OBJECTIVES: To investigate the mechanism by which circ_EPHB4 regulates temozolomide (TMZ) sensitivity of glioma cells through the miR-424-5p/Wnt3 signal axis. METHODS: We detected the expression levels of circ_EPHB4, miR-424-5p and Wnt3 mRNA in glioma specimens from 25 patients with primary glioma and 25 patients experiencing relapse following temozolomide-based chemotherapy and in TMZ-sensitive and -resistant glioma A172 and SHG44 cells with circ_EPHB4 knockdown using qRT-PCR, and Wnt3 protein expression level was detected with Western blotting. Cell viability, colony-forming ability, and apoptosis of the cells with circ_EPHB4 knockdown were assessed, and the targeted regulation relationship between circ_EPHB4, miR-424-5p, and Wnt3 was verified by dual luciferase reporter assay and RNA immunoprecipitation (RIP) experiments. The effect of circ_EPHB4 knockdown on tumorigenesis of glioma cells was evaluated in subcutaneous tumor-bearing nude mouse models. RESULTS: The expression of circ_EPHB4 was significantly increased in glioma tissues and cells as compared with normal neural tissues and astrocytes (P=0.014). In TMZ-resistant glioma cells, circ_EPHB4 knockdown resulted in an obvious reduction of IC50 value of TMZ, inhibited cell colony formation, and promoted cell apoptosis, and these effects were reversed by miR-424-5p knockdown. The expressions of miR-424-5p and circ_EPHB4 were negatively correlated in glioma tissues (P=0.011). MiR-424-5p knockdown also attenuated the effect of circ_EPHB4 knockdown on expressions of PCNA, P-gp, MRP1 and bax. CONCLUSIONS Circ_EPHB4 regulates Wnt3 expression through "sponge adsorption" of miR-424-5p, thereby modulating TMZ-resistant glioblastoma cell clonogenesis, apoptosis, and TMZ sensitivity, suggesting the potential of circ_EPHB4 as a therapeutic target for reversing drug resistance of gliomas.
MicroRNAs/genetics* ; Humans ; Temozolomide ; Glioma/genetics* ; Animals ; Mice, Nude ; Cell Line, Tumor ; Wnt3 Protein/metabolism* ; Mice ; Apoptosis ; RNA, Circular ; Drug Resistance, Neoplasm ; Brain Neoplasms/pathology* ; Signal Transduction

OBJECTIVES: To investigate the oncogenic role of circular RNA circ_EPHB4 in glioma and its molecular mechanism. METHODS: Microarray analysis was performed to identify the differentially expressed circRNAs in glioma tissues. The effects of circ_EPHB4 on glioma cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro and tumorigenicity in vivo were assessed using scratch wound healing assay, Transwell invasion assay and nude mouse models bearing subcutaneous tumors. RNA immunoprecipitation (RIP), RNA stability assays, and gene overexpression and silencing techniques were employed to validate the synergistic regulatory effect of circ_EPHB4 and the N6-methyladenosine (m⁶A) reader protein YTHDF3 on Wnt3 expression. RESULTS: Circ_EPHB4 was significantly overexpressed by 2.3 folds (|log2FC|=1.2, P<0.01) in glioma tissues compared to the adjacent tissues, and by 2.5 folds in glioma cell line U373 compared to normal cells (P<0.001). Overexpression of circ_EPHB4 significantly enhanced migration and invasion of glioma cells, and promoted the expressions of EMT markers N-cadherin and vimentin. In the tumor-bearing mouse models, the tumor volume in circ_EPHB4 overexpression group was significantly greater than that in the control group, and the lung metastatic foci increased by 4.2 folds. Overexpression of circ_EPHB4 promoted oncogenesis by upregulating Wnt3 expression, while YTHDF3 extended the half-life of Wnt3 mRNA in an m⁶A-dependent manner. Simultaneous knockdown of circ_EPHB4 and YTHDF3 resulted in an obvious reduction of Wnt3 mRNA expression by up to 47% compared to its level following knocking down either circ_EPHB4 or YTHDF3 alone. CONCLUSIONS Circ_EPHB4 and YTHDF3 promote glioma progression by jointly targeting the Wnt3 signaling pathway, which may provide a new therapeutic strategy for gliomas.
Glioma/genetics* ; Humans ; Animals ; Cell Line, Tumor ; RNA-Binding Proteins/genetics* ; RNA, Circular ; Epithelial-Mesenchymal Transition ; Mice, Nude ; Cell Movement ; Wnt3 Protein/genetics* ; Mice ; Disease Progression ; Adenosine/metabolism* ; Brain Neoplasms/metabolism* ; Gene Expression Regulation, Neoplastic

Esophageal cancer is a malignant tumor with high incidence and mortality rate in the world and its pathogenic factors are complex and diverse.There are no obvious symptoms in the early stage,and most patients are in the middle to late stage at the initial diagnosis.The prognosis of esophageal cancer is poor.The treatment mode of conventional surgical resection combined with chemoradiotherapy can no longer meet the current treatment needs of disease,and new treatment strategies are urgently needed.Molecular targeted therapy and immunotherapy are new treatment methods that have emerged in recent years,which have broken the therapeutic bottleneck and have been proven to play important roles in the treatment of esophageal cancer.The current research progress of the main targets and their related targeted drugs in molecular targeted therapy and immunotherapy for esophageal cancer were reviewed in this article,which provided reference for the application of precision medicine in the field of esophageal cancer.

