Aberrant regulation of EGFR is common in non-small cell lung carcinomas (NSCLC), and tumor resistance to targeted therapies has been attributed to emergence of other cooccurring oncogenic events, parallel bypass receptor tyrosine kinase pathways including IGF1R, and TNFadriven adaptive response via NF-kB. TNFAIP8, TNFa-inducible protein 8, is an NF-kB-activated prosurvival and oncogenic molecule. TNFAIP8 expression protects NF-kB-null cells from TNFa-induced cell death by inhibiting caspase-8 activity. Here, we demonstrate that knockdown of TNFAIP8 inhibited EGF and IGF-1-stimulated migration in NSCLC cells. TNFAIP8 knockdown cells showed decreased level of EGFR and increased expression of sorting nexin 1 (SNX1), a key regulator of the EGFR trafficking through the endosomal compartments, and treatment with SNX1 siRNA partially restored EGFR expression in these cells. TNFAIP8 knockdown cells also exhibited downregulation of IGF-1-induced pIGF1R and pAKT, and increased expression of IGF-1-binding protein 3 (IGFBP3), a negative regulator of the IGF-1/IGF1R signaling. Consistently, treatment of TNFAIP8 knockdown cells with IGFBP3 siRNA restored pIGF1R and pAKT levels. TNFAIP8 knockdown cells had enhanced sensitivities to inhibitors of EGFR, PI3K, and AKT. Furthermore, IHC expression of TNFAIP8 was associated with poor prognosis in NSCLC. These findings demonstrate TNFAIP8-mediated regulation of EGFR and IGF1R via SNX1 and IGFBP3, respectively. We posit that TNFAIP8 is a viable, multipronged target downstream of the TNFa/NF-kB axis, and silencing TNFAIP8 may overcome adaptive response in NSCLC. Implications: TNFAIP8 and its effectors SNX1 and IGFBP3 may be exploited to improve the efficacy of molecular-targeted therapies in NSCLC and other cancers.

Blastomycosis is a fungal infection rarely seen in clinical practice. Endemic to the Midwestern United States as well as the Canadian provinces of Manitoba and Ontario, Blastomyces dermatitidis characteristically involves the skin and lungs. Central nervous system (CNS) involvement, although a rare complication of this disease, can be fatal. The current literature on CNS blastomycosis primarily centers on the spectrum of traditional imaging features of T1- and T2-weighted imaging with which this entity can present. However, here we present the direct histopathologic correlation of the imaging findings of solitary mass like CNS blastomycosis, with an emphasis on the association of diffusion restriction within the lesion with a granulomatous immune response.

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<p>IGFBP3 in culture medium</p>

<p>Suppression of pIGF1R</p>