According to its incidence patterns, colorectal cancer (CRC) tends to occur more frequently in males than in females, and the evidence shows that CRC is a hormone-related tumor. These findings indicate that androgen receptor (AR) gene methylation might be important for the regulation of the CRC risk in the different sexes. We used a case–control study to investigate the association between AR methylation in peripheral blood (PBL) and CRC risk. A cohort study was conducted to analyze the effect of AR methylation levels in both PBL and tissue on the prognosis of CRC. AR methylation levels were detected using methylation-sensitive high-resolution melting (MS-HRM). The results indicate that the hypomethylation of AR was significantly associated with the risk of CRC (OR = 1.869, 95% CI: 1.629–2.141, P < 0.001), and the results remained similar after adjusting for the propensity score (PS) (OR = 1.344, 95% CI: 1.147–1.575, P < 0.001) and PS matching (OR = 1.138, 95% CI: 1.000–1.292 P = 0.049). The hypomethylation of AR was significantly associated with CRC in males (OR = 2.309, 95% CI: 1.200–4.245; P = 0.012) but not females (OR = 1.000, 95% CI: 0.567–1.765; P = 0.999). The methylation status of AR in PBL and tissue does not seem to be associated with prognosis in colorectal cancer (OR = 1.425, 95% CI: 0.895–2.269, P = 0.135; OR = 0.930, 95% CI: 0.674–1.285, P = 0.661). We conclude that AR hypomethylation in PBL is associated with a high risk of CRC and may serve as a biomarker. Further studies involving large sample sizes are needed to validate the results of this study.
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Tingting Xia, Hongru Sun, Hao Huang, Haoran Bi, Rui Pu, Lei Zhang, Yuanyuan Zhang, Ying Liu, Jing Xu, Justina Ucheojor Onwuka, Yupeng Liu, Binbin Cui and Yashuang Zhao
Lena-Maria Levin, Henry Volzke, Markus M Lerch, Jens-Peter Kühn, Matthias Nauck, Nele Friedrich and Stephanie Zylla
Objective: Chemerin and adiponectin are adipokines assumed to be involved in the development of metabolic syndrome-related phenotypes like hepatic steatosis. We aimed to evaluate the associations of circulating chemerin and adiponectin concentrations with liver enzymes, liver fat content, and hepatic steatosis in the general population.
Methods: Data of 3951 subjects from the population-based Study of Health in Pomerania (SHIP-TREND) were used. Hepatic steatosis was assumed when either a hyperechogenic liver (assessed via ultrasound) or a magnetic resonance imaging (MRI)-quantified liver fat content >5% was present. Adjusted sex-specific quantile and logistic regression models were applied to analyse the associations of chemerin and adiponectin with liver enzymes, liver fat content, and hepatic steatosis.
Results: The observed associations of chemerin and adiponectin with liver enzymes were very divergent depending on sex, fasting status, and the specific enzyme. More consistent results were seen in the analyses of these adipokines in relation to MRI-quantified liver fat content. Here, we observed inverse associations to adiponectin in both sexes as well as a positive (men) or U-shaped (women) association to chemerin. Similarly, the MRI-based definition of hepatic steatosis revealed strongly consistent results: in both sexes high chemerin concentrations were associated with higher odds of hepatic steatosis whereas high adiponectin concentrations were associated with lower odds.
Conclusion: Our results suggest a role of these adipokines in the pathogenesis of hepatic steatosis independent of metabolic or inflammatory disorders. However, experimental studies are needed to further clarify the underlying mechanisms and the inter-play between adipokine concentrations and hepatic steatosis.
Simon Schimmack, Yongchao Yang, Klaus Felix, Markus Herbst, Yixiong Li, Miriam Schenk, Frank Bergmann, Thilo Hackert and Oliver Strobel
Elevated pre-operative C-reactive protein (CRP) serum values have been reported to be associated with poor overall survival for patients with pancreatic neuroendocrine neoplasms (pNEN). The aim of this study was to identify mechanisms linking CRP to poor prognosis in pNEN.
The malignant properties of pNENs were investigated using the human pNEN cell-lines BON1 and QGP1 exposed to CRP or IL-6. Analyses were performed by ELISA, Western blot, flow cytometry and immunocytochemistry as well as invasion and proliferation assays. To compare cytokine profiles and CRP levels, 76 serum samples of pNEN patients were analyzed using Luminex technology. In parallel, the expression of CRP and growth signaling pathway proteins was assessed on cell lines and paraffin-embedded primary pNEN.
