A5012356468- Immunotherapy and Immune Responses
- Genomics, phytochemicals, and oxidative stress
- Estrogen and related hormone effects
- Multiple Myeloma Research and Treatments
- Immune Response and Inflammation
- NF-κB Signaling Pathways
- Bone health and treatments
- Atherosclerosis and Cardiovascular Diseases
- Histone Deacetylase Inhibitors Research
- Cell Adhesion Molecules Research
- Cancer, Lipids, and Metabolism
- T-cell and B-cell Immunology
- interferon and immune responses
- Reproductive System and Pregnancy
- Cancer Immunotherapy and Biomarkers
- Cytokine Signaling Pathways and Interactions
- Epigenetics and DNA Methylation
- Immune Cell Function and Interaction
- Cancer-related molecular mechanisms research
- Bone Metabolism and Diseases
- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- melanin and skin pigmentation
- Immune cells in cancer
- RNA and protein synthesis mechanisms
APT Therapeutics (United States)
2023-2024
Rapt Therapeutics (United States)
2023-2024
Parker Institute for Cancer Immunotherapy
2020-2023
University of California, San Francisco
2020-2023
UPMC Hillman Cancer Center
2013-2021
University of Pittsburgh
2013-2019
McGowan Institute for Regenerative Medicine
2018-2019
Duquesne University
2009-2013
Bayer (United States)
2013
Abstract Cellular metabolism underpins immune cell functionality, yet our understanding of metabolic influences in human dendritic biology and their ability to orchestrate responses is poorly developed. Here, we map single-cell states profiles inflammatory tolerogenic monocytic cells using recently developed multiparametric approaches. Single-cell pathway activation scores reveal simultaneous engagement multiple pathways distinct differentiation stages. GM-CSF/IL4-induce rapid reprogramming...
In multiple myeloma, osteolytic lesions rarely heal because of persistent suppressed osteoblast differentiation resulting in a high fracture risk. Herein, chromatin immunoprecipitation analyses reveal that myeloma cells induce repressive epigenetic histone changes at the Runx2 locus prevent differentiation. The most pronounced myeloma-induced were Runx2-P1 promoter, converting it from poised bivalent state to repressed state. Previously, was observed induces transcription repressor GFI1...
Extracellular vesicles (EVs) are characterized by complex cargo composition and carry a wide array of signalling cargo, including growth factors (GFs). Beyond surface-associated GFs, it is unclear if EV intralumenal biologically active. Here, bone morphogenetic protein-2 (BMP2), loaded directly into the lumen EVs designated engineered BMP2-EVs (eBMP2-EVs), was comprehensively its regulation osteoblastogenesis. eBMP2-EVs non-EV 'free' BMP2 were observed to similarly regulate Furthermore, cell...
α-Fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell (DC) differentiation maturation block oxidative phosphorylation. To identify the critical metabolic pathways leading human DC functional suppression, here, we used two recently described single-cell profiling methods, scMEP (single-cell profiling) SCENITH energetic metabolism translation inhibition). Glycolytic capacity...
Abstract Efficacy of cancer vaccines remains low and mechanistic understanding antigen presenting cell function in may improve vaccine design outcomes. Here, we analyze the transcriptomic immune-metabolic profiles Dendritic Cells (DCs) from 35 subjects enrolled a trial DC late-stage melanoma (NCT01622933). Multiple platforms identify metabolism as an important biomarker patient overall survival (OS). We demonstrate multiple immune metabolic gene expression pathway alterations, functional...
ABSTRACT Key osteoclast (OCL) regulatory gene promoters in bone marrow–derived monocytes harbor bivalent histone modifications that combine activating Histone 3 lysine 4 tri-methyl (H3K4me3) and repressive H3K27me3 marks, which upon RANKL stimulation resolve into or architecture. Enhancer of zeste homologue 2 (EZH2) is the methyltransferase component polycomb complex 2, catalyzes modifications. Immunofluorescence microscopy reveals EZH2 localization during murine osteoclastogenesis...
Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity disease. Our study revealed major mechanistic distinctions the Toll-like receptor (TLR) signaling-dependent induction for rapidly expressed genes (IL1B TNF) coding these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels both TBP...
Multiple myeloma bone disease (MMBD) is characterized by non-healing lytic lesions that persist even after a patient has achieved hematologic remission. We previously reported p62 (sequestosome-1) in marrow stromal cells (BMSC) critical for the formation of MM-induced signaling complexes mediate OB suppression. Importantly, XRK3F2, an inhibitor p62-ZZ domain, blunted Runx2 suppression vitro, and induced new remodeling presence tumor vivo. Additionally, we MM induce repressive chromatin on...
Immune and molecular profiling of CD8 T cells patients receiving DC vaccines expressing three full-length melanoma antigens (MAs) was performed. Antigen expression levels in DCs had no significant impact on cell or clinical responses. Patients who received checkpoint blockade before vaccination higher baseline MA-specific responses but evidence for improved functional to the vaccine. showed best low PD-1 after vaccination; however, during antigen presentation by minimal PD-1high cells. Gene...
Abstract Therapeutic cancer vaccines targeting melanoma-associated antigens are commonly immunogenic but rarely effective in promoting objective clinical responses. To identify critical molecules for activation of antitumor immunity, we have profiled autologous dendritic cell (DC) used to treat 35 patients with melanoma. We showed that checkpoint induced by ex vivo maturation correlated DC vaccine activity. Melanoma patient DCs had reduced expression surface inducible T-cell costimulator...
Bone is the most preferred site for colonization of metastatic breast cancer cells each subtype disease. The standard therapeutic care patients with bone metastasis includes bisphosphonates (e.g., zoledronic acid), which have poor oral bioavailability, and a humanized antibody (denosumab). However, these therapies are palliative, subset still develop new lesions and/or experience serious adverse effects. Therefore, safe orally bioavailable intervention therapy osteolytic resorption...
We previously reported that transcription of the human IL1B gene, encoding proinflammatory cytokine interleukin 1β, depends on long-distance chromatin looping is stabilized by a mutual interaction between DNA-binding domains (DBDs) two factors: Spi1 proto-oncogene at promoter and CCAAT enhancer–binding protein (C/EBPβ) far-upstream enhancer. have also C-terminal tail sequence beyond C/EBPβ leucine zipper critical for its association with via an exposed residue (Arg-232) located within pocket...
Abstract Interleukin 1β (IL-1β) and Tumor Necrosis Factor α (TNFα) expression by monocytes is stringently regulated, whereas sustained associated with chronic inflammation. Transcriptional kinetics of IL1B gene mRNA in THP-1 cells treated either Lipopolysaccharide (LPS) or Phorbol 12-Myristate 13-Acetate (PMA) revealed two distinct phases, an early vigorous transient (0–4 hours) followed a decreased continuous (4–24 hours). In contrast, the TNF showed only induction complete shutdown...
Abstract Cancers evade immune surveillance through multiple mechanisms including the recruitment of immunosuppressive regulatory T cells (Treg). Tivumecirnon (formerly known as FLX475), a small molecule oral CCR4 antagonist under clinical evaluation, blocks binding to its ligands CCL17 and CCL22 thereby reduces Treg infiltration into tumor microenvironment (TME). This relieves Treg-mediated suppression resulting in increased antitumor immunity. Our study (NCT03674567) demonstrated that...
<div>Abstract<p>Alpha-fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell differentiation maturation block oxidative phosphorylation. To identify the critical metabolic pathways leading human functional suppression, here we utilized two recently described single profiling methods, scMEP (single-cell profiling) SCENITH energetic metabolism translation inhibition)....