1,721,004 research outputs found
Evaluation of the role of AIP, CDKN1B, miR-107 and AHRR in the pathogenesis of sporadic and familial pituitary adenomas
Full text linkPituitary adenomas are common benign intracranial neoplasms, with the vast majority of such tumours being sporadic. The pathogenesis of sporadic pituitary adenomas remains unclear; however, abnormal microRNAs (miRNAs) expression profiles have been recently associated with these adenomas, suggesting that miRNAs can contribute to tumour formation. In about 5% of cases, pituitary adenomas occur in a familial setting, often as part of multiple endocrine tumours syndromes, such as multiple endocrine neoplasia type 1 (MEN1) or Carney complex (CNC). Recently, germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) and in the CDKN1B (encoding the p27Kip1 protein) genes have been identified as causing pituitary adenoma predisposition (PAP) or associated to the development of multiple endocrine tumours, respectively. Several studies revealed AIP mutations in about 15% of kindreds with familial isolated pituitary adenomas (FIPA), a clinical entity in which pituitary tumours are the sole phenotypic manifestation among family members, while sporadic cases are only rarely mutated. Regarding CDKN1B, so far point mutations have been reported only in few subjects with clinical features of MEN1, including pituitary adenomas, but without MEN1 mutations, suggesting that they rarely cause a MEN-like phenotype in both sporadic and familial MEN1 patients.
The aim of the present investigation was to study some of the tumorigenic mechanisms involved in pituitary adenoma formation both in sporadic and familial settings.
Genomic DNA of a homogeneous cohort of Italian patients with either sporadic acromegaly or FIPA was analysed for point mutations and gross rearrangements in the AIP and CDKN1B genes. I detected three novel, presumably pathogenic, AIP variants in four apparently sporadic cases, and one known mutation (p.R304X) in a FIPA family. Interestingly, I found that another Italian FIPA family shares the same mutation and haplotype associated with the mutated gene, strongly supporting the presence of a founder effect. No known mutations were found in the CDKN1B gene.
The analysis of miR-107, a miRNA involved in the pathogenesis of different types of tumours and predicted to downregulate AIP expression, revealed that it is overexpressed in pituitary adenomas and may act as a tumour suppressor gene. I also provided experimental evidences that AIP-3’UTR is a functional and direct target of miR-107.
The study of aryl hydrocarbon receptor repressor (AHRR), a molecule which participates in one of the AIP-related pathways potentially involved in pituitary tumorigenesis, demonstrated an increased expression in GH-secreting adenomas compared to normal pituitaries.
In conclusion, the main contribution of this PhD thesis was to provide new knowledge about the pathogenesis of pituitary adenomas. In particular, I found that:
- mutations in the AIP and CDKN1B genes seem relatively uncommon in the Italian sporadic acromegalic patients, confirming what already reported in the literature for other populations;
- a founder effect for the AIP p.R304X mutation exists in a region of central Italy;
- the miRNA miR-107 interacts with AIP and may play roles in pituitary adenoma pathogenesis;
- AHRR is overexpressed in somatotropinomas.Gli adenomi ipofisari rappresentano delle comuni neoplasie intracraniche benigne, che nella maggior parte dei casi insorgono in maniera sporadica. La patogenesi degli adenomi ipofisari sporadici rimane tuttora poco chiara; recentemente, tuttavia, degli anormali livelli di espressione dei microRNA (miRNA) sono stati associati con questi adenomi, suggerendo che i miRNA possano contribuire al loro sviluppo. In circa il 5% dei casi, gli adenomi ipofisari insorgono invece in forma familiare, spesso come componenti di neoplasie endocrine multiple, quali la neoplasia endocrina multipla di tipo 1 (MEN1) o il complesso di Carney (CNC). Recentemente, mutazioni germinali nei geni aryl hydrocarbon receptor-interacting protein (AIP) e CDKN1B (codificante la proteina p27Kip1) sono state identificate, rispettivamente, come predisponenti l’insorgenza di adenomi ipofisari o associate allo sviluppo di tumori endocrini multipli. Diversi studi hanno dimostrato come mutazioni in AIP siano presenti in circa il 15% delle famiglie con adenoma ipofisario isolato (FIPA), un’entità clinica nella quale i tumori ipofisari sono l’unica manifestazione fenotipica tra i soggetti affetti, mentre siano solo raramente ritrovate nei casi sporadici. Relativamente a CDKN1B, ad oggi mutazioni puntiformi sono state descritte solo in alcuni pazienti con caratteristiche cliniche associabili al fenotipo MEN1, tra cui la presenza di adenomi ipofisari, ma privi di mutazioni nel gene MEN1. Ciò fa quindi ritenere che tali mutazioni causino solo raramente un fenotipo associabile a MEN sia nei casi sporadici che familiari.
