SNP rs1533428 at 2p16.3 as a marker for late-onset primary open-angle glaucoma

Purpose: To investigate the associations between gene variants in cholesterol 24S-hydroxylase (CYP46A1), LIM homeobox transcription factor 1-beta (LMX1B), plexin domain containing 2 (PLXDC2), toll-like receptor 4 (TLR4), transmembrane and tetratricopeptide repeat containing 2 (TMTC2), zona pellucida glycoprotein 4 (ZP4), chromosome 2p16.3, and primary open-angle glaucoma (POAG). Methods: We studied 462 POAG patients and 577 controls from three cohorts (Hong Kong, Shantou, and Beijing, China). Twelve single-nucleotide polymorphisms (SNPs) were genotyped in the Hong Kong cohort using TaqMan genotyping assay. Significant associations were validated in the Shantou and Beijing cohorts. Results: Association of POAG with TLR4 rs7037117, in a recessive model, was identified in the Hong Kong and Shantou cohorts (both southern Chinese, $p_{rec}$=0.0019) but not the Beijing cohort (northern Chinese). rs1533428 at chromosome 2p16.3 showed a consistent trend of age-specific association in all three cohorts. Genotypes TT + CT conferred a 2.16 fold of significantly increased risk to late-onset POAG ($p_{dom}$=0.00025), but no significant risk to POAG of younger ages of onset in the combined cohort. A joint effect was found between rs7037117 and rs1533428, with carriers of both higher-risk genotypes having a 4.53 fold of increased disease risk (p=0.00028). Conclusions: Our study reveals discrepant association patterns of 12 candidate SNPs in 7 genes/loci with POAG in Chinese, provides positive replications for POAG markers rs1533428 at 2p16.3 and TLR4 rs7037117, and suggests that rs1533428 is a putative risk variant for late-onset POAG. The identification of an age-specific association between rs1533428 and late-onset POAG highlights a new genotype-phenotype association in POAG. Further studies are warranted to confirm the age-specific association

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53

Additional file 1. Table S1: Clinicopathologic and molecular characteristics of DLBCL patients with high or low XPO1 expression. Table S2: Significantly differentially expressed genes between XPO1high and XPO1low DLBCL patients with concurrent TP53 mutation and high MYC expression. Figure S1: Biomarker study for XPO1 and selinexor. (A–B) XPO1high expression showed significant adverse prognostic impact in the ABC subtype but not the GCB subtype of DLBCL. (C) XPO1high expression showed a trend of unfavorable prognostic effect on PFS in MYC-rearranged (MYC-R+) DLBCL. (D) XPO1high expression was associated with significantly poorer survival in DLBCL patients with wild type (Wt) TP53. (E) ABC-DLBCL and GCB-DLBCL cells showed similar sensitivity to the cytotoxicity of selinexor. (F) TP53 mutation (Mut-TP53) significantly reduced the anti-lymphoma efficacy of selinexor in HGBCL-DH cells. IC50 values were calculated by GraphPad Prism 8 based on the cell viability data after 72-hour treatment

A Systematic Analysis on DNA Methylation and the Expression of Both mRNA and microRNA in Bladder Cancer

Background: DNA methylation aberration and microRNA (miRNA) deregulation have been observed in many types of cancers. A systematic study of methylome and transcriptome in bladder urothelial carcinoma has never been reported. Methodology/Principal Findings: The DNA methylation was profiled by modified methylation-specific digital karyotyping (MMSDK) and the expression of mRNAs and miRNAs was analyzed by digital gene expression (DGE) sequencing in tumors and matched normal adjacent tissues obtained from 9 bladder urothelial carcinoma patients. We found that a set of significantly enriched pathways disrupted in bladder urothelial carcinoma primarily related to "neurogenesis" and "cell differentiation" by integrated analysis of -omics data. Furthermore, we identified an intriguing collection of cancer-related genes that were deregulated at the levels of DNA methylation and mRNA expression, and we validated several of these genes (HIC1, SLIT2, RASAL1, and KRT17) by Bisulfite Sequencing PCR and Reverse Transcription qPCR in a panel of 33 bladder cancer samples. Conclusions/Significance: We characterized the profiles between methylome and transcriptome in bladder urothelial carcinoma, identified a set of significantly enriched key pathways, and screened four aberrantly methylated and expressed genes. Conclusively, our findings shed light on a new avenue for basic bladder cancer research

The DNA Methylome of Human Peripheral Blood Mononuclear Cells

Analysis across the genome of patterns of DNA methylation reveals a rich landscape of allele-specific epigenetic modification and consequent effects on allele-specific gene expression

