OBJECTIVE: The effects of Brequinar Sodium (BQR) and 4SC-101 on lymphoblastoid cell lines were investigated.

METHODS: DHODH expression and cell proliferation inhibition of lymphoblastoid and lymphoma cell lines were analyzed using Western blot analysis and XTT assay, respectively. JC-1 probe and ATP biochemiluminescence kit were used to evaluate the mitochondrial membrane potential and ATP generation in these cell lines. Furthermore, we explored the cell cycle progression using Muse™ Cell Cycle Kit.

RESULTS: Ramos, SUDHL-1 and RPMI-1788 cells are fast-growing cells with equal expression of DHODH enzyme and sensitivity to DHODH inhibitors that showed that the inhibition of DHODH was not cancer-specific. In ATP depletion assay, the non-cancerous RPMI-1788 cells showed only a minor ATP reduction compared to Ramos and SUDHL-1 (cancer) cells. In the mechanistic impact of DHODH inhibitors on non-cancerous vs cancerous cells, the mitochondrial membrane potential assay revealed that significant depolarization and cytochrome c release occurred with DHODH inhibitors treatment in Ramos but not in the RPMI-1788 cells, indicating a different mechanism of proliferation inhibition in normal cells.

METHODS: Data for this study, consisting of 2202 older adults aged 60 years and above, were taken from a population-based survey entitled "Identifying Psychosocial and Identifying Economic Risk Factor of Cognitive Impairment among Elderly. Data analysis was conducted using the IBM SPSS Version 23.0.

METHODS: A cross-sectional study was conducted from June to December 2021. Institutions were selected via stratified random sampling and students via convenience sampling. A self-administered questionnaire comprising questions on socio-demographic characteristics, academic background, substance abuse, childhood abuse, religiosity and the Depression Anxiety Stress Scale-21 was used. Data were analysed using SPSS version 27; descriptive, point-biserial correlation, chi-square and multiple binary logistic regression analyses were conducted.

RESULTS: Sex and adverse childhood experiences significantly predicted all three MHDs (P<0.05). The students from public institutions (odds ratio [OR]=0.71, 95% confidence interval [CI]=0.56-0.90, P=0.004) had a lower risk of depression than those from private institutions. The smokers/vapers (OR=1.43, 95% CI=1.02-2.02, P=0.041) a higher risk of depression than the non-smokers/non-vapers. The social science students (OR=1.29, 95% CI= 1.01-1.65, P=0.039) had a higher risk of anxiety than the science students. The students who highly engaged in organisational religious activity (OR=0.91, 95% CI=0.84-0.98, P=0.015) had a lower risk of anxiety than their counterparts.

METHODS: We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset.

FINDINGS: Associations exceeding the genome-wide significance threshold (p<5 × 10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10(-19), odds ratio [OR] 1·84 [95% CI 1·61-2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection.

INTERPRETATION: To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL.