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JCI table of contents: December 15, 2005

JCI Journals

EDITOR'S PICK
Fantastic voyage into the heart delivers a protector against heart failure
Reminiscent of the 1966 sci-fi thriller Fantastic Voyage, where a surgical team is miniaturized and injected into a dying man, researchers from Harvard Medical School have used injectable self-assembling peptide nanofibers loaded with the pro-survival factor PDGF-BB to protect rat cardiomyocytes from injury and subsequent heart failure. Their study appears online on December 15 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation.

Narrowed or blocked blood vessels are unable to deliver sufficient levels of oxygen to cardiomyocytes, which results in cardiomyocyte death, loss of the middle layer of the heart wall (the myocardium), and ultimately, heart failure. Therefore, therapies that protect cardiomyocytes from death may help prevent heart failure. In normal heart tissue, cardiomyocytes are surrounded by an intricate network of capillaries, and interaction of cardiomyocytes with endothelial cells that line the vessel wall and secrete PDGF-BB is integral to cardiomyocyte development and function. In the current study, Richard Lee and colleagues show that PDGF-BB has a direct pro-survival effect on cardiomyocytes. The authors went on to design a strategy in which short, self-assembling peptide nanofibers bind this pro-survival growth factor and, following injection into rat myocardium, facilitated prolonged and controlled delivery of PDGF-BB to the infarcted heart for up to 14 days. This strategy protected cardiomyocytes from injury, reduced infarct size, and preserved cardiac function. This effect could not be achieved by injecting nanofibers or PDGF-BB alone.

These nanofibers represent unique biomaterials able to deliver therapeutic agents directly to the injured tissue and as such hold great potential in the field of tissue regeneration, particularly following cardiac injury.

TITLE: Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers

AUTHOR CONTACT:
Richard T. Lee
Harvard Medical School, Boston, Massachusetts, USA
Phone: 617-768-8282; Fax: 617-768-8270; E-mail: rlee@rics.bwh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25878

EDITOR'S PICK
Standing up to paraplegia with gene therapy
Elena Rugarli and colleagues from the National Neurological Institute in Milan have used gene therapy to save sensory and skeletal muscle nerve fibers from degeneration in mice with hereditary spastic paraplegia (HSP). This strategy, reported online on December 15 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, holds promise for many other disorders characterized by nerve degeneration due to loss of function of a known gene.

Hereditary spastic paraplegia (HSP), a neurodegenerative disorder caused by progressive loss of sensory and skeletal muscle nerve fibers (axons), is characterized by weakness, spasticity, and impaired function of the lower limbs. The disorder is often due to mutations in the gene encoding the paraplegin protein. HSP sufferers are ultimately confined to a wheelchair, and currently there is no cure for the disease. In the current study, Rugarli and colleagues have shown that a one-time delivery of normal paraplegin by a viral vector to the spinal motor neurons of mice with HSP, before the onset of symptoms, was able to save axons from degeneration for up to 10 months.

Delivery of this mitochondrial energy-dependent protease improved motor function in the mice and these data show that delivery of an intracellular protein to spinal motor neurons by gene transfer may be useful not only for the treatment of HSP patients but also for those individuals with other forms of peripheral nerve damage of known genetic origin.

TITLE: Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia

AUTHOR CONTACT:
Elena I. Rugarli
National Neurological Institute, Milan, Italy
Phone: 39-02-23942614; Fax: 39-02-23942619; E-mail: rugarli@istituto-besta.it

View the PDF of this article at: https://www.the-jci.org/article.php?id=26210

ONCOLOGY
Chromosomal quality control keeps leukemia in check

Researchers from Tokyo Medical and Dental University have discovered how failure of a quality control checkpoint in the cell cycle during replication and division allows incorrectly re-joined breaks in chromosomal DNA to go unrepaired, causing leukemia. Their results will be reported online on December 15 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation.

After DNA replication (known as G2 phase in the cell cycle), but before mitosis (M phase), the enzyme topoisomerase II (Topo II) drives the momentary breaking and rejoining of double-stranded DNA, a process that controls DNA over- and under-winding. With nearly 6 feet of DNA rotating at high speed and being twisted and folded into a microscopic space during cell replication, our cells require several systems or "checkpoints" for interrupting the cell cycle if something goes wrong. In normal cells, the checkpoint kinase ATM (ataxia telangiectasia mutated) can halt the cell cycle and prompt any necessary DNA repair.

