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The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl-protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP-deficient cells, lower sDMA modification prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post-translational regulation.

KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.

Objectives To compare the risk of PsA in psoriasis (PsO) patients treated with acitretin vs DMARDs. Methods This retrospective study used Taiwan's National Health Insurance Research Database from 1997 to 2013. Adult PsO patients without PsA prescribed acitretin or DMARDs for ≥30 days within a year were assigned to the acitretin cohort or DMARDs cohort, respectively. Patients in the acitretin cohort prescribed DMARDs for >7 days, or in the DMARDs cohort prescribed acitretin for >7 days, were excluded. Cumulative incidence of PsA were determined within both cohorts using the Kaplan–Meier method. The hazard ratio (HR) comparing acitretin to DMARDs was calculated with Cox regression models, adjusting for demographic and clinical covariates including the use of NSAIDs and comorbidities. Results The study included 1948 patients in each cohort. The 5-year cumulative incidence of PsA in the acitretin cohort was lower than that in the reference cohort (7.52% vs 9.93%; P  = 0.005), with a more pronounced difference in the subpopulation receiving NSAIDs treatment. However, in subpopulations without NSAIDs treatment, the 5-year cumulative incidence of PsA in the acitretin cohort was comparable to the DMARDs cohort (5.26% vs 6.98%; P  = 0.106). Acitretin was not associated with PsA development in PsO (HR 0.83, 95% confidence interval 0.65–1.05). This risk remained consistent regardless of adjustments for NSAID treatment and comorbidities. Other independent risk factors for PsA included female and NSAIDs treatment. Conclusion Compared with DMARDs, acitretin was not associated with increased PsA risk in PsO patients. [ABSTRACT FROM AUTHOR]

Background In the era of biologic therapy, phototherapy and methotrexate (MTX) are still commonly used for treatment in patients with moderate-to-severe psoriasis. However, the skin cancer risk following a combination of MTX and narrowband ultraviolet B (NB-UVB) has rarely been explored. Objectives To investigate whether MTX plus NB-UVB increases skin cancer risk in patients with psoriasis. Methods We conducted a retrospective cohort study of data in the Taiwan National Health Insurance Research Database from 1997 to 2013. Cumulative incidences and multivariate analysis were investigated using a competing risk regression model, comparing skin cancer risk between cohorts of people having combination therapy and those using NB-UVB alone, matched for relative confounders. We further conducted a sensitivity analysis for those receiving a higher MTX dose. Standardized incidence ratios (SIRs) were calculated for skin cancer risk. Results We enrolled 3203 participants in each cohort. No significant differences in skin cancers were noted between the two cohorts for the cumulative incidences (log-rank test, P = 0.28) and for the hazard ratio (HRs) [adjusted HR 0.50, 95% confidence interval (CI) 0.15–1.63, P = 0.247] in the competing risk regression model. There were also no significant differences between those receiving higher-dose MTX and UVB alone in the cumulative incidences of skin cancers (P = 0.23) and the HR (adjusted HR = 0.29, 95% CI 0.04–2.21, P = 0.23) in the multivariate analysis. There was no significant difference in the SIR between the two cohorts compared with the general population. Conclusions In the Taiwanese population, MTX does not increase skin cancer risk in patients with moderate-to-severe psoriasis receiving NB-UVB. [ABSTRACT FROM AUTHOR]