Unusual Cause of Hematochezia Horvat, Natally; Monti, Serena; Mannelli, Lorenzo
Gastroenterology (New York, N.Y. 1943),
07/2017, Letnik:
153, Številka:
1
Journal Article
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•The global fractional anisotropy (gFA) is a marker of white matter integrity.•gFA is negatively correlated with age.•gFA influences neural activity and connectivity at various ...levels.
The global fractional anisotropy (gFA) is a structural marker of white matter myelination and integrity. Previous studies already evidenced that aging-related reduced integrity of specific white matter tracts is associated with decreased functional connectivity in several hubs. However, the correlations between gFA and functional brain connectivity remain unknown. In this cross-sectional study, we analyzed structural and functional MR datasets of 79 healthy participants from the Leipzig Study for Mind–Body–Emotion Interactions. DTI model-based method was used to quantify gFA values. We tested associations between gFA, age, and gender. The fractional amplitude of low-frequency fluctuations (fALFF) and ROI-to-ROI connectivity were analyzed in a regression model for evaluating the effects of gFA on brain activity and networking, respectively. A negative correlation was found between gFA and age (ρ = −0.343; p = 0.002). No statistically significant correlation as found between gFA and gender (p = 0.229). Higher values of gFA were associated with increased brain regional activity, including areas of the default mode network. There was a higher degree of correlation between some regions, particularly those that conform to the limbic system. Our study demonstrates that gFA influences regional neural activity and brain networking on resting, particularly the limbic system.
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the ...cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.
Context:
Somatic mutations in PRKACA gene, encoding the catalytic subunit of protein kinase A (PKA), have been recently found in a high proportion of sporadic adenomas associated with Cushing's ...syndrome. The aim was to analyze the PRKACA mutation in a large cohort of patients with adrenocortical masses.
Methods:
Samples from nine European centers were included (Germany, n = 4; Italy, n = 4; France, n = 1). Samples were drawn from 149 patients with nonsecreting adenomas (n = 32 + 2 peritumoral), subclinical hypercortisolism (n = 36), Cushing's syndrome (n = 64 + 2 peritumoral), androgen-producing tumors (n = 4), adrenocortical carcinomas (n = 5 + 2 peritumoral), and primary bilateral macronodular adrenal hyperplasias (n = 8). Blood samples were available from patients with nonsecreting adenomas (n = 15), subclinical hypercortisolism (n = 10), and Cushing's syndrome (n = 35). Clinical and hormonal data were collected. DNA amplification by PCR of exons 6 and 7 of the PRKACA gene and direct sequencing were performed.
Results:
PRKACA heterozygous mutations were found in 22/64 samples of Cushing's syndrome patients (34%). No mutations were found in peritumoral tissue and blood samples or in other tumors examined. The c.617A>C (p.Leu206Arg) occurred in 18/22 patients. Furthermore, two novel mutations were identified: c.600_601insGTG/p.Cys200_Gly201insVal in three patients and c.639C>G+c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg) in one. All the mutations involved a region implicated in interaction between PKA regulatory and catalytic subunits. Patients with somatic PRKACA mutations showed higher levels of cortisol after dexamethasone test and a smaller adenoma size, compared with nonmutated subjects.
Conclusions:
These data confirm and extend previous observations that somatic PRKACA mutations are specific for adrenocortical adenomas causing Cushing's syndrome.
Purpose
Adrenocortical carcinoma (ACC), a rare malignancy of the adrenocortex, is characterized by a crosstalk between the adipose microenvironment and tumor. Here, we assessed the involvement of ...carbonic anhydrase (CA) enzymes III and IX (CAIII and CAIX), in the metabolic alterations of the adipose tissue characterizing obesity and in the local crosstalk between the tumor adipose microenvironment and ACC.
Results/methods
CAIII and CAIX expression is altered in visceral adipose tissue (VAT) in obesity and in ACC. A significant CAIX upregulation was present in ACC at advanced stages (
n
= 14) (fold increase FI = 7.4 ± 0.1,
P
< 0.05) associated with lower CAIII levels (FI = 0.25 ± 0.06,
P
< 0.001), compared with lower stages (
n
= 9). In vitro coculture between visceral adipose stem cells (ASCs) and ACC cell lines, H295R and MUC-1, mimicking the interaction occurring between VAT and advanced ACC, showed a significant CAIX upregulation in H295R but not in MUC-1 cells, and a decreased expression of CAIII. The effect on adipose cells was different when cocultured with H295R or MUC-1 cells. Coculture did not modulate CAIII expression in ASCs, which, however, was significantly downregulated with H295R (FI = 0.34 ± 0.11,
P
< 0.05) and upregulated by MUC-1 when cocultured ASCs were induced to differentiate toward adipocytes, with an expression profile similar to what found in VAT of obese subjects. CAIX expression was markedly increased in ASCs cocultured with H295R and to a less extent following adipogenesis induction (FI = 150.9 ± 46.5 and FI = 4.6 ± 1.1,
P
< 0.01, respectively).
Conclusion
Our findings highlight a modulation of CAIII and CAIX in the metabolic crosstalk between ACC and its local adipose microenvironment, suggesting that CAs might represent a potential target for novel anticancer therapies.
