Remote electrical tilt (RET) optimization involves maximizing the coverage and minimizing interference for antennas in a cellular network. A RET optimization problem typically has many of antennas, each of which has little data. Reinforcement learning (RL) agents have recently been deployed to solve RET optimization problems [1, 2]. These algorithms generally require large amounts of data, and therefore they are not applied for individual antennas but rather for groups of antennas. We show that this leads to degraded performance than agents personalized for individual antennas with extensive data. Furthermore, we design a reward shaping (RS) agent, which augments the reward signal to learn quicker than agents trained only on individual antennas while still retaining their performance. / Remote electrical tilt (RET) optimering innebär att försöka maximera täckningen och minimera störningar för antenner i ett mobilnät. Ett RET-optimeringsproblem har vanligtvis ett stort antal antenner, som var och en har lite data. Reinforcement learning (RL)-agenter har nyligen använts för att lösa RET-optimeringsproblem [1, 2]. Dessa algoritmer kräver i allmänhet stora mängder data och därför används de inte för enskilda antenner utan snarare för grupper av antenner. Vi visar att detta leder till försämrad prestanda jämfört med agenter anpassade för individuella antenner med stora datamängder. Dessutom designar vi en Reward shaping (RS)-agent, som förstärker belöningssignalen för att lära sig snabbare än agenter som bara tränas på individuella antenner samtidigt som deras behåller sin prestanda.

Le cancer papillaire de la thyroïde (PTC) est celui le plus fréquent de la thyroïde. Il est caractérisé par des réarrangements chromosomique affectant le gène RET, dont les plus fréquemment observés sont RET/PTC1 et RET/PTC3. Les oncogène de jonction sont spécifiques à la tumeur et représentent une cible privilégiée pour une thérapie ciblée par des petits ARN interférents (siRNA). Notre but est d’introduire une nouvelle approche pharmacologique par siRNA pour les PTC. Pour réaliser nos expériences, la lignée cellulaire humaine PTC, BHP10-3 SCmice exprimant l’oncogène RET/PTC1 a été utilisé. En absence de lignée RET/PTC3 commercialisée nous avons établi la lignée cellulaire RP3 (stablement transfecté la lignée NIH/3T3 issue de fibroblastes de souris par un vecteur d’expression RET/PTC3) qui s’est avérée tumorigène chez la souris. Ensuite, des siRNAs dirigés contre la jonction ont été dessinés. Les siRNAs ont été trouvés efficaces et spécifiques contre leurs propres oncogènes de jonction et ne sont pas capables d'inhiber l'expression de séquences alternées. Les siRNAs ont été vectorisés sous forme de nanoparticules (NPs) de squalène (SQ). In vitro, les NPs siRNA RET/PTC1-SQ et NPs siRNA RET/PTC3-SQ sont incapables d’inhiber l’expression de l’oncogène et l’oncoprotéine sauf transfectés par lipofectamine. Pour cela, un peptide, le GALA-Chol a été combiné aux NPs siRNA RET/PTC1-SQ ce qui les a rendu efficace in vitro dans l’inhibition de l’oncogène et de l’oncoprotéine mais inefficace sur la croissance tumorale in vivo probablement par agrégation des NPs siRNA RET/PTC1-SQ GALA-Chol dans la circulation sanguine. En revanche les NPs siRNA RET/PTC1-SQ (0.5mg/kg/souris) et NPs siRNA RET/PTC3-SQ (2.5mg/kg/souris) sont efficaces in vivo, ils inhibent considérablement la croissance tumorale, réduisent l’expression des oncogènes et des oncoprotéines RET/PTCs, induisent la mort cellulaire par clivage de la caspase-3 et de PARP-1 et restaurent partiellement la différenciation (diminution de marqueur Ki67). Ces résultats suggèrent l'utilisation des NPs siRNAs-SQ en tant que traitement pour les patients atteints de PTC exprimant les oncogènes de jonctions RET/PTCs. / Papillary thyroid carcinoma (PTC) is the most common of thyroid cancers. PTC is characterized by chromosomal rearrangements affecting chromosome 10 and leading to