Objective : To explore the role of semaphoring 6d(SEMA6D) in the malignant progression of triple-negative breast cancer(TNBC). Methods : Bioinformatics and Immunohistochemistry(IHC) were used to analyze the expression level of SEMA6D in TNBC and paracancer non-tumor tissues and its relationship with patients′ clinicopathological features. MDA-MB-231 cell line stably knocking down the expression of SEMA6D was constructed, and the effects of SEMA6D on migration and invasion of TNBC cells were investigated by Wound-healing assays and Transwell assays. cBioPortal and GEPIA2 databases were used to screen out the gene negatively associated with it, namely aurora kinase A(AURKA). Bioinformatics and IHC were used to analyze the expression level of AURKA in TNBC and paracancer non-tumor tissues and its relationship with patients' clinicopathological features. Western blot assay was used to analyze the expression of AURKA and the effect of epithelial-mesenchymal transition(EMT) makers Claudin-1, N-cadherin and Vimentin after knocking downSEMA6D. Results: Bioinformatics analysis and IHC results showed that the expression of SEMA6D in TNBC tissues was significantly lower than that in paracancer non-tumor tissues(bothP<0.05). The expression of AURKA in TNBC tissues was significantly higher than that in paracancer non-tumor tissues(bothP<0.05), SEMA6D and AURKA were significantly negatively correlated in TNBC(P<0.01). Both low expression of SEMA6D and high expression of AURKA were positively correlated with tumor size, tumor histological grade, clinical stage and lymph node metastasis in TNBC patients(allP<0.05). The knockdown ofSEMA6Dsignificantly promoted the migration and invasion ability of TNBC cells(bothP<0.01). Western blot results showed that the knockdown ofSEMA6Dupregulated AURKA expression, promoted the expression of N-cadherin and Vimentin, and inhibited the expression of Claudin-1 in tumor cells. Conclusion Down-regulation of SEMA6D expression in TNBC may be involved in the malignant progression of TNBC through up-regulation of AURKA expression and promotion of EMT.

The catalytic activity of 3-mercaptopyruvate (3MP) sulfurtransferase (MPST) converts 3MP to hydrogen sulfide (H₂S). However, the regulatory mechanisms governing MPST and its impact on the brain remain largely unexplored. Our study reveals the neuroprotective role of endothelial MPST-generated H₂S, regulated by protein phosphatase 2A (PP2A). Bioinformatics analysis and RNA sequencing demonstrated that endothelial PP2A is associated with neurodegenerative disease pathways. Cerebral ischemic mice exhibited significant inactivation of endothelial PP2A, evidenced by the reduction of PP2Acα in the brain endothelium. Mice with endothelium-specific null PP2A (PP2A^EC-cKO) exhibited neuronal loss, cognitive dysfunction, and long-term potentiation deficits. Postnatal inactivation of endothelial PP2A also contributes to cognitive dysfunction and neuronal loss. However, regaining endothelial PP2A activity by overexpressing Ppp2ca rescued neuronal dysfunction. Mechanistically, PP2A deficiency is intricately linked to the MPST-H₂S signaling pathway. A robust reduction in endothelial MPST-dependent H₂S production followed PP2A deficiency. Exogenous H₂S treatment and AAV-mediated overexpression of MPST in brain endothelial cells significantly mitigated neuronal dysfunction in PP2A^EC-cKO mice. Furthermore, PP2A deficiency promotes an increase in calcium influx and calpain2 phosphorylation, subsequently leading to MPST degradation. The PP2A activator (FTY720) and MPST activator (3MP sodium) both remarkably restored endothelial MPST-dependent H₂S production, subsequently rescuing ischemia-induced neurological deficits. In conclusion, our study demonstrates that endothelial PP2A deficiency leads to MPST degradation by activating calpain2, thus damaging neuronal function.

