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FOXM1 acts as an oncogenic transcription factor and is involved in multiple hallmarks of human malignancies. Recent studies have demonstrated that FOXM1 is upregulated and correlated with poor prognosis in a majority of cancers. However, there are few pan-cancer analyses of FOXM1. This study aimed to investigate the expression profiles and clinical significance of FOXM1 in 31 types of solid tumors. We explored the expression profiles and the prognostic value of FOXM1 in pan-cancer across The Cancer Genome Atlas (TCGA). We further used lung adenocarcinoma (LUAD) tissues combined with quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) for experimental validation of FOXM1 expression. Besides, we verified the function of FOXM1 in a lung cancer cell line. Gene set enrichment analysis (GSEA) was conducted to explore signaling pathways related to FOXM1 expression. We observed that up-regulated FOXM1 was significantly related to poor survival in most tumors. Furthermore, there are significant correlations between FOXM1 expression and the infiltrating levels of different types of immune cells, TMB, MSI and immune checkpoint genes in a variety of cancers. Additional analysis based on IMvigor 210 cohort confirmed that patients with high level of FOXM1 exhibited a superior response to anti-PD-L1 therapy, and had a prolonged OS. In conclusion, this study indicated that FOXM1 could serve as a prognostic biomarker for most types of cancers and played a crucial role in the tumor immune microenvironment.

To investigate the relationship between systemic inflammatory response and short-term mortality in patients with non-cirrhotic chronic severe hepatitis (CSH) by using several indicators of inflammation including neutrophil-to-lymphocyte ratio (NLR), neutrophil (NEU), white blood cell (WBC), platelet-to lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR).Data were collected from two prospectively enrolled CATCH-LIFE noncirrhotic cohorts. Cox regression analysis was used to investigate the association between systemic inflammatory biomarkers and 90-day liver transplant (LT)-free mortality. A generalized additive model (GAM) was used to illustrate the quantitative curve relationship between NLR and 90-day LT-free mortality. Kaplan-Meier method was used to estimate the 90-year LT-free survival.The prevalence of CSH was 20.5% (226/1103). The 28-day and 90-day LT-free mortality rates were 17.7% and 26.1%, respectively, for patients with non-cirrhotic CSH. Patients with no infection accounted for 75.0% of all CSH patients, and NLR was independently associated with 90-day LT-free mortality. NLR of 2.9 might be related to disease deterioration in CSH patients without infection.NLR may be an independent risk factor for 90-day LT-free mortality in patients with non-cirrhotic chronic liver disease. A NLR of 2.9 as the cut-off value can be used to predict disease aggravation in CSH patients without infection.

Human respiratory syncytial virus (HRSV) is a leading cause worldwide of severe respiratory illness in infants and the elderly. The ideal HRSV vaccine should induce a systemic immune response, especially mucosal immunity. In this study, mice were immunized twice with F protein combined with CpG adjuvant to compare the safety and efficacy of 4 immunization routes, including intranasal primed/intramuscular boosted immunization (CpG + F/in+im), intramuscular primed/intranasal boosted immunization (CpG + F/im+in), intramuscular primed/intramuscular boosted immunization (CpG + F/im + im) and intranasal primed/intranasal boosted immunization (CpG + F/in+in). Compared with the control group (CpG/in+im, CpG/im+in, CpG/im + im and CpG/in+in), all 4 immunization routes induced a high titer of neutralizing antibodies and a strong cellular immune response. Mice in the CpG + F/in+in group induced the highest antibody neutralization titer, and IgA antibody in bronchoalveolar lavage fluid (BALF) was the highest. The copy of HRSVs in the lung decreased by approximately 3 log10. As seen from the IgG1/IgG2a and IFN-γ/IL-4-secreting lymphocyte ratios, compared with the mice in the CpG + F/im + im group, mice in the CpG + F/in+in group induced Th1-baised humoral and cellular immune responses and significantly reduced lung pathological injury. In conclusion, among the 4 immunization routes, the safety and efficacy induced by the mice in the CpG + F/in+in group were the best. We can conclude that intranasal immunization is superior to intramuscular immunization using F protein with CpG adjuvant as vaccine candidates.

Background The abnormal expression of long non-coding RNA (lncRNA) Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) has been observed in many human cancers and the underlying mechanisms have been well studied. However, the function of OIP5-AS1 in acute kidney injury (AKI) remains unclear. Material and methods To explore the role of OIP5-AS1 in the progression of AKI, the cisplatin-induced AKI mouse and cell model were established. To confirm the potential protective effect of OIP5-AS1 during cisplatin-induced AKI, rescue experiments were performed. Targetscan was used to predict the potential targets of miR-144-5p. To further determine whether the effect of miR-144-5p during cisplatin-induced AKI was mediated by PMK2, the recuse experiments using PMK2 overexpressing vector was applied. Results OIP5-AS1 was significantly downregulated both in cisplatin-induced AKI mice and human renal tubular cell line HK-2 cells. Moreover, overexpression of OIP5-AS1 efficiently promoted cell growth and reduced cisplatin-induced apoptosis of HK-2 cells. Furthermore, OIP5-AS1 was identified as a sponge of miR-144-5p, and upregulation of miR-144-5p could significantly reverse overexpression of OIP5-AS1-induced protective effect on the damage of cisplatin to HK-2 cells. In addition, pyruvate kinase M2 (PKM2) was found to be a direct target of miR-144-5p, and overexpression of PKM2 efficiently reversed the effect of miR-144-5p mimics on the damage in cisplatin-stimulated HK-2 cells. Conclusions OIP5-AS1 reduced the apoptosis of cisplatin-stimulated renal epithelial cells by targeting the miR-144-5p/PKM2 axis, which extended the regulatory network of lncRNAs in cisplatin-induced AKI and also provided a novel therapeutic target for AKI treatment.

The aim of the study is to investigate the diagnostic accuracy of radiomics on iodine maps from dual-energy computed tomography (DECT) in distinguishing lung cancer from benign pulmonary nodules.This retrospective study was approved by the institutional review board, and written informed consent was waived. A total of 109 patients with 55 malignant nodules and 62 benign nodules underwent contrast-enhanced DECT. Eight iodine uptake parameters on iodine maps generated by DECT were calculated and established a predictive model. Eighty-seven radiomics features of entire tumor were extracted from iodine maps and established a radiomics model. The iodine uptake model and radiomics model were independently built based on the highly reproducible features using the least absolute shrinkage and selection operator method. The diagnostic accuracy of 2 models were assessed using receiver operating curve analysis. For external validation, 47 patients (25 benign and 22 malignant) from another hospital were assigned to testing data set.All iodine uptake features showed significant association with malignancy ( P0.01) and 2 selected features (mean value of virtual noncontrast images and mean value of vital part on contrast-enhanced image) constituted the iodine model. The radiomics model comprised 2 features (original shape sphericity and original glszm small area high gray level emphasis), which showed good discrimination both in the training cohort (area under the curve, 0.957) and validation cohort (area under the curve, 0.800). Radiomics model showed superior performance than iodine uptake model (accuracy, 89.7% vs 80.6%).Radiomics model extracted from iodine maps provided a robust diagnostic tool for discriminating pulmonary malignant nodules and had high potential in clinical application.

Laparoscopic liver resection (LLR) has become a safe surgical procedure that needs additional summarization.To review 4 years of total LLR surgeries, exceeding 1000 cases, which were performed at a single center.Patients who underwent LLR at West China Hospital of Sichuan University between January 2015 and December 2018 were identified. Surgical details, including the interventional year, category of liver disease, and malignant liver tumors prognosis, were evaluated. The learning curve for LLR was evaluated using the cumulative sum method. The Kaplan-Meier method was used to perform survival analysis.Ultimately, 1098 patients were identified. Hepatocellular carcinoma (HCC) was the most common disease that led to the need for LLR at the center (LLR may be considered a first-line surgical intervention for liver resection that can be performed safely for a variety of primary, secondary, and recurrent liver tumors and for benign diseases once technical competence is proficiently attained.

To develop and validate a pretreatment magnetic resonance imaging (MRI)-based radiomic-clinical model to assess the treatment response of whole-brain radiotherapy (WBRT) by using SHapley Additive exPlanations (SHAP), which is derived from game theory, and can explain the output of different machine learning models.We retrospectively enrolled 228 patients with brain metastases from two medical centers (184 in the training cohort and 44 in the validation cohort). Treatment responses of patients were categorized as a non-responding group vs. a responding group according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For each tumor, 960 features were extracted from the MRI sequence. The least absolute shrinkage and selection operator (LASSO) was used for feature selection. A support vector machine (SVM) model incorporating clinical factors and radiomic features wase used to construct the radiomic-clinical model. SHAP method explained the SVM model by prioritizing the importance of features, in terms of assessment contribution.Three radiomic features and three clinical factors were identified to build the model. Radiomic-clinical model yielded AUCs of 0.928 (95%CI 0.901-0.949) and 0.851 (95%CI 0.816-0.886) for assessing the treatment response in the training cohort and validation cohort, respectively. SHAP summary plot illustrated the feature's value affected the feature's impact attributed to model, and SHAP force plot showed the integration of features' impact attributed to individual response.The radiomic-clinical model with the SHAP method can be useful for assessing the treatment response of WBRT and may assist clinicians in directing personalized WBRT strategies in an understandable manner.• Radiomic-clinical model can be useful for assessing the treatment response of WBRT. • SHAP could explain and visualize radiomic-clinical machine learning model in a clinician-friendly way.

Due to respiratory motion, precise tracking of lung nodule movement is a persistent challenge for guiding percutaneous lung biopsy during image-guided intervention. We developed an automated image-guided system incorporating effective and robust tracking algorithms to address this challenge. Accurate lung motion prediction and personalized image-guided intervention are the key technological contributions of this work.A patient-specific respiratory motion model is developed to predict pulmonary movements of individual patients. It is based on the relation between the artificial 4D CT and corresponding positions tracked by position sensors attached on the chest using an electromagnetic (EM) tracking system. The 4D CT image of the thorax during breathing is calculated through deformable registration of two 3D CT scans acquired at inspiratory and expiratory breath-hold. The robustness and accuracy of the image-guided intervention system were assessed on a static thorax phantom under different clinical parametric combinations.Real 4D CT images of ten patients were used to evaluate the accuracy of the respiratory motion model. The mean error of the model in different breathing phases was 1.59 ± 0.66 mm. Using a static thorax phantom, we achieved an average targeting accuracy of 3.18 ± 1.2 mm across 50 independent tests with different intervention parameters. The positive results demonstrate the robustness and accuracy of our system for personalized lung cancer intervention.The proposed system integrates a patient-specific respiratory motion compensation model to reduce the effect of respiratory motion during percutaneous lung biopsy and help interventional radiologists target the lesion efficiently. Our preclinical studies indicate that the image-guided system has the ability to accurately predict and track lung nodules of individual patients and has the potential for use in the diagnosis and treatment of early stage lung cancer.

Although sorafenib (Sora) shows improved efficacy in clinical liver cancer therapy, its therapeutic efficacy is still greatly limited due to side effects as well as drug resistance. Thus new drug intervention strategies are imperative. Our research showed the combined application of Dihydroartemisinin (DHA) and Sora had a synergistic inhibitory effect on HepG2 and SW480 cells, and DHA enhanced Sora efficacy on xenograft tumor in nude mice. DHA and Sora significantly inhibited the cell energy metabolism by decreasing the glycolysis rate and ATP synthesis rate of oxidative phosphorylation and induced ferroptosis by increasing the level of lipid reactive oxygen species (L-ROS), labile iron pool (LIP) as well as malondialdehyde (MDA) and decreasing the level of glutathione (GSH) in HepG2 cells. In addition, DHA and Sora significantly decreased the levels of SLC7A11 (xCT), GCLC, GPX4, and HO-1 protein in HepG2 cells. Importantly, the above-mentioned indicators changed more significantly after the combined application of DHA and Sora as compared with Sora. In conclusion, DHA and Sora had the same mechanism, and the combined application of them could have a synergistic anti-tumor effect by inducing ferroptosis and inhibiting energy metabolism in HepG2 cells.

Background The cell cycle is at the center of cellular activities and is orchestrated by complex regulatory mechanisms, among which transcriptional regulation is one of the most important components. Alternative splicing dramatically expands the regulatory network by producing transcript isoforms of genes to exquisitely control the cell cycle. However, the patterns of transcript isoform expression in the cell cycle are unclear. Therapies targeting cell cycle checkpoints are commonly used as anticancer therapies, but none of them have been designed or evaluated at the alternative splicing transcript level. The utility of these transcripts as markers of cell cycle-related drug sensitivity is still unknown, and studies on the expression patterns of cell cycle-targeting drug-related transcripts are also rare. Methods To explore alternative splicing patterns during cell cycle progression, we performed sequential transcriptomic assays following cell cycle synchronization in colon cancer HCT116 and breast cancer MDA-MB-231 cell lines, using flow cytometry and reference cell cycle transcripts to confirm the cell cycle phases of samples, and we developed a new algorithm to describe the periodic patterns of transcripts fluctuating during the cell cycle. Genomics of Drug Sensitivity in Cancer (GDSC) drug sensitivity datasets and Cancer Cell Line Encyclopedia (CCLE) transcript datasets were used to assess the correlation of genes and their transcript isoforms with drug sensitivity. We identified transcripts associated with typical drugs targeting cell cycle by determining correlation coefficients. Cytotoxicity assays were used to confirm the effect of ENST00000257904 against cyclin dependent kinase 4/6 (CDK4/6) inhibitors. Finally, alternative splicing transcripts associated with mitotic (M) phase arrest were analyzed using an RNA synthesis inhibition assay and transcriptome analysis. Results We established high-resolution transcriptome datasets of synchronized cell cycle samples from colon cancer HCT116 and breast cancer MDA-MB-231 cells. The results of the cell cycle assessment showed that 43,326, 41,578 and 29,244 transcripts were found to be periodically expressed in HeLa, HCT116 and MDA-MB-231 cells, respectively, among which 1280 transcripts showed this expression pattern in all three cancer cell lines. Drug sensitivity assessments showed that a large number of these transcripts displayed a higher correlation with drug sensitivity than their corresponding genes. Cell cycle-related drug screening showed that the level of the CDK4 transcript ENST00000547281 was more significantly associated with the resistance of cells to CDK4/6 inhibitors than the level of the CDK4 reference transcript ENST00000257904. The transcriptional inhibition assay following M phase arrest further confirmed the M-phase-specific expression of the splicing transcripts. Combined with the cell cycle-related drug screening, the results also showed that a set of periodic transcripts, for example, ENST00000314392 (a dolichyl-phosphate mannosyltransferase polypeptide 2 isoform transcript), was more associated with drug sensitivity than the levels of their corresponding gene transcripts. Conclusions In summary, we identified a panel of cell cycle-related periodic transcripts and found that the levels of transcripts of drug target genes showed different values for predicting drug sensitivity, providing novel insights into alternative splicing-related drug development and evaluation.

We aimed to analyze the expression of Cyclin D1 (CCND1) gene in ovarian cancer and the influence of silencing its expression on ovarian cancer cells based on the Oncomine database. The expression of CCND1 gene in ovarian cancer was analyzed by utilizing the relevant information in different tumors and Oncomine database. The correlation between CCDN1 expression level and prognosis of ovarian cancer was analyzed by the online database Kaplan-Meier (kmplot.com). The expression of CCND1 gene in ovarian cancer and the effect of silencing its expression on cancer cells were analyzed by cell experiments. After mining and comprehensively analyzing 7 studies on the differential expression of CCND1 gene in ovarian cancer tissue and normal ovarian tissue included in the Oncomine database, it was found that the median value of CCND1 gene ranked 218.0 (P = 8.03 × 10−6) among all differentially expressed genes, suggesting that CCND1 gene expression in ovarian cancer tissue was higher than that in normal ovarian tissue. Adib Ovarian, Bonome Ovarian and Hendrix Ovarian microarrays revealed that the expression of CCND1 gene in ovarian cancer tissue was significantly higher than that in normal ovarian tissue (P

BACKGROUND Chronic liver diseases (CLD), including cirrhosis and non-cirrhotic liver diseases, are globally widespread and create a serious disease burden. Platelet count is a clinically accessible and affordable prognostic indicator of liver disease. We investigated the relationship between platelet count and 90-day prognosis in patients with acute-on-chronic liver diseases (AoCLD). METHODS A total of 3,970 patients with AoCLD from the Chinese Acute-on-Chronic Liver Failure (CATCH-LIFE) study, which included two prospective multi-center cohorts, were included in the study. We grouped the patients according to the platelet count and analyzed the 90-day adverse outcome (death or liver transplantation). RESULTS In the final analysis, 3,939 patients with AoCLD were included, of whom 2,802 had definite liver cirrhosis. The cumulative incidence of 90-day adverse outcomes in patients increased with the change of platelet group (log-rank P

This paper proposes a real-time detection method for gear contact fatigue pitting based on machine vision in order to improve the detection accuracy and detection efficiency of specimen fatigue pitting in gear contact fatigue tests and to realize the visualization, quantification, and real-time detection of gear pitting. Under the principle of gear meshing and the shooting principle of a line-scan camera, a test detection system for gear contact fatigue is established, and the optimal centrifugal shooting distance for the gear tooth surface is obtained by analyzing the gear rotation process. In response to the phenomenon of image overlap caused by the inconsistency between the speed of each point on the gear tooth profile and the line frequency set by the camera, an image correction algorithm of the gear meshing surface has been proposed, which has been proven to have improved the accuracy of the detection results of gear contact fatigue pitting corrosion. The detection accuracy of fatigue pitting corrosion is improved by combining the preliminary detection and the accurate detection of the fatigue features. The depth information of the extracted contour pitting pits is extracted by the sequential forward selection (SFS) algorithm. The experimental results showed that 0.1216 m m 2 is the average absolute error of pitting corrosion detection, the average relative error is 2.2188%, and the detection accuracy is 97.7812%. The proposed pitting corrosion detection system advances in visualization, quantification, real-time monitoring, and failure judgment with a new, to the best of our knowledge, experimental approach for gear contact fatigue pitting corrosion detection.

Background In China diabetes care is gradually shifting from secondary to primary care with great infrastructure investment and GP training. However, most GPs in China lack communication skills training, which is a huge obstacle in communication with their patients in primary care. In this study we seek to identify training priorities that is evidence-based, appropriate for the context of primary care in China, and that meet the real needs of both GPs and people with diabetes. Methods A mixed method approach was used. A conceptual framework was designed based on the MRC framework, action research and adult learning theories. Through a systematic review of the literature and qualitative research with GPs and patients with diabetes, a list of communication skills training components was developed by the research team. A modified nominal group technique (NGT) with GPs was used to evaluate these contents. Purposive sampling was used to recruit a variation of participants (age, work area, practice years and education background) from general practices in Guangzhou city, China. Eight structured nominal groups were facilitated to elicit the views of group members, and participants rated the 9-point Likert scale of importance and feasibility of the training items independently, before and after focus groups. The ranking of each item was calculated, based on the mean Likert score ratings from all participants. Video recordings of four NGT group discussions were thematically analysed using the Framework Method to explore reasons for any differences in rating items. Results 29 males and 29 female GPs from 28 general practices participated in NGT group discussions, with a mean age of 38.5 years and mean 12.3 years of practice experience. Based on the mean scores of importance and feasibility rating scores, the top 3 ranked priorities for communication training were ‘health education’ (importance 8.39, feasibility 7.67), ‘discussing and explaining blood glucose monitoring’ (8.31, 7.46), and ‘diabetes complications and cardiovascular disease risk communication’ (8.36, 7.12). Five main themes were identified from focus group discussions through qualitative analysis: ‘impact on diabetes patients’, ‘GP attitudes towards communication skills’, ‘patient-related factors influencing the application of communication skills by GPs, ‘local contextual factors’, and ‘training implementation’. Conclusions Priorities for communication skills training for Chinese GPs in diabetes care were identified. These are set in the context of GPs’ current experience of communication with patients in China who have diabetes, which is often unsatisfactory. This study describes the baseline from which better primary care for diabetes in China needs to be developed. Based on suggestions from GPs themselves, it identifies an agenda for improvement in communication as a key component of diabetes care in China.

The pharmaceutical industry and clinical trials have been revolutionized mesenchymal stem cell–based therapeutics. However, the pharmacokinetics of transplanted cells has been little characterized in their target tissues under healthy or disease condition. A quantitative polymerase chain reaction analytical method with matrix effect was developed to track the biodistribution of human mesenchymal stem cells in normal mice and those with Concanavalin A (Con A)–induced liver injury. Mesenchymal stem/stromal cell (MSC) disposition in blood and different organs were compared, and relevant pharmacokinetic parameters were calculated. Human MSCs (hMSCs) and mouse MSCs (mMSCs) displayed a very similar pharmacokinetic profile in all tested doses: about 95% of the detected hMSCs accumulated in the lung and 3% in the liver, and almost negligible cells were detected in other tissues. A significant double peak of hMSC concentration emerged in the lung within 1–2 hours after intravenous injection, as with mMSCs. Prazosin, a vasodilator, could eliminate the second peak in the lung and increase its Cmax and area under the concentration-time curve (AUC) by 10% in the first 2 hours. The injury caused by Con A was significantly reduced by hMSCs, and the Cmax and AUC0–8 (AUC from time 0 to 8 hours) of cells in the injured liver decreased by 54 and 50%, respectively. The Cmax and AUC would be improved with the alleviation of congestion through the administration of heparin. The study provides a novel insight into the pharmacokinetics of exogenous MSCs in normal and Con A–induced liver injury mice, which provides a framework for optimizing cell transplantation. SIGNIFICANCE STATEMENT Mesenchymal stem/stromal cells (MSCs) are known for their potential as regenerative therapies in treating several diseases, but an insufficient understanding of the pharmacokinetics of MSCs restricts their future application. The current study was the first to elucidate the pharmacokinetics and possible factors, including dosage, species, and derived sources, in a systematic way. The study further revealed that Concanavalin A–induced liver injury significantly prevented cells from entering the injury site, which could be reversed by the diminished congestion achieved by heparin.

Background A few studies have reported that administration of lidocaine and dexmedetomidine relieves the incidence of postoperative nausea and vomiting (PONV). We explored whether combined infusion of lidocaine plus dexmedetomidine had lower occurrence of PONV undergoing laparoscopic hysterectomy with general anesthesia. Methods A total of 248 women undergoing elective laparoscopic hysterectomy were allocated into the following four groups: the control group (group C, n = 62) received an equal volume of saline, the lidocaine group (group L, n = 62) received intravenous lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion), the dexmedetomidine group (group D, n = 62) received dexmedetomidine administration (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion), and the lidocaine plus dexmedetomidine group (group LD, n = 62) received combination of lidocaine (bolus infusion of 1.5 mg/kg over 10 min, 1.5 mg/kg/h continuous infusion) and dexmedetomidine administration (bolus infusion of 0.5 µg/kg over 10 min, 0.4 µg/kg/h continuous infusion). The primary outcome was the incidence of nausea, vomiting, and PONV during the first 48 h after surgery. The secondary outcomes included the incidence of total 24 h PONV after surgery, intraoperative remifentanil requirement, postoperative pain visual analogue scale (VAS) scores and fentanyl consumption, the incidence of bradycardia, agitation, shivering, and mouth dry during post-anesthesia care unit (PACU) stay period. Results The occurrence of nausea and PONV in group LD (5.0 and 8.3%) at 0–2 h after operation was lower than group C (21.7 and 28.3%) (P P P P P P Conclusions Lidocaine combined with dexmedetomidine infusion markedly decreased the occurrence of nausea and PONV at 0–2 h as well as the total 24 h PONV. However, it significantly increased the incidence of mouth dry, bradycardia, and over sedation during the PACU stay period after laparoscopic hysterectomy with general anesthesia. Trial registration ClinicalTrials.gov (NCT03809923), registered on January 18, 2019.

Objective: To evaluate systematically the association between TBX21 gene polymorphisms (rs17250932, rs2240017, and rs4794067) and the risk of autoimmune diseases in Asian populations. Methods: The Medline, Web of Science, and Chinese Biomedical Literature Database were used to retrieve eligible studies that were published before July 2020. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by using the dominant model, heterozygote contrast model, and allelic contrast model. Publication bias was evaluated using contour-enhanced funnel plots and Egger’s regression test. Sensitivity analysis was conducted to assess the robustness of this meta-analysis.Results: A total of 12 eligible studies, including 3834 patients and 4824 healthy controls, were recruited in this meta-analysis. The pooled data demonstrated that TBX21 rs2240017 and rs4794067 polymorphisms were significantly associated with the risk of autoimmune diseases in Asian populations in allelic contrast model (OR: 1.456, 95% CI: 1.131–1.875, P = 0.004; OR: 0.766, 95% CI: 0.615–0.954, P = 0.017), heterozygote comparison model (OR: 1.647, 95% CI: 1.239–2.189, P = 0.001; OR: 0.796, 95% CI: 0.634–0.999, P = 0.049), and dominant model (OR: 1.572, 95% CI: 1.194–2.071, P = 0.004; OR: 0.767, 95% CI: 0.607–0.970, P = 0.027). The G allele of rs2240017 may be a risk factor for autoimmune diseases, and the T allele of rs4794067 may increase the risk of autoimmune diseases. However, we failed to find evidence of the association between TBX21 rs17250932 polymorphism and susceptibility to autoimmune diseases. No publication bias was established in this meta-analysis.Conclusion: This meta-analysis indicated that TBX21 rs2240017 and rs4794067 polymorphism confer susceptibility to autoimmune diseases, but not rs17250932.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as Coronavirus disease-2019 (COVID-19), has caused the sixth world’s public health emergency. Healthcare staff, as the frontline population fighting the pandemic, are exposed to a high risk of infection. Therefore, developing a protective intervention for medical staff is of significant importance. Objective: The aim of the study was to explore the effectiveness and safety of recombinant human interferon alpha (rhIFN-α) nasal drops for the prevention of coronavirus disease 2019 (COVID-19) through administering it to medical staff. Methods: This was a prospective open-label clinical trial with parallel intervention assignment conducted on 2944 medical staff including both doctors and nurses from Taihe Hospital, Shiyan City, Hubei Province, China from January 21, 2020 to July 30, 2020. The participants were bifurcated into two groups of low risk and high risk groups according to the level of direct exposure to COVID-19 patients. The individuals of the low-risk group received rhIFN-α nasal drops for one month in addition to first level protection, and the high-risk group received a combination of rhIFN-α nasal drops coupled with thymosin-α1 with either second or third-level protection protocol. Moreover, the new-outset of COVID-19 pneumonia diagnosed by chest computed tomography (CT), after thirty days, was the primary outcome. The adverse reactions were recorded in all participants. Results: 2415 of 2944 individuals belonged to the low-risk group, while 529 to the high-risk group. There was no COVID-19 pneumonia in either of the group after thirty days. The pulmonary CT scans were negative for COVID-19 pneumonia in both the groups with no new clinical symptoms. No serious adverse event was observed during the course of the intervention. Conclusion: The rhIFN-α nasal drops along with augmented safeguards based on standard physical isolation could effectively protect medical staff against COVID-19 pneumonia.

