Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (TIC) within the tumor bulk. Therefore, targeting liver TICs may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver TIC properties, including self-renewal, tumorigenicity, and liver TIC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver TIC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced TIC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC. IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway regulates cancer stemness and drug resistance and may be a novel therapeutic target in HCC. .
This paper describes the design and development of a computer interface for blind and visually‐impaired users, who are native speakers of Cantonese (i.e. a Chinese dialect). Apart from enabling the interface to (1) produce Chinese voice output, (2) convert Chinese characters to Braille codes, (3) facilitate Chinese Braille input, and (4) operate in a Microsoft Chinese Windows environment, the significant aspects of this paper include the following: (1) the description of an integrated architecture, which can be used for other languages; (2) a general bilingual Braille input mechanism; (3) a sentence‐based input method that can be used for contracted‐Braille‐to‐text conversion with an error rate of about 6%, operating at about 700 characters/second using a Pentium II 300 MHz PC; (4) a code‐mixed synthesis module for general bilingual and multilingual applications; (5) the potential to directly adopt the system for use with other ideographic languages (like Japanese and Korean), as well as agglutinating languages like Finnish and Turkish, which have no space between words. Copyright © 2003 John Wiley & Sons, Ltd.
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