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"Gamble, Adam"
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Good night America
Easy-to-read text introduces the sights of America through a full day of sightseeing.
Book
Correction: Protocol for research examination of individual suicides occurring in chronic pain: A qualitative approach to psychological autopsy methodology
[This corrects the article DOI: 10.1371/journal.pone.0329874.].
Journal Article
Good night, farm
Easy-to-read text enumerates the sights and chores of a farm throughout the days and across the seasons.
Book
Whole exome sequencing of adenoid cystic carcinoma
Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.
Journal Article
Count to sleep Yosemite
Learn to count and see the sights of Yosemite National Park at the same time.
Book
RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia
Peter Campbell, Mel Greaves and colleagues use exome and whole-genome sequencing to characterize somatic mutations in childhood acute lymphoblastic leukemias with the
ETV6
-
RUNX1
fusion gene. They find that RAG-mediated deletions are the dominant mutational process.
The
ETV6
-
RUNX1
fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired
in utero
but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies
ATF7IP
and
MGA
as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms
ETV6
-
RUNX1
–positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.
Journal Article
Good night families
Diverse families enjoy spending a day together engaging in such activities as playing at the park, biking, reading, and going to the beach.
Book
ATF4‐mediated stress response as a therapeutic vulnerability in chordoma
Chordoma, a rare primary bone malignancy, currently lacks effective targeted therapies. Despite surgical resection and adjuvant radiotherapy, prognosis remains poor. Recent preclinical studies have highlighted potential therapeutic targets, including the transcription factor T‐box transcription factor T (TBXT). However, clinical outcomes associated with therapies targeting TBXT remain underexplored or have been modest, warranting further investigation. In this study, we investigated the therapeutic potential of transfer RNA (tRNA) synthetase inhibitors in chordoma treatment. Focused compound screening identified distinct chemotypes targeting human glutamyl‐prolyl‐tRNA synthetase (EPRS) as being effective in reducing cell viability in chordoma cell lines through a cyclic AMP‐dependent transcription factor (ATF4)‐mediated stress response rather than through TBXT regulation. Mechanistically significant upregulation of ATF4 and associated stress response genes was identified with consecutive pro‐apoptotic DNA damage‐inducible transcript 3 protein (DDIT3)‐mediated cell death. The prototypic EPRS inhibitor halofuginone demonstrated significant tumour growth inhibition in an in vivo patient‐derived xenograft model. These results suggest that targeting metabolic stress pathways via ATF4 activation presents a novel therapeutic approach for chordoma, warranting further clinical investigation. We screened 5 chordoma cell lines against 100+ inhibitors of epigenetic and metabolic pathways and kinases and identified halofuginone, a tRNA synthetase inhibitor. Mechanistically halofuginone induces an integrated stress response, with eIF2alpha phosphorylation, activation of ATF4 and its target genes CHOP, ASNS, INHBE leading to cell death. Halofuginone significantly reduced tumour growth in a chordoma PDX model.
Journal Article