Browse

You are looking at 61 - 70 of 585 items for

  • Open access x
Clear All
Open access

Anna Malczewska, Magdalena Witkowska, Karolina Makulik, Agnes Bocian, Agata Walter, Joanna Pilch-Kowalczyk, Wojciech Zajęcki, Lisa Bodei, Kjell Oberg and Beata Kos-Kudła

Introduction

Current monoanalyte biomarkers are ineffective in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). NETest, a novel multianalyte signature, provides molecular information relevant to disease biology.

Aim(s)

Independently validate NETest to diagnose GEP-NETs and identify progression in a tertiary referral center.

Materials and methods

Cohorts are 67 pancreatic NETs (PNETs), 44 small intestine NETs (SINETs) and 63 controls. Well-differentiated (WD) PNETs, n = 62, SINETs, all (n = 44). Disease extent assessment at blood draw: anatomical (n = 110) CT (n = 106), MRI (n = 7) and/or functional 68Ga-SSA-PET/CT (n = 69) or 18F-FDG-PET/CT (n = 8). Image-positive disease (IPD) was defined as either CT/MRI or 68Ga-SSA-PET/CT/18F-FDG-PET/CT-positive. Both CT/MRI and 68Ga-SSA-PET/CT negative diagnosis in WD-NETs was considered image-negative disease (IND). NETest (normal: 20): PCR (spotted plates). Data: mean ± SD.

Results

Diagnosis

NETest was significantly increased in NETs (n = 111; 26 ± 21) vs controls (8 ± 4, p < 0.0001). Seventy-five (42 PNET, 33 SINET) were image positive. Eleven (8 PNET, 3 SINET; all WD) were IND. In IPD, NETest was significantly higher (36 ± 22) vs IND (8 ± 7, P < 0.0001). NETest accuracy, sensitivity and specificity are 97, 99 and 95%, respectively

Concordance with imaging

NETest was 92% (101/110) concordant with anatomical imaging, 94% (65/69) with 68Ga-SSA-PET/CT and 96% (65/68) dual modality (CT/MRI and 68Ga-SSA-PET/CT). In 70 CT/MRI positive, NETest was elevated in all (37 ± 22). In 40 CT/MRI negative, NETest was normal (11 ± 10) in 31. In 56 68Ga-SSA-PET/CT positive, NETest was elevated (36 ± 22) in 55. In 13 68Ga-SSA-PET/CT negative, NETest was normal (9 ± 8) in ten.

Disease status

NETest was significantly higher in progressive (61 ± 26; n = 11) vs stable disease (29 ± 14; n = 64; P < 0.0001) (RECIST 1.1).

Conclusion

NETest is an effective diagnostic for PNETs and SINETs. Elevated NETest is as effective as imaging in diagnosis and accurately identifies progression.

Open access

Ming Zhu, Bingxin Xu, Meng Wang, Shangyun Liu, Yue Zhang and Chao Zhang

Melanocortin receptors (MCRs) and their accessory proteins (MRAPs) evolutionarily first appear in the genome of sea lamprey. The most ancient melanocortin system consists of only two melanocortin receptors (slMCa and slMCb) and one MRAP2 (slMRAP2) protein, but the physiological roles have not been fully explored in this primitive species. Here, we synthesize and characterize the pharmacological features of slMRAP2 protein on two slMCRs. Our results show that the slMRAP2 protein lacks the long carboxyl terminus; it directly interacts and decreases the surface expression but enhances the α-MSH-induced agonism of slMCa and slMCb. In comparison with higher organisms such as elephant shark and zebrafish, we also demonstrate the constantly evolving regulatory function of the carboxyl terminus of MRAP2 protein, the unique antiparallel topology of slMRAP2 dimer and the homo- and hetero-dimerization of two slMCRs. This study elucidates the presence and modulation of melanocortin receptor by the accessory protein of the agnathans for the first time, which provides a better insight of the melanocortin system in ancient species of chordates.

Open access

Shuang Ye, Yuanyuan Xu, Jiehao Li, Shuhui Zheng, Peng Sun and Tinghuai Wang

The role of G protein-coupled estrogen receptor 1 (GPER) signaling including promoting Ezrin phosphorylation, which could be also activated by estrogen has not yet been clearly identified in triple negative breast cancer (TNBC). This study is to evaluate the prognostic value of GPER and Ezrin in TNBC patients. Clinico-pathologic features including age, menopausal status, tumor size, nuclear grade, lymph node metastasis, AJCC TNM stage and ER, PR, HER-2 expression were evaluated from 249 TNBC cases. Immunohistochemistry staining of GPER and Ezrin was performed on TNBC pathological sections. The Kaplan-Meier analyses, as well as Logistic regressive and Cox regression model were applied to evaluate the prognostic significant between different subgroups. Compare to GPER-low group, GPER-high group exhibited higher TNM staging (P=0.021), more death (P<0.001), relapse (P<0.001) and distant event (P<0.001). Kaplan-Meier analysis showed that GPER-high patients had a decreased OS (P<0.001), PFS (P<0.001), LRFS (P<0.001) and DDFS (P<0.001) than GPER-low patients. But these differences in prognosis are no longer statistically in post-menopausal patients (OS, P=0.8617; PFS, P=0.1905; LRFS, P=0.4378; DDFS, P=0.2538). There was significant positive correlation between GPER and Ezrin expression level (R=0.508, P<0.001) and the effect of Ezrin on survival prognosis was consistent with GPER. Moreover, the multivariable analysis also confirmed that GPER and Ezrin level were both significantly associated with poor DDFS (HR: 0.346, 95%CI 0.182-0.658, P=0.001; HR: 0.320, 95%CI 0.162-0.631, P=0.001). Thus, over expression of GPER and Ezrin may contribute to aggressive behavior and indicate unfavorable prognosis in TNBC and it’s may rely on individual’s estrogen levels.

Open access

Jia Li, Yan Zhao, Caoxin Huang, Zheng Chen, Xiulin Shi, Long Li, Zhong Chen and Xuejun Li

Objective

Exercise benefits people with nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify a panel of biomarkers and to provide the possible mechanism for the effect of exercise on NAFLD patients via an untargeted mass spectrometry-based serum metabolomics study.

Methods

NAFLD patients were classified randomly into a control group (n = 74) and a 6-month vigorous exercise (n = 68) group. Differences in serum metabolic profiles were analyzed using untargeted ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technology. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to validate the differences between these two groups, and altered metabolites were obtained by ANOVA (fold change >2, P < 0.05) and identified with the online database Metlin and an in-house database.

Results

Metabolic profiling and multiple statistical analyses of the serum samples indicated significant differences between the NAFLD patients in the control and the 6-month vigorous exercise groups. Finally, 36 metabolites were identified between the control vs exercise groups. These metabolites were mainly associated with glycerophospholipid- and sphingolipid-related pathways.

Conclusion

Our study demonstrates that glycerophospholipid and sphingolipid alterations may contribute to the mechanism underlying the effect of exercise on NAFLD patients. A LC-MS-based metabolomics approach has a potential value for screening exercise-induced biomarkers.

Open access

Martin Schuijt, Fred C.g.j Sweep, Rob Van der Steen, André Olthaar, Nike M Stikkelbroeck, Alec Ross and Antonius Eduard van Herwaarden

Objective: Increased maternal testosterone concentration during pregnancy may affect the fetus. Therefore it is clinically relevant to have a quick and reliable method to determine free testosterone levels. Current calculators for free testosterone are suspected to perform poorly during pregnancy due to suggested competition between high levels of estradiol and free (bio-active) testosterone for sex hormone-binding globulin (SHBG) binding. Therefore, it is claimed that reliable calculation of free testosterone concentration is not possible. However, recent evidence on SHBG binding sites questions the estradiol effect on the testosterone-SHBG binding during pregnancy. In this study, we investigated whether the free testosterone concentration can be calculated in pregnant women.

Design and Methods: Free testosterone was measured with a specially developed equilibrium dialysis method combined with liquid chromatography tandem mass spectrometry (LC-MS/MS). Free testosterone was also calculated with the formulas of Vermeulen et al. and Ross et al.

Results: Total and free testosterone measured in healthy men and women were in good agreement with earlier reports. In pregnant women, total testosterone values were higher than in non-pregnant women, whereas free testosterone values were comparable. Calculated free testosterone levels in pregnant women were highly correlated, but marginally higher, compared to measured free testosterone levels.

Conclusions: We developed an equilibrium dialysis–LC-MS/MS method for the measurement of free testosterone in the low range of pregnant en non-pregnant women. Although during pregnancy total testosterone is increased, this is not the case for free testosterone. The free testosterone formulas perform well in pregnant women.

Open access

Ananda A Santana-Ribeiro, Giulliani A Moreira-Brasileiro, Manuel H Aguiar-Oliveira, Roberto Salvatori, Vitor O Carvalho, Claudia K Alvim-Pereira, Carlos R Araújo-Daniel, Júlia G Reis-Costa, Alana L Andrade-Guimarães, Alécia A Oliveira-Santos, Edgar R Vieira and Miburge B Gois-Junior

Objectives

Walking and postural balance are extremely important to obtain food and to work. Both are critical for quality of life and ability to survive. While walking reflects musculoskeletal and cardiopulmonary systems, postural balance depends on body size, muscle tone, visual, vestibular and nervous systems. Since GH and IGF-I act on all these systems, we decided to study those parameters in a cohort of individuals with severe short stature due to untreated isolated GH deficiency (IGHD) caused by a mutation in the GHRH receptor gene. These IGHD subjects, despite reduction in muscle mass, are very active and have normal longevity.

Methods

In a cross-sectional study, we assessed walking (by a 6-min walk test), postural balance (by force platform) and fall risk (by the 'Timed Up and Go' test) in 31 IGHD and 40 matched health controls.

Results

The percentage of the walked distance measured in relation to the predicted one was similar in groups, but higher in IGHD, when corrected by the leg length. Absolute postural balance data showed similar velocity of unipodal support in the two groups, and better values, with open and closed eyes and unipodal support, in IGHD, but these differences became non-significant when corrected for height and lower-limb length. The time in 'Timed Up and Go' test was higher in IGHD cohort, but still below the cut-off value for fall risk.

Conclusion

IGHD subjects exhibit satisfactory walking and postural balance, without increase in fall risk.

Open access

Weixi Wang, Rulai Han, Lei Ye, Jing Xie, Bei Tao, Fukang Sun, Ran Zhuo, Xi Chen, Xiaxing Deng, Cong Ye, Hongyan Zhao and Shu Wang

Objective

Up to 40% of multiple endocrine neoplasia type 1 (MEN1) patients may have adrenal cortical tumors. However, adrenocortical carcinoma (ACC) is rare. The clinical manifestations, prevalence, inheritance and prognosis of ACC associated with MEN1 remain unclear. Here we report the clinical manifestations and prevalence of ACC in patients with MEN1.

Design and methods

A retrospective analysis of ACC associated with MEN1 patients at a single tertiary care center from December 2001 to June 2017. Genetic analysis of MEN1 and other ACC associated genes, loss of heterozygosity (LOH) of MEN1 locus, immunohistochemistry staining of menin, P53 and β-catenin in ACC tissue were performed.

Results

Two related patients had ACC associated with MEN1. The father had ENSAT stage IV tumor with excessive production of cortisol; the daughter had nonfunctional ENSAT stage I tumor. Both patients carried novel germline heterozygous mutation (c.400_401insC) of MEN1. The wild-type MEN1 allele was lost in the resected ACC tissue from the daughter with no menin staining. The ACC tissue had nuclear β-catenin staining, with heterozygous CTNNB1 mutation of 357del24 and P53 staining in only 20% cells.

Conclusions

ACC associated with MEN1 is rare and may occur in familial aggregates.

Open access

Nicola Tufton, Lucy Shapiro, Anju Sahdev, Ajith V Kumar, Lee Martin, William M Drake, Scott A Akker and Helen L Storr

Objective

Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare in children. A large proportion of these are now understood to be due to underlying germline mutations. Here we focus on succinate dehydrogenase subunit B (SDHB) gene mutation carriers as these tumours carry a high risk of malignant transformation. There remains no current consensus with respect to optimal surveillance for asymptomatic carriers and those in whom the presenting tumour has been resected.

