We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.
The evaporating sessile droplet of a mono/didisperse colloid on a plate is a very useful and handy technique in micro/nano/bioapplications to separate, pattern, and control the particles. Although the fundamental nature of the evaporation phenomena and its applications have been extensively proposed, the crucial forces affecting a single particle motion in an evaporating droplet are not reported yet. To elucidate the impact of various forces including the drag, electrostatic, van der Waals, and surface tension forces on the particle motion in suspension, the magnitudes of them are compared using the scale analysis. In the early stage of the evaporation, in which the contact line is fixed, the motion of a single particle suspended in liquid are mostly affected by drag force. Later, with the incidence of the contact line recession, the surface tension force takes over the control of the single particle motion.
The lateral migration of neutrally-buoyant particles transported through square microchannels has been experimentally investigated over a Reynolds number range of 0.06 Re 58.65 at the ratio of channel hydraulic diameter to particle size, λ ≈ 14. Flow Reynolds numbers are determined by applying a conventional particle-tracking algorithm to small tracer particles, while novel imaging techniques have been proposed for identifying and defining the measurement depth of large test particles. By analyzing the spatial distributions of spherical particles, it is revealed that lateral migration of particles markedly occurs even at very low Re, which is induced by the high shear rate due to the small-scale effect. The particle equilibrium position is obtained as a function of Re, and the critical Re at which the particle equilibrium position starts to increase is found in the range 20 Re 30. The outermost edge of the particle cluster is also in good agreement with previously available data, which provides a good quantitative basis for designing microfluidic devices that are to be used for plasma separation from whole blood.
GM-CSF induces proinflammatory macrophages, but the underlying mechanisms have not been studied thus far. In this study, we investigated the mechanisms of how GM-CSF induces inflammatory macrophages. First, we observed that GM-CSF increased the extent of LPS-induced acute glycolysis in murine bone marrow-derived macrophages. This directly correlates with an inflammatory phenotype because glycolysis inhibition by 2-deoxyglucose abolished GM-CSF-mediated increase of TNF-α, IL-1β, IL-6, and IL-12p70 synthesis upon LPS stimulation. Increased glycolytic capacity is due to de novo synthesis of glucose transporter (GLUT)-1, -3, and -4, as well as c-myc. Meanwhile, GM-CSF increased 3-hydroxy-3-methyl-glutaryl-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway. Inhibition of acute glycolysis or 3-hydroxy-3-methyl-glutaryl-CoA reductase abrogated the inflammatory effects of GM-CSF priming in macrophages. Finally, mice with inflamed colons exposed to dextran sodium sulfate containing GLUT-1 macrophages led to massive uptake of [F]-fluorodeoxyglucose, but GM-CSF neutralization reduced the positron-emission tomography signal in the intestine and also decreased GLUT-1 expression in colonic macrophages. Collectively, our results reveal glycolysis and lipid metabolism created by GM-CSF as the underlying metabolic constructs for the function of inflammatory macrophages.
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