No description available.

No description available.

Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), clinical outcome has remained disappointing, with 5-year overall survival rates hovering around 40-50%, underscoring an urgent need to better understand the biological bases of this disease. We chose to address this challenge by studying the role of micro-RNAs (miRNAs), and iron in HNSCC. We performed global profiling on 51 primary HNSCC compared to 4 normal laryngeal epithelial tissues, and identified 38 differentially expressed miRNAs between cancer vs. normal patient tissues. Functional validation confirmed a tumour promoting phenotype for miR-106b and miR-375. Integrating these findings with global miR profiling of HNSCC revealed two significantly over expressed miRNAs in HNSCC cell lines and patient samples: miR-193b and miR-205. Knockdown of miR-205 and miR-193b in HNSCC cell lines significantly decreased cell proliferation and colony formation. Moreover, NF1 was identified as a target of miR-193b. Downstream targets of NF1 including active-RAS and p-ERK were also suppressed after miR-193b knockdown. Finally, HNSCC patients with high levels of miR-193b experienced a lower disease-free survival than patients with low miR-193b expression. The second approach we took to better understand the biology of HNSCC was to examine the involvement of iron in the disease. In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. Knockdown of HFE in HNSCC cell lines significantly decreased intracellular iron levels, resulting in a significant decrease in HNSCC cell proliferation, DNA synthesis, and Wnt signalling. When iron was re-introduced back into the cell after HFE knockdown, these cellular changes were reversed, indicating that iron was mediating this phenotype. Concordantly, HNSCC cells treated with an iron chelator ciclopirox olamine (CPX) significantly reduced proliferation and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression, corroborating the oncogenic role of HFE in HNSCC. In summary, using two independent methods, we have identified two potential prognostic biomarkers for HNSCC, namely miR-193b and HFE. Characterization of these two molecules, exposed critically dysregulated pathways driving disease progression. Specifically, the miR-193b~NF1 axis uncovered a novel mechanism of RAS and p-ERK activation in HNSCC; similarly, HFE exposed a novel tumour promotion role of iron in this disease.

Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), clinical outcome has remained disappointing, with 5-year overall survival rates hovering around 40-50%, underscoring an urgent need to better understand the biological bases of this disease. We chose to address this challenge by studying the role of micro-RNAs (miRNAs), and iron in HNSCC. We performed global profiling on 51 primary HNSCC compared to 4 normal laryngeal epithelial tissues, and identified 38 differentially expressed miRNAs between cancer vs. normal patient tissues. Functional validation confirmed a tumour promoting phenotype for miR-106b and miR-375. Integrating these findings with global miR profiling of HNSCC revealed two significantly over expressed miRNAs in HNSCC cell lines and patient samples: miR-193b and miR-205. Knockdown of miR-205 and miR-193b in HNSCC cell lines significantly decreased cell proliferation and colony formation. Moreover, NF1 was identified as a target of miR-193b. Downstream targets of NF1 including active-RAS and p-ERK were also suppressed after miR-193b knockdown. Finally, HNSCC patients with high levels of miR-193b experienced a lower disease-free survival than patients with low miR-193b expression. The second approach we took to better understand the biology of HNSCC was to examine the involvement of iron in the disease. In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. Knockdown of HFE in HNSCC cell lines significantly decreased intracellular iron levels, resulting in a significant decrease in HNSCC cell proliferation, DNA synthesis, and Wnt signalling. When iron was re-introduced back into the cell after HFE knockdown, these cellular changes were reversed, indicating that iron was mediating this phenotype. Concordantly, HNSCC cells treated with an iron chelator ciclopirox olamine (CPX) significantly reduced proliferation and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression, corroborating the oncogenic role of HFE in HNSCC. In summary, using two independent methods, we have identified two potential prognostic biomarkers for HNSCC, namely miR-193b and HFE. Characterization of these two molecules, exposed critically dysregulated pathways driving disease progression. Specifically, the miR-193b~NF1 axis uncovered a novel mechanism of RAS and p-ERK activation in HNSCC; similarly, HFE exposed a novel tumour promotion role of iron in this disease.

