1,720,964 research outputs found
Aberrant Glycosylation Promotes Lung Cancer Metastasis through Adhesion to Galectins in the Metastatic Niche
Get PDFMetastasis is the leading cause of cancer-associated deaths. Although dissemination of tumor cells likely occurs early in tumorigenesis, the constituents of the microenvironment play essential rate-limiting roles in determining whether these cells will form clinically relevant tumors. Recent studies have uncovered many molecular factors that contribute to the establishment of a protumorigenic metastatic niche. Here, we demonstrate that galectin-3, whose expression has clinical associations with advanced malignancy and poor outcome, contributes to metastatic niche formation by binding to carbohydrates on metastatic cells. We show that galectin-3 is expressed early during tumorigenesis by both CD11b[superscript +]Gr-1[superscript + ]and CD11b[superscript +]Ly-6C[superscript hi] leukocytes. Tumors mobilize these myeloid populations through secretion of soluble factors, including IL6. We find that metastatic cancer cells exhibit elevated presentation of the oncofetal galectin-3 carbohydrate ligand, the Thomsen–Friedenreich antigen, on their surfaces as a result of altered C2GnT2 and St6GalNAc4 glycosyltransferase activity that inhibits further glycosylation of this carbohydrate motif and promotes metastasis.National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)Ludwig Center for Molecular Oncology (Graduate Fellowship)Stand Up To Cancer (Translational Research Grant SU2C-AACR-DT0309)Howard Hughes Medical InstituteDavid H. Koch Institute for Integrative Cancer Research at MIT (CTC Project
Engineered approaches to querying the microenvironment of cancer metastasis
No full textThesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (pages 165-191).Cancer metastasis is the underlying mechanism of 90% of cancer-related deaths, yet few therapeutics exist that directly target it. Part of this scarcity is attributable to a general lack of knowledge with regards to the underlying mechanisms that mediate traversal of the sequential steps required for malignant dissemination. Recently, biologists and clinicians have gained appreciation for the role that the microenvironment plays in promoting or inhibiting metastasis. This thesis sought to expand our understanding of the involvement of extracellular matrix (ECM) interactions during metastasis through the development and use of a novel ECM microarray screening platform. This platform consists of 768 unique single and pairwise combinations spotted in quintuplicate as 150pm features onto polyacrylamide coated glass slides. Cells are seeded onto these arrays and queried for their adhesion, proliferation, and marker expression using automated fluorescence microscopy in conjunction with automated cell counting and image analysis. In the first part of this thesis, this platform is used in conjunction with a mouse model of lung adenocarcinoma metastasis (KraLSL-G12D/+; p53flox/flOx) where distinct stages of metastasis are defined by characteristic cell lines derived from these mice. Hierarchical clustering of the adhesion profiles revealed conserved alterations in ECM adhesion signatures that correlate with metastasis. Additionally, they identify a role for combinations of ECM composed of fibronectin with any of galectin-3, galectin-8, or laminin. In the next part of this thesis, these molecules are investigated for their involvement in mice bearing the autochthonous tumors or in humans with lung cancer. The integrin Q3p1 is found to mediate adhesion to the fibronectin-galectin combinations in vitro and promote metastasis in vivo. Subsequently, this thesis investigates the role of carbohydrate-mediated interactions in promoting galectin adhesion. The oncofetal T-Antigen glycan motif is found to be increasingly expressed on cells with elevated metastatic potential, and is found to be the result of aberrant glycosyltransferase activity. Finally the role of galectin-3 in the metastatic niche and its presentation on bone marrow derived cells recruited to tumors is investigated. The results of this thesis suggest a role for novel phenotypic screening platforms in investigating regulation of the cancer microenvironment. Additionally, we extend these studies to the role of ECM in the epithelial-mesenchymal transition (EMT) and lay the groundwork for the development of nanoparticle-based therapeutics targeting the conserved glycan-ECM interactions. Such technologies will likely prove useful to study other disease mechanisms as well as identify novel biomarkers.by Nathan E. Reticker-Flynn.Ph. D. in Biomedical Engineerin
Design and fabrication of microfluidic valves using poly(N-isopropylacrylamide)
Get PDFThesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2008.In title on title page, "N" appears as italic.Includes bibliographical references (leaves [181]-185).A compact printable microfluidic valve composed of poly(N-isopropylacrylamide) has been designed, fabricated, and tested. The design of the valve consists of filling microwells with poly(NIPAAm) and bonding PDMS channels above them. This filling is achieved using thermal inkjet printing of a prepolymer solution and subsequent polymerization using UV irradiation. When the gel is swollen, it blocks flow from passing through the channel. Upon heating, the gel shrinks and allows flow in the channel. Poly(NIPAAm) is a thermosensitive hydrogel that exhibits an inverse temperature expansion behavior. When the temperature of the swollen gel is raised above a lower critical solution temperature (LCST) of approximately 32°C, the gel becomes hydrophobic. This change in hydrophobicity results in expulsion of the water molecules from within the hydrogel network, thus resulting in shrinking of the gel. By adding magnetic nanoparticles to the hydrogel and exposing it to an external magnetic field, volumetric change of the hydrogel can be locally and externally induced. External heating of the magnetic nanoparticles, however, is not included in this thesis. In order to ensure shrinkage that is predictable in favor of flow control, microanchor structures have been designed, modeled, and fabricated at the bottom of the microwells. These microanchors hold the poly(NIPAAm) at the bottom of the plug such that the shrinkage of the gel always acts to open the flow channel at the top yielding a minimum pressure drop. Design decisions were made using the principles of Axiomatic Design in order to minimize the response time and pressure drops in the valve. Modeling of the underlying mechanisms is described along with the application of these models to the final device. Results of fabrication suggest the feasibility while also eliciting possible improvements to the fabrication process.(cont.) Profilometry measurements of the swollen and shrunken valves reveal flow control operation as intended. Additionally, design and modeling of magnetic heating using mixed-in nanoparticles is presented. A fabrication plan designed to include this mechanism is proposed.by Nathan Edward Reticker-Flynn.S.M
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
A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis
No full textExtracellular matrix interactions have essential roles in normal physiology and many pathological processes. Although the importance of extracellular matrix interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Here we report a novel-screening platform capable of measuring phenotypic responses to combinations of extracellular matrix molecules. Using a genetic mouse model of lung adenocarcinoma, we measure the extracellular matrix-dependent adhesion of tumour-derived cells. Hierarchical clustering of the adhesion profiles differentiates metastatic cell lines from primary tumour lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8 or laminin. We show that these molecules correlate with human disease and that their interactions are mediated in part by α3β1 integrin. Thus, our platform allowed us to interrogate interactions between metastatic cells and their microenvironments, and identified extracellular matrix and integrin interactions that could serve as therapeutic targets.National Institutes of Health (U.S.) (Grant K99-CA151968)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service AwardStand Up To Cancer (SU2C/AACR)David H. Koch Institute for Integrative Cancer Research at MIT (CTC Project)Harvard Stem Cell Institute (SG-0046-08-00)National Cancer Center (Postdoctoral Fellowship)National Cancer Institute (U.S.) (U54CA126515)National Cancer Institute (U.S.) (U54CA112967)Howard Hughes Medical InstituteMassachusetts Institute of Technology. Ludwig Center for Molecular Oncolog
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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