LiCl-induced immunomodulatory periodontal regeneration via the activation of the Wnt/ß-catenin signaling pathway.

BACKGROUND: Growing evidence suggests that excessive inflammation hampers the regenerative capacity of periodontal ligament cells (PDLCs) and that activation of the Wnt/ß-catenin pathway is crucial in suppressing immune dysregulation. OBJECTIVE: This study aimed to establish the role of the Wnt/ß-catenin in regulating the immune microenvironment and its subsequent impact on periodontal regeneration. METHODS: Lithium chloride (LiCl, Wnt activator) was administered daily into the standard periodontal defects created in 12-week-old Lewis rats. Harvested at 1-week and 2-week post-surgery, samples were then subjected to histological and immunohistochemical evaluation of macrophage distribution and phenotype (pro-inflammatory M1 and anti-inflammatory M2). A murine macrophage cell line, RAW 264.7, was stimulated with LiCl to activate Wnt/ß-catenin. Following treatment with the conditioned medium derived from the LiCl-activated macrophages, the expression of bone- and cementum-related markers of the PDLCs was determined. The involvement of Wnt/ß-catenin in the immunoregulation and autophagic activity was further investigated with the addition of cardamonin, a commercially available Wnt inhibitor. RESULTS: A significantly increased number of macrophages were detected around the defects during early healing upon receiving the Wnt/ß-catenin signaling cue. The defect sites in week 2 exhibited fewer M1 and more M2 macrophages along with an enhanced regeneration of alveolar bone and cementum in the Wnt/ß-catenin activation group. LiCl-induced immunomodulatory effect was accompanied with the activation Wnt/ß-catenin signaling, which was suppressed in the presence of Wnt inhibitor. Exposure to LiCl could induce autophagy in a dose-dependent manner, thus maintaining macrophages in a regulatory state. The expression level of bone- and cementum-related markers was significantly elevated in PDLCs stimulated with LiCl-activated macrophages. CONCLUSION: The application of Wnt activator LiCl facilitates the recruitment of macrophages to defect sites and regulates their phenotypic switching in favor of periodontal regeneration. Suppression of Wnt/ß-catenin pathway could attenuate the LiCl-induced immunomodulatory effect. Taken together, the Wnt/ß-catenin pathway may be targeted for therapeutic interventions in periodontal diseases.

Down-regulation of KIAA1199/CEMIP by miR-216a suppresses tumor invasion and metastasis in colorectal cancer.

Colorectal cancer is one of the major causes of death from cancer. Metastasis is the leading cause of treatment failure, in which cancer stem cells and circulating tumor cells play crucial roles. Identifying the involved metastatic biomarkers and clarifying the regulation mechanisms are of great importance for targeting tumor metastasis. In the current research, we discovered that KIAA1199, a cell-migration inducing protein, showed higher expression in CD44+ cancer cells from metastatic compared with the paired primary tissues, and was upregulated in colorectal cancer and positively correlated with numbers and mesenchymal phenotype of circulating tumor cells, and predicted shorter progress-free survival. Moreover, we indicated that down-regulation of KIAA1199 suppressed migration and invasion of colorectal cancer cells in vitro, and inhibited metastasis in vivo. Furthermore, we demonstrated that KIAA1199 was one of the direct and functional targets of miR-216a, and miR-216a overexpression led to decreased migration and invasion of colorectal cancer cells in vitro, and inhibited metastasis in vivo. Collectively, KIAA1199 plays a critical role in maintaining an aggressive phenotype of tumor cells, and suppression of KIAA1199-related motilities of tumor cells contributes to reduced tumor metastasis in colorectal cancer.

Circulating tumor microemboli (CTM) and vimentin+ circulating tumor cells (CTCs) detected by a size-based platform predict worse prognosis in advanced colorectal cancer patients during chemotherapy.

BACKGROUND: Circulating tumor cells (CTCs) detected in peripheral blood (PB) of cancer patients can be identified as isolated CTCs and circulating tumor microemboli (CTM). This study aimed to evaluate the prognostic value of CTM detection and CTC phenotype in advanced colorectal cancer (CRC) patients during chemotherapy. METHODS: A size-based platform for CTC isolation was applied. PB samples (5 ml) from 98 advanced CRC patients during 2-6 cycles chemotherapy were collected for CTC detection, and CTC count was correlated to patient's clinicopathological characteristics and clinical outcome. And CTC phenotype was measured by immunofluorescent staining and evaluate the predictive significance on survival in 32 CTCs-positive patients with advanced CRC. RESULTS: Forty-eight of 98 patients were CTCs-positive, including 18 CTM-positive patients, and CTC detection was positively correlated with lymphatic invasion (P = 0.049), TNM stage (P = 0.023), and serum CEA level (P = 0.014). Moreover, Kaplan-Meier survival and Cox regression analyses revealed that the presence of CTCs was an independent factor for poor PFS and OS (P < 0.05) in advanced CRC patients during chemotherapy, and CTM-positive patients had shooter survival than isolated CTCs-positive patients (P < 0.05). Furthermore, patients with vimentin+ isolated CTCs/CTM had shorter PFS and OS compared with CK+ CTCs (P < 0.05). CONCLUSIONS: This study provided evidence that the presence of CTCs was positively correlated with poor prognosis, and furthermore, CTM and vimentin+ CTCs predicted poorer survival, which indicated that CTM and vimentin+ CTCs detected by a sensitive platform could be used to improve prognostic value of CTCs in advanced CRC patients under treatment.

Bifidobacterium animalis subsp. lactis F1-7 Alleviates Lipid Accumulation in Atherosclerotic Mice via Modulating Bile Acid Metabolites to Downregulate Intestinal FXR.

The dysfunction of intestinal microbiota and bile acid metabolism is related to the pathogenesis of atherosclerosis. This study we explored the mechanism of Bifidobacterium animalis subsp. lactis F1-7 (Bif. animalis F1-7), improving atherosclerosis by regulating the bile acid metabolism and intestinal microbiota in the ApoE-/- mice. The Bif. animalis F1-7 effectively reduced aortic plaque accumulation and improved the serum and liver lipid levels in atherosclerotic mice. The untargeted metabolomics revealed that Bif. animalis F1-7 reduced the glycine-conjugated bile acids and the levels of differential metabolite lithocholic acid (LCA) significantly. Downregulation of LCA decreased the intestinal levels of the farnesoid X-activated receptor (FXR) and regulated the bile acid metabolism through the FXR/FGF15/CYP7A1 pathway. Furthermore, the 16srRNA gene sequencing analysis revealed that structural changes in intestinal microbiota with an increase in the abundance of Bifidobacterium, Lactobacillus, Faecalibaculum, Desulfovibrio, and a decrease in Dubosiella, Clostridium_sensu_stricto_1, and Turicibacter following the Bif. animalis F1-7 intervention. Correlation analysis showed that the changes in intestinal microbiota mentioned above were significantly correlated with bile acid metabolism in atherosclerotic mice. In conclusion, this study sheds light on the mechanisms by which Bif. animalis F1-7 regulates atherosclerosis.

Temporal and topological properties of dynamic networks reflect disability in patients with neuromyelitis optica spectrum disorders.

Approximately 36% of patients with neuromyelitis optica spectrum disorders (NMOSD) suffer from severe visual and motor disability (blindness or light perception or unable to walk) with abnormalities of whole-brain functional networks. However, it remains unclear how whole-brain functional networks and their dynamic properties are related to clinical disability in patients with NMOSD. Our study recruited 30 NMOSD patients (37.70 ± 11.99 years) and 45 healthy controls (HC, 41.84 ± 11.23 years). The independent component analysis, sliding-window approach and graph theory analysis were used to explore the static strength, time-varying and topological properties of large-scale functional networks and their associations with disability in NMOSD. Compared to HC, NMOSD patients showed significant alterations in dynamic networks rather than static networks. Specifically, NMOSD patients showed increased occurrence (fractional occupancy; P < 0.001) and more dwell times of the low-connectivity state (P < 0.001) with fewer transitions (P = 0.028) between states than HC, and higher fractional occupancy, increased dwell times of the low-connectivity state and lower transitions were related to more severe disability. Moreover, NMOSD patients exhibited altered small-worldness, decreased degree centrality and reduced clustering coefficients of hub nodes in dynamic networks, related to clinical disability. NMOSD patients exhibited higher occurrence and more dwell time in low-connectivity states, along with fewer transitions between states and decreased topological organizations, revealing the disrupted communication and coordination among brain networks over time. Our findings could provide new perspective to help us better understand the neuropathological mechanism of the clinical disability in NMOSD.

Affect under need satisfaction and need thwarting: A new classification for the prediction of creative performance.

Affect plays a pivotal role in fostering creative performance, and there is increasing recognition that different levels and types of affect may exert distinct impacts on creative performance. Drawing upon self-determination theory, this study aims to explore a novel classification of affect-affect under need satisfaction and need thwarting-and examine its relationship with creative performance. Study 1 involved 75 participants to investigate the content of affect under need satisfaction and need thwarting. Study 2 explores the relationship between affect and creative performance using a sample of 115 employees from Beijing. The findings unveiled nine types of affect under need satisfaction (e.g., moderate levels of excited) and eleven types of affect under need thwarting (e.g., low levels of afraid). Positive associations were observed between affect under need satisfaction and creativity, while negative associations were found between affect under need thwarting and creativity. Empirical evidence corroborating the significant role of the new classification of affect in enhancing employee creativity within the context of Chinese academia and researchers is presented.

Application of periodontal tissue regeneration combined with orthodontics in oral prosthodontics and its influence and significance on the expressions of IL-1ß, TNF-α and IL-5 in periodontal tissue.

The aim is to investigate the application of periodontal tissue regeneration combined with orthodontics in oral restoration, and explore its effect and significance on the expressions of Interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and interleukin-5 (IL-5) in periodontal tissue. The patients in observation group were treated with orthodontics combined with periodontal tissue regeneration, and the control group was treated with periodontal tissue regeneration. The total effective rate, adverse reactions, recurrence rate and treatment satisfaction were compared. The masticatory function, language function, aesthetic level, VAS score, quality of life, gingival index (GI), plaque index (PLI), periodontal pocket probing depth (PD), sulcus bleeding index (SBI), IL-1ß, TNF-α and IL-5 levels were compared. The recurrence rate of observation group was lower than control group, while the treatment satisfaction was higher after treatment. After treatment, the scores of masticatory, language, aesthetics, physiological, social, emotional, cognitive, and emotional functions and overall health score were higher than before treatment. After treatment, the scores of masticatory and language functions, aesthetics and quality of life of observation group were significantly higher than control group. After treatment, the VAS score, GI, PLI, SBI, PD, IL-1ß, TNF-α and IL-5 levels were lower than before. The VAS score, GI, PLI, SBI, PD levels, IL-1ß, TNF-α and IL-5 levels of observation group were lower after treatment. Orthodontics combined with periodontal tissue regeneration can help improve the periodontal condition of patients with periodontitis, reduce inflammatory response, improve the level of efficacy and overall safety, and further improve patients' quality of life and treatment satisfaction.

Curcumin prevents high-fat diet-induced hepatic steatosis in ApoE-/- mice by improving intestinal barrier function and reducing endotoxin and liver TLR4/NF-κB inflammation.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and has become a public health concern worldwide. The hallmark of NAFLD is hepatic steatosis. Therefore, there is an urgent need to develop new therapeutic strategies that are efficacious and have minimal side effects in hepatic steatosis and NAFLD treatment. The present study aimed to investigate the effect of dietary supplement of curcumin on high-fat diet (HFD)-induced hepatic steatosis and the underlying mechanism. METHODS: ApoE-/- mice were fed a normal diet, high-fat diet (HFD) or HFD supplemented with curcumin (0.1% w/w) for 16 weeks. Body and liver weight, blood biochemical.parameters, and liver lipids were measured. Intestinal permeability, hepatic steatosis and mRNA and protein expressions of TLR4-related inflammatory signaling molecule were analyzed. RESULTS: The administration of curcumin significantly prevented HFD-induced body weight gain and reduced liver weight. Curcumin attenuated hepatic steatosis along with improved serum lipid profile. Moreover, curcumin up-regulated the expression of intestinal tight junction protein zonula occluden-1 and occludin, which further improved gut barrier dysfunction and reduced circulating lipopolysaccharide levels. Curcumin also markedly down-regulated the protein expression of hepatic TLR4 and myeloid differentiation factor 88 (MyD88), inhibited p65 nuclear translocation and DNA binding activity of nuclear factor-κB (NF-κB) in the liver. In addition, the mRNA expression of hepatic tumour necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) as well as the plasma levels of TNF-α and IL-1ß were also lowered by curcumin treatment. CONCLUSION: These results indicated that curcumin protects against HFD-induced hepatic steatosis by improving intestinal barrier function and reducing endotoxin and liver TLR4/NF-κB inflammation. The ability of curcumin to inhibit hepatic steatosis portrayed its potential as effective dietry intervention for NAFLD prevention.

