ABSTRACT
Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.
Subject(s)
Algorithms , Artificial Intelligence , Blood Platelets/physiology , Carcinoma, Non-Small-Cell Lung/diagnosis , Diagnosis, Computer-Assisted/methods , Lung Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Cohort Studies , Female , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Humans , Inflammation/blood , Inflammation/diagnosis , Inflammation/genetics , Lung Neoplasms/blood , Lung Neoplasms/genetics , Male , Middle Aged , Support Vector MachineABSTRACT
The Wnt/beta-catenin signaling pathway plays an important role in the commitment and development of thymic epithelial precursors. Here we document similarities of thymic epithelial development during embryogenesis in human and mouse. We stained for thymic epithelial surface markers (EpCAM1, Ly51, K8) and ligand/receptor pair (Wnt4, Fz4). Our results confirm the relevance of using murine test systems to model human embryonic thymic epithelial cell development. We have efficiently transduced murine embryonic epithelial cells using mock (GFP) and Wnt/beta-catenin-inhibiting (ICAT-encoding) recombinant adenoviral vectors. The effect of Wnt4 was assayed in the form of Wnt4-containing supernatant. Gene expressional changes were assessed by Q-PCR and also morphology using conventional and confocal fluorescent microscopy. Functional aberration caused by ICAT was assessed through evaluation of thymocyte maturation. Our results demonstrate that ICAT and Wnt4 have reciprocal effects during embryonic thymic epithelial cell development. While Wnt4 is capable of increasing the expression level of characteristic intracellular (FoxN1), surface (MHCII) and secreted (IL7) molecules, Wnt/beta-catenin inhibition through ICAT can moderately decrease their expression. Morphological changes induced by ICAT resulted in the development of hollow, inflated thymic lobes with reduced epithelial cell numbers. The ICAT-treated thymic lobes also showed significant impairment in supporting thymocyte development and maturation.