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Sleep deprivation (SD) contributes to cognitive impairment. Astrocytic cholesterol biosynthesis is crucial for brain cholesterol homeostasis and cognitive function. However, the underlying mechanism of astrocytic cholesterol metabolism in SD-induced cognitive impairment has not been fully explored. Trimethylamine N-oxide (TMAO), a product of liver flavin-containing monooxygenase-3 (FMO3), has been shown to be increased in the urine of sleep-deprived humans and implicated with peripheral cholesterol metabolism. Nevertheless, how TMAO affects brain cholesterol metabolism remains unclear. In our study, increased FMO3 and brain TMAO levels were observed in the SD mice, and elevated levels of TMAO were confirmed to lead to SD-induced cognitive dysfunction. In addition, we found that the expression of sterol regulatory element-binding protein 2 (SREBP2) is decreased in the brain of SD mice, resulting in the reduction in brain cholesterol content, which in turn causes synaptic damage. Moreover, we demonstrated that TMAO inhibits the expression of SREBP2. In contrast, FMO3 inhibitor 3,3′-diindolylmethane (DIM) alleviates SD-induced cognitive impairment by targeting the liver–brain axis. In conclusion, our study revealed that the TMAO pathway is involved in memory impairment in SD mice through deregulating astrocytic cholesterol metabolism.

ObjectiveThe aim of this study was to verify TCGA subtypes in endometrial clear cell carcinoma (ECCC) and determine their clinical and molecular characteristics.MethodsWe summarized and compared the clinical features of 28 clear cell carcinoma and 112 endometrioid carcinoma patients. Of the 28 ECCCs, 19 underwent TCGA classification, and other markers (ER, PR, ARID1A, ARIB1B, TAF1, and HER-2) were also detected by IHC, and outcomes were assessed.ResultsCompared to endometrioid carcinoma, ECCC had an older age of onset (median age, 64.5 years, range 31–81 years), higher rate of myometrial invasion (42.8% vs. 21.5% in endometrioid carcinoma), LVSI (33% vs. 16%), and more advanced FIGO stage. Among the ECCCs, LVSI was a poor prognostic factor. TCGA classification was performed for 19 ECCCs: two POLEmut cases (10.5%), three MMRd (15.8%), 11 p53wt (57.9%), and three p53abn (15.8%). Of the 19 ECCCs, six (31.6%) showed HER-2 positive expression, and eight (42.1%) had TAF1 expression loss. ECCCs possessed HER-2 and TAF1 expression had worse outcomes.ConclusionOur study summarized the clinical features of ECCC. The outcomes of patients with ECCC with TCGA subtypes differed from those of patients with endometrioid carcinoma. HER-2 and TAF1 may be new prognostic factors.

ObjectiveTo examine the effects of lifestyle interventions, including dietary guidance, health education and weight management, on pregnancy outcomes in women at high risk of gestational diabetes mellitus (GDM).MethodsOur study included 251 women at high risk of GDM and 128 randomized to lifestyle interventions (dietary guidance, health education, and weight management); One hundred and twenty-three people were randomly assigned to a control group (regular pregnancy check-ups). Counts between groups were compared using either chi-square test or Fisher’s exact test.ResultsCompared with the control group, the risk of GDM was reduced by 46.9% (16.4% vs 30.9%, P = 0.007) and the risk of pregnancy induced hypertension (PIH) was reduced by 74.2% (2.3% vs 8.9%, P = 0.034) in the intervention group. There were no significant differences in macrosomia, cesarean section, or preterm birth (P >0.05).ConclusionThe lifestyle intervention in this study helped pregnant women to better understand knowledge related to pregnancy, reduce stress and anxiety, and increase intake of adequate prenatal nutrition. This intervention prevented metabolic abnormalities that may occur due to inadequate nutrient intake during pregnancy. In addition, it helped women to control weight gain, maintain appropriate weight gain during pregnancy, and reduce the risk of excessive or insufficient weight gain, ultimately lowering the incidence of GDM and PIH. This highlights the importance of early screening and intervention for high-risk pregnant women.Clinical Trial Registrationhttps://www.chictr.org.cn, identifier ChiCTR2300073766.

Taking the Jiangluling Carbonaceous Shale Tunnel as an example, this study aims to investigate the mechanism of large deformation and design construction technology of carbonaceous shale tunnels. Using theoretical analysis and comparative analysis of numerical simulation and field measured data, the mechanism, mechanical properties, and causes of large squeezing deformation of the Jiangluling Tunnel were analyzed. The study results are as follows: 1) Six failure modes of the support structure can be generated due to the large deformation of the surrounding rocks during the construction of Jiangluling Carbonaceous Shale Tunnel; 2) The causes of large deformation during the construction can be divided into internal and external causes; 3) The deformation degree of the surrounding rock of Jiangluling Carbonaceous Shale Tunnel increases with the burial depth in an approximately linear manner. Under deep-buried conditions, horizontal convergence is more severe than vault settlement in carbonaceous shale tunnels; 4) The deformation of the construction cavern of the Jiangluling Carbonaceous Shale Tunnel typically includes the displacement before tunnel face excavation, tunnel face deformation, and deformation behind the tunnel face. The advance displacement accounts for 30.73% of the total displacement. The influence range of advance displacement is 1-1.2D in front of the tunnel face. These results can provide a reference for the design and construction of carbonaceous shale tunnels.

