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JCI online early table of contents: April 1, 2010

JCI Journals

EDITOR'S PICK: Combinatorial therapy allows viruses to destroy tumors

For several years, researchers have been developing a new approach to treating cancer that uses viruses to infect and kill cancer cells while leaving normal cells unharmed. Recent data have indicated that this approach, which is known as oncolytic virotherapy, has potential. Now, Richard Vile and colleagues, at the Mayo Clinic, Rochester, have found that this approach can be combined with a standard clinical therapy to provide substantial regression and cure of tumors in mice, leading them to suggest that this combinatorial approach could be of tremendous benefit in the clinic.

Tumors that grow to a certain size need to form new blood vessels if they are to continuing growing and spread to other sites. One of the molecules that controls this new blood vessel growth, VEGF, is the target of drugs used to treat several forms of cancer. In this study, the authors found that modulating VEGF signaling, for example by transiently stopping anti-VEGF therapy in mice harboring cancer cells expressing high levels of VEGF, allowed the cells that line tumor blood vessels to be targeted and killed by viruses. Importantly, as this approach targets the cells lining tumor blood vessels, rather than specific types of tumor cells, the authors suggest that this combinatorial approach to therapy could be used to treat a wide range of cancers.

TITLE: Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice

Richard Vile
Mayo Clinic, Rochester, Minnesota, USA.
Phone: 507.284.3178; Fax: 507.266.2122; E-mail:

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EDITOR'S PICK: Genetic form of anemia defined molecularly

Sideroblastic anemia is a form of anemia caused by an inability to incorporate iron into hemoglobin, something that is essential if the molecule is to perform its vital function of carrying oxygen from the lungs to the tissues. Recently, a patient with sideroblastic anemia was found to have a mutation in their GLRX5 gene that led to GLRX5 protein deficiency. Tracey Rouault and colleagues, at the National Institute of Child Health and Human Development, Bethesda, have now provided insight into how GLRX5 protein deficiency causes sideroblastic anemia. Specifically, they find that in human cells, GLRX5 is essential for generating iron-sulfur clusters (molecular groups that facilitate a wide range of cellular activities, including sensing of iron and oxygen) and maintaining normal levels of iron in cellular compartments known as mitochondria and the cytosol. Further analysis revealed a molecular explanation for why GLRX5 protein deficiency caused disease in only one cell type in the body, the red blood cell.

TITLE: Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts

Tracey A. Rouault
National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
Phone: 301.496.7060; Fax: 301.402.0078; E-mail:

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CARDIOLOGY: Protecting heart muscle cells from death

A team of researchers, led by Uta Hoppe, at the University of Cologne, Germany, has identified a role for the protein connexin 43 in protecting mouse heart muscle cells from death. The team therefore suggest that it might be an attractive target for therapies that help protect cells from injuries that normally result in death, such as the injuries suffered by cells as a result of heart attack.

Several lines of evidence indicate that the PKC protein and mitoKATP potassium channels in the inner mitochondrial membrane have a central role in protecting cells from death. In the study, connexin 43 was found to be required for mitoKATP activation of PKC. Importantly, this pathway was crucial for protecting mouse heart muscle cells from death.

TITLE: Connexin 43 acts as a cytoprotective mediator of signal transduction by stimulating mitochondrial KATP channels in mouse cardiomyocytes

Uta C. Hoppe
University of Cologne, Cologne, Germany.
Phone: 49.221.478.32396; Fax: 49.221.478.32397; E-mail:

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BACTERIOLOGY: Staph infections in the skin controlled by the immune molecule IL-17

In recent years, antibiotic-resistant strains of the bacterium Staphylococcus aureus, which is the most common cause of skin and soft tissue infections such as cellulitis, have emerged and are creating a serious public health concern. If we are to develop therapies that provide an alternative to antibiotics, greater understanding is needed of the immune response to Staphylococcus aureus skin infection. Lloyd Miller and colleagues, at the University of California at Los Angeles, have now provided new insight into this by studying a mouse model of the condition. Specifically, they found that the immune molecule IL-17 has an important role in controlling Staphylococcus aureus infection in the mouse skin. The authors therefore suggest that therapies aimed at inducing IL-17 responses in the skin may provide a new approach to treating individuals susceptible to Staphylococcus aureus skin infections.

TITLE: IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice

Lloyd S. Miller
University of California at Los Angeles, Los Angeles, California, USA.
Phone: 310.206.6174; Fax: 310.206.9878; E-mail:

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VACCINES: CD4+ immune cells control vaccinia virus, the smallpox vaccine

Immunization against smallpox was always considered successful if a skin lesion formed at the site of vaccination. As researchers are looking to use vaccinia virus, the virus in the smallpox vaccine, in other therapeutics and preventative vaccines, it is important to characterize more extensively the mechanisms by which the immune system controls vaccinia virus and thereby protects against smallpox. In this regard, Behazine Combadière and colleagues, at INSERM U945, France, have now determined that immune cells known as CD4+ T cells have an important role in controlling skin lesion size at sites of revaccination.

In the study, the number of effector CD4+ T cells targeting vaccinia virus that a person who was immunized against smallpox many years previously had in their blood prior to revaccination was the only immune correlate that determined the size of their skin lesion upon revaccination. Specifically, high numbers of these cells correlated with small skin lesion size upon revaccination. These data provide new insight into the mechanisms of immune control of vaccinia virus, highlighting a role for an immune cell not previously thought to be centrally involved in the process.

