The Role of Telomere Dysfunction in Driving Genomic Instability

The mechanistic role of radiation-induced genomic instability in radiation carcinogenesis is an attractive hypothesis that remains to be rigorously tested. There are few in vivo studies on which to base judgments, but work in our laboratory with mouse models of radiogenic mammary neoplasia provided the first indications that certain forms of genetically predisposed radiation-induced genomic instability may contribute to tumor development. The central goal of this research project is to more firmly establish the mechanistic basis of this radiation-associated genomic instability and, from this, to assess whether such induced instability might play a major role in tumorigenesis at low doses of low LET radiation. In the case of mouse mammary tumors, susceptibility to induced instability is expressed as an autosomal recessive trait in mammary epithelial cells and is manifest largely as excess chromatid damage. Recently published studies associate this form of instability with DNA repair deficiency, polymorphic variation in the gene encoding DNA-PKcs (Prkdc), and mammary associated susceptibility. The underlying hypothesis being tested in this project is that tumor-associated genomic instability is preferentially expressed in certain recombinogenic genomic domains and that these may be cell lineage/individual-specific

The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Sequential and Direct Two-Photon Double Ionization of D₂ at Flash

Sequential and direct two-photon double ionization (DI) of D2 molecule is studied experimentally and theoretically at a photon energy of 38.8 eV. Experimental and theoretical kinetic energy releases of D++D+fragments, consisting of the contributions of sequential DI via the D2+(1sσg) state and direct DI via a virtual state, agree well with each other

Revisiting metal fluorides as lithium-ion battery cathodes.

Metal fluorides, promising lithium-ion battery cathode materials, have been classified as conversion materials due to the reconstructive phase transitions widely presumed to occur upon lithiation. We challenge this view by studying FeF3 using X-ray total scattering and electron diffraction techniques that measure structure over multiple length scales coupled with density functional theory calculations, and by revisiting prior experimental studies of FeF2 and CuF2. Metal fluoride lithiation is instead dominated by diffusion-controlled displacement mechanisms, and a clear topological relationship between the metal fluoride F- sublattices and that of LiF is established. Initial lithiation of FeF3 forms FeF2 on the particle's surface, along with a cation-ordered and stacking-disordered phase, A-LixFeyF3, which is structurally related to α-/β-LiMn2+Fe3+F6 and which topotactically transforms to B- and then C-LixFeyF3, before forming LiF and Fe. Lithiation of FeF2 and CuF2 results in a buffer phase between FeF2/CuF2 and LiF. The resulting principles will aid future developments of a wider range of isomorphic metal fluorides.X.H. is supported by funding from EPSRC Doctoral Prize, Adolphe Merkle and the Swiss National Science Foundation (Program NRP70 No. 153990) and European Commission via MSCA (Grant 798169). A.S.E. acknowledges financial support from the Royal Society. E.C.M. acknowledges funding from European Commission via MSCA (Grant 747449) and RTI2018-094550-A-100 from MICINN. Z. L. acknowledges funding from the Faraday Institution via the FutureCat consortium. C.J.P. is supported by the Royal Society through a Royal Society Wolfson Research Merit award, and EPSRC grant EP/P022596/1. A.L.G. acknowledges funding from the ERC (Grant 788144). This research was supported as part of the North Eastern Center for Chemical Energy Storage, an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, and Office of Basic Energy Sciences under Award Number DE-SC0001294. Work done at Argonne and use of the Advanced Photon Source, an Office of Science User Facility operated for the US Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the US DOE under Contract No. DE-AC02-06CH11357. Work done at Diamond Light Source was under Proposal EE17315-1. The authors are grateful to Prof. G. Ceder and other NECCES members for many stimulating discussions concerning fluoride-based conversion reactions and on the origins of structural hysteresis. The authors also acknowledge the help from S. Dutton, T. Dean, A. Docker, M. Leskes and D. Keeble

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Charged and strange hadron elliptic flow in Cu+Cu collisions at sNN\sqrt{s_{NN}} = 62.4 and 200 GeV

We present the results of an elliptic flow analysis of Cu+Cu collisions recorded with the STAR detector at 62.4 and 200GeV. Elliptic flow as a function of transverse momentum is reported for different collision centralities for charged hadrons and strangeness containing hadrons $K_{S}^{0}$, $\Lambda$, $\Xi$, $\phi$ in the midrapidity region $|eta|<1.0$. Significant reduction in systematic uncertainty of the measurement due to non-flow effects has been achieved by correlating particles at midrapidity, $|\eta|<1.0$, with those at forward rapidity, $2.5<|\eta|<4.0$. We also present azimuthal correlations in p+p collisions at 200 GeV to help estimating non-flow effects. To study the system-size dependence of elliptic flow, we present a detailed comparison with previously published results from Au+Au collisions at 200 GeV. We observe that $v_{2}$($p_{T}$) of strange hadrons has similar scaling properties as were first observed in Au+Au collisions, i.e.: (i) at low transverse momenta, $p_T<2GeV/c$, $v_{2}$ scales with transverse kinetic energy, $m_{T}-m$, and (ii) at intermediate $p_T$, $2<p_T<4GeV/c$, it scales with the number of constituent quarks, $n_q$. We have found that ideal hydrodynamic calculations fail to reproduce the centrality dependence of $v_{2}$($p_{T}$) for $K_{S}^{0}$ and $\Lambda$. Eccentricity scaled $v_2$ values, $v_{2}/\epsilon$, are larger in more central collisions, suggesting stronger collective flow develops in more central collisions. The comparison with Au+Au collisions which go further in density shows $v_{2}/\epsilon$ depend on the system size, number of participants $N_{part}$. This indicates that the ideal hydrodynamic limit is not reached in Cu+Cu collisions, presumably because the assumption of thermalization is not attained.Comment: 18 pages, 14 figure

Studying Parton Energy Loss in Heavy-Ion Collisions via Direct-Photon and Charged-Particle Azimuthal Correlations

Charged-particle spectra associated with direct photon ($\gamma_{dir}$) and $\pi^0$ are measured in $p$+$p$ and Au+Au collisions at center-of-mass energy $\sqrt{s_{_{NN}}}=200$ GeV with the STAR detector at RHIC. A hower-shape analysis is used to partially discriminate between $\gamma_{dir}$ and $\pi^0$. Assuming no associated charged particles in the $\gamma_{dir}$ direction (near side) and small contribution from fragmentation photons ($\gamma_{frag}$), the associated charged-particle yields opposite to $\gamma_{dir}$ (away side) are extracted. At mid-rapidity ($|\eta|<0.9$) in central Au+Au collisions, charged-particle yields associated with $\gamma_{dir}$ and $\pi^0$ at high transverse momentum ($8< p_{T}^{trig}<16$ GeV/$c$) are suppressed by a factor of 3-5 compared with $p$ + $p$ collisions. The observed suppression of the associated charged particles, in the kinematic range $|\eta|<1$ and $3< p_{T}^{assoc} < 16$ GeV/$c$, is similar for $\gamma_{dir}$ and $\pi^0$, and independent of the $\gamma_{dir}$ energy within uncertainties. These measurements indicate that the parton energy loss, in the covered kinematic range, is insensitive to the parton path length.Comment: submitted to Phys. Rev. Lett, 6 pages, 4 figure