Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.
ObjectiveThe aim of this study was to develop a radiomics signature for prediction of progression-free survival (PFS) in lower-grade gliomas and to investigate the genetic background behind the radiomics signature.MethodsIn this retrospective study, training (n = 216) and validation (n = 84) cohorts were collected from the Chinese Glioma Genome Atlas and the Cancer Genome Atlas, respectively. For each patient, a total of 431 radiomics features were extracted from preoperative T2-weighted magnetic resonance images. A radiomics signature was generated in the training cohort, and its prognostic value was evaluated in both the training and validation cohorts. The genetic characteristics of the group with high-risk scores were identified by radiogenomic analysis, and a nomogram was established for prediction of PFS.ResultsThere was a significant association between the radiomics signature (including 9 screened radiomics features) and PFS, which was independent of other clinicopathologic factors in both the training (P < 0.001, multivariable Cox regression) and validation (P = 0.045, multivariable Cox regression) cohorts. Radiogenomic analysis revealed that the radiomics signature was associated with the immune response, programmed cell death, cell proliferation, and vasculature development. A nomogram established using the radiomics signature and clinicopathologic risk factors demonstrated high accuracy and good calibration for prediction of PFS in both the training (C-index, 0.684) and validation (C-index, 0.823) cohorts.ConclusionsPFS can be predicted non-invasively in patients with LGGs by a group of radiomics features that could reflect the biological processes of these tumors.
Natural-killer/T cell lymphoma (NKTCL) is a malignant proliferation of CD56+/cytoCD3+ lymphocytes and constitutes a heterogeneous group of aggressive lymphoma prevalent in Asian and South American populations. NKTCL represents a distinct clinicopathologic entity of non-Hodgkin’s lymphoma, characterized by male predominance, strong association with Epstein-Barr virus (EBV) infection, prominent tissue necrosis and aggressive clinical course. However, molecular pathogenesis of NKTCL remains largely elusive. Here we identified somatic mutations by whole-exome sequencing in 25 NKTCL patients and extended validation through targeted sequencing in an additional 80 cases. Functional experiments including RNA unwinding test, colony forming assay, cell proliferation assay and gene expression profiling were also performed. Overall, 50.5% of NKTCL patients displayed somatic mutations of RNA helicase family, tumor suppressors (TP53 and MGA), and/or epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). Recurrent mutations were most frequently discovered in RNA helicase gene DDX3X (21/105 cases, 20.0%). Mutations of DDX3X were seldom overlapped with those of TP53. Functionally, DDX3X mutants exhibited reduced RNA unwinding activity and enhanced cell proliferation. Similar stimulatory effect on cell proliferation was observed in cells transfected with specific siRNA targeting DDX3X. Gene expression profiling revealed an association of DDX3X mutations with activation of NF-kB and MAPK pathways. The clinical follow-up data showed that DDX3X-mutated patients presented a poor prognosis. Our work suggests the heterogeneity of gene mutational spectrum of NKTCL and provides a potential therapeutic target for relevant cases. Disclosures No relevant conflicts of interest to declare.
Functional ingredients in blueberry have the best health benefits. To obtain a better understanding of the health role of blueberry in chronic disease, we conducted systematic preventive strategies for functional ingredients in blueberry, based on comprehensive databases, especially PubMed, ISI Web of Science, and CNKI for the period 2008–2018. Blueberry is rich in flavonoids (mainly anthocyanidins), polyphenols (procyanidin), phenolic acids, pyruvic acid, chlorogenic acid, and others, which have anticancer, anti-obesity, prevent degenerative diseases, anti-inflammation, protective properties for vision and liver, prevent heart diseases, antidiabetes, improve brain function, protective lung properties, strong bones, enhance immunity, prevent cardiovascular diseases, and improve cognitive decline. The anthocyanins and polyphenols in blueberry are major functional ingredients for preventive chronic disease. These results support findings that blueberry may be one of the best functional fruits, and further reveals the mechanisms of anthocyanins and polyphenols in the health role of blueberry for chronic disease. This paper may be used as scientific evidence for developing functional foods, nutraceuticals, and novel drugs of blueberry for preventive chronic diseases.
• ATRX in lower-grade gliomas could be predicted using radiomic analysis. • The LASSO regression algorithm and SVM performed well in radiomic analysis. • Nine radiomic features were screened as an ATRX-predictive radiomic signature. • The machine-learning model for ATRX-prediction was validated by an independent database.
Ramie, Boehmeria nivea (L.) Gaudich, family Urticaceae, is a plant native to eastern Asia, and one of the world's oldest fibre crops. It is also used as animal feed and for the phytoremediation of heavy metal-contaminated farmlands. Thus, the genome sequence of ramie was determined to explore the molecular basis of its fibre quality, protein content and phytoremediation. For further understanding ramie genome, different paired-end and mate-pair libraries were combined to generate 134.31 Gb of raw DNA sequences using the Illumina whole-genome shotgun sequencing approach. The highly heterozygous B. nivea genome was assembled using the Platanus Genome Assembler, which is an effective tool for the assembly of highly heterozygous genome sequences. The final length of the draft genome of this species was approximately 341.9 Mb (contig N50 = 22.62 kb, scaffold N50 = 1,126.36 kb). Based on ramie genome annotations, 30,237 protein-coding genes were predicted, and the repetitive element content was 46.3%. The completeness of the final assembly was evaluated by benchmarking universal single-copy orthologous genes (BUSCO); 90.5% of the 1,440 expected embryophytic genes were identified as complete, and 4.9% were identified as fragmented. Phylogenetic analysis based on single-copy gene families and one-to-one orthologous genes placed ramie with mulberry and cannabis, within the clade of urticalean rosids. Genome information of ramie will be a valuable resource for the conservation of endangered Boehmeria species and for future studies on the biogeography and characteristic evolution of members of Urticaceae.
Amplification of epidermal growth factor receptor (EGFR) and active mutant EGFRvIII occurs frequently in glioblastoma (GBM) and contributes to chemo/radio‐resistance in various cancers, especially in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in GBM could benefit cancer patients. A genome‐wide screening under a clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 library is conducted to identify the genes that confer resistance to TMZ in EGFRvIII‐expressing GBM cells. Deep sgRNA sequencing reveals 191 candidate genes that are responsible for TMZ resistance in EGFRvIII‐expressing GBM cells. Notably, E2F6 is proven to drive a TMZ resistance, and E2F6 expression is controlled by the EGFRvIII/AKT/NF‐κB pathway. Furthermore, E2F6 is shown as a promising therapeutic target for TMZ resistance in orthotopic GBM cell line xenografts and GBM patient‐derived xenografts models. After integrating clinical data with paired primary–recurrent RNA sequencing data from 134 GBM patients who received TMZ treatment after surgery, it has been revealed that the E2F6 expression level is a predictive marker for TMZ response. Therefore, the inhibition of E2F6 is a promising strategy to conquer TMZ resistance in GBM.
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