RESUMO
Mobile nuclear magnetic resonance (NMR) operating in Earth's magnetic field is adapted to detect leaked or spilled oil trapped in or under sea ice without the need to place any personnel on the ice. A helicopter placed a 6-meter diameter NMR coil system weighing approximately 1000â¯kg on 92â¯cm-thick ice surrogate and detected the equivalent of 1â¯cm thick oil under the ice surrogate in 3-1/2â¯min.
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Aeronaves , Monitoramento Ambiental/métodos , Camada de Gelo/química , Espectroscopia de Ressonância Magnética , Poluição por Petróleo/análise , Tecnologia de Sensoriamento Remoto/métodos , Monitoramento Ambiental/instrumentação , Desenho de Equipamento , Terra Nova e Labrador , Tecnologia de Sensoriamento Remoto/instrumentaçãoRESUMO
Recent studies suggest that targeting transcriptional machinery can lead to potent and selective anticancer effects in cancers dependent on high and constant expression of certain transcription factors for growth and survival. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of the CDK-activating kinase complex. Its function is required for both cell-cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive cancer target because its inhibition leads to decreased transcript levels of oncogenic transcription factors, especially those associated with super-enhancers. Here, we describe a selective CDK7 inhibitor SY-1365, which is currently in clinical trials in populations of patients with ovarian and breast cancer (NCT03134638). In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL2L1 (BCL-XL) expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial antitumor effects in multiple AML xenograft models as a single agent; SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax. Antitumor activity was also observed in xenograft models of ovarian cancer, suggesting the potential for exploring SY-1365 in the clinic in both hematologic and solid tumors. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers. SIGNIFICANCE: These findings demonstrate the molecular mechanism of action and potent antitumor activity of SY-1365, the first selective CDK7 inhibitor to enter clinical investigation.
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Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Neoplasias Ovarianas/patologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/enzimologia , Inibidores de Proteínas Quinases/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Quinase Ativadora de Quinase Dependente de CiclinaRESUMO
Purpose: Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. This mutational complexity has spurred the development of pan-target inhibitors, i.e., therapies for which no single target mutation can cause resistance. Because the propensity for on- versus off-target resistance varies across cancer types, a deeper understanding of the mutational burden in drug targets could rationalize treatment outcomes and prioritize pan-target inhibitors for indications where on-target mutations are most likely.Experimental Design: To measure and model the mutational landscape of a drug target at high resolution, we integrated single-molecule Duplex Sequencing of the ABL1 gene in Philadelphia-positive (Ph+) leukemias with computational simulations.Results: A combination of drug target mutational burden and tumor-initiating cell fraction is sufficient to predict that most patients with chronic myeloid leukemia are unlikely to harbor ABL1 resistance mutations at the time of diagnosis, rationalizing the exceptional success of targeted therapy in this setting. In contrast, our analysis predicts that many patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) harbor multiple preexisting resistant cells with single mutants. The emergence of compound mutations can be traced to initial use of an ABL1 inhibitor that is susceptible to resistance from single point mutations.Conclusions: These results argue that early use of therapies that achieve pan-inhibition of ABL1 resistance mutants might improve outcomes in Ph+ ALL. Our findings show how a deep understanding of the mutational burden in drug targets can be quantitatively coupled to phenotypic heterogeneity to rationalize clinical phenomena. Clin Cancer Res; 24(21); 5321-34. ©2018 AACR.
