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Yuegui Wang Department of Ultrasound, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, China

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Liwei Hong Department of Nuclear Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, China

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Caiyun Yang Department of Ultrasound, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, China
School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, China

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Guorong Lv School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, China
Quanzhou Medical College, Quanzhou, Fujian, China

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Kangjian Wang Department of Ultrasound, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, China

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Xuepeng Huang Department of Nuclear Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, China

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Haolin Shen Department of Ultrasound, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, China

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The aim of this study was to develop a prognostic model for radioactive iodine (RAI) therapy outcome in patients with Graves‘ disease. We enrolled 127 patients. Information on RAI therapy, ultrasound indexes of thyroid, and other lifestyle factors was collected. The competing risk model was used to estimate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for nonhealing or recurrence of hyperthyroidism (NHRH). The performance of the model was assessed by receiver operator characteristic analysis and the Brier score and internally validated by bootstrap resampling. Then, a nomogram was developed. Forty-one cases (32.2%) of NHRH were documented. Positive Ki-67 expression, a higher dose of per-unit thyroid volume, and females showed lower risks of NHRH (all P < 0.05). The HR values (95% CI) were 0.42 (0.23, 0.79), 0.01 (0.00, 0.02), and 0.47 (0.25, 0.89), respectively. The bootstrap validation showed that the model had the highest accuracy and good calibration for predicting cumulative risk of NHRH at 180 days after RAI therapy (AUC = 0.772; 95% CI: 0.640–0.889, Brier score = 0.153). By decision curve analysis, the nomogram was shown to have a satisfactory net benefit between thresholds of 0.20 and 0.40. Ki-67, ultrasound volumetry, and scintigraphy techniques can play important roles in evaluating RAI therapy outcome in Graves‘ disease patients. The prediction nomogram shows reasonable accuracy in predicting NHRH.

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Richard W Carroll Endocrine, Diabetes, and Research Centre, Wellington Regional Hospital, New Zealand

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Brian Corley Endocrine, Diabetes, and Research Centre, Wellington Regional Hospital, New Zealand
Department of Medicine, University of Otago, Wellington, New Zealand

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Joe Feltham Department of Radiology, Wellington Regional Hospital, New Zealand

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Patricia Whitfield Endocrine, Diabetes, and Research Centre, Wellington Regional Hospital, New Zealand
Department of Medicine, University of Otago, Wellington, New Zealand

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William Park University of Otago, Wellington, New Zealand

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Rowena Howard Diabetes and Endocrinology Service, Hutt Hospital, New Zealand

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Melissa Yssel Department of Biochemistry & Endocrinology, Awanui Labs, New Zealand

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Ian Phillips Department of Biochemistry, Awanui Labs, Dunedin, New Zealand

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Simon Harper Department of Surgery & Anaesethesia, University of Otago, Wellington, New Zealand
Department of General Surgery, Wellington Regional Hospital, New Zealand

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Jun Yang Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria, Australia
Department of Medicine, Monash University, Clayton, Victoria, Australia

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Objective

The assessment of primary aldosteronism incorporates adrenal vein sampling (AVS) to lateralize aldosterone excess. Current adrenal vein sampling protocols rely on concurrent cortisol measurements to assess successful cannulation and lateralization and may be inaccurate in the setting of autonomous cortisol secretion. We aimed to compare the measurement of plasma cortisol and metanephrine concentrations to assess cannulation and lateralization during AVS.

Design

This is a diagnostic accuracy study in a tertiary referral endocrinology department.

Methods

Forty-one consecutive patients with confirmed primary aldosteronism undergoing AVS (49 procedures) were included. None had cortisol autonomy. The use of plasma metanephrine-based ratios were compared with standard cortisol-based ratios to assess cannulation and lateralization during ACTH-stimulated AVS.

Results

There was strong agreement between a cortisol selectivity index (SI) ≥5.0 and an adrenal vein (AV) to peripheral vein (PV) plasma metanephrine ratio (AVmet–PVmet) of ≥12.0 to indicate successful cannulation of the AV (n = 117, sensitivity 98%, specificity 89%, positive predictive value (PPV) 95%, negative predictive value (NPV) 94%). There was strong agreement between the standard cortisol-based SI and an AV plasma metanephrine-to-normetanephrine ratio (AVmet–AVnormet) of ≥2.0 to indicate successful cannulation (n = 117, sensitivity 93%, specificity 86%, PPV 94%, NPV 84%). There was strong agreement between the cortisol- or metanephrine-derived lateralization index (LI) > 4.0 for determining lateralization (n = 26, sensitivity 100%, specificity 94.1%, PPV 91.6%, NPV 100%).

Conclusions

Ratios incorporating plasma metanephrines provide comparable outcomes to standard cortisol-based measurements for interpretation of AVS. Further studies are required to assess the use of metanephrine-derived ratios in the context of confirmed cortisol autonomy.

Significance statement

Primary aldosteronism is a common cause of secondary hypertension, and adrenal vein sampling remains the gold standard test to assess lateralization. Cortisol-derived ratios to assess cannulation and lateralization may be affected by concurrent cortisol dysfunction, which is not uncommon in the context of primary aldosteronism. Our study showed comparable outcomes when using accepted cortisol-derived or metanephrine-derived ratios to determine cannulation and lateralization during adrenal vein sampling. Further research is required to validate these findings and to assess the use of metanephrine-derived ratios in the context of confirmed concurrent cortisol dysfunction.

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Sonja Kunz Department of Medicine IV, University Hospital, Ludwig Maximilian University Munich, Munich, Germany

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Xiao Wang Department of Medicine IV, University Hospital, Ludwig Maximilian University Munich, Munich, Germany

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Uta Ferrari Department of Medicine IV, University Hospital, Ludwig Maximilian University Munich, Munich, Germany

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Michael Drey Department of Medicine IV, University Hospital, Ludwig Maximilian University Munich, Munich, Germany

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Marily Theodoropoulou Department of Medicine IV, University Hospital, Ludwig Maximilian University Munich, Munich, Germany

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Katharina Schilbach Department of Medicine IV, University Hospital, Ludwig Maximilian University Munich, Munich, Germany

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Martin Reincke Department of Medicine IV, University Hospital, Ludwig Maximilian University Munich, Munich, Germany

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Margit Heier Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
KORA Study Centre, University Hospital of Augsburg, Augsburg, Augsburg, Germany

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Annette Peters Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
German Centre for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Munich, Germany

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Wolfgang Koenig German Centre for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Munich, Germany
German Heart Centre Munich, Technical University of Munich, Munich, Germany
Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany

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Tanja Zeller Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany

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Barbara Thorand Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

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Martin Bidlingmaier Department of Medicine IV, University Hospital, Ludwig Maximilian University Munich, Munich, Germany

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Objective

Measurements utilizing commercially available sets of reagents for determination of steroid hormone profiles by liquid chromatography–tandem mass spectrometry (LC-MS/MS) have become increasingly important for routine laboratories. However, method-specific publications of reference intervals obtained from sufficiently large studies are often missing.

Methods

After validation of performance characteristics, a widely available kit for steroid analysis by LC-MS/MS was used to measure concentrations of 15 endogenous steroids (aldosterone, cortisol, cortisone, corticosterone, 11-deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate, estradiol, testosterone, androstenedione, dihydrotestosterone, dehydroepiandrosterone, 17-hydroxyprogesterone, 11-deoxycorticosterone, progesterone) in more than 500 blood samples from a population-based study. While randomly selected from a larger cohort, the samples equally represented both sexes and covered a wide range of adult age groups. Age- and sex-specific reference intervals were calculated, and correlation with BMI was assessed.

Results

Performance characteristics of the assay matched expectations for 9 of 15 steroids. For most of them, reference intervals obtained from our study population were comparable to those reported by others, with age and sex being the major determinants. A sex-specific correlation with BMI was found for seven steroids. We identified limitations regarding sensitivity of the method for quantification of progesterone in males and postmenopausal females. Concentrations of aldosterone, 21-deoxycortisol, estradiol, 11-deoxycorticosterone, and dihydrotestosterone could not be quantified in a large percentage of samples.

Conclusions

The reference intervals for nine steroids will support meaningful interpretation for steroid profiles as measured by a widely used kit for LC-MS/MS-based quantification. Laboratories using such kits must be aware of potential limitations in sensitivity for some steroids included in the profile.

Significance Statement

Quantification of steroid hormones is a cornerstone for diagnosis of several diseases. Commonly used immunoassays have limitations in specificity. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) is a promising alternative, particularly if methods are harmonized across laboratories. The use of kits from commercial suppliers might support this. Clinical interpretation of steroid concentrations requires availability of appropriate reference intervals (RIs), but studies on RIs reported in the literature differ in preanalytical and analytical procedures. Here, we provide RIs for steroids measured by a widely available kit under preanalytical conditions mirroring common clinical practice. Such RIs might facilitate interpretation for those using the same method and comparable conditions in clinical routine.

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Yuting Shao Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Xiaole Hu Department of Operating Room, Qilu Hospital of Shandong University, Shandong, China

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Yuxi Wang Department of Breast and Thyroid Surgery, People’s Hospital of Mengyin County, Linyi, Shandong, China

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Yi Shao Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Luchuan Li Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Qingdong Zeng Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Hong Lai Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Lei Sheng Department of Thyroid Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

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Objective

Serum 25-hydroxyvitamin D (25(OH)D) deficiency has been known to be associated with the risk and mortality of several cancers. However, the role of 25(OH)D in papillary thyroid cancer (PTC) remains controversial. This study aimed to investigate the association between 25(OH)D and clinicopathologic features of PTC.

Methods

Patients who underwent thyroidectomy were retrospectively reviewed. Serum 25(OH)D levels were measured within a week prior to surgery. The patients were categorized into four quartiles according to season-specific 25(OH)D levels. The association between 25(OH)D levels and clinicopathologic features of PTC was analyzed.

