Resistance to chemotherapy causes cancer treatment to be unsuccessful and is responsible for high mortality rates as a result. A number of genetic alterations are involved in chemotherapy resistance. In a study appearing online on May 12 in advance of the print publication of the June issue of the Journal of Clinical Investigation, Isabella Tai and colleagues from the University of British Columbia identify a new protein involved in tumor therapy resistance.
The authors use microarray analysis to identify genes that were involved in the resistance of cancer to chemotherapy. They identified a protein called SPARC, which was poorly expressed in human colon cells that were noncompliant to radiation and chemotherapy. Restoration of treatment sensitivity was achieved by re-expressing SPARC in these resistant cells. Treating mice with SPARC increased their sensitivity to chemotherapy and caused reduction of tumors. SPARC-based therapy could thus be useful for enhancing cancer treatment.
TITLE: Genome-wide expression analysis of therapy resistant tumors reveals SPARC as a novel target for cancer therapy
AUTHOR CONTACT:
Isabella Tai
University of British Columbia, Vancouver, BC Canada
Phone: 604 707-5965; Fax: 604 875-5447; E-mail: itai@bcgsc.ca
View the PDF of this article at: https://www.the-jci.org/article.php?id=23002
PHYSIOLOGY
No breathing easy with C5
Asthma is characterized by chronic inflammation and obstruction of the airways. The role of one protein, called complement component C5, in asthma has remained controversial. In a study appearing online on May 12 in advance of the print publication of the June issue of the Journal of Clinical Investigation, Yi Wang and colleagues from Alexion Pharmaceuticals examine the contribution of C5 during the course of asthma. The authors find that C5 is activated in the lungs after infection or exposure to allergens. C5 contributes to airway inflammation, development of hyperreactivity, and to sustained airway responses to allergens by triggering the release of inflammatory molecules. Thus, blocking C5 in the lung may be useful for treating patients with asthma.
TITLE: Role of C5 in the development of airway inflammation, airway hyperresponsiveness and ongoing airway response
AUTHOR CONTACT:
Yi Wang
Alexion Pharmaceuticals Inc, Cheshire, CT USA
Phone: 203 271 8247; Fax: 203 271 8195; E-mail: wangy@alxn.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=22906
PHYSIOLOGY
BMP bumps up hope for joint diseases
Spondyloarthropathies are chronic joint diseases characterized by inflammation associated with pathological cartilage and bone formation at the attachment of tendons and ligaments. Immune-modulating drugs are used to treat these diseases, but it is not clear whether these drugs inhibit disease progression. New strategies targeting cartilage and bone formation are likely to be required to control the disease.
In a study appearing online on May 12 in advance of the print publication of the June issue of the Journal of Clinical Investigation, Frank Luyten and colleagues from Katholieke University in Leuven use a mouse model to identify the potential role of a protein involved in embryonic bone formation – called bone morphogenetic protein (BMP) – in spondyloarthropathies. The authors find that inhibiting BMP with a molecule called noggin halts the disease process both as a preventive and as a therapeutic strategy. The data suggest that BMP signaling pathways may be therapeutic targets for ameliorating spondyloarthropathies.
TITLE: Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis
AUTHOR CONTACT:
Frank P. Luyten
Katholieke Universiteit Leuven, Leuven, BEL
Phone: 32-16-346341; Fax: 32-16-346200; E-mail: Frank.Luyten@uz.kuleuven.ac.be
View the PDF of this article at: https://www.the-jci.org/article.php?id=23738
PHYSIOLOGY
Gitelman's syndrome gets a clue
Thiazide diuretics are used to treat hypertension and they work be enhancing sodium excretion by inhibiting a protein in the kidney called NCC. Mutations in the gene that encodes the NCC protein cause a disease called Gitelman's Syndrome, which is characterized by low calcium and magnesium levels and kidney problems.
The molecular mechanisms explaining hypocalciuria resulting from NCC mutations and thiazides were unknown. In a study appearing online on May 12 in advance of the print publication of the June issue of the Journal of Clinical Investigation, Rene Bindels and colleagues from Radboud University explore these mechanisms. The authors show that hypocaliuria is caused by increased calcium reabsorption in the kidney. This paper explains the mechanism of thiazide-induced hypocalciuria and provides new insight into thiazide treatment and Gitelman's syndrome.
TITLE: Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia
AUTHOR CONTACT:
Rene Bindels
Radboud University Medical Center, Nijmegen The Netherlands
Phone: +31-24-3614211; Fax: +31-24-3616413; E-mail: r.bindels@ncmls.ru.nl
View the PDF of this article at: https://www.the-jci.org/article.php?id=24134
CARDIOLOGY
Heart defects may find a cure in Gata4
Congenital heart defects are the most common abnormality in newborns. Mutations in single genes involved in development have been found to cause some cases of congenital heart defects. One such gene is Gata4, mutations of which are found in humans, and which have been associated with a congenital heart disease due to muscular defects.
In a study appearing online on May 12 in advance of the print publication of the June issue of the Journal of Clinical Investigation, William Pu and colleagues from Harvard University evaluate the function of Gata4 in the heart muscle. The researchers inactivate Gata4 in the myocardium early or late in heart development. They find that Gata4 regulates the formation of the right ventricle in a stage-specific and dose-specific manner. Gata4 is also essential for normal rates of cardiomyocyte proliferation, and for formation of the heart valves. These results suggest that Gata4 is a candidate gene for congenital heart disease associated with defective development of the right ventricle.
TITLE: Formation of the right ventricle requires myocardial expression of Gata4
AUTHOR CONTACT:
Williams Pu
Harvard Medical School, Boston, MA USA
Phone: 617-667-4619; Fax: 617-730-0140; E-mail: wpu@enders.tch.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23769
Journal
Journal of Clinical Investigation