Endogenous tumor suppressor microRNA-193b: Therapeutic and prognostic value in acute myeloid leukemia

Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo. Results miR-193b exerted important, endogenous, tumor-suppressive functions on the hematopoietic system. miR-193b-3p was downregulated in several cytogenetically defined subgroups of pediatric and adult AML, and low expression served as an independent indicator for poor prognosis in pediatric AML (risk ratio 6 standard error, 20.56 6 0.23; P = .016). miR-193b-3p expression improved the prognostic value of the European LeukemiaNet risk-group stratification or a 17-gene leukemic stemness score. In knockout mice, loss of miR-193b cooperated with Hoxa9/Meis1 during leukemogenesis, whereas restoring miR-193b expression impaired leukemic engraftment. Similarly, expression of miR-193b in AML blasts from patients diminished leukemic growth in vitro and in mouse xenografts. Mechanistically, miR-193b induced apoptosis and a G1/S-phase block in various human AML subgroups by targeting multiple factors of the KIT-RAS-RAF-MEK-ERK (MAPK) signaling cascade and the downstream cell cycle regulator CCND1. Conclusion The tumor-suppressive function is independent of patient age or genetics; therefore, restoring miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms

Russian Sentence Corpus: Benchmark measures of eye movements in reading in Russian

This article introduces a new corpus of eye movements in silent reading—the Russian Sentence Corpus (RSC). Russian uses the Cyrillic script, which has not yet been investigated in cross-linguistic eye movement research. As in every language studied so far, we confirmed the expected effects of low-level parameters, such as word length, frequency, and predictability, on the eye movements of skilled Russian readers. These findings allow us to add Slavic languages using Cyrillic script (exemplified by Russian) to the growing number of languages with different orthographies, ranging from the Roman-based European languages to logographic Asian ones, whose basic eye movement benchmarks conform to the universal comparative science of reading (Share, 2008). We additionally report basic descriptive corpus statistics and three exploratory investigations of the effects of Russian morphology on the basic eye movement measures, which illustrate the kinds of questions that researchers can answer using the RSC. The annotated corpus is freely available from its project page at the Open Science Framework: https://osf.io/x5q2r/