EDITOR'S PICK: TNF-alpha antagonist stops inflammation-induced colon cancer in its tracks
Individuals with the inflammatory bowel disease ulcerative colitis are at increased risk of developing colon cancer. New data generated by Naofumi Mukaida and colleagues at Kanazawa University, Japan, identified a central role for the soluble factor TNF-alpha in the development of colon cancer in mice in which inflammation of the bowel was induced by administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion. Expression of TNF-alpha was increased in the colon of normal mice treated with AOM and DSS and this was followed by the development of tumors in the colon. Mice lacking one of the receptors for TNF-alpha and mice treated with an antagonist of TNF-alpha were markedly protected from the effects of treatment with AOM and DSS, developing less inflammation of the colon and fewer tumors in the colon. As suggested by the authors, and by Ezra Burstein and Eric R. Fearon in an accompanying commentary, these data provide clear rationale for the idea that drugs antagonizing TNF-alpha (such as those used to treat individuals with rheumatoid arthritis) might be useful in reducing the risk of colon cancer in individuals with ulcerative colitis.
TITLE: Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis
Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Phone: 81-76-265-2767; Fax: 81-76-234-4520; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32453
ACCOMPANYING COMMENTARY TITLE: Colitis and cancer: a tale of inflammatory cells and their cytokines
Eric R. Fearon
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: (734) 764-1549; Fax: (734) 647-7950; E-mail: firstname.lastname@example.org.
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: (734) 615-1172; Fax: (734) 647-7950; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34831
EDITOR'S PICK: Building stronger bones, one stem cell at a time
Mesenchymal stem cells (MSCs) are bone marrowderived cells that are capable of giving rise to various cell types through a process known as differentiation. Although it has been proposed that drugs targeting the in vivo differentiation of these cells might provide a new strategy for regenerative medicine, identifying drugs that are capable of specifically targeting MSCs and that can also regulate their differentiation has proven an enormous obstacle. In a new study, David Scadden and colleagues at Massachusetts General Hospital, Boston, have determined that the antitumor drug bortezomib (Bzb) targets MSCs and leads to bone cellspecific differentiation. Human and mouse MSCs treated with Bzb effectively differentiated into osteoblasts, the cell type responsible for bone formation. Bzb treatment increased bone formation in normal mice and recovered bone loss in mice with an induced form of osteoporosis. The authors therefore concluded that Bzb might be a novel therapy for bone loss in individuals with some types of cancer as well as those with osteoporosis. The clinical importance of these data for the treatment of patients with cancer accompanied by severe bone disease, such as often occurs in individuals with myeloma, is further highlighted in an accompanying commentary by David Roodman at the VA Pittsburgh Healthcare System.
TITLE: Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice
David T. Scadden
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 726-5615; Fax: (617) 724-2662; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33102
ACCOMPANYING COMMENTARY TITLE: Bone building with bortezomib
G. David Roodman
Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.
Phone: (412) 688-6571; Fax: (412) 688-6960; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34734
NEUROBIOLOGY: Understanding a cause of Lou Gehrigs disease
Amyotrophic lateral sclerosis (ALS), often known as Lou Gehrigs disease, is the most common adult-onset motor neuron disease. Although most cases of ALS arise randomly, a sizeable proportion of individuals inherit the disease. Among these inherited cases, mutations in the SOD1 gene are the most frequently identified cause. A new study in mice, by John Engelhardt and colleagues at Iowa University, Iowa City, has identified a new mechanism by which SOD1 mutations associated with ALS can alter normal cellular function and trigger cell damage. As there is no known cure for ALS, the authors hope that these data might provide potential targets for the development of drugs to treat individuals with ALS caused by mutations in the SOD1 gene.
In the study, SOD1 was shown to regulate the production of the potentially dangerous oxygen radical superoxide by a protein known as Nox. In normal cells, SOD1 was found to bind and stabilize an activator of Nox known as Rac1, as concentrations of superoxide and the product to which it is converted, hydrogen peroxide, increased SOD1 dissociated from Rac1 and Nox stopped making superoxide. However, mutant forms of SOD1 found in individuals with ALS never dissociated from Rac1 and so Nox never stopped making superoxide. Treating mice that develop an ALS-like disease because they have been engineered to express an ALS-associated mutant form of SOD1 with the inhibitor of Nox apocynin decreased disease and increased their lifespan. However, as discussed in an accompanying commentary by Sverine Boille and Don Cleveland from the University of California at San Diego, there are several questions that need to be addressed before the potential of apocynin as a human therapeