Specific oncogene activation of the cell of origin in mucosal melanoma.

Mucosal melanoma (MM) is a deadly cancer derived from mucosal melanocytes. To test the consequences of MM genetics, we developed a zebrafish model in which all melanocytes experienced CCND1 expression and loss of PTEN and TP53. Surprisingly, melanoma only developed from melanocytes lining internal organs, analogous to the location of patient MM. We found that zebrafish MMs had a unique chromatin landscape from cutaneous melanoma. Internal melanocytes could be labeled using a MM-specific transcriptional enhancer. Normal zebrafish internal melanocytes shared a gene expression signature with MMs. Patient and zebrafish MMs have increased migratory neural crest gene and decreased antigen presentation gene expression, consistent with the increased metastatic behavior and decreased immunotherapy sensitivity of MM. Our work suggests the cell state of the originating melanocyte influences the behavior of derived melanomas. Our animal model phenotypically and transcriptionally mimics patient tumors, allowing this model to be used for MM therapeutic discovery.

Topological Data Analysis and Use of Mapper for Cerebral Aneurysm Rupture Status Discrimination Based on 3-Dimensional Shape Analysis.

BACKGROUND AND OBJECTIVES: Topological data analysis (TDA), which identifies patterns in data through simplified topological signatures, has yet to be applied to aneurysm research. We investigate TDA Mapper graphs (Mapper) for aneurysm rupture discrimination. METHODS: Two hundred sixteen bifurcation aneurysms (90 ruptured) from 3-dimensional rotational angiography were segmented from vasculature and evaluated for 12 size/shape and 18 enhanced radiomics features. Using Mapper, uniformly dense aneurysm models were represented as graph structures and described by graph shape metrics. Mapper dissimilarity scores (MDS) were computed between pairs of aneurysms based on shape metrics. Lower MDS described similar shapes, whereas high MDS represented shapes that do not share common characteristics. Ruptured/unruptured average MDS scores (how "far" an aneurysm is shape-wise to ruptured/unruptured data sets, respectively) were evaluated for each aneurysm. Rupture status discrimination univariate and multivariate statistics were reported for all features. RESULTS: The average MDS for pairs of ruptured aneurysms were significantly larger compared with unruptured pairs (0.055 ± 0.027 vs 0.039 ± 0.015, P < .0001). Low MDS suggest that, in contrast to ruptured aneurysms, unruptured aneurysms have similar shape characteristics. An MDS threshold value of 0.0417 (area under the curve [AUC] = 0.73, 80% specificity, 60% sensitivity) was identified for rupture status classification. Under this predictive model, MDS scores <0.0417 would identify unruptured status. MDS statistical performance in discriminating rupture status was similar to that of nonsphericity and radiomics Flatness (AUC = 0.73), outperforming other features. Ruptured aneurysms were more elongated ( P < .0001), flatter ( P < .0001), and showed higher nonsphericity ( P < .0001) compared with unruptured. Including MDS in multivariate analysis resulted in AUC = 0.82, outperforming multivariate analysis on size/shape (AUC = 0.76) and enhanced radiomics (AUC = 0.78) alone. CONCLUSION: A novel application of Mapper TDA was proposed for aneurysm evaluation, with promising results for rupture status classification. Multivariate analysis incorporating Mapper resulted in high accuracy, which is particularly important given that bifurcation aneurysms are challenging to classify morphologically. This proof-of-concept study warrants future investigation into optimizing Mapper functionality for aneurysm research.

Oncogenic CDK13 mutations impede nuclear RNA surveillance.

RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We found that disrupted nuclear RNA surveillance is oncogenic. Cyclin-dependent kinase 13 (CDK13) is mutated in melanoma, and patient-mutated CDK13 accelerates zebrafish melanoma. CDK13 mutation causes aberrant RNA stabilization. CDK13 is required for ZC3H14 phosphorylation, which is necessary and sufficient to promote nuclear RNA degradation. Mutant CDK13 fails to activate nuclear RNA surveillance, causing aberrant protein-coding transcripts to be stabilized and translated. Forced aberrant RNA expression accelerates melanoma in zebrafish. We found recurrent mutations in genes encoding nuclear RNA surveillance components in many malignancies, establishing nuclear RNA surveillance as a tumor-suppressive pathway. Activating nuclear RNA surveillance is crucial to avoid accumulation of aberrant RNAs and their ensuing consequences in development and disease.

Spinal anesthesia in contemporary and complex lumbar spine surgery: experience with 343 cases.

