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.

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.

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.

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.

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.

China Public Psychology Analysis About COVID-19 Under Considering Sina Weibo Data.

COVID-19 not only poses a huge threat to public health, but also affects people's mental health. Take scientific and effective psychological crisis intervention to prevent large-scale negative emotional contagion is an important task for epidemic prevention and control. This paper established a sentiment classification model to make sentiment annotation (positive and negative) about the 105,536 epidemic comments in 86 days on the official Weibo of People's Daily, the test results showed that the accuracy of the model reached 88%, and the AUC value was greater than 0.9. Based on the marked data set, we explored the potential law between the changes in Internet public opinion and epidemic situation in China. First of all, we found that most of the Weibo users showed positive emotions, and the negative emotions were mainly caused by the fear and concern about the epidemic itself and the doubts about the work of the government. Secondly, there is a strong correlation between the changes of epidemic situation and people's emotion. Also, we divided the epidemic into three period. The proportion of people's negative emotions showed a similar trend with the number of newly confirmed cases in the growth and decay period, and the extinction period. In addition, we also found that women have more positive emotional performance than men, and the high-impact groups is also more positive than the low-impact groups. We hope that these conclusions can help China and other countries experiencing severe epidemics to guide publics respond.

Exploring the Immunopathogenesis of Pregnancy With COVID-19 at the Vaccination Era.

Since December 2019, Wuhan, China, has experienced an outbreak of coronavirus disease (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pregnant women are deductively considered to be in immunosuppressive condition for the safety of semi-allograft fetuses, which increases the risk of being infected by the virus. In this review, we analyzed the unique immunological characteristics of pregnant women and reviewed their known outcomes at different trimesters from the perspective of underlying mechanisms that have been studied and speculated so far.

Molecular evidence suggesting the persistence of residual SARS-CoV-2 and immune responses in the placentas of pregnant patients recovered from COVID-19.

OBJECTIVES: Recent studies have shown the presence of SARS-CoV-2 in the tissues of clinically recovered patients and persistent immune symptoms in discharged patients for up to several months. Pregnant patients were shown to be a high-risk group for COVID-19. Based on these findings, we assessed SARS-CoV-2 nucleic acid and protein retention in the placentas of pregnant women who had fully recovered from COVID-19 and cytokine fluctuations in maternal and foetal tissues. MATERIALS AND METHODS: Remnant SARS-CoV-2 in the term placenta was detected using nucleic acid amplification and immunohistochemical staining of the SARS-CoV-2 protein. The infiltration of CD14+ macrophages into the placental villi was detected by immunostaining. The cytokines in the placenta, maternal plasma, neonatal umbilical cord, cord blood and amniotic fluid specimens at delivery were profiled using the Luminex assay. RESULTS: Residual SARS-CoV-2 nucleic acid and protein were detected in the term placentas of recovered pregnant women. The infiltration of CD14+ macrophages into the placental villi of the recovered pregnant women was higher than that in the controls. Furthermore, the cytokine levels in the placenta, maternal plasma, neonatal umbilical cord, cord blood and amniotic fluid specimens fluctuated significantly. CONCLUSIONS: Our study showed that SARS-CoV-2 nucleic acid (in one patient) and protein (in five patients) were present in the placentas of clinically recovered pregnant patients for more than 3 months after diagnosis. The immune responses induced by the virus may lead to prolonged and persistent symptoms in the maternal plasma, placenta, umbilical cord, cord blood and amniotic fluid.

COVID-19 and Pregnancy: A Case Study.

The 2019 novel coronavirus disease is spreading all over the world. Pregnant women and infants require particular concern, owing to the special immune conditions. A case of a pregnant woman who was exposed to SARS-CoV-2 at 34+1 weeks gestation and chose to continue pregnancy is reported. Without obvious symptoms or signs, the woman did not receive any treatment before delivery, and gave birth at 37+5 weeks to a neonate with positive immunoglobulin G for SARS-CoV-2 and negative nucleic acid tests. The mother was given anti-infection, oxytocin, and fluid rehydration treatment after delivery. Both mother and infant recovered well after a three-month follow-up. Continued expectation to deliver at term instead of preterm can decrease the potential risk of severe perinatal and infant complications and is beneficial to the development of the neonate. More studies are required to confirm the presence of vertical transmission.

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.

RNA Sequencing of Decidua Reveals Differentially Expressed Genes in Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) is affecting 3-5% of the women who are expecting to have babies annually. However, the molecular changes of RPL patients have not been well characterized before. In the current study, we aimed to discover the differentially expressed genes (DEGs) in decidua from RPL patients by utilizing RNA sequencing (RNA-seq) technology. Four RPL patients and three control women were recruited to conduct RNA-seq, and 153 genes comprising 69 were upregulated and 84 downregulated showed different expression levels between the health control and RPL groups. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to identify potential biological processes associated with RPL. We recognized that type I interferon signaling pathway and TNF signaling pathway are significantly upregulated in women with RPL. Upregulated expression of MX1, IFI27, and ISG15 in type I interferon signaling pathway and TNFRSF21 in TNF signaling pathway were validated by an extended sample of 15 RPL patients and 12 control women, by quantitative real-time polymerase chain reaction (qRT-PCR). In conclusion, the results of the current study revealed molecular changes in decidua which may reflect the intrauterine circumstance when pregnancy loss happens and potentially contributes to RPL.

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.

An Online Questionnaire Survey on the Sexual Life and Sexual Function of Chinese Adult Men During the Coronavirus Disease 2019 Epidemic.

INTRODUCTION: There has been no report regarding the impact on male sexual life or sexual function by changes in lifestyle during the coronavirus disease 2019 (COVID-19) epidemic. AIM: To investigate the changes in sexual life and sexual function of Chinese men during the COVID-19 epidemic. METHODS: An online questionnaire was created and the survey was administered through social media to Chinese adult men. MAIN OUTCOME MEASURE: The main end point was the deteriorated erectile function or ejaculatory control ability, defined by self-evaluation or by decreased International Index of Erectile Function-5 items (IIEF-5) scores or increased premature ejaculation diagnostic tool (PEDT) scores. RESULTS: Altogether, 612 questionnaires were collected. About 322 (52.6%) subjects were unmarried. About 8.4% and 8.5% subjects reported deteriorated erectile function or ejaculation control ability by self-evaluation, whereas 31.9% and 17.9% subjects showed decreased IIEF-5 scores or increased PEDT scores. Subjects with deteriorated erectile function by self-evaluation and decreased IIEF-5 scores had higher General Anxiety Disorder-7 (P < .001 and P = .001) and higher Patient Health Questionnaire-9 score (P < .001 and P = .002) after the epidemic, decreased frequency of sexual life (P < .001 and P < .001) and physical exercise (P = .009 and .007) after the epidemic. Subjects with deteriorated ejaculation control ability by self-evaluation and increased PEDT scores had higher General Anxiety Disorder-7 (P < .001 and P < .001) and higher Patient Health Questionnaire-9 score (P < .001 and P = .002) after the epidemic. Subjects with decreased frequency of sexual life had reduced income (P < .001), increased anxiety (P < .001) and depression (P < .001). Married subjects had higher proportion of improved depression (P = .048) and increased frequency of sexual life (P = .010). CONCLUSION: During the COVID-19 epidemic, decreased sexual function was present in a certain proportion of adult men, and the risk factors include increased anxiety and depression, and decreased frequency of sexual life. Fang D, Peng J, Liao S, et al. An Online Questionnaire Survey on the Sexual Life and Sexual Function of Chinese Adult Men During the Coronavirus Disease 2019 Epidemic. Sex Med 2021;9:100293.

Management of Pregnancy during the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) is spreading worldwide. All aspects of pregnancy management from conception to delivery to puerperium as risks facing newborns are herein, reviewed. Maternal home management and prenatal care management protection, delivery timing or mode selection, delivery process management, and subsequent puerperal protection are crucial. In this Review, the features and treatment strategies, especially emphasizing the safety of antiviral drugs for pregnant women, the wearing of face masks, and practicing of personal hygiene (e.g., handwashing, disinfection, home cleaning, and ventilation) are reviewed as essential protective measures. It is recommended to provide online consultation, telemedicine, and remote fetal heart rate monitoring and set the flow point for prenatal examination to encourage prenatal examination at home or postponing examinations (except nuchal translucency at 11-13+6 weeks, Oscar Test at 16 weeks, and fetal ultrasound at 20-24 weeks). It is shown that the precise formulation of follow-up strategies for pregnant women with COVID-19 is necessary.

[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.

Development of a Dynamic Diagnosis Grading System for Infertility Using Machine Learning.

