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1.
Genome Res ; 22(12): 2315-27, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23033341

RESUMO

Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole-genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and three lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators, including KDM6A, ASH1L, SMARCA4, and ATAD2, are frequently altered by mutations or copy number changes. A systematic survey of splice-site mutations identified 106 splice site mutations associated with cancer specific aberrant splicing, including mutations in several known cancer-related genes. RAC1b, an isoform of the RAC1 GTPase that includes one additional exon, was found to be preferentially up-regulated in lung cancer. We further show that its expression is significantly associated with sensitivity to a MAP2K (MEK) inhibitor PD-0325901. Taken together, these data present a comprehensive genomic landscape of a large number of lung cancer samples and further demonstrate that cancer-specific alternative splicing is a widespread phenomenon that has potential utility as therapeutic biomarkers. The detailed characterizations of the lung cancer cell lines also provide genomic context to the vast amount of experimental data gathered for these lines over the decades, and represent highly valuable resources for cancer biology.


Assuntos
Processamento Alternativo , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Neoplasias Pulmonares/genética , Mutação , Transcriptoma , ATPases Associadas a Diversas Atividades Celulares , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigenômica , Éxons , Marcadores Genéticos , Heterozigoto , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase , Humanos , Cariotipagem/métodos , Neoplasias Pulmonares/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
2.
Int J Exerc Sci ; 17(1): 480-490, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38665162

RESUMO

The 'loaded carry' is a popular resistance training activity that activates core musculature across multiple movement planes while the body is in locomotion. 'Hold' exercises are similar to carry exercises but lack the locomotive aspect. Both carry and hold exercises can be completed bilaterally (farmer's carry (FC) and hold (FH)) or unilaterally (suitcase carry (SC) and hold (SH)). A deeper understanding of muscle activation between the FC and SC and intensity-matched FH and SH might improve their application. Healthy, college-aged individuals were recruited and surface electromyography of the rectus abdominis (RA), external oblique (EO), longissimus (LT), and multifidus (MF) was measured bilaterally using standard procedures. Participants completed time- and intensity-matched randomized sets of the plank, FC, SC, FH, and SH separated by 5-minute rests. A one-way ANOVA was utilized to compare exercises. The FC/FH load averaged 50.7±1.9 kg, where it was used across equally weighted dumbbells. The FC elicited higher activation bilaterally in the LT, MF, RA, and EO, compared to the FH. The SC/SH single-dumbbell load averaged 25.3±0.95 kg. There was greater activation bilaterally in the LT and MF during the SC compared to the SH. However, on the ipsilateral side of the SC, the RA and EO displayed greater activation compared to the SH, but this was not different on the contralateral side. The FC and SC were characterized by increased core muscle activation bilaterally, with the SC exhibiting unique additions to ipsilateral muscle activation.

3.
N Engl J Med ; 361(12): 1173-8, 2009 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-19726761

RESUMO

Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms. Molecular analyses of tumor specimens obtained before treatment suggested that there was activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched homologue 1 (PTCH1), a key negative regulator of hedgehog signaling.


Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Proteínas Hedgehog/antagonistas & inibidores , Meduloblastoma/tratamento farmacológico , Adulto , Anilidas , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Expressão Gênica , Humanos , Masculino , Meduloblastoma/metabolismo , Meduloblastoma/secundário , Receptores Patched , Receptor Patched-1 , Reação em Cadeia da Polimerase , Piridinas , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína GLI1 em Dedos de Zinco
4.
Cancer Immunol Res ; 8(7): 844-850, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32321776

RESUMO

Prostate cancer is the second leading cause of cancer-related death in men. Despite having a relatively lower tumor mutational burden than most tumor types, multiple gene fusions such as TMPRSS2:ERG have been characterized and linked to more aggressive disease. Individual tumor samples have been found to contain multiple fusions, and it remains unknown whether these fusions increase tumor immunogenicity. Here, we investigated the role of fusion burden on the prevalence and expression of key molecular and immune effectors in prostate cancer tissue specimens that represented the different stages of disease progression and androgen sensitivity, including hormone-sensitive and castration-resistant prostate cancer. We found that tumor fusion burden was inversely correlated with tumor mutational burden and not associated with disease stage. High fusion burden correlated with high immune infiltration, PD-L1 expression on immune cells, and immune signatures, representing activation of T cells and M1 macrophages. High fusion burden inversely correlated with immune-suppressive signatures. Our findings suggest that high tumor fusion burden may be a more appropriate biomarker than tumor mutational burden in prostate cancer, as it more closely associates with immunogenicity, and suggests that tumors with high fusion burden could be potential candidates for immunotherapeutic agents.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Mutação , Fusão Oncogênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Macrófagos/imunologia , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias da Próstata/patologia , RNA-Seq/métodos
5.
Cancer Res ; 79(15): 3916-3927, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31182547

