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JCI table of contents: March 23, 2009

EDITOR'S PICK: Licorice extract blocks colorectal cancer in mice

Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, and drugs that selectively target a protein known as COX-2 prevent the development of intestinal polyps, the precursors of colorectal cancer. However, these drugs have severe side effects that preclude their routine use in the prevention of colorectal cancer. But now, a team of researchers, at Vanderbilt University School of Medicine, Nashville, has found that inhibiting an enzyme known as 11-beta-HSD2 (both genetically and using an extract from licorice) blocks COX-2 activity in human and mouse colorectal tumor cells, inhibiting their growth and metastasis in experimental models of colorectal cancer. Importantly, long-term inhibition of 11-beta-HSD2 did not have side effects on the heart and blood vessels of mice, as long-term treatment with selective COX-2 inhibitors does. The authors therefore suggest that inhibiting 11-beta-HSD2 might provide a new approach to preventing colorectal cancer.

In an accompanying commentary, Paul Stewart and Stephen Prescott, highlight the importance of these data for the development of a potential new therapeutic option in colorectal cancer.

TITLE: Inhibition of 11-betahydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans

Ming-Zhi Zhang
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Phone: (615) 343-1548; Fax: (615) 343-2675; E-mail:

Raymond C. Harris
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: (615) 322-2150; Fax: (615) 343-2675; E-mail:

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TITLE: Can licorice lick colon cancer?

Paul M. Stewart
University of Birmingham, Birmingham, United Kingdom
Phone: 44-121-415-8708; Fax: 44-121-415-8712; Email:

Stephen M. Prescott
Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Phone: (405) 271-7210; Fax: (405) 227-5809; Email:

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EDITOR'S PICK: Approach to treat bone loss might increase bone cancer risk

One approach being considered as a new way to treat osteoporosis is the development of molecules that block the action of proteins that inhibit the Wnt signaling pathway. However, dysregulated Wnt signaling is associated with several cancers. Further, David Thomas and colleagues, at Peter MacCallum Cancer Centre, Australia, have now shown that the gene responsible for making the Wnt signaling pathway inhibitor WIF1 is silenced in human osteosarcomas (the most common form of bone cancer) and that its absence in mice accelerated the development of radiation-induced osteosarcomas. The authors therefore conclude that targeting Wnt signaling pathway inhibitors is likely to increase susceptibility to osteosarcomas. Thus, both the authors and, in an accompany commentary, Greg Enders, at Fox Chase Cancer Center, Philadelphia, note that caution is needed before this approach is used in clinical trials to treat patients with bone loss disorders such as osteoporosis.

TITLE: Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice

David M. Thomas
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Phone: 613-9656-1111; Fax: 613-9656-1411; E-mail:

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TITLE: Wnt therapy for bone loss: golden goose or Trojan horse?

Greg H. Enders
Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Phone: (215) 214-3956; Fax: (215) 728-4333; E-mail:

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GENE THERAPY: Making gene therapy safer using self-inactivating LTRs

Several patients in gene therapy clinical trials have developed leukemia as a result of their treatment. The underlying cause of leukemia is thought to be that the viral vectors used to carry the therapeutic gene into cells (gamma-RVs) integrate into the genome of the cells disrupting the natural control of cancer-associated genes (a process known as insertional mutagenesis). By analyzing specific elements of gamma-RVs and another type of viral vector, LVs, in a tumor-prone mouse model, a team of researchers, at San Raffaele-Telethon Institute for Gene Therapy, Italy, has now provided evidence that LVs are substantially less likely to cause insertional mutagenesis and tumors than gamma-RVs. Further, they found that modifying an element (known as the LTR) of both LVs and gamma-RVs such that it is self-inactivating (SIN) further improved safety. The authors therefore conclude that SIN viral vectors should be the preferred choice in future gene therapy trials.

In an accompanying commentary, Ute Modlich and Christopher Baum, at Hannover Medical School, Germany, discuss the clinical importance of these data and the numerous questions that they pose for future research.

TITLE: The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy

Eugenio Montini
San Raffaele-Telethon Institute for Gene Therapy, Milan, Italy.
Phone: 39-02-26433869; Fax: 39-02-26434621, E-mail:

Luigi Naldini
San Raffaele-Telethon Institute for Gene Therapy, Milan, Italy.
Phone: 39-02-26434681; Fax: 39-02-26434621, E-mail:

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TITLE: Preventing and exploiting the oncogenic potential of integrating gene vectors

Christopher Baum
Hannover Medical School, Hannover, Germany.
Phone: 49-511-532-6069; Fax: 49-511-532-6068; E-mail:

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ONCOLOGY: Too much oxygen not a good thing for tumors

As tumors grow, some regions lack a blood supply adequate to maintain good levels of oxygen, that is some regions become hypoxic. This is a hallmark of malignant tumors and has been suggested, but not experimentally proven, to promote tumor progression. However, Paolo Michieli and colleagues, at the University of Turin Medical School, Italy, have now developed xenograft models to examine how human lung tumors without regions of hypoxia develop and found that tumors rely on hypoxia to promote their own expansion.

In the study, human lung cancer cells were engineered to express the protein myoglobin, which specializes in oxygen transport, storage, and buffering. When these cells were injected into mice, the tumors that developed exhibited no regions of hypoxia, and this was associated with both markedly reduced tumor growth and an inability to metastasize to secondary locations. Further analysis confirmed that the effects were mainly a result of decreased tumor hypoxia, leading the authors to conclude that hypoxia seems to be a key factor driving tumor progression.

