Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Percolation and cluster distribution. II. layers, variable-range interactions, and exciton cluster model

Monte Carlo simulations for the site percolation problem are presented for lattices up to 64 x 10 6 sites. We investigate for the square lattice the variable-range percolation problem, where distinct trends with bond-length are found for the critical concentrations and for the critical exponents β and γ . We also investigate the layer problem for stacks of square lattices added to approach a simple cubic lattice, yielding critical concentrations as a functional of layer number as well as the correlation length exponent ν . We also show that the exciton migration probability for a common type of ternary lattice system can be described by a cluster model and actually provides a cluster generating function.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45139/1/10955_2005_Article_BF01011724.pd

Percolation and cluster distribution. III. Algorithms for the site-bond problem

Algorithms for estimating the percolation probabilities and cluster size distribution are given in the framework of a Monte Carlo simulation for disordered lattices for the generalized site-bond problem. The site-bond approach is useful when a percolation process cannot be exclusively described in the context of pure site or pure bond percolation. An extended multiple labeling technique (ECMLT) is introduced for the generalized problem. The ECMLT is applied to the site-bond percolation problem for square and triangular lattices. Numerical data are given for lattices containing up to 16 million sites. An application to polymer gelation is suggested.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45140/1/10955_2005_Article_BF01011170.pd

System Architecture Tools and Assumptions

This conference features the work of authors from: Georgia Tech’s Space Systems Design Lab, Aerospace Systems Design Lab, School of Aerospace Engineering, Georgia Tech Research Institute; NASA’s Jet Propulsion Laboratory, Marshall Space Flight Center, Goddard Space Flight Center, Langley Research Center; and other aerospace industry and academic institutionsDiscussion of various system architecture tools and assumptions available to modify existing architectures for new requirements and mission objectives. This study started from proven Apollo concept and adjusted it for new requirements and mission objectives. New technologies were included to decrease size and cost. A crew size trade study is presented to demonstrate how mass size, propulsion size, and trajectory are calculated for an unmanned and up to four man crew in lunar exploration missionsAIAA Space Systems Technical Committee ; AIAA Space Transportation Systems Technical Committee ; Space Technology Advanced Research Cente