T1-weighted images-based radiomics for structural lesions evaluation in patients with suspected axial spondyloarthritis.

PURPOSE: The aim of this study was to investigate the feasibility of radiomics based on T1-weighted images (T1WI) for assessing sacroiliac joint (SIJ) structural lesions in patients with suspected axial spondyloarthritis (axSpA). MATERIALS AND METHODS: A total of 266 patients with clinical suspicion of axSpA between December 2016 and January 2022 were enrolled. Structural lesions were assessed on low-dose CT (ldCT) and MRI, respectively. Radiomic features, extracted from SIJ T1WI, were included to generate the radiomics model. The performance of the radiomics model was evaluated using receiver operating characteristic (ROC) curve. Furthermore, point-biserial correlation analysis was used to interpret the associations between the radiomic feature and structural lesions. RESULTS: Using ldCT as the reference standard, the radiomics model showed favorable performance for detecting positive global structural lesions in the training cohort (AUC, 0.82 [95% CI: 0.76, 0.88]) and validation cohort (AUC, 0.82 [95% CI: 0.72, 0.91]. Experienced MRI raters yielded predictive AUCs of 0.73 (95% CI: 0.67, 0.79), and 0.74 (95% CI: 0.66, 0.83) in the training and validation cohort, respectively. The seven radiomic features included in the radiomics model showed significant correlation with different kinds of structural lesions (P all < 0.05). Among them, Wavelet.LHL_firstorder_90Percentile showed the strongest association with fat lesion (r = 0.48, P < 0.05). CONCLUSION: The radiomics analysis with T1WI could effectively detect SIJ structural lesions and achieved expert-level performance. Each radiomic feature was correlated with different structural lesions significantly, which might inform radiomic-based applications for axSpA intelligent diagnosis.

Can radiomics replace the SPARCC scoring system in evaluating bone marrow edema of sacroiliac joints in patients with axial spondyloarthritis?

OBJECTIVES: To develop an objective and efficient method based on radiomics to evaluate bone marrow edema (BMO) of sacroiliac joints (SIJs) by magnetic resonance imaging (MRI) in patients with axial spondyloarthritis (axSpA) and to compare with the Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system. METHODS: From September 2013 to March 2022, patients with axSpA who underwent 3.0T SIJ-MRI were included and were randomly divided into training and validation cohorts at a ratio of 7:3. The optimal radiomics features selected from the SIJ-MRI in the training cohort were included to generate the radiomics model. The performance of the model was evaluated by ROC analysis and decision curve analysis (DCA). Rad scores were calculated using the radiomics model. The responsiveness was compared for Rad scores and SPARCC scores. We also assessed the correlation between the Rad score and SPARCC score. RESULTS: A total of 558 patients were finally included. The radiomics model showed favorable discrimination of a SPARCC score <2 or ≥2 both in the training (AUC, 0.90; 95% CI: 0.87-0.93) and validation cohorts (AUC, 0.90; 95% CI, 0.86-0.95). DCA confirmed that the model was clinically useful. Rad score showed higher responsiveness to treatment-related change than SPARCC score. Furthermore, a significant correlation was noted between the Rad score and SPARCC score when scoring the status of BMO (rs=0.80, P < 0.001), and a strong correlation was noted when scoring the change in BMO (r=0.70, P < 0.001). CONCLUSION: The study proposed a radiomics model to accurately quantify the BMO of SIJs in patients with axSpA, providing an alternative to the SPARCC scoring system. Key Points • The Rad score is an index with high validity for the objective and quantitative evaluation of bone marrow edema (BMO) of the sacroiliac joints in axial spondyloarthritis. • The Rad score is a promising tool to monitor the change of BMO upon treatment.

MicroRNA-151 Attenuates Apoptosis of Endothelial Cells Induced by Oxidized Low-density Lipoprotein by Targeting Interleukin-17A (IL-17A).