PurposeTo evaluate the relationship between novel serum lipid index and chemoresistance as well as prognosis of epithelial ovarian cancer (EOC).Patients and methodsPatients’ serum lipid profiles of 249 cases diagnosed with epithelial ovarian cancer, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) as well as their ratios, the novel indicators HDL-C/TC and HDL-C/LDL-C, and clinicopathologic characteristics were retrospectively collected and calculated from January 2016 to January 2020 and correlation between serum lipid index and clinicopathological features such as chemoresistance as well as prognosis were evaluated.Results249 patients pathologically diagnosed EOC who underwent cytoreductive surgery were included in our cohort. The mean age of these patients was 55.20 ± 11.07 years. Binary logistic regression analyses indicated Federation International of Gynecology and Obstetrics (FIGO(stage and HDL-C/TC ratio had significant association with chemoresistance. Univariate analyses demonstrated pathological type, chemoresistance, FIGO stage, neoadjuvant chemotherapy, maintenance treatment, HDL-C/LDL-C ratio, HDL-C/TC ratio were related to Progression-Free Survival (PFS) and Overall Survival (OS) (P

The reliability of the immersed tunnel element joint is the key to determine whether the immersed tunnel can operate safely. At present, the immersed tunnel monitoring mostly pays attention to the joint opening and closing amount and neglects the differential deformation of the joint. Based on the immersed tunnel of Hong Kong-Zhuhai-Macao Bridge, combined with the operating environment and structural characteristics of the immersed tunnel, this paper introduces a close-range photogrammetry method to monitor the differential deformation of the immersed tunnel element joint. Through theoretical analysis, software and hardware development, laboratory test and field test, the paper puts forward puts forward a comprehensive multi-parameter evaluation and screening algorithm of boundary fitting ellipse based on fitting rate, ellipticity and area difference and a micro-displacement correction algorithm for camera based on three-dimensional calibration object, and develops an automatic monitoring system equipment for differential deformation of immersed tunnel element joint. Upon tests in tunnels, the monitoring equipment is proven in automatic monitoring on differential deformation of immersed tunnel element joints. This equipment has been successfully applied to the E31~E32 element joint of Hong Kong-Zhuhai-Macao Bridge immersed tunnel, which verifies the effectiveness of the equipment from the perspective of practical engineering application.

Tumors with BRCA1/2 mutations or homologous recombination repair defects are sensitive to PARP inhibitors through the mechanism of synthetic lethality. Several PARP inhibitors are currently approved for ovarian, breast and pancreatic cancer in clinical practice. However, more than 40% of patients with BRCA1/2 mutations are insensitive to PARP inhibitors, which has aroused attention to the mechanism of PARP resistance and sensitization schemes. PARP inhibitor resistance is related to homologous recombination repair, stability of DNA replication forks, PARylation and epigenetic modification. Studies on epigenetics have become the hotspots of research on PARP inhibitor resistance. As an important epigenetic regulator of transcription mediated by histone methylation, EZH2 interacts with PARP through DNA homologous recombination, DNA replication, posttranslational modification, tumor immunity and other aspects. EZH2 inhibitors have been just shifting from the bench to the bedside, but the combination scheme in cancer therapy has not been fully explored yet. Recently, a revolutionary drug design combining PARP inhibitors and EZH2 inhibitors based on PROTAC techniques has shed light on the resolution of PARP inhibitor resistance. This review summarizes the interactions between EZH2 and PARP, suggests the potential PARP inhibitor sensitization effect of EZH2 inhibitors, and further discusses the potential populations that benefit from the combination of EZH2 inhibitors and PARP inhibitors.