Abstract Neurofibromatosis type 1 syndrome (NF1) is caused by mutations of the NF1 gene. The NF1 protein (neurofibromin) contains a domain which is related to the GTPase-activating protein (GAP) and accelerates the switch of active Ras-GTP to inactive Ras-GDP. The NF1 protein has been referred to as a tumor suppressor, since the cells of malignant schwannomas of NF1 patients may display a loss of heterozygosity of the NF1 gene. Psoriasis is characterized by hyperproliferation of the epidermis and by down-regulated levels of NF1 mRNA and protein. Ca2+ is an universal signal transduction element modulating cell growth and differentiation. Many cell types coordinate their activities by transmitting waves of elevated intracellular calcium levels from cell to cell. The propagation of calcium waves had not been studied previously in human keratinocytes. Thus, the aim of the present study was to find out which pathways may play a role in Ca2+ signaling at different extracellular calcium concentrations in NF1 and and psoriatic keratinocytes versus normal control keratinocytes. The results demonstrated that NF1 and psoriatic keratinocytes have a tendency to form cultures characterized by altered Ca2+-mediated cell signaling compared to normal keratinocytes. Specifically, the main route of calcium-mediated signaling was gap-junctional in normal keratinocytes. In contrast, ATP-mediated calcium signaling predominated and capacitative calcium influx was defective in NF1 and psoriatic keratinocytes. The results of the present study suggest that mutations of the NF1 tumor suppressor gene or lowered levels of NF1 protein/mRNA may eventually lead to altered intercellular communication.

No description available.

No description available.

No description available.

Os gliomas de vias ópticas (GVO) representam 5% dos tumores cerebrais pediátricos e geralmente aparecem histologicamente como astrocitomas de baixo grau. Por causa do curso imprevisto dos GVO, as opções de tratamento ainda são controversas, envolvendo vigilância, cirurgia, quimioterapia e radioterapia. Neste estudo, realizamos a análise volumétricas de gliomas de vias ópticas envolvendo as regiões óptico-quiasmáticas e hipotalâmica (GOQH) para comparar a evolução as neoplasias tratadas com e sem quimioterapia, comparando o volume e componentes das lesões. Foram analisados retrospectivamente 14 pacientes com (GOQH) que foram submetidos a Ressonância Magnética em nosso departamento de janeiro de 2000 a outubro de 2015. Um total de 45 RM de encéfalo foram incluídas, com uma média de 3,2 estudos/paciente. A avaliação das lesões foi realizada manualmente por um Neurorradiologista, usando o Software DISPLAY. Quatro destes pacientes eram portadores de NF-1. Oito foram tratados com quimioterapia, sendo carboplatina e vincristina (Carbo/VCR) os agentes de primeira linha. As medidas volumétricas foram realizadas com separação entre os componentes sólidos e císticos das neoplasia, usando as sequências FLAIR e T1 pós contraste, com o apoio de imagens ponderadas em T1 e T2. Um aumento de aproximadamente 30% do volume para as lesões sólidas e uma redução de 19,4% no volume das lesões sólido-císticas foram observados no período global após o tratamento com quimioterapia, porém ambos sem significância estatística. Entre os pacientes não tratados, observou-se uma redução de 16,6 % do volume global das lesões durante o período de acompanhamento. A avaliação da eficácia do tratamento para pacientes com GOQH é difícil, dada a raridade de casos e heterogeneidade radiológica. Os dados de algumas publicações argumentam que o valor da quimioterapia é controverso e não se correlaciona com a resposta radiológica. Em nosso estudo observamos uma pequena redução do volume de neoplasias entre os pacientes tratados e não tratados com quimioterapia, porém sem significância estatística. Ensaios clínicos prospectivos são necessários para melhor avaliar o efeito da quimioterapia sobre OPG. / Optic pathway gliomas (OPG) represent 5% of pediatric brain tumors and generally appear histologically as low-grade astrocytomas. Because of the unpredictable course of OPG, adequate treatment method has been controversial, involving surveillance, surgery, chemotherapy and radiotherapy. In this study, we use volumetric imaging to compare evolution between OPG treated with and without chemotherapy, analyzing the volume and components of the lesions. We retrospectively analyzed 14 patients with OPG who underwent MRI in our department from January 2000 to October 2015. A total of 45 brain MRI were included, with an average of 3,2 studies/patient. The assessment of lesions was manually performed by a neuroradiologist, using software DISPLAY. Four of these patients had NF-1. Eight were treated with chemotherapy, using carboplatin and vincristine (Carbo/VCR) as first-line agents. Volumetric measurements of tumors were segmented into solid and cystic components using FLAIR and T1 weighted images after Gadolinium sequences, with support of T1 and T2 weighted images. An increase of approximately 30% of volume for solid lesions and a decrease of 19,4% for solid-cystic lesions were noted following chemotherapy in overall period, both with no statistical significance. Among patients not treated with chemotherapy, we observed a reduction of 16% in overall volume of the lesions Evaluation of treatment efficacy for OPG patients is difficult, given the rarity of cases and radiological heterogeneity. Data from some publications argued that the value of chemotherapy is controversial and does not correlate with radiological response. From our study we observed a small volume reduction of neoplasms among patients treated and not treated with chemotherapy. Larger prospective clinical trials are needed to better evaluate the effect of chemotherapy on OPG.

