Combinations of drug treatments based on bortezomib or lenalidomide plus steroids have resulted in very high response rates in multiple myeloma. However, most patients still relapse, indicating the ...need for novel combination partners to increase duration of response or to treat relapsed disease. We explored the antimyeloma activity of triple combinations of these well-established schemes with panobinostat, a novel deacetylase inhibitor with a multi-targeted profile.
The activity of these combinations was explored in vitro in cell lines by using MTT and annex-in V, ex vivo by flow cytometry, and in vivo using two different murine models of human myeloma: one bearing a subcutaneous plasmacytoma and another with a disseminated myeloma. Moreover, gene expression profiling and immunohistochemical studies were performed.
The addition of panobinostat (LBH589) to dexamethasone and either bortezomib or lenalidomide resulted in clear potentiation in multiple myeloma cell lines, freshly isolated plasma cells, and murine models of multiple myeloma. The quantification of the potency of these combinations by using the Chou-Talalay method showed synergistic combination indices for all of them. This effect derived from the deregulation of a cluster of genes that was completely different from the sum of genes affected by the single agents (895 and 1323 genes exclusively deregulated by panobinostat and dexamethasone plus bortezomib or lenalidomide, respectively). Functional experiments, such as annexin V staining, cell cycle analysis, and immunohistochemical studies also supported this potentiation. Anti-myeloma efficacy was confirmed in an extramedullary plasmacytoma model and a disseminated luciferized model, in which panobinostat also provided a marked benefit in bone disease.
The potent activity, together with the exclusive mechanistic profile, provides the rationale for the clinical evaluation of these drug combinations in multiple myeloma.
Lactobacillus johnsonii NCC 533 is a member of the acidophilus group of intestinal lactobacilli that has been extensively studied for their "probiotic" activities that include, pathogen inhibition, ...epithelial cell attachment, and immunomodulation. To gain insight into its physiology and identify genes potentially involved in interactions with the host, we sequenced and analyzed the 1.99-Mb genome of L. johnsonii NCC 533. Strikingly, the organism completely lacked genes encoding biosynthetic pathways for amino acids, purine nucleotides, and most cofactors. In apparent compensation, a remarkable number of uncommon and often duplicated amino acid permeases, peptidases, and phosphotransferase-type transporters were discovered, suggesting a strong dependency of NCC 533 on the host or other intestinal microbes to provide simple monomeric nutrients. Genome analysis also predicted an abundance (>12) of large and unusual cell-surface proteins, including fimbrial subunits, which may be involved in adhesion to glycoproteins or other components of mucin, a characteristic expected to affect persistence in the gastrointestinal tract (GIT). Three bile salt hydrolases and two bile acid transporters, proteins apparently critical for GIT survival, were also detected. In silico genome comparisons with the >95% complete genome sequence of the closely related Lactobacillus gasseri revealed extensive synteny punctuated by clear-cut insertions or deletions of single genes or operons. Many of these regions of difference appear to encode metabolic or structural components that could affect the organisms competitiveness or interactions with the GIT ecosystem.
Objective:To investigate the potential antioxidant effects of Phyllanthus niruri(P.niruri.Euphorhiaceae)tea on healthy subjects.Methods:Five non-smoking,male healthy volunteers,20 to 31 years ...old.were enrolled.Kach subject was treated twice,following a randomized crossover fashion regarding the ingestion of P.niruri infusion(5 g/750 mL)(tea group)or 750 mL of water(control group).Fasting venous blood samples were collected prior to and at 1.2 and 4 h after infusion drinking.Samples were tested for plasmatic gallic acid and ascorbic acid levels,erythrocytic catalase and superoxide dismutase activities,and intracellular DCFH fluorescence in granulocytes,monocytes and lymphocytes.Results:Catalase and superoxide dismutase activities were not altered by tea ingestion.Plasma levels of gallic acid were significantly increased at1,2 and 4 h after P.niruri ingestion and plasma ascorbic acid at 1 h after P.niruri ingestion.Conclusions:Ingestion of P.niruri tea is associated with a slight increase in antioxidant markers in human blood(ascorbic acid and gallic acid),which may contribute to its pharmacological effects.
