[Purpose]To analyze irinotecan-related adverse events(AEs)signals,to provide references for clinically safe prescribing practices.[Methods]A retrospective pharmacovigilance analysis was con-ducted using Food and Drug Administration Adverse Event Reporting System(FAERS)database from the first quarter of 2004 to the last quarter of 2024.After duplicate removal,four disproportionality analysis methods were applied:reporting odds ratio(ROR),proportional reporting ratio(PRR),Bayesian confi-dence propagation neural network(BCPNN),and empirical Bayes geometric mean(EBGM),and subgroups were analyzed by age(≥65 years old vs＜65 years old)and outcome(death vs non-death).[Results]A total of 8 456 irinotecan-related reports comprising 27 177 AEs were identified.The most frequently reported AEs included diarrhea,nausea,neutropenia,vomiting,and fatigue.Additionally,several unexpected and significant AEs signals were detected,such as cell-mediated cytotoxicity,pyomyositis,neuropathic muscular atrophy,administration site recall reaction and ischemic neuropathy.Subgroup analysis indicated that elderly patients showed higher reported frequencies of diarrhea,neutropenia and leukopenia,while younger patients had more frequent reports of nausea,vomiting and peripheral neuropathy.The median time to AEs onset was 31 d,with 49.8％occurring within the first month of treatment.[Conclusion]The AEs related to irinotecan should be paid attention to.When using irinotecan for the treatment of digestive system cancer,symptoms such as diarrhea,nausea and neutropenia should be closely monitored to reduce the risk of drug use.

Objective To investigate the mechanism of action of Guizhi Fuling pill in treating chro-nic prostatitis(CP)using network pharmacology and molecular docking techniques.Methods Compo-nents of Guizhi Fuling pill were collected from the Traditional Chinese Medicines Systems Pharmacolo-gy Platform(TCMSP),and target information was obtained from the SwissTarget database.Targets for chronic prostatitis were screened from the GeneCards,OMIM,CTD,and DisGeNET disease data-bases.A protein-protein interaction(PPI)network was established and analyzed.Gene ontology(GO)functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway en-richment analysis were performed using the DAVID database.The Cytoscape software was employed to construct an association network linking the components of Guizhi Fuling Pill,their targets,and the targets of chronic prostatitis.Molecular docking was conducted using AutoDock Vina software to verify the binding stability between the components of Guizhi Fuling pill and their targets.Results After screening and deduplication in the TCMSP database,76 components of Guizhi Fuling Pill were iden-tified,and 655 component targets were retrieved from the SwissTarget database.There were 190 intersecting targets between GuizhiFuling Pill and chronic prostatitis.GO analysis indicated that Guizhi Fuling Pill may treat chronic prostatitis by participating in processes such asapoptosis,ATP binding,and signal transduction.KEGG analysis suggested that Guizhi Fuling Pill can regulate pathways such as phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)and mitogen-acti-vated protein kinase(MAPK)to intervene in chronic prostatitis.Molecular docking data demonstra-ted that the components of Guizhi Fuling pill exhibited stable conformations with their targets.Con-clusion The components of Guizhi Fuling Pill can stably bind to their targets and exert therapeutic effects on chronic prostatitis through multiple targets and pathways.

