Dual Targeting of EGFR and IGF1R in the TNFAIP8 Knockdown Non-Small Cell Lung Cancer Cells.

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 co-occurring oncogenic events, parallel bypass receptor tyrosine kinase pathways including IGF1R, and TNFα-driven adaptive response via NF-κB. TNFAIP8, TNFα-inducible protein 8, is an NF-κB-activated prosurvival and oncogenic molecule. TNFAIP8 expression protects NF-κB-null cells from TNFα-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 TNFα/NF-κB 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.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/5/1207/F1.large.jpg.

Comparative assessment of conventional chromosomal analysis and fluorescence in situ hybridization in the evaluation of suspected myelodysplastic syndromes: a single institution experience.

BACKGROUND: Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic neoplasms, roughly half of which harbor cytogenetic abnormalities with diagnostic, prognostic, and therapeutic significance. Fluorescence in situ hybridization (FISH) for the most commonly seen abnormalities (5/5q, -7/7q, +8, and -20/20q-) is routinely performed alongside conventional cytogenetics (CC) in the evaluation of suspected MDS despite conflicting reports of its relative contribution compared to CC alone. OBJECTIVES: To assess the additional diagnostic and prognostic value of performing concurrent FISH versus CC alone in cases of suspected MDS. MATERIALS AND METHODS: A total of 127 bone marrow samples submitted to our cytogenetic laboratory with a presumptive diagnosis of MDS were evaluated by concurrent CC and an MDS FISH panel. RESULTS: CC was used as the gold standard method with 100% sensitivity in detecting suspected MDS-associated cytogenetic abnormalities. FISH alone had a sensitivity of 76%, whereas CC alone achieved a sensitivity of 97%. The addition of FISH did not change the diagnosis nor change the Revised International Prognostic Scoring System score in any patient. Moreover, in 12 cases identified as positive by both CC and FISH, CC identified multiple chromosomal aberrations of clinical significance not interrogated by the FISH probe panel. CONCLUSION: CC alone is sufficiently sensitive in detecting suspected MDS-associated cytogenetic abnormalities that influence clinical decision-making. Routine FISH testing does not provide a significant increase in test sensitivity when an adequate karyotype is obtained. Therefore, FISH testing is best reserved for suspected MDS cases lacking sufficient metaphases.

Cerebral Blastomycosis: Radiologic-Pathologic Correlation of Solitary CNS Blastomycosis Mass-Like Infection.

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.