Objective:To investigate the anti-tumor effect of the Histone Deacetylase 6 (HDAC6) inhibitor ACY-738 and its underlying mechanisms in Diffuse Large B-cell Lymphoma (DLBCL) .Methods:The expression of HDAC6 in various tumors and DLBCL was analyzed using bioinformatics. DLBCL cells were treated with different concentrations of ACY-738. Cell viability, DNA synthesis, and clone formation were assessed by CCK-8 assay, EdU assay, and soft agar assay, respectively. Intracellular reactive oxygen species (ROS) levels were detected by fluorescence microscopy. Morphological changes in cells were observed using transmission electron microscopy (TEM). Mitochondrial ROS levels and apoptosis were measured by flow cytometry. The expression levels of apoptosis-related and autophagy-related proteins were detected by Western blotting.Results:HDAC6 was highly expressed in DLBCL ( P<0.05). ACY-738 inhibited the proliferation, DNA synthesis, and colony formation of DLBCL cells in a dose-dependent manner ( P<0.05). Treatment with ACY-738 increased intracellular and mitochondrial ROS levels in DLBCL cells in a dose-dependent manner ( P<0.05). TEM revealed that after ACY-738 treatment, mitochondria in cells were swollen and ruptured, mitochondrial cristae were reduced or absent, autolysosomes appeared, and features characteristic of apoptosis were observed. Western blotting showed that after ACY-738 treatment, the expression of the anti-apoptotic protein BCL-2 was downregulated, while the expression of Cleaved-PARP, Cleaved caspase-3, and BAX was upregulated ( P<0.05). The expression of autophagy-related proteins Atg7, Atg3, LC3B, and P62 was downregulated, and the expression of acetylated P53 protein was upregulated ( P<0.05) . Conclusion:The HDAC6 inhibitor ACY-738 induces mitochondria-dependent apoptosis and autophagy in DLBCL cells by acetylating P53, thereby inhibiting DLBCL cell proliferation.

Objective To analyze the relationship between apolipoprotein E(APOE)genotype and cognitive impairment among individuals aged 40 and above in rural Xi'an and to explore the potential influence of education on this relationship.Methods All permanent residents aged 40 and above from two villages in Huyi District,Xi'an City,were selected as research subjects,employing a cross-sectional survey approach.The Mini-Mental State Examination(MMSE)was utilized to assess overall cognitive function,with MMSE scores below the threshold values(illiterate ≤17,primary school ≤20,junior high and above ≤24)considered as cognitive impairment.Fasting elbow venous blood was drawn in the morning,and the APOE genotype was determined.The population was divided into low-education(LE,≤9 years)and high-education(HE,＞9 years)groups based on educational level.Univariate and multivariate analyses were applied to explore the association between APOE genotype and cognitive impairment,as well as MMSE scores in both the total and stratified populations.Results Out of the 1 692 participants,there were 263 APOE ε4 allele carriers(E2/4,E3/4,E4/4)(15.3％),and 205 individuals met the criteria for cognitive impairment(12.1％).Multivariate Logistic regression and linear regression analyses revealed that in both the total population and the LE population,compared to APOE ε4 allele non-carriers(E2/2,E2/3,E3/3),APOE ε4 allele carriers exhibited a higher risk of cognitive impairments(total population:OR=1.509,95％CI:1.030-2.211,P=0.035;LE:OR=1.604,95％CI:1.080-2.381,P=0.019),and their MMSE scores were lower(total population:β=-0.053,95％CI:-0.983--0.162,P=0.006;LE:β=-0.052,95％CI:-1.052--0.124,P=0.013).However,in the HE population,there was no statistically significant difference in the prevalence of cognitive impairment(OR=1.883,95％CI:0.254-13.980,P=0.536)and MMSE scores(β=0.001,95％CI:-0.635-0.642,P=0.992)between APOE ε4 allele carriers and non-carriers.Conclusion The APOE ε4 allele was associated with an increased risk of cognitive impairment in individuals aged 40 and above in rural areas of Xi'an,while HE attainment may offer protective effects against cognitive impairment in APOE ε4 allele carriers.

Objective To investigate the effect of drug-eluting bead DACE(DEB-TACE)combined with systemic treatment for hepatocellular carcinoma(HCC)in different locations.Methods A total of 204 HCC patients who underwent DEB-TACE combined with systemic therapy(targeted and immunotherapy)were retrospectively collected.According to the anatomical location of HCC,86 cases with lesions located at the main trunk of portal vein(PV)or within 1 cm of the first PV branch were classified into central type group,while 118 cases with lesions located at the other areas were classified as peripheral type group.Follow-up was regularly performed after DEB-TACE until August,2024.The objective response rate(ORR)and disease control rate(DCR)at 1,3,6 and 12 months after DEB-TACE,also patients'progression-free survival(PFS)and overall survival(OS)were compared between groups.Results All patients were followed up for a median of 32.6 months,during which 164 cases died.Significant differences of ORR at 1 and 3 months after DEB-TACE(77.91％[67/86]vs.89.83％[106/118],34.88％[30/86]vs.54.24％[64/118])and DCR at 3 and 6 months after DEB-TACE(51.16％[44/86]vs.66.95％[79/118],34.88％[30/86]vs.50.00％[59/118])were found between groups(all P＜0.05).Patients'PFS(30.18[9.12,48.54]months)and OS(37.36[17.79,56.68])in peripheral type group were better than those in central type group(20.11[11.35,28.87]months and 23.24[3.11,43.47]months,x2=3.971,4.162,P=0.048,0.041).Conclusion The effect of DEB-TACE combined with systemic treatment for peripheral type HCC was better than for central type HCC.

Objective To investigate the effect of drug-eluting bead DACE(DEB-TACE)combined with systemic treatment for hepatocellular carcinoma(HCC)in different locations.Methods A total of 204 HCC patients who underwent DEB-TACE combined with systemic therapy(targeted and immunotherapy)were retrospectively collected.According to the anatomical location of HCC,86 cases with lesions located at the main trunk of portal vein(PV)or within 1 cm of the first PV branch were classified into central type group,while 118 cases with lesions located at the other areas were classified as peripheral type group.Follow-up was regularly performed after DEB-TACE until August,2024.The objective response rate(ORR)and disease control rate(DCR)at 1,3,6 and 12 months after DEB-TACE,also patients'progression-free survival(PFS)and overall survival(OS)were compared between groups.Results All patients were followed up for a median of 32.6 months,during which 164 cases died.Significant differences of ORR at 1 and 3 months after DEB-TACE(77.91％[67/86]vs.89.83％[106/118],34.88％[30/86]vs.54.24％[64/118])and DCR at 3 and 6 months after DEB-TACE(51.16％[44/86]vs.66.95％[79/118],34.88％[30/86]vs.50.00％[59/118])were found between groups(all P＜0.05).Patients'PFS(30.18[9.12,48.54]months)and OS(37.36[17.79,56.68])in peripheral type group were better than those in central type group(20.11[11.35,28.87]months and 23.24[3.11,43.47]months,x2=3.971,4.162,P=0.048,0.041).Conclusion The effect of DEB-TACE combined with systemic treatment for peripheral type HCC was better than for central type HCC.

