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JCI table of contents: Feb. 21, 2008

EDITOR'S PICK: Deficiency in the protein MBL2 is linked to increased cystic fibrosis severity

Cystic fibrosis (CF), a hereditary disorder causing thick mucous production and frequent lung infections, is associated with a high mortality rate primarily due to lung failure. Although it is known that mutations in the CFTR gene cause the disease, variations in other genes between individuals with CF modify the severity of the disease. For example, the gene responsible for making the MBL2 protein has been suggested to modify lung function in individuals with CF; however, its precise roles in the disease have not been well understood. In a new study, Julian Zielenski and his colleagues at the Hospital for Sick Children, Toronto, found that genetic variations that modify MBL2 expression were associated with more severe clinical symptoms of CF.

The researchers compared levels of MBL2 in the blood of more than 1,000 CF patients and found that patients deficient in MBL2 were often younger when first infected with the bacteria Pseudomonas aeruginosa, and that their lung function declined more rapidly than patients with normal or high levels of the protein. These associations between MBL2 and CF severity were even more pronounced in patients that overproduced the protein TGF-beta-1. The authors argue that these findings might provide a basis for new approaches for treating those individuals with CF who are at risk of such increased disease severity. In an accompanying commentary, Frank Accurso and Marci Sontag at the University of Colorado Denver further suggest that it might be useful to screen for gene variants that cause the production of high levels of MBL2 and TGF-beta-1, as well as other genes that modify the course of CF, in newborn CF screening.

TITLE: Complex two-gene modulation of lung disease severity in children with cystic fibrosis

Julian Zielenski
Hospital for Sick Children, Toronto, Ontarioticle at:

, Canada.
Phone: (416) 813-5064; Fax: (416) 813-8856; E-mail:

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TITLE: Gene modifiers in cystic fibrosis

Frank J. Accurso
University of Colorado Denver, Aurora, Colorado, USA.
Phone: (720) 777-6181; Fax: (720) 777-7284; E-mail:

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VIROLOGY: Growth hormone boosts immune cell numbers

Individuals who are infected with HIV-1 are often highly susceptible to life-threatening infections because they are depleted of a subset of immune cells known as CD4+ T cells. A new study of individuals infected with HIV-1 by Laura Napolitano and colleagues at the Institute of Virology and Immunology, San Francisco, has indicated that daily administration of growth hormone can increase the numbers of CD4+ T cells in the blood. Further analysis indicated that growth hormone increased the mass of the thymus, the organ in the body that gives rise to new CD4+ T cells, and that the frequency of a marker of cells that have just been made in the thymus was increased in those individuals infected with HIV-1 who were taking growth hormone. The authors therefore suggested that growth hormone induces de novo T cell production and might be of use not just for the treatment of individuals infected with HIV-1 who have low numbers of CD4+ T cells but also for the treatment of individuals with other conditions in which CD4+ T cell function is impaired, such as following myeloablative chemotherapy prior to bone marrow transplantation. However, in an accompanying commentary, Kiki Tesselaar and Frank Miedema, at University Medical Center Utrecht, The Netherlands, warn that the long-term immunological and clinical benefits of growth hormone administration need to be thoroughly determined before this approach can be used more widely in the clinic.

TITLE: Growth hormone enhances thymic function in HIV-1-infected adults

Laura A. Napolitano
Gladstone Institute of Virology and Immunology, San Francisco, California, USA.
Phone: (415) 734-4814; Fax: (415) 553-6299; E-mail:

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TITLE: Growth hormone resurrects adult human thymus during HIV-1 infection

Frank Miedema
University Medical Center Utrecht, Utrecht, The Netherlands.
Phone: 31-88-755-7674; Fax: 31-30-250-4305; E-mail:

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PHYSIOLOGY: Two roles are better than one: the protein p22phox has roles in host defense and balancing

The production of oxygen radicals, such as superoxide, by immune cells known as phagocytes is crucial in the fight against infection with microorganisms. Phagocytes use a protein complex known as phagocyte NADPH oxidase to produce superoxide. In humans, inactivation of either of the components of the core of phagocyte NADPH oxidase, p22phox and gp91phox, leads to a severe immune disorder known as chronic granulomatous disease (CGD). Although a mouse model of gp91phox deficiency has been described, the study of p22phox-dependent immune deficiency has been stifled by the lack of an animal model. However, Botond Banfi and colleagues, at the University of Iowa, Iowa City, have now identified the nmf333 mouse strain as the first animal model of p22phox-deficiency. Surprisingly, the nmf333 mice were found to have a severe balance disorder in addition to a CGD-like immune defect. Further investigation revealed that the balance disorder was caused by the aberrant development of gravity-sensing organs due to inactivation of an NADPH oxidase in the inner ear. These data led the authors to propose that development of the balance center in the inner ear is controlled by an NADPH oxidase and that patients with the form of CGD caused by a p22phox deficiency might have unrecognized symptoms of a balance disorder.

TITLE: Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice

Botond Banfi
University of Iowa, Iowa City, Iowa, USA.
Phone: (319) 335-4228; Fax: (319) 335-4194; E-mail:

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METABOLIC DISEASE: How sweet ChREBP is: the role of ChREBP and LXR liver proteins in glucose sensing

The liver regulates the conversion of excess dietary carbohydrates, including glucose, into triglycerides, a primary building block of fat in animals. The protein ChREBP and members of the LXR family of proteins are important mediators of this process, although the precise mechanisms of their function are not clear. In a new study, Catherine Postic and her colleagues at the Institut Cochin, France, investigated the role of LXRs in glucose-mediated liver genes. They found that although glucose is necessary for ChREBP activity in the liver, LXR proteins were not required for the stimulation of glucose-sensing genes. The authors concluded that these findings may aid the development of therapies for lipid-metabolism and glucose dysfunction-related diseases. In an accompanying commentary, Masakazu Shiota and Mark Magnuson at Vanderbilt University School of Medicine, Nashville, explain how these findings convincingly contradict a recent study proposing that LXR proteins act as glucose sensors in the liver.

TITLE: ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver

Catherine Postic
Institut Cochin, Paris, France.
Phone: 33-1-53-73-27-07; Fax: 33-1-53-73-27-03; E-mail:

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TITLE: Hepatic glucose sensing: does flux matter?

Mark A. Magnuson
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: (615) 322-7006; Fax: (615) 322-7236; E-mail:

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CARDIOVASCULAR DISEASE: Spicing up heart failure

New data generated in rodents that is to be published in two independent reports in the March issue of the Journal of Clinical Investigation have shown that curcumin, the agent responsible for the yellow color of the curry spice turmeric, might have beneficial effects on the heart in settings that would normally lead to heart failure. However, as Jonathan Epstein, at the University of Pennsylvania, Philadelphia, notes in an accompanying commentary, 'translation of these data to humans is not clear cut' because previous studies indicating a beneficial effect of curcumin in animal models of other diseases have not proven as successful as hoped.

Koji Hasegawa and colleagues at Kyoto Medical Center, Japan, found that oral administration of curcumin reduced the deterioration of the function of the heart in two rat models of heart failure. Peter Liu and colleagues from the University of Toronto observed similar beneficial effects of oral administration of curcumin in two mouse models of heart failure. Both groups uncovered the same mechanism by which curcumin exerted its effects -- it was shown to modify the availability of genetic material in the heart muscle cells. More specifically, it was shown to abrogate histone acetylation, and GATA4 acetylation and DNA-binding activity through blocking p300-HAT activity.

TITLE: The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats

Koji Hasegawa
Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
Phone: 81-75-641-9161; Fax: 81-75-641-9252; E-mail:

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TITLE: Curcumin prevents and reverses murine cardiac hypertrophy

Peter. P. Liu
University of Toronto, Toronto, Ontario, Canada.
Phone: (416) 340-3035; Fax: (416) 340-4753; E-mail:

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TITLE: Currying favor for the heart

Jonathan A. Epstein
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-8731; Fax: (215) 573-2094; E-mail:

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ONCOLOGY: A white-cell paradox: a mutation in patients with too few white blood cells may lead to leukemia

Neutropenia is a disease characterized by low numbers of white blood cells called neutrophils and a propensity toward developing life-threatening bacterial infections. A high proportion of patients who have severe congenital neutropenia have mutations in their CSFR3 gene, which is responsible for making the protein G-CSFR, and these mutations are believed to be responsible for leukemia progression in these patients. To explore the mechanisms underlying this relationship, Daniel Link and his colleagues at Washington University, St. Louis, studied mice carrying mutated Csf3r genes. They observed the enhanced proliferation of hematopoietic stem cells carrying these mutations, but only in the presence of the related protein G-CSF and activation of STAT5 proteins. As G-CSF is the only effective therapy for severe congenital neutropenia, the authors warn that its use may exacerbate or even cause leukemia in these patients. In an accompanying commentary, Grover Bagby at the Northwest Veteran's Affairs Medical Center, Portland, suggest that this study may help pave the way for 'molecularly targeted leukemia prevention for patients at high risk'.

TITLE: Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5

Daniel C. Link
Washington University, St. Louis, Missouri, USA.
Phone: (314) 362-8771; Fax: (314) 362-9333; E-mail:

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TITLE: Discovering early molecular determinants of leukemogenesis

Grover C. Bagby
Northwest Veterans Affairs Medical Center, Portland, Oregon, USA.
Phone: (503) 494-0524; Fax: (503) 494-7086; E-mail:

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ONCOLOGY: Immune system versus solid tumor: an example of the immune system winning

It is possible to cure some individuals with leukemia by infusing them with immune cells known as lymphocytes during a surgical procedure known as hematopoietic stem cell transplantation (HCT). However, little is known about effective HCT approaches to treating individuals with solid tumors. In a new study, Richard Childs and colleagues, at the National Institutes of Health, Bethesda, have outlined an HCT approach for the treatment of metastatic kidney cancer that caused tumor regression associated with a tumor-targeted lymphocyte response in several patients.

The authors detected tumor-targeted lymphocytes known as CD8+ T cells in the blood of patients with metastatic kidney cancer who had received nonmyeloablative HCT. Further analysis identified the tumor peptide recognized by these CD8+ T cells and it was found to be a fragment of a protein not expressed by healthy cells. The gene responsible for making this protein was part of a region of human chromosome 6 derived from a human endogenous retrovirus (HERV) type E. The authors therefore suggested that HERV-E is activated in metastatic kidney cancer providing a protein target for the immune system. This information might be useful when considering the development of immunotherapeutic approaches to treating individuals with this form of cancer.

TITLE: Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells

Richard W. Childs,
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 451-7128; Fax: (301) 480-2664; E-mail:

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HEMATOLOGY: New protein seen to have a role in blood clot formation

New data generated by Bruce Furie and colleagues at the Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, have identified a role for protein disulfide isomerase (PDI) in blood clot formation (also known as thrombus formation) in mice.

Using in vivo imaging techniques it was observed that the expression of PDI increased in a thrombus that was forming following blood vessel damage. Furthermore, inhibition of PDI using either an agent known as bacitracin or an antibody specific for PDI inhibited thrombus formation. More detailed analysis indicated that PDI was also important for the generation of fibrin following damage to the wall of a blood vessel, a key step in thrombus formation. However, further studies are required to determine whether inhibiting PDI might provide a new approach to treating human conditions associated with aberrant blood clot formation, such as several forms of heart diseases and strokes, or whether the risks of such an approach would outweigh the benefits.

TITLE: A critical role for extracellular protein disulfide isomerase during thrombus formation in mice

Bruce Furie
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 754-1200; Fax: (617) 754-1234; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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