Long non-coding RNAs (lncRNAs) are known to competitively bind with microRNAs (miRNAs) to participate in human cancers. We aim to explore the role of non-coding RNA activated by DNA damage (NORAD) binding to miR-323a-3p in breast cancer (BC) with the involvement of pumilio RNA-binding family member 1 (PUM1)/eukaryotic initiation factor 2 (eIF2) axis. Expression of NORAD, miR-323a-3p and PUM1 in tissues and cell lines was detected, and the correlation between NORAD expression and clinicopathological features of BC patients was analyzed. The screened cell line was respectively transfected with altered NORAD or miR-323a-3p to reveal their roles in viability, migration, invasion and apoptosis of BC cells in vitro. The tumor growth in vivo was observed in nude mice. The binding relationships among NORAD, miR-323a-3p and PUM1 were analyzed, and the regulatory role of NORAD and miR-323a-3p in the eIF2 signaling pathway was assessed. NORAD and PUM1 were upregulated and miR-323a-3p was downregulated in BC. High NORAD expression indicated a poor prognosis of BC patients. NORAD inhibition or miR-323a-3p elevation inhibited malignant behaviors of BC cells. The in vivo assay revealed that NORAD inhibition or miR-323a-3p elevation inhibited tumor growth as well. MiR-323a-3p inhibition reversed the role of NORAD knockdown in the biological functions of BC cells while silencing PUM1 reversed the influence of NORAD overexpression on BC cells. NORAD bound with miR-323a-3p and miR-323a-3p targeted PUM1. NORAD and miR-323a-3p functioned through the PUM1/eIF2 axis. NORAD inhibition or miR-323a-3p elevation suppresses the development of BC through the PUM1/eIF2 axis.

Plant-derived diterpenoids are indispensable to plant development, stress-resistance and interaction with environmental microorganisms. Besides significant roles in plant fitness and adaption, many bioactivities beneficial to human beings are also found in diterpenoids from terrestrial plants. However, these high-value compounds are always present in limited species with low-abundance. Complicated chemosynthesis hardly meets the needs of sufficient supplies. To overcome these obstacles, it is necessary to investigate how diterpenoids are biosynthesized in planta, and followed by engineering the biosynthetic pathway to achieve high yield production. This review will summarize the recent progress of plant diterpenoid biosynthetic pathway discovery and engineering, hoping to offer an inspiration for concerned researchers.

The acute-on-chronic liver failure (ACLF) development is highly dynamic. Currently, no satisfactory algorithm identifies patients with HBV at risk of this complication. The aim of the study was to characterize ACLF development in hospitalized HBV-related patients without previous decompensation and to test the performance of traditional prognostic models in ruling out ACLF development within 28 days on admission we conducted a cohort study. Two multi-center cohorts with hospitalized HBV-related previous compensated patients were analyzed. Performances of MELD, MELD-Na, CLIF-C AD, and CLIF-C ACLF-D in ruling out ACLF development within 28 days were compared and further validated by ROC analyses. In the derivation cohort (n = 892), there were 102 patients developed ACLF within 28 days, with profound systemic inflammatory levels and higher 28-day mortality rate (31.4% vs. 1.0%) than those without ACLF development. The MELD score (cut-off = 18) achieved acceptable missing rate (missed/total ACLF development) at 2.9%. In the validation cohort (n = 1656), the MELD score (18) was able to rule out ACLF development within 28 days with missing rate at 3.0%. ACLF development within 28 days were both lower than 1% (0.6%, derivation cohort; 0.5%, validation cohort) in patients with MELD 18. While in patients with MELD ≥ 18, 26.6% (99/372, derivation cohort) and 17.8% (130/732, validation cohort) developed into ACLF within 28 days, respectively. While MELD-Na score cut-off at 20 and CLIF-AD score cut-off at 42 did not have consistent performance in our two cohorts. MELD 18 was able to safely rule out patients with ACLF development within 28 days in HBV-related patients without previous decompensation, which had a high 28-day mortality.

Human respiratory syncytial virus (HRSV) is a major cause of lower respiratory tract infection in infants. The lack of ideal animal models is one of the major obstacles in evaluateing the efficacy of HRSV vaccines. In this study, HRSV-50 was obtained from Hep-2 cells at the 50th passage of the original Long strain (ATCC VR-26). BALB/c mice (6 weeks) were challenged with different titers of HRSV-50. Shockingly, all mice died after 4 days of challenge (6 × 10

Human respiratory syncytial virus (HRSV) is a leading cause of lower respiratory tract infections in elderly individuals and young children/infants and can cause bronchiolitis and even death. There is no licensed HRSV vaccine. An ideal vaccine should induce high titers of neutralizing antibodies and a Th1-biased immune response. In this study, we used EXPI293 cells to express the fusion (F) protein with a prefusion conformation (PrF) and compared the safety and efficacy of intranasal immunization with PrF in combination with two mucosal adjuvants (CpG ODN and liposomes) in mice. After two intranasal administrations, mice in the PrF + CpG group produced high titers of neutralizing antibodies (4961) and a Th1-biased immune response compared with the PrF + Lipo group. The lung viral load of mice in the PrF + CpG group was significantly reduced (3.5 log) compared with that in the adjuvant control group, and the survival rate was 100 %, while the survival rate of mice in the PrF + Lipo group was only 67 %. At the same time, this immunization strategy reduced the pathological damage to the lungs in mice. In conclusion, the combination of PrF and CpG adjuvant is immunogenic, elicits a Th1 type immune response, and completely protects mice from a lethal HRSV challenge. It is worthy of further evaluation as an HRSV vaccine in clinical trials. Clinical trial registration. This study was not related to human participation or experimentation.

Background Colorectal cancer (CRC) is a common malignant tumor of digestive tract which has high incidence and mortality rates. Accurate prognosis prediction of CRC patients is pivotal to reduce the mortality and disease burden. Methods In this study, we comprehensively analyzed the gene expression and methylation data of CRC samples from The Cancer Genome Atlas (TCGA). Differential expression genes (DEGs) and methylation CpGs (DMCs) in tumor tissues compared with adjacent normal tissues of CRC were first identified. Functional enrichment analysis of DEGs and DMCs was performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). Spearman correlation analysis was used to screen DMCs that negatively correlated with gene expressions which were subsequently applied to sure independence screening (SIS) along with stepwise regression for screening optimal CpGs for CRC prognosis prediction model construction by Cox regression analysis. Results We identified a total of 1774 DEGs (663 upregulated and 1111 downregulated) and 11,975 DMCs (7385 hypermethylated and 4590 hypomethylated) in CRC tumor samples compared with adjacent normal samples. The hypermethylated loci were mainly located on CpG island, while the hypomethylated loci were mainly located on N-shore. Spearman correlation analysis screened 321 DMCs that negatively correlated with expressions of their annotated genes. Cox regression model consist of 10 CpGs was finally established which could effectively stratified CRC patients that exhibited significantly different overall survival probability independent of age, gender, and pathological staging. Conclusion We established a prognosis prediction model based on 10 methylation sites, which could evaluate the prognosis of CRC patients.

Objective:Previous studies have reported inverse associations between certain healthy lifestyle factors and non-alcoholic fatty liver disease (NAFLD), but limited evidence showed the synergistic effect of those lifestyles. This study examined the relationship of a combination of lifestyles, expressed as Healthy Lifestyle Score (HLS), with NAFLD.Design:A community-based cross-sectional study. Questionnaires and body assessments were used to collect data on the six-item HLS (ranging from 0 to 6, where higher scores indicate better health). The HLS consists of non-smoking (no active or passive smoking), normal BMI (18·5–23·9 kg/m2), physical activity (moderate or vigorous physical activity ≥ 150 min/week), healthy diet pattern, good sleep (no insomnia or Setting:Guangzhou, China.Participants:Two thousand nine hundred and eighty-one participants aged 40–75 years.Results:The overall prevalence of NAFLD was 50·8 %. After adjusting for potential covariates, HLS was associated with lower presence of NAFLD. The OR of NAFLD for subjects with higher HLS (3, 4, 5–6 v. 0–1 points) were 0·68 (95 % CI 0·51, 0·91), 0·58 (95 % CI 0·43, 0·78) and 0·35 (95 % CI 0·25, 0·51), respectively (P-values < 0·05). Among the six items, BMI and physical activity were the strongest contributors. Sensitivity analyses showed that the association was more significant after weighting the HLS. The beneficial association remained after excluding any one of the six components or replacing BMI with waist circumference.Conclusions:Higher HLS was associated with lower presence of NAFLD, suggesting that a healthy lifestyle pattern might be beneficial to liver health.

