Background: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands ...(fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Methods: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. Results: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. Conclusions: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.
•Body weight and BMI decrease in both the EG and CG groups during the period of caloric restriction. •For both the EG and CG groups, fat-free mass decreases during food restriction. •Subjects on a ...high-fiber diet have reduced fasting glucose and basal insulin as well as improved insulin resistance, as attested by the lower HOMA-IR index. •Obese women on a high-fiber diet have suppressed postprandial (after 60 min) acylated ghrelin, confirming that the diet composition influences ghrelin levels from the first day. •In the present study, it was possible to verify that fasting leptin concentration diminishes in obese women on a high-fiber diet. Background - Several mechanisms, including excessive hunger, account for patients' difficulties in maintaining weight loss and dietary changes after caloric restriction. Objective - To evaluate the effect of short-term high-fiber calorie-restricted diet in appetite-regulating hormones, and hunger and satiety sensations in women with obesity. In a randomized controlled trial study, thirty women with body mass index (BMI) higher than 30 kg/m2, and aged from 20 to 50 years were hospitalized following a calorie-restricted diet (1000 kcal/day) for three days. The experimental group (n=15) received high-fiber diet and the control group (n=15), conventional diet. Results - Body weight, BMI, resting energy expenditure (REE), acylated and total ghrelin, leptin, insulin and glucose, and hunger and satiety sensations were evaluated. Linear regression models with mixed effects (fixed and random effects) helped to assess the variables between the two groups and within the groups. Body weight and BMI decreased in both the experimental and control groups (P<0.001). After the high-fiber diet, postprandial acylated ghrelin (P=0.04), glucose (P<0.001), insulin (P=0.04), and leptin (P=0.03) levels as well as the HOMA-IR index (P=0.01) decreased, whereas satiety improved (P=0.02). Obese women that followed the conventional diet had increased body fat percentage (P=0.04) and lower REE (P=0.02). The two diets did not differ in terms of hunger sensation. Conclusion - A short-term high-fiber diet improves satiety sensations and metabolic parameters while suppressing postprandial acylated ghrelin (60 minutes) and maintaining the resting energy expenditure.
Aldosterone-secreting adrenocortical carcinomas (ACCs) are rare and usually present as large tumors. The only potentially curative treatment for ACC is surgical resection. However, surgery may be ...unfeasible in some patients who have multiple comorbidities or decline the procedure. We describe herein the case of a 44-year-old man with aldosterone-secreting ACC who declined surgery because of religious convictions. As a Jehovah’s Witness, the patient was concerned about requiring blood transfusion during surgery. Treatment with mitotane was started but interrupted due to hepatotoxicity. Subsequently, the patient was successfully treated with stereotactic ablative radiotherapy (SABR). After SABR, the patient had progressive improvement of pain, reduction in antihypertensive drugs, control of blood pressure and hypokalemia, normalization of serum aldosterone and renin levels, and reduction in tumor size and weight. To our knowledge, this is the first report of a patient with a pure aldosterone-secreting ACC who received SABR. The patient’s response was substantial, showing that SABR could be considered as an alternative local treatment for aldosterone-secreting ACCs when surgery is unfeasible.
Epigenetic control of adamantinomatous craniopharyngiomas Marrero-Gutiérrez, Junier; Bueno, Ana Carolina; Martins, Clarissa Silva ...
The journal of clinical endocrinology and metabolism,
2024-Jan-05, 2024-01-05, 20240105
Journal Article
Recenzirano
Odprti dostop
Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking.
To identify methylation signatures in ACPs regarding clinical presentation and outcome.
Clinical ...and pathology data were collected from 35 ACP patients (54% male; 18.1 years 2-68). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multi-dimensional scaling. Statistical associations between clusters and clinical features were achieved using Fisher's test and global biological process interpretations were aided by Gene Ontology enrichment analyses.
Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = 0.0006), hypomethylated in CpG Island (CGI), non-CGI sites, and globally (P < 0.001), and associated with greater tumor size (24.1 vs 9.5cm3, P = 0.04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell-adhesion, cytoskeleton organization, and cytokine binding, and also cell-type specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation.
Two clusters of ACP patients were consistently revealed by unsupervised machine learning methods, being one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment.
