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JCI online early table of contents: June 1, 2011
Date:6/1/2011

EDITOR'S PICK: Reducing a severe side effect of a common anticancer drug

Cisplatin is one of the most widely used anticancer chemotherapeutics. However, it has some severe side effects in normal tissues, in particular it is toxic to the kidneys. Understanding the mechanisms underlying this toxicity could identify targets for drugs that could be given together with cisplatin to protect the kidney during chemotherapy. In this context, a team of researchers, led by Zheng Dong, at Georgia Health Sciences University, Augusta, has now identified the signaling protein PKC-delta as a critical regulator of cisplatin-mediated kidney toxicity in mice. Importantly, inhibiting PKC-delta not only protected the kidneys from the toxic effects of cisplatin but also enhanced the antitumor effects of the drug in several xenograft and syngeneic mouse tumor models. The team therefore suggests that targeting PKC-delta could help reduce the severe kidney toxicity that occurs in cancer patients undergoing chemotherapy with cisplatin and other cisplatin-based chemotherapeutics.

TITLE: Inhibition of PKC-delta reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer

AUTHOR CONTACT:
Zheng Dong
Medical College of Georgia and Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
Phone: 706.721.2825; Fax: 706.721.6120; E-mail: zdong@mail.mcg.edu.

View this article at: http://www.jci.org/articles/view/45586?key=93f34735232ae0bf2ab0


ONCOLOGY: Subdivisions reveal effective therapies in triple-negative breast cancer

Breast cancers can be divided into different types based on several criteria, including the marker proteins they express. Treatment of breast cancers lacking expression of the proteins to which hormones bind (so called triple-negative breast cancers [TNBCs]) is difficult because they are a highly diverse group of cancers and associated with poor clinical outcome. If TNBCs could be divided into different subtypes it might be easier to identify good treatment options. A team of researchers, led by Jennifer Pietenpol, at Vanderbilt University School of Medicine, Nashville, has generated new insight into this issue by analyzing gene expression profiles from 587 TNBC cases. Using this approach, they characterized 6 subtypes of TNBC. For each subtype, the team identified a therapeutic that impaired growth more effectively for cells of that subtype than for cells of the other subtypes. The authors hope that their data will help physicians target therapeutic strategies more effectively in TNBC patients, improving clinical outcome.

TITLE: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

AUTHOR CONTACT:
Jennifer A. Pietenpol
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: 615.936.1512; Fax: 615.936.2294; E-mail: j.pietenpol@vanderbilt.edu.

View this article at: http://www.jci.org/articles/view/45014?key=492c9f001d43d8687d1f


ONCOLOGY: Not all breast tumor cells are created equal: how to target the bad guys

Not all cells in a tumor are identical. It has been proposed that cells in a tumor with stem celllike characteristics drive both the spread of the tumor to distant sites and the development of resistance to commonly used anticancer drugs. A team of researchers, led by Kornelia Polyak, at Dana-Farber Cancer Institute and Harvard Medical School, Boston, has now identified a potential way to target human breast cancer stem celllike cells.

In previous studies, Polyak and colleagues identified in human breast tumors cells expressing the protein CD44 but lacking the protein CD24 as having stem celllike characteristics. In the current study, they identified a signaling pathway that was preferentially active in these stem celllike human breast tumor cells compared with other cells in human breast tumors. Inhibiting one component of the pathway (JAK2) decreased the number of CD44+CD24 stem celllike cells in human breast tumor xenografts and blocked tumor growth. The team therefore suggests that targeting JAK2 might provide an effective breast cancer therapy.

TITLE: The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24 stem celllike breast cancer cells in human tumors

AUTHOR CONTACT:
Kornelia Polyak
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.632.2106; Fax: 617.582.8490; E-mail: Kornelia_Polyak@dfci.harvard.edu.