Background Temporary hemiepiphysiodesis (TH) using an eight-Plate implant is one of the most common surgeries used for the correction of coronal angular deformities around the knee in adolescents. However, few studies have focused on children aged less than 10 years treated with TH using an eight-Plate implant. The purpose of this study was to investigate the efficacy, correction velocity, and complications of TH with an eight-Plate implant as well as the occurrence of rebound and risk factors in this population. Methods This retrospective study included a total of 135 physes (101 knees) from 66 children (mean age of 4.69 years old, range from 1 to 10 years old) who underwent TH with an eight-Plate implant to correct coronal genu angular deformities in our hospital. Related clinical factors were recorded and analysed by multivariable linear and logistic regression models. Results The mean deformity correction period was 13.26 months, and the mean follow-up after eight-Plate removal was 12.71 months. In all, 94.06% (95/101 knees) of the genu angular deformities were completely corrected. Non-idiopathic genu angular deformity was found to be an independent risk factor for deformity correction failure (odds ratio (OR) = 2.47). The femoral correction velocity was significantly higher than the tibial correction velocity (1.28° vs. 0.83° per month, p Conclusions TH using an eight-Plate implant is an effective procedure for coronal genu angular deformities with a low incidence of complications and rebound in patients younger than 10 years old. For this population, TH using an eight-Plate should be considered as soon as the deformity stops responding to conservative treatments. The parents of children younger than 10 years of age with non-idiopathic deformities should be informed preoperatively that the deformity may be prone to correction failure or screw loosening after eight-Plate implantation.

Ventilators are currently the most commonly used auxiliary mechanical ventilation equipment in clinical practice, and play an important role in the treatment of hypoxemia. Ventilator-associated pneumonia (VAP) is a special type of pulmonary parenchymal inflammation of nosocomial infection in patients with mechanical ventilation, which leads the increase of mortality and affects the prognosis of patients. The non-standard management of ventilator pipeline joints and the aerosol formed by bacterial condensate splashed from ventilator pipeline pollute the air, resulting in cross infection, which are the important reasons for VAP. The existing ventilator pipeline joint cap can achieve the effect of preventing pollution, but the clinical application compliance is not high. Based on the above factors, teachers, students and medical staff of the School of Public Health and Management, Guangxi University of Chinese Medicine and other units have designed a device for preventing pollution and air pollution of the ventilator pipeline joint, and obtained the national utility model patent of China (ZL 2020 2 1361981.X). The device is composed of a model lung, a mask body, a suspension part and a beam mouth part, etc. The use method is simple, and can be applied to the pollution avoidance of invasive ventilator and non-invasive ventilator pipeline joints, to reduce the occurrence of VAP in patients and the occupational exposure of medical staff.

To investigate the effect of intra-articular berberine injection on the structural remodeling of subchondral bone plate and osteoprotegerin/receptor activator of nuclear factor kappa-B ligand(OPG/RANKL) system expression in rabbits with osteoarthritis(OA).Forty 12-month-old male rabbits with an average of(2.73±0.18) kg of body weight, underwent left anterior cruciate ligament transection(ACLT), and were divided into berberine group and placebo groups after operation, 20 rabbits in each group. The berberine group received intra-articular injection of 100 μmol/L berberine 0.3 ml every week for 6 weeks. In placebo group, the same dose of 0.9% sodium chloride injection was injected into the left knee joint cavity every week for 6 weeks. Another 20 12-month-old male rabbits, weighing (2.68±0.18) kg, underwent sham operation on the left knee joint without intra-articular injection intervention (sham operation group). On the last day of the sixth week after operation, three groups of animals were sacrificed to obtain knee joint specimens. The femoral medial condyle samples were obtained for histological evaluation of cartilage and subchondral bone, Mankin scoring system was used to evaluate articular cartilage structure. Image-Pro Plus(IPP) software was used to evaluate subchondral bone plate bone volume(BV), bone volume/total volume(BV/TV), trabecular circumference(TC), mean trabecular thickness (Tb.Th). Real-time quantitative reverse transcription polymerization Enzyme chain reaction(reverse transcription-polymerase chain reaction, RT-PCR) was used to detect the mRNA expression levels of OPG and RANKL in subchondral bone tissue at 6 weeks after operation.The cartilage structure evaluation showed that the surface of cartilage tissue in the sham operation group was smooth and flat, and the safranin coloration was full in the full thickness of the cartilage;the cartilage tissue in the berberine group showed uneven surface layer, and the staining of safranin O was mildly decreased;the surface layer fibrosis was seen in placebo group, Safranin O faded significantly. The Mankin score in the berberine group was lower than that in placebo group(Intra-articular injection of berberine can effectively inhibit the resorption of subchondral bone in the early stage of OA and delay the development of the disease. The specific mechanism may be that berberine maintains the balance of OPG/RANKL system by up-regulating the expression of OPG gene in subchondral bone.

Bariatric surgery (BS) is an effective treatment for obesity. Adipose tissue, liver tissue and skeletal muscle are important metabolic tissues. This study investigated hub genes and their association with immune infiltration in these metabolic tissues of obese patients after BS by bioinformatic analysis with Gene Expression Omnibus datasets. Differentially expressed genes (DEGs) were identified, and a protein-protein interaction network was constructed to identify hub genes. As a result, 121 common DEGs were identified and mainly enriched in cytokine-cytokine receptor interactions, chemokine signaling pathway, neutrophil activation and immune responses. Immune cell infiltration analysis showed that the abundance of M1 macrophages was significantly lower in adipose and liver tissue after BS (p0.05). Ten hub genes (TYROBP, TLR8, FGR, NCF2, HCK, CCL2, LAPTM5, MNDA and S100A9) that were all downregulated after BS were also associated with immune cells. Consistently, results in the validated dataset showed that the expression levels of these hub genes were increased in obese patients and mice, and decreased after BS. In conclusion, this study analysed the potential immune and inflammatory mechanisms of BS in three key metabolic tissues of obese patients, and revealed hub genes associated with immune cell infiltration, thus providing potential targets for obesity treatment.

Autoimmune liver disease (AILD) has been considered a relatively uncommon disease in China, epidemiological data for AILD in patients with cirrhosis and acute decompensation (AD) is sparse.To investigate the prevalence, outcome and risk factors for AILD in cirrhotic patients complicated with AD in China.We collected data from patients with cirrhosis and AD from two prospective, multicenter cohorts in hepatitis B virus endemic areas. Patients were regularly followed up at the end of 28-d, 90-d and 365-d, or until death or liver transplantation (LT). The primary outcome in this study was 90-d LT-free mortality. Acute-on-chronic liver failure (ACLF) was assessed on admission and during 28-d hospitalization, according to the diagnostic criteria of the European Association for the Study of the Liver (EASL). Risk factors for death were analyzed with logistic regression model.In patients with cirrhosis and AD, the overall prevalence of AILD was 9.3% (242/2597). Prevalence of ACLF was significantly lower in AILD cases (14%) than those with all etiology groups with cirrhosis and AD (22.8%) (AILD was not rare in hospitalized patients with cirrhosis and AD in China, among which PBC was the most common etiology. 90-d LT-free mortality were independently associated with TB, HE and BUN.

Background and purpose — Proximal femoral osteotomy (PFO) is commonly performed to treat children with developmental dysplasia of the hip (DDH). Implant-related femoral fractures after osteotomy are sometimes reported, but the potential risk factors for these fractures remain unclear. We investigated the association of implant-related fractures with PFO and potential risk factors for these fractures. Patients and methods — We retrospectively reviewed 1,385 children undergoing PFO for DDH in our institution from 2009 to 2016 after obtaining institutional review board (IRB) approval and identified 27 children (28 hips, fracture group) with implant-related femoral fractures after PFO. We selected 137 children (218 hips, control group) without fractures who matched the children in the fracture group by age, weight, surgeon, and surgical period. Relevant clinical data were collected and compared between the 2 groups. Multiple analyses of risk factors for implant-related fractures were conducted by logistic regression with the stepwise regression method. Results — The occurrence rate of implant-related fractures was 1.9% (27/1,385). Compared with the control group, the fracture group more commonly exhibited bilateral involvement (74% vs. 53%, p = 0.04), used a spica orthosis for immobilization after osteotomy (43% vs 21%, p = 0.01) and exhibited mild remodeling at the osteotomy site (46% vs. 19%, p = 0.003), and less commonly required capsulotomy during osteotomy (61% vs. 79%, p = 0.03). According to the multiple regression analysis, the only factor identified as an independent risk factor for implant-related fractures was mild remodeling at the osteotomy site (OR = 3.2, 95% CI 1.4–7.5). Remodeling at the osteotomy site was significantly associated with varus osteotomy (coefficient = 1.4, CI 1.03–1.8). The fracture occurred at a mean of 12 months (2.2–25) after osteotomy or 3.3 months (0–12) after implant removal. In children undergoing implant removal, the fractures mostly occurred at the osteotomy site (n = 13/15), while in those with the implant remaining, the fractures mostly occurred in the screw hole (n = 8/13). Interpretation — The type of PFO performed is not associated with implant-related fractures in children with DDH. Children with mild remodeling at the osteotomy site should be closely followed up, regardless of whether the hardware is removed, and high-intensity activity should not be permitted until moderate or extensive remodeling is confirmed. After PFO, the implants should be removed when solid union is achieved at the osteotomy site.

