Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach.
Electron paramagnetic resonance (EPR) spectroscopy was used to study the point defects in 2 × 1017–1019 cm−3 C-doped GaN substrates grown by hydride vapor phase epitaxy. The intensity of an isotropic signal with g = 1.987 ± 0.001 increased monotonically with the carbon concentration, indicating that the EPR signal represents a carbon-related defect. In each sample, the signal intensity increased under illumination with photon energy greater than 2.75 eV, and the photo-induced signal decreased with subsequent illumination at 0.95 eV. A second signal, well-documented to be a shallow donor, appeared along with the g = 1.987 signal in the most lightly doped samples. The appearance of the donor confirms that the photo-induced increase is caused by excitation of an electron to the conduction band and implies that a defect level for the carbon-related center is about 1 eV above the valence band edge, consistent with temperature-dependent Hall measurements.
The electron paramagnetic resonance (EPR) spectrum of the Mg acceptor is studied in a variety of GaN samples, including mm-thick free-standing substrates and sub-micron heteroepitaxial films. The former allows a view of the acceptor unique for EPR—in an environment with less than 107 cm−3 dislocations and doping densities ranging from 4 × 1016 to 6 × 1018 cm−3. By probing Mg in a broad range of samples in one study a new feature of the acceptor emerges. The EPR data reveal an anisotropic line shape that reflects a change in the crystal field in the vicinity of the Mg acceptor. This feature must be accommodated by any of the models proposed for the Mg acceptor. Here, we show that one such previously proposed model agrees well with the EPR data obtained from the wide variety of samples studied. The work implies that Mg-doped GaN contains a common Mg-related defect which can be affected by local crystal fields established during growth.
We studied thin-film and free-standing Mg-doped GaN using multi-frequency electron paramagnetic resonance (EPR) at 3–3.5 K and 9.4–130 GHz. Free-standing samples exhibit a highly anisotropic intensity, varying by a factor of 20 from 0° to 60°. In contrast, the intensity of the thin-film samples is significantly more isotropic, varying by no more than 10% over the same range of angles. The angular dependent intensity can be modeled in both free-standing and thin-film samples similarly to the g-factor anisotropy reported for thin films, supporting the theoretical predictions that the hole is on a basal site around the Mg acceptor. In addition, frequency-dependent transmission EPR measurements reveal a distribution of in free-standing samples, indicating that the local basal crystal field is non-uniform.
InxGa1–xN and AlxGa1–xN alloys are used in many optoelectronic applications due to their tunable band gap, but p‐type doping remains a challenge. To better understand the Mg acceptor in nitride alloys, we investigate the effects of In or Al mole fraction, growth temperature and sample thickness on the amount of un‐ionized (neutral) Mg using electron paramagnetic resonance (EPR) spectroscopy. The results show that neither temperature nor thickness effects the concentration of the neutral Mg‐related acceptor defects; however, the mole fraction of metal, In or Al, alters the behavior of the dopant. For InxGa1–xN, a broadening of the EPR linewidth is shown to be directly related to the presence of a nearby In and is consistent with a lowering of the acceptor level. Incorporation of Al into GaN, on the other hand, produces a systematic decrease in the concentration of neutral Mg‐related acceptors as the amount of Al increases. Earlier studies indicate that the reduction is caused by incomplete hydrogen removal from the acceptor impurity. (© 2014 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
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