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  1. Article ; Online: A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

    Vandenput, Liesbeth / Johansson, Helena / McCloskey, Eugene V / Liu, Enwu / Schini, Marian / Åkesson, Kristina E / Anderson, Fred A / Azagra, Rafael / Bager, Cecilie L / Beaudart, Charlotte / Bischoff-Ferrari, Heike A / Biver, Emmanuel / Bruyère, Olivier / Cauley, Jane A / Center, Jacqueline R / Chapurlat, Roland / Christiansen, Claus / Cooper, Cyrus / Crandall, Carolyn J /
    Cummings, Steven R / da Silva, José A P / Dawson-Hughes, Bess / Diez-Perez, Adolfo / Dufour, Alyssa B / Eisman, John A / Elders, Petra J M / Ferrari, Serge / Fujita, Yuki / Fujiwara, Saeko / Glüer, Claus-Christian / Goldshtein, Inbal / Goltzman, David / Gudnason, Vilmundur / Hall, Jill / Hans, Didier / Hoff, Mari / Hollick, Rosemary J / Huisman, Martijn / Iki, Masayuki / Ish-Shalom, Sophia / Jones, Graeme / Karlsson, Magnus K / Khosla, Sundeep / Kiel, Douglas P / Koh, Woon-Puay / Koromani, Fjorda / Kotowicz, Mark A / Kröger, Heikki / Kwok, Timothy / Lamy, Olivier / Langhammer, Arnulf / Larijani, Bagher / Lippuner, Kurt / McGuigan, Fiona E A / Mellström, Dan / Merlijn, Thomas / Nguyen, Tuan V / Nordström, Anna / Nordström, Peter / O'Neill, Terence W / Obermayer-Pietsch, Barbara / Ohlsson, Claes / Orwoll, Eric S / Pasco, Julie A / Rivadeneira, Fernando / Schott, Anne-Marie / Shiroma, Eric J / Siggeirsdottir, Kristin / Simonsick, Eleanor M / Sornay-Rendu, Elisabeth / Sund, Reijo / Swart, Karin M A / Szulc, Pawel / Tamaki, Junko / Torgerson, David J / van Schoor, Natasja M / van Staa, Tjeerd P / Vila, Joan / Wareham, Nicholas J / Wright, Nicole C / Yoshimura, Noriko / Zillikens, MCarola / Zwart, Marta / Harvey, Nicholas C / Lorentzon, Mattias / Leslie, William D / Kanis, John A

    Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA

    2024  Volume 35, Issue 3, Page(s) 469–494

    Abstract: The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and ... ...

    Abstract The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm.
    Introduction: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD).
    Methods: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients.
    Results: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men.
    Conclusions: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.
    MeSH term(s) Male ; Humans ; Female ; Osteoporotic Fractures/epidemiology ; Osteoporotic Fractures/etiology ; Prospective Studies ; Risk Assessment ; Cohort Studies ; Risk Factors ; Bone Density ; Hip Fractures/etiology ; Hip Fractures/complications
    Language English
    Publishing date 2024-01-17
    Publishing country England
    Document type Meta-Analysis ; Journal Article
    ZDB-ID 1064892-6
    ISSN 1433-2965 ; 0937-941X
    ISSN (online) 1433-2965
    ISSN 0937-941X
    DOI 10.1007/s00198-023-07012-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: 3D Conformations of Thick Synthetic Polymer Chains Observed by Cryogenic Electron Microscopy.

    Messmer, Daniel / Böttcher, Christoph / Yu, Hao / Halperin, Avraham / Binder, Kurt / Kröger, Martin / Schlüter, A Dieter

    ACS nano

    2019  Volume 13, Issue 3, Page(s) 3466–3473

    Abstract: The backbone conformations of individual, unperturbed synthetic macromolecules have so far not been observed directly in spite of their fundamental importance to polymer physics. Here we report the dilute solution conformations of two types of linear ... ...

    Abstract The backbone conformations of individual, unperturbed synthetic macromolecules have so far not been observed directly in spite of their fundamental importance to polymer physics. Here we report the dilute solution conformations of two types of linear dendronized polymers, obtained by cryogenic transmission electron stereography and tomography. The three-dimensional trajectories show that the wormlike chain model fails to adequately describe the scaling of these thick macromolecules already beyond a few nanometers in chain length, in spite of large apparent persistence lengths and long before a signature of self-avoidance appears. This insight is essential for understanding the limitations of polymer physical models, and it motivated us to discuss the advantages and disadvantages of this approach in comparison to the commonly applied scattering techniques.
    Language English
    Publishing date 2019-03-08
    Publishing country United States
    Document type Journal Article
    ISSN 1936-086X
    ISSN (online) 1936-086X
    DOI 10.1021/acsnano.8b09621
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Gene transfer into neural cells in vitro using adenoviral vectors.

