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JCI online early table of contents: May 17, 2010
Date:5/10/2010

EDITOR'S PICK: Eliminating the source of asthma-causing immune molecules

Asthma and other allergic diseases are caused by inappropriate immune responses. Soluble IgE molecules, produced by immune cells known as B cells, are key immune mediators of these diseases. Therapeutic targeting of IgE in the blood can neutralize its effects and is an effective treatment for moderate-to-severe allergic asthma. However, this approach does not halt IgE production and patients need to be treated repeatedly. But now, a team of researchers, at Genentech Inc., South San Francisco, has developed a way to specifically eliminate IgE-producing B cells, providing a potential new long-lasting therapeutic approach to treating asthma and other allergic diseases.

IgE-producing B cells express on their surface an IgE molecule that is slightly different to the IgE molecules that they secrete. The team, led by Lawren Wu, generated a therapeutic molecule known as a monoclonal antibody that targets the portion of human IgE that is contained in IgE molecules on the surface of B cells but not in IgE molecules in the blood. When mice expressing human IgE were treated with this monoclonal antibody, their levels of IgE in the blood decreased substantially as did their numbers of IgE-producing B cells. As the monoclonal antibody provided mice with protection in a model of allergic asthma, the authors suggest that targeting IgE-producing B cells using monoclonal antibodies similar to those described in this study might be of benefit to individuals with asthma and other allergic diseases.

TITLE: Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice

AUTHOR CONTACT:
Lawren C. Wu
Genentech Inc., South San Francisco, California, USA.
Phone: 650.225.1548; Fax: 650.742.1521; E-mail: lawren@gene.com.

View this article at: http://www.jci.org/articles/view/40141?key=dc42b930fbb1a36725f5


GASTROENTEROLOGY: Reducing colon cancer risk in a model of inflammatory bowel disease

Individuals with inflammatory bowel disease (IBD) have an increased risk of developing colon cancer because of the chronic inflammation in their guts. A potential new therapeutic approach to reducing this risk has now been suggested by Deborah Rubin and colleagues, at Washington University School of Medicine, Saint Louis, as a result of their work in a mouse model of IBD-induced colon cancer.

In the study, they find that mice lacking the protein epimorphin are protected from inflammation-induced colon cancer, likely as a result of increased repair of the lining of the gut and decreased levels of the proinflammatory factor IL-6. They therefore suggest that modulating epimorphin levels may have therapeutic benefits and help protect individuals with IDB from going on to develop colon cancer.

TITLE: Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion

AUTHOR CONTACT:
Deborah C. Rubin
Washington University School of Medicine, Saint Louis, Missouri, USA.
Phone: 314.362.8935; Fax: 314.362.8959; E-mail: drubin@wustl.edu.

View this article at: http://www.jci.org/articles/view/40676?key=a68a794497995c07a248


ONCOLOGY: COMManDing a role in tumor invasion

Little is known about the function of the COMMD family of proteins. However, a team of researchers, at the University of Texas Southwestern Medical Center, Dallas, and University Medical Centre Maastricht, The Netherlands, has now found that COMMD1, the prototypic member of the COMMD family, has a role in tumor invasion.

COMMD1 is known to inhibit two gene regulatory proteins linked to tumor growth, survival, and metastasis. The team, led by Ezra Burstein and Marc Vooijs, therefore set out to test the hypothesis that COMMD1 is inactivated or repressed in tumors. Their initial analysis indicated that COMMD1 expression is indeed decreased in a variety of cancers and that for both prostate cancer and endometrial cancer patients this is associated with increased tumor invasion and worse clinical outcomes. A substantial amount of additional data, including information generated in a chick xenograft model of tumor invasion and a mouse model of tumor spread, led the authors to their conclusion that COMMD1 has an important role in tumor invasion.

TITLE: COMMD1 disrupts HIF-1alpha/beta dimerization and inhibits human tumor cell invasion

AUTHOR CONTACT:
Ezra Burstein
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214.648.2008; Fax: 214.648.2019; E-mail: ezra.burstein@utsouthwestern.edu.

Marc Vooijs
University Medical Centre Maastricht, Maastricht, The Netherlands.
Phone: 31.0.43.388.2972; Fax: 31.0.43.388.4540; E-mail: marc.vooijs@maastro.unimaas.nl.

View this article at: http://www.jci.org/articles/view/40583?key=7ad73f0c4cf8f031dc76


ONCOLOGY: New way to inactivate a key tumor suppressor

A key step in the formation and progression of many tumors is inactivation of the protein PTEN. While this often occurs through mutation of the gene responsible for generating PTEN, it has been suggested that affects via negative regulators of PTEN might also be important, but it has been hard to identity these proteins. Now, Damu Tang and colleagues, at McMaster University, Hamilton, have identified the protein SIPL1 as a negative regulator of PTEN in human cancer cells. Of clinical relevance, SIPL1 was expressed at higher levels in human cervical cancer tissue expressing the PTEN protein than in human cervical cancer tissue lacking PTEN, and this coexpression was associated with reduced PTEN activity. These observations, together with data from several xenograft tumor models, lead the authors to suggest that SIPL1 contributes to PTEN inactivation during the formation and growth of some tumors.

TITLE: Shank-interacting proteinlike 1 promotes tumorigenesis via PTEN inhibition in human tumor cells

AUTHOR CONTACT:
Damu Tang
St. Joseph's Hospital, McMaster University, Hamilton, Ontario, Canada.
Phone: 905.522.1155, ext. 35168; Fax: 905.540.6549 or 905.521.6181; E-mail: damut@mcmaster.ca.

View this article at: http://www.jci.org/articles/view/40778?key=87ba058de8cc3ba82cce


TUMOR IMMUNOLOGY: Directing immune destruction of tumors

Immunotherapeutic approaches to treating cancer hold a lot of promise, but clinical results thus far have been disappointing. Identifying the proteins expressed by an individual's cancer that are most likely to trigger that individual's immune system to attack are thought likely to enhance the efficacy of cancer immunotherapies. However, current techniques do not efficiently identify such proteins.

But now, a team of researchers, led by Christel Herold-Mende, at the University of Heidelberg, Germany, has developed a new method of comprehensively identifying candidate tumor proteins that spontaneously trigger immune responses. Applying this method, the authors identified two tumor proteins that were targeted by the immune system of a patient with a malignant brain tumor and found that the immune system of 4 of 10 other brain tumor patients also targeted these proteins. As this method is fast and inexpensive, the authors hope that it will be suitable for identifying candidate tumor proteins to develop individualized cancer immunotherapies.

TITLE: Rapid T cellbased identification of human tumor tissue antigens by automated two-dimensional protein fractionation

AUTHOR CONTACT:
Christel Herold-Mende
University of Heidelberg, Germany.
Phone: 49.6221.566405; Fax: 49.6221.565362; E-mail: H.Mende@med.uni-heidelberg.de.

View this article at: http://www.jci.org/articles/view/37646?key=b7e528440941c5a0fa90


INFLAMMATION: Learning our A, P, C's in sepsis

Sepsis is a life-threatening condition characterized by a whole-body inflammatory response. In some instances, patients with sepsis are treated with activated protein C (APC). APC is best known for its role as a negative regulator of blood clotting, which it mediates by binding to the protein EPCR. In contrast, the mechanism(s) by which APC mediates its anti-inflammatory effect to benefit individuals with sepsis has not been determined. However, Li Zhang and colleagues, at the University of Maryland School of Medicine, Baltimore, have now determined that the anti-inflammatory effects of APC in mice occur via a molecular pathway initiated upon APC interaction with the CD11b/CD18 protein complex. Furthermore, the pathway activated by this interaction reduced mortality in a mouse model of lethal sepsis. Additional in vitro and in vivo analyses indicated that the anti-inflammatory function of APC is distinct from its function as a negative regulator of blood clotting.

