Augmented-reality template guided transorbital approach for intradural tumors

For “minimally invasive” approaches to a deep-lying skull base lesion, the bone opening must be precisely placed and adequately wide to accomplish the surgical goal. Surgical rehearsal in virtual reality (VR) can generate navigation-integrated augmented reality (AR) templates to ensure precise surgical openings. In this video, the authors used AR templates for the transpalpebral, transorbital approach for intradural tumors. VR renderings of patient-specific anatomy were used in surgical rehearsal. The optimal openings were saved and, at surgery, projected into the eyepiece of the navigation-tracked microscope. The template enhanced the planning of the incision and soft-tissue exposure and guided the drill toward the target. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21172

Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA Polymerases

8-oxo-guanine (8OG) is a common base lesion, generated by reactive oxygen species, which has been associated with human diseases such as cancer, aging-related neurodegenerative disorders and atherosclerosis. 8OG is highly mutagenic, due to its dual-coding potential it can pair both with adenine or cytidine. Therefore, it creates a challenge for DNA polymerases striving to correctly replicate and/or repair genomic or mitochondrial DNA. Numerous structural studies provide insights into the mechanistic basis of the specificity of 8OG bypass by DNA polymerases from different families. Here, we focus on how repair polymerases from Family X (Pols β, λ and µ) engage DNA substrates containing the oxidized guanine. We review structures of binary and ternary complexes for the three polymerases, which represent distinct steps in their catalytic cycles—the binding of the DNA substrate and the incoming nucleotide, followed by its insertion and extension. At each of these steps, the polymerase may favor or exclude the correct C or incorrect A, affecting the final outcome, which varies depending on the enzyme.

NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice

Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases affect cognition in mice, while the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in knockout mouse models. Neil1−/−Neil2−/− mice display hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels are comparable between genotypes and no mutator phenotype is found. Thus, impaired canonical repair is not likely to explain the altered behavior. Electrophysiology suggests reduced axonal activation in the hippocampal CA1 region in Neil1−/−Neil2−/− mice and lack of NEIL1 and NEIL2 causes dysregulation of genes in CA1 relevant for synaptic function. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation, beyond canonical BER, modulating behavior in mice.

Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress

Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can contribute to either cellular senescence and aging, or tumorigenesis. Human reproductive cells, some stem cells, and most cancer cells, express the enzyme telomerase to restore telomeric DNA. Numerous studies have shown that oxidative stress caused by excess reactive oxygen species is associated with accelerated telomere shortening and dysfunction. Telomeric repeat sequences are remarkably susceptible to oxidative damage and are preferred sites for the production of the mutagenic base lesion 8-oxoguanine, which can alter telomere length homeostasis and integrity. Therefore, knowledge of the repair pathways involved in the processing of 8-oxoguanine at telomeres is important for advancing understanding of the pathogenesis of degenerative diseases and cancer associated with telomere instability. The highly conserved guanine oxidation (GO) system involves three specialized enzymes that initiate distinct pathways to specifically mitigate the adverse effects of 8-oxoguanine. Here we introduce the GO system and review the studies focused on investigating how telomeric 8-oxoguanine processing affects telomere integrity and overall genome stability. We also discuss newly developed technologies that target oxidative damage selectively to telomeres to investigate roles for the GO system in telomere stability.

MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis

Abstract8-Oxoguanine (8-oxoG), a major oxidative base lesion, is highly accumulated in Alzheimer’s disease (AD) brains during the pathogenic process. MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby avoiding 8-oxo-dG incorporation into DNA. 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired with cytosine in DNA, thereby minimizing 8-oxoG accumulation in DNA. Levels of MTH1 and OGG1 are significantly reduced in the brains of sporadic AD cases. To understand how 8-oxoG accumulation in the genome is involved in AD pathogenesis, we established an AD mouse model with knockout of Mth1 and Ogg1 genes in a 3xTg-AD background. MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and, to a lesser extent, mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4–5 months of age. Furthermore, minocycline, which inhibits microglial activation and reduces neuroinflammation, markedly decreased the nuclear accumulation of 8-oxoG in microglia, and inhibited microgliosis and neuronal loss. Gene expression profiling revealed that MTH1 and OGG1 efficiently suppress progression of AD by inducing various protective genes against AD pathogenesis initiated by Aß/Tau accumulation in 3xTg-AD brain. Our findings indicate that efficient suppression of 8-oxoG accumulation in brain genomes is a new approach for prevention and treatment of AD.

