RESUMO
Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Análise Espacial , Transcriptoma/genética , Microambiente Tumoral , Proteômica , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.
Assuntos
Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Neoplasias , Análise da Expressão Gênica de Célula Única , Humanos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Neoplasias/classificação , Neoplasias/genética , Neoplasias/patologia , Microambiente TumoralRESUMO
BACKGROUND: The recent increase in enterococcal urinary tract infections (EUTI) and the potential morbidity and mortality associated with inappropriate antimicrobial treatment underscores the need for early risk assessment and institution of appropriate empirical antimicrobial therapy. OBJECTIVES: To identify high-risk features associated with hospitalized patients with EUTI. METHODS: Demographic, clinical, laboratory, and bacteriological data of 285 patients hospitalized with UTI during 2016 were retrieved from the computerized database of Shamir Medical Center. Patients were divided into two groups: EUTI and non-EUTI (NEUTI), according to the presence or absence of enterococcus in the urine culture. The features of the two groups were compared. RESULTS: We obtained 300 urine cultures from 285 patients. Of the total, 80 patients (26.6%) had EUTI and 220 patients (73.3%) had NEUTI. A higher prevalence of urinary multi-bacterial cultures was found in EUTI compared to NEUTI patients (P < 0.01). Higher prevalence of permanent indwelling urinary catheter and dementia were found in hospitalized patients with community-acquired EUTI and nosocomial EUTI respectively (P = 0.02, P = 0.016) compared to patients with NEUTI. CONCLUSIONS: Indwelling urinary catheter and dementia are risk factors for EUTI in patients with community and hospital acquired infection, respectively.