In BON1 and QGP1 cells, inflammation (exposure to IL-6) significantly upregulated CRP expression and secretion as well as migratory properties. CRP stimulation of BON1 cells increased IL-6 secretion and invasion. This was accompanied by activation/phosphorylation of the ERK, AKT and/or STAT3 pathways. Although known CRP receptors – CD16, CD32 and CD64 – were not detected on BON1 cells, CRP uptake of pNEN cells was shown after CRP exposure. In patients, increased pre-operative CRP levels (≥5 mg/L) were associated with significantly higher serum levels of IL-6 and G-CSF, as well as with an increased CRP expression and ERK/AKT/STAT3 phosphorylation in pNEN tissue.
The malignant properties of pNEN cells can be stimulated by CRP and IL-6 promoting ERK/AKT/STAT pathways activation as well as invasion, thus linking systemic inflammation and poor prognosis.
Miranda Scharff, Chantal Maria Wiepjes, Maartje Klaver, Thomas Schreiner, Guy T’Sjoen and Martin den Heijer
Gender-affirming hormonal treatment (HT) in trans people changes physical appearance. Muscle mass and strength are important aspects of physical appearance, but few data exist on the effect of HT on grip strength and muscle mass. This study aimed to investigate the change in grip strength in trans people during the first year of HT and to study the possible determinants of this change and the associations between changes in grip strength, lean body mass and bone mineral density (BMD).
Design and methods
A multicenter, prospective study was performed, including 249 transwomen and 278 transmen. Grip strength, lean body mass and BMD were measured at baseline and after 1 year.
After 1 year of HT, grip strength decreased with −1.8 kg (95% CI −2.6; −1.0) in transwomen and increased with +6.1 kg (95% CI +5.5; +6.7) in transmen. No differences in grip strength change was found between age groups, BMI groups, hormonal administration routes or hormone concentrations. In transmen, increase in grip strength was associated with increase in lean body mass (per kg increase in grip strength: +0.010 kg, 95% CI +0.003; +0.017), while this was not found in transwomen (per kg increase in grip strength: +0.004 kg, 95% CI −0.000; +0.009). Change in grip strength was not associated with change in BMD in transwomen and transmen.
After 1 year of HT, grip strength decreased in transwomen, and increased in transmen. In transmen only, change in grip strength was associated with change in lean body mass.
Chiara Mele, Maria Teresa Samà, Alessandro Angelo Bisoffi, Marina Caputo, Valentina Bullara, Stefania Mai, Gillian Elisabeth Walker, Flavia Prodam, Paolo Marzullo, Gianluca Aimaretti and Loredana Pagano
The associative link relating insulin resistance (IR) and adipokines to the occurrence and phenotype of differentiated thyroid cancer (DTC) is unknown. The aim of this study was to evaluate the relationship between IR and adipokines in DTC patients, as compared with carriers of benign thyroid diseases (BTD) and healthy controls. This observational study enrolled 77 subjects phenotyped as DTC (N = 30), BTD (N = 27) and healthy subjects (N = 20). Each subject underwent preoperative analysis of anthropometric parameters, thyroid function and autoimmunity, insulin resistance (HOMA-IR) and levels of unacylated (UAG) and acylated ghrelin (AG), obestatin, leptin and adiponectin. Multivariate regression models were used to test the predictive role of metabolic correlates on thyroid phenotypes and DTC extension. The three groups showed similar age, gender distribution, smoking habit, BMI and thyroid parameters. Obestatin was significantly higher in DTC group compared to BTD (P < 0.05) and control subjects (P < 0.0001). DTC and BTD groups showed higher levels of UAG (P < 0.01) and AG (P < 0.05). Leptin levels were comparable between groups, whereas adiponectin levels were lower in DTC compared to BTD group (P < 0.0001) and controls (P < 0.01). In parallel, HOMA-IR was higher in DTC than BTD (P < 0.05) and control group (P < 0.01). Stepwise multivariable regression analysis showed that obestatin and UAG were independent predictors of DTC (P = 0.01 for both). In an analysis restricted to the DTC group, obestatin levels were associated with the absence of lymph node metastases (P < 0.05). Our results highlight a potential association between metabolic setting, circulating adipokines and thyroid cancer phenotype.
