Triple-negative breast cancer (TNBC) is aggressive, with high recurrence rates and poor prognosis. Paclitaxel (PTX) remains a key chemotherapeutic agent for TNBC, but its efficacy diminishes due to the emergence of drug resistance, largely driven by cancer stem-like cells (CSCs), vasculogenic mimicry (VM) formation and tumor immunosuppressive microenvironment (TIME). Pyruvate kinase M2 (PKM2) is highly expressed in TNBC, and is a potential target for TNBC treatment. In this study, we developed a biomimetic codelivery system using albumin nanoparticles (termed S/P NP) to co-encapsulate PTX and shikonin (SHK), a natural inhibitor of PKM2. By inhibiting PKM2, SHK suppressed β-Catenin signaling, thereby reversing CSC stemness and preventing VM formation. The S/P NP system exhibited tumor-targeting delivery effect and significantly inhibited TNBC growth and lung metastasis. Mechanistically, the treatment reversed epithelial-mesenchymal transition (EMT) and stem-like properties of TNBC cells, suppressed VM formation, and remodeled the TIME. It reduced immunosuppressive cells (M2 macrophages, MDSCs) while promoting anti-tumor immunity (M1 macrophages, dendritic cells, cytotoxic T cells, and memory T cells). This dual-action strategy holds promise for improving TNBC therapy by targeting CSCs, VM, and the immune microenvironment, and for overcoming PTX resistance and reducing metastasis.

Objective:To investigate the role of ubiquitin-specific protease 21 (USP21) in enterovirus group A type 71 (EV-A71) infection.Methods:Peripheral blood mononuclear cells (PBMC) were obtained from a cohort of 24 children infected with EV-A71 and 24 healthy children. Expression of USP21 was determined by real-time fluorescence quantitative PCR (qPCR). Additionally, the impact of USP21 overexpression or knockout on EV-A71 replication was evaluated using a combination of qPCR and western blot (WB) analysis. Furthermore, WB was employed to measure the levels of EV-A71 structural protein VP1, phosphorylated interferon regulatory factor 3 (IRF3) and other key molecules in the RIG-I-like receptor (RLR) signaling pathway. Co-immunoprecipitation (Co-IP) was utilized to investigate the effects of USP21 on the ubiquitin levels of EV-A71 nonstructural protein 2A protease (2A pro). Results:In comparison to healthy children, the expression of USP21 mRNA in PBMC of children infected with EV-A71 was notably elevated. The overexpression of USP21 significantly enhanced the cytopathic effects induced by EV-A71, upregulated levels of VP1 mRNA and protein, and facilitated EV-A71 replication, leading to a decrease in cell activity with increasing levels of USP21 transfection. Following the knockout of the USP21 gene, the VP1 mRNA levels were significantly declined in comparison to the control group. Furthermore, the overexpression of USP21 was found to have no impact on the transcriptional activity of EV-A71 2A pro. However, it was observed to enhance the expression of 2A pro protein, reduce the ubiquitination of 2A pro, suppress the protein levels of mitochondrial antiviral signaling protein (MAVS) and melanoma differentiation-associated gene 5 (MDA5), as well as decrease the phosphorylation of IRF3. Additionally, the induction of IFN-β mRNA by EV-A71 infection was downregulated. Conclusions:USP21 has been shown to enhance the replication of EV-A71 through the downregulation of 2A pro ubiquitination, suppression of MAVS and MDA5 protein expression, and inhibition of the interferon signaling pathway.

Objective To explore the characteristics of acupoint selection and the law of acupoint compatibility in the treatment of Guillain-Barré syndrome(GBS)based on data mining.Methods Literature on acupuncture treatment of GBS was searched and screened from China National Knowledge Infrastructure,Wanfang Data Knowledge Service Platform,VIP,SioMed,PubMed,Embase,Web of Science,and Cochrane Library from the establishment of the database to December 1,2024 and to build database.The author information and acupuncture prescriptions were modified and imported according to the data entry requirements of the Traditional Chinese medicine inheritance computing platform V3.5,the relevant data were analyzed and integrated through the"Acupoint Analysis"module of the platform.Results A total of 140 related papers,145 valid prescriptions,involving 237 acupoints.The acupoints with higher frequency were Zusanli,Hegu,Quchi,Yanglingquan and etc.The analysis yielded 42 core acupoints,22 sets of strong association rules for core acupoints,and 5 new core acupuncture prescriptions.Conclusion Acupuncture treatment for GBS follows the principle of"treating impotence by taking Yangming alone",takes"benefiting Qi and draining heat,supporting the correctness and opening up the collaterals"as the main method,and attaches importance to"regulating the spirit and connecting the internal organs".

OBJECTIVE: To investigate the clinical characteristics and genetic etiology of a Chinese pedigree affected with Hereditary dentin dysplasia type II (DD-II) due to variant of dentin sialophosphoprotein (DSPP) gene. METHODS: A child diagnosed with DD- II at the Third Clinical Division of Peking University Hospital of Stomatology in December 2021 and her family members were selected as study subjects. Clinical data were retrospectively analyzed. Saliva samples were collected from the proband, her parents and sister for genomic DNA extraction. Whole exome sequencing (WES) was carried out. Candidate variant was verified by Sanger sequencing and TOPO-TA cloning sequencing. The candidate variant was also subjected to bioinformatics analysis using Mutation Taster v2021. Secondary and tertiary structures of the wild-type and variant DSPP proteins were predicted with psipred v4.0 and PyMOL v2.3 software, respectively. The pathogenicity of the variant was classified based on the guidelines from American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Peking University Hospital of Stomatology (Ethics No.: PKUSSIRB-202162021). RESULTS: The proband and her mother and sister had all exhibited typical clinical manifestations of hereditary DD-II. The primary dentition of the proband displayed yellowish brown discoloration, wear, and obliteration in the chamber and root canal, while the permanent teeth of the proband's sister and mother appeared nearly normal in both color and appearance, though with obliteration in the chamber and root canal. Her father showed normal dentition. WES identified a heterozygous c.1915_1918delAAGT, p.(Lys639Glnfs*674) frameshift variant in the DSPP gene. Sanger sequencing and TOPO-TA cloning sequencing confirmed the presence of this variant in the proband, the proband's sister, and the mother, while the proband's father was negative for the variant, indicating an autosomal dominant inheritance pattern. The variant was predicted to be pathogenic by Mutation Taster v2021. Prediction of the secondary structure of the DSPP protein showed that the variant has changed it from coil to helix. The tertiary structure prediction of the DSPP protein showed change of the spatial structure of the variant DSPP, with the loops in the variant region replaced by helices at multiple sites. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+PM2_Supporting+PP1+PP4). CONCLUSION Phenotypic analysis and genetic testing of this family has clarified the clinical diagnosis of hereditary DD- II. The c.1915_1918delAAGT variant probably underlay the pathogenesis of DD-II in this family. Above results have expanded the phenotypic spectrum of the disease and may contribute to further clinical and genetic research on this disease.
Humans ; Pedigree ; Female ; Extracellular Matrix Proteins/chemistry* ; Male ; Sialoglycoproteins/chemistry* ; Dentin Dysplasia/genetics* ; Asian People/genetics* ; Phosphoproteins/chemistry* ; Child ; Mutation ; China ; Exome Sequencing ; Adult ; East Asian People

Per- and polyfluoroalkyl substances (PFAS) are a class of persistent organic pollutants widely present in the environment. They can enter the human body through multiple pathways such as air, water, and diet, and tend to bioaccumulate. In recent years, increasing attention has been paid to the potential impacts of PFAS exposure on male reproductive health. This review systematically summarizes the characteristics of PFAS exposure in men and its effects on semen quality. Epidemiological evidence indicates that PFAS exposure is significantly associated with reduced sperm concentration, motility, and normal morphologyrate. Mechanistic studies suggest that PFAS may induce male reproductive toxicity through various pathways, including germ cell cytotoxicity, dysfunction of Sertoli cells, endocrine disruption, oxidative stress, and epigenetic regulation. This review aims to integrate current evidence to support the assessment of male reproductive risks associated with PFAS exposure and to inform the development of preventive strategies.

Objective Advances in synthetic DNA technology have made it much easier to fake human DNA samples.There are literature reports that fake human DNA can be synthesized by different methods and implanted in the field to confuse the investigation or mislead the trial.Therefore,distinguishing authentic human DNA from synthetic DNA and performing individual identification has become a critical scientific challenge.Methods We define a novel composite genetic marker(methylation-microhaplotype)by combining CpG sites stably hypermethylated or hypomethylated in natural human DNA and nearby immediately adjacent microhaplotype sites.A total of 19 locis were obtained according to the screening criteria,and a composite detection system for methylation-microhaplotypes was established using MPS technology.Random volunteer DNA samples were extracted and synthetic DNA samples were prepared based on whole genome amplification techniques.Population DNA samples were analyzed to evaluate forensic parameters and methylation variability of the methylation-microhaplotype markers.Comparative analyses of human and synthetic DNA were conducted to assess the markers'ability to discriminate between the two and to detect/type both components in mixed mixed samples.Results The composite detection system composed of 19 locis demonstrated high individual identification ability,achieving a cumulative individual identification probability of 0.999 999 999 996 86.12 hypermethylated locis and 7 hypomethylated locis had relatively stable methylation levels in 57 human DNA samples.According to the allele methylation rate(Ram)value,the system can effectively identify natural and synthetic DNA samples.Meanwhile,for mixed DNA samples,the presence of human and synthetic DNA samples can be found and genotyped.Conclusion Methylation-microhaplotype genetic markers,which can discover human DNA and synthetic DNA and can detect the presence and genotyping of them from mixed samples,is a potential useful tool for forensic DNA analysis.

