Primary biliary cholangitis （PBC） is a cholestatic autoimmune liver disease characterized by the injury of small intrahepatic bile ducts， and at present， the pathogenesis of PBC remains unclear. Recent studies have shown that bile acid metabolism disorder and gut microbiota imbalance play a key role in the development and progression of PBC， and they form a complex and dynamic interaction network via the “gut-liver axis” and regulate core physiopathological processes such as immune response， metabolic homeostasis， and inflammatory response in a synergistic manner. This article systematically elaborates on the abnormal features of bile acid metabolism and gut microbiota in PBC， discusses their synergistic mechanisms in PBC， and then proposes a combined strategy of targeting bile acid receptors and modulating gut microbiota， in order to overcome the limitations of current treatment modalities and provide new insights and directions for the clinical management of PBC.

OBJECTIVES: To investigate the expression of apolipoprotein C1 (APOC1) in papillary thyroid carcinoma (PTC) and its effects on proliferation and apoptosis of PTC cells. METHODS: The expression level of APOC1 in PTC and its impact on prognosis were analyzed using GEPIA 2 and Kaplan-Meier databases. Immunohistochemistry (IHC) and Western blotting were used to detect the expression of APOC1 in PTC and adjacent tissues and in 3 PTC cell lines and normal thyroid Nthyori 3-1 cells. In TPC-1 and BCPAP cells, the effect of Lipofectamine 2000-mediated transfection with APOC1 siRNA or an APOC1-overexpressing plasmid on cell growth and colony formation ability were examined by observing the growth curves and using colony-forming assay. The changes in cell cycle and apoptosis of the transfected cells were analyzed with flow cytometry. RT-qPCR and Western blotting were used to detect the changes in expressions of P21, P27, CDK4, cyclin D1, Bcl-2, Bax, caspase-3 and caspase-9 and the key proteins in the JAK2/STAT3 signaling pathway. RESULTS: APOC1 expression was significantly higher in PTC tissues and the 3 PTC cell lines than in the adjacent tissues and Nthyori 3-1 cells, respectively. In TPC-1 and BCPAP cells, APOC1 knockdown obviously reduced cell proliferative activity, increased the percentage of G0/G1 phase cells, lowered the percentages of S and G2 phase cells, promoted cell apoptosis, and downregulated mRNA and protein expression levels of CDK4, cyclin D1 and Bcl-2 and the protein levels of p-JAK2 and p-STAT3. APOC1 overexpression in the cells produced the opposite effects on cell proliferation, apoptosis, cell cycle and the mRNA and protein expressions. The application of AG490, a JAK2 inhibitor, strongly attenuated APOC1 overexpression-induced activation of the JAK2/STAT3 signaling pathway in BCPAP cells. CONCLUSIONS APOC1 overexpression promotes proliferation and inhibits apoptosis of PTC cells possibly by activating the JAK2/STAT3 signaling pathway and accelerating cell cycle progression.
Humans ; Apoptosis ; Cell Proliferation ; STAT3 Transcription Factor/metabolism* ; Signal Transduction ; Janus Kinase 2/metabolism* ; Thyroid Neoplasms/pathology* ; Thyroid Cancer, Papillary ; Cell Line, Tumor ; Carcinoma, Papillary

