A5078508725- Gastrointestinal Tumor Research and Treatment
- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- Sarcoma Diagnosis and Treatment
- Tumors and Oncological Cases
- Immunotherapy and Immune Responses
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Glioma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- Gastrointestinal disorders and treatments
- Venous Thromboembolism Diagnosis and Management
- Chromatin Remodeling and Cancer
- Hedgehog Signaling Pathway Studies
- Adenosine and Purinergic Signaling
- Radiomics and Machine Learning in Medical Imaging
- Patient Satisfaction in Healthcare
- Pituitary Gland Disorders and Treatments
- Acute Ischemic Stroke Management
- Ovarian cancer diagnosis and treatment
- Genetic factors in colorectal cancer
- Intracranial Aneurysms: Treatment and Complications
- Multiple Myeloma Research and Treatments
- Cancer Cells and Metastasis
- Immune cells in cancer
- Genetic and Kidney Cyst Diseases
Harvard University
2012-2024
Brigham and Women's Hospital
2013-2024
Center for Systems Biology
2021-2024
University of Missouri
2021
Center for Neuro-Oncology
2018
University of Toronto
2018
Boston Children's Hospital
2018
Dartmouth–Hitchcock Medical Center
2017-2018
Dartmouth College
2015-2017
Incheon St. Mary's Hospital
2012
Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, unknown. Here, we show in human cells that copper-dependent, regulated death distinct from known mechanisms dependent on mitochondrial respiration. We copper-dependent occurs means of direct binding to lipoylated components the tricarboxylic acid (TCA) cycle. This results...
Advanced solid cancers are complex assemblies of tumor, immune, and stromal cells characterized by high intratumoral variation. We use highly multiplexed tissue imaging, 3D reconstruction, spatial statistics, machine learning to identify cell types states underlying morphological features known diagnostic prognostic significance in colorectal cancer. Quantitation these high-plex marker space reveals recurrent transitions from one tumor morphology the next, some which coincident with...
Precision medicine is critically dependent on better methods for diagnosing and staging disease predicting drug response. Histopathology using hematoxylin eosin (H&E)-stained tissue (not genomics) remains the primary diagnostic method in cancer. Recently developed highly multiplexed imaging promise to enhance research studies clinical practice with precise, spatially resolved single-cell data. Here, we describe 'Orion' platform collecting H&E high-plex immunofluorescence images from same...
Craniopharyngiomas are neoplasms of the sellar/parasellar region that classified into adamantinomatous craniopharyngioma (ACP) and papillary (PCP) subtypes. Surgical resection craniopharyngiomas is challenging, recurrence common, frequently leading to profound morbidity. BRAF V600E mutations render PCP susceptible BRAF/MEK inhibitors, but effective targeted therapies needed for ACP. We explored feasibility targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1)...
How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize composition, spatial organization, clinical significance of extracellular purinergic signaling in glioma. We show that microglia are predominant source CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, increased adenosine,...
Organ development is a highly regulated process involving the coordinated proliferation and differentiation of diverse cellular populations. The pathways regulating cell their effects on organ growth are complex for many organs incompletely understood. In all vertebrate species, cardiac natriuretic peptides (ANP BNP) produced by cardiomyocytes in developing heart. However, role during cardiogenesis not defined. Using embryonic zebrafish neonatal mammalian we explored peptide signaling...
Pituitary tumors are the second most common adult primary brain tumor, with a variable clinical course. Recent work has identified number of genetic determinants pituitary tumor subtypes, which may augment traditional histopathologic classification schemes. We sought to determine whether could be stratified based on objective molecular characteristics using genomics assay. performed retrospective analysis patients operated at Brigham and Women's Hospital from 2012 2016 whose were profiled...
BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms its action, and ultimately resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss function ORF/cDNA driven rescue screens, cell-based models spontaneous we identify bHLH/homeobox transcription factors cell-cycle regulators as key genes mediating BETi's response resistance. Cells that acquire...
