RIG-I modulates Src-mediated AKT activation to restrain leukemic stemness.

Retinoic acid (RA)-inducible gene I (RIG-I) is highly upregulated and functionally implicated in the RA-induced maturation of acute myeloid leukemia (AML) blasts. However, the underlying mechanism and the biological relevance of RIG-I expression to the maintenance of leukemogenic potential are poorly understood. Here, we show that RIG-I, without priming by foreign RNA, inhibits the Src-facilitated activation of AKT-mTOR in AML cells. Moreover, in a group of primary human AML blasts, RIG-I reduction renders the Src family kinases hyperactive in promoting AKT activation. Mechanistically, a PxxP motif in RIG-I, upon the N-terminal CARDs' association with the Src SH1 domain, competes with the AKT PxxP motif for recognizing the Src SH3 domain. In accordance, mutating PxxP motif prevents Rig-I from inhibiting AKT activation, cytokine-stimulated myeloid progenitor proliferation, and in vivo repopulating capacity of leukemia cells. Collectively, our data suggest an antileukemia activity of RIG-I via competitively inhibiting Src/AKT association.

Accuracy of using computer-aided rapid prototyping templates for mandible reconstruction with an iliac crest graft.

BACKGROUND: This study aimed to evaluate the accuracy of surgical outcomes in free iliac crest mandibular reconstructions that were carried out with virtual surgical plans and rapid prototyping templates. METHODS: This study evaluated eight patients who underwent mandibular osteotomy and reconstruction with free iliac crest grafts using virtual surgical planning and designed guiding templates. Operations were performed using the prefabricated guiding templates. Postoperative three-dimensional computer models were overlaid and compared with the preoperatively designed models in the same coordinate system. RESULTS: Compared to the virtual osteotomy, the mean error of distance of the actual mandibular osteotomy was 2.06 ± 0.86 mm. When compared to the virtual harvested grafts, the mean error volume of the actual harvested grafts was 1412.22 ± 439.24 mm3 (9.12% ± 2.84%). The mean error between the volume of the actual harvested grafts and the shaped grafts was 2094.35 ± 929.12 mm3 (12.40% ± 5.50%). CONCLUSIONS: The use of computer-aided rapid prototyping templates for virtual surgical planning appears to positively influence the accuracy of mandibular reconstruction.

Digital surgical templates for managing high-energy zygomaticomaxillary complex injuries associated with orbital volume change: a quantitative assessment.

PURPOSE: This study sought to introduce 3-dimensional (3D) virtual surgical planning and digital rapid-prototyping templates for zygomaticomaxillary complex (ZMC) injuries associated with orbital volume change and to evaluate the surgical outcomes quantitatively. PATIENTS AND METHODS: Eight patients who underwent open reduction and fixation for a ZMC injury with orbital volume change were studied. Computed tomographic (CT) scan of the zygomaticomaxillary area was performed before the operation in each case. Scanned data were converted into 3D models using Mimics software (Materialise, Brussels, Belgium) for surgical designs. Virtual surgical reductions and correlated guiding templates were designed using Mimics and Magics software (Materialise). The operations were performed with the help of prefabricated templates to reduce the fractures. A postoperative CT scan of each patient was obtained within 2 weeks after surgery, and quantitative measurements were made to assess the surgical outcomes. Preoperative volumes of the bilateral orbits were compared, and concordance with postoperative volumes of the bilateral orbits was assessed. Twenty-one pairs of distances from 7 marker points to 3 reference planes were measured to assess postoperative facial symmetry. RESULTS: Volumes of the injured orbits were significantly different from volumes of the uninjured orbits preoperatively (P < .05), whereas bilateral orbital volumes showed no statistically significant difference postoperatively (P > .05). In addition, 19 of the 21 pairs of bilateral distances showed no significant difference postoperatively (P > .05). CONCLUSIONS: Quantitative assessment showed that digitally designed, rapid-prototyping templates for ZMC fractures have a positive impact on restoring facial symmetry and concordance of bilateral orbital volumes.

JMJD3 facilitates C/EBPß-centered transcriptional program to exert oncorepressor activity in AML.

JMJD3, a stress-inducible H3K27 demethylase, plays a critical regulatory role in the initiation and progression of malignant hematopoiesis. However, how this histone modifier affects in a cell type-dependent manner remains unclear. Here, we show that in contrast to its oncogenic effect in preleukemia state and lymphoid malignancies, JMJD3 relieves the differentiation-arrest of certain subtypes (such as M2 and M3) of acute myeloid leukemia (AML) cells. RNA sequencing and ChIP-PCR analyses revealed that JMJD3 exerts anti-AML effect by directly modulating H3K4 and H3K27 methylation levels to activate the expression of a number of key myelopoietic regulatory genes. Mechanistic exploration identified a physical and functional association of JMJD3 with C/EBPß that presides the regulatory network of JMJD3. Thus, the leukemia regulatory role of JMJD3 varies in a disease phase- and lineage-dependent manner, and acts as a potential oncorepressor in certain subsets of AML largely by coupling to C/EBPß-centered myelopoietic program.