Objective To investigate the relationship between vitamin D receptor(VDR)gene TaqI rs731236 and BsmI rs1544410 polymorphisms and benign paroxysmal positional vertigo(BPPV),the relationship and clinical significance of BPPV.Methods A total of 263 patients with confirmed BPPV admitted to Dongguan People's Hospital from January 2021 to October 2023 were retrospectively selected,and another 100 healthy subjects in the same period were selected as controls.Single nucleotide polymorphisms(SNPs)at the locus of TaqI rs731236 and BsmI rs1544410 gene locus of the were detected by fluorescence quantitative PCR.Single nucleotide polymorphisms(SNP)at TaqI rs731236 and BsmI rs1544410 were detected by fluorescence quantitative PCR.The genetic balance of TaqI and BsmI genes was tested by Hardy-Weinberg balance.Genotype and allele distribution were compared between the two groups.The correlation between TaqI and BsmI genotype and clinical features of BPPV was analyzed.The risk factors of BPPV were analyzed by Logistic regression.Results Compared with the clinical data of the two groups,the levels of diabetes(22.05%),hypertension(28.90%),blood uric acid(345.38±36.69μmol/L),cholesterol(4.98±0.68mmol/L)and low density lipoprotein(3.48±0.67mmol/L)in BPPV group were significantly higher than those in control group(11.00%,15.00%,328.76±32.24μmol/L,4.36±0.57mmol/L,3.07±0.62mmol/L),and the serum 25(OH)D level(62.78±8.69nmol/L)was significantly lower than that in control group(97.65±9.54nmol/L),and the differences were statistically significant(t/χ2=3.982～33.233,all P<0.05).Hardy-Weinberg test showed that the genotype distribution of the SNP locus of TaqI and BsmI genes conforms s to the law of genetic equilibrium and is representative of the population(χ2=1.406～2.851,all P>0.05).The frequencies of AG genotype(53.99%)and A allele(57.41%)at TaqI rs731236 in BPPV group were significantly higher than those in control group(44.00%,48.00%),while the frequencies of GG genotype(15.59%)at TaqI rs731236 in BPPV group were significantly lower than those in control group(30.00%),the frequencies of CC genotype(32.32%)and C allele(54.56%)at BsmI rs1544410 locus in BPPV group were significantly higher than those in control group(18.00%,38.00%),while the frequencies of TT genotype(23.19%)and T allele(45.44%)at BsmI rs1544410 locus were significantly lower than those in control group(42.00%,62.00%),and the differences were statistically significant(χ2=9.589,5.185;14.603,15.900,all P<0.05).BPPV patients carrying AG and AA genotypes at TaqI rs731236 and CT and CC genotypes at BsmI rs1544410 had higher blood uric acid and cholesterol levels and lower serum 25(OH)D levels,and the differences were statistically significant(t=4.256～12.742,all P<0.05).The AG genotype and A allele at TaqI rs731236,CC genotype and C allele at BsmI rs1544410 were one of the independent risk factors for BPPV(Wald χ2=8.651,7.269;5.010,6.793,all P<0.05).Conclusion Carrier of AG genotype and A allele at TaqⅠ rs731236 and CC genotype and C allele at BsmI rs1544410 are closely associated with blood uric acid,cholesterol and serum 25(OH)D levels,and insrease the risk of BPPV.The polymorphism of VDR gene is an independent risk factor for BPPV.

Per- and polyfluoroalkyl substances (PFAS) are a class of persistent organic pollutants widely present in the environment. They can enter the human body through multiple pathways such as air, water, and diet, and tend to bioaccumulate. In recent years, increasing attention has been paid to the potential impacts of PFAS exposure on male reproductive health. This review systematically summarizes the characteristics of PFAS exposure in men and its effects on semen quality. Epidemiological evidence indicates that PFAS exposure is significantly associated with reduced sperm concentration, motility, and normal morphologyrate. Mechanistic studies suggest that PFAS may induce male reproductive toxicity through various pathways, including germ cell cytotoxicity, dysfunction of Sertoli cells, endocrine disruption, oxidative stress, and epigenetic regulation. This review aims to integrate current evidence to support the assessment of male reproductive risks associated with PFAS exposure and to inform the development of preventive strategies.