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Resistencia a Medicamentos Antineoplásicos/genética , Leucemia/genética , Cromossomo Filadélfia , Linhagem Celular Tumoral , Evolução Clonal , Análise Mutacional de DNA , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia/diagnóstico , Leucemia/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Análise de Sequência de DNARESUMO
Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Rearranjo Gênico , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ret/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
Radon is a naturally occurring gas, classified as a Class 1 human carcinogen, being the second most significant cause of lung cancer after tobacco smoking. A robust spatial definition of radon distribution in the built environment is therefore essential for understanding the relationship between radon exposure and its adverse health effects on the general population. Using Ireland as a case study, we present a methodology to estimate an average indoor radon concentration and calculate the expected radon-related lung cancer incidence. We use this approach to define Radon Priority Areas at the administrative level of Electoral Divisions (EDs). Geostatistical methods were applied to a data set of almost 32,000 indoor radon measurements, sampled in Ireland between 1992 and 2013. Average indoor radon concentrations by ED range from 21 to 338â¯Bqâ¯m-3, corresponding to an effective dose ranging from 0.8 to 13.3â¯mSvâ¯y-1 respectively. Radon-related lung cancer incidence by ED was calculated using a dose-effect model giving between 15 and 239 cases per million people per year, depending on the ED. Based on these calculations, together with the population density, we estimate that of the approximately 2,300 lung cancer cases currently diagnosed in Ireland annually, about 280 may be directly linked to radon exposure. This figure does not account for the synergistic effect of radon exposure with other factors (e.g. tobacco smoking), so likely represents a minimum estimate. Our approach spatially defines areas with the expected highest incidence of radon-related lung cancer, even though indoor radon concentrations for these areas may be moderate or low. We therefore recommend that both indoor radon concentration and population density by small area are considered when establishing national radon action plans.
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Poluição do Ar em Ambientes Fechados , Exposição por Inalação , Neoplasias Pulmonares/epidemiologia , Radônio , Poluição do Ar em Ambientes Fechados/efeitos adversos , Poluição do Ar em Ambientes Fechados/estatística & dados numéricos , Estudos de Coortes , Humanos , Incidência , Exposição por Inalação/análise , Exposição por Inalação/estatística & dados numéricos , Irlanda/epidemiologia , Radônio/efeitos adversos , Radônio/análiseRESUMO
The time of onset and subsequent degree and progression of clinical signs, bacterial colonization and tissue pathology during experimental disease induced by intratracheal inoculation of either a UK or USA isolate of Pasteurella multocida serotype A recovered from clinical cases of bovine pneumonia were determined. Calves aged 8 weeks were challenged with 300 ml phosphate buffered saline (PBS) alone (group 1, n = 3, negative control) or containing 7.1 × 10(8) colony forming units (cfu) of UK isolate (group 2, n = 8) or 5.8 × 10(8) cfu of USA isolate (group 3, n = 8). Bronchoalveolar lavage (BAL) at 0, 1 and 4 days post challenge (dpc) and at the time of necropsy examination (7-8 dpc) showed no significant differences between groups 2 and 3 in bacterial numbers recovered. No P. multocida were recovered from group 1 animals. No clinical disease was present in group 1 calves and in group 3 was limited to scour in 1 calf at 1 dpc. All calves in group 2 had reduced food intake at 4-5 dpc, five had periods of dullness, three a mild nasal discharge at 1 dpc, four had mild to substantial respiratory stridor and one was killed at 6 dpc for humane reasons. Rectal temperatures remained about 39°C in group 1 calves, but increased in P. multocida-challenged calves to 40-41°C within 8-12 h of challenge. Significantly (P = 0.01) greater percentages of lung surface area were consolidated in group 2 (mean ± SD, 21 ± 10.1) compared with group 3 (7 ± 8.6) calves. Significantly more extensive and severe histological lesions were present in the lung lobes (P = 0.006) and lymph nodes (P = 0.02) of group 2 compared with group 3 calves. Pleurisy was present in group 2 calves only and no pathology was present in group 1. Pulsed-field gel electrophoresis (PFGE) produced 11 (group 2, UK isolate) or 10 (group 3, USA isolate) bands with differences in banding patterns. Results overall showed that two isolates, distinct geographically and genetically (by PFGE), caused pneumonic pasteurellosis in a single host with significantly different severity of pathology. This information is relevant to the development of novel vaccine control and interpretation of diagnostic results.
