Case Report: Low-grade glioma with NF1 loss of function mimicking diffuse intrinsic pontine glioma.

Intrinsic, expansile pontine tumors typically occur in the pediatric population. These tumors characteristically present as diffuse intrinsic pontine glioma (DIPG), which is now considered as diffuse midline glioma (DMG), H3K27-mutated of the pons. DIPG has limited treatment options and a poor prognosis, and the value of tissue diagnosis from an invasive biopsy remains controversial. This study presents the case of a 19-year-old female with clinical and imaging hallmarks of DIPG, who underwent a biopsy of a tumor in the region of the right middle cerebellar peduncle. Her lesional cells were negative for H3K27M alterations and had low-grade histologic features. Next-generation sequencing revealed a frameshift mutation in the NF1 gene as the likely driver mutation. These features suggest a diagnosis of a low-grade glioma associated with NF1 loss of function, with far-reaching consequences regarding both treatment strategy and prognosis. This case provides support for the utility of diagnostic tissue biopsy in cases of suspected DIPG.

Cyclonite-Induced Seizures After Voluntary C-4 Ingestion.

Cyclonite (cyclotrimethylenetrinitramine, RDX, hexogen) is the active agent in the plastic explosive, composition 4 (C-4). It has been used globally since the Vietnam War for both military and civilian applications due to its metastable nature. Ingestion or inhalation of C-4 can cause euphoric effects such as those commonly seen with alcohol toxicity, in addition to seizures and rarely fulminant liver and kidney failure. We report the case of a patient who ingested 75 g of C-4 and presented with a generalized tonic-clonic seizure four hours after ingestion. Our patient made a full recovery after being stabilized with temporizing anticonvulsants in the intensive care unit.

Positioning SUMO as an immunological facilitator of oncolytic viruses for high-grade glioma.

Oncolytic viral (OV) therapies are promising novel treatment modalities for cancers refractory to conventional treatment, such as glioblastoma, within the central nervous system (CNS). Although OVs have received regulatory approval for use in the CNS, efficacy is hampered by obstacles related to delivery, under-/over-active immune responses, and the "immune-cold" nature of most CNS malignancies. SUMO, the Small Ubiquitin-like Modifier, is a family of proteins that serve as a high-level regulator of a large variety of key physiologic processes including the host immune response. The SUMO pathway has also been implicated in the pathogenesis of both wild-type viruses and CNS malignancies. As such, the intersection of OV biology with the SUMO pathway makes SUMOtherapeutics particularly interesting as adjuvant therapies for the enhancement of OV efficacy alone and in concert with other immunotherapeutic agents. Accordingly, the authors herein provide: 1) an overview of the SUMO pathway and its role in CNS malignancies; 2) describe the current state of CNS-targeted OVs; and 3) describe the interplay between the SUMO pathway and the viral lifecycle and host immune response.

Adaptive conductive electrotherapeutic scaffolds for enhanced peripheral nerve regeneration and stimulation.

BACKGROUND: While peripheral nerve stimulation (PNS) has shown promise in applications ranging from peripheral nerve regeneration to therapeutic organ stimulation, clinical implementation has been impeded by various technological limitations, including surgical placement, lead migration, and atraumatic removal. METHODS: We describe the design and validation of a platform technology for nerve regeneration and interfacing: adaptive, conductive, and electrotherapeutic scaffolds (ACESs). ACESs are comprised of an alginate/poly-acrylamide interpenetrating network hydrogel optimized for both open surgical and minimally invasive percutaneous approaches. FINDINGS: In a rodent model of sciatic nerve repair, ACESs significantly improved motor and sensory recovery (p < 0.05), increased muscle mass (p < 0.05), and increased axonogenesis (p < 0.05). Triggered dissolution of ACESs enabled atraumatic, percutaneous removal of leads at forces significantly lower than controls (p < 0.05). In a porcine model, ultrasound-guided percutaneous placement of leads with an injectable ACES near the femoral and cervical vagus nerves facilitated stimulus conduction at significantly greater lengths than saline controls (p < 0.05). CONCLUSION: Overall, ACESs facilitated lead placement, stabilization, stimulation, and atraumatic removal, enabling therapeutic PNS as demonstrated in small- and large-animal models. FUNDING: This work was supported by K. Lisa Yang Center for Bionics at MIT.

SUMOtherapeutics for Ischemic Stroke.

The small, ubiquitin-like modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes, including the mammalian stress response. Of particular interest are its neuroprotective effects, first recognized in the 13-lined ground squirrel (Ictidomys tridecemlineatus), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and the preconditioning of neural stem cells make it a promising therapeutic target for acute cerebral ischemia. Recent advances in high-throughput screening have enabled the identification of small molecules that can upregulate SUMOylation, some of which have been validated in pertinent preclinical models of cerebral ischemia. Accordingly, the present review aims to summarize current knowledge and highlight the translational potential of the SUMOylation pathway in brain ischemia.

