Background: Gliomas account for the major part of primary brain tumors. Based on their histology and molecular alternations, adult gliomas have been classified into four grades, each with distinct biology and outcome. Previous studies have focused on cell-line-based models and patient-derived xenografts (PDXs) from patient-derived glioma cultures for grade IV glioblastoma. However, the PDX of lower grade diffuse gliomas, particularly those harboring the endogenous IDH mutation, are scarce due to the difficulty growing glioma cells in vitro and in vivo. The purpose of this study was to develop a panel of patient-derived subcutaneous xenografts of different grade gliomas that represented the heterogeneous histopathologic and genetic features of human gliomas. Methods: Tumor pieces from surgical specimens were subcutaneously implanted into flanks of NOD-Prkdc^scid ll2rg^null mice. Then, we analyzed the association between the success rate of implantation with clinical parameters using the Chi square test and resemblance to the patient’s original tumor using immunohistochemistry, immunofluorescence, short tandem repeat analysis, quantitative real-time polymerase chain reaction, and whole-exome sequencing. Results: A total of 11 subcutaneous xenografts were successfully established from 16 surgical specimens. An increased success rate of implantation in gliomas with wild type isocitrate dehydrogenase (IDH) and high Ki67 expression was observed compared to gliomas with mutant IDH and low Ki67 expression. Recurrent and distant aggressive xenografts were present near the primary implanted tumor fragments from WHO grades II to IV. The xenografts histologically represented the corresponding patient tumor and reconstituted the heterogeneity of different grade gliomas. However, increased Ki67 expression was found in propagated xenografts. Endothelial cells from mice in patient-derived xenografts over several generations replaced the corresponding human tumor blood vessels. Short tandem repeat and whole-exome sequencing analyses indicated that the glioma PDX tumors maintained their genomic features during engraftments over several generations. Conclusions: The panel of patient-derived glioma xenografts in this study reproduced the diverse heterogeneity of different grade gliomas, thereby allowing the study of the growth characteristics of various glioma types and the identification of tumor-specific molecular markers, which has applications in drug discovery and patient-tailored therapy.

Introduction: The purpose of this study was to replicate genetic factors associated with the susceptibility to Behçet's disease (BD). We conducted a two-stage candidate genes association and functional study, involving 477 BD patients and 1,334 normal controls of Chinese Han descent. Methods: The genotyping of five candidate genes/loci, including LOC100129342, KIAA1529, CPVL, UBASH3B and UBAC2, were performed using TaqMan single nucleotide polymorphism (SNP) assays. Real-time PCR and luciferase reporter assay were performed to test the function of the identified promoter polymorphism. The main outcome measures were genotype frequencies and expression levels in BD patients. Results: The first-stage study results showed that UBAC2 (rs9513584, Pc = 0.018, OR = 1.4), but not LOC100129342, KIAA1529, CPVL, UBASH3B was associated with the susceptibility to BD in Chinese Han. The fine-mapping association study of UBAC2 identified six risk SNPs for BD in the Chinese cohort; three of them were verified in validation study (rs3825427, first-stage Pc = 2.2 × 10^-3, second-stage Pc = 9.3 × 10^-3, combined Pc = 6.9 × 10^-6; rs9517668, first-stage Pc = 1.7 × 10^-3, second-stage Pc = 0.03, combined Pc = 3.3 × 10^-4; rs9517701, first-stage Pc = 5.1 × 10^-3, second-stage Pc = 9.0 × 10^-3, combined Pc = 2.9 × 10^-5; respectively). Functional analysis showed that the risk T allele of the promoter polymorphism rs3825427 had a significantly lower promoter activity than the non-risk G allele (P = 0.002) and a decreased expression of UBAC2 transcript variant 1 in peripheral blood mononuclear cells (PBMCs) and skin of normal controls carrying the risk T allele than that in individuals with the G allele (P = 0.045, P = 0.025; respectively). The mRNA expression of UBAC2 transcript variant 1 was significantly decreased in PBMCs and skin of BD patients as compared with controls (P = 0.025; P = 0.047, respectively). The mRNA expression of UBAC2 transcript variant 2 was significantly increased in skin of BD patients as compared with controls (P = 0.004). Conclusions: This study replicates a predisposition gene to BD, UBAC2, and suggests that UBAC2 may be involved in the development of BD through its transcriptional modulation.

Genome-wide association studies (GWAS) and candidate gene studies have identified the REL and PRKCQ genes as risk loci for various autoimmune diseases. The purpose of the present study was to investigate the association of the REL and PRKCQ genes with Behcet’s disease (BD) in a Chinese Han population. A case-control study was conducted on three single nucleotide polymorphisms (SNPs), rs13031237, rs702873, and rs842647 of the REL gene and three SNPs (rs4750316, rs11258747, and rs947474) of the PRKCQ gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a total of 623 BD patients and 1,074 healthy controls. Multiple variables were assessed, including age, sex distribution, and extra-ocular findings. In the present study, the frequencies of rs842647 GG genotypes and rs842647 G alleles were significantly higher in patients than in controls and those of the rs842647 AG genotypes were lower in patients than in controls [GG genotype: Bonferroni corrected P-value for gender adjustment (P_c^a) = 0.0074, odds ratio (OR) = 1.63; G allele: P_c^a = 0.0072, OR = 1.57; AG genotype: P_c^a = 0.024, OR = 0.63, respectively]. No statistically significant differences in the frequencies of rs702873, rs13031237, rs4750316, rs11258747, and rs947474 between BD patients and controls were observed. Stratification analysis indicated that the REL rs842647 polymorphism was associated with BD patients with skin lesions. No significant association of the other five SNPs between BD patients with other extra-ocular findings, including genital ulcer, arthritis, and positive pathergy test results was found. The REL rs842647 polymorphism may be a susceptibility factor for BD pathogenesis and skin lesions, which indicate that c-Rel may be involved in the pathogenesis and skin lesions of BD through the NF-κB pathway.

Purpose: Previous studies have shown that parental abnormal physiological conditions such as inflammation, stress, and obesity can be transferred to offspring. The purpose of this study was to investigate the impact of parental uveitis on the development and susceptibility to experimental autoimmune uveitis (EAU) in offspring. Methods: Parental male and female B10RIII mice were immunized with interphotoreceptor retinoid binding protein (IRBP) 161–180 in complete Freund's adjuvant and were immediately allowed to mate. Gross examination of the offspring gestated with EAU was performed to determine the influence of parental uveitis on offspring development after birth. Gene expression profiles were analyzed in the affected eyes of offspring under EAU to identify differentially expressed genes (DEGs). Adult offspring were given 5, 25, and 50 μg IRBP_161−180 to compare their susceptibility to EAU. Immunized mice were clinically and pathologically evaluated for the development of EAU. Ag-specific T-cell proliferation and IL-17 production from spleens and lymph nodes were evaluated on day 14 or 35 after immunization. Results: Hair loss, delay of eye opening, and swollen spleens in the offspring from parents with uveitis were observed from day 14 to 39 after birth. DEGs were involved in the immune system process, muscle system process, and cell development. The altered antigen processing and presentation, cell adhesion molecules, and phagosome in the eyes of the offspring from uveitis-affected parents were enriched. Offspring gestated with EAU showed a susceptibility to EAU and an earlier onset and higher severity of EAU compared to the control group mice. IRBP-specific lymphocyte proliferation and IL-17 production were observed in the EAU offspring with exposure to parental uveitis. Conclusions: The results suggest that mouse parents with uveitis can increase their offspring's susceptibility to EAU, probably through altering cell adhesion molecules and antigen processing and presentation related to the T-cell proliferation and Th17 response.