Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma.

OBJECTIVE: Aberrant epigenetic remodeling represents a molecular hallmark in lung adenocarcinoma (LUAD). We aim to investigate the biological roles of SETDB2 and its underlying associations with oxidative stress, providing therapeutic targets for individualized treatment of LUAD. METHODS: Differential analysis was conducted via Limma package, and Kaplan-Meier analysis was performed with survival package. CCK-8, cell proliferation assay, transwell assay, and in vivo assays were conducted to assess the function of SETDB2. Western blot assay, RT-qPCR, and immunohistochemistry (IHC) were conducted to assess the expression levels of SETDB2/NRF2. Chromatin immunoprecipitation (ChIP) assay and ChIP-qPCR were conducted to assess the epigenetic roles of SETDB2. RESULTS: We found that SETDB2 expression is decreased in tumor samples versus normal tissues in TCGA-LUAD cohort, LUAD-EAS cohort, GSE72094 dataset, and independent Soochow-LUAD dataset. Patients with low SETDB2 levels had a worse prognosis relative to those with high SETDB2. SETDB2 inhibition could significantly promote cell growth, migration ability, and stemness maintenance. Gene set enrichment analysis (GSEA) suggested that SETDB2 correlated with oxidative stress crosstalk and regulated NRF2 mRNA levels. ChIP assay suggested that SETDB2 mainly recruited the H3K9me3 enrichment at the NRF2 promoter region to suppress the mRNA levels of NRF2. Downregulated SETDB2 could activate NRF2 transcription and expression, thereby promoting its downstream targets, like NQO1, FTH1, and ME1. Functional experiments demonstrated that low SETDB2 allowed NRF2 to drive malignant processes of LUAD. SETDB2 overexpression attenuated the ability of NRF2 signaling to neutralize cellular reactive oxygen species (ROS) levels, leading to enhanced cell apoptosis. Overexpressed SETDB2 could inhibit tumor progression in vivo and further render LUAD cells sensitive to chemotherapy. CONCLUSIONS: In conclusion, these findings uncovered the suppressive role of SETDB2 in LUAD. SETDB2 negatively regulates NRF2 signaling to modulate tumor progression, which creates a therapeutic vulnerability in LUAD.

Embryonic stem cell-derived extracellular vesicles promote the recovery of kidney injury.

BACKGROUND: Embryonic stem cell-derived extracellular vesicles (ESC-EVs) possess therapeutic potential for a variety of diseases and are considered as an alternative of ES cells. Acute kidney injury (AKI) is a common acute and severe disease in clinical practice, which seriously threatens human life and health. However, the roles and mechanisms of ESC-EVs on AKI remain unclear. METHODS: In this study, we evaluated the effects of ESC-EVs on physiological repair and pathological repair using murine ischemia-reperfusion injury-induced AKI model, the potential mechanisms of which were next investigated. EVs were isolated from ESCs and EVs derived from mouse fibroblasts as therapeutic controls. We then investigated whether ESC-EVs can restore the structure and function of the damaged kidney by promoting physiological repair and inhibiting the pathological repair process after AKI in vivo and in vitro. RESULTS: We found that ESC-EVs significantly promoted the recovery of the structure and function of the damaged kidney. ESC-EVs increased the proliferation of renal tubular epithelial cells, facilitated renal angiogenesis, inhibited the progression of renal fibrosis, and rescued DNA damage caused by ischemia and reperfusion after AKI. Finally, we found that ESC-EVs play a therapeutic effect by activating Sox9+ cells. CONCLUSIONS: ESC-EVs significantly promote the physiological repair and inhibit the pathological repair after AKI, enabling restoration of the structure and function of the damaged kidney. This strategy might emerge as a novel therapeutic strategy for ESC clinical application.

Diagnostic potential of extracellular vesicle-associated microRNA-10b and tumor markers for lung adenocarcinoma.

