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https://www.readbyqxmd.com/read/28087429/analysis-of-parameters-that-affect-human-hematopoietic-cell-outputs-in-mutant-c-kit-immunodeficient-mice
#1
Paul H Miller, Gabrielle Rabu, Margarita MacAldaz, David Jhf Knapp, Alice Ms Cheung, Kiran Dhillon, Naoto Nakamichi, Philip A Beer, Leonard D Shultz, R Keith Humphries, Connie J Eaves
Xenograft models are transforming our understanding of the output capabilities of primitive human hematopoietic cells in vivo. However, many variables that affect post-transplant reconstitution dynamics remain poorly understood. Here we show an equivalent level of human chimerism can be regenerated from human CD34(+) cord blood cells transplanted intravenously either with or without additional radiation-inactivated cells into 2-6 month-old NOD-Rag1(-/-)-IL2Rγc(-/-) (NRG) mice given a more radioprotective conditioning regimen than is possible in conventionally used, repair-deficient, NOD-Prkdc(scid/scid)-IL2Rγc(-/-) (NSG) hosts...
January 10, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28059624/pre-clinical-development-of-gene-modification-of-hematopoietic-stem-cells-with-chimeric-antigen-receptors-for-cancer-immunotherapy
#2
Sarah M Larson, Laurel C Truscott, Tzu-Ting Chiou, Amie Patel, Roy Kao, Andy Tu, Tulika Tyagi, Xiang Lu, David Elashoff, Satiro N De Oliveira
Patients with refractory or recurrent B-lineage hematologic malignancies have less than 50% of chance of cure despite intensive therapy and innovative approaches are needed. We hypothesize that gene modification of hematopoietic stem cells (HSC) with an anti-CD19 chimeric antigen receptor (CAR) will produce a multi-lineage, persistent immunotherapy against B-lineage malignancies that can be controlled by the HSVsr39TK suicide gene. High-titer third-generation self-inactivating lentiviral constructs were developed to deliver a second-generation CD19-specific CAR and the herpes simplex virus thymidine kinase HSVsr39TK to provide a suicide gene to allow ablation of gene-modified cells if necessary...
January 6, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28053325/effects-of-mirna-15-and-mirna-16-expression-replacement-in-chronic-lymphocytic-leukemia-implication-for-therapy
#3
G Cutrona, S Matis, M Colombo, C Massucco, G Baio, F Valdora, L Emionite, S Fabris, A G Recchia, M Gentile, C E Neumaier, D Reverberi, R Massara, S Boccardo, L Basso, S Salvi, F Rosa, M Cilli, S Zupo, M Truini, P Tassone, M Calabrese, M Negrini, A Neri, F Morabito, F Fais, M Ferrarini
Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, [del(13)(q14)] involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion...
January 5, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28042144/novel-bet-protein-proteolysis-targeting-chimera-bet-protac-exerts-superior-lethal-activity-than-bromodomain-inhibitor-beti-against-post-myeloproliferative-neoplasm-mpn-secondary-s-aml-cells
#4
D T Saenz, W Fiskus, Y Qian, T Manshouri, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, C P Mill, B Sun, P Qiu, T M Kadia, N Pemmaraju, C DiNardo, M-S Kim, A J Nowak, C Coarfa, C M Crews, S Verstovsek, K N Bhalla
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells...
January 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28006930/systemic-administration-of-mirna-mimics-by-liposomal-delivery-system-in-animal-model-of-colorectal-carcinoma
#5
J Merhautová, P Vychytilová-Faltejsková, R Demlová, O Slabý
MiRNAs are important regulators of gene expression and changes in their levels are linked with various pathological states, including solid tumors. MiR-215 has been identified as a tumor suppressor in colorectal cancer (CRC). Following our previous in vitro and in vivo experiments, the aim of this project was to study the possibility of increasing the levels of miR-215 in tumor cells by systemic administration of miRNA mimics in liposomal delivery system in vivo. By subcutaneous xenotransplantation of human cancer cells to NSG mice, CRC model was established...