A 67-year-old woman was admitted to the hospital for 3 months of new-onset headaches and meningismus that progressed focal neurologic deficits. These first manifested as episodes flashing lights black blotches obscuring her vision minutes. She also began have visual hallucinations with formed letters words projected onto nearby walls. developed gait unsteadiness difficulty using phone reading a clock. seen by neuro-ophthalmology found left homonymous hemianopsia, at which point she further...
To assess the effects during cardiac development of mutations that cause human cardiomyopathy, we modeled a sarcomeric gene mutation in embryonic zebrafish. We designed morpholino antisense oligonucleotides targeting exon 13 splice donor site zebrafish troponin T (tnnt2) gene, order to precisely recapitulate TNNT2 causes hypertrophic cardiomyopathy (HCM). HCM is disease characterized by myocardial hypertrophy, myocyte and myofibrillar disarray, as well an increased risk sudden death. Similar...
Despite increased understanding of the fundamental biology regulating cardiomyocyte hypertrophy and heart failure, it has been challenging to find novel chemical or genetic modifiers these pathways. Traditional cell-based methods do not model complexity an intact cardiovascular system mammalian models are readily adaptable screens. Our objective was create in vivo suitable for screens failure Using developing zebrafish, we established that cardiac natriuretic peptide genes (nppa nppb), known...
SUMMARY Advanced solid cancers are complex assemblies of tumor, immune, and stromal cells characterized by high intratumoral variation. We use highly multiplexed tissue imaging, 3D reconstruction, spatial statistics, machine learning to identify cell types states underlying morphological features known diagnostic prognostic significance in colorectal cancer. Quantitation these high-plex marker space reveals recurrent transitions from one tumor morphology the next, some which coincident with...
Hedgehog (Hh) signaling promotes tumorigenesis. The accumulation of the membrane protein Smoothened (Smo) within primary cilium (PC) is a key event in Hh signal transduction, and many pharmacological inhibitors identified to date target Smo's actions. Smo ciliary translocation inhibited by some pathway antagonists, while others promote accumulation, an outcome that can lead hypersensitive state on renewal signaling. To identify novel inhibitory compounds acting critical mechanistic...
Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) is a powerful analytical technique that provides spatially preserved detection and quantification of analytes in tissue specimens. However, clinical translation still requires improved throughput, precision, accuracy. To accomplish this, we created "Chemical QuantArray", gelatin microarray (TMA) mold filled with serial dilutions isotopically labeled endogenous metabolite standards. The then cryo-sectioned onto...
Abstract BACKGROUND: The association of operative duration with the risk venous thromboembolism (VTE) has not been quantified in neurosurgery. OBJECTIVE: To investigate surgical for several neurosurgical procedures and incidence VTE. METHODS: We performed a retrospective cohort study involving patients who underwent from 2005 to 2012 were registered American College Surgeons National Quality Improvement Project registry. In order control confounding, we used multivariable regression models,...
Gastrointestinal stromal tumor (GIST) arises from interstitial cells of Cajal (ICC) or their precursors, which are present throughout the gastrointestinal tract. Although gastric GIST is commonly indolent and small intestine more aggressive, a molecular understanding disease behavior would inform therapy decisions in GIST. core transcription factor (TF) network conserved across GIST, accessory TFs HAND1 BARX1 expressed state-specific pattern. Here, we characterize two divergent...
Abstract Background Antibody–drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid and hematologic malignancies, including those HER2, TROP2, NECTIN4. Recently, an ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival reduced growth brain metastases in treatment-refractory metastatic breast cancer, even tumors with low expression. Thus, low-level expression targets may be...
Inspection of tissues using a light microscope is the primary method diagnosing many diseases, notably cancer. Highly multiplexed tissue imaging builds on this foundation, enabling collection up to 60 channels molecular information plus cell and morphology antibody staining. This provides unique insight into disease biology promises help with design patient-specific therapies. However, substantial gap remains respect visualizing resulting multivariate image data effectively supporting...