MicroRNAs (miRNAs/miRs) in extracellular vesicles (EVs) are potential diagnostic markers. The purpose of the present study was to investigate potential EV miRNA biomarkers for lung adenocarcinoma (LUAD). Potential miRNAs were identified by searching public databases and verified by examining clinical samples. The diagnostic value of EV-associated miR-10b, plasma miR-10b and tumor markers (TMs), including α-fetoprotein (AFP), neuron-specific enolase, carcinoembryonic antigen (CEA), cytokeratin 19 fragment 21-1 (CYFRA211), pro-gastrin-releasing-peptide, carbohydrate antigen (CA)125, CA153, CA199 and CA724, was evaluated via receiver operating characteristic curve analysis. By searching the Gene Expression Omnibus and The Cancer Genome Atlas databases, miR-10b was identified as a potential biomarker. The analysis of clinical samples suggested that EV-associated miR-10b from plasma was significantly differentially expressed between LUAD and control samples. EV-associated miR-10b could function as a diagnostic marker for LUAD, with an AUC of 0.998, which was higher than the AUCs for TMs such as AFP, CEA, CYFRA211, CA125, CA153, CA199, CA724, pro-gastrin-releasing-peptide and neuron-specific enolase. In conclusion, EV-associated miR-10b may be a potential diagnostic biomarker for LUAD that is superior to plasma miR-10b and TMs.

CT Texture Analysis for Preoperative Identification of Lymphoma from Other Types of Primary Small Bowel Malignancies.

OBJECTIVES: To explore the application of computed tomography (CT) texture analysis in differentiating lymphomas from other malignancies of the small bowel. METHODS: Arterial and venous CT images of 87 patients with small bowel malignancies were retrospectively analyzed. The subjective radiological features were evaluated by the two radiologists with a consensus agreement. The region of interest (ROI) was manually delineated along the edge of the lesion on the largest slice, and a total of 402 quantified features were extracted automatically from AK software. The inter- and intrareader reproducibility was evaluated to select highly reproductive features. The univariate analysis and minimum redundancy maximum relevance (mRMR) algorithm were applied to select the feature subsets with high correlation and low redundancy. The multivariate logistic regression analysis based on texture features and radiological features was employed to construct predictive models for identification of small bowel lymphoma. The diagnostic performance of multivariate models was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: The clinical data (age, melena, and abdominal pain) and radiological features (location, shape, margin, dilated lumen, intussusception, enhancement level, adjacent peritoneum, and locoregional lymph node) differed significantly between the nonlymphoma group and lymphoma group (p < 0.05). The areas under the ROC curve of the clinical model, arterial texture model, and venous texture model were 0.93, 0.92, and 0.87, respectively. CONCLUSION: The arterial texture model showed a great diagnostic value and fitted performance in preoperatively discriminating lymphoma from nonlymphoma of the small bowel.

Computed tomography and magnetic resonance imaging of adenoid cystic carcinoma in the maxillary sinus: a retrospective study with radiologic-histopathologic correlations.

OBJECTIVE: The aim of this study was to investigate computed tomography (CT) and magnetic resonance imaging (MRI) findings in adenoid cystic carcinoma (ACC) in the maxillary sinus and their correlations with the tubular, cribriform, and solid histopathologic types of ACC. STUDY DESIGN: Twenty cases of histopathologically proven ACC in the maxillary sinus were retrospectively reviewed. CT and MRI findings were correlated with histopathologic results. RESULTS: On CT, significant differences were discovered among the 3 histopathologic ACC types in range, size, shape, margins, type of bone destruction, and time intensity curve (TIC) (P ≤ .018). Tubular lesions were limited in range, were smaller than the other types, produced small cystic patterns with well-defined margins, and caused a cribriform pattern of bone destruction. All tumors demonstrated heterogeneous intensity signal on T1- and T2-weighted images (T1WI and T2WI) and appeared as hypo- or isointense small cystic lesions on T1WI and hyperintense on T2WI (n = 6). Postcontrast MRI revealed marked heterogeneous enhancement for all lesions. The TIC showed a rapidly enhancing and slow washout pattern in all tubular lesions and a rapidly enhancing and rapid washout pattern in solid tumors. CONCLUSIONS: Different histologic patterns of ACCs have distinctive radiologic features, which can facilitate accurate preoperative diagnosis.