December 21, 2016: Physiological Research
https://www.readbyqxmd.com/read/28000125/prevalence-and-risk-factors-for-early-seizure-in-patients-with-traumatic-brain-injury-analysis-from-national-trauma-data-bank
#6
Shahram Majidi, Yamane Makke, Amr Ewida, Bahareh Sianati, Adnan I Qureshi, Mohamad Z Koubeissi
BACKGROUND: Traumatic brain injury (TBI) is a well-known risk factor for seizures. We aimed to identify the frequency and risk factors for seizure occurrence during hospitalization for TBI. METHODS: We used ICD-9-CM codes to identify patients 18 years of age or older from the National Trauma Data Bank who were admitted with TBI. We also used ICD-9-CM codes to identify the subset who had seizures during hospitalization. Patient demographics, comorbidities, Glasgow Coma Scale (GCS) score, Injury Severity Score Abbreviated Injury Scale (ISSAIS), in-hospital complications, and discharge disposition were compared in the seizure group (SG) and no-seizure group (NSG)...
December 20, 2016: Neurocritical Care
https://www.readbyqxmd.com/read/27980777/improved-b-cell-development-in-humanized-nod-scid-il2r%C3%AE-null-mice-transgenically-expressing-human-stem-cell-factor-granulocyte-macrophage-colony-stimulating-factor-and-interleukin-3
#7
Sonal Jangalwe, Leonard D Shultz, Anuja Mathew, Michael A Brehm
INTRODUCTION: Immunodeficient mice engrafted with human immune systems support studies of human hematopoiesis and the immune response to human-specific pathogens. A significant limitation of these humanized mouse models is, however, a severely restricted ability of human B cells to undergo class switching and produce antigen-specific IgG after infection or immunization. METHODS: In this study, we have characterized the development and function of human B cells in NOD-scid IL2Rγ(null) (NSG) mice transgenically expressing human stem cell factor (SCF), granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-3 (NSG-SGM3) following engraftment with human hematopoietic stem cells, autologous fetal liver, and thymic tissues (bone marrow, liver, thymus or BLT model)...
December 2016: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/27980047/practical-immunopet-radiotracer-design-considerations-for-human-immune-checkpoint-imaging
#8
Aaron Thomas Mayer, Arutselvan Natarajan, Sydney Gordon, Roy Maute, Melissa McCracken, Aaron Ring, Irving Weissman, Sam Sanjiv Gambhir
Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy. A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression. Here we sought to optimize noninvasive ImmunoPET (positron emission tomography) imaging of human PD-L1 expression, in a pre-clinical model, using a small high affinity engineered protein scaffold (HAC-PD1)...
December 15, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/27935045/patient-derived-xenografts-of-gastrointestinal-cancers-are-susceptible-to-rapid-and-delayed-b-lymphoproliferation
#9
Sebastian M Dieter, Klara M Giessler, Mark Kriegsmann, Taronish D Dubash, Lino Möhrmann, Erik R Schulz, Christine Siegl, Sarah Weber, Hendrik Strakerjahn, Ava Oberlack, Ulrike Heger, Jianpeng Gao, Eva-Maria Hartinger, Felix Oppel, Christopher M Hoffmann, Nati Ha, Benedikt Brors, Felix Lasitschka, Alexis Ulrich, Oliver Strobel, Manfred Schmidt, Christof von Kalle, Martin Schneider, Wilko Weichert, K Roland Ehrenberg, Hanno Glimm, Claudia R Ball
Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl) /SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro...
December 9, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27917411/ptpn22-inhibition-resets-defective-human-central-b-cell-tolerance
#10
Jean-Nicolas Schickel, Marcel Kuhny, Alessia Baldo, Jason M Bannock, Christopher Massad, Haowei Wang, Nathan Katz, Tyler Oe, Laurence Menard, Pauline Soulas-Sprauel, Till Strowig, Richard Flavell, Eric Meffre
The 1858T protein tyrosine phosphatase nonreceptor type 22 (PTPN22 T) allele is one of the main risk factors associated with many autoimmune diseases and correlates with a defective removal of developing autoreactive B cells in humans. To determine whether inhibiting PTPN22 favors the elimination of autoreactive B cells, we first demonstrated that the PTPN22 T allele interfered with the establishment of central B cell tolerance using NOD-scid-common γ chain knockout (NSG) mice engrafted with human hematopoietic stem cells expressing this allele...
