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https://www.readbyqxmd.com/read/29159964/blocking-antibodies-induced-by-allergen-specific-immunotherapy-ameliorate-allergic-airway-disease-in-a-human-mouse-chimeric-model
#1
Caterina Vizzardelli, Miriam Gindl, Simone Roos, Christian Möbs, Birgit Nagl, Felix Zimmann, Veronika Sexl, Lukas Kenner, Alina Neunkirchner, Gerhard J Zlabinger, Winfried F Pickl, Wolfgang Pfützner, Barbara Bohle
BACKGROUND: Allergen-specific immunotherapy (AIT) induces specific blocking antibodies (Ab) which are claimed to prevent IgE-mediated reactions to allergens. Additionally, AIT modulates cellular responses to allergens, e.g. by desensitizing effector cells, inducing regulatory T and B lymphocytes and immune deviation. It is still enigmatic which of these mechanisms mediate(s) clinical tolerance. We sought to address the role of AIT-induced blocking Ab separately from cellular responses in a chimeric human/mouse model of respiratory allergy...
November 21, 2017: Allergy
https://www.readbyqxmd.com/read/29146734/humanized-mice-in-studying-efficacy-and-mechanisms-of-pd-1-targeted-cancer-immunotherapy
#2
Minan Wang, Li-Chin Yao, Mingshan Cheng, Danying Cai, Jan Martinek, Chong-Xian Pan, Wei Shi, Ai-Hong Ma, Ralph W De Vere White, Susan Airhart, Edison T Liu, Jacques Banchereau, Michael A Brehm, Dale L Greiner, Leonard D Shultz, Karolina Palucka, James G Keck
Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, non-obese diabetic (NOD).Cg-Prkdc(scid)IL2rg(tm1Wjl) /Sz (null; NSG) mice were transplanted with human (h)CD34(+) hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; nonsmall cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX)...
November 16, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29143813/ship1-but-not-an-aml-derived-ship1-mutant-suppresses-myeloid-leukemia-growth-in-a-xenotransplantation-mouse-model
#3
M Täger, S Horn, E Latuske, P Ehm, M Schaks, M Nalaskowski, B Fehse, W Fiedler, C Stocking, J Wellbrock, M Jücker
Constitutive activation of the PI3K/AKT signaling pathway is found in ~50-70% of AML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP1) is a negative regulator of PI3K/AKT signaling in hematopoietic cells. SHIP1 knockout mice develop a myeloproliferative syndrome and concomitant deletion of SHIP1 and the tumor suppressor PTEN leads to the development of lethal B-cell lymphomas. In the study presented here, we investigated the role of SHIP1 as a tumor suppressor in myeloid leukemia cells in an in vivo xenograft transplantation model...
November 16, 2017: Gene Therapy
https://www.readbyqxmd.com/read/29142217/fbxo32-promotes-microenvironment-underlying-epithelial-mesenchymal-transition-via-ctbp1-during-tumour-metastasis-and-brain-development
#4
Sanjeeb Kumar Sahu, Neha Tiwari, Abhijeet Pataskar, Yuan Zhuang, Marina Borisova, Mustafa Diken, Susanne Strand, Petra Beli, Vijay K Tiwari
The set of events that convert adherent epithelial cells into migratory cells are collectively known as epithelial-mesenchymal transition (EMT). EMT is involved during development, for example, in triggering neural crest migration, and in pathogenesis such as metastasis. Here we discover FBXO32, an E3 ubiquitin ligase, to be critical for hallmark gene expression and phenotypic changes underlying EMT. Interestingly, FBXO32 directly ubiquitinates CtBP1, which is required for its stability and nuclear retention...
November 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/29137359/granulysin-expressed-in-a-humanized-mouse-model-induces-apoptotic-cell-death-and-suppresses-tumorigenicity
#5
Ya-Wen Hsiao, Tsung-Ching Lai, Yu-Hsiang Lin, Chia-Yi Su, Jih-Jong Lee, Albert Taiching Liao, Yuan-Feng Lin, Shu-Chen Hsieh, Alexander T H Wu, Michael Hsiao
Granulysin (GNLY) is a cytolytic and proinflammatory protein expressed in activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Conventional mouse models cannot adequately address the triggering mechanism and immunopathological pathways in GNLY-associated diseases due to lack of the GNLY gene in the mouse genome. Therefore, we generated a humanized immune system (HIS) mouse model by transplanting human umbilical cord blood mononuclear cells into NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl) /SzJ (NSG) mice after sublethally irradiation...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29128556/pro-140-monoclonal-antibody-to-ccr5-prevents-acute-xenogeneic-graft-versus-host-disease-in-nod-scid-il-2ry-null-mice
#6
Denis R Burger, Yvonne Parker, Kathryn Guinta, Daniel Lindner
Graft-versus-Host Disease (GvHD) is a prevalent and potentially lethal complication of hematopoietic stem cell transplantation (HSCT). Humanized mouse models of xenogeneic-GvHD are important tools used to study the human immune response in vivo. Here we used NOD-scid IL-2Ry(null) mice (NSG) transplanted with human bone marrow stem cells to evaluate the role of immune cell engraftment in the production of acute GvHD. PRO 140, a humanized monoclonal antibody targeting the chemokine receptor, CCR5, was used to evaluate its influence on bone marrow cell engraftment and modulation of acute GvHD...