ObjectiveBrain-derived neurotrophic factor (BDNF) and its receptor TrkB-T1 were recently found to be expressed in cardiomyocytes. However, the functional role of cardiomyocyte-derived BDNF in heart pathophysiology is not yet fully known. Recent studies revealed that BDNF-TrkB pathway plays a critical role to maintain integrity of cardiac structure and function, cardiac pathology and regeneration of myocardial infarction (MI). Therefore, the BDNF-TrkB pathway may be a novel target for myocardial pathophysiology in the adult heart.Approach and resultsIn the present study, we established a cardiomyocyte-derived BDNF conditional knockout mouse in which BDNF expression in developing cardiomyocytes is ablated under the control of the Myosin heavy chain 6 (MYH6) promoter. The results of the present study show that ablation of cardiomyocyte-derived BDNF during development does not impair survival, growth or reproduction; however, in the young adult heart, it causes cardiomyocyte death, degeneration of the myocardium, cardiomyocyte hypertrophy, left atrial appendage thrombosis, decreased cardiac function, increased cardiac inflammation and ROS activity, and metabolic disorders, leading to heart failure (HF) in the adult heart and eventually resulting in a decrease in the one-year survival rate. In addition, ablation of cardiomyocyte-derived BDNF during the developmental stage leads to exacerbation of cardiac dysfunction and poor regeneration after MI in adult hearts.ConclusionCardiomyocyte-derived BDNF is irreplaceable for maintaining the integrity of cardiac structure and function in the adult heart and regeneration after MI. Therefore, the BDNF-TrkB pathway will be a novel target for myocardial pathophysiology in the adult heart.

Senescent T cells are reported to be increased in patients with cancer and are poor prognostic indicators. However, the distribution of senescent T cells and their correlation with clinical features in high-grade serous ovarian cancer (HGSOC) is unknown. We detected the percentage of senescent T cells in the peripheral blood and ascites of patients with advanced HGSOC (n = 86) at diagnosis by flow cytometry. Compared with healthy donors, patients with HGSOC exhibited an accumulation of CD28−CD57+ (Tsen) CD8+ T cells in the peripheral blood and ascites. The frequency of Tsen CD8+ T cells in the peripheral blood was positively correlated with age and pretreatment serum CA125 and increased in patients with large volume ascites, whereas the frequency of Tsen CD8+ T cells in ascites was elevated in patients with lymph node metastasis. Patients with Tsen-high in ascites (>19.92%), but not in the peripheral blood, were more likely to be resistant to chemotherapy and had shorter progression-free survival. Tsen CD8+ T cells exhibited common senescence features including increased SA-β-gal activity, declines in proliferation, loss of CD27 and gain of KLRG-1, and the production of cytokines. In ascites, the percentage of Tsen CD8+ T cells was positively correlated with levels of interleukin-10 and granzyme B. This study suggests the potential of ascitic Tsen CD8+ T cells at diagnosis as a prognostic biomarker in HGSOC.

Recurrent respiratory tract infections (RRTi) cause a high burden of disease and lead to negative impact on quality of life, frequent school/work absenteeism, and doctor visits, which remain a great challenge to pediatricians because RRTi can increase the risk of various complications including antibiotic overuse and resistance, which is one of the biggest threats to global health, and there is no confirmed effective treatment. In this study, we aimed to assess the clinical efficacy and safety of oropharyngeal probiotic ENT-K12 as a dietary intervention or a complementary treatment along with standard medical treatment during acute respiratory infections among children with RRTi during cold season. The results of this study show that when comparing to practicing of standard medical treatment only, the complementary intake of oropharyngeal probiotic ENT-K12 can effectively reduce episodes of both acute and RRTi in school children, shorten the course of respiratory symptoms onset, reduce the use of antibiotics and antiviral drugs, and reduce the absence days from both children's school and parents' work. Using oropharyngeal probiotics as a complementary dietary intervention to stabilize oropharyngeal microflora, specifically inhibiting respiratory pathogens and enhancing host immunity, could possibly be a promising approach to reduce RRTi burden and combating antibiotic resistance in long term, more clinical studies will be needed to further confirm the clinical practicing guide to ensure its clinical benefit.MethodsA total of 100 susceptible children with RRTi aged 3–10 years, living in Wuhan, China, were selected. They were randomized to the probiotic group and control group at the beginning of the trial during the cold season. Fifty children in the probiotic group took oropharyngeal probiotic ENT-K12 for 30 days, along with standard medical treatment when there was an onset of respiratory symptoms and medical treatment was needed, and fifty children in the control group did not take oropharyngeal probiotics but only had standard medical treatment when there was an onset of respiratory symptoms and medical treatment was needed. Patients were followed up for 30 days during the cold season. The primary objective of this study is to assess the complementary dietary interventional efficacy of oropharyngeal probiotic ENT-K12 on episodes of respiratory tract infections during the cold season, and the secondary objective is to assess the interventional efficacy of oropharyngeal probiotic on days of respiratory symptoms onset, using antiviral drugs, antibiotics, and antipyretics, days of children absent from school, and days of parents absent from work, as well as to confirm tolerability and safety judged by adverse event reporting.ResultsThere were 47 children, 22 male and 25 female children, with an average age of 5.71 years (SD = 1.99) in the probiotic group finishing the study, and 50 children, 32 male and 18 female children, in the control group with an average age of 6.12 years (SD = 1.98) finishing the study. During the 30-day period of oropharyngeal probiotic intake, children in the probiotic group totally had 7 episodes of upper respiratory tract infections, while children in the control group totally had 17 episodes of upper respiratory tract infections, indicating that the incidence of upper respiratory tract infection in the probiotic group (14.89%) was significantly lower than that in the control group (34.00%) during the intervention period. The days of using antibiotics and antiviral drugs in the probiotic group were significantly lower than that in the control group, and the course of respiratory symptoms onset was shorter and more moderate in the probiotic group than that in the control group; in addition, compared with the control group, both the days of children absent from school and parents' absence from work in the probiotic group were significantly lower. Children treated with oropharyngeal probiotic ENT-K12 had excellent tolerability with no side effects reported, hence confirmed safety of applying oropharyngeal probiotic ENT-K12 as a prophylactic use or an effective dietary intervention along with standard medication during respiratory infections onset.ConclusionIntake of oropharyngeal probiotic ENT-K12 as a dietary intervention can effectively reduce episodes of upper respiratory tract infections in school children with RRTi during high peak season, reduce the days of using antibiotics and antiviral drugs, and reduce children's sick leave days, parents' absence days from work, and shorten the course of respiratory infections; the safety of oropharyngeal probiotic ENT-K12 has been confirmed with no side effects reported, excellent tolerability, and easy acceptance. Notably, this study opens up a new research idea in the field of microbe promoting human health by supplying direct proof to support its efficiency and safety.

