A Prognostic Model of Pseudogenes in Acute Myeloid Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the abnormal proliferation of myeloid hematopoietic cells and it is urgently needed to develop new molecular biomarkers to predict clinical outcomes and improve therapeutic effects. METHODS: The differentially expressed genes were identified by comparing TCGA with GETx data. Univariate LASSO and multivariate cox regression analysis were performed to identify prognosis-associated pseudogenes. Based on the overall survival of related pseudogenes, we used them to construct a prognostic model for AML patients. Moreover, we built the pseudogenes-miRNA-mRNA ceRNA networks and explored their involved biological functions and pathways via GO and KEGG enrichment analysis. RESULTS: Seven prognosis-associated pseudogenes were identified, including CCDC150P1, DPY19L1P1, FTH1P8, GTF2IP4, HLA-K, NAPSB, and PDCD6IPP2. The risk model based on these 7 pseudogenes could accurately predict the 1-year, 3-year, and 5-year survival rates. The GO and KEGG enrichment analyses demonstrated that these prognosis-associated pseudogenes were significantly enriched in cell cycle, myeloid leukocyte differentiation, regulation of hemopoiesis, and other critical cancer-related biological functions and pathways. We systematically and comprehensively analyzed the prognostic role of pseudogenes in AML. CONCLUSIONS: The prognostic model of pseudogenes we identified is an independent predictor of overall survival in AML and could be used as biomarker for AML treatment.

Temporal visualization of femtosecond laser pulses with single-edge transport in turbid media via Monte Carlo simulation.

We study the propagation of femtosecond laser pulses with a single (front or rear) edge or dual edge through turbid media via Monte Carlo simulation. The results show that both the transmitted pulses spread on the basis of the incident pulse width ${t_{p}} = {{100}}\;{\rm{fs}}$, arising from the scattering effect. Further, the broadening width of the incident laser with a dual-edge pulse is wider than that of the incident laser width a single-edge pulse. The effect of the scattering particles on the front edge and the rear edge of the femtosecond laser can be distinguished in the time domain for femtosecond laser pulses through turbid media with the optical depth (OD) less than 10. In this scattering regime, the front-edge pulse scattered by the particles contributes more to diffused photons, but the effect of the scattering particles on the front edge and the rear edge of the femtosecond laser cannot be discriminated in turbid media with the OD more than 10, where the scattering is dominated by multiple scattering.

Identifying key genes and functionally enriched pathways in acute myeloid leukemia by weighted gene co-expression network analysis.

Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of myeloid leukemia cells in the bone marrow and other hematopoietic tissues and is highly heterogeneous. While with the progress of sequencing technology, understanding of the AML-related biomarkers is still incomplete. The purpose of this study is to identify potential biomarkers for prognosis of AML. Based on WGCNA analysis of gene mutation expression, methylation level distribution, mRNA expression, and AML-related genes in public databases were employed for investigating potential biomarkers for the prognosis of AML. This study screened a total of 6153 genes by analyzing various changes in 103 acute myeloid leukemia (AML) samples, including gene mutation expression, methylation level distribution, mRNA expression, and AML-related genes in public databases. Moreover, seven AML-related co-expression modules were mined by WGCNA analysis, and twelve biomarkers associated with the AML prognosis were identified from each top 10 genes of the seven co-expression modules. The AML samples were then classified into two subgroups, the prognosis of which is significantly different, based on the expression of these twelve genes. The differentially expressed 7 genes of two subgroups (HOXB-AS3, HOXB3, SLC9C2, CPNE8, MEG8, S1PR5, MIR196B) are mainly involved in glucose metabolism, glutathione biosynthesis, small G protein-mediated signal transduction, and the Rap1 signaling pathway. With the utilization of WGCNA mining, seven gene co-expression modules were identified from the TCGA database, and there are unreported genes that may be potential driver genes of AML and may be the direction to identify the possible molecular signatures to predict survival of AML patients and help guide experiments for potential clinical drug targets.

DNA methylation-based subtypes of acute myeloid leukemia with distinct prognosis and clinical features.

