Evidence for a Nonspecific Factor Interfering in the Radioimmunoassay of Somatoliberin-Like Immunoreactivity in Human Seminal Plasma

Peer Reviewe

Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas.

Background. Cushing\u2019s disease presents gender disparities in prevalence and clinical course. Little is known, however, about sexual dimorphism at the level of the corticotrope adenoma itself. The aim of the present study was to evaluate molecular features of ACTH-secreting pituitary adenomas collected from female and male patients with Cushing\u2019s disease. (2) Methods. We analyzed 153 ACTH-secreting adenomas collected from 31 men and 122 women. Adenomas were established in culture and ACTH synthesis and secretion assessed in basal conditions as well as during incubation with CRH or dexamethasone. Concurrently, microarray analysis was performed on formalin-fixed specimens and differences in the expression profiles between specimens from male and female patients identified. (3) Results. ACTH medium concentrations in adenomas obtained from male patients were significantly lower than those observed in adenomas from female patients. This could be observed for baseline as well as modulated secretion. Analysis of corticotrope transcriptomes revealed considerable similarities with few, selected differences in functional annotations. Differentially expressed genes comprised genes with known sexual dimorphism, genes involved in tumour development and genes relevant to pituitary pathophysiology. (4) Conclusions. Our study shows for the first time that human corticotrope adenomas present sexual dimorphism and underlines the need for a gender-dependent analysis of these tumours. Differentially expressed genes may represent the basis for gender-tailored target therapy

Derecho y control 1

Se reúnen en el presente libro diversos textos producto del trabajo en un grupo de investigación. El trabajo grupal giró en torno al análisis de las ideas de derecho y su relación con el control individual o social. Se abordaron lecturas con enfoques conceptuales, sociológicos y normativos

Specific Jak3 Downregulation in Lymphocytes Impairs γc Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo

Jak3, one of the four members comprising the Jak family of cytosolic tyrosine kinases, has emerged as a promising target for nontoxic immunotherapies. Although a number of Jak inhibitors has already demonstrated efficacy, they suffer from secondary effects apparently associated to their pan-Jak activity. However, whether selective Jak3 inhibition would afford therapeutic efficacy remains unclear. To address this question we have investigated the immunosuppressive potential of selective Jak3 intervention in lymphocytes using RNA interference (RNAi) technology in vitro and in vivo. Using synthetic small interference RNA (siRNA) sequences we achieved successful transfections into human and mouse primary T lymphocytes. We found that Jak3 knockdown was sufficient to impair not only interleukin-2 (IL-2) and T cell receptor (TCR)-mediated cell activation in vitro, but also antigen-triggereds welling, inflammatory cell infiltration, and proinflammatory cytokine raise in vivo. Furthermore, Jak1 (which mediates gamma c cytokine signaling in conjunction with Jak3) cosilencing did not provide higher potency to the aforementioned immunosuppressant effects. Our data provides direct evidences indicating that Jak3 protein plays an important role in gamma c cytokine and antigen-mediated T cell activation and modulates Th1-mediated inflammatory disorders, all in all highlighting its potential as a target in immunosuppressive therapies

Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more "typical" corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas

SEOM clinical guideline on unknown primary cancer (2017)

Cancer of unknown primary site is a histologically confirmed cancer that manifests in advanced stage, with no identifiable primary site following standard diagnostic procedures. Patients are initially categorized based on the findings of the initial biopsy: adenocarcinoma, squamous-cell carcinoma, neuroendocrine carcinoma, and poorly differentiated carcinoma. Appropriate patient management requires understanding several clinical and pathological features that aid in identifying several subsets of patients with more responsive tumors

The control on growth hormone release by free fatty acids is maintained in acromegaly

