A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAF(V600E) may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice

Silent gonadotroph pituitary neuroendocrine tumor in a patient with tuberous sclerosis complex: evaluation of a possible molecular link

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem hereditary cutaneous condition, characterized by multiple hamartomas. In rare cases, pituitary neuroendocrine tumors (PitNETs) have been described in patients with TSC, but the causal relationship between these two diseases is still under debate. TSC is mostly caused by mutations of two tumor suppressor genes, encoding for hamartin (TSC1) and tuberin (TSC2), controlling cell growth and proliferation. Here, we present the case of a 62-year-old Caucasian woman with TSC and a silent gonadotroph PitNET with suprasellar extension, treated with transsphenoidal endoscopic neurosurgery with complete resection. Therapeutic approaches based on mTOR signaling (i.e. everolimus) have been successfully used in patients with TSC and tested in non-functioning PitNET cellular models with promising results. Here, we observed a reduction of cell viability after an in vitro treatment of PitNET's derived primary cells with everolimus. TSC analysis retrieved no disease-associated variants with the exception of the heterozygous intronic variant c.4006-71C>T found in TSC2: the computational tools predicted a gain of a new splice site with consequent intron retention, not confirmed by an in vitro analysis of patient's lymphocyte-derived RNA. Further analyses are therefore needed to provide insights on the possible mechanisms involving the hamartin-tuberin complex in the pathogenesis of pituitary adenomas. However, our data further support previous observations of an antiproliferative effect of everolimus on PitNET

The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp(-) somatotropinomas

Glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression has been recently described in a proportion of gsp(-) somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load

A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype

PubMed ID: 23555276This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Virtual reality telerehabilitation for postural instability in Parkinson's Disease: a multicenter, single-blind, randomized, controlled trial

Introduction: Telerehabilitation enables patients to access remote rehabilitation services for patient-physiotherapist videoconferencing in their own homes. Home-based virtual reality (VR) balance training has been shown to reduce postural instability in patients with Parkinson's disease (PD). The primary aim was to compare improvements in postural stability after remotely supervised in-home VR balance training and in-clinic sensory integration balance training (SIBT). Methods: In this multicenter study, 76 PD patients (modified Hoehn and Yahr stages 2.5-3) were randomly assigned to receive either in-home VR telerehabilitation (n = 38) or in-clinic SIBT (n = 38) in 21 sessions of 50 minutes each, 3 days/week for 7 consecutive weeks. VR telerehabilitation consisted of graded exergames using the Nintendo Wii Fit system; SIBT included exercises to improve postural stability. Patients were evaluated before treatment, after treatment, and at 1-month follow-up. Results: Analysis revealed significant between-group differences in improvement on the Berg Balance Scale for the VR telerehabilitation group (p = 0.04) and significant Time 7 Group interactions in the Dynamic Gait Index (p = 0.04) for the in-clinic group. Both groups showed differences in all outcome measures over time, except for fall frequency. Cost comparison yielded between-group differences in treatment and equipment costs. Conclusions: VR is a feasible alternative to in-clinic SIBT for reducing postural instability in PD patients having a caregiver

Bioactive peptides from milk proteins: focusing on peptides displaying immunomodulatory activity

Milk-derived peptides are milk components able to influence specific physiologicalfunctions, finally acting on body health condition. At present, the bioactivitiesdescribed for milk-derived peptides include opiate, antithrombotic, antihypertensive, immunomodulating, antioxidative, antimicrobial, anticancer, mineral-carrying andgrowth-promoting activities. In this thesis, special attention has been given to bioactive peptides with ACE-inhibitory and immunomodulatory activities. In the Experiment 1 Enterococcus faecalis TH563 (E. faecalis TH563) and Lactobacillus delbrueckii subsp. bulgaricus LA2 (L. delb. bulgaricus LA2), two bacterial strains isolated from traditional North Eastern Italy dairy products, have been evaluated for their ability to produce fermented milk rich in ACE-inhibitory and immunomodulatory activities. The preliminary results obtained from this experiment demonstrated that E. faecalis TH563 produced a fermented milk with high ACEinhibitory activity while L. delb. bulgaricus LA2 showed an immunomodulatory activity on bovine lymphocytes. To better understand the mechanisms underlying the immunomodulatory activity of fermented milks, in the Experiment 2 the immunomodulatory effects of the milkderived bioactive tri-peptide YGG have been examined. YGG could be generated during milk fermentation from a–lactalbumin hydrolysis operated by bacterial enzymes, so it could be present in milk fermented by L. delb. bulgaricus LA2. YGG has been administered to purified peripheral blood lymphocytes in different culture conditions (presence/absence of activators of lymphocyte proliferation, different concentration of newborn calf serum) and its effects on lymphocyte proliferation and cytokine RNA expression (IL2 and INFg) have been analyzed. YGG modulated lymphocytes proliferation, in a manner dependent from culture conditions but its effects did not seem mediated by the modulation of IL2 or INFg RNA expression. An important limiting factor of the large-scale diffusion of food carrying potential bioactivities is the bioavailability of the peptides responsible of such bioactivities. The main factors influencing the bioavailability of peptides are the resistance to digestion enzymes of and the absorption by the intestinal epithelium. In the Experiments 3 and 4 the sensitivity to gastrointestinal enzymes and the mechanisms of absorption of the peptide b-CN (193-209) have been evaluated. b-CN (193-209) is a long hydrophobic peptide derived from b-casein that has been already isolated and identified from fermented milks and yogurt and displayed immunomodulatory properties. The pattern of digestion and the mechanisms of absorption have been evaluated in well-known in vitro models for the intestinal epithelium, as the brush border membrane vesicles (BBMV) and the Caco-2 cell line. The results of these studies demonstrated that the b-CN (193-209) peptide is absorbed intact by the Caco-2 monolayer, probably via a vesicles-mediated mechanism. In conclusion, the main contribution of this PhD thesis was to provide new knowledge about milk-derived products with bioactivities. In particular, original contributions are in relation to the mechanisms by which milk-derived bioactive peptides are generated, express their bioactivities, and their fate in the gastrointestinal tract. As a result, new questions have arisen on this area that could constitute the objective of further research programs in the future.I peptidi bioattivi derivati dal latte costituiscono una parte importante del latte, in grado di influenzare lo stato di salute. Attualmente nel latte e nei suoi derivati sono stati identificati e caratterizzati peptidi ad azione oppioide, anti-trombotica, antiipertensiva, immunomodulatoria, antiossidante, antimicrobica, anticancro, stimolanti l’assorbimento di minerali e la crescita. In questa tesi particolare attenzione è stata rivolta ai peptidi bioattivi ad attività ACE-inibitoria e immunomodulatoria. Nell'Esperimento 1 Enterococcus faecalis TH563 (E. faecalis TH563) e Lactobacillus delbrueckii subsp. bulgaricus LA2 (L. delb. bulgaricus LA2), due ceppi batterici isolati da formaggi tradizionali del Nord Italia, sono stati caratterizzati per la loro capacità di produrre latti fermentati arricchiti in attività ACE-inibitoria e immunomodulatoria. I risultati preliminari hanno dimostrato che il ceppo E. faecalis TH563 è in grado di produrre un latte fermentato con elevata attività ACE-inibitoria mentre il ceppo L. delb. bulgaricus LA2 produce un latte fermentato con attività immunomodulatoria su linfociti bovini. Per meglio comprendere i meccanismi che regolano l’attività immunomodulatoria manifestata dal latte fermentato, nell’Esperimento 2 sono stati riportati i risultati di un esperimento atto a valutare gli effetti immunomodulatori del peptide bioattivo YGG. Tale tripeptide può essere generato durante il processo di fermentazione del latte dalla proteina alfa–lattoalbumina mediante l’azione proteolitica degli enzimi batterici, e quindi anche durante la fermentazione operata dai ceppi E. faecalis TH563 e L. delb. bulgaricus LA2. YGG è stato somministrato a linfociti isolati da sangue bovino e ne è stata studiata la capacità di modulare la proliferazione dei linfociti e l’espressione (RNA) di due citochine (IL2 e INFg) in diverse condizioni di coltura (presenza/assenza di attivatori della proliferazione, diverse concentrazioni di siero bovino). Lo studio ha dimostrato che il peptide YGG è in grado di modulare la proliferazione delle cellule e che tale modulazione è influenzata dalle condizioni di coltura ma non sembra essere mediata dalle citochine oggetto di studio. Un fattore importante che limita l’impiego su larga scala di alimenti con proprietà bioattive è la biodisponibilità dei peptidi portatori di tali bioattività. I fattori che maggiormente influenzano la biodisponibilità dei peptidi sono la resistenza alla digestione operata dagli enzimi gastrointestinali e la possibilità che tali peptidi possano essere assorbiti dall’epitelio intestinale. A questo scopo, negli Esperimenti 3 e 4 sono stati esaminati il profilo di digestione e i meccanismi di assorbimento del peptide b-CN (193-209). b-CN (193-209) è un peptide bioattivo lungo e idrofobico,derivato dalla b-caseina ed è già stato isolato e identificato in diversi prodotti derivati dal latte come yogurt e latte fermentati. Tale peptide possiede inoltre diverse attività immunomodulatorie. Il profilo di digestione di tale peptide e i meccanismi di assorbimento intestinale sono stati studiati in modelli in vitro adatti a rappresentare la mucosa intestinale, come le vescicole della membrana a orletto a spazzola (BBMV) e la linea cellulare Caco-2. Tali esperimenti hanno dimostrato che il peptide viene assorbito intatto dalle cellule Caco-2, probabilmente attraverso un trasporto mediato da vescicole. In conclusione, il contributo principale di questa tesi di dottorato è stato il fornire nuova conoscenza sui prodotti derivati dal latte ad azione bioattiva. Più specificatamente, questa tesi ha permesso di ottenere nuove informazioni sui meccanismi di produzione dei peptidi bioattivi derivati dal latte, sul loro meccanismo d’azione e sulla loro stabilità nel sistema gastrointestinale. Infine, i risultati ottenuti hanno contribuito a generare nuove idee che potranno costituire nuovi spunti per futuri progetti di ricerca

The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas

Adrenocorticotropic Hormone (ACTH)-secreting pituitary adenomas are rare tumors characterized by autonomous ACTH secretion with a consequent increase in circulating cortisol levels. The resulting clinical picture is called Cushing's disease (CD), a severe condition burdened with high morbidity and mortality. Apart from increased cortisol levels, CD patients exhibit a partial resistance to the negative glucocorticoid (GC) feedback, which is of paramount clinical utility, as the lack of suppression after dexamethasone administration is one of the mainstays for the differential diagnosis of CD. Since the glucocorticoid receptor (GR) is the main regulator of negative feedback of the hypothalamic-pituitary-adrenal axis in normal conditions, its implication in the pathophysiology of ACTH-secreting pituitary tumors is highly plausible. In this paper, we review GR function and structure and the mechanisms of GC resistance in ACTH-secreting pituitary tumors and assess the effects of the available medical therapies targeting GR on tumor growth