revealed that injection of E5 peptide+CpG resulted in strong cell-mediated immunity (CMI) and protected mice from tumor growth, meanwhile, prolonged the survival time after tumor cell loading. This study provides new insights into HPV16 E5 as a possible target on the therapeutic strategies about cervical cancer.

Fusarium equiseti-inoculation altered rhizosphere soil microbial community, potentially driving perennial ryegrass growth and salt tolerance.

Fusarium equiseti is an effective plant growth-promoting fungi that induce systemic disease resistance in plants. However, the role of F. equiseti in regulating salt stress response and the underlying mechanisms remain largely unknown. Here, we investigated the effect of F. equiseti Z7 strain on the growth and salt stress response in perennial ryegrass. Additionally, the role of Z7 in regulating the abundance, composition, and structure of native microbial communities in the rhizosphere soil was determined. We observed that Z7 could produce indole-3-acetic acid (IAA) and siderophores. Hence, Z7 inoculation further enhanced plant growth and salt tolerance in perennial ryegrass. Inoculating Z7 increased K+ and decreased Na+ in plant tissues. Z7 inoculation also enhanced soil quality by reducing soluble salt and increasing available phosphorus. Moreover, inoculating Z7 altered the compositions of bacterial and fungal communities in the rhizosphere soil. For instance, beneficial bacterial genera, such as Flavobacterium, Enterobacter, Agrobacterium, and Burkholderiales were dominantly enriched in Z7-inoculated soil. Interestingly, the relative abundance of these genera showed significantly positive correlations with the fresh weight of perennial ryegrass. Our results demonstrate that Z7 could remarkably promote plant growth and salt tolerance by regulating ion homeostasis in plant tissues and microbial communities in the rhizosphere soil. This study provides a scientific foundation for applying microbes to improve plant growth under extreme salt stress conditions.

Immunodiagnosis - the promise of personalized immunotherapy.

Immunotherapy showed remarkable efficacy in several cancer types. However, the majority of patients do not benefit from immunotherapy. Evaluating tumor heterogeneity and immune status before treatment is key to identifying patients that are more likely to respond to immunotherapy. Demographic characteristics (such as sex, age, and race), immune status, and specific biomarkers all contribute to response to immunotherapy. A comprehensive immunodiagnostic model integrating all these three dimensions by artificial intelligence would provide valuable information for predicting treatment response. Here, we coined the term "immunodiagnosis" to describe the blueprint of the immunodiagnostic model. We illustrated the features that should be included in immunodiagnostic model and the strategy of constructing the immunodiagnostic model. Lastly, we discussed the incorporation of this immunodiagnosis model in clinical practice in hopes of improving the prognosis of tumor immunotherapy.

Prospects for fertility preservation: the ovarian organ function reconstruction techniques for oogenesis, growth and maturation in vitro.

Today, fertility preservation is receiving more attention than ever. Cryopreservation, which preserves ovarian tissue to preserve fertility in young women and reduce the risk of infertility, is currently the most widely practiced. Transplantation, however, is less feasible for women with blood-borne leukemia or cancers with a high risk of ovarian metastasis because of the risk of cancer recurrence. In addition to cryopreservation and re-implantation of embryos, in vitro ovarian organ reconstruction techniques have been considered as an alternative strategy for fertility preservation. In vitro culture of oocytes in vitro Culture, female germ cells induction from pluripotent stem cells (PSC) in vitro, artificial ovary construction, and ovaria-related organoids construction have provided new solutions for fertility preservation, which will therefore maximize the potential for all patients undergoing fertility preservation. In this review, we discussed and thought about the latest ovarian organ function reconstruction techniques in vitro to provide new ideas for future ovarian disease research and fertility preservation of patients with cancer and premature ovarian failure.

[Preparation of HPV18 E7 peptide plus CpG vaccine and its immunologic effects in vitro].

OBJECTIVE: To screen and prepare the vaccine of human papillomavirus (HPV) 18 E7 peptide target at human leukocyte antigen (HLA)-A2 plus CpG through SYFPEITHI. METHODS: (1) The SYFPEITHI database was employed for predicting and screening of HPV18 E7 HLA-A2 restricted T cell epitopes.(2) The peripheral blood and tumor tissue sample of HLA-A2 positive and HPV18 positive/negative patients were collected and randomly divided into 7 groups, i.e. E7PA + CpG, E7PB + CpG, E7PC + CpG, E7PD + CpG, CpG, IR-T + CpG and control groups respectively. T cell proliferation was detected by thiazolyl blue tetrazolium bromide (MTT) assay at different timepoints. Lactate dehydrogenase delivery method (LDH) was used to test the cytolytic t lymphocyte (CTL) activity of peripheral blood mononuclear cell (PBMC) in different ratios of effect and target (E:T). And the level of activity T cells was evaluated by interferon gamma (IFN-γ)-related enzyme-linked immuno-spot assay (ELISPOT). RESULTS: (1) Four peptides named E7PA, E7PB, E7PC and E7PD were obtained separately with high levels of affinity and specificity. (2) During continuous observations after vaccination, the E7PA + CpG group had the most pronounced proliferation rate. When E:T = 100:1, the E7PA + CpG group had more powerful CTL effect than the control group with statistic significance (P < 0.00). E:T was concentration-dependent. Except for IR-T + CpG, all other groups had great difference than control group with statistic significance (P < 0.05) but no significant difference between the groups. The levels of IFN-γ spot-forming T cells were higher in the E7PA + CpG group than the control group with statistic significance (P < 0.01). In terms of specificity, E7PA + CpG in the HPV18 positive group could induce the proliferation of IFN-γ-secreting T cells. And there was statistical difference with the control group (P < 0.05). CONCLUSION: Screening the HPV18 E7 peptide target at HLA-A2 plus CpG as the candidate targets by SYFPEITHI may active specific immunological cellular responses to HPV18 positive disease.

Mesenchymal stem cells as carriers and amplifiers in CRAd delivery to tumors.

BACKGROUND: Mesenchymal stem cells (MSCs) have been considered to be the attractive vehicles for delivering therapeutic agents toward various tumor diseases. This study was to explore the distribution pattern, kinetic delivery of adenovirus, and therapeutic efficacy of the MSC loading of E1A mutant conditionally replicative adenovirus Adv-Stat3(-) which selectively replicated and expressed high levels of anti-sense Stat3 complementary DNA in breast cancer and melanoma cells. METHODS: We assessed the release ability of conditionally replicative adenovirus (CRAd) from MSC using crystal violet staining, TCID(50) assay, and quantitative PCR. In vitro killing competence of MSCs carrying Adv-Stat3(-) toward breast cancer and melanoma was performed using co-culture system of transwell plates. We examined tumor tropism of MSC by Prussian blue staining and immunofluorescence. In vivo killing competence of MSCs carrying Adv-Stat3(-) toward breast tumor was analyzed by comparison of tumor volumes and survival periods. RESULTS: Adv-Stat3(-) amplified in MSCs and were released 4 days after infection. MSCs carrying Adv-Stat3(-) caused viral amplification, depletion of Stat3 and its downstream proteins, and led to significant apoptosis in breast cancer and melanoma cell lines. In vivo experiments confirmed the preferential localization of MSCs in the tumor periphery 24 hours after tail vein injection, and this localization was mainly detected in the tumor parenchyma after 72 hours. Intravenous injection of MSCs carrying Adv-Stat3(-) suppressed the Stat3 pathway, down-regulated Ki67 expression, and recruited CD11b-positive cells in the local tumor, inhibiting tumor growth and increasing the survival of tumor-bearing mice. CONCLUSIONS: These results indicate that MSCs migrate to the tumor site in a time-dependent manner and could be an effective platform for the targeted delivery of CRAd and the amplification of tumor killing effects.