scholarly journals COMP-14. MOLECULAR PROFILING AND CELLULAR DECONVOLUTION OF GLIOBLASTOMA BRAIN TUMORS USING CHROMATIN RUN-ON AND SEQUENCING

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi64-vi64
Author(s):  
Tinyi Chu ◽  
Edward Rice ◽  
Hans Salamanca ◽  
Zhong Wang ◽  
Sharon Longo ◽  
...  
Keyword(s):  
New York ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Medical Center ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Specific Cell ◽  
State University ◽  
Cellular Composition ◽  
Cell Type Specific

Abstract Glioblastoma is among the most heterogeneous malignancies, making difficult the identification of clinically-relevant interactions between tumor cells and their supportive tumor microenvironment. Moreover, whether the heterogeneity of tumor cells is reflected by changes in the composition of the tumor microenvironment remains poorly defined. To further understand the cellular heterogeneity of GBM, we used our previously validated chromatin run-on and sequencing (ChRO-seq) method to analyze 61 GBMs from a retrospective cohort of patients banked at the State University of New York (Upstate Medical Center) between 1987 and 2007 (characteristics: Male:Female ratio= 2:1; median age at diagnosis= 59 years; median KPS=80; median overall survival= 343 days). We developed a new Bayesian statistical model that uses transcription at cell-type specific enhancers to identify the cellular composition of the tumor microenvironment in each patient. We validated our tool using simulations and scATAC-seq data from the same specimens, showing large improvements in sensitivity and accuracy compared with CYBERSORT. Integrative analysis of cellular composition and matching clinical data revealed correlations between the presence of specific cell types in the tumor mass and clinical variables. Finally, our analysis allowed us to identify transcription factors (e.g., NF-kB, C/EBPB) that control gene expression changes, revealing which cell types are controlled by each transcription factor in the GBM microenvironment. Our study uncovers new insights into the cellular heterogeneity of GBM and its impact on clinical progression and survival.

scholarly journals Single-cell transcriptome analysis of tumor and stromal compartments of pancreatic ductal adenocarcinoma primary tumors and metastatic lesions

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Lin ◽  
Pawan Noel ◽  
Erkut H. Borazanci ◽  
Jeeyun Lee ◽  
Albert Amini ◽  
...  
Keyword(s):  
Single Cell ◽  
Tumor Cells ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Cellular Composition ◽  
Primary Tumors ◽  
Metastatic Lesions ◽  
Tumor Tissues ◽  
Cell Type Specific ◽  
Different Cell Types

Abstract Background Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells but also a microenvironment with which the tumor cells constantly interact. Detailed characterization of the cellular composition of the tumor microenvironment is critical to the understanding of the disease and treatment of the patient. Single-cell transcriptomics has been used to study the cellular composition of different solid tumor types including PDAC. However, almost all of those studies used primary tumor tissues. Methods In this study, we employed a single-cell RNA sequencing technology to profile the transcriptomes of individual cells from dissociated primary tumors or metastatic biopsies obtained from patients with PDAC. Unsupervised clustering analysis as well as a new supervised classification algorithm, SuperCT, was used to identify the different cell types within the tumor tissues. The expression signatures of the different cell types were then compared between primary tumors and metastatic biopsies. The expressions of the cell type-specific signature genes were also correlated with patient survival using public datasets. Results Our single-cell RNA sequencing analysis revealed distinct cell types in primary and metastatic PDAC tissues including tumor cells, endothelial cells, cancer-associated fibroblasts (CAFs), and immune cells. The cancer cells showed high inter-patient heterogeneity, whereas the stromal cells were more homogenous across patients. Immune infiltration varies significantly from patient to patient with majority of the immune cells being macrophages and exhausted lymphocytes. We found that the tumor cellular composition was an important factor in defining the PDAC subtypes. Furthermore, the expression levels of cell type-specific markers for EMT+ cancer cells, activated CAFs, and endothelial cells significantly associated with patient survival. Conclusions Taken together, our work identifies significant heterogeneity in cellular compositions of PDAC tumors and between primary tumors and metastatic lesions. Furthermore, the cellular composition was an important factor in defining PDAC subtypes and significantly correlated with patient outcome. These findings provide valuable insights on the PDAC microenvironment and could potentially inform the management of PDAC patients.

