OBJECTIVE To confirm trigger items for adverse drug reaction （ADR） induced by bevacizumab， to identify and analyze the occurrence of related ADR， and to establish a predictive model for severe adverse reaction （SAR） caused by this drug. METHODS Based on the global trigger tool （GTT） theory， and referencing the GTT White Paper， drug package inserts and relevant literature， trigger items for bevacizumab-related ADR were confirmed using a single-round Delphi method. Utilizing these established items， electronic medical records of relevant patients at Guilin People’s Hospital from January 2020 to September 2024 were actively screened via the China Hospital Pharmacovigilance System. Pharmacists then identified and tallied the occurrence of bevacizumab-induced ADR. Data from patients with any positive trigger item served as the study subjects （divided into training and test sets at a ratio of 7∶3）， candidate feature variables were selected from 39 related variables using the Boruta algorithm， and the multivariable Logistic regression analysis was performed with the occurrence of SAR as the dependent variable. Based on these candidate features， Logistic Regression， Extreme Gradient Boosting， Light Gradient Boosting Machine， Random Forest， and Categorical Boosting models were constructed. Model performance was evaluated using metrics including the area under the curve （AUC） of receiver operating characteristic curve and recall rate. The Shapley Additive exPlanations （SHAP） method was applied to analyze and interpret the contribution of each variable. A nomogram was constructed based on the optimal model. RESULTS A total of 38 trigger items for active monitoring of bevacizumab-related ADR were determined， comprising 17 laboratory indicators， 13 clinical manifestations， and 8 intervention measures. In total， 483 patients with positive trigger items were included， and 318 patients with bevacizumab-induced ADR were identified， including 83 SARs. The positive predictive values for the trigger items and cases were 43.57% （708/1 625） and 63.84% （318/483）， respectively. Bevacizumab-induced ADR involved 7 systems/organs， with the hematological system being the most frequently involved （64.15%）. The Boruta algorithm selected 7 vari ables： serum potassium， hematocrit， albumin-to-globulin ratio， prealbumin， hypertension history， age and red blood cell count. Multivariable Logistic regression showed that elevated serum potassium levels were associated with a decreased risk of bevacizumab-induced SAR （OR＝0.234， P ＝0.002）， while a history of hypertension （OR＝2.642， P ＝0.006） and increased age （OR＝1.040， P ＝0.025） were associated with an increased risk. The Logistic Regression model demonstrated superior performance with higher AUC， F1 score and recall rate （0.761， 0.447， 0.607）， compared to other models. SHAP evaluation results indicated that variables such as serum potassium， hematocrit， and age ranked highest in importance. CONCLUSIONS Totally 38 trigger entries have been successfully identified for active screening of bevacizumab-related ADR. Elevated serum potassium levels are a protective factor against bevacizumab-induced SAR， whereas the hypertension history and increased age are risk factors. The Logistic Regression model is the optimal predictive model.

BACKGROUND:The immune-related pathogenesis of Alzheimer's disease is still unclear.Exploring the correlation between natural killer cells and cuproptosis mechanism in Alzheimer's disease patients through bioinformatics can provide a new direction for the study of the occurrence and development of Alzheimer's disease. OBJECTIVE:To screen the key genes related to cuproptosis of natural killer cells in peripheral blood of patients with Alzheimer's disease by bioinformatics analysis and verify them in clinical specimens. METHODS:The GEO online database was used to screen the transcriptome differentially expressed genes and natural killer cell related genes in the peripheral blood of patients with Alzheimer's disease,and intersected with the reported cuproptosis factors.Differentially expressed cuproptosis-related genes were obtained.Then RT-qPCR technology was used to verify the relative gene expression levels.The experimental samples were all from peripheral blood of hospitalized patients in the Department of Neurology of Anhui Provincial Hospital from 2021 to 2023,and 30 patients in the disease group and 20 in the control group were included according to the inclusion and exclusion criteria.The protein-protein interaction network was further constructed using the online GeneMANIA website.R language was used for immune infiltration analysis.Transcription factor prediction was conducted based on ENCODE database. RESULTS AND CONCLUSION:(1)The differential expression genes of peripheral blood transcriptome of Alzheimer's disease patients in GSE63060 data set,natural killer cell related genes in GSE168522 data set,and reported cuproptosis genes were used to screen and obtain four differentially expressed cuproptosis-related genes by using online Venn diagram tool,LASSO algorithm,and random forest machine learning methods:ferredoxin 1(FDX1),ATPase Cu2+transporting alpha polypeptide(ATP7A),pyruvate dehydrogenase El subunit beta(PDHB),and dihydrolipoamide succinyltransferase(DLST).(2)Clinical sample experiments showed that FDX1 and ATP7A were up-regulated in peripheral blood of patients with Alzheimer's disease(P<0.001),and were differentially expressed in different genotypes of apolipoprotein E4(P<0.01,P<0.001).The expression of PDHB and DLST in peripheral blood of patients with Alzheimer's disease was down-regulated(P<0.001),and there was no difference in apolipoprotein E4 genotypes(P>0.05).(3)Protein-protein interaction network found that 20 functional proteins were associated with key genes,and immunoinfiltration analysis showed that key genes were significantly associated with 12 immune cells(P<0.05 was considered to be relevant).(4)Bioinformatics analysis and experimental verification results suggest that FDX1,ATP7A,PDHB,and DLST are differentially expressed in Alzheimer's disease,may participate in the occurrence and development of Alzheimer's disease through the cuproptosis mechanism in peripheral blood natural killer cells,and also provide potential targets for the diagnosis and treatment of Alzheimer's disease.