Transcription factor SP1 could manipulate pathways involved in ovarian cancer progression. LncRNAs are involved in SP1‐mediated tumorigenesis. LncRNA DANCR could promote metastasis of ovarian cancer. However, the regulatory function and involvement of SP1‐induced lncRNA DANCR in ovarian cancer remain elusive. Data from this study showed that SP1 was up‐regulated in ovarian cancer tissues and cells (CAOV3, SKOV3, A2780), and SP1 could bind to the promoter region of DANCR through chromatin immunoprecipitation and leuciferase activity assays. Therefore, DANCR was transcriptionally induced by SP1 in ovarian cancer tissues and cells (CAOV3, SKOV3, A2780). Functionally, reduced expression of DANCR suppressed cell viability, migration and invasion of CAOV3, while enhanced DANCR expression contributed to SKOV3 growth. Over‐expression of SP1 reversed the suppressive effects of DANCR interference on ovarian cancer progression. In conclusion, SP1‐induced DANCR contributed to oncogenic potential of ovarian cancer, suggesting a promising therapeutic target for ovarian cancer.

Channelrhodopsins are light-gated ion channels widely used to control neuronal firing with light (optogenetics). We report two previously unknown families of anion channelrhodopsins (ACRs), one from the heterotrophic protists labyrinthulea and the other from haptophyte algae. Four closely related labyrinthulea ACRs, named RubyACRs here, exhibit a unique retinal-binding pocket that creates spectral sensitivities with maxima at 590 to 610 nm, the most red-shifted channelrhodopsins known, long-sought for optogenetics, and more broadly the most red-shifted microbial rhodopsins thus far reported. We identified three spectral tuning residues critical for the red-shifted absorption. Photocurrents recorded from the RubyACR from Aurantiochytrium limacinum (designated AlACR1) under single-turnover excitation exhibited biphasic decay, the rate of which was only weakly voltage dependent, in contrast to that in previously characterized cryptophyte ACRs, indicating differences in channel gating mechanisms between the two ACR families. Moreover, in A. limacinum we identified three ACRs with absorption maxima at 485, 545, and 590 nm, indicating color-sensitive photosensing with blue, green, and red spectral variation of ACRs within individual species of the labyrinthulea family. We also report functional energy transfer from a cytoplasmic fluorescent protein domain to the retinal chromophore bound within RubyACRs.

BACKGROUND Hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is an important type of liver failure in Asia. There is a direct relationship between HBV-ACLF and gastrointestinal barrier function. However, the nutritional status of HBV-ACLF patients has been poorly studied. AIM To investigate the nutritional risk and nutritional status of HBV-ACLF patients and evaluated the impact of nutritional support on the gastrointestinal barrier and 28-d mortality. METHODS Nutritional risk screening assessment and gastrointestinal barrier biomarkers of patients with HBV-ACLF (n = 234) and patients in the compensatory period of liver cirrhosis (the control group) (n = 234) were compared during the period between 2016 and 2018. Changes were analyzed after nutritional support in HBV-ACLF patients. Valuable biomarkers have been explored to predict 28-d death. The 28-d survival between HBV-ACLF patients with nutritional support (n = 234) or no nutritional support (2014-2016) (n = 207) was compared. RESULTS The nutritional risk of the HBV-ACLF patients was significantly higher than that of the control group. The nutritional intake of the patients with HBV-ACLF was lower than that of the control group. The decrease in skeletal muscle and fat content and the deficiency of fat intake were more obvious (P < 0.001). The coccus-bacillus ratio, secretory immunoglobulin A, and serum D-lactate were significantly increased in HBV-ACLF patients. The survival group had a lower nutritional risk, lower D-lactate, and cytokine levels (endotoxin, tumor necrosis factor alpha, interleukin-10, and interleukin-1). Interleukin-10 may be a potential predictor of death in HBV-ACLF patients. The 28-d survival of the nutritional support group was better than that of the non-nutritional support group (P = 0.016). CONCLUSION Patients with HBV-ACLF have insufficient nutritional intake and high nutritional risk, and their intestinal barrier function is impaired. Individualized and dynamic nutritional support is associated with a better prognosis of 28-d mortality in HBV-ACLF patients.

In in vitro cell assays, nominal concentrations of a test chemical are most frequently used in the description of its dose-response curves. Although the biologically effective concentration (BEC) is considered as the most relevant dose metric, in practice, it is very difficult to measure. In this work, we attempted to determine the BEC of long-chain perfluoroalkyl carboxylic acids (PFCAs) in peroxisome proliferator-activated receptor γ (PPARγ) activity assays. In both adipogenesis and transcriptional activity assays with human and mouse cells, PPARγ activity of 7 PFCAs first increased and then decreased with their carbon chain length. The binding affinity of these PFCAs with the ligand-binding domain of PPARγ was measured by fluorescence competitive binding assay and showed very poor correlation with their receptor activity (r2 = 0.002-0.047). Internal concentrations of the PFCAs in the cells were measured by LC-MS/MS. Although their correlation with the receptor activity increased significantly, it is still low (r2 = 0.41-0.82). Using the binding affinity constant, internal concentration, and PPARγ concentration measured by immunoassays, concentrations of receptor-bound PFCAs in cells were calculated, which exhibited excellent correlation with PPARγ activity in both adipogenesis and transcriptional activity assays (r2 = 0.91-0.93). These results demonstrate that the concentration of receptor-bound PFCA is the BEC that dictates its activity on human and mouse PPARγ in cell assays. In the absence of any direct detection method, our approach can be used to calculate the target-site concentration of other ligands.

BackgroundBoth diabetes and obesity are risk factors for perioperative major adverse events. This study aims to evaluate the association between prior bariatric surgery (prior-BS) and perioperative cardiovascular outcomes following noncardiac surgery in patients with type 2 diabetes mellitus (T2DM).MethodsWe used the National Inpatient Sample Database to identify T2DM patients undergoing major noncardiac surgery from 2006 to 2014. The primary outcome was major perioperative adverse cardiovascular and cerebrovascular events (MACCEs), which include death, acute myocardial infarction and acute ischaemic stroke. In-hospital outcomes between patients with prior BS and morbid obesity were compared using unadjusted logistic, multivariable logistic and propensity score matching analyses.ResultsA weighted of 1,526,820 patients diagnosed with T2DM who underwent noncardiac surgery were included. The rates of both prior BS and morbid obesity significantly increased during the study period (P ConclusionsPrior bariatric surgery in T2DM patients undergoing noncardiac surgery is associated with a lower risk of MACCEs. Prospective studies are needed to verify the benefits of bariatric surgery in patients undergoing noncardiac surgery.

Background Although thrombospondins 4 (THBS4) participates in controlling the biology of prostate cancer (PCa), the mechanism underlying this regulation remains unknown. Hence, this study aims to identify the regulatory effects of THBS4 on the PCa stem cell-like properties and the potential mechanism associated with the phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (Akt) pathway. Methods PCa stem cells were sorted and identified using flow cytometry and THBS4 expression in the identified PCa stem cells was measured using Western blot assay. THBS4 was overexpressed or silenced in PCa stem cells, following which, self-renewal, proliferation, cell cycle distribution, and apoptosis of PCa stem cells were assessed as well as tumorigenicity in vivo was evaluated. PI3K/Akt pathway inhibitor was applied to identify its involvement in the regulatory roles of THBS4 in PCa stem cells. Results THBS4 was expressed at a higher level in PCa stem cells than in PCa cells. The overexpression of THBS4 promoted the self-renewal and proliferation, curbed the apoptosis of PCa stem cells, and enhanced the in vivo tumorigenicity, which was achieved by activating the PI3K/Akt pathway. On the contrary, short-hairpin RNA-mediated silencing of THBS4 exhibited suppressive effects on those cancer stem cell (CSC)-like properties and promotive effects on their apoptosis. Conclusion THBS4 silencing can impede the CSC-like properties in PCa via blockade of the PI3K/Akt pathway, which provides patients with PCa a new therapeutic target.

Background: The role of T cell Ig and ITIM domain (TIGIT) and programmed cell death-1 (PD-1) in colorectal cancer (CRC) with mismatch repair deficiency is unknown.Methods: This was a study of 60 CR...

