A5023421069- CAR-T cell therapy research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Single-cell and spatial transcriptomics
- Immune cells in cancer
- Gene Regulatory Network Analysis
- Monoclonal and Polyclonal Antibodies Research
- Viral Infectious Diseases and Gene Expression in Insects
- Cancer Immunotherapy and Biomarkers
- DNA and Nucleic Acid Chemistry
- Chronic Lymphocytic Leukemia Research
- Cytokine Signaling Pathways and Interactions
- Chemokine receptors and signaling
- Synthesis and Biological Evaluation
- Receptor Mechanisms and Signaling
- Immunodeficiency and Autoimmune Disorders
- Advanced biosensing and bioanalysis techniques
- Lymphoma Diagnosis and Treatment
- Phagocytosis and Immune Regulation
- Virus-based gene therapy research
- Bioinformatics and Genomic Networks
- Adenosine and Purinergic Signaling
- vaccines and immunoinformatics approaches
- Cell Image Analysis Techniques
Center for Cancer Research
2016-2024
National Cancer Institute
2016-2024
National Institutes of Health
2002-2023
Memorial Sloan Kettering Cancer Center
2011-2023
Laboratoire d’immunologie intégrative du cancer
2023
Cancer Institute (WIA)
2023
National Cancer Institute
2022-2023
Government of the United States of America
2020
Center for Systems Biology
2015-2019
Cornell University
2009-2017
Fluorescence correlation spectroscopy (FCS) is an experimental technique using statistical analysis of the fluctuations fluorescence in a system order to decipher dynamic molecular events, such as diffusion or conformational biomolecules. First introduced by Magde et al measure and binding ethidium bromide onto double-stranded DNA, has been undergoing renaissance since 1993 with implementation confocal microscopy FCS. Since then, flurry experiments implemented FCS characterize photochemistry...
Molecular beacons are DNA probes that form a stem-and-loop structure and possess an internally quenched fluorophore. When they bind to complementary nucleic acids, undergo conformational transition switches on their fluorescence. These recognize targets with higher specificity than cannot hairpin stem, easily discriminate differ from one another by only single nucleotide. Our results show molecular can exist in three different states: bound target, free the of structure, random coil....
The kinetics of DNA hairpin-loop fluctuations has been investigated by using a combination fluorescence energy transfer and correlation spectroscopy. We measure the chemical rates activation energies associated with opening closing hairpin for different sizes sequences loop various salt concentrations. rate unzipping stem is essentially independent characteristics loop, whereas varies greatly length sequence. scales length, an exponent 2.6 ± 0.3. increased at higher For closing, adenosine...
T-lymphocyte activation displays a remarkable combination of speed, sensitivity, and discrimination in response to peptide-major histocompatibility complex (pMHC) ligand engagement clonally distributed antigen receptors (T cell or TCRs). Even few foreign pMHCs on the surface an antigen-presenting trigger effective signaling within seconds, whereas 1 x 10(5)-1 10(6) self-pMHC ligands that may differ from stimulus by only single amino acid fail elicit this response. No existing model accounts...
Background Systems biology has embraced computational modeling in response to the quantitative nature and increasing scale of contemporary data sets. The onslaught is accelerating as molecular profiling technology evolves. Dialogue for Reverse Engineering Assessments Methods (DREAM) a community effort catalyze discussion about design, application, assessment systems models through annual reverse-engineering challenges. Methodology Principal Findings We describe our assessments four...
We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels IL-6 were found at leading edge positively correlated with advanced stage, suggesting a mechanistic link between cell production invasion. support this hypothesis, we showed that IL-6/Janus kinase (JAK)/signal transducer activator transcription 3 (Stat3) pathway drives progression through stroma metastatic niche. Overexpression lines promoted...
Adoptive T cell therapy (ACT) using ex vivo-expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact TIL phenotypes on clinical success TIL-ACT is currently unclear. Using high-dimensional analysis ACT products, we identified a memory-progenitor CD39-negative stem-like phenotype (CD39
In T cells, the stochasticity of protein expression could contribute to useful diversification biological functions within a clonal population or interfere with accurate antigen discrimination. Combining computer modeling and single-cell measurements, we examined how endogenous variation in levels signaling proteins might affect responsiveness during cell activation. We found that CD8 co-receptor fine-tunes activation thresholds, whereas soluble hematopoietic phosphatase 1 (SHP-1) digitally...
Single stranded DNA (ssDNA) equilibrium dynamics are investigated using a fluorophore/quencher-labeled hairpin structure which thermally fluctuates between open and closed states. Temporal correlations of the fluorescence fluctuations used to determine energy barrier conformational change. We find that ssDNA distortion is purely entropic for poly(T) but requires an additional enthalpy +0.5 kcal x mol(-1) base(-1) poly(A), consistent with disruption base stacking. Such sequence dependent...
We report the first measurement of dynamics bubble formation in double-stranded DNA. Fluctuations fluorescence a synthetic DNA construct, internally tagged with fluorophore and quencher, are monitored by correlation spectroscopy. The relaxation follow multistate kinetics, characteristic time scale $50\text{ }\ensuremath{\mu}\mathrm{s}$. A simple model based on constant zipping-unzipping rates is proposed to account for our experimental data. role different secondary structures stabilizing...
Understanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified dynamics of interleukin‐2 (IL‐2) signaling in population T cells during an response combining silico modeling single‐cell measurements vitro . demonstrate that IL‐2 receptor expression levels vary widely among creating large variability ability individual to consume, produce participate within population. Our model reveals...
Evaluation of myeloid-derived suppressor cells (MDSC), a cell type implicated in T-cell suppression, may inform immune status. However, uniform methodology is necessary for prospective testing as biomarker. We report the use computational algorithm-driven analysis whole blood and cryopreserved samples monocytic MDSC (m-MDSC) quantity that removes variables related to processing user definitions. Applying these methods from patients with melanoma identifies differing frequency distribution...
The immunological synapse formed by a T lymphocyte on the surface of target cell contains peripheral ring filamentous actin (F-actin) that promotes adhesion and facilitates directional secretion cytokines cytolytic factors. We show growth maintenance this F-actin is dictated annular accumulation phosphatidylinositol trisphosphate (PIP3) in synaptic membrane. PIP3 functions context recruiting exchange factor Dock2 to periphery synapse, where it drives polymerization through Rho-family GTPase...
Significance Early immune response has to discriminate a few foreign peptides rapidly from vast excess of self-peptides, and it is unclear in quantitative terms how this possible. We show that generic proofreading cascade supplemented by single negative feedback mediated the Src homology 2 domain phosphatase-1 (SHP-1) accounts quantitatively for discrimination. Our model, with minimal variables parameters, can fit large body experimental data phenotypes T-cell activation. New experiments...
In this review we discuss how the competition for cytokines between different cells of immune system can shape wide response. We focus on interleukin-2 (IL-2) secretion by activated effector T (T(eff)) and IL-2 consumption T(eff) regulatory (T(reg)). evidence mechanism in which depletion T(reg) would be sufficient to suppress an autoimmune response, yet not strong enough prevent present quantitative estimations summarize our modeling effort show that tug-of-war molecules won case weak...
X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the transporter 1 (MAGT1) gene. We studied 23 patients XMEN, 8 whom were naive. observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to previously described features an inverted CD4/CD8 ratio, CD4+ lymphocytopenia, B cells, dysgammaglobulinemia, decreased expression natural...