EPHB2 as a key mediator of glioma progression: Insights from microenvironmental receptor ligand-related prognostic gene signature.

Malignant gliomas, characterized by pronounced heterogeneity, a complex microenvironment, and a propensity for relapse and drug resistaniguree, pose significant challenges in oncology. This study aimed to investigate the prognostic value of Ligand and Receptor related genes (LRRGs) within the glioma microenvironment. An intersection of 71 ligand-related genes (LRGs) and 2628 receptor-related genes (RRGs) yielded a total of 69 LRRGs. Utilizing the least absolute shrinkage and selection operator (LASSO) regression analysis, a prognostic RiskScore model comprising 28 LRRGs was constructed. The model demonstrated robust prognostic value, further validated in the TCGA-GBMLGG dataset. Subsequent analyses included differential gene expression, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment (GSEA), and gene set variation (GSVA) within RiskScore groups. Additionally, evaluations of PPI, mRNA-RBP, mRNA-TF, and mRNA-drug interaction networks were conducted. Four hub genes were identified through differential expression analysis of the 28 LRRGs across various GSE datasets. A multivariate Cox prognostic model was constructed for nomogram analysis, gene mutation analysis, and related expression distribution. This study underscores the role of LRRGs in intercellular communication within the glioma microenvironment and identifies four hub genes crucial for prognostic assessment in clinical glioma patients. These findings offer a potential evaluation framework for glioma patients, enhancing our understanding of the disease and informing future therapeutic strategies.

Effect of Boron Additions on the Microstructural Evolution and Properties of Fe-Mo-Cu-Ni-C Sintered Steel.

The effects of different boron (B) additions from 0 to 0.5 wt.% on the microstructure and properties of Fe-Mo-Cu-Ni-xB-C powder metallurgy (PM) steels were investigated in this work. The results indicated that the ferrite phase quantity decreased and disappeared, Ni/Cu became more homogeneous, and M2B phase formed, with the addition of B. The density and hardness of the sintered steels monotonously increased with increasing B content, whereas the tensile strength and impact toughness first increased and then decreased. The tensile strength of the steels reached a maximum value of 1097 MPa at a 0.2% B content, whereas the impact toughness reached a maximum value of 25.7 J/cm2 at a 0.1% B content and then sharply decreased when the B content exceeded 0.2%. Frictional wear experiments showed that the weight loss of the steels decreased with an increasing B content under low load conditions (100 N), and the lowest weight loss of 0.043 g occurred at a 0.2% B content. Under high load conditions (200 N), the 0.1% B content steel saw the lowest weight loss 0.075 g, exhibiting excellent wear resistance, but the abrasive resistance of the steels decreased with a further increase in the B content due to the germination of microcracks and large spalling caused by the high hardness and brittleness.

Potential significance of changes in serum levels of IL-17, TNF-α and DKK-1 in the progression of the rheumatoid arthritis.

To detect the value of serum interleukin-17 (IL-17), tumour necrosis factor-α (TNF-α), and Dickkopf-1 (DKK-1) in rheumatoid arthritis (RA) at different disease stages. 141 RA patients were randomly obtained and diagnosed in a large tertiary first-class hospital in Jiangxi Province from November 2021 to January 2022. RA was divided into 38 low activity and remission phase (low remission patients), 72 moderate activity patients, 41 high activity patients, according to the disease activity score 28 (DAS28) of RA and 70 healthy controls. IL-17 and TNF-α in serum detected by flow cytometry; DKK-1by ELISA; rheumatoid factor (RF) and C-reactive protein (CRP) by rate scattering turbidimetry; erythrocyte sedimentation rate (ESR) by Widmanstat method; anti-cyclic citrullinated polypeptide antibody (Anti-CCP) by chemiluminescence. The changes among the groups were statistically analysed and evaluated their diagnostic value. ①Anti-CCP, CRP, and ESR levels in the moderate-to-high activity group were higher than controls, while IL-17, TNF-α, and DKK-1levels higher than low remission group, moderate activity group and controls (p < 0.05). ②IL-17, TNF-α and DKK-1 were positively correlated with RA disease activity, with the correlations of IL-17, TNF-α and DKK-1 all over 0.5 (p < 0.05). ③The ROC curve showed that among all indices the AUC of DKK-1 was the largest, 0. 922, and has the highest sensitivity and negative predictive value for RA, 0.965 and 0.953, respectively. The specificity and positive predictive value of TNF-α is highest, 0.918 and 0.921, respectively, combined them had the highest predictive value in moderate-to-high activity RA, with AUC of 0.968, and had the highest sensitivity of 0.965. The IL-17, TNF-α and DKK-1 levels were elevated in RA and positively correlated with disease activity, involved in the Wnt signalling pathway of inflammatory and joint destructive effects, combining them to monitor the RA disease process and biologically treat the cytokines in the pathogenesis of RA were valuable.

Cationic Oxidative Leaching Engineering Modulated In Situ Self-Reconstruction of Nickel Sulfide for Superior Water Oxidation.

Tuning the electroactive surface species of electrocatalysts remains a significant challenge for achieving highly efficient oxygen evolution reactions. Herein, we propose an innovative in situ leaching strategy, modulated by cationic oxidation, to achieve active self-reconstruction of these catalysts. Vanadium is introduced as a cation into Ni3S2 and oxidized under low oxidative potential, leading to subsequent leaching into the electrolyte and triggering self-reconstruction. The structural evolution from V-Ni3S2 to Ni(OH)2 and subsequently to NiOOH is identified by operando Raman as a three-step transition. In contrast, V-free Ni3S2 is unable to bypass the thermodynamically predicted nickel oxysulfide products to transform into active NiOOH. As a result, the self-restructured V-Ni3S2 only needs an ultralow overpotential of 155 mV at 10 mA cm-2, outperforming V-free Ni3S2 and many other advanced catalysts. This work provides new guidelines for manipulating in situ leaching to modulate the self-reconstruction of catalysts.

The topoisomerase inhibitor CPT-11 prevents the growth and metastasis of lung cancer cells in nude mice by inhibiting EGFR/MAPK signaling pathway.

Objective: The topoisomerase inhibitor CPT-11 has been applied in treatment of multiple cancer types. Here, we probed into the possible mechanism of CPT-11 in affecting growth and metastasis of lung cancer (LC) cells, with involvement of the EGFR/MAPK pathway. Methods: The target protein of CPT-11 was screened through bioinformatics analysis, and the LC-related microarray datasets GSE29249, GSE32863 and GSE44077 were obtained for differential analysis for identifying the target protein. A subcutaneous xenograft tumor model and a metastatic tumor model were constructed in nude mice for in vivo mechanism verification of the regulatory role of CPT-11 in LC through modulation of EGRF/MAPK pathway. Results: Bioinformatics analysis showed that EGFR was the target protein of CPT-11. In vivo animal experiments confirmed that CPT-11 enhanced LC cell growth and metastasis in nude mice. CPT-11 could inhibit activation of EGFR/MAPK pathway. EGFR promoted LC cell growth and metastasis in nude mice through activation of the MAPK pathway. Conclusion: The topoisomerase inhibitor CPT-11 may prevent LC growth and metastasis by inhibiting activation of EGFR/MAPK pathway.

Circular RNA XRCC5 aggravates glioma progression by activating CLC3/SGK1 axis via recruiting IGF2BP2.

