Fluoxetine Inhibits STAT3-mediated Survival and Invasion of Osteosarcoma Cells.

BACKGROUND/AIM: Osteosarcoma (OS) is a common primary malignancy of bone in adolescents. Its highly metastatic characteristics can lead to treatment failure and poor prognosis. Although standard treatments, including surgery, radiotherapy, and chemotherapy, have progressed in the past decade, treatment options to overcome metastatic progression remain sparse. Fluoxetine, an anti-depressant, has been widely used in patients with cancer for their mental issues and was reported to possess antitumor potential. However, the effect of fluoxetine on OS remains unclear. MATERIALS AND METHODS: In this study, we used cell viability, invasion/migration transwell, wound-healing and aortic ring assays to identify the effects of fluoxetine on metastasis and progression in OS. RESULTS: Fluoxetine induced cytotoxicity in OS cells by activating both extrinsic/intrinsic apoptosis signaling pathways. Proliferation and anti-apoptosis-related factors such as cyclin D1 and X-linked inhibitor of apoptosis were suppressed by fluoxetine. Additionally, fluoxetine suppressed the invasive/migratory abilities of OS and inhibited the development of angiogenesis by reducing the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Metastasis-associated factors, vascular endothelial growth factors, matrix metallopeptidase 2 and -9, were all reduced in OS cells by fluoxetine treatment. CONCLUSION: Fluoxetine not only induces cytotoxicity and apoptosis of OS cells, but also suppresses metastasis and angiogenesis by targeting STAT3.

Comparison of ultrasound and dorsal tangential view for dorsal cortex screw penetration in volar plating of the distal radius.

We compared the accuracy of the fluoroscopic dorsal tangential view (DTV) and an ultrasound (US) examination in detecting dorsal screw penetration during volar distal radius plating. In six fresh cadaveric distal radii, seven periarticular locking screws in two rows for each plate were inserted according to the measured length using a depth gauge and then replaced with another that was 1 and 2 mm longer, respectively. The actual protruded length of each screw was determined using computed tomography (CT) images. The accuracy of US and DTV measurements was determined using the intraclass correlation coefficient (ICC), as both measurements were compared with CT measurements. The ICC of US and DTV was 0.96 and 0.75, respectively, for all screws. After excluding the data for proximal-row screws, the ICC of US remained unchanged at 0.96, and that of DTV improved to 0.86. The ICC of US was significantly higher than that of DTV (p < 0.01). US had a 100% detection rate for screw protrusion of more than 1.0 mm. US examination showed excellent consistency with CT measurements and its accuracy was not affected by screw location. US might thus be a practical tool for detecting dorsal cortex screw penetration during volar distal radius plating.

Parallel versus orthogonal plate osteosynthesis of adult distal humerus fractures: a meta-analysis of biomechanical studies.

PURPOSE: There are two widely used distal humerus fracture (DHF) fixation methods with either orthogonal or parallel double-plate osteosynthesis. However, biomechanical studies have shown inconsistent results on which technique is more effective. We performed a meta-analysis to compare these two fixation methods for adult DHF fixation. METHODS: We searched the literature for entries discussing the biomechanical testing of orthogonal and parallel fixation techniques for DHFs. We then performed a meta-analysis of the following biomechanical outcome measures: axial/sagittal/coronal/torsional stiffness, load to failure, and torque to failure. RESULTS: Seventeen studies comparing both constructs were included. The parallel configuration exhibited greater mechanical strength with respect to axial stiffness/load to failure, torsional stiffness, and posterior bending load to failure than the orthogonal constructs. Subgroup analysis revealed that parallel constructs also had higher torsional stiffness in supracondylar fractures. CONCLUSIONS: This meta-analysis shows that parallel constructs provide greater axial stiffness, axial strength, and torsional stiffness than orthogonal plate for DHF fixation. A subgroup analysis revealed that parallel constructs had better torsional stiffness in supracondylar fracture fixation. LEVEL OF EVIDENCE: IA.

Transcriptional activation of C/EBPbeta gene by c-Jun and ATF2.

C/EBPbeta is one of the key transcription factors responsible for the induction of a wide array of genes. Like many proto-oncogenes and transcription factors, transcription of C/EBPbeta gene can be induced by multiple extracellular signals. Using nuclear extracts from lipopolysaccharide (LPS)-stimulated mouse liver, five trans-acting factor-binding motifs, URE1 (-376 to -352), URE2 (-253 to -223), URE3 (-220 to -190), URE4 (-123 to -103), and URE5 (-72 to -45) were identified by DNAse I footprinting assays. Competition and supershift analysis of the complexes formed at the URE2 and URE4 indicated that they contain CREB/ATF and AP-1 family factors. Furthermore, recombinant ATF2 and c-Jun proteins from mammalian and bacterial cells can bind to URE2 and URE4 but not URE1. Cotransfection experiments showed that ATF2 and c-Jun activate the C/EBPbeta gene expression cooperatively through URE2 and URE4, and this activation was greatly increased under the treatment of low concentration of anisomycin. During acute phase response, the phosphorylation of c-Jun and ATF2 was found to correlate with C/EBPbeta gene expression. Taken together, our results provide the evidences that both c-Jun and ATF2 are the regulators of C/EBPbeta gene.

An RNA helicase, DDX1, interacting with poly(A) RNA and heterogeneous nuclear ribonucleoprotein K.

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a multifunctional protein known to be involved in the regulation of transcription, translation, nuclear transport, and signal transduction. To systematically obtain insight into mechanisms of hnRNP K activities, we set out to identify protein factors that interact with hnRNP K by using glutathione S-transferase-hnRNP K affinity chromatography followed by liquid chromatography/mass spectrometry/mass spectrometry analysis. Several partner proteins in the K562 cell lysates were identified through this method. One of them is a DEAD box-containing putative RNA helicase, DDX1. In vitro binding and co-immunoprecipitation studies confirmed the protein-protein interaction between hnRNP K with DDX1, and the region spanning amino acids 1-276 of hnRNP K is apparently responsible for its physical interaction with DDX1. Interestingly, their interaction was disrupted by the addition of poly(C), poly(A), and poly(U) RNA substrates. We found that DDX1 was a homopolymeric poly(A) RNA-binding protein. On the other hand, the ATPase activity of the purified recombinant DDX1 protein was stimulated by these homopolymeric RNAs and yeast total RNA but not by DNA. Moreover, the immunoprecipitated DDX1 complex but not purified DDX1 can unwind double-stranded RNA having single-stranded poly(A) overhangs.