Mécanismes d'inhibition de l'apoptose par la procaspase-2S : effet sur la formation des corps apoptotiques

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mécanismes d'inhibition de l'apoptose par la procaspase-2S : effet sur la formation des corps apoptotiques

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Resolution of the chiral (1R,2S) enantiomer of cis-cyclohexane-1,2-dicarboxylic acid in the brucinium salt 2,3-dimethoxy-10-oxostrychnidinium (1R,2S)-2-carboxycyclohexane-1-carboxylate dihydrate

The structure of the 1:1 brucinium salt of cis-cyclohexane-1,2-dicarboxylic acid, 2,3-dimethoxy-10-oxostrychnidinium (1R,2S)-2-carboxycyclohexane-1-carboxylate dihydrate, has revealed the resolved (1R,2S) enantiomer of the acid. Crystals of the compound are orthorhombic, space group P212121, with unit cell dimensions a = 8.1955(3), b = 12.4034(3), c = 29.9073(9)Å, and Z = 4. The asymmetric unit comprises the brucinium cation, the hydrogen cis-cyclohexane-1,2-dicarboxylate cation, in which the carboxylate group is disordered over two sites (58, 42%), and two water molecules of solvation, one of which is occupies two 50% occupancy sites. The classic undulating brucinium cation substructures are present with the anion and the water molecules occupying the interstitial cavities and are hydrogen-bonded to them in a two-dimensional network structure.

Procaspase 8 overexpression in non-small-cell lung cancer promotes apoptosis induced by FLIP silencing

We found that procaspase 8 was overexpressed in non-small-cell lung cancers (NSCLCs) compared with matched normal tissues. The caspase 8 inhibitor FLICE-inhibitory protein (FLIP) was also overexpressed in the majority of NSCLCs. Silencing FLIP induced caspase 8 activation and apoptosis in NSCLC cell lines, but not in normal lung cell lines. Apoptosis induced by FLIP silencing was mediated by the TRAIL death receptors DR4 and DR5, but was not dependent on ligation of the receptors by TRAIL. Furthermore, the apoptosis induced by FLIP silencing was dependent on the overexpression of procaspase 8 in NSCLC cells. Moreover, in NSCLC cells, but not in normal cells, FLIP silencing induced co-localization of DR5 and ceramide, and disruption of this co-localization abrogated apoptosis. FLIP silencing supra-additively increased TRAIL-induced apoptosis of NSCLC cells; however, normal lung cells were resistant to TRAIL, even when FLIP was silenced. Importantly, FLIP silencing sensitized NSCLC cells but not normal cells to chemotherapy in vitro, and silencing FLIP in vivo retarded NSCLC xenograft growth and enhanced the anti-tumour effects of cisplatin. Collectively, our results suggest that due to frequent procaspase 8 overexpression, NSCLCs may be particularly sensitive to FLIP-targeted therapies.

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

Production of psi(2S) Mesons in ppbar Collisions at 1.96 TeV

We have measured the differential cross section for the inclusive production of psi(2S) mesons decaying to mu^{+} mu^{-1} that were produced in prompt or B-decay processes from ppbar collisions at 1.96 TeV. These measurements have been made using a data set from an integrated luminosity of 1.1 fb^{-1} collected by the CDF II detector at Fermilab. For events with transverse momentum p_{T} (psi(2S)) > 2 GeV/c and rapidity |y(psi(2S))| psi(2S)X) Br(psi(2S) -> mu^{+} mu^{-}) to be 3.29 +- 0.04(stat.) +- 0.32(syst.) nb.

Production of ψ(2S) mesons in pp̅ collisions at 1.96 TeV

We have measured the differential cross section for the inclusive production of psi(2S) mesons decaying to mu^{+} mu^{-1} that were produced in prompt or B-decay processes from ppbar collisions at 1.96 TeV. These measurements have been made using a data set from an integrated luminosity of 1.1 fb^{-1} collected by the CDF II detector at Fermilab. For events with transverse momentum p_{T} (psi(2S)) > 2 GeV/c and rapidity |y(psi(2S))| psi(2S)X) Br(psi(2S) -> mu^{+} mu^{-}) to be 3.29 +- 0.04(stat.) +- 0.32(syst.) nb.

Apsidal motion in 4U 0115+63 and orbital parameters of 2S 1417-624 and V0332+53

Be/X-ray binary pulsars have wide eccentric orbits and hence the angle of periastron of the orbit is very well defined in these sources. The presence of an X-ray pulsar allows for accurate measurements of orbital elements. A Be star usually is a rapidly rotating star and hence will deviate from spherical geometry. The tidal interaction between the neutron star and the Be star will add to the distortion of the Be star and alter its mass distribution. Thus a measurable rate of apsidal motion is expected from these systems. In this paper, we present the first conclusive detection of apsidal motion of the binary 4U 0115+63. We also present new and accurate orbital parameters of the Be/X-ray binaries V0332+53 and 2S 1417-624.

Theoretical investigation on excitation, ionization and capture in H(1s, 2s)+H(1s, 2s) collisions

Cross sections of electron- loss in H( 1s)+ H( 1s) collisions and total collisional destruction of H( 2s) in H( 1s) + H( 2s) collisions are calculated by four- body classical- trajectory Monte Carlo ( CTMC) method and compared with previous theoretical and experimental data over the energy range of 4 - 100 keV. For the former a good agreement is obtained within di. erent four- body CTMC calculations, and for the incident energy Ep > 10 keV, comparison with the experimental data shows a better agreement than the results calculated by the impact parameter approximation. For the latter, our theory predicts the correct experimental behaviour, and the discrepancies between our results and experimental ones are less than 30%. Based on the successive comparison with experiments, the cross sections for excitation to H( 2p), single- and double- ionization and H- formation in H( 2s)+ H( 2s) collisions are calculated in the energy range of 4 - 100 keV for the. rst time, and compared with those in H( 1s)+ H( 1s) and H( 1s)+ H( 2s) collisions.

Interference Effects in Hyperfine Induced 2s2p P-3(0), P-3(2) -> 2s(2) S-1(0) Transitions of Be-like Ions

In this paper, we explored the characteristics of the interference effects between perturbative states in hyperfine induced 2s2p P-3(0), P-3(2) -> 2s(2) S-1(0) transitions of Be-like ions. It was found that the interference effects non-monotonically change with increasing atomic number Z in these two transitions. The strongest interference effect is near Z = 9 for 2s2p P-3(0), -> 2s(2) (1)S(0)transition and near Z = 7 for the other.

Two-electron-one-photon M1 and E2 transitions between the states of the 2p(3) and 2s(2)2p odd configurations for B-like ions with 18 <= Z <= 92

Two-electron-one-photon (TEOP) M1 and E2 transition energies, line strengths and transition probabilities between the states of the 2p(3) and 2s(2)2p odd configurations for B-like ions with 18 <= Z <= 92 have been calculated using the GRASP2K package based on the multiconfiguration Dirac-Hartree-Fock (MCDHF) method. Employing active-space techniques to expand the configuration list, we have systematically considered the valence, core-valence and core-core electron correlation effects. Breit interaction and quantum electrodynamical (QED) effects were also included to correct atomic state wavefunctions and the corresponding energies. Influences of electron correlation, Breit interaction and QED effects on transition energies and line strengths of the TEOP M1 and E2 transitions were analysed in detail. The present results were also compared with other theoretical and experimental values.