Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations

Abstract. Thyroid hormones play an important role in body homeostasis by facilitating metabolism of lipids and glucose, regulating metabolic adaptations, responding to changes in energy intake, and controlling thermogenesis. Proper metabolism and action of these hormones requires the participation of various nutrients. Among them is zinc, whose interaction with thyroid hormones is complex. It is known to regulate both the synthesis and mechanism of action of these hormones. In the present review, we aim to shed light on the regulatory effects of zinc on thyroid hormones. Scientific evidence shows that zinc plays a key role in the metabolism of thyroid hormones, specifically by regulating deiodinases enzymes activity, thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) synthesis, as well as by modulating the structures of essential transcription factors involved in the synthesis of thyroid hormones. Serum concentrations of zinc also appear to influence the levels of serum T3, T4 and TSH. In addition, studies have shown that Zinc transporters (ZnTs) are present in the hypothalamus, pituitary and thyroid, but their functions remain unknown. Therefore, it is important to further investigate the roles of zinc in regulation of thyroid hormones metabolism, and their importance in the treatment of several diseases associated with thyroid gland dysfunction.

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ACUTE ENZYME HISTOCHEMICAL CHANGES IN THE ZONA GLOMERULOSA OF THE RAT ADRENAL CORTEX

Acta Endocrinologica ◽

10.1530/acta.0.0590508 ◽

1968 ◽

Vol 59 (3) ◽

pp. 508-518

Author(s):

J. D. Elema ◽

M. J. Hardonk ◽

Joh, Koudstaal ◽

A. Arends

Keyword(s):

Peritoneal Dialysis ◽

Succinate Dehydrogenase ◽

Dehydrogenase Activity ◽

Adrenal Cortex ◽

Isocitrate Dehydrogenase ◽

Hydroxysteroid Dehydrogenase ◽

Zona Glomerulosa ◽

Acute Changes ◽

Glucose 6 Phosphate Dehydrogenase ◽

Histochemical Changes

ABSTRACT Acute changes in glucose-6-phosphate dehydrogenase and isocitrate dehydrogenase activity in the zona glomerulosa of the rat adrenal cortex were induced by peritoneal dialysis with 5 % glucose. Although less clear, the activity of 3β-ol-hydroxysteroid dehydrogenase also seemed to increase as well. No changes were seen in the activity of succinate dehydrogenase. Dialysis with 0.9 % NaCl had no effect on any of the enzymes investigated. The possible significance of these observations is discussed.

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Intraoperative assessment of isocitrate dehydrogenase mutation status in human gliomas using desorption electrospray ionization–mass spectrometry

Journal of Neurosurgery ◽

10.3171/2018.8.jns181207 ◽

2020 ◽

Vol 132 (1) ◽

pp. 180-187 ◽

Cited By ~ 3

Author(s):

Clint M. Alfaro ◽

Valentina Pirro ◽

Michael F. Keating ◽

Eyas M. Hattab ◽

R. Graham Cooks ◽

...

Keyword(s):

Mass Spectrometry ◽

Electrospray Ionization ◽

Isocitrate Dehydrogenase ◽

Tumor Resection ◽

Desorption Electrospray Ionization ◽

Extent Of Resection ◽

Ionization Mass ◽

Idh Mutation ◽

Mutation Status ◽

Desi Ms

OBJECTIVEThe authors describe a rapid intraoperative ambient ionization mass spectrometry (MS) method for determining isocitrate dehydrogenase (IDH) mutation status from glioma tissue biopsies. This method offers new glioma management options and may impact extent of resection goals. Assessment of the IDH mutation is key for accurate glioma diagnosis, particularly for differentiating diffuse glioma from other neoplastic and reactive inflammatory conditions, a challenge for the standard intraoperative diagnostic consultation that relies solely on morphology.METHODSBanked glioma specimens (n = 37) were analyzed by desorption electrospray ionization–MS (DESI-MS) to develop a diagnostic method to detect the known altered oncometabolite in IDH-mutant gliomas, 2-hydroxyglutarate (2HG). The method was used intraoperatively to analyze tissue smears obtained from glioma patients undergoing resection and to rapidly diagnose IDH mutation status (< 5 minutes). Fifty-one tumor core biopsies from 25 patients (14 wild type [WT] and 11 mutant) were examined and data were analyzed using analysis of variance and receiver operating characteristic curve analysis.RESULTSThe optimized DESI-MS method discriminated between IDH-WT and IDH-mutant gliomas, with an average sensitivity and specificity of 100%. The average normalized DESI-MS 2HG signal was an order of magnitude higher in IDH-mutant glioma than in IDH-WT glioma. The DESI 2HG signal intensities correlated with independently measured 2HG concentrations (R2 = 0.98). In 1 case, an IDH1 R132H–mutant glioma was misdiagnosed as a demyelinating condition by frozen section histology during the intraoperative consultation, and no resection was performed pending the final pathology report. A second craniotomy and tumor resection was performed after the final pathology provided a diagnosis most consistent with an IDH-mutant glioblastoma. During the second craniotomy, high levels of 2HG in the tumor core biopsies were detected.CONCLUSIONSThis study demonstrates the capability to differentiate rapidly between IDH-mutant gliomas and IDH-WT conditions by DESI-MS during tumor resection. DESI-MS analysis of tissue smears is simple and can be easily integrated into the standard intraoperative pathology consultation. This approach may aid in solving differential diagnosis problems associated with low-grade gliomas and could influence intraoperative decisions regarding extent of resection, ultimately improving patient outcome. Research is ongoing to expand the patient cohort, systematically validate the DESI-MS method, and investigate the relationships between 2HG and tumor heterogeneity.

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