Objective : To investigate the diagnostic value of combined detection of folate receptor-positive circulat- ing tumor cells ( FR + -CTCs) and hemostatic function indicators in improving the diagnosis of gastrointestinal tumors ( GITs) metastasis． Methods: A retrospective analysis was conducted on the clinical data of 115 patients aged 18 to 80 years who were diagnosed with gastrointestinal tumors via pathology and received treatment，including data on FR + -CTCs，hemostatic function indicators，and pathological staging．The collected data encompassed FR + -CTCs levels，coagulation parameters，and pathological staging．Statistical analysis included t-tests，chi-square tests，fish- er ’s exact test，Logistic regression analysis，and receiver operating characteristic ( ROC) curves to assess the diag- nostic value of combined FR + -CTCs and coagulation parameters in detecting tumor metastasis． Results: FR + -CTCs levels and positive rates demonstrated significant associations with clinicopathological characteristics ( gender，histo- logical type，N staging) in GITs patients ( P＜0. 05) ．In patients with metastasis，elevated fibrinogen levels were observed．Adithonallly，platelet counts showed significant increases in N1 －N3 stages ( P＜0. 05) ．Logistic regres- sion analysis showed that PLT and antithrombin Ⅲ ( AT-Ⅲ) were independent risk factors for GITs metastasis ( P＜0. 05) ． The areas under the ROC curves for predicting GITs metastasis were 0. 678 ( 95% CI: 0. 540 - 0. 816) and 0. 664 ( 95% CI: 0. 512 －0. 815) ，respectively．When combining multiple factors，including FR + - CTCs，PLT，AT-Ⅲ , pathological type，FIB，TT，and gender，for the diagnosis of GITs metastasis，the AUC in- creased to 0. 757 ( 95% CI: 0. 621 －0. 893) ，indicating higher sensitivity and specificity compared to using each indicator alone． Conclusion The combined detection of FR + -CTCs and anticoagulation function indicators has a higher diagnostic value for the diagnosis of GITs，providing a valuable basis for the early diagnosis of GITs，espe- cially in metastasis surveillance．

OBJECTIVE: To observe the effects of the "Zhibian" (BL54)-toward-"Shuidao" (ST28) acupuncture on key regulatory factors during mitochondrial apoptosis of testicular tissue in asthenozoospermia mice, and explore the potential mechanism of the protective effect of acupuncture on reproductive function. METHODS: Thirty C57BL/6 male mice were randomly divided into a blank group, a model group and an acupuncture group, 10 mice in each group. In the model and the acupuncture groups, the intraperitoneal injection of cyclophosphamide (30 mg•kg^-1•d^-1) was delivered for 7 days to prepare the asthenozoospermia model. After the success of modeling, the modeled mice in the acupuncture group were intervened with "Zhibian" (BL54)-toward-"Shuidao" (ST28) acupuncture, once daily and the needles were retained for 20 min. The duration of the intervention was 2 weeks. The general condition of each mouse was observed, and the body mass was recorded before modeling, after modeling and after intervention completion. After intervention, the testicular mass was recorded and the weight coefficient was calculated, and the mouse sperm quality was examined; the serum contents of testosterone (T), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were detected using ELISA, the morphology of testicular tissue was observed using HE, the mitochondrial ultra-microstructure of testicular tissue was observed under transmission electrone microscopy, the mitochondrial membrane potential level of testicular tissue was detected using JC-1 staining, the positive rate of apoptosis cell of testicular tissue was observed using TUNEL; and the mRNA and protein expression of b-cell lymphocytoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), cytochrome c (Cyt C), apoptotic protease-activating factor1 (Apaf-1), Caspase-9 and Caspase-3 of testicular tissue was detected using real-time quantitative fluorescence PCR and Western blot methods separately; and the positive expression of Cleaved Caspase-3 of the testicular tissue was detected using immunohistochemistry. RESULTS: Compared with the blank group, the mice were in listless spirits, had shaggy hairs, the reduced appetite and movement, and weight loss in the model group (P<0.01); the testicular mass and the weight coefficient decreased (P<0.01); the total number of sperms, sperm motility, and sperm viability were declined (P<0.01); while the levels of serum T, FSH, and LH were dropped (P<0.01). The morphology of seminiferous tubules in testicular tissue was abnormal, the number of spermatogenic cells and the number of mitochondria decreased, the inner mitochondrial crest was fractured and lost, and vacuoles appeared. The level of mitochondrial membrane potential was reduced (P<0.01); and the positive rate of apoptosis cell in testicular tissue increased (P<0.01). The mRNA and protein expression of Bax, Cyt C, Apaf-1, Caspase-9 and Caspase-3 was elevated (P<0.01, P<0.05), the mRNA and protein expression of Bcl-2 was dropped (P<0.01), and the average absorbance value of Cleaved Caspase-3 increased (P<0.01). When compared with the model group, in the acupuncture group, the general condition of mice was improved, the testicular mass and the weight coefficient elevated (P<0.01); the total number of sperms, sperm motility, and sperm viability increased (P<0.01); while the levels of serum T, FSH, and LH rose (P<0.01). The pathological morphology of testicular tissue and the inner mitochondrial ultra-microstructure were ameliorated, the level of mitochondrial membrane potential was elevated (P<0.01); the positive rate of apoptosis cell was reduced (P<0.01). The mRNA and protein expression of Bax, Cyt C, Apaf-1, Caspase-9 and Caspase-3 was dropped (P<0.01, P<0.05), the mRNA and protein expression of Bcl-2 elevated (P<0.05), and the average absorbance value of Cleaved Caspase-3 declined (P<0.01). CONCLUSION "Zhibian" (BL54)-toward- "Shuidao" (ST28) acupuncture may ameliorate mouse reproductive function by inhibiting mitochondrial apoptosis pathway, alleviating testicular tissue damage in the asthenospermia mice induced by cyclophosphamide.
Animals ; Male ; Mice ; Apoptosis ; Acupuncture Therapy ; Mitochondria/metabolism* ; Asthenozoospermia/genetics* ; Humans ; Testis/metabolism* ; Mice, Inbred C57BL ; Spermatozoa/metabolism* ; Acupuncture Points ; Sperm Motility ; Testosterone/blood* ; Proto-Oncogene Proteins c-bcl-2/genetics* ; Caspase 3/genetics* ; Follicle Stimulating Hormone/blood* ; Reproduction ; Cytochromes c/genetics* ; bcl-2-Associated X Protein/genetics* ; Apoptotic Protease-Activating Factor 1/genetics*