In an accompanying commentary, Ulrich Flgel and Chi Dang, highlight the importance of these data and discus other ways in which myoglobin might affect tumor progression.

TITLE: Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis

Paolo Michieli
University of Turin Medical School, Turin, Italy.
Phone: 39-011-993-3219; Fax: 39-011-993-3225; E-mail:

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TITLE: Myoglobin tames tumor growth and spread

Ulrich Flgel,
Institut fr Herz- und Kreislaufphysiologie, Heinrich-Heine-Universitt, Dsseldorf, Germany.
Phone: 49-211-8112785; Fax: 49-211-8112672; E-mail:

Chi Dang
Johns Hopkins Medicine, Baltimore, Maryland, USA.
Phone: (410) 955-2411; Fax: (410) 955-0185; E-mail:

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NEPHROLOGY: New gene linked to low levels of magnesium

A small number of individuals have genetic mutations that cause them to have very low levels of magnesium (Mg2+), which can cause altered heart beats, seizures, and involuntary muscle contraction. Study of these patients has provided a lot of our information about how Mg2+ levels are normally controlled, which is of clinical importance as it has been estimated that up to 60% of critically ill patients have low Mg2+ levels, and this is associated with increased mortality. Ren Bindels and colleagues, at Radboud University Nijmegen Medical Centre, The Netherlands, have now identified a new gene mutation in a family with hypomagnesemia, providing new insight into the mechanisms that regulate Mg2+ levels.

In the study, a mutation in the KCNA1 gene, which makes a protein known as Kv1.1, was found to cause hypomagnesemia in a large family with many individuals suffering from the disease. Detailed analysis revealed that the mutation generated a nonfunctional Kv1.1 protein and that it affected Mg2+ reabsorption by the protein TRPM6 in a region of the kidney known as the distal convoluted tubule. In an accompanying commentary, David Ellison, at Oregon Health & Science University, Portland, discusses the importance of the data and suggests how they might explain some of the clinical situations in which critically ill patients have low Mg2+ levels.

TITLE: A missense mutation in the Kv1.1 voltage-gated potassium channelencoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia

Ren J. Bindels
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Phone: 31-24-3614211; Fax: 31-24-3616413; E-mail:

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TITLE: The voltage-gated K+ channel subunit, Kv1.1, links kidney and brain

David H. Ellison
Oregon Health & Science University, Portland, Oregon, USA.
Phone: (503) 494 7159; Fax: (503) 494-5330; E-mail:

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NEPHROLOGY: Protective role for kallikrein proteins in kidney disease

A team of researchers, at the University of Texas Southwestern Medical Center, Dallas, and Uppsala University, Sweden, has shed new light on several forms of the kidney disease known as nephritis. Specifically, the data indicate a protective role for kallikrein proteins in anti-GBM antibodyinduced nephritis (a mouse model of Goodpasture syndrome) and spontaneous lupus nephritis in mice and humans.

In the study, which was led by Chandra Mohan, Edward Wakeland, and Marta Alarcn-Riquelme, kallikrein genes were found to be underexpressed in the kidneys of mouse strains sensitive to anti-GBM antibodyinduced nephritis. Conversely, mouse strains that upregulated kallikreins in the kidneys showed fewer signs of disease. Consistent with this, antagonizing the kallikrein pathway enhanced disease and agonists dampened disease severity. As both human systemic lupus erythematosus and spontaneous lupus nephritis were found to be associated with kallikrein genes, the authors conclude that kallikreins are protective disease-associated genes in anti-GBM antibodyinduced nephritis and lupus. In an accompanying commentary, Claudio Ponticelli and Pier Luigi Meroni, at IRCCS Istituto Clinico Humanitas, Italy, discuss this possibility and suggest alternative roles for kallikreins in lupus nephritis.

TITLE: Kallikrein genes are associated with lupus and glomerular basement membranespecific antibodyinduced nephritis in mice and humans

Chandra Mohan
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-9675; Fax: (214) 648-7995; E-mail:

Edward Wakeland
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-7332; Fax: (214) 648-7995; E-mail:

Marta Alarcn-Riquelme
Uppsala University, Uppsala, Sweden.
Phone: 46-18-4714805; Fax: 46-18-4714808; E-mail:

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TITLE: Kallikreins and lupus nephritis

Claudio Ponticelli
IRCCS Istituto Clinico Humanitas, Milano, Italy.
Phone: 39-0226112952; Fax: 39-0226112951; E-mail:

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DERMATOLOGY: The protein SRF keeps the skin healthy

Sabine Werner and colleagues, at the Institute of Cell Biology, ETH Zrich, Switzerland, have determined a role for the protein SRF in the skin and found that its expression is markedly decreased in the diseased areas of skin of individuals with psoriasis.

In the study, human skin cells known as keratinocytes were found to express high levels of SRF when healthy but only low levels when psoriatic and when wounded. Mice lacking SRF in keratinocytes during embryonic development died in utero, whereas mice in which SRF was absent in keratinocytes only after birth developed psoriasis-like skin lesions. Further analysis characterized the lesions and led the authors to suggest that SRF is critical for normal maintenance of healthy skin and that it may have a role in the development of skin diseases such as psoriasis.

TITLE: Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice

Sabine Werner
Institute of Cell Biology, ETH Zrich, Zrich, Switzerland.
Phone: 41-44-633-3941; Fax: 41-44-633-1174; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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