Angiogenesis has a pivotal role in the growth and metastasis of pancreatic neuroendocrine tumors (PNETs). Apatinib inhibits angiogenesis as a highly selective KDR inhibitor and has been used to treat advanced gastric cancer and malignancies in clinical settings. However, the efficacy of apatinib in PNETs remains unclear. The aim of this study was to compare the antitumor efficacy of apatinib with that of the standard PNET drug sunitinib in our subcutaneous and liver metastasis models of insulinoma and non-functional PNET. Our results revealed that apatinib had a generally comparable or even superior antitumor effect to that of sunitinib on primary PNET, and it inhibited angiogenesis without directly causing tumor cell cytotoxicity. Apatinib inhibited the tumor in a dose-dependent manner, and the high dose was well tolerated in mice. We also found that the apatinib efficacy in liver metastasis models was cell-type (disease) selective. Although apatinib efficiently inhibited INR1G9-represented non-functional PNET liver metastasis, it led to the emergence of a hypoxic area in the INS-1-represented insulinoma and promoted liver metastasis. Our study demonstrated that apatinib has promise for clinical applications in certain malignant PNETs, and the application of anti-angiogenesis drugs to benign insulinomas may require careful consideration.
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Shan Wu, Jianjun Zhou, Jing Guo, Zhan Hua, Jianchen Li and Zai Wang
Shuhui Ma, Zixu Wang, Jing Cao, Yulan Dong and Yaoxing Chen
The avian pineal gland, an independent circadian oscillator, receives external photic cues and translates them for the rhythmical synthesis of melatonin. Our previous study found that monochromatic green light could increase the secretion of melatonin and expression of CLOCK and BMAL1 in chick pinealocytes. This study further investigated the role of BMAL1 and CLOCK in monochromatic green light-induced melatonin secretion in chick pinealocytes using siRNAs interference and overexpression techniques. The results showed that si-BMAL1 destroyed the circadian rhythms of AANAT and melatonin, along with the disruption of the expression of all the seven clock genes, except CRY1. Furthermore, overexpression of BMAL1 also disturbed the circadian rhythms of AANAT and melatonin, in addition to causing arrhythmic expression of BMAL1 and CRY1/2, but had no effect on the circadian rhythms of CLOCK, BMAL2 and PER2/3. The knockdown or overexpression of CLOCK had no impact on the circadian rhythms of AANAT, melatonin, BMAL1 and PER2, but it significantly deregulated the circadian rhythms of CLOCK, BMAL2, CRY1/2 and PER3. These results suggested that BMAL1 rather than CLOCK plays a critical role in the regulation of monochromatic green light-induced melatonin rhythm synthesis in chicken pinealocytes. Moreover, both knockdown and overexpression of BMAL1 could change the expression levels of CRY2, it indicated CRY2 may be involved in the BMAL1 pathway by modulating the circadian rhythms of AANAT and melatonin.
Elena Valassi, Natalia García-Giralt, Jorge Malouf, Iris Crespo, Jaume Llauger, Adolfo Díez-Pérez and Susan M Webb
Biochemical control of GH/IGF-I excess in acromegaly (ACRO) is associated with persistent impairment of trabecular microstructure leading to increased risk of vertebral fractures. Circulating miRNAs modulate the activity of osteoblasts and osteoclasts, and may be potential biomarkers of osteoporosis.
Identify differentially expressed miRNAs in the serum of patients with controlled ACRO vs controls and correlate miRNA levels with both biochemical and structural bone parameters.
Patients and methods
Twenty-seven patients with controlled ACRO (11 males, 16 females; mean age, 48 ± 5 years; BMI, 28 ± 4 kg/m2) and 27 age-, gender- and BMI-matched controls were recruited. Areal BMD at lumbar spine and femur, and trabecular bone score were assessed; volumetric BMD was measured by quantitative computed tomography QCT-Pro (Mindways). Twenty miRNAs, chosen by their putative role in bone, were quantified in serum using real-time qPCR.
In ACRO patients, miR-103a-3p and miR-191-5p were found overexpressed, whereas miR-660-5p was underexpressed (P < 0.001). miR-103a-3p levels were negatively associated with both trabecular vBMD at trochanter and serum osteoprotegerin concentrations (P < 0.05) and positively with vitamin D concentrations (P < 0.01) and total cross-sectional area of the femoral neck (P < 0.05). miR-660-5p levels were correlated with both trabecular vBMD at trochanter and OPG concentrations (P < 0.05), but were negatively associated with vitamin D levels (P < 0.05). A negative correlation between miR-103-a-3p and miR-660-5p was found in both groups (P < 0.001).