OBJECTIVE: To observe the effect of "Zhibian" (BL54)-toward-"Shuidao" (ST28) needling technique on the relative protein expression of the signaling pathway of nucleotide-binding oligomerization domain-containing protein 1 (NOD1)/ receptor-interacting protein 2 (RIP2)/nuclear factor kappa-B (NF-κB) and the expression of proinflammatory cytokines in the rats with primary dysmenorrhea (PD), so as to explore the underlying mechanism of this acupuncture technique for pain alleviation in PD. METHODS: Thirty female SD rats of SPF grade with normal estrous cycle were randomized into a blank group, a model group and an acupuncture group, 10 rats in each one. Using the intraperitoneal injection with estradiol benzoate combined with oxytocin, PD model was prepared in the model group and the acupuncture group. In the acupuncture group, during model preparation, the intervention with "Zhibian" (BL54)-toward-"Shuidao" (ST28) needling technique was delivered simultaneously, 20 min each time, once daily for consecutive 10 days. On day 11, within 30 min after the intraperitoneal injection with oxytocin, the writhing reaction (latency, frequency and score) was recorded; the morphology of uterine tissue was observed with HE staining, the contents of prostaglandin E₂ (PGE₂), prostaglandin F_2α (PGF_2α), interleukin (IL)-1β, IL-18, cyclooxygenase-2 (COX-2), and tumor necrosis factor-α(TNF-α) in the serum were detected using ELISA method; the relative protein expression of NOD1, RIP2, NF-κB p65, phosphorylation-NF-κB p65 (p-NF-κB p65) was detected in the uterine tissue using Western blot method; and the mRNA expression of NOD1, RIP2 and NF-κB p65 was detected with the quantitative real-time PCR employed. RESULTS: Compared with the blank group, in the model group, the writhing latency was prolonged (P<0.01), the writhing frequency and score increased (P<0.01) in the rats; the endometrial epithelial cells showed massive degeneration and necrosis, with severe endometrial edema and widespread shedding, combined with neutrophil infiltration; the serum PGE₂ content was dropped (P<0.01), while those of PGF_2α, IL-1β, IL-18, COX-2, and TNF-α elevated (P<0.01); the protein expression of NOD1, RIP2, NF-κB p65 and p-NF-κB p65, and the mRNA expression of NOD1, RIP2 and NF-κB p65 in uterine tissue increased (P<0.01). In comparison with the model group, in the acupuncture group, the writhing latency was prolonged (P<0.01), the writhing frequency and score were reduced (P<0.01) in the rats; there was less degeneration and necrosis of endometrial epithelial cells, with mild endometrial edema and very little neutrophil infiltration; the serum PGE₂ content increased (P<0.01), while those of PGF_2α, IL-1β, IL-18, COX-2, and TNF-α decreased (P<0.01); the protein expression of NOD1, RIP2, NF-κB p65 and p-NF-κB p65 and the mRNA expression of NOD1, RIP2 and NF-κB p65 in uterine tissue were dropped (P<0.05, P<0.01). CONCLUSION "Zhibian" (BL54)-toward-"Shuidao" (ST28) needling technique can alleviate the pain symptom of PD rats, and its action mechanism may be related to inhibiting the active expression of NOD1/RIP2/NF-κB signaling pathway in the uterine tissue, thereby reducing the inflammatory response.
Animals ; Female ; Rats, Sprague-Dawley ; Rats ; Signal Transduction ; Dysmenorrhea/metabolism* ; NF-kappa B/metabolism* ; Acupuncture Points ; Humans ; Acupuncture Analgesia ; Nod1 Signaling Adaptor Protein/metabolism* ; Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism* ; Acupuncture Therapy