Crigler-Najjar syndrome (CNS) and Gilbert syndrome (GS; OMIM: 143500) are rare autosomal recessive diseases that cause unconjugated hyperbilirubinemia due to decreased UGT1A1 enzyme activity. Crigler-Najjar syndrome type 2 (CNS2; OMIM: 606785) increases the risk of gallbladder stone formation and cholecystitis, while GS seldom causes health issues. We found a 28-year-old male patient with recurring right upper abdomen pain who experienced persistent jaundice from birth. CNS2 with gallbladder stones and cholecystitis was diagnosed after genetic testing revealed rare double homozygous mutations A(TA)₇TAA (rs3064744) and P229Q (rs35350960) in the UGT1A1 gene. After pedigree investigation, we found that the patient's parents with modestly increased bilirubin had compound heterozygous mutations A(TA)₇TAA and P229Q, which were GS. Bioinformatics analysis showed that A(TA)₇TAA is in the TATA-box region of the gene UGT1A1 promoter, affecting gene transcriptional initiation, whereas P229Q modifies protein three-dimensional structure and may be harmful. In this pedigree, double homozygous mutations have a more severe phenotype than compound heterozygous mutations. Inherited causes of hyperbilirubinemia should be suspected after ruling out biliary obstruction, and early bilirubin reduction (< 103 µmol/L (6 mg/dL)) may reduce the risk of complications like cholecystitis in CNS2 patients, though further studies with longer follow-up are needed to confirm this observation.
Humans ; Male ; Glucuronosyltransferase/genetics* ; Adult ; Crigler-Najjar Syndrome/complications* ; Cholecystitis/etiology* ; Homozygote ; Mutation ; Pedigree

Lead is one of the most important occupational hazards in China, and occupational exposure is the leading cause of lead poisoning. Lead can be absorbed by the body through air, food, drinking water and skin, and accumulate in multiple organs in the body, posing health risks to humans, especially to lead workers. Many previous studies have shown that lead can affect the function of glial cells such as microglia, astrocytes and oligodendrocytes, resulting in irreversible neurological damage. This article provides an overview of the neurotoxic mechanism induced by lead through glial cells, elucidates that lead can induce neurodegenerative diseases such as Alzheimer′s disease, Parkinson′s disease, and amyotrophic lateral sclerosis, and reviews the relationship between lead and glial cells, in order to provide reference for further research on the neurotoxic mechanism of lead on glial cells.

Lead is one of the most important occupational hazards in China, and occupational exposure is the leading cause of lead poisoning. Lead can be absorbed by the body through air, food, drinking water and skin, and accumulate in multiple organs in the body, posing health risks to humans, especially to lead workers. Many previous studies have shown that lead can affect the function of glial cells such as microglia, astrocytes and oligodendrocytes, resulting in irreversible neurological damage. This article provides an overview of the neurotoxic mechanism induced by lead through glial cells, elucidates that lead can induce neurodegenerative diseases such as Alzheimer′s disease, Parkinson′s disease, and amyotrophic lateral sclerosis, and reviews the relationship between lead and glial cells, in order to provide reference for further research on the neurotoxic mechanism of lead on glial cells.