RET/PTC junction oncogenes. The most frequent ones are RET/PTC1 and RET/PTC3. Because the junction oncogenes are present only in the tumour cells, they represent a good target for a specific therapy such as small interfering RNA (siRNA). Our aim is to introduce a new pharmacological approach by siRNA for PTC. To perform the experiments, human BHP10-3 SCmice cell line expressing RET/PTC1 was used. Due to absence of commercially available RET/PTC3 cell line, we established a new RP3 cell line (from NIH/3T3 mouse fibroblasts, transfected stably with the RET/PTC3 expression vector) which was found to become tumorigenic in nude mice. siRNAs were designed within the junction sequences of both RET/PTC1 and RET/PTC3. Both siRNAs were found efficient and specific against their own junction oncogenes and were not able to inhibit the expression of alternate sequences. Then, siRNAs were vectorized in the form of nanoparticles (NPs) of squalene (SQ). In vitro, both siRNA RET/PTC1-SQ NPs and siRNA RET/PTC3-SQ NPs were found to be inefficient in gene and protein inhibitions except once transfected with lipofectamine. Therefore, a peptide GALA-Chol was added in siRNA RET/PTC1-SQ NPs which rendered them efficient in vitro in gene and protein inhibitions but found to be inefficient in vivo. The nanoparticles of siRNA RET/PTC1-SQ NPs (0.5 mg/kg/mouse) and siRNA RET/PTC3-SQ NPs (2.5 mg/kg/mouse) were found to drastically reduce the tumor growth and RET/PTCs oncogene and oncoprotein expressions. Moreover, they induced cell death by cleavage of both caspase-3 and PARP-1 and partially restored differentiation (decrease of Ki67 marker). Our findings highly support the use of siRNAs-SQ NPs as a treatment for patients affected by PTC expressing RET/PTCs.

Le cancer papillaire de la thyroïde (PTC) représente 70-80% des cas de cancers de la thyroïde. Il est principalement caractérisé par des réarrangements chromosomiques affectant le gène RET. Le réarrangement RET/PTC1, dans lequel RET est réarrangé avec un gène proapoptotique H4, représente 30% des cas sporadiques et jusqu’à 60% des cas survenus après irradiation. Afin d’inhiber l’oncogène de fusion RET/PTC1, nous avons utilisé un siRNA ciblant la zone de jonction RET/PTC1 (siRNA RET/PTC1) au niveau de l’ARN messager des cellules tumorales et montré sa spécificité et son efficacité. Néanmoins, le développement des siRNAs comme molécule d’intérêt thérapeutique se heurte in vivo à des difficultés liées à leur administration. Sous forme libre, ces molécules sont, en effet, très vite dégradées par les nucléases extracellulaires et leur pénétration intracellulaire est limitée. C’est la raison pour laquelle il est nécessaire de les vectoriser. Nous avons choisi de le faire par la méthode de « squalénisation » et avons couplé d’une manière covalente le squalène, un lipide naturel précurseur de la biosynthèse du cholestérol, au siRNA RET/PTC1. Le bioconjugué formé s’autoassemble spontanément en milieu aqueux sous forme de nanoparticules stables de 170 nm de diamètre. L’efficacité et la toxicité des nanoparticules siRNA RET/PTC1-squalène ont été étudiées in vitro dans deux lignées de PTC exprimant RET/PTC1 (BHP10-3 et TPC-1) et l’activité antitumorale a été évaluée in vivo sur des souris athymiques xénogreffées par BHP10-3 puis traitées en i.v. par ces nanoparticules. Les nanoparticules siRNA RET/PTC1-squalène ont montré une bonne efficacité antitumorale. En revanche, aucune activité inhibitrice n’a été retrouvée in vitro. En conclusion, nous avons réussi à vectoriser le siRNA RET/PTC1 par la méthode de squalénisation. Cette étude ouvre des perspectives thérapeutiques pour certains patients atteints de PTC et réfractaires au traitement conventionnel. / The papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy. This tumour is associated with somatic mutations of the RET proto-oncogene, due to gene rearrangements of the proto-RET. RET/PTC1 rearrangement is the most