Objective Cardiopulmonary bypass is associated with ischemia–reperfusion injury to multiple organs. We aimed to evaluate whether remote ischemic preconditioning performed the day before surgery for ...congenital heart disease with cardiopulmonary bypass attenuates the postoperative inflammatory response and myocardial dysfunction. Methods This was a prospective, randomized, single-blind, controlled trial. Children allocated to remote ischemic preconditioning underwent 4 periods of 5 minutes of lower limb ischemia by a blood pressure cuff intercalated with 5 minutes of reperfusion. Blood samples were collected 4, 12, 24, and 48 hours after cardiopulmonary bypass to evaluate nuclear factor kappa B activation in leukocytes by quantification of mRNA of I kappa B alpha by real-time quantitative polymerase chain reaction and for interleukin-8 and 10 plasma concentration measurements by enzyme-linked immunosorbent assay. Myocardial dysfunction was assessed by N-terminal pro-B-type natriuretic peptide and cardiac troponin I plasma concentrations, measured by chemiluminescence, and clinical parameters of low cardiac output syndrome. Results Twelve children were allocated to remote ischemic preconditioning, and 10 children were allocated to the control group. Demographic data and Risk Adjustment for Congenital Heart Surgery 1 classification were comparable in both groups. Remote ischemic preconditioning group had lower postoperative values of N-terminal pro-B-type natriuretic peptide, but cardiac troponin I levels were not significantly different between groups. Interleukin-8 and 10 concentrations and I kappa B alpha gene expression were similar in both groups. Postoperative morbidity was similar in both groups; there were no postoperative deaths in either group. Conclusions Late remote ischemic preconditioning did not provide clinically relevant cardioprotection to children undergoing cardiopulmonary bypass.
Summary
Objectives
To determine the dopamine receptor subtype 2 (DR2) mRNA levels and protein expression and to evaluate the effect of adjuvant cabergoline therapy on tumour volume (TV) in patients ...with postoperative residual nonfunctioning pituitary adenoma (NFPA).
Methods
The mRNA expression was quantified by real‐time RT‐PCR (TaqMan®), and protein expression was evaluated by immunohistochemistry. Tumours were classified according to the percentage of immunostained cells for DR2 as scores 1 (<50% of stained cells) or 2 (≥50%). Cabergoline was started at least 6 months after surgery in nine patients with residual tumours (3 mg/week). The cabergoline effect was prospectively evaluated by magnetic resonance imaging using three‐dimensional volume calculation. TV reduction >25% was considered significant.
Results
The DR2 mRNA expression was variable but was observed in 100% of the samples (N = 20). DR2 protein expression was also observed in all the tumours (N = 34). Twenty‐nine tumours (85%) were classified as score 2. The median DR2 mRNA expression was higher in the tumours classified as score 2 compared with score 1 (P = 0·007). TV reduction with cabergoline therapy was observed in 67% of the patients (6/9). The median TV before and after 6 months of treatment was 1·90 cm3 (0·61–8·74) and 1·69 cm3 (0·36–4·20) P = 0·02, respectively.
Conclusion
In conclusion, DR2 is expressed in all adenomas and the majority of the patients in this study displayed tumour shrinkage on cabergoline (CAB) therapy. Thus, CAB might be useful in adjuvant therapy in NFPA patients with residual tumours after surgery.
The present study was designed to evaluate the relationship between bone traits bone mineral density (BMD) and trabecular bone score (TBS) and the accumulation of fat in adipose tissues abdominal ...subcutaneous (SAT), visceral (VAT), marrow (MAT) and intrahepatic lipids (IHL), as well as insulin resistance, in subjects with Cushing's disease (CD). The study included control (C = 27), paired (P = 16) and Cushing's disease (CD = 10) groups, which underwent biochemical assessment, dual X-ray absorptiometry, TBS, and magnetic resonance imaging to determine fat deposits. The CD group showed higher serum levels of glucose and insulin, as well as HOMA-IR values, but lower circulatory levels of osteocalcin, in comparison to C and P. The CD group exhibited lower L1-L4 BMD than P (P = 1.059 ± 0.141 vs CD = 0.935 ± 0.093 g/cm2, p < 0.05) (Fig 1A). The lumbar spine BMD from the C group was similar to the other groups. TBS was lower in CD than in P and C (C = 1.512±0.077 vs P = 1.405±0.150 vs CD = 1.135±0.136; p<0.05); there was also significant difference between C and P (p<0.05). MAT, VAT, and IHL were higher in CD than in C and P (p<0.05). Considering all subjects, there was a positive association between TBS with both lumbar spine BMD (R2 = 0.45; p<0.0001) and osteocalcin (R2 = 0.44; p = 0.05). TBS was negatively associated with MAT (R2 = 0.49; p = 0.01), VAT (R2 = 0.55; p<0.05), and HOMA-IR (R2 = 0.44; p<0.01). MAT was positively related with VAT (R2 = 0.44; p<0.01) and IHL (R2 = 0.41; p<0.05). In CD, insulin resistance and adipose tissue dysfunction, including high MAT, are active players in bone deterioration, as confirmed by lower lumbar spine BMD and lower TBS. Thus, our findings point to an additional component of the already well-known complex mechanisms of osteoporosis associated with hypercortisolism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context
Metabolic syndrome (MetS) shares several similarities with hypercortisolism.