Acute myeloid leukemia (AML) is a malignancy of the stem cell precursors of the myeloid lineage. DNA methylation is an important DNA modification that regulates gene expression. Investigating AML heterogeneity based on DNA methylation could be clinically informative for improving clinical diagnosis and prognosis. The AML subtypes based on DNA methylation were identified by unsupervised consensus clustering. The association of these subtypes with gene mutation, copy number variations, immune infiltration and clinical features were further explored. Finally, univariate, LASSO and multivariate cox regression analyses were used to identify prognosis-associated genes and construct risk model for AML patients. In addition, we validated this model by using other datasets and explored the involved biological functions and pathways of its related genes. Three CpG island methylator phenotypes (CIMP-H, CIMP-M and CIMP-L) were identified using the 91 differential CpG sites. Overall survival, morphology, macrophages M0 and monocytes were distinct from each other. The most frequently mutated gene in CIMP-L was DNMT3A while which in CIMP-M that was RUNX1. In addition, the TIDE scores, used to predict the response to immune checkpoint inhibitors, were significantly different among CIMPs. The CIMP-associated prognosis risk model (CPM) using 32 key genes had convinced accuracy of prediction to forecast 0.5-year, 1-year, 3-year and 5-year survival rates. Moreover, the risk score-related genes were significantly enriched in pattern specification process, regionalization, embryonic organ morphogenesis and other critical cancer-related biological functions. We systematically and comprehensively analyzed the DNA methylation in AML. The risk model we constructed is an independent predictor of overall survival in AML and could be used as prognostic factor for AML treatment.

Single-shot decoherence polarization gated imaging through turbid media.

We propose a method for imaging through a turbid medium by using a single-shot decoherence polarization gate (DPG). The DPG is made up of a polarizer, an analyzer, and a weakly scattering medium. Contrary to intuition, we discover that the preferential utilization of sparsely scattered photons by introducing weakly scattering mediums can lead to better image quality. The experimental results show that the visibilities of the images acquired from the DPG imaging method are obviously improved. The contrast of the bar can be increased by 50% by the DPG imaging technique. Furthermore, we study the effect of the volume concentration of the weakly scattering medium on the speckle suppression and the enhancement of the visibilities of the images. The variances of the contrasts of the image show that there exists an optimum optical depth (∼0.8) of the weakly scattering medium for DPG imaging through a specific turbid medium.

SLED1 Promoting Cell Proliferation and Inhibiting Apoptosis in Acute Myeloid Leukemia: a Study.

In this study, we aimed to explore long non-coding RNA (lncRNA) sustained low-efficiency dialysis (SLED1) correlated with Bcl-2 apoptosis pathway in acute myeloid leukemia (AML). This study further aimed to determine its role in the regulation of AML progression and its action as a potential biomarker for better prognosis. AML microarray profiles GSE97485 and probe annotation from the Gene Expression Omnibus (GEO) database from the National Center for Biotechnology Information (NCBI) were detected using the GEO2R tool ( http://www.ncbi.nlm.nih.gov/geo/geo2r/ ). The expression of AML was downloaded from the TCGA database ( http://cancergenome.nih.gov/ ). The statistical analysis of the database was processed with R software. Bioinformatic analysis found that lncRNA SLED1 is highly expressed in AML patients and is associated with poor prognosis. We found that the increased SLED1 expression levels in AML were significantly correlated with FAB classification, human race, and age. Our study has shown that upregulation of SLED1 promoted AML cell proliferation and inhibited cell apoptosis in vitro; RNA sequencing showed increased expression of BCL-2 and indicated that SLED1 might promote the development of AML by regulating BCL-2. Our results showed that SLED1 could promote the proliferation and inhibit the apoptosis of AML cells. SLED1 might promote the development of AML by regulating BCL-2, but the mechanism involved in the progression of AML is unclear. SLED1 plays an important role in AML progression, may be applied as a rapid and economical AML prognostic indicator to predict the survival of AML patients, and help guide experiments for potential clinical drag targets.

Sunitinib malate inhibits intestinal tumor development in male ApcMin/+ mice by down-regulating inflammation-related factors with suppressing ß-cateinin/c-Myc pathway and re-balancing Bcl-6 and Caspase-3.

