A5041089077- Cancer Genomics and Diagnostics
- Advanced Breast Cancer Therapies
- PI3K/AKT/mTOR signaling in cancer
- Multiple Myeloma Research and Treatments
- Cancer Treatment and Pharmacology
- HER2/EGFR in Cancer Research
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Protein Degradation and Inhibitors
- Renal cell carcinoma treatment
- Genomics and Chromatin Dynamics
- Cancer Immunotherapy and Biomarkers
- Epigenetics and DNA Methylation
- Chronic Lymphocytic Leukemia Research
- Chemokine receptors and signaling
- CAR-T cell therapy research
- Lung Cancer Research Studies
- Bladder and Urothelial Cancer Treatments
- Single-cell and spatial transcriptomics
- RNA Research and Splicing
- Acute Myeloid Leukemia Research
- Genomics and Phylogenetic Studies
- Hematopoietic Stem Cell Transplantation
- Lung Cancer Treatments and Mutations
- Myeloproliferative Neoplasms: Diagnosis and Treatment
Broad Institute
2018-2025
Massachusetts Institute of Technology
2021-2025
Harvard University
2021-2023
Massachusetts General Hospital
2023
University of Massachusetts Chan Medical School
2014-2022
Brigham and Women's Hospital
2021
The University of Tokyo
2010-2015
National Institute of Advanced Industrial Science and Technology
2014
Japan Science and Technology Agency
2014
Mitochondria provide numerous essential functions for cells and their dysfunction leads to a variety of diseases. Thus, obtaining complete mitochondrial proteome should be crucial step toward understanding the roles mitochondria. Many proteins have been identified experimentally but list is not yet available. To fill this gap, methods computationally predict from amino acid sequence developed are widely used, unfortunately, accuracy far perfect. Here we describe MitoFates, an improved...
Clonal hematopoiesis (CH) can be transmitted from a donor to recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on outcomes and graft alloimmune function uncertain.
It is well known that remnants of partial or whole copies mitochondrial DNA, as Nuclear MiTochondrial sequences (NUMTs), are found in nuclear genomes. Since genome have become available, many bioinformatics studies identified putative NUMTs and from those attempted to infer the factors involved NUMT creation. These conclude represent randomly chosen regions genome. There less consensus regarding insertion sites - previous discussed possible role retrotransposons, but some recent ones...
Abstract The morphologically and functionally distinct cell types of a multicellular organism are maintained by their unique epigenomes gene expression programs. Phase III the ENCODE Project profiled 66 mouse across twelve tissues at daily intervals from embryonic day 11.5 to birth. Applying ChromHMM algorithm these epigenomes, we annotated eighteen chromatin states with characteristics promoters, enhancers, transcribed regions, repressed quiescent regions. Our integrative analyses delineate...
Blood-based 'liquid biopsy' is increasingly utilized in clinical care of cancer patients and fraction tumor-derived DNA circulation ('tumor fraction', TFx) has demonstrated validity across multiple types. To determine TFx, shallow whole genome sequencing cell-free can be performed from a single blood sample, using an established computational pipeline (ichorCNA), without prior knowledge tumor mutations, highly cost effective manner. We describe assay validation this approach to facilitate...
Abstract Analysis of bisulfite sequencing data usually requires two tasks: to call methylated cytosines (mCs) in a sample, and detect differentially regions (DMRs) between paired samples. Although numerous tools have been proposed for mC calling, methods DMR detection largely limited. Here, we present Bisulfighter, new software package detecting mCs DMRs from data. Bisulfighter combines the LAST alignment tool novel framework based on hidden Markov models (HMMs). Unlike previous attempts...
Novel biomarkers are needed to differentiate outcomes in intermediate-risk rhabdomyosarcoma (IR RMS). We sought evaluate strategies for identifying circulating tumor DNA (ctDNA) IR RMS and determine whether ctDNA detection before therapy is associated with outcome.
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder resulting from expansion of CAG repeats in the Huntingtin (HTT) gene. Previous studies have shown mutant HTT can alter expression genes associated with dysregulated epigenetic modifications. One most widely studied chromatin modifications trimethylated lysine 4 histone 3 (H3K4me3). Here, we conducted first comprehensive study H3K4me3 ChIP-sequencing neuronal prefrontal cortex six HD cases and non-neurologic...
Abstract Purpose: This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored TSC1/TSC2 or MTOR mutations. Patients and Methods: inactivating activating mutations identified any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. treated everolimus 10 mg once daily until disease progression unacceptable toxicity. The...