RESUMO

Regulatory T cells (Treg) are immunosuppressive and negatively impact response to cancer immunotherapies. CREB-binding protein (CBP) and p300 are closely related acetyltransferases and transcriptional coactivators. Here, we evaluate the mechanisms by which CBP/p300 regulate Treg differentiation and the consequences of CBP/p300 loss-of-function mutations in follicular lymphoma. Transcriptional and epigenetic profiling identified a cascade of transcription factors essential for Treg differentiation. Mass spectrometry analysis showed that CBP/p300 acetylates prostacyclin synthase, which regulates Treg differentiation by altering proinflammatory cytokine secretion by T and B cells. Reduced Treg presence in tissues harboring CBP/p300 loss-of-function mutations was observed in follicular lymphoma. Our findings provide novel insights into the regulation of Treg differentiation by CBP/p300, with potential clinical implications on alteration of the immune landscape. SIGNIFICANCE: This study provides insights into the dynamic role of CBP/p300 in the differentiation of Tregs, with potential clinical implications in the alteration of the immune landscape in follicular lymphoma.


Assuntos
Proteína de Ligação a CREB/imunologia , Proteína p300 Associada a E1A/imunologia , Linfoma Folicular/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Acetilação , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteína de Ligação a CREB/antagonistas & inibidores , Proteína de Ligação a CREB/genética , Diferenciação Celular/fisiologia , Regulação para Baixo , Proteína p300 Associada a E1A/antagonistas & inibidores , Proteína p300 Associada a E1A/genética , Histonas/metabolismo , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Mutação , Pirazóis/farmacologia , Piridinas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Transcrição Gênica , Transcriptoma
6.
Cancer Res ; 66(1): 283-9, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16397241

RESUMO

Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of somatic intronic mutations of Met kinase that lead to an alternatively spliced transcript in lung cancer, which encodes a deletion of the juxtamembrane domain resulting in the loss of Cbl E3-ligase binding. The mutant receptor exhibits decreased ubiquitination and delayed down-regulation correlating with elevated, distinct Met expression in primary tumors harboring the deleted receptor. As a consequence, phospho-Met and downstream mitogen-activated protein kinase activation is sustained on ligand stimulation. Cells expressing the Met deletion reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth. A hepatocyte growth factor competitive Met antagonist inhibits receptor activation and proliferation in tumor cells harboring the Met deletion, suggesting the important role played by ligand-dependent Met activation and the potential for anticancer therapy. These results support a critical role for Met in lung cancer and somatic mutation-driven splicing of an oncogene that leads to a different mechanism for tyrosine kinase activation through altered receptor down-regulation in human cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Deleção de Genes , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas/genética , Receptores de Fatores de Crescimento/genética , Processamento Alternativo , Animais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Regulação para Baixo , Ativação Enzimática , Éxons , Feminino , Humanos , Íntrons , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Fosforilação , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteínas Proto-Oncogênicas c-met , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/biossíntese , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais , Ubiquitina/metabolismo
7.
Cell Rep ; 16(10): 2605-2617, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27568559

RESUMO

The Nrf2 pathway is frequently activated in human cancers through mutations in Nrf2 or its negative regulator KEAP1. Using a cell-line-derived gene signature for Nrf2 pathway activation, we found that some tumors show high Nrf2 activity in the absence of known mutations in the pathway. An analysis of splice variants in oncogenes revealed that such tumors express abnormal transcript variants from the NFE2L2 gene (encoding Nrf2) that lack exon 2, or exons 2 and 3, and encode Nrf2 protein isoforms missing the KEAP1 interaction domain. The Nrf2 alterations result in the loss of interaction with KEAP1, Nrf2 stabilization, induction of a Nrf2 transcriptional response, and Nrf2 pathway dependence. In all analyzed cases, transcript variants were the result of heterozygous genomic microdeletions. Thus, we identify an alternative mechanism for Nrf2 pathway activation in human tumors and elucidate its functional consequences.


