Funnel plots of publication bias for OS of all patients.

<p>Funnel plots of publication bias for OS of all patients.</p

Characteristics of studies included in the meta-analysis.

<p>Characteristics of studies included in the meta-analysis.</p

Flow diagram of study selection.

<p>Flow diagram of study selection.</p

Forest plots of pooled HRs and 95% CIs for OS assessing the prognostic value of <i>SRSF2</i> mutations in the cohort of MDS patients.

<p>Forest plots of pooled HRs and 95% CIs for OS assessing the prognostic value of <i>SRSF2</i> mutations in the cohort of MDS patients.</p

Prognostic value of <i>SRSF2</i> mutations in patients with de novo myelodysplastic syndromes: A meta-analysis

<div><p>Background</p><p>The recent application of gene-sequencing technology has identified many new somatic mutations in patients with myelodysplastic syndromes (MDS). Among them, <i>serine and arginine rich splicing factor 2</i> (<i>SRSF2</i>) mutations belonging to the RNA splicing pathway were of interest. Many studies have already reported the potential prognostic value of <i>SRSF2</i> mutations in MDS patients, with controversial results. Therefore, a meta-analysis was performed to investigate their prognostic impact on MDS.</p><p>Methods</p><p>Databases, including PubMed, Embase and the Cochrane Library, were searched for relevant studies published up to 14 October 2016. Overall survival (OS) was selected as the primary endpoint, and acute myeloid leukemia (AML) transformation was the secondary endpoint. We extracted the corresponding hazard ratios (HRs) and their 95% confidence intervals (CIs) for OS and AML transformation from multivariate Cox proportional hazards models. The combined HRs with their 95% CIs were calculated using fixed or random effect models.</p><p>Results</p><p>A total of 10 cohort studies, covering 1864 patients with de novo MDS and 294 patients with <i>SRSF2</i> mutations, were included in the final meta-analysis. Our results indicated that <i>SRSF2</i> mutations had an adverse prognostic impact on OS (p<0.0001) and AML transformation (p = 0.0005) in the total population. Among the MDS patients with low or intermediate-1 risk defined according to the International Prognostic Scoring System (IPSS), <i>SRSF2</i> mutations predicted a shorter OS (p = 0.009) and were more likely to transform to AML (p = 0.007).</p><p>Conclusions</p><p>This meta-analysis indicates an independent, adverse prognostic impact of <i>SRSF2</i> mutations on OS and AML transformation in patients with de novo MDS. This also applies to the subgroup of low- or intermediate-1-IPSS risk MDS. The identification of mutations in <i>SRSF2</i> can improve current risk stratification and help make treatment decisions.</p></div

Forest plots of pooled HRs and 95% CIs for OS assessing the prognostic value of <i>SRSF2</i> mutations in MDS patients after adjusting for age in COX multivariable models.

<p>Forest plots of pooled HRs and 95% CIs for OS assessing the prognostic value of <i>SRSF2</i> mutations in MDS patients after adjusting for age in COX multivariable models.</p

Ribavirin Inhibits the Activity of mTOR/eIF4E, ERK/Mnk1/eIF4E Signaling Pathway and Synergizes with Tyrosine Kinase Inhibitor Imatinib to Impair Bcr-Abl Mediated Proliferation and Apoptosis in Ph+ Leukemia

<div><p>The eukaryotic translation initiation factor 4E (eIF4E), which is the main composition factor of eIF4F translation initiation complex, influences the growth of tumor through modulating cap-dependent protein translation. Previous studies reported that ribavirin could suppress eIF4E-controlled translation and reduce the synthesis of onco-proteins. Here, we investigated the anti-leukemic effects of ribavirin alone or in combination with tyrosine kinase inhibitor imatinib in Philadelphia chromosome positive (Ph+) leukemia cell lines SUP-B15 (Ph+ acute lymphoblastic leukemia cell line, Ph+ ALL) and K562 (chronic myelogenous leukemia cell line, CML). Our results showed that ribavirin had anti-proliferation effect; it down-regulated the phosphorylation levels of Akt, mTOR, 4EBP1, and eIF4E proteins in the mTOR/eIF4E signaling pathway, and MEK, ERK, Mnk1 and eIF4E proteins in ERK/Mnk1/eIF4E signaling pathway; reduced the expression of Mcl-1 (a translation substrates of eIF4F translation initiation complex) at protein synthesis level not mRNA transcriptional level; and induced cell apoptosis in both SUP-B15 and K562. 7-Methyl-guanosine cap affinity assay further demonstrated that ribavirin remarkably increased the eIF4E binding to 4EBP1 and decreased the combination of eIF4E with eIF4G, consequently resulting in a major inhibition of eIF4F complex assembly. The combination of ribavirin with imatinib enhanced antileukemic effects mentioned above, indicating that two drugs have synergistic anti-leukemic effect. Consistent with the cell lines, similar results were observed in Ph+ acute lymphoblastic primary leukemic blasts; however, the anti-proliferative role of ribavirin in other types of acute primary leukemic blasts was not obvious, which indicated that the anti-leukemic effect of ribavirin was different in cell lineages.</p></div

eIF4F complex formation is inhibited by ribavirin in SUP-B15 and K562 cell lines.

<p>A. The SUP-15 cells were treated with ribavirin, imatinib alone, or ribavirin plus imatinib for 48h. 1×10⁷ cells were lysed in 500μl of RIPA lysis buffer. 7^mGTP-Sepharose beads were added into part of supernatants, incubated for 1–2h, and solubilized in 50μl of SDS-PAGE sample buffer. The buffer was boiled for 7 min and was immunoblotted with the primary antibodies against eIF4G, eIF4E, and 4EBP1. The retained supernatants were analyzed by western blot with primary antibodies against eIF4G, eIF4E, 4E-BP1, and GAPDH, as control. B. The K562 cells were conducted by 7^mGTP pull-down analysis, like SUP-B15 cells.</p

Ribavirin inhibited the signaling pathway of mTOR/eIF4E in SUP-B15.

<p>A. The SUP-B15 cells were treated with different concentrations of ribavirin for 48h, and the proteins in mTOR/eIF4E signaling pathway and Mcl-1 were detected by western bolt analysis. B. The SUP-B15 cells were incubated in 60μM ribavirin for 24, 48, 72h, and the mTOR/eIF4E pathway expression was detected by western bolt analysis. C. The expression of mTOR/eIF4E pathway and Mcl-1 in SUP-B15 cells after treated with ribavirin (30μM), imatinib (10μM) alone, and 30μM ribavirin plus 10μM imatinib for 48h.</p

Ribavirin inhibited the MEK/ERK/Mnk1/eIF4E signaling pathway in SUP-B15.

<p>A. The expression of MEK/ERK/Mnk1/eIF4E pathway and Mcl-1 in SUP-B15 cells was detected after treated with ribavirin (30μM), imatinib (10μM) alone, and 30μM ribavirin plus10μM imatinib for 48h. B. Indicated concentrates of U0126 (MEK1/2 inhibitor) or CGP57380 (Mnk1 inhibitor) alone treated SUP-B15 cells and the MEK/ERK/Mnk1/ eIF4E signaling pathway expression were analyzed. C. The SUP-B15 cells were treated with 60μM ribavirin alone or plus 10μM U0126 (MEK1/2 inhibitor) for 6, 24, 48, and 72h, and the expression of MEK/ERK/Mnk1/eIF4E pathway and Mcl-1 was detected by western bolt analysis.</p