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

ObjectiveTo investigate the expression level of lysophosphatidyllecithin acyltransferase 4 （LPCAT4） in pancreatic cancer and its effect on the proliferation of pancreatic cancer cells. MethodsIn this study， the differentially expressed genes of patients with KRAS mutant and wild-type pancreatic cancer were analyzed by online database LinkedOmics. The LPCAT4 expression in pancreatic cancer tissues was analyzed online by the University of Alabama at Birmingham Cancer Data Analysis （UALCAN）， Sangerbox and gene expression profile interaction analysis 2 （GEPIA2）. Kaplan-Meier Plotter database was used to explore the correlation between LPCAT4 and the prognosis of patients with pancreatic cancer. The expression of LPCAT4 in human pancreatic cancer cells were detected by quantitative real-time PCR and Western blot analysis. LPCAT4 was knocked down in the high-expressing SW1990 cell line and overexpressed in the low-expressing MIA PaCa-2 cell line. The effects of LPCAT4 expression on cell proliferation were assessed using CCK-8 and EdU assays. STRING and GEPIA2 databases were used to obtain LPCAT4 binding and coexpressed genes in tumors， which were then analyzed by GO and KEGG. ResultsAnalysis of the LinkedOmics online database revealed a significant upregulation of LPCAT4 in patients with KRAS mutant pancreatic cancer compared to patients with KRAS wild-type pancreatic cancer. The online analysis of GEPIA2， UALCAN and Sangerbox 3.0 showed that the expression of LPCAT4 was higher in pancreatic cancer than in normal tissues. Analysis of the Kaplan-Meier Plotter database revealed that high LPCAT4 expression was associated with poorer prognosis in pancreatic cancer patients.Western blot and qPCR results showed that expression of LPCAT4 in pancreatic cancer cell lines was significantly higher than in normal pancreatic ductal epithelial cells. Knockdown of LPCAT4 in SW1990 cells inhibited proliferation， while overexpression in MIA PaCa-2 cells promoted proliferation. Enrichment analysis indicated that LPCAT4 was closely related to sulfur metabolism. ConclusionsLPCAT4 is highly expressed in pancreatic cancer and is associated with poor prognosis of patients. It plays a significant regulatory role in the proliferation of pancreatic cancer cells， with its expression level closely correlated with cell proliferation capacity. These findings reveal the critical role of LPCAT4 in the malignant progression of pancreatic cancer and provide important evidence for its potential as a therapeutic target.

Objective:To compare the cumulative live birth rate (CLBR) per oocyte retrieval cycle between gonadotropin-releasing hormone agonist (GnRH-a) long protocol and GnRH antagonist (GnRH-A) protocol in overweight and obese women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Methods:A retrospective cohort study was conducted to analyze the clinical characteristics of overweight and obese patients who underwent IVF/ICSI at the Center of Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University between January 2013 and December 2019. A total of 3 707 cycles were executed in overweight and obese patients who fulfilled the prescribed inclusion criteria, comprising 1 555 GnRH-a long protocol cycles and 2 152 GnRH-A protocol cycles. To mitigate confounding factors, post hoc randomization and propensity score matching (PSM) at a 1∶1 ratio were applied to match female age, anti-Müllerian hormone levels, and antral follicle count. The primary outcome observation indicator was the CLBR of the oocyte retrieval cycle. Analysis of subgroups of the population was conducted by the women's body mass index, age, and polycystic ovarian syndrome (PCOS) status.Results:After PSM, a total of 2 496 cycles were included comprising 1 248 GnRH-a long protocol cycles and 1 248 GnRH-A protocol cycles. GnRH-a long protocol had a higher CLBR [71.88% (897/1 248)] than that in GnRH-A protocol [62.98% (786/1 248), P<0.001]. No statistically significant difference was observed in the interval from gonadotropin initiation to live birth delivery day between the GnRH-a long protocol and GnRH-A protocol ( P>0.05). Subgroup analysis revealed that after PSM, the CLBR of GnRH-a long protocol in the patients with a body mass index of 25.0-29.9 kg/m 2 [71.36% (856/1 195)] and ≥30.0 kg/m 2 [77.36% (41/53)] were higher than those of the GnRH-A protocol patients [63.30% (759/1 199), P<0.001; 55.10% (27/49), P=0.017]. The CLBR of GnRH-a long protocol in women aged 20-34 [73.32% (805/1 098)] and ≥35 years [61.33% (92/150)] were higher than those of the GnRH-A protocol patients [67.18% (696/1 036), P=0.002; 42.45% (90/212), P<0.001]; among patients without PCOS, the CLBR with the GnRH-a long protocol [71.55% (850/1 188)] was significantly higher than that with GnRH-A protocol [60.95% (654/1 073), P<0.001]. However, in overweight and obese patients with PCOS, there was no statistically significant difference in CLBR between the two protocols ( P>0.05). The incidence of moderate-severe ovarian hyperstimulation syndrome (OHSS) was significantly lower in the overweight and obese population using GnRH-A protocol [0.64% (8/1 248)] compared with GnRH-a long protocol [1.76% (22/1 248), P=0.016]. Conclusion:For overweight and obese patients, GnRH-a long protocol demonstrates higher CLBR compared with GnRH-A protocol, indicating superior efficacy. For those with PCOS, both protocols show comparable CLBR, while the incidence of severe OHSS is lower in the GnRH-A.