Clinical value of CT-guided percutaneous fine-needle aspiration biopsy for peritoneal lesions.

BACKGROUND: To investigate the clinical value of CT-guided percutaneous fine-needle aspiration biopsy for peritoneal lesions of unknown nature. METHODS: A retrospective analysis was conducted of 84 patients with peritoneal thickening for unknown reasons. There were 26 males and 58 females who underwent CT-guided percutaneous fine-needle aspiration biopsy for peritoneal lesions. RESULT: Among these 84 patients, no definite pathologic diagnosis was made in 3 patients, who were lost to the follow-up. The accuracy rate of CT-guided percutaneous fine-needle aspiration biopsy was 95.1% (77/81). Sixty lesions were pathologically-diagnosed with malignancies (74.1%), including 55 with peritoneal metastases, 4 with malignant mesotheliomas, and 1 with a lymphoma. Twenty-four patients (33.8%) were diagnosed as benign lesions, including 11 with tuberculosis and 13 with inflammatory lesions. The complications of CT-guided percutaneous fine-needle aspiration biopsy included bleeding in 1 patient and ascites leakage in 2 patients. CONCLUSION: CT-guided percutaneous fine-needle aspiration biopsy is a safe and effective method for diagnosing peritoneal lesions.

Exploratory Study of a CT Radiomics Model for the Classification of Small Cell Lung Cancer and Non-small-Cell Lung Cancer.

Background: Radiomics can quantify tumor phenotypic characteristics non-invasively by applying feature algorithms to medical imaging data. In this study, we investigated the association between radiomics features and the tumor histological subtypes, and we aimed to establish a nomogram for the classification of small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Methods: This was a retrospective single center study. In total, 468 cases including 202 patients with SCLC and 266 patients with NSCLC were enrolled in our study, and were randomly divided into a training set (n = 327) and a validation set (n = 141) in a 7:3 ratio. The clinical data of the patients, including age, sex, smoking history, tumor maximum diameter, clinical stage, and serum tumor markers, were collected. All patients underwent enhanced computed tomography (CT) scans, and all lesions were pathologically confirmed. A radiomics signature was generated from the training set using the least absolute shrinkage and selection operator algorithm. Independent risk factors were identified by multivariate logistic regression analysis, and a radiomics nomogram based on the radiomics signature and clinical features was constructed. The capability of the nomogram was evaluated in the training set and validated in the validation set. Results: Fourteen of 396 radiomics parameters were screened as important factors for establishing the radiomics model. The radiomics signature performed well in differentiating SCLC and NSCLC, with an area under the curve (AUC) of 0.86 (95% CI: 0.82-0.90) in the training set and 0.82 (95% CI: 0.75-0.89) in the validation set. The radiomics nomogram had better predictive performance [AUC = 0.94 (95% CI: 0.90-0.98) in the validation set] than the clinical model [AUC = 0.86 (95% CI: 0.80-0.93)] and the radiomics signature [AUC = 0.82 (95% CI: 0.75-0.89)], and the accuracy was 86.2% (95% CI: 0.79-0.92) in the validation set. Conclusion: The enhanced CT radiomics signature performed well in the classification of SCLC and NSCLC. The nomogram based on the radiomics signature and clinical factors has better diagnostic performance for the classification of SCLC and NSCLC than the simple application of the radiomics signature.

Influence and mechanism of lung cavitation development on antiangiogenic therapy.

