Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a multifunctional cytokine displaying broad-spectrum anticancer activity in vitro or in vivo in preclinical animal cancer models and in a phase 1/2 clinical trial in patients with advanced cancers.mda-7/IL-24targets specific miRNAs, including miR-221 and miR-320, for down-regulation in a cancer-selective manner. We demonstrate thatmda-7/IL-24, administered through a replication incompetent type 5 adenovirus (Ad.mda-7) or with His-MDA-7/IL-24 protein, down-regulates DICER, a critical regulator in miRNA processing. This effect is specific for mature miR-221, as it does not affect Pri-miR-221 expression, and the DICER protein, as no changes occur in other miRNA processing cofactors, including DROSHA, PASHA, or Argonaute. DICER is unchanged by Ad.mda-7/IL-24in normal immortal prostate cells, whereas Ad.mda-7down-regulates DICER in multiple cancer cells including glioblastoma multiforme and prostate, breast, lung, and liver carcinoma cells. MDA-7/IL-24 protein down-regulates DICER expression through canonical IL-20/IL-22 receptors. Gain- and loss-of-function studies confirm that overexpression of DICER rescues deregulation of miRNAs bymda-7/IL-24, partially rescuing cancer cells frommda-7/IL-24-mediated cell death. Stable overexpression of DICER in cancer cells impedes Ad.mda-7or His-MDA-7/IL-24 inhibition of cell growth, colony formation, PARP cleavage, and apoptosis. In addition, stable overexpression of DICER renders cancer cells more resistant to Ad.mda-7inhibition of primary and secondary tumor growth. MDA-7/IL-24-mediated regulation of DICER is reactive oxygen species-dependent and mediated by melanogenesis-associated transcription factor. Our research uncovers a distinct role ofmda-7/IL-24in the regulation of miRNA biogenesis through alteration of the MITF-DICER pathway.

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Bone grafts are widely used to successfully restore structure and function to patients with a broad range of musculoskeletal ailments and bone defects. Autogenous bone grafts are historically preferred because they theoretically contain the three essential components of bone healing (ie, osteoconductivity, osteoinductivity, and osteogenicity), but they have inherent limitations. Allograft bone derived from deceased human donors is one alternative that is also capable of providing both an osteoconductive scaffold and osteoinductive potential but, until recently, lacked the osteogenic component of bone healing. Relatively new, cellular bone allografts (CBAs) were designed to address this need by preserving viable cells. Although most commercially-available CBAs feature mesenchymal stem cells (MSCs), osteogenic differentiation is time-consuming and complex. A more advanced graft, a viable bone allograft (VBA), was thus developed to preserve lineage-committed bone-forming cells, which may be more suitable than MSCs to promote bone fusion. The purpose of this paper was to present the results of preclinical research characterizing VBA. Through a comprehensive series of in vitro and in vivo assays, the present results demonstrate that VBA in its final form is capable of providing all three essential bone remodeling properties and contains viable lineage-committed bone-forming cells, which do not elicit an immune response. The results are discussed in the context of clinical evidence published to date that further supports VBA as a potential alternative to autograft without the associated drawbacks.

Category: Trauma; Ankle Introduction/Purpose: Talar neck fractures are uncommon and are characterized by displacement, comminution, and soft tissue injury. Treatment of talar neck fractures while avoiding complications, such as osteonecrosis and long-term morbidity, presents a unique challenge to surgeons. One option for treating talar neck fractures is cellular bone allograft containing viable lineage- committed bone cells (V-CBA), which provides the osteoconductive, osteoinductive, and osteogenic properties needed for bone formation. Additionally, a structural textured allograft (STA) wedge designed to resist migration and sustain compressive force can also be used in repairing talar neck fractures. This case study describes the successful repair of a comminuted talar neck fracture using V-CBA combined with an STA wedge. Methods: A 46-year-old male patient sustained a talar neck fracture following a fall from a 12-foot ladder. Radiographic and computed tomography (CT) imaging revealed significant comminution, consequent varus angulation, and a large bony void, as well as dislocation of the posterior subtalar joint. The patient was otherwise healthy with no comorbidities. Open reduction internal fixation was performed laterally to reduce the posterior subtalar dislocation. Medially, a 6.5mm STA wedge was used to correct the varus deformity and 1cc of V-CBA was used to fill the void. Results: At 6 months, the talar neck fracture had healed with solid osseous consolidation evident on radiographic images. Conclusion: These results demonstrate that an STA wedge, with a textured design that resists migration, used in combination with a V-CBA successfully repaired a comminuted talar neck fracture.

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