scholarly journals Single nucleus analysis of the chromatin landscape in mouse forebrain development

2017 ◽  
Author(s):  
Sebastian Preissl ◽  
Rongxin Fang ◽  
Yuan Zhao ◽  
Ramya Raviram ◽  
Yanxiao Zhang ◽  
...  
Keyword(s):  
Neuronal Cell ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Regulatory Sequences ◽  
Specific Cell ◽  
Cell Type ◽  
Tissue Samples ◽  
Forebrain Development ◽  
Cell Type Specific ◽  
Accessible Chromatin

ABSTRACTGenome-wide analysis of chromatin accessibility in primary tissues has uncovered millions of candidate regulatory sequences in the human and mouse genomes1–4. However, the heterogeneity of biological samples used in previous studies has prevented a precise understanding of the dynamic chromatin landscape in specific cell types. Here, we show that analysis of the transposase-accessible-chromatin in single nuclei isolated from frozen tissue samples can resolve cellular heterogeneity and delineate transcriptional regulatory sequences in the constituent cell types. Our strategy is based on a combinatorial barcoding assisted single cell assay for transposase-accessible chromatin5 and is optimized for nuclei from flash-frozen primary tissue samples (snATAC-seq). We used this method to examine the mouse forebrain at seven development stages and in adults. From snATAC-seq profiles of more than 15,000 high quality nuclei, we identify 20 distinct cell populations corresponding to major neuronal and non-neuronal cell-types in foetal and adult forebrains. We further define cell-type specific cis regulatory sequences and infer potential master transcriptional regulators of each cell population. Our results demonstrate the feasibility of a general approach for identifying cell-type-specific cis regulatory sequences in heterogeneous tissue samples, and provide a rich resource for understanding forebrain development in mammals.

scholarly journals Identifying the Landscape of Intratumoral Microbes via a Single Cell Transcriptomic Analysis

2020 ◽  
Author(s):  
Welles Robinson ◽  
Fiorella Schischlik ◽  
E. Michael Gertz ◽  
Alejandro A. Schäffer ◽  
Eytan Ruppin
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Tumor Cells ◽  
Malignant Tumors ◽  
Cell Types ◽  
Specific Cell ◽  
Cancer Sample ◽  
Bona Fide ◽  
Cell Type Specific ◽  
Tumor Expression

AbstractMicrobial taxa that are differentially abundant between cell types are likely to be intracellular. Here we describe a new computational pipeline called CSI-Microbes (computational identification of Cell type Specific Intracellular Microbes) that aims to identify such putative intracellular species from single cell RNA-seq data in a given tumor sample. CSI-microbes also includes additional steps that can be applied to filter out microbial contaminants from the bona fide microbial residents of cells in the patients. We first test and validate CSI-microbes on a dataset of immune cells deliberately infected with Salmonella. We then apply CSI-microbes to identify intracellular microbes in breast cancer and melanoma. We identify Streptomyces as differentially abundant in the tumor cells of one breast cancer sample. We further identify three bacterial genera and four fungal genera that are differentially abundant and hence likely to be intracellular in the tumor cells in melanoma samples. No cell type specific bacteria were identified in our analysis of brain tumor samples. In sum, CSI-Microbes offers a new way to identify likely intracellular microbes living within specific cell populations in malignant tumors, markedly extending upon previous studies aimed at inferring microbial abundance from bulk tumor expression data.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

Salivary Adenocarcinoma, Not Otherwise Specified: A Collection of Orphans

2004 ◽  
Vol 128 (12) ◽  
pp. 1385-1394 ◽  
Author(s):  
Jiang Li ◽  
Beverly Yiyao Wang ◽  
Magalie Nelson ◽  
Lei Li ◽  
Yuhua Hu ◽  
...  
Keyword(s):  
New York ◽  
Parotid Gland ◽  
Medical Center ◽  
Cell Types ◽  
Carcinoma Ex Pleomorphic Adenoma ◽  
High Grade ◽  
Not Otherwise Specified ◽  
Architectural Patterns ◽  
Social Security Death Index ◽  
Disease Free

