Anaplastic lymphoma kinase expression in small-cell lung cancer.

AIMS: Anaplastic lymphoma kinase (ALK) immunohistochemistry has shifted from being a screening tool to being a sole determinant for ALK-targeted therapy. Recent articles have referred to small-cell lung cancer (SCLC) transformation as a resistance mechanism after ALK inhibitor treatments, but few reports have addressed ALK expression in treatment-naive SCLC in a comprehensive manner. Therefore, we examined ALK expression and the mechanisms in treatment-naive SCLCs. METHODS AND RESULTS: We examined ALK expression in a consecutive series of SCLC tumours, and the expression mechanism was analysed regarding gene rearrangement, copy number changes, and point mutations. We also examined whether SCLC with ALK expression can be suppressed by crizotinib treatment in vitro. Immunohistochemical results revealed that ALK was expressed in 16 of 142 (11.3%) SCLCs. The expression was focal and less intense, which is in contrast to strong and uniform expression in adenocarcinoma with ALK rearrangement. Two combined SCLCs showed a positive reaction restricted to the SCLC component. None of the known genetic alterations, including rearrangement, amplification, copy number gain, or point mutations, were associated with ALK expression. A SCLC cell line, SKLC2, which expressed ALK without known genetic alterations, was not inhibited by a practically achievable serum concentration of crizotinib. CONCLUSIONS: Anaplastic lymphoma kinase immunohistochemistry for treatment-naive SCLCs should not be used as a predictive biomarker for ALK inhibitor therapy, because the positive reactions were due to intrinsic expression of normal ALK transcript.

A case of isolated tricuspid valve infective endocarditis caused by Abiotrophia defectiva.

A 17-year-old man with a history of dental caries was admitted to our hospital because of 1-week high fever. There was no history of previous cardiac disease. He denied drug abuse. Blood culture was positive for Abiotrophia defectiva. Echocardiography demonstrated large vegetation attached to the anterior cusp of the tricuspid valve with moderate regurgitation. Although he was treated with antibiotics for more than 3 weeks, he had chest pain due to septic pulmonary emboli on chest computed tomography. Surgical resection of the vegetation was performed. The postoperative course was uneventful and he is doing well at the time of follow-up.

Fas-associated factor 1 is a negative regulator of PYRIN-containing Apaf-1-like protein 1.

PYRIN-containing apoptotic protease-activating factor 1-like proteins (PYPAFs, also called NALPs) participate in inflammatory signaling by regulating nuclear factor-kappaB (NF-kappaB) activation and cytokine processing, and have been implicated in autoimmune and inflammatory disorders. However, the precise mechanisms that regulate the signal pathway leading to NF-kappaB activation are not completely understood. Here, we used yeast two-hybrid assays to identify Fas-associated factor 1 (FAF1) as a protein interacting with the pyrin domains of several PYPAFs. In these assays, FAF1 interacted strongly with PYPAF1, PYPAF3 and PYPAF7, moderately with PYPAF2 and PYNOD but not at all with the pyrin domains of pyrin or the adaptor molecule apoptosis-associated speck-like protein containing a caspase activation and recruit domain (ASC). The interaction between FAF1 and PYPAF1 in mammalian cells was confirmed by immunoprecipitation assays, and the Fas-interacting domain of FAF1 was critical for this interaction. When co-expressed in HEK293 cells, FAF1 interfere with the NF-kappaB activation induced by PYPAF1 and ASC. A FAF1 mutant lacking the Fas-interacting domain showed significantly reduced ability to inhibit NF-kappaB activation. In THP-1 cells, the stimulation of NF-kappaB up-regulated the level of endogenous FAF1. Taken together, these findings suggest that FAF1 functions as a negative regulator of an NF-kappaB signal pathway that involves PYPAF1 and ASC.