Sunitinib is a tyrosine kinase inhibitor for many tumors. Inflammation is one of the most important factors in the development of intestinal tumors. Many inflammation-related factors are regulated by tyrosine kinase receptors. It is reasonable to hypothesize that sunitinib can regulate the development of intestinal tumors by regulating the expression and/or activity of inflammation-related factors. Here, ApcMin/+ male mouse model was used to investigate the effect and mechanism of sunitinib malate against intestinal cancer. Results show that compared to vehicle, after sunitinib malate treatment, overall survival of ApcMin/+ mice was lengthened up to 25 days, with a gain of body weight, reduction of spleen/body weight index, and RBC, WBC and HGC regulated to normal levels of wild type mice, and a number of polyps no less than 1 mm significantly reduced. Meanwhile, in the intestines, the nuclear ß-Catenin protein and c-Myc mRNA were both down-regulated, and Bcl-6 was significantly reduced with Caspase-3 up regulated. Furthermore, inflammation-related factors including IL-6, TNF-α, IL-1α, IL-1ß and IFN-γ were down-regulated at mRNA levels in the intestines. These results suggest that sunitinib malate can significantly improve the survival status and inhibit intestinal tumor development in male ApcMin/+ mice, through inhibiting inflammation-related factors, while suppressing ß-cateinin/c-Myc pathway and re-balancing protein levels of Bcl-6 and Caspase-3.

PRKD2 Promotes Progression and Chemoresistance of AML via Regulating Notch1 Pathway.

INTRODUCTION: Progression and chemoresistance of acute myeloid leukemia (AML) contribute to most of the treatment failure. Notch pathway has been proven to be involved in many biological processes and diseases, especially AML. In this study, we aimed to explore genes correlated with Notch1 pathway in AML and determine their roles in the regulation of AML progression and chemoresistance. METHODS: TCGA database was used to explore Notch1 associated genes. Kaplan-Meier survival analysis was performed to evaluate the prognostic significance of genes. Quantitative RT-PCR (qRT-PCR) and Western blot were performed to examine the expression of genes. The expression of PRKD2 was up-regulated or knocked down in AML cell lines by lentivirus or siRNAs. CCK-8 and flow cytometry were used to analyze the effect of PRKD2 on cell proliferation and chemoresistance. RESULTS: Based on TCGA database, PRKD2 was found to be positively correlated with Notch1 expression, cytogenetic risk status and poorer prognosis in AML. Moreover, the expression level of PRKD2 was higher in AML chemo-resistant cells than in chemo-sensitive cells. Functionally, knockdown of PRKD2-induced apoptosis and increased chemosensitivity of AML cells. PRKD2 overexpression promoted proliferation and chemoresistance of AML cells. Furthermore, we found PRKD2 could regulate Notch1 pathway. Besides, high PRKD2 expression was correlated with higher risk group of AML patients which indicated that PRKD2 was an independent prognostic marker for AML. CONCLUSION: Taken together, our results showed that PRKD2 could promote the proliferation and chemoresistance of AML cells by regulating Notch1 pathway. The study broadened our insights into the underlying mechanisms in chemoresistance and proliferation of AML, and provided a new prognostic marker and treatment target for AML.

Development and immunological evaluation of HLA-specific chronic myeloid leukemia polyepitope vaccine in Chinese population.

BACKGROUND: BCR/ABL and Wilms' tumor 1 (WT1) are an ideal tumor associated antigens which can be used to develop a potential chronic myeloid leukemia (CML) dentritic cell (DC) vaccine. Here, we constructed a novel polyepitope vaccine which used recombinant lentiviral vector carrying BCR/ABL and WT1 genes, and determined the immunological effects of this vaccine in vitro. METHODS: The DC vaccine was constructed using lentiviral vector transduced DCs. T lymphocytes were stimulated with DC vaccine and then co-cultured in vitro with peripheral blood mononuclear cells (PBMCs) from CML or ALL patients, respectively. The cytotoxicity of proliferous cytotoxic T lymphocytes (CTLs) was determined by the LDH assay. The IFN-γ production of CTLs was detected using ELISPOT assay. RESULTS: We constructed an lentiviral vector encoding 50 different epitopes from BCR/ABL and WT1 antigens, and transferred it into DCs to prepare the DC vaccine successfully. The in vivo stimulation of CTLs with this DC vaccine were proved to show strong cytotoxicity and produce high level of IFN-γ. CONCLUSIONS: The novel recombinant lentiviral polyepitope DC vaccine is a promising candidate for clinical trials and may be an effective approach for CML immunotherapy.