Objective: To investigate the sleep quality in patients with burning mouth syndrome (BMS) and its influencing factors, providing a basis for developing sleep intervention measures to reduce the impact of BMS symptoms. Methods: This study was reviewed and approved by the Medical Ethics Committee, and informed consent was obtained from patients. A total of 150 patients with BMS and 150 healthy volunteers were enrolled as subjects in this study. The Pittsburgh sleep quality index (PSQI) was used to assess the sleep quality of patients with BMS. Visual analog scale (VAS) was used to assess the degree of oral mucosal pain, generalized anxiety disorder 7-item scale (GAD-7) was used to assess the frequency of anxiety symptoms, and the patient health questionnaire depression questionnaire (PHQ-9) was used to assess the frequency of depression symptoms. Univariate analysis was performed to identify potential influencing factors affecting sleep quality in patients with BMS, and multiple linear regression analysis was employed to determine independent risk factors. Results: The PSQI score for patients with BMS was 7.61 ± 4.29, which was significantly higher than that of healthy controls (P = 0.016). In the PSQI subscale analysis, patients with BMS exhibited increased sleep latency, decreased sleep duration, and lower sleep efficiency compared to healthy controls (P<0.05). Patients with BMS and comorbid sleep difficulties had significantly higher scores on GAD-7 and PHQ-9 compared to the patients with BMS without sleep difficulties (P<0.001), but there was no significant difference in pain VAS scores between the two (P = 0.068). Multiple linear regression analysis revealed that longer disease duration (>6 months), the presence of systemic concomitant symptoms (such as headache and mental stress), and higher depression scores were identified as independent risk factors affecting sleep quality in patients with BMS. Conclusion For patients with BMS, long course of illness, presence of headaches, high mental stress, and depressive symptoms may be independent factors affecting their sleep quality.

OBJECTIVE: To analyze the distribution characteristics of glucose-6-phosphate-dehydrogenase (G6PD) mutations and their enzyme activity in newborns patients with G6PD deficiency in Guilin region. METHODS: From July 2022 to July 2024, umbilical cord blood samples from 4 554 newborns in Guilin were analyzed for G6PD mutations using fluorescence PCR melting curve analysis. Enzyme activity was detected in 4 467 cases using the rate assay. RESULTS: Among 4 467 newborns who underwent G6PD activity testing, 162 newborns (3.63%) were identified as G6PD-deficient, including 142 males (6.04%) and 20 females (0.94%), the prevalence of G6PD deficiency was significantly higher in males than in females (P < 0.001). Genetic analysis of 4 554 newborns detected G6PD mutations in 410 cases (9%), including 171 males (7.13%) and 239 females (11.09%), with a significantly higher mutation detection rate in females than in males (P < 0.001). A total of nine single mutations and four compound heterozygous mutations were identified. The most common mutations were c.1388G>A (33.66%), c.1376G>T (23.66%) and c.95A>G (16.34%). Among newborns who underwent both enzyme activity and genetic mutation testing, males with G6PD mutations had significantly lower enzyme activity than that of females with G6PD mutations(P < 0.001). Specifically, among newborns carrying the mutations c.1388G>A, c.1376G>T, c.95A>G, c.1024C>T or c.871G>A, males consistently exhibited lower enzymatic activity than females with the same mutations (P < 0.001). Furthermore, in male G6PD-deficient newborns, the enzyme activity levels in those carrying c.1388G>A, c.1376G>T, c.95A>G, c.1024C>T, or c.871G>A were lower than those in both the control group and the c.519C>T group (P < 0.05). CONCLUSION This study provides a comprehensive profile of G6PD deficiency incidence and mutation spectrum in the Guilin region. By analyzing enzyme activity and genetic mutation results, this study provides insights into potential intervention strategies and personalized management approaches for the prevention and treatment of neonatal G6PD deficiency in the region.
Humans ; Infant, Newborn ; Glucosephosphate Dehydrogenase Deficiency/epidemiology* ; Glucosephosphate Dehydrogenase/genetics* ; Female ; Male ; Mutation ; China/epidemiology*