Abstract Purpose: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from combination of palbociclib plus ET in hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer. Bazedoxifene a third-generation selective estrogen receptor (ER) modulator and ER degrader with activity preclinical models endocrine-resistant cancer, including harboring ESR1 mutations. Clinical trials healthy women showed that bazedoxifene well tolerated. Patients Methods: We...
Waldenstrom's Macroglobulinemia (WM) is an IgM-secreting bone marrow (BM) lymphoma that preceded by asymptomatic state (AWM). To dissect tumor-intrinsic and immune mechanisms of progression, we perform single-cell RNA-sequencing on 294,206 BM tumor cells from 30 patients with AWM/WM, 26 Smoldering Myeloma, 23 healthy donors. Despite their early stage, AWM present extensive dysregulation, including in normal B cells, disease-specific hallmarks. Patient T NK show systemic hypo-responsiveness...
Background: Understanding the biological mechanisms underlying differential responses to immunotherapy is critical for advancing treatment strategies in metastatic melanoma. We analyzed single-nucleus RNA sequencing data from 66 melanoma samples, including 18 with matched spatial transcriptomics via MERFISH, across sites such as lymph nodes, colon, skin, lung, brain, and liver. Our study aimed identify tumor-intrinsic transcriptional programs their association durable clinical benefit....
Abstract Background: Immune checkpoint inhibitor (ICI) therapies have markedly improved the prognosis for patients with stage III & IV metastatic melanoma by prolonging progression-free and overall survival rates. However, variability in immune evasion resistance mechanisms presents significant challenges to clinical efficacy of ICIs. This project aims define drivers immunotherapy response employing advanced genomic, single-cell mRNA analyses, spatial profiling techniques on tissue...
Introduction: Multiple Myeloma (MM) is a bone marrow (BM) plasma cell malignancy that preceded by asymptomatic stages; Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering (SMM). Despite their early stage, patients with MGUS/SMM exhibit immune dysregulation. Understanding how dysregulation evolves tumor cells interact to promote progression MM may help predict intercept it. Methods: We performed single-cell RNA/BCR/TCR-seq (10X Genomics) on ∼6 million from 877 samples,...
Abstract Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have significantly improved the treatment of hormone receptor (HR+) positive breast cancer. Clinical trials demonstrated that addition CDK4/6i to endocrine therapy (ET) improves both progression-free and overall survival in patients with HR+ metastatic cancer (MBC). Nevertheless, their impact remains limited by eventual development resistance. While a number resistance mechanisms been identified using preclinical model systems...
Cytosine methylation regulates many biological processes such as gene expression, chromatin structure and chromosome stability. The whole genome bisulfite sequencing (WGBS) technique measures the level at each cytosine throughout genome. There are an increasing number of publicly available pipelines for analyzing WGBS data, reflecting choices read mapping algorithms well preprocessing postprocessing methods. We simulated single-end paired-end reads based on three experimental data sets,...
With the rapid accumulation of publicly available small RNA sequencing datasets, third-party meta-analysis across many datasets is becoming increasingly powerful. Although removing 3´ adapter an essential step for analysis, sequence information not always in metadata. The can be also erroneous even when it available. In this study, we developed DNApi, a lightweight Python software package that predicts de novo and provides user with cleansed sequences ready down stream analysis. Tested on...
Alternative splicing is the critical process in a single gene coding, which removes introns and joins exons, branchpoints are indicators for alternative splicing. Wet experiments have identified great number of human branchpoints, but many still unknown. In order to guide wet experiments, we develop computational methods predict branchpoints.Considering fact that an intron may multiple transform branchpoint prediction as multi-label learning problem, attempt sites from sequences. First,...
Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit previous studies of lenalidomide with or without dexamethasone. Triplets and quadruplet have been examined this same population. However, to date, none these the impact depth response on long-term outcomes participants treated lenalidomide-based therapy, whether use 20/2/20 model addition genomic alterations can further define population that would most from early intervention. Here, we present results phase II...
Abstract Tobacco use is the leading preventable cause of mortality in world. The limited number smoking cessation aids currently available are minimally effective, highlighting need for novel therapeutic interventions. We describe a genome-wide approach to identify potential candidates such Next-generation sequencing was performed using RNA isolated from habenulo-interpeduncular circuit male mice withdrawn chronic nicotine treatment. This plays central role withdrawal response....
An experiment was carried out to determine when fluctuations began in peripheral plasma androgen secretion male dogs. Seventeen linebred beagles produced at the authors' laboratory were used. They ranged from 12 102 weeks of age and divided into 13 groups 1 or 2 dogs each (a total 20 dog-times). Blood samples taken anterior vena brachiocephalica 2- 4-hr intervals beginning with 4:00 p.m. In them, androstenedione (A), 5α-dihydrotestosterone (DHT), testosterone (T) measured by RIA method. The...