ABSTRACT
Identifying biomarkers of the resistance in multiple myeloma (MM) is a key research challenge. We aimed to identify proteins that differentiate plasma cells in patients with refractory/relapsed MM (RRMM) who achieved at least very good partial response (VGPR) and in those with reduced response to PAD chemotherapy (bortezomib, doxorubicin and dexamethasone). Comparative proteomic analysis was conducted on pretreatment plasma cells from 77 proteasome inhibitor naïve patients treated subsequently with PAD due to RRMM. To increase data confidence we used two independent proteomic platforms: isobaric Tags for Relative and Absolute Quantitation (iTRAQ) and label free (LF). Proteins were considered as differentially expressed when their accumulation between groups differed by at least 50% in iTRAQ and LF. The proteomic signature revealed 118 proteins (35 up-regulated and 83 down-regulated in ≥ VGPR group). Proteins were classified into four classes: (1) involved in proteasome function; (2) involved in the response to oxidative stress; (3) related to defense response; and (4) regulating the apoptotic process. We confirmed the differential expression of proteasome activator complex subunit 1 (PSME1) by enzyme-linked immunosorbent assay. Increased expression of proteasomes and proteins involved in protection from oxidative stress (eg., TXN, TXNDC5) plays a major role in bortezomib resistance.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Drug Resistance, Neoplasm , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Neoplasm Recurrence, Local/metabolism , Aged , Antineoplastic Agents , Apoptosis , Bortezomib/administration & dosage , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Enzyme-Linked Immunosorbent Assay , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Oxidative Stress , Proteomics , Tandem Mass Spectrometry , Thioredoxins/chemistry , Treatment OutcomeSubject(s)
Antineoplastic Agents/therapeutic use , Hypereosinophilic Syndrome/drug therapy , Oncogene Proteins, Fusion , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Receptor, Platelet-Derived Growth Factor alpha , mRNA Cleavage and Polyadenylation Factors , Adult , Aged , Aged, 80 and over , Benzamides , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Hypereosinophilic Syndrome/genetics , Imatinib Mesylate , Male , Middle Aged , Young AdultABSTRACT
INTRODUCTION: The search for risk factors of gastric cancer has a long history: H. pylori infection is one of them. Unfortunately, there is no reliable method for the identification of patients at significant risk of gastric cancer among those infected. AIM: To disclose the role of IL-1B gene polymorphism in gastric cancer by comparing IL-1B genotypes of patients with different, almost mutually exclusive clinical courses. SUBJECTS: We initially enrolled 273 patients and continued with 259 patients who tested positive for antibodies against H. pylori, including 121 patients with gastric cancer, 119 patients with duodenal ulcer, and 19 patients with asymptomatic gastritis. The study group included 19 families (48 patients) with 14 cases of gastric cancer, 15 cases of duodenal ulcer, and 19 asymptomatic individuals. MATERIAL AND METHODS: The IL-1B gene was sequenced at position -511 and -31 using primer extension and mass spectrometry. Intron 2 of the IL-1RN gene was studied using PCR and agarose gel electrophoresis. The odds ratio (OR) with 95% confidence intervals was computed using logistic regression. RESULTS: No association was found between IL-1B gene polymorphism and clinical presentation in 19 families. The differences between patients with gastric cancer and duodenal ulcer applied only to the C/T variant at position -511 of the IL-1B gene after adjustment for family history. Patients with the IL-1B-511 CT genotype and negative family history of gastric cancer demonstrated a greater risk of gastric cancer compared with patients with positive family history. CONCLUSION: Our results suggest a complex association between IL-1B gene polymorphism, H. pylori infection, and gastric secretion.