Objective To explore the perioperative safety and prognostic factors of sequential hepatectomy after conversion therapy using vascular interventional therapy(including transarterial chemoembolization and hepatic arterial infusion chemotherapy)combined with tyrosine kinase inhibitors(TKI)and programmed death-1(PD-1)inhibitors in patients with initially unresectable hepatocellular carcinoma.Methods The clinical data of 106 eligible HCC patients treated in Tumor Hospital Affiliated to Guangxi Medical University from Nov.2019 to Apr.2024 were retrospectively analyzed.The perioperative parameters and postoperative pathological outcomes were described in detail,and factors influencing prognosis were analyzed.Results The median operative time for hepatectomy after conversion therapy was 240 min,with a median blood loss of 200 mL.Intraoperative blood transfusion was required in 24(22.6％)patients.Postoperative adverse reactions occurred in 49.1％(52/106)of patients,with liver failure being the most common adverse reactions(23 patients,21.7％).One(0.9％)patient died during the perioperative period,while the remaining 105 patients were followed up for a median duration of 14.7 months,during which 49(46.2％)patients experienced recurrence.Among them,39(36.8％)cases experienced early recurrence(within 1 year),and 33(31.1％)cases had intrahepatic recurrence.Thirteen(12.3％)patients died during follow-up.The median recurrence-free survival(RFS)was 15.7 months,with 1-year and 2-year RFS rates being 56.9％and 40.3％,respectively.The median overall survival(OS)was not reached,with 1-year and 2-year OS rates being 94.2％and 85.3％,respectively.Multivariate Cox regression analysis demonstrated that achieving complete pathological response(hazard ratio[HR]=0.410,95％confidence interval[CI]0.172-0.980,P=0.045),presence of microvascular invasion(HR=2.423,95％CI 1.269-4.625,P=0.007),satellite nodules(HR=1.916,95％CI 1.014-3.620,P=0.045),and multiple tumors(HR=1.818,95％CI 1.012-3.241,P=0.046)were independent factors associated with postoperative recurrence.Conclusion For patients with initially unresectable hepatocellular carcinoma,vascular interventional therapy combined with TKI and PD-1 inhibitors followed by sequential hepatectomy may be a feasible treatment strategy,with manageable adverse reactions and promising efficacy.

Pyroptosis, a form of inflammatory cell death mediated by the Gasdermins family, promotes the release of inflammatory mediators and activates immune cell populations such as NK cells, T cells and macrophages in the tumor microenvironment(TME) to exert immune-regulating and anti-tumor effects. Glioblastoma(GBM) is the most serious and malignant glioma, and the median survival of patients diagnosed with GBM is less than 2 years, and the presence of the blood-brain barrier makes it difficult to deliver drugs to the brain, thus affecting the effect of drugs against GBM. Therefore, it is important to explore new measures and mechanisms to treat GBM, which has a complex TME with a large number of immune cell populations that are often immunosuppressed by GBM. Cellular pyroptosis as a mode of cell death capable of activating immunity, has the effect of activating the body’s immunity to help reverse TME immunosuppression. This review will focus on the relationship between cell pyroptosis and the immune system, how cell pyroptosis affects the immune cell population of TME in GBM, and the new progress in drug research on cell pyroptosis pathways in GBM treatment, providing new directions and strategies for future clinical treatment of GBM.

