Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole-transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54.1% of patients (n = 125), 31 of which have not been reported previously. In particular, we described a distinct ALL subtype with a characteristic gene expression signature predominantly driven by chromosomal rearrangements of the ZNF384 gene with histone acetyltransferases EP300 and CREBBP. ZNF384-rearranged ALL showed significant up-regulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wild-type ZNF384 in vitro. Ectopic expression of EP300-ZNF384 and CREBBP-ZNF384 fusion altered differentiation of mouse hematopoietic stem and progenitor cells and also potentiated oncogenic transformation in vitro. EP300-and CREBBP-ZNF384 fusions resulted in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation and increased sensitivity of leukemia cells to histone deacetylase inhibitors. In conclusion, our results indicate that gene fusion is a common class of genomic abnormalities in childhood ALL and that recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potential for therapeutic targeting.

Background There is still some debate as to whether transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation (RFA) is better than TACE or RFA alone. This meta-analysis aimed to compare the efficacy and safety of TACE plus RFA for hepatocellular carcinoma (HCC) with RFA or TACE alone. Methods We searched PubMed, MEDLINE, Embase, Cochrane Library, and CNKI (China National Knowledge Infrastructure) for all relevant randomized controlled trials and retrospective studies reporting overall survival (OS), recurrence-free survival (RFS), and complications of TACE plus RFA for HCC, compared with RFA or TACE alone. Results Twenty-one studies involving 3413 patients were included. TACE combined with RFA was associated with better OS (hazard ratio [HR]=0.62, 95% confidence intervals [CI] = 0.55–0.71, P < 0.001) and RFS (HR = 0.52, 95% CI = 0.39–0.69, P < 0.001) than TACE alone; compared with RFA alone, TACE plus RFA resulted in longer OS (HR = 0.63, 95% CI = 0.53–0.75, P < 0.001) and RFS (HR = 0.60, 95% CI = 0.51–0.71, P < 0.001). Subgroup analyses by tumor size also showed that combined treatment resulted in better OS and RFS compared with RFA alone in patients with HCC larger than 3 cm. Combined treatment resulted in similar rate of major complications compared with TACE or RFA alone (OR = 1.78, 95% CI = 0.99–3.20, P = 0.05; OR = 1.00, 95% CI = 0.42–2.38, P = 1.00, respectively). Conclusions TACE combined with RFA was more effective for HCC than TACE alone. For patients with a tumor larger than 3 cm, the combined treatment also achieved a better effect than RFA alone.

A near-infrared ratiometric fluorophore (NIR-HBT) was rationally designed and constructed by expanding both the excitation and emission wavelength of the classical ratiometric fluorophore 2-(benzothiazol-2-yl)phenol (HBT) into the near-infrared region. The NIR-HBT was easily synthesized by incorporating the HBT module into the hemicyanine skeleton and showed evident NIR ratiometric fluorophore characteristics. Further application of the new fluorophore for pH detection demonstrated that NIR-HBT possesses superior overall analytical performance and NIR-HBT was successfully applied for detection of acidosis caused by inflammation in living animal tissue, which indicated the potential application value of NIR-HBT in biological imaging and sensing.

Background Roses are famous ornamental plants worldwide. Floral coloration is one of the most prominent traits in roses and is mainly regulated through the anthocyanin biosynthetic pathway. In this study, we investigated the key genes and metabolites of the anthocyanin biosynthetic pathway involved in color mutation in miniature roses. A comparative metabolome and transcriptome analysis was carried out on the Neptune King rose and its color mutant, Queen rose, at the blooming stage. Neptune King rose has light pink colored petals while Queen rose has deep pink colored petals. Result A total of 190 flavonoid-related metabolites and 38,551 unique genes were identified. The contents of 45 flavonoid-related metabolites, and the expression of 15 genes participating in the flavonoid pathway, varied significantly between the two cultivars. Seven anthocyanins (cyanidin 3-O-glucosyl-malonylglucoside, cyanidin O-syringic acid, cyanidin 3-O-rutinoside, cyanidin 3-O-galactoside, cyanidin 3-O-glucoside, peonidin 3-O-glucoside chloride, and pelargonidin 3-O-glucoside) were found to be the major metabolites, with higher abundance in the Queen rose. Thirteen anthocyanin biosynthetic related genes showed an upregulation trend in the mutant flower, which may favor the higher levels of anthocyanins in the mutant. Besides, eight TRANSPARENT TESTA 12 genes were found upregulated in Queen rose, probably contributing to a high vacuolar sequestration of anthocyanins. Thirty transcription factors, including two MYB and one bHLH, were differentially expressed between the two cultivars. Conclusions This study provides important insights into major genes and metabolites of the anthocyanin biosynthetic pathway modulating flower coloration in miniature rose. The results will be conducive for manipulating the anthocyanin pathways in order to engineer novel miniature rose cultivars with specific colors.

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Methotrexate (MTX) during maintenance therapy is essential to cure acute lymphoblastic leukemia (ALL), but dosing strategies to achieve adequate treatment intensity are challenged by inter-individual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Paediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic SNP rs1382539 located in a regulatory element of DHFR was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10-8) due to suppression of enhancer activity, while rs35789560 in FPGS (p.R466C, P = 5.6 × 10-9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = 0.044). These findings show a genetic basis for inter-patient variability in MTX response and could be used to improve future dosing algorithms.

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The organization of organic chromophores to form H-/J-aggregates can result in new biomaterials with unique properties and applications. DNA-template self-assembly is one of the most attractive strategies to guide the formation of chromophore aggregates. However, the DNA templates are mainly limited to canonical nucleic acids structures [single (ss)- and double (ds)-stranded DNA]. DNA G-quadruplexes (GQs), with distinct and various structural features, were rarely exploited to guide the formation of dye aggregates. In this study, we present the spontaneous assembly of cyanine dye IR786 to form H-aggregates on DNA GQs exclusively, but no IR786 aggregates formed by adjusting the experimental parameters or on ss-/ds-DNA. Furthermore, on the basis of the assembly entity (GQs–IR786), an adaptive GQs-FID (fluorescence intercalator displacement) assay for screening of GQs ligands was developed. In contrast with the existing GQs-FID screening schemes, this assay displayed attractive performance in many aspects (such as turn-on signal output, broad screening range, and time saving). All these results have undoubtedly demonstrated the great values of DNA GQs as a template to guide the formation of dye aggregates. We hope that more GQs structures would be exploited as templates to expand the variety of functional materials in the future. Moreover, the specifically formed H-aggregates of IR786 on GQs are significant for GQs’ detection, and we also expect that this GQs-FID assay would be further studied and finally applied to screen GQs ligands in a high-throughput manner in the future.