FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036

Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy

Modelling Jets, Tori and Flares in Pulsar Wind Nebulae

In this contribution we review the recent progress in the modelling of Pulsar Wind Nebulae (PWN). We start with a brief overview of the relevant physical processes in the magnetosphere, the wind-zone and the inflated nebula bubble. Radiative signatures and particle transport processes obtained from 3D simulations of PWN are discussed in the context of optical and X-ray observations. We then proceed to consider particle acceleration in PWN and elaborate on what can be learned about the particle acceleration from the dynamical structures called GwispsG observed in the Crab nebula. We also discuss recent observational and theoretical results of gamma-ray flares and the inner knot of the Crab nebula, which had been proposed as the emission site of the flares. We extend the discussion to GeV flares from binary systems in which the pulsar wind interacts with the stellar wind from a companion star. The chapter concludes with a discussion of solved and unsolved problems posed by PWN

Temperature related factors as selection criteria in apple breeding

SIGLEAvailable from British Library Document Supply Centre- DSC:DX187568 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Latin America and the Great War A study of the effects of the First World War on economic and social conditions in Peru and Chile

SIGLEAvailable from British Library Lending Division - LD:D56096/85 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Institutions and (short-run) macroeconomic performance

SIGLEAvailable from British Library Document Supply Centre- DSC:3597.7765(EAU-ERC-DP--9124) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Minimum wage legislation, investment and human capital

SIGLEAvailable from British Library Document Supply Centre- DSC:3597.7765(UEA-ERC-DP--9508) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Permanent family placement for children of minority ethnic origin

SIGLEAvailable from British Library Document Supply Centre-DSC:99/17218 / BLDSC - British Library Document Supply CentreGBUnited Kingdo