NEW FINDINGS What is the central question of this study? What is the role of lncRNA PRRT3-AS1 in the regulation of peroxisome proliferator-activated receptor γ (PPARγ) gene-mediated mechanistic target of rapamycin (mTOR) signalling pathway in proliferation, apoptosis and autophagy of prostate cancer cells? What is the main finding and its importance? The targeting relation between lncRNA PRRT3-AS1 and PPARγ was verified, and it was demonstrated that silencing of lncRNA PRRT3-AS1 can upregulate apoptosis and autophagy yet downregulate proliferation, migration and invasion of prostate cancer cells through the mTOR signalling pathway. Further work is needed to consolidate the therapeutic value of lncRNA PRRT3-AS1 in clinical trials and treatment of prostate cancer. ABSTRACT Although long non-coding RNAs (lncRNAs) are correlated with multiple cancers, their molecular mechanisms in prostate cancer (PC) remain inadequately understood. This study investigated the effects of lncRNA PRRT3-AS1 on the progression of prostate cancer (PC) with involvement of peroxisome proliferator-activated receptor γ (PPARγ). Microarray analysis was used to identify the differentially expressed genes and lncRNAs associated with PC. RT-qPCR and western blot analysis were employed to test the expression of lncRNA PRRT3-AS1, mammalian target of rapamycin (mTOR) signalling pathway-, apoptosis- and autophagy-related genes. A scratch test, Transwell assay, CCK-8 assay, colony formation assay, flow cytometry and monodansylcadaverine staining were employed to identify the migration, invasion, proliferation activity, cell cycle and apoptosis and autophagy of PC3 cells, respectively. Tumorigenicity assays in nude mice were used to detect the tumorigenic ability. GSE55945 and GSE46602 datasets indicated that lncRNA PRRT3-AS1 was highly expressed in PC. PPARγ was predicted as a target gene of lncRNA PRRT3-AS1. Ectopic overexpression of PPARγ or lncRNA PRRT3-AS1 silencing led to inhibited cell viability, migration and invasion, and accelerated apoptosis. Furthermore, the delivery of si-PRRT3-AS1 or PPARγ vector to PC3 cells resulted in the regression of xenografts in nude mice. Based on the in vitro and in vivo experiments, silencing of lncRNA PRRT3-AS1 was observed to activate the PPARγ gene, which in turn could inhibit PC cell proliferation and promote apoptosis and autophagy by blocking the mTOR signalling pathway.

Background Acute mountain sickness has become a heavily researched topic in recent years. However, the genetic mechanism and effects have not been elucidated. Our goal is to construct a gene co-expression network to identify the key modules and hub genes associated with high altitude hypoxia. Results The GSE46480 dataset of rapidly transported healthy adults with acute mountain sickness was selected and analyzed by weighted gene co-expression network analysis (WGCNA) to construct a co-expression network. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the data set were carried out using Database for Annotation Visualization and Integrated Discovery (DAVID), and the hub genes were selected. We found that the turquoise module was most significantly correlated with acute mountain sickness. The functional enrichment analysis showed that the turquoise module was related to the apoptotic process, protein transport, and translation processes. The metabolic pathway analysis identified hsa03010:ribosome and hsa04144:endocytosis as the most important pathways in the turquoise module. Ten top 10 hub genes (MRPL3, PSMC6, AIMP1, HAT1, DPY30, ATP5L, COX7B, UQCRB, DPM1, and COMMD6) for acute mountain sickness were identified. Conclusion One module and 10 hub genes were identified, which were related to acute mountain sickness. The reference provided by this module may help to elucidate the mechanism of acute mountain sickness. In addition, the hub genes may be used in the future as a biomarker and therapeutic target for accurate diagnosis and treatment.

BACKGROUND Intestinal inflammation is a common digestive tract disease, which is usually treated with hormone medicines. Hormone medicines are effective to some extent, but long-term use of them may bring about many complications. AIM To explore the protective effects of panax notoginseng saponin (PNS) against dextran sulfate sodium (DSS)-induced intestinal inflammatory injury through phosphoinositide-3-kinase protein kinase B (PI3K/AKT) signaling pathway inhibition in rats. METHODS Colitis rat models were generated via DSS induction, and rats were divided into control (no modeling), DSS, DSS + PNS 50 mg/k, and DSS + PNS 100 mg/kg groups. Then, the intestinal injury, oxidative stress parameters, inflammatory indices, tight junction proteins, apoptosis, macrophage polarization, and TLR4/AKT signaling pathway in colon tissues from rats in each of the groups were detected. The PI3K/AKT signaling pathway in the colon tissue of rats was blocked using the PI3K/AKT signaling pathway inhibitor, LY294002. RESULTS Compared with rats in the control group, rats in the DSS group showed significantly shortened colon lengths, and significantly increased disease activity indices, oxidative stress reactions and inflammatory indices, as well as significantly decreased expression of tight junction-associated proteins. In addition, the DSS group showed significantly increased apoptotic cell numbers, and showed significantly increased M1 macrophages in spleen and colon tissues. They also showed significantly decreased M2 macrophages in colon tissues, as well as activation of the PI3K/AKT signaling pathway (all P < 0.05). Compared with rats in the DSS group, rats in the DSS + PNS group showed significantly lengthened colon lengths, decreased disease activity indices, and significantly alleviated oxidative stress reactions and inflammatory responses. In addition, this group showed significantly increased expression of tight junction-associated proteins, significantly decreased apoptotic cell numbers, and significantly decreased M1 macrophages in spleen and colon tissues. This group further showed significantly increased M2 macrophages in colon tissues, and significantly suppressed activation of the PI3K/AKT signaling pathway, as well as a dose dependency (all P < 0.05). When the PI3K/AKT signaling pathway was inhibited, the apoptosis rate of colon tissue cells in the DSS + LY294002 group was significantly lower than that of the DSS group (P < 0.05). CONCLUSION PNS can protect rats against DSS-induced intestinal inflammatory injury by inhibiting the PI3K/AKT signaling pathway, and therefore may be potentially used in the future as a drug for colitis.

Oncolytic viruses armed with therapeutic transgenes of interest show great potential in cancer immunotherapy. Here, a novel oncolytic adenovirus carrying a signal regulatory protein‐α (SIRPα)‐IgG1 Fc fusion gene (termed SG635‐SF) was constructed, which could block the CD47 ‘don't eat me’ signal of cancer cells. A strong promoter sequence (CCAU) was chosen to control the expression of the SF fusion protein, and a 5/35 chimeric fiber was utilized to enhance the efficiency of infection. As a result, SG635‐SF was found to specifically proliferate in hTERT‐positive cancer cells and largely increased the abundance of the SF gene. The SF fusion protein was effectively detected, and CD47 was successfully blocked in SK‐OV3 and HO8910 ovarian cancer cells expressing high levels of CD47. Although the ability to induce cell cycle arrest and cell death was comparable to that of the control empty SG635 oncolytic adenovirus in vitro, the antitumor effect of SG635‐SF was significantly superior to that of SG635 in vivo. Furthermore, CD47 was largely blocked and macrophage infiltration distinctly increased in xenograft tissues of SK‐OV3 cells but not in those of CD47‐negative HepG2 cells, indicating that the enhanced antitumor effect of SG635‐SF was CD47‐dependent. Collectively, these findings highlight a potent antitumor effect of SG635‐SF in the treatment of CD47‐positive cancers., A SIRPα‐Fc fusion protein enhances the antitumor effect of oncolytic adenovirus against CD47‐positive ovarian cancer.

Background Pediatric femoral neck fracture is a rare injury but yields frequent complications. However, there is a paucity of data regarding the risk factors for these complications. Purpose The present article reports the rate of complications after femoral neck fracture in pediatric patients and investigates the possible risk factors. Methods We retrospectively reviewed 44 children (mean age of 9.0 years, range from 2 to 14 years) who were surgically treated for femoral neck fracture in a single trauma center with a mean follow-up of 57.75 months (range from 11 to 224 months). Related clinical factors were recorded and analyzed by multivariable logistic regression. Results Fracture displacement or Delbet-type fracture had no relation to the injury mechanism. However, younger children experienced severe trauma, combined injury, and low fracture location more than older individuals did. Children with combined injuries were more likely to have a longer waiting time for surgical reduction. Common complications included avascular necrosis (AVN) in 14 cases, nonunion of fracture in 2 cases, coxa vara in 4 cases, and premature physeal closure (PPC) in 7 cases. Only the Delbet type was an independent predictor of AVN (OR = 0.14, p = 0.030). Inadequate reduction was associated with higher rates of coxa vara (OR = 33.19, p = 0.032). Epiphysis penetration in children younger than 10 years old increased the rate of PPC (p = 0.032). No significant risk factor was found for fracture nonunion. Conclusion For femoral neck fracture in pediatric patients, both the injury mechanism and fracture characteristics have age-related distributions. Early reduction should be carried out as early as possible based on the safe condition of the child, but for younger children, transepiphyseal fixation should be avoided. AVN may be intrinsic to injury characteristics rather than resulting from the choice of treatment mode.

The present study aimed to evaluate the underlying mechanism of microRNA-203 (miR-203) in renal cell carcinoma (RCC) involving the PI3K/AKT signaling pathway. The results revealed downregulated miR-203 and upregulated CAV1 in RCC tissues. Upregulated miR-203 and downregulated CAV1 increased E-cadherin expression and cell apoptosis, decreased β-catenin and N-cadherin expression and cell proliferation, migration and invasion, and blocked cell cycle entry. CAV1, a target gene of miR-203, decreased by up-regulated miR-203, and silencing CAV1 led to the inactivation of PI3K/AKT signaling pathway. In conclusion, our findings suggested that miR-203-mediated direct suppression of CAV1 inhibits EMT of RCC cells via inactivation of the PI3K/AKT signaling pathway.

