6 research outputs found

    ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells

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    Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers

    ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells

    No full text
    Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers

    Finska tingsdomares bedömningar av partsutlåtanden givna på plats i rätten eller via videokonferens

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    Professionals within the judicial system sometimes believe they can assess whether someone is lying or not based on cues such as body language and emotional expression. Research has, however, shown that this is impossible. The Finnish Supreme Court has also given rulings in accordance with this demonstrated fact. There has also been previous research on whether party or witness statements are assessed differently in court depending on whether they are given live, via videoconference, or via prerecorded video. In the present study, we investigated how a Finnish sample of district judges (N=47) assigned probative value to different variables concerning the statement or the statement giver, such as body language and emotional expression. We also investigated the connection between the judges’ beliefs about the relevance of body language and emotional expression and their preference for live statements or statements via videoconference. The judges reported assigning equal amounts of probative value to statements given live and statements given via videoconference. However, judges found it easier to detect deception live, and this preference correlated with how relevant they thought body language is when assessing the probative value of the statement. In other words, a slight bias to assess live statements more favorably than statements given via videoconference might still exist. More effort needs to be put into making judges and Supreme Courts aware of robust scientific results that have been the subject of decades of research, such as the fact that one cannot assess whether someone is lying or not based on cues such as body language

    Measurement of differential J/ψJ/\psi production cross-sections and forward-backward ratio in p+Pb collisions with the ATLAS detector

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    Measurements of differential cross-sections for J/ψJ/\psi production in p+Pb collisions at sNN\sqrt{s_{NN}} = 5.02 TeV at the LHC with the ATLAS detector are presented. The data set used corresponds to an integrated luminosity of 28.1 nb1^{-1}. The J/ψJ/\psi mesons are reconstructed in the dimuon decay channel over the transverse momentum range 8<pT<308<p_{\mathrm{T}}<30 GeV and over the center-of-mass rapidity range 2.87<y<1.94-2.87<y^{*}<1.94. Prompt J/ψJ/\psi are separated from J/ψJ/\psi resulting from bb-hadron decays through an analysis of the distance between the J/ψJ/\psi decay vertex and the event primary vertex. The differential cross-section for production of nonprompt J/ψJ/\psi is compared to a FONLL calculation that does not include nuclear effects. Forward-backward production ratios are presented and compared to theoretical predictions. These results constrain the kinematic dependence of nuclear modifications of charmonium and bb-quark production in p+Pb collisions
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