Apoptosis of endothelial cells plays an important role in atherosclerosis (AS). MicroRNAs (miRNAs) have been confirmed to participate in the process of endothelial cell apoptosis. The main purpose of this study was to investigate the mechanism of miR-151 and interleukin-17A (IL-17A) in apoptosis of atherosclerotic endothelial cells. The expression levels of miR-151 in human aortic endothelial cells (HAEC) after Ox-LDL treatment were detected by qRT-PCR. The expression levels of IL-17A were detected by qRT-PCR and Western blot. The effects of miR-151 and IL-17A on the apoptosis rate were detected by flow cytometry. The relationship between miR-151 and IL-17A was assessed by bioinformatics analysis and luciferase assay. The expression levels of miR-151 in HAEC after Ox-LDL treatment were reduced, and the expression of IL-17A was upregulated. MiR-151 and si-IL-17A inhibited the apoptosis rate of aortic endothelial cells treated by Ox-LDL. MiR-151 and si-IL-17A reduced the expression levels of c-caspase-9, c-caspase-3, and BAX proteins in Ox-LDL-treated HAEC and increased the expression levels of Bcl-2. MiR-151 inhibited the apoptosis of endothelial cells in AS, and IL-17A was a new target for miR-151. Our findings provided a potential treatment for atherosclerosis in the treatment of AS. Graphical abstract.

Arsenic trioxide (ATO) induced degradation of Cyclin D1 sensitized PD-1/PD-L1 checkpoint inhibitor in oral and esophageal squamous cell carcinoma.

Arsenic trioxide (ATO) is widely studied for its antitumor efficacy and several recent studies suggested the immune modulatory effects of ATO in animal models. In this study we found ATO treatment induced increased ROS production and DNA damage in esophageal squamous cell carcinoma (ESCC) cells, led to DNA damage mediated degradation of Cyclin D1 and upregulation of PD-L1 in these cancer cells. Mechanistically, we found ATO induced a transient upregulation and nuclear translocation of Cyclin D1 by sumoylation. Followed with increased ubiquitination and degradation of Cyclin D1 through T286 phosphorylation, and at least partly mediated by Stat1 Y701 phosphorylation. We observed inversed correlations between Cyclin D1 and PD-L1 expression levels in human ESCC tissues. With 4NQO induced PD-L1 humanized mouse oral and esophageal squamous carcinoma model, we found combinatory administration of ATO and check point inhibitor resulted in a significant reduction of tumor volumes. Inversed correlation between Cyclin D1 with PD-L1 was also observed in the 4NQO induced mouse ESCC and OSCC model. Together, these data suggested ATO induced degradation of Cyclin D1 and functional suppression of CDK4/6 pathway sensitized OSCC and ESCC to checkpoint inhibitor treatment.

The transcription factor c-Jun regulates Smad4 expression by upregulating pre-miR-183 expression to promote invasion and metastasis of esophageal squamous cell carcinomas.

MiR-183 is a tumor onco-miR and has been shown by our previous studies to be overexpressed in esophageal squamous cell carcinomas (ESCCs). In this study, we sought to determine the possible mechanisms of miR-183 in ESCC. In our study, cell migration and invasion, real-time PCR, Western blot, and chromatin immunoprecipitation (ChIP) assays were used to explore the mechanism of miR-183 in three ESCC cell lines. We found several potential transcription factors, including c-Jun, by bioinformatics methods. Using a ChIP assay, we identified that c-Jun binds to the promoter region of pre-miR-183 and that upregulated c-Jun expression is related to increased expression of miR-183. We found that downregulation of miR-183 significantly reduced the cell invasiveness and migration of ESCC cells, whereas upregulation of miR-183 via a mimic increased the cell migration and invasion of ESCC cells. We further discovered one direct miR-183 target gene, Smad4, which has been implicated in invasion and metastasis. Furthermore, miR-183 promoted epithelial-mesenchymal transition (EMT), which is involved in the invasion and migration of ESCC cells. Dysregulation of miR-183 has an important role in tumor growth and invasion because miR-183 targets Smad4. Therefore, suppression of miR-183 may provide a potential approach for treatment.

Role of Frailty and Comorbidity Status in Predicting Morbidity and Mortality in Patients with Acute Mesenteric Ischemia.