TITLE: The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b

AUTHOR CONTACT:
Li Zhang
University of Maryland School of Medicine, Baltimore, Maryland, USA.
Phone: 410.706.8040; Fax: 410.706.8121; E-mail: lizhang@som.umaryland.edu.

View this article at: http://www.jci.org/articles/view/40380?key=5d28ec5e44ef710a94f1


DEVELOPMENT: How HOXD13 is all fingers and thumbs

A team of researchers, led by Stefan Mundlos, at the Institute for Medical Genetics, Charit, Germany, has provided new insight into the molecular control of the formation of the bones that make up the hands and feet by studying mice carrying a mutant form of the protein HOXD13 that leads in humans to limb malformations, including a characteristic extra digit between digits 3 and 4 and a fusion between these digits.

Our bones are formed from one of two types of tissue: cortical bone or trabecular bone. In the study, it was found that the bones of the hands and feet of the HOXD13 mutant mice failed to develop as cortical bone, rather they aberrantly developed as trabecular bone. In addition, the bones of the hand took on characteristics of wrist bones. Further analyses identified several mechanisms by which the mutant HOXD13 affected bone formation, increasing our understanding of the variable limb malformations seen in individuals with mutations in HOXD13 and RUNX2.

TITLE: Homeobox genes d11d13 and a13 control mouse autopod cortical bone and joint formation

AUTHOR CONTACT:
Stefan Mundlos
Institute for Medical Genetics, Charit, Universittsmedizin Berlin, Berlin, Germany.
Phone: 49.30.450.569.121; Fax: 49.30.450.569.915; E-mail: stefan.mundlos@charite.de.

View this article at: http://www.jci.org/articles/view/41554?key=44fe92b173a11d73a694


HEMATOLOGY: Keeping blood cells in check with the protein Lnk

Genetic mutations that lead to aberrant activation of the signaling protein JAK2 have been linked to several myeloproliferative diseases, a group of diseases of the bone marrow that includes chronic myeloid leukemia. Wei Tong and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have now generated several lines of evidence in mice indicating that the protein Lnk acts as a suppressor of the development of JAK2-induced myeloproliferative diseases. For example, loss of Lnk accelerated and exacerbated JAK2-induced myeloproliferative diseases in mice. Furthermore, as old mice lacking Lnk spontaneously developed a myeloproliferative disease resembling chronic myeloid leukemia, the authors suggest that Lnk dysfunction might contribute to the development of cancers of the blood and bone marrow in humans.

TITLE: Lnk constrains myeloproliferative diseases in mice

AUTHOR CONTACT:
Wei Tong
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 267.426.0930; Fax: 267.426.5476; E-mail: tongw@email.chop.edu.

View this article at: http://www.jci.org/articles/view/42032?key=344a892df66bb135b5fd


NEUROBIOLOGY: Cellular help to activate thyroid hormone in the brain

Hypothyroidism is a medical condition caused by insufficient production of thyroid hormone. Although iodine deficiency is the most common cause of hypothyroidism, it can be inherited. In neonates, this form of hypothyroidism is accompanied by severe neurological consequences, indicating a role for thyroid hormone in the brain. However, little is known about the mechanisms regulating thyroid hormone action in the brain.

A team of researchers, led by Antonio Bianoc, at the University of Miami Miller School of Medicine, Miami, has now provided new insight into the mechanisms regulating thyroid hormone action in the brain by modeling the process in an in vitro coculture system of human glioma cells and human neuroblastoma cells. Specifically, they find that human glial cells express a protein that increases the amount of active thyroid hormone available to act on nerve cells. Importantly, this pathway was activated in vivo in rat models of stroke and mouse models of inflammation. The authors therefore conclude that this pathway contributes to the regulation of thyroid hormone signaling in the brain during health and disease.

TITLE: Paracrine signaling by glial cellderived triiodothyronine activates neuronal gene expression in the rodent brain and human cells

AUTHOR CONTACT:
Antonio C. Bianco
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone: 305.243.5631; Fax: 305.243.7268; E-mail: abianco@med.miami.edu.

View this article at: http://www.jci.org/articles/view/41977?key=410293de40a91b71ef70


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