November 8, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29121805/prostate-cancer-xenograft-inhibitory-activity-and-pharmacokinetics-of-decursinol-a-metabolite-of-angelica-gigas-pyranocoumarins-in-mouse-models
#7
Wei Wu, Su-Ni Tang, Yong Zhang, Manohar Puppala, Timothy K Cooper, Chengguo Xing, Cheng Jiang, Junxuan Lü
We have previously shown that the ethanol extract of dried Angelica gigas Nakai (AGN) root exerts anticancer activity against androgen receptor (AR)-negative human DU145 and PC-3 prostate cancer xenografts and primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The major pyranocoumarin isomers decursin (D) and decursinol angelate (DA), when provided at equi-molar intake to that provided by AGN extract, accounted for the inhibitory efficacy against precancerous epithelial lesions in TRAMP mice...
November 9, 2017: American Journal of Chinese Medicine
https://www.readbyqxmd.com/read/29105567/in-vivo-survival-of-human-endometrial-mesenchymal-stem-cells-transplanted-under-the-kidney-capsule-of-immunocompromised-mice
#8
Shanti Gurung, James A Deane, Saeedeh Darzi, Jerome A Werkmeister, Caroline E Gargett
Human endometrial mesenchymal stem cells (eMSCs) are a well-characterised adult stem cell type with potential for use in regenerative medicine or cell-therapy. As a proof of principle, we demonstrated that eMSCs promoted wound healing by reducing the inflammatory response through a paracrine action in a subcutaneous rat model of wound repair. However, an efficient protocol for culturing eMSCs in the undifferentiated state and a reliable method of labelling them for cell tracking were lacking. Here, we investigated the use of a lentiviral vector containing the mCherry fluorescent reporter gene to transduce and label eMSCs following in vitro culturing in A83-01-containing medium, and different methods of tracing the labelled cells following transplantation under the kidney capsule of immunocompromised NSG mice...
November 4, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/29103912/optimization-of-il13r%C3%AE-2-targeted-chimeric-antigen-receptor-t-cells-for-improved-anti-tumor-efficacy-against-glioblastoma
#9
Christine E Brown, Brenda Aguilar, Renate Starr, Xin Yang, Wen-Chung Chang, Lihong Weng, Brenda Chang, Aniee Sarkissian, Alfonso Brito, James F Sanchez, Julie R Ostberg, Massimo D'Apuzzo, Behnam Badie, Michael E Barish, Stephen J Forman
T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8(+) T cells that had shown evidence for bioactivity in patients...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29102562/prostaglandin-e2-increases-lentiviral-vector-transduction-efficiency-of-adult-human-hematopoietic-stem-and-progenitor-cells
#10
Garrett C Heffner, Melissa Bonner, Lauryn Christiansen, Francis J Pierciey, Dakota Campbell, Yegor Smurnyy, Wenliang Zhang, Amanda Hamel, Seema Shaw, Gretchen Lewis, Kendrick A Goss, Olivia Garijo, Bruce E Torbett, Holly Horton, Mitchell H Finer, Philip D Gregory, Gabor Veres
Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34(+) hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E2 (PGE2) as a positive mediator of lentiviral transduction of CD34(+) cells. Supplementation with PGE2 increased lentiviral vector (LVV) transduction of CD34(+) cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34(+) cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29100346/inhibition-of-hiv-1-infection-in-humanized-mice-and-metabolic-stability-of-protein-phosphatase-1-targeting-small-molecule-1e7-03
#11
Xionghao Lin, Namita Kumari, Catherine DeMarino, Yasemin Saygideğer Kont, Tatiana Ammosova, Amol Kulkarni, Marina Jerebtsova, Guelaguetza Vazquez-Meves, Andrey Ivanov, Kovalskyy Dmytro, Aykut Üren, Fatah Kashanchi, Sergei Nekhai
We recently identified the protein phosphatase-1 - targeting compound, 1E7-03 which inhibited HIV-1 in vitro. Here, we investigated the effect of 1E7-03 on HIV-1 infection in vivo by analyzing its metabolic stability and antiviral activity of 1E7-03 and its metabolites in HIV-1 infected NSG-humanized mice. 1E7-03 was degraded in serum and formed two major degradation products, DP1 and DP3, which bound protein phosphatase-1 in vitro. However, their anti-viral activities were significantly reduced due to inefficient cell permeability...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29079368/p14-methylation-an-epigenetic-signature-of-salivary-gland-mucoepidermoid-carcinoma-in-the-serbian-population
#12
Nadja Nikolic, Jelena Carkic, Ivana Ilic Dimitrijevic, Najib Eljabo, Milena Radunovic, Boban Anicic, Nasta Tanic, Markus Falk, Jelena Milasin
OBJECTIVE: To investigate the prevalence of p16(INK4 a), p14(ARF), tumor protein p53 (TP53), and human telomerase reverse transcriptase (hTERT) promoter hypermethylation in mucoepidermoid carcinomas (MECs) and search for a possible association between methylation status and clinicopathological parameters. STUDY DESIGN: DNA extracted from 35 formalin-fixed and paraffin-embedded MEC samples and 10 normal salivary gland (NSG) tissue samples was analyzed for the presence of promoter hypermethylation using methylation-specific polymerase chain reaction testing...
September 28, 2017: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
https://www.readbyqxmd.com/read/29078283/humanized-mouse-model-supports-development-function-and-tissue-residency-of-human-natural-killer-cells
#13
Dietmar Herndler-Brandstetter, Liang Shan, Yi Yao, Carmen Stecher, Valerie Plajer, Melanie Lietzenmayer, Till Strowig, Marcel R de Zoete, Noah W Palm, Jie Chen, Catherine A Blish, Davor Frleta, Cagan Gurer, Lynn E Macdonald, Andrew J Murphy, George D Yancopoulos, Ruth R Montgomery, Richard A Flavell
Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2(-/-) Il2rg(-/-) background (SRG-15)...
November 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29074954/functional-activation-of-osteoclast-commitment-in-chronic-lymphocytic-leukaemia-a-possible-role-for-rank-rankl-pathway
#14
Cecilia Marini, Silvia Bruno, Francesco Fiz, Cristina Campi, Roberta Piva, Giovanna Cutrona, Serena Matis, Alberto Nieri, Maurizio Miglino, Adalberto Ibatici, Anna Maria Orengo, Anna Maria Massone, Carlo Emanuele Neumaier, Daniela de Totero, Paolo Giannoni, Matteo Bauckneht, Michele Pennone, Claudya Tenca, Elena Gugiatti, Alessandro Bellini, Anna Borra, Elisabetta Tedone, Hülya Efetürk, Francesca Rosa, Laura Emionite, Michele Cilli, Davide Bagnara, Valerio Brucato, Paolo Bruzzi, Michele Piana, Franco Fais, Gianmario Sambuceti
Skeletal erosion has been found to represent an independent prognostic indicator in patients with advanced stages of chronic lymphocytic leukaemia (CLL). Whether this phenomenon also occurs in early CLL phases and its underlying mechanisms have yet to be fully elucidated. In this study, we prospectively enrolled 36 consecutive treatment-naïve patients to analyse skeletal structure and bone marrow distribution using a computational approach to PET/CT images. This evaluation was combined with the analysis of RANK/RANKL loop activation in the leukemic clone, given recent reports on its role in CLL progression...
October 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29070697/overcoming-mutational-complexity-in-acute-myeloid-leukemia-by-inhibition-of-critical-pathways
#15
Yoriko Saito, Yoshiki Mochizuki, Ikuko Ogahara, Takashi Watanabe, Leah Hogdal, Shinsuke Takagi, Kaori Sato, Akiko Kaneko, Hiroshi Kajita, Naoyuki Uchida, Takehiro Fukami, Leonard D Shultz, Shuichi Taniguchi, Osamu Ohara, Anthony G Letai, Fumihiko Ishikawa
Numerous variant alleles are associated with human acute myeloid leukemia (AML). However, the same variants are also found in individuals with no hematological disease, making their functional relevance obscure. Through NOD.Cg-Prkdc(scid)Il2rg(tmlWjl)/Sz (NSG) xenotransplantation, we functionally identified preleukemic and leukemic stem cell populations present in FMS-like tyrosine kinase 3 internal tandem duplication-positive (FLT3-ITD)(+) AML patient samples. By single-cell DNA sequencing, we identified clonal structures and linked mutations with in vivo fates, distinguishing mutations permissive of nonmalignant multilineage hematopoiesis from leukemogenic mutations...