2016: Science Immunology
https://www.readbyqxmd.com/read/27903679/the-bruton-s-tyrosine-kinase-btk-inhibitor-acalabrutinib-demonstrates-potent-on-target-effects-and-efficacy-in-two-mouse-models-of-chronic-lymphocytic-leukemia
#11
Sarah E M Herman, Arnau Montraveta, Carsten U Niemann, Helena Mora-Jensen, Michael Gulrajani, Fanny Krantz, Rose Mantel, Lisa L Smith, Fabienne McClanahan, Bonnie Harrington, Dolors Colomer, Todd Covey, John C Byrd, Raquel Izumi, Allard Kaptein, Roger Ulrich, Amy Johnson, Brian J Lannutti, Adrian Wiestner, Jennifer A Woyach
PURPOSE: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27902604/the-use-of-delta-neutrophil-index-and-myeloperoxidase-index-as-diagnostic-predictors-of-strangulated-mechanical-bowel-obstruction-in-the-emergency-department
#12
Yong Sung Cha, Kang Hyun Lee, Jong Wook Lee, Eun Hee Choi, Hyung Il Kim, Oh Hyun Kim, Kyoung Chul Cha, Hyun Kim, Sung Oh Hwang
Early detection of bowel strangulation is difficult in patients with mechanical bowel obstruction (MBO). There have been no previous reports of predicting strangulation in MBO cases using the delta neutrophil index (DNI), which is a measure of the proportion of circulating immature granulocytes, or the myeloperoxidase index (MPXI), which is a measure of serum myeloperoxidase level. Therefore, we evaluated differences in initial DNI and MPXI upon presentation at the emergency department (ED) according to strangulation presence in MBO patients...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27892637/distribution-of-follicles-in-canine-ovarian-tissues-and-xenotransplantation-of-cryopreserved-ovarian-tissues-with-even-distribution-of-follicles
#13
I Wakasa, M Hayashi, Y Abe, H Suzuki
Ovarian follicles are not homogeneously distributed within the ovarian cortex in several species of mammals. Yet to maximize the reproducibility of experimental results of ovarian transplantation, it is essential to assess the degree of density and distribution of follicles in ovarian tissues before their transplantation. In this study, the ovarian cortex from 13 immature bitches (ten purebred and three mongrels) was sectioned into 1.0- to 1.5-mm(3) cubes, those were fixed, sectioned and stained with haematoxylin and eosin...
November 28, 2016: Reproduction in Domestic Animals, Zuchthygiene
https://www.readbyqxmd.com/read/27890379/synthesis-characterization-and-antineoplastic-activity-of-bis-aziridinyl-dimeric-naphthoquinone-a-novel-class-of-compounds-with-potent-activity-against-acute-myeloid-leukemia-cells
#14
Brandon A Carter-Cooper, Steven Fletcher, Dana Ferraris, Eun Yong Choi, Dahlia Kronfli, Smaraki Dash, Phuc Truong, Edward A Sausville, Rena G Lapidus, Ashkan Emadi
The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported...
January 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882356/intra-osseous-co-transplantation-of-cd34-selected-umbilical-cord-blood-and-mesenchymal-stromal-cells
#15
Leland Metheny, Saada Eid, Karen Lingas, Jane Reese, Howard Meyerson, Alexander Tong, Marcos de Lima, Alex Y Huang
Human mesenchymal stromal cells (MSC) have been shown to support the growth and differentiation of hematopoietic stem cells (HSC). We hypothesized that intra-osseous (IO) co-transplantation of MSC and umbilical cord blood (UCB) may be effective in improving early HSC engraftment, as IO transplantation has been demonstrated to enhance UCB engraftment in NOD SCID-gamma (NSG) mice. Following non-lethal irradiation (300rads), 6 groups of NSG mice were studied: 1) intravenous (IV) UCB CD34(+) cells, 2) IV UCB CD34(+) cells and MSC, 3) IO UCB CD34(+) cells, 4) IO UCB CD34(+) cells and IO MSC, 5) IO UCB CD34(+) cells and IV MSC, and 6) IV UCB CD34(+) and IO MSC...
2016: Hematol Med Oncol
https://www.readbyqxmd.com/read/27872864/f4-80-host-macrophages-are-a-barrier-to-murine-embryonic-stem-cell-derived-hematopoietic-progenitor-engraftment-in-vivo
#16
Heather L Thompson, Nico van Rooijen, Bryce T McLelland, Jennifer O Manilay
Understanding how embryonic stem cells and their derivatives interact with the adult host immune system is critical to developing their therapeutic potential. Murine embryonic stem cell-derived hematopoietic progenitors (ESHPs) were generated via coculture with the bone marrow stromal cell line, OP9, and then transplanted into NOD.SCID.Common Gamma Chain (NSG) knockout mice, which lack B, T, and natural killer cells. Compared to control mice transplanted with adult lineage-negative bone marrow (Lin(-) BM) progenitors, ESHP-transplanted mice attained a low but significant level of donor hematopoietic chimerism...
2016: Journal of Immunology Research
https://www.readbyqxmd.com/read/27859428/low-p16-ink4a-expression-in-early-passage-human-prostate-basal-epithelial-cells-enables-immortalization-by-telomerase-expression-alone
#17
Mindy Kim Graham, Lorenzo Principessa, Lizamma Antony, Alan K Meeker, John T Isaacs
BACKGROUND: There are two principal senescence barriers that must be overcome to successfully immortalize primary human epithelial cells in culture, stress-induced senescence, and replicative senescence. The p16(INK4a) /retinoblastoma protein (p16/Rb) pathway mediates stress-induced senescence, and is generally upregulated by primary epithelial cells in response to the artificial conditions from tissue culture. Replicative senescence is associated with telomere loss. Following each round of cell division, telomeres progressively shorten...
November 8, 2016: Prostate
https://www.readbyqxmd.com/read/27856463/ccl-2-is-a-kit-d816v-dependent-modulator-of-the-bone-marrow-microenvironment-in-systemic-mastocytosis
#18
Georg Greiner, Nadine Witzeneder, Angelika Berger, Klaus Schmetterer, Gregor Eisenwort, Ana-Iris Schiefer, Simone Roos, Theresia Popow-Kraupp, Leonhard Müllauer, Johannes Zuber, Veronika Sexl, Lukas Kenner, Wolfgang R Sperr, Peter Valent, Matthias Mayerhofer, Gregor Hoermann
Systemic mastocytosis (SM) is characterized by abnormal accumulation of neoplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal organs. Similar to other myeloproliferative neoplasms, increased production of pro-fibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, only little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the pro-angiogenic cytokine CCL-2 in neoplastic mast cells...
November 16, 2016: Blood
https://www.readbyqxmd.com/read/27846885/autophagy-is-associated-with-chemoresistance-in-neuroblastoma
#19
Assila Belounis, Carine Nyalendo, Roxane Le Gall, Tina V Imbriglio, Mohamed Mahma, Pierre Teira, Mona Beaunoyer, Sonia Cournoyer, Elie Haddad, Gilles Vassal, Hervé Sartelet
BACKGROUND: Neuroblastoma (NB) is a frequent pediatric tumor characterized by a poor prognosis where a majority of tumors progress despite intensive multimodality treatments. Autophagy, a self-degradative process in cells, could be induced by chemotherapy and be associated with chemoresistance. The aim of this study was to determine whether: 1) autophagy is present in NB, 2) chemotherapy modified its levels, and 3) its inhibition decreased chemoresistance. METHODS: Immunohistochemical stainings were performed on samples from 184 NB patients in order to verify the expression of LC3B, a specific marker for autophagy, and Beclin 1, a positive regulator of autophagy...
November 15, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27827995/nod-scid-gamma-mice-are-permissive-to-allogeneic-hsc-transplantation-without-prior-conditioning
#20
Tom Verbiest, Rosemary Finnon, Natalie Brown, Paul Finnon, Simon Bouffler, Christophe Badie
Scid hematopoietic stem cells (HSCs) have an intrinsic defect in their maintenance within the bone marrow (BM) niche which facilitates HSC transplantation without the absolute requirement of prior conditioning. Nevertheless, NOD scid mice have a significantly altered life span due to early development of thymic lymphomas, which compromises the ability to study the long-term fate of exogenous HSCs and their progeny. Here, we present data on the transplantation of HSCs into NOD scid gamma (NSG) mice to achieve long-term engraftment without prior conditioning...
November 7, 2016: International Journal of Molecular Sciences
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