Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

Experimental support of the scaling rule for demographic stochasticity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73613/1/j.1461-0248.2006.00903.x.pd

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Investigation of Uniaxial Induced Anisotropy in Co0.02Ni0.58Cd0.20Fe2.20O4 and Co0.02Ni0.58Cd0.20Cr0.20Fe2O4 Ferrites

The NiCd ferrites with Fe excess in comparison with stoichiometry composition and with Fe excess amount substituting by Cr, moreover containing small amount of Co are prepared. The formation of preminvar effect and uniaxial induced anisotropy in these ferrites are examined under the heat treatment with and without magnetic field. The appearence of uniaxial induced anisotropy causes unexpected changes of some magnetic and electric properties of ferrites

The Influence of La2O3 Substitution on the Structure and Properties of Sr Hexaferrite

The influence of La substitution on the structure, magnetic and electric properties of Sr hexaferrite is examined in isotropic and anisotropic samples. High quality hard ferrite is obtained with 1 weight % of La substitution (for SiO2 doping samples as well)