A5080769435- Glioma Diagnosis and Treatment
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- PI3K/AKT/mTOR signaling in cancer
- Immune cells in cancer
- Lung Cancer Treatments and Mutations
- Colorectal Cancer Treatments and Studies
- Melanoma and MAPK Pathways
- Ferroptosis and cancer prognosis
- Cancer therapeutics and mechanisms
- NF-κB Signaling Pathways
- Cancer, Hypoxia, and Metabolism
- Cancer-related Molecular Pathways
- Natural product bioactivities and synthesis
- Cancer Research and Treatments
- Synthesis and biological activity
- Single-cell and spatial transcriptomics
- Lung Cancer Research Studies
- Cell death mechanisms and regulation
- CRISPR and Genetic Engineering
- interferon and immune responses
- RNA regulation and disease
- RNA Interference and Gene Delivery
- Microtubule and mitosis dynamics
- Reproductive biology and impacts on aquatic species
Harvard University
2013-2024
Beth Israel Deaconess Medical Center
2017-2024
Cancer Research Institute
2017-2024
Tufts University
2017-2023
Boston University
2011-2019
Massachusetts General Hospital
2012-2014
Dana-Farber Cancer Institute
2014
Tufts Medical Center
2013
Multiple mechanisms of crizotinib resistance were identified in lung cancer patients including new secondary ALK mutations and activation receptor tyrosine kinases.
Abstract Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM microenvironment during tumor evolution and standard care treatments limited. Using single-cell transcriptomics flow cytometry, we unveiled large-scale comprehensive longitudinal changes in cell composition throughout progression epidermal growth factor receptor-driven genetic mouse model. We identified subsets proinflammatory...
Abstract Colorectal cancers harboring KRAS or BRAF mutations are refractory to current targeted therapies. Using data from a high-throughput drug screen, we have developed novel therapeutic strategy that targets the apoptotic machinery using BCL-2 family inhibitor ABT-263 (navitoclax) in combination with TORC1/2 inhibitor, AZD8055. This leads efficient apoptosis specifically KRAS- and BRAF-mutant but not wild-type (WT) colorectal cancer cells. specific susceptibility results inhibition...
Significance Small-cell lung cancer (SCLC) is an aggressive carcinoma with few effective treatment options beyond first-line chemotherapy. BH3 mimetics, such as ABT-263, promote apoptosis in SCLC cell lines, but early phase clinical trials demonstrated no significant benefit. Here, we examine the sensitivity of a large panel including SCLC, to ABT-263 and find that high Bcl2-interacting mediator death (BIM) low myeloid leukemia 1 (MCL-1) expression together predict sensitivity. cells...
Abstract Although several groups have demonstrated that concomitant use of MEK and phosphoinositide 3-kinase (PI3K) inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models KRAS-mutant non–small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy been underwhelming to date. While efficacy may be hampered by a narrow therapeutic index, the contribution biologic heterogeneity response NSCLCs MEKi/PI3Ki has largely unexplored. In study, we find...
The composition of the tumor immune microenvironment (TIME) is considered a key determinant patients' response to immunotherapy. mechanisms underlying TIME formation and development over time are poorly understood. Glioblastoma (GBM) lethal primary brain cancer for which there no curative treatments. GBMs immunologically heterogeneous impervious checkpoint blockade immunotherapies. Utilizing clinically relevant genetic mouse models GBM, we identified distinct landscapes associated with...
Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFRα and for which there are no effective therapies. Herein, we report the development a genetically engineered mouse model GBM based on autocrine, chronic stimulation overexpressed PDGFRα, analysis signaling pathways using proteomics. We discover tubulin-binding protein Stathmin1 (STMN1) as phospho-regulated target, this mis-regulation confers sensitivity to vinblastine (VB)...
Human NEMO (NF-κB essential modulator) is a 419 residue scaffolding protein that, together with catalytic subunits IKKα and IKKβ, forms the IκB kinase (IKK) complex, key regulator of NF-κB pathway signaling. an elongated homodimer comprising mostly α-helix. It has been shown that fragment spanning residues 44–111, which contains IKKα/β binding site, structurally disordered in absence bound IKKβ. Herein we show enforcing dimerization NEMO1–120 or NEMO44–111 constructs through introduction one...
The use of alternative promoters for the cell type-specific expression a given mRNA/protein is common strategy. NEMO scaffold protein required canonical NF-κB signaling. Transcription gene primarily controlled by two promoters: one (promoter B) drives transcription in most types and second D) largely responsible liver cells. Herein, we have used CRISPR/Cas9-based approach to disrupt core sequence element promoter B, this genetic editing essentially eliminates mRNA 293T human kidney By...
The possibility that chronic, multigenerational exposure to environmental estrogens selects for adaptive hormone-response phenotypes is a critical unanswered question. Embryos/larvae of killifish from an estrogenic-polluted environment (New Bedford Harbor, MA [NBH]) compared with those reference site overexpress estrogen receptor alpha (ERα) mRNA but are hyporesponsive estradiol. Analysis ERα mRNAs in the two populations revealed differences splicing gene encoding (esr1). Here we tested...
<div>Abstract<p>The composition of the tumor immune microenvironment (TIME) is considered a key determinant patients’ response to immunotherapy. The mechanisms underlying TIME formation and development over time are poorly understood. Glioblastoma (GBM) lethal primary brain cancer for which there no curative treatments. GBMs immunologically heterogeneous impervious checkpoint blockade immunotherapies. Utilizing clinically relevant genetic mouse models GBM, we identified distinct...
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Increased activity of transcription factor NF-κB has been implicated in many B-cell lymphomas. We investigated effects synthetic compound calafianin monomer (CM101) on biochemical and biological properties NF-κB. In human 293 cells, CM101 selectively inhibited DNA binding by overexpressed subunits REL (human c-Rel) p65 as compared to p50, inhibition required a conserved cysteine residue. also B-lymphoma cell lines, the sensitivity several lines CM101-induced proliferation arrest apoptosis...
ABSTRACT The use of alternative promoters for the cell type-specific expression a given mRNA/protein is common strategy. NEMO scaffold protein required canonical NF-κB signaling. Transcription gene primarily controlled by two promoters: one (promoter B) drives transcription in most types and second A) largely responsible liver cells. Herein, we have used CRISPR/Cas9-based approach to disrupt core sequence element promoter B, this genetic editing essentially eliminates mRNA 293T human kidney...
The molecular alterations underlying progression of low-grade glial/glioneuronal tumors remain to be elucidated. We present a case 56-year-old male with an enhancing left temporal lobe tumor. Histology revealed high-grade glioma adjacent glioneuronal component abundant Rosenthal fibers, focal eosinophilic granular bodies, and CD34-positive neurons. tumor was negative for IDH1 (R132H), BRAF-V600E, the KIAA1549-BRAF fusion. Comparative genomic hybridization detected large amplification (> 15...