BACKGROUND: Antiangiogenic agent-treated patients usually develop cavitation in their lung lesions. The clinical significance of lung cavitation development during antiangiogenic therapy has not been determined yet. Herein, we evaluated the clinical outcomes of patients who developed tumor cavitation following apatinib treatment and explored the mechanisms. METHODS: In this study (Clinical Trial No. NCT03629691), 187 patients (77 lung cancer and 110 gastric adenocarcinoma patients) who had progressed or relapsed after undergoing at least two lines of systemic therapy in accordance with the NCCN guidelines for primary or metastatic lung tumors were treated with apatinib at a dosage of 250 mg per day between February 1, 2015 and May 19, 2017. The effect of lung cavitation development on locoregional control (LRC), progression-free survival (PFS), and overall survival (OS) was analyzed with Kaplan-Meier estimates and compared with the log-rank test. Zebrafish experiments were used to study the anticancer mechanism of apatinib in different tumors. Western-blotting was used to analyze the expression of Cyclin D1, p53, HIF-α, and VEGFR before and after apatinib treatment in both normoxia and hypoxia. RESULTS: Cavitation development was beneficial in patients receiving apatinib therapy regardless of whether they had primary or metastatic lung cancer. Zebrafish experiments showed that apatinib inhibited tumor growth by both suppressing vascular growth and inhibiting cell proliferation. Vascular proliferation induced by the H1299 cell lines showed higher sensitivity to apatinib than that induced by the SCG-7901 cell line. However, apatinib showed weak tumor type selectivity on cell proliferation inhibition in vivo. Under hypoxic conditions, apatinib could not inhibit the protein expression of VEGFR and HIF-α in both cell lines; however, apatinib decreased the expression of cyclin D1 and P53 significantly. CONCLUSIONS: Lung cavitation development is common with apatinib therapy and is a potential prognostic marker. Apatinib inhibits tumor growth by both vessel growth inhibition and proliferation inhibition.

Application value of coaxial biopsy system in needle cutting biopsy for focal ground glass-like density nodule.

OBJECTIVE: The objective of the study is to evaluate the clinical efficacy and accuracy of coaxial biopsy puncture applied to make a diagnosis in 76 patients diagnosed with focal ground-glass density nodule (GGN). MATERIALS AND METHODS: In total, 76 patients were diagnosed with pure GGN (pGGN), 24 males and 52 females, aged (52 ± 1.2) years on average (range: 47-72 years). All patients underwent computed tomography (CT)-guided coaxial biopsy puncture to localize the position and measure the size of pGGN. The maximal diameter of the pGGN and the length of puncture needle into the lung were quantitatively measured. The diagnostic accuracy rate of CT-guided biopsy was subsequently validated by histological pathological examination. The incidence of postoperative complications was observed after biopsy. RESULTS: The pGGN diameter was measured from 5 to 45 mm, 21 mm on average. The pGGN depth ranged from 0 to 48 mm with a mean depth of 15 mm. Compared with the final diagnosis, the sensitivity, specificity, and accuracy rates of CT-guided needle aspiration biopsy in the diagnosis of pGGN were calculated as 97.3% (54/56), 85.0% (17/20), and 93.4% (71/76), respectively. Fourteen cases (18.4%) suffered from slight pneumothorax, 17 (22.4%) with mild errhysis surrounding the biopsy needle or lesions. CONCLUSION: CT-guided needle aspiration biopsy yields higher diagnostic accuracy and similar postoperative complications compared with the conventional histological diagnosis. For those undiagnosed by conventional CT scan and nontolerable of surgery, CT-guided needle aspiration biopsy serves as a safe and effective intervention.

Computed Tomography and Magnetic Resonance Imaging Manifestations of Spinal Monostotic Fibrous Dysplasia.

