Interaction network of proteins associated with unfavorable prognosis in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic stem and progenitor cells, characterized by accumulation of immature blasts in the bone marrow and peripheral blood of affected patients. Standard induction therapy leads to complete remission in approximately 50% to 75% of patients. In spite of favorable primary response rates, only 20% to 30% of patients enjoy long-term disease free survival. Identifying proteins involved in prognosis is important for proposing biomarkers that can aid in the clinical management of the disease. The aim of this study was to construct a protein-protein interaction (PPI) network based on serum proteins associated with unfavorable prognosis of AML, and analyze the biological pathways underlying molecular complexes in the network. We identified 16 candidate serum proteins associated with unfavorable prognosis (in terms of poor response to treatment, poor overall survival, short complete remission, and relapse) in AML via a search in the literature: IL2RA, FTL, HSP90AA1, D2HGDH, PLAU, COL18A1, FGF19, SPP1, FGA, PF4, NME1, TNF, ANGPT2, B2M, CD274, LGALS3. The PPI network was constructed with Cytoscape using association networks from String and BioGRID, and Gene Ontology enrichment analysis using the ClueGo pluggin was performed. The central protein in the network was found to be PTPN11 which is involved in modulating the RAS-ERK, PI3K-AKT and JAK-STAT pathways, as well as in hematopoiesis, and in the regulation of apoptotic genes. Therefore, a dysregulation of this protein and/or of the proteins connected to it in the network leads to the defective activation of these signaling pathways and to a reduction in apoptosis. Together, this could cause an increase in the frequency of leukemic cells and a resistance to apoptosis in response to treatment.

Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma.

PURPOSE: Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment. PATIENTS AND METHODS: Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS). RESULTS: Higher baseline tumor levels of CD8 showed a trend toward longer PFS (HR 0.4; P = 0.091). Higher baseline serum levels of CXCL10 (P = 0.0197) and CEACAM1 (P = 0.085) showed a trend toward better ORR and longer PFS, respectively. Patients for whom IL6 was not detected at baseline had longer PFS versus patients for whom it was detected (HR 0.4; P = 0.028). At C2D1 and/or EOT, mainly immune-related biomarkers showed any association with better outcomes. The genes CA9 (P = 0.084), HIF1A (P = 0.064), and IFNG (P = 0.073) showed trending associations with ORR, and AKT3 (P = 0.0145), DDX58 (P = 0.0726), GZMA (P = 0.0666), LCN2 (NGAL; P = 0.0267), and PTPN11 (P = 0.0287) with PFS. CONCLUSIONS: With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.

Protein and fat intake interacts with the haplotype of PTPN11_rs11066325, RPH3A_rs886477, and OAS3_rs2072134 to modulate serum HDL concentrations in middle-aged people.

BACKGROUND & AIMS: Low serum HDL cholesterol (HDL-C) concentration is a risk factor for cardiovascular diseases and it is influenced by genetic and environmental factors. We hypothesized that genetic variants that decrease serum HDL-C concentrations may interact with nutrient intakes in ways that increase or decrease the risk of cardiovascular disease. METHODS: Candidate genetic variants that can lower serum HDL-C concentrations were explored by genome-wide association studies (GWAS), after adjusting for covariates, in the Ansan/Ansung cohort (n = 8842) from KoGES. The best genetic variants were selected and used to form a haplotype. According to the haplotype frequencies of SNPs, they were divided into major allele, heterozygote allele, and minor allele. The association of haplotype with serum HDL-C levels was determined using logistic regression after adjusting for confounding factors. Interaction of the haplotype with nutrient intake was also determined. RESULTS: PTPN11_rs11066325, RPH3A_rs886477 and OAS3_rs2072134 were selected to modulate serum HDL-C levels from GWAS(P = 1.09E-09, 7.04E-10, and 1.27E-09, respectively). The adjusted odds ratios (ORs) for a decrease in serum HDL-C concentration in the minor-allele group of the haplotype were elevated by 1.534 fold, compared to the major-allele group of the haplotype. Furthermore, the adjusted ORs for serum LDL cholesterol and levels increased by 1.645 in the minor-alleles compared to the major-alleles of the haplotype without a significant change of serum cholesterol levels. Interestingly, the adjusted ORs for serum triglyceride were lower in the minor-alleles than in the major-alleles. The haplotype had a significant interaction with the intake of protein, fat, saturated fatty acids (SAF) and polyunsaturated fatty acids (PUFA; P < 0.05). In particular, the minor alleles of the haplotype decreased serum HDL-C levels compared to the major-alleles in the high intake of protein, fat, SFA, and PUFA, not in the low intake. CONCLUSIONS: People carrying the minor-allele of haplotypes should avoid diets that are high in protein and fat, especially rich in SFA and PUFA.