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This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up. This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18–45 years, with intact cervix and 1–4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18–26 and 27–45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006. Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2–100·0) against high-grade genital lesions (0 [0%] of 3310 participants in the vaccine group and 13 [0·4%] of 3302 participants in the control group) and 97·3% (89·9–99·7) against persistent infection (2 [0·1%] of 3262 participants in the vaccine group and 73 [2·2%] of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 [7·2%] of 3691 participants) and control groups (290 [7·9%] of 3681); none were considered related to vaccination. The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention. National Natural Science Foundation of China, National Key R&D Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.

Trichosanthes kirilowii Maxim. is one of the original plants for traditional Chinese medicines Trichosanthis Fructus, Trichosanthis Semen, Trichosanthis Pericarpium and Trichosanthis Radix. Amino acids, nucleosides and carbohydrates are usually considered to have nutritional value and health-care efficacy. In this study, methods involving high-performance liquid chromatography coupled with evaporative light scattering detector (HPLC-ELSD), UV-visible spectrophotometry and ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) were established for quantifying carbohydrates (fructose, glucose, stachyose, raffinose and polysaccharide), fourteen nucleosides and twenty one amino acids. Moreover, sixty-three samples from nine different parts, including pericarp, seed, fruit pulp, stem, leaf, main root, main root bark, lateral root and lateral root bark of T. kirilowii from different cultivated varieties were examined. The established methods were validated with good linearity, precision, repeatability, stability, and recovery. The results showed that the average content of total amino acids in roots (15.39 mg/g) and root barks (16.38 mg/g) were relatively higher than for others. Contents of nucleosides in all parts of T. kirilowii were below 1.5 mg/g. For carbohydrates, fruit pulp has a higher content than others for glucose (22.91%), fructose (20.63%) and polysaccharides (27.29%). By using partial least-squared discriminate analysis (PLS-DA), Variable importance in the projection (VIP) plots and analysis of variance (ANOVA) analysis, the characteristic components of the different organs (fruit, stems and leaves, roots) were found. This analysis suggested there were potential medicinal and nutritive health care values in various parts of the T. kirilowii, which provided valuable information for the development and utilization of T. kirilowii.

Three new cyclic tetrapeptides (nectriatidels A-C, 1–3), two new curvularin analogs (6 and 7), and four known compounds (4 and 5, 8 and 9) were isolated from the marine-derived fungal-bacterial symbiont Aspergillus spelaeus GXIMD 04541/Sphingomonas echinoides GXIMD 04532, which was obtained from Mauritia arabica in shallow coastal waters. Their structures were elucidated through NMR spectroscopy and HRESIMS, and their absolute configurations were determined by Marfey’s method and quantum chemical calculations. Compounds 1–5 showed moderate amphotericin B (AmB)-potentiating activity against Candida albicans. Compounds 7 and 8 exhibited significant activities against Mycobacterium tuberculosis, with MIC values of 32 and 16 μg/mL, respectively. Additionally, compounds 7 and 8 exhibited moderate cytotoxicity against human colorectal cancer cell lines DLD-1 and SW480, with IC50 values of 25~36 μM. Whole-genome sequencing of A. spelaeus revealed a 35.91 Mb assembly encoding 106 biosynthetic gene clusters (BGCs). antiSMASH analysis revealed that 79 of these BGCs (74.5%) displayed no significant similarity to known pathways in the MIBiG database, which is dominated by hybrid clusters, terpene, T1PKS, NRPS, and NRPS-like types. Genomic analysis identified the putative biosynthetic gene clusters for these metabolites and confirmed the fungal host as the predominant producer.