Assuntos
Pasteurella multocida/genética , Pasteurella multocida/patogenicidade , Pasteurelose Pneumônica/genética , Pasteurelose Pneumônica/virologia , Animais , Bovinos , Pasteurelose Pneumônica/patologia , Reino Unido , Estados Unidos , VirulênciaRESUMO
The third-generation tyrosine kinase inhibitor (TKI) ponatinib shows activity against all common BCR-ABL1 single mutants, including the highly resistant BCR-ABL1-T315I mutant, improving outcome for patients with refractory chronic myeloid leukemia (CML). However, responses are variable, and causal baseline factors have not been well-studied. The type and number of low-level BCR-ABL1 mutations present after imatinib resistance has prognostic significance for subsequent treatment with nilotinib or dasatinib as second-line therapy. We therefore investigated the impact of low-level mutations detected by sensitive mass-spectrometry before ponatinib initiation (baseline) on treatment response in 363 TKI-resistant patients enrolled in the PONATINIB for Chronic Myeloid Leukemia Evaluation and Ph(+)Acute Lymphoblastic Leukemia trial, including 231 patients in chronic phase (CP-CML). Low-level mutations were detected in 53 patients (15%, including low-level T315I in 14 patients); most, however, did not undergo clonal expansion during ponatinib treatment and, moreover, no specific individual mutations were associated with inferior outcome. We demonstrate however, that the number of mutations detectable by mass spectrometry after TKI resistance is associated with response to ponatinib treatment and could be used to refine the therapeutic approach. Although CP-CML patients with T315I (63/231, 27%) had superior responses overall, those with multiple mutations detectable by mass spectrometry (20, 32%) had substantially inferior responses compared with those with T315I as the sole mutation detected (43, 68%). In contrast, for CP-CML patients without T315I, the inferior responses previously observed with nilotinib/dasatinib therapy for imatinib-resistant patients with multiple mutations were not seen with ponatinib treatment, suggesting that ponatinib may prove to be particularly advantageous for patients with multiple mutations detectable by mass spectrometry after TKI resistance.
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Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Piridazinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos , Humanos , Espectrometria de Massas , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
BCR-ABL1 kinase domain mutations can confer resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In preclinical studies, clinically achievable concentrations of the third-generation BCR-ABL1 TKI ponatinib inhibit T315I and all other single BCR-ABL1 mutants except T315M, which generates a single amino acid exchange, but requires 2 sequential nucleotide exchanges. In addition, certain compound mutants (containing ≥2 mutations in cis) confer resistance. Initial analyses based largely on conventional Sanger sequencing (SS) have suggested that the preclinical relationship between BCR-ABL1 mutation status and ponatinib efficacy is generally recapitulated in patients receiving therapy. Thus far, however, such analyses have been limited by the inability of SS to definitively identify compound mutations or mutations representing less than ~20% of total alleles (referred to as "low-level mutations"), as well as limited patient follow-up. Here we used next-generation sequencing (NGS) to define the baseline BCR-ABL1 mutation status of 267 heavily pretreated chronic phase (CP)-CML patients from the PACE trial, and used SS to identify clonally dominant mutants that may have developed on ponatinib therapy (30.1 months median follow-up). Durable cytogenetic and molecular responses were observed irrespective of baseline mutation status and included patients with compound mutations. No single or compound mutation was identified that consistently conferred primary and/or secondary resistance to ponatinib in CP-CML patients. Ponatinib is effective in CP-CML irrespective of baseline mutation status.
