No abstract

Each tumor contains malignant cells that differ in genotype, phenotype, and in their interactions with the tumor micro-environment (TME). This results in distinct integrated cellular states that govern intra-tumor heterogeneity (ITH), a central challenge of cancer therapeutics. Dozens of recent studies have begun to describe ITH by single cell RNA-seq, but each study typically profiledonly a small number of tumors and provided a narrow view of transcriptional ITH. Here, we curate, annotate and integrate the data from 77 different studies to reveal the patterns of ITH across 1,163 tumor samples covering 24 tumor types. Focusing on the malignant cells, we find thousands of transcriptional ITH programs that can be described by 41 consensus meta-programs (MPs), each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many different tumors. The MPs cover diverse cellular processes and differ in their cancer-type distribution. General MPs associated with processes such as cell cycle and stress vary within most tumors, while context-specific MPs reflect the unique biology of particular cancer types, often resembling developmental cell types and suggesting the co-existence of variable differentiation states within tumors. Some of the MPs are further associated with overall tumor proliferation or immune state, highlighting their potential clinical significance. Based on functional similarities among MPs, we propose a set of 11 hallmarks that together account for the majority of observed ITH programs. Given the breadth and scope of the investigated cohort, the MPs and hallmarks described here reflect the first comprehensive pan-cancer description of transcriptional ITH.

The dermal scratch provides a well-tolerated, standardized, and reproducible wound model for investigating the healing response to dermal injury of different depths. There is a threshold depth of dermal injury at which scarring develops.

In order to assess the influence of the vertebral heart scale (VHS) on the accuracy of the radiographic diagnosis of cardiac disease, thoracic radiographs of 50 dogs with proven cardiac disease, 26 with other thoracic diseases, and 50 with no clinical signs of cardiovascular or respiratory disease were mixed and examined by three independent, blinded observers chosen to represent a range of radiographic abilities. They first examined all the radiographs without making measurements of VHS and made a diagnosis. They then re-examined the radiographs, and measured VHS on both lateral and dorsoventral or ventrodorsal radiographs before again recording a diagnosis without reference to their original diagnoses. For all the observers, the dogs with cardiac disease had a higher mean VHS than the normal dogs. A VHS over 10.7 on the lateral radiograph was a moderately accurate sign of cardiac disease. The observers' accuracy of diagnosis did not change significantly as a result of using VHS as an adjunct to a subjective assessment of the radiographs.