with engineered tandem elements). Applying MACHETE to a syngeneic mouse model of pancreatic cancer, we found that co-deletion of the IFN cluster promoted immune evasion, metastasis and immunotherapy resistance. Mechanistically, IFN co-deletion disrupted type I IFN signaling in the tumor microenvironment, leading to marked changes in infiltrating immune cells and escape from CD8⁺ T-cell surveillance, effects largely driven by the poorly understood interferon epsilon. These results reveal a chromosomal deletion that disables both cell-intrinsic and cell-extrinsic tumor suppression and provide a framework for interrogating large deletions in cancer and beyond.22:T50f,Little is known about the spectrum of mitochondrial DNA (mtDNA) mutations across pediatric malignancies. In this study, we analyzed matched tumor and normal whole genome sequencing data from 616 pediatric patients with hematopoietic malignancies, solid tumors, and brain tumors. We identified 391 mtDNA mutations in 284 tumors including 45 loss-of-function mutations, which clustered at four statistically significant hotspots in MT-COX3, MT-ND4, and MT-ND5, and at a mutation hotspot in MT-tRNA-MET. A skewed ratio (4.83) of nonsynonymous versus synonymous (dN/dS) mtDNA mutations with high statistical significance was identified on the basis of Monte Carlo simulations in the tumors. In comparison, opposite ratios of 0.44 and 0.93 were observed in 616 matched normal tissues and in 249 blood samples from children without cancer, respectively. mtDNA mutations varied by cancer type and mtDNA haplogroup. Collectively, these results suggest that deleterious mtDNA mutations play a role in the development and progression of pediatric cancers. SIGNIFICANCE: This pan-cancer mtDNA study establishes the landscape of germline and tumor mtDNA mutations and identifies hotspots of tumor mtDNA mutations to pinpoint key mitochondrial functions in pediatric malignancies.23:T4be,Alchemical free energy calculations have made a dramatic impact upon the field of structure-based drug design by allowing functional group modifications to be explored computationally prior to experimental synthesis and assay evaluation, thereby informing and directing synthetic strategies. In furthering the advancement of this area, a series of 21 β-secretase 1 (BACE1) inhibitors developed by Janssen Pharmaceuticals were examined to evaluate the ability to explore large substituent perturbations, some of which contain scaffold modifications, with multisite λ-dynamics (MSλD), an innovative alchemical free energy framework. Our findings indicate that MSλD is able to efficiently explore all structurally diverse ligand end-states simultaneously within a single MD simulation with a high degree of precision and with reduced computational costs compared to the widely used approach TI/MBAR. Furthermore, computational predictions were shown to be accurate to within 0.5-0.8 kcal/mol when CM1A partial atomic charges were combined with CHARMM or OPLS-AA-based force fields, demonstrating that MSλD is force field independent and a viable alternative to FEP or TI approaches for drug design.

	Year	Citations

About