Under the COVID-19 epidemic, the families of front-line rescue workers are under unusual pressure. We aim to understand the extent of their psychological distress in this epidemic and whether they have received sufficient support. Thus targeted to provide support for them and indirectly reduce the concerns of the rescue workers. From February 27 to March 1, 2020, we used the scales of Perceived Stress Scale, 10-items Connor-Davidson Resilience Scale, Generalized Anxiety Disorder-7, Patient Health Questionnaire-2, and primary care-posttraumatic stress disorder (PTSD) to evaluate the mental health level of the family members of front-line rescue workers online. Six hundred and seventy one family members voluntarily filled out the questionnaire after reading the purpose of the study. A total of 671 family members of front-line rescue workers participated in the survey, including 194 husbands/wives, 52 parents, 49 children, 76 brothers and sisters, and 300 other relationships. Among them, 55% of the family members reported sleep problems, 49.0% of the family members had mild, and above anxiety symptoms, 12.2% of the family members reported clinically significant depression symptoms, and 10.4% of the family members may have PTSD, 8.3% of family members had thoughts of self-injury or suicide. The feeling of stress was positively correlated with anxiety and depression, but there was no significant correlation between psychological elasticity and various symptoms. Family members who are more worried about the safety, physical condition and living security of front-line rescue workers are more likely to report symptoms such as sleep disorders, anxiety, and depression. Family members' first-line rescue has a significant impact on their daily life, raising children and supporting the elderly, which is also related to the occurrence of mental and psychological symptoms. During the period of front-line support, they received support from the units or organizations of the first-line workers, mainly including telephone greetings and daily necessities. The top three concerns about the information of the epidemic were the time of the end of the epidemic, the time of the return of the family and the progress of COVID-19's treatment. After the end of the epidemic, what they most want to do is to pay more attention to and accompany their families, family gatherings, and do more exercise. The psychological impact of this epidemic on the families of front-line rescue workers is mainly sleep problems and anxiety. The psychological intervention of family members should mainly start from the relief of stress and increase of material and spiritual support.

Cervical cancer is the most common malignant gynecological tumor. Circular RNA (circRNA) circ_0023404 is reported to be upregulated in cervical cancer cells. This aim is to explore the role and mechanism of circ_0023404 in cervical cancer. circ_0023404, microRNA‐636 (miR‐636), and cytochrome P450 2S1 (CYP2S1) levels were detected by real‐time quantitative polymerase chain reaction (RT‐qPCR). Cell proliferation, migration, invasion, and apoptosis were detected by 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) assay, 5‐ethynyl‐2′‐deoxyuridine (EDU) assay, colony formation assay, transwell assay, and cytometry assay. Protein levels of cyclin D1, matrix metallopeptidase 9 (MMP9), Bcl‐2‐associated X protein (Bax), and CYP2S1 were examined by western blot assay. The binding relationship between miR‐636 and circ_0023404 or CYP2S1 was predicted by Circinteractome or targetscan, and then verified by a dual‐luciferase reporter assay and RNA pull‐down assay. circ_0023404 and CYP2S1 expression were increased, and miR‐636 was decreased in cervical cancer tissues and cells. Moreover, circ_0023404 knockdown could repress proliferation, migration, invasion, and promote apoptosis of cervical cancer cells in vitro. Mechanically, circ_0023404 could regulate CYP2S1 expression by sponging miR‐636. circ_0023404 silencing could attenuate the progression of cervical cancer cells partly by targeting the miR‐636/CYP2S1 axis, hinting at a promising therapeutic target for cervical cancer.

