Lin-Feng Yan

Intravoxel incoherent motion diffusion-weighted MR imaging of gliomas: efficacy in preoperative grading

The preoperative grading of gliomas, which is critical for guiding therapeutic strategies, remains unsatisfactory. We aimed to retrospectively assess the efficacy of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in the grading of gliomas. Forty-two newly diagnosed glioma patients underwent conventional MR imaging, DWI, and contrast-enhanced MR imaging. Parameters of apparent diffusion coefficient (ADC), slow diffusion coefficient (D), fast diffusion coefficient (D*), and fraction of fast ADC (f) were generated. They were tested for differences between low- and high-grade gliomas based on one-way ANOVA. Receiver-operating characteristic (ROC) analyses were conducted to determine the optimal thresholds as well as the sensitivity and specificity for grading. ADC, D, and f were higher in the low-grade gliomas, whereas D* tended to be lower (all P<0.05). The AUC, sensitivity, specificity and the cutoff value, respectively, for differentiating low- from high-grade gliomas for ADC, D and f, and differentiating high- from low-grade gliomas for D* were as follows: ADC, 0.926, 100%, 82.8%, and 0.7 × 10−3 mm2/sec; D, 0.942, 92.3%, 86.2%, and 0.623 × 10−3 mm2/sec; f, 0.902, 92.3%, 86.2%, and 35.3%; D*, 0.798, 79.3%, 84.6%, and 0.303 × 10−3 mm2/sec. The IVIM DWI demonstrates efficacy in differentiating the low- from high-grade gliomas.

Pulmonary microvascular endothelial cells from bleomycin-induced rats promote the transformation and collagen synthesis of fibroblasts.

Accumulation and activation of myofibroblasts are the hallmark of progressive pulmonary fibrosis, and the resident fibroblasts are the major source of myofibroblasts. However, the key factors involved in the transformation of fibroblasts are unknown. Pulmonary microvascular endothelial cells (PMVECs), major effector cells against pathogenesis in early stages of the disease, can secrete cytokines to induce the differentiation of mesenchymal cells. We speculated that PMVECs could secrete pro‐fibrotic cytokines and promote the transformation of fibroblasts into myofibroblasts. Accordingly, we established a co‐culture system with PMVECs and fibroblasts to examine the specific transformation and collagen synthesis of the co‐cultured fibroblasts by FACS and Western blot, prior to and after treatment with neutralizing antibodies against transforming growth factor‐beta1 (TGF‐β1) and connective tissue growth factor (CTGF). We also analyzed expression of TGF‐β1 and CTGF in PMVECs. The synthesis and secretion of TGF‐β1 and CTGF protein were up‐regulated in PMVECs isolated from bleomycin (BLM)‐treated rats, most prominently at 7 days post‐instillation. We showed that the PMVECs isolated from BLM‐induced rats could induce the transformation of normal fibroblasts and their secretion of collagen I, which was inhibited by both neutralizing anti‐TGF‐β1 and anti‐CTGF antibodies. Therefore, up‐regulation of TGF‐β1 and CTGF in PMVECs plays an important role in activation, transformation, and collagen synthesis of fibroblasts; in particular, these effects in PMVECs are likely to be the key factors for activation and stimulation of static fibroblasts in lung interstitium in early stages of pulmonary fibrosis disease. J. Cell. Physiol. 226: 2091–2102, 2011.

Remifentanil protects liver against ischemia/reperfusion injury through activation of anti-apoptotic pathways

