[ Back to EurekAlert! ] Public release date: 22-Nov-2010
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Journal of Clinical Investigation

JCI table of contents: Nov. 22, 2010

EDITOR'S PICK: Who is in your poo?

Working with mice and human patients, Eric Pamer, Carles Ubdea, and colleagues, at Memorial Sloan-Kettering Cancer Center, New York, have generated data that suggest that high-throughput DNA sequencing of bacteria in the gut could identify patients at high-risk of life-threatening bloodstream infection with the antibiotic-resistant bacterium vancomycin-resistant Enterococcus (VRE).

Bacterial infections acquired as a result of treatment in a hospital or health-care unit kill approximately 100,000 people a year in the US. Many of these lethal infections are caused by antibiotic-resistant bacteria such as VRE. Fatal VRE infections occur when VRE leaves the gut and invades the bloodstream. Although patients with a compromised immune system are most at risk of these infections, not all become infected. It would therefore be useful to develop ways to identify more precisely those at greatest risk. In the study, high-throughput DNA sequencing of bacteria in the gut (a process done by analyzing the feces) confirmed previous studies that antibiotic treatment dramatically disturbs the pattern of bacteria present. Of immense potential clinical value was the observation that subsequent colonization of the gut predominantly with Enterococcal bacteria preceded bloodstream invasion with VRE. Thus, as the authors and, in an accompanying commentary, Colby Zaph, at the University of British Columbia, Vancouver, suggest, monitoring fecal bacteria content could identify patients at high risk of bloodstream infection with VRE and provide a window for therapeutic intervention.

TITLE: Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans

AUTHOR CONTACT:
Eric G. Pamer
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 646.888.2361; Fax: 646.422.0502; E-mail: pamere@mskcc.org.

Carles Ubeda
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 646.888.2361; Fax: 646.422.0502; E-mail: ubedamoc@mskcc.org.

View this article at: http://www.jci.org/articles/view/43918?key=a12d386b0ab4011c03af

ACCOMPANYING COMMENTARY
TITLE: Which species are in your feces?

AUTHOR CONTACT:
Colby Zaph
University of British Columbia, Vancouver, British Columbia, Canada.
Phone: 604.822.7231; Fax: 604.822.7815; E-mail: colby@brc.ubc.ca.

View this article at: http://www.jci.org/articles/view/45263?key=f08384b8eba59bfc4a87


EDITOR'S PICK: Successful treatment for mice with beta-thalassemia

Beta-thalassemia is an inherited blood disorder that results in chronic anemia. A major complication of the condition is iron overload, which damages organs such as the liver and heart. The iron overload has been linked to low levels of the protein hepcidin, a negative regulator of intestinal iron absorption and iron recycling. A team of researchers, led by Stefano Rivella, at Weill Cornell Medical College, New York, has now shown that increasing the concentration of hepcidin in beta-thalassemic mice limits iron overload and markedly reduces their anemia. They therefore suggest that therapeutic approaches that increase hepcidin levels in patients with beta-thalassemia could be therapeutic, limiting iron overload and mitigating anemia.

In an accompanying commentary, Mark Fleming and Thomas Bartnikas, at Children's Hospital Boston, discuss these data and suggest that modulating hepcidin levels could be a new approach to treating a multitude of diseases associated with iron overload or deficiency.

TITLE: Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice

AUTHOR CONTACT:
Stefano Rivella
Weill Cornell Medical College, New York, New York, USA.
Phone: 212.746.4941; Fax: 212.746.8423; E-mail: str2010@med.cornell.edu.

View this article at: http://www.jci.org/articles/view/41717?key=c4981adf3d5ea08a7e57

ACCOMPANYING COMMENTARY
TITLE: A tincture of hepcidin cures all: the potential for hepcidin therapeutics

AUTHOR CONTACT:
Mark D. Fleming
Children's Hospital Boston, Boston, Massachusetts, USA.
Phone: 617.919.2664; Fax: 617.730.0168; E-mail: mark.fleming@childrens.harvard.edu.

View this article at: http://www.jci.org/articles/view/45043?key=a84ffb2845dc5e10e863


VACCINE DESIGN: Vaccine for cytomegalovirus within reach?

Human cytomegalovirus (HCMV) is a major cause of disability and death in individuals whose immune system is compromised and in the developing fetus. Developing a vaccine is a priority for those in vaccine research, but has thus far proven challenging. A team of researchers, led by Stipan Jonjic, at the University of Rijeka, Croatia, has now developed a vaccine that induced in mice robust immune protection from mouse CMV (MCMV).