Background：Pelvic lymph node metastasis （LNM） is an important prognostic factor in cervical cancer.Cervical squamous cell carcinoma accounts for approximately 75-80% of all cervical cancers.Analyses of the effects of the number of positive lymph nodes （LNs）,unilateral vcrsus bilateral pelvic LNM and a single group versus multiple groups of pelvic LNM on survival and recurrence of cervical squamous cell carcinoma are still lacking.The study aimed to analyze the effects of the number of positive pelvic LNs and a single group versus multiple groups of pelvic LNM on survival and recurrence.Methods：We performed a retrospective review of 296 patients diagnosed with Stage ⅠA-ⅡB cervical squamous cell carcinoma who received extensive/sub-extensive hysterectomy with pelvic lymphadenectomy/pelvic LN sampling at Peking University People＇s Hospital from November 2004 to July 2013.Ten clinicopathological variables were evaluated as risk factors for pelvic LNM：Age at diagnosis,gravidity,clinical stage,histological grade,tumor diameter,lymph-vascular space involvement （LVSI）,depth of cervical stromal invasion,uterine invasion,parametrial invasion,and neoadjuvant chemotherapy.Results：The incidence of pelvic LNM was 20.27% （60/296 cases）.Pelvic LNM （P =0.00） was significantly correlated with recurrence.Pelvic LNM （P =0.00）,the number of positive pelvic LNs （P =0.04） and a single group versus multiple groups of pelvic LNM （P =0.03）had a significant influence on survival.Multivariate analysis revealed that LVSI （P =0.00）,depth of cervical stromal invasion （P =0.00）and parametrial invasion （P =0.03） were independently associated with pelvic LNM.Conclusions：Patients with pelvic LNM had a higher recurrence rate and poor survival outcomes.Furthermore,more than 2 positive pelvic LNs and multiple groups of pelvic LNM appeared to identify patients with worse survival outcomes in node-positive ⅠA-ⅡB cervical squamous cell carcinoma.LVSI,parametrial invasion,and depth of cervical stromal invasion were identified as independent clinicopathological risk factors for pelvic LNM.

Epidemiological studies have demonstrated that type 2 diabetes mellitus (T2DM) and hyperinsulinemia are associated closely with endometrial carcinoma risk, although the molecular mechanism remains unclear. Insulin receptor isoformA expression is upregulated in many cancer cells and tissues, which suggests that IR-A-mediated signaling pathways may have important implications for cancer pathogenesis. We measured the expression of insulin receptor isoforms (IR-A and IR-B in the normal endometrium tissues, the endometrial carcinoma tissues and the endometrial carcinoma cell lines. We found that the total insulin receptor (IR) and IR-A expression mRNA levels and the ratio of IR-A to total IR in endometrial carcinoma specimens were significantly higher than them in control endometrial tissue specimens(P<0.05). Further analysis indicated that the tendency was more prominently in patients with T2DM. IR-A mRNA was differentially expressed in four endometrial carcinoma cell lines (Ishikawa, KLE, RL95-2 and HEC-1-A. RL95-2 cells have a low endogenous IR-A expression, and these were used to construct a stable cell line overexpressing IR-A. We found that IR-A overexpression significantly increased cell proliferation, the proportion of cells in S phase, activation of the Akt pathway and tumorigenicity of xenografts in nude mice. In contrast, there was no significant difference in the the percentage of apoptotic cells between cells overexpressing IR-A and control cells. Moreover, levels of phosphorylated ERK1/2 protein were significantly decreased in cells overexpressing IR-A relative to controls. These findings reveal the pivotal role of IR-A in endometrial cancer carcinogenesis, and suggest that the association of elevated IR-A levels with cell proliferation and tumorigenicity may be causally linked to its effect on the proportion of cells in S phase and the activation of the Akt pathway.

Cervical cancer is the most common malignant gynecological tumor. Circular RNA (circRNA) circ_0023404 is reported to be upregulated in cervical cancer cells. This aim is to explore the role and mechanism of circ_0023404 in cervical cancer. circ_0023404, microRNA-636 (miR-636), and cytochrome P450 2S1 (CYP2S1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, migration, invasion, and apoptosis were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, 5-ethynyl-2′-deoxyuridine (EDU) assay, colony formation assay, transwell assay, and cytometry assay. Protein levels of cyclin D1, matrix metallopeptidase 9 (MMP9), Bcl-2-associated X protein (Bax), and CYP2S1 were examined by western blot assay. The binding relationship between miR-636 and circ_0023404 or CYP2S1 was predicted by Circinteractome or targetscan, and then verified by a dual-luciferase reporter assay and RNA pull-down assay. circ_0023404 and CYP2S1 expression were increased, and miR-636 was decreased in cervical cancer tissues and cells. Moreover, circ_0023404 knockdown could repress proliferation, migration, invasion, and promote apoptosis of cervical cancer cells in vitro. Mechanically, circ_0023404 could regulate CYP2S1 expression by sponging miR-636. circ_0023404 silencing could attenuate the progression of cervical cancer cells partly by targeting the miR-636/CYP2S1 axis, hinting at a promising therapeutic target for cervical cancer.