Circulating miR-103a-3p and miR-660-5p are differentially expressed in controlled ACRO patients and associated with bone structural parameters. miRNAs may be one of the mechanisms involved in the pathogenesis of bone disease and could be used as biomarkers in ACRO patients.
Ladan Younesi, Zeinab Safarpour Lima, Azadeh Akbari Sene, Zahra Hosseini Jebelli and Ghazaleh Amjad
Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders. The aim of this study was to find the correlation between color Doppler ultrasound and serum tests as auxiliary diagnostic criteria in areas where there is no possibility of some tests. A total of 108 patients were enrolled. They were divided into three groups including patients with PCOS, patients with PCOA ultrasound, patients with ovaries and normal hormone tests. Transvaginal sonography was performed from three groups and the results were evaluated in gray scale. The volume of the ovary, the number of follicles and the placement of follicles were recorded using using Doppler spectrum of uterine artery and ovarian stroma. Their arterial resistance index was also calculated. In the next step, serum samples were evaluated to determine the level of LH, FSH, free testosterone, DHEAS and 17-OHP hormones in the early follicular phase. Gray scale ultrasonographic findings (volume and number of ovarian follicles) as well as LH values were higher in patients with PCOS than those in the other two groups. These results proved the reliability of using these factors in the prediction of PCOS. In this study, Doppler indexes did not correlate with the size of the ovaries, the number of ovarian follicles and the measured hormone levels. The findings of transvaginal ultrasound and investigating the relationship with clinical and laboratory outcomes, a more suitable pattern could be chosen for more accurate patient selection and, leading to timely treatment and reducing the complications of the disease.
Julia H Goedecke, Mehreen Tootla and Dheshnie Keswell
Studies have shown ethnic differences in body fat distribution, characterised by greater peripheral and less central fat accumulation in black compared to white South African (SA) women. As sex hormones play an important role in body fat distribution, our study aimed to determine whether differences in body fat distribution between black and white SA women were associated with subcutaneous adipose tissue (SAT) expression of oestrogen receptors (ERA and ERB) and aromatase (CYP19A1). Body fat distribution (DXA and CT) and ERA, ERB and CYP19A1 expression in abdominal and gluteal SAT were measured in 26 black and 22 white SA women. Abdominal SAT ERA and ERB did not differ by ethnicity or BMI. Gluteal ERA was higher (1.08 ± 0.06 vs 0.99 ± 0.05, P < 0.001) and ERB was lower (0.99 ± 0.06 vs 1.10 ± 0.07, P < 0.001) in black vs white SA women. CYP19A1 increased with obesity in all depots (P < 0.001). In both black and white SA women, gluteal ERA was associated with lower central fat mass (FM) and greater gynoid FM (P < 0.05), while the inverse association was shown for CYP19A1 in all depots (P < 0.01). In conclusion, ethnic differences in gluteal ERA expression were associated with differences in body fat distribution previously reported between black and white SA women.
Kamran Iqbal, Kate Halsby, Robert D Murray, Paul V Carroll and Robert Petermann
Background and objectives
Glucocorticoids are used to manage adrenal insufficiency (AI). We describe treatments used in the United Kingdom and real-world clinical outcomes for each treatment.
We used 2010–2016 primary care data from The Health Improvement Network (THIN). Descriptive analyses were conducted, and differences in variables between patients prescribed immediate-release hydrocortisone (IR HC), prednisolone or modified-release hydrocortisone (MR HC) were assessed using Fisher’s exact test.
Overall, 2648 patients were included: 1912 on IR HC (72%), 691 on prednisolone (26%) and 45 (2%) on MR HC. A total of 1174 (44.3%) had primary and 1150 (43.4%) had secondary AI. Patients on prednisolone were older (P < 0.001) and had a greater history of smoking (292/691, P < 0.001) and CVD (275/691, P < 0.001). Patients on MR HC had more PCOS (3/45, P = 0.001) and diabetes (27/45, P = 0.004). The number of GP visits/patient/year was 6.50 in IR HC, 9.54 in prednisolone and 9.11 in MR HC cohorts. The mean number of A&E visits and inpatient and outpatient hospital admissions ranged from 0.42 to 0.93 visits/patient/year. The mean number of adrenal crises/patient/year was between 0.02 and 0.03 for all cohorts.
IR HC is most commonly used for the management of AI in the United Kingdom, followed by prednisolone. Few patients receive MR HC. The prednisolone and MR HC cohorts displayed a greater prevalence of vascular risk factors compared with IR HC. The occurrence of AC and primary and secondary resource use were similar between treatment cohorts, and they indicate significant resource utilisation. Improved treatment and management of patients with AI is needed.