ObjectiveThe aim of the present study was to determine overall survival (OS) and risk factors associated with early recurrence in patients with FIGO I–II stage endometrial carcinoma (EC).MethodsClinical features were retrospectively extracted from the database of China Endometrial Cancer Consortium from January 2000 to December 2019. A total of 2,974 patients with Federation International of Gynecology and Obstetrics (FIGO) I–II stage endometrial cancer were included. Kaplan-Meier survival analysis was used to assess OS and disease-specific survival. Cox proportional hazard model and Fine-Gray model were used to determine the factors related to OS. Binary logistic regression model was used to determine independent predictors of early relapse patients.ResultsOf these 2,974 ECs, 189 patients were confirmed to have relapse. The 5-year OS was significantly different between the recurrence and non-recurrence patients (p < 0.001). Three quarters of the relapse patients were reported in 36 months. The 5-year OS for early recurrence patients was shorter than late recurrence [relapse beyond 36 months, p < 0.001]. The grade 3 [odds ratio (OR) = 1.55, 95%CI 1.17–2.05, p = 0.002], lymphatic vascular infiltration (LVSI; OR = 3.36; 95%CI 1.50–7.54, p = 0.003), and myometrial infiltration (OR = 2.07, 95%CI 1.17—3.65, p = 0.012) were independent risk factors of early relapse. The protective factor of that is progesterone receptor (PR)-positive (OR = 0.50, 95%CI 0.27–0.92, p = 0.02). Bilateral ovariectomy could reduce recurrence risk rate (OR = 0.26, 95%CI 0.14–0.51, p < 0.001).ConclusionThe OS of early relapse EC is worse. Grade 3, LVSI, and myometrial infiltration are independent risk factors for early relapse EC. In addition, the protective factor is PR-positive for those people and bilateral salpingo-oophorectomy could reduce the risk of recurrence.

ObjectivePatients with endometrial cancer (EC) combined with metabolic syndrome (MetS) have a worse prognosis than those without MetS. This study aimed to investigate whether partial metabolic disorder significantly influenced early-stage endometrioid EC (EEC) survival and searched for a more efficient method to evaluate metabolic status.MethodsThis is a nationwide, multicenter cohort study that included 998 patients with primary early-stage EEC from 2001 to 2018. Patients were divided into different metabolic groups based on the diagnostic criteria of the Chinese Medical Association (CDC). The progression-free survival (PFS) time was compared between various metabolic status. Meanwhile, we established an EC Prognostic-Related Metabolic Score (ECPRM Score) to explore the association of the severity of metabolic status and early-stage EEC PFS. A nomogram was established for predicting PFS, which was externally validated in a testing set that includes 296 patients.ResultsA partial metabolic disorder, as well as MetS, was an independent risk factor of poor survival of patients with early-stage EEC [hazard ratio (HR) = 7.6, 95% CI = 1.01–57.5, p < 0.05]. A high ECPRM Score was associated with lower PFS (HR = 2.1, 95% CI = 1.05–4.0, p < 0.001). The nomogram, in which the ECPRM Score contributed most to the prognosis, exhibited excellent discrimination of survival supported by the internal and external validations. In addition, the calibration curve supports its robust predicting ability.ConclusionEven though they do not meet the criteria of MetS, partial metabolic disorders were also associated with adverse outcomes in early-stage EEC. The ECPRM Score is beneficial for clinicians to evaluate the severity of metabolic abnormalities and guide patients to ameliorate the poor prognosis of metabolic disorders.

Herpes simplex virus type 1 (HSV1) remains one of the most ubiquitous human pathogens on earth. The classical presentation of HSV1 infection occurs as a recurrent lesions of the oral mucosa commonly refer to as the common cold sore. However, HSV1 also is responsible for a range of ocular diseases in immunocompetent persons that are of medical importance, causing vision loss that may result in blindness. These include a recurrent corneal disease, herpes stromal keratitis, and a retinal disease, acute retinal necrosis, for which clinically relevant animal models exist. Diverse host immune mechanisms mediate control over herpesviruses, sustaining lifelong latency in neurons. Programmed cell death (PCD) pathways including apoptosis, necroptosis, and pyroptosis serve as an innate immune mechanism that eliminates virus-infected cells and regulates infection-associated inflammation during virus invasion. These different types of cell death operate under distinct regulatory mechanisms but all server to curtail virus infection. Herpesviruses, including HSV1, have evolved numerous cell death evasion strategies that restrict the hosts ability to control PCD to subvert clearance of infection and modulate inflammation. In this review, we discuss the key studies that have contributed to our current knowledge of cell death pathways manipulated by HSV1 and relate the contributions of cell death to infection and potential ocular disease outcomes.

Pathway-level analysis is a powerful approach enabling the interpretation of post-genomic data at a higher level than that of individual molecules. Molecular-targeted therapy focusing on cascade signaling pathways has become a new paradigm in anticancer therapy, instead of a single protein. However, the approaches to narrowing down the long list of biological pathways are limited. Here, we proposed a strategy for in silico Drug Prescription on biological pathways across pan-Cancers (CDP), by connecting drugs to candidate pathways. Applying on a list of 120 traditional Chinese medicines (TCM), we especially identified the “TCM–pathways–cancers” triplet and constructed it into a heterogeneous network across pan-cancers. Applying them into TCMs, the computational prescribing methods deepened the understanding of the efficacy of TCM at the molecular level. Further applying them into Western medicines, CDP could promote drug reposition avoiding time-consuming developments of new drugs.

BackgroundsOvarian cancer (OC) is still the leading aggressive and lethal disease of gynecological cancers, and platinum-based regimes are the standard treatments. However, nearly 20%–30% of patients with OC are initial platinum resistant (IPR), and there is a lack of valid tools to predict whether they will be primary platinum resistant or not prior to chemotherapy.MethodsTranscriptome data from The Cancer Genome Atlas (TCGA) was downloaded as the training data, and transcriptome data of GSE15622, GSE102073, GSE19829, and GSE26712 were retrieved from Gene Expression Omnibus (GEO) as the validation cohorts. Differentially expressed genes (DEGs) were selected between platinum-sensitive and platinum-resistant patients from the training cohort, and multiple machine-learning algorithms [including random forest, XGboost, and least absolute shrinkage and selection operator (LASSO) regression] were utilized to determine the candidate genes from DEGs. Then, we applied logistic regression to establish the IPR signature based on the expression. Finally, comprehensive clinical, genomic, and survival feature were analyzed to understand the application value of the established IPR signature.ResultsA total of 532 DEGs were identified between platinum-resistant and platinum-sensitive samples, and 11 of them were shared by these three-machine learning algorithms and utilized to construct an IPR prediction signature. The area under receiver operating characteristic curve (AUC) was 0.841 and 0.796 in the training and validation cohorts, respectively. Notably, the prediction capacity of this signature was stable and robust regardless of the patients’ homologous recombination deficiency (HRD) and mutation burden status. Meanwhile, the genomic feature was concordant between samples with high- or low-IPR signature, except a significantly higher prevalence of gain at Chr19q.12 (regions including CCNE1) in the high-IPR signature samples. The efficacy of prediction of platinum resistance of IPR signature successfully transferred to the precise survival prediction, with the AUC of 0.71, 0.72, and 0.66 to predict 1-, 3-, and 5-year survival, respectively. At last, we found a significantly different tumor-infiltrated lymphocytes feature, including lower abundance of CD4+ naive T cells in the samples with high-IPR signature. A relatively lower tumor immune dysfunction and exclusion (TIDE) value and more sensitivity to multiple therapies including Gefitinib may suggest the potency to transfer from platinum-based therapy to immunotherapy or target therapies in patients with high-IPR signature.ConclusionOur study established an IPR signature based on the expression of 11 genes that could stably and robustly distinguish OC patients with IPR and/or poor outcomes, which may guide therapeutic regimes tailoring.

ObjectiveTo evaluate the effect of maintenance therapy for patients with atypical endometrial hyperplasia (AEH) and early endometrial cancer (EC) after successful fertility-preserving management on prognosis and pregnancy outcome.MethodsWe performed a retrospectively analysis of 109 young women with atypical endometrial hyperplasia and early endometrioid endometrial cancer who had received complete response after fertility-preserving treatment at 5centers between May 2005 and March 2021. Maintenance therapy regimes included low-dose oral progesterone, levonorgestrel intrauterine device(LNG-IUD) and combination oral contraceptive (COC). The patients were divided into two groups, maintenance therapy group and non-maintenance therapy group. Clinical characteristics, treatment regimens, prognosis, and pregnancy outcome were compared between the two groups.ResultsThe overall disease recurrence rate of the maintenance therapy group was significantly lower than that of the non-maintenance therapy group (P < 0.001). The recurrence rate of atypical endometrial hyperplasia and endometrial cancer in the maintenance therapy group were significantly lower than those in the non-maintenance group (P < 0.001). Maintenance therapy can reduce pregnancy rates and live birth rates. Maintenance therapy can protect the endometrium in patients treated with assisted reproductive technology (ART), greatly reducing the recurrence rate after ART (P

Objective: To systematically evaluate lymph node metastasis (LNM) patterns in patients with endometrial cancer (EC) who underwent complete surgical staging, which included systematic pelvic and para-aortic lymphadenectomy.Methods: Four thousand and one patients who underwent complete surgical staging including systematic pelvic and para-aortic lymphadenectomy for EC were enrolled from 30 centers in China from 2001 to 2019. We systematically displayed the clinical and prognostic characteristics of patients with various LNM patterns, especially the PLN-PAN+ [para-aortic lymph node (PAN) metastasis without pelvic lymph node (PLN) metastasis]. The efficacy of PAN+ (para-aortic lymph node metastasis) prediction with clinical and pathological features was evaluated.Results: Overall, 431 of the 4,001 patients (10.8%) showed definite LNM according to pathological diagnosis. The PAN+ showed the highest frequency (6.6%) among all metastatic sites. One hundred fourteen cases (26.5%) were PLN-PAN+ (PAN metastasis without PLN metastasis), 167 cases (38.7%) showed PLN+PAN-(PLN metastasis without PAN metastasis), and 150 cases (34.8%) showed metastasis to both regions (PLN+PAN+). There was also 1.9% (51/2,660) of low-risk patients who had PLN-PAN+. There are no statistical differences in relapse-free survival (RFS) and disease-specific survival (DSS) among PLN+PAN-, PLN-PAN+, and PLN+PAN+. The sensitivity of gross PLNs, gross PANs, and lymphovascular space involvement (LVSI) to predict PAN+ was 53.8 [95% confidence interval (CI): 47.6–59.9], 74.2 95% CI: 65.6–81.4), and 45.8% (95% CI: 38.7–53.2), respectively.Conclusion: Over one-fourth of EC patients with LMN metastases were PLN-PAN+. PLN-PAN+ shares approximate survival outcomes (RFS and DSS) with other LNM patterns. No effective clinical methods were achieved for predicting PAN+. Thus, PLN-PAN+ is a non-negligible LNM pattern that cannot be underestimated in EC, even in low-risk patients.

The tumor metabolic reprogramming contributes to the progression and prognosis of cervical cancer (CC). However, the potential remodeling mechanisms of tumor metabolism in the immune microenvironment of CC remain largely unknown. In this study, we first performed microarray analysis to identify differential metabolic gene expression. A novel 5-metabolic-related genes (MRGs) signature comprising P4HA1, P4HA2, ABL2, GLTP, and CYP4F12 was established to better predict prognosis of CC using LASSO-Cox regression analysis. This signature could reveal the metabolic features and monitor the immune status of tumor microenvironment (TME). Among them, P4HA2 was significantly upregulated in CC tissues and negatively correlated with CD8+T cells. Knockdown of P4HA2 inhibited lipid droplets (LDs) accumulation and cancer cells invasion. Moreover, P4HA2 knockdown significantly suppressed PD-L1 expression. This study provides a new and feasible method for evaluating the prognosis of CC and explores the potential value to navigate metabolic pathways to enhance anti-tumor immunity and immunotherapy.