AIM: The purpose of the study was to analyze and summarize the computed tomography (CT) and magnetic resonance imaging (MRI) findings of spinal monostotic fibrous dysplasia (MFD) as well as evaluate the clinical value of CT and MRI in MFD diagnosis. MATERIALS AND METHODS: CT (n = 4) and MRI (n = 5) images of six patients with pathologically confirmed spinal MFD were examined. The assessed image features included location, shape, rib involvement, vertebral collapse, margin, attenuation, and sclerotic rim on CT, as well as signal intensity, dark signal rim, and enhancement pattern on MRI. RESULTS: In total, four of six patients underwent CT scanning. The most common findings on CT scanning were expansile lesions (n = 4), sclerotic rims (n = 4), and ground-glass opacity (GGO) (n = 4). In total, five of six patients underwent MRI. The lesions were low-signal intensity (n = 2), low-to-isointense signal intensity (n = 1), and low-signal intensity with several isointense portions (n = 2) on T1-weighted imaging (T1WI). The lesions were low-signal intensity (n = 1), isointense to high intensity (n = 1), and isointense signal intensity with several high portions (n = 3) on T2WI. A dark signal rim was found in most cases on T1WI and T2WI (n = 4). The lesions (n = 2) showed obvious enhancement. CONCLUSIONS: The CT and MRI manifestations of spinal MFD have the following characteristics: expansile lesion, GGO, sclerotic rim, and no obvious soft-tissue mass. The combined use of CT and MRI examinations is necessary for patients with suspected spinal MFD.

Primary Intraosseous Hemangioma of the Foreman Rotundum Area.

The primary intraosseous hemangioma is extremely rare in foreman rotundum area. However, it is very important for radiologists and otolaryngologists to be aware of it, in order to be able to provide accurately diagnosis as well choose the best treatment plan. The purpose of this article is to describe imaging features of this kind of tumor.

Evaluate of the effect of low tube voltage on the radiation dosage using 640-slice coronary CT angiography.

BACKGROUND: 640-slice coronary CT angiography is becoming an accurate and reliable method of diagnosing coronary heart disease. However, how to reduce the radiation dosage while ensuring the clinically acceptable image quality remains a quite challenging issue. OBJECTIVE: To evaluate the effect of low tube voltage on radiation dosage under 640-slice coronary CT angiography (CCTA). METHODS: Four hundred patients (236 males, 164 females) with coronary heart disease and underwent CCTA using DCVT were classified into A1 (tube voltage: 120 kV; exposure phase window: 30-80%), B1 (120 kV; 70-80%), A2 (100 kV; 30-80%) and B2 group (100 kV; 70-80%), respectively. Image qualities and effective dose (ED) were assessed and compared. RESULTS: No significant differences were observed among the groups in terms of age, height, weight and body mass index (BMI) (P > 0.05). ED were significantly lower in 100 kV group (P < 0.05). CT values of coronary artery in 100 kV groups were 13.5% and 17.3% higher than 120 kV group. ED in B1 group were 64.5% and 67.0% lower than A1 group. ED in B2 group were 65.4% and 65.2% lower than A2 group. CONCLUSION: When using a 640-slice CCTA prospective ECG-gating scanning mode, it is preferable to use a 100 kV tube voltage setting because compared to 120 kV tube voltage protocol, it seems to significantly decrease the mean effective radiation dose, without significantly lowering both the subjective and objective image quality.

Application of Gemstone Spectral Computed Tomography Imaging in the Characterization of Solitary Pulmonary Nodules: Preliminary Result.

