A5031217170- Neuroblastoma Research and Treatments
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Monoclonal and Polyclonal Antibodies Research
- Receptor Mechanisms and Signaling
- vaccines and immunoinformatics approaches
- SARS-CoV-2 and COVID-19 Research
- Cardiac electrophysiology and arrhythmias
- Immune Cell Function and Interaction
- Hippo pathway signaling and YAP/TAZ
- Glycosylation and Glycoproteins Research
- T-cell and B-cell Immunology
- Ubiquitin and proteasome pathways
- Cancer Immunotherapy and Biomarkers
- RNA Interference and Gene Delivery
- RNA and protein synthesis mechanisms
- Cancer, Hypoxia, and Metabolism
- Virus-based gene therapy research
- interferon and immune responses
- Peptidase Inhibition and Analysis
- Cancer Mechanisms and Therapy
- Hepatitis B Virus Studies
- Chronic Lymphocytic Leukemia Research
- Viral Infectious Diseases and Gene Expression in Insects
- RNA regulation and disease
Children's Hospital of Philadelphia
2018-2024
New York University
2023-2024
University of Pennsylvania
2016-2020
Philadelphia University
2014-2020
CURE Childhood Cancer
2020
Baylor College of Medicine
2015
Oceanside Public Library
2014
California University of Pennsylvania
2014
Abstract High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream genomic alterations, including chromosomal alterations. Our identified three subtypes high-risk neuroblastomas, consistent with and subtype-specific master regulator proteins that were conserved across independent...
Abstract The majority of oncogenic drivers are intracellular proteins, thus constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes 1 . However, most cancers have a modest mutational burden that is insufficient generate responses using neoantigen-based therapies 2,3 Neuroblastoma paediatric cancer harbours few mutations and instead driven epigenetically deregulated transcriptional networks 4 Here we show...
Here we propose a SARS-CoV-2 vaccine design concept based on identification of highly conserved regions the viral genome and newly acquired adaptations, both predicted to generate epitopes presented major histocompatibility complex (MHC) class I II across vast majority population. We further prioritize genomic that dissimilar peptides from human proteome are also produce B cell epitopes. sixty-five 33-mer peptide sequences, subset which can be tested using DNA or mRNA delivery strategies....
Abstract The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes 1 . However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies 2,3 Neuroblastoma paediatric cancer harbours few mutations and instead driven epigenetically deregulated transcriptional networks 4 Here we...
Inconsistent detection of plant-based dietary small RNAs in circulation has thwarted the use RNA therapeutics. Here we demonstrate mice consuming diets rich vegetables displayed enhanced serum levels plant specific MIR2911. Differential centrifugation, size-exclusion chromatography, and proteinase K treatment extracts suggest this resides within a K-sensitive complex. Plant derived MIR2911 was more bioavailable than synthetic RNA. Furthermore, exhibited unusual digestive stability compared...
Peptide exchange technologies are essential for the generation of pMHC-multimer libraries used to probe diverse, polyclonal TCR repertoires in various settings. Here, using molecular chaperone TAPBPR, we develop a robust method capture stable, empty MHC-I molecules comprising murine H2 and human HLA alleles, which can be readily tetramerized loaded with peptides choice high-throughput manner. Alternatively, catalytic amounts TAPBPR placeholder high affinity interest. Using same system,...
Glycosylation is an important post-translational modification during protein production in eukaryotic cells, and it essential for structure, stability, half-life, biological functions. In this study, we produced various monoclonal antibody (mAb) glycoforms from Chinese hamster ovary (CHO) including the natively glycosylated antibody, enriched G0 form, deglycosylated afucosylated high mannose compared their intrinsic properties, side-by-side, through biophysical biochemical approaches....
Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric tumor that expresses cell-surface GPC2 and GD2 with a microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells express GPC2-directed CAR simultaneously secrete bispecific cell engager (BiCE) targeting both CD16a. In vitro, GPC2.CAR-GD2.BiCE induce GPC2-dependent cytotoxicity GD2.BiCE...
Despite recent advances in cancer immunotherapy, the process of immunoediting early tumorigenesis remains obscure. Here, we employ a mathematical model that utilizes Cancer Genome Atlas (TCGA) data to elucidate contribution individual mutations and HLA alleles process. We find common including BRAF-V600E KRAS-G12D are predicted bind none alleles, thus "immunogenically silent" human population. identify regions proteins not presented by at population scale, coinciding with frequently mutated...
The identification of recurrent HLA neoepitopes driving T cell responses against tumors poses a significant bottleneck in the development approaches for precision cancer therapeutics. Here, we employ bioinformatics method, Prediction Of Cell Epitopes Cancer Therapy (ProTECT) to analyze sequencing data from neuroblastoma patients and identify Anaplastic Lymphoma Kinase mutation (ALK R1275Q) that leads two high affinity when expressed complex with common alleles. Analysis X-ray structures...
Peptide-centric chimeric antigen receptors (PC-CARs) recognize oncoprotein epitopes displayed by cell-surface human leukocyte antigens (HLAs) and offer a promising strategy for targeted cancer therapy. We have previously developed PC-CAR targeting neuroblastoma-associated PHOX2B peptide, leading to robust tumor cell lysis restricted two common HLA allotypes. Here, we determine the 2.1-angstrom crystal structure of PC-CAR–PHOX2B–HLA-A*24:02–β 2 m complex, which reveals basis antigen-specific...
Despite recent advances in cancer immunotherapy, the process of immunoediting early tumorigenesis remains obscure. Here, we employ a mathematical model that utilizes Cancer Genome Atlas (TCGA) data to elucidate contribution individual mutations and HLA alleles process. We find common including BRAF-V600E KRAS-G12D are predicted bind none alleles, thus “immunogenically silent” human population. identify regions proteins not presented by at population scale, coinciding with frequently mutated...
MotivationSelecting immunotherapeutic targets with tumor-specific expression is crucial for effective immunotherapy and minimized off-target toxicity. Current strategies often rely on arbitrary cutoffs across multiple modalities, introducing subjectivity hindering cross-study consistency. We present BayesTS, a Bayesian index that flexibly integrates diverse molecular tissue data while accounting inferential uncertainty. BayesTS accurately captures profiles modalities can identify both...
Here we propose a vaccination strategy for SARS-CoV-2 based on identification of both highly conserved regions the virus and newly acquired adaptations that are presented by MHC class I II across vast majority population, dissimilar from human proteome, predicted B cell epitopes. We present 65 peptide sequences expect to result in safe effective vaccine which can be rapidly tested DNA, mRNA, or synthetic constructs. These include epitopes contained within evolutionarily divergent spike...
Abstract BACKGROUND: Neuroblastoma (NBL) is the most common extracranial solid tumor in children. High-risk NBLs progress to metastatic disease and have 5-year survival of only ∼40%, despite intensive multimodal therapy. This malignancy characterized by significant heterogeneity, both clinical molecular, which still poorly understood. Rather than focusing on its initiating genetic events, are highly idiosyncratic, we focused core regulatory machinery responsible for implementation...
<div>Abstract<p>High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream genomic alterations, including chromosomal alterations. Our identified three subtypes high-risk neuroblastomas, consistent with and subtype-specific master regulator proteins that were conserved...
<p>Differential expression and biological pathway enrichment analysis of neuroblastoma molecular subtypes</p>
<p>Neuroblastoma Molecular subtypes and clinical information.</p>
<p>Master Regulator Analysis results from msVIPER</p>
<p>Neuroblastoma Molecular subtypes and clinical information.</p>
<p>ARACNe-AP transcriptional network from gene expression profiles</p>