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The positional accuracy of multi-leaf collimators (MLC) is important in stereotactic body radiotherapy (SBRT). The aim of this study was to investigate the impact between MLC positional error and dosimetry of volume intensity modulated (VMAT) and general intensity modulated (IMRT) plans for non-small cell lung cancer (NSCLC). Fifteen patients with NSCLC were selected to design the 360 SBRT-VMAT plans and the 360 SBRT-IMRT error plans. The DICOM files for these treatment plans were imported into a proprietary computer program that introduced delivery errors. Random and systematic MLC position (0.1, 0.2, 0.5, 1.0, 1.5, and 2.0 mm) errors were introduced. The systematic errors were shift errors (caused by gravity), opening errors, and closing errors. The CI, GI, d2cm and generalized equivalent uniform dose (gEUD) were calculated for the original plan and all treatment plans, accounting for the errors. Dose sensitivity was calculated using linear regression for MLC position errors. The random MLC errors were relatively insignificant. MLC shift, opening, and closing errors had a significant effect on the dose distribution of the SBRT plan. VMAT was more significant than IMRT. To ensure that the gEUD variation of PTV is controlled within 2%, the shift error, opening error, and closing error of IMRT should be less than 2.4 mm, 1.15 mm, and 0.97 mm, respectively. For VMAT, the shift error, opening error, and closing error should be less than 0.95 mm, 0.32 mm, and 0.38 mm, respectively. The dose sensitivity results obtained in this study can be used as a guide for patient-based quality assurance efforts. The position error of the MLC system had a significant impact on the gEUD of the SBRT technology. The MLC systematic error has a greater dosimetric impact on the VMAT plan than on the IMRT plan for SBRT, which should be carefully monitored.

Long non-coding RNAs (lncRNAs) play important roles in the malignant behavior of cancer. HOTAIR, a well-studied lncRNA, contributes to breast cancer development, and overexpression of HOTAIR predicts a poor prognosis. However, the regulatory role of HOTAIR in the cancer stem-like cell (CSC) subpopulation remains largely unknown. Our goal was to determine the regulatory functions of HOTAIR in the processes of self-renewal capacity, tumor formation and proliferation of CSCs derived from breast cancer.We first enriched and incubated the CSC population derived from breast cancer cell line MCF7 (CSC-MCF7) or MDA-MB-231 (MB231, CSC-MB231). Self-renewal capacity and tumor formation were assessed in vitro and in vivo to determine the stemness of CSCs. We assessed the impact on ectopically upregulated or downregulated expression of HOTAIR in CSCs by soft agar, self-renewal capacity and CCK-8 assays. The functional domain of HOTAIR was determined by truncation. RT-qPCR and semiquantitative Western blotting were performed to detect the expression levels of genes of interest. Chromatin IP (ChIP) was employed to detect the transcriptional regulatory activity of p53 on its target gene.After the identification of CSC properties, RT-qPCR analysis revealed that HOTAIR, but not other cancer-associated lncRNAs, is highly upregulated in both CSC-MCF7 and CSC-MB231 populations compared with MCF7 and MB231 populations. By modulating the level of HOTAIR expression, we showed that HOTAIR tightly regulates the proliferation, colony formation, migration and self-renewal capacity of CSCs. Moreover, full-length HOTAIR transcriptionally inhibits miR-34a specifically, leading to upregulation of Sox2, which is targeted by miR-34a. Ectopic introduction of miR-34a mimics reverses the effects of HOTAIR on the physiological processes of CSCs, indicating that HOTAIR affects these processes, including self-renewal capacity; these effects are dependent on the regulation of Sox2 via miR-34a. Interestingly, tight transcriptional regulation of p53 by HOTAIR was found; accordingly, p21 is indirectly regulated by HOTAIR, resulting in cell cycle entry.These results suggest that HOTAIR is a key regulator of proliferation, colony formation, invasion and self-renewal capacity in breast CSCs, which occurs in part through regulation of Sox2 and p53.

Increasing evidence suggests that cirrhosis may affect the connectivity among different brain regions in patients before overt hepatic encephalopathy (OHE) occurs. However, there has been no study investigating the structural reorganization of these altered connections at the network level. The primary focus of this study was to investigate the abnormal topological organization of the structural network in patients with hepatitis B virus-related cirrhosis (HBV-RC) without OHE using structural MRI.Using graph theoretical analysis, we compared the global and regional topological properties of gray matter structural networks between 28 patients with HBV-RC without OHE and 30 age-, sex- and education-matched healthy controls. The structural correlation networks were constructed for the two groups based on measures of gray matter volume.The brain network of the HBV-RC group exhibited a significant decrease in the clustering coefficient and reduced small-worldness at the global level across a range of network densities. Regionally, brain areas with altered nodal degree/betweenness centrality were observed predominantly in association cortices (frontal and temporal regions) (p < 0.05, uncorrected), including a significantly decreased nodal degree in the inferior temporal gyrus (p < 0.001, uncorrected). Furthermore, the HBV-RC group exhibited a loss of association hubs and the emergence of an increased number of non-association hubs compared with the healthy controls.The results of this large-scale gray matter structural network study suggest reduced topological organization efficiency in patients with HBV-RC without OHE. Our findings provide new insight concerning the mechanisms of neurobiological reorganization in the HBV-RC brain from a network perspective.

BackgroundTumor cells acquire the capacity of resistance to chemotherapy or radiotherapy via cell-matrix and cell-cell crosstalk. Integrins are the most important cell adhesion molecules, in which αV integrin mainly mediating the tight contact between tumor cells.Methodology/principal findingsTo investigate the role of αV integrin in multi-cellular radioresistance (MCR) of human nasopharyngeal carcinoma (NPC), we performed immunohistochemistry and Western blotting to find that the expression of αV integrin in the tumor tissue of radioresistant patients is much higher than that in radiosensitive patients. In vitro, we cultured human NPC cell line CNE-2 cells as multi-cellular spheroids (MCSs) or as monolayer cells (MCs), and found that the expression of αV integrin in MCSs is significantly higher than that in MCs. MTT, flow cytometry and clonogenic survival assays showed that MCSs are less sensitive to X-ray irradiation than MCs while blocking of αV integrin in MCSs dramatically reversed their radioresistance. Furthermore, as detected by Western blotting, MCSs displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway in presence of irradiation. Blocking of αV integrin in MCSs decreased the expression of phosphorylated JNK. Additionally, blocking of SAPK/JNK signaling pathway synergistically induced apoptosis of MCSs exposed to irradiation by increasing the expression of cleaved caspase-3. In vivo, we found that irradiation combined with αV integrin blocking treatment significantly enhanced the radiosensitivity of NPC xenografts.ConclusionsOur results indicate a novel role of αV integrin in multi-cellular radioresistance of NPCs.