1,721,077 research outputs found
Abstract 3196: Genetic and pharmacologic approaches to overcome epithelial to mesenchymal mediated chemoresistance in breast cancer
No full textAbstract
Development of resistance to conventional chemotherapy remains a major barrier to effective treatment of breast cancer. We and others have recently demonstrated in breast and pancreatic cancer models that epithelial-mesenchymal transition (EMT) may not be a critical mediator of cancer metastasis, however, it contributes to cancer drug resistance (Fischer et al. Nature 2015; Zeng et al Nature 2015). Importantly, blocking EMT through miR-200 family abrogated chemoresistance, indicating potentials for clinical translation. Using our novel EMT lineage tracing system, we have performed both genetic (CRISPR/Cas9 mediated genome-wide targeted mutagenesis) and pharmacological (high-throughput small molecule libraries) screens, to identify potential candidates to overcome EMT-mediated chemoresistance in breast cancer metastasis. The identified molecules provide not only novel mechanistic insights but also attractive anti-metastatic strategies for breast cancer treatment and the design of future clinical trials.
Citation Format: Michael J. Crowley, Nasser Altorki, Vivek Mittal, Dingcheng Gao. Genetic and pharmacologic approaches to overcome epithelial to mesenchymal mediated chemoresistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3196. doi:10.1158/1538-7445.AM2017-3196</jats:p
Abstract 1670: Identification and characterization of novel mediators of tumor-induced T-cell dysfunction
No full textAbstract
Immunotherapies targeting T-cell functionality have been shown to have efficacy in numerous cancers, including non-small cell lung cancer (NSCLC). However, treatment with currently available therapeutics, such as anti-PD-1 and anti-CTLA-4, induce responses only in a subset of patients. This raises the possibility that numerous other effectors of T-cell dysfunction remain to be elucidated. To evaluate possible novel mediators of T-cell dysfunction, we isolated CD8+ T-cells from orthotopic KrasG12D/p53-/- murine lung adenocarcinomas (HKP-1) that exhibited either stable or progressive disease as a function of tumor growth. RNAseq analysis revealed increased expression of several genes including Tim3, PD-1, Lag3, 2B4, and CISH, and decreased expression of GzmB and Eomes in CD8+ T-cells isolated from progressive tumors indicative of a dysfunctional state, as well as multiple novel genes not previously associated with T-cell dysfunction. To explore the functional role of the novel candidate genes, we have developed in vitro and in vivo assays leveraging Ova and GFP overexpression in our HKP-1 cell line (KP1-Ova-GFP). We have begun to target these unique set of candidate genes in tumor-specific T-cells associated with dysfunction through innovative RNAi/shRNA and adoptive transfer approaches to facilitate therapeutic reprogramming and enhanced T-cell-mediated immunity in lung cancer. We expect to provide novel strategies for designing rational immunotherapies targeting dysfunctional tumor-specific CD8+ T-cells to generate durable anti-tumor immune responses for the treatment of lung adenocarcinoma.
Citation Format: Geoffrey J. Markowitz, Mary Philip, Andrea Schietinger, Vivek Mittal. Identification and characterization of novel mediators of tumor-induced T-cell dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1670. doi:10.1158/1538-7445.AM2017-1670</jats:p
Abstract 4944: Modeling tumor dormancy by using EMT lineage tracing under chemotherapy
No full textAbstract
Tumor dormancy and recurrence after initial effective treatment arose as one of most challenging questions in cancer research. Up to now, there is still no established animal model of tumor dormancy, which significantly hurdles our exploration in this field. In an effort to trace the phenotypic changes of metastatic tumor cells in vivo, we found that the dormant tumor cells were derived through a mechanism of epithelial to mesenchymal transition (EMT). We established an EMT lineage tracing model in triple transgenic mice (Tri-MMTV) carrying Fsp1-cre, Rosa26-RFP-GFP and MMTV-PyMT alleles. Tumor cells from these mice are able to switch their fluorescent marker from RFP to GFP due to the specific activation of CRE recombinase during the EMT process. Using this EMT lineage tracing model, we confirmed that within a predominantly epithelial primary tumor, a small portion of tumor cells undergo EMT. Strikingly, lung metastases were mainly derived from non-EMT tumor cells maintaining their epithelial phenotype. However, under chemotherapy condition, EMT cells significantly contributed to recurrent lung metastasis. The EMT tumor cells survived the chemotherapy due to reduced proliferation and apoptotic tolerance, which are common characters of dormant tumor cells. More interestingly, the GFP+ EMT tumor cells reversed back to epithelial phenotype through mesenchymal to epithelial transition (MET) and formed recurrent metastatic lesions in the lung. These results suggest that our EMT lineage tracing model may provide a unique tool to study tumor dormancy and recurrence. The EMT process may represent a major mechanism for tumor dormancy under chemotherapy condition, while MET is a driving mechanism for tumor recurrence.
Citation Format: Jay Lopez, Robert Bednarczyk, Nasser Altorki, Vivek Mittal, Dingcheng Gao. Modeling tumor dormancy by using EMT lineage tracing under chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4944. doi:10.1158/1538-7445.AM2017-4944</jats:p
Elevation of Seprase Expression and Promotion of an Invasive Phenotype by Collagenous Matrices in Ovarian Tumor Cells
No full textStony Brook University Libraries.
SBU Graduate School in Genetics.
Lawrence Martin (Dean of Graduate School), Wen-Tien Chen – Dissertation Advisor
Professor, Department of Medicine, Howard Crawford – Chairperson of Defense
Assistant Professor, Department of Pharmacology, Vivek Mittal
Assistant Professor, Cold Spring Harbor Laboratory, Stanley Zucker
Professor, Department of Medicine, Michael Pearl
Associate Professor, Stony Brook University School of Medicine
Department of Obstetrics and Gynecology
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Derivation of the Lineage and Function in Tumor Angiogenesis of Bone Marrow-Derived Endothelial Cells
No full textStony Brook University Libraries.
SBU Graduate School in genetics.
Lawrence Martin (Dean of Graduate School), Dr. Vivek Mittal - Dissertation Advisor
Assistant Professor, Cold Spring Harbor Laboratories, Dr. Scott Powers – Chairperson of Defense
Associate Professor, Cold Spring Harbor Laboratories, Dr. Alea Mills
Associate Professor, Cold Spring Harbor Laboratories, Dr. Robert Lucito
Assistant Professor, Cold Spring Harbor Laboratories, Dr. Robert Benezra
Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center
RNA Interference Screens as a Tool for Discovering Gene Function
No full textStony Brook University Libraries.
SBU Graduate School in Genetics.
Lawrence Martin (Dean of Graduate School), Greg Hannon-Dissertation Advisor
Professor, Cold Spring Harbor Laboratory, Genetics Program, Stony Brook University, Scott Lowe- Chairperson of Defense
Professor, Cold Spring Harbor Laboratory, Genetics Program, Stony Brook University, Scott Powers
Associate Professor, Cold Spring Harbor Laboratory,Genetics Program, Stony Brook University, Vivek Mittal
Assistant Professor, Cold Spring Harbor Laboratory,
Genetics Program, Stony Brook University, Mike Hemann
Assistant Professor, Massachusetts Institute of Technology
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