Cadmium (Cd) is a well-known occupational and environmental pollutant worldwide, and its toxicity is widely recognised. Cd is reported to increase the permeability of the blood-brain barrier (BBB) ...and to penetrate and accumulate in the brain. Although many lines of evidence show that Cd toxicity is induced by different mechanisms, one of the best known is the Cd-dependent production of reactive oxygen species (ROS). Zinc is a trace element known as coenzyme and cofactor for many antioxidant proteins, such as metallothioneins and superoxide dismutase enzymes. To date, very little is known about the role of Zn in preventing Cd-induced blood-brain barrier (BBB) alterations. The goal of this study was to test the Zn antioxidant capacity against Cd-dependent alterations in a rat brain endothelial cell line (RBE4), as an in vitro model for BBB. In order to mimic acute Cd poisoning, RBE4 cells were treated with CdCl
30 µM for 24 h. The protective role of ZnCl
(50 µM) was revealed by evaluating the cell viability, reactive oxygen species (ROS) quantification, cytochrome C distribution, and the superoxide dismutase (SOD) protein activity. Additionally, the effectiveness of Zn in counteracting the Cd-induced damage was investigated by evaluating the expression levels of proteins already known to be involved in the Cd signalling pathway, such as GRP78 (an endoplasmic reticulum (ER) stress protein), caspase3 pro- and cleaved forms, and BAX. Finally, we evaluated if Zn was able to attenuate the alterations of zonula occludens-1 (ZO-1), one of the tight-junction (TJ) proteins involved in the formation of the BBB. Our data clearly demonstrate that Zn, by protecting from the SOD activity impairment induced by Cd, is able to prevent the triggering of the Cd-dependent signalling pathway that leads to ZO-1 dislocation and downregulation, and BBB damage.
Differential diagnosis of adrenocortical adenoma (ACA) and carcinoma is of pivotal clinical relevance, as the prognosis and clinical management of benign and malignant adrenocortical tumors (ACTs) is ...entirely different. Circulating microRNAs (miRNAs) are promising biomarker candidates of malignancy in several tumors; however, there are still numerous technical problems associated with their analysis. The objective of our study was to investigate circulating miRNAs in ACTs and to evaluate their potential applicability as biomarkers of malignancy. We have also addressed technical questions including the choice of profiling and reference gene used. A total of 25 preoperative plasma samples obtained from patients with ACAs and carcinomas were studied by microarray and quantitative real-time PCR. None of the three miRNAs (hsa-miR-192, hsa-mir-197 and hsa-miR-1281) found as differentially expressed in plasma samples in our microarray screening could be validated by quantitative real-time PCR. In contrast, of the selected eight miRNAs reported in the literature as differentially expressed in ACT tissues, five (hsa-miR-100, hsa-miR-181b, hsa-miR-184, hsa-miR-210 and hsa-miR-483-5p) showed a statistically significant overexpression in adrenocortical cancer vs adenoma when normalized on hsa-miR-16 as a reference gene. Receiver operator characteristic analysis of data revealed that the combination of dCThsa-miR-210 - dCThsa-miR-181b and dCThsa-miR-100/dCThsa-miR-181b showed the highest diagnostic accuracy (area under curve 0.87 and 0.85, respectively). In conclusion, we have found significant differences in expression of circulating miRNAs between ACAs and carcinomas, but their diagnostic accuracy is not yet high enough for clinical application. Further studies on larger cohorts of patients are needed to assess the diagnostic and prognostic potential application of circulating miRNA markers.
Intensive poultry rearing needs preventive strategies against diseases, several of which are little or not containable by vaccinations. Short- and medium-chain fatty acids (SMCFAs) and chestnut ...tannin (CHT), both by-products of two different industrial production chains, are very effective antimicrobials. The inclusion level of these additives in the diet is fundamental because a detrimental effect on the gut microbiome can occur if the dose is too high, compromising the animal welfare and performance. Hence, the aim of this trial was to test the effect of a blend (BL; 1:1, w/w) of SMCFAs (fatty acids from C4:0 to C9:0) and CHT extract (CTE) as feed additive in broiler feeding. One hundred one-day-old Ross 308 male chicks were randomly assigned to 5 dietary treatments (4 replicates; 20 pens; 5 animals per pen): control diet (CON), FAS diet (with 1.5 g/100g on dry matter (DM) of SMCFAs), CTE diet (with 1.5 g/100g on DM of CHT extract), BL1 diet (with 1.5 g/100g on DM of BL), and BL2 diet (with 3.0 g/100g on DM of BL). Among the parameters evaluated (weight gain; feed intake; feed efficiency; dressing out), the only differences were observed for the feed intake. In particular, the feed intake of CON (2.876 kg), FAS (2.773 kg), CTE (2.882 kg), and BL1 (2.858 kg) were comparable while the feed intake of BL2 (2.717 kg) was lower than the other diets except for FAS which was similar (p = 0.0010). The microbial community in the caecum was described by high-throughput sequencing of 16S rRNA gene amplicons and was similar between the treatments both in terms of alpha-diversity and beta-diversity. The results of this trial evidenced that no detrimental effect on growth performances or on gut microbiome occurred when birds were fed the blend of SMCFAs and CHT extracts at the inclusion levels tested in this study.HIGHLIGHTS Short- and medium-chain fatty acids and chestnut tannins are alternatives to conventional antimicrobials Natural antimicrobials improve the sustainability of poultry production Short- and medium-chain fatty acids and chestnut tannins did not alter the gut microbiota of broiler
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