Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Biotechnol ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907405

RESUMO

Despite the global rapid increase in the number of clinical trials employing chimeric antigen receptors (CARs), no comprehensive survey of their scope, targets and design exists. In this study, we present an interactive CAR clinical trial database, spanning 64 targets deployed in T cells (CAR-T), natural killer cells (CAR-NK) or mixtures (CAR-NK/T) from over 500 clinical trials in 20 countries, encompassing >20,000 patients. By combining these data with transcriptional and proteomic data, we create a 'targetable landscape' for CAR cell therapies based on 13,206 proteins and RNAs across 78 tissues, 124 cell types and 20 cancer types. These data suggest a landscape of over 100 single targets and over 100,000 target pairs using logical switches for CAR cell engineering. Our analysis of the CAR cellular therapeutic landscape may aid the design of future therapies, improve target-to-patient matching, and ultimately help inform our understanding of CAR therapy's safety and efficacy.

2.
Cancer Discov ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601552

RESUMO

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTCs) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from breast cancer patients are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D (SEMA4D) as a regulator of tumor cell transmigration through the blood-brain-barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis.

3.
Cell Syst ; 8(5): 446-455.e8, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31078526

RESUMO

Recent studies have shown that mutations at non-coding elements, such as promoters and enhancers, can act as cancer drivers. However, an important class of non-coding elements, namely CTCF insulators, has been overlooked in the previous driver analyses. We used insulator annotations from CTCF and cohesin ChIA-PET and analyzed somatic mutations in 1,962 whole genomes from 21 cancer types. Using the heterogeneous patterns of transcription-factor-motif disruption, functional impact, and recurrence of mutations, we developed a computational method that revealed 21 insulators showing signals of positive selection. In particular, mutations in an insulator in multiple cancer types, including 16% of melanoma samples, are associated with TGFB1 up-regulation. Using CRISPR-Cas9, we find that alterations at two of the most frequently mutated regions in this insulator increase cell growth by 40%-50%, supporting the role of this boundary element as a cancer driver. Thus, our study reveals several CTCF insulators as putative cancer drivers.

4.
Science ; 364(6436)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30975860

RESUMO

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.


Assuntos
Adaptação Fisiológica , Astronautas , Voo Espacial , Imunidade Adaptativa , Peso Corporal , Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Dano ao DNA , Metilação de DNA , Microbioma Gastrointestinal , Instabilidade Genômica , Humanos , Masculino , Homeostase do Telômero , Fatores de Tempo , Estados Unidos , United States National Aeronautics and Space Administration
5.
Front Genet ; 10: 8, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881372

RESUMO

The importance of diversity and cellular specialization is clear for many reasons, from population-level diversification, to improved resiliency to unforeseen stresses, to unique functions within metazoan organisms during development and differentiation. However, the level of cellular heterogeneity is just now becoming clear through the integration of genome-wide analyses and more cost effective Next Generation Sequencing (NGS). With easy access to single-cell NGS (scNGS), new opportunities exist to examine different levels of gene expression and somatic mutational heterogeneity, but these assays can generate yottabyte scale data. Here, we model the importance of heterogeneity for large-scale analysis of scNGS data, with a focus on the utilization in oncology and other diseases, providing a guide to aid in sample size and experimental design.

6.
Br J Radiol ; 91(1088): 20180158, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29848017

RESUMO

OBJECTIVE: Acute abdominal pain is the most common reason for surgical admission. CT scans are increasingly used to aid early diagnosis. Excessive use of CT scans is associated with increased length of stay, healthcare costs and radiation. The aim of this study was to evaluate the appropriateness of CT scans for patients presenting with acute abdominal pain. METHODS: We examined 100 consecutive patients presenting with new acute abdominal pain who underwent a CT scan. Clinical information available at the time the scan was ordered, was summarised and reviewed independently by five consultant general surgeons and five consultant radiologists. RESULTS: A CT scan was judged to be not indicated in a median of 21% of cases (range 12-53%), more information was required in a median of 16% (0-41%) and in a median of 58% (37-88%) the CT scan was considered indicated. There was a good level of agreement (Cronbach's α 0.704) across the 10 experts. CONCLUSION: These data suggest that a large proportion of CT scans for patients with acute abdominal pain are not clinically indicated or are being performed prior to adequate clinical work-up. Optimising CT scan requests for this patient group will improve use of healthcare resources. Advances in knowledge: Both radiologists and general surgeons agree that there is no indication for an abdominal CT scan for a patient presenting with acute abdominal pain in a median of 21% of the cases.


Assuntos
Dor Abdominal/diagnóstico por imagem , Dor Aguda/diagnóstico por imagem , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Procedimentos Desnecessários/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
7.
Nat Med ; 23(11): 1369-1376, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28920958

RESUMO

N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.


Assuntos
Adenosina/análogos & derivados , Células da Medula Óssea/citologia , Diferenciação Celular/fisiologia , Leucemia Mieloide Aguda/patologia , Metiltransferases/fisiologia , Adenosina/biossíntese , Células Cultivadas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Células Tumorais Cultivadas
8.
PLoS One ; 8(2): e56572, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23437173

RESUMO

Despite advances in non-invasive medical imaging, accurate nodal staging of malignancy continues to rely on surgery. Superparamagnetic iron oxide nanoparticles (IONP) with lymphotropic qualities have shown some promise as contrast agents for MRI of the lymph nodes, but recent large-scale studies failed to show consistent detection of tumours below 5 mm. Herein we compare imaging of splenic and lymph node tissue using iron/iron oxide core/shell nanoparticles (Fe NP) that have superior magnetic qualities to IONP, to determine whether improved negative contrast in T(2)-weighted MRI can enhance the diagnosis of small tumours in the reticuloendothelial system. To provide an in vivo pre-clinical model of human lymph node micrometastases, breast cancer cells were injected into the spleens of mice, providing localised areas of tumour growth. MR images of groups of tumour-bearing and sham-treated animals were generated using a 1.5 T imaging system and analysed by two independent, blinded radiologists. Fe NP improved the sensitivity and specificity of MRI when compared to IONP, enabling accurate detection of tumours as small as 1-3 mm. The use of Fe NP as contrast agents have the potential to improve the diagnostic accuracy of MRI in cancer patients, leading to more rapid and effective treatment.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Ferro , Imagem por Ressonância Magnética/métodos , Sistema Fagocitário Mononuclear/diagnóstico por imagem , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Meios de Contraste , Feminino , Humanos , Nanopartículas de Magnetita , Nanopartículas Metálicas , Camundongos , Sistema Fagocitário Mononuclear/patologia , Radiografia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA