A5090689057- Single-cell and spatial transcriptomics
- Acute Myeloid Leukemia Research
- Cell Image Analysis Techniques
- T-cell and B-cell Immunology
- Chronic Lymphocytic Leukemia Research
- Gene expression and cancer classification
- Genomics and Chromatin Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Protein Degradation and Inhibitors
- Gene Regulatory Network Analysis
- vaccines and immunoinformatics approaches
- Advanced Proteomics Techniques and Applications
- Bioinformatics and Genomic Networks
- Diabetes and associated disorders
- Epigenetics and DNA Methylation
- Acute Lymphoblastic Leukemia research
- Immune responses and vaccinations
- Diabetes Management and Research
- Pancreatic function and diabetes
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- HIV Research and Treatment
- IL-33, ST2, and ILC Pathways
- Evolution and Genetic Dynamics
- Cancer, Lipids, and Metabolism
Princess Margaret Cancer Centre
2023-2025
University Health Network
2023-2025
University of Toronto
2023-2025
Vector Institute
2024-2025
University of Pennsylvania
2017-2022
Cancer Research Institute
2018-2022
Abramson Cancer Center
2020
Cancer Research Institute of the Slovak Academy of Sciences
2018-2020
Drexel University
2013-2017
T-lineage acute lymphoblastic leukemia (ALL) is an aggressive cancer comprising diverse subtypes that are challenging to stratify using conventional immunophenotyping. To gain insights into subset-specific therapeutic vulnerabilities, we performed integrative multiomics analysis of bone marrow samples from newly diagnosed T cell ALL, early precursor and T/myeloid mixed phenotype leukemia. Leveraging cellular indexing transcriptomes epitopes in conjunction with receptor sequencing, identified...
Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anticancer target. However, only fraction of patients with cancer benefit from angiogenesis inhibitors. Whether antiangiogenic therapy would be more effective if targeted individuals specific characteristics is unknown. To better characterize the vascular environment both within between types, we developed standardized metric - endothelial index (EI) estimate density in over 10,000 human...
Abstract Inflammation activates many blood cell types, driving aging and malignancy. Yet, hematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long production. To understand HSC adaptation inflammation, we developed xenograft inflammation-recovery models performed single multiomics on isolated human HSC. Two transcriptionally epigenetically distinct subsets expressing canonical programs were identified. Only one showed sustained transcriptional epigenetic changes...
Cellular composition and anatomical organization influence normal aberrant organ functions. Emerging spatial single-cell proteomic assays such as Image Mass Cytometry (IMC) Co-Detection by Indexing (CODEX) have facilitated the study of cellular enabling high-throughput measurement cells their localization directly in intact tissues. However, annotation cell types quantification relative tissues remain challenging. To address these unmet needs for atlas-scale datasets like Human Pancreas...
The 10x Genomics single cell Multiome (scMultiome) assay enables the simultaneous profiling of chromatin accessibility and gene expression from same nucleus, has increasingly been utilized in revealing cellular heterogeneity regulation cancers. However, a dedicated bioinformatics pipeline specifically designed for this type data is still lacking. Here we present iSHARC, streamlined quality control, modality integration, clustering, annotation, regulatory mechanism analysis individual...
In chronic infections, the immune response fails to control virus, leading persistent antigen stimulation and progressive development of T cell exhaustion. effector differentiation is poorly understood in context exhaustion, but targeting programs may provide new strategies for reinvigorating function. We identified Tribbles pseudokinase 1 (Trib1) as a central regulator antiviral immunity, where loss Trib1 led sustained enrichment effector-like KLRG1+ cells, enhanced function, improved viral...
The immune system can detect most invading pathogens. potential for detection of pathogens is dependent on the somatic diversity repertoires. While it known that this carefully generated, unclear how distributed in different genes encoding receptors cells. Utilizing metrics richness and at level small sequence fragments, we present here an analysis entire human germline repertoire as represented by sequences from ImMunoGeneTics database receptors. We have developed a fragment quantification...