OBJECTIVE: Spinal anesthesia (SA) is an alternative to general anesthesia (GA) for lumbar spine surgery, including complex instrumented fusion, although there are relatively few outcome data available. The authors discuss their experience using SA in a modern complex lumbar spine surgery practice to describe its utility and implementation. METHODS: Data from patients receiving SA for lumbar spine surgery by one surgeon from March 2017 to December 2020 were collected via a retrospective chart review. Cases were divided into nonfusion and fusion procedure categories and analyzed for demographics and baseline medical status; pre-, intra-, and postoperative events; hospital course, including Acute Pain Service (APS) consults; and follow-up visit outcome data. RESULTS: A total of 345 consecutive lumbar spine procedures were found, with 343 records complete for analysis, including 181 fusion and 162 nonfusion procedures and spinal levels from T11 through S1. The fusion group was significantly older (mean age 65.9 ± 12.4 vs 59.5 ± 15.4 years, p < 0.001) and had a significantly higher proportion of patients with American Society of Anesthesiologists (ASA) Physical Status Classification class III (p = 0.009) than the nonfusion group. There were no intraoperative conversions to GA, with infrequent need for a second dose of SA preoperatively (2.9%, 10/343) and rare preoperative conversion to GA (0.6%, 2/343) across fusion and nonfusion groups. Rates of complications during hospitalization were comparable to those seen in the literature. The APS was consulted for 2.9% (10/343) of procedures. An algorithm for the integration of SA into a lumbar spine surgery practice, from surgical and anesthetic perspectives, is also offered. CONCLUSIONS: SA is a viable, safe, and effective option for lumbar spine surgery across a wide range of age and health statuses, particularly in older patients and those who want to avoid GA. The authors' protocol, based in part on the largest set of data currently available describing complex instrumented fusion surgeries of the lumbar spine completed under SA, presents guidance and best practices to integrate SA into contemporary lumbar spine practices.

Enhanced Radiomics for Prediction of Rupture Status in Cerebral Aneurysms.

BACKGROUND: Radiomics is a powerful tool for automatic extraction of morphological features, but when applied to cerebral aneurysms, it is inferior to established descriptors in classifying rupture status. We sought a strategy to recover neck orientation and parent vessel caliber to enhance Radiomics performance and facilitate its adoption for aneurysm risk stratification. METHODS: We analyzed 135 sidewall (32 ruptured) and 216 bifurcation (90 ruptured) aneurysms from three-dimensional rotational catheter angiography datasets. Clinical three-dimensional rotational catheter angiography defined in arbitrary orientation underwent affine transformations enabling aneurysm neck alignment to XY plane before analysis in PyRadiomics, facilitating automatic extraction of aneurysm height and width, previously not possible with random alignment. Additionally, parent vessel size was estimated from aneurysm location and incorporated into enhanced Radiomics (height, width, height/width, size ratio). Rupture status classification was compared across methodologies for 31 automatically computed conventional Radiomics, enhanced Radiomics, and established size/shape descriptors using univariate, multivariate, and area under the curve (AUC) statistics. RESULTS: Enhanced Radiomics-derived height/width and size ratio were significantly higher in both ruptured subsets. Using multivariate analysis in sidewall lesions, enhanced Radiomics (AUC = 0.85) matched established features (AUC = 0.86) and outperformed conventional Radiomics (AUC = 0.82); in bifurcation lesions, enhanced Radiomics (AUC = 0.78) outperformed both established features (AUC = 0.76) and conventional Radiomics (AUC = 0.74). CONCLUSIONS: Enhanced Radiomics incorporating neck orientation and parent vessel estimate is an efficient operator-independent methodology that offers superior rupture status classification for both sidewall and bifurcation aneurysms and should be considered a strong candidate for larger-scale multicenter and multimodality validation.

Arf GAPs as Regulators of the Actin Cytoskeleton-An Update.

Arf GTPase-activating proteins (Arf GAPs) control the activity of ADP-ribosylation factors (Arfs) by inducing GTP hydrolysis and participate in a diverse array of cellular functions both through mechanisms that are dependent on and independent of their Arf GAP activity. A number of these functions hinge on the remodeling of actin filaments. Accordingly, some of the effects exerted by Arf GAPs involve proteins known to engage in regulation of the actin dynamics and architecture, such as Rho family proteins and nonmuscle myosin 2. Circular dorsal ruffles (CDRs), podosomes, invadopodia, lamellipodia, stress fibers and focal adhesions are among the actin-based structures regulated by Arf GAPs. Arf GAPs are thus important actors in broad functions like adhesion and motility, as well as the specialized functions of bone resorption, neurite outgrowth, and pathogen internalization by immune cells. Arf GAPs, with their multiple protein-protein interactions, membrane-binding domains and sites for post-translational modification, are good candidates for linking the changes in actin to the membrane. The findings discussed depict a family of proteins with a critical role in regulating actin dynamics to enable proper cell function.