common genetic alteration identified to date, it is formed by an intra chromosomic rearrangement which leads to the juxtaposition of the RET Tyrosine Kinase domain of the proto-RET with the gene H4. The fusion RET/PTC1 oncogene represents an interesting target for small interfering RNA (siRNA) strategies since it is present only in the tumour cells and not in the surrounding normal cells. However, the biological efficacy of the siRNAs is hampered by their short plasma half-life due to poor stability in biological fluids and low intracellular penetration. In order to protect siRNA from degradation, and to improve their intracellular capture, we applied the concept of “squalenoylation”, ie. The bioconjugation of a drug substance to squalene, for the delivery of siRNA targeted toward the RET/PTC1 fusion oncogene. The acyclic isoprenoid chain of squalene was covalently coupled with RET/PTC1 siRNA at the 3’-terminus of the sense strand via a stable thioether linkage. The linkage of RET/PTC1 siRNA to squalene leads to an amphiphilic molecule that self-organise in water as RET/PTC1 siRNA-SQ nanoassemblies of 170 nm and Zeta potential of -26.4 mV. These RET/PTC1 siRNA-SQ NPs did not showed any cytotoxicity in vitro. Interestingly, in vivo, in a mouse xenografted RET/PTC1 experimental model, RET/PTC1 siRNA-SQ nanoparticles inhibited tumour growth, RET/PTC1 oncogene and oncoprotein expression, after intravenous injections of 2.5 mg/kg cumulative dose. In the last of this work, GALA-cholesterol combination with siRNA-SQ NPs further enhanced nucleic acid internalization, promoted their escape into the cytosol and consequently their gene silencing efficiency in vitro. In conclusion, these results showed that the “squalenoylation” offers a new non cationic plate-form for the siRNA delivery.

No câncer, alterações em microRNAs (miRNAs), pequenos RNAs que regulam a tradução protéica, exerce efeito oncogênico (oncomiR). Os oncomiRs regulam genes chave para a proliferação celular e apoptose, sendo importantes para a biologia do câncer. O carcinoma papilífero de tiróide apresenta alterações genéticas alinhadas na via MAPK (RET>RAS>BRAF>ERK). Observamos que a indução do oncogene RET/PTC diminui a expressão de let-7 em células foliculares tiroidianas. Na linhagem TPC-1 (com RET/PTC-1), a introdução de let-7 diminui a proliferação celular e a fosforilaçãode ERK, indicando papel de gene supressor tumoral. No carcinoma anaplásico, avaliamos o papel da introdução do cluster miR-17-92 na linhagem ARO. Observamos que in vitro miR-17-92 atua de forma oncogênica aumentando proliferação e viabilidade celular de ARO. No entanto, estas células apresentam diminuição no crescimento em soft-agar. No xenotransplante, os tumores de ARO-miR-17-92 apresentam menor volume e expressam MMP-9 de forma reduzida, indicando também um papel de gene supressor tumoral para o cluster. / In cancer, alteration in microRNA, small RNAs (~22nt) that regulate post-transcriptionally protein levels, exerts oncogenic role (oncomiR). OncomiRs control genes involved in cell proliferation and apoptosis, influencing cancer biology. Papillary thyroid cancer displays activating genetic alterations in MAPK signaling pathway (RET>RAS>BRAF>ERK). Using conditional induction of oncogenes in thyroid cells, we observed that RET/PTC decreases let-7 miRNA expression. In papillary thyroid cancer cell TPC-1 (with RET/PTC-1) we observed that let-7 introduction inhibits cell proliferation and ERK phosphorylation, indicating tumor suppressor role for let-7. In anaplastic thyroid cancer, we evaluate the role of introduction of miR-17-92 cluster in ARO cell line. We observed in vitro that miR-17-92 increases ARO cell proliferation and viability, acting as oncogene. However, these cells show impaired soft agar growth. In xenotransplant, ARO-miR-17-92 tumors are smaller in volume and express reduced levels of MMP-9, indicating a tumor suppressor role for the cluster.

Le système immunitaire joue un rôle complexe, tantôt protecteur, tantôt facilitateur dans la relation hôte-tumeur. La souris transgénique pour le proto-oncogène humain RET développe un mélanome spontané et métastatique et constitue un remarquable modèle pour étudier les facteurs immunitaires et génétiques de la réponse de l’hôte. Ce modèle a été essentiellement examiné sur le fond C57BL/6. La tumeur primaire se situe au niveau de l’œil et se propage ensuite à la face et au dos ainsi qu’aux viscères. La pathogenèse du mélanome est cependant multifactorielle et le contexte génétique peut donc moduler de façon déterminante l’expression du transgène, la surveillance immunitaire et l’évolutivité des tumeurs. Par croisements en retour, nous avons transféré le transgène RET du fond génétique B6 sur le fond NOD (Non-Obese Diabetic), connu par sa propension à l’auto-immunité. Une accélération du développement tumoral a été observée chez les souris NOD.RET+, au site primitif et surtout à distance, par comparaison aux souris B6.RET+. L’objectif de ce travail était ensuite de caractériser les modifications immunitaires en relation avec le fond pro-inflammatoire de la souris NOD et l’accélération du développement tumoral. Nous avons observé une augmentation des cellules T régulatrices, CD4+Foxp3+ dans les tumeurs des souris NOD.RET+ comparées aux souris B6.RET+. Cette augmentation était corrélée avec celle des cellules CD8 exprimant l’interféron-gamma (IFNγ). Surtout, le phénotype agressif chez les souris NOD.RET+ était associé à une perte de l’expression de la Dectin-1 sur les cellules myéloïdes. La Dectin-1 est un récepteur de type C-lectine, connu pour son rôle essentiel dans la réponse anti-infectieuse. De ce fait, le traitement des souris avec le curdlan, un ligand de la Dectin-1, prévenait le développement des métastases. Par ailleurs, l’inactivation du gène Nos2, codant la synthase du monoxyde d’azote de type 2, protégeait également les souris vis-à-vis des métastases. De façon remarquable, l’expression de la Dectin-1 était restaurée chez les souris Nos2-KO, suggérant pour la première fois un lien entre ce récepteur et la voie Nos2. Parallèlement, une étude de la valeur pronostique de l’expression quantitative du gène NOS2 a été entreprise par qPCR sur des biopsies de tumeurs humaines obtenues chez 108 patients tunisiens (sein, n=27 ; côlon/Rectum, 24 ; cavum, 28 ; mélanome, 29). D’une façon générale, l’expression de NOS2 était plus élevée dans les tumeurs du sein comparées à celle du côlon et du cavum, et surtout aux mélanomes où NOS2 était faiblement exprimé. De plus, l’expression de NOS2 était plutôt de mauvais pronostic. En effet, elle était corrélée avec l’indice de Breslow, le niveau de Clark et le sous-type histologique dans les mélanomes. Dans le cancer du cavum, elle était corrélée avec l’âge, le stade TNM, la présence de métastases, la réponse au traitement et l’expression de COX-2. Dans les cancers coliques, elle était corrélée avec le stade TNM, la taille et la localisation des tumeurs et leur type histologique. Dans le cancer du sein, elle était associée avec la taille des tumeurs, le stade tumoral, le grade SBR et les cas triples négatifs. Notre étude a ainsi permis d’établir un nouveau modèle murin de mélanome spontané et agressif, la souris NOD.RET+, qui devrait permettre de mieux comprendre les facteurs de l’hôte qui influencent le pronostic des mélanomes murins et donc peut-être humains et plus généralement la relation hôte-tumeur. Par ailleurs, le rôle de NOS2 a été souligné et surtout relié à l’expression de la Dectin-1. Ces deux protéines pourraient constituer des cibles thérapeutiques intéressantes, d’autant plus que nous avons confirmé la valeur de mauvais pronostic de l’expression de NOS2 dans quatre cancers humains d’origine épithéliale. / Mice transgenic for the RET oncogene provide a remarkable model for investigating the mechanisms underlying the promotion and the development of