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Department of Clinical Science, Department of Medicine, Division of Medicine, University of Bergen, 5021 Bergen, Norway
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Department of Clinical Science, Department of Medicine, Division of Medicine, University of Bergen, 5021 Bergen, Norway
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Department of Clinical Science, Department of Medicine, Division of Medicine, University of Bergen, 5021 Bergen, Norway
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the sequences of B. taurus and S. scrofa 21OH ( Fig. 2 ), and was predicted as harmless ( Table 3 ), again in line with a normal enzyme activity. Discussion In the present study, we introduced a novel method for functional studies of CYP21A2
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://www.mutationtaster.org/ ), SIFT ( http://sift.jcvi.org/ ) and Polyphen-2 ( http://genetics.bwh.harvard.edu/pph2/ ) was performed for prediction of the pathological effects of the substitutions on protein sequence. Functional studies Luciferase reporter assays Signalling activity
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Objective
Gestational diabetes mellitus (GDM) is characterized by glucose intolerance during gestation. It is associated with a series of maternal and foetal complications. Interleukin (IL)-34 is a recently discovered pro-inflammatory cytokine that functions as a ligand for colony-stimulating factor-1 receptor (CSF-1R). The contribution of IL-34 in the development of multiple chronic inflammatory diseases and autoimmune diseases has been recently discovered. The aim of this study was to evaluate whether IL-34 participates in the pathogenesis of GDM.
Method
A total of 120 women were enrolled in this study, which included 60 GDM patients and age- and sex-matched healthy pregnant women. The expression of IL-34 in serum, cord blood and placental tissues was analysed by ELISA and Western blot assays. The association between IL-34 levels and clinical features was also studied. We additionally evaluated the effect of recombinant mouse IL-34 (rmIL-34) on apoptosis and pancreatic β cell function.
Results
We found that IL-34 expression is highly increased in serum, cord blood and placental tissues in patients with GDM. In addition, there was a positive association between serum IL-34 and insulin resistance and glucose concentrations. Our data also revealed that IL-34 contributes to the apoptosis of pancreatic β cells in GDM caused by CSF-1R. Furthermore, functional studies found that IL-34 inhibited pancreatic β cell function and cell viability, while CSF-1R inhibitor blocked this effect.
Conclusion
IL-34 plays a crucial role in the development of GDM by targeting CSF-1R, insulin production and β cell function.
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Cancer Genetics Laboratory, Department of Endocrinology, Kolling Institute of Medical Research, Sydney, New South Wales, Australia
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Cancer Genetics Laboratory, Department of Endocrinology, Kolling Institute of Medical Research, Sydney, New South Wales, Australia
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Metastatic differentiated thyroid cancers (DTC) are resistant to traditional chemotherapy. Kinase inhibitors have shown promise in patients with progressive DTC, but dose-limiting toxicity is commonplace. HSP90 regulates protein degradation of several growth-mediating kinases such as RET, and we hypothesized that HSP90 inhibitor (AUY922) could inhibit RET-mediated medullary thyroid cancer (MTC) as well as papillary thyroid cancer (PTC) cell growth and also radioactive iodine uptake by PTC cells. Studies utilized MTC cell lines TT (C634W) and MZ-CRC-1 (M918T) and the PTC cell line TPC-1 (RET/PTC1). Cell viability was assessed with MTS assays and apoptosis by flow cytometry. Signaling target expression was determined by western blot and radioiodine uptake measured with a gamma counter. Prolonged treatment of both MTC cell lines with AUY922 simultaneously inhibited both MAPK and mTOR pathways and significantly induced apoptosis (58.7 and 78.7% reduction in MZ-CRC-1 and TT live cells respectively, following 1 μM AUY922; P<0.02). Similarly in the PTC cell line, growth and signaling targets were inhibited, and also a 2.84-fold increase in radioiodine uptake was observed following AUY922 administration (P=0.015). AUY922 demonstrates in vitro activity against MTC and PTC cell lines. We observed a potent dose-dependent increase in apoptosis in MTC cell lines following drug administration confirming its anti-tumorigenic effects. Western blots confirm inhibition of pro-survival proteins including AKT suggesting this as the mechanism of cell death. In a functional study, we observed an increase in radioiodine uptake in the PTC cell line following AUY922 treatment. We believe HSP90 inhibition could be a viable alternative for treatment of RET-driven chemo-resistant thyroid cancers.
