CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus.

Combining cell-cycle checkpoint kinase inhibitors with the DNA-damaging chemotherapeutic agent gemcitabine offers clinical appeal, with a mechanistic rationale based chiefly on abrogation of gemcitabine-induced G2-M checkpoint activation. However, evidence supporting this mechanistic rationale from chemosensitization studies has not been consistent. Here we report a systematic definition of how pancreatic cancer cells harboring mutant p53 respond to this combination therapy, by combining mathematical models with large-scale quantitative biologic analyses of single cells and cell populations. Notably, we uncovered a dynamic range of mechanistic effects at different ratios of gemcitabine and CHK1 inhibitors. Remarkably, effective synergy was attained even where cells exhibited an apparently functional G2-M surveillance mechanism, as exemplified by a lack of both overt premature CDK1 activation and S-phase mitotic entry. Consistent with these findings, S-G2 duration was extended in treated cells, leading to a definable set of lineage-dependent catastrophic fates. At synergistic drug concentrations, global replication stress was a distinct indicator of chemosensitization as characterized molecularly by an accumulation of S-phase cells with high levels of hyperphosphorylated RPA-loaded single-stranded DNA. In a fraction of these cells, persistent genomic damage was observed, including chromosomal fragmentation with a loss of centromeric regions that prevented proper kinetochore-microtubule attachment. Together, our results suggested a "foot-in-the-door" mechanism for drug synergy where cells were destroyed not by frank G2-M phase abrogation but rather by initiating a cumulative genotoxicity that deregulated DNA synthesis.This study was funded by Cancer Research UK via Institute Senior Group Leader funding (C14303/A17197) to DI Jodrell, and by Sentinel Oncology through an award from Innovate UK.This is the author accepted manuscript. The final version is available from American Association for Cancer Research via http://dx.doi.org/10.1158/0008-5472.CAN-14-334

Міхал Бобжинський: суспільно-політична діяльність

Розглянута суспільно-політична діяльність визначного представника краківської історичної школи М. Бобжинського. Акцентовано увагу на зв’язку наукових поглядів історика з його політичною практикою. Охарактеризовано дискусії, які досьогодні точаться серед науковців щодо оцінки результатів його діяльності.Рассмотрена общественно-политическая деятельность выдающегося представителя краковской исторической школы М. Бобжинского. Акцентировано внимание на связи научных взглядов историка с его политической практикой. Охарактеризованы дискуссии, которые досегодня ведутся среди ученых относительно оценки результатов его деятельности.The socio-political activities of M. Bobzhynski – a prominent representative of the Krakow historical school – are reviewed. Attention is given to the connection of the historian scholarly views with his political practice. The discussions that until now are going on among scholars in evaluating the results of his work are characterised

Clusters in Light Nuclei

A great deal of research work has been undertaken in the alpha-clustering study since the pioneering discovery, half a century ago, of 12C+12C molecular resonances. Our knowledge of the field of the physics of nuclear molecules has increased considerably and nuclear clustering remains one of the most fruitful domains of nuclear physics, facing some of the greatest challenges and opportunities in the years ahead. In this work, the occurence of "exotic" shapes in light N=Z alpha-like nuclei is investigated. Various approaches of superdeformed and hyperdeformed bands associated with quasimolecular resonant structures are presented. Results on clustering aspects are also discussed for light neutron-rich Oxygen isotopes.Comment: 12 pages, 5 figures. Invited Talk presented by C. Beck at the Zakopane Conference on Nuclear Physics "Extremes of the Nuclear Landscape" XLV in the series of Zakopane Schools of Physics - International Symposium - Zakopane, Poland, August 30 - September 5, 2010.To be publihed in Acta Physica Polonica B42 no 3, March 201

Gamma Efficiency Simulations towards Coincidence Measurements for Fusion Cross Sections

With the experimental station STELLA (STELlar LAboratory) we will measure fusion cross sections of astrophysical relevance making use of the coincident detection of charged particles and gamma rays for background reduction. For the measurement of gamma rays from the de-excitation of fusion products a compact array of 36 UK FATIMA LaBr3 detectors is designed based on efficiency studies with Geant4. The photo peak efficiency in the region of interest compares to other gamma detection systems used in this field. The features of the internal decay of 138La is used in a background study to obtain an online calibration of the gamma detectors. Background data are fit to the Monte Carlo model of the self activity assuming crude exponential behavior of external background. Accuracy in the region of interest is of the order of some keV in this first study

Deformation of the N=Z nucleus 76Sr using beta-decay studies

A novel method of deducing the deformation of the N=Z nucleus 76Sr is presented. It is based on the comparison of the experimental Gamow-Teller strength distribution B(GT) from its beta decay with the results of QRPA calculations. This method confirms previous indications of the strong prolate deformation of this nucleus in a totally independent way. The measurement has been carried out with a large Total Absorption gamma Spectrometer, "Lucrecia", newly installed at CERN-ISOLDE.Comment: Accepted in Phys. Rev. Letter

Binary reaction decays from 24Mg+12C

Charged particle and gamma decays in 24Mg* are investigated for excitation energies where quasimolecular resonances appear in 12C+12C collisions. Various theoretical predictions for the occurence of superdeformed and hyperdeformed bands associated with resonance structures with low spin are discussed within the measured 24Mg* excitation energy region. The inverse kinematics reaction 24Mg+12C is studied at E_lab(24Mg) = 130 MeV, an energy which enables the population of 24Mg states decaying into 12C+12C resonant break-up states. Exclusive data were collected with the Binary Reaction Spectrometer in coincidence with EUROBALL IV installed at the VIVITRON Tandem facility at Strasbourg. Specific structures with large deformation were selectively populated in binary reactions and their associated gamma decays studied. Coincident events associated with inelastic and alpha-transfer channels have been selected by choosing the excitation energy or the entry point via the two-body Q-values. The analysis of the binary reaction channels is presented with a particular emphasis on 24Mg-gamma, 20Ne-gamma and 16O-gamma coincidences. New information (spin and branching ratios) is deduced on high-energy states in 24Mg and 16O, respectively.Comment: 27 pages, 8 figures, 1 tabl

Reaction mechanisms in 24Mg+12C and 32S+24Mg

The occurence of "exotic" shapes in light N=Z alpha-like nuclei is investigated for 24Mg+12C and 32S+24Mg. Various approaches of superdeformed and hyperdeformed bands associated with quasimolecular resonant structures with low spin are presented. For both reactions, exclusive data were collected with the Binary Reaction Spectrometer in coincidence with EUROBALL IV installed at the VIVITRON Tandem facility of Strasbourg. Specific structures with large deformation were selectively populated in binary reactions and their associated $\gamma$-decays studied. The analysis of the binary and ternary reaction channels is discussed.Comment: 7 pages, 4 figures, Paper presented at the Fusion08 International Conference on New Aspects of Heavy Ion Collisions Near the Coulomb Barrier, Chicago. Proceedings to be published by AIP Conference Proceedings Illinois, USA, September 22-26, 200

Coupled-channels description of the 40Ca + 58,64Ni transfer and fusion reactions

Preliminary experimental data for nucleon transfer reactions of the 40Ca + 58Ni and 40Ca + 64Ni systems are analyzed with the coupled-channels approach. It is shown that a simple treatment for the transfer in the coupled-channels method cannot reproduce simultaneously the transfer probabilities and the subbarrier enhancement of fusion cross sections