Objective:To compare the cumulative live birth rate (CLBR) per oocyte retrieval cycle between gonadotropin-releasing hormone agonist (GnRH-a) long protocol and GnRH antagonist (GnRH-A) protocol in overweight and obese women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Methods:A retrospective cohort study was conducted to analyze the clinical characteristics of overweight and obese patients who underwent IVF/ICSI at the Center of Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University between January 2013 and December 2019. A total of 3 707 cycles were executed in overweight and obese patients who fulfilled the prescribed inclusion criteria, comprising 1 555 GnRH-a long protocol cycles and 2 152 GnRH-A protocol cycles. To mitigate confounding factors, post hoc randomization and propensity score matching (PSM) at a 1∶1 ratio were applied to match female age, anti-Müllerian hormone levels, and antral follicle count. The primary outcome observation indicator was the CLBR of the oocyte retrieval cycle. Analysis of subgroups of the population was conducted by the women's body mass index, age, and polycystic ovarian syndrome (PCOS) status.Results:After PSM, a total of 2 496 cycles were included comprising 1 248 GnRH-a long protocol cycles and 1 248 GnRH-A protocol cycles. GnRH-a long protocol had a higher CLBR [71.88% (897/1 248)] than that in GnRH-A protocol [62.98% (786/1 248), P<0.001]. No statistically significant difference was observed in the interval from gonadotropin initiation to live birth delivery day between the GnRH-a long protocol and GnRH-A protocol ( P>0.05). Subgroup analysis revealed that after PSM, the CLBR of GnRH-a long protocol in the patients with a body mass index of 25.0-29.9 kg/m 2 [71.36% (856/1 195)] and ≥30.0 kg/m 2 [77.36% (41/53)] were higher than those of the GnRH-A protocol patients [63.30% (759/1 199), P<0.001; 55.10% (27/49), P=0.017]. The CLBR of GnRH-a long protocol in women aged 20-34 [73.32% (805/1 098)] and ≥35 years [61.33% (92/150)] were higher than those of the GnRH-A protocol patients [67.18% (696/1 036), P=0.002; 42.45% (90/212), P<0.001]; among patients without PCOS, the CLBR with the GnRH-a long protocol [71.55% (850/1 188)] was significantly higher than that with GnRH-A protocol [60.95% (654/1 073), P<0.001]. However, in overweight and obese patients with PCOS, there was no statistically significant difference in CLBR between the two protocols ( P>0.05). The incidence of moderate-severe ovarian hyperstimulation syndrome (OHSS) was significantly lower in the overweight and obese population using GnRH-A protocol [0.64% (8/1 248)] compared with GnRH-a long protocol [1.76% (22/1 248), P=0.016]. Conclusion:For overweight and obese patients, GnRH-a long protocol demonstrates higher CLBR compared with GnRH-A protocol, indicating superior efficacy. For those with PCOS, both protocols show comparable CLBR, while the incidence of severe OHSS is lower in the GnRH-A.