Results

A total of 2932 patients were enrolled in the study. The 25(OH)D levels were significantly higher in patients with lymph node metastasis (LNM; P < 0.001), lateral LNM (P < 0.001), and multifocal tumors (P < 0.001). Compared to the first quartile (Q1) of 25(OH)D level, the third quartile (Q3) and the fourth quartile (Q4) showed an unadjusted OR of 1.36 (95% CI: 1.09–1.69; P = 0.006) and 1.76 (95% CI: 1.42–2.19; P < 0.001) for LNM (P for trend < 0.001), respectively. An increased risk of multifocal tumors was strongly associated with high 25(OH)D concentration (P for trend <0.001). Similar results were obtained after adjusting for confounding factors.

Conclusion

High 25(OH)D levels are associated with aggressive features of PTC, such as lymph node metastasis and multifocality.

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Vanderlan O Batista Division of Psychiatry, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Michael Kellner Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Hamburg, Germany and Technical University of Munich, Munich, Germany

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Roberto Salvatori Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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Walter Lisboa Department of Psychology, Federal University of Sergipe, São Cristovão, Sergipe, Brazil

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André Faro Postgraduate Program in Psychology, Federal University of Sergipe, São Cristovão, Sergipe, Brazil

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Lucas B Santos Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Enaldo V Melo Statistics division, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Alécia A Oliveira-Santos Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Carla R P Oliveira Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Viviane C Campos Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Cynthia S Barros-Oliveira Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Elenilde G Santos Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Nathalie O Santana Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Keila R Villar-Gouy Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Ângela C Leal Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Rivia S Amorim Division of Geriatrics, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Davi A Oliveira Simões Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Manuel H Aguiar-Oliveira Division of Endocrinology, Health Sciences Graduate Program, Federal University of Sergipe, Aracaju, Sergipe, Brazil

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Individuals with untreated isolated GH deficiency (IGHD) due to a mutation in the GHRH receptor gene from Itabaianinha Brazil have increased insulin sensitivity, normal life expectancy, and an extended health span, i.e. the period of life free from disabilities. We hypothesize that their prolonged health span is accompanied by a delayed cognitive decline in senescence. To test this hypothesis, we have administered the Literacy-Independent Cognitive Assessment (LICA) to 15 IGHD individuals aged over 50 years and 15 controls matched by age, sex, years of education, and percentage of illiteracy. All individuals were negative for HIV and syphilis serology, and there were no differences in serum levels of folate, vitamin B12 and TSH between the two groups, while free T4 was higher in the IGHD group. IGHD subjects had a higher total LICA score than controls, 215 (22.7) vs 204.2 (18.1), without reaching statistical significance. Scores of memory, visuoconstruction, language and calculation were similar between the two groups, with better attention (9.5 (1.4) vs 8.3 (1.1), P = 0.01) and executive function (38.3 (4.8) vs 35.1 (2.5), P = 0.03) scores in IGHD. MANCOVA revealed that group (but no age) had a significant effect on the LICA variables (partial eta squared of 0.455, power of 0.812, P = 0.02). This effect is verified on attention (partial eta squared 0.216, power of 0.749, P = 0.01) and executive function (partial eta squared 0.154, power of 0.570, P = 0.03. In conclusion, IGHD in senescence is associated with similar total cognitive performance but better attention and executive function than controls.

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Iben Rix Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
Zealand Pharma A/S, Søborg, Denmark

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Marie L Johansen Department of Medicine, Herlev Hospital, University of Copenhagen, Herlev, Denmark

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Asger Lund Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

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Malte P Suppli Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

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Elizaveta Chabanova Department of Radiology, Herlev Hospital, University of Copenhagen, Herlev, Denmark

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Gerrit van Hall Clinical Metabolomics Core Facility, Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Jens J Holst Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Nicolai J Wewer Albrechtsen Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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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Caroline Kistorp Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Filip K Knop Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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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Zherui Fu Department of Emergency, The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China

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Yi Lai Department of Emergency, The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China

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Qianfei Wang Department of Emergency, The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China

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Feng Lin Department of Orthopedics, The First People's Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China

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Jiaping Fang Department of Emergency, The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China

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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.

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Xiuhua Liao Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China
Fujian Maternal-Fetal Clinical Medicine Research Center, Fuzhou, China
Fujian Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, China

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Suqin Zhu Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China

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Shumin Qiu Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China

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Hua Cao Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China

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Wenwen Jiang Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China

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Huiling Xu Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China

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Yan Sun Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China

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Beihong Zheng Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China
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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Emily Warmington Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK

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Gabrielle Smith Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK

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Vasileios Chortis Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK

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Raimunde Liang Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany
Department of Neurosurgery, Technical University Munich (TMU), Munich, Germany

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Juliane Lippert Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany

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Sonja Steinhauer Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany

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Laura-Sophie Landwehr Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany

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Constanze Hantel Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
Medizinische Klinik Und Poliklinik III, University Hospital Carl Gustav Carus, Dresden, Germany

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Katja Kiseljak-Vassiliades Division of Endocrinology Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Margaret E Wierman Division of Endocrinology Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Barbara Altieri Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany

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Paul A Foster Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK

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Cristina L Ronchi Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK
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.

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