Zelfevaluatie: programma Thematische wetsevaluatie: opbrengsten en gebruik. (Reeks evaluatie regelgeving)

The politics and administration of institutional chang

Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling

Although conventional therapies for acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) are effective in inducing remission, many patients relapse upon treatment. Hence, there is an urgent need for novel therapies. PIM kinases are often overexpressed in AML and DLBCL and are therefore an attractive therapeutic target. However, in vitro experiments have demonstrated that intrinsic resistance to PIM inhibition is common. It is therefore likely that only a minority of patients will benefit from single agent PIM inhibitor treatment. In this study, we performed an shRNA-based genetic screen to identify kinases whose suppression is synergistic with PIM inhibition. Here, we report that suppression of p38α (MAPK14) is synthetic lethal with the PIM kinase inhibitor AZD1208. PIM inhibition elevates reactive oxygen species (ROS) levels, which subsequently activates p38α and downstream AKT/mTOR signaling. We found that p38α inhibitors sensitize hematological tumor cell lines to AZD1208 treatment in vitro and in vivo. These results were validated in ex vivo patient-derived AML cells. Our findings provide mechanistic and translational evidence supporting the rationale to test a combination of p38α and PIM inhibitors in clinical trials for AML and DLBCL

Low-lying octupole isovector excitation in Nd-144

International audienceThe nature of low-lying 3− levels in Nd144 was investigated in the Nd143(n,γγ) cold neutron-capture reaction. The combination of the high neutron flux from the research reactor at the Institut Laue-Langevin and the high γ-ray detection efficiency of the EXILL setup allowed the recording of γγ coincidences. From the coincidence data precise branching ratios were extracted. Furthermore, the octagonal symmetry of the setup allowed angular-distribution measurements to determine multipole-mixing ratios. Additionally, in a second measurement the ultra-high resolution spectrometer GAMS6 was employed to conduct lifetime measurements using the gamma-ray induced Doppler-shift technique (GRID). The confirmed strong M1 component in the 33−→31− decay strongly supports the assignment of the 33− level at 2779keV as low-lying isovector octupole excitation. Microscopic calculations within the quasiparticle phonon model confirm an isovector component in the wave function of the 33− level, firmly establishing this fundamental mode of nuclear excitation in near-spherical nuclei

Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition

In most colorectal cancer (CRC) patients, outcome cannot be predicted because tumors with similar clinicopathological features can have differences in disease progression and treatment response. Therefore, a better understanding of the CRC biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for other patients. Based on unsupervised classification of whole genome data from 188 stages I–IV CRC patients, a molecular classification was developed that consist of at least three major intrinsic subtypes (A-, B- and C-type). The subtypes were validated in 543 stages II and III patients and were associated with prognosis and benefit from chemotherapy. The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in high mutation frequency associated with microsatellite instability and cellular proliferation. A-type tumors, observed in 22% of the patients, have the best prognosis, have frequent BRAF mutations and a deficient DNA mismatch repair system. C-type patients (16%) have the worst outcome, a mesenchymal gene expression phenotype and show no benefit from adjuvant chemotherapy treatment. Both A-type and B-type tumors have a more proliferative and epithelial phenotype and B-types benefit from adjuvant chemotherapy. B-type tumors (62%) show a low overall mutation frequency consistent with the absence of DNA mismatch repair deficiency. Classification based on molecular subtypes made it possible to expand and improve CRC classification beyond standard molecular and immunohistochemical assessment and might help in the future to guide treatment in CRC patients.Intelligent SystemsElectrical Engineering, Mathematics and Computer Scienc

Decay properties of the level 31−^-_1 in 96^{96}Mo

International audienceThe first excited level of 96Mo was investigated in a high-statistics experiment using the 95Mo(n, γγ) cold neutron capture reaction. The measurements used the high cold neutron flux from the research reactor at Institut Laue-Langevin and employed the highly-efficient EXILL array to detect γ-ray coincidences. The recorded statistics allow identification of decay branches with only a small relative intensity including the E3 decay. With the knowledge of the newly measured branching ratio and the known transition probability, the lifetime of the level was determined and, subsequently, the strength of the other decay branches of the octupole phonon were calculated. The extracted electromagnetic decay strengths are compared to the systematics of the stable even–even molybdenum isotopes and values calculated in a Skyrme-force based quasiparticle random phase approximation and in a cluster approach. Additionally, the decay branch to the low-lying quadrupole isovector level was observed