Lachlan Angus, Shalem Leemaqz, Olivia Ooi, Pauline Cundill, Nicholas Silberstein, Peter Locke, Jeffrey D Zajac and Ada S Cheung
Oestradiol with or without an anti-androgen (cyproterone acetate or spironolactone) is commonly prescribed in transfeminine individuals who have not had orchidectomy; however, there is no evidence to guide optimal treatment choice.
We aimed to compare add-on cyproterone acetate versus spironolactone in lowering endogenous testosterone concentrations in transfeminine individuals.
Retrospective cross-sectional study.
We analysed 114 transfeminine individuals who had been on oestradiol therapy for >6 months in two gender clinics in Melbourne, Australia. Total testosterone concentrations were compared between three groups; oestradiol alone (n = 21), oestradiol plus cyproterone acetate (n = 21) and oestradiol plus spironolactone (n = 38). Secondary outcomes included serum oestradiol concentration, oestradiol valerate dose, blood pressure, serum potassium, urea and creatinine.
Median age was 27.0 years (22.5–45.1) and median duration of hormone therapy was 1.5 years (0.9–2.6), which was not different between groups. On univariate analysis, the cyproterone group had significantly lower total testosterone concentrations (0.8 nmol/L (0.6–1.20)) compared with the spironolactone group (2.0 nmol/L (0.9–9.4), P = 0.037) and oestradiol alone group (10.5 nmol/L (4.9–17.2), P < 0.001), which remained significant (P = 0.005) after adjustments for oestradiol concentration, dose and age. Serum urea was higher in the spironolactone group compared with the cyproterone group. No differences were observed in total daily oestradiol dose, blood pressure, serum oestradiol, potassium or creatinine.
The cyproterone group achieved serum total testosterone concentrations in the female reference range. As spironolactone may cause feminisation without inhibition of steroidogenesis, it is unclear which anti-androgen is more effective at feminisation. Further prospective studies are required.
Gamze Akkuş, Isa Burak Güney, Fesih Ok, Mehtap Evran, Volkan Izol, Şeyda Erdoğan, Yıldırım Bayazıt, Murat Sert and Tamer Tetiker
The management of adrenal incidentaloma is still a challenge with respect to determining its functionality (hormone secretion) and malignancy. In this light, we performed 18F-FDG PET/CT scan to assess the SUVmax values in different adrenal masses including Cushing syndrome, pheochromocytoma, primary hyperaldosteronism and non-functional adrenal adenomas.
Total 109 (73 F, 36 M) patients with adrenal mass (incidentaloma), mean age of 53.3 ± 10.2 years (range, 24–70) were screened by 18F-FDG PET/CT. Data of 18F-FDG PET/CT imaging of the patients were assessed by the same specialist. Adrenal masses were identified according to the calculated standardized uptake values (SUVs). Clinical examination, 24-h urine cortisol, catecholamine metabolites, 1-mg dexamethasone suppression test, aldosterone/renin ratio and serum electrolytes were analyzed.
Based on the clinical and hormonal evaluations, there were 100 patients with non-functional adrenal mass, four with cortisol-secreting, four with pheochromocytomas and one with aldosterone-secreting adenoma. Mean adrenal mass diameter of 109 patients was 2.1 ± 4.3 (range, 1–6.5 cm). The 18F-FDG PET/CT imaging of the patients revealed that lower SUVmax values were found in non-functional adrenal masses (SUVmax 3.2) when compared to the functional adrenal masses including four with cortisol-secreting adenoma (SUVmax 10.1); four with pheochromcytoma (SUVmax 8.7) and one with aldosterone-secreting adenomas (SUVmax 3.30). Cortisol-secreting (Cushing syndrome) adrenal masses showed the highest SUVmax value (10.1), and a cut-off SUVmax of 4.135 was found with an 84.6% sensitivity and 75.6% specificity cortisol-secreting adrenal adenoma.
Consistent with the similar studies, non-functional adrenal adenomas typically do not show increased FDG uptake and a certain form of functional adenoma could present various FDG uptake in FDG PET/CT. Especially functional adrenal adenomas (cortisol secreting was the highest) showed increased FDG uptake in comparison to the non-functional adrenal masses. Therefore, setting a specific SUVmax value in the differentiation of malignant adrenal lesion from the benign one is risky and further studies, including a high number of functional adrenal mass are needed.