Method

We undertook a retrospective analysis of longitudinal clinical data of all children and adolescents with SDHB mutations followed up in a single UK tertiary referral centre. This included index cases that pre-dated the introduction of surveillance screening and asymptomatic carriers identified through cascade genetic testing. We also conducted a literature review to inform a suggested surveillance protocol for children and adolescents harbouring SDHB mutations.

Results

Clinical outcomes of a total of 38 children are presented: 8 index cases and 30 mutation-positive asymptomatic carriers with 175 patient years of follow-up data. Three of the eight index cases developed metachronous disease and two developed metastatic disease. Of the 30 asymptomatic carriers, 3 were found to have PGLs on surveillance screening.

Conclusions

Surveillance screening was well tolerated in our paediatric cohort and asymptomatic paediatric subjects. Screening can identify tumours before they become secretory and/or symptomatic, thereby facilitating surgical resection and reducing the chance of distant spread. We propose a regular screening protocol commencing at age 5 years in this at-risk cohort of patients.

Open access

Weiwei He, Bin Wang, Kaida Mu, Jing Zhang, Yanping Yang, Wei Yao, Sheli Li and Jin-an Zhang

Background

Accumulating data have shown that interleukin-27 (IL27) polymorphisms are linked to the susceptibility of some autoimmune diseases. We assessed whether there was an association between three single-nucleotide polymorphisms (SNPs) of IL27 gene and autoimmune thyroid diseases (AITDs).

Methods

Three SNPs (rs153109, rs17855750 and rs181206) of IL27 gene were genotyped by Hi-SNP high-throughput genotyping in 843 patients with AITDs (516 Graves’ disease (GD) and 327 Hashimoto’s thyroiditis (HT)) and 677 healthy controls in Chinese Han population.

Results

Compared with controls, rs153109 displayed significant associations with GD in allele and genotype frequencies (P = 0.002 and P = 0.008, respectively) and rs17855750 displayed significant associations with HT in allele frequencies (P = 0.02), whereas no differences in genotype or allele frequencies were found between AITD patients and controls at rs181206.

Conclusion

Our study, for the first time, showed the significant association of the IL27 gene SNPs with AITD.

Open access

Anna C Simcocks, Kayte A Jenkin, Lannie O’Keefe, Chrishan S Samuel, Michael L Mathai, Andrew J McAinch and Deanne H Hryciw

Atypical cannabinoid compounds O-1602 and O-1918 are ligands for the putative cannabinoid receptors G protein-coupled receptor 55 and G protein-coupled receptor 18. The role of O-1602 and O-1918 in attenuating obesity and obesity-related pathologies is unknown. Therefore, we aimed to determine the role that either compound had on body weight and body composition, renal and hepatic function in diet-induced obesity. Male Sprague–Dawley rats were fed a high-fat diet (40% digestible energy from lipids) or a standard chow diet for 10 weeks. In a separate cohort, male Sprague–Dawley rats were fed a high-fat diet for 9 weeks and then injected daily with 5 mg/kg O-1602, 1 mg/kg O-1918 or vehicle (0.9% saline/0.75% Tween 80) for a further 6 weeks. Our data demonstrated that high-fat feeding upregulates whole kidney G protein receptor 55 expression. In diet-induced obesity, we also demonstrated O-1602 reduces body weight, body fat and improves albuminuria. Despite this, treatment with O-1602 resulted in gross morphological changes in the liver and kidney. Treatment with O-1918 improved albuminuria, but did not alter body weight or fat composition. In addition, treatment with O-1918 also upregulated circulation of pro-inflammatory cytokines including IL-1α, IL-2, IL-17α, IL-18 and RANTES as well as plasma AST. Thus O-1602 and O-1918 appear not to be suitable treatments for obesity and related comorbidities, due to their effects on organ morphology and pro-inflammatory signaling in obesity.