BACKGROUND: Increasing evidences have reported the critical roles of circular RNA (circRNA) in gliomas. Whereas, the role of circXRCC5 in glioma and its underlying molecular mechanism has not been reported. METHODS: The RNA transcripts and protein levels were detected using qRT-PCR, immunohistochemistry (IHC) and in situ hybridization (ISH) assays. Cell proliferation was characterized by CCK-8 and clone formation assays. The formation of NLRP3-inflammasomes was identified using immunofluorescence (IF) and Western blot assays. The cytokines were determined using immunosorbent assay (ELISA) and Western blot assays. The molecular interactions were validated using RIP and pull-down assays. RESULTS: circXRCC5 was over-expressed in glioma and positively related to the shorter survival rate, advanced TNM stage and larger tumor volume. circXRCC5 knockdown inhibited cell proliferation and NLRP3-mediated inflammasome activation of glioma cells. Subsequently, we found that circXRCC5 maintained mRNA stability of CLC3 by binding to IGF2BP2. Furthermore, CLC3 accelerated SGK1 expression via PI3K/PDK1/AKT pathway. The rescue experiments showed that both overexpression of CLC3 or SGK1 dramatically alleviated circXRCC5 knockdown-induced inhibition of cell proliferation and NLRP3-mediated inflammasome activation of glioma cells. In vivo, our study proved that circXRCC5 accelerated glioma growth by regulating CLC3/SGK1 axis. CONCLUSION: Our data concluded that circXRCC5 formed a complex with IGF2BP2 to regulate inflammasome activation and tumor growth via CLC3/SGK1 axis.

Investigation of Diagnostic and Prognostic Value of CLEC4M of Non-Small Cell Lung Carcinoma Associated with Immune Microenvironment.

Purpose: C-type lectin domain family 4 member M (CLEC4M) has been found to be involved in the occurrence and development of cancer, but its role in NSCLC remains to be fully explored. Our work aims to evaluate the diagnostic and prognostic value of CLEC4M in NSCLC and to investigate the underlying mechanisms of CLEC4M in the immune microenvironment of NSCLC. Methods: Integrating publicly accessible data and clinical tissue samples to verify the expression of CLEC4M in NSCLC. The diagnostic value of CLEC4M was determined by receiver operating characteristic (ROC) curve. Kaplan-Meier survival analysis, nomogram plot, univariate and multivariate Cox regression models were performed to evaluate the prognostic impact of CLEC4M on NSCLC patients. The correlation between CLEC4M and tumor immune infiltration was estimated using TIMER and UALCAN databases. Functional assessments including GO, KEGG pathway and GSEA analyses were implemented to illustrate the potential mechanisms of CLEC4M in NSCLC. Results: CLEC4M was significantly downregulated in NSCLC tissue, as confirmed by immunohistochemistry of clinical tissues. The high AUC value of ROC curves demonstrated the diagnostic accuracy of CLEC4M in NSCLC. Additionally, low CLEC4M expression was associated with poor survival in NSCLC patients. Furthermore, CLEC4M was found to be significantly associated with tumor immune infiltration, and CLEC4M may be involved in immune activation and proliferation inhibition through the functional assessment, suggesting that CLEC4M may be a therapeutic target for NSCLC patients. Conclusion: Our findings reveal CLEC4M is significantly downregulated in NSCLC tissues, and illustrate the diagnostic and prognostic value of CLEC4M in NSCLC, as well as its potential serve as an immune-related therapeutic target.

Serum sirtuin-1 a potential marker in the diagnosis of rheumatoid arthritis.

Introduction: To explore the value of serum sirtuin-1 (SIRT1) in the diagnosis and evaluation of joint mobility of rheumatoid arthritis (RA). Materials and Methods: Serum was randomly obtained from 212 RA patients,210 non-RA patients and 58 healthy controls in a large tertiary first-class hospital in Jiangxi province from November 2021 to June 2022. The level of serum Sirt1,anti-cyclic citrulline polypeptide antibody (anti-CCP), anti-mutant citrulline vimentin antibody (anti-MCV), rheumatoid factor (RF),high-mobility group box 1 (HMGB1), collagen triple helix repeat containing 1 (CTHRC1), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were detected by ELISA, to explore the correlation between them and their value in the diagnosis and evaluation of joint range of motion of RA and statistically analyse their diagnostic efficiency. Results: ① The level of all markers was higher in the RA group than in the non-RA group and the healthy controls (p < 0.05). ② The AUC of the SIRT1 was 0.882, second only to the anti-MCV and anti-CCP. ③ The anti-CCP showed the highest sensitivity to RA diagnosis of 0.948. The specificity and positive predictive value of SIRT1 for the diagnosis of RA were the highest, which are 0.959 and 0.934 respectively. ④ In serial combination, SIRT1/anti-CCP、SIRT1/anti-MCV showed the highest specificity.SIRT1/anti-CCP in parallel combination had the highest sensitivity. ⑤ SIRT1 showed a significant correlation with other markers and DAS28 scores (p < 0.01). Conclusion: SIRT1 can be used as a new serological marker for RA diagnosis, which has a significant correlation with RA joint mobility and has a certain reference value in RA differential diagnosis, providing a new detection basis for RA differential diagnosis.

The value of serum TRAP1 in diagnosing small cell lung cancer and tumor immunity.

This study set out to investigate the clinical significance of serum tumor necrosis factor receptor-associated protein 1 (TRAP1) in diagnosing small cell lung cancer (SCLC) with different clinical stages, and to compare the diagnostic efficiency with neuron-specific enolase (NSE), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). Besides, to analyze the role of serum TRAP1 in tumor immunity. A total of 91 patients with SCLC, 99 patients with non-small cell lung cancer (NSCLC), 102 patients with pulmonary nodules (PN), and 75 healthy people were included. The concentrations of serum TRAP1 was detected by enzyme-linked immunosorbent assay (ELISA). NSE, CEA, and CA19-9 were detected by chemiluminescence. The results showed that level of TRAP1 in Group SCLC was lower than other three groups (P < 0.01), whereas NSE in SCLC was significantly higher than the others (P < 0.01), and the levels of CEA and CA19-9 were higher than healthy people and PN patients (P < 0.01). There was a significant difference in TRAP1 levels between patients with limited-stage disease SCLC (LD-SCLC) and extensive-stage disease SCLC (ED-SCLC) (P < 0.0001). The sensitivity and specificity of TRAP1 in diagnosing LD-SCLC were 0.964 and 0.560, respectively, and the area under the curve (AUC) was 0.819. The sensitivity and specificity in diagnosing ED-SCLC were 0.810 and 0.868, respectively, and the AUC was 0.933, which showed high diagnostic value. The AUC of these two groups can be increased to 0.946 and 0.947 in combination of four biomarkers, effectively improving the diagnosis rate of SCLC. Our findings have revealed that serum TRAP1 has high diagnostic value for SCLC and high diagnostic sensitivity for LD-SCLC. It is a potential biomarker for SCLC. Combined detection can effectively improve the diagnosis rate of SCLC. TRAP1 may be secreted into the circulation by mature immune cells and participates in tumor immunity as a carrier of tumor antigens.

Prevention of breast cancer-related lymphoedema: Quality of clinical practice guidelines and variations in recommendations.

AIM: We aimed to evaluate the quality of clinical practice guidelines (CPGs) for breast cancer related lymphoedema (BCRL) and compare the similarities and differences in recommendations. BACKGROUND: Many CPGs of BCRL have been developed; however, their recommendations and quality are controversial. METHODS: Relevant papers were retrieved from electronic databases, professional associations and guideline development organizations, from 1 January 2015 to 30 September 2021. The Appraisal of Guidelines Research and Evaluation (AGREE) II instrument was used to evaluate the quality of the guidelines. Intraclass correlation coefficient (ICC) analysis was used to evaluate the overall consistency among evaluators. RESULTS: Eight CPGs were included. The ICC values evaluation for CPGs ranged from 0.76 to 0.95, with good consensus among evaluators. The highest median score was 68.75% (61.46, 72.22%) for clarity, and the lowest was 37.50% (25.78, 51.30%) for applicability. The NICE, ACS/ACSO and APTA CPGs were rated well in most areas. Professional health education, individualized exercise programme and regular surveillance are the main methods to prevent lymphoedema. CONCLUSION: In the past 6 years, the quality of BCRL guidelines has varied greatly, especially in the domains of rigour and applicability. Interrater agreement was excellent, but recommendation showed some inconsistencies in the details.

Glycosylation modification patterns reveal distinct tumor metabolism and immune microenvironment landscape in lower-grade gliomas.

