A comparative analysis of RAS variants in patients with disorders of somatic mosaicism.

PURPOSE: RAS genes (HRAS, KRAS, and NRAS) are commonly found to be mutated in cancers, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the mutational spectrum of RAS variants in DoSM has not been performed. METHODS: A total of 938 individuals with suspected DoSM underwent high-sensitivity clinical next-generation sequencing-based testing. We investigated the mutational spectrum and genotype-phenotype associations of mosaic RAS variants. RESULTS: In this article, we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority of RAS variants observed in DoSM. Furthermore, we present 12 individuals with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain. Among the 18.3% individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular malformations. Hotspots were associated with a broad phenotypic spectrum, including vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth, digital anomalies, and combinations of these. The median age at testing was higher and the variant allelic fraction was lower in individuals with in-frame dup/ins variants than those in individuals with mosaic RAS hotspots. CONCLUSION: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.

Quantification of DAS VSP Quality: SNR vs. Log-Based Metrics.

The initial quantification of data quality is an important step in seismic data acquisition design, including the choice of sensing strategy. The signal-to-noise ratio (SNR) often drives the choice of distributed acoustic sensing (DAS) parameters in vertical seismic profiling (VSP). We compare this established approach for data quality assessment with metrics comparing DAS data products to available well logs. First, we create kinematic and dynamic data products derived from original seismic data, such as the interval velocity and amplitude of P-wave arrivals. Next, we quantify the quality of derived data products using well log data by calculating various statistical metrics. Using a large dataset of 220 different VSP experiments with a fixed source location and various DAS acquisition parameters, such as gauge length (GL), conveyance type, and lead-in length, we analyzed the statistical distribution of various metrics. The results indicate the decoupling between seismic-based and log-based metrics as well as between the quality of dynamic and kinematic data-products for the same record. Therefore, we propose using fit-for-purpose metrics to optimize the acquisition cost. In particular, for ray-based tomographic processing, it is sufficient to use traveltime-based metrics. On the other hand, for advanced dynamic analysis, amplitude-based metrics define the quality of final processing products. Hence, it is crucial to use fit-for-purpose metrics to optimize DAS VSP acquisition.

Modulating endothelial barrier function by targeting vimentin phosphorylation.

Vimentin is a major intermediate filament protein in vascular endothelial cells which might be involved in their function as a barrier tissue. It is proposed to dynamically maintain integrity of the endothelium as a tightly regulated permeability barrier that is subjected to a variety of shear and contractile forces. The results described in this report demonstrate that vimentin plays that role through mechanisms that are dependent on its phosphorylation state. Withaferin A (WFA), a vimentin targeting drug is shown to disrupt endothelial barrier function through its effects on vimentin filament distribution and physical properties. These effects are related to WFA's ability to increase vimentin phosphorylation. Through overexpressing a non-phosphorylatable vimentin mutant we can block the effects of WFA on vimentin distribution and barrier permeability. The barrier augmentation effect appears to extend to endothelial cells that do not express detectable mutant vimentin which might suggest transmissible effects across cells. Blocking vimentin phosphorylation also protects the endothelial barrier against LPS endotoxin, implicating it as a target for drug development against pulmonary edema and acute respiratory distress syndrome (ARDS).

Troisier sign and Virchow node: the anatomy and pathology of pulmonary adenocarcinoma metastasis to a supraclavicular lymph node.

Metastatic spread of cancer via the thoracic duct may lead to an enlargement of the left supraclavicular node, known as the Virchow node (VN), leading to an appreciable mass that can be recognized clinically - a Troisier sign. The VN is of profound clinical importance; however, there have been few studies of its regional anatomical relationships. Our report presents a case of a Troisier sign/VN discovered during cadaveric dissection in an individual whose cause of death was, reportedly, chronic obstructive pulmonary disease. The VN was found to arise from an antecedent pulmonary adenocarcinoma. Our report includes a regional study of the anatomy as well as relevant gross pathology and histopathology. Our anatomical findings suggest that the VN may contribute to vascular thoracic outlet syndrome as well as the brachial plexopathy of neurogenic thoracic outlet syndrome. Further, the VN has the potential to cause compression of the phrenic nerve, contributing to unilateral phrenic neuropathy and subsequent dyspnea. Recognition of the Troisier sign/VN is of great clinical importance. Similarly, an appreciation of the anatomy surrounding the VN, and the potential for the enlarged node to encroach on neurovascular structures, is also important in the study of a patient. The presence of a Troisier sign/VN should be assessed when thoracic outlet syndrome and phrenic neuropathy are suspected. Conversely, when a VN is identified, the possibility of concomitant or subsequent thoracic outlet syndrome and phrenic neuropathy should be considered.

Troisier sign and Virchow node: the anatomy and pathology of pulmonary adenocarcinoma metastasis to a supraclavicular lymph node

ABSTRACT: Metastatic spread of cancer via the thoracic duct may lead to an enlargement of the left supraclavicular node, known as the Virchow node (VN), leading to an appreciable mass that can be recognized clinically ­ a Troisier sign. The VN is of profound clinical importance; however, there have been few studies of its regional anatomical relationships. Our report presents a case of a Troisier sign/VN discovered during cadaveric dissection in an individual whose cause of death was, reportedly, chronic obstructive pulmonary disease. The VN was found to arise from an antecedent pulmonary adenocarcinoma. Our report includes a regional study of the anatomy as well as relevant gross pathology and histopathology. Our anatomical findings suggest that the VN may contribute to vascular thoracic outlet syndrome as well as the brachial plexopathy of neurogenic thoracic outlet syndrome. Further, the VN has the potential to cause compression of the phrenic nerve, contributing to unilateral phrenic neuropathy and subsequent dyspnea. Recognition of the Troisier sign/VN is of great clinical importance. Similarly, an appreciation of the anatomy surrounding the VN, and the potential for the enlarged node to encroach on neurovascular structures, is also important in the study of a patient. The presence of a Troisier sign/VN should be assessed when thoracic outlet syndrome and phrenic neuropathy are suspected. Conversely, when a VN is identified, the possibility of concomitant or subsequent thoracic outlet syndrome and phrenic neuropathy should be considered.