OBJECTIVE: This study aimed to observe the value of computed tomography (CT) spectral imaging parameters in the diagnosis of solitary pulmonary nodules, during the contrast-enhanced early phase and late phase. MATERIALS AND METHODS: This study was approved by the institutional review board and written informed consent was obtained from all patients. One hundred thirty-nine patients with solitary pulmonary nodules proved by pathology underwent double-phase enhanced CT scan using gemstone spectral imaging mode on a Discovery CT750 HD, and were divided into an active inflammatory group (43 cases), a malignant group (65 cases), and a tuberculosis group (31 cases). The slope rate was calculated from the spectral curve. Iodine concentrations (ICs) were derived from iodine-based material decomposition CT images and normalized to the IC in the aorta. The Kruskal-Wallis test and Nemenyi test were performed to compare quantitative parameters among the 3 groups or between each of the 2 groups. RESULTS: There were significant differences in the slope rate, IC, and normalized IC (NIC) among the 3 groups. In the active inflammatory group, malignant group, and tuberculosis group, the mean slope rate were 3.03 ± 0.71 (SD), 1.96 ± 0.91, and 1.37 ± 0.43, respectively, during the early phase and 3.28 ± 0.67, 2.24 ± 0.82, and 1.67 ± 0.64, respectively, during the late phase. The ICs were 2.68 mg/mL ± 0.56, 1.65 mg/mL ± 0.76, and 1.10 mg/mL ± 0.34, respectively, during the early phase and 2.79 mg/mL ± 0.57, 1.90 mg/mL ± 0.71, and 1.29 mg/mL ± 0.44, respectively, during the late phase. The NIC were 0.24 ± 0.06, 0.16 ± 0.04, and 0.10 ± 0.04, respectively, during the early phase and 0.57 ± 0.10, 0.43 ± 0.11, and 0.25 ± 0.09, respectively, during the late phase. The mean slope rate, IC, and NIC for the active inflammatory group were significantly higher than these parameters for the malignant group (P < 0.05), and the parameters for malignant group were significantly higher than the tuberculosis group (P < 0.05). CONCLUSIONS: Dual-energy CT gemstone spectral imaging provides a novel method to better characterize pulmonary nodules in double-phase contrast-enhanced scanning.

Effect of lipiodol and methylene blue on the thoracoscopic preoperative positioning.

The aim of this study was to compare and analyze the site-specific accuracy of mixture of lipiodol and methylene blue (MLM) (0.6 ml, 1:5) and pure methylene blue (0.5 ml) on the rabbit lungs. In this study, CT-guided percutaneous injection of MLM and methylene blue. Compare the staining degree by biopsy of lung tissue. Use 4 points system to evaluate the site-specific accuracy at 6h and 24 h after injection. For MLM, evaluate its radiopacity by radiation. When evaluate the positioning, 2 points mean acceptable, 3 points mean excellent. The results indicated that the staining range of MLM is obvious less than that of methylene blue (0.6 vs. 1.0 cm, P<0.01), but the staining capacity of MLM is higher than that of methylene blue (2.8 vs. 2.2, P = 0.01). About the staining abilities which are evaluated as excellent, MLM group accounts for 81%, methylene blue group accounts for 38% (P = 0.011). About the radiopacity which are evaluated as acceptable or excellent, MLM group accounts for 62%. With good direct vision, the suitable positioning rate of MLM can be 100%, which is better than that of methylene blue. In conclusion, percutaneous injection of MLM can be used to lung positioning. The result shows that use MLM is better than only using methylene blue. But it is necessary to do the investigation in human beings in order to confirm the feasibility of its clinical application.

Diagnostic value of computed tomography scanning in differentiating malignant from benign solitary pulmonary nodules: a meta-analysis.

An early diagnosis of lung cancer is crucial for early treatment and management. The objective of this systematic review was to assess the overall diagnostic accuracy of chest computed tomography (CT) scanning in differentiating malignant from benign solitary pulmonary nodules (SPNs) with meta-analysis. The PubMed and China National Knowledge Infrastructure (CNKI) database were searched for eligible studies published up to March 2014. The sensitivity, specificity, and other measures of accuracy of chest CT scanning in the diagnosis of SPNs were pooled along with 95 % confidence intervals (CI). Summary receiver operating characteristic (ROC) curves were used to summarize overall test performance. Thirty-two studies met our inclusion criteria. The summary estimates for chest CT scanning in the diagnosis of SPNs in the meta-analysis were as follows: pooled sensitivity, 0.89 (95 % CI, 0.88 to 0.91); pooled specificity, 0.70 (95 % CI, 0.68 to 0.73); positive likelihood ratio, 2.88 (95 % CI, 2.46 to 3.37); negative likelihood ratio, 0.16 (95 % CI, 0.12 to 0.21); and diagnostic odds ratio, 23.83 (95 % CI, 16.18 to 35.11). The results indicate that CT scanning has relatively high sensitivity and moderate specificity for the diagnosis of SPNs. Given the low cost and growing prevalence of the technology, CT scanning should be recommended as the initial test for the evaluation of SPNs.