Ewing's sarcomas contain specific chromosomal translocations that fuse EWS to ETS family members, including FLI, ERG, FEV, ETV1 and ETV4. Prior work has suggested that functional differences exist between some of these EWS-ETS fusions. However, as the cell of origin of Ewing's sarcoma is unknown, this prior work was conducted in NIH3T3 cells, which have not been validated as an appropriate model for the study of EWS-ETS fusions. To determine if NIH3T3 cells are a good model for Ewing's sarcoma, we introduced all five EWS-ETS fusions into these cells, and analyzed their phenotypes and gene expression patterns. EWS-FLI, EWS-ERG, and EWS-FEV caused NIH3T3 cells to exhibit anchorage independent growth whereas EWS-ETV1 and EWS-ETV4 did not. In contrast, all the EWS-ETS fusions induced tumor formation in a xenograft model. We defined the core transcriptional profile of the EWS-ETS fusions using cDNA microarrays, and compared these to data derived from patient-derived Ewing's sarcoma cell lines. The NIH3T3 model did not recapitulate the gene expression pattern of bona fide Ewing's sarcoma. Based on these results, we conclude that while there may be functional differences between the various EWS-ETS fusions, the NIH3T3 cell model is inadequate to study the gene expression pattern induced by EWS-ETS proteins in Ewing's sarcoma. Thus, data derived from the NIH3T3 model system needs to be appropriately validated before they can be accepted as relevant to the human disease.
Precision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, making it difficult to cohort patients with MODS, but presenting a prime target for testing/developing tools for precision medicine. Using multitime point whole blood (cellular/acellular) total transcriptomics in 27 patients, we highlight the promise of simultaneously mapping viral/bacterial load, cell composition, tissue damage biomarkers, balance between syndromic biology versus environmental response, and unique biological insights in each patient using a single platform measurement. Integration of a transcriptome workflow yielded unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms, highlighted by a unique case of virally induced genetics (VIG) within one of these 27 patients. The power of RNA-Seq to study unique patient biology while investigating environmental contributions can be a critical tool moving forward for translational sciences applied to precision medicine.
Essentials Data is scarce on enoxaparin dosing for obese adolescents with venous thromboembolism (VTE).Overweight and obese adolescents treated with reduced enoxaparin dose (RD) were reviewed.Initial enoxaparin doses calculated using actual body weight may be greater than what is needed.Trials are warranted to evaluate RD enoxaparin for overweight and obese adolescents with VTE. BackgroundThe global obesity epidemic has created new challenges, including venous thromboembolisms (VTE) in obese adolescents. The data on whether to reduce the dose of low‐molecular heparin in obese adults is conflicting, and information on adolescent patients is scarce.ObjectivesOur primary goal was to describe dosing, anti‐Xa levels, and outcomes of overweight and obese adolescents who received reduced doses of enoxaparin at the initiation of therapy. The secondary goal was to compare their outcomes to overweight and obese adolescents who received standard 1 mg/kg dosing to determine if future trials for dose reduction are warranted.Patients/MethodsWe performed a retrospective cohort study of overweight and obese patients between the ages of 12 and 18 years old diagnosed with VTE who were treated with reduced dosing (RD) of enoxaparin, comparing their dosing, anti‐Xa levels, and outcomes to overweight and obese adolescents who received standard dosing (SD).Results RD patients (n=19) achieved therapeutic mean initial anti‐Xa levels that were similar to SD patients (n=11). Of the RD patients, 53% did not require dose adjustments during treatment. Two RD patients had thrombus progression. A total of 25 patients ultimately completed therapy with RD.ConclusionsFuture trials are warranted to evaluate the efficacy and safety of reduced dosing of enoxaparin to treat overweight and obese adolescents with VTE.
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