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https://www.readbyqxmd.com/read/28209904/noninvasive-imaging-of-human-immune-responses-in-a-human-xenograft-model-of-graft-versus-host-disease
#1
Catharina H M J Van Elssen, Mohammad Rashidian, Vladimir Vrbanac, Kai W Wucherpfennig, Zeina El Habre, Jana Sticht, Christian Freund, Johanne Jacobsen, Juanjo Cragnolini, Jessica Ingram, Loes Plaisier, Eric Spierings, Andrew M Tager, Hidde Ploegh
The immune system plays a crucial role in many diseases. Activation or suppression of immunity is often related to clinical outcome. Methods to explore the dynamics of immune responses are important to elucidate their role in conditions characterized by inflammation, such as infectious disease, cancer or auto-immunity. Immuno-PET is a non-invasive method by which disease and immune cell infiltration can be explored simultaneously. Using radiolabeled antibodies or fragments derived from them, it is possible to image disease-specific antigens and immune cell subsets...
February 16, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28209618/the-stat3-mirna-92-wnt-signaling-pathway-regulates-spheroid-formation-and-malignant-progression-in-ovarian-cancer
#2
Min-Wei Chen, Shu-Ting Yang, Ming-Hsien Chien, Kuo-Tai Hua, Chin-Jui Wu, Sheng-Mou Hsiao, Hao Lin, Michael Hsiao, Jen-Liang Su, Lin-Hung Wei
Ovarian cancer spheroids constitute a metastatic niche for transcoelomic spread that also engenders drug resistance. Spheroid-forming cells express active STAT3 signaling and display stem cell-like properties that may contribute to ovarian tumor progression. In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity...
February 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28196514/defining-the-contribution-of-neuroinflammation-to-parkinson-s-disease-in-humanized-immune-system-mice
#3
Gunjan Dhawan Manocha, Angela Marie Floden, Kendra Lynn Puig, Kumi Nagamoto-Combs, Clemens R Scherzer, Colin Kelly Combs
BACKGROUND: Reactive microglia have been associated with the histological changes that occur in Parkinson's disease brains and mouse models of the disease. Multiple studies from autopsy brains have verified the presence of microgliosis in several brain regions including substantia nigra, striatum, hippocampus and various cortical areas. MPTP injections in rodents have also shown striato-nigral microgliosis correlating with the loss of dopaminergic neurons. However, consistent data with respect to cytokine and immune cell changes during Parkinson's disease have not been fully defined...
February 14, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28194440/transient-antibody-targeting-of-cd45rc-induces-transplant-tolerance-and-potent-antigen-specific-regulatory-t-cells
#4
Elodie Picarda, Séverine Bézie, Laetitia Boucault, Elodie Autrusseau, Stéphanie Kilens, Dimitri Meistermann, Bernard Martinet, Véronique Daguin, Audrey Donnart, Eric Charpentier, Laurent David, Ignacio Anegon, Carole Guillonneau
Rat and human CD4(+) and CD8(+) Tregs expressing low levels of CD45RC have strong immunoregulatory properties. We describe here that human CD45 isoforms are nonredundant and identify distinct subsets of cells. We show that CD45RC is not expressed by CD4(+) and CD8(+) Foxp3(+) Tregs, while CD45RA/RB/RO are. Transient administration of a monoclonal antibody (mAb) targeting CD45RC in a rat cardiac allotransplantation model induced transplant tolerance associated with inhibition of allogeneic humoral responses but maintained primary and memory responses against cognate antigens...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28160330/forced-expression-of-human-m-csf-in-cd34-cells-promotes-monocyte-differentiation-in-vitro-and-in-vivo-but-blunts-osteoclastogenesis-in-vitro
#5
Carmen P Montano Almendras, Christian S Thudium, Henrik Löfvall, Ilana Moscatelli, Axel Schambach, Kim Henriksen, Johan Richter
OBJECTIVES: Here we tested the hypothesis that human M-CSF (hM-CSF) overexpressed in CB CD34(+) cells would induce differentiation and survival of monocytes and osteoclasts in vitro and in vivo. METHODS: Human M-CSF was overexpressed in cord blood CD34(+)  cells using a lentiviral vector. RESULTS: We show that LV-hM-CSF-transduced CB CD34(+) cells expand 3.6 and 8.5 fold more with one or two exposures to the hM-CSF expressing vector, respectively, when compared to control cells...
February 3, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28153602/comparison-of-allograft-and-polyetheretherketone-peek-cage-subsidence-rates-in-anterior-cervical-discectomy-and-fusion-acdf
#6
Sharon C Yson, Jonathan N Sembrano, Edward Rainier G Santos
Structural allografts and PEEK cages are commonly used interbody fusion devices in ACDF. The subsidence rates of these two spacers have not yet been directly compared. The primary aim of this study was to compare the subsidence rate of allograft and PEEK cage in ACDF. The secondary aim was to determine if the presence of subsidence affects the clinical outcome. We reviewed 67 cases (117 levels) of ACDF with either structural allograft or PEEK cages. There were 85 levels (48 cases) with PEEK and 32 levels (19 cases) with allograft spacers...