AIM:To evaluate the efficacy,safety,and economy of camrelizumab(CAM)combined with platinum-containing chemotherapy(CT)for the first-line treatment of locally advanced/meta-static non-small cell lung cancer(NSCLC).METH-ODS:Chinese and English databases such as Pubmed,the Cochrane Library,China Knowledge Network,Wanfang Data,and other related web-sites were systematically searched.After literature screening,quality assessment,and data extraction of the literature according to the inclusion and ex-clusion criteria,two researchers conducted a rapid health technology assessment(HTA).RESULTS:A total of 7 systematic evaluations/Meta-analyses and 17 economics evaluations were included.In terms of effectiveness,compared to docetaxel che-motherapy,CAM+CT significantly prolonged the overall survival(OS),progression-free survival(PFS),and improved the objective remission rate(ORR)of mutation-negative patients with locally ad-vanced/metastatic NSCLC.Compared with CT and pembrolizumab(PEM),CAM+CT significantly pro-longed the PFS,and improved the ORR of mutation-negative patients with locally advanced/metastatic NSCLC.Subgroup analysis showed that CAM+CT significantly prolonged PFS in patients with PD-L1 ≥1％and PD-L1 ≥ 50％compared with CT.Compared with CT,CAM+CT significantly prolonged the OS and PFS of mutation-negative patients with locally advanced/metastatic squamous NSCLC.Compared with sintilimab(SIN),CAM+CT significantly pro-longed the PFS of mutation-negative patients with locally advanced/metastatic squamous NSCLC.Sub-group analysis showed that CAM+CT significantly prolonged OS in patients with PD-L1＜1％com-pared with CT.In terms of safety,CAM+CT was comparable in terms of the occurrence of all grades of adverse events,but the incidence of grade 3 or higher treatment-related adverse events was significantly increased compared with CT and PEM for mutation-negative locally advanced/meta-static NSCLC patients.CAM+CT was significantly in-creased the occurrence of all grades of adverse events compared with CT,but was comparable in terms of the occurrence of grade 3 or higher treat-ment-related adverse events.In terms of economy,CAM+CT has a cost-effectiveness advantage over CT for patients with mutation-negative advanced/metastatic squamous NSCLC.CAM+CT has a cost-effectiveness advantage over CT and PEM+CT;and CAM+CT does not have a cost-effectiveness ad-vantage over SIN+CT for patients with mutation-negative locally advanced/metastatic non-squa-mous NSCLC.CONCLUSION:CAM+CT has good ef-ficacy and cost-effectiveness for the first-line treat-ment of locally advanced/metastatic NSCLC,and the safety aspect is compared with CT,PEM or slightly worse.

AIM:To study the mechanism of Sihei-fang(SHF)in improving pigment deficiency disease(PD)by combining network pharmacology and me-tabolomics.METHODS:Using zebrafish embryos with pigment deficiency disease induced by 1-phe-nyl-2-thiourea(PTU)as an animal model,the ef-fects of SHF extract(0.01,0.02,0.04 mg/mL)on the morphology,melanin area,tyrosinase activity,and melanin content of zebrafish embryos were an-alyzed.Ultra high performance liquid chromatogra-phy-mass spectrometry(UHPLC-MS)was used to screen differential metabolites and obtain relevant metabolic pathways in the SHF treatment of mela-nin deficient zebrafish embryos model.Network pharmacology was used to obtain key targets for SHF treatment of PD and conduct KEGG pathway enrichment analysis.Import The identified differen-tial metabolites and SHF PD intersection targets were imported into the Metscape plugin,to estab-lish a"metabolite reaction enzyme gene"network,and search for key metabolites,targets,and meta-bolic pathways.RESULTS:SHF treatment could in-crease the formation of zebrafish melanin,activate tyrosinase activity,and increase melanin content.Metabolomics analysis obtained 54 differential me-tabolites,and metabolic pathway analysis was con-ducted on these metabolites,involving the biosyn-thesis of phenylalanine,tyrosine,and tryptophan,glycerol phospholipid metabolism,tyrosine metab-olism,linoleic acid metabolism,and aminoacyl tRNA biosynthesis pathways.Network pharmacolo-gy had obtained 55 cross targets of components and diseases.KEGG involved pancreatic cancer,TNF,cancer and other signal pathways.The joint analysis of metabolomics and network pharmacolo-gy identified four key targets:COMT,CYP1B1,TYR,and ALDH2;three key metabolites:L-tyrosine,ho-movanllate,L-lysine;three important metabolic pathways:tyrosine metabolism,valine/leucine/iso-leucine degradation,and lysine metabolism.CON-CLUSION:SHF has a good improvement effect on PD,and combined with metabolomics and network pharmacology,SHF may enhance its influence on the tyrosine metabolism pathway by regulating the metabolite L-tyrosine,thereby promoting the for-mation of melanin.