MicroRNA-145 Regulates Human Corneal Epithelial Differentiation

Epigenetic factors, such as microRNAs, are important regulators in the self-renewal and differentiation of stem cells and progenies. Here we investigated the microRNAs expressed in human limbal-peripheral corneal (LPC) epithelia containing corneal epithelial progenitor cells (CEPCs) and early transit amplifying cells, and their role in corneal epithelium.Human LPC epithelia was extracted for small RNAs or dissociated for CEPC culture. By Agilent Human microRNA Microarray V2 platform and GeneSpring GX11.0 analysis, we found differential expression of 18 microRNAs against central corneal (CC) epithelia, which were devoid of CEPCs. Among them, miR-184 was up-regulated in CC epithelia, similar to reported finding. Cluster miR-143/145 was expressed strongly in LPC but weakly in CC epithelia (P = 0.0004, Mann-Whitney U-test). This was validated by quantitative polymerase chain reaction (qPCR). Locked nucleic acid-based in situ hybridization on corneal rim cryosections showed miR-143/145 presence localized to the parabasal cells of limbal epithelium but negligible in basal and superficial epithelia. With holoclone forming ability, CEPCs transfected with lentiviral plasmid containing mature miR-145 sequence gave rise to defective epithelium in organotypic culture and had increased cytokeratin-3/12 and connexin-43 expressions and decreased ABCG2 and p63 compared with cells transfected with scrambled sequences. Global gene expression was analyzed using Agilent Whole Human Genome Oligo Microarray and GeneSpring GX11.0. With a 5-fold difference compared to cells with scrambled sequences, miR-145 up-regulated 324 genes (containing genes for immune response) and down-regulated 277 genes (containing genes for epithelial development and stem cell maintenance). As validated by qPCR and luciferase reporter assay, our results showed miR-145 suppressed integrin β8 (ITGB8) expression in both human corneal epithelial cells and primary CEPCs.We found expression of miR-143/145 cluster in human corneal epithelium. Our results also showed that miR-145 regulated the corneal epithelium formation and maintenance of epithelial integrity, via ITGB8 targeting

A common variant near TGFBR3 is associated with primary open angle glaucoma

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis

Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma

Dysregulated NF-κB signaling is critical for lymphomagenesis. The regulation, function, and clinical relevance of c-Rel/NF-κB activation in diffuse large B-cell lymphoma (DLBCL) have not been well studied. In this study we analyzed the prognostic significance and gene-expression signature of c-Rel nuclear expression as surrogate of c-Rel activation in 460 patients with de novo DLBCL. Nuclear c-Rel expression, observed in 137 (26.3%) DLBCL patients frequently associated with extranoal origin, did not show significantly prognostic impact in the overall- or germinal center B-like-DLBCL cohort, likely due to decreased pAKT and Myc levels, up-regulation of FOXP3, FOXO3, MEG3 and other tumor suppressors coincided with c-Rel nuclear expression, as well as the complicated relationships between NF-κB members and their overlapping function. However, c-Rel nuclear expression correlated with significantly poorer survival in p63+ and BCL-2− activated B-cell-like-DLBCL, and in DLBCL patients with TP53 mutations. Multivariate analysis indicated that after adjusting clinical parameters, c-Rel positivity was a significantly adverse prognostic factor in DLBCL patients with wild type TP53. Gene expression profiling suggested dysregulations of cell cycle, metabolism, adhesion, and migration associated with c-Rel activation. In contrast, REL amplification did not correlate with c-Rel nuclear expression and patient survival, likely due to co-amplification of genes that negatively regulate NF-κB activation. These insights into the expression, prognostic impact, regulation and function of c-Rel as well as its crosstalk with the p53 pathway underscore the importance of c-Rel and have significant therapeutic implications

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Abstract Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array ), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, OR G-allele = 1.13, P meta = 1.60 × 10 −8 ). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis

Marine-Derived Penicillium Species as Producers of Cytotoxic Metabolites

Since the discovery of penicillin, Penicillium has become one of the most attractive fungal genera for the production of bioactive molecules. Marine-derived Penicillium has provided numerous excellent pharmaceutical leads over the past decades. In this review, we focused on the cytotoxic metabolites * (* Cytotoxic potency was referred to five different levels in this review, extraordinary (IC50/LD50: <1 μM or 0.5 μg/mL); significant (IC50/LD50: 1~10 μM or 0.5~5 μg/mL); moderate (IC50/LD50: 10~30 μM or 5~15 μg/mL); mild (IC50/LD50: 30~50 μM or 15~25 μg/mL); weak (IC50/LD50: 50~100 μM or 25~50 μg/mL). The comparative potencies of positive controls were referred when they were available). produced by marine-derived Penicillium species, and on their cytotoxicity mechanisms, biosyntheses, and chemical syntheses