Glycosylation alterations, a key driver throughout tumorigenesis and tumor progression, could regulate the microenvironment and immune response as well as lead to harmful metabolism and cell signaling. In this study, we first comprehensively evaluated the glycosylation modification patterns of LGGs based on glycosyltransferase family genes and systematically integrated these modification patterns with tumor metabolism and immune microenvironment characteristics. Glycosylation score was also developed to quantify glycosylation modification patterns of individuals. As a result, two glycosylation modification patterns were identified, with distinct prognosis, metabolism, and immune microenvironment features. The glycosylation subtype A and cluster A were characterized by higher carbohydrates and amino acid metabolism activity, higher levels of infiltrating cells, and poor prognosis, whereas an opposite modification pattern was observed in glycosylation subtype B and cluster B. In addition, a high glycosylation score is closer to a microenvironment characterized by chronic inflammation, immunosuppression, and tumor promotion. Following analysis and validation, the glycosylation score was a reliable and independent prognostic index. More importantly, the glycosylation score influenced the response to immunotherapy, chemotherapy, or targeted therapy, which provided a novel insight into promoting personalized therapy in the future and may contribute to developing novel therapeutic drugs or exploring promising drug combination therapy strategies.

Genetic Variants in Double-Strand Break Repair Pathway Genes to Predict Platinum-Based Chemotherapy Prognosis in Patients With Lung Cancer.

Objective: The purpose of this study was to investigate the associations of genetic variants in double-strand break (DSB) repair pathway genes with prognosis in patients with lung cancer treated with platinum-based chemotherapy. Methods: Three hundred ninety-nine patients with lung cancer who received platinum-based chemotherapy for at least two cycles were included in this study. A total of 35 single nucleotide polymorphisms (SNPs) in DSB repair, base excision repair (BER), and nucleotide excision repair (NER) repair pathway genes were genotyped, and were used to evaluate the overall survival (OS) and the progression-free survival (PFS) of patients who received platinum-based chemotherapy using Cox proportional hazard models. Results: The PFS of patients who carried the MAD2L2 rs746218 GG genotype was shorter than that in patients with the AG or AA genotypes (recessive model: p = 0.039, OR = 5.31, 95% CI = 1.09-25.93). Patients with the TT or GT genotypes of TNFRSF1A rs4149570 had shorter OS times than those with the GG genotype (dominant model: p = 0.030, OR = 0.57, 95% CI = 0.34-0.95). We also investigated the influence of age, gender, histology, smoking, stage, and metastasis in association between SNPs and OS or PFS in patients with lung cancer. DNA repair gene SNPs were significantly associated with PFS and OS in the subgroup analyses. Conclusion: Our study showed that variants in MAD2L2 rs746218 and TNFRSF1A rs4149570 were associated with shorter PFS or OS in patients with lung cancer who received platinum-based chemotherapy. These variants may be novel biomarkers for the prediction of prognosis of patients with lung cancer who receive platinum-based chemotherapy.

C(sp3)-H oxidation and chlorination catalysed by a bioinspired pincer iron(III) complex.

A pincer iron(III) catalyst for the oxidation and chlorination of C(sp3)-H bonds was developed. Oxidation of a diagnostic substrate cis-decalin implies that a long-lived carbon-centred radical is involved. Mechanistic studies suggest that an Fe-oxo species could be responsible for the rate-determining C-H activation step. This report expands the scope of non-heme catalysts for C-H functionalisation.

lncRNA PINK1-AS Aggravates Cerebral Ischemia/Reperfusion Oxidative Stress Injury through Regulating ATF2 by Sponging miR-203.