Jes Sloth Mathiesen, Jens Peter Kroustrup, Peter Vestergaard, Per Løgstrup Poulsen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Sten Schytte, Stefano Christian Londero, Henrik Baymler Pedersen, Christoffer Holst Hahn, Jens Bentzen, Sören Möller, Mette Gaustadnes, Maria Rossing, Finn Cilius Nielsen, Kim Brixen, Christian Godballe and Danish Thyroid Cancer Group (DATHYRCA)
A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38–4.57) vs 3.04 (95% CI: 1.38–6.67) for stage II, 2.06 (95% CI: 0.45–9.39) vs 3.59 (95% CI: 1.61–8.03) for stage III and 5.87 (95% CI: 2.02–17.01) vs 59.26 (20.53–171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.
Emmi Naskali, Katja Dettmer, Peter J Oefner, Pedro A B Pereira, Kai Krohn, Petri Auvinen, Annamari Ranki and Nicolas Kluger
Intestinal autoimmunity with gastrointestinal (GI) dysfunction has been shown in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Patients lack entero-endocrine (EE) cells and have circulating autoantibodies (Aabs) against critical enzymes in serotonin (5-HT) biosynthesis.
We sought to determine the serum levels of 5-HT, tryptophan (Trp) metabolites and L-DOPA in 37 Finnish APECED patients and to correlate their abundance with the presence of TPH and AADC Aabs, GI dysfunction and depressive symptoms. We also performed an exploratory analysis of the gut microbiome.
Serum 5-HT, L-DOPA and Trp metabolite levels were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). TPH and AADC Aabs were measured by ELISA. Depression was assessed with a structured RBDI questionnaire. The V3–V4 regions of the bacterial 16S rRNA gene were sequenced for gut microbiome exploration.
Serum 5-HT levels were significantly decreased (130 ± 131 nmol/L vs 686 ± 233 nmol/L, P < 0.0001) in APECED patients with TPH-1 (±AADC) Aabs compared to controls and patients with only AADC Aabs. Reduced 5-HT levels correlated with constipation. The genus Escherichia/Shigella was overrepresented in the intestinal microbiome. No correlation between serum Trp, 5-HT or l-DOPA levels and the RBDI total score, fatigue or sleep disorders was found.
This exploratory study found low serum levels of 5-HT to be associated with constipation and the presence of TPH-1 and AADC Aabs, but not with symptoms of depression. Hence, serum 5-HT, TPH1 and AADC Aabs should be determined in APECED patients presenting with GI symptoms.
Alessandra Gambineri and Carla Pelusi
An imbalance in sex hormones has an important impact on type 2 diabetes (T2DM) mainly through the involvement of visceral adipose tissue. Androgens have an interesting sex-dimorphic association with T2DM, since hyperandrogenism in females and hypogonadism in males are risk factors for T2DM. Thus, treatments aimed at correcting hyperandrogenism in females and hypogonadism in males may prevent the development of T2DM or help in its treatment.
Zi-Di Xu, Wei Zhang, Min Liu, Huan-Min Wang, Pei-Pei Hui, Xue-Jun Liang, Jie Yan, Yu-Jun Wu, Yan-Mei Sang, Cheng Zhu and Gui-Chen Ni
This study aims to summarize and analyze the clinical manifestations, genetic characteristics, treatment modalities and long-term prognosis of congenital hyperinsulinemia (CHI) in Chinese children. Sixty children with CHI, who were treated at Beijing Children’s Hospital from January 2014 to August 2017, and their families, were selected as subjects. The CHI-related causative genes in children were sequenced and analyzed using second-generation sequencing technology. Furthermore, the genetic pathogenesis and clinical characteristics of Chinese children with CHI were explored. Among the 60 CHI children, 27 children (27/60, 45%) carried known CHI-related gene mutations: 16 children (26.7%) carried ABCC8 gene mutations, seven children (11.7%) carried GLUD1 gene mutations, one child carried GCK gene mutations, two children carried HNF4α gene mutations and one child carried HADH gene mutations. In these 60 patients, eight patients underwent 18F-L-DOPA PET scan for the pancreas, and five children were found to be focal type. The treatment of diazoxide was ineffective in these five patients, and hypoglycemia could be controlled after receiving partial pancreatectomy. In conclusion, ABCC8 gene mutation is the most common cause of CHI in Chinese children. The early genetic analysis of children’s families has an important guiding significance for treatment planning and prognosis assessment.