Osteoporosis is a skeleton disease affecting 55% of people over age 60, and the number is still increasing due to an ageing population. One method to prevent osteoporosis is to increase the formation of new bone while preventing the resorption of older bone. Thus, osteogenic differentiation of bone marrow‐derived mesenchymal stem cells (BMSCs) is of great importance in improving the treatment of osteoporosis. On the other hand, glucocorticoids (GCs) are widely used to treat the chronic inflammatory disorders, but long‐term exposure to GCs can induce osteoporosis. In present study, we treated BMSCs with dexamethasone (DEX) to simulate GC‐induced osteoporosis. MTT assay, ALP activity, and Alizarin Red were used to evaluate the role miRNA‐291a‐3p in the DEX‐induced osteogenic differentiation suppression. Further, we used qPCR and western blot to investigate the mechanisms of miRNA‐291a‐3p affecting BMSCs differentiation. The results showed that miRNA‐291a‐3p could improve the cell viability, osteogenic differentiation, and ALP activity, which are suppressed by DEX in BMSCs. Furthermore, we found that the osteogenesis genes Runx2, DMP1, and ALP were upregulated whereas the lipogenic genes C/EBPα and PPARγ were downregulated when miRNA‐291a‐3p mimics were transfected. Additionally, we demonstrated that miRNA‐291a‐3p promoted BMSCs' osteogenic differentiation by directly suppressing DKK1 mRNA and protein expression and subsequently activating Wnt/β‐catenin signaling pathway. Our study suggests that miR‐291a‐3p plays an important role in preventing osteoporosis and may serve as a potential miRNA osteoporosis biomarker.

Colorectal cancer (CRC) is the second leading cause of death globally. Integrin α1 (ITGA1) belongs to integrin family and involves in regulating cell adhesion, invasion, proliferation and tumorigenicity, its expression is up-regulated in various cancers, including CRC. However, the molecular understanding and clinical relevance of ITGA1 in the development and progression of CRC remain unclear. In the present study, we detected ITGA1 in 50 CRC tissues and adjacent non-cancerous tissues, sera from 100 CRC patients and 50 healthy subjects, and four CRC cell lines using immunohistochemistry staining, enzyme-linked immunosorbent assay and Western blotting. We found that the ITGA1 protein was significantly higher in human CRC tissues and cell lines than both paired non-tumor tissues and normal cells, respectively. In addition, the serum concentration of ITGA1 was also higher in CRC patients compared to the healthy subjects (p

Secoisolariciresinol diglucoside (SDG) is the main component of lignans with various biological activities, including anticancer activity. However, whether SDG has obvious anticancer effects on colorectal cancer (CRC) is unclear. Pyroptosis, a form of programmed cell death, has received increasing attention in cancer-related research. In this study, we aimed to test the anticancer properties and relatecd functional mechanisms of SDG. we found that SDG not only inhibited the cell viability of HCT116 cells, but also induced HCT116 cells to swell with apparent large bubbles, which are typical signs of pyroptosis. Furthermore, SDG induced cell pyroptosis by enhancing cleavage of the N-terminal fragment of gasdermin D (GSDMD) in CRC cells, accompanied by increased caspase-1 cleavage. Consistent with this, SDG-induced GSDMD-N-terminal fragment cleavage and pyroptosis were reduced by siRNA-mediated silencing of caspase-1 or treatment with the specific caspase-1 inhibitor VX-765 treatment, suggesting that active caspase-1 further induces pyroptosis. A mechanistic study showed that SDG induced reactive oxygen species (ROS) accumulation and inhibits phosphatidylinositol 3-kinase (PI3K) phosphorylation and increases pyroptosis, while increasing GSDMD and caspase-1 cleavage and enhancing expression of BCL2-associated X (BAX), which could be rescued by the ROS scavenger (NAC), suggesting that SDG-induced GSDME-dependent pyroptosis is related to the ROS/PI3K/AKT/BAX-mitochondrial apoptotic pathway. In vivo results showed that SDG significantly inhibited tumor growth and induced pyroptosis in the HCT116-CRC nude mouse model. In conclusion, our findings suggest that the anticancer activity of SDG in CRC is associated with the induction of GSDMD-dependent pyroptosis by SDG through the generation of ROS/P13K/AKT/BAK-mitochondrail apoptosis pathway, providing insights into SDG in its potential new application in cancer treatment.

The present study was to investigate the clinical features of foreign body (FB) residues in children's knee joints, surgical retrieval, and postoperative function of knee joints.This retrospective study included a total of 13 children (8 boys and 5 girls; the mean age is 6.69 years old, range from 2 to 16 years old) who underwent retrieval surgery of knee FBs in our hospital. Related clinical factors were recorded and analyzed to find the influence factors of surgical methods and FBs' location change.The FBs in 11 cases were removed completely by arthroscopy, two cases by open surgery changed from arthroscopy. Besides glass pieces (n = 4, 31%) and wooden splinter (n = 1, 7%), sewing needle fragments were the most common type of knee foreign body (n = 8, 62%). There were two patients with FBs whom open surgery changed from arthroscopy was performed. The FBs of patients with open surgery changed from arthroscopy were more likely to locate in the posterior compartment (p = 0.04), and had a higher interval between injury and surgery than that in patients with arthroscopy (p = 0.01). The location of FBs (all were needle fragments) had changed intra-operatively in three patients, whose mean weight was lower than patients with fixed FBs (p = 0.04). The FB (small glass piece) of one patient was flushed out of the joint during arthroscopy.Arthroscopic retrieval surgery was an effective procedure to remove the FBs of the children's knee joint. The earlier it is detected, the easier it is to be treated. The location change of FBs should be cautioned in arthroscopic surgery and they are more likely to migrate into the posterior compartment of the knee joint.

Ghost imaging plays an important role in the field of optical imaging. To realize color ghost imaging through the scattering media, we propose a deep learning method with high generation ability. Through our method, we can efficiently reconstruct color images with rich details, in line with human perception and close to the target color pictures. Experimental results show that our method can image through the scattering media with different scattering intensities and achieve good results even at a sampling rate of 0.1.

To explore the effectiveness of free lobed perforator flaps in repairing of complex wounds of limbs.Between January 2018 and January 2021, 10 patients with complex wounds of limbs were admitted. There were 7 males and 3 females, aged from 32 to 64 years, with an average age of 45 years. There were 4 cases of traffic accident injuries, 3 cases of machine strangulation injuries, 1 case of machine crush injury, and 2 cases of heavy object crush injuries. There were 5 cases of upper limb wounds and 5 cases of lower limb wounds. The size of wounds ranged from 11 cm×10 cm to 25 cm×18 cm. The wounds were repaired with tri-lobed flaps of the descending branch of the lateral femoral circumflex artery in 7 cases, four-lobed flaps in 2 cases, and with tri-lobed flaps of the descending branch of the lateral femoral circumflex artery combined with oblique branch in 1 case. The size of flaps ranged from 12.0 cm×10.5 cm to 28.0 cm×12.0 cm. The donor sites were sutured directly in 9 cases and repaired with superficial iliac circumflex artery perforator flap in 1 case.Sinus formed at the edge of the flap in 1 patient, which healed after dressing change and drainage; other flaps survived well, and the wounds healed by first intention. The skin flap at donor site survived, and the incisions healed by first intention. All patients were followed up 6-24 months (mean, 11 months). All flaps had good appearance and function, and linear scars were left at the donor site without obvious complications.Free lobed perforator flap is an alternative method to repair complex wounds of limbs with high safety, good effectiveness, and less complications.探讨游离分叶穿支皮瓣修复四肢复杂创面的疗效。.2018 年1月—2021 年1月，收治10例四肢复杂创面患者。男7例，女3例；年龄32～64岁，平均45岁。致伤原因：交通事故伤 4例，机器绞伤 3例，机器挤压伤 1 例，重物压砸伤 2 例。上肢创面5例，下肢创面5例。创面范围11 cm×10 cm～25 cm×18 cm。采用旋股外侧动脉降支穿支三叶皮瓣7例、四叶皮瓣2例，旋股外侧动脉降支联合斜支穿支三叶皮瓣1例。皮瓣切取范围12.0 cm×10.5 cm～28.0 cm×12.0 cm。供区直接缝合9例，接力旋髂浅动脉穿支皮瓣修复1例。.术后1例皮瓣边缘窦道形成，经换药、引流后愈合；其余皮瓣均顺利成活，创面Ⅰ期愈合。供区皮瓣成活，切口均Ⅰ期愈合。患者均获随访，随访时间6～24个月，平均11个月。皮瓣无明显臃肿，色泽、质地良好。供区仅遗留线性瘢痕。.游离分叶穿支皮瓣能有效修复四肢复杂创面，术后皮瓣成活率高，并发症少。.