BACKGROUND Remifentanil protects against ischemia/reperfusion (I/R)-induced organ injury, although its underlying mechanism remains elusive. This study was designed to examine the protective effect of remifentanil preconditioning, if any, against hepatic I/R injury in rats and the underlying mechanism involved. MATERIALS AND METHODS Adult Sprague-Dawley rats were randomly divided into sham operation (S group), ischemia/reperfusion (I/R group), and remifentanil preconditioning (R group) groups. Rats in the I/R group were subjected to a partial (70%) hepatic ischemia for 45 min, followed by 1 h, 3 h, and 6 h of reperfusion. Rats in the R group received venous injection of remifentanil (2 μg/kg/min) from 30 min prior to hepatic ischemia to the end of ischemia. Hepatic morphology and apoptosis were examined. Markers of liver damage, oxidative stress, and inflammation were evaluated. Mitochondrial function was assessed using mitochondrial membrane potential and appearance of mitochondrial swelling. RESULTS Compared with the S group, rats in the I/R group displayed a massive degenerative death in liver tissues and significantly enhanced cell apoptosis. Remifentanil preconditioning significantly reduced I/R-induced hepatocyte apoptosis. In addition, remifentanil protected against I/R-induced mitochondrial swelling and loss of membrane potential. Remifentanil preconditioning inhibited I/R-induced increases in tumor necrosis factor α, intercellular adhesion molecule 1, and nuclear factor κB p65 levels in liver tissues. Remifentanil preconditioning also inhibited the loss in superoxide dismutase and rise in malondialdehyde levels in liver tissues going through I/R injury. CONCLUSIONS Our data revealed that remifentanil preconditioning may turn on multiple cellular pathways in hepatocytes to protect the liver from I/R injury by alleviating hepatic apoptosis.

Alteration of tight junctions in pulmonary microvascular endothelial cells in bleomycin-treated rats.

Macrophages and eosinophils that infiltrate the lung interstitium are active promoters of bleomycin (BLM)-induced pulmonary fibrosis. Leukocyte infiltration indicates disrupted barrier function in endothelial cells. The aims of this study were to investigate tight junctions (TJs) and their regulation of zonula occludens-1 (ZO-1) proteins in pulmonary microvascular endothelial cells (PMVECs) during BLM-induced pulmonary fibrosis and to compare the BLM model with the pneumococcus-induced pneumonia model of lung injury. The results revealed that the majority of PMVEC TJs were in an open state in BLM-treated tissue, where PMVEC paracellular permeability remained consistently higher than in controls. Macrophage accumulation in the lung interstitium was also significantly higher than in controls. Alteration of ZO-1 protein expression further supported the apparent disruption in PMVEC TJs in tissues from BLM-treated rats. These changes were markedly different from the concurrent changes in pneumococcus-infected rats. The findings suggest that changes in the ZO-1 proteins of PMVECs underlie the sustained disruption of TJs in BLM-treated animal models of pulmonary fibrosis. This dysfunction of paracellular barriers directly leads to the sustained infiltration of leukocytes and corresponding cytokine secretion, proliferation of fibroblasts, and progression of pulmonary fibrosis.

Proliferative phenotype of pulmonary microvascular endothelial cells plays a critical role in the overexpression of CTGF in the bleomycin-injured rat.

The pathogenesis of idiopathic pulmonary fibrosis (IPF) is not very clear, with evidence for the involvement of both inflammation and aberrant vascular remodeling (associated with angiogenesis). Pulmonary microvascular endothelial cells (PMVECs), which play a major role in inflammation, secrete cytokines that promote the transformation and collagen synthesis of fibroblasts. Moreover, angiogenesis is characterized by PMVEC proliferation. The main aim of this study was to confirm the role of PMVECs in pulmonary fibrosis. Accordingly, we observed the functional changes in PMVECs in bleomycin (BLM)-treated rats (pulmonary fibrosis model) in vivo, and compared them with those of rats with pneumonia. The proliferation phenotype and intracellular ionized calcium concentration ([Ca(2+)]i) of PMVECs from BLM-treated rats were also investigated. The functioning of PMVECs was abnormal in BLM-injured rats, particularly with regard to their proliferation and secretion of connective tissue growth factor (CTGF). [Ca(2+)]i was increased in the proliferated PMVECs from BLM-treated rats. The findings suggest that dysfunction of PMVECs characterized by overexpression of CTGF is critical in rat pulmonary injury induced by BLM, and is probably related with the proliferative phenotype and [Ca(2+)]i overload. It can be concluded from the results that proliferation of PMVECs plays an important role in the pathogenesis of BLM-induced PF.

