Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective To investigate the effect of β-arrestin1(ARRB1)on cell proliferation,migration and invasion in oral squamous cell carcinoma(OSCC).Methods Based on The Cancer Genome Atlas(TCGA)database,the expression profiles of ARRB1 in OSCC were analyzed,and then Gene Set Enrichment Analysis(GSEA)was used to suggest the possible signaling pathways involved,and to explore its potential impact on the prognosis of OSCC patients.Immuinohistochemistry(IHC)was performed to detect the expression of ARRB1 in OSCC tumor tissues and adjacent tissues,and the correlation between ARRB1 expression and clinicopathological features was statistically analyzed.The expression profiles of ARRB1 in SCC-15,CAL-27 and HOK cell lines were verified by qPCR and Western blotting.The ARRB1 overexpression plasmid model was constructed,and its effects on the proliferation,migration and invasion of OSCC cells were analyzed by clone formation,EdU,scratch and Transwell assays.Results TCGA showed that the expression level of ARRB1 was significantly lower in head and neck squamous cell carcinoma(HNSC)and OSCC tissues than the corresponding normal tissues(P<0.01).The expression of ARRB1 in OSCC tissues was correlated with tumor differentiation,lymph node metastasis and TNM stage(P<0.05).The OSCC patients with high expression of ARRB1 had a lower survival rate than those with low expression(P<0.01),which was consistent with the results of bioinformatics analysis.The expression level of ARRB1 in SCC-15 and CAL-27 cells was lower than that of HOK cells(P<0.01),and its overexpression significantly inhibited cell proliferation(P<0.05),migration(P<0.01)and invasion(P<0.01).Conclusion ARRB1 is lowly expressed in OSCC,its overexpression inhibits the proliferation,migration and invasion of OSCC cells,and it is related to prognosis improvement.

Endoscopy ; Health Services Needs and Demand

BACKGROUND:MicroRNA(miRNA)levels are closely related to cell apoptosis and proliferation,extracellular matrix metabolism and inflammatory response in intervertebral disc cells.However,the specific role of miR-142-3p in lumbar intervertebral disc degeneration remains unclear. OBJECTIVE:To investigate the correlation between the expression of miRNA-142-3p,mixed lineage kinase 3 and interleukin-1β in nucleus pulposus tissue and degree of human lumbar intervertebral disc degeneration. METHODS:A total of 82 patients with lumbar intervertebral disc degenerative diseases in Suzhou Ninth People's Hospital from January 2020 to March 2022 were collected as the study subjects,all of whom underwent MRI examination before operation.According to the Videman classification,the patients were divided into mild degeneration group(n=36),moderate degeneration group(n=26)and severe degeneration group(n=20).Eighty-two specimens of the nucleus pulposus were obtained.The mRNA expression of miRNA-142-3p as well as the mRNA and protein expression of mixed lineage kinase 3,interleukin-1β,type I collagen,type II collagen in nucleus pulposus tissue were detected by qPCR and western blot assay.The correlation between the degree of human lumbar intervertebral disc degeneration and the expression levels of miRNA-142-3p,mixed lineage kinase 3,and interleukin-1β was also assessed using the Spearman correlation coefficient method.Thirty adult Sprague-Dawley rats were divided into sham-operated group(executed after puncturing skin and muscle only),mild degeneration group(executed 1 week after puncturing Co7/8 segments)and severe degeneration group(executed 2 weeks after puncturing Co7/8 segments),with 10 rats in each group.After that,we detected the protein expression of mixed lineage kinase 3 and interleukin-1β as well as the gene expression of miRNA-142-3p,mixed lineage kinase 3 and interleukin-1β in the nucleus pulposus tissue. RESULTS AND CONCLUSION:In human nucleus pulposus tissue,the miRNA-142-3p expression ranked from high to low as follows:mild degeneration group>moderate degeneration group>severe degeneration group(P<0.05);the gene and protein expression of mixed lineage kinase 3 and interleukin-1β from low to high was as follows:mild degeneration groupmoderate degeneration group>severe degeneration group(P<0.05).Spearman correlation analysis showed that the degree of disc degeneration was negatively correlated with miRNA-142-3p expression(P<0.05)and positively correlated with mixed lineage kinase 3 and interleukin-1β expression(P<0.05).In rat nucleus pulposus tissue,compared with the sham-operated group,the expression of mixed lineage kinase 3 and interleukin-1β gene and protein was elevated in the mild degeneration group(P<0.05)while miRNA-142-3p expression was decreased(P<0.05);compared with the mild degeneration group,the expression of mixed lineage kinase 3 and interleukin-1β gene and protein was increased in the severe degeneration group(P<0.05)while miRNA-142-3p expression was decreased(P<0.05).To conclude,the degree of human lumbar intervertebral disc degeneration is negatively correlated with miRNA-142-3p expression and positively correlated with mixed lineage kinase 3 and interleukin-1β expression in nucleus pulposus tissue.