Celastrol(Cel) is a active ingredient extracted from the natural compound Tripterygium wilfordii, which has good anti-tumor activity and other pharmacological effects. In recent years, studies have found that Cel has good anti-tumor activity and the ability to penetrate the blood-brain barrier(BBB), which is a potential drug for treating brain tumors. However, due to its severe liver toxicity, its clinical application prospects are questioned. Glioma(GMA) is a high incidence tumor in the brain, with a survival rate of<5% after diagnosis. Currently, there are few drugs available in clinical practice, so it is urgent to explore new drugs or drug delivery strategies to treat neuro GMA. Some studies have found that Cel has good anti-tumor activity and also has a good inhibitory effect on GMA, but the relevant mechanisms have not yet been systematically summarized and expanded. Since Cel still faces many problems in its clinical application in GBA, it is necessary to further consider what means to use in the future to enable Cel to efficiently pass through BBB and deliver it to the GMA site for Targeted therapy while reducing its hepatotoxicity. This article summarizes and expands the mechanisms and research results of Cel in various tumors and GMA in recent years. This article also reviews the new applications of Cel combined with nanocarriers in enhancing efficacy and reducing toxicity in recent years, in order to more clearly summarize the role of Cel in the treatment of GMA and how to systematically summarize the delivery methods of Cel through BBB, providing new treatment methods for clinical treatment of GMA.

Objective : To investigate the role of early inhibition of Toll⁃like receptor 4 (TLR4) in regulating hippampal neuroimmune responseto adolescent ratsafter neonatal hypoxic⁃ischemic brain damage(HIBD) . Methods: Postnatal day 7 rats were randomized into controlgroup , hypoxic ischemia (HI) group , and HI + TAK⁃242( the specific inhibitor of TLR4)(TAK⁃242) group. The expression of TLR4 in rat hippocampus was detected by immunohistochemistry at 3 days after HI. Immunofluorescence were used to determine the number of Iba⁃1 + , GFAP + , CD161 + , MPO + and CD3 + cells in the hippocampus at 21 days after HI. Immunohistochemistry was used to detect ICAM⁃1 and C3a expression in the hippocampal CA1 region ; and Western blot was used to detect tumor necrosis factor interleukin IL⁃1β , TNF⁃α and IL⁃10 expression. Results : Compared with control group , significantly raised TLR4 expression was observed in the left hippocampal CA1 , CA3 and DG regions(P < 0. 01 or P < 0. 05) , while the expression in the TAK⁃242 group lowered compared to the HI group (P < 0. 05) . The number of GFAP + cells in the CA1 area of the hippocampus in the TAK⁃242 group of neonatal rats decreased compared to which in the HI group at 21 days after HI(P < 0. 05) , but the number of CD3 + T lymphocytes in the hippocampal CA1 area of new born rats in the HI group increased compared to which in the Control group (P < 0. 05) , but the difference between TAK⁃242 and the Control group was not statistically significant. The number of Iba⁃1 + cells , MPO + cells , CD161 + cells , the expression of ICAM⁃1 and C3a in hippocampal CA1 region , and the expression of TNF⁃α , IL⁃1β and IL⁃10 in hippocampus of rats were not different among groups at 21 days after HIBD. Conclusion Early inhibition of TLR4 may ameliorate adolescent neuroimmune disorders by reducing the increase of hippocampal astrocytesafter neonatal HIBD.

Humans ; Female ; Fumarate Hydratase/genetics* ; Kidney Neoplasms ; Carcinoma, Renal Cell ; Leiomyomatosis ; Uterine Neoplasms

Burning mouth syndrome (BMS) is a chronic oral and facial pain disorder characterized by burning pain in the oral mucosa, with multiple pathogenic factors including psychosocial, neuropathological, endocrine, and immune factors. There is still a lack of effective treatment options that have been demonstrated to work. With the development of research on the pathogenesis and treatment of BMS, multidisciplinary comprehensive treatment has gradually been introduced and become a new trend of diagnosis and treatment. Before multidisciplinary treatment, it is necessary to go through a full and comprehensive diagnosis and analysis, select the best comprehensive treatment plan, take the diagnosis and treatment of stomatology as the basis and premise, and apply other multidisciplinary combined treatment, including the treatment of concurrent diseases, psychological interventions, correction of bad habits, etc. A combination of laser therapy and psychological intervention is a more effective treatment method among the current treatment methods, with high comfort and good acceptance by patients. If necessary, mecobalamin tablets, clonazepam α-lipoic acid and other drugs can be used to nourish nerves and provide symptomatic treatment. The comprehensive multidisciplinary treatment of BMS is expected to become a new trend and provide a new strategy for improving the therapeutic effect.