Predicting Subtypes of Thymic Epithelial Tumors Using CT: New Perspective based on a Comprehensive Analysis of 216 Patients

It is highly necessary to identify low versus high risk thymic epithelial tumors (TETs) before operation to guide optimal treatment strategies. Current CT diagnostic parameters could not effectively achieve this goal. We evaluated three parameters of CT scan in a cohort of 216 TETs patients. Parameters of contrast enhancement, risk of aggressiveness, and nodule with fibrous septum were evaluated in low (A, AB) versus high risk (B1, B2, B3 and thymic carcinoma) TETs. Grade of contrast enhancement showed predictive value in classifying low and high risk TETs well. A maximal contrast-enhanced range of 25.5 HU could produce 78.8% sensitivity and 68.5% specificity in determining low risk subtypes. Additionally, risk of aggressiveness parameter was demonstrated to be associated with TETs subtype (r = 0.801, P < 0.001) and may add confidence in determining low versus high risk subtypes. Furthermore, multiple nodule with fibrous septum could suggest subtype AB. Findings from this study support role of studied parameters of CT manifestations in predicting the low and high risk stages of TETs. These findings provide empirical evidence for incorporating these parameters in clinical practice for identifying TETs stage before operation, if validated in additional studies.

Comparison between ultra-high and conventional mono b-value DWI for preoperative glioma grading

To compare the efficacy of ultra-high and conventional mono-b-value DWI for glioma grading, in 109 pathologically confirmed glioma patients, ultra-high apparent diffusion coefficient (ADCuh)was calculated using a tri-exponential mode, distributed diffusion coefficients (DDCs) and α values were calculated using a stretched-exponential model, and conventional ADC values were calculated using a mono-exponential model. The efficacy and reliability of parameters for grading gliomas were investigated using receiver operating characteristic (ROC) curve and intra-class correlation (ICC) analyses, respectively. The ADCuh values differed (P < 0.001) between low-grade gliomas (LGGs; 0.436 ×10−3 mm2/sec) and high-grade gliomas (HGGs; 0.285 × 10−3 mm2/sec). DDC, a and various conventional ADC values were smaller in HGGs (all P ≤ 0.001, vs. LGGs). The ADCuh parameter achieved the highest diagnostic efficacy with an area under curve (AUC) of 0.993, 92.9% sensitivity and 98.8% specificity for glioma grading at a cutoff value of 0.362×10−3 mm2/sec. ADCuh measurement appears to be an easy-to-perform technique with good reproducibility (ICC = 0.9391, P < 0.001). The ADCuh value based in a tri-exponential model exhibited greater efficacy and reliability than other DWI parameters, making it a promising technique for glioma grading.

Optimizing a machine learning based glioma grading system using multi-parametric MRI histogram and texture features

Current machine learning techniques provide the opportunity to develop noninvasive and automated glioma grading tools, by utilizing quantitative parameters derived from multi-modal magnetic resonance imaging (MRI) data. However, the efficacies of different machine learning methods in glioma grading have not been investigated.A comprehensive comparison of varied machine learning methods in differentiating low-grade gliomas (LGGs) and high-grade gliomas (HGGs) as well as WHO grade II, III and IV gliomas based on multi-parametric MRI images was proposed in the current study. The parametric histogram and image texture attributes of 120 glioma patients were extracted from the perfusion, diffusion and permeability parametric maps of preoperative MRI. Then, 25 commonly used machine learning classifiers combined with 8 independent attribute selection methods were applied and evaluated using leave-one-out cross validation (LOOCV) strategy. Besides, the influences of parameter selection on the classifying performances were investigated. We found that support vector machine (SVM) exhibited superior performance to other classifiers. By combining all tumor attributes with synthetic minority over-sampling technique (SMOTE), the highest classifying accuracy of 0.945 or 0.961 for LGG and HGG or grade II, III and IV gliomas was achieved. Application of Recursive Feature Elimination (RFE) attribute selection strategy further improved the classifying accuracies. Besides, the performances of LibSVM, SMO, IBk classifiers were influenced by some key parameters such as kernel type, c, gama, K, etc. SVM is a promising tool in developing automated preoperative glioma grading system, especially when being combined with RFE strategy. Model parameters should be considered in glioma grading model optimization.

Potential role of the Jagged1/Notch1 signaling pathway in the endothelial-myofibroblast transition during BLM-induced pulmonary fibrosis

Endothelial cell myofibroblast transition (EndoMT) is found during the process of bleomycin (BLM)‐induced pulmonary fibrosis in rats, and plays a very important role in sustaining inflammation and collagen secretion. Moreover, some studies have suggested that the Notch1 signaling pathway may be involved in the expression of α‐smooth muscle actin (α‐SMA) in pulmonary microvascular endothelial cells (PMVECs), a protein marker of EndoMT. Therefore, we aimed to investigate the expression level of α‐SMA and Notch1‐related signaling molecules in PMVECs from BLM‐induced rats and determine the relationship between the Notch1 signaling pathway and the expression of α‐SMA in PMVECs. We found that the expression levels of α‐SMA, Notch1, and Jagged1 were upregulated, while the expression levels of Dll4 were downregulated. Furthermore, there was a positive correlation between the expression of Jagged1 and the α‐SMA proteins in PMVECs, and NF‐κB was downregulated by decreasing the expression of Jagged1. In conclusion, the Jagged1/Notch1 signaling pathway is activated in PMVECs during the pathogenesis of BLM‐induced pulmonary fibrosis in rats, and it may induce α‐SMA expression via a non‐canonical pathway involving NF‐κB as the target molecule. The precise mechanism and the molecules involved in this signaling pathway need to be further elucidated.

Combination of IVIM-DWI and 3D-ASL for differentiating true progression from pseudoprogression of Glioblastoma multiforme after concurrent chemoradiotherapy: study protocol of a prospective diagnostic trial

BackgroundStandard therapy for Glioblastoma multiforme (GBM) involves maximal safe tumor resection followed with radiotherapy and concurrent adjuvant temozolomide. About 20 to 30% patients undergoing their first post-radiation MRI show increased contrast enhancement which eventually recovers without any new treatment. This phenomenon is referred to as pseudoprogression. Differentiating tumor progression from pseudoprogression is critical for determining tumor treatment, yet this capacity remains a challenge for conventional magnetic resonance imaging (MRI). Thus, a prospective diagnostic trial has been established that utilizes multimodal MRI techniques to detect tumor progression at its early stage. The purpose of this trial is to explore the potential role of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and three-dimensional arterial spin labeling imaging (3D-ASL) in differentiating true progression from pseudoprogression of GBM. In addition, the diagnostic performance of quantitative parameters obtained from IVIM-DWI and 3D-ASL, including apparent diffusion coefficient (ADC), slow diffusion coefficient (D), fast diffusion coefficient (D*), perfusion fraction (f), and cerebral blood flow (CBF), will be evaluated.MethodsPatients that recently received a histopathological diagnosis of GBM at our hospital are eligible for enrollment. The patients selected will receive standard concurrent chemoradiotherapy and adjuvant temozolomide after surgery, and then will undergo conventional MRI, IVIM-DWI, 3D-ASL, and contrast-enhanced MRI. The quantitative parameters, ADC, D, D*, f, and CBF, will be estimated for newly developed enhanced lesions. Further comparisons will be made with unpaired t-tests to evaluate parameter performance in differentiating true progression from pseudoprogression, while receiver-operating characteristic (ROC) analyses will determine the optimal thresholds, as well as sensitivity and specificity. Finally, relationships between these parameters will be assessed with Pearson’s correlation and partial correlation analyses.DiscussionThe results of this study may demonstrate the potential value of using multimodal MRI techniques to differentiate true progression from pseudoprogression in its early stages to help decision making in early intervention and improve the prognosis of GBM.Trial registrationThis study has been registered at ClinicalTrials.gov (NCT02622620) on November 18, 2015 and published on March 28, 2016.