Supplementation with curcumin inhibits intestinal cholesterol absorption and prevents atherosclerosis in high-fat diet-fed apolipoprotein E knockout mice.

Atherosclerosis is a major cause of cardiovascular disease caused by high cholesterol. Reduced intestinal cholesterol absorption has been shown to exert strong cholesterol-lowering and antiatherogenic effects. Previously, we reported that curcumin reduced cholesterol absorption in high-fat diet-fed hamster by downregulating the intestinal expression of Niemann-Pick C1-like 1. Here, we tested the hypothesis that supplementation with curcumin can also reduce intestinal cholesterol absorption in high-fat diet-fed apolipoprotein E knockout (ApoE-/-) mice and prevent atherosclerosis development. ApoE-/- mice were fed a high-fat diet supplemented with or without curcumin (0.1% w/w) for 16 weeks. Aortic sinus sections revealed that curcumin supplementation reduced the extent of atherosclerotic lesions by 45%. Curcumin treatment also reduced cholesterol accumulation in the aortas by 56% and lowered plasma total cholesterol and low-density lipoprotein cholesterol levels. Moreover, the antiatherogenic and cholesterol-lowering effects of curcumin coincided with a significant decrease in intestinal cholesterol absorption. It was reduced by nearly 51%, and the decreased cholesterol absorption was modulated by inhibiting the intestinal expression of Niemann-Pick C1-like 1, predominantly in the duodenal and jejunal segments of the small intestine. These findings support the hypothesis that curcumin supplementation reduces intestinal cholesterol absorption and prevents atherosclerosis in high-fat diet-fed ApoE-/- mice. Curcumin affords a potent antiatherogenic action by inhibiting intestinal cholesterol absorption in the mouse.

Curcumin Protects against Atherosclerosis in Apolipoprotein E-Knockout Mice by Inhibiting Toll-like Receptor 4 Expression.

Toll-like receptor 4 (TLR4) has been reported to play a critical role in the pathogenesis of atherosclerosis, the current study aimed to investigate whether curcumin suppresses atherosclerosis development in ApoE-knockout (ApoE-/-) mice by inhibiting TLR4 expression. ApoE-/- mice were fed a high-fat diet supplemented with or without curcumin (0.1% w/w) for 16 weeks. Curcumin supplementation significantly reduced TLR4 expression and macrophage infiltration in atherosclerotic plaques. Curcumin also reduced aortic interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression, nuclear factor-κB (NF-κB) activity, and plasma IL-1ß, TNF-α, soluble VCAM-1 and ICAM-1 levels. In addition, aortic sinus sections revealed that curcumin treatment reduced the extent of atherosclerotic lesions and inhibited atherosclerosis development. In vitro, curcumin inhibited NF-κB activation in macrophages and reduced TLR4 expression induced by lipopolysaccharide. Our results indicate that curcumin protects against atherosclerosis at least partially by inhibiting TLR4 expression and its related inflammatory reaction.

CD133 expression and α-fetoprotein levels define novel prognostic subtypes of HBV-associated hepatocellular carcinoma: A long-term follow-up analysis.

Hepatocellular carcinoma (HCC) is a highly heterogeneous type of tumor, which may be caused by the stem/progenitor cell features of particular HCC cells. Recent studies have subclassified HCC into different prognostic subtypes according to just one stemness-associated marker. However, one stemness-associated marker is not sufficient to clearly define cancer stem cells, or to decipher the heterogeneous nature of HCC. For a more precise subtype classification for prognostic application, a combination of multiple stemness-associated markers is required. Cluster of differentiation 133 (CD133) and α-fetoprotein (AFP) are common stemness-associated markers for HCC that have not yet been employed for HCC subtype classification. In the present study, CD133 expression was assessed by immunohistochemistry in 127 hepatitis B virus-associated HCC tumor specimens. Based on CD133 immunostaining and serum AFP levels, the HCC cases were subclassified into four subtypes, which demonstrated different clinicopathological features and varying prognoses. Among the four subtypes, the number of tumor lesions, histological grade and vascular invasion were significantly different (P=0.002, P=0.018 and P=0.022, respectively). CD133+AFP+ HCC was associated with a relatively poor prognosis, CD133-AFP- HCC was associated with a relatively good prognosis, while CD133+AFP- HCC and CD133-AFP+ HCC were associated with an intermediate prognosis. These prognostic values were confirmed by borderline or statistical significance (between all groups, overall survival, P=0.061; recurrence-free survival, P=0.015). These results define a novel and simple system, based on CD133 and AFP, for classifying HCC into four distinct prognostic subtypes. This classification system may aid the assessment of patients with HCC for personalized therapy.

53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM-CHK2-P53 pathway.

PURPOSE: Loss of P53 binding protein 1 (53BP1) is considered a poor prognostic factor for colorectal cancer. However, its effect on chemosensitivity of colorectal cancer to 5-fluorouracil (5-FU) remains elusive. This study aimed to examine the association of 53BP1 expression with chemosensitivity of colorectal cancer cells to 5-FU. METHODS: Immunohistochemistry was performed on 30 metastatic colorectal cancer samples to assess the associations of 53BP1 levels with clinical therapeutic effects. In vitro, IC50 values for 5-FU and 53BP1 levels were determined by MTT assay and Western blot in 5 colorectal cancer cell lines. Then, 53BP1 was silenced in HCT116 and HT29 cells, and cell proliferation, apoptosis and cell cycle distribution were evaluated. Relative protein levels of ATM-CHK2-P53 pathway effectors and Bcl-2 family members were measured by Western blot. Finally, the effects of 53BP1 knockdown on tumor growth and 5-FU chemoresistance were investigated in vivo. RESULTS: 53BP1 expression was closely related to time to progression (TTP) after first-line chemotherapy. Namely, 53BP1 downregulation resulted in reduced TTP. In addition, 53BP1 silencing increased proliferation, inhibited apoptosis and induced S phase arrest in HCT116 and HT29 cells after 5-FU treatment. Moreover, 53BP1 knockdown also reduced the protein levels of ATM-CHK2-P53 apoptotic pathway effectors, caspase9 and caspase3, while increasing Bcl-2 expression. In vivo, 53BP1 silencing accelerated tumor proliferation in nude mice and enhanced resistance to 5-FU. CONCLUSIONS: These findings confirmed that 53BP1 loss might be a negative factor for chemotherapy efficacy, promoting cell proliferation and inhibiting apoptosis by suppressing ATM-CHK2-P53 signaling, and finally inducing 5-FU resistance.

Peritumoral EpCAM Is an Independent Prognostic Marker after Curative Resection of HBV-Related Hepatocellular Carcinoma.

Accumulating evidence suggests that the tumor microenvironment has a profound influence on tumor initiation and progression, opening a new avenue for studying tumor biology. Nonetheless, the prognostic values of the peritumoral expression of EpCAM and CD13 remain to be elucidated in hepatocellular carcinoma (HCC) patients. In this study, the expression of EpCAM and CD13 was assessed by immunohistochemistry in peritumoral liver hepatocytes from 106 hepatitis B virus- (HBV-) related HCC patients who had undergone curative hepatectomy. The peritumoral EpCAM-positive group had a significantly worse overall survival (OS) (p = 0.003) and recurrence-free survival (RFS) (p = 0.022) compared to the negative group. Peritumoral CD13-positive patients were also associated with poor OS (p = 0.038), while not significantly associated with RFS. The adjusted multivariate COX proportional hazard regression analysis suggested that only the positive expression of peritumoral EpCAM precisely predicted poor OS. Being peritumoral EpCAM positive was also significantly associated with a larger tumor size, liver cirrhosis, and more frequent vascular invasion; however, no statistically significant association was observed between CD13 and any clinicopathological features. Taken together, peritumoral EpCAM and CD13 expression was associated with a poor prognosis, but EpCAM may be a better prognostic marker than CD13 in HBV-related HCC patients. In the future, peritumoral EpCAM could be a good target for adjuvant therapy after curative hepatectomy.