Free fatty acids (FFA) physiologically regulate GH release via a negative feedback. The aim of this study was to examine whether such feedback is preserved in acromegaly, a condition in which alterations in other regulatory mechanisms of GH release occur. Eight acromegalic patients (group 1: five women and three men, 43.0 +/- 4.2 yr old, mean +/- SE) received per os on two different days, at a 3 day-interval, in a random order, placebo or 250 mg of acipimox, an inhibitor of lipolysis analogous to nicotinic acid, at 0700 and 1100 h. In both tests GHRH (1-29 NH2), 50 microg, was administered i.v. at 1300 h. Blood samples for GH, FFA, immunoreactive insulin (IRI), and glucose were taken from 0900 to 1500 h, and the time period considered for statistical analysis was 1200-1500 h, representative of steady-state condition for FFA, IRI, and glucose. Mean plasma FFA levels (1200-1500 h) were significantly lower after acipimox than after placebo (0.05 +/- 0.01 vs. 0.17 +/- 0.01 g/L, P < 0.01). In contrast, both mean basal GH levels (1200-1300 h) and the mean GH response to GHRH (GH delta area, 1300-1500 h) were significantly higher after acipimox than after placebo (12.0 +/- 1.9 vs. 7.8 +/- 1.2 microg/L, P < 0.01; 2937 +/- 959 vs. 1154 +/- 432 microg/L x 120 min, P < 0.01). The increase in both basal GH levels and GH delta area occurred in all eight patients. Acipimox also reduced mean serum IRI (83 +/- 12 vs. 112 +/- 14 pmol/L) and blood glucose (5.1 +/- 0.1 vs. 5.7 +/- 0.1 mmol/L) levels, as compared with placebo (P < 0.03 or less). Eight acromegalic patients (group 2: six women and two men, 46.6 +/- 5.7 yr old) underwent a constant i.v. 10% lipid infusion (150 mL/h), started at 0900 h and continued until 1500 h. Mean plasma FFA levels (1200-1500 h) were significantly higher during lipid infusion than after placebo (0.27 +/- 0.01 vs. 0.16 +/- 0.01 g/L, P < 0.02); in contrast, mean basal GH levels (1200-1300 h) were reduced by lipid infusion, as compared with placebo (9.9 +/- 3.1 vs. 16.6 +/- 4.4 microg/L, P < 0.01), and the same occurred for the GH delta area after GHRH (2498 +/- 1643 vs. 4512 +/- 1988 microg/L x 120 min, P < 0.01). Serum IRI and blood glucose levels were similar after placebo and during lipid infusion. These data indicate that, in acromegaly, the acute reduction of circulating FFA levels results in increased GH release, whereas the increase in circulating FFA levels is accompanied by a reduced GH release. Taken together, these findings suggest that, in acromegaly, the control of FFA on GH release is preserved

The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells

Rapamycin and its analogues have significant antiproliferative action against a variety of tumors. However, sensitivity to rapamycin is reduced by Akt activation that results from the ablative effects of rapamycin on a p70 S6K-induced negative feedback loop that blunts phosphoinositide 3-kinase (PI3K)-mediated support for Akt activity. Thus, sensitivity to rapamycin might be increased by imposing an upstream blockade to the PI3K/Akt pathway. Here, we investigated this model using the somatostatin analogue octreotide as a tool to decrease levels of activated Ser(473)-phosphorylated Akt (pAkt-Ser(473)) in pituitary tumor cells that express somatostatin receptors. Octreotide increased levels of phosphorylated insulin receptor substrate-1 that were suppressed by rapamycin, subsequently decreasing levels of pAkt-Ser(473) through effects on phosphotyrosine phosphatase SHP-1. Octreotide potentiated the antiproliferative effects of rapamycin in immortalized pituitary tumor cells or human nonfunctioning pituitary adenoma cells in primary cell culture, sensitizing tumor cells even to low rapamycin concentrations. Combined treatment of octreotide and rapamycin triggered G(1) cell cycle arrest, decreasing E2F transcriptional activity and cyclin E levels by increasing levels of p27/Kip1. These findings show that adjuvant treatment with a somatostatin analogue can sensitize pituitary tumor cells to the antiproliferative effects of rapamycin

Assessment of Child, Mother, and Environmental Factors Associated with Undernutrition in Children Less than Five Years Old in a Maya Community in Yucatan, Mexico

The objective of this study was to examine child, mother, and environmental factors associated with undernutrition in children less than five years old in a Maya community in Yucatan, Mexico. This investigation was designed as a case-control study. All cases (n=42) of undernutrition were included, and a sample of 52 controls was randomly selected from the study population. The frequency of investigated exposure factors was compared between cases and controls by using logistic regression. Undernutrition was associated with child’s age (&gt; 36 months old; OR = 3.53; 95% CI = 1.04, 18.40) and mother’s marital status (married; OR = 0.29; 95% CI = 0.09, 0.90). The odds of undernutrition were 2.81 times higher in children infected with Giardia spp, but this association was not significant (P = 0.18) after controlling for child’s age and mother’s marital status. In conclusion, child’s age and mother’s marital status were associated with child undernutrition in study subjects. Futures studies on undernutrition in children should examine more carefully how mother’s marital status alone or in combination with other factors (e.g. socio-economic, psychological factors) can influence child nutrition