Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC. Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines. Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90ß. Within a cohort of ACC patients, HSP90ß expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2-and AKT-pathways by luminespib and ganetespib treatment. Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC.

A perceptual interference account of acquisition difficulties for non-native phonemes.

This article presents an account of how early language experience can impede the acquisition of non-native phonemes during adulthood. The hypothesis is that early language experience alters relatively low-level perceptual processing, and that these changes interfere with the formation and adaptability of higher-level linguistic representations. Supporting data are presented from an experiment that tested the perception of English /r/ and /l/ by Japanese, German, and American adults. The underlying perceptual spaces for these phonemes were mapped using multidimensional scaling and compared to native-language categorization judgments. The results demonstrate that Japanese adults are most sensitive to an acoustic cue, F2, that is irrelevant to the English /r/-/l/ categorization. German adults, in contrast, have relatively high sensitivity to more critical acoustic cues. The results show how language-specific perceptual processing can alter the relative salience of within- and between-category acoustic variation, and thereby interfere with second language acquisition.