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Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Imidazóis/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Mutação/fisiologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Substituição de Aminoácidos , Quimioterapia Adjuvante , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide de Fase Crônica/genética , Terapia NeoadjuvanteRESUMO
We have investigated the effects of the major polyphenol in coffee, chlorogenic acid (CGA), on obesity, glucose intolerance, insulin resistance, systemic oxidative stress and endothelial dysfunction in a mouse model of the metabolic syndrome. Thirty C57BL6 mice were randomly divided into (n=10/group) (i) normal diet (ND), (ii) high fat diet (HFD), or (iii) high fat diet supplemented with 0.5% w/w green coffee bean extract (GCE) rich in chlorogenic acid (HFD+GCE). The high fat diet consisted of 28% fat and all animals were maintained on their diets for 12 weeks. The mice fed a HFD and HFD+GCE displayed symptoms of the metabolic syndrome compared to their normal fed counterparts, although no endothelial dysfunction was detected in the abdominal aortas after 12 weeks. GCE did not attenuate HFD-induced obesity, glucose intolerance, insulin resistance or systemic oxidative stress. Furthermore, GCE did not protect against ex vivo oxidant (hypochlorous acid)-induced endothelial dysfunction.
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Café/química , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/patologia , Polifenóis/farmacologia , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/fisiopatologia , Peso Corporal/efeitos dos fármacos , Endotélio Vascular/metabolismo , Teste de Tolerância a Glucose , Resistência à Insulina , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/isolamento & purificação , Polifenóis/uso terapêutico , Vasodilatação/efeitos dos fármacosRESUMO
Medulloblastoma is the most common malignant brain tumor in children, and a substantial number of patients die as a result of tumor progression. Overexpression of CDK6 is present in approximately one-third of medulloblastomas and is an independent poor prognostic marker for this disease. MicroRNA (miR)-124 inhibits expression of CDK6 and prevents proliferation of glioblastoma and medulloblastoma cells in vitro. We examined the effects of miR-124 overexpression on medulloblastoma cells both in vitro and in vivo and compared cell lines that have low and high CDK6 expression. MiR-124 overexpression inhibits the proliferation of medulloblastoma cells, and this effect is mediated mostly through the action of miR-124 upon CDK6. We further show that induced expression of miR-124 potently inhibits growth of medulloblastoma xenograft tumors in rodents. Further testing of miR-124 will help define the ultimate therapeutic potential of preclinical models of medulloblastoma in conjunction with various delivery strategies for treatment.
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Ciclo Celular , Proliferação de Células , Neoplasias Cerebelares/prevenção & controle , Meduloblastoma/prevenção & controle , MicroRNAs/genética , Animais , Apoptose , Western Blotting , Linhagem Celular Tumoral , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Analysis of occupational mortality in England and Wales during 1991-2000 showed no decline in work-attributable deaths from asbestosis. AIMS: To explore why there was no decline in mortality from asbestosis despite stricter controls on asbestos exposure over recent decades. METHODS: Using data from registers of all deaths in Great Britain with mention of mesothelioma or asbestosis on the death certificate, we plotted death rates by 5 year age group within 5 year birth cohorts for(a) mesothelioma and (b) asbestosis without mention of mesothelioma. RESULTS: Analysis was based on a total of 33,751 deaths from mesothelioma and 5396 deaths from asbestosis. For both diseases, mortality showed a clear cohort effect; within birth cohorts, death rates increased progressively with age through to 85 years and older. However, highest mortality from mesothelioma was in men born during 1939-43, whereas, mortality from asbestosis peaked in men born during 1924-38. CONCLUSIONS: Our findings suggest that mortality, in Britain, from asbestosis has been determined mainly by cumulative exposure to asbestos before 45 years of age and that the effect of such exposure continues through to old age. That mortality from asbestosis peaked in earlier birth cohorts than mortality from mesothelioma may reflect a difference in exposure-response relationships for the two diseases. The discrepancy could be explained if risk of asbestosis increased more steeply than that of mesothelioma at higher levels of exposure to asbestos and if the highest prevalence of heavy exposure occurred in earlier birth cohorts than the highest prevalence of less intense exposures.
