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Zealand Pharma A/S, Søborg, Denmark
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Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Steno Diabetes Center Copenhagen, Herlev, Denmark
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Aims
Hyperglucagonaemia contributes to the pathophysiology in type 2 diabetes (T2D), but the mechanisms behind the inappropriate glucagon secretion are not fully understood. Glucagon and amino acids are regulated in a feedback loop referred to as the liver–α cell axis. Individuals with non-alcoholic fatty liver disease (NAFLD) appear to be glucagon resistant, disrupting the liver–α cell axis resulting in hyperglucagonaemia and hyperaminoacidaemia. We investigated the associations between circulating glucagon, amino acids, and liver fat content in a cohort of individuals with T2D.
Methods
We included 110 individuals with T2D in this cross-sectional study. Liver fat content was quantified using 1H magnetic resonance spectroscopy (MRS). Associations between liver fat content and plasma glucagon and amino acids, respectively, were estimated in multivariate linear regression analyses.
Results
Individuals with NAFLD (n = 52) had higher plasma glucagon concentrations than individuals without NAFLD (n = 58). The positive association between plasma glucagon concentrations and liver fat content was confirmed in the multivariable regression analyses. Plasma concentrations of isoleucine and glutamate were increased, and glycine and serine concentrations were decreased in individuals with NAFLD. Concentrations of other amino acids were similar between individuals with and without NAFLD, and no clear association was seen between liver fat content and amino acids in the regression analyses.
Conclusion
MRS-diagnosed NAFLD in T2D is associated with hyperglucagonaemia and elevated plasma concentrations of isoleucine and glutamate and low plasma concentrations of glycine and serine. Whether NAFLD and glucagon resistance per se induce these changes remains to be elucidated.
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Background
The diagnostic and prognostic value of the leucine-rich alpha-2-glycoprotein 1 (LRG1) gene in thyroid cancer remains unclear. Using the Cancer Genome Atlas (TCGA) database, we conducted a bioinformatics analysis to determine the role of LRG1 in thyroid cancer.
Methods
Data from 512 patients with thyroid cancer and 59 normal individuals were collected from TCGA database. The Kruskal–Wallis test and logistic analysis were used to examine the relationship between LRG1 expression and clinicopathologic characteristics. Cox regression and Kaplan–Meier analysis were used to determine the predictive value of LRG1 on clinical outcomes. Single-sample gene set enrichment analysis (ssGSEA) was used to reveal associations between LRG1 expression and immune infiltration levels in thyroid cancer.
Results
LRG1 was highly expressed in thyroid cancer (P < 0.001) and could effectively distinguish tumor tissue (area under the curve = 0.875) from normal tissue. Moreover, LRG1 was significantly correlated with pathological N stage (odds ratio (OR) = 2.411 (1.659–3.505), P < 0.001). Kaplan–Meier survival analysis revealed that patients with high LRG1 expression had better overall survival (hazard ratio (HR) = 0.30, P = 0.038). Cox regression analysis indicated that pathological M stage was a risk factor for progression-free interval (HR = 5.964 (2.010–17.694), P < 0.001). Using ssGSEA, we found that LRG1 expression was positively correlated with the number of T helper 1 cells (R = 0.435, P < 0.001), dendritic cells (R = 0.442, P < 0.001), and macrophages (R = 0.459, P < 0.001).
Conclusion
LRG1 may be an important biomarker for predicting the prognosis of thyroid cancer and represent a suitable target for immunotherapy associated with immune infiltration.
Fujian Maternal-Fetal Clinical Medicine Research Center, Fuzhou, China
Fujian Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, China
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Fujian Maternal-Fetal Clinical Medicine Research Center, Fuzhou, China
Fujian Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, China
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This study aimed to investigate the role of mitochondrial-related protein Mfn2 in polycystic ovary syndrome (PCOS) and its impact on oocyte development. The pathological features of PCOS model mice were confirmed by hematoxylin–eosin staining and immunohistochemistry. The expression of Mfn2 and mitochondrial-related proteins in PCOS oocytes and granulosa cells was detected by qRT-PCR and Western blot. Mitochondrial quantity was measured by Mito-Tracker staining, and the structure of mitochondria-associated ER membranes (MAMs) was observed by transmission electron microscopy. The results showed that Mfn2 was significantly downregulated in PCOS oocytes and granulosa cells, and its expression was inhibited in oocytes at different developmental stages. Moreover, the structure of MAMs was also disrupted. Downregulation of Mfn2 expression led to a reduction in mitochondrial quantity in oocytes and granulosa cells, as well as disruption of MAM structure, while overexpression of Mfn2 had the opposite effect. In conclusion, this study indicates that Mfn2 affects the development of PCOS oocytes by regulating MAMs and may be involved in maintaining the stability of MAM structure and function, thereby affecting mitochondrial quantity and function. These findings provide new insights into the pathogenesis and treatment of PCOS.