Assuntos
Éxons/genética , Mutação/genética , Fator 2 Relacionado a NF-E2/genética , Neoplasias/genética , Transdução de Sinais , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Deleção de Sequência/genética
8.
Epigenomics ; 6(1): 59-72, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24579947

RESUMO

Lung cancer remains the primary cause of cancer-related deaths worldwide. Improved tools for early detection and therapeutic stratification would be expected to increase the survival rate for this disease. Alterations in the molecular pathways that drive lung cancer, which include epigenetic modifications, may provide biomarkers to help address this major unmet clinical need. Epigenetic changes, which are defined as heritable changes in gene expression that do not alter the primary DNA sequence, are one of the hallmarks of cancer, and prevalent in all types of cancer. These modifications represent a rich source of biomarkers that have the potential to be implemented in clinical practice. This perspective describes recent advances in the discovery of epigenetic biomarkers in lung cancer, specifically those that result in the methylation of DNA at CpG sites. We discuss one approach for methylation-based biomarker assay development that describes the discovery at a genome-scale level, which addresses some of the practical considerations for design of assays that can be implemented in the clinic. We emphasize that an integrated technological approach will enable the development of clinically useful DNA methylation-based biomarker assays. While this article focuses on current literature and primary research findings in lung cancer, the principles we describe here apply to the discovery and development of epigenetic biomarkers for other types of cancer.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Epigenômica/métodos , Histonas/fisiologia , Neoplasias Pulmonares/genética , RNA não Traduzido/genética , Ilhas de CpG , Epigênese Genética , Epigenômica/instrumentação , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Reprodutibilidade dos Testes
9.
J Plankton Res ; 36(6): 1528-1542, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25954055

RESUMO

During the summers of 2002-2013, we measured rates of carbon metabolism in surface waters of six sites across a land-to-lake gradient from the upstream end of drowned river-mouth Muskegon Lake (ML) (freshwater estuary) to 19 km offshore in Lake Michigan (LM) (a Great Lake). Despite considerable inter-year variability, the average rates of gross production (GP), respiration (R) and net production (NP) across ML (604 ± 58, 222 ± 22 and 381 ± 52 µg C L-1 day-1, respectively) decreased steeply in the furthest offshore LM site (22 ± 3, 55 ± 17 and -33 ± 15 µg C L-1day-1, respectively). Along this land-to-lake gradient, GP decreased by 96 ± 1%, whereas R only decreased by 75 ± 9%, variably influencing the carbon balance along this coastal zone. All ML sites were consistently net autotrophic (mean GP:R = 2.7), while the furthest offshore LM site was net heterotrophic (mean GP:R = 0.4). Our study suggests that pelagic waters of this Great Lakes coastal estuary are net carbon sinks that transition into net carbon sources offshore. Reactive and dynamic estuarine coastal zones everywhere may contribute similarly to regional and global carbon cycles.

10.
Clin Cancer Res ; 19(24): 6912-23, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24097869

RESUMO

PURPOSE: We sought to identify predictive biomarkers for a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor. EXPERIMENTAL DESIGN: We use a NAMPT inhibitor, GNE-617, to evaluate nicotinic acid rescue status in a panel of more than 400 cancer cell lines. Using correlative analysis and RNA interference (RNAi), we identify a specific biomarker for nicotinic acid rescue status. We next determine the mechanism of regulation of expression of the biomarker. Finally, we develop immunohistochemical (IHC) and DNA methylation assays and evaluate cancer tissue for prevalence of the biomarker across indications. RESULTS: Nicotinate phosphoribosyltransferase (NAPRT1) is necessary for nicotinic acid rescue and its expression is the major determinant of rescue status. We demonstrate that NAPRT1 promoter methylation accounts for NAPRT1 deficiency in cancer cells, and NAPRT1 methylation is predictive of rescue status in cancer cell lines. Bisulfite next-generation sequencing mapping of the NAPRT1 promoter identified tumor-specific sites of NAPRT1 DNA methylation and enabled the development of a quantitative methylation-specific PCR (QMSP) assay suitable for use on archival formalin-fixed paraffin-embedded tumor tissue. CONCLUSIONS: Tumor-specific promoter hypermethylation of NAPRT1 inactivates one of two NAD salvage pathways, resulting in synthetic lethality with the coadministration of a NAMPT inhibitor. NAPRT1 expression is lost due to promoter hypermethylation in most cancer types evaluated at frequencies ranging from 5% to 65%. NAPRT1-specific immunohistochemical or DNA methylation assays can be used on archival formalin paraffin-embedded cancer tissue to identify patients likely to benefit from coadministration of a Nampt inhibitor and nicotinic acid.


