First results on
-dependence measurements in inclusive
meson production in
interactions (
, Al, Cu, Sn, and W) are presented at
GeV/
c
. The ratios of the differential cross sections of four of these ...nuclei to the differential cross section on aluminum were measured and the dependence of these cross sections on the atomic of the nucleus was studied. The measurements were carried out in the kinematic region of the Feynman variable
and transverse momentum
GeV/
c
.
mesons were detected in the decay mode
at the SPASCHARM experimental setup using negative charged beams at beamline 14 of the U-70 accelerator complex.
Changes in the transparency of lead tungstate crystals under continuous ∼1200-h irradiation with γ rays of a radionuclide
60
Co source were investigated. The crystal temperature was maintained at a ...level of −15°C at a dose rate of 0.1 Gy/h. The crystal transparency recovery process was investigated after the irradiation at temperatures varying from −15 to +38°C. The study was performed while preparing for the PANDA experiment in the FAIR project in Germany.
The momentum dispersion of the proton beam extracted from the vacuum chamber of the U-70 accelerator by channeling was measured for the first time. At an 80-mrad bending angle of the Si single ...crystal, the following beam parameters were attained: an intensity of 10
7
protons/s for 10
12
protons/s hitting the crystal, momentum dispersion of the beam Δ
p
/
p
= 0.13%, and a background particle admixture of 0.03% or less.
The radiation hardness of a test batch of lead tungstate crystals grown by a new technology at the Bogoroditsk Technochemical Plant for the PANDA experiment has been measured. The optical properties ...of the crystals have been investigated at temperatures ranging from +20 to −20°C under irradiation with a
137
Cs radionuclide source. The light yield in the crystal is seen to considerably increase with a decrease in its temperature. In addition, the loss of the crystal transparency under irradiation at low temperatures is higher than under irradiation at room temperature. As a result, at a fixed dose rate, the signal from the crystal at a negative temperature may be considerably greater than the signal at room temperature even if the accumulated dose is high.
The STAR Barrel Electromagnetic Calorimeter Beddo, M.; Bielick, E.; Fornek, T. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
03/2003, Letnik:
499, Številka:
2
Journal Article
Recenzirano
Details concerning the design, fabrication and performance of the STAR Barrel Electromagnetic Calorimeter are presented.
BCL6 was initially discovered as an oncogene in B-cell lymphomas, where it drives the malignant phenotype by repressing proliferation and DNA damage checkpoints and blocking B-cell terminal ...differentiation. BCL6 mediates its effects by binding to hundreds of target genes and then repressing these genes by recruiting several different chromatin-modifying corepressor complexes. Structural characterization of BCL6-corepressor complexes suggested that BCL6 might be a druggable target. Accordingly, a number of compounds have been designed to bind to BCL6 and block corepressor recruitment. These compounds, based on peptide or small-molecule scaffolds, can potently block BCL6 repression of target genes and kill lymphoma cells. In the case of diffuse large B-cell lymphomas (DLBCL), BCL6 inhibitors are equally effective in suppressing both the germinal center B-cell (GCB)- and the more aggressive activated B-cell (ABC)-DLBCL subtypes, both of which require BCL6 to maintain their survival. In addition, BCL6 is implicated in an expanding scope of hematologic and solid tumors. These include, but are not limited to, B-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer. BCL6 inhibitors have been shown to exert potent effects against these tumor types. Moreover, mechanism-based combinations of BCL6 inhibitors with other agents have yielded synergistic and often quite dramatic activity. Hence, there is a compelling case to accelerate the development of BCL6-targeted therapies for translation to the clinical setting.
.
Chronic inflammation is a hallmark of atherosclerosis, but its transcriptional underpinnings are poorly understood. We show that the transcriptional repressor Bcl6 is an anti-inflammatory regulator ...whose loss in bone marrow of Ldlr−/− mice results in severe atherosclerosis and xanthomatous tendonitis, a virtually pathognomonic complication in patients with familial hypercholesterolemia. Disruption of the interaction between Bcl6 and SMRT or NCoR with a peptide inhibitor in vitro recapitulated atherogenic gene changes in mice transplanted with Bcl6-deficient bone marrow, pointing to these cofactors as key mediators of Bcl6 inflammatory suppression. Using ChIP-seq, we reveal the SMRT and NCoR corepressor cistromes, each consisting of over 30,000 binding sites with a nearly 50% overlap. While the complete cistromes identify a diversity of signaling pathways, the Bcl6-bound subcistromes for each corepressor are highly enriched for NF-κB-driven inflammatory and tissue remodeling genes. These results reveal that Bcl6-SMRT/NCoR complexes constrain immune responses and contribute to the prevention of atherosclerosis.
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► Bcl6 is a critical antiatherogenic regulator ► Inhibition of Bcl6-SMRT/NCoR interactions induces atherogenic gene expression ► SMRT and NCoR cistromes each exceed 30,000 sites, with a nearly 50% overlap ► Bcl6 recruits SMRT and NCoR to NF-κB-driven inflammatory and tissue remodeling genes
Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that ...respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.
PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma ...(DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.
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