Yiyan Wang, Yaoyao Dong, Yinghui Fang, Yao Lv, Qiqi Zhu, Xiaoheng Li, Qingquan Lian and Ren-Shan Ge
Glucocorticoid hormone might cause intrauterine growth restriction. The glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) in the placenta eliminates excess levels of glucocorticoids during pregnancy. The aim of the current study was to define the effects of diethylstilbestrol (DES) on HSD11B2 activity in the mammalian placentas and identify its mode of action. Rat and human placental microsomal HSD11B2 were incubated with different concentrations of DES, and IC50 values were determined. The mode of action was analyzed by incubation of DES together with substrates, glucocorticoid and NAD+. DES suppressed rat and human HSD11B2 with IC50 values of 5.33 and 12.62 μM, respectively. DES was a competitive inhibitor of rat and human HSD11B2 when steroid substrates were added, while it was an uncompetitive inhibitor when cofactor NAD+ was exposed. Oral administration of DES (0.5 mg/kg) to the rat delayed the cortisol metabolism in adult female Sprague–Dawley rats, as indicated by the increases in cortisol’s elimination half-life, maximum concentration and area under the curve. In conclusion, DES is a potent HSD11B2 inhibitor, possibly contributing to the intrauterine growth restriction.
V Guarnotta, C Di Stefano, A Santoro, A Ciresi, A Coppola and C Giordano
Dual-release hydrocortisone (DR-HC) improves metabolism in patients with adrenal insufficiency. The aims of this study were to compare the cardiovascular and metabolic effects of conventional glucocorticoids (GCs) vs. DR-HC and of high vs. low doses of GCs, after 48 months of observation.
We selected 27 patients on hydrocortisone (mean dose 17.5 ± 4.2 mg/day) and 20 patients on cortisone acetate (mean dose 37.5 ± 12.1 mg/day) who maintained this treatment (group A) and 53 patients switched to DR-HC (mean dose 22 ± 4.8 mg/day) (group B). At baseline and after 48 months, clinical and metabolic parameters and Framingham Risk Score (FRS) were obtained.
After 48 months, patients in group A had a significant increase from baseline in BMI (P < 0.001), waist circumference (P = 0.001), systolic blood pressure (P = 0.001), LDL cholesterol (P = 0.018), HbA1c (P = 0.020) and FRS (P = 0.002). By contrast, patients in group B had a significant decrease in BMI (P = 0.002), waist circumference (P = 0.015), diastolic blood pressure (P = 0.031), total (P = 0.006) and LDL cholesterol (P = 0.005), HbA1c (P < 0.001) and FRS (P = 0.015) compared to baseline. No significant differences between high and low doses of both conventional GCs and DR-HC were observed.
DR-HC is associated with an improvement of metabolic parameters and cardiovascular risk compared to conventional GCs, which are associated with a worsening of these parameters, regardless of the dose used.
Marra Jai Aghajani, Tara Laurine Roberts, Tao Yang, Charles Eugenio McCafferty, Nicole J Caixeiro, Paul DeSouza and Navin Niles
To date, no research evaluating the predictive capabilities of soluble programmed cell death-ligand 1 (sPD-L1) in thyroid cancer patients has been performed. We aimed to investigate the prognostic significance of sPD-L1 expression in papillary thyroid cancer (PTC) and to evaluate the association between sPD-L1 levels with tumoural PD-L1 expression and patient outcomes. Pre-treatment levels of serum and plasma sPD-L1 were measured by ELISA in 101 PTC patients. Tissue microarrays were stained with an anti-PD-L1 antibody, clone SP263 (Ventana). The median serum sPD-L1 concentration in PTC patients was significantly higher compared to healthy controls (P = 0.028). An increased incidence of extrathyroidal extension was significantly associated with an elevated serum sPD-L1 level (P = 0.015). Patients with high serum sPD-L1 levels had significantly shorter median disease-free survival (DFS) as compared to those with low sPD-L1 levels (P = 0.011). Following multivariate analysis, serum sPD-L1 was the only statistically significant predictor for DFS. Patients with both positive serum and tumoural PD-L1 expression had a significantly shorter DFS than those in any other subgroup (P = 0.007). Our study is the first to confirm that sPD-L1 concentration is significantly associated with patient outcome in PTC. Soluble PD-L1 may provide clinicians with a non-invasive biomarker that can lessen dependence on tissue biopsies and diagnose aggressive thyroid cancers at a more treatable stage.