Characterization of Non-Small-Cell Lung Cancers With MET Exon 14 Skipping Alterations Detected in Tissue or Liquid: Clinicogenomics and Real-World Treatment Patterns.

Purpose: exon 14 (ex14) skipping alterations are oncogenic drivers in non-small-cell lung cancer (NSCLC). We present a comprehensive overview of ex14 samples from 1,592 patients with NSCLC, associated clinicogenomic characteristics, potential mechanisms of acquired resistance, treatment patterns, and outcomes to MET inhibitors.

Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on samples from 69,219 patients with NSCLC.

Characterization of Clinical Cases of Malignant PEComa via Comprehensive Genomic Profiling of DNA and RNA.

Purpose: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa.

Patients And Methods: Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEC-oma.

Targetable BRAF and RAF1 Alterations in Advanced Pediatric Cancers.

RAF family protein kinases signal through the MAPK pathway to orchestrate cellular proliferation, survival, and transformation. Identifying BRAF alterations in pediatric cancers is critically important as therapeutic agents targeting BRAF or MEK may be incorporated into the clinical management of these patients. In this study, we performed comprehensive genomic profiling on 3,633 pediatric cancer samples and identified a cohort of 221 (6.

Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the Gene Have Durable Responses to ALK Kinase Inhibitors.

Background: fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex variants that may predict sensitivity to multiple approved ALK inhibitors.

Novel rearrangement in multifocal infantile myofibromatosis is tumorigenic and sensitive to imatinib.

Infantile myofibromatosis (IM) is an aggressive neoplasm composed of myofibroblast-like cells in children. Although typically localized, it can also present as multifocal disease, which represents a challenge for effective treatment. IM has previously been linked to activating somatic and germline point mutations in the PDGFRβ tyrosine kinase encoded by the gene.

in Lung Cancers: Analysis of Patient Cases Reveals Recurrent Mutations, Fusions, Kinase Duplications, and Concurrent Alterations.

Purpose: Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 B alterations in lung cancer.

Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling.

Background: Papillary renal cell carcinoma (PRCC) is a rare subset of RCC. The Cancer Genome Atlas (TCGA) data largely reflect localized disease, and there are limited data for advanced PRCC.

Objective: To characterize the frequency of genomic alterations (GAs) in patients with advanced PRCC for whom comprehensive genomic profiling (CGP) was performed in the context of routine clinical care.

Identification of NTRK fusions in pediatric mesenchymal tumors.

Background: NTRK fusions are known oncogenic drivers and have recently been effectively targeted by investigational agents in adults. We sought to assess the frequency of NTRK fusions in a large series of pediatric and adolescent patients with advanced cancers.

Procedure: Genomic profiles from 2,031 advanced cancers from patients less than 21 years old who were assayed with comprehensive genomic profiling were reviewed to identify NTRK fusions.

Characterization of 298 Patients with Lung Cancer Harboring MET Exon 14 Skipping Alterations.

Background: The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-to-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs).

Methods: Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians.

Results: Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.

Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting.

The spectrum of somatic alterations in hematologic malignancies includes substitutions, insertions/deletions (indels), copy number alterations (CNAs), and a wide range of gene fusions; no current clinically available single assay captures the different types of alterations. We developed a novel next-generation sequencing-based assay to identify all classes of genomic alterations using archived formalin-fixed paraffin-embedded blood and bone marrow samples with high accuracy in a clinically relevant time frame, which is performed in our Clinical Laboratory Improvement Amendments-certified College of American Pathologists-accredited laboratory. Targeted capture of DNA/RNA and next-generation sequencing reliably identifies substitutions, indels, CNAs, and gene fusions, with similar accuracy to lower-throughput assays that focus on specific genes and types of genomic alterations.

Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.

Unlabelled: Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.

Human Capital Investment and the Gender Division of Labor in a Brawn-Based Economy.

We use a model of human capital investment and activity choice to explain facts describing gender differentials in the levels and returns to human capital investments. These include the higher return to and level of schooling, the small effect of healthiness on wages, and the large effect of healthiness on schooling for females relative to males. The model incorporates gender differences in the level and responsiveness of brawn to nutrition in a Roy-economy setting in which activities reward skill and brawn differentially.

TrpA1 regulates thermal nociception in Drosophila.

Pain is a significant medical concern and represents a major unmet clinical need. The ability to perceive and react to tissue-damaging stimuli is essential in order to maintain bodily integrity in the face of environmental danger. To prevent damage the systems that detect noxious stimuli are therefore under strict evolutionary pressure.

A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an evolutionarily conserved pain gene.

Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the α2δ family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (α2δ3) also exhibit impaired behavioral heat pain sensitivity.

Navigational decision making in Drosophila thermotaxis.

A mechanistic understanding of animal navigation requires quantitative assessment of the sensorimotor strategies used during navigation and quantitative assessment of how these strategies are regulated by cellular sensors. Here, we examine thermotactic behavior of the Drosophila melanogaster larva using a tracking microscope to study individual larval movements on defined temperature gradients. We discover that larval thermotaxis involves a larger repertoire of strategies than navigation in smaller organisms such as motile bacteria and Caenorhabditis elegans.

Distinct TRP channels are required for warm and cool avoidance in Drosophila melanogaster.

The ability to sense and respond to subtle variations in environmental temperature is critical for animal survival. Animals avoid temperatures that are too cold or too warm and seek out temperatures favorable for their survival. At the molecular level, members of the transient receptor potential (TRP) family of cation channels contribute to thermosensory behaviors in animals from flies to humans.

An internal thermal sensor controlling temperature preference in Drosophila.

Animals from flies to humans are able to distinguish subtle gradations in temperature and show strong temperature preferences. Animals move to environments of optimal temperature and some manipulate the temperature of their surroundings, as humans do using clothing and shelter. Despite the ubiquitous influence of environmental temperature on animal behaviour, the neural circuits and strategies through which animals select a preferred temperature remain largely unknown.

The Drosophila ortholog of vertebrate TRPA1 regulates thermotaxis.

Thermotaxis is important for animal survival, but the molecular identities of temperature sensors controlling this behavior have not been determined. We demonstrate dTRPA1, a heat-activated Transient Receptor Potential (TRP) family ion channel, is essential for thermotaxis in Drosophila. dTrpA1 knockdown eliminates avoidance of elevated temperatures along a thermal gradient.

Recovery from brain injury in animals: relative efficacy of environmental enrichment, physical exercise or formal training (1990-2002).

In the 1960s, it was shown for the first time that enriched housing enhances functional recovery after brain damage. During the 1970s and 1980s, many findings similar to this initial one have been reported, enlarging greatly its generality. Over the last 13 years, many different kinds of brain damage were modelled in animals or even directly studied in humans.

Effects of differential experience on the brain and behavior.

This review of plasticity of brain and behavior ranges from examples of plasticity restricted to an early critical period to other examples that show lifelong plasticity, but these two polar opposites are far from covering the field. Rather, it appears that there are a number of patterns by which different measures of plasticity vary as a function of age. Even in cases that indicate the existence of a critical period for development of neural circuits and of behavior, it is not yet possible to define the period exactly, because different methods yield different results, and much parametric work remains to be done.

Axon targeting meets protein trafficking: Comm takes Robo to the cleaners.

Axon guidance at the Drosophila midline relies on dynamic regulation of the guidance receptor Robo by its negative regulator Comm. Recent findings demonstrate that Comm collaborates with the ubiquitin-protein ligase DNedd4 to inhibit Robo signaling by promoting the sorting of Robo into the endocytic pathway.