Objective Network pharmacology and molecular docking techniques were used to predict the potential mechanisms by which the active components of Piper nigrum(PN)regulate depressive-like behaviors in chronic restraint stress(CRS)mice.Methods The major chemical components and targets of PN were screened using the Traditional Chinese Medicine Systems Pharmacology database.Targets related to ferroptosis and depression were obtained from the Online Mendelian Inheritance in Man,GeneCards,and FerrDB databases.The intersecting targets were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Gnomes(KEGG)pathway enrichment analyses,and molecular docking was performed to validate the binding capacities between the core targets and their corresponding active components.Finally,we established a CRS mouse model.Mice were treated with PN 75,150,and 300 mg/kg for 4 weeks,followed by behavioral assessments and reverse transcription-quantitative polymerase chain reaction(RT-qPCR)to verify the expression of core genes.Results Nine active components were screened from PN,corresponding to 27 targets,and 8377 targets related to depression and 547 targets associated with ferroptosis were screened from the databases.The intersection of these three sets resulted in 25 target genes.KEGG enrichment analysis revealed that these core targets were predominantly enriched in signaling pathways,including cholinergic synapses,serotonergic synapses,and neuroactive ligand-receptor interactions.Molecular docking result showed that the main active components of PN had strong binding affinities for the targets CHRM2,SLC6A4,PTGS2,and SLC6A2.Behavioral assessments demonstrated that PN significantly increased the sucrose preference index(P＜0.01,P＜0.001),reduced immobility time in the tail suspension and forced swimming tests(P＜0.01,P＜0.001),and enhanced exploratory behavior in the open field test(P＜0.05.P＜0.01,P＜0.001).PN significantly reduced the serum levels of inflammation markers(P＜0.05.P＜0.01,P＜0.001),as shown by enzyme-linked immunosorbent assay,and neurotransmitter analysis revealed that PN significantly increased the levels of serotonin and acetylcholine in the mouse hippocampus(P＜0.05).RT-qPCR showed that PN demonstrated the mRNA expression of SLC6A4(P＜0.05.P＜0.01,P＜0.001).Conclusions PN may improve depressive-like behavior in mice by modulating serotonin and acetylcholine levels,inhibiting inflammatory responses,participating in immune regulation,and exerting neuroprotective effects.

Objective Network pharmacology and molecular docking techniques were used to predict the potential mechanisms by which the active components of Piper nigrum(PN)regulate depressive-like behaviors in chronic restraint stress(CRS)mice.Methods The major chemical components and targets of PN were screened using the Traditional Chinese Medicine Systems Pharmacology database.Targets related to ferroptosis and depression were obtained from the Online Mendelian Inheritance in Man,GeneCards,and FerrDB databases.The intersecting targets were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Gnomes(KEGG)pathway enrichment analyses,and molecular docking was performed to validate the binding capacities between the core targets and their corresponding active components.Finally,we established a CRS mouse model.Mice were treated with PN 75,150,and 300 mg/kg for 4 weeks,followed by behavioral assessments and reverse transcription-quantitative polymerase chain reaction(RT-qPCR)to verify the expression of core genes.Results Nine active components were screened from PN,corresponding to 27 targets,and 8377 targets related to depression and 547 targets associated with ferroptosis were screened from the databases.The intersection of these three sets resulted in 25 target genes.KEGG enrichment analysis revealed that these core targets were predominantly enriched in signaling pathways,including cholinergic synapses,serotonergic synapses,and neuroactive ligand-receptor interactions.Molecular docking result showed that the main active components of PN had strong binding affinities for the targets CHRM2,SLC6A4,PTGS2,and SLC6A2.Behavioral assessments demonstrated that PN significantly increased the sucrose preference index(P＜0.01,P＜0.001),reduced immobility time in the tail suspension and forced swimming tests(P＜0.01,P＜0.001),and enhanced exploratory behavior in the open field test(P＜0.05.P＜0.01,P＜0.001).PN significantly reduced the serum levels of inflammation markers(P＜0.05.P＜0.01,P＜0.001),as shown by enzyme-linked immunosorbent assay,and neurotransmitter analysis revealed that PN significantly increased the levels of serotonin and acetylcholine in the mouse hippocampus(P＜0.05).RT-qPCR showed that PN demonstrated the mRNA expression of SLC6A4(P＜0.05.P＜0.01,P＜0.001).Conclusions PN may improve depressive-like behavior in mice by modulating serotonin and acetylcholine levels,inhibiting inflammatory responses,participating in immune regulation,and exerting neuroprotective effects.