Objective:To systematically evaluate the recurrence risk prediction model of diabetic foot ulcers (DFU) .Methods:Research on DFU recurrence risk prediction models was electronically searched in PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang Data, and China Biomedical Service System. The search period was from database establishment to July 20, 2023. Two researchers independently screened literature and conducted data extraction and quality evaluation using the prediction model research data extraction table and the Prediction Model Risk of Bias Assessment Tool (PROBAST) .Results:A total of 8 articles were included, including 14 models. The area under the receiver operating characteristic (ROC) curve included in the model ranged from 0.660 to 0.940. The most common five predictors in the model were ulcers location, glycosylated hemoglobin, smoking, combined peripheral neuropathy and diabetes course. All 8 articles had a high risk of bias, mainly due to insufficient sample size, improper handling and reporting of missing data, and a lack of internal validation, which might lead to overfitting of the model. Only one article was subjected to external validation.Conclusions:The research on DFU recurrence risk prediction models is still in the development stage, and the predictive performance of various studies is still acceptable, but there is a high risk of bias. Future research still needs to use rigorous statistical analysis methods to construct new risk prediction models and improve internal and external validation.

Purpose To investigate the expression differ-ence of p16 in lung gland precursor lesions and lung adenocarci-noma and its correlation with HPV infection.Method The ex-pression of p16 in the tissues of 30 cases of pulmonary atypical adenomatous hyperplasia(AAH),40 cases of adenocarcinoma in situ(AIS),33 cases of microinvasive adenocarcinoma(MIA),and 45 cases of invasive adenocarcinoma(IAC)mainly of the acinar type was detected by immunohistochemical(IHC)method,and the relationship between p16 expression and the clinicopathological characteristics of the patients was analyzed.The PCR was used to detect HPV infection in IAC,and the cor-relation between p16 expression and HPV infection was ana-lyzed.Results The results of IHC showed that the expression of p16 protein was positively correlated with the precursors of lung glands and the histological grade of lung adenocarcinoma(P＜0.05).Compared with non-infiltrating components,the expression of p16 protein in MIA and IAC infiltrating compo-nents was significantly increased(P＜0.05).The PCR results showed that the positive detection rate of HPV DNA in the high expression group of p16 was significantly higher than that in the low expression group of IAC(P＜0.05).Conclusion The ex-pression of p16 protein is significantly correlated with the malig-nant progression of lung adenocarcinoma,which may be an ideal molecular marker to accurately identify the infiltrating compo-nents of lung adenocarcinoma.High expression of p16 in IAC may suggest HPV infection.

Purpose To investigate the expression differ-ence of p16 in lung gland precursor lesions and lung adenocarci-noma and its correlation with HPV infection.Method The ex-pression of p16 in the tissues of 30 cases of pulmonary atypical adenomatous hyperplasia(AAH),40 cases of adenocarcinoma in situ(AIS),33 cases of microinvasive adenocarcinoma(MIA),and 45 cases of invasive adenocarcinoma(IAC)mainly of the acinar type was detected by immunohistochemical(IHC)method,and the relationship between p16 expression and the clinicopathological characteristics of the patients was analyzed.The PCR was used to detect HPV infection in IAC,and the cor-relation between p16 expression and HPV infection was ana-lyzed.Results The results of IHC showed that the expression of p16 protein was positively correlated with the precursors of lung glands and the histological grade of lung adenocarcinoma(P＜0.05).Compared with non-infiltrating components,the expression of p16 protein in MIA and IAC infiltrating compo-nents was significantly increased(P＜0.05).The PCR results showed that the positive detection rate of HPV DNA in the high expression group of p16 was significantly higher than that in the low expression group of IAC(P＜0.05).Conclusion The ex-pression of p16 protein is significantly correlated with the malig-nant progression of lung adenocarcinoma,which may be an ideal molecular marker to accurately identify the infiltrating compo-nents of lung adenocarcinoma.High expression of p16 in IAC may suggest HPV infection.