A5019172379- Multiple Myeloma Research and Treatments
- Protein Degradation and Inhibitors
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- Histone Deacetylase Inhibitors Research
- Signaling Pathways in Disease
- T-cell and B-cell Immunology
- Cytomegalovirus and herpesvirus research
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Monoclonal and Polyclonal Antibodies Research
- Ubiquitin and proteasome pathways
- 14-3-3 protein interactions
- Tuberculosis Research and Epidemiology
- Escherichia coli research studies
- Immunodeficiency and Autoimmune Disorders
- Cancer Mechanisms and Therapy
- Chronic Lymphocytic Leukemia Research
- IL-33, ST2, and ILC Pathways
- Immune Response and Inflammation
- Immune cells in cancer
- Glycosylation and Glycoproteins Research
- Chemokine receptors and signaling
- PI3K/AKT/mTOR signaling in cancer
- Immune responses and vaccinations
Mayo Clinic in Arizona
2019-2025
WinnMed
2023
Mayo Clinic in Florida
2023
Oregon Health & Science University
2014-2022
VA Portland Health Care System
2018
Drexel University
2015
Albert Einstein College of Medicine
2015
Portland VA Medical Center
2014
A diverse array of microbial metabolites binds to MR1 and selectively activates MR1-restricted T cells.
Abstract Mucosal-associated invariant T (MAIT) cells are thought to detect microbial antigens presented by the HLA-Ib molecule MR1 through exclusive use of a TRAV1-2-containing TCRα. Here we tetramer staining and ex vivo analysis with mycobacteria-infected MR1-deficient demonstrate presence functional human MR1-restricted that lack TRAV1-2. We characterize an clone expresses TRAV12-2 TCRα, which lacks residues previously shown be critical for MR1-antigen recognition. In contrast TRAV1-2 +...
Abstract BCMA/CD3-targeting bispecific antibodies (BsAb) are a recently developed immunotherapy class that shows potent tumor killing activity in multiple myeloma. Here, we investigated murine BsAb the immunocompetent Vk*MYC model and its immunomodulatory imide drug (IMiD)–sensitive derivative Vk*MYChCRBN of The BCMA/CD3 was safe efficacious subset mice but failed those with high burden, consistent clinical reports leukemia. combination pomalidomide expanded lytic T cells improved even...
Abstract Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization established VTX-resistant isogenic human cell lines (HMCL) and primary MM patient samples pre- post-VTX treatment. Transcriptomic proteomic analysis revealed that was largely associated with BCL-2 family protein dysregulation, including upregulation anti-apoptotic proteins such as MCL-1,...
Abstract Mucosal-associated invariant T (MAIT) cells typically express a TRAV1-2 + semi-invariant TCRα that enables recognition of bacterial, mycobacterial, and fungal riboflavin metabolites presented by MR1. MAIT are associated with immune control bacterial mycobacterial infections in murine models. Here, we report population pro-inflammatory CD8 present the airways lungs healthy individuals enriched bronchoalveolar fluid patients active pulmonary tuberculosis (TB). High-throughput cell...
Tuberculosis (TB) is the leading cause of mortality from a single infectious agent, Mycobacterium tuberculosis Relevant immune targets partially efficacious TB vaccine bacille Calmette-Guérin (BCG) remain poorly defined. Mucosal-associated invariant T (MAIT) cells are MHC-related protein 1 (MR1)-restricted cells, which reactive against M. tuberculosis, and underexplored as potential targets. We sought to determine whether BCG vaccination activated mycobacteria-specific MAIT cell responses in...
Mucosal-associated Invariant T (MAIT) cells are an innate-like cell subset that recognize a broad array of microbial pathogens, including respiratory pathogens. Here we investigate the transcriptional profile MAIT localized to human lung, and postulate may play role in maintaining homeostasis at this mucosal barrier. Using MR1/5-OP-RU tetramer, identified non-MAIT CD8
Abstract Multiple myeloma (MM) is a malignancy that often driven by MYC and sustained IRF4, which are upregulated super-enhancers. IKZF1 IKZF3 bind to super-enhancers can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate IRF4; however, this fails in IMiD-resistant cells. IRF4 downregulation also achieved tumors inhibitors of BET EP300 transcriptional coactivator proteins; vivo these have narrow therapeutic window. By combining IMiDs with...
Infections with monkeypox, cowpox and weaponized variola virus remain a threat to the increasingly unvaccinated human population, but little is known about their mechanisms of virulence immune evasion. We now demonstrate that B22 proteins, encoded by largest genes these viruses, render T cells unresponsive stimulation cell receptor MHC-dependent antigen presentation or MHC-independent stimulation. In contrast, stimuli bypass TCR-signaling are not inhibited. non-human primate model lacking...
Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase effectiveness of antimalarial treatment. However, no compound date has shown single-dose activity against both blood-stage Plasmodium parasites that cause disease liver-stage initiate infection. Here, we describe subset cytochrome bc 1 (cyt ) inhibitors, including novel 4(1 H )-quinolone ELQ-400, with liver, blood, transmission-stage in mouse models malaria. Although cyt inhibitors are generally...
The cellular cytotoxicity of APY0201, a PIKfyve inhibitor, against multiple myeloma was initially identified in an unbiased vitro chemical library screen. activity APY0201 confirmed all 25 cell lines tested and 40% 100 ex vivo patient-derived primary samples, with increased samples harboring trisomies lacking t(11;14). broad anti-multiple inhibitors further demonstrated confirmatory screens showed the superior potency when compared to YM201636 apilimod, mid-point half maximal effective...
Abstract The most common genetic abnormality in multiple myeloma is the deletion of chromosome 13, seen almost half newly diagnosed patients. Unlike chronic lymphocytic leukemia, where a recurrent minimally deleted region including MIR15A/MIR16-1 has been mapped, deletions predominantly involve entire and no specific driver gene identified. Additional candidate loci include RB1 DIS3, but while biallelic associated with disease progression, DIS3 essential complete inactivation not observed....
Mucosal associated invariant T (MAIT) cells are a class of innate-like that utilize semi-invariant αβ cell receptor to recognize small molecule ligands produced by bacteria and fungi. Despite growing evidence immune at mucosal surfaces often phenotypically functionally distinct from those in the peripheral circulation, knowledge about characteristics MAIT lung surface, site exposure respiratory pathogens, is limited. HIV infection has been shown have profound effect on number function blood,...
Recent therapeutic advances have significantly improved the outcome for patients with multiple myeloma (MM). The backbone of successful standard therapy is combination Ikaros degraders, glucocorticoids, and proteasome inhibitors that interfere integrity myeloma-specific superenhancers by directly or indirectly targeting enhancer-bound transcription factors coactivators control expression MM dependency genes. T cell engagers chimeric antigen receptor cells redirect patients' own onto defined...
Abstract Multiple myeloma (MM) is a heterogeneous disease characterized by frequent MYC translocations. Sporadic activation in the germinal center of genetically engineered Vk*MYC mice sufficient to induce plasma cell tumors which variety secondary mutations are spontaneously acquired and selected over time. Analysis 119 reveals recurrent copy number alterations, structural variations, chromothripsis, driver mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)...
Abstract The nonclassical HLA molecule MHC-related protein 1 (MR1) presents metabolites of the vitamin B synthesis pathways to mucosal-associated invariant T (MAIT) cells and other MR1-restricted cells. This new class Ags represents a variation on classical paradigm self/non-self discrimination because these are activated through their TCR by small organic compounds generated during microbial B2 synthesis. Beyond fundamental significance, nature MR1 across human population is tantalizing...
Mucosal-associated invariant T (MAIT) cells are key players in the immune response against microbial infection. The MAIT T-cell receptor (TCR) recognizes a diverse array of ligands, and recent reports have highlighted variability TCR that could further contribute to discrimination ligand. complementarity determining region (CDR)3β sequence displays high level diversity across individuals, clonotype usage appears be dependent on antigenic exposure. To address relationship between ligand, we...
MR1 presents vitamin B-related metabolites to mucosal associated invariant T (MAIT) cells, which are characterized, in part, by the TRAV1-2
<ns4:p>The elimination of tuberculosis (TB) cannot reasonably be achieved by treatment individual cases and will require an improved vaccine or immunotherapy. A challenge in developing TB has been the lack understanding what is needed to generate sterilizing immunity against <ns4:italic>Mycobacterium tuberculosis</ns4:italic> (Mtb) infection. Several epidemiological observations support hypothesis that humans can eradicate Mtb following exposure. This termed early clearance defined as...
Abstract Mucosal Associated Invariant T (MAIT) cells can sense intracellular infection by a broad array of pathogens. These are activated upon encountering microbial antigen(s) displayed MR1 on the surface an infected cell. Human undergoes alternative splicing. The full-length isoform, MR1A, activate MAIT cells, while function isoforms, MR1B and MR1C, incompletely understood. In this report, we sought to characterize expression these splice variants. Using transcriptomic analysis in...
Despite advancements in profiling multiple myeloma (MM) and its precursor conditions, there is limited information on mechanisms underlying disease progression. Clincal efforts designed to deconvolute such are challenged by the long lead time between monoclonal gammopathy transformation MM. MM mouse models represent an opportunity overcome this temporal limitation. Here, we profile genomic landscape of 118 genetically engineered Vk*MYC reveal that it recapitulates heterogenenity life history...