Importance: Many indicators need to be considered when judging the condition of patients with infertility, which makes diagnosis and treatment complicated. Objective: To construct a dynamic scoring system for infertility to assist clinicians in efficiently and accurately assessing the condition of patients with infertility. Design, Setting, and Participants: This prognostic study reviewed 95 868 medical records of couples with infertility in which women had undergone in vitro fertilization and embryo transfer at the Reproductive Center of Tongji Medical College, Huazhong University of Science and Technology, in Wuhan, Hubei, China, from January 2006 to May 2019. A dynamic diagnosis and grading system for infertility was constructed. The analysis was conducted between May 20, 2019, and April 15, 2020. Main Outcomes and Measures: Patients were divided into pregnant and nonpregnant groups according to eventual pregnancy results. The evaluation index system was constructed based on the test results of the significant difference between the 2 groups of indicators and the clinician's experience. Random forest machine learning was used to determine the weight of the index, and the entropy-based feature discretization algorithm classified the abnormality of the index and the patient's condition. A 10-fold cross-validation method was used to test the validity of the system. Results: A total of 60 648 couples with infertility were enrolled, in which 15 021 women became pregnant, with a mean (SD) age of 30.30 (4.02) years. A total of 45 627 couples were in the nonpregnant group, with a mean (SD) age among women of 32.17 (5.58) years. Seven indicators were selected to build the dynamic grading system for patients with infertility: age, body mass index, follicle-stimulating hormone level, antral follicle count, anti-Mullerian hormone level, number of oocytes, and endometrial thickness. The importance weight of each indicator obtained by the random forest algorithm was 0.1748 for age, 0.0785 for body mass index, 0.0581 for follicle-stimulating hormone level, 0.1214 for antral follicle count, 0.1616 for anti-Mullerian hormone level, 0.2307 for number of oocytes, and 0.1749 for endometrial thickness. The grading system divided the condition of the patient with infertility into 5 grades from A to E. The worst E grade represented a 0.90% pregnancy rate, and the pregnancy rate in the A grade was 53.82%. The cross-validation results showed that the stability of the system was 95.94% (95% CI, 95.14%-96.74%). Conclusions and Relevance: This machine learning-derived algorithm may assist clinicians in making an efficient and accurate initial judgment on the condition of patients with infertility.

Chloride intracellular channel protein 2: prognostic marker and correlation with PD-1/PD-L1 in breast cancer.

Immune checkpoint inhibition has emerged as an effective treatment for multiple solid tumors, including advanced-stage breast cancer (BC). During the past decade, the US Food and Drug Administration has approved a number of agents for immune checkpoint blockade (ICB). However, the limited data on monotherapy anti-tumor activity in BC underscores the need for robust predictive biomarker development. Here, we used weighted gene coexpression network analysis of genes differentially expressed between BC and normal tissue to identify genes coexpressed with programmed death-1 (PD-1) and its ligand (PD-L1). Tumor Immune Estimation Resource and Gene Expression Profiling Interaction Analysis were used to assess the relationship between gene expression and the abundance of tumor-infiltrating lymphocytes (TILs). We found that chloride intracellular channel protein 2 (CLIC2) was not only coexpressed with PD-1 and PD-L1, but its increased expression was associated with a favorable prognosis and enrichment of multiple TIL types, particularly CD8+ T cells. These results suggest that CLIC2 is a potentially useful biomarker for identifying BC patients who could benefit from ICB.

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.

PDL1 blockage increases fetal resorption and Tfr cells but does not affect Tfh/Tfr ratio and B-cell maturation during allogeneic pregnancy.

A successful pregnancy requires sophisticated regulation of uterine microenvironment to guarantee the existence of semi-allogeneic conceptus without immune rejection. T follicular regulatory (Tfr) cells exert a suppressive effect on Tfh-cell expansion, B-cell response, and antibody production. Although accumulating evidence has demonstrated that dysregulations of Tfr cells can bring on various immunological diseases, their immunomodulatory roles during pregnancy still remain unheeded. Herein, we introduced an allogeneic normal-pregnant mouse model and found that CD4+CXCR5hiPD-1hiFoxp3+ Tfr cells were preferentially accumulated in the uterus at mid-gestation and displayed a distinct phenotype. In addition, the absence of PDL1 resulted in increased fetal resorption by favoring Tfr cells accumulation and upregulating PD-1 expression on these cells. However, PDL1 blockade affected neither the ratio of Tfh/Tfr cells nor the maturation and differentiation of B cells. Overall, our results are the first to present a correlation of Tfr cells accumulation with healthy allogeneic pregnancy and PDL1 blockade-induced miscarriage, and to indicate that appropriate assembly of Tfr cells is important for pregnancy maintenance. Since blockade of PD-1-PDL1 pathway leads to more Tfr cells and fetal losses, the reproductive safety must be taken into consideration when PD-1/PD-L1 checkpoint blockade immunotherapy is used in pregnancy.