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Lau, E.,Kluger, H.,Varsano, T.,Lee, K.,Scheffler, I.,Rimm, David L.,Ideker, T.,Ronai, Ze'ev A. Cell Press ; MIT Press 2012 Cell Vol.148 No.3
The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress. The ability of ATF2 to reach the mitochondria is determined by PKCε, which directs ATF2 nuclear localization. Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor samples, high PKCε levels associate with poor prognosis. Overall, our findings provide the framework for understanding how subcellular localization enables ATF2 oncogenic or tumor suppressor functions.
YongYan Cui,Lauren G. Khanna,Anjali Saqi,John P. Crapanzano,James M. Mitchell,Amrita Sethi,Tamas A. Gonda,Michael D. Kluger,Beth A. Schrope,John Allendorf,John A. Chabot,John M. Poneros 대한소화기내시경학회 2020 Clinical Endoscopy Vol.53 No.2
Background/Aims: The management of small, incidentally discovered nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs)has been a matter of debate. Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) is a tool used to identify and risk-stratifyPNETs. This study investigates the concordance rate of Ki67 grading between EUS-FNA and surgical pathology specimens in NF-PNETs and whether certain NF-PNET characteristics are associated with disease recurrence and disease-related death. Methods: We retrospectively reviewed the clinical history, imaging, endoscopic findings, and pathology records of 37 cases of NF-PNETs that underwent pre-operative EUS-FNA and surgical resection at a single academic medical center. Results: There was 73% concordance between Ki67 obtained from EUS-FNA cytology and surgical pathology specimens; concordancewas the highest for low- and high-grade NF-PNETs. High-grade Ki67 NF-PNETs based on cytology (p=0.028) and histology (p=0.028)were associated with disease recurrence and disease-related death. Additionally, tumors with high-grade mitotic rate (p=0.005), tumorsize >22.5 mm (p=0.104), and lymphovascular invasion (p=0.103) were more likely to have poor prognosis. Conclusions: NF-PNETs with high-grade Ki67 on EUS-FNA have poor prognosis despite surgical resection. NF-PNETs withintermediate-grade Ki67 on EUS-FNA should be strongly considered for surgical resection. NF-PNETs with low-grade Ki67 on EUS-FNA can be monitored without surgical intervention, up to tumor size 20 mm.