Objective To explore the characteristics of acupoint selection and the law of acupoint compatibility in the treatment of Guillain-Barré syndrome(GBS)based on data mining.Methods Literature on acupuncture treatment of GBS was searched and screened from China National Knowledge Infrastructure,Wanfang Data Knowledge Service Platform,VIP,SioMed,PubMed,Embase,Web of Science,and Cochrane Library from the establishment of the database to December 1,2024 and to build database.The author information and acupuncture prescriptions were modified and imported according to the data entry requirements of the Traditional Chinese medicine inheritance computing platform V3.5,the relevant data were analyzed and integrated through the"Acupoint Analysis"module of the platform.Results A total of 140 related papers,145 valid prescriptions,involving 237 acupoints.The acupoints with higher frequency were Zusanli,Hegu,Quchi,Yanglingquan and etc.The analysis yielded 42 core acupoints,22 sets of strong association rules for core acupoints,and 5 new core acupuncture prescriptions.Conclusion Acupuncture treatment for GBS follows the principle of"treating impotence by taking Yangming alone",takes"benefiting Qi and draining heat,supporting the correctness and opening up the collaterals"as the main method,and attaches importance to"regulating the spirit and connecting the internal organs".

Objective To investigate the relationship between vitamin D receptor(VDR)gene TaqI rs731236 and BsmI rs1544410 polymorphisms and benign paroxysmal positional vertigo(BPPV),the relationship and clinical significance of BPPV.Methods A total of 263 patients with confirmed BPPV admitted to Dongguan People's Hospital from January 2021 to October 2023 were retrospectively selected,and another 100 healthy subjects in the same period were selected as controls.Single nucleotide polymorphisms(SNPs)at the locus of TaqI rs731236 and BsmI rs1544410 gene locus of the were detected by fluorescence quantitative PCR.Single nucleotide polymorphisms(SNP)at TaqI rs731236 and BsmI rs1544410 were detected by fluorescence quantitative PCR.The genetic balance of TaqI and BsmI genes was tested by Hardy-Weinberg balance.Genotype and allele distribution were compared between the two groups.The correlation between TaqI and BsmI genotype and clinical features of BPPV was analyzed.The risk factors of BPPV were analyzed by Logistic regression.Results Compared with the clinical data of the two groups,the levels of diabetes(22.05%),hypertension(28.90%),blood uric acid(345.38±36.69μmol/L),cholesterol(4.98±0.68mmol/L)and low density lipoprotein(3.48±0.67mmol/L)in BPPV group were significantly higher than those in control group(11.00%,15.00%,328.76±32.24μmol/L,4.36±0.57mmol/L,3.07±0.62mmol/L),and the serum 25(OH)D level(62.78±8.69nmol/L)was significantly lower than that in control group(97.65±9.54nmol/L),and the differences were statistically significant(t/χ2=3.982～33.233,all P<0.05).Hardy-Weinberg test showed that the genotype distribution of the SNP locus of TaqI and BsmI genes conforms s to the law of genetic equilibrium and is representative of the population(χ2=1.406～2.851,all P>0.05).The frequencies of AG genotype(53.99%)and A allele(57.41%)at TaqI rs731236 in BPPV group were significantly higher than those in control group(44.00%,48.00%),while the frequencies of GG genotype(15.59%)at TaqI rs731236 in BPPV group were significantly lower than those in control group(30.00%),the frequencies of CC genotype(32.32%)and C allele(54.56%)at BsmI rs1544410 locus in BPPV group were significantly higher than those in control group(18.00%,38.00%),while the frequencies of TT genotype(23.19%)and T allele(45.44%)at BsmI rs1544410 locus were significantly lower than those in control group(42.00%,62.00%),and the differences were statistically significant(χ2=9.589,5.185;14.603,15.900,all P<0.05).BPPV patients carrying AG and AA genotypes at TaqI rs731236 and CT and CC genotypes at BsmI rs1544410 had higher blood uric acid and cholesterol levels and lower serum 25(OH)D levels,and the differences were statistically significant(t=4.256～12.742,all P<0.05).The AG genotype and A allele at TaqI rs731236,CC genotype and C allele at BsmI rs1544410 were one of the independent risk factors for BPPV(Wald χ2=8.651,7.269;5.010,6.793,all P<0.05).Conclusion Carrier of AG genotype and A allele at TaqⅠ rs731236 and CC genotype and C allele at BsmI rs1544410 are closely associated with blood uric acid,cholesterol and serum 25(OH)D levels,and insrease the risk of BPPV.The polymorphism of VDR gene is an independent risk factor for BPPV.