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1.
Nature ; 529(7586): 351-7, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26760213

RESUMO

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.


Assuntos
Neoplasias Cerebelares/terapia , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Meduloblastoma/terapia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Seleção Genética/efeitos dos fármacos , Animais , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/radioterapia , Neoplasias Cerebelares/cirurgia , Células Clonais/patologia , Radiação Cranioespinal , Análise Mutacional de DNA , Modelos Animais de Doenças , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Feminino , Genoma Humano/genética , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/patologia , Meduloblastoma/radioterapia , Meduloblastoma/cirurgia , Camundongos , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia/terapia , Radioterapia Guiada por Imagem , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Genet ; 49(5): 780-788, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28394352

RESUMO

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.


Assuntos
Neoplasias Cerebelares/genética , Regulação Neoplásica da Expressão Gênica , Meduloblastoma/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Análise por Conglomerados , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Estudo de Associação Genômica Ampla , Humanos , Mutação INDEL , Masculino , Meduloblastoma/patologia , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
IET Syst Biol ; 9(3): 88-94, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26021329

RESUMO

The usefulness of a genetic clock lies in its role to stimulate a sequence of logic reactions for sequential biological circuits. A clock signal is a periodic square wave, its amplitude alternates at a steady frequency between fixed minimal and maximal levels. Transition between the minimum and the maximum is instantaneous for an ideal square wave; however, the function is unrealisable in physical bio-systems. This research develops a new genetic clock generator based on a genetic oscillator, in which, a sine wave generator is adopted as a signal oscillator. It is shown that combination of a genetic oscillator with a toggle switch is able to generate clock signals forming an efficient way to generate a near square wave. In silico study confirms the proposed idea.


Assuntos
Relógios Biológicos/genética , Regulação da Expressão Gênica/genética , Genes de Troca/genética , Modelos Genéticos , Ativação Transcricional/genética , Animais , Simulação por Computador , Humanos
4.
Clin. transl. oncol. (Print) ; 24(12): 2295-2304, dec. 2022.
Artigo em Inglês | IBECS (Espanha) | ID: ibc-216077

RESUMO

Colorectal cancer (CRC) is a malignant tumor initiating from the mucosa of the colorectum. According to the 2020 statistics from the World Health Organization, there are 10.0% CRC cases among all 19.3 million new cancers, followed by lung and breast cancer, and 9.4% CRC cases among all 9.9 million cancer deaths, ranking second. The population of CRC patients in China is large, and its incidence and mortality continue to increase each year. Despite the continuous development of surgical methods, chemotherapy, radiotherapy, targeted therapy and immunotherapy, the overall survival of CRC patients remains low. Past research has suggested that c-myc plays a pivotal role in the development of CRC. A higher expression level of c-Myc is a negative prognostic marker in CRC. However, there are few drugs targeting c-myc directly. Therefore, we focused on discovering the mechanism of c-myc in CRC to provide a reference for a better therapy choice for patients (AU)


Assuntos
Humanos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , China
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