Machine Learning Applications of Surgical Imaging for the Diagnosis and Treatment of Spine Disorders: Current State of the Art.

Recent developments in machine learning (ML) methods demonstrate unparalleled potential for application in the spine. The ability for ML to provide diagnostic faculty, produce novel insights from existing capabilities, and augment or accelerate elements of surgical planning and decision making at levels equivalent or superior to humans will tremendously benefit spine surgeons and patients alike. In this review, we aim to provide a clinically relevant outline of ML-based technology in the contexts of spinal deformity, degeneration, and trauma, as well as an overview of commercial-level and precommercial-level surgical assist systems and decisional support tools. Furthermore, we briefly discuss potential applications of generative networks before highlighting some of the limitations of ML applications. We conclude that ML in spine imaging represents a significant addition to the neurosurgeon's armamentarium-it has the capacity to directly address and manifest clinical needs and improve diagnostic and procedural quality and safety-but is yet subject to challenges that must be addressed before widespread implementation.

Toward Development of a Higher Flow Rate Hemocompatible Biomimetic Microfluidic Blood Oxygenator.

The recent emergence of microfluidic extracorporeal lung support technologies presents an opportunity to achieve high gas transfer efficiency and improved hemocompatibility relative to the current standard of care in extracorporeal membrane oxygenation (ECMO). However, a critical challenge in the field is the ability to scale these devices to clinically relevant blood flow rates, in part because the typically very low blood flow in a single layer of a microfluidic oxygenator device requires stacking of a logistically challenging number of layers. We have developed biomimetic microfluidic oxygenators for the past decade and report here on the development of a high-flow (30 mL/min) single-layer prototype, scalable to larger structures via stacking and assembly with blood distribution manifolds. Microfluidic oxygenators were designed with biomimetic in-layer blood distribution manifolds and arrays of parallel transfer channels, and were fabricated using high precision machined durable metal master molds and microreplication with silicone films, resulting in large area gas transfer devices. Oxygen transfer was evaluated by flowing 100% O2 at 100 mL/min and blood at 0-30 mL/min while monitoring increases in O2 partial pressures in the blood. This design resulted in an oxygen saturation increase from 65% to 95% at 20 mL/min and operation up to 30 mL/min in multiple devices, the highest value yet recorded in a single layer microfluidic device. In addition to evaluation of the device for blood oxygenation, a 6-h in vitro hemocompatibility test was conducted on devices (n = 5) at a 25 mL/min blood flow rate with heparinized swine donor blood against control circuits (n = 3). Initial hemocompatibility results indicate that this technology has the potential to benefit future applications in extracorporeal lung support technologies for acute lung injury.

Nanotechnology approaches for global infectious diseases.

Infectious diseases are a major driver of morbidity and mortality globally. Treatment of malaria, tuberculosis and human immunodeficiency virus infection are particularly challenging, as indicated by the ongoing transmission and high mortality associated with these diseases. The formulation of new and existing drugs in nano-sized carriers promises to overcome several challenges associated with the treatment of these diseases, including low on-target bioavailability, sub-therapeutic drug accumulation in microbial sanctuaries and reservoirs, and low patient adherence due to drug-related toxicities and extended therapeutic regimens. Further, nanocarriers can be used for formulating vaccines, which represent a major weapon in our fight against infectious diseases. Here we review the current burden of infectious diseases with a focus on major drivers of morbidity and mortality. We then highlight how nanotechnology could aid in improving existing treatment modalities. We summarize our progress so far and outline potential future directions to maximize the impact of nanotechnology on the global population.

Gastrointestinal synthetic epithelial linings.

Epithelial tissues line the organs of the body, providing an initial protective barrier as well as a surface for nutrient and drug absorption. Here, we identified enzymatic components present in the gastrointestinal epithelium that can serve as selective means for tissue-directed polymerization. We focused on the small intestine, given its role in drug and nutrient absorption and identified catalase as an essential enzyme with the potential to catalyze polymerization and growth of synthetic biomaterial layers. We demonstrated that the polymerization of dopamine by catalase yields strong tissue adhesion. We characterized the mechanism and specificity of the polymerization in segments of the gastrointestinal tracts of pigs and humans ex vivo. Moreover, we demonstrated proof of concept for application of these gastrointestinal synthetic epithelial linings for drug delivery, enzymatic immobilization for digestive supplementation, and nutritional modulation through transient barrier formation in pigs. This catalase-based approach to in situ biomaterial generation may have broad indications for gastrointestinal applications.