We present various properties of the production of the X(3872) and ψ(2S) states based on 10.4 fb−1 collected by the D0 experiment in Tevatron pp collisions at √s = 1.96 TeV. For both states, we ...measure the nonprompt fraction fNP of the inclusive production rate due to decays of b-flavored hadrons. We find the fNP values systematically below those obtained at the LHC. The fNP fraction for ψ(2S) increases with transverse momentum, whereas for the X(3872) it is constant within large uncertainties, in agreement with the LHC results. The ratio of prompt to nonprompt ψ(2S) production, (1 − fNP)=fNP, decreases only slightly going from the Tevatron to the LHC, but for the X(3872), this ratio decreases by a factor of about 3. We test the soft-pion signature of the X(3872) modeled as a weakly bound charm-meson pair by studying the production of the X(3872) as a function of the kinetic energy of the X(3872) and the pion in the X(3872)π center-of-mass frame. For a subsample consistent with prompt production, the results are incompatible with a strong enhancement in the production of the X(3872) at the small kinetic energy of the X(3872) and the π in the X(3872)π center-of-mass frame expected for the X þ soft-pion production mechanism. For events consistent with being due to decays of b hadrons, there is no significant evidence for the soft-pion effect, but its presence at the level expected for the binding energy of 0.17 MeV and the momentum scale Λ ¼ M(π) is not ruled out.
The production of single- and multi-photon events has been studied in the reaction e(+) e(-) --> gamma(gamma) + invisible particles. The data collected with the DELPHI detector during the years 1999 ...and 2000 at centre-of-mass energies between 191 GeV and 209 GeV was combined with earlier data to search for phenomena beyond the Standard Model. The measured number of light neutrino families was consistent with three and the absence of an excess of events beyond that predicted by the Standard Model processes was used to set limits on new physics. Both model-independent searches and searches for new processes predicted by supersymmetric and extra-dimensional models have been made. Limits on new non-standard model interactions between neutrinos and electrons were also determined.
The first comprehensive comparative analysis of lactobacilli was done by comparing the genomes of Lactobacillus plantarum (3.3 Mb) and Lactobacillus johnsonii (2.0 Mb). L. johnsonii is predominantly ...found in the gastrointestinal tract, while L. plantarum is also found on plants and plant-derived material, and is used in a variety of industrial fermentations. The L. plantarum and L. johnsonii chromosomes have only 28 regions with conservation of gene order, totalling about 0.75 Mb; these regions are not co-linear, indicating major chromosomal rearrangements. Metabolic reconstruction indicates many differences between L. johnsonii and L. plantarum: numerous enzymes involved in sugar metabolism and in biosynthesis of amino acids, nucleotides, fatty acids and cofactors are lacking in L. johnsonii. Major differences were seen in the number and types of putative extracellular proteins, which are of interest because of their possible role in host-microbe interactions. The differences between L. plantarum and L. johnsonii, both in genome organization and gene content, are exceptionally large for two bacteria of the same genus, emphasizing the difficulty in taxonomic classification of lactobacilli.
We present the first search for CPT-violating effects in the mixing of ${B_s^0}$ mesons using the full Run II data set with an integrated luminosity of 10.4 fb$^{-1}$ of proton-antiproton collisions ...collected using the D0 detector at the Fermilab Tevatron Collider. We measure the CPT-violating asymmetry in the decay $B_s^0 \to \mu^\pm D_s^\pm$ as a function of celestial direction and sidereal phase. We find no evidence for CPT-violating effects and place limits on the direction and magnitude of flavor-dependent CPT- and Lorentz-invariance violating coupling coefficients. We find 95\% confidence intervals of $\Delta a_{\perp} < 1.2 \times 10^{-12}$ GeV and $(-0.8 < \Delta a_T - 0.396 \Delta a_Z < 3.9) \times 10^{-13}$ GeV.
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