RESUMO
Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include EP2, EP4, A2AR, ß1AR and ß2AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs-DREADD to activate CD8-restricted Gαs signaling and show that a Gαs-PKA signaling axis promotes CD8+ T cell dysfunction and immunotherapy failure. These data indicate that Gαs-GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Camundongos , Animais , Transdução de Sinais , Camundongos Transgênicos , Imunoterapia , Microambiente TumoralRESUMO
RNA has the intrinsic property to base pair, forming complex structures fundamental to its diverse functions. Here, we develop PARIS, a method based on reversible psoralen crosslinking for global mapping of RNA duplexes with near base-pair resolution in living cells. PARIS analysis in three human and mouse cell types reveals frequent long-range structures, higher-order architectures, and RNA-RNA interactions in trans across the transcriptome. PARIS determines base-pairing interactions on an individual-molecule level, revealing pervasive alternative conformations. We used PARIS-determined helices to guide phylogenetic analysis of RNA structures and discovered conserved long-range and alternative structures. XIST, a long noncoding RNA (lncRNA) essential for X chromosome inactivation, folds into evolutionarily conserved RNA structural domains that span many kilobases. XIST A-repeat forms complex inter-repeat duplexes that nucleate higher-order assembly of the key epigenetic silencing protein SPEN. PARIS is a generally applicable and versatile method that provides novel insights into the RNA structurome and interactome. VIDEO ABSTRACT.
Assuntos
Ficusina/química , RNA de Cadeia Dupla/química , Animais , Pareamento de Bases , Células HEK293 , Células HeLa , Humanos , Camundongos , Células-Tronco Embrionárias Murinas , RNA Longo não Codificante/químicaRESUMO
Wnt/ß-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic ß-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of ß-catenin in transformation, we classified ß-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that ß-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with ß-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of ß-catenin-dependent cancers in both cell lines and animal models. These observations define a ß-catenin-YAP1-TBX5 complex essential to the transformation and survival of ß-catenin-driven cancers.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transformação Celular Neoplásica , Neoplasias do Colo/metabolismo , Fosfoproteínas/metabolismo , Proteínas com Domínio T/metabolismo , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Colo/embriologia , Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Proteínas Inibidoras de Apoptose/genética , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-yes/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-yes/metabolismo , Survivina , Fatores de Transcrição , Transcrição Gênica , Proteínas de Sinalização YAP , Peixe-Zebra/embriologia , Proteína bcl-X/genética , Quinases da Família src/antagonistas & inibidoresRESUMO
Due to genome instability, most cancers exhibit loss of regions containing tumor suppressor genes and collateral loss of other genes. To identify cancer-specific vulnerabilities that are the result of copy number losses, we performed integrated analyses of genome-wide copy number and RNAi profiles and identified 56 genes for which gene suppression specifically inhibited the proliferation of cells harboring partial copy number loss of that gene. These CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes are enriched for spliceosome, proteasome, and ribosome components. One CYCLOPS gene, PSMC2, encodes an essential member of the 19S proteasome. Normal cells express excess PSMC2, which resides in a complex with PSMC1, PSMD2, and PSMD5 and acts as a reservoir protecting cells from PSMC2 suppression. Cells harboring partial PSMC2 copy number loss lack this complex and die after PSMC2 suppression. These observations define a distinct class of cancer-specific liabilities resulting from genome instability.
Assuntos
Genes Essenciais , Instabilidade Genômica , Neoplasias/genética , ATPases Associadas a Diversas Atividades Celulares , Animais , Linhagem Celular Tumoral , Deleção Cromossômica , Dosagem de Genes , Genes Supressores de Tumor , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Transplante HeterólogoRESUMO
SUMMARY: Copy number variation (CNV) and alteration (CNA) analysis is a crucial component in many genomic studies and its applications span from basic research to clinic diagnostics and personalized medicine. CNVpytor is a tool featuring a read depth-based caller and combined read depth and B-allele frequency (BAF) based 2D caller to find CNVs and CNAs. The tool stores processed intermediate data and CNV/CNA calls in a compact HDF5 file-pytor file. Here, we describe a new track in igv.js that utilizes pytor and whole genome variant files as input for on-the-fly read depth and BAF visualization, CNV/CNA calling and analysis. Embedding into HTML pages and Jupiter Notebooks enables convenient remote data access and visualization simplifying interpretation and analysis of omics data. AVAILABILITY AND IMPLEMENTATION: The CNVpytor track is integrated with igv.js and available at https://github.com/igvteam/igv.js. The documentation is available at https://github.com/igvteam/igv.js/wiki/cnvpytor. Usage can be tested in the IGV-Web app at https://igv.org/app and also on https://github.com/abyzovlab/CNVpytor.
Assuntos
Variações do Número de Cópias de DNA , Genômica , Software , Genômica/métodos , HumanosRESUMO
Gene-expression profiling has become a mainstay in immunology, but subtle changes in gene networks related to biological processes are hard to discern when comparing various datasets. For instance, conservation of the transcriptional response to sepsis in mouse models and human disease remains controversial. To improve transcriptional analysis in immunology, we created ImmuneSigDB: a manually annotated compendium of â¼5,000 gene-sets from diverse cell states, experimental manipulations, and genetic perturbations in immunology. Analysis using ImmuneSigDB identified signatures induced in activated myeloid cells and differentiating lymphocytes that were highly conserved between humans and mice. Sepsis triggered conserved patterns of gene expression in humans and mouse models. However, we also identified species-specific biological processes in the sepsis transcriptional response: although both species upregulated phagocytosis-related genes, a mitosis signature was specific to humans. ImmuneSigDB enables granular analysis of transcriptomic data to improve biological understanding of immune processes of the human and mouse immune systems.
Assuntos
Bases de Dados Genéticas , Inflamação/imunologia , Transcriptoma , Animais , Humanos , Camundongos , Especificidade da EspécieRESUMO
SUMMARY: igv.js is an embeddable JavaScript implementation of the Integrative Genomics Viewer (IGV). It can be easily dropped into any web page with a single line of code and has no external dependencies. The viewer runs completely in the web browser, with no backend server and no data pre-processing required. AVAILABILITY AND IMPLEMENTATION: The igv.js JavaScript component can be installed from NPM at https://www.npmjs.com/package/igv. The source code is available at https://github.com/igvteam/igv.js under the MIT open-source license. IGV-Web, the end-user application built around igv.js, is available at https://igv.org/app. The source code is available at https://github.com/igvteam/igv-webapp under the MIT open-source license. SUPPLEMENTARY INFORMATION: Supplementary information is available at Bioinformatics online.
Assuntos
Genômica , Software , NavegadorRESUMO
Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFß-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
Assuntos
Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Caderinas/metabolismo , Morte Celular , Linhagem Celular Tumoral , Linhagem da Célula , Transdiferenciação Celular , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal , Humanos , Ferro/metabolismo , Peróxidos Lipídicos/metabolismo , Masculino , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Melanoma/metabolismo , Melanoma/patologia , Mesoderma/efeitos dos fármacos , Mesoderma/enzimologia , Mesoderma/metabolismo , Mesoderma/patologia , Neoplasias/genética , Neoplasias/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteômica , Proteínas Proto-Oncogênicas B-raf/genética , Reprodutibilidade dos Testes , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actionable mutations have hindered the development of targeted therapies, especially for G3 MB, which has a particularly poor prognosis. To identify novel therapeutic targets for MB, we performed mass spectrometry-based deep expression proteomics and phosphoproteomics in 20 orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3, and G4 subgroups. We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models. SHH PDXs were enriched for NFκB and p38 MAPK signaling, while G3 PDXs were characterized by MYC activity. Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes. Our results highlight several candidate pathways that may serve as targets for new MB therapies. Mass spectrometry data are available via ProteomeXchange with identifier PXD035070.
Assuntos
Neoplasias Encefálicas , Neoplasias Cerebelares , Meduloblastoma , Animais , Neoplasias Encefálicas/genética , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Criança , Modelos Animais de Doenças , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/uso terapêutico , Xenoenxertos , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/patologia , ProteômicaRESUMO
Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.
Assuntos
Bortezomib/farmacologia , Processos Neoplásicos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , TYK2 Quinase/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética , Animais , Linhagem Celular Tumoral , Feminino , Edição de Genes , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mieloma Múltiplo , Fosforilação , Complexo de Endopeptidases do Proteassoma/genética , Inibidores de Proteassoma/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Neoplasias de Mama Triplo Negativas/patologia , Quinases DyrkRESUMO
Functional genomics networks are widely used to identify unexpected pathway relationships in large genomic datasets. However, it is challenging to compare the signal-to-noise ratios of different networks and to identify the optimal network with which to interpret a particular genetic dataset. We present GeNets, a platform in which users can train a machine-learning model (Quack) to carry out these comparisons and execute, store, and share analyses of genetic and RNA-sequencing datasets.