High-throughput analysis of the transcriptome and proteome individually are used to interrogate complex oncogenic processes in cancer. However, an outstanding challenge is how combine these complementary, yet partially disparate data sources accurately identify tumor-specific gene products clinical biomarkers. Here, we introduce inteGREAT for robust scalable differential integration high-throughput measurements. With inteGREAT, each source represented as a co-expression network, which...
HIV-1 entry is a receptor-mediated process directed by the interaction of viral envelope with host cell CD4 molecule and one two co-receptors, CCR5 or CXCR4. The amino acid sequence third variable (V3) loop highly predictive co-receptor utilization preference during entry, machine learning algorithms have been developed to characterize sequences as CCR5-utilizing (R5) CXCR4-utilizing (X4). It was hypothesized that while V3 predominantly responsible for determining binding, additional...
Serine is the only amino acid that encoded by two disjoint codon sets (TCN & AGY) so a tandem substitution of nucleotides required to switch between sets. We show these underlie distinct patterns at positions subject purifying and diversifying selections. found in humans, are conserved among ~100 vertebrates, thus subjected selection, enriched for substitutions involving serine (TCN, denoted S'), proline, alanine, (S'PA). In contrast, less with AGY codons (denoted S″), glycine asparagine,...
Emerging single-cell epigenomic assays are used to investigate the heterogeneity of chromatin activity and its function. However, identifying cells with distinct regulatory elements clearly visualizing their relationships remains challenging. To this end, we introduce TooManyPeaks address need for simultaneous study state in both rare abundant subpopulations. Our analyses existing data from three widely transposase-accessible using sequencing (scATAC-seq) show superior performance...
Abstract Background As single-cell sequencing technologies continue to advance, the growing volume and complexity of ensuing data present new analytical challenges. Large cellular populations from atlases are more difficult visualize require extensive processing identify biologically relevant subpopulations. Managing these workflows is also laborious for technical users unintuitive nontechnical users. Results We TooManyCellsInteractive (TMCI), a browser-based JavaScript application...
The diversity of the immune repertoire is important for adaptive system's ability to detect pathogens. Much this generated in two steps, first through recombination germline gene segments and second hypermutation during an response. While both steps are some extent based on level genes, final structure selection specific receptors at somatic level. How relate has not been clear. To investigate how relates selection, we considered published Ig heavy chain V genes taken from blood 12...
Recent advances in high-resolution mapping of spatial interactions among regulatory elements support the existence complex topological assemblies enhancers and promoters known as enhancer-promoter hubs or cliques. Yet, organization principles these multi-interacting their potential role regulating gene expression cancer remain unclear. Here, we systematically identify breast cancer, lymphoma, leukemia. We find that highly interacting form at key oncogenes lineage-associated transcription...
Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD tyrosine kinase receptor FLT3 associated with poor prognostic outcomes. Several inhibitors (FLT3i) clinical trials for high-risk FLT3-ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that mere presence FLT3-ITD might not guarantee effective response. Motivated by heterogeneity mutations, we investigated effects...
Abstract Type 1 diabetes (T1D) is an autoimmune disease of only partially defined etiology in which immune cells destroy insulin-producing beta cells. Using single-cell transcriptomics and advanced analytical strategy to assess pancreatic islets T1D, autoantibody-positive, non-diabetic organ donors, we identified both canonical cell types rare insulin-expressing with a hybrid mixture endocrine exocrine gene signatures within all donors. We further found elevated expression MHC Class II...
Abstract As single-cell sequencing data sets grow in size, visualizations of large cellular populations become difficult to parse and require extensive processing identify subpopulations cells. Managing many these charts is laborious for technical users unintuitive non-technical users. To address this issue, we developed TooManyCellsInteractive (TMCI), a browser-based JavaScript application visualizing hierarchical as an interactive radial tree. TMCI allows explore, filter, manipulate...
Abstract Transcriptional programs contribute to phenotypic and functional cell states. While elucidation of state heterogeneity its role in biology pathobiology has been advanced by studying single level measurements, the underlying assumptions current analytical methods limit identification exploration clades. Unlike other methods, which produce a uni-layer partition cells ignoring echelons states, we present TooManyCells , software consisting suite graph-based tools for efficient, global,...