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1.
Cell ; 184(11): 3056-3074.e21, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33932339

RESUMO

The choroid plexus (ChP) in each brain ventricle produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. Here, we construct a single-cell and spatial atlas of each ChP in the developing, adult, and aged mouse brain. We delineate diverse cell types, subtypes, cell states, and expression programs in epithelial and mesenchymal cells across ages and ventricles. In the developing ChP, we predict a common progenitor pool for epithelial and neuronal cells, validated by lineage tracing. Epithelial and fibroblast cells show regionalized expression by ventricle, starting at embryonic stages and persisting with age, with a dramatic transcriptional shift with maturation, and a smaller shift in each aged cell type. With aging, epithelial cells upregulate host-defense programs, and resident macrophages upregulate interleukin-1ß (IL-1ß) signaling genes. Our atlas reveals cellular diversity, architecture and signaling across ventricles during development, maturation, and aging of the ChP-brain barrier.


Assuntos
Plexo Corióideo/embriologia , Plexo Corióideo/metabolismo , Fatores Etários , Envelhecimento/fisiologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiologia , Encefalopatias/genética , Encefalopatias/fisiopatologia , Diferenciação Celular/genética , Linhagem da Célula/genética , Plexo Corióideo/fisiologia , Células Epiteliais/metabolismo , Feminino , Masculino , Camundongos/embriologia , Camundongos Endogâmicos C57BL , Transdução de Sinais , Análise de Célula Única
2.
Cell ; 176(6): 1325-1339.e22, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827679

RESUMO

Lineage tracing provides key insights into the fate of individual cells in complex organisms. Although effective genetic labeling approaches are available in model systems, in humans, most approaches require detection of nuclear somatic mutations, which have high error rates, limited scale, and do not capture cell state information. Here, we show that somatic mutations in mtDNA can be tracked by single-cell RNA or assay for transposase accessible chromatin (ATAC) sequencing. We leverage somatic mtDNA mutations as natural genetic barcodes and demonstrate their utility as highly accurate clonal markers to infer cellular relationships. We track native human cells both in vitro and in vivo and relate clonal dynamics to gene expression and chromatin accessibility. Our approach should allow clonal tracking at a 1,000-fold greater scale than with nuclear genome sequencing, with simultaneous information on cell state, opening the way to chart cellular dynamics in human health and disease.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Sequência de Bases , Linhagem da Célula , Cromatina , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Genômica/métodos , Células HEK293 , Células-Tronco Hematopoéticas/fisiologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Análise de Célula Única , Transposases
3.
Cell ; 178(4): 835-849.e21, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31327527

RESUMO

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.


Assuntos
Neoplasias Encefálicas/genética , Plasticidade Celular/genética , Glioblastoma/genética , Adolescente , Idoso , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Linhagem da Célula/genética , Criança , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Heterogeneidade Genética , Glioblastoma/patologia , Xenoenxertos , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Mutação , RNA-Seq , Análise de Célula Única/métodos , Microambiente Tumoral/genética
4.
Cell ; 175(4): 984-997.e24, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388455

RESUMO

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.


Assuntos
Antineoplásicos/uso terapêutico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Melanoma/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Linfócitos T/imunologia , Evasão Tumoral , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia/métodos , Masculino , Melanoma/tratamento farmacológico , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia
5.
Cell ; 171(7): 1611-1624.e24, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29198524

RESUMO

The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Metástase Neoplásica/patologia , Carcinoma de Células Escamosas/genética , Células Cultivadas , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Análise de Célula Única , Microambiente Tumoral
6.
Am J Ind Med ; 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38989775

RESUMO

BACKGROUND: Construction workers have the second highest suicide death rate; despite this, there is limited literature examining suicides in the industry, which is necessary to identify those at higher risk of death by suicide. The objective of this study was to examine the characteristics of those who died by suicide in construction to address this knowledge gap. METHODS: Data from the National Center for Health Statistics National Vital Statistics System 2021 public use Mortality Multiple Cause-of-Death file were used to identify deaths by suicide, while denominator data for rates come from the 2021 Current Population Survey. RESULTS: In 2021, construction workers were disproportionately affected by suicide deaths. Almost a fifth (17.9%) of deaths by suicide with a reported industry code were in construction, despite construction workers accounting for only 7.4% of the workforce. Male construction workers accounted for a majority (97.8%) of suicide deaths. The highest percent of deaths by suicide were among individuals who were white, non-Hispanic, completed high school or equivalent, and single, across construction and all industries for males and females. DISCUSSION AND CONCLUSIONS: Male and female construction workers had the highest rates of suicide across all characteristics when compared to all industries. Our findings support the need for ongoing prevention efforts within the industry. Future research is needed to understand suicide risk among certain characteristics and occupations. In addition, the work environment or other work-related factors should be studied to understand how the unique nature of the construction industry may be associated with higher suicide rates.

7.
Nature ; 549(7672): 351-356, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28902842

RESUMO

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.


Assuntos
Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Inflamação/imunologia , Inflamação/patologia , Pulmão/patologia , Linfócitos/imunologia , Neuropeptídeos/metabolismo , Animais , Feminino , Regulação da Expressão Gênica , Imunidade Inata/imunologia , Interleucina-17/imunologia , Interleucina-33/imunologia , Ligantes , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Neurotransmissores/biossíntese , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Transdução de Sinais , Transcrição Gênica
9.
Am J Public Health ; 112(S1): S77-S87, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35143279

RESUMO

Objectives. To examine prescription opioid and nonopioid analgesic use among US construction workers and their associations with pain conditions and sociodemographic factors. Methods. We analyzed data for about 9000 (weighted 11.5 million per year) construction workers who responded to the Medical Expenditure Panel Survey from 2011 to 2018. We applied both descriptive statistics and multiple logistic regression procedures in the analyses. Results. An estimated 1.2 million (10.0%) of construction workers used prescription opioid analgesics annually. The adjusted odds of prescription opioid use were significantly higher for workers suffering from work-related injuries (adjusted odds ratio [AOR] = 3.82; 95% confidence interval [CI] = 2.72, 5.37), non‒work-related injuries (AOR = 3.37; 95% CI = 2.54, 4.46), and musculoskeletal disorders (AOR = 2.31; 95% CI = 1.80, 2.95) after we controlled for potential confounders. Adjusted odds of prescription opioid use were also higher among workers with poorer physical health (AOR = 1.95; 95% CI = 1.42, 2.69) or mental health disorders (AOR = 1.95; 95% CI = 1.41, 2.68). Conclusions. Work- and non‒work-related injuries and musculoskeletal disorders significantly increased prescription opioid use among construction workers. To prevent opioid use disorders, multipronged strategies should be approached. (Am J Public Health. 2022;112(S1):S77-S87. https://doi.org/10.2105/AJPH.2021.306510).


Assuntos
Analgésicos Opioides/uso terapêutico , Indústria da Construção/estatística & dados numéricos , Traumatismos Ocupacionais/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/tratamento farmacológico , Traumatismos Ocupacionais/epidemiologia , Fatores de Risco
10.
Nature ; 539(7628): 309-313, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27806376

RESUMO

Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.


Assuntos
Células-Tronco Neoplásicas/patologia , Oligodendroglioma/genética , Oligodendroglioma/patologia , Análise de Sequência de RNA , Análise de Célula Única , Diferenciação Celular , Proliferação de Células , Variações do Número de Cópias de DNA/genética , Humanos , Isocitrato Desidrogenase/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Filogenia , Mutação Puntual
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