A5049217703- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- Histone Deacetylase Inhibitors Research
- Epigenetics and DNA Methylation
- Advanced Biosensing Techniques and Applications
- Advanced Fluorescence Microscopy Techniques
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Tendon Structure and Treatment
- Ubiquitin and proteasome pathways
- Immunotherapy and Immune Responses
- Cancer-related gene regulation
- Synthesis and biological activity
- Radiomics and Machine Learning in Medical Imaging
- Cancer Genomics and Diagnostics
- CAR-T cell therapy research
- Biochemical and Molecular Research
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related Molecular Pathways
- Cancer Immunotherapy and Biomarkers
- Tryptophan and brain disorders
- Cancer-related molecular mechanisms research
- Immune cells in cancer
- 3D Printing in Biomedical Research
- Viral Infectious Diseases and Gene Expression in Insects
Center for Systems Biology
2017-2025
Harvard University
2016-2025
University of Oxford
2010-2024
Harvard University Press
2024
Center for Cancer Research
2019-2022
Nuffield Orthopaedic Centre
2010-2020
Brigham and Women's Hospital
2019
Genomics (United Kingdom)
2013-2017
Structural Genomics Consortium
2017
Genomics England
2013-2017
The architecture of normal and diseased tissues strongly influences the development progression disease as well responsiveness resistance to therapy. We describe a tissue-based cyclic immunofluorescence (t-CyCIF) method for highly multiplexed immuno-fluorescence imaging formalin-fixed, paraffin-embedded (FFPE) specimens mounted on glass slides, most widely used histopathological diagnosis cancer other diseases. t-CyCIF generates up 60-plex images using an iterative process (a cycle) in which...
Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent selective ligands for module human lysine acetyl transferase CBP/p300, developed from a series 5-isoxazolyl-benzimidazoles. Our starting point was fragment hit, which optimized into more lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, reductive aminations. The selectivity compound against...
Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling highly multiplexed single-cell imaging on tumor samples from patients enrolled a Phase I/II trial of niraparib pembrolizumab cancer (NCT02657889). identify two determinants response; mutational signature 3 reflecting defective homologous recombination DNA repair, positive score as surrogate interferon-primed exhausted...
Improved understanding of the role inflammation in tendon disease is required to facilitate therapeutic target discovery. We studied supraspinatus tendons from patients experiencing pain before and after surgical subacromial decompression treatment. Tendons were classified as having early, intermediate, or advanced disease, was characterized through activation pathways mediated by interferon (IFN), nuclear factor κB (NF-κB), glucocorticoid receptor, signal transducer activator transcription...
Abstract The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and key regulators of cell growth. Therefore, efforts to generate inhibitors clinical value. We developed a specific potent acetyl-lysine competitive protein–protein interaction inhibitor, I-CBP112, that targets the bromodomains. Exposure human mouse leukemic lines I-CBP112 resulted substantially impaired colony formation induced cellular differentiation without...
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...
Highly multiplexed tissue imaging makes detailed molecular analysis of single cells possible in a preserved spatial context. However, reproducible large multichannel images poses substantial computational challenge. Here, we describe modular and open-source pipeline, MCMICRO, for performing the sequential steps needed to transform whole-slide into single-cell data. We demonstrate use MCMICRO on tumor acquired using multiple platforms, thereby providing solid foundation continued development software.
Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized transcriptome 880,000 nuclei from 18 control 61 failing, nonischemic human hearts with pathogenic DCM ACM or idiopathic disease. We performed genotype-stratified analyses ventricular cell lineages transcriptional states. The resultant atlas demonstrated distinct...
Cutaneous melanoma is a highly immunogenic malignancy that surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion immunoediting in primary melanoma. We find recurrent cellular neighborhoods involving tumor, immune, stromal cells change significantly along progression axis precursor states, situ, invasive tumor. Hallmarks of...
Abstract Motivation Stitching microscope images into a mosaic is an essential step in the analysis and visualization of large biological specimens, particularly human animal tissues. Recent approaches to highly multiplexed imaging generate high-plex data from sequential rounds lower-plex imaging. These methods promise yield precise molecular single-cell information on cellular neighborhoods tissue architecture. However, attaining with accuracy requires robust image stitching registration...
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...
2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) 4-carboxy-8-hydroxyquinoline (4C8HQ) with that two other commonly used inhibitors, N-oxalylglycine (NOG) 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal IOX1 has broad spectrum activity, as demonstrated by inhibition transcription factor hydroxylases, representatives all...
Abstract The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and current cancer targets; however, very few highly selective inhibitors for these available. Here we report cyclic peptide of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures biochemical analyses one (CP2) KDM4A reveals that CP2 binds differently to, but competes with, substrates in active site. Substitution site binding arginine N...
Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays key role in chromatin structure and gene regulation. Members the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) Fe
In prostate cancer, two different types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are coexpressed colocalize with the androgen receptor. We designed synthesized hybrid LSD1/JmjC or "pan-KDM" inhibitors 1–6 by coupling skeleton tranylcypromine 7, a known LSD1 inhibitor, 4-carboxy-4′-carbomethoxy-2,2′-bipyridine 8 5-carboxy-8-hydroxyquinoline 9, 2-oxoglutarate competitive templates developed for JmjC inhibition. Hybrid compounds able to simultaneously target both KDM...
Abstract The architecture of normal and diseased tissues strongly influences the development progression disease as well responsiveness resistance to therapy. We describe a tissue-based cyclic immunofluorescence (t-CyCIF) method for highly multiplexed immuno-fluorescence imaging formalin-fixed, paraffin-embedded (FFPE) specimens mounted on glass slides, most widely used histopathological diagnosis cancer other diseases. t-CyCIF generates up 60-plex images using an iterative process (a cycle)...
Changes in lung ACE2 expression and apoptotic priming throughout life span may affect COVID severity.
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,...
Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines potent inhibitors of both the BET bromodomains such BRD4 well outside family BRD9, CECR2, CREBBP. This new series compounds is first example submicromolar subfamily. Representative active in cells exhibiting cellular inhibition activity a FRAP model CREBBP chromatin association. The described valuable starting points for discovery selective...
Acetylation of lysine residues in histone tails plays an important role the regulation gene transcription. Bromdomains are readers acetylated marks, and, consequently, bromodomain-containing proteins have a variety chromatin-related functions. Moreover, they increasingly being recognised as mediators wide range diseases. The first potent and selective bromodomain inhibitors beginning to be described, but diverse or unknown functions present challenges systematically demonstrating cellular...
Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these display unusual binding modes involving water displacement from the KAc site. The best compound binds fifth PB1 with a KD 124 nM, SMARCA2B SMARCA4 values 262 417 respectively, displays excellent selectivity over bromodomains other than SMARCA2, SMARCA4.