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Molecular Therapy: the Journal of the American Society of Gene Therapy

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https://www.readbyqxmd.com/read/27669655/robust-oncolytic-virotherapy-induces-tumor-lysis-syndrome-and-associated-toxicities-in-the-mpc-11-plasmacytoma-model
#1
Lianwen Zhang, Michael B Steele, Nathan Jenks, Jacquelyn Grell, Marshall Behrens, Rebecca Nace, Shruthi Naik, Mark J Federspiel, Stephen J Russell, Kah-Whye Peng
Tumor-selective oncolytic vesicular stomatitis viruses (VSVs) are being evaluated in clinical trials. Here, we report that the MPC-11 murine plasmacytoma model is so extraordinarily susceptible to oncolytic VSVs that a low dose of virus leads to extensive intratumoral viral replication, sustained viremia, intravascular coagulation, and a rapidly fatal tumor lysis syndrome (TLS). Rapid softening, shrinkage and hemorrhagic necrosis of flank tumors was noted within 1-2 days after virus administration, leading to hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, increase in plasma cell free DNA, lymphopenia, consumptive coagulopathy, increase in fibrinogen degradation products, decreased liver function tests, dehydration, weight loss, and euthanasia or death after 5-8 days...
November 1, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27633443/linc00152-functions-as-a-competing-endogenous-rna-to-confer-oxaliplatin-resistance-and-holds-prognostic-values-in-colon-cancer
#2
Ben Yue, Donglan Cai, Chenchen Liu, Changyi Fang, Dongwang Yan
Long noncoding RNAs act as crucial regulators in plenty of human cancers, yet their potential roles and molecular mechanisms in chemoresistance are poorly understood. This study showed that a novel lncRNA, long intergenic noncoding RNA 152 (Linc00152 ), promoted tumor progression and conferred resistance to oxaliplatin (L-OHP)-induced apoptosis in vitro and in vivo. It antagonized chemosensitivity through acting as a competing endogenous RNA to modulate the expression of miR-193a-3p, and then erb-b2 receptor tyrosine kinase 4 (ERBB4)...
October 18, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27633441/intracellular-delivery-of-anti-ppkc%C3%AE-thr538-via-protein-transduction-domain-mimics-for-immunomodulation
#3
E Ilker Ozay, Gabriela Gonzalez-Perez, Joe A Torres, Jyothi Vijayaraghavan, Rebecca Lawlor, Heather L Sherman, Daniel T Garrigan, Amy S Burnside, Barbara A Osborne, Gregory N Tew, Lisa M Minter
Targeting cellular proteins with antibodies, to better understand cellular signaling pathways in the context of disease modulation, is a fast-growing area of investigation. Humanized antibodies are increasingly gaining attention for their therapeutic potential, but the collection of cellular targets is limited to those secreted from cells or expressed on the cell surface. This approach leaves a wealth of intracellular proteins unexplored as putative targets for antibody binding. Protein kinase Cθ (PKCθ) is essential to T cell activation, proliferation, and differentiation, and its phosphorylation at specific residues is required for its activity...
October 18, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27731313/targeted-delivery-of-an-anti-inflammatory-pde4-inhibitor-to-immune-cells-via-an-antibody-drug-conjugate
#4
Shan Yu, Aaron D Pearson, Reyna K V Lim, David T Rodgers, Sijia Li, Holly B Parker, Meredith Weglarz, Eric N Hampton, Michael J Bollong, Jiayin Shen, Claudio Zambaldo, Danling Wang, Ashley K Woods, Timothy M Wright, Peter G Schultz, Stephanie A Kazane, Travis S Young, Matthew S Tremblay
Phosphodiesterase 4 (PDE4) inhibitors are approved for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects in the central nervous system and gastrointestinal tract, including nausea, emesis, headache, and diarrhea, have impeded the broader therapeutic application of PDE4 inhibitors. We sought to exploit the wealth of validation surrounding PDE4 inhibition by improving the therapeutic index through generation of an antibody-drug conjugate (ADC) that selectively targets immune cells through the CD11a antigen...
October 12, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27502608/gdf11-protects-against-endothelial-injury-and-reduces-atherosclerotic-lesion-formation-in-apolipoprotein-e-null-mice
#5
Wen Mei, Guangda Xiang, Yixiang Li, Huan Li, Lingwei Xiang, Junyan Lu, Lin Xiang, Jing Dong, Min Liu
Growth differentiation factor 11 (GDF11) reduces cardiac hypertrophy, improves cerebral vasculature and enhances neurogenesis in ageing mice. Higher growth differentiation factor 11/8 (GDF11/8) is associated with lower risk of cardiovascular events in humans. Here, we showed that adeno-associated viruses-GDF11 and recombinant GDF11 protein improve endothelial dysfunction, decrease endothelial apoptosis, and reduce inflammation, consequently decrease atherosclerotic plaques area in apolipoprotein E(-/-) mice...