October 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29065481/cd47-car-t-cells-effectively-kill-target-cancer-cells-and-block-pancreatic-tumor-growth
#16
Vita Golubovskaya, Robert Berahovich, Hua Zhou, Shirley Xu, Hizkia Harto, Le Li, Cheng-Chi Chao, Mike Ming Mao, Lijun Wu
CD47 is a glycoprotein of the immunoglobulin superfamily that is often overexpressed in different types of hematological and solid cancer tumors and plays important role in blocking phagocytosis, increased tumor survival, metastasis and angiogenesis. In the present report, we designed CAR (chimeric antigen receptor)-T cells that bind CD47 antigen. We used ScFv (single chain variable fragment) from mouse CD47 antibody to generate CD47-CAR-T cells for targeting different cancer cell lines. CD47-CAR-T cells effectively killed ovarian, pancreatic and other cancer cells and produced high level of cytokines that correlated with expression of CD47 antigen...
October 21, 2017: Cancers
https://www.readbyqxmd.com/read/29040282/colorectal-carcinoma-tumour-budding-and-podia-formation-in-the-xenograft-microenvironment
#17
Friedrich Prall, Claudia Maletzki, Maja Hühns, Mathias Krohn, Michael Linnebacher
Tumour budding and podia formation are well-appreciated in surgical pathology as an aggressive invasion phenotype of colorectal carcinoma cells that is attained in the microenvironment of the invasive margin. In this study, we addressed how tumour budding and podia formation feature in xenografts. Primary colorectal carcinomas (N = 44) of various molecular types (sporadic standard type, high-degree microsatellite-unstable, CpG island methylator phenotype) were transplanted subcutaneously into T and B cell-deficient NSG mice, making possible immunohistochemistry with routine surgical pathology antibodies...
2017: PloS One
https://www.readbyqxmd.com/read/29032169/survival-advantage-of-both-human-hepatocyte-xenografts-and-genome-edited-hepatocytes-for-treatment-of-%C3%AE-1-antitrypsin-deficiency
#18
Florie Borel, Qiushi Tang, Gwladys Gernoux, Cynthia Greer, Ziqiong Wang, Adi Barzel, Mark A Kay, Leonard D Shultz, Dale L Greiner, Terence R Flotte, Michael A Brehm, Christian Mueller
Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In α-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver...
November 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29031704/evaluation-of-cooperative-antileukemic-effects-of-nilotinib-and-vildagliptin-in-ph-chronic-myeloid-leukemia
#19
Michael Willmann, Irina Sadovnik, Gregor Eisenwort, Martin Entner, Tina Bernthaler, Gabriele Stefanzl, Emir Hadzijusufovic, Daniela Berger, Harald Herrmann, Gregor Hoermann, Peter Valent, Thomas Rülicke
Chronic myeloid leukemia (CML) is a stem cell (SC) neoplasm characterized by the BCR/ABL1 oncogene. Although the disease can be kept under control using BCR/ABL1 tyrosine kinase inhibitors (TKIs) in most cases, some patients relapse or have resistant disease, so there is a need to identify new therapeutic targets in this malignancy. Recent data suggest that leukemic SCs (LSCs) in CML display the stem-cell (SC)-mobilizing cell surface enzyme dipeptidyl-peptidase IV (DPPIV = CD26) in an aberrant manner. In the present study, we analyzed the effects of the DPPIV blocker vildagliptin as single agent or in combination with the BCR/ABL1 TKI imatinib or nilotinib on growth and survival of CML LSCs in vitro and on LSC engraftment in an in vivo xenotransplantation nonobese diabetic SCID-IL-2Rγ(-/-) (NSG) mouse model...
October 12, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28993511/cell-cycle-dependent-tumor-engraftment-and-migration-are-enabled-by-aurora-a
#20
Tony L H Chu, Marisa Connell, Lixin Zhou, Zhengcheng He, Jennifer R Won, Seyed M Rahavi, Helen Chen, Pooja Mohan, Oksana Nemirovsky, Abbas Fotovati, Miguel Angel Pujana, Gregor Sd Reid, Torsten O Nielsen, Nelly Pante, Christopher A Maxwell
Cell cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells that are perceived as independent processes but may be interconnected by molecular pathways that control microtubule nucleation at centrosomes. Here, cell cycle progression dramatically impacts the engraftment kinetics of 4T1-luciferase2 breast cancer cells in immunocompetent BALB/c or immunocompromised NOD-SCID gamma (NSG) mice. Multi-parameter imaging of wound closure assays was used to track cell cycle progression, cell migration, and associated phenotypes in epithelial cells or carcinoma cells expressing a fluorescence ubiquitin cell cycle indicator...
October 9, 2017: Molecular Cancer Research: MCR
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