Objective:To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test.Methods:This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ2 test. A kappa test was used to compare the consistency between groups. Results:After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea ( Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences ( P < 0.001). Conclusion:The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

Objective:To investigate a time series deep learning model for respiratory motion prediction.Methods:Eighty pieces of respiratory motion data from lung cancer patients were used in this study. They were divided into a training set and a test set at a ratio of 8∶2. The Informer deep learning network was employed to predict the respiratory motions with a latency of about 600 ms. The model performance was evaluated based on normalized root mean square errors (nRMSEs) and relative root mean square errors (rRMSEs).Results:The Informer model outperformed the conventional multilayer perceptron (MLP) and long short-term memory (LSTM) models. The Informer model yielded an average nRMSE and rRMSE of 0.270 and 0.365, respectively, at a prediction time of 423 ms, and 0.380 and 0.379, respectively, at a prediction time of 615 ms.Conclusions:The Informer model performs well in the case of a longer prediction time and has potential application value for improving the effects of the real-time tracking technology.

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.

Objective:To retrieve and evaluate the evidence on breastfeeding associated nipple pain and trauma management both domestically and internationally, so as to provide reference for clinical practice.Methods:According to the evidence pyramid "6S", all evidence on breastfeeding associated nipple pain and trauma management, including guidelines, evidence summary, best clinical practice manual, systematic review, expert consensus, and randomized controlled trial was retrieved by computer on China National Knowledge Infrastructure (CNKI), WanFang Data, VIP, China Biomedical Literature Database, PubMed, Embase, Web of Science, Cochrane Library, Joanna Briggs Institute (JBI) in Australia, National Institute for Health and Clinical Excellence (NICE), National Guideline Clearinghouse (NGC), Scottish Intercollegiate Guidelines Network (SIGN), Registered Nurses' Association of Ontario (RNAO), medlive and other websites or databases. The retrieval period was from January 1, 2012 to June 1, 2022.Results:A total of 22 articles were included, including 5 guidelines, 3 evidence summaries, 6 systematic reviews, 1 expert consensus and 7 RCTs. 26 pieces of evidence were summarized from 6 aspects: pain assessment, education and training, non-pharmacological interventions, pharmacological interventions, self-management and precautions.Conclusions:This study summarizes the best evidence for managing breastfeeding associated nipple pain and trauma, providing evidence-based evidence for regulating breastfeeding associated nipple pain and trauma management. It is recommended that nurses comprehensively consider the clinical situation when applying evidence, selectively apply the best evidence, extend breastfeeding time, and promote maternal and infant health.

Objective:To systematically evaluate women's real experience of childbirth trauma.Methods:Qualitative research on women's views and emotional experience of childbirth trauma were retrieved in Embase, Cochrane Library, PubMed, Medline, ClinicalKey, China Biology Medicine disc, China National Knowledge Infrastructure, VIP and Wanfang Data. The search time limit was from database building to July 1, 2021. Quality Evaluation Standard for Qualitative Research of Australia Joanna Briggs Institute (JBI) Evidence-based Health Care Center was used to evaluate the article. Meta synthesis was adopted to integrate the results.Results:A total of 12 articles were included. Besides, a total of 10 new categories were formed and 5 synthesis results were integrated, namely, the influencing factors of trauma, physical and psychological dual trauma, lack of control and participation in decision-making, interpersonal relationships and multiple ways to solve problems.Conclusions:Childbirth trauma causes a series of adverse effects on women's physiology and psychology. Hospitals, communities, and families should understand the emotional experience and needs of people with childbirth trauma, give adequate support and guidance, and provide reasonable medical interventions for people with childbirth trauma to protect their physical and psychological health.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment. Hyperactivation of mTOR complex 1 (mTORC1) and subsequent impairment of the transcription factor EB (TFEB)-mediated autophagy-lysosomal pathway (ALP) are implicated in the development of NAFLD. Accordingly, agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD. The objective of this study was to investigate the effects of nuciferine, a major active component from lotus leaf, on NAFLD and its underlying mechanism of action. Here we show that nuciferine activated ALP and alleviated steatosis, insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner. Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases, thereby suppressing lysosomal localization and activity of mTORC1, which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance. Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORC1-TFEB-ALP axis could represent a novel pharmacological strategy to combat NAFLD.

Objective To analyze the clinical key points of minimally invasive tracheostomy with percutaneous horn expansion applicated in ICU,and to discuss the problems encountered in minimally invasive surgery and the solutions.Methods The clinical data of 25 patients of minimally invasive tracheostomy with percutaneous horn expansion in ICU were analyzed retrospectively.Results Twenty-one patients with minimally invasive tracheostomy with percutaneous horn expansion were successfully performed in 25 patients of ICU (no incision sputum,subcutaneous emphysema,pneumothorax and other complications),2 patients had more postoperative bleeding,2 patients were difficult to imbedding catheter,of which 1 case abandoned the catheter and received conventional tracheotomy.Conclusion Percutaneous horn expansion minimally invasive tracheostomy has the advantages of small incision,less injury,less operative time,less blood loss and low incidence of complications.However,ICU patients are in severe condition and easy to change.Adequate preoperative preparation,controlling the key steps in the operation can find a solution to the problme.