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Contact: Corinne Williams
Journal of Clinical Investigation

JCI early table of contents for Nov. 15, 2013

Tipping the balance between senescence and proliferation

An arrest in cell proliferation, also referred to as cellular senescence, occurs as a natural result of aging and in response to cellular stress. Senescent cells accumulate with age and are associated with many aging phenotypes, and removal of these cells by the immune system is important for preventing cancer and other disorders. The tumor suppressor p53 coordinates a signaling network that is important for cell arrest. p53 is produced as various isoforms as the result of alternative splicing and promoter usage. One isoform, p53β, accelerates cellular arrest, while another isoform, Δ133p53 represses replicative senescence in cultured cells. In this issue of the Journal of Clinical Investigation, Abdul Mondal and colleagues at the National Cancer Institute evaluated the expression of these two p53 isoforms in T lymphocytes from healthy donors and donors with lung cancer. In healthy patients, the authors observed an age dependent accumulation of senescent cells and that these cells had an increase in p53β compared to Δ133p53. In lung tumor-associated cells, there was a higher level of the Δ133p53 isoform. Furthermore, in senescent cells, expression of Δ133p53 induced replication and proliferation, while induction of p53β in tumor-associated cells promoted senescence. This study defines the contribution of two p53 isoforms to senescence regulation, and suggests that altering the Δ133p53:p53β ratio may be an effect therapeutic strategy for treating immunosenescence disorders.

TITLE: p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes

Center for Cancer Research, NCI, NIH, Bethesda, MD, USA
Phone: 301-496-7358; Fax: 301-496-0497; E-mail: mondalam@mail.nih.gov

View this article at: http://www.jci.org/articles/view/70355?key=054fc22a1c3c779c7719

Persistent gene therapy in muscle may not require immunosuppression

Successful gene therapy is based on the effective delivery and maintained expression of healthy copies of a gene into tissues of individuals with a disease-associated genetic mutation. Recombinant adeno-associated virus (rAAV) vectors have shown promise in early clinical trials as effective therapies for several genetic diseases, including Leber congenital amaurosis, Parkinson disease, and hemophilia. Unfortunately, delivery of rAAV vectors to tissues other than the retina and CNS often results in development of an immune response against the viral capsid. The development of a neutralizing response against the rAAV vector prevents sustained expression of the healthy gene in the absence of immunosuppression. In this issue of the Journal of Clinical Investigation, Christian Mueller and colleagues at the University of Massachusetts Medical School evaluated the persistence of rAAV-mediated expression the gene encoding M-type α-1 antitrypsin (M-AAT) in patients that were AAT deficient. Patients received multiple intramuscular doses without immunosuppression, and M-ATT expression was evaluated in muscle biopsies. The authors determined that subjects sustained M-ATT expression in muscle tissue for at least one year, despite an initial influx of immune cells. Further evaluation of muscle fibers revealed a substantial population of regulatory T cells in patients with persistent M-ATT expression. Together, the results from this study suggests that delivery of an M-ATT-encoding rAAV vector promotes a regulatory immune response that allows for long term gene expression that does not require immune suppression.

TITLE: Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression

AUTHOR CONTACT: hristian Mueller
UMass Medical School, Worcester, MA, USA
Phone: 5088564358; E-mail: chris.mueller@umassmed.edu

View this article at: http://www.jci.org/articles/view/70314?key=27723e971d599c2f6ce6


Title: Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks

AUTHOR CONTACT: Michael Michaelides
Icahn School of Medicine at Mount Sinai, New York, USA.
Phone: 2128239002; E-mail: michael.michaelides@mssm.edu

View this article at: http://www.jci.org/articles/view/72117?key=6aa20a801c27a6da6766


TITLE: Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression

Icahn School of Medicine at Mount Sinai, New York, NY, USA
Phone: 2128249314; E-mail: yasmin.hurd@mssm.edu

View this article at: http://www.jci.org/articles/view/70395?key=fac41744fa3d85cad83b

TITLE: Systems pharmacology identifies drug targets for Stargardt disease-associated retinal degeneration

AUTHOR CONTACT: Krzysztof Palczewski
Case Western Reserve University, Cleveland, OH, USA
Phone: 216-368-4631; E-mail: kxp65@case.edu

View this article at: http://www.jci.org/articles/view/69076?key=93e58d97fb12d4d2be4d

TITLE: Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, , NLD
Phone: +31 88 755 4358; E-mail: hwang@umcutrecht.nl

View this article at: http://www.jci.org/articles/view/66241?key=606cb47333584245d158

TITLE: Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression

AUTHOR CONTACT: Sarah Ann Anderson
Icahn School of Medicine at Mount Sinai, New York, NY, USA
Phone: 2122419975; E-mail: sarahann.anderson@mssm.edu

View this article at: http://www.jci.org/articles/view/70395?key=fac41744fa3d85cad83b

TITLE: Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation

Peter MacCallum Cancer Center, East Melbourne, UNK, AUS
Phone: +61396561111; Fax: +61396561411; E-mail: david.thomas@petermac.org

View this article at: http://www.jci.org/articles/view/70559?key=a87386390e351e79063b

TITLE: Topical hypochlorite ameliorates NF-κB-mediated skin diseases in mice

Stanford University, School of Medicine, Stanford, CA, USA
Phone: 3102108988; E-mail: thomas.leung@gmail.com

View this article at: http://www.jci.org/articles/view/70895?key=1ea46ed9b18966f13390

TITLE: Inhibition of mitochondrial fragmentation diminishes Huntington's disease-associated neurodegeneration

Case Western Reserve University, Cleveland, , USA
Phone: 2163684459; E-mail: xxq38@case.edu

View this article at: http://www.jci.org/articles/view/70911?key=019d526fef8962547156

TITLE: Inhibition of the TRPC5 ion channel protects the kidney filter

Massachusetts General Hospital, Charlestown, MA, USA
Phone: (617) 726-9363; Fax: (617) 726-5669; E-mail: greka.anna@mgh.harvard.edu

View this article at: http://www.jci.org/articles/view/71165?key=e26e1234395ef52d73c5


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