View this article at: http://www.jci.org/articles/view/44745?key=53886a638d416428eb9a


HIV/AIDS: Combating exhaustion in immune cells

Infection with HIV compromises the immune system, making it hard for infected individuals to fight off the HIV infection. It also makes them more susceptible to infection with other microbes. The compromised function of immune cells known as B cells arises because they are exhausted by continually having to respond to HIV. Exhaustion manifests itself by the expression of proteins on the B cell surface that inhibit function. Susan Moir and colleagues, at the National Institutes of Health, Bethesda, have now found that downregulating the expression of any one of 9 known and putative B cell inhibitory cell-surface proteins on exhausted B cells from individuals infected with HIV enhanced their in vitro proliferation and function. Moir and colleagues therefore suggest that strategies aimed at reversing the effects of inhibitory cell-surface proteins may enhance immune responses in individuals infected with HIV. As exhausted B cells are also found in individuals infected with other persisting viruses, this approach might also be of benefit for these individuals.

TITLE: Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors

AUTHOR CONTACT:
Susan Moir
National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.402.4559; Fax: 301.402.5920; E-mail: smoir@niaid.nih.gov.

View this article at: http://www.jci.org/articles/view/45685?key=d4d8ca7298e021ee9273


CARDIOVASCULAR DISEASE: Pinpointing a new role for immune cells in hardening of the arteries

One of the major causes of heart attack and stroke is atherosclerosis a disease of the major arterial blood vessels that is sometimes known as hardening of the arteries. While it is known that atherosclerosis is a chronic inflammatory condition, the role of some immune cells, including dendritic cells, has not been clearly determined. However, a team of researchers led by Alma Zernecke, at the University of Wrzburg, Germany, and Christian Weber, at Ludwig-Maximilians-Universitt, Germany has now generated data in mice and humans that define a role for dendritic cells in the development of atherosclerosis. As atherosclerosis-prone mice lacking the protein CCL17 (which attracts dendritic cells) or treated with an inhibitor of CCL17 showed reduced atherosclerosis, the team suggests that CCL17 might provide a viable target for the treatment of atherosclerosis.

TITLE: CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice

AUTHOR CONTACT:
Alma Zernecke
Rudolf-Virchow-Zentrum/DFGForschungszentrum fr Experimentelle Biomedizin der Universitt Wrzburg, Wrzburg, Germany.
Phone: 49.0.931.31.80373; Fax: 49.0.931.31.83255; E-mail: alma.zernecke@virchow.uni-wuerzburg.de.

Christian Weber
Klinikum der Universitt Mnchen, Ludwig-Maximilians-Universitt, Munich, Germany.
Phone: 49.89.5160.4350; Fax: 49.89.5160.4352; E-mail: christian.weber@med.uni-muenchen.de.

View this article at: http://www.jci.org/articles/view/44925?key=641d5041af0225762156


CARDIOLOGY: The protein GATA5 ensures one-way traffic in the heart

Critical to the functioning of the heart are the heart valves. Heart valves ensure that blood flows in only one direction through the heart; valve dysfunction results in severe complications. The aortic valve lies between the major blood vessel that leaves the heart and the lower left chamber of the heart. It usually has three leaflets, but 1%𔃀% of the population is born with only two aortic valve leaflets, making bicuspid aortic valve (BAV) the leading congenital heart disease. Thus far, mutations in only one gene (NOTCH1) have been linked to BAV in humans. However, Mona Nemer and colleagues, at the University of Montreal, Montreal, have now generated data in mice that suggest that mutations in GATA5 could be responsible for congenital heart disease in humans.

TITLE: Loss of GATA5 in mice leads to bicuspid aortic valve

AUTHOR CONTACT:
Mona Nemer
University of Ottawa, Ottawa, Ontario, Canada.
Phone: 613.562.5270; Fax: 613.562.5271; E-mail: mona.nemer@uottawa.ca.