January 30, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/28125559/o-011-low-dose-il-2-administration-expands-human-regulatory-t-cells-in-patients-with-uc-and-humanized-mice-and-protects-against-experimental-colitis
#7
Jeremy Goettel, Daniel Kotlarz, David Illig, James Canavan, Jessica Allegretti, Matthew Hamilton, Ryan Kelly, Alexandra Griffith, Madeline Carellas, Anastasia Nelina, Athos Bousvaros, Joshua Korzenik, Scott Snapper
BACKGROUND: Treg dysfunction or deficiency results in unopposed immune activation and autoimmunity. Interleukin-2 (IL-2) is critical for the expansion, suppressive function, and maintenance of Tregs. Although conventional T cells and NK cells respond to IL-2, Tregs are more sensitive to lower concentrations of IL-2 due to constitutive expression of CD25, the high affinity IL-2 receptor. Low-dose IL-2 therapies have shown to preferentially expand Tregs and ameliorate manifestations of graft versus host disease (Koreth et al...
February 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28112582/the-allosteric-akt-inhibitor-mk2206-decreases-tumor-growth-and-invasion-in-patient-derived-xenografts-of-endometrial-cancer
#8
Abigail Winder, Kenji Unno, Yanni Yu, John Lurain, J Julie Kim
The purpose of this study was to test the effect of MK2206, an allosteric inhibitor of AKT, on the growth and invasion of patient-derived xenografts (PDX) of endometrial cancer. Three PDX lines, USC1 (uterine serous), EEC2 (endometrioid grade 2) and EEC4 (endometrioid grade 3) of endometrial cancer were grafted under the renal capsule of NSG mice. After 2 weeks of tumor growth the mice were treated with vehicle or 120mg/kg MK2206 twice a week for three weeks. Growth of all three PDX lines of different type and grade was significantly inhibited in response to MK2206 compared to vehicle control...
January 23, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28103576/a-new-model-of-multi-visceral-and-bone-metastatic-prostate-cancer-with-perivascular-niche-targeting-by-a-novel-endothelial-specific-adenoviral-vector
#9
Zhi Hong Lu, Sergey Kaliberov, Rebecca E Sohn, Lyudmila Kaliberova, Yingqiu Du, Julie L Prior, Daniel J Leib, Anne Chauchereau, Jennifer K Sehn, David T Curiel, Jeffrey M Arbeit
While modern therapies for metastatic prostate cancer (PCa) have improved survival they are associated with an increasingly prevalent entity, aggressive variant PCa (AVPCa), lacking androgen receptor (AR) expression, enriched for cancer stem cells (CSCs), and evidencing epithelial-mesenchymal plasticity with a varying extent of neuroendocrine transdifferentiation. Parallel work revealed that endothelial cells (ECs) create a perivascular CSC niche mediated by juxtacrine and membrane tethered signaling. There is increasing interest in pharmacological metastatic niche targeting, however, targeted access has been impossible...
January 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28096272/anti-leukemia-efficacy-and-mechanisms-of-action-of-sl-101-a-novel-anti-cd123-antibody-conjugate-in-acute-myeloid-leukemia
#10
Lina Han, Jeffrey L Jorgensen, Christopher Brooks, Ce Shi, Qi Zhang, Graciela M Nogueras González, Antonio Cavazos, Rongqing Pan, Hong Mu, Sa Wang, Jin Zhou, Gheath Alatrash, Stefan O Ciurea, Michael Rettig, John F DiPersio, Jorge E Cortes, Xuelin Huang, Hagop Kantarjian, Michael Andreeff, Farhad Ravandi-Kashani, Marina Konopleva
PURPOSE: The persistence of leukemia stem cells (LSC)-containing cells after induction therapy may contribute to minimal residual disease (MRD) and relapse in acute myeloid leukemia (AML). We investigated the clinical relevance of CD34+CD123+ LSC-containing cells and anti-leukemia potency of a novel antibody-conjugate SL-101 in targeting CD123+ LSCs. Experimental Methods and Results: In a retrospective study on 86 newly diagnosed AML patients, we demonstrated that a higher proportion of CD34+CD123+ LSC-containing cells in remission was associated with persistent MRD, and predicted shorter relapse-free survival in patients with poor-risk cytogenetics...
January 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28087429/analysis-of-parameters-that-affect-human-hematopoietic-cell-outputs-in-mutant-c-kit-immunodeficient-mice
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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...
March 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27917411/ptpn22-inhibition-resets-defective-human-central-b-cell-tolerance
#20
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
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