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Background: The EGFR signaling pathway is frequently activated in human ovarian cancer and associated with poor prognosis. However, inhibition of EGFR signaling in patients with recurrent ovarian cancer has been disappointing. It remains to be addressed whether ovarian cancer patients could benefit from targeting EGFR signaling. Here we investigated the mechanisms underlying the resistance to EGFR inhibition in ovarian cancer and developed a strategy to overcome it. Results: We found that treatment of human ovarian cancer cells with an EGFR inhibitor, gefitinib, resulted in increased STAT3 phosphorylation in a dose- and time-dependent manner. Inhibiting STAT3 activation with a small molecule inhibitor of JAK, an upstream kinase that phosphorylates and activates STAT3, synergistically increased the anti-tumor activity of gefitinib in vitro. Similar results were obtained when STAT3 or JAK1 expression was knocked down. In contrast, inhibiting other signaling pathways, such as AKT/mTOR, MEK or SRC, was relatively less effective. The combined treatment resulted in simultaneous attenuation of multiple survival pathways and increased inhibition of ERK pathway. In addition, the dual inhibition showed a stronger suppression of xenograft tumor growth than either single inhibition. Conclusions: Our findings demonstrate that feedback activation of STAT3 pathway might contribute to the resistance to EGFR inhibition. Combined blockade of both pathways appears to be more effective against human ovarian cancer than inhibition of each pathway alone both in vitro and in vivo. This study may provide a strategy to improve clinical benefit of targeting EGFR pathway in ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to study narrative skills in Mandarinspeaking children with language impairment (LI) to compare with children with LI speaking Indo-European languages. Method: Eighteen Mandarin-speaking children with LI. Method: Eighteen Mandarin-speaking children with LI (mean age 6;2 [years;months]) and 18 typically developing (TD) age controls told 3 stories elicited using the Mandarin Expressive Narrative Test (de Villiers & Liu, 2014). We compared macrostructure-evaluating descriptions of characters, settings, initiating events, internal responses, plans, actions, and consequences. We also studied general microstructure, including productivity, lexical diversity, syntactic complexity, and grammaticality. In addition, we compared the use of 6 fine-grained microstructure elements that evaluate particular Mandarin linguistic features. Results: Children with LI exhibited weaknesses in 5 macrostructure elements, lexical diversity, syntactic complexity, and 3 Mandarin-specific, fine-grained microstructure elements. Children with LI and TD controls demonstrated comparable performance on 2macrostructure elements, productivity, grammaticality, and the remaining 3 fine-grained microstructure features. Conclusions: Similarities and differences are noted in narrative profiles of children with LI who speak Mandarin versus those who speak Indo-European languages. The results are consistent with the view that profiles of linguistic deficits are shaped by the ambient language. Clinical implications are discussed. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA) holds promise as a novel therapeutic tool for cancer treatment. However, the transfection efficiency of current delivery systems represents a bottleneck for clinical applications. Here, we demonstrate that gap junctions mediate an augmentative effect on the antiproliferation mediated by miR-124-3p in U87 and C6 glioblastoma cells. The functional inhibition of gap junctions using either siRNA or pharmacological inhibition eliminated the miR-124-3p-mediated antiproliferation, whereas the enhancement of gap junctions with retinoic acid treatment augmented this miR-124-3p-mediated antiproliferation. A similar effect was observed in glioblastoma xenograft models. More importantly, patch clamp and co-culture assays demonstrated the transmission of miR-124-3p through gap junction channels into adjacent cells. In further exploring the impact of gap junction-mediated transport of miR-124-3p on miR-124-3p target pathways, we found that miR-124-3p inhibited glioblastoma cell growth in part by decreasing the protein expression of cyclin-dependent kinase 6, leading to cell cycle arrest at the G0/G1 phase; moreover, pharmacological regulation of gap junctions affected this cell cycle arrest. In conclusion, our results indicate that the 'bystander' effects of functional gap junctions composed of connexin 43 enhance the antitumor effect of miR-124-3p in glioblastoma cells by transferring miR-124-3p to adjacent cells, thereby enhancing G0/G1 cell cycle arrest. These observations provide a new guiding strategy for the clinical application of miRNA therapy in tumor treatment. J. Cell. Physiol. 230: 2476-2488, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of childhood associated with a poor prognosis. Recently, massively parallel sequencing has identified recurrent mutations in the SKI domain of SETBP1 in a variety of myeloid disorders. These lesions were detected in nearly 10% of patients with JMML and have been characterized as secondary events. We hypothesized that rare subclones with SETBP1 mutations are present at diagnosis in a large portion of patients who relapse, but are below the limits of detection for conventional deep sequencing platforms. Using droplet digital polymerase chain reaction (ddPCR) we identified SETBP1 mutations in 17/56 (30%) of patients who were treated on Children's Oncology Group sponsored clinical trial, AAML0122. Five-year event free survival (EFS) in patients with SETBP1 mutations was 18% ± 9% compared to 51% ± 8% for those without mutations (p=0.006). [ABSTRACT FROM AUTHOR]

The article presents a study, which examined oxidative damage to nucleic acids in severe emphysematous lungs. It investigates the nucleic acid oxidation level of patients receiving lung transplantation. Researchers of this study concluded that nucleic acids, particularly RNA, are oxidized in human emphysematous lungs.