Healthcare workers at the frontline are facing a substantial risk of respiratory tract infection during the COVID-19 outbreak due to an extremely stressful work schedule and public health event. A well-established first-line defense on oropharyngeal microbiome could be a promising strategy to protect individuals from respiratory tract infections including COVID-19. The most thoroughly studied oropharyngeal probiotic product which creates a stable upper respiratory tract microbiota capable of preventing upper respiratory tract infections was chosen to evaluate the safety and efficacy on reducing episodes of upper respiratory tract infections for COVID-19 healthcare workers. To our knowledge to date, this is the very first study describing the beneficial effects of oropharyngeal probiotic been administered by healthcare workers during the COVID-19 pandemic. In this randomized controlled trial, we provided the probiotics to frontline medical staff who work in the hospitals in Wuhan and had been in close contact with hospitalized COVID-19 patients for prophylactic use on a daily basis. Our finding suggests that oropharyngeal probiotic administration significantly reduced the incidence of respiratory tract infections by 64.8%, reduced the time experiencing respiratory tract infections and oral ulcer symptoms by 78%, shortened the days absent from work by 95.5%, and reduced the time under medication where there is no record of antibiotic and anti-viral drug intake in the probiotic group. Furthermore, medical staff treated with Bactoblis experienced sustained protection from respiratory tract infections since the 10th day of oropharyngeal probiotic administration resulting in an extremely low incidence rate of respiratory tract infections.

BackgroundHigh grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet.MethodsNinety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients.ResultsA high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1–100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%.ConclusionsA multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.

Ovarian cancer (OC) is one of the most lethal malignant gynecologic tumors, characterized by an uncertain presentation and poor outcomes. With or without neoadjuvant chemotherapy, surgery followed by platinum-based chemotherapy and maintenance therapy are the basis for the treatment of ovarian cancer patients, but the outcome is still highly restricted by their advanced stage when diagnosed and high recurrence rate after chemotherapy. To enhance the anti-tumor effect and postpone recurrence, anti-VEGF agents and PARP inhibitors are suggested as maintenance therapy, but the population that can benefit from these treatments is small. Based on the interactions of immune cells in the tumor microenvironment, immunotherapies are being explored for ovarian cancer treatment. Disappointingly, the immune checkpoint inhibitors show relatively low responses in ovarian cancer. As shown in several studies that have uncovered a relationship between DC infiltration and outcome in ovarian cancer patients, dendritic cell (DC)-based treatments might have a potential effect on ovarian cancer. In this review, we summarize the functions of dendritic cells (DCs) in the tumor microenvironment, as well as the responses and drawbacks of existing clinical studies to draw a comprehensive picture of DC vaccine treatment in ovarian cancer and to discuss the promising future of immune biomarkers.

BackgroundFractures are a medical disease with a high incidence, and about 5–10% of patients need bone transplantation to fill the defect. In this study, we aimed to synthesize a new type of coralline hydroxyapatite (CHA)/silk fibroin (SF)/glycol chitosan (GCS)/difunctionalized polyethylene glycol (DF-PEG) self-healing hydrogel and to evaluate the therapeutic effects of this novel self-healing hydrogel as a human umbilical cord mesenchymal stem cells (hucMSC)-derived exosome carrier on bone defects in SD rat.MethodsHucMSCs were isolated from fetal umbilical cord tissue and characterized by surface antigen analysis and pluripotent differentiation in vitro. The cell supernatant after ultracentrifugation was collected to isolate exosomes, which were characterized by transmission electron microscopy and western blot analysis. In vitro cell induction experiments were performed to observe the effects of hucMSC-derived exosomes on the biological behavior of mouse osteoblast progenitor cells (mOPCs) and human umbilical vein endothelial cells (HUVECs). The CHA/SF/GCS/DF-PEG hydrogels were prepared using DF-PEG as the gel factor and then structural and physical properties were characterized. HucMSCs-derived exosomes were added to the hydrogel and their effects were evaluated in SD rats with induced femoral condyle defect. These effects were analyzed by X-ray and micro-CT imaging and H&E, Masson and immunohistochemistry staining.ResultsHucMSC-derived exosomes can promote osteogenic differentiation of mOPCs and promote the proliferation and migration of HUVECs. The CHA/SF/GCS/DF-PEG hydrogel has a high self-healing capacity, perfect surface morphology and the precipitated CHA crystals have a small size and low crystallinity similar to natural bone minerals. The MTT results showed that the hydrogel was non-toxic and have a good biocompatibility. The in vivo studies have shown that the hydrogel containing exosomes could effectively promote healing of rat bone defect. The histological analysis revealed more new bone tissue and morphogenetic protein 2 (BMP-2) in the hydrogel-exosome group. In addition, the hydrogel-exosome group had the highest microvessel density.ConclusionA self-healing CHA/SF/GCS/DF-PEG hydrogel was successfully prepared. The hydrogel has excellent comprehensive properties and is expected to become a new type of bone graft material. This hydrogel has the effect of promoting bone repair, which is more significant after the addition of hucMSC-derived exosomes.