Ischemic stroke is a common disease that led to high mortality and high disability. NADPH oxidase 2- (NOX2-) mediated oxidative stress and long noncoding RNA have important roles in cerebral ischemia/reperfusion (CI/R) injury, whereas whether there is interplay between them remains to be clarified. This study was performed to observe the role of lncRNA PINK1-antisense RNA (PINK1-AS) in NOX2 expression regulation. An in vivo rat model (MCAO) and an in vitro cell model (H/R: hypoxia/reoxygenation) were utilized for CI/R oxidative stress injury investigation. The expression levels of lncRNA PINK1-AS, activating transcription factor 2 (ATF2), NOX2, and caspase-3 and the production level of ROS and cell apoptosis were significantly increased in CI/R injury model rats or in H/R-induced SH-SY5Y cells, but miR-203 was significantly downregulated. There was positive correlation between PINK1-AS expression level and ROS production level. PINK1-AS and ATF2 were found to be putative targets of miR-203. Knockdown of lncRNA PINK1-AS or ATF2 or the overexpression of miR-203 significantly reduced oxidative stress injury via inhibition of NOX2. Overexpression of lncRNA PINK1 significantly led to oxidative stress injury in SH-SY5Y cells through downregulating miR-203 and upregulating ATF2 and NOX2. lncRNA PINK1-AS and ATF2 were the targets of miR-203, and the lncRNA PINK1-AS/miR-203/ATF2/NOX2 axis plays pivotal roles in CI/R injury. Therefore, lncRNA PINK1-AS is a possible target for CR/I injury therapy by sponging miR-203.

Optimizing the Thermomechanical Process of Nickel-Based ODS Superalloys by an Efficient Method.

Thermo-mechanical process of nickel-based oxide dispersion strengthened (ODS) superalloys is critical to produce desired components. In this study, an efficient method of consolidating powder is introduced to optimize the preparation process, microstructure and properties of nickel-based ODS superalloys. The influences of consolidation temperature, strain rate and ball milling time on the hardness of nickel-based superalloys were studied. The relationship among process, microstructure and hardness was established, the nanoparticles strengthening and grain boundary strengthening in nickel-based ODS superalloys were discussed. The results indicate that long ball milling time, moderately low consolidation temperature and high strain rates are beneficial to improving properties of nickel-based superalloys. Moreover, dispersion strengthening of nanoparticles and grain boundary strengthening play important roles in enhancing nickel-based ODS superalloys.

Pharmacoepitranscriptomic landscape revealing m6A modification could be a drug-effect biomarker for cancer treatment.

RNA chemical modifications are a new but rapidly developing field. They can directly affect RNA splicing, transport, stability, and translation. Consequently, they are involved in the occurrence and development of diseases that have been studied extensively in recent years. However, few studies have focused on the correlation between chemical modifications and drug effects. Here, we provide a landscape of six RNA modifications in pharmacogene RNA (pharmacoepitranscriptomics) to fully clarify the correlation between chemical modifications and drugs. We performed systematic and comprehensive analyses on pharmacoepitranscriptomics, including basic characteristics of RNA modification and modification-associated mutations and drugs affected by them. Our results show that chemical modifications are common in pharmacogenes, especially N6-methyladenosine (m6A) modification. In addition, we found a very close relationship between chemical modifications and anti-tumor drugs. More interestingly, the results demonstrate the importance of m6A modification for anti-tumor drugs, especially for drugs in triple-negative breast cancer (TNBC), ovarian cancer, and acute myelocytic leukemia (AML). These results indicate that pharmacoepitranscriptomics could be a new source of drug-effect biomarkers, especially for m6A and anti-tumor drugs.

Application of collagen triple helix repeat containing-1 and mitotic spindle apparatus antibody in small cell lung cancer diagnosis.

