A5041429014- Epigenetics and DNA Methylation
- Viral-associated cancers and disorders
- RNA modifications and cancer
- Renal cell carcinoma treatment
- DNA Repair Mechanisms
- Histiocytic Disorders and Treatments
- Cancer, Hypoxia, and Metabolism
- Cancer, Lipids, and Metabolism
- Cancer-related Molecular Pathways
- Myasthenia Gravis and Thymoma
- CRISPR and Genetic Engineering
- Metabolomics and Mass Spectrometry Studies
- Cytomegalovirus and herpesvirus research
- HIV Research and Treatment
- Cancer Immunotherapy and Biomarkers
- IgG4-Related and Inflammatory Diseases
- Histone Deacetylase Inhibitors Research
- Parvovirus B19 Infection Studies
- Cell death mechanisms and regulation
- Immune Cell Function and Interaction
- Eosinophilic Disorders and Syndromes
- Immunotherapy and Immune Responses
- Cancer Genomics and Diagnostics
- T-cell and B-cell Immunology
- Adenosine and Purinergic Signaling
Massachusetts General Hospital
2018-2025
Harvard University
2019-2024
Massachusetts Institute of Technology
2019-2024
Koch Institute for Integrative Cancer Research At MIT
2024
Boston University
2024
Allen Institute
2023
Dana-Farber Cancer Institute
2018-2019
Cancer Research Institute
2019
University of Pennsylvania
2011-2018
Brigham and Women's Hospital
2016-2017
Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in cohort immunocompromised patients, etiology HHV-8-negative MCD is idiopathic (iMCD). Recently, limited series iMCD cases Japan sharing constellation clinical features, including thrombocytopenia (T),...
Abstract Nucleotide metabolism supports RNA synthesis and DNA replication to enable cell growth division. depletion can inhibit proliferation, but how cells sense respond changes in the relative levels of individual nucleotides is unclear. Moreover, nucleotide requirement for biomass production over course cycle, coordinate differential demands with cycle progression not well understood. Here we find that excess proliferation by disrupting bases needed impeding replication. The resulting...
Abstract Eukaryotic microorganisms are important but understudied components of the human microbiome. Here we present a pipeline for analysis deep sequencing data on single cell eukaryotes. We designed new 18S rRNA gene-specific PCR primer set and compared published gene internal transcribed spacer (ITS) set. Amplicons were tested against 24 specimens from defined eukaryotes eight well-characterized stool samples. A software https://sourceforge.net/projects/brocc/ was developed taxonomic...
Cellular RNA interference (RNAi) provides a natural response against viral infection, but some viruses have evolved mechanisms to antagonize this form of antiviral immunity. To determine whether Ebolavirus (EBOV) counters RNAi by encoding suppressors silencing (SRSs), we screened all EBOV proteins using an assay initiated exogenously delivered small interfering RNAs (siRNAs) either or reporter gene. In addition protein 35 (VP35), found that VP30 and VP40 independently act as SRSs. Here,...
Small cell lung cancer (SCLC) is an aggressive subtype with extremely poor prognosis. No targetable genetic driver events have been identified, and the treatment landscape for this disease has remained nearly unchanged over 30 years. Here, we taken a CRISPR-based screening approach to identify vulnerabilities in SCLC that may serve as potential therapeutic targets. We used single-guide RNA (sgRNA) library targeting ~5000 genes deemed encode "druggable" proteins perform loss-of-function...
BACKGROUND. Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6 (IL-6) blockade–refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6 iMCD with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin...
Human Herpesvirus‐8 (HHV‐8)‐negative/idiopathic multicentric Castleman disease (iMCD) is a poorly understood involving polyclonal lymphoproliferation with dysmorphic germinal centers, constitutional symptoms, and multi‐organ failure. Patients can experience thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly, normal immunoglobulin levels, – iMCD‐TAFRO. Others thrombocytosis, milder effusions, hypergammaglobulinemia, –iMCD‐Not Otherwise Specified (iMCD‐NOS). Though...
AID/APOBEC family enzymes are best known for deaminating cytosine bases to uracil in single-stranded DNA, with characteristic sequence preferences that can produce mutational signatures targets such as retroviral and cancer cell genomes. These deaminases have also been proposed function DNA demethylation via deamination of either 5-methylcytosine (mC) or TET-oxidized mC (ox-mCs), which include 5-hydroxymethylcytosine, 5-formylcytosine 5-carboxylcytosine. One specific member, APOBEC3A (A3A),...
Modification of cytosine-guanine dinucleotides (CpGs) is a key part mammalian epigenetic regulation and helps shape cellular identity. Tet enzymes catalyze stepwise oxidation 5-methylcytosine (mC) in CpGs to 5-hydroxymethylcytosine (hmC), or onward 5-formylcytosine (fC) 5-carboxylcytosine (caC). The multiple mC products, while intricately linked, are postulated play independent roles, making it critical understand how the products established maintained. Using highly sensitive isotope-based...
ABSTRACT The organization of immune cells in human tumors is not well understood. Immunogenic harbor spatially-localized multicellular ‘immunity hubs’ defined by expression the T cell-attracting chemokines CXCL10/CXCL11 and abundant cells. Here, we examined immunity hubs pre-immunotherapy lung cancer specimens, found that they were associated with beneficial responses to PD-1-blockade. Immunity enriched for many interferon-stimulated genes, multiple differentiation states, CXCL9/10/11 +...
The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it established that the local abundance specific nutrients defines metabolic parameters for growth, factors guiding in compared to normal tissue blood remain poorly understood. To define these renal cell carcinoma (RCC), we performed quantitative metabolomic comprehensive lipidomic analyses interstitial fluid (TIF), adjacent kidney (KIF),...
Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD unknown, interleukin-6 (IL-6) an established driver in approximately one-third patients. Anti-IL-6 therapy, siltuximab, only US Food Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, no validated tests are...
Abstract The rarity of thymic epithelial tumors and absence targetable alterations present significant challenges for identifying improved systemic therapies. Recent advances in single-cell sequencing have enhanced our understanding normal thymus development the factors underlying malignant transformation. During medullary differentiation adulthood, anti-apoptotic are expressed, potentially increasing resistance to cell death thus facilitating tumorigenic processes. We hypothesized that this...
Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD subset patients has led to the hypotheses UCD...
Activation-induced deaminase (AID), a member of the larger AID/APOBEC family, is key catalyst in initiating antibody somatic hypermutation and class-switch recombination. The DNA deamination model accounting for AID's functional role posits that AID deaminates genomic deoxycytosine bases within immunoglobulin locus, activating downstream repair pathways result maturation. Although this well supported, molecular basis selectivity over RNA remains an open pressing question, reflecting broader...