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Department of Neurosurgery, Technical University Munich (TMU), Munich, Germany
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Medizinische Klinik Und Poliklinik III, University Hospital Carl Gustav Carus, Dresden, Germany
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. Polo-like kinase 1 (PLK1) is a promising drug target; PLK1 inhibitors (PLK1i) have been investigated in solid cancers and are more effective in TP53-mutated cases. We evaluated PLK1 expression in ACC samples and the efficacy of two PLK1i in ACC cell lines with different genetic backgrounds. PLK1 protein expression was investigated by immunohistochemistry in tissue samples and correlated with clinical data. The efficacy of rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53 wild-type CU-ACC1. Effects on proliferation, apoptosis, and viability were determined. PLK1 immunostaining was stronger in TP53-mutated ACC samples vs wild-type (P = 0.0017). High PLK1 expression together with TP53 mutations correlated with shorter progression-free survival (P= 0.041). NCI-H295R showed a time- and dose-dependent reduction in proliferation with both PLK1i (P< 0.05at 100 nM RGS and 30 µM Pol). In MUC-1, a less pronounced decrease was observed (P< 0.05at 1000 nM RGS and 100 µM Pol). 100 nM RGS increased apoptosis in NCI-H295R (P< 0.001), with no effect on MUC-1. CU-ACC2 apoptosis was induced only at high concentrations (P < 0.05 at 3000 nM RGS and 100 µM Pol), while proliferation decreased at 1000 nM RGS and 30 µM Pol. CU-ACC1 proliferation reduced, and apoptosis increased, only at 100 µM Pol. TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.
Sahlgrenska Osteoporosis Centre, Center for Bone and Arthritis Research (CBAR), Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
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Sahlgrenska Osteoporosis Centre, Center for Bone and Arthritis Research (CBAR), Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
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Sahlgrenska Osteoporosis Centre, Center for Bone and Arthritis Research (CBAR), Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
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Department of Endocrinology, Skaraborg Central Hospital, Skövde, Sweden
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Objective
Sex steroids exert important biological functions within the CNS, but the underlying mechanisms are poorly understood. The contribution of circulating sex steroids to the levels in CNS tissue and cerebrospinal fluid (CSF) has been sparsely investigated in human and with inconclusive results. This could partly be due to lack of sensitive validated assays. To address this, we validated a gas chromatography–tandem mass spectrometry (GC-MS/MS) assay for quantification of sex steroid hormones/precursors in CSF.
Methods
GC-MS/MS quantification of dihydrotestosterone (DHT, CSF lower limit of quantification, 1.5 pg/mL), testosterone (4.9), estrone (E1, 0.88), estradiol (E2, 0.25), dehydroepiandrosterone (DHEA, 38.4), androstenedione (4D, 22.3), and progesterone (P, 4.2) in CSF, and corresponding serum samples from 47 men.
Results
Analyses of CSF revealed that DHEA was the major sex steroid (73.5 ± 31.7 pg/mL) followed by 4D (61.4 ± 29.6 pg/mL) and testosterone (49.5 ± 18.9 pg/mL). The CSF levels of DHT, E2, and E1 were substantially lower, and P was in general not detectable in CSF. For all sex steroids except E2, strong associations between corresponding CSF and serum levels were observed. We propose that testosteronein CSF is derived from circulating testosterone, DHT in CSF is from local conversion from testosterone, while E2 in CSF is from local conversion from 4D in CNS.
Conclusions
We describe the first thoroughly validated highly sensitive mass spectrometric assay for a broad sex steroid hormone panel suitable for human CSF. This assay constitutes a new tool for investigation of the role of sex steroid hormones in the human CNS.
Significance statement
In this study, a fully validated highly sensitive mass spectrometric assay for sex steroids was applied to human CSF. The results were used to describe the relative contribution of peripheral circulating sex steroids together with locally transformation of sex steroids to the levels in CSF. The results are of importance to understand the biological processes of the human brain.
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Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Objective
The aim was to explore the effects of preoperative calcium and activated vitamin D3 supplementation on post-thyroidectomy hypocalcemia and hypo-parathyroid hormone-emia (hypo-PTHemia).
Methods
A total of 209 patients were randomly divided into control group (CG) and experimental group (EG). Oral calcium and activated vitamin D3 supplementation were preoperatively administered to EG, whereas a placebo was administered to CG. Data on serum calcium, phosphorus, and PTH concentrations before operation, on postoperative day 1 (POPD1), at postoperative week 3 (POPW3), and on the length of postoperative hospitalization were collected.
