Purpose Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNETs). Experimental design In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors. Results In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, while microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, p<0.001). ALT also strongly correlated with lymphovascular (p<0.001) and perineural invasion (p=0.001), and the presence of lymph node (p<0.001) and distant metastases (p=0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival (HR=3.38, 95% CI=1.83–6.27; p<0.001). Interestingly, when limiting to patients with distant metastases, those with ALT-positive primary tumors had significantly better overall survival (HR=0.23, 95% CI=0.08–0.68; p=0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (p<0.001), aggressive clinical behavior, and reduced recurrence-free survival (p<0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (p=0.003). Conclusions Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of the disease.

Chitosan‐functionalized graphene oxides (FGOCs) were successfully synthesized. FGOCs were found to significantly improve the solubility of the GO in aqueous acidic media. The presence of organic groups was confirmed by means of XPS and TGA. Restoration of the sp2 carbon network and exfoliation of graphene sheets were confirmed by Raman spectroscopy, UV‐visible spectroscopy and WAXD. The SEM and AFM investigations of the resultant FGOCs showed that most of the graphene sheets were individual and few were layered. Controlled release behavior of Ibuprofen and 5‐fluorouracil was then investigated. We found that FGOCs are a promising new material for biological and medical applications. magnified image

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Bcr-Abl-independent signaling pathways are known to be involved in imatinib resistance in some patients with chronic myelogenous leukemia (CML). In this study, to find new targets for imatinib-resistant CML displaying loss of Bcr-Abl kinase target dependence, we isolated imatinib-resistant variants, K562/R1, K562/R2, and K562/R3, which showed profound declines of Bcr-Abl levels and its tyrosine kinase activity, from K562 cells. Importantly, the imatinib resistance mechanism in these variants also included aberrant acetylation of nonhistone proteins such as p53, Ku70, and Hsp90 that was due to upregulation of histone deacetylases (HDACs) and down-regulation of histone acetyltransferase (HAT). In comparison with K562 cells, the imatinib-resistant variants showed up-regulation of HDAC1, -2, and -3 (class I HDACs) and class III SIRT1 and down-regulation of CBP/p300 and PCAF with HAT activity, and thereby p53 and cytoplasmic Ku70 were aberrantly acetylated. In addition, these were associated with down-regulation of Bax and up-regulation of Bcl-2. In contrast, the class II HDAC6 level was significantly decreased, and this was accompanied by an increase of Hsp90 acetylation in the imatinibresistant variants, which was closely associated with loss of Bcr-Abl. These results indicate that alteration of the normal balance of HATs and HDACs leads to deregulated acetylation of Hsp90, p53, and Ku70 and thereby leads to imatinib resistance, suggesting the importance of the acetylation status of apoptosis-related nonhistone proteins in Bcr-Abl-independent imatinib resistance. We also revealed that imatinib-resistant K562 cells were more sensitive to suberoylanilide hydroxamic acid, an HDAC inhibitor, than K562 cells. These findings may have implications for HDAC as a molecular target in imatinibresistant leukemia cells.

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