melanoma. This model was established on the C57BL/6 genetic background. In the present study, we investigated an effect of the strongly proinflammatory and autoimmune genetic makeup of the non-obese diabetic (NOD) strain. We bred (NODxB6)F1 mice and backcrossed them with NOD mice. F1 mice and mice at subsequent generations of backcrossing showed marked acceleration of tumor development, in particular with a more frequent and earlier extension of the primary uveal melanoma. In close relation with this severe evolution, we observed a profound drop in Dectin-1 expression on CD11b+Ly6G+ granulocytic myeloid cells correlating with an expansion of CD4+Foxp3+ T regulatory cell and of interferon (IFN)-γ producing CD8+ T cell subsets in tumors. IFNγ is a major inducer of the type 2 nitric-oxide synthase (Nos2) gene whose products are known to be tumorigenic. Germline inactivation of the Nos2 gene was associated with a dramatically improved tumor prognosis and a restoration of Dectin-1 expression on myeloid cells. Moreover, in vivo treatment of (NODxB6)F1.RET+ mice with curdlan, a glucose polymer that binds Dectin-1, prevented tumor extension and was associated with marked reduction of the CD4+Foxp3+ T cell subset. In parallel, we study the prognostic value of iNOS expression in four types of human tumors of 108 Tunisian patients: (breast n=27, colorectal=24, nasopharyngeal=28, and melanoma=29). The level of iNOS was measured by RT-QPCR in tumor specimens. We showed that the expression of iNOS was higher in breast compared to colorectal and nasopharyngeal tumors whereas in melanoma, the level of iNOS expression was low. Furthermore, iNOS expression correlated with the Breslow thickness, Clark level and histological subtype in melanoma while in nasopharyngeal carcinoma, significant association was seen with age at diagnosis, TNM, metastasis, response to treatment and expression of COX-2. Furthermore, the expression of iNOS correlated with tumor size, TNM, tumor location, and histological type in colorectal cancer, and with tumor size, tumor stage, SBR grade and triple negative cases in breast cancer. These observations highlight the (NODxB6)F1.RET+ mice as a new model to investigate the role of the immune system in the host-tumor relationship. Furthermore, the role of NOS2 was emphasized and mainly related to the expression of the Dectin-1. These two proteins could constitute a potentially promising therapeutic target, especially as we confirmed the poor prognostic value of the expression of NOS2 in four epithelial human cancers.

As Neoplasias endócrinas múltiplas (NEMs) são síndromes herdadas de modo dominante e causadas por mutações germinativas em genes específicos. Caracterizam-se pela presença de tumores em um conjunto de glândulas endócrinas, conjunto este típico de cada tipo-específico de NEM. Dentre os diferentes tipos de NEMs, há a neoplasia endócrina múltipla tipo 2 (NEM2) que envolve os fenótipos, carcinoma medular de tireóide (CMT), hiperparatiroidismo primário (HPT), feocromocitoma (FEO) e megacólon congênito (doença de Hirschsprung, HSCR). Apesar da prevalência da NEM2 na população em geral ser baixa (~ 1:30.000), o número de casos afetados por família pode ser expressivo, uma vez que sua penetrância é praticamente completa (~100%). A doença de HSCR ou aganglionose intestinal congênita quando ocorre está geralmente associada à mutações RET nos códons 609, 618 e 620; apresenta ampla variação fenotípica, padrão de herança complexa e baixa penetrancia. Poucos casos de HSCR podem apresentar mutações em outros genes. Mutações no gene RET são responsáveis por aproximadamente metade (~50%) dos casos familiares de HSCR e alguns casos esporádicos (~10-20%), sugerindo fortemente que a HSCR seja doença poligenica. Tem-se também sugerido que polimorfismos genéticos no RET podem influenciar o fenotipo da NEM2/HSCR. No presente estudo, analisamos o gene RET no sentido de investigar se o desenvolvimento de megacólon em pacientes com a mutação germinativa RET p.C620R estaria associado à presença de ou a) a uma segunda mutação germinativa ou b) a um SNP, ou c) a um haplótipo informativo, que possivelmente poderia estar potencialmente interagindo genicamente com a mutação RET principal e eventualmente modulando o fenótipo HSCR / The multiple endocrine neoplasias (MENs) are inherited multi-tumoral conditions caused by germline mutations in specific genes. Specifically, the multiple endocrine neoplasia type 2 (NEM2) is a hereditary endocrine disorder transmitted dominantly and involving three main tumors, medullary thyroid carcinoma (CMT), primary hyperparathyroidism (HPT) and pheochromocytoma (PHEO). Despite the low prevalence of MEN2 in general population, the number of affected individuals per family can be significant as the penetrance of MEN2 is almost complete (~100%). In addition to CMT, PHEO and HPT, other conditions as congenital megacólon (Hirschsprung disease, HSCR or congenital intestinal aganglionosis) may occur in MEN2 (HSCR/MEN2). HSCR/MEN2 usually is due to RET mutations in codons 609, 618 and 620. HSCR has a wide phenotypic variation; is a complex multigenic disease; and has a low penetrance. Mutations in the RET gene are responsible for approximately 50% of the familial HSCR cases and ~10% of the sporadic HSCR cases, supporting that HSCR is a polygenic disease and this is confirmed by a few HSCR cases associated with mutations in the EDNRB and EDN3 genes. In the present study, we focused in the analysis of the RET gene in order to investigate whether the development of congenital megacólon in patients with RET mutation p.C620R is associated with the presence of, a) a second RET germline mutation, b) a SNP, or with a haplotype that co-segregate with the disease

No câncer, alterações em microRNAs (miRNAs), pequenos RNAs que regulam a tradução protéica, exerce efeito oncogênico (oncomiR). Os oncomiRs regulam genes chave para a proliferação celular e apoptose, sendo importantes para a biologia do câncer. O carcinoma papilífero de tiróide apresenta alterações genéticas alinhadas na via MAPK (RET>RAS>BRAF>ERK). Observamos que a indução do oncogene RET/PTC diminui a expressão de let-7 em células foliculares tiroidianas. Na linhagem TPC-1 (com RET/PTC-1), a introdução de let-7 diminui a proliferação celular e a fosforilaçãode ERK, indicando papel de gene supressor tumoral. No carcinoma anaplásico, avaliamos o papel da introdução do cluster miR-17-92 na linhagem ARO. Observamos que in vitro miR-17-92 atua de forma oncogênica aumentando proliferação e viabilidade celular de ARO. No entanto, estas células apresentam diminuição no crescimento em soft-agar. No xenotransplante, os tumores de ARO-miR-17-92 apresentam menor volume e expressam MMP-9 de forma reduzida, indicando também um papel de gene supressor tumoral para o cluster. / In cancer, alteration in microRNA, small RNAs (~22nt) that regulate post-transcriptionally protein levels, exerts oncogenic role (oncomiR). OncomiRs control genes involved in cell proliferation and apoptosis, influencing cancer biology. Papillary thyroid cancer displays activating genetic alterations in MAPK signaling pathway (RET>RAS>BRAF>ERK). Using conditional induction of oncogenes in thyroid cells, we observed that RET/PTC decreases let-7 miRNA expression. In papillary thyroid cancer cell TPC-1 (with RET/PTC-1) we observed that let-7 introduction inhibits cell proliferation and ERK phosphorylation, indicating tumor suppressor role for let-7. In anaplastic thyroid cancer, we evaluate the role of introduction of miR-17-92 cluster in ARO cell line. We observed in vitro that miR-17-92 increases ARO cell proliferation and viability, acting as oncogene. However, these cells show impaired soft agar growth. In xenotransplant, ARO-miR-17-92 tumors are smaller in volume and express reduced levels of MMP-9, indicating a tumor suppressor role for the cluster.

No description available.

As Neoplasias endócrinas múltiplas (NEMs) são síndromes herdadas de modo dominante e causadas por mutações germinativas em genes específicos. Caracterizam-se pela presença de tumores em um conjunto de glândulas endócrinas, conjunto este típico de cada tipo-específico de NEM. Dentre os diferentes tipos de NEMs, há a neoplasia endócrina múltipla tipo 2 (NEM2) que envolve os fenótipos, carcinoma medular de tireóide (CMT), hiperparatiroidismo primário (HPT), feocromocitoma (FEO) e megacólon congênito (doença de Hirschsprung, HSCR). Apesar da prevalência da NEM2 na população em geral ser baixa (~ 1:30.000), o número de casos afetados por família pode ser expressivo, uma vez que sua penetrância é praticamente completa (~100%). A doença de HSCR ou aganglionose intestinal congênita quando ocorre está geralmente associada à mutações RET nos códons 609, 618 e 620; apresenta ampla variação fenotípica, padrão de herança complexa e baixa penetrancia. Poucos casos de HSCR podem apresentar mutações em outros genes. Mutações no gene RET são responsáveis por aproximadamente metade (~50%) dos casos familiares de HSCR e alguns casos esporádicos (~10-20%), sugerindo fortemente que a HSCR seja doença poligenica. Tem-se também sugerido que polimorfismos genéticos no RET podem influenciar o fenotipo da NEM2/HSCR. No presente estudo, analisamos o gene RET no sentido de investigar se o desenvolvimento de megacólon em pacientes com a mutação germinativa RET p.C620R estaria associado à presença de ou a) a uma segunda mutação germinativa ou b) a um SNP, ou c) a um haplótipo informativo, que possivelmente poderia estar potencialmente interagindo genicamente com a mutação RET principal e eventualmente modulando o fenótipo HSCR / The multiple endocrine neoplasias (MENs) are inherited multi-tumoral conditions caused by germline mutations in specific genes. Specifically, the multiple endocrine neoplasia type 2 (NEM2) is a hereditary endocrine disorder transmitted dominantly and involving three main tumors, medullary thyroid carcinoma (CMT), primary hyperparathyroidism (HPT) and pheochromocytoma (PHEO). Despite the low prevalence of MEN2 in general population, the number of affected individuals per family can be significant as the penetrance of MEN2 is almost complete (~100%). In addition to CMT, PHEO and HPT, other conditions as congenital megacólon (Hirschsprung disease, HSCR or congenital intestinal aganglionosis) may occur in MEN2 (HSCR/MEN2). HSCR/MEN2 usually is due to RET mutations in codons 609, 618 and 620. HSCR has a wide phenotypic variation; is a complex multigenic disease; and has a low penetrance. Mutations in the RET gene are responsible for approximately 50% of the familial HSCR cases and ~10% of the sporadic HSCR cases, supporting that HSCR is a polygenic disease and this is confirmed by a few HSCR cases associated with mutations in the EDNRB and EDN3 genes. In the present study, we focused in the analysis of the RET gene in order to investigate whether the development of congenital megacólon in patients with RET mutation p.C620R is associated with the presence of, a) a second RET germline mutation, b) a SNP, or with a haplotype that co-segregate with the disease

Made available in DSpace on 2015-04-14T14:40:53Z (GMT). No. of bitstreams: 1 409728.pdf: 3056812 bytes, checksum: c24e4ab1ee070477fc3b05c65038c2b1 (MD5) Previous issue date: 2009-03-04 / O presente trabalho prop?e-se a fazer um estudo das titula??es polemistas nos blogs dos tr?s jornalistas pol?ticos mais lidos do Brasil. Al?m disso, a proposta ? a da verifica??o da ret?rica da intransig?ncia desta mesma amostra. O m?todo utilizado foi o estudo de caso, atrav?s o ranking do Technorati. Entende-se que, em fun??o de ser uma m?dia nova, ainda inexplorada, esta ? uma forma peculiar de se fazer jornalismo, at? mesmo em fun??o da fisiologia da internet, pois necessita do insight/despertar do leitor em um texto menor do que o texto impresso. Assim, as defini??es cl?ssicas de jornalismo tornaram-se superadas, pois a neutralidade, idealizada em outros s?culos, d? lugar ? editorializa??o da not?cia