Daily profiles of plasma phenylalanine and tyrosine in patients with osteogenic sarcoma during treatment with high‐dose methotrexate‐citrovorum rescue

Wang

et al. 2022

Journal of Oncology

Osteosarcoma remains a major health problem in teenagers. However, its pathogenesis mechanism remains not fully elucidated. This study aims to identify the prognostic biomarkers for osteosarcoma. In this study, we selected genes with a median absolute deviation (MAD) value of the top 5000 in the GSE32981 dataset for subsequent analysis. Weighted correlation network analysis (WGCNA) was used to construct a coexpression network. WGCNA showed that the tan module and midnight blue module were highly correlated with origin and metastases of osteosarcoma, respectively. Enrichment analysis was conducted using genes in the tan module and midnight blue module. A gene coexpression network was constructed by calculating the Spearman correlation coefficients. Four key genes (LTF, C10orf107, HIST1H2AK, and NEXN) were identified to be correlated with the prognosis of osteosarcoma patients. LTF has the highest AUC value, and its effect on osteosarcoma cells was then evaluated. The effect of LTF overexpression on proliferation, migration, and invasion of MG63 and 143B cells was detected by the CCK-8 assay, transwell cell migration assay, and transwell invasion assay, respectively. The overexpression of LTF promoted the proliferation, migration, and invasion of MG63 and 143B cells. In conclusion, LTF may serve as a prognostic biomarker for osteosarcoma.

Section: Discussionmentioning

confidence: 99%

Identification of LTF as a Prognostic Biomarker for Osteosarcoma

Wang

et al. 2022

Journal of Oncology

“…Higher levels of serum phenylalanine have been previously reported clinically following treatment with MTX and were linked to the inhibition of dihydropteridine reductase (Hilton et al. , 1989). However, the observed elevation of hepatic phenylalanine in our study is likely to be influenced by additional mechanisms because the levels of hepatic tyrosine remained unperturbed.…”

Section: Discussionmentioning

confidence: 99%

Systems Level Metabolic Phenotype of Methotrexate Administration in the Context of Non-alcoholic Steatohepatitis in the Rat

Kyriakides

Hardwick

Jin

et al. 2014

Toxicological Sciences

Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs.

“…In our previous studies we have focused on neopterin as a biomarker part in the pterin pathway in both of patients with thyroid and breast disorders (23,24). Still there is only a limited number of studies on changes in BH 4 pathway and/or DHPR activity in cancer patients (25)(26)(27)(28)(29)(30)(31)(32)(33). Therefore, in the present study we evaluated the alteration in biopterin excretion and DHPR activity which would reflect impairment of BH 4 maintenance in patients with breast and thyroid disorders.…”

Section: 678-tetrahydrobiopterin (Bhmentioning

confidence: 99%

Urinary Biopterin Levels and Blood Dihydropteridine Reductase Activities in Patients with Thyroid and Breast Disorders

et al. 2010

Biopterin as a stable metabolite is produced by oxidation of 5,6,7, ). It is known that many diseases may cause changes in BH 4 concentration and/or dihydropteridine reductase (DHPR) enzyme activity. There is only a limited number of studies correlating DHPR activity in malignancies. The main goal of the present study was to evaluate alterations in the DHPR activity and biopterin levels in patients with breast and thyroid cancers. The breast cancer patients (n=24) were compared to patients with benign breast diseases (n=19) and controls (n=30). In addition; the patients with thyroid cancer (n=17) were compared to patients with benign thyroid diseases (n=42) and the control group. We did not observe any significant difference between the benign disorders and the malignancies. Biopterin concentrations in patients with benign and malign thyroid and breast diseases were lower than the controls (all p <0.05). DHPR activities in thyroid diseases were significantly higher than the controls while insignificant decreases in DHPR activities in breast patients were detected. Our results suggested significant alterations in unconjugated pteridine pathway in thyroid and breast disorders.