Objectives
To evaluate hypothalamic‐pituitary‐adrenal (HPA) axis sensitivity to dexamethasone (DEX), NR3C1 single ...nucleotide polymorphisms (SNPs), and expression of glucocorticoid receptor (GR) isoforms and cytokines in peripheral immune cells of MetS patients and controls.
Design
Prospective study with 40 MetS patients and 40 controls was conducted at the Ribeirão Preto Medical School University Hospital.
Methods
Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5, and 1 mg of DEX given at 2300 h. In addition, p.N363S (rs6195), p.ER22/23EK (rs6189‐6190), and BclI (rs41423247) SNPs were evaluated by quantitative polymerase chain reaction allelic discrimination. Exons 3 to 9 and exon/intron boundaries of NR3C1 were sequenced. GR isoforms and cytokines (IL1B, IL2, IL4, IL6, IL8, IL10, IFNγ, TNFα) expression were assessed by quantitative polymerase chain reaction.
Results
Plasma and salivary cortisol (nmol/L) after 1‐mg DEX were higher in MetS patients compared with controls (PF: 70.2 ± 17.3 vs 37.9 ± 2.6, P = .02, and SF: 4.9 ± 1.7 vs 2.2 ± 0.3, P < .0001). After all DEX doses, a lower number of MetS patients suppressed plasma and salivary cortisol compared with controls. The BclI genotypic frequencies (%) differed between patients (CC:56/CG:44) and controls (CC:50/CG:32.5/GG:17.5) (P = .03). The GRβ was overexpressed (fold = 100.0; P = .002) and IL4 (fold = −265.0; P < .0001) was underexpressed in MetS.
Conclusion
MetS patients exhibited decreased HPA sensitivity to glucocorticoid feedback. Moreover, the BclI polymorphism lower frequency, GRβ overexpression, and IL4 underexpression might underlie the molecular mechanism of glucocorticoid resistance in MetS. Thus, HPA axis dysregulation might contribute to MetS pathogenesis.
Purposes
Increasing evidence suggests that the FGF-Klotho endocrine system and the somatotropic system (pituitary and extra-pituitary GH) may have important metabolic and immune relationships, thus ...contributing to the pathophysiology of aging-related disorders, including diabetes, atherosclerosis, and cancer. The status of these interactions in isolated GH deficiency (IGHD) is unknown. The objective of this study was to assess the response of both FGF21 and β-Klotho levels to a standard meal in a homogeneous group of adults with congenital untreated IGHD due to a homozygous mutation in the GHRH receptor gene.
Methods
In a cross-sectional study, we measured the levels of FGF21 and β-Klotho, before and 30, 60, 120, and 180 min after a standardized test meal in 20 (11 males) IGHD and 20 (11 males) age-matched controls. Areas under the curves (AUC) of FGF21 and β-Klotho were calculated.
Results
Baseline levels of FGF21 were similar, but baseline levels of β-Klotho were lower in IGHD subjects. The IGHD individuals exhibited lower AUC for FGF21 and β-Klotho levels than control subjects. There was a positive correlation between IGF1 and β-Klotho levels in the pooled groups. No correlation was found between IGF1 and FGF21 levels.
Conclusions
Subjects with lifetime, untreated IGHD exhibit reduced FGF21 and β-Klotho levels response to a mixed meal. This difference may have consequences on metabolism and aging.
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