BACKGROUND: This study was performed to determine the association of frailty and comorbidity status with postoperative morbidity and mortality in patients with acute mesenteric ischemia (AMI). METHODS: Patients diagnosed with AMI between April 2006 and September 2019 were enrolled in this study. Frailty was evaluated by sarcopenia which was diagnosed by third lumbar vertebra psoas muscle area (PMA). Comorbidity status was evaluated by the Charlson Comorbidity Index (CCI) score. Univariate and multivariate analyses evaluating the risk factors for postoperative morbidity and mortality were performed. RESULTS: Of the 174 patients, 86 were managed conservatively and 88 underwent surgery. In surgically managed patients, 39.8% developed complications within 30 days of surgery. Ten patients died within 30 days of the operation. In the univariate analyses, white blood cell >10 g/L, low PMA, CCI score ≥2, and bowel resection were associated with postoperative complications. Multivariate analysis revealed that low PMA, CCI score ≥2, and bowel resection were independent predictors of postoperative complications. CONCLUSIONS: This study demonstrated that low PMA, CCI score ≥2, and bowel resection were independent risk factors for postoperative complications in patients with AMI. Preoperative assessment of frailty using PMA and the evaluation of comorbidity status using CCI may serve as helpful tools in preoperative risk assessment and should be integrated into scoring systems for surgically treated AMI.

PD-L1 expression and T cells infiltration in patients with uncommon EGFR-mutant non-small cell lung cancer and the response to immunotherapy.

OBJECTIVES: The efficacy of immunotherapy in epidermal growth factor receptor (EGFR)-activating non-small cell lung cancer (NSCLC) is limited. However, a series of patients with uncommon EGFR alterations was reported to derive clinical benefit from PD-1 blockade. To characterize the tumor immune microenvironment, we retrospectively evaluated tumor PD-L1 expression and T cells infiltration among NSCLC patients with uncommon EGFR mutations. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expression of PD-L1 and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs). Chi-square test and Cox proportional hazards regression were conducted to investigate the correlations between the immune microenvironment features and clinicopathological variables and survival, as well as to explore the potential of immunotherapy in this patient population. RESULTS: Among 600 NSCLC patients with EGFR alterations, we identified 49 (8.2 %) bearing uncommon mutations, including G719X, L861Q, S768I, and Ex20 ins. In total, 49.0 % (24/49) of these patients showed positive PD-L1 expression in tumor cells, markedly higher than the proportion in patients with classic sensitive mutations (19del and L858R, 12.2 % [67/551], P < 0.05). Furthermore, PD-L1 expression was associated with relatively short overall survival (OS; 15.2 vs 29.3 months, P = 0.006) and was identified as an independent predictor of OS (hazard ratio=2.57, 95 % confidence interval: 1.03-7.12, P = 0.045). Additionally, PD-L1 positivity was predominantly observed among tumors with CD8+ TILs infiltration (P = 0.001). Uncommon EGFR-mutant tumors had a high frequency (36.7 %) of concurrent PD-L1 expression and abundant CD8 + TILs infiltration. Moreover, this dual-positive group exhibited the most unfavorable prognosis (P = 0.023). Notably, patients with PD-L1 and CD8 dual positivity showed a favorable response to PD-1 inhibitors. CONCLUSIONS: High rates of concomitant PD-L1 expression and CD8 + TILs within the tumor microenvironment were observed in NSCLC patients with uncommon EGFR mutations. Further investigations are needed to confirm the therapeutic sensitivity to PD-1 blockade in this subgroup.

Correction to: Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC).

In the original publication of this manuscript [1], Fig. 6 contains a repeated image in error (the left image of 'Migration' and the left image of 'Invasion').

Efficacy of apatinib on multiple advanced-stage nongastric cancers.

BACKGROUND: Apatinib has been approved for the treatment of advanced gastric adenocarcinoma and gastric-esophageal junctional adenocarcinoma, but its efficacy is unknown for other advanced solid tumors. AIMS AND OBJECTIVES: We retrospectively reviewed the use of apatinib for multiple advanced-stage non-gastric cancers. Ninety-two patients from 7 hospitals who received additional treatment except apatinib more than once were enrolled. MATERIALS AND METHODS: The primary end-point was the overall response rate (ORR), and the secondary end-points included progression-free survival (PFS), disease control rate (DCR), overall survival, and adverse reactions. We categorized all the patients into six groups according to their cancer type. RESULTS: In the lung cancer group, the ORR was 9% (95% confidence interval [CI], 3%-23%), DCR was 88% (95% CI, 74%-96%), and median PFS was 3 months (95% CI, 1.9-5.4 months). In the cervical cancer group, the ORR was 25% (95% CI, 3%-65%), DCR reached 100%, and median PFS was 3.5 months (95% CI, 0.6-9.0 months). There were different ORRs between the other cancer groups. In addition, the most common adverse effect of apatinib was palmar-plantar erythrodysesthesia syndrome (37%), followed by proteinuria (14%) and hypertension (13%). CONCLUSION: These results suggest that apatinib might be effective for not only gastric cancer but also other carcinomas including lung cancer, colorectal cancer, cervical cancer, liver cancer, breast cancer, and nasopharyngeal cancer. Thus, apatinib is a promising targeted drug for multiple types of cancer.