Assuntos
Amianto/efeitos adversos , Asbestose/mortalidade , Neoplasias Pulmonares/mortalidade , Mesotelioma/mortalidade , Doenças Profissionais/mortalidade , Exposição Ocupacional/estatística & dados numéricos , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Asbestose/fisiopatologia , Asbestose/prevenção & controle , Carcinógenos , Materiais de Construção/efeitos adversos , Atestado de Óbito , Progressão da Doença , Humanos , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/prevenção & controle , Masculino , Mesotelioma/fisiopatologia , Mesotelioma/prevenção & controle , Pessoa de Meia-Idade , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/prevenção & controle , Exposição Ocupacional/prevenção & controle , Prevalência , Sistema de Registros , Reino Unido/epidemiologiaRESUMO
Glioblastoma (GBM) is a highly malignant brain tumor with a dismal prognosis. Gene expression profiling of GBM has revealed clinically relevant tumor subtypes, and this provides exciting opportunities to better understand disease pathogenesis. Results from an increasing number of studies demonstrate a role for the immune response in cancer progression, yet it is unclear how the immune response differs across tumor subtypes and how it affects outcome. Utilizing gene expression data from The Cancer Genome Atlas Project and the Gene Expression Omnibus database, we demonstrate an enrichment of immune response-related gene expression in the mesenchymal subtype of adult GBM (n = 173) and pediatric high-grade gliomas (n = 53). In an independent cohort of pediatric astrocytomas (n = 24) from UCSF, we stratified tumors into subtypes and confirmed these findings. Using novel immune cell-specific gene signatures we demonstrate selective enrichment of microglia/macrophage-related genes in adult and pediatric GBM tumors of the mesenchymal subtype. Furthermore, immunostaining of adult GBM tumors showed significantly higher cell numbers of microglia/macrophages in mesenchymal versus non-mesenchymal tumors (p = 0.04). Interestingly, adult GBM tumors with the shortest survival had significant enrichment of microglia/macrophage-related genes but this was not true for pediatric GBMs. Consistent with an association with poor outcome, immune response-related genes were highly represented in an adult poor prognosis gene signature, with the expression of genes related to macrophage recruitment and activation being most strongly associated with survival (p<0.05) using CoxBoost multivariate modeling. Using a microglia/macrophage high gene signature derived from quantification of tumor-infiltrating cells in adult GBM, we identified enrichment of genes characteristic of CD4 T cells, granulocytes, and microglia/macrophages (n = 573). These studies support a role for the immune response, particularly the microglia/macrophage response, in the biology of an important subset of GBM. Identification of this subset may be important for future therapeutic stratification.
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Astrocitoma/metabolismo , Glioblastoma/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Adolescente , Feminino , Humanos , Técnicas In Vitro , MasculinoRESUMO
To develop a comprehensive overview of copy number aberrations (CNAs) in stage-II/III colorectal cancer (CRC), we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS) samples (n = 269) had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%), 7 (41.8%), 8 q (33.1%) and 13 q (51.0%) and losses on 18 (58.6%), 4 q (26%) and 21 q (21.6%). MSS tumors have significantly more CNAs than microsatellite-instable (MSI) tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01). Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease.
Assuntos
Neoplasias Colorretais/genética , Dosagem de Genes , Genoma Humano , Oncogenes , Cromossomos Humanos Par 16 , Humanos , Repetições de Microssatélites/genéticaRESUMO
PURPOSE: Malignant astrocytomas (MA) are aggressive central nervous system tumors with poor prognosis. Activating mutation of BRAF (BRAF(V600E)) has been reported in a subset of these tumors, especially in children. We have investigated the incidence of BRAF(V600E) in additional pediatric patient cohorts and examined the effects of BRAF blockade in preclinical models of BRAF(V600E) and wild-type BRAF MA. EXPERIMENTAL DESIGN: BRAF(V600E) mutation status was examined in two pediatric MA patient cohorts. For functional studies, BRAF(V600E) MA cell lines were used to investigate the effects of BRAF shRNA knockdown in vitro, and to investigate BRAF pharmacologic inhibition in vitro and in vivo. RESULTS: BRAF(V600E) mutations were identified in 11 and 10% of MAs from two distinct series of tumors (six of 58 cases total). BRAF was expressed in all MA cell lines examined, among which BRAF(V600E) was identified in four instances. Using the BRAF(V600E)-specific inhibitor PLX4720, pharmacologic blockade of BRAF revealed preferential antiproliferative activity against BRAF(V600E) mutant cells in vitro, in contrast to the use of shRNA-mediated knockdown of BRAF, which inhibited cell growth of glioma cell lines regardless of BRAF mutation status. Using orthotopic MA xenografts, we show that PLX4720 treatment decreases tumor growth and increases overall survival in mice-bearing BRAF(V600E) mutant xenografts, while being ineffective, and possibly tumor promoting, against xenografts with wild-type BRAF. CONCLUSIONS: Our results indicate a 10% incidence of activating BRAF(V600E) among pediatric MAs. With regard to implications for therapy, our results support evaluation of BRAF(V600E)-specific inhibitors for treating BRAF(V600E) MA patients.
Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Substituição de Aminoácidos , Animais , Astrocitoma/metabolismo , Astrocitoma/patologia , Astrocitoma/prevenção & controle , Sequência de Bases , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/prevenção & controle , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Indóis/farmacologia , Lactente , Estimativa de Kaplan-Meier , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Interferência de RNA , Sulfonamidas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
BACKGROUND: Mesothelioma mortality has increased more than ten-fold over the past 40 years in Great Britain, with >1700 male deaths recorded in the British mesothelioma register in 2006. Annual mesothelioma deaths now account for >1% of all cancer deaths. A Poisson regression model based on a previous work by Hodgson et al has been fitted, which has allowed informed statistical inferences about model parameters and predictions of future mesothelioma mortality to be made. METHODS: In the Poisson regression model, the mesothelioma risk of an individual depends on the average collective asbestos dose for the individual in a given year and an age-specific exposure potential. The model has been fitted to the data within a Bayesian framework using the Metropolis-Hastings algorithm, a Markov Chain Monte Carlo technique, providing credible intervals for model parameters as well as prediction intervals for the number of future cases of mortality. RESULTS: Males were most likely to have been exposed to asbestos between the ages of 30 and 49 years, with the peak year of asbestos exposure estimated to be 1963. The estimated number of background cases was 1.08 cases per million population. CONCLUSION: Mortality among males is predicted to peak at approximately 2040 deaths in the year 2016, with a rapid decline thereafter. Approximately 91,000 deaths are predicted to occur from 1968 to 2050 with around 61,000 of these occurring from 2007 onwards.
Assuntos
Mesotelioma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Teorema de Bayes , Exposição Ambiental , Feminino , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Biológicos , Método de Monte Carlo , Distribuição de Poisson , Valor Preditivo dos Testes , Análise de Regressão , Caracteres Sexuais , Fatores de Tempo , Reino Unido/epidemiologia , Adulto JovemRESUMO
The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.
Assuntos
Neoplasias Encefálicas/genética , Receptores ErbB/genética , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Neurofibromatose 1/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Idoso , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/patologia , Análise Mutacional de DNA , Análise Fatorial , Dosagem de Genes , Expressão Gênica , Perfilação da Expressão Gênica , Glioblastoma/classificação , Glioblastoma/patologia , Humanos , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , PrognósticoRESUMO
Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP), which increases the secretion of cytokines and other factors that alter the behavior of neighboring cells. We show here that "senescent" mouse fibroblasts, which arrested growth after repeated passage under standard culture conditions (20% oxygen), do not express a human-like SASP, and differ from similarly cultured human cells in other respects. However, when cultured in physiological (3%) oxygen and induced to senesce by radiation, mouse cells more closely resemble human cells, including expression of a robust SASP. We describe two new aspects of the human and mouse SASPs. First, cells from both species upregulated the expression and secretion of several matrix metalloproteinases, which comprise a conserved genomic cluster. Second, for both species, the ability to promote the growth of premalignant epithelial cells was due primarily to the conserved SASP factor CXCL-1/KC/GRO-alpha. Further, mouse fibroblasts made senescent in 3%, but not 20%, oxygen promoted epithelial tumorigenesis in mouse xenographs. Our findings underscore critical mouse-human differences in oxygen sensitivity, identify conditions to use mouse cells to model human cellular senescence, and reveal novel conserved features of the SASP.