    Southgate, Thomas / Kroeger, Kurt M / Liu, Chunyan / Lowenstein, Pedro R / Castro, Maria G

    Current protocols in neuroscience

    2008  Volume Chapter 4, Page(s) Unit 4.23

    Abstract: Adenoviral vectors are excellent vehicles to transfer genes into the nervous system due to their ability to transduce dividing and nondividing cells, their ability to be grown to very high titers, and their relatively large insert capacity. Also, ... ...

    Abstract Adenoviral vectors are excellent vehicles to transfer genes into the nervous system due to their ability to transduce dividing and nondividing cells, their ability to be grown to very high titers, and their relatively large insert capacity. Also, adenoviral vectors can sustain very long-term transgene expression in the CNS of rodents and in neurons and glial cells in culture. Successful gene transfer into the nervous system is dependent on the development, production, and quality control of vector preparations, which need to be of the highest quality. This unit provides protocols to clone, rescue, amplify, and purify first-generation adenoviral vectors. Detailed quality control assays are provided to ensure that vector preparations are devoid of contamination from replication-competent adenovirus and lipopolysaccharides. Also included are methodologies related to adenoviral-mediated gene transfer into neurons and glial cells in culture, and the analysis of transgene expression using immunocytochemistry, enzymatic assays, and fluorescence-activated cell sorting (FACS) analysis.
    MeSH term(s) Adenoviridae/genetics ; Animals ; Cell Culture Techniques/methods ; Cell Culture Techniques/standards ; Gene Expression/genetics ; Gene Transfer Techniques ; Genetic Vectors/genetics ; Mice ; Neuroglia/cytology ; Neuroglia/metabolism ; Neurons/cytology ; Neurons/metabolism ; Rats ; Transgenes/genetics
    Language English
    Publishing date 2008-09-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2179072-3
    ISSN 1934-8576 ; 1934-8584
    ISSN (online) 1934-8576
    ISSN 1934-8584
    DOI 10.1002/0471142301.ns0423s45
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Engineering the brain tumor microenvironment enhances the efficacy of dendritic cell vaccination: implications for clinical trial design.

    Mineharu, Yohei / King, Gwendalyn D / Muhammad, A K M G / Bannykh, Serguei / Kroeger, Kurt M / Liu, Chunyan / Lowenstein, Pedro R / Castro, Maria G

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2011  Volume 17, Issue 14, Page(s) 4705–4718

    Abstract: Purpose: Glioblastoma multiforme (GBM) is a deadly primary brain tumor. Clinical trials for GBM using dendritic cell (DC) vaccination resulted in antitumor immune responses. Herein, we tested the hypothesis that combining in situ (intratumoral) Ad-Flt3L/ ...

    Abstract Purpose: Glioblastoma multiforme (GBM) is a deadly primary brain tumor. Clinical trials for GBM using dendritic cell (DC) vaccination resulted in antitumor immune responses. Herein, we tested the hypothesis that combining in situ (intratumoral) Ad-Flt3L/Ad-TK-mediated gene therapy with DC vaccination would increase therapeutic efficacy and antitumor immunity.
    Experimental design: We first assessed the immunogenicity of tumor lysates generated by Ad-TK (+GCV), temozolomide (TMZ), or freeze/thawing cycles (FTC) in a syngeneic brain tumor model. We also assessed phenotypic markers, cytokine release, and phagocytosis of bone marrow-derived DCs generated by fms-like tyrosine kinase 3 ligand (Flt3L) + IL-6 or by granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL) 4. Inhibition of tumor progression and production of anti-GBM antibodies was assessed following vaccination with (i) tumor cell lysates, (ii) DCs generated with either Flt3L/IL-6 or GM-CSF/IL-4 loaded with either Ad-TK/GCV-, TMZ-, or FTC-generated tumor lysates, or (iii) DCs in combination with in situ Ad-Flt3L/Ad-TK gene therapy.
    Results: DCs loaded with tumor cell lysates generated with either Ad-TK/GCV or TMZ led to increased levels of phagocytosis, therapeutic efficacy, and humoral immune response. In situ immunogene therapy in combination with DC vaccination led to brain tumor regression and long-term survival in about 90% of animals, a significant increase when compared with either therapy alone.
    Conclusions: Our results indicate that modifying the tumor microenvironment using intratumoral Ad-Flt3L/Ad-TK-mediated gene therapy potentiates therapeutic efficacy and antitumor immunity induced by DC vaccination. These data support novel phase I clinical trials to assess the safety and efficacy of this combined approach.
    MeSH term(s) Adenoviridae/genetics ; Animals ; Brain Neoplasms/genetics ; Brain Neoplasms/immunology ; Brain Neoplasms/therapy ; Cancer Vaccines/immunology ; Cancer Vaccines/therapeutic use ; Cell Death/immunology ; Cell Line, Tumor ; Clinical Trials as Topic ; Cytokines/metabolism ; Dendritic Cells/immunology ; Dendritic Cells/transplantation ; Disease Models, Animal ; Gene Expression Regulation, Viral ; Genetic Therapy ; Genetic Vectors/genetics ; Glioblastoma/genetics ; Glioblastoma/immunology ; Glioblastoma/therapy ; Rats ; Thymidine Kinase/genetics ; Thymidine Kinase/metabolism ; Tumor Microenvironment/genetics ; Tumor Microenvironment/immunology
    Chemical Substances Cancer Vaccines ; Cytokines ; Thymidine Kinase (EC 2.7.1.21)
    Language English
    Publishing date 2011-06-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-11-0915
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Transforming an Academic Radiochemistry Facility for Positron Emission Tomography Drug cGMP Compliance.

    Zhu, Shaojun / Mosessian, Sherly / Kroeger, Kurt / Sadeghi, Saman / Slavik, Roger / Kinloch, Simon / Moore, Melissa / Allen-Auerbach, Martin / Czernin, Johannes / Phelps, Michael

    Molecular imaging and biology

    2019  Volume 22, Issue 2, Page(s) 256–264

    Abstract: In light of the United States Food and Drug Administration (FDA) requirement of 21 CFR 212 current Good Manufacturing Practice (cGMP) for FDA-approved position emission tomography (PET) drugs, the University of California Los Angeles (UCLA) Biomedical ... ...

    Abstract In light of the United States Food and Drug Administration (FDA) requirement of 21 CFR 212 current Good Manufacturing Practice (cGMP) for FDA-approved position emission tomography (PET) drugs, the University of California Los Angeles (UCLA) Biomedical Cyclotron (BMC) transformed from a pre-cGMP era academic cyclotron and radiochemistry facility to a current cGMP-compliant PET drug manufacturer. In this article, we share the financial and regulatory compliance aspects of the "transformation" required to develop a sustainable quality system to support the production of two PET drugs under Abbreviated New Drug Applications (ANDAs).
    MeSH term(s) California ; Cyclotrons ; Drug Approval ; Drug Industry/standards ; Facility Regulation and Control/standards ; Guideline Adherence ; Humans ; Positron-Emission Tomography/standards ; Quality Control ; Radiochemistry/methods ; Radiopharmaceuticals ; United States ; United States Food and Drug Administration ; Universities
    Chemical Substances Radiopharmaceuticals
    Language English
    Publishing date 2019-06-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2079160-4
    ISSN 1860-2002 ; 1536-1632
    ISSN (online) 1860-2002
    ISSN 1536-1632
    DOI 10.1007/s11307-019-01395-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Gene transfer into rat brain using adenoviral vectors.

    Puntel, Mariana / Kroeger, Kurt M / Sanderson, Nicholas S R / Thomas, Clare E / Castro, Maria G / Lowenstein, Pedro R

    Current protocols in neuroscience

    2010  Volume Chapter 4, Page(s) Unit 4.24

    Abstract: Viral vector-mediated gene delivery is an attractive procedure for introducing genes into the brain, both for purposes of basic neuroscience research and to develop gene therapy for neurological diseases. Replication-defective adenoviruses possess many ... ...

    Abstract Viral vector-mediated gene delivery is an attractive procedure for introducing genes into the brain, both for purposes of basic neuroscience research and to develop gene therapy for neurological diseases. Replication-defective adenoviruses possess many features which make them ideal vectors for this purpose-efficiently transducing terminally differentiated cells such as neurons and glial cells, resulting in high levels of transgene expression in vivo. Also, in the absence of anti-adenovirus immunity, these vectors can sustain very long-term transgene expression within the brain parenchyma. This unit provides protocols for the stereotactic injection of adenoviral vectors into the brain, followed by protocols to detect transgene expression or infiltrates of immune cells by immunocytochemistry or immunofluorescence. ELISPOT and neutralizing antibody assay methodologies are provided to quantitate the levels of cellular and humoral immune responses against adenoviruses. Quantitation of adenoviral vector genomes within the rat brain using qPCR is also described.
    MeSH term(s) Adenoviridae/genetics ; Animals ; Animals, Genetically Modified ; Brain/metabolism ; Brain/pathology ; Brain/virology ; Fluorescent Antibody Technique/methods ; Gene Transfer Techniques/adverse effects ; Genetic Vectors/adverse effects ; Immunohistochemistry/methods ; Neuroimmunomodulation ; Polymerase Chain Reaction/methods ; Rats ; Stereotaxic Techniques
    Language English
    Publishing date 2010-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2179072-3
    ISSN 1934-8576 ; 1934-8584
    ISSN (online) 1934-8576
    ISSN 1934-8584
    DOI 10.1002/0471142301.ns0424s50
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Gene therapy for brain cancer: combination therapies provide enhanced efficacy and safety.