Corrigendum to "Peritumoral EpCAM Is an Independent Prognostic Marker after Curative Resection of HBV-Related Hepatocellular Carcinoma".

[This corrects the article DOI: 10.1155/2017/8495326.].

Detection of Circulating Tumor Cells and Circulating Tumor Microemboli in Gastric Cancer.

PURPOSE: Gastric cancer studies indicated a potential correlation between circulating tumor cells (CTCs) in peripheral blood and tumor relapse/metastasis. The prevalence and significance of circulating tumor microemboli (CTM) in gastric cancer remain unknown. We investigated the prevalence and prognostic value of CTCs and CTM for progression-free survival (PFS) and overall survival (OS) in gastric cancer patients. METHODS: Eighty-one gastric cancer patients consented to provide 5ml of peripheral blood before systematic therapy. CTCs and CTM were isolated using isolation by size of epithelial tumor cells and characterized by cytopathologists. For 41 stage IV gastric cancer patients, CTM was investigated as a potential biomarker to predict prognosis. RESULTS: CTCs were detected in 51 patients; the average count was 1.81. In clinical stage I, II, III, and IV patients, the average CTC counts were 1.40, 0.67, 1.24, and 2.71, respectively. CTM were detected in 3 of 33 clinical stage I to IIIb patients, at an average of 0.12 (0-2). CTM were detected in 13 of 53 clinical stage IIIc to IV patients, at an average of 1.26 (0-22). In stage IV patients, CTM positivity correlated with the CA125 level. PFS and OS in CTM-positive patients were significantly lower than in CTM-negative patients (P<.001). CTM positivity was an independent factor for determining the PFS (P=.016) and OS (P=.003) of stage IV patients in multivariate analysis. Using markers of the epithelial-mesenchymal transition, single CTCs were divided into three phenotypes including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs. For CTM, CK-/Vimentin+/CD45- and CK+/Vimentin+/CD45- phenotypes were observed, but the CK+/Vimentin-/CD45- CTM phenotype was not. CA125 was detected in gastric cancer cell lines BGC823 and MGC803. CONCLUSIONS: In stage IV patients, CTM positivity was correlated with serum CA125 level. CTM were an independent predictor of shorter PFS and OS in stage IV patients. Thus, CTM detection may be a useful tool to predict prognosis in stage IV patients.

Deficiency of 53BP1 inhibits the radiosensitivity of colorectal cancer.

The present study aimed to observe the influence of p53 binding protein 1 (53BP1) silencing on the radiosensitivity of colorectal cancer (CRC) cells and investigated the potential underlying mechanisms. The differences in radiosensitivity among four CRC cells were detected by the clone formation assay, while the expression of their 53BP1 was detected by the western blot analysis. HCT116 cells with relatively high expression of 53BP1 were selected to silence the expression of 53BP1 by shRNA intervention. The influence on proliferation, apoptosis, and cell cycle distribution was detected by immunofluorescent staining of Ki-67 and flow cytometry. The expression of relevant proteins in the apoptotic pathway ATM-CHK2-p53 was further analyzed by western blot analysis. The expression of 53BP1 was found to be closely related to the radiosensitivity of the CRC cells. Decreased expression of 53BP1 led to the tolerance of HCT116 cells to radiation. The detection of tumor proliferation, apoptosis, and cell cycle showed that decreased expression of 53BP1 resulted in an increased S-phase percentage of HCT116 cells, an increased proliferating rate, and a decreased apoptotic rate after radiation. The analysis of the molecular pathway showed that the reduced expression of 53BP1 decreased the protein expression of ATM, CHK2, and the phosphorylated products associated with the p53 apoptotic pathway. In conclusion, decreased expression of 53BP1 leads to radiotolerance of CRC cells, and the underlying mechanism is probably related to the decreased expression of relevant proteins in the ATM-CHK2-p53 pathway, which affects cell cycle, apoptosis and proliferation.