Transcriptional reprogramming by mutated IRF4 in lymphoma.

Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.

Push-out bond strengths of endodontic posts bonded with different resin-based luting cements.

PURPOSE: To compare the push-out bond strengths of endodontic posts bonded with different resin-based luting cements and to verify that bond strengths did not vary with cement thickness. METHODS: 48 root canals were shaped using 6% NiTi rotary files, obturated with gutta-percha and AH Plus sealer and prepared for post cementation using Panavia F, Parapost cement, SuperBond and Unicem Rely X. All roots were sectioned into 0.7 mm thick slices and digital photographs of each slice were analyzed using Scion Image to measure the surface area of the luting cement. The root slices were stressed to failure at 1 mm/minute using a push-out test. Push-out strength was calculated as the force at failure divided by the bonded surface area. Least squares linear regression analysis was used to assess the effect of cement thickness on bond strength. Fractured specimens were further observed under the SEM. RESULTS: Mean push-out bond strengths were: Panavia F (8.8 +/- 3.6 MPa), Parapost cement (9.1 +/- 4.4 MPa) SuperBond (14.6 +/- 2.9 MPa) and Rely X Unicem (12.4 +/- 3.3 MPa). The Panavia F and the Parapost cement were not significantly different from each other, but both were significantly lower (P < or = 0.05) than SuperBond and Rely X Unicem. Although there were large variations in cement thickness, the cementation of fiber posts with thicker cement layers did not affect the performance of the adhesive luting cements applied to root canal dentin.