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

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

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

Constraints on Titan's middle atmosphere ammonia abundance from Herschel/SPIRE sub-millimetre spectra

Sub-millimetre spectra measured with Herschel's SPIRE Fourier Transform Spectrometer were used to search for ammonia (NH3) in Titan's stratosphere. Observations were taken during 2010 and 2011, just after Titan's northern spring equinox, which occurred in mid-2009. In our analysis we used high spectral resolution data (0.074 cm-1 apodised) from the SPIRE shortwave spectrometer array (SSW), which provided the best possible signal-to-noise ratio for detecting any NH3 emission features. These data have the most sensitivity to NH3 spectral emission of any currently available observations, although despite this we did not detect any significant emission features above the noise. However, we can place an improved 3-sigma upper limit on NH3 abundance of <0.19ppb for altitudes 65-110 km (75 km peak sensitivity), or alternatively a column abundance of <1.23×1015molecules/cm2. These observations provide modest constraint for future photochemical models and are consistent with most current stratospheric predictions. Scaling of photochemical model profiles, in order to fit elevated abundances observed at 1100 km by Cassini's INMS instrument, are for the most part also consistent with our observations. © 2012 Elsevier Ltd

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

The Atlas of human African trypanosomiasis: a contribution to global mapping of neglected tropical diseases

<p>Abstract</p> <p>Background</p> <p>Following World Health Assembly resolutions 50.36 in 1997 and 56.7 in 2003, the World Health Organization (WHO) committed itself to supporting human African trypanosomiasis (HAT)-endemic countries in their efforts to remove the disease as a public health problem. Mapping the distribution of HAT in time and space has a pivotal role to play if this objective is to be met. For this reason WHO launched the HAT Atlas initiative, jointly implemented with the Food and Agriculture Organization of the United Nations, in the framework of the Programme Against African Trypanosomosis.</p> <p>Results</p> <p>The distribution of HAT is presented for 23 out of 25 sub-Saharan countries having reported on the status of sleeping sickness in the period 2000 - 2009. For the two remaining countries, i.e. Angola and the Democratic Republic of the Congo, data processing is ongoing. Reports by National Sleeping Sickness Control Programmes (NSSCPs), Non-Governmental Organizations (NGOs) and Research Institutes were collated and the relevant epidemiological data were entered in a database, thus incorporating (i) the results of active screening of over 2.2 million people, and (ii) cases detected in health care facilities engaged in passive surveillance. A total of over 42 000 cases of HAT and 6 000 different localities were included in the database. Various sources of geographic coordinates were used to locate the villages of epidemiological interest. The resulting average mapping accuracy is estimated at 900 m.</p> <p>Conclusions</p> <p>Full involvement of NSSCPs, NGOs and Research Institutes in building the Atlas of HAT contributes to the efficiency of the mapping process and it assures both the quality of the collated information and the accuracy of the outputs. Although efforts are still needed to reduce the number of undetected and unreported cases, the comprehensive, village-level mapping of HAT control activities over a ten-year period ensures a detailed and reliable representation of the known geographic distribution of the disease. Not only does the Atlas serve research and advocacy, but, more importantly, it provides crucial evidence and a valuable tool for making informed decisions to plan and monitor the control of sleeping sickness.</p

Restricted Application of Insecticides: A Promising Tsetse Control Technique, but What Do the Farmers Think of It?

Restricted application of insecticides to cattle is a cheap and safe farmer-based method to control tsetse and the diseases they transmit, i.e. human and animal African trypanosomoses. The efficiency of this new control method has been demonstrated earlier but no data is available on its perception and adoption intensity by farmers. We studied these two features in Burkina Faso, where the method has diffused thanks to two development projects. The study allowed identifying three groups of farmers with various adoption intensities, of which one was modern and two traditional. The economic benefit and the farmers' knowledge of the epidemiological system appeared to have a low impact on the early adoption process whereas some modern practices, as well as social factors appeared critical. The quality of technical support provided to the farmers had also a great influence on the adoption rate. The study highlighted individual variations in risk perceptions and benefits, as well as the prominent role of the socio-technical network of cattle farmers. The results of the study are discussed to highlight the factors that should be taken into consideration, to move discoveries from bench to field for an improved control of trypanosomoses vectors