Dohndiaz6755

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is characterized by aberrant activation of signaling pathways and high risk of relapse. Approximately 50% of Ph-like ALL cases overexpress cytokine receptor-like factor 2 (CRLF2) associated with gene rearrangement. Activated by its ligand thymic stromal lymphopoietin (TSLP), CRLF2 signaling is critical for the development, proliferation, and survival of normal lymphocytes. To examine activation of tyrosine kinases regulated by TSLP/CRLF2, phosphotyrosine (P-Tyr) profiling coupled with stable isotope labeling of amino acids in cell culture (SILAC) was conducted using two CRLF2-rearranged (CRLF2r) Ph-like ALL cell lines stimulated with TSLP. As a result, increased P-Tyr was detected in previously reported TSLP-activated tyrosine kinases and substrates, including JAK1, JAK2, STAT5, and ERK1/2. Interestingly, TSLP also increased P-Tyr of insulin growth factor 1 receptor (IGF1R) and fibroblast growth factor receptor 1 (FGFR1), both of which can be targeted with small-molecule inhibitors. Fixed-ratio combination cytotoxicity assays using the tyrosine kinase inhibitors BMS-754807 and ponatinib that target IGF1R and FGFR1, respectively, revealed strong synergy against both cell line and patient-derived xenograft (PDX) models of CRLF2r Ph-like ALL. Further analyses also indicated off-target effects of ponatinib in the synergy, and novel association of the Ras-associated protein-1 (Rap1) signaling pathway with TSLP signaling in CRLF2r Ph-like ALL. When tested in vivo, the BMS-754807/ponatinib combination exerted minimal efficacy against 2 Ph-like ALL PDXs, associated with low achievable plasma drug concentrations. Although this study identified potential new targets in CRLF2r Ph-like ALL, it also highlights that in vivo validation of synergistic drug interactions is essential. IMPLICATION Quantitative phosphotyrosine profiling identified potential therapeutic targets for high-risk CRLF2-rearranged Ph-like ALL.Platinum resistance is a common occurrence in high-grade serous ovarian cancer and a major cause of ovarian cancer deaths. Platinum agents form DNA cross-links, which activate nucleotide excision repair (NER), Fanconi anemia, and homologous recombination repair (HRR) pathways. Chromatin modifications occur in the vicinity of DNA damage and play an integral role in the DNA damage response (DDR). Gefitinib Chromatin modifiers, including polycomb repressive complex 1 (PRC1) members, and chromatin structure are frequently dysregulated in ovarian cancer and can potentially contribute to platinum resistance. However, the role of chromatin modifiers in the repair of platinum DNA damage in ovarian cancer is not well understood. We demonstrate that the PRC1 complex member RING1A mediates monoubiquitination of lysine 119 of phosphorylated H2AX (γH2AXub1) at sites of platinum DNA damage in ovarian cancer cells. After platinum treatment, our results reveal that NER and HRR both contribute to RING1A localization and γH2AX monoubiquitination. Importantly, replication protein A, involved in both NER and HRR, mediates RING1A localization to sites of damage. Furthermore, RING1A deficiency impairs the activation of the G2-M DNA damage checkpoint, reduces the ability of ovarian cancer cells to repair platinum DNA damage, and increases sensitivity to platinum. IMPLICATIONS Elucidating the role of RING1A in the DDR to platinum agents will allow for the identification of therapeutic targets to improve the response of ovarian cancer to standard chemotherapy regimens.Regulator of chromosome condensation 2 (RCC2) is a protein located in the centrosome, which ensures that cell division proceeds properly. Previous reports show that RCC2 is overexpressed in some cancers and could play a key role in tumor development, but the mechanisms concerning how this occurs are not understood. Furthermore, no evidence exists regarding its role in esophageal cancer. We studied the relevance of RCC2 in esophageal cancer growth and its regulation on Sox2, an important transcription factor promoting esophageal cancer. RCC2 was overexpressed in esophageal tumors compared with normal tissue, and this overexpression was associated with tumorigenicity by increasing cell proliferation, anchorage-independent growth, and migration. These oncogenic effects were accompanied by overexpression of Sox2. RCC2 upregulated and stabilized Sox2 expression and its target genes by inhibiting ubiquitination-mediated proteasome degradation. Likewise, RCC2 increased the transcriptional activity and promoter binding of Sox2. In vivo studies indicated that RCC2 and Sox2 were overexpressed in esophageal tumors compared with normal tissue, and this upregulation occurs in the esophageal basal cell layer for both proteins. In conditional knockout mice, RCC2 deletion decreased the tumor nodule formation and progression in the esophagus compared with wild-type mice. Proliferating cell nuclear antigen expression, a cell proliferation marker, was also downregulated in RCC2 knockout mice. Overall, our data show for the first time that RCC2 is an important protein for the stabilization and transcriptional activation of Sox2 and further promotion of malignancy in esophageal cancer. IMPLICATIONS This study shows that RCC2 controls Sox2 expression and transcriptional activity to mediate esophageal cancer formation.

Extracorporeal life support (ECLS) has been used for >30 years as a life-sustaining therapy in critically ill patients for a variety of indications. In the current study, we aimed to examine trends in use, mortality, length of stay (LOS), and costs for pediatric ECLS hospitalizations.

We performed a retrospective cohort study of pediatric patients (between the ages of 28 days and <21 years) on ECLS using the 2008-2015 National Inpatient Sample, the largest all-payer inpatient hospitalization database generated from hospital discharges. Nonparametric and Cochran-Armitage tests for trend were used to study in-hospital mortality, LOS, and hospitalization costs.

Of the estimated 5847 patients identified and included for analysis, ECLS was required for respiratory failure (36.4%), postcardiotomy syndrome (25.9%), mixed cardiopulmonary failure (21.7%), cardiogenic shock (13.1%), and transplanted graft dysfunction (2.9%). The rate of ECLS hospitalizations increased 329%, from 11 to 46 cases per 100 000 pediatric hospitalizations, from 2008 to 2015 (

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