Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

Instrument separation is a critical complication during root canal therapy, impacting treatment success and long-term tooth preservation. The etiology of instrument separation is multifactorial, involving the intricate anatomy of the root canal system, instrument-related factors, and instrumentation techniques. Instrument separation can hinder thorough cleaning, shaping, and obturation of the root canal, posing challenges to successful treatment outcomes. Although retrieval of separated instrument is often feasible, it carries risks including perforation, excessive removal of tooth structure and root fractures. Effective management of separated instruments requires a comprehensive understanding of the contributing factors, meticulous preoperative assessment, and precise evaluation of the retrieval difficulty. The application of appropriate retrieval techniques is essential to minimize complications and optimize clinical outcomes. The current manuscript provides a framework for understanding the causes, risk factors, and clinical management principles of instrument separation. By integrating effective strategies, endodontists can enhance decision-making, improve endodontic treatment success and ensure the preservation of natural dentition.
Humans ; Root Canal Therapy/adverse effects* ; Consensus ; Root Canal Preparation/adverse effects*

OBJECTIVE: To identify prognostic genes associated with lysosome-dependent cell death (LDCD) in patients with gastric cancer (GC). METHODS: Differentially expressed genes (DEGs) were identified using The Cancer Genome Atlas - Stomach Adenocarcinoma. Weighted gene co-expression network analysis was performed to identify the key module genes associated with LDCD score. Candidate genes were identified by DEGs and key module genes. Univariate Cox regression analysis, and least absolute shrinkage and selection operator regression and multivariate Cox regression analyses were performed for the selection of prognostic genes, and risk module was established. Subsequently, key cells were identified in the single-cell dataset (GSE183904), and prognostic gene expression was analyzed. Cell proliferation and migration were assessed using the Cell Counting Kit-8 assay and the wound healing assay. RESULTS: A total of 4,465 DEGs, 95 candidate genes, and 4 prognostic genes, including C19orf59, BATF2, TNFAIP2, and TNFSF18, were identified in the analysis. Receiver operating characteristic curves indicated the excellent predictive power of the risk model. Three key cell types (B cells, chief cells, and endothelial/pericyte cells) were identified in the GSE183904 dataset. C19orf59 and TNFAIP2 exhibited predominant expression in macrophage species, whereas TNFAIP2 evolved over time in endothelial/pericyte cells and chief cells. Functional experiments confirmed that interfering with C19orf59 inhibited proliferation and migration in GC cells. CONCLUSION C19orf59, BATF2, TNFAIP2, and TNFSF18 are prognostic genes associated with LDCD in GC. Furthermore, the risk model established in this study showed robust predictive power.
Stomach Neoplasms/pathology* ; Humans ; Prognosis ; Lysosomes/physiology* ; RNA-Seq ; Cell Death ; Single-Cell Analysis ; Gene Expression Regulation, Neoplastic ; Cell Proliferation ; Single-Cell Gene Expression Analysis

Background/Aims: The histological characteristics and natural history of precirrhotic primary biliary cholangitis (PBC) with portal hypertension (PH) are unclear. Our aim was to clarify the prevalence, risk factors, and histological characteristics of precirrhotic PBC patients with PH. Methods: This retrospective study compared the clinical features, histological characteristics, and response to ursodeoxycholic acid (UDCA) between the PH and non-PH groups of precirrhotic PBC patients. Results: Out of 165 precirrhotic PBC patients, 40 (24.2%) also had PH. According to histological stage 1, 2 and 3 disease, 5.3% (1/19), 17.3% (17/98), and 45.8% (22/48) of patients also had PH, respectively. Precirrhotic PBC with PH was significantly positively correlated with bile duct loss, degree of cytokeratin 7 positivity, and degree of fibrosis in the portal area, but significantly negatively correlated with lymphoid follicular aggregation. Compared to the non-PH group, patients in the PH group showed a higher prevalence of obliterative portal venopathy, incomplete septal fibrosis, portal tract abnormalities and non-zonal sinusoidal dilatation (p<0.05). In addition, patients with PH were more likely to present with symptoms of jaundice, ascites, epigastric discomfort, a poorer response to UDCA, and more decompensation events (p<0.05). High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values were risk factors for precirrhotic PBC with PH. Conclusions Approximately 24.2% of precirrhotic PBC patients have PH, which is histologically related to the injury of bile ducts. High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values are associated with increased risk of precirrhotic PBC with PH.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

Primary signet ring cell carcinoma (SRCC) of the prostate is a rare neoplasm. However, its potential tumorigenic mechanism, clinicopathological features, and prognostic outcome have not been systematically described. To determine the pathogenic mechanism, we detected distributions of programmed cell death-ligand 1 (PD-L1), programmed death 1 (PD-1), and cellular components in the tumor microenvironment, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (TAMs; CD163 and CD68), and tumor-associated fibroblasts (vimentin and alpha-smooth muscle actin [α-SMA]), in tumor tissues from four patients with primary prostatic SRCC compared with corresponding adjacent tissues and tumor tissues from 30 patients with prostate adenocarcinoma (PCa) by immunohistochemical staining. We found higher expression of PD-L1, CD163, and CD68 in primary SRCC specimens than that in both corresponding adjacent nontumor specimens and PCa specimens with different Gleason scores, indicating that TAMs may participate in the malignant biological behavior of primary SRCC of the prostate. For further analysis, we searched electronic journal databases and Surveillance, Epidemiology, and End Results (SEER) to identify 200 eligible patients including our four cases. According to Kaplan-Meier survival curve analysis, patients <68 years old, with radical prostatectomy (RP), Gleason score of 7-8, and lower clinical stage had longer overall survival (OS). Moreover, Cox multivariate analysis indicated that race (hazard ratio [HR] = 1.422), surgical approach (HR = 1.654), and Gleason score (HR = 2.162) were independent prognostic factors for OS. Therefore, primary SRCC of the prostate represents a distinct and aggressive subtype of prostate cancer associated with a higher distribution of PD-L1 and TAMs, which warrants further clinical investigation.
Aged ; B7-H1 Antigen ; Carcinoma, Signet Ring Cell ; Humans ; Lymphocytes, Tumor-Infiltrating ; Male ; Prognosis ; Prostate ; Prostatic Neoplasms ; Tumor Microenvironment

Objective: To understand the characteristics and associated factors of viral nucleic acid conversion in children infected with Omicron variant strain of SARS-CoV-2 in Shanghai. Methods: The clinical symptoms, laboratory results and other data of 177 children infected with SARS-CoV-2 who were hospitalized in Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University (designated hospital for SARS-CoV-2 infection in Shanghai) from April 25 to June 8, 2022 were retrospectively analyzed. According to the chest imaging findings, the children were divided into mild and common type groups. According to their age, the unvaccinated children were divided into<3 years old group and 3-<18 years old group. According to the vaccination status, the children aged 3-<18 year were divided into non-vaccination group, 1-dose vaccination group and 2-dose vaccination group. Comparison between groups was performed by independent sample t-test and analysis of variance, and multivariate linear regression analysis was used for multivariate analysis. Results: Among the 177 children infected with Omicron variant of SARS-CoV-2, 96 were males and 81 were females, aged 3 (1, 6) years. The time of viral nucleic acid negative conversion was (10.3±3.1) days. The 177 children were 138 cases of mild type and 39 cases of common type. Among the children aged 3-<18 years old, 55 cases were not vaccinated, 5 cases received 1-dose and 36 cases received 2-dose vaccination. Among the 36 children who received 2 doses of vaccination, the time of viral nucleic acid negative conversion was shorter in those vaccinated within 6 months than those over 6 months ((7.1±1.9) vs. (10.8±3.0) d, t=-3.23, P=0.004). Univariate analysis showed that the time of nucleic acid negative conversion of SARS-CoV-2 was associated with age, underlying diseases, gastrointestinal symptoms, white blood cell count, proportion of neutrophils, proportion of lymphocytes, and the number of doses of SARS-CoV-2 vaccine (t=3.87, 2.55, 2.04, 4.24, 3.51, 2.92, F=16.27, all P<0.05). Multiple linear regression analysis showed that older age (β=-0.33, 95% CI -0.485--0.182, P<0.001) and more doses of vaccination (β=-0.79, 95% CI -1.463--0.120, P=0.021) were associated with shortened nucleic acid negative conversion time in children, while lower lymphocyte proportion (β=-0.02, 95% CI -0.044--0.002, P=0.031) and underlying diseases (β=1.52, 95% CI 0.363-2.672, P=0.010) were associated with prolonged nucleic acid negative conversion time in children. Conclusion: The children infected with Omicron variant of SARS-CoV-2 with reduced lymphocyte proportion and underlying diseases may have longer time of viral nucleic acid negative conversion,while children with older age and more doses of vaccination may have shorter time of viral nucleic acid negative conversion.
Child ; Female ; Male ; Humans ; Child, Preschool ; Adolescent ; SARS-CoV-2 ; COVID-19 Vaccines ; Nucleic Acids ; COVID-19 ; Retrospective Studies ; China/epidemiology* ; Translocation, Genetic ; Hospitals, Pediatric