Endometrial cancer is one of the most common malignancies of the reproductive system. Effective and cost-effective screening method for populations at high risk is not available. This study aimed to investigate specimen adequacy and the influencing factors in microscale endometrial sampling biopsy and to evaluate the diagnostic accuracy and medical cost of biopsy in endometrial cancer and atypical hyperplasia screenings in comparison with hysteroscopic endometrial biopsy. A total of 1551 patients at high risk for endometrial lesions who required hysteroscopic endometrial biopsy from November 2017 to August 2018 were included. Microscale endometrial sampling biopsy was performed, followed by hysteroscopic endometrial biopsy. We evaluated the specimen adequacy and influencing factors of microscale endometrial sampling. Diagnostic consistency between microscale endometrial sampling biopsy and hysteroscopic endometrial biopsy was evaluated. The sensitivity, specificity, positive predictive value, and negative predictive value of microscale endometrial sampling biopsy in screening for endometrial cancer and atypical hyperplasia were analyzed, and the medical costs of the two procedures were compared. The specimen adequacy was 81.2%. Patient age, menopausal status, endometrial thickness, and endometrial lesion type were correlated with specimen adequacy. There was good consistency in distinguishing benign and malignant endometrial diseases between microscale endometrial sampling biopsy and hysteroscopic biopsy (kappa 0.950, 95% CI 0.925-0.975). The sensitivity, specificity, positive predictive value, and negative predictive value of microscale endometrial sampling biopsy were 91.7%, 100.0%, 100.0%, and 99.3% for endometrial cancer screening, respectively, and 82.0%, 100.0%, 100.0%, and 99.4% for atypical hyperplasia screening. The medical cost of endometrial sampling biopsy was only 22.1% of the cost of hysteroscopic biopsy. Microscale endometrial sampling biopsy is a minimally invasive alternative technique for obtaining adequate endometrial specimens for histopathological examination. It has the potential to be used in detecting endometrial cancer and atypical hyperplasia with high efficiency and low cost.

Management of tumors has become more complex owing to tumor heterogeneity. Fewer studies have been performed on intra-tumor heterogeneity of endometrial cancer (EC) until now. Therefore, it is of great clinical value to explore the intra-tumor heterogeneity of EC based on clinical features and gene expression profiles. A total of 1688 patients with EC were screened and 114 patients were finally selected, including specimens from 84 patients with primary EC without relapse (PE) and the paired metastases (P-M) specimens, as well as specimens from 30 patients with primary EC with relapse (RPE) and the paired relapsed EC (P-RE) specimens. Microarray and RNA-seq were used to detect gene expression of EC samples. Clinicopathological characteristics and molecular data were compared between PE and P-M groups and between RPE and P-RE groups to explore the intra-tumor heterogeneity of EC. The clinical intra-tumor spatial heterogeneity of pathological type, grade, ER status, and PR status between PE and P-M were 17.9%, 13.1%, 28.6%, and 28.6%, respectively. The clinical intra-tumor spatiotemporal heterogeneity of pathological type, grade, ER status, and PR status between RPE and P-RE were 16.7%, 33.3%, 25.0%, and 37.5%, respectively. Cluster analysis sorts EC samples based on progression type of lesion and their pathological type. There were differentially expressed genes between PE and P-M and between RPE and P-RE, of which gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis were mainly enriched in cell proliferation, the p53 signaling pathway, etc. CONCLUSIONS:: Clinical and molecular data showed that there was spatiotemporal heterogeneity in intra-tumor of EC, which may add to the complexity of diagnosis and therapeutics for EC. Considering the intra-tumor heterogeneity, sequential chemotherapy and precision medicine may be a more suitable treatment plan for EC.