Oncolytic adenoviruses, such as Delta-24-RGD, are promising therapies for patients with brain tumor. Clinical trials have shown that the potency of these cancer-selective adenoviruses should be increased to optimize therapeutic efficacy. One potential strategy is to increase the efficiency of adenovirus-induced cell lysis, a mechanism that has not been clearly described. In this study, for the first time, we report that autophagy plays a role in adenovirus-induced cell lysis. At the late stage after adenovirus infection, numerous autophagic vacuoles accompany the disruption of cellular structure, leading to cell lysis. The virus induces a complete autophagic process from autophagosome initiation to its turnover through fusion with the lysosome although the formation of the autophagosome is sufficient for virally induced cell lysis. Importantly, downmodulation of autophagy genes (ATG5 or ATG10) rescues the infected cells from being lysed by the virus. Moreover, autophagy triggers caspase activity via the extrinsic FADD/caspase 8 pathway, which also contributes to adenovirus-mediated cell lysis. Therefore, our study implicates autophagy and caspase activation as part of the mechanism for cell lysis induced by adenovirus and suggests that manipulation of the process is a potential strategy to optimize clinical efficacy of oncolytic adenoviruses.We reported previously the antiglioma effect of the E1A mutant oncolytic adenovirus Delta-24, which is targeted to the aberrant Rb/E2F1 pathway in cancer cells (10). In subsequent reports, we described how Delta-24-RGD, a version of Delta-24 whose infectivity in cancer cells is enhanced through insertion of an RGD-4C motif in the HI loop of the adenoviral fiber protein (37), showed oncolytic potency in intracranial models of human glioma xenografts derived from both malignant glioma cell lines (9) and brain tumor stem cells (15). On the basis of these preliminary data and toxicity studies performed under the guidance of the National Cancer Institute, we have translated Delta-24-RGD to the clinical setting, and it is currently being tested for toxicity in patients with recurrent malignant glioma at The University of Texas M. D. Anderson Cancer Center. Although we anticipate that the studies will show negligible toxicity, we expect that further improvements in the oncolytic potency of Delta-24-RGD will be necessary to induce optimal therapeutic effect. One of the potential avenues to increasing adenovirus potency that remains understudied is the mechanism by which adenoviruses induce cell lysis. In this regard, we along with other groups have shown that adenovirus infection results in macroautophagy (here referred to as autophagy) (12,15,41). Although it has been suggested that this cellular process might be linked to adenovirus-induced cell lysis (17), the underlying mechanism is still largely unknown.

Introduction: Glioblastoma (GBM) is the most common and lethal of the central nervous system (CNS) malignancies. The initiation, progression, and infiltration ability of GBMs are attributed in part to the dysregulation of microRNAs (miRNAs). Thus, targeting dysregulated miRNAs with RNA oligonucleotides (RNA interference, RNAi) has been proposed for GBM treatment. Despite promising results in the laboratory, RNA oligonucleotides have clinical limitations that include poor RNA stability and off-target effects. RNAi therapies against GBM confront an additional obstacle, as they need to cross the blood-brain barrier (BBB). Methods: Here, we developed gold-liposome nanoparticles conjugated with the brain targeting peptides apolipoprotein E (ApoE) and rabies virus glycoprotein (RVG). First, we functionalized gold nanoparticles with oligonucleotide miRNA inhibitors (OMIs), creating spherical nucleic acids (SNAs). Next, we encapsulated SNAs into ApoE, or RVG-conjugated liposomes, to obtain SNA-Liposome-ApoE and SNA-Liposome-RVG, respectively. We characterized each nanoparticle in terms of their size, charge, encapsulation efficiency, and delivery efficiency into U87 GBM cells in vitro. Then, they were administered intravenously (iv) in GBM syngeneic mice to evaluate their delivery efficiency to brain tumor tissue. Results: SNA-Liposomes of about 30-50 nm in diameter internalized U87 GBM cells and inhibited the expression of miRNA-92b, an aberrantly overexpressed miRNA in GBM cell lines and GBM tumors. Conjugating SNA-Liposomes with ApoE or RVG peptides increased their systemic delivery to the brain tumors of GBM syngeneic mice. SNA-Liposome-ApoE demonstrated to accumulate at higher extension in brain tumor tissues, when compared with non-treated controls, SNA-Liposomes, or SNA-Liposome-RVG. Discussion: SNA-Liposome-ApoE has the potential to advance the translation of miRNAbased therapies for GBM as well as other CNS disorders.

Posterior clinoid process (PCP) meningiomas are veritable "unicorns" of skull base surgery. Whereas, the incidence of its anterior clinoid counterpart is up to one-third of all intracranial meningiomas, and there are fewer than 20 reported cases of PCP meningiomas. [1][2][3][4][5][6][7][8] Despite their scarcity, these tumors present with a variety of symptoms dependent on the growth pattern. A predominantly posterior and downward growth could affect mainly oculomotility and the brainstem, whereas an upward growth affects the optic apparatus and leads to visual disturbance as the dominant symptoms. The same growth pattern influences the choice of surgical approach. We present a 56-year-old patient who presented with disequilibrium, diplopia, and fine motor dysfunction of the hands. His posterior clinoid meningioma drops down along the clivus from the tip of the PCP. After surgical rehearsal in virtual reality, a transsulcal, transchoroidal approach 9 through the temporal horn of the right lateral ventricle was chosen for resection. In preparation for surgery, markers were placed in the virtual reality model of the patient's specific anatomy. These markers and the trajectory between them were then projected through the eyepiece of a navigation-tracked microscope as augmented reality objects, and by "connecting the dots," the surgical plan through the choroidal fissure was executed efficiently and precisely. Despite waking up from surgery with left hemiplegia and right oculomotor palsy, the patient recovered fully from these symptoms, as well as a wound complication, within 3 months of surgery. A near-total resection was achieved. The patient consented to the procedure and the publication of his image.

BACKGROUND Cranioplasties are routinely performed to restore cosmesis and to protect intracranial contents after trauma, resection of tumors, or other pathologies. Traditionally done as a second-stage procedure, new single-stage cranioplasty protocols have been developed to minimize recovery periods, decrease complications, and improve patient satisfaction. These protocols, however, still require the use of larger than planned implants or use larger than ideal incisions to accommodate three-dimensional (3D) templates, which may not be optimal in regions with complex bony anatomy. OBSERVATIONS A 50-year-old woman with a painful and progressively enlarging hemangioma of the left frontal bone underwent a single-stage resection followed by custom cranioplasty using a new extended reality (XR)-based workflow. Excellent cosmetic results, decreased operative time, and a feasible workflow were achieved. LESSONS The use of an XR-based visualization platform allows the surgeon to treat lesions and perform custom cranioplasties in one session while avoiding common pitfalls of current single-stage workflows, such as increased operative times for tailoring implants, as well as minimizing the use of 3D overlay models, which may not appropriately conform to complex regional bony anatomy intraoperatively.