Purpose: This study examined the diagnostic value of high-frequency ultrasound (HFUS) features in differentiating between benign and malignant skin lesions. Methods: A total of 1,392 patients with 1,422 skin lesions who underwent HFUS examinations were included in an initial dataset (cohort 1) to identify features indicative of malignancy. Qualitative clinical and HFUS characteristics were recorded for all lesions. To determine which HFUS and clinical features were suggestive of malignancy, univariable and multivariable logistic regression analyses were employed. The diagnostic performance of HFUS features combined with clinical information was evaluated. This assessment was validated using internal data (cohort 2) and multicenter external data (cohort 3). Results: Features significantly associated with malignancy included age above 60 years; lesion location in the head, face, and neck or genital regions; changes in macroscopic appearance; crawling or irregular growth pattern; convex or irregular base; punctate hyperechogenicity; blood flow signals; and feeding arteries. The area under the receiver operating characteristic curve, sensitivity, and specificity of HFUS features combined with clinical information were 0.946, 92.5%, and 86.9% in cohort 1; 0.870, 93.1%, and 80.8% in cohort 2 (610 lesions); and 0.864, 86.2%, and 86.6% in cohort 3 (170 lesions), respectively. However, HFUS is not suitable for evaluating lesions less than 0.1 mm in thickness or lesions exhibiting surface hyperkeratosis. Conclusion In a clinical setting, the integration of HFUS with clinical information exhibited good diagnostic performance in differentiating malignant and benign skin lesions. However, its utility was limited in evaluating extremely thin lesions and those exhibiting hyperkeratosis.

Purpose: This study examined the diagnostic value of high-frequency ultrasound (HFUS) features in differentiating between benign and malignant skin lesions. Methods: A total of 1,392 patients with 1,422 skin lesions who underwent HFUS examinations were included in an initial dataset (cohort 1) to identify features indicative of malignancy. Qualitative clinical and HFUS characteristics were recorded for all lesions. To determine which HFUS and clinical features were suggestive of malignancy, univariable and multivariable logistic regression analyses were employed. The diagnostic performance of HFUS features combined with clinical information was evaluated. This assessment was validated using internal data (cohort 2) and multicenter external data (cohort 3). Results: Features significantly associated with malignancy included age above 60 years; lesion location in the head, face, and neck or genital regions; changes in macroscopic appearance; crawling or irregular growth pattern; convex or irregular base; punctate hyperechogenicity; blood flow signals; and feeding arteries. The area under the receiver operating characteristic curve, sensitivity, and specificity of HFUS features combined with clinical information were 0.946, 92.5%, and 86.9% in cohort 1; 0.870, 93.1%, and 80.8% in cohort 2 (610 lesions); and 0.864, 86.2%, and 86.6% in cohort 3 (170 lesions), respectively. However, HFUS is not suitable for evaluating lesions less than 0.1 mm in thickness or lesions exhibiting surface hyperkeratosis. Conclusion In a clinical setting, the integration of HFUS with clinical information exhibited good diagnostic performance in differentiating malignant and benign skin lesions. However, its utility was limited in evaluating extremely thin lesions and those exhibiting hyperkeratosis.

Purpose: This study examined the diagnostic value of high-frequency ultrasound (HFUS) features in differentiating between benign and malignant skin lesions. Methods: A total of 1,392 patients with 1,422 skin lesions who underwent HFUS examinations were included in an initial dataset (cohort 1) to identify features indicative of malignancy. Qualitative clinical and HFUS characteristics were recorded for all lesions. To determine which HFUS and clinical features were suggestive of malignancy, univariable and multivariable logistic regression analyses were employed. The diagnostic performance of HFUS features combined with clinical information was evaluated. This assessment was validated using internal data (cohort 2) and multicenter external data (cohort 3). Results: Features significantly associated with malignancy included age above 60 years; lesion location in the head, face, and neck or genital regions; changes in macroscopic appearance; crawling or irregular growth pattern; convex or irregular base; punctate hyperechogenicity; blood flow signals; and feeding arteries. The area under the receiver operating characteristic curve, sensitivity, and specificity of HFUS features combined with clinical information were 0.946, 92.5%, and 86.9% in cohort 1; 0.870, 93.1%, and 80.8% in cohort 2 (610 lesions); and 0.864, 86.2%, and 86.6% in cohort 3 (170 lesions), respectively. However, HFUS is not suitable for evaluating lesions less than 0.1 mm in thickness or lesions exhibiting surface hyperkeratosis. Conclusion In a clinical setting, the integration of HFUS with clinical information exhibited good diagnostic performance in differentiating malignant and benign skin lesions. However, its utility was limited in evaluating extremely thin lesions and those exhibiting hyperkeratosis.

Purpose: This study examined the diagnostic value of high-frequency ultrasound (HFUS) features in differentiating between benign and malignant skin lesions. Methods: A total of 1,392 patients with 1,422 skin lesions who underwent HFUS examinations were included in an initial dataset (cohort 1) to identify features indicative of malignancy. Qualitative clinical and HFUS characteristics were recorded for all lesions. To determine which HFUS and clinical features were suggestive of malignancy, univariable and multivariable logistic regression analyses were employed. The diagnostic performance of HFUS features combined with clinical information was evaluated. This assessment was validated using internal data (cohort 2) and multicenter external data (cohort 3). Results: Features significantly associated with malignancy included age above 60 years; lesion location in the head, face, and neck or genital regions; changes in macroscopic appearance; crawling or irregular growth pattern; convex or irregular base; punctate hyperechogenicity; blood flow signals; and feeding arteries. The area under the receiver operating characteristic curve, sensitivity, and specificity of HFUS features combined with clinical information were 0.946, 92.5%, and 86.9% in cohort 1; 0.870, 93.1%, and 80.8% in cohort 2 (610 lesions); and 0.864, 86.2%, and 86.6% in cohort 3 (170 lesions), respectively. However, HFUS is not suitable for evaluating lesions less than 0.1 mm in thickness or lesions exhibiting surface hyperkeratosis. Conclusion In a clinical setting, the integration of HFUS with clinical information exhibited good diagnostic performance in differentiating malignant and benign skin lesions. However, its utility was limited in evaluating extremely thin lesions and those exhibiting hyperkeratosis.

Purpose: This study examined the diagnostic value of high-frequency ultrasound (HFUS) features in differentiating between benign and malignant skin lesions. Methods: A total of 1,392 patients with 1,422 skin lesions who underwent HFUS examinations were included in an initial dataset (cohort 1) to identify features indicative of malignancy. Qualitative clinical and HFUS characteristics were recorded for all lesions. To determine which HFUS and clinical features were suggestive of malignancy, univariable and multivariable logistic regression analyses were employed. The diagnostic performance of HFUS features combined with clinical information was evaluated. This assessment was validated using internal data (cohort 2) and multicenter external data (cohort 3). Results: Features significantly associated with malignancy included age above 60 years; lesion location in the head, face, and neck or genital regions; changes in macroscopic appearance; crawling or irregular growth pattern; convex or irregular base; punctate hyperechogenicity; blood flow signals; and feeding arteries. The area under the receiver operating characteristic curve, sensitivity, and specificity of HFUS features combined with clinical information were 0.946, 92.5%, and 86.9% in cohort 1; 0.870, 93.1%, and 80.8% in cohort 2 (610 lesions); and 0.864, 86.2%, and 86.6% in cohort 3 (170 lesions), respectively. However, HFUS is not suitable for evaluating lesions less than 0.1 mm in thickness or lesions exhibiting surface hyperkeratosis. Conclusion In a clinical setting, the integration of HFUS with clinical information exhibited good diagnostic performance in differentiating malignant and benign skin lesions. However, its utility was limited in evaluating extremely thin lesions and those exhibiting hyperkeratosis.

Objective: To investigate the role and mechanism of S100 calcium binding protein B (S100B) in osteoarthritis (OA) cartilage damage repair. Methods: Twenty New Zealand rabbits were randomly divided into control group and model group, with 10 rabbits in each group. Rabbits in the model group were injured by the right knee joint immobilization method to make the artilage injury model, while the control group did not deal with any injury. After 4 weeks, the levels of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) in synovial fluid were detected by ELISA method; the mRNA and protein expressions of S100B, fibroblast growth factor 2 (FGF-2), and FGF receptor 1 (FGFR1) in cartilage tissue were examined by real-time fluorescence quantitative PCR (qRT-PCR) and Western blot assay. Human synovial fibroblasts (SF) were isolated and cultured in vitro. The effects of S100B overexpression and knockdown on the levels of IL-1β and TNF-α (ELISA method) and the expressions of FGF-2 and FGFR1 gene (qRT-PCR) and protein (Western blot) were observed. Moreover, the effects of FGFR1 knockdown in above S100 overexpression system on the levels of IL-1β and TNF-α (ELISA method) and the expressions of FGF-2 and FGFR1 gene (qRT-PCR) and protein (Western blot) were observed. Results: ELISA detection showed that the expressions of IL-1β and TNF-α in the synovial fluid of the model group were significantly higher than those of the control group ( P<0.05); qRT-PCR and Western blot detection showed that the mRNA and protein expressions of S100B, FGF-2, and FGFR1 in cartilage tissue were significantly higher than those of the control group ( P<0.05). Overexpression and knockdown S100 could respectively significantly increase and decrease lipopolysaccharides (LPS) induced IL-1β and TNF-α levels elevation and the mRNA and protein expressions of FGF-2 and FGFR1 ( P<0.05); whereas FGFR1 knockdown could significantly decrease LPS induced IL-1β and TNF-α levels elevation and the mRNA and protein expressions of FGF-2 and FGFR1 ( P<0.05). Conclusion: S100B protein can regulate the inflammatory response of SF and may affect the repair of cartilage damage in OA, and the mechanism may be related to the activation of FGF-2/FGFR1 signaling pathway.