BACKGROUND: The clinical significance of serum collagen triple helix repeat protein-1 (CTHRC1) and mitotic spindle apparatus antibody (MSA) in the diagnosis of small cell lung cancer (SCLC). METHODS: Of the 229 lung tumor patients selected, 62 patients were divided into SCLC, 94 patients with non-small cell lung cancer (NSCLC), and 73 patients with benign lung disease (BLD). The health controls (HC) had a span of 66 cases with normal physical condition. The serum extracted from each participator and enzyme-linked immunosorbent assay was adopted for measuring the serum CTHRC1 and MSA; in the meantime, automatic electrochemiluminescence immunoassay was used for the quantitative determination of serum NSA and CEA. And then, the differences in serum CTHRC1, MSA, NSE, and CEA were compared among involved groups. RESULTS: ① Compared with other groups, the concentrations of CTHRC1, MSA, and NSE showed a marked increase in the group of SCLC (all p < 0.01). Especially for SCLC patients with lymph node metastasis, CTHRC1 provided a notably higher level than those without metastasis. ② CTHRC1 and MSA established a diagnostic criterion with the specificity of 90.99% and 86.27% for SCLC, respectively. ③ In series, the specificity of CTHRC1 and NSE was the highest (99.30%), while MSA and NSE had the highest sensitivity (96.72%) in parallel. ④ Both CTHRC1 and MSA were hazardous factors interconnected with SCLC. CONCLUSION: Serum CTHRC1 and MSA had a more exciting prospect of application. When used in conjunction with NSE and CEA, they could optimize the clinical diagnosis value of SCLC.

Tumor necrosis factor-alpha stimulated gene-6: A biomarker reflecting disease activity in rheumatoid arthritis.

BACKGROUND: To explore the serum tumor necrosis factor-alpha stimulated gene-6 (TSG-6) level and its association with disease activity in rheumatoid arthritis (RA) patients. METHODS: We recruited 176 RA patients, 178 non-RA patients (lupus erythematosus, osteoarthritis, ulcerative colitis, ankylosing spondylitis and psoriasis) and 71 healthy subjects. Serum TSG-6 levels were detected by enzyme-linked immunosorbent assay (ELISA). RA patients were divided into inactive RA and active RA groups by disease activity score of 28 joints based on C-reactive protein (DAS28-CRP). The receiver operating characteristic (ROC) curve and Spearman's rank correlation test analyzed the correlation between TSG-6 concentration and RA disease activity. RESULTS: Tumor necrosis factor-alpha stimulated gene-6 levels in the RA group were increased (p < 0.01). TSG-6 concentrations indicated an upward tendency with increased disease activity; The area under the curve (AUC) of TSG-6 for diagnosing RA and assessing the severity of RA were 0.78 and 0.80, respectively; The combination of TSG-6 and anti-mutated citrullinated vimentin antibodies (anti-MCV) (sensitivity:98.4%)improved the diagnostic accuracy of RA. Binary logistic regression analysis showed that TSG-6 was an independent risk factor related to the severity of RA, and OR (95% CI) was 1.2 (1.003-1.453). CONCLUSION: The TSG-6 levels in RA patients were elevated and related to disease activity. Therefore, TSG-6 may serve as a new potential biomarker for evaluating RA disease activity.

eIF3a-PPP2R5A-mediated ATM/ATR dephosphorylation is essential for irinotecan-induced DNA damage response.

OBJECTIVES: The individual differences and pervasive resistance seriously hinder the optimization of irinotecan-based therapeutic effectiveness. Eukaryotic translation initiation factor 3a (eIF3a) plays a key role in tumour occurrence, prognosis and therapeutic response. This study focused on the role of eIF3a in irinotecan-induced DNA damage response. MATERIALS AND METHODS: The cck8 cell viability and clone survival analyses were used to test the regulatory role of eIF3a on irinotecan sensitivity in HT29 and CACO2 cell lines in vitro. This regulatory role was also verified in vivo by conducting subcutaneous xenograft model. Irinotecan-induced DNA damage, cell cycle arrest and apoptosis were tested by flow cytometry analysis, TUNEL staining, western blot and comet assays. The immunofluorescence, co-IP, luciferase reporter assay, RIP and flow cytometric analyses were carried out to investigate the underline mechanism. RESULTS: We demonstrated that eIF3a continuously activates ATM/ATR signal by translationally inhibiting PPP2R5A, a phosphatase that directly dephosphorylates and inactivates ATM/ATR after DNA repair complete. Suppression of PPP2R5A resulted in chronic ATM/ATR phosphorylation and activation, impairing DNA repair and enhancing irinotecan sensitivity. CONCLUSIONS: Our study suggested eIF3a with a high potential to influence phenotypic functions, which may contribute substantially to the early identification of susceptible individuals and the provision of personalized medication to irinotecan-treated patients.