Inflammatory bowel disease(IBD)is a chronic inflammatory bowel disease with a complex etiology,mainly including two types:ulcerative colitis(UC)and Crohn's disease(CD),whose risk factors for its development are still incompletely understood.In recent years,Mendelian randomization(MR)has gained increasing attention in IBD research.MR mainly uses genetic variation as an instrumental variable to infer causality between exposure and outcome,effectively avoiding confounding and reverse causality in observational studies and randomised controlled trials.This review summarises currently published MR studies related to IBD,focusing on causal relationships between different risk factors and IBD development.Current findings support a causal relation-ship between IBD and selected oral diseases,skin diseases,psychiatric disorders,autoimmune diseases,bone diseases,gut diseases,gut microbiota,cytokines and nutrients,but not between IBD and lifestyle,cardiovascular diseases and neurodegenerative diseases.Despite its limitations,MR studies are of great significance in improving understanding of etiology of IBD and in identifying potential therapeutic interventions.

Objective To propose a classification model based on a pseudo-bag strategy and feature adjustment for whole slide imaging in pathology.Methods A pseudo-bag generator was constructed to divide a parent bag into 3 pseudo-bags for increasing the number of training bags.Then,a pseudo-bag learning method based on Nystr?m-based algorithm for approximating self-attention and a selective feature fusion method were employed to process the pseudo-bags.Specifically,the pseudo-bag learning method based on Nystr?m-based algorithm for approximating self-attention reduced computational complexity through an improved multi-head self-attention mechanism while deeply extracting instance features to obtain pseudo-bag classification predictions,thereby enhancing pseudo-bag classification accuracy;and the selective feature fusion method refined pseudo-bag features by filtering and extracting relevant instances.Finally,the model adjusted bag features by extracting confounding factors to avoid interference from irrelevant information and further improve classification accuracy.Results The proposed model was evaluated on two datasets(CAMELYON-16 and TCGA-NSCLC)and compared with 10 other methods,and the results demonstrated that the proposed model achieved the best performance.The proposed method reached an accuracy of 0.943 on the CAMELYON-16 dataset and 0.906 on the TCGA-NSCLC dataset.Conclusion The proposed model can significantly improve the accuracy of whole-slide pathological image classification by effectively mitigating the overfitting and avoiding interference from irrelevant information.