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Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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Objective
The associations between adrenal histopathology, lateralization studies, and surgical outcomes in primary aldosteronism remain poorly characterized. We examined the value of immunohistochemical analysis of CYP11B2 for evaluation of adrenalectomy outcomes after anatomical versus functional subtyping.
Design
A retrospective multicenter study of 277 patients operated for primary aldosteronism who had an adrenalectomy sample available in the Finnish biobanks from 1 January 2000 to 31 December 2019. Adrenal slides from biobanks were analyzed centrally after CYP11B2 and CYP11B1 staining. Clinical data were obtained from patient registries. Histopathological diagnosis and cure after surgery were assessed as outcome measures.
Results
Re-evaluation with CYP11B2 staining changed the histopathological diagnosis in 91 patients (33%). The presence of a CYP11B2-positive adenoma and the use of functional subtyping independently predicted clinical cure of primary aldosteronism. CYP11B2-positive <7 mm nodules were more frequent in patients without clinical cure, whereas CYP11B2-positive micronodules were common in all patients and had no impact on adrenalectomy outcomes. Small CYP11B2-positive nodules and micronodules were equally prevalent regardless of the subtyping method applied. Clinical cure rates were lower and CYP11B2-negative adenomas more common after adrenalectomy based on anatomical imaging than functional studies.
Conclusions
Incorporating CYP11B2 staining in histopathological diagnosis enhances the prediction of surgical outcomes in primary aldosteronism. A finding of CYP11B2-positive adenoma is indicative of cure of primary aldosteronism, whereas smaller CYP11B2-positive nodules associate with poorer results at postoperative evaluation. Functional subtyping methods decrease the operations of CYP11B2-negative adenomas and are superior to anatomical imaging in identifying unilateral primary aldosteronism.
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on the protein (NT), which included missense variants, in-frame insertions, and duplications. This analysis excluded four splice-site variants, whose effects on the protein truncation were not clear. Additionally, variants whose functional studies
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Universidade de São Paulo, Zebrafish Facility, São Paulo, São Paulo, Brazil
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variant in CDH2 in a CPHD patient, p.Val289Ile. In silico analysis and functional studies suggest that this variant affects the ability of N-cadherin to promote cell-cell interaction. No other suitable candidate genes were identified in the WES or CNV
Diagnósticos da América SA, Rio de Janeiro, Rio de Janeiro, Brazil
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Neuroendocrinology Unit, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Rio de Janeiro, Brazil
Endocrinology Unit, Hospital Federal de Bonsucesso, Rio de Janeiro, Rio de Janeiro, Brazil
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National Cancer Institute, Rio de Janeiro, Rio de Janeiro, Brazil
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Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Rio de Janeiro, Brazil
Neuroendocrinology Unit, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Rio de Janeiro, Brazil
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patients with AIP germline mutations. Dx Sex Age at Dx (years) Adenoma size at Dx (mm) Mut Protein change Protein location Functional study Sig PolyPhen2 ( in silico ) Alamut ( in silico ) (SIFT/Mut Taster) MAF Type
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acids are nonpolar and the codon 162 is not conserved among the mammalian orthologs ( Fig. 1 ). In functional studies, V162A mutant showed no significant difference from the WT receptor ( Table 1 ). However, the patient harboring the V162A mutation
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Cardiology Institute of Rio Grande do Sul/University Foundation of Cardiology (IC/FUC), Porto Alegre, Rio Grande do Sul, Brazil
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glucagon as one of the mechanisms of such alterations. Although, functional studies involving glucagon-related mechanisms are obviously needed to fully understand its role in the metabolic changes observed in Mas-KO mice, our current data indicate that an
