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david piwnica-worms

Sandun Perera, David Piwnica-Worms, Mian M Alauddin
Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, has emerged as a therapeutic target in solid and hematologic tumors. Although several ALK inhibitors have gained recent approval for therapy, non-invasive indicators of target engagement or for use as predictive biomarkers in vivo are lacking. Therefore, we designed and synthesized a radiolabeled analogue of the ALK inhibitor ceritinib, [(18)F]fluoroethyl-ceritinib ([(18)F]-FEC), for use with positron emission tomography. We used two methods to synthesize [(18)F]-FEC...
March 2016: Journal of Labelled Compounds & Radiopharmaceuticals
Emily Powell, Jiansu Shao, Yuan Yuan, Hsiang-Chun Chen, Shirong Cai, Gloria V Echeverria, Nipun Mistry, Keith F Decker, Christopher Schlosberg, Kim-Anh Do, John R Edwards, Han Liang, David Piwnica-Worms, Helen Piwnica-Worms
BACKGROUND: Despite advances in early diagnosis and treatment of cancer patients, metastasis remains the major cause of mortality. TP53 is one of the most frequently mutated genes in human cancer, and these alterations can occur during the early stages of oncogenesis or as later events as tumors progress to more aggressive forms. Previous studies have suggested that p53 plays a role in cellular pathways that govern metastasis. To investigate how p53 deficiency contributes to late-stage tumor growth and metastasis, we developed paired isogenic patient-derived xenograft (PDX) models of triple-negative breast cancer (TNBC) differing only in p53 status for longitudinal analysis...
2016: Breast Cancer Research: BCR
Kelsey L Tinkum, Kristina M Stemler, Lynn S White, Andrew J Loza, Sabrina Jeter-Jones, Basia M Michalski, Catherine Kuzmicki, Robert Pless, Thaddeus S Stappenbeck, David Piwnica-Worms, Helen Piwnica-Worms
Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival...
December 22, 2015: Proceedings of the National Academy of Sciences of the United States of America
Maximillian Rosario, Bai Liu, Lin Kong, Lynne I Collins, Stephanie E Schneider, Xiaoyue Chen, Kaiping Han, Emily K Jeng, Peter R Rhode, Jeffrey W Leong, Timothy Schappe, Brea A Jewell, Catherine R Keppel, Keval Shah, Brian Hess, Rizwan Romee, David R Piwnica-Worms, Amanda F Cashen, Nancy L Bartlett, Hing C Wong, Todd A Fehniger
PURPOSE: Anti-CD20 monoclonal antibodies (mAb) are an important immunotherapy for B-cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. We hypothesized that ALT-803 would enhance anti-CD20 mAb-directed NK-cell responses and antibody-dependent cellular cytotoxicity (ADCC)...
February 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Rajarshi Sengupta, Amy Barone, Jayne Marasa, Sara Taylor, Erin Jackson, Nicole M Warrington, Shyam Rao, Albert H Kim, Jeffrey R Leonard, David Piwnica-Worms, Joshua B Rubin
Tumor growth is not solely a consequence of autonomous tumor cell properties. Rather, tumor cells act upon and are acted upon by their microenvironment. It is tumor tissue biology that ultimately determines tumor growth. Thus, we developed a compound library screen for agents that could block essential tumor-promoting effects of the glioblastoma (GBM) perivascular stem cell niche (PVN). We modeled the PVN with three-dimensional primary cultures of human brain microvascular endothelial cells in Matrigel. We previously demonstrated stimulated growth of GBM cells in this PVN model and used this to assay PVN function...
July 30, 2015: Oncotarget
Sonia A Melo, Linda B Luecke, Christoph Kahlert, Agustin F Fernandez, Seth T Gammon, Judith Kaye, Valerie S LeBleu, Elizabeth A Mittendorf, Juergen Weitz, Nuh Rahbari, Christoph Reissfelder, Christian Pilarsky, Mario F Fraga, David Piwnica-Worms, Raghu Kalluri
Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1(+) circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer...
July 9, 2015: Nature
David Piwnica-Worms
No abstract text is available yet for this article.
May 2015: Cancer Journal
Linda G Eissenberg, Michael P Rettig, Julie K Ritchey, Julie L Prior, Sally W Schwarz, Jennifer Frye, Brian S White, Robert S Fulton, Armin Ghobadi, Matthew L Cooper, Daniel R Couriel, Muhammad Esa Seegulam, David Piwnica-Worms, Farrokh Dehdashti, Kenneth Cornetta, John F DiPersio
Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man...
