The Polyamine Inhibitor Alpha-Difluoromethylornithine Modulates Hippocampus-Dependent Function after Single and Combined Injuries

Exposure to uncontrolled irradiation in a radiologic terrorism scenario, a natural disaster or a nuclear battlefield, will likely be concomitantly superimposed on other types of injury, such as trauma. In the central nervous system, radiation combined injury (RCI) involving irradiation and traumatic brain injury may have a multifaceted character. This may entail cellular and molecular changes that are associated with cognitive performance, including changes in neurogenesis and the expression of the plasticity-related immediate early gene Arc. Because traumatic stimuli initiate a characteristic early increase in polyamine metabolism, we hypothesized that treatment with the polyamine inhibitor alpha-difluoromethylornithine (DFMO) would reduce the adverse effects of single or combined injury on hippocampus structure and function. Hippocampal dependent cognitive impairments were quantified with the Morris water maze and showed that DFMO effectively reversed cognitive impairments after all injuries, particularly traumatic brain injury. Similar results were seen with respect to the expression of Arc protein, but not neurogenesis. Given that polyamines have been found to modulate inflammatory responses in the brain we also assessed the numbers of total and newly born activated microglia, and found reduced numbers of newly born cells. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, the present study provides new and compelling data regarding the potential use of DFMO as a potential countermeasure against the adverse effects of single or combined injury

Interpretative and predictive modelling of Joint European Torus collisionality scans

Transport modelling of Joint European Torus (JET) dimensionless collisionality scaling experiments in various operational scenarios is presented. Interpretative simulations at a fixed radial position are combined with predictive JETTO simulations of temperatures and densities, using the TGLF transport model. The model includes electromagnetic effects and collisions as well as □(→┬E ) X □(→┬B ) shear in Miller geometry. Focus is on particle transport and the role of the neutral beam injection (NBI) particle source for the density peaking. The experimental 3-point collisionality scans include L-mode, and H-mode (D and H and higher beta D plasma) plasmas in a total of 12 discharges. Experimental results presented in (Tala et al 2017 44th EPS Conf.) indicate that for the H-mode scans, the NBI particle source plays an important role for the density peaking, whereas for the L-mode scan, the influence of the particle source is small. In general, both the interpretative and predictive transport simulations support the experimental conclusions on the role of the NBI particle source for the 12 JET discharges

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults with Chronic Myeloid Leukemia: A CIBMTR Cohort Analysis

Chronic myeloid leukemia (CML) in children and young adults is uncommon. Young patients have long life expectancies and low morbidity with hematopoietic cell transplantation (HCT). Prolonged tyrosine kinase inhibitor (TKI) use may cause significant morbidity. In addition indication for HCT in patients in first chronic phase is not established

Rational Design, Synthesis and Biological Evaluation of Bis(pyrimido[5,6,1-de]acridines) and Bis(pyrazolo[3,4,5-kl]acridine-5-carboxamides) as New Anticancer Agents

The good results obtained with pyrimido[5,6,1-de]acridines 7 and with pyrazolo[3,4,5-kl]-acridinecarboxamides 8 prompted us to the synthesis of two new series of his acridine derivatives: the bis(pyrimidoacridines) 5 and the bis(pyrazoloacridinecarboxamides) 6. Compounds 5 can be regarded also as cyclized derivatives of bis(acridine-4-carboxamides) 3 and compounds 6 as cyclized derivatives of bis(acridine-4-carboxamides) 4. The noncovalent DNA-binding properties of these compounds have been examined using fluorometric techniques. The results indicate that (i) the target compounds are excellent DNA ligands; (ii) the his derivatives 5 and 6 are more DNA-affinic than corresponding monomers 7 and 8; (iii) the new bis 5 and 6 result always less efficient in binding than related bis(acridine-4-carboxamides) 3 and 4; and GO in both series 5 and 6 a clear, remarkable in some cases, preference for binding to AT rich duplexes can be noted. In vitro cytotoxic potency of these derivatives toward the human colon adenocarcinoma cell line (HT29) is described and compared to that of reference drugs. Structure- activity relationships are discussed. We could identify six very potent cytotoxic compounds for further in vitro studies: a cytotoxic screening against six human cancer cell lines and the National Cancer Institute (NCI) screening on 60 human tumor cell lines. Finally, compound 6a was selected for evaluation in a NCI in vivo hollow fiber assay

