Project description:There is a need to identify biomarkers of radiation exposure for use in development of circulating biodosimeters for radiation exposure and for clinical use as markers of radiation injury. Most research approaches for biomarker discovery rely on a single animal model. The current study sought to take advantage of a novel aptamer-based proteomic assay which has been validated for use in many species to characterize changes to the blood proteome after total-body irradiation (TBI) across four different mammalian species including humans. Plasma was collected from C57BL6 mice, Sinclair minipigs, and Rhesus non-human primates (NHPs) receiving a single dose of TBI at a range of 3.3 Gy to 4.22 Gy at 24 h postirradiation. NHP and minipig models were irradiated using a 60Co source at a dose rate of 0.6 Gy/min, the C57BL6 mouse model using an X-ray source at a dose rate of 2.28 Gy/min and clinical samples from a photon source at 10 cGy/min. Plasma was collected from human patients receiving a single dose of 2 Gy TBI collected 6 h postirradiation. Plasma was screened using the aptamer-based SomaLogic SomaScan® proteomic assay technology to evaluate changes in the expression of 1,310 protein analytes. Confirmatory analysis of protein expression of biomarker HIST1H1C, was completed using plasma from C57BL6 mice receiving a 2, 3.5 or 8 Gy TBI collected at days 1, 3, and 7 postirradiation by singleplex ELISA. Summary of key pathways with altered expression after radiation exposure across all four mammalian species was determined using Ingenuity Pathway Analysis (IPA). Detectable values were obtained for all 1,310 proteins in all samples included in the SomaScan assay. A subset panel of protein biomarkers which demonstrated significant (p < 0.05) changes in expression of at least 1.3-fold after radiation exposure were characterized for each species. IPA of significantly altered proteins yielded a variety of top disease and biofunction pathways across species with the organismal injury and abnormalities pathway held in common for all four species. The HIST1H1C protein was shown to be radiation responsive within the human, NHP and murine species within the SomaScan dataset and was shown to demonstrate dose dependent upregulation at 2, 3.5 and 8 Gy at 24 h postirradiation in a separate murine cohort by ELISA. The SomaScan proteomics platform is a useful screening tool to evaluate changes in biomarker expression across multiple mammalian species. In our study, we were able to identify a novel biomarker of radiation exposure, HIST1H1C, and characterize panels of radiation responsive proteins and functional proteomic pathways altered by radiation exposure across murine, minipig, NHP and human species. Our study demonstrates the efficacy of using a multispecies approach for biomarker discovery.

Project description:Multiple myeloma (MM) is a hematological malignancy characterized by an expansion of malignant plasma cells in the bone marrow. For newly diagnosed MM (NDMM), standard three-drug treatment regimens—such as the combination of bortezomib, lenalidomide, and dexamethasone (VRd)—and the more recent inclusion of a fourth drug, anti-CD38 antibody immunotherapy, have significantly improved patient outcomes by targeting multiple mechanisms of tumorigenesis. This treatment approach typically involves several cycles of VRd induction therapy, followed by high dose melphalan (HDM) and autologous stem cell transplant (ASCT), and maintenance therapy. Treatment responses vary widely, with some patients requiring longer and more intense therapy and others exhibiting more rapid responses and longer relapse-free remission.This cycle of remission, maintenance, and eventual relapse persists despite advancements in treatment modalities, including immunotherapy, leaving MM incurable. This study characterizes the tumor state and immune microenvironment in MM patients across variable graded patient responses. Using a multimodal, longitudinal approach, we investigate immune and microenvironmental cellular changes during treatment in NDMM patients and in a second cohort of RRMM patients. For the NDMM cohort, longitudinal blood and bone marrow aspirate samples were collected at diagnosis, throughout induction therapy, following autologous stem cell transplant (ASCT), and at post-transplant intervals of 60 days, 90 days, and 1 and 2 years. Multi-omic profiling of these samples magnifies the individual heterogeneity between tumor and therapeutic response. The longitudinal aspect of the study allowed us to focus on individual-level longitudinal responses instead of cross-patient effects, enabling detailed insights into tumor and microenvironment dynamics. Using Olink proteomic analysis of plasma and bone marrow interstitial fluid (BMIF), and single-cell analyses (3’ CITE-seq, scRNA-seq, flow cytometry) of peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) we longitudinally characterized tumor, the immune microenvironment, and therapeutic responses. This revealed distinct immune states and pathways associated with therapeutic response, and tumor survival, highlighting potential targets and therapeutic strategies to improve patient outcomes.

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Proteomic Longitudinal ARIC Study: SOMAscan of Multiple Visits

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