Antiangiogenesis with bevacizumab, an antibody against vascular endothelial growth factor (VEGF), has been used for devascularization to limit the growth of malignant glioma. However, the benefits are transient due to elusive mechanisms underlying resistance to the antiangiogenic therapy. Glioma stem cells (GSCs) are capable of forming vasculogenic mimicry (VM), an alternative microvascular circulation independent of VEGF-driven angiogenesis. Herein, we report that the formation of VM was promoted by bevacizumab-induced macroautophagy/autophagy in GSCs, which was associated with tumor resistance to antiangiogenic therapy. We established a 3-dimensional collagen scaffold to examine the formation of VM and autophagy by GSCs, and found that rapamycin increased the number of VM and enhanced KDR/VEGFR-2 phosphorylation. Treatment with chloroquine, or knockdown of the autophagy gene ATG5, inhibited the formation of VM and KDR phosphorylation in GSCs. Notably, neutralization of GSCs-produced VEGF with bevacizumab failed to recapitulate the effect of chloroquine treatment and ATG5 knockdown, suggesting that autophagy-promoted formation of VM was independent of tumor cell-derived VEGF. ROS was elevated when autophagy was induced in GSCs and activated KDR phosphorylation through the phosphoinositide 3-kinase (PI3K)-AKT pathway. A ROS inhibitor, N-acetylcysteine, abolished KDR phosphorylation and the formation of VM by GSCs. By examination of the specimens from 95 patients with glioblastoma, we found that ATG5 and p-KDR expression was strongly associated with the density of VM in tumors and poor clinical outcome. Our results thus demonstrate a crucial role of autophagy in the formation of VM by GSCs, which may serve as a therapeutic target in drug-resistant glioma.

Aberrant expression of TRIM‐containing protein 44 (TRIM44) acts as a promoter in multiple cancers. Here, we investigated the biological functions and clinical significance of TRIM44 in human esophageal cancer (HEC). TRIM44 expression was significantly higher in HEC tissues than corresponding normal tissues at both the mRNA (2.42 ± 0.52 vs 0.99 ± 0.25) and protein (1.01 ± 0.27 vs 0.30 ± 0.13) levels. Patients with high TRIM44 expression showed poor differentiation (P = 1.39 × 10−5), advanced TNM stage (P = 3.87 × 10−4) and, most importantly, significantly poorer prognosis (P = 2.80 × 10−5). TRIM44 played a crucial role in epithelial mesenchymal transition (EMT). A significant correlation was observed between TRIM44 and Ki67 expression. We demonstrated that TRIM44 markedly enhanced HEC cell proliferation, migration, and invasion. Additionally, TRIM44 was involved in the AKT/mTOR signaling pathway and its downstream targets, such as STAT3 phosphorylation. Thus, elevated TRIM44 expression promotes HEC development by EMT via the AKT/mTOR pathway, and TRIM44 may be a novel prognostic indicator for HEC patients after curative resection.

Three-dimensional (3D) culture, which can simulate in vivo microenvironments, has been increasingly used to study tumor cell biology. Since most preclinical anti-glioma drug tests still rely on conventional 2D cell culture, we established a collagen scaffold for 3D glioma cell culture. Glioma cells cultured on these 3D scaffolds showed greater degree of dedifferentiation and quiescence than cells in 2D culture. 3D-cultured cells also exhibited enhanced resistance to chemotherapeutic alkylating agents, with a much higher proportion of glioma stem cells and upregulation of O6-methylguanine DNA methyltransferase (MGMT). Importantly, tumor cells in 3D culture showed chemotherapy resistance patterns similar to those observed in glioma patients. Our results suggest that 3D collagen scaffolds are promising in vitro research platforms for screening new anti-glioma therapeutics.

The objective this study was to measure the changes of sphenoid sinusin the Chinese in AsiausingCT sagittal thin-slice reconstruction images, and to clarify the three-dimensional anatomical features of sphenoid sinus with its surrounding structures, relevant to the performing of the endoscopic sphenoidotomy. The sagittal reconstruction images were obtained from 178 CT images of 89 cases of normal adult participants (54 males and 35 females) with sphenoid sinus. We took the high-resolution axial CT images, from all the subjects, of the thickness by 0.625 mm, and reconstructed 1-mm-thick gapless sagittal CT images to measure the distance of all the sellar and pre-sellar types on the three-dimensional reconstructable sagittal plane under the bone window (4,000 at its width, and 400 at its level) in the CT images. The length of mean vertical line from the center of sphenoid ostium to the roof of sphenoid sinus of Non Onodi cell type is 10.6 ± 1.5 mm, and of Onodi cell type is 3.3 ± 1.5 mm. The length of vertical line from the center of sphenoid ostium to the lowest level of the bottom of sphenoid sinus is 12 mm ± 3.7 mm. The length of mean horizontal line from the sphenoid ostium to the posterior wall of sphenoid sinus is 18 ± 1.5 mm or 28 ± 2.5 mm. The mean horizontal line from the lowest point of the sella to the anterior wall of sphenoid sinus is 17.5 ± 1.3 mm in length. The mean horizontal distance from anterior wall to posterior wall of sphenoid sinus of Non Onodi cell type lining skull base is 10.1 ± 1.0 mm, and of Onodi cell type, is 5.2 ± 4.3 mm. The longest horizontal distance from the anterior wall to the posterior wall of sphenoid sinus is 22.0 ± 7.7 mm. The present study provides atomical information about sphenoid sinus of the Chinese in Asia with some surgical distance measured between the sphenoid ostium and the surrounding structures, which is essential to avoid the complications during surgery.

This prospective study compares different clinical characteristics and outcomes of patients with two types of sacral extradural spinal meningeal cysts (SESMC) undergoing different means of surgical excision. Using the relationship between the cysts and spinal nerve roots fibers (SNRF) as seen under microscope, SESMCs were divided into two types: cysts with SNRF known as Tarlov cysts and cysts without. The surgical methods were tailored to the different types of SESMCs. The improved Japanese Orthopedic Association (IJOA) scoring system was used to evaluate preoperative and postoperative neurological function of the patients. Preoperative IJOA scores were 18.5±1.73, and postoperative IJOA scores were 19.6±0.78. The difference between preoperative and postoperative IJOA scores was statistically significant (t = -4.52, p = 0.0001), with a significant improvement in neurological function after surgery. Among the improvements in neurological functions, the most significant was sensation (z=-2.74, p=0.006), followed by bowel/bladder function (z=-2.50, p=0.01). There was a statistically significant association between the types of SESMC and the number (F=12.57, p=0.001) and maximum diameter (F=8.08, p=0.006) of the cysts. SESMC with SNRF are often multiple and small, while cysts without SNRF tend to be solitary and large. We advocate early surgical intervention for symptomatic SESMCs in view of significant clinical improvement postoperatively.

This study analyzed the clinical characteristics and outcomes of sacral extradural spinal meningeal cysts with spinal nerve root fibers treated by reconstruction of the nerve root sheaths. The relationships between the cysts and spinal nerve root fibers were examined microscopically, the cysts were partially excised, and the defects were oversewn to reconstruct the nerve root sheaths. The Improved Japanese Orthopedic Association (IJOA) scoring system was used to evaluate preoperative and postoperative neurological function. Thirty-eight patients were included in this study, with a mean age of 41.4±15.57 years. The mean IJOA score was 18.8±1.32 preoperatively and 19.6±0.65 postoperatively, which was a significant difference (t=-3.77, P=0.001). These results indicate a significant improvement in neurological function after surgery. The most significant improvement in neurological function was sensation (z=-2.86, P=0.004), followed by bowel/bladder function (z=-2.31, P=0.02). The pathophysiological mechanism underlying the formation of SESMCs with SNRFs is congenital weakness of the nerve root sheath [3]. High hydrostatic pressure generated by upright walking and a ball-valve effect result in cyst enlargement [3][4][5]. The walls of the cysts are formed by enlargement of the perineural nerve root sheaths, resulting in alteration of the environment around the spinal nerve root fibers. This alteration causes malfunction of the involved spinal nerve root fibers, similar to axonal transport dysfunction [6]. This malfunction differs from malfunction associated with compression against adjacent bone or other nerve

Objectives: Ring finger protein 38 (RNF38), as an E3 ubiquitin ligase, plays an essential role in multiple biological processes by controlling cell apoptosis, cell cycle and DNA repair, and resides in chromosome 9 (9p13) which is involvement in cancer pathogenesis including lung cancer. However, its function in tumorigenesis remains unclear. Hence, this study set out to investigate the biological function and clinical implications of RNF38 in non-small cell lung cancer (NSCLC).Materials and Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to detect RNF38 protein and mRNA levels in NSCLC and corresponding paratumor tissues. Tissue microarrays (TMA) analysis of 208 NSCLC cases were used to evaluate the relationship between RNF38 expression and clinical implications. Prognostic value was assessed by Kaplan-Meier analysis and log-rank tests. Wound-healing assays, trans-well assays, colony formation assays and CCK8 were used to assess cell migration, invasion and proliferative ability respectively. The analysis of epithelial-to-mesenchymal transition (EMT) phenotype was carried out by immunofluorescence and western blot.Results: Our data revealed that elevated RNF38 expression were more common in NSCLC tissues than paired normal tissues in both mRNA (2.82 ± 0.29 vs. 1.23 ± 0.13) and protein (2.75 ± 0.09 vs. 1.24 ± 0.02) level. High levels of RNF38 expression were significantly associated with lymph node metastases, higher TNM stages (p=0.011), larger tumor size (p=2.09E-04) and predicted poor prognosis. RNF38 expression was inversely correlated with E-cadherin expression (P= 0.025). Moreover, downregulation of RNF38 impaired the proliferation, metastatic and invasive abilities in NSCLC cells. In addition, aberrant RNF38 expression could modulate the key molecules of EMT.Conclusions: Our results indicate that elevated expression of RNF38 is significantly associated with the proliferation and metastatic capacity of NSCLC cells, and RNF38 overexpression can serve as a biomarker of NSCLC poor prognosis.

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