Aim To study the variations of endogenous differential metabolites and metabolic pathways in PF rat model induced by bleomycin based on GC-MS.Methods The rat model for pulmonary fibrosis was induced by intratracheal instillation of bleomycin.Model rats were randomly divided into 7 days group of PF model(M7), 14 days group of model(M14), 21 days group of model(M21)and 28 days group of model(M28), with 6-8 rats in each group.On the 8th, 15th, 22nd and 29th days of the modeling, the rat model was evaluated by histopathology and hydroxyproline(HYP)detection.The non-targeted metabolomics was studied by GC-MS in order to find the related metabolites in the serum of PF rats and the metabolic pathways were analysed by MetaboAnalyst.Results Compared with control group, the phenomenon of rat lung lesions gradually appeared in each model group(M7, M14, M21, M28)with the modeling process.9, 14, 35, and 13 statistically significant metabolites were screened and identified respectively in M7, M14, M21 and M28.Among them, glycerol and phosphate were the early significant changes of pulmonary fibrosis.3-(3-hydroxyphenyl)propionic acid, alanine, galactonic acid, and serine changed significantly in the later stages of pulmonary fibrosis, and linoleic acid was the common main different metabolite.The main pathways affecting metabolism involved lipid metabolism, amino acid metabolism.Conclusion Abnormal amino acid metabolism and lipid metabolism are the main metabolic characteristics during the formation and development of PF by BLM.

Objective To investigate the effect of budesonide ( BUD) inhalation on the proliferation and apoptosis of airway smooth muscle cells ( ASMCs) in asthmatic rats and its molecular biological mechanism. Methods Totally 40 SD rats were randomly divided into control group, asthma model group, low (0. 25 mg/kg) and high (2 mg/kg) BUD group. The rat asthma model was induced by ovalbumin (VOA) combined with aluminium hydroxide Gel sensitization stimulation. After sensitization, the intervention group inhaled different doses of BUD before stimulation. The related parameters of lung tissue and airway were measured and calculated by medical image analysis system, immunofluorescence was used to detect the expression of type I collagen ( Col I ) and Col III in rat airway smooth muscle ( ASM ), and the protein expressions of Bcl-2, Bax, Caspase-3, phosphorylated ERK 1 and 2(p-ERK 1 / 2), p-p38 MAPK were detected by Western blotting. The proliferation activity of ASMCs was detected by MTT method, and the apoptosis rate of ASMCs was detected by flow cytometry. Results Compared with the control group, airway remodeling occurred in the asthmatic model group, and the airway wall thickness ( WAt/Pbm ), inner wall thickness ( WAi/Pbm ) and smooth muscle thickness ( WAm/Pbm ) increased, compared with the model group, the airway remodeling was inhibited in BUD intervention group, and the tracheal WAt/Pbm, WAi/Pbm and WAm/Pbm decreased in bud treatment group. BUD could decrease the proliferation activity of ASMCs, increase the apoptosis rate of ASMCs, inhibit the expression of Col I and Col III, deregulate the expression of Bcl-2, upregulate the expression of Bax and Caspase-3 ( all P<0. 05), and inhibit the activity of ERK 1/2 and p38 MAPK signal pathway. Conclusion BUD can inhibit the proliferation and the promote apoptosis of ASMCs in asthmatic rats, which may be related to the inhibition of ERK 1/2 and p38 MAPK signal pathways.

Objective To investigate the effect of berberine on proliferation of neural stem cells(NSCs)induced by hydrogen peroxide(H2O2). Methods NSCs from Sprague-Dawley rats were isolated and purified by suspension culture. Cells were divided into a control group,H2O2group(NSCs exposed to H2O2injury),berberine group(NSCs were incubated with berberine concentrations ranging from 0.5 to 20 μmol/L and exposed to H2O2), and DAPT(a blocker of the Notch signaling pathway)group. Cell viability was evaluated using the Cell Counting Kit-8 assay. Proliferation of NSCs was evaluated by a neurosphere formation assay and Ki67 protein expression. Expression of key proteins in the Notch signaling pathway(including notch1 and hes1)in response to berberine treatment or DAPT(a Notch inhibitor)was determined by Western blotting. Results Cell viability of NSCs was significantly increased by berberine compared with the H2O2group. The neurosphere growth assay showed that 5 or 10 μmol/L berberine increased NSC proliferation. The ratio of Ki67 +/DAPI cells and notch1 and hes1 protein expression increased significantly compared with the H2O2group. Conclusions Berberine treatment upregulates Notch signaling in NSCs,whereas DAPT attenuates these effects. Berberine is a drug that promotes NSC proliferation and exerts a protective effect on NSCs via the Notch signaling pathway.