ABSTRACT
Anatomical variations of the extensor pollicis longus (EPL) tendon are rare. Variations are typically asymptomatic, yet knowledge of these variations poses significance in the setting of dorsal approaches to wrist surgery. We present a case of an accessory EPL tendon that was discovered intraoperatively in the fourth dorsal compartment during open repair of a distal radius fracture with a dorsal spanning plate. If not correctly identified, the accessory EPL could have been entrapped beneath the plate, resulting in limited thumb extension and potentially tendon rupture.
ABSTRACT
Background: Glioblastoma (GBM) is difficult to treat. Phosphoinositide 3-kinase (PI3K) is an attractive therapeutic target for GBM; however, targeting this pathway to effectively treat GBM is not successful because the roles of PI3K isoforms remain to be defined. The aim of this study is to determine whether PIK3CB/p110ß, but not other PI3K isoforms, is a biomarker for GBM recurrence and important for cell survival. Methods: Gene expression and clinical relevance of PI3K genes in GBM patients were analyzed using online databases. Expression/activity of PI3K isoforms was determined using immunoblotting. PI3K genes were inhibited using short hairpin RNAs or isoform-selective inhibitors. Cell viability/growth was assessed by the MTS assay and trypan blue exclusion assay. Apoptosis was monitored using the caspase activity assay. Mouse GBM xenograft models were used to gauge drug efficacy. Results: PIK3CB/p110ß was the only PI3K catalytic isoform that significantly correlated with high incidence rate, risk, and poor survival of recurrent GBM. PIK3CA/p110α, PIK3CB/p110ß, and PIK3CD/p110δ were differentially expressed in GBM cell lines and primary tumor cells derived from patient specimens, whereas PIK3CG/p110γ was barely detected. PIK3CB/p110ß protein levels presented a stronger association with the activities of PI3K signaling than other PI3K isoforms. Blocking p110ß deactivated PI3K signaling, whereas inhibition of other PI3K isoforms had no effect. Specific inhibitors of PIK3CB/p110ß, but not other PI3K isoforms, remarkably suppressed viability and growth of GBM cells and xenograft tumors in mice, with minimal cytotoxic effects on astrocytes. Conclusions: PIK3CB/p110ß is a biomarker for GBM recurrence and selectively important for GBM cell survival.
Subject(s)
Biomarkers, Tumor/metabolism , Class I Phosphatidylinositol 3-Kinases/metabolism , Glioblastoma/pathology , Neoplasm Recurrence, Local/pathology , Animals , Apoptosis , Biomarkers, Tumor/genetics , Cell Proliferation , Class I Phosphatidylinositol 3-Kinases/genetics , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Mice , Mice, SCID , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/metabolism , Prognosis , Signal Transduction , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Ischemia-reperfusion (I/R) injury leads to increased mortality and morbidity in lung transplant patients. Lung I/R injury involves inflammation contributed by innate immune responses. IL-17 and TNF-α, from iNKT cells and alveolar macrophages, respectively, contribute importantly to lung I/R injury. This study tests the hypothesis that IL-17 and TNF-α synergistically mediate CXCL1 (a potent neutrophil chemokine) production by alveolar type II epithelial (ATII) cells via an NADPH oxidase-dependent mechanism during lung I/R. Using a hilar clamp model, wild-type and p47(phox-/-) (NADPH oxidase-deficient) mice underwent left lung I/R, with or without recombinant IL-17 and/or TNF-α treatment. Wild-type mice undergoing I/R treated with combined IL-17 and TNF-α had significantly enhanced lung dysfunction, edema, CXCL1 production, and neutrophil infiltration compared with treatment with IL-17 or TNF-α alone. However, p47(phox-/-) mice had significantly less pulmonary dysfunction, CXCL1 production, and lung injury after I/R that was not enhanced by combined IL-17-TNF-α treatment. Moreover, in an acute in vitro hypoxia-reoxygenation model, murine ATII cells showed a multifold synergistic increase in CXCL1 expression after combined IL-17-TNF-α treatment compared with treatment with either cytokine alone, which was significantly attenuated by an NADPH oxidase inhibitor. Conditioned media transfer from hypoxia-reoxygenation-exposed iNKT cells and macrophages, major sources of IL-17 and TNF-α, respectively, to ATII cells significantly enhanced CXCL1 production, which was blocked by NADPH oxidase inhibitor. These results demonstrate that IL-17 and TNF-α synergistically mediate CXCL1 production by ATII cells after I/R, via an NADPH oxidase-dependent mechanism, to induce neutrophil infiltration and lung I/R injury.
