Novel bioinformatic classification system for genetic signatures identification in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a spectrum of disease comprising more than 30% of non-Hodgkin lymphomas. Although studies have identified several molecular subgroups, the heterogeneous genetic background of DLBCL remains ambiguous. In this study we aimed to develop a novel approach and to provide a distinctive classification system to unravel its molecular features. METHOD: A cohort of 342 patient samples diagnosed with DLBCL in our hospital were retrospectively enrolled in this study. A total of 46 genes were included in next-generation sequencing panel. Non-mutually exclusive genetic signatures for the factorization of complex genomic patterns were generated by random forest algorithm. RESULTS: A total of four non-mutually exclusive signatures were generated, including those with MYC-translocation (MYC-trans) (n = 62), with BCL2-translocation (BCL2-trans) (n = 69), with BCL6-translocation (BCL6-trans) (n = 108), and those with MYD88 and/or CD79B mutations (MC) signatures (n = 115). Comparison analysis between our model and traditional mutually exclusive Schmitz's model demonstrated consistent classification pattern. And prognostic heterogeneity existed within EZB subgroup of de novo DLBCL patients. As for prognostic impact, MYC-trans signature was an independent unfavorable prognostic factor. Furthermore, tumors carrying three different signature markers exhibited significantly inferior prognoses compared with their counterparts with no genetic signature. CONCLUSION: Compared with traditional mutually exclusive molecular sub-classification, non-mutually exclusive genetic fingerprint model generated from our study provided novel insight into not only the complex genetic features, but also the prognostic heterogeneity of DLBCL patients.

[Apoptosis of human hepatocellular carcinoma HepG-2 cells upon inhibition of STAT3 by 5,2',4'-trihydroxy-6,7,5'-trimethoxy flavone nanoparticle].

This study was designed to investigate the mechanism of 5,2',4'-trihydroxy-6,7,5'-trimethoxy flavone nanoparticle (TTF1-NP) in the induction of apoptosis of human hepatocellular carcinoma HepG-2 cells. MTT assay, immunocytochemical staining and flow cytometry with Annexin V-FITC/PI were used to demonstrate inhibition of proliferation of HepG-2 cells and cell apoptosis. The inhibition was studied in a dose- and time-dependent manner. Western blot results showed that TTF1-NP down-regulated the signals of survivin, p-STAT3 and STAT3, but up-regulated the expression level of cleaved caspase-3. Taken together, our results showed that TTF1-NP induced HepG-2 cell apoptosis through inhibition of the STAT3 expression.

Inherited Genetic Susceptibility to Nonimmunosuppressed Epstein-Barr Virus-associated T/NK-cell Lymphoproliferative Diseases in Chinese Patients.

Epstein-Barr virus (EBV) T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells, including chronic active EBV infection of T/NK-cell type (CAEBV+T/NK), EBV-associated hemophagocytic lymphohistiocytosis (EBV+HLH), extranodal NK/T-cell lymphoma of nasal type (ENKTL), and aggressive NK-cell leukemia (ANKL). However, the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown. A total of 171 nonimmunosuppressed patients with EBV+T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed. The 94 gene variants, mostly located in UNC13D, LYST, ITK, and PRF1 genes were detected, and mutations covered 28/50 (56.00%) of CAEBV-T/NK, 31/51 (60.78%) of EBV+HLH, 13/28 (46.42%) of ENKTL, and 13/48 (27.09%) of ANKL. Most mutations represented monoallelic and missense. Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations (P=0.0284, P=0.0137). Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV+T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.

Clinical Features and MicroRNA Expression Patterns Between AML Patients With DNMT3A R882 and Frameshift Mutations.

Background: DNA methyltransferase 3A (DNMT3A) plays a unique role in hematopoiesis and acute myeloid leukemia (AML) pathogenesis. While the influences of DNMT3A mutation subtypes are still under debate. Purpose: Exploration of the clinical and molecular differences between AML patients carrying DNMT3A R882 mutations and DNMT3A frameshift mutations. Methods: Next generation of sequencing (NGS) and clinical data of 118 AML patients in our center were analyzed and compared. NGS, mRNA and miRNA profiling and clinical data from 12 patients in TCGA database were integrative analyzed. Results: Among all patients enrolled, 113 patients were positive for the variants of interest. Overall, a total of 295 variants were discovered, among which 24 DNMT3A mutations were detected, including 1 non-sense, 20 missense, 3 frameshift mutations. And 7 DNMT3A R882 mutations (3 R882H, 2 R882C, and 2 R882P) were found. Clinical analysis from our cohort and TCGA database indicated that patients carrying DNMT3A R882 mutation exhibited significantly higher levels of peripheral blood hemoglobin and non-significantly inferior prognosis compared with patients with DNMT3A frameshift mutations. Integrative analysis indicated that miR-10b, miR-143, and miR-30a were significantly decreased in the DNMT3A R882 group. High miR-143 expression is significantly associated with better prognosis in AML patients with DNMT3A mutations. Conclusion: Different molecular and clinical characteristics existed between patients with DNMT3A variant subtypes. The distinct microRNA expression pattern for DNMT3A R882 AML patients might not only act as markers to predict disease prognosis, but also could be further investigated to develop novel therapeutic targets for patients with DNMT3A mutations.

Distribution and temporal trend of polybrominated diphenyl ethers in one Shanghai municipal landfill, China.

The scarcity of information on polybrominated diphenyl ethers' (PBDEs) flow in landfill restricts the life cycle analysis of PBDEs. In this study, eight PBDE congeners (BDEs 28, 47, 99, 100, 153, 154, 183, and 209) in topsoil, vegetation leaves, leachate, and municipal aged refuse collected from Shanghai Laogang Municipal Landfill (SLML) were investigated. The present study revealed elevated PBDE concentrations in topsoil and proved PBDE leakage from SLML and vegetation uptake. BDE-209 was the predominant congener, and this could be due to massive usage of deca-BDE mixture in Shanghai. ΣPBDE concentrations in leachates treated by reed wetland and A(2)/O process fell in the low end of the worldwide range. ΣPBDE concentrations in aged refuse samples rose from under 50 ng/g dw in 1989 to the range of 5,150-5,718 ng/g dw in 2002. PBDE concentrations increase in aged refuse samples throughout the 1990s into the 2000s paralleled municipal solid waste output from 1991 to 2002 in Shanghai. Exponential increase in BDE-209 concentration in aged refuse suggested the increasing market demands for deca-BDE mixture after 1990 in China. Notably, the inventory of PBDEs in SLML was 28.7 MT, and the doubling time of BDE-209 in aged refuse was calculated to be 1.6 year. SLML can be considered as a source of PBDE and one main recipient of PBDE as well, receiving inputs predominantly from the PBDE-containing waste. Priority should be given to formulate regulation on PBDEs and sorting work before landfill disposal.