Objective To propose a classification model based on a pseudo-bag strategy and feature adjustment for whole slide imaging in pathology.Methods A pseudo-bag generator was constructed to divide a parent bag into 3 pseudo-bags for increasing the number of training bags.Then,a pseudo-bag learning method based on Nystr?m-based algorithm for approximating self-attention and a selective feature fusion method were employed to process the pseudo-bags.Specifically,the pseudo-bag learning method based on Nystr?m-based algorithm for approximating self-attention reduced computational complexity through an improved multi-head self-attention mechanism while deeply extracting instance features to obtain pseudo-bag classification predictions,thereby enhancing pseudo-bag classification accuracy;and the selective feature fusion method refined pseudo-bag features by filtering and extracting relevant instances.Finally,the model adjusted bag features by extracting confounding factors to avoid interference from irrelevant information and further improve classification accuracy.Results The proposed model was evaluated on two datasets(CAMELYON-16 and TCGA-NSCLC)and compared with 10 other methods,and the results demonstrated that the proposed model achieved the best performance.The proposed method reached an accuracy of 0.943 on the CAMELYON-16 dataset and 0.906 on the TCGA-NSCLC dataset.Conclusion The proposed model can significantly improve the accuracy of whole-slide pathological image classification by effectively mitigating the overfitting and avoiding interference from irrelevant information.

Inflammatory bowel disease(IBD)is a chronic inflammatory bowel disease with a complex etiology,mainly including two types:ulcerative colitis(UC)and Crohn's disease(CD),whose risk factors for its development are still incompletely understood.In recent years,Mendelian randomization(MR)has gained increasing attention in IBD research.MR mainly uses genetic variation as an instrumental variable to infer causality between exposure and outcome,effectively avoiding confounding and reverse causality in observational studies and randomised controlled trials.This review summarises currently published MR studies related to IBD,focusing on causal relationships between different risk factors and IBD development.Current findings support a causal relation-ship between IBD and selected oral diseases,skin diseases,psychiatric disorders,autoimmune diseases,bone diseases,gut diseases,gut microbiota,cytokines and nutrients,but not between IBD and lifestyle,cardiovascular diseases and neurodegenerative diseases.Despite its limitations,MR studies are of great significance in improving understanding of etiology of IBD and in identifying potential therapeutic interventions.

[Purpose]To analyze irinotecan-related adverse events(AEs)signals,to provide references for clinically safe prescribing practices.[Methods]A retrospective pharmacovigilance analysis was con-ducted using Food and Drug Administration Adverse Event Reporting System(FAERS)database from the first quarter of 2004 to the last quarter of 2024.After duplicate removal,four disproportionality analysis methods were applied:reporting odds ratio(ROR),proportional reporting ratio(PRR),Bayesian confi-dence propagation neural network(BCPNN),and empirical Bayes geometric mean(EBGM),and subgroups were analyzed by age(≥65 years old vs＜65 years old)and outcome(death vs non-death).[Results]A total of 8 456 irinotecan-related reports comprising 27 177 AEs were identified.The most frequently reported AEs included diarrhea,nausea,neutropenia,vomiting,and fatigue.Additionally,several unexpected and significant AEs signals were detected,such as cell-mediated cytotoxicity,pyomyositis,neuropathic muscular atrophy,administration site recall reaction and ischemic neuropathy.Subgroup analysis indicated that elderly patients showed higher reported frequencies of diarrhea,neutropenia and leukopenia,while younger patients had more frequent reports of nausea,vomiting and peripheral neuropathy.The median time to AEs onset was 31 d,with 49.8％occurring within the first month of treatment.[Conclusion]The AEs related to irinotecan should be paid attention to.When using irinotecan for the treatment of digestive system cancer,symptoms such as diarrhea,nausea and neutropenia should be closely monitored to reduce the risk of drug use.