Journal of Personalized Medicine

Background: Pharmacogenetic markers associated with the need to switch patients from methotrexate (MTX) to biologic agents in moderate-to-severe psoriasis remain insufficiently studied. The pharmacokinetics of MTX depend on the individual characteristics of the patient, as well as on the function of specific transporters and enzymes involved in its absorption, distribution, metabolism, and elimination; therefore, polymorphisms in genes encoding these proteins may be considered pharmacogenetic predictors of MTX intolerance or insufficient efficacy. This study aimed to investigate genetic variants associated with MTX intolerance or insufficient efficacy leading to therapy switch. Methods: A total of 80 patients with moderate-to-severe psoriasis were included: 43 who required switching from MTX to biologics and 37 who continued MTX therapy. Twelve polymorphisms in transporter and metabolism-related genes (ABCB1 (rs1045642), MTHFR (rs1801133), ABCB1 (rs1128503), ABCC2 (rs3740066), ABCC2 (rs717620), ABCG2 (rs2231137), GSTP1 (rs1695), SLC19A1 (rs1051266), COL18A1 (rs9977268), SLCO1B1 (rs2306283), SLCO1B1 (rs4149056), and ABCB1 (rs2229109)) were analyzed using next-generation sequencing. Results: Significant differences in genotype frequencies were observed for SLC19A1 rs1051266 (p = 0.03) and COL18A1 rs9977268 (p = 0.02). Carriers of the T allele in both genes were more frequent among patients requiring biologic therapy, suggesting a possible association with MTX intolerance or reduced efficacy. Conclusions: The study revealed an association between polymorphisms in the SLC19A1 rs1051266 and COL18A1 rs9977268 genes and the need to switch from MTX to biologic therapy in patients with moderate-to-severe psoriasis. These findings suggest that carriers of the C allele in these genes may have an increased risk of methotrexate intolerance.

Background/Objectives: Propionic acidemia (PA) and methylmalonic acidemia (MMA) affect methionine, threonine, valine (Val), and isoleucine (Ile) (MTVI) metabolism, leading to the production of highly neurotoxic organic acids. Treatment involves a diet restricted in natural proteins and supplemented with a protein substitute (PS) with traces of MTVI. The aim was to analyze natural protein and PS intake in relation to linear growth impairment in individuals with PA and MMA. Methods: We followed the PRISMA protocol. We considered articles published between 1970 and 2025. We determined the eligibility criteria for selecting articles and evaluated the quality. Results: Thirteen studies were selected: two case reports, eight longitudinal, three cohorts, and one cross-sectional. Articles demonstrated that natural protein intake decreases with age, consistent with previous reports, underscoring the need for PS supplementation to meet protein requirements. Subjects with PA and non-responsive MMA had greater restriction of natural proteins, and the majority required PS; a higher PS intake was negatively correlated with a higher height-for-age (H/A) z-score. When analyzing the ratio of protein to energy (P:E), a negative correlation was found between the intake of natural proteins and energy, and a positive correlation with H/A z-score (p-value < 0.05). Supplementation with PS increased leucine levels, causing an imbalance with MTVI amino acids. This imbalance led to the paradoxical need to supplement L-Val and L-Ile, both propiogenic amino acids. As a result, a decrease in the H/A z-score was observed, particularly in PA and non-responsive MMA. Responsive MMA tolerated more natural proteins, received a lower intake of PS, and had a better H/A z-score. Conclusions: Restriction of natural proteins and PS is associated with a lower H/A z-score, primarily in subjects with PA and non-responsive MMA.

Objective(s): To delineate the somatic mutational landscape of follicular thyroid carcinoma (FTC) from a large, real-world cohort to identify molecular subtypes and actionable targets for personalized therapeutic interventions. Methods: Genomic and clinical data for 168 FTC samples were retrieved from the AACR Project GENIE^® registry via cBioPortal. This study assessed mutation frequencies, copy number alterations, and subgroup differences (primary vs. metastatic; adult vs. pediatric) using statistical tests. Results: NRAS was the most common mutation (33.9%), followed by TERT (22.6%), DICER1 (15.5%), HRAS (11.9%), and PTEN (10.7%). DICER1 mutations were significantly enriched in pediatric cases (44.4% vs. 4.6% in adults, p < 0.001), while TERT mutations were exclusive to adults (42%). NRAS mutations were more frequent in metastatic tumors (42.4%) than primary tumors (29.2%). Conclusions: FTC tumorigenesis is driven by distinct molecular pathways, with significant heterogeneity between pediatric and adult patients as well as primary and metastatic disease. These findings underscore the necessity of molecular profiling for patient stratification and provide a strong rationale for developing personalized treatment strategies to improve clinical outcomes.