Verteporfin (VP), a light-activated drug used in photodynamic therapy for the treatment of choroidal neovascular membranes, has also been shown to be an effective inhibitor of malignant cells. Recently, studies have demonstrated that, even without photo-activation, VP may still inhibit certain tumor cell lines, including ovarian cancer, hepatocarcinoma and retinoblastoma, through the inhibition of the YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human glioma cell lines (LN229 and SNB19). Through western blot analysis, we identified that human glioma cells that were exposed to VP without light activation demonstrated a downregulation of YAP-TEAD-associated downstream signaling molecules, including c-myc, axl, CTGF, cyr61 and survivin and upregulation of the tumor growth inhibitor molecule p38 MAPK. In addition, we observed that expression of VEGFA and the pluripotent marker Oct-4 were also decreased. Verteporfin did not alter the Akt survival pathway or the mTor pathway but there was a modest increase in LC3-IIB, a marker of autophagosome biogenesis. This study suggests that verteporfin should be further explored as an adjuvant therapy for the treatment of glioblastoma.
Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and transcriptional regulators of glioblastoma subtypes. Our model identified Annexin A2 (ANXA2) as a novel methylation-controlled positive regulator of the mesenchymal subtype. Subsequent evaluation in two independent cohorts established ANXA2 expression as a prognostic factor that is dependent on ANXA2 promoter methylation. ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion. Our results place ANXA2 at the apex of a regulatory cascade that determines glioblastoma mesenchymal transformation and validate aSICS as a general methodology to uncover regulators of cancer subtypes.
The goal of this study was to identify correlations between metabolites from proton MR spectroscopy and genetic pathway activity in glioblastoma multiforme (GBM). Twenty patients with primary GBM were analysed by short echo-time chemical shift imaging and genome-wide expression analyses. Weighed Gene Co-Expression Analysis was used for an integrative analysis of imaging and genetic data. N-acetylaspartate, normalised to the contralateral healthy side (nNAA), was significantly correlated to oligodendrocytic and neural development. For normalised creatine (nCr), a group with low nCr was linked to the mesenchymal subtype, while high nCr could be assigned to the proneural subtype. Moreover, clustering of normalised glutamine and glutamate (nGlx) revealed two groups, one with high nGlx being attributed to the neural subtype, and one with low nGlx associated with the classical subtype. Hence, the metabolites nNAA, nCr, and nGlx correlate with a specific gene expression pattern reflecting the previously described subtypes of GBM. Moreover high nNAA was associated with better clinical prognosis, whereas patients with lower nNAA revealed a shorter progression-free survival (PFS).
Objective: To compare the radiation exposure with the scrub nurse, assistant surgeon, and anesthetist during minimally invasive transforaminal lumbar interbody fusion using conventional 2-dimensional (2D) fluoroscopy or 3D fluoroscopy-based navigation.Summary of Background Data: Minimally invasive spinal fusion techniques are related to higher radiation exposures compared with open techniques. Especially the routinely exposed surgical staff faces the risks of increased radiation exposure.Methods: In total, 41 patients with planned monosegmental minimally invasive transforaminal lumbar interbody fusion were randomized into the intraoperative imaging techniques 2D fluoroscopy or 3D navigation. Eye lens and film dosemeters were attached to defined locations of the scrub nurse, assistant surgeon, and anesthetist. Mann-Whitney U and Wilcoxon-matched pairs signed-rank test were used to compare dosemeter readings. This study was registered with the German Clinical Trials Register (DRKS00004514). Results:The radiation exposure per surgery was low for the scrub nurse, assistant surgeon, and anesthetist in both the 2D fluoroscopy and 3D navigation groups. The maximum average value of 0.057 ± 0.031 mSv was measured on the unprotected chest of the assistant surgeon and was thus slightly above the lower detection limit of the dosemeters (0.044 mSv). The annual occupational dose limit would be exceeded at the earliest after 571 operations for the unprotected eye lens of the assistant surgeon.Conclusions: Minimally invasive lumbar fusion surgery is possible with comparatively low radiation exposure to the assisting operating room personnel without exceeding the annual maximum occupational radiation exposure. However, there is no definite dose value below which ionizing radiation poses no risk. Consequently, radiation sparing work routines should be strictly followed.
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