One of the obstacles to developing an HCMV vaccine is that the virus has evolved many ways to evade the antiviral immune response. MCMV has evolved similar immune evasion mechanisms; for example, its genome includes a gene (m152) that generates a protein that decreases expression in infected cells of the protein RAE-1-gamma, which promotes the antiviral effects of immune cells known as NK cells. The team engineered the MCMV genome such that it no longer included the m152 gene and instead included the gene responsible for making the protein RAE-1-gamma. The resulting virus functioned as a safe and effective vaccine when administered to mice. Furthermore, maternal vaccination protected neonatal mice from MCMV infection. The authors therefore suggest that a similar approach could yield a safe and effective HCMV vaccine, a hope echoed in an accompanying commentary by Mark Schleiss, at the University of Minnesota Medical School, Minneapolis.

TITLE: Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties

AUTHOR CONTACT:
Stipan Jonjic
University of Rijeka, Rijeka, Croatia.
Phone: 385.51.651.206; Fax: 385.51.651.176; E-mail: jstipan@medri.hr.

View this article at: http://www.jci.org/articles/view/43961?key=887487a7679e8f64e28c

ACCOMPANYING COMMENTARY
TITLE: Can we build it better? Using BAC genetics to engineer more effective cytomegalovirus vaccines

AUTHOR CONTACT:
Mark R. Schleiss
University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Phone: 612.624.1112; Fax: 612.624.8927; E-mail: schleiss@umn.edu.

View this article at: http://www.jci.org/articles/view/45250?key=efe4292efd17406899ee


TRANSPLANTATION: Targeting the protein LFA-1 brings transplant rejection to a halt

Organ transplantation has changed the life of many individuals. However, outcomes remain sub-optimal, with poor long-term graft survival and severe side effects associated with the current drugs that need to be taken by transplant recipients to stop their immune cells rejecting the transplanted organs. Researchers have therefore been seeking to develop alternative immunosuppressive strategies that have fewer side effects than the drugs currently in use. Christian Larsen and colleagues, at Emory University, Atlanta, have now developed a new immuosuppressive protocol that substantially prolongs the survival of transplanted pancreatic islets in nonhuman primates. Specifically, they added short-term treatment with a molecule that targets the protein LFA-1 on immune cells known as T cells to long-term treatment with drug combinations that have previously failed to prevent graft rejection in nonhuman primates. These data provide rationale for the further investigation of therapies targeting LFA-1 as a treatment for transplantation.

TITLE: LFA-1–specific therapy prolongs allograft survival in rhesus macaques

AUTHOR CONTACT:
Christian P. Larsen
Emory University, Atlanta, Georgia, USA.
Phone: 404.727.5800; Fax: 404.727.4716; E-mail: clarsen@emory.edu.

View this article at: http://www.jci.org/articles/view/43895?key=0b5c1f7fcb2f2cdfb41b


ONCOLOGY: New role for the tumor suppressor protein RB

The protein RB is a tumor suppressor protein that has a key role in preventing tumors from first developing. Indeed, inactivation of RB function is a common early event in human cancers. However, a team of researchers, led by Karen Knudsen, at Thomas Jefferson University, Philadelphia, has now found that in human prostate cancer, RB loss is a late event that it is associated with the transition from treatable disease to incurable castrate-resistant metastatic disease. Detailed analyses by the team provided mechanistic insight into why RB loss leads to the transition from drug-responsive to drug-unresponsive disease, providing potential new therapeutic targets.

In an accompanying commentary, Kay Macleod, at the University of Chicago, Chicago, discusses this novel finding and suggests that it might be prudent to reassess RB loss in other cancers in terms of timing, function in disease, and relevance for therapy.

TITLE: The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

AUTHOR CONTACT:
Karen E. Knudsen
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Phone: 215.503.8574; Fax: 215.923.4498; E-mail: karen.knudsen@kimmelcancercenter.org.

View this article at: http://www.jci.org/articles/view/44239?key=2bd4fc3cf9867b929e0f

ACCOMPANYING COMMENTARY
TITLE: The RB tumor suppressor: a gatekeeper to hormone independence in prostate cancer?

AUTHOR CONTACT:
Kay F. Macleod
University of Chicago, Chicago, Illinois, USA.
Phone: 773.834.8309; Fax: 773.702.4476; E-mail: kmacleod@uchicago.edu.

View this article at: http://www.jci.org/articles/view/45406?key=4888b6a88373ff150d2e


IMMUNOLOGY: Targeting cells key to autoimmune disease via the protein alpha-v integrin

Key to the immune response to certain bacteria and fungi is a subset of immune cells known as Th17 cells. However, these cells have a downside — they have been implicated in deleterious inflammatory and autoimmune disorders such as multiple sclerosis. Two independent research groups have now identified a new molecular step that seems critical to the generation of Th17 cells in mice, which they suggest could be targeted therapeutically for the treatment of inflammatory and autoimmune diseases, a conclusion with which Jay Kolls and Derek Pociask, at Louisiana State University, New Orleans, concur in an accompanying commentary.

The molecule TGF-beta has been shown to be required for the generation of Th17 cells. However, TGF-beta is secreted from cells in an inactive form, and how it is locally processed to support the generation of Th17 cells has not been determined. The two research groups — one led by Dean Sheppard, at the University of California at San Francisco, and one led by Adam Lacy-Hulbert, at Harvard Medical School, Boston, — have now found that inactive TGF-beta is processed by protein complexes containing alpha-v integrin at the interface between T cells and the immune cells that activate them (dendritic cells). Importantly, both groups found that this alpha-v integrin–mediated activation of TGF-beta was required for the generation of Th17 cells in mice and the development of disease in a mouse model of multiple sclerosis. These data led both teams of researchers to suggest that alpha-v integrins could be targets for the treatment of Th17-driven inflammatory and autoimmune disorders.

TITLE: Expression of alpha-v-beta-8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice

AUTHOR CONTACT:
Dean Sheppard
University of California at San Francisco, San Francisco, California, USA.
Phone: 415.514.4269; Fax: 415.514.4278; E-mail: dean.sheppard@ucsf.edu.

View this article at: http://www.jci.org/articles/view/43786?key=63c454175a65af5f3866

ACCOMPANYING ARTICLE
TITLE: alpha-v Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice

AUTHOR CONTACT:
Adam Lacy-Hulbert
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.643.5346; Fax: 617.724.3248; E-mail: alacy-hulbert@partners.org.

View this article at: http://www.jci.org/articles/view/43796?key=a40efa06dfb7d641fe33

ACCOMPANYING COMMENTARY
TITLE: Integral role of integrins in Th17 development

AUTHOR CONTACT:
Jay K. Kolls
Louisiana State University, Health Sciences Center, New Orleans, Louisiana, USA.
Phone: 504.568.6117; Fax: 504.568.8500; E-mail: jkolls@lsuhsc.edu.

View this article at: http://www.jci.org/articles/view/45450?key=48e9ab4d06819716a61a


IMMUNOLOGY: Disease-causing immune cells boost the cells that suppress them

Autoimmune diseases arise when an individual's immune system turns on a cell type or tissue of their body. For example, type 1 diabetes arises when the immune system attacks and destroys cells in the pancreas that produce the hormone insulin. One of the main ways in which autoimmune diseases are kept at bay is through the ability of immune cells known as Tregs to suppress the function of cells that could mount deleterious immune responses (Teffs). Understanding how Tregs do this has been an area of intensive research, but little has been uncovered about how Teffs affect Tregs. Benoît Salomon, Eliane Piaggio, and colleagues, at Université Pierre et Marie Curie, France, have now changed this with their study of the effects of diabetes-causing Teffs on Tregs in mice. Surprisingly, they found that diabetes-causing Teffs (the very cells that the Tregs suppress) act to boost the expansion and suppressive activity of Tregs and that this provided sustained protection from type 1 diabetes in two mouse models of the disease.

In an accompanying commentary, Juan Lafaille and Angelina Bilate, at New York University School of Medicine, discuss the implications of these data and the fact that Salomon, Piaggio, and colleagues found that the effects of Teffs on Tregs were partially dependent on TNF-alpha, a molecule normally considered proinflammatory.

TITLE: Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs

AUTHOR CONTACT:
Benoît L. Salomon
Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France.
Phone: 33.1.42.17.74.66; Fax: 33.1.42.17.74.41; E-mail: benoit.salomon@upmc.fr.

Eliane Piaggio
Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France.
Phone: 33.1.42.17.74.66; Fax: 33.1.42.17.74.41; E-mail: elianepiaggio@yahoo.com.

View this article at: http://www.jci.org/articles/view/42945?key=05bcc3219465c67c9c88

ACCOMPANYING COMMENTARY
TITLE: Can TNF-alpha boost regulatory T cells?

AUTHOR CONTACT:
Juan J. Lafaille
New York University School of Medicine, New York, New York, USA.
Phone: 212.263.1489; Fax: 212.263.1171; E-mail: juan.lafaille@med.nyu.edu.

View this article at: http://www.jci.org/articles/view/45262?key=f4367af087d5130940f8


HEMATOLOGY: Disease-causing mutation linked to control of gene expression

Hereditary spherocytosis is an inherited blood disorder characterized by anemia, jaundice, and an enlarged spleen. It is most commonly caused by mutations in the gene responsible for making ankyrin, a protein that is key to maintaining the integrity of the red blood cell membrane. In some patients, the disease-causing mutations are upstream of this gene, and how they cause defective ankyrin expression was not clear. However, a team of researchers — led by Patrick Gallagher, at Yale University School of Medicine, New Haven, and David Bodine, at the National Institutes of Health, Bethesda — has now determined how these mutations cause hereditary spherocytosis. Specifically, they found that the mutations are in a region of DNA that functions to protect ("insulate") the ankyrin gene from the general shutdown in gene expression that occurs as a red blood cell matures. DNA sequences with this function are known as barrier insulators, and these data are the first to show that disruption of a barrier insulator can cause human disease.

Edward Benz, at Harvard Medical School, Boston, distils the complexities of this study in his accompanying commentary and suggests that perhaps other disease-linked DNA variants could reside in barrier insulators.

TITLE: Mutation of a barrier insulator in the human ankyrin-1 gene is associated with hereditary spherocytosis

AUTHOR CONTACT:
Patrick G. Gallagher
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203.688.2896; Fax: 203.785.6974; E-mail: patrick.gallagher@yale.edu.

David M. Bodine
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.402.0902; Fax: 301.402.4929; E-mail: tedyaz@mail.nih.gov.

View this article at: http://www.jci.org/articles/view/42240?key=4602a0acc17f84c6f636

ACCOMPANYING COMMENTARY
TITLE: Learning about genomics and disease from the anucleate human red blood cell

AUTHOR CONTACT:
Edward J. Benz Jr.
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.632.2159; Fax: 617.632.2161; E-mail: ebenz@comcast.net.

View this article at: http://www.jci.org/articles/view/45433?key=20ba755db44c04553868


CARDIOLOGY: Be still my beating heart: understanding the role of the protein RyR2 in the heart's response to stress

The heart beats stronger and faster in situations of stress. If the stress is experienced for only a short time it promotes the fight-or-flight response that enables us to endure physical and emotional exercise, but if it is prolonged it leads to heart failure. Two reports from the laboratory of Andrew Marks, at Columbia University, New York, provide new insight into the mechanisms underlying the response of the mouse heart to the stress.

Previous data from Marks' laboratory has indicated that a key part of the response of the heart to prolonged stress is the modification (by phosphorylation on building block serine 2808) of the protein RyR2. In the first of the new reports, Marks and colleagues generated mice in which serine 2808 was replaced with a building block that cannot be phosphorylated and found that their hearts did not beat stronger and faster in response to a chemical substitute for short term stress. Thus, they conclude that phosphorylation of RyR2 at serine 2808 is important for the short-term response to stress, the fight-or-flight response. In the second paper, they generated mice in which serine 2808 was replaced with a building block that mimics phosphorylated serine. These mice developed heart problems as they aged that could be mitigated with a beta-blocker (the main drugs used to treat heart failure). Thus, Marks and colleagues conclude that one of the mechanisms by which beta-blockers benefit patients with heart failure is by targeting phosphorylated RyR2.

In an accompanying commentary, Thomas Eschenhagen, at the University Medical Center Hamburg Eppendorf, Germany, discusses how the new data generated by Marks and colleagues might help resolve controversies in the field.

TITLE: Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice

AUTHOR CONTACT:
Andrew R. Marks
College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Phone: 212.851.5337; Fax: 212.851.5346; E-mail: arm42@columbia.edu.

View this article at: http://www.jci.org/articles/view/32726?key=9f207d9439e4134ca491

ACCOMPANYING ARTICLE
TITLE: Role of chronic ryanodine receptor phosphorylation in heart failure and beta-adrenergic receptor blockade in mice

AUTHOR CONTACT:
Andrew R. Marks
College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Phone: 212.851.5337; Fax: 212.851.5346; E-mail: arm42@columbia.edu.

View this article at: http://www.jci.org/articles/view/37649?key=a39f04ea02303a745ac9

ACCOMPANYING COMMENTARY
TITLE: Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure?

AUTHOR CONTACT:
Thomas Eschenhagen
Cardiovascular Research Center Hamburg, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
Phone: 49.40.74105.2180; Fax: 49.40.74105.4876; E-mail: t.eschenhagen@uke.de.

View this article at: http://www.jci.org/articles/view/45251?key=f2fc562157d6dbf70e08

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