Os gliomas de vias ópticas (GVO) representam 5% dos tumores cerebrais pediátricos e geralmente aparecem histologicamente como astrocitomas de baixo grau. Por causa do curso imprevisto dos GVO, as opções de tratamento ainda são controversas, envolvendo vigilância, cirurgia, quimioterapia e radioterapia. Neste estudo, realizamos a análise volumétricas de gliomas de vias ópticas envolvendo as regiões óptico-quiasmáticas e hipotalâmica (GOQH) para comparar a evolução as neoplasias tratadas com e sem quimioterapia, comparando o volume e componentes das lesões. Foram analisados retrospectivamente 14 pacientes com (GOQH) que foram submetidos a Ressonância Magnética em nosso departamento de janeiro de 2000 a outubro de 2015. Um total de 45 RM de encéfalo foram incluídas, com uma média de 3,2 estudos/paciente. A avaliação das lesões foi realizada manualmente por um Neurorradiologista, usando o Software DISPLAY. Quatro destes pacientes eram portadores de NF-1. Oito foram tratados com quimioterapia, sendo carboplatina e vincristina (Carbo/VCR) os agentes de primeira linha. As medidas volumétricas foram realizadas com separação entre os componentes sólidos e císticos das neoplasia, usando as sequências FLAIR e T1 pós contraste, com o apoio de imagens ponderadas em T1 e T2. Um aumento de aproximadamente 30% do volume para as lesões sólidas e uma redução de 19,4% no volume das lesões sólido-císticas foram observados no período global após o tratamento com quimioterapia, porém ambos sem significância estatística. Entre os pacientes não tratados, observou-se uma redução de 16,6 % do volume global das lesões durante o período de acompanhamento. A avaliação da eficácia do tratamento para pacientes com GOQH é difícil, dada a raridade de casos e heterogeneidade radiológica. Os dados de algumas publicações argumentam que o valor da quimioterapia é controverso e não se correlaciona com a resposta radiológica. Em nosso estudo observamos uma pequena redução do volume de neoplasias entre os pacientes tratados e não tratados com quimioterapia, porém sem significância estatística. Ensaios clínicos prospectivos são necessários para melhor avaliar o efeito da quimioterapia sobre OPG. / Optic pathway gliomas (OPG) represent 5% of pediatric brain tumors and generally appear histologically as low-grade astrocytomas. Because of the unpredictable course of OPG, adequate treatment method has been controversial, involving surveillance, surgery, chemotherapy and radiotherapy. In this study, we use volumetric imaging to compare evolution between OPG treated with and without chemotherapy, analyzing the volume and components of the lesions. We retrospectively analyzed 14 patients with OPG who underwent MRI in our department from January 2000 to October 2015. A total of 45 brain MRI were included, with an average of 3,2 studies/patient. The assessment of lesions was manually performed by a neuroradiologist, using software DISPLAY. Four of these patients had NF-1. Eight were treated with chemotherapy, using carboplatin and vincristine (Carbo/VCR) as first-line agents. Volumetric measurements of tumors were segmented into solid and cystic components using FLAIR and T1 weighted images after Gadolinium sequences, with support of T1 and T2 weighted images. An increase of approximately 30% of volume for solid lesions and a decrease of 19,4% for solid-cystic lesions were noted following chemotherapy in overall period, both with no statistical significance. Among patients not treated with chemotherapy, we observed a reduction of 16% in overall volume of the lesions Evaluation of treatment efficacy for OPG patients is difficult, given the rarity of cases and radiological heterogeneity. Data from some publications argued that the value of chemotherapy is controversial and does not correlate with radiological response. From our study we observed a small volume reduction of neoplasms among patients treated and not treated with chemotherapy. Larger prospective clinical trials are needed to better evaluate the effect of chemotherapy on OPG.