A5007578114- CAR-T cell therapy research
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Virus-based gene therapy research
- Plant Molecular Biology Research
- Cancer Genomics and Diagnostics
- Cancer-related Molecular Pathways
- RNA modifications and cancer
- Chromosomal and Genetic Variations
- Ubiquitin and proteasome pathways
- Biosimilars and Bioanalytical Methods
- Advanced biosensing and bioanalysis techniques
- DNA Repair Mechanisms
- Cancer, Hypoxia, and Metabolism
- Cancer Immunotherapy and Biomarkers
- Molecular Biology Techniques and Applications
- Immunotherapy and Immune Responses
- Plant Gene Expression Analysis
- Genetics and Neurodevelopmental Disorders
- Glioma Diagnosis and Treatment
- Plant nutrient uptake and metabolism
- Bioinformatics and Genomic Networks
- Genetic factors in colorectal cancer
University of California, Berkeley
2019-2020
Dana-Farber Cancer Institute
2012-2018
Harvard University
2017
The organization of chromatin into higher order structures is essential for chromosome segregation, the repair DNA-damage, and regulation gene expression. Using Micro-C XL to detect chromosomal interactions, we observed pervasive presence cohesin-dependent loops with defined positions throughout genome budding yeast, as seen in mammalian cells. In early S phase, cohesin stably binds associated regions (CARs) genome-wide. Subsequently, positioned accumulate CARs at bases loops. Cohesin...
Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used genome-scale shRNA viability screen cancer cell lines to systematically identify genes that are essential the context particular copy-number alterations (copy-number associated gene dependencies). The most enriched class dependencies was CYCLOPS (Copy-number Yielding Cancer Liabilities Owing Partial losS) genes, spliceosome components were prevalent. One these, pre-mRNA...
Abstract Programmable, RNA-guided nucleases are diverse enzymes that have been repurposed for biotechnological applications. However, to further expand the therapeutic application of these tools there is a need targetable systems small enough be delivered efficiently. Here, we mined an extensive genome-resolved metagenomics database and identified families uncharacterized RNA-guided, compact (between 450 1,050 aa). We report Cas9d, new CRISPR type II subtype, contains Zinc-finger motifs high...
Development of medicines using gene editing has been hampered by enzymological and immunological impediments. We described previously the discovery characterization improved, novel gene-editing systems from metagenomic data. In this study, we substantially advance work with three such systems, demonstrating their utility for cell therapy development. All are capable reproducible, high-frequency in primary immune cells. human T cells, disruption receptor (TCR) alpha-chain was induced >95%...
Condensin mediates chromosome condensation, which is essential for proper segregation during mitosis. Prior to anaphase of budding yeast, the ribosomal DNA (RDN) condenses a thin loop that distinct from rest chromosomes. We provide evidence establishment and maintenance this RDN condensation requires regulation condensin by Cdc5p (polo) kinase. show recruited site binding in cohesin, complex related condensin. cohesin prevent misfolding into an irreversibly decondensed state. From these...
Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nucleases have been extensively used in biotechnology and therapeutics. However, many applications are not possible owing to the size, targetability, potential off-target effects associated with currently known systems. In this study, we identified thousands of CRISPR type effectors by mining an extensive, genome-resolved metagenomics database encompassing hundreds microbial genomes. We developed a...
ABSTRACT The organization of chromatin into higher-order structures is essential for chromosome segregation, the repair DNA-damage, and regulation gene expression. Using Micro-C XL to detect chromosomal interactions, we observed pervasive presence cohesin-dependent loops with defined positions throughout genome budding yeast, as seen in mammalian cells. In early S phase, cohesin stably binds associated regions (CARs) genome-wide. Subsequently, positioned accumulate CARs at bases loops....
Abstract Adoptive T cell therapy (ACT) has demonstrated antitumor efficacy in patients with solid cancers but requires further optimization to become a reproducibly effective treatment. receptor (TCR)-engineered cells recognize peptides derived from intracellular and surface proteins presented the context of MHC class I. Targeting mutated oncogenic drivers addresses many major obstacles this modality, that antigenic epitope is: 1) tumor-specific, 2) essential for tumor survival, 3) stably...
Abstract The KRASG12D mutation is an ideal target for anti-cancer therapies as its expression typically clonal, restricted to cancer tissue, and among the most common oncogenic drivers in solid tumors. TCR-T cell have demonstrated clinical activity some cancers but been limited by heterogeneous antigen unfavorable tumor microenvironments. By targeting which has established genetic dependency, AFNT-212 designed selectively all cells while avoiding on-target/off-tumor toxicities. non-virally...
<h3>Background</h3> Adoptive T cell therapy (ACT) has demonstrated antitumor activity in solid tumor patients but requires further optimization. receptor (TCR)-engineered cells recognize peptides derived from intracellular and surface proteins presented the context of MHC class I. <i>TP53</i> is most frequently mutated gene across human cancers, with a recurrent arginine to histidine hotspot alteration codon 175 that generates peptide HLA-A*02:01. AFNT-313 engineered overcome challenges...
Abstract Condensin mediates chromosome condensation, which is essential for proper segregation during mitosis. Prior to anaphase of budding yeast, the ribosomal DNA (RDN) condenses a thin loop that distinct from rest chromosomes. We provide evidence establishment and maintenance this RDN condensation require regulation condensin by Cdc5p (polo) kinase. show recruited site binding in cohesin, complex related condensin. cohesin prevent misfolding into an irreversibly decondensed state. From...
Abstract Introduction. Glioblastoma multiforme (GBM) is the most common and malignant brain tumor. This single histopathological entity includes a devastating collection of heterogeneous high-grade tumors showing broad spectrum cellular morphologies molecular diversity. These display uniform very short survival time. Until now in spite improvements achieved neurosurgery tools biology understanding, there still no effective treatment. For this purpose we pursue systematic analysis genetic...
Abstract Genomic instability is a hallmark of cancer resulting in widespread somatic copy number alterations. We integrated genome-scale shRNA viability screen and profiles from 179 cell lines to perform an unbiased analysis copy-number associated gene-dependency interactions. found most gene dependencies result losses genetic material rather than gains. Strikingly, the enriched class these was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing Partial losS) genes. Hemizygous...
Abstract Introduction: Glioblastoma is the most malignant and deleterious brain tumor. Average patient survival less than 14 months there no effective cure. Glioma cell lines, grown in serum, have been used to explore new therapeutic approaches, but they are poor representatives of primary tumors. At genomic level, exhibit many allelic imbalances mutations that likely associated with long-term passages selective pressure fit an artificial environment. gene expression do not clearly...
<h3>Background</h3> Adoptive T cell therapy has demonstrated clinical activity in a subset of patients with solid tumors; however, consistent responses will require further optimization. receptor (TCR)-engineered cells recognize peptides derived from intracellular and surface proteins presented the context MHC class I. Immunologic targeting recurrently mutated oncogenic drivers, such as KRAS, overcomes many major obstacles this modality because resulting epitope is: 1) tumor-specific, 2)...
<h3>Background</h3> The AFNT-212 cell therapy consists of autologous CD8+ and CD4+ T cells expressing 1) a Cell Receptor (TCR) specific for the prevalent oncogenic driver KRAS G12D mutation presented by HLA-A*11:01, 2) chimeric cytokine receptor, 3) CD8α/β coreceptor enabling coordinated CD4+/CD8+ anti-tumor response to promote activity while minimizing exhaustion. While viral vectors, including lentivirus (LVV), have been standard modality deliver transgenes therapies, they are limited...
Many pediatric cancers exhibit widespread somatic copy number alterations. We integrated a genome-scale shRNA viability screen and profiles from 179 cancer cell lines to perform an unbiased analysis of copy-number associated gene-dependency interactions. found most gene dependencies result losses genetic material rather than gains. Strikingly, the enriched class these was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing Partial losS) genes. Hemizygous loss genes sensitizes...
Abstract Glioblastoma (GBM) is the most common and malignant brain tumor. These tumors display a uniform very short survival time even with treatment, but are highly heterogeneous at histological genomic level. To identify effective treatments dependencies, we profiled sensitivity of panel cancer cell lines to small molecules integrated this systematic analysis genetic non-genetic determinants associated chemical response. Methods. We 381 drugs described in Cancer Therapeutics Response...
Abstract Introduction: Glioblastoma (GBM) is a lethal disease without effective treatments. To advance toward therapeutic approaches that are biomarker driven, we need new targeted agents and to develop accurate preclinical cell line models encompass its cellular molecular diversity. Experimental Procedures: identify targets therapies profiled across 78 GBM lines 381 drugs described in the Cancer Therapeutics Response Portal (CTRP) at 16 different duplicated concentrations. The consisted of...