October 11, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27600399/contributions-of-mouse-and-human-hematopoietic-cells-to-remodeling-of-the-adult-auditory-nerve-after-neuron-loss
#6
Hainan Lang, Eishi Nishimoto, Yazhi Xing, LaShardai N Brown, Kenyaria V Noble, Jeremy L Barth, Amanda C LaRue, Kiyoshi Ando, Bradley A Schulte
The peripheral auditory nerve (AN) carries sound information from sensory hair cells to the brain. The present study investigated the contribution of mouse and human hematopoietic stem cells (HSCs) to cellular diversity in the AN following the destruction of neuron cell bodies, also known as spiral ganglion neurons (SGNs). Exposure of the adult mouse cochlea to ouabain selectively killed type I SGNs and disrupted the blood-labyrinth barrier. This procedure also resulted in the upregulation of genes associated with hematopoietic cell homing and differentiation, and provided an environment conducive to the tissue engraftment of circulating stem/progenitor cells into the AN...
October 4, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27562586/in-vivo-gene-delivery-to-lymph-node-stromal-cells-leads-to-transgene-specific-cd8-t-cell-anergy-in-mice
#7
Séverine Ciré, Sylvie Da Rocha, Maxime Ferrand, Mary K Collins, Anne Galy
Lymph node stromal cells play a role in self-tolerance by presenting tissue antigens to T cells. Yet, immunomodulatory properties of lymphoid tissue stroma, particularly toward CD4+ T cells, remain insufficiently characterized by lack of tools to target antigens for presentation by stromal cells. A lentiviral vector was therefore designed for antigen delivery to MHC class II(+) cells of nonhematopoietic origin. Following intravenous vector delivery, the transgene was detected in lymph node gp38+ stromal cells which were CD45- MHCII+ and partly positive for CD86 and CTLA4 or B7-H4...
October 4, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27545313/viral-vector-based-targeting-of-mir-21-in-cardiac-nonmyocyte-cells-reduces-pathologic-remodeling-of-the-heart
#8
Deepak Ramanujam, Yassine Sassi, Bernhard Laggerbauer, Stefan Engelhardt
Systemic inhibition of miR-21 has proven effective against myocardial fibrosis and dysfunction, while studies in cardiac myocytes suggested a protective role in this cell type. Considering potential implications for therapy, we aimed to determine the cell fraction where miR-21 exerts its pathological activity. We developed a viral vector-based strategy for gene targeting of nonmyocyte cardiac cells in vivo and compared global to cardiac myocyte-specific and nonmyocyte-specific deletion of miR-21 in chronic left ventricular pressure overload...
October 4, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27506452/adaptive-immune-response-impairs-the-efficacy-of-autologous-transplantation-of-engineered-stem-cells-in-dystrophic-dogs
#9
Clementina Sitzia, Andrea Farini, Luciana Jardim, Paola Razini, Marzia Belicchi, Letizia Cassinelli, Chiara Villa, Silvia Erratico, Daniele Parolini, Pamela Bella, Joao Carlos da Silva Bizario, Luis Garcia, Marcelo Dias-Baruffi, Mirella Meregalli, Yvan Torrente
Duchenne muscular dystrophy is the most common genetic muscular dystrophy. It is caused by mutations in the dystrophin gene, leading to absence of muscular dystrophin and to progressive degeneration of skeletal muscle. We have demonstrated that the exon skipping method safely and efficiently brings to the expression of a functional dystrophin in dystrophic CD133+ cells injected scid/mdx mice. Golden Retriever muscular dystrophic (GRMD) dogs represent the best preclinical model of Duchenne muscular dystrophy, mimicking the human pathology in genotypic and phenotypic aspects...
October 4, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27439899/tumor-regression-and-delayed-onset-toxicity-following-b7-h4-car-t-cell-therapy
#10
Jenessa B Smith, Evripidis Lanitis, Denarda Dangaj, Elizabeth Buza, Mathilde Poussin, Caitlin Stashwick, Nathalie Scholler, Daniel J Powell
B7-H4 protein is frequently overexpressed in ovarian cancer. Here, we engineered T cells with novel B7-H4-specific chimeric antigen receptors (CARs) that recognized both human and murine B7-H4 to test the hypothesis that B7-H4 CAR T cell therapy can be applied safely in preclinical models. B7-H4 CAR T cells specifically secreted IFN-γ and lysed B7-H4(+) targets. In vivo, B7-H4 CAR T cells displayed antitumor reactivity against B7-H4(+) human ovarian tumor xenografts. Unexpectedly, B7-H4 CAR T cell treatment reproducibly showed delayed, lethal toxicity 6-8 weeks after therapy...
