Anti-NAPSA monoclonal antibody, clone 21D5C9

Brain metastatic papillary thyroid carcinomas (PTCs) are afflicted with unfavorable prognosis; however, the underlying molecular genetics of these rare metastases are virtually unknown. In this study, we compared whole transcript microarray expression profiles of a BRAF mutant, brain metastasis from a PTC, including its technical replicate (TR), with eight non-brain metastatic PTCs and eight primary brain tumors. The top 95 probe sets (false discovery rate (FDR) p-value < 0.05 and fold change (FC) > 2) that were differentially expressed between the brain metastatic PTC, including the TR, and both, non-brain metastatic PTCs and primary brain tumors were in the vast majority upregulated and comprise, e.g. ROS1, MYBPH, SLC18A3, HP, SAA2-SAA4, CP, CCL20, GFAP, RNU1-120P, DMBT1, XDH, CXCL1, PI3, and NAPSA. Cytokines were represented by 10 members in the top 95 probe sets. Pathway and network analysis (p-value < 0.05 and FC > 2) identified granulocytes adhesion and diapedesis as top canonical pathway. Most significant upstream regulators were lipopolysaccharide, TNF, NKkB (complex), IL1A, and CSF2. Top networks categorized under diseases & functions were entitled migration of cells, cell movement, cell survival, apoptosis, and proliferation of cells. Probe sets that were significantly shared between the brain metastatic PTC, the TR, and primary brain tumors include CASP1, CASP4, C1R, CC2D2B, RNY1P16, WDR72, LRRC2, ZHX2, CITED1, and the noncoding transcript AK128523. Taken together, this study identified a set of candidate genes and biofunctions implicated in, so far nearly uncharacterized, molecular processes of a brain metastasis from a PTC.

ELF5, an Ets family transcription factor found exclusively in epithelial cells, is expressed in the distal lung epithelium during embryogenesis, then becomes restricted to proximal airways at the end of gestation and postnatally. To test the hypothesis that ELF5 represses distal epithelial differentiation, we generated a transgenic mouse model in which a doxycycline inducible HA-tagged mouse Elf5 transgene was placed under the control of the lung epithelium-specific human SFTPC promoter. We found that expressing high levels of ELF5 during early lung development disrupted branching morphogenesis and produced a dilated epithelium. The effects of ELF5 on morphogenesis were stage-dependent, since inducing the transgene on E16.5 had no effect on branching. ELF5 reduced expression of the distal lung epithelial differentiation markets Erm, Napsa and Sftpc, and type II cell ultrastructural differentiation was immature. ELF5 overexpression did not induce the proximal airway epithelial markers Ccsp and Foxj1, but did induce expression of p63, a marker of basal cells in the trachea and esophagus. High ELF5 levels also induced the expression of genes found in other endodermal epithelia but not normally associated with the lung. These results suggest that precise levels of ELF5 regulate the specification and differentiation of epithelial cells in the lung. (C) 2008 Elsevier Inc. All rights reserved.