Objective:To explore the distribution characteristics and antibiotic resistance of pathogen in children with hematological disorders and cancers complicated with sepsis in pediatric intensive care unit (PICU).Methods:The clinical data of children with hematological disorders and cancers complicated with sepsis hospitalized at Shenzhen Children′s Hospital affiliated to China Medical University from January 2016 to August 2023 were retrospectively analyzed. Patients were divided into survival group and death group based on the outcome of sepsis on 28 days after diagnosis.Results:A total of 202 sepsis episodes occurred in 176 children were enrolled in this study. Among all, 144 (71.3%) cases of bloodstream infection, 59 (29.2%) cases of pulmonary infection, 21 (10.4%) cases of abdominal infection, 9 (4.5%) cases of soft tissue infection, 9 (4.5%) cases of nervous system infection, and 3 (1.5%) cases of urinary tract infection. A total of 244 pathogenic strains were identified, in which 74 (30.3%) cases were gram-positive bacteria. The top 3 pathogens isolated were Coagulase negative Staphylococcus (21 strains), Staphylococcus aureus (19 strains) and Streptococcus pneumoniae (13 strains). Gram-negative bacteria accounted for 122 (50.0%) strains, in which top 3 were Klebsiella pneumonia (33 strains), Escherichia coli (25 strains), and Pseudomonas aeruginosa (23 strains). Fungi comprised 48 (19.7%) strains:the top 3 were Candida tropicalis (14 strains), Candida albicans (10 strains), Aspergillus and Pneumocystis jirovecii (7 strains each). The incidence of Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa were significantly higher in death group compared to survival group[9.0%（6/67）vs. 2.3%（4/177）, χ2＝3.971 ，P＝0.046; 9.0%（6/67）vs. 1.1%（2/177）, χ2＝7.080 ，P＝0.008;16.4%（11/67）vs. 6.8%（12/177）, χ2＝5.288 ，P＝0.021]. The samples of 57 cases were simultaneously detected by both culture and metagenomic next-generation sequencing (mNGS). Pathogens were detected in 25 cases by both culture and mNGS. In 30 cases, pathogen detection were mNGS positive but culture negative. Two cases showed positive results only with culture. A total of 79 (46.8%) strains were multi-drug resistant bacteria, including 27 (34.2%) strains of gram-positive bacteria and 52 (65.8%) strains of gram-negative bacteria. A total of 174 (86.1%) children with sepsis received empirical anti-infective drugs within 24 hours of fever onset. A total of 124 (61.4%) cases were appropriately covered by the initial empirical antibiotics, while 40 (19.8%) cases were not adequately covered and 10 (5.0%) cases had incomplete coverage. Despite the inclusion of pathogenic in the coverage, resistance to initial antibiotics was observed in 22 (10.9%) cases. Fifty-one patients died. Conclusion:The predominant pathogens responsible for sepsis in PICU with hematological disorders and cancers is gram-negative bacteria, followed by gram-positive bacteria and fungi. In comparison to healthy children with sepsis, there is a higher incidence of fungal infections among hematological disorders and cancers. The proportion of multi-drug resistant bacteria infection is high. Early identification and combination of local etiological distribution and drug resistance, along with the empirical selection of appropriate anti-infection treatment strategies, can greatly enhance survival rate.

BACKGROUND: Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear. METHODS: We retrospectively analyzed 431 HCC patients: 251 received hepatectomy alone, and the other 180 received sorafenib as adjuvant treatment after hepatectomy. Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining. mRNA sequencing and immunostaining to detect progenitor markers (cytokeratin 19 [CK19] and epithelial cell adhesion molecule [EpCAM]) and mutant TP53 were also conducted. RESULTS: Up to 72.4% (312/431) of HCC tumors were GS positive (GS+). Of the patients receiving hepatectomy alone, GS negative (GS-) patients had significantly better overall survival (OS) and recurrence-free survival (RFS) than GS+ patients; negative expression of Arg1, which is exclusively expressed in GS- hepatocytes in the healthy liver, had a negative effect on prognosis. Of the patients with a high risk of recurrence who received additional sorafenib treatment, GS- patients tended to have better RFS than GS+ patients, regardless of the expression status of Arg1. GS+ HCC tumors exhibit many features of the established proliferation molecular stratification subtype, including poor differentiation, high alpha-fetoprotein levels, increased progenitor tumor cells, TP53 mutation, and upregulation of multiple tumor-related signaling pathways. CONCLUSIONS GS- HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy. Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.
Humans ; Carcinoma, Hepatocellular/metabolism* ; Sorafenib/therapeutic use* ; Liver Neoplasms/metabolism* ; Glutamate-Ammonia Ligase/metabolism* ; Hepatectomy ; Retrospective Studies ; Prognosis ; Neoplasm Recurrence, Local/surgery*