Cannabis is one of the most important industrial crops distributed worldwide. However, the phylogeographic structure and domestication knowledge of this crop remains poorly understood. In this study, sequence variations of five chloroplast DNA (cpDNA) regions were investigated to address these questions. For the 645 individuals from 52 Cannabis accessions sampled (25 wild populations and 27 domesticated populations or cultivars), three haplogroups (Haplogroup H, M, L) were identified and these lineages exhibited distinct high-middle-low latitudinal gradients distribution pattern. This pattern can most likely be explained as a consequence of climatic heterogeneity and geographical isolation. Therefore, we examined the correlations between genetic distances and geographical distances, and tested whether the climatic factors are correlated with the cpDNA haplogroup frequencies of populations. The “isolation-by-distance” models were detected for the phylogeographic structure, and the day-length was found to be the most important factor (among 20 BioClim factors) that influenced the population structures. Considering the distinctive phylogeographic structures and no reproductive isolation among members of these lineages, we recommend that Cannabis be recognized as a monotypic genus typified by Cannabis sativa L., containing three subspecies: subsp. sativa, subsp. Indica, and subsp. ruderalis. Within each haplogroup which possesses a relatively independent distribution region, the wild and domesticated populations shared the most common haplotypes, indicating that there are multiregional origins for the domesticated crop. Contrast to the prevalent Central-Asia-Origin hypothesis of C. saltiva, molecular evidence reveals for the first time that the low latitude haplogroup (Haplogroup L) is the earliest divergent lineage, implying that Cannabis is probably originated in low latitude region.

Methamphetamine (METH) abuse causes serious health problems worldwide, and long-term use of METH disrupts the blood–brain barrier (BBB). Herein, we explored the potential mechanism of endoplasmic reticulum (ER) stress in METH-induced BBB endothelial cell damage in vitro and the therapeutic potential of endoplasmic reticulum stress inhibitors for METH-induced BBB disruption in C57BL/6J mice. Exposure of immortalized BMVEC (bEnd.3) cells to METH significantly decreased cell viability, induced apoptosis, and diminished the tightness of cell monolayers. METH activated ER stress sensor proteins, including PERK, ATF6, and IRE1, and upregulated the pro-apoptotic protein CHOP. The ER stress inhibitors significantly blocked the upregulation of CHOP. Knockdown of CHOP protected bEnd.3 cells from METH-induced cytotoxicity. Furthermore, METH elevated the production of reactive oxygen species (ROS) and induced the dysfunction of mitochondrial characterized by a Bcl2/Bax ratio decrease, mitochondrial membrane potential collapse, and cytochrome c. ER stress release was partially reversed by ROS inhibition, and cytochrome c release was partially blocked by knockdown of CHOP. Finally, PBA significantly attenuated METH-induced sodium fluorescein (NaFluo) and Evans Blue leakage, as well as tight junction protein loss, in C57BL/6J mice. These data suggest that BBB endothelial cell damage was caused by METH-induced endoplasmic reticulum stress, which further induced mitochondrial dysfunction, and that PBA was an effective treatment for METH-induced BBB disruption.

Plant hormone auxin regulates most, if not all aspects of plant growth and development, including lateral root formation, organ pattering, apical dominance, and tropisms. Peptide hormones are peptides with hormone activities. Some of the functions of peptide hormones in regulating plant growth and development are similar to that of auxin, however, the relationship between auxin and peptide hormones remains largely unknown. Here we report the identification of OsCLE48, a rice (Oryza sativa) CLE (CLAVATA3/ENDOSPERM SURROUNDING REGION) gene, as an auxin response gene, and the functional characterization of OsCLE48 in Arabidopsis and rice. OsCLE48 encodes a CLE peptide hormone that is similar to Arabidopsis CLEs. RT-PCR analysis showed that OsCLE48 was induced by exogenously application of IAA (indole-3- acetic acid), a naturally occurred auxin. Expression of integrated OsCLE48p:GUS reporter gene in transgenic Arabidopsis plants was also induced by exogenously IAA treatment. These results indicate that OsCLE48 is an auxin responsive gene. Histochemical staining showed that GUS activity was detected in all the tissue and organs of the OsCLE48p:GUS transgenic Arabidopsis plants. Expression of OsCLE48 under the control of the 35S promoter in Arabidopsis inhibited shoot apical meristem development. Expression of OsCLE48 under the control of the CLV3 native regulatory elements almost completely complemented clv3-2 mutant phenotypes, suggesting that OsCLE48 is functionally similar to CLV3. On the other hand, expression of OsCLE48 under the control of the 35S promoter in Arabidopsis has little, if any effects on root apical meristem development, and transgenic rice plants overexpressing OsCLE48 are morphologically indistinguishable from wild type plants, suggesting that the functions of some CLE peptides may not be fully conserved in Arabidopsis and rice. Taken together, our results showed that OsCLE48 is an auxin responsive peptide hormone gene, and it regulates shoot apical meristem development when expressed in Arabidopsis. [ABSTRACT FROM AUTHOR]