June 2015: Molecular Therapy: the Journal of the American Society of Gene Therapy
Reece J Goiffon, Sara C Martinez, David Piwnica-Worms
Myeloperoxidase (MPO) is a circulating cardiovascular disease (CVD) biomarker used to estimate clinical risk and patient prognosis. Current enzyme-linked immunosorbent assays (ELISA) for MPO concentration are costly and time-intensive. Here we report a novel bioluminescence assay, designated MPO activity on a polymer surface (MAPS), for measuring MPO activity in human plasma samples using the bioluminescent substrate L-012. The method delivers a result in under an hour and is resistant to confounding effects from endogenous MPO inhibitors...
2015: Nature Communications
Lulu Sun, Hiroyuki Miyoshi, Sofia Origanti, Timothy J Nice, Alexandra C Barger, Nicholas A Manieri, Leslie A Fogel, Anthony R French, David Piwnica-Worms, Helen Piwnica-Worms, Herbert W Virgin, Deborah J Lenschow, Thaddeus S Stappenbeck
The host immune system functions constantly to maintain chronic commensal and pathogenic organisms in check. The consequences of these immune responses on host physiology are as yet unexplored, and may have long-term implications in health and disease. We show that chronic viral infection increases epithelial turnover in multiple tissues, and the antiviral cytokines type I interferons (IFNs) mediate this response. Using a murine model with persistently elevated type I IFNs in the absence of exogenous viral infection, the Irgm1(-/-) mouse, we demonstrate that type I IFNs act through nonepithelial cells, including macrophages, to promote increased epithelial turnover and wound repair...
January 14, 2015: Cell Host & Microbe
Linda G Eissenberg, Michael Rettig, Farrokh Dehdashti, David Piwnica-Worms, John F DiPersio
Clinical trials increasingly incorporate suicide genes either as direct lytic agents for tumors or as safety switches in therapies based on genetically modified cells. Suicide genes can also be used as non-invasive reporters to monitor the biological consequences of administering genetically modified cells to patients and gather information relevant to patient safety. These genes can monitor therapeutic outcomes addressable by early clinical intervention. As an example, our recent clinical trial used (18)F-9-(4-fluoro-3-hydroxymethylbutyl)guanine ((18)FHBG) and positron emission tomography (PET)/CT scans to follow T cells transduced with herpes simplex virus thymidine kinase after administration to patients...
2014: Frontiers in Pharmacology
Vijay Sharma, Jothilingam Sivapackiam, Scott E Harpstrite, Julie L Prior, Hannah Gu, Nigam P Rath, David Piwnica-Worms
Lipophilic cationic technetium-99m-complexes are widely used for myocardial perfusion imaging (MPI). However, inherent uncertainties in the supply chain of molybdenum-99, the parent isotope required for manufacturing 99Mo/99mTc generators, intensifies the need for discovery of novel MPI agents incorporating alternative radionuclides. Recently, germanium/gallium (Ge/Ga) generators capable of producing high quality 68Ga, an isotope with excellent emission characteristics for clinical PET imaging, have emerged...
2014: PloS One
Brandon A Kocher, Lynn S White, David Piwnica-Worms
UNLABELLED: Death-associated protein kinase (DAPK3) is a serine/threonine kinase involved in various signaling pathways important to tissue homeostasis and mammalian biology. Considered to be a putative tumor suppressor, the molecular mechanism by which DAPK3 exerts its suppressive function is not fully understood and the field lacks an appropriate mouse model. To address these gaps, an in vitro three-dimensional tumorigenesis model was used and a constitutive DAPK3-knockout mouse was generated...
February 2015: Molecular Cancer Research: MCR
Amy Barone, Rajarshi Sengupta, Nicole M Warrington, Erin Smith, Patrick Y Wen, Rolf A Brekken, Barbara Romagnoli, Garry Douglas, Eric Chevalier, Michael P Bauer, Klaus Dembowsky, David Piwnica-Worms, Joshua B Rubin
Glioblastoma recurrence involves the persistence of a subpopulation of cells with enhanced tumor-initiating capacity (TIC) that reside within the perivascular space, or niche (PVN). Anti-angiogenic therapies may prevent the formation of new PVN but have not prevented recurrence in clinical trials, suggesting they cannot abrogate TIC activity. We hypothesized that combining anti-angiogenic therapy with blockade of PVN function would have superior anti-tumor activity. We tested this hypothesis in an established intracranial xenograft model of GBM using a monoclonal antibody specific for murine and human VEGF (mcr84) and a Protein Epitope Mimetic (PEM) CXCR4 antagonist, POL5551...
