The authors compared human tumor tissues to non-malignant, inflamed tissues and observed extensive phenotypic and functional overlap in regards to the immune infiltrate, but also identified a human tumor-unique regulatory T cell population. They report that this intratumoral Treg population is highly suppressive and can be distinguished from all other hematopoietic cells (in blood and tumor!) by expression of just 2 surface proteins (IL-1R1 and ICOS). Overall, they provide both a highly sought after, human tumor-specific therapeutic target as well as novel insight for disentangling tumor-mediated immune changes from general inflammation-mediated immune changes.
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Although somatic mutations in colorectal cancer are well characterized, little is known about the accumulation of cancer mutations in the normal colon before cancer. Here, we have developed and applied an ultrasensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (<0.001) in normal colon from patients with and without colorectal cancer. This testing…
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The authors showed that TGF-β signaling in smooth muscle cells during embryogenesis and early postnatal life is essential for normal aortic development. This observation left open the possibility that antagonism of TGF-β signaling in adult life might not be harmful. To address this question, they used a genetic approach to ablate TGF-β signaling in smooth muscle cells of adult (11-month-old) mice. Ablation of smooth muscle cell TGF-β signaling caused structural and functional abnormalities of the proximal aorta.
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Read the Publication This week we profile a recent publication in Leukemia from Dr. George Laszlo (pictured, left) and the laboratory of Dr. Roland Walter (right) at Fred Hutch. Can you provide a brief overview of your lab’s current research focus? Our translational research is focused on acute myeloid leukemia (AML). We are particularly interested in improving antibody-based therapies, both…
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The authors show that a commonly occurring type of somatic mutation, loss of heterozygosity (LOH), can be detected at the single-cell level by scRNA-seq. Consequently, in one fell swoop, they show it is possible using scRNA-seq to both identify a cell based on its gene expression signature and infer its lineage based on LOH events shared with other cells. They further show that in females, we can register the branches of the resulting phylogeny to the time in development, around gastrulation, when X-chromosome activation takes place.
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Differential interleukin-2 (IL-2) signaling and production are associated with disparate effector and memory fates. Whether the IL-2 signals perceived by CD8 T cells come from autocrine or paracrine sources, the timing of IL-2 signaling and their differential impact on CD8 T cell responses remain unclear. Using distinct models of germline and conditional IL-2 ablation in post-thymic CD8 T cells, this study shows that…
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Human Cerebellar Development and Transcriptomics: Implications for Neurodevelopmental Disorders

Developmental abnormalities of the cerebellum are among the most recognized structural brain malformations in human prenatal imaging. Yet reliable information regarding their cause in humans is sparse, and few outcome studies are available to inform prognosis. We know very little about human cerebellar development, in stark contrast to the wealth of knowledge from decades of research on cerebellar developmental biology…
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The authors show that only a subset of the CD4+ T cells that are present in human melanoma actually are specific for tumor antigens and that there is another set of cells that are bystanders that don't recognize tumor cells. They are confident in their finding that the cells specific for tumor antigens have a particular "signature" of what genes and surface markers they express because several groups have independently validated similar findings using complementary methods. They then use this "signature" of CD4+ T cells that recognize tumor antigens to begin to ask questions about what these cells might be doing.
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BRCA1/BARD1 Is a Nucleosome Reader and Writer

Mutations in BRCA1 and BARD1 predispose carriers to breast and ovarian cancers. The BRCA1 and BARD1 proteins form a heterodimeric complex (BRCA1/BARD1) that regulates many biological processes, including transcription and DNA double-stranded break repair. These functions are mediated by the only known enzymatic activity of BRCA1/BARD1 in its capacity as an E3 ubiquitin ligase and its role as a central hub for many large protein complexes. But the…
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Familial Long-Read Sequencing Increases Yield of De Novo Mutations

Studies of de novo mutation (DNM) have typically excluded some of the most repetitive and complex regions of the genome because these regions cannot be unambiguously mapped with short-read sequencing data. To better understand the genome-wide pattern of DNM, we generated long-read sequence data from an autism parent-child quad with an affected female where no pathogenic variant had been discovered in short-read…
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