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- Brown, TC, et al.
(author)
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Recurrent Amplification of the Osmotic Stress Transcription Factor NFAT5 in Adrenocortical Carcinoma
- 2020
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In: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 4:7, s. bvaa060-
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Journal article (peer-reviewed)abstract
- Tumorigenesis requires mitigation of osmotic stress and the transcription factor nuclear factor of activated T cells 5 (NFAT5) coordinates this response by inducing transcellular transport of ions and osmolytes. NFAT5 modulates in vitro behavior in several cancer types, but a potential role of NFAT5 in adrenocortical carcinoma (ACC) has not been studied. A discovery cohort of 28 ACCs was selected for analysis. Coverage depth analysis of whole-exome sequencing reads assessed NFAT5 copy number alterations in 19 ACCs. Quantitative real-time PCR measured NFAT5 mRNA expression levels in 11 ACCs and 23 adrenocortical adenomas. Immunohistochemistry investigated protein expression in representative adrenal samples. The Cancer Genome Atlas database was analyzed to corroborate NFAT5 findings from the discovery cohort and to test whether NFAT5 expression correlated with ion/osmolyte channel and regulatory protein expression patterns in ACC. NFAT5 was amplified in 10 ACCs (52.6%) and clustered in the top 6% of all amplified genes. mRNA expression levels were 5-fold higher compared with adrenocortical adenomas (P < 0.0001) and NFAT5 overexpression had a sensitivity and specificity of 81.8% and 82.7%, respectively, for malignancy. Increased protein expression and nuclear localization occurred in representative ACCs. The Cancer Genome Atlas analysis demonstrated concomitant NFAT5 amplification and overexpression (P < 0.0001) that correlated with increased expression of sodium/myo-inositol transporter SLC5A3 (r2 = 0.237, P < 0.0001) and 14 other regulatory proteins (P < 0.05) previously shown to interact with NFAT5. Amplification and overexpression of NFAT5 and associated osmotic stress response related genes may play an important role adrenocortical tumorigenesis.
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- Calissendorff, J, et al.
(author)
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Pheochromocytomas and Abdominal Paragangliomas: A Practical Guidance
- 2022
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In: Cancers. - : MDPI AG. - 2072-6694. ; 14:4
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Journal article (peer-reviewed)abstract
- Pheochromocytomas and abdominal paragangliomas (PPGLs) are rare tumors arising from the adrenal medulla or the sympathetic nervous system. This review presents a practical guidance for clinicians dealing with PPGLs. The incidence of PPGLs has risen. Most cases are detected via imaging and less present with symptoms of catecholamine excess. Most PPGLs secrete catecholamines, with diffuse symptoms. Diagnosis is made by imaging and tests of catecholamines. Localized disease can be cured by surgery. PPGLs are the most heritable of all human tumors, and germline variants are found in approximately 30–50% of cases. Such variants can give information regarding the risk of developing recurrence or metastases as well as the risk of developing other tumors and may identify relatives at risk for disease. All PPGLs harbor malignant potential, and current histological and immunohistochemical algorithms can aid in the identification of indolent vs. aggressive tumors. While most patients with metastatic PPGL have slowly progressive disease, a proportion of patients present with an aggressive course, highlighting the need for more effective therapies in these cases. We conclude that PPGLs are rare but increasing in incidence and management should be guided by a multidisciplinary team.
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