October 30, 2014: Oncotarget
Michael D Brooks, Erin Jackson, Nicole M Warrington, Jingqin Luo, Jason T Forys, Sara Taylor, Diane D Mao, Jeffrey R Leonard, Albert H Kim, David Piwnica-Worms, Robi D Mitra, Joshua B Rubin
Cell-cell interactions between tumor cells and constituents of their microenvironment are critical determinants of tumor tissue biology and therapeutic responses. Interactions between glioblastoma (GBM) cells and endothelial cells (ECs) establish a purported cancer stem cell niche. We hypothesized that genes regulated by these interactions would be important, particularly as therapeutic targets. Using a computational approach, we deconvoluted expression data from a mixed physical co-culture of GBM cells and ECs and identified a previously undescribed upregulation of the cAMP specific phosphodiesterase PDE7B in GBM cells in response to direct contact with ECs...
2014: PloS One
Andrew Nickless, Erin Jackson, Jayne Marasa, Patrick Nugent, Robert W Mercer, David Piwnica-Worms, Zhongsheng You
The nonsense-mediated mRNA decay (NMD) pathway selectively eliminates aberrant transcripts containing premature translation termination codons and regulates the levels of a number of physiological mRNAs. NMD modulates the clinical outcome of a variety of human diseases, including cancer and many genetic disorders, and may represent a target for therapeutic intervention. Here, we have developed a new multicolored bioluminescence-based reporter system that can specifically and effectively assay NMD in live human cells...
August 2014: Nature Medicine
Harvey Hensley, Karthik Devarajan, James R Johnson, David Piwnica-Worms, Andrew K Godwin, Margaret von Mehren, Lori Rink
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the US. The majority (~85%) of GISTs possess gain-of-function mutations in KIT or PDGFRA, causing constitutive activation of the kinase receptor. GIST management has been transformed by the identification of tumor driver mutations leading to unprecedented disease control of advanced GIST with the introduction of imatinib mesylate (IM). Despite IM's efficacy, most patients experience primary and/or secondary resistance within 2 y of treatment...
July 2014: Cancer Biology & Therapy
Adnan Elhammali, Joseph E Ippolito, Lynne Collins, Jan Crowley, Jayne Marasa, David Piwnica-Worms
UNLABELLED: Recently identified isocitrate dehydrogenase (IDH) mutations lead to the production of 2-hydroxyglutarate (2HG), an oncometabolite aberrantly elevated in selected cancers. We developed a facile and inexpensive fluorimetric microplate assay for the quantitation of 2HG and performed an unbiased small-molecule screen in live cells to identify compounds capable of perturbing 2HG production. Zaprinast, a phosphodiesterase 5 inhibitor, was identified as an efficacious modulator of 2HG production and confirmed to lower 2HG levels in vivo...
July 2014: Cancer Discovery
Han Liu, Todd D Westergard, Amanda Cashen, David R Piwnica-Worms, Lori Kunkle, Ravi Vij, Can G Pham, John DiPersio, Emily H Cheng, James J Hsieh
Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by caspase-8 and upregulation of p27, respectively...
April 14, 2014: Cancer Cell
Elise Alspach, Kevin C Flanagan, Xianmin Luo, Megan K Ruhland, Hui Huang, Ermira Pazolli, Maureen J Donlin, Timothy Marsh, David Piwnica-Worms, Joseph Monahan, Deborah V Novack, Sandra S McAllister, Sheila A Stewart
UNLABELLED: Neoplastic cells rely on the tumor microenvironment (TME) for survival and progression factors. Indeed, senescent and cancer-associated fibroblasts (CAF) express factors that promote tumorigenesis that are collectively referred to as the senescence-associated secretory phenotype (SASP). Despite their importance in tumorigenesis, the mechanisms that control TME-derived factor expression remain poorly understood. Here, we address a key unanswered question: how the SASP is sustained in senescent fibroblasts and CAFs...
June 2014: Cancer Discovery
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