Assuntos
Senescência Celular/fisiologia , Fibroblastos/fisiologia , Oxigênio/fisiologia , Proteoma/metabolismo , Animais , Western Blotting , Células Cultivadas , Senescência Celular/genética , Proteínas Cromossômicas não Histona , Dano ao DNA , Proteínas de Ligação a DNA , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Fibroblastos/metabolismo , Instabilidade Genômica , Humanos , Proteína 6 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 6 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Oxigênio/metabolismo , Fenótipo , Proteoma/genética , Proteômica/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie , Transplante Heterólogo , Carga Tumoral , Proteína 1 de Ligação à Proteína Supressora de Tumor p53RESUMO
PURPOSE: To determine whether magnetic resonance (MR) imaging is influenced by genetic and cellular features of glioblastoma multiforme (GBM) aggressiveness. MATERIALS AND METHODS: In this HIPAA-compliant institutional review board-approved study, multiple enhancing and peritumoral nonenhancing stereotactic neurosurgical biopsy samples from treatment-naïve GBMs were collected prospectively, with guidance from cerebral blood volume (CBV) MR imaging measurements. By using monoclonal antibodies, tissue specimens were examined for microvascular expression, hypoxia, tumor and overall cellular density, and histopathologic features of GBM aggressiveness. Genetic expression patterns were investigated with RNA microarrays. Imaging and histopathologic variables were compared with the Welch t test and Pearson correlations. Microarray analysis was performed by using false discovery rate (FDR) statistics. RESULTS: Tumor biopsy of 13 adult patients yielded 16 enhancing and 14 peritumoral nonenhancing specimens. Enhancing regions had elevated relative CBV and reduced relative apparent diffusion coefficient (ADC) measurements compared with peritumoral nonenhancing biopsy regions (P < .01). A positive correlation was found between relative CBV and all histopathologic features of aggressiveness (P < .04). An inverse correlation was found between relative ADC and all histopathologic features of aggressiveness (P < .05). RNA expression patterns between tumor regions were found to be significantly different (FDR < 0.05), with hierarchical clustering by biopsy region only. CONCLUSION: These findings suggest MR imaging is significantly influenced by GBM genetic and cellular biologic features of aggressiveness and imply physiologic MR imaging may be useful in pinpointing regions of highest malignancy within heterogeneous tissues, thus facilitating histologic grading of primary glial brain tumors.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioblastoma/patologia , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Biópsia , Meios de Contraste , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imageamento Tridimensional , Modelos Lineares , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Estudos Prospectivos , RNA/metabolismoRESUMO
Malignant astrocytomas are a deadly solid tumor in children. Limited understanding of their underlying genetic basis has contributed to modest progress in developing more effective therapies. In an effort to identify such alterations, we performed a genome-wide search for DNA copy number aberrations (CNA) in a panel of 33 tumors encompassing grade 1 through grade 4 tumors. Genomic amplifications of 10-fold or greater were restricted to grade 3 and 4 astrocytomas and included the MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13), and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26), and TP53 (17p3.1) were evident among grade 2 to 4 tumors. BRAF gene rearrangements that were indicated in three tumors prompted the discovery of KIAA1549-BRAF fusion transcripts expressed in 10 of 10 grade 1 astrocytomas and in none of the grade 2 to 4 tumors. In contrast, an oncogenic missense BRAF mutation (BRAF(V600E)) was detected in 7 of 31 grade 2 to 4 tumors but in none of the grade 1 tumors. BRAF(V600E) mutation seems to define a subset of malignant astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A (five of seven cases). Taken together, these findings highlight BRAF as a frequent mutation target in pediatric astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4 tumors.