eIF4A inhibitors suppress cell-cycle feedback response and acquired resistance to CDK4/6 inhibition in cancer

CDK4/6 inhibitors are FDA-approved drugs for estrogen receptor-positive (ER+) breast cancer and are being evaluated to treat other tumor types, including KRAS-mutant non-small cell lung cancer (NSCLC). However, their clinical utility is often limited by drug resistance. Here, we sought to better understand the resistant mechanisms and help devise potential strategies to overcome this challenge. We show that treatment with CDK4/6 inhibitors in both ER+ breast cancer and KRAS-mutant NSCLC cells induces feedback upregulation of cyclin D1, CDK4, and cyclin E1, mediating drug resistance. We demonstrate that rocaglates, which preferentially target translation of key cell-cycle regulators, effectively suppress this feedback upregulation induced by CDK4/6 inhibition. Consequently, combination treatment of CDK4/6 inhibitor palbociclib with the eukaryotic initiation factor (eIF) 4A inhibitor, CR-1-31-B, is synergistic in suppressing the growth of these cancer cells in vitro and in vivo Furthermore, ER+ breast cancer and KRAS-mutant NSCLC cells that acquired resistance to palbociclib after chronic drug exposure are also highly sensitive to this combination treatment strategy. Our findings reveal a novel strategy using eIF4A inhibitors to suppress cell-cycle feedback response and to overcome resistance to CDK4/6 inhibition in cancer.Accepted manuscrip

Exploring the performance of the spectrometer prisma in heavy zirconium and xenon mass regions

We present results from two recent runs which illustrate the performance of the PRISMA spectrometer in the proximity of the upper limit of its operational interval, namely 96Zr + 124Sn at Elab = 500 MeV and 136Xe + 208Pb at Elab = 930 MeV. In the latter run, the γ array CLARA also allowed us to identify previously unknown γ transitions in the nuclides 136Cs and 134I

Multifragmentation process for different mass asymmetry in the entrance channel around the Fermi energy

The influence of the entrance channel asymmetry upon the fragmentation process is addressed by studying heavy-ion induced reactions around the Fermi energy. The data have been recorded with the INDRA 4pi array. An event selection method called the Principal Component Analysis is presented and discussed. It is applied for the selection of central events and furthermore to multifragmentation of single source events. The selected subsets of data are compared to the Statistical Multifragmentation Model (SMM) to check the equilibrium hypothesis and get the source characteristics. Experimental comparisons show the evidence of a decoupling between thermal and compresional (radial flow) degrees of freedom in such nuclear systems.Comment: 28 pages, 15 figures, article sumitted to Nuclear Physics

Dynamical effects in multifragmentation at intermediate energies

The fragmentation of the quasi-projectile is studied with the INDRA multidetector for different colliding systems and incident energies in the Fermi energy range. Different experimental observations show that a large part of the fragmentation is not compatible with the statistical fragmentation of a fully equilibrated nucleus. The study of internal correlations is a powerful tool, especially to evidence entrance channel effects. These effects have to be included in the theoretical descriptions of nuclear multifragmentation.Comment: 13 pages, 26 figures, submitted to Physical Review

Anticoagulant Therapy and Risk of Cerebrovascular Events After Catheter Ablation of Atrial Fibrillation in the Elderly

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90264/1/j.1540-8167.2011.02141.x.pd

Multinucleon transfer reactions in closed-shell nuclei

Multinucleon transfer reactions in 40Ca+96Zr and 90Zr+208Pb have been measured at energies close to the Coulomb barrier in a high resolution gamma-particle coincidence experiment. The large solid angle magnetic spectrometer PRISMA coupled to the CLARA gamma-array has been employed. Trajectory reconstruction has been applied for the complete identification of transfer products. Mass and charge yields, total kinetic energy losses, gamma transitions of the binary reaction partners, and comparison of data with semiclassical calculations are reported. Specific transitions in 95Zr populated in one particle transfer channels are discussed in terms of particle-phonon couplings. The gamma decays from states in 42Ca in the excitation energy region expected from pairing vibrations are also observed

Multidisciplinary approach to reconstructing local pastoral activities: an example from the Pyrenean Mountains (Pays Basque)

International audienceIn this study archaeology, history and palaeoecology (modern and fossil data sets of pollen and nonpollen palynomorphs) were used to reconstruct small-scale pastoral activities in the Pyrenees Mountains during the last two millennia. Modern pollen assemblages from the major vegetation units (both natural andanthropogenic) are studied on one restricted watershed area. A correlative model (RDA) of 61 modern pollen spectra and 35 external variables distinguishes two groups of taxa, providing information on the nature and spatial extent of human impact on the landscape. The first pool indicates local pastoral activities, and the second one implies regional input from outside the studied watershed, and is not characteristic of a specific land use. These pools are described as 'Local Pastoral Pollen Indicators' (LPPI) for this particular mountain region on crystalline bedrock and 'Regional Human Activities Pollen Indicators' (RHAPI). The modern data set is used to aid interpretation of the local pollen sequence of Sourzay that covers the last 2000 calendar years BP, using RDA reconstructions, and best modern analogues as a means of comparing modern and fossil spectra. The study also demonstrates agreement between the independent interpretations of two fossil proxies, LPPI and coprophilous fungi

European summer temperatures since Roman times

The spatial context is critical when assessing present-day climate anomalies, attributing them to potential forcings and making statements regarding frequency and severity in the long-term perspective. Recent initiatives have expanded the number of high-quality proxy-records and developed new reconstruction methods. These advances allow more rigorous regional past temperature reconstructions and the possibility of evaluating climate models on policy-relevant, spatio-temporal scales. We provide a new proxy-based, annually-resolved, spatial reconstruction of the European summer temperature fields back to 755 CE based on a Bayesian hierarchical modelling (BHM), together with estimates of the European mean temperature variation since 138 BCE based on Composite-plus-Scaling. Our reconstructions compare well with independent instrumental and proxy-based temperature estimates, but suggest a larger amplitude in summer temperature variability than previously reported. Temperature differences between the medieval period, the recent period and Little Ice Age are larger in reconstructions than simulations. This may indicate either inflated variability of the reconstructions, a lack of sensitivity to external forcing on sub-hemispheric scales in the climate models and/or an underestimation of internal variability on centennial and longer time scales including the representation of internal feedback mechanisms