Mucormycosis originated total maxillary and cranial base osteonecrosis: a possible misdiagnosis to malignancy

Background This is a case of mucormycosis originated osteonecrosis of the maxilla extended to the cranial base, initially suspected of malignancy. The patient was first suspected with osteolytic sarcomatous lesion but was later diagnosed with total maxillary necrosis and cranial base through biopsy-proven invasive mucormycosis. Case presentation A 71-year-old male was presented with unknown total maxillary osteonecrosis. CT and MRI results showed extensive osteolytic change with bone destruction of the cranial base, and PET-CT showed irregular hypermetabolic lesion in the area suspected of malignancy. The first biopsy results only presented tissue inflammation. Thus, several further endoscopic biopsy were performed through posterior pharyngeal wall. The patient was eventually diagnosed with mucormycosis and associated osteomyelitis with subsequent bone necrosis. With confirmed diagnosis, partial maxillectomy of the necrosed bone was performed under general anesthesia. At the 4 week follow-up, the patient showed full mucosal healing and no recurrence or aggravation of the maxilla and cranial base lesion was observed. Conclusions Accurate diagnosis of atypical symptoms, timely diagnosis, and proper combination therapy of surgical intervention, antifungal agent, and antibiotic use for skull base osteomyelitis are all critical for proper treatment planning. In addition, biopsy and CT scans are essential in differentiating osteonecrosis from malignancy.

NEIL1 and NEIL2 DNA glycosylases regulate anxiety and learning in a cooperative manner

Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases alter cognition in mice, the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in single and double knock-out mouse models. Neil1-/-Neil2-/- mice displayed hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels were comparable between genotypes, no mutator phenotype was found. Impaired canonical repair was thus not the cause of altered behavior. Electrophysiology indicated reduced stratum oriens afferents in the hippocampal CA1 region in Neil1-/-Neil2-/-. Within CA1, NEIL1 and NEIL2 jointly regulated transcription in genes relevant for synaptic function. Thus, we postulate a cooperative function of NEIL1 and NEIL2 in genome regulation beyond canonical BER modulating memory formation and anxiety.

Mini-Pterional Craniotomy and Extradural Clinoidectomy for Clinoid Meningioma: Optimization of Exposure Using Augmented Reality Template: 2-Dimensional Operative Video

A “keyhole” approach to a deep-lying skull base lesion, as such a clinoid meningioma, can be a daunting challenge.1-3 The minimally invasive exposure must be precisely placed and adequately wide to accomplish the surgical goal. Surgical rehearsal in virtual reality (VR) can not only increase the confidence of the surgeon through practice on patient-specific anatomy,4 but it can also generate navigation-integrated templates to ensure precise placement and adequate bone openings. In this operative video, we demonstrate the use of an augmented reality (AR) template in a 69-yr-old woman with a growing clinoid meningioma. The 3-dimensional, VR rendering (SNAP VR360, Surgical Theater Inc, Cleveland, Ohio) of her right clinoid meningioma was used in surgical rehearsal for the mini-pterional approach with extradural clinoidectomy. The optimal opening was saved as a VR file and, at surgery, projected into the eye-piece of the navigation-tracked microscope (Synchronized AR v3.8.0, Surgical Theater Inc). In this manner, the surgical opening in the template was visible in AR on the patient's anatomy in real time during surgery. The template enhanced the planning of the incision and soft-tissue exposure, guided the drilling of the sphenoid wing, facilitated the extradural clinoidectomy,5 and ultimately facilitated the accomplishment of the surgical goal of total resection of the meningioma. With this application of novel technology, the surgeon is no longer using navigation to get her/his bearings. Instead, the surgeon is using AR-enhanced navigation to duplicate a plan that is known to work. This is a fundamental paradigm shift. Patient consent was obtained prior to the creation of the video and is available on request.

Allergic Fungal Sinusitis Imitating an Aggressive Skull Base Lesion in the Setting of Pembrolizumab Immunotherapy

Objectives: We report a case of acutely worsening allergic fungal sinusitis in a patient receiving immunotherapy with pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor. Methods: A 53-year-old man with a history of metastatic melanoma and recent initiation of pembrolizumab therapy presented with acutely worsening headaches, left abducens nerve palsy, and neuroimaging demonstrating an erosive skull base lesion with bilateral cavernous sinus involvement. Results: Intraoperative findings were consistent with non-invasive allergic fungal sinus disease. Microbiology and histopathologic data ruled out malignancy and demonstrated Aspergillus fumigatus without concern for angioinvasion. After treatment with antifungal therapy, the patient’s symptoms and abducens nerve palsy resolved. Symptoms were well-controlled 7 months after his initial presentation. Conclusions: Inflammatory sinusitis in patients receiving anti-PD-1 therapy may be secondary to T-cell infiltration, a similar pathophysiology as immune-related adverse events, and warrants appreciation by otolaryngologists given our increasing exposure to immunotherapy and its head and neck manifestations.