View this article at: http://www.jci.org/articles/view/44555?key=3e05f5f35193f7574355


GENETICS: New gene linked to the developmental disorder Joubert syndrome

Joubert syndrome (JBTS) is a developmental disorder characterized by a specific brain malformation and various other problems, including degeneration of the retina. Until now, mutations in any one of ten genes have been implicated in JBTS. A new gene has now been added to this list by a team of researchers led by Hanno Bolz, at the Bioscientia Center for Human Genetics, Germany, and Bernhard Schermer, at the University of Cologne, Germany that identified several individuals with JBTS caused by mutations in the gene KIF7. Further analysis led the team to suggest that loss-of-function mutations in KIF7 likely contribute to JBTS by altering the stability and dynamics of cellular components known as microtubules and thereby modifying the direction of cell growth.

TITLE: Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics

AUTHOR CONTACT:
Hanno J. Bolz
Bioscientia Center for Human Genetics, Ingelheim, Germany.
Phone: 496132.781.206; Fax: 496132.781.298; E-mail: hanno.bolz@uk-koeln.de.

Bernhard Schermer
University of Cologne, Cologne, Germany.
Phone: 49.221.478.89030; Fax: 49.221.478.89041; E-mail: bernhard.schermer@uk-koeln.de.

View this article at: http://www.jci.org/articles/view/43639?key=ac3acb482f0dda5b6442


VASCULAR BIOLOGY: Integrated approach to controlling blood vessel growth

After birth, blood vessel growth occurs via two distinct processes, angiogenesis and arteriogenesis. Angiogenesis refers to the sprouting of new blood vessels from pre-existing vessels, arteriogenesis refers to an increase in the diameter of existing arterial blood vessels. Blood vessel growth requires the integrated action of several growth factors, including FGF and VEGF; but how the signaling pathways triggered by these two critical factors interact has not been determined. Now, a team of researchers, led by Michael Simons, at Yale University, New Haven, has determined in mice that basal FGF stimulation of blood vessellining cells is required for them to maintain expression of a protein to which VEGF binds (VEGFR2) and to respond to VEGF stimulation. Importantly, FGF-driven VEGFR2 expression was found to be required for both angiogenesis and arteriogenesis in mice. The team suggests that combined anti-FGF and anti-VEGF therapy might provide a more effective way to prevent blood vessel growth than anti-VEGF therapy alone, which is currently used for the treatment of some forms of cancer.

TITLE: FGF-dependent regulation of VEGF receptor 2 expression in mice

AUTHOR CONTACT:
Michael Simons
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203.785.7000; Fax: 203.785.5144; E-mail: michael.simons@yale.edu.

View this article at: http://www.jci.org/articles/view/44762?key=ba64bffd2aa607a85c6b


HEPATOLOGY: Pathway to proliferation in the liver

The drug rapamycin is used to suppress the immune system of patients who have received a kidney transplant. Among its many effects on cells is an ability to stop them proliferating; hence, there are ongoing clinical trails investigating its potential as an anticancer therapeutic. Identifying the molecular pathway downstream of the protein that is the target of rapamycin (mTOR) that promotes cell proliferation is important for understanding how rapamycin and related drugs might work in the disease states in which they are expected to be beneficial. In this context, a team of researchers, led by Mario Pende, at Universit Paris Descartes, UMRS-845, France, has now determined that the protein S6K1 is required for rapamycin-sensitive proliferation of liver cells. S6K1 was found to control level of the protein cyclin D1, expression of which was required to promote liver cell proliferation. The authors suggest this pathway is likely to be behind the high rate of proliferation of cancer cells with high levels of mTOR activity and cyclin D1 expression.

TITLE: S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy

AUTHOR CONTACT:
Mario Pende
Universit Paris Descartes, UMRS-845, Paris, France.
Phone: 33.1.40.61.53.15; Fax: 33.1.43.06.04.43; E-mail: mario.pende@inserm.fr.

View this article at: http://www.jci.org/articles/view/44203?key=d2002b7295c59ec30d62


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