Abstract Context.—Salivary adenocarcinoma, not otherwise specified, refers to gland-forming malignancies that do not satisfy the diagnostic requirements of other “named” malignancies. Objective.—To review the features of 11 patients with salivary adenocarcinoma, not otherwise specified. To also compare the diagnostic frequencies of 2 databases, one from the Mount Sinai Medical Center (New York, NY), the other from the Shanghai Ninth People's Hospital (Shanghai, People's Republic of China). Design.—Pathology files were searched to establish a database of salivary tumors. All available hematoxylin-eosin– stained slides from the resection specimens diagnosed as either adenocarcinoma, not otherwise specified, or with vague or unusual diagnoses (eg, probable carcinoma-ex-pleomorphic adenoma) were pulled from our files and reexamined. Dates of death were confirmed with the Social Security Death Index. Results.—We identified 11 patients with salivary adenocarcinoma, not otherwise specified, ranging in age from 49 to 80 years (median, 67 years), with a male preponderance. The parotid gland was the most common site of tumor origin. Ten of these tumors were high grade, and 1 was intermediate grade. Two patients were diagnosed at stage II, while the remaining patients were diagnosed at stage III or IV. Histologically, all tumors were invasive, with variable glandular differentiation and diverse architectural patterns. The diverse cytologic tumor cell types included cuboidal, columnar, epithelioid, polygonal, oncocytoid, clear, melanoma-like, mucinous, sebaceous, and plasmacytoid. Four patients died after 4 to 27 months (mean, 15 months), 1 patient is alive with disease at 12 months, 1 patient is disease-free at 14 years, and 3 patients remain disease-free after short follow-ups (10, 12, and 12 months). One patient had surgery just recently, and the remaining patient had no follow-up. Conclusions.—Salivary adenocarcinoma, not otherwise specified, is an aggressive, high-grade malignancy, with a predisposition for the parotid gland. It is characterized by cytologic and architectural diversity and an invasive growth pattern.

NEWS AND ANNOUNCEMENTS

PEDIATRICS ◽  
1949 ◽  
Vol 4 (1) ◽  
pp. 142-144
Keyword(s):  
New York ◽  
Medical Center ◽  
Associate Professor ◽  
Johns Hopkins Hospital ◽  
State University ◽  
New York University ◽  
Louisiana State University ◽  
School Of Medicine ◽  
National Foundation ◽  
Infantile Paralysis

The National Foundation for Infantile Paralysis has awarded postgraduate fellowships in the fields of scientific research, physical medicine and public health. Three of the new fellows will devote their time to research projects in the field of pediatrics. Dr. John J. Osborn, of Larchmont, N.Y., has already begun his project at New York University—Bellevue Medical Center under Drs. L. Emmett Holt, Jr., Professor of Pediatrics, and Colin MacLeod, Professor of Microbiology; Dr. Paul Harold Hardy, Jr., of Baltimore, Md., and Dr. David I. Schrum, of Houston, Texas, will start their work July 1, respectively, at Johns Hopkins Hospital, under Drs. Francis F. Schwentker, Pediatrician-in-Chief, and Horace L. Hodes, Associate Professor of Pediatrics; and at Louisiana State University School of Medicine under Drs. Myron E. Wegman, Professor of Pediatrics, and G. John Buddingh, Professor of Microbiology.

Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor-Mesenchymal Stem Cell Interaction for therapeutic interventions

2021 ◽  
Vol 22 ◽  
Author(s):  
Soheila Montazersaheb ◽  
Ezzatollah Fathi ◽  
Ayoub Mamandi ◽  
Raheleh Farahzadi ◽  
Hamid Reza Heidari
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Cell Interaction ◽  
Therapeutic Interventions ◽  
Tumorigenic Potential ◽  
Different Types

: Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

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