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Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.
Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer
Identification of Collaborative Cross Mouse Strains Permissive to Salmonella Enterica Serovar Typhi Infection
Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in humans is far greater and more complex than that in a single inbred strain of mice. The Collaborative Cross (CC) is a large panel of recombinant inbred strains which has a wider range of genetic diversity than laboratory inbred mouse strains. We found that the CC003/Unc and CC053/Unc strains are permissive to intraperitoneal but not oral route of S. Typhi infection and show histopathological changes characteristic of human typhoid. These CC strains are immunocompetent, and immunization induces antigen-specific responses that can kill S. Typhi in vitro and control S. Typhi in vivo. Our results indicate that CC003/Unc and CC053/Unc strains can help identify the genetic basis for typhoid susceptibility, S. Typhi virulence mechanism(s) in vivo, and serve as a preclinical mammalian model system to identify effective vaccines and therapeutics strategies
CMS physics technical design report : Addendum on high density QCD with heavy ions
Peer reviewe
Substituent Effects on Drug–Receptor H‑bond Interactions: Correlations Useful for the Design of Kinase Inhibitors
Investigation of
troponin I-interacting kinase (TNNI3K) as a potential
target for the treatment of heart failure has produced a series of
substituted <i>N</i>-methyl-3-(pyrimidin-4-ylamino)benzenesulfonamide
inhibitors that display excellent potency and selectivity against
a broad spectrum of protein kinases. Crystal structures of prototypical
members bound to the ATP-binding site of TNNI3K reveal two anchoring
hydrogen bond contacts: (1) from the hinge region amide N–H
to the pyrimidine nitrogen and (2) from the sulfonamide N–H
to the gatekeeper threonine. Evaluation of various <i>para</i>-substituted benzenesulfonamides defined a substituent effect on
binding affinity resulting from modulation of the sulfonamide H-bond
donor strength. An opposite electronic effect emerged for the hinge
NH-pyrimidine H-bond interaction, which is further illuminated in
the correlation of calculated H-bond acceptor strength and TNNI3K
affinity for a variety of hinge binding heterocycles. These fundamental
correlations on drug–receptor H-bond interactions may be generally
useful tools for the optimization of potency and selectivity in the
design of kinase inhibitors
4,6-Diaminopyrimidines as Highly Preferred Troponin I‑Interacting Kinase (TNNI3K) Inhibitors
Structure-guided
progression of a purine-derived series of TNNI3K
inhibitors directed design efforts that produced a novel series of
4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif.
Herein, we report a detailed understanding of the intrinsic conformational
preferences of the scaffold, which impart high specificity for TNNI3K.
Further manipulation of the template based on the conformational analysis
and additional structure–activity relationship studies provided
enhancements in kinase selectivity and pharmacokinetics that furnished
an advanced series of potent inhibitors. The optimized compounds (e.g.,
GSK854) are suitable leads for identifying new cardiac medicines and
have been employed as <i>in vivo</i> tools in investigational
studies aimed at defining the role of TNNI3K within heart failure
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