While etoposide, a Topo II inhibitor, has been used for over 20 years in the treatment of a variety of malignancies, an unfortunate complication of this treatment is increased DNA strand breaks, which damages DNA and leads to chromosomal breakage. When these breaks are repaired there is a high risk of rearrangement of the chromosome where segments are moved from one location to another either within the same chromosome or to another chromosome. Translocations involving the MLL gene on chromosome 11 often correlate with secondary leukemia. Shuki Mizutani and colleagues have now shown that in fibroblasts deficient in ATM it is failure of the early G2/M phase checkpoint to detect these etoposide-induced chromosomal abnormalities and arrest cell cycle progression that allows structural abnormalities in chromosome 11 to be retained during cell division.

The study demonstrates the important role of the early G2/M checkpoint in preventing permanent chromosomal abnormalities being carried through the cell cycle. The study also reveals how both environmental and genetic risk factors (exposure to Topo II inhibitors and dysfunctional G2/M checkpoint control, respectively) contribute to chromosome 11 band 23 translocations associated with secondary leukemia.

TITLE: Early G2/M checkpoint failure as a molecular mechanism underlying etoposide-induced chromosomal aberrations

AUTHOR CONTACT:
Shuki Mizutani
Tokyo Medical and Dental University, Tokyo, Japan
Phone: 81-3-5803-5244; Fax: 81-3-3818-7181; E-mail: smizutani.ped@tmd.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=25716

IMMUNOLOGY
Silencing SOCS1 cajoles the immune system to mount an anti-tumor response

By silencing a signaling inhibitor known as SOCS1 in dendritic cells, Baylor College of Medicine researchers have shown how a dendritic cell-based vaccine can cajole the immune system to break with convention and attack tumors and normal tissues that express self tumor-associated antigens. The study establishes a new principle for breaking "self-tolerance" - a concept that has long challenged anti-cancer vaccine scientists. The data will be reported online on December 15 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation.

One of the most important capabilities of the immune system is its ability to distinguish between the body's own tissues (self) and foreign invaders (non-self). The lack of an immune response against self is known as tolerance. One of the challenges in designing anti-cancer vaccines that trigger an effective anti-tumor immune response is that the majority of antigens that are recognized by tumor-killing T lymphocytes are also expressed in healthy tissue. This has left researchers asking how can we break "self-tolerance" and trigger the immune system to attack what it sees as self? In the current study, Si-Yi Chen and colleagues show that it is a signaling inhibitor - SOCS1 - that restricts the ability of dendritic cells to break self-tolerance and induce anti-tumor immunity. In tumor-bearing mice, immunization with SOCS1-deficient dendritic cells allowed unbridled IL-12 production and signaling, which triggered an effective anti-tumor immune response. The data may lay a foundation for developing more effective anti-tumor vaccines.

TITLE: SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling

AUTHOR CONTACT:
Si-Yi Chen
Baylor College of Medicine, Houston, Texas, USA
Phone: 713-798-1236; Fax: 713-798-1083; E-mail: sychen@bcm.tmc.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26169

IMMUNOLOGY
First link shown between LIG4 mutations and new SCID subtype

Patients with severe combined immunodeficiency (SCID) are devoid of mature B and T cells. A subset of these individuals are sensitive to ionizing radiation like that generated during X-rays, and the majority of these patients have mutations in the gene Artemis. In a study reported online on December 15 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, Dik van Gent and colleagues from University Medical Center Rotterdam document a patient with a new type of radiosensitive SCID. This individual had a defect in LIG4, a ligase crucial to DNA repair. The patient had very low levels of T and B cells, but showed no developmental defects. To date, LIG4 mutations have only been described in a radiosensitive leukemia patient and 4 individuals with a LIG4 syndrome characterized by developmental and growth abnormalities. The current study demonstrates that different LIG4 mutations can cause either a developmental defect with minor immunological abnormalities or a SCID syndrome characterized by normal development.

TITLE: A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation

AUTHOR CONTACT:
Dik C. van Gent
University Medical Center Rotterdam, The Netherlands
Phone: 31-10-4087932; Fax: 31-10-4089468; E-mail: d.vangent@erasmusmc.nl

View the PDF of this article at: https://www.the-jci.org/article.php?id=26121

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