Assuntos
Genômica/métodos , Internet , Aprendizado de Máquina , DNA/genética , Bases de Dados de Ácidos Nucleicos , Técnicas de Amplificação de Ácido Nucleico , RNA/genética , SoftwareRESUMO
Signaling pathways are orchestrated by post-translational modifications (PTMs) such as phosphorylation. However, pathway analysis of PTM data sets generated by mass spectrometry (MS)-based proteomics is typically performed at a gene-centric level because of the lack of appropriately curated PTM signature databases and bioinformatic tools that leverage PTM site-specific information. Here we present the first version of PTMsigDB, a database of modification site-specific signatures of perturbations, kinase activities and signaling pathways curated from more than 2,500 publications. We adapted the widely used single sample Gene Set Enrichment Analysis approach to utilize PTMsigDB, enabling PTMSignature Enrichment Analysis (PTM-SEA) of quantitative MS data. We used a well-characterized data set of epidermal growth factor (EGF)-perturbed cancer cells to evaluate our approach and demonstrated better representation of signaling events compared with gene-centric methods. We then applied PTM-SEA to analyze the phosphoproteomes of cancer cells treated with cell-cycle inhibitors and detected mechanism-of-action specific signatures of cell cycle kinases. We also applied our methods to analyze the phosphoproteomes of PI3K-inhibited human breast cancer cells and detected signatures of compounds inhibiting PI3K as well as targets downstream of PI3K (AKT, MAPK/ERK) covering a substantial fraction of the PI3K pathway. PTMsigDB and PTM-SEA can be freely accessed at https://github.com/broadinstitute/ssGSEA2.0.
Assuntos
Neoplasias da Mama/metabolismo , Biologia Computacional/métodos , Fosfoproteínas/metabolismo , Proteômica/métodos , Animais , Linhagem Celular Tumoral , Curadoria de Dados , Bases de Dados de Proteínas , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , RatosRESUMO
Complex biomedical analyses require the use of multiple software tools in concert and remain challenging for much of the biomedical research community. We introduce GenomeSpace (http://www.genomespace.org), a cloud-based, cooperative community resource that currently supports the streamlined interaction of 20 bioinformatics tools and data resources. To facilitate integrative analysis by non-programmers, it offers a growing set of 'recipes', short workflows to guide investigators through high-utility analysis tasks.
Assuntos
Algoritmos , Mapeamento Cromossômico/métodos , Biologia Computacional/métodos , Bases de Dados Genéticas , Genoma Humano/genética , Software , Mineração de Dados , Humanos , Internet , Integração de SistemasRESUMO
The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to 'omics'-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.
Assuntos
Ensaios Clínicos como Assunto/métodos , Genômica , Projetos de Pesquisa , Lista de Checagem , Ensaios Clínicos como Assunto/economia , Ensaios Clínicos como Assunto/ética , Ensaios Clínicos como Assunto/normas , Estudos de Avaliação como Assunto , Genômica/ética , Humanos , Modelos Biológicos , National Cancer Institute (U.S.)/economia , Medicina de Precisão/ética , Medicina de Precisão/métodos , Medicina de Precisão/normas , Projetos de Pesquisa/normas , Manejo de Espécimes , Estados UnidosRESUMO
Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system's ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative.
Assuntos
Neoplasias/imunologia , Neoplasias/prevenção & controle , Lesões Pré-Cancerosas/patologia , Células Germinativas/metabolismo , Humanos , Sistema Imunitário/patologia , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Microambiente TumoralRESUMO
The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
Assuntos
Bases de Dados Factuais , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Enciclopédias como Assunto , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Linhagem da Célula , Cromossomos Humanos/genética , Ensaios Clínicos como Assunto/métodos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes ras/genética , Genoma Humano/genética , Genômica , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Farmacogenética , Plasmócitos/citologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Medicina de Precisão/métodos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Análise de Sequência de DNA , Inibidores da Topoisomerase/farmacologiaRESUMO
Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, ß-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic ß-catenin signalling in medulloblastoma.
Assuntos
Neoplasias Cerebelares/genética , Exoma/genética , Genoma Humano/genética , Meduloblastoma/genética , Mutação/genética , Neoplasias Cerebelares/classificação , Criança , RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA Helicases/química , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Proteínas Hedgehog/metabolismo , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Meduloblastoma/classificação , Modelos Moleculares , Proteínas de Neoplasias/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Receptores Patched , Receptor Patched-1 , Regiões Promotoras Genéticas/genética , Estrutura Terciária de Proteína/genética , Proteínas Proto-Oncogênicas/genética , Receptores de Superfície Celular/genética , Proteínas Repressoras/genética , Transdução de Sinais , Fatores de Transcrição TCF/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Background: Pediatric acute respiratory distress in tropical settings is very common. Bacterial pneumonia is a major contributor to morbidity and mortality rates and requires adequate diagnosis for correct treatment. A rapid test that could identify bacterial (vs other) infections would have great clinical utility. Methods and Results: We performed RNA (RNA-seq) sequencing and analyzed the transcriptomes of 68 pediatric patients with well-characterized clinical phenotype to identify transcriptional features associated with each disease class. We refined the features to predictive models (support vector machine, elastic net) and validated those models in an independent test set of 37 patients (80%-85% accuracy). Conclusions: We have identified sets of genes that are differentially expressed in pediatric patients with pneumonia syndrome attributable to different infections and requiring different therapeutic interventions. Findings of this study demonstrate that human transcription signatures in infected patients recapitulate the underlying biology and provide models for predicting a bacterial diagnosis to inform treatment.