TITLE: Control of vaccinia virus skin lesions by long-term-maintained IFN-gamma+TNF-alpha+ effector/memory CD4+ lymphocytes in humans

Behazine Combadière
INSERM U953, Paris, France.
Phone: 33140779888; Fax: 33140779734; E-mail:

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METABOLIC DISEASE: Differential drug response in lean and obese patients explained

One thing that predisposes individuals who are obese to type 2 diabetes is the persistent, low-level inflammation that results, in part, from dysregulation of the function of white fat tissue in the abdominal cavity between the internal organs (visceral white fat tissue). New insight into the signaling pathways that contribute to visceral white fat tissue dysregulation has now been provided by Philippe Lefebvre and colleagues, at INSERM, UMR1011, France, who determined that the PPAR-gamma signaling pathway operates differently in the visceral white fat tissue of lean and obese mice and humans. Specifically, it shows increased sensitivity to activation by the anti-diabetic drug rosiglitazone in obese mice and humans. These data therefore provide a mechanistic explanation why rosiglitazone acts differently in lean and obese patients.

TITLE: Proteasomal degradation of retinoid X receptor-alpha reprograms transcriptional activity of PPAR-gamma in obese mice and humans

Philippe Lefebvre
INSERM, UMR1011, Lille, France.
Phone: 33.3.20974220; Fax: 33.3.20974201; E-mail:

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GASTROENTEROLOGY: Enteroendocrine cells in the gut needed for optimal postnatal survival

Enteroendocrine cells are cells found in the wall of the gut that secrete hormones that regulate numerous processes in the body, including controlling glucose levels, food intake, and stomach emptying. There are at least ten types of enteroendocrine cell and it has been hard to determine the exact role of each cell type and hormone they secrete because many of the hormones have partially overlapping functions. However, a team of researchers, led by Georg Mellitzer and Gérard Gradwohl, at INSERM U964, Université de Strasbourg, France, has now generated mice lacking all enteroendocrine cells and hormones by deleting the gene Ngn3 and found that a lack of these cells leads to a high chance of dying during the first week of life. Surviving mice were smaller than normal littermates, had soft stool, and were impaired in their ability to absorb fat in the intestines. The clinical relevance of these data are highlighted by the recent identification of several patients with NGN3 gene mutations who show an almost complete lack of all enteroendocrine cells and suffer, from the first days of life, from malabsorptive chronic diarrhea.

TITLE: Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival

Georg Mellitzer
Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, Université de Strasbourg, Illkirch, France.
Phone: 33.0.388.653340; Fax: 33.0.388.653201; E-mail:

Gérard Gradwohl
Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, Université de Strasbourg, Illkirch, France.
Phone: 33.0.388.653312; E-mail:

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LYMPHATIC SYSTEM: Regulator of lymph vessel growth uncovered

In addition to our network of blood vessels, humans have a network of vessels known as lymphatic vessels. These vessels have a role in many processes in the body, including regulating fluid levels in tissues and immune surveillance. Although dysfunction in the lymphatic system contributes to human diseases such as the spread of cancer to other sites and lymphademas (localized fluid retention and tissue swelling), little is known about the molecules that regulate the formation of new lymphatic vessels, a process known as lymphangiogenesis. However, a team of researchers, led by Sophia Tsai and Ming-Jer Tsai, at Baylor College of Medicine, Houston, has now identified a role for the gene regulatory protein COUP-TFII in lymphangiogenesis in mouse embryonic development and tumor lymphangiogenesis in adult mice. The authors therefore suggest that COUP-TFII might be an effective molecular target in pro-lymphangiogenic treatment of lymphedemas or in antilymphangiogenic therapy targeting tumor spreading via the lymphatic vessels.

TITLE: Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development

Sophia Y. Tsai
Baylor College of Medicine, Houston, Texas, USA.
Phone: 713.798.6251; Fax: 713.798.8227; E-mail:

Ming-Jer Tsai
Baylor College of Medicine, Houston, Texas, USA.
Phone: 713.798.6253; Fax: 713.798.8227; E-mail:

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CARDIOLOGY: Switching energy source in stressed hearts under the control of the protein Myc

When heart muscle cells are put under stress, for example by high blood pressure or by oxygen deprivation (such as occurs during a heart attack), they switch from using fatty acids as their source of energy to using glucose. Robb MacLellan and colleagues, at the David Geffen School of Medicine at UCLA, have now generated several lines of evidence to indicate that the gene regulatory protein Myc is responsible for inducing the expression of the genes involved in using glucose as an energy source in mice and that this helps protect the heart from stress.

Initial analysis by the authors indicated that expression of Myc was increased in the hearts of mice under conditions that model high blood pressure as well as conditions that model the oxygen deprivation associated with a heart attack. Furthermore, increasing Myc expression in the heart in the absence of any stress condition made the heart muscle cells switch from fatty acids to glucose as their source of energy. Importantly, the Myc-mediated switch to using glucose as an energy source was associated with preserving heart function and improving recovery from oxygen deprivation. Thus, Myc has an important adaptive role in the mouse heart, equipping it with an enhanced ability to respond to oxygen deprivation.

TITLE: Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice

W. Robb MacLellan
David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Phone: 310.825.2556; Fax: 310.206.5777; E-mail:

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