Gas-phase Heteroaromatic Substitution .14. Attack of Dimethylfluoronium Ion On 2-methyl-pyrroles and 3-methyl-pyrroles, 3-methyl-furans, and 3-methyl-thiophenes

The gas-phase methylation of 2- and 3-methyl-pyrroles (2P and 3P), -furans (2F and 3F), and -thiophenes (2T and 3T) by (CH3)2F+ ions, from gamma-radiolysis of CH3F, has been investigated at pressures ranging from 50 to 760 Torr, in the presence of a thermal radical scavenger (O2) and variable concentrations of an added base (NMe3: 0-10 Torr). The mechanism of the methylation process is discussed and the intrinsic positional selectivity of the (CH3)2F+ ions evaluated in the framework of the Charge and Frontier Orbital Control concept. Owing to the very large energy gap between the LUMO of (CH3)2F+ and the HOMOs of the selected heteroaromatic substrates, their gas-phase methylation is characterized by a distinct affinity of the ionic electrophile toward those substrate positions with the highest net negative charge, i.e., the C3 in 2P (100%), the C4 in 3P (100%), the heteroatom of 2F and 3F (> 80%), the C5 of 2T (32%), and the C2 of 3T (47%). Analysis of the methylated product distribution from 2F and 3F as a function of the experimental conditions reveals that the interaction of the (CH3)2F+ with the heteroatom of furans gives rise to the reversible formation of two sets of electrostatic adducts, i.e., a ''chelate'' adduct (III) and a single proton-bonded adduct (IV), the first rapidly evolving to the alpha-substituted heteroarenium intermediate by proximity effects and the latter slowly rearranging to the chelate structure III. Formation of these categories of electrostatic adducts from furans, which is much less extensive in the case of thiophenes and absent in pyrroles, accounts for the apparent pronounced affinity of gaseous alkylating electrophiles, irrespective of their LUMO energy, for the alpha-carbons of furans

Gas-phase Protonation of Spiropentane - A Novel Entry Into the C5h9+ Potential-energy Surface

The structures, stabilities, and isomerization patterns of C5H9+ ions arising from the gas-phase protonation of spiropentane have been investigated by nuclear-decay, radiolytic, and FT-ICR techniques combined with ab initio calculations. The experimental and theoretical results are consistent with the initial formation of a corner-protonated spiropentane intermediate 17, whose lifetime in the gas phase exceeds 7 X 10(-9) s. This local C5H9+ minimum is separated from the ca. 30 kcal mol-1 more stable cyclopentyl cation as well as from dimethylallyl open-chain isomers by significant energy barriers. Persistency of 17 in the gas phase does not find any correspondence in solution. Solvation and ion-pairing effects may explain the failure to detect C5H9+ structures retaining the spirobicyclic framework of spiropentane in the condensed phase

Lecithin microemulsion gels: A NMR study of molecular mobility based on line widths

Microemulsion gels obtained from solutions of lecithin in organic solvents (in particular isooctane) in the presence of a small amount of water are studied by NMR line width measurements. The ‘H, 13C, and slP resonances of the lecithin molecule are investigated as a function of added water w, (w, = [HzO]/ [LEC]). The line width of the 31P resonance increases sharply at the w, value that induces the maximal viscosity (w, = 3), and similar to the viscosity, the 1H resonance of the -N+(CH& polar head, as well as the l3C resonances of the -CH2CH2N+ group, shows a maximum in their line width (i.e. a minimal molecular mobility) around w, = 3. Conversely, at this w, the mobility of water does not appear to be particularly restricted; actually an effect is noticed only by the addition of the first molecule, which induces a significant increase of mobility both in the polar head of the phospholipid moiety and in the water itself. More in general, the molecular details obtained by NMR data are compared with the data obtained by other chemical physical techniques that are only sensitive to the macroscopic molecular structure. The bulk of data indicates that (i) the highly flexible, transient network constituting the gel consists of entangled polymer rodlike lecithin reverse micelles, (ii) such a network structure is formed continuously upon addition of water rather than in an all-or-nothing transition, (iii) solvent and water mobility do not correlate with macroscopic gel viscosity, whereas there is a clear correlation between viscosity and stiffening of the phosphorus atom, (iv) during water addition and gel formation significant change in mobility of specific lecithin groups occur, and (v) in particular, the first added water molecule induces a conformational change of the lecithin polar head