RESPIRATION DEFECTS LIMIT SERINE SYNTHESIS REQUIRED FOR LUNG CANCER GROWTH AND SURVIVAL.

Mitochondrial function is important for both energetic and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations directly impact these functions, resulting in the detrimental consequences seen in human mitochondrial diseases. The role of pathogenic mtDNA mutations in human cancers is less clear; while pathogenic mtDNA mutations are observed in some cancer types, they are almost absent in others. We report here that the proofreading mutant DNA polymerase gamma ( PolG D256A ) induced a high mtDNA mutation burden in non-small-cell lung cancer (NSCLC), and promoted the accumulation of defective mitochondria, which is responsible for decreased tumor cell proliferation and viability and increased cancer survival. In NSCLC cells, pathogenic mtDNA mutations increased glycolysis and caused dependence on glucose. The glucose dependency sustained mitochondrial energetics but at the cost of a decreased NAD+/NADH ratio that inhibited de novo serine synthesis. Insufficient serine synthesis, in turn, impaired the downstream synthesis of GSH and nucleotides, leading to impaired tumor growth that increased cancer survival. Unlike tumors with intact mitochondrial function, NSCLC with pathogenic mtDNA mutations were sensitive to dietary serine and glycine deprivation. Thus, mitochondrial function in NSCLC is required specifically to sustain sufficient serine synthesis for nucleotide production and redox homeostasis to support tumor growth, explaining why these cancers preserve functional mtDNA. In brief: High mtDNA mutation burden in non-small-cell lung cancer (NSCLC) leads to the accumulation of respiration-defective mitochondria and dependency on glucose and glycolytic metabolism. Defective respiratory metabolism causes a massive accumulation of cytosolic nicotinamide adenine dinucleotide + hydrogen (NADH), which impedes serine synthesis and, thereby, glutathione (GSH) and nucleotide synthesis, leading to impaired tumor growth and increased survival. Highlights: Proofreading mutations in Polymerase gamma led to a high burden of mitochondrial DNA mutations, promoting the accumulation of mitochondria with respiratory defects in NSCLC.Defective respiration led to reduced proliferation and viability of NSCLC cells increasing survival to cancer.Defective respiration caused glucose dependency to fuel elevated glycolysis.Altered glucose metabolism is associated with high NADH that limits serine synthesis, leading to impaired GSH and nucleotide production.Mitochondrial respiration defects sensitize NSCLC to dietary serine/glycine starvation, further increasing survival.

Network analysis of neurosurgical literature: an increased focus on training during the COVID-19 pandemic.

The COVID-19 pandemic led to stringent guidelines to restrict the conduct of non-emergent surgical procedures. Consequently, neurosurgery departments experienced a decline in case volumes and greater educational time being spent on virtual research projects. In our report, we reveal how neurosurgical research has changed during the pandemic compared to the pre-pandemic phase. The WebOfScience database was searched for neurosurgical articles published between 2012-2019 (pre-pandemic) and 2020-2022 (pandemic). From this data, the keywords, terms, and countries were analyzed using networks formed by the VOS Viewer software. In addition, the analysis was repeated for neurosurgical articles specific to COVID-19. Network analyses of terms and keywords revealed an increased popularity of virtual research projects, including case reports, meta-analyses, reviews, surveys, and database studies. Additionally, there was increased interest in research pertaining to neurosurgical education during the post-pandemic era, including topics regarding virtual training modalities, mental health, and telemedicine. Our bibliometrics analysis suggests that the impact of COVID-19 restrictions on hospital systems affected neurosurgical training programs. Future investigations should explore the effects of the trainee experience during the COVID-19 pandemic on the outlook for neurosurgical education.

Applying Shear Wave and Magnetic Resonance Elastography to Grade Brain Tumors: Systematic Review and Meta-Analysis.

BACKGROUND: Reports find that magnetic resonance elastography (MRE) and shear wave elastography (SWE) can classify intracranial tumors according to stiffness. However, systematic syntheses of these articles are lacking. In this report, a systematic review and meta-analysis was performed to evaluate whether SWE and MRE can predict meningioma and glioma grades. METHODS: PubMed and Scopus were searched between February 10, 2022. and March 2, 2022. using manual search criteria. Eight out of 106 non-duplicate records were included, encompassing 84 patients with low-grade tumors (age 42 ± 13 years, 71% female) and 92 patients with high-grade tumors (age 50 ± 13 years, 42% female). Standardized mean difference in stiffness between high-grade and low-grade tumors were measured using a forest plot. The I2, χ2, and t tests were performed, and bubble plots were constructed to measure heterogeneity. An adapted QUADAS-2 scale evaluated study quality. Additionally, a funnel plot was constructed, and an Egger's intercept test determined study bias. RESULTS: Low-grade tumors were stiffer than high-grade tumors (Cohen's D = -1.25; 95% CI -1.88, -0.62). Moderate heterogeneity was observed (I2 = 67%; P = 0.006) but controlling for publication year (I2 = 0.2%) and age (I2 = 0.0%-17%) reduced heterogeneity. Included studies revealed unclear or high bias for the reference standard and flow and timing (>50%). CONCLUSIONS: Elastography techniques have potential to grade tumors intraoperatively and postoperatively. More studies are needed to evaluate the clinical utility of these technologies.