Assuntos
Citocinas/metabolismo , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Neoplasias/genética , Niacina/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Pentosiltransferases/metabolismo , Sulfonas/administração & dosagem , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Citocinas/antagonistas & inibidores , Citocinas/genética , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/patologia , Niacina/administração & dosagem , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/genética , Pentosiltransferases/antagonistas & inibidores , Pentosiltransferases/deficiência , Regiões Promotoras Genéticas
11.
Clin Cancer Res ; 18(8): 2360-73, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22261801

RESUMO

PURPOSE: Non-small cell lung cancers (NSCLC) comprise multiple distinct biologic groups with different prognoses. For example, patients with epithelial-like tumors have a better prognosis and exhibit greater sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) pathway than patients with mesenchymal-like tumors. Here, we test the hypothesis that epithelial-like NSCLCs can be distinguished from mesenchymal-like NSCLCs on the basis of global DNA methylation patterns. EXPERIMENTAL DESIGN: To determine whether phenotypic subsets of NSCLCs can be defined on the basis of their DNA methylation patterns, we combined microfluidics-based gene expression analysis and genome-wide methylation profiling. We derived robust classifiers for both gene expression and methylation in cell lines and tested these classifiers in surgically resected NSCLC tumors. We validate our approach using quantitative reverse transcriptase PCR and methylation-specific PCR in formalin-fixed biopsies from patients with NSCLC who went on to fail front-line chemotherapy. RESULTS: We show that patterns of methylation divide NSCLCs into epithelial-like and mesenchymal-like subsets as defined by gene expression and that these signatures are similarly correlated in NSCLC cell lines and tumors. We identify multiple differentially methylated regions, including one in ERBB2 and one in ZEB2, whose methylation status is strongly associated with an epithelial phenotype in NSCLC cell lines, surgically resected tumors, and formalin-fixed biopsies from patients with NSCLC who went on to fail front-line chemotherapy. CONCLUSIONS: Our data show that patterns of DNA methylation can divide NSCLCs into two phenotypically distinct subtypes of tumors and provide proof of principle that differences in DNA methylation can be used as a platform for predictive biomarker discovery and development.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA/genética , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Ilhas de CpG/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Fenótipo , Prognóstico , Receptor ErbB-2/genética , Proteínas Repressoras/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco
12.
Am Ann Deaf ; 154(5): 471-8; discussion 493-6, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20415282

RESUMO

The standard epistemology requires the use of hard science to gain knowledge and discover the truth. In contrast, Deaf epistemology relies heavily on personal testimonies, personal experiences, and personal accounts to document knowledge. In recent years, a number of deaf schools have adopted deaf-centric policies shaped by Deaf epistemology in an effort to improve academic performance of deaf students. Because of federal laws, all schools are now expected to show accountability in the performance of their students, with data becoming increasingly available for public scrutiny. The preliminary data from three well-known deaf schools are beginning to show that the effectiveness of deaf-centric approaches can be substantiated by the standard epistemology. For this reason, Deaf epistemology and the standard epistemology should not always be viewed as having an oxymoronic relationship.


Assuntos
Correção de Deficiência Auditiva/educação , Surdez/psicologia , Educação de Pessoas com Deficiência Auditiva , Educação Inclusiva/métodos , Conhecimento , Estudantes/psicologia , Compreensão , Correção de Deficiência Auditiva/psicologia , Surdez/reabilitação , Escolaridade , Humanos , Aprendizagem , Modelos Educacionais , Pessoas com Deficiência Auditiva/psicologia , Pessoas com Deficiência Auditiva/reabilitação , Terminologia como Assunto
13.
Science ; 326(5952): 572-4, 2009 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-19726788

RESUMO

The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein-coupled receptor can serve as a mechanism of drug resistance in human cancer.


Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Proteínas Hedgehog/metabolismo , Meduloblastoma/tratamento farmacológico , Meduloblastoma/genética , Piridinas/uso terapêutico , Receptores Acoplados a Proteínas G/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Anilidas/metabolismo , Anilidas/farmacologia , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Cinamatos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/genética , Humanos , Meduloblastoma/patologia , Camundongos , Dados de Sequência Molecular , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Metástase Neoplásica , Receptores Patched , Conformação Proteica , Piridinas/metabolismo , Piridinas/farmacologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Receptor Smoothened , Alcaloides de Veratrum/farmacologia
14.
Lang Speech Hear Serv Sch ; 28(4): 384-394, 1997 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27764369

RESUMO

With a historical context as a foundation, the current trends, practices, and perspectives regarding the manual component of educating deaf children is examined, including Manually Coded English systems and American Sign Language. As decisions are considered regarding various approaches to sign communication, it is necessary to investigate issues that support and also question the appropriateness of any given language/system. In addition to the sign language/systems, an equally important aspect is the instructional strategy that supports sign usage, such as Total Communication, Simultaneous Communication, and Bilingual Education. Issues affecting the selection and use of sign language/systems conclude this article.

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