Circulating uPA as a potential prognostic biomarker for resectable esophageal squamous cell carcinoma.

Previous research showed that the 4 genes of matrix metallopeptidase 9 (MMP9), cyto-keratin 20 (CK20), cyto-keratin 19 (CK19) and urokinase type plasminogen activator (uPA) are detectable in the peripheral blood. All the 4 genes are related to tumor invasion and metastasis. However, whether their expression is associated with clinicopathologic factors and the prognosis of patients with esophageal squamous cell carcinoma (ESCC) is still confused. Expression levels of MMP9, CK20, CK19, and uPA were evaluated by quantificational real-time polymerase chain reaction (qRT-PCR) in peripheral blood of 205 ESCC patients who received radical resection. The cut-off value was 1000 copy numbers. Their impacts on clinicopathologic factors and survival were investigated. The uPA expression positively correlated with gender (P = .046) and tumor size (P = .046). Meanwhile, CK19 expression positively correlated with tumor size (P = .029), vascular invasion (P = .024), and CK20 expression positively correlated with tumor size (P = .035) and degrees of differentiation (P = .032). Moreover, the overexpression of MMP9 has a correlation with postoperative radiotherapy (P = .041) and chemotherapy (P = .012). Among the 4 genes, only uPA is a prognostic indicator for disease-free survival and overall survival both in univariate analysis and multivariate analysis (P = .015). This study suggests that circulating uPA mRNA in peripheral blood can serve as a potential unfavorable prognosis biomarker in ESCC. Further perspective, multi-center and large-scale study is still needed.

Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC).

BACKGROUND: Esophageal cancer is a high incident cancer worldwide with poor survival and limited therapeutic options. Alterations of microRNAs are common in cancers, and many of these micro RNAs are potential therapeutic and diagnostic targets to treat these cancers. miR-10b-3p located in chromosome region 2q31.1, and its expression is frequently increased in esophageal squamous cell carcinoma (ESCC). However, the biological functions, clinical significance and therapeutic implications of miR-10b-3p in ESCC remain unclear. METHODS: The expression levels of miR-10b-3p in ESCC specimens were analyzed by in situ hybridization (ISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Ectopic overexpression of miR-10b-3p in ESCC cells, mouse xenograft model, and metastasis model were used to evaluate the effects of miR-10b-3p on proliferation, and migration of cancer cells. Luciferase reporter assay and Western blot were performed to validate the potential targets of miR-10b-3p after the preliminary screening by computer-aided microarray analysis. RESULTS: We found that miR-10b-3p expression levels were significantly upregulated in the tumor tissues and serum samples of patients with ESCC. The expression levels of miR-10b-3p in both tumor tissues and serum samples were inversely associated with lymph node metastasis and clinical stages. We identified the expression level of miR-10b-3p in ESCC cancer samples as an independent prognostic marker of the overall survival rates of ESCC patients. We found more frequent hypomethylation of the CpG sites located upstream of the miR-10b-3p gene in the ESCC tissues compared with in the adjacent normal tissues, and the DNA methylation status of miR-10b-3p promoter region inversely correlated with the expression levels of miR-10b-3p. Ectopic overexpression of miR-10b-3p promoted cell proliferation, colony formation, migration and invasion in ESCC. While knockdown of miR-10b-3p had the opposite effects, particularly in promoting apoptosis. Mouse xenograft model confirmed that miR-10b-3p functions as a potent oncogenic miRNA in ESCC, which also promoting ESCC metastasis. Mechanistically, we found miR-10b-3p regulated FOXO3 expression by directly binding to the 3'-untranslated region. And systemic delivery of miR-10b-3p antagomir reduced tumor growth and inhibit FOXO3 protein expression in nude mice. CONCLUSIONS: Collectively, our findings suggested upregulated expression of miR-10b-3p caused by promoter hypomethylation contributed to the progression of ESCC; Thus, miR-10b-3p is a potentially effective biomarker for ESCC that could have further therapeutic implications.