October 4, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27506449/dual-therapeutic-action-of-a-neutralizing-anti-fgf2-aptamer-in-bone-disease-and-bone-cancer-pain
#11
Ling Jin, Yosuke Nonaka, Shin Miyakawa, Masatoshi Fujiwara, Yoshikazu Nakamura
Fibroblast growth factor 2 (FGF2) plays a crucial role in bone remodeling and disease progression. However, the potential of FGF2 antagonists for treatment of patients with bone diseases has not yet been explored. Therefore, we generated a novel RNA aptamer, APT-F2, specific for human FGF2 and characterized its properties in vitro and in vivo. APT-F2 blocked binding of FGF2 to each of its four cellular receptors, inhibited FGF2-induced downstream signaling and cells proliferation, and restored osteoblast differentiation blocked by FGF2...
September 27, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27658524/low-dose-gene-therapy-reduces-the-frequency-of-enzyme-replacement-therapy-in-a-mouse-model-of-lysosomal-storage-disease
#12
Marialuisa Alliegro, Rita Ferla, Edoardo Nusco, Chiara De Leonibus, Carmine Settembre, Alberto Auricchio
Enzyme replacement therapy (ERT) is the standard of care for several lysosomal storage diseases (LSDs). ERT, however, requires multiple and costly administrations and has limited efficacy. We recently showed that a single high dose administration of adeno-associated viral vector serotype 8 (AAV2/8) is at least as effective as weekly ERT in a mouse model of mucopolysaccharidosis type VI (MPS VI). However, systemic administration of high doses of AAV might result in both cell-mediated immune responses and insertional mutagenesis...
September 23, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27646604/the-mucus-barrier-to-inhaled-gene-therapy
#13
Gregg A Duncan, James Jung, Justin Hanes, Jung Soo Suk
Recent evidence suggests that the airway mucus gel layer may be impermeable to the viral and synthetic gene vectors used in past inhaled gene therapy clinical trials for diseases like cystic fibrosis. These findings support the logic that inhaled gene vectors that are incapable of penetrating the mucus barrier are unlikely to provide meaningful benefit to patients. In this review, we discuss the biochemical and biophysical features of mucus that contribute its barrier function, and how these barrier properties may be reinforced in patients with lung disease...
September 20, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27633444/remodeling-of-the-extracellular-matrix-by-endothelial-cell-targeting-sirna-improves-the-epr-based-delivery-of-100-nm-particles
#14
Yu Sakurai, Tomoya Hada, Shoshiro Yamamoto, Akari Kato, Wataru Mizumura, Hideyoshi Harashima, Akari Kato, Wataru Mizumura, Hideyoshi Harashima
A number of nano drug delivery systems (DDSs) have recently been developed for cancer treatment, most of which are based on the enhanced permeability and retention (EPR) effect. The advantages of the EPR effect can be attributed to immature vasculature. Herein we evaluated the intratumoral distribution of lipid nanoparticles (LNPs) when the VEGF receptor 2 (VEGFR2) on tumor endothelial cells was inhibited by liposomal siRNA. VEGFR2 inhibition resulted in an increase in intratumoral distribution and therapeutic efficacy despite the maturation of the tumor vasculature...
September 16, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27633442/the-niemann-pick-c1-inhibitor-np3-47-enhances-gene-silencing-potency-of-lipid-nanoparticles-containing-sirna
#15
Haitang Wang, Yuen Yi C Tam, Sam Chen, Josh Zaifman, Roy van der Meel, Marco A Ciufolini, Pieter R Cullis
The therapeutic applications of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA) are hampered by inefficient delivery of encapsulated siRNA to the cytoplasm following endocytosis. Recent work has shown that up to 70% of endocytosed LNP-siRNA particles are recycled to the extracellular medium and thus cannot contribute to gene silencing. Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal membrane protein required for efficient extracellular recycling of endosomal contents. Here we assess the influence of NP3...
September 16, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27818496/writing-the-next-chapter-for-the-molecular-therapy-family-of-journals
#16
EDITORIAL
Robert M Frederickson, Seppo Ylä-Herttuala
No abstract text is available yet for this article.
October 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27818495/corrigendum-to-inducible-hgf-secreting-human-umbilical-cord-blood-derived-mscs-produced-via-talen-mediated-genome-editing-promoted-angiogenesis
#17
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27818494/in-this-issue
#18
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27818493/preliminary-reports-of-stereotaxic-stem-cell-transplants-in-chronic-stroke-patients
#19
Cesar V Borlongan
No abstract text is available yet for this article.
October 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27818492/research-highlights
#20
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
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