Results
The serum calcium, phosphorus, and PTH concentrations, as well as the incidence of postoperative hypocalcemia and hypo-PTHemia, did not significantly differ between EG and CG. Subgroup analysis revealed that the serum calcium concentrations of the experimental bilateral thyroidectomy subgroup (eBTS) on POPD1 and POPW3 were higher than that of the control bilateral thyroidectomy subgroup (cBTS) (P < 0.05); the reduction of serum calcium in eBTS on POPD1 and POPW3 was less than those in cBTS (P < 0.05). However, significant differences were not observed between the unilateral thyroidectomy subgroups (UTS) (P > 0.05). Moreover, the incidence of postoperative hypocalcemia in cBTS on POPD1 was significantly higher than that in eBTS (65.9% vs 41.7%) (P < 0.05). The length of hospitalization in cBTS (3.55 ± 1.89 days) was significantly longer than that (2.79 ± 1.15 days) in eBTS (P < 0.05).
Conclusion
Short-term preoperative prophylactic oral calcium and activated vitamin D3 supplementation could effectively reduce the incidence of postoperative hypocalcemia and decrease the length of postoperative hospitalization in patients who have undergone bilateral thyroidectomy.
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Universidad La Salle, Posgrado de la Facultad de Ciencias Químicas, Ciudad de México, México
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The incidence of ovarian cancer has been epidemiologically related to female reproductive events and hormone replacement therapy after menopause. This highlights the importance of evaluating the role of sexual steroid hormones in ovarian cancer by the expression of enzymes related to steroid hormone biosynthesis in the tumor cells. This study was aimed to evaluate the presence of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), aromatase and estrogen receptor alpha (ERα) in the tumor cells and their association with the overall survival in 111 patients diagnosed with primary ovarian tumors. Positive immunoreactivity for 17β-HSD1 was observed in 74% of the tumors. In the same samples, aromatase and ERα revealed 66% and 47% positivity, respectively. No association was observed of 17β-HSD1 expression with the histological subtypes and clinical stages of the tumor. The overall survival of patients was improved in 17β-HSD1-positive group in Kaplan–Meier analysis (P = 0.028), and 17β-HSD1 expression had a protective effect from multivariate proportional regression evaluation (HR = 0.44; 95% CI 0.24–0.9; P = 0.040). The improved survival was observed in serous epithelial tumors but not in nonserous ovarian tumors. The expression of 17β-HSD1 in the cells of the serous epithelial ovarian tumors was associated with an improved overall survival, whereas aromatase and ERα were not related to a better survival. The evaluation of hazard risk factors demonstrated that age and clinical stage showed worse prognosis, and 17β-HSD1 expression displayed a protective effect with a better survival outcome in patients of epithelial ovarian tumors.
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Department of Endocrinology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
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We applied 24-h Holter monitoring to analyze the characteristics of arrhythmias and heart rate variability in Chinese patients with primary aldosteronism (PA) and compared them with age-, sex-, and blood pressure-matched primary hypertension (PH) patients. A total of 216 PA patients and 261 PH patients were enrolled. The nonstudy data were balanced using propensity score matching (PSM), and the risk variables for developing arrhythmias were then analyzed using logistic regression analysis. Before PSM, the proportion of PA patients with combined atrial premature beats and prolonged QT interval was higher than the corresponding proportion in the PH group. After PSM, the PA group had a larger percentage of transient atrial tachycardia and frequent atrial premature beats, and it had higher heart rate variability metrics. The proportion of unilateral PA combined with multiple ventricular premature beats was higher than that of bilateral PA. Older age, grade 3 hypertension, and hypokalemia were independent risk factors for the emergence of arrhythmias in PA patients. PA patients suffer from a greater prevalence of arrhythmias than well-matched PH patients.
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Purpose
The aim was to investigate the effect of radioactive iodine (RAI) treatment for differentiated thyroid cancer (DTC) on male gonadal function.
Methods
PubMed, Embase, Web of Science, OVID, Scopus, and Wanfang databases were searched up to June 10, 2022, to identify published studies related to RAI and male gonadal function. ReviewManager version 5.4.1 software was used to calculate mean differences (MDs) with 95% CIs.
Results
Initially, 1958 articles were retrieved from the databases, and 6 articles were included in the quantitative analysis. The meta-analysis results showed that follicle-stimulating hormone (FSH) increased when the follow-up duration was ≥12 months after RAI, but the difference was not statistically significant (MD = −2.64, 95% CI = (−5.61, 0.33), P = 0.08). But the results of the subgroup analysis showed that when the follow-up time was ≤6 months, FSH levels were significantly higher after RAI (MD = −7.65, 95% CI = (−13.95, −1.34), P = 0.02). The level of inhibin B was significantly lower at ≥12 months and ≤6 months after RAI (MD = 66.38, 95% CI = (8.39, 124.37), P = 0.02) and (MD = 116.27, 95% CI = (43.56, 188.98), P = 0.002). Additionally, luteinizing hormone (LH) and testosterone have similar results – that is, LH and testosterone levels were higher after RAI, but the difference was not statistically significant (MD = –0.87, 95% CI = (−2.04, 0.30), P = 0.15) and (MD = −1.69, 95% CI (−7.29, 3.90), P = 0.55).
Conclusions
Male gonadal function may be temporarily impaired within 6 months after RAI but may return to normal levels afterward.