Objective To analyze the relationship between apolipoprotein E(APOE)genotype and cognitive impairment among individuals aged 40 and above in rural Xi'an and to explore the potential influence of education on this relationship.Methods All permanent residents aged 40 and above from two villages in Huyi District,Xi'an City,were selected as research subjects,employing a cross-sectional survey approach.The Mini-Mental State Examination(MMSE)was utilized to assess overall cognitive function,with MMSE scores below the threshold values(illiterate ≤17,primary school ≤20,junior high and above ≤24)considered as cognitive impairment.Fasting elbow venous blood was drawn in the morning,and the APOE genotype was determined.The population was divided into low-education(LE,≤9 years)and high-education(HE,＞9 years)groups based on educational level.Univariate and multivariate analyses were applied to explore the association between APOE genotype and cognitive impairment,as well as MMSE scores in both the total and stratified populations.Results Out of the 1 692 participants,there were 263 APOE ε4 allele carriers(E2/4,E3/4,E4/4)(15.3％),and 205 individuals met the criteria for cognitive impairment(12.1％).Multivariate Logistic regression and linear regression analyses revealed that in both the total population and the LE population,compared to APOE ε4 allele non-carriers(E2/2,E2/3,E3/3),APOE ε4 allele carriers exhibited a higher risk of cognitive impairments(total population:OR=1.509,95％CI:1.030-2.211,P=0.035;LE:OR=1.604,95％CI:1.080-2.381,P=0.019),and their MMSE scores were lower(total population:β=-0.053,95％CI:-0.983--0.162,P=0.006;LE:β=-0.052,95％CI:-1.052--0.124,P=0.013).However,in the HE population,there was no statistically significant difference in the prevalence of cognitive impairment(OR=1.883,95％CI:0.254-13.980,P=0.536)and MMSE scores(β=0.001,95％CI:-0.635-0.642,P=0.992)between APOE ε4 allele carriers and non-carriers.Conclusion The APOE ε4 allele was associated with an increased risk of cognitive impairment in individuals aged 40 and above in rural areas of Xi'an,while HE attainment may offer protective effects against cognitive impairment in APOE ε4 allele carriers.

Objective:To investigate the anti-tumor effect of the Histone Deacetylase 6 (HDAC6) inhibitor ACY-738 and its underlying mechanisms in Diffuse Large B-cell Lymphoma (DLBCL) .Methods:The expression of HDAC6 in various tumors and DLBCL was analyzed using bioinformatics. DLBCL cells were treated with different concentrations of ACY-738. Cell viability, DNA synthesis, and clone formation were assessed by CCK-8 assay, EdU assay, and soft agar assay, respectively. Intracellular reactive oxygen species (ROS) levels were detected by fluorescence microscopy. Morphological changes in cells were observed using transmission electron microscopy (TEM). Mitochondrial ROS levels and apoptosis were measured by flow cytometry. The expression levels of apoptosis-related and autophagy-related proteins were detected by Western blotting.Results:HDAC6 was highly expressed in DLBCL ( P<0.05). ACY-738 inhibited the proliferation, DNA synthesis, and colony formation of DLBCL cells in a dose-dependent manner ( P<0.05). Treatment with ACY-738 increased intracellular and mitochondrial ROS levels in DLBCL cells in a dose-dependent manner ( P<0.05). TEM revealed that after ACY-738 treatment, mitochondria in cells were swollen and ruptured, mitochondrial cristae were reduced or absent, autolysosomes appeared, and features characteristic of apoptosis were observed. Western blotting showed that after ACY-738 treatment, the expression of the anti-apoptotic protein BCL-2 was downregulated, while the expression of Cleaved-PARP, Cleaved caspase-3, and BAX was upregulated ( P<0.05). The expression of autophagy-related proteins Atg7, Atg3, LC3B, and P62 was downregulated, and the expression of acetylated P53 protein was upregulated ( P<0.05) . Conclusion:The HDAC6 inhibitor ACY-738 induces mitochondria-dependent apoptosis and autophagy in DLBCL cells by acetylating P53, thereby inhibiting DLBCL cell proliferation.

Objective To observe the reproducibility of radiomics feature(RF)extracted from virtual monoenergetic image(VMI)of rabbit VX2 hepatoma models obtained with 3 different dual-energy CT(DECT)systems,and to explore relationship of reproducibility and diagnostic performance of RF.Methods Fifteen rabbits with VX2 hepatoma were randomly divided into 3 groups(each n=5).Contrast-enhanced abdominal CT scanning under volume CT dose index(CTDIvol)levels of 6,9 and 12 mGy were performed with dual-source DECT(dsDECT),rapid kV switching DECT(rsDECT)and dual-layer detector DECT(dlDECT),respectively.VMI were reconstructed at 10 keV increments from 40 to 140 keV.RF were extracted from VMI,the reproducibility was assessed using intra-class correlation coefficient(ICC),and those with ICC≥0.8 were considered as reproducible RF.The percentage of reproducible features(denoted by R)were compared among different scanner pairings and different CTDIvol levels.Within each CTDIvol group,the reconstruction energy levels yielding the maximum number(denoted by N)of common RF across different scanner pairings were identified.The receiver operating characteristic(ROC)curve was drawn,the area under the curve(AUC)was calculated,and the diagnostic efficacies of reproducible RF and other RF were compared under optimal reproducible conditions.Spearman correlation coefficient between ICC and the corresponding AUC of RF were calculated.Results RrsDECT-dsDECT(6.45％,95％CI[2.36％,8.87％])was higher than RdlDECT-dsDECT(0.72％,95％CI[0.15％,1.79％])and RrsDECT-dlDECT(1.43％,95％CI[0.60％,4.06％])(all adjusted P＜0.05),R9mGy(3.70％,95％CI[1.31％,5.73％])and R12mGy(2.63％,95％CI[0.60％,6.69％])were higher than R6mGy(1.31％,95％CI[0.12％,1.55％])(all adjusted P＜0.05).The optimal reproducible reconstruction energy levels of RF under CTDIvol of 6,9 and 12 mGy concentrated at 50-70 keV.AUC of reproducible RFs were higher than of other RF(all adjusted P＜0.05)and had certain correlation with the reproducibility(rs=0.102-0.516,P＜0.05).Conclusion The reproducibility of RF extracted from contrast-enhanced VMI CT images of rabbit VX2 hepatoma models associated with DECT scanner,CTDIvol level and reconstruction energy level.RF with higher reproducibility might have better diagnostic performance.

Objective To investigate the value of CT radiomics combined with CT and preoperative pathological features for predicting postoperative early recurrence(ER)of local advanced esophageal squamous cell carcinoma(LAESCC).Methods Data of 334 patients with LAESCC were retrospectively analyzed.The patients were divided into training set(n=234)and verification set(n=100)at the ratio of 7:3 and were followed up to observe ER(recurrence within 12 months after surgery)or not.Univariate and multivariate logistic regression were used to analyze clinical,CT and preoperative pathological features of LAESCC in patients with or without ER in training set.The independent risk factors of ER were screened,and a CT-preoperative pathology model was constructed.Based on venous phase CT in training set,the radiomics features of lesions were extracted and screened to establish radiomics model,and finally a combined model was established based on radiomics model and the independent risk factors.Receiver operating characteristic(ROC)curves were drawn,and the area under the curve(AUC)was calculated to evaluate the diagnostic efficacy of each model.Results Among 334 cases,168 were found with but 166 without ER.In training set,117 cases were found with while the rest 117 without ER,while in verification set,51 were found with but 49 without ER.The length of lesions,cT stage and cN stage shown on CT and tumor differentiation degree displayed with preoperative pathology were all independent risk factors for ER of LAESCC(all P＜0.05).The AUC of CT-preoperative pathology model in training set and validation set was 0.759 and 0.783,respectively.Ten best radiomics features of LAESCC were selected,and AUC of the established radiomics model in training set and validation set was 0.770 and 0.730,respectively.The AUC of combined model in training and validation set was 0.838 and 0.826,respectively.The AUC of CT radiomics combined with CT and preoperative pathological features in training set was higher than that of CT-preoperative pathologymodel and radiomics model(both P＜0.01).Conclusion CT radiomics combined with CT and preoperative pathological features could effectively predict postoperative ER of LAESCC.

Objective:To establish and validate a clinical and CT radiomics combined model for predicting lymph node metastasis (LNM) risk in patients with hilar cholangiocarcinoma (HCCA).Methods:This was a case-control study. Data from 158 pathologically confirmed HCCA patients between January 2016 and January 2022 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. Using stratified random sampling, the patients were randomly divided into a training set ( n=95) and an internal validation set ( n=63) at a 6∶4 ratio. According to postoperative pathology, 31 LNM-positive cases and 64 LNM-negative cases were in the training set, and 22 LNM-positive cases and 41 LNM-negative cases were in the internal validation set. A cohort of 50 HCCA patients was retrospectively collected from West China Hospital of Sichuan University between October 2018 and June 2021 as an external validation set, including 21 LNM-positive and 29 LNM-negative cases. Clinical features were selected by multivariate logistic regression analysis to establish a clinical model. Radiomics features were extracted from portal venous phase CT images using 3D Slicer software. A radiomics model was developed using the least absolute shrinkage and selection operator regression algorithm. A clinical-radiomics model was constructed by integrating clinical features and Radscore, and a nomogram was developed. The prediction performance of models was evaluated by the area under the receiver operating characteristic curve (AUC). The AUC values were compared using the DeLong test. Calibration curves and decision curves were plotted to assess calibration and clinical net benefit. Results:Clinical N (cN) staging was an independent risk factor for LNM ( OR=6.86, 95% CI 2.70-18.49, P<0.001). Totally 12 optimal features were selected to construct the radiomics model, and the clinical-radiomics nomogram model was constructed by combining cN staging and Radscore. In the external validation set, the AUC (95% CI) of the clinical model, radiomics model, and clinical-radiomics nomogram were 0.706 (0.576-0.836), 0.768 (0.637-0.899), and 0.803 (0.680-0.926), respectively. The nomogram achieved higher AUC than clinical and radiomics models with statistical significance ( Z=2.01, 2.21; P=0.044, 0.027). The calibration and decision curves demonstrated good model fit, providing clinical net benefits for patients. Conclusion:The clinical-radiomics nomogram model combining cN staging and CT radiomics features can effectively predict LNM risk in HCCA patients.

Objective To preliminarily investigate the anti-tumor effects of phytosphingosine(PHS)and the involvement of inducing apoptosis of leukemia cells.Methods Cellular model of leukemia was established in leukemia cell lines K562 and SUP-B15.CCK-8 assay and EdU assay were used to measure the viability and DNA synthesis of K562 and SUP-B15 cells.RNA-seq was carried out to verify the differentially expressed genes(DEGs)after PHS treatment.Gene Ontology(GO)enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were applied to analyze the involved functions and signaling pathways.Comparative Toxicogenomics Database(CTD)and Discovery Studio software were employed to predict the underlying targets of PHS and molecular docking.Cell apoptosis was detected by flow cytometry,mitochondrial membrane potential was evaluated by JC-1 probe,and protein expression of key molecules was validated by Western blotting.Results PHS inhibited the proliferation of K562 and SUP-B15 cells in a time-and dose-dependent manner.The half-maximal inhibitory concentration(IC50)of K562 cells was 17.67 and 12.52 pmol/L for 24 and 48 h,respectively,and the IC50 value of SUP-B15 cells was 17.58 and 14.86 μmol/L for 24 and 48 h,respectively.PHS treatment at a dose of 20 μmol/L for 48 h resulted in significant inhibition of DNA synthesis.GO enrichment analysis of the K562 cells showed that PHS might be involved in positive regulation of apoptotic process,plasma membrane and its integral components,and protein kinase binding and activity.Reverse predictive analysis showed that BCL-2 protein was the most likely target of PHS.PHS significantly increased the apoptotic rate of leukemia cells(P＜0.05)in a dose-dependent manner,reduced the mitochondrial membrane potential,and down-regulated BCL-2 level(P＜0.05)and up-regulated the levels of Cleaved caspase-3 and Cleaved caspase-9(P＜0.05).Conclusion PHS may inhibit the proliferation of leukemia cells by inducing mitochondria-dependent apoptosis,possibly through PHS and BCL-2 interaction.