A major obstacle to the management of malignant glioma is the inability to effectively deliver therapeutic agent to the tumor. In this study, we describe a polymeric nanoparticle vector that not only delivers viable therapeutic, but can also be tracked in vivo using MRI. Nanoparticles, produced by a non-emulsion technique, were fabricated to carry iron oxide within the shell and the chemotherapeutic agent, temozolomide (TMZ), as the payload. Nanoparticle properties were characterized and subsequently their endocytosis-mediated uptake by glioma cells demonstrated. Convection enhanced delivery (CED) can disperse nanoparticles through the rodent brain and their distribution is accurately visualized by MRI. Infusion of nanoparticles does not result in observable animal toxicity relative to control. CED of TMZ bearing nanoparticles prolongs the survival of animals with intracranial xenografts compared to control. In conclusion, the described nanoparticle vector represents a unique multifunctional platform that can be used for image-guided treatment of malignant glioma.

Alkylating chemotherapy is a central component of the management of glioblastoma (GBM). Among the factors that regulate the response to alkylation damage, NF-kB acts to both promote and block cytotoxicity. In this study, we used genome-wide expression analysis in U87 GBM to identify NF-kB-dependent factors altered in response to temozolomide and found the long noncoding RNA (lncRNA) MALAT1 as one of the most significantly upregulated. In addition, we demonstrated that MALAT1 expression was coregulated by p50 (p105) and p53 via novel kBand p53-binding sites in the proximal MALAT1 coding region. Temozolomide treatment inhibited p50 recruitment to its cognate element as a function of Ser329 phosphorylation while concomitantly increasing p53 recruitment. Moreover, luciferase reporter studies demonstrated that both kB and p53 cis-elements were required for efficient transactivation in response to temozolomide. Depletion of MALAT1 sensitized patient-derived GBM cells to temozolomide cytotoxicity, and in vivo delivery of nanoparticleencapsulated anti-MALAT1 siRNA increased the efficacy of temozolomide in mice bearing intracranial GBM xenografts. Despite these observations, in situ hybridization of GBM specimens and analysis of publicly available datasets revealed that MALAT1 expression within GBM tissue was not prognostic of overall survival. Together, these findings support MALAT1 as a target for chemosensitization of GBM and identify p50 and p52 as primary regulators of this ncRNA. Significance: These findings identify NF-kB and p53 as regulators of the lncRNA MALAT1 and suggest MALAT1 as a potential target for the chemosensitization of GBM.

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Objective: To determine the long-term follow-up of the various operations for lumbar disc herniation in a large patient population. Subjects and Methods: Patients who had operations for lumbar disc herniation (microdiscectomy, endoscopic microdiscectomy and the ‘classical operation', i.e. laminectomy/laminotomy with discectomy) were collected from the world literature. Patients who had follow-ups for at least 2 years were analyzed relative to the outcome. The outcome was graded by the patients themselves, and the operative groups were compared to one another. Results: 39,048 patients collected from the world literature had had lumbar disc operations for disc herniations. The mean follow-up period was 6.1 years, and 30,809 (78.9%) patients reported good/excellent results. Microdiscectomy was performed on 3,400 (8.7%) patients. The mean follow-up was 4.1 years with 2,866 (84.3%) good/excellent results, while 1,101 (3.6%) patients had endoscopic microdiscectomy. There, the mean follow-up was 2.9 years with 845 (79.5%) good/excellent results. The classical operation was performed on 34,547 (88.5%) patients with a mean follow-up period of 6.3 years, and 27,050 (78.3%) patients had good/excellent results. These results mirror those with discectomy and the placement of prosthetic discs. Conclusions: The analysis of 39,048 patients with various operations for lumbar disc herniation revealed the same pattern of long-term results. Patients who had microdiscectomy, endoscopic microdiscectomy or the classical operation (laminectomy/laminotomy with discectomy) all had approximately 79% good/excellent results. None of the operative procedures gave a different outcome.

Temozolomide is used widely to treat malignant glioma but the overall response to this agent is generally poor. Resistance to DNA damaging drugs such as temozolomide has been related to the induction of anti-apoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB binding sequence (κB-site) was identified in the proximal promoter and demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance, and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.