Lo scopo di questo lavoro è stato quello di studiare alcuni dei meccanismi tumorigenici coinvolti nello sviluppo degli adenomi ipofisari, sia nelle loro forme sporadiche che in quelle familiari.
Il DNA genomico di una coorte omogenea di pazienti acromegalici Italiani sia sporadici che familiari è stato analizzato per ricercare la presenza di mutazioni puntiformi e grossi riarrangiamenti nei geni AIP e CDKN1B. Ho individuato tre nuove varianti, presumibilmente patogeniche, nel gene AIP in quattro pazienti apparentemente sporadici, e una mutazione nota (p.R304X) sempre in AIP in una famiglia FIPA. E’ interessante notare come un’altra famiglia FIPA Italiana condivida la stessa mutazione e lo stesso aplotipo associato con il gene mutato, dimostrando quindi la presenza di un effetto fondatore. Nessuna mutazione nota nel gene CDKN1B è stata invece riscontrata nella coorte analizzata.
L’analisi di miR-107, un miRNA coinvolto nella patogenesi di diversi tipi di tumore e predetto regolare negativamente l’espressione di AIP, ha rivelato come tale miRNA sia sovraespresso negli adenomi ipofisari e svolga verosimilmente un ruolo da gene oncosopressore. Ho inoltre dimostrato sperimentalemente che il 3’UTR di AIP è un reale e diretto bersaglio di miR-107.
Lo studio del repressore del recettore degli idrocarburi (AHRR), una molecola coinvolta in una delle vie correlate ad AIP e potenzialmemente coinvolta nella tumorigenesi ipofisaria, ha dimostrato una sua incrementata espressione nei tumori GH-secernenti rispetto alle ipofisi normali.
In conclusione, il contributo principale di questa tesi di dottorato è stato il fornire nuova conoscenza sui meccanismi patogenetici negli adenomi ipofisari. Più specificatamente, ho dimostrato che:
- mutazioni nei geni AIP e CDKN1B sono relativamente rare nei pazienti acromegalici sporadici Italiani, in accordo con quanto riportato in letteratura per altre popolazioni;
- esiste un effetto fondatore in una regione del centro Italia per la mutazione p.R304X del gene AIP;
- il miRNA miR-107 interagisce con AIP e potrebbe avere un ruolo nella patogenesi degli adenomi ipofisari;
- AHRR è sovraespresso nei somatotropinomi
Adrenal lesions in acromegaly: do metabolic aspects and aryl hydrocarbon receptor interacting protein gene have a role? Evaluation at baseline and after long-term follow-up.
No full textBackground: Adrenal lesions are discovered in acromegaly more frequently than in general population, without relationship with primary disease. Some patients, carriers of aryl hydrocarbon receptor interacting protein (AIR) gene mutations, developed an adrenal neoplasm. Aim: To evaluate the role of metabolic and genetic aspects and the follow-up of adrenal nodules in acromegaly. Material and methods: We studied 69 acromegalic patients (30 male and 39 female, 56 +/- 15 yr) who had been referred to the Endocrinology Unit of Padua. In all patients we determined body mass index (BMI) and waist-to-hip ratio (WHR); we performed an oral glucose tolerance test (OGTT) whenever possible. If adrenal computed tomography revealed a lesion, the patient underwent an endocrine and genetic study. Results: Adrenal lesions were identified in 14 patients and were not related to gender, duration of disease, GH or IGF-I concentrations, basal and after-OGTT glucose and insulin levels, log(HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) values, whereas BMI and WHR were higher in patients with adrenal lesions. Baseline endocrine and radiological study revealed benign lesions; during mean 4-yr follow-up none of the patients showed hormone excess, even though some lesions increased in size. We did not find any mutation in AIP gene, except heterozygous silent alteration (T48T). Conclusions: The frequency of non-functioning adrenal lesions in acromegaly is not associated with the considered aspects, except BMI and WHR. The prolonged follow-up showed that these lesions have a tendency to increase in size independently of the control of acromegaly, so a morphological follow-up is recommended
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
- …
