The CDC estimates 6.2 million adults in the US have heart failure, which is a serious condition whereby the heart is no longer able to provide adequate blood and oxygen to all organs in the body. Mitochondria are subcellular organelle in heart muscle cells or cardiomyocytes, that produce the ATP required for the heart to provide blood supply. Since ATP production is decreased in heart failure, the collaborative work described in this publication aimed to identify interactome changes to improve understanding of metabolic alterations involved in decreased ATP production.
The authors use patient-derived tumor cells to identify and validate new drug targets as well as to identify potentially effective therapies for drug-resistant cancers, in other words, functional precision oncology. There are few effective therapies specific to RAS or TP53 mutant cancers. Here, the authors identify a broad set of targetable dependencies in SCCs which carry mutations in RAS, TP53, or both. Importantly, they find that targetable dependencies (e.g. synthetic lethality) in RAS mutant tumors is context-dependent and modified by co-mutations, especially in TP53. The next steps include further validation of the novel targets in human cancer models and development of inhibitors.
T cells modified to express a chimeric-antigen receptor (CAR)targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the co-stimulatory signaling module of the…
Group B Streptococcus (GBS) transmission during pregnancy causes preterm labor, stillbirths, fetal injury, or neonatal infections. Rates of adult infections are also rising. The GBS-NN vaccine, engineered by fusing N-terminal domains of GBS alpha C and Rib proteins, is safe in healthy, non-pregnant women, but further assessment is needed for use during pregnancy. Here, we tested GBS-NN vaccine efficacy using mouse…
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.
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…
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.
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…
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.
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…