News From The Journal Of Clinical Investigation May 18, 2009
The muscle damage that occurs in individuals with Duchenne muscular dystrophy (DMD) is associated with inflammation that, in turn, can make the muscle damage worse. To identify potential drug targets that could break this cycle of progressive muscle degeneration, Melissa Spencer and colleagues, at the UCLA David Geffen School of Medicine, Los Angeles, analyzed the inflammatory and immune responses in damaged muscle in mdx mice, a model of DMD. Of particular interest, a molecule known as OPN, which promotes immune cell migration and survival, was found to be expressed at high levels in the serum of mdx mice and muscle biopsies after disease onset. Further, increased levels of OPN were also detected in muscle biopsies from individuals with DMD. As mdx mice lacking OPN exhibited increased muscle strength and reduced scarring of the diaphragm and heart, the authors suggest that targeting OPN might be of benefit to individuals with DMD.
TITLE: Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta
Melissa J. Spencer
UCLA David Geffen School of Medicine, Los Angeles, California, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37662
ONCOLOGY: New tool for predicting drug responsiveness in non-small cell lung cancer
A team of researchers, at the Max Planck Institute for Neurological Research, Germany, and the Dana-Farber Cancer Institute, Harvard Medical School, Boston, has developed a new genomics approach that enabled them to predict whether non-small cell lung cancers (NSCLCs) will respond to specific therapeutics in vitro and in mouse models of lung cancer. They hope that this information can be translated into clinical practice.
The team, led by Roman Thomas, Kwok-Kin Wong, and Matthew Meyerson, determined that the genomes of a large panel of human NSCLC cell lines are highly representative of those of primary NSCLC tumors. Using this panel of cell lines they identified genomic and molecular indicators of a response to clinically relevant drugs. For example, cell lines with an increased number of copies of the ABL2 gene and/or an increased number of copies of the Ephrin receptor kinase and SRC kinase family genes were sensitive to treatment with a clinically used SRC/ABL inhibitor (dasatinib), both in vitro and when they were xenografted into mice. The authors suggest that the cell line collection characterized here will provide a tool for investigating the effect of potential new anticancer drugs in genomically defined cancer types and thereby help define the patients for which a drug will be most effective.
TITLE: Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions
Roman K. Thomas
Max Planck Institute for Neurological Research, Köln, Germany.
Kwok-Kin Wong, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37127
ONCOLOGY: No response to TGF-beta is bad for those with breast cancer
In human breast cancer, poor prognosis has been associated with loss of the cancer cell's response to signaling triggered by the molecule TGF-beta. To understand this association more clearly, Harold Moses and colleagues, at Vanderbilt University, Nashville, used mouse breast cancer cell lines to generate gene expression signatures of breast cancer cells not responsive to TGF-beta and those cells responsive to the molecule. These gene expression signatures were then compared with four existing human breast cancer data sets containing gene expression profiles and associated clinical outcome data for 1,319 patients. The gene signature representative of no response to TFG-beta correlated with reduced, relapse-free survival in all patients. This association was particularly strong in patients with estrogen receptor-positive cancer, specifically those with the luminal A subtype of breast cancer. The authors therefore suggest that assessing TGF-beta responsiveness might provide an accurate prognosis to patients with estrogen receptor-positive breast cancer and indicate those patients that would benefit most from aggressive therapy.
TITLE: Abrogation of TGF-beta signaling enhances chemokine production and correlates with prognosis in human breast cancer
Harold L. Moses
Vanderbilt University, Nashville, Tennessee, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37480
IMMUNOLOGY: New insights into a rare human syndrome
Individuals with LigIV syndrome have any combination of a number of symptoms including immunodeficiency and growth retardation. It is caused by mutations in the LIG4 gene that decrease but do not eliminate gene expression. Mice with a Lig4 gene mutation that dramatically reduces LigIV activity (Lig4Y288C mice) have recently been identified and shown to recapitulate the immunodeficiency and growth retardation seen in human patients with LigIV syndrome. Richard Cornall and colleagues, at Oxford University, United Kingdom, have now characterized in these mice defects in the development, function, survival, and proliferation of immune cells known as lymphocytes that may well bring about the immunodeficiency observed in individuals with LigIV syndrome. They also observed an abnormally high incidence of cancers arising in the thymus, the organ where T cells develop, leading them to suggest that these tumors and the T cell leukemias reported in some patients with LigIV syndrome may arise through similar mechanisms.
TITLE: Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome
Richard J. Cornall
Oxford University, Oxford, United Kingdom.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32743
NEPHROLOGY: The protein midkine is a regulator of blood pressure
A hormone cascade known as the renin-angiotensin system has a key role in regulating blood pressure and kidney function. Kenji Kadomatsu and his colleagues, at Nagoya University Graduate School of Medicine, Japan, have now identified a new regulator of the mouse renin-angiotensin system: the protein midkine.
In the study, both normal mice and mice lacking the protein midkine were studied after they had undergone a surgical procedure known as 5/6 nephrectomy, which is when one kidney is completely removed and two thirds of the other kidney is removed. Using this approach it was determined that midkine regulates the activity of ACE, a known controller of blood pressure that is the target of many drugs that lower blood pressure. Furthermore, midkine administration to midkine-deficient mice that had undergone 5/6 nephrectomy restored blood pressure and ACE activity to levels found in 5/6 nephrectomized normal mice. The authors conclude from these results that midkine is an important regulator of the renin-angiotensin system.
TITLE: The growth factor midkine regulates the renin-angiotensin system in mice
Nagoya University Graduate School of Medicine, Nagoya, Japan.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37249
HEMATOLOGY: How to get gene signatures from small clinical samples
Timothy Ley and colleagues, at Washington University Medical School, St. Louis, have used a newly developed high throughput digital technology (NanoString nCounter) to show that biomarkers of disease can be measured using very small amounts of clinical material.
In the study, traditional microarray approaches were used to identify a gene expression signature that is specific to a subtype (M3) of acute myeloid leukemia. The new high throughput technology was then used to validate the M3-specific gene signature because of the small size of the patient samples. Nearly all of the genes tested demonstrated highly significant statistical agreement with the microarray data and were enriched in a mouse model of the condition. The authors therefore conclude that the NanoString nCounter Analysis System is a useful tool to quantify the mRNA abundance of a large number of genes from an expression signature using very small amounts of clinical material and that this method will provide a valuable diagnositic tool.
TITLE: High throughput digital quantification of mRNA abundance in primary human acute myeloid leukemia samples
Timothy J. Ley
Washington University Medical School, St. Louis, Missouri, USA.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38248
Journal of Clinical Investigation