No abstract

Purpose: Tumor hypoxia is one of the crucial microenvironments to promote therapy resistance (TR) in glioblastoma multiforme (GBM). Livin, a member of the family of inhibitor of apoptosis proteins, contributes antiapoptosis. However, the role of tumor hypoxia in Livin regulation and its impact on TR are unclear.Experimental Design: Livin expression and apoptosis for tumor hypoxic cells derived from human glioblastoma xenografts or in vitro hypoxic stress-treated glioblastoma cells were determined by Western blotting, immunofluorescence imaging, and annexin V staining assay. The mechanism of hypoxia-induced Livin induction was investigated by chromatin immunoprecipitation assay and reporter assay. Genetic and pharmacologic manipulation of Livin was utilized to investigate the role of Livin on tumor hypoxia-induced TR in vitro or in vivo.Results: The upregulation of Livin expression and downregulation of caspase activity were observed under cycling and chronic hypoxia in glioblastoma cells and xenografts, concomitant with increased TR to ionizing radiation and temozolomide. However, knockdown of Livin inhibited these effects. Moreover, hypoxia activated Livin transcription through the binding of hypoxiainducible factor-1a to the Livin promoter. The targeted inhibition of Livin by the cell-permeable peptide (TAT-Lp15) in intracerebral glioblastoma-bearing mice demonstrated a synergistic suppression of tumor growth and increased the survival rate in standardof-care treatment with radiation plus temozolomide.Conclusions: These findings indicate a novel pathway that links upregulation of Livin to tumor hypoxia-induced TR in GBM and suggest that targeting Livin using cell-permeable peptide may be an effective therapeutic strategy for tumor microenvironmentinduced TR.

Medulloblastoma (MB) is a malignant primary brain tumor with poor prognosis. MB-derived CD133/Nestin double-positive cells (MB-DPs) exhibit cancer stem-like cell (CSC)-like properties that may contribute to chemoradioresistance, tumorigenesis and recurrence. In various tumors, signal transducer and activator of transcription 3 (STAT3) upregulation including MB which can regulate the expression of Nestin. Celecoxib, a selective COX-2 inhibitor, has been shown to potentially reduce STAT3 phosphorylation. The aim of the present study was to investigate the role of celecoxib in enhancing the effects of ionizing radiotherapy (IR) on MB-DP. MB-DPs and MB-derived CD133/Nestin double-negative cells (MB-DNs) were isolated from medulloblastoma cell line Daoy. Then, both of them were treated with celecoxib in different concentrations, and cell viability was assessed. The assays of cell survival, sphere formation, radiosensitivity, colony formation, apoptotic activity and mouse xenografting experiments in MB-DPs and MB-DNs treated with celecoxib alone, radiation alone, or celecoxib combined with radiation were further evaluated. We isolated MB-DPs from MB cell line Daoy, which exhibited typical CSC-like characteristics. Microarray analysis and Western blotting both indicated the upregulation of Janus kinase (JAK)-STAT cascade and STAT3 phosphorylation. Incubation with celecoxib dose-dependently suppressed the CSC-like properties and enhanced the IR effect on the induction of apoptosis, as detected by TUNEL assay and staining for Caspase 3 and Annexin V. Finally, celecoxib also enhanced the IR effect to suppress tumorigenesis and synergistically improve the recipient survival in orthotopic MB-derived CD133/Nestin double-positive cells (MB-DP cells) bearing mice.

Object The authors assessed the effectiveness of percutaneous pulsed radiofrequency treatment for providing pain relief in patients with chronic low-back pain with or without lower-limb pain. Methods Data were obtained in 127 patients who had chronic low-back pain with or without lower-limb pain due to a herniated intervertebral disc or previous failed back surgery and who underwent pulsed radiofrequency treatment. Their conditions were proven by clinical features, physical examination, and imaging studies. Low-back pain was treated with pulsed radiofrequency applied to the L-2 dorsal root ganglion (DRG) and lower-limb pain was treated with pulsed radiofrequency applied to the L3–S1 DRG. Patients underwent uni- or bilateral treatment depending on whether their low-back pain was unilateral or bilateral. A visual analog scale was used to assess pain. The patients were followed up for 3 years postoperatively. Results In patients without lower-limb pain (Group A), 27 (55.10%) of 49 patients had initial improvement ≥ 50% at 3-month follow-up. At 1-year follow-up, 20 (44.44%) of 45 patients in Group A had pain relief ≥ 50%. An analysis of patients with pain relief ≥ 50% for at least 1 month showed that the greatest effect was at 3 months after treatment. In patients with low-back pain and lower-limb pain (Group B), 37 (47.44%) of 78 patients had initial improvement ≥ 50% at 3-month follow-up. At 1-year follow-up, 34 (45.95%) of 74 patients had pain relief effect ≥ 50%. An analysis of patients in Group B with pain relief ≥ 50% for at least 1 month showed that the greatest effect was at 1 month after treatment. Conclusions The results of this prospective analysis showed that treatment with pulsed radiofrequency applied at the L-2 DRG is safe and effective for treating for chronic low-back pain. Satisfactory pain relief was obtained in the majority of patients in Group A with the effect persisting for at least 3 months. The results indicate that pulsed radiofrequency provided intermediate-term relief of low-back pain. Further studies with long-term follow-up are necessary.