    Candolfi, Marianela / Kroeger, Kurt M / Muhammad, A K M G / Yagiz, Kader / Farrokhi, Catherine / Pechnick, Robert N / Lowenstein, Pedro R / Castro, Maria G

    Current gene therapy

    2009  Volume 9, Issue 5, Page(s) 409–421

    Abstract: Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive ... ...

    Abstract Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM.
    MeSH term(s) Animals ; Behavior, Animal ; Brain Neoplasms/therapy ; Combined Modality Therapy ; Disease Models, Animal ; Dogs ; Genetic Therapy ; Glioblastoma/therapy ; Humans ; Rats
    Language English
    Publishing date 2009-05-16
    Publishing country United Arab Emirates
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2146187-9
    ISSN 1875-5631 ; 1566-5232
    ISSN (online) 1875-5631
    ISSN 1566-5232
    DOI 10.2174/156652309789753301
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Immune-mediated loss of transgene expression from virally transduced brain cells is irreversible, mediated by IFNγ, perforin, and TNFα, and due to the elimination of transduced cells.

    Zirger, Jeffrey M / Puntel, Mariana / Bergeron, Josee / Wibowo, Mia / Moridzadeh, Rameen / Bondale, Niyati / Barcia, Carlos / Kroeger, Kurt M / Liu, Chunyan / Castro, Maria G / Lowenstein, Pedro R

    Molecular therapy : the journal of the American Society of Gene Therapy

    2012  Volume 20, Issue 4, Page(s) 808–819

    Abstract: The adaptive immune response to viral vectors reduces vector-mediated transgene expression from the brain. It is unknown, however, whether this loss is caused by functional downregulation of transgene expression or death of transduced cells. Herein, we ... ...

    Abstract The adaptive immune response to viral vectors reduces vector-mediated transgene expression from the brain. It is unknown, however, whether this loss is caused by functional downregulation of transgene expression or death of transduced cells. Herein, we demonstrate that during the elimination of transgene expression, the brain becomes infiltrated with CD4(+) and CD8(+) T cells and that these T cells are necessary for transgene elimination. Further, the loss of transgene-expressing brain cells fails to occur in the absence of IFNγ, perforin, and TNFα receptor. Two methods to induce severe immune suppression in immunized animals also fail to restitute transgene expression, demonstrating the irreversibility of this process. The need for cytotoxic molecules and the irreversibility of the reduction in transgene expression suggested to us that elimination of transduced cells is responsible for the loss of transgene expression. A new experimental paradigm that discriminates between downregulation of transgene expression and the elimination of transduced cells demonstrates that transduced cells are lost from the brain upon the induction of a specific antiviral immune response. We conclude that the anti-adenoviral immune response reduces transgene expression in the brain through loss of transduced cells.
    MeSH term(s) Adenoviridae/genetics ; Animals ; Brain/cytology ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Flow Cytometry ; Immunohistochemistry ; Interferon-gamma/metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; Perforin/metabolism ; Transduction, Genetic/methods ; Transgenes/genetics ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances Tumor Necrosis Factor-alpha ; Perforin (126465-35-8) ; Interferon-gamma (82115-62-6)
    Keywords covid19
    Language English
    Publishing date 2012-01-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1038/mt.2011.243
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Cytotoxic immunological synapses do not restrict the action of interferon-γ to antigenic target cells.

    Sanderson, Nicholas Stephen Rennie / Puntel, Mariana / Kroeger, Kurt M / Bondale, Niyati S / Swerdlow, Mark / Iranmanesh, Niloufar / Yagita, Hideo / Ibrahim, Ahmed / Castro, Maria G / Lowenstein, Pedro R

    Proceedings of the National Academy of Sciences of the United States of America

    2012  Volume 109, Issue 20, Page(s) 7835–7840

    Abstract: Following antigen recognition on target cells, effector T cells establish immunological synapses and secrete cytokines. It is thought that T cells secrete cytokines in one of two modes: either synaptically (i.e., toward antigenic target cells) or ... ...

    Abstract Following antigen recognition on target cells, effector T cells establish immunological synapses and secrete cytokines. It is thought that T cells secrete cytokines in one of two modes: either synaptically (i.e., toward antigenic target cells) or multidirectionally, affecting a wider population of cells. This paradigm predicts that synaptically secreted cytokines such as IFN-γ will preferentially signal to antigenic target cells contacted by the T cell through an immunological synapse. Despite its physiological significance, this prediction has never been tested. We developed a live-cell imaging system to compare the responses of target cells and nonantigenic bystanders to IFN-γ secreted by CD8+, antigen-specific, cytotoxic T cells. Both target cells and surrounding nontarget cells respond robustly. This pattern of response was detected even at minimal antigenic T-cell stimulation using low doses of antigenic peptide, or altered peptide ligands. Although cytotoxic immunological synapses restrict killing to antigenic target cells, the effects of IFN-γ are more widespread.
    MeSH term(s) Adenoviridae ; Analysis of Variance ; Astrocytes/immunology ; Genetic Vectors/genetics ; Green Fluorescent Proteins ; Image Processing, Computer-Assisted ; Immunological Synapses/immunology ; Interferon-gamma/immunology ; Interferon-gamma/metabolism ; Microscopy/methods ; T-Lymphocytes, Cytotoxic/immunology
    Chemical Substances Green Fluorescent Proteins (147336-22-9) ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2012-04-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1116058109
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: implications for a glioma phase 1 clinical trial.

    Muhammad, A K M Ghulam / Xiong, Weidong / Puntel, Mariana / Farrokhi, Catherine / Kroeger, Kurt M / Salem, Alireza / Lacayo, Liliana / Pechnick, Robert N / Kelson, Kyle R / Palmer, Donna / Ng, Philip / Liu, Chunyan / Lowenstein, Pedro R / Castro, Maria G

    Human gene therapy methods

    2012  Volume 23, Issue 4, Page(s) 271–284

    Abstract: Adenoviral vectors (Ads) have been evaluated in clinical trials for glioma. However, systemic immunity against the vectors can hamper therapeutic efficacy. We demonstrated that combined immunostimulation and cytotoxic gene therapy provides long-term ... ...

    Abstract Adenoviral vectors (Ads) have been evaluated in clinical trials for glioma. However, systemic immunity against the vectors can hamper therapeutic efficacy. We demonstrated that combined immunostimulation and cytotoxic gene therapy provides long-term survival in preclinical glioma models. Because helper-dependent high-capacity Ads (HC-Ads) elicit sustained transgene expression, in the presence of antiadenoviral immunity, we engineered HC-Ads encoding conditional cytotoxic herpes simplex type 1 thymidine kinase and immunostimulatory cytokine Fms-like tyrosine kinase ligand-3 under the control of the TetOn system. Escalating doses of combined HC-Ads (1×10(8), 1×10(9), and 1×10(10) viral particles [VP]) were delivered into the rat brain. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points after vector delivery. Histopathological analysis did not reveal any evidence of toxicity or long-term inflammation at the lower doses tested. Vector genomes were restricted to the injection site. Serum chemistry did not uncover adverse systemic side effects at any of the doses tested. Taken together, our data indicate that doses of up to 1×10(9) VP of each HC-Ad can be safely administered into the normal brain. This comprehensive toxicity and biodistribution study will lay the foundations for implementation of a phase 1 clinical trial for GBM using HC-Ads.
    MeSH term(s) Adenoviridae/genetics ; Animals ; Behavior, Animal/drug effects ; Blood Chemical Analysis ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Clinical Trials, Phase I as Topic ; Disease Models, Animal ; Genetic Vectors/genetics ; Genetic Vectors/metabolism ; Genetic Vectors/toxicity ; Glioma/therapy ; Herpesvirus 1, Human/enzymology ; Humans ; Male ; Rats ; Rats, Inbred Lew ; Thymidine Kinase/genetics ; Tissue Distribution ; Transduction, Genetic ; fms-Like Tyrosine Kinase 3/genetics
    Chemical Substances Thymidine Kinase (EC 2.7.1.21) ; FLT3 protein, human (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
    Language English
    Publishing date 2012-09-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2654800-8
    ISSN 1946-6544 ; 1946-6536
    ISSN (online) 1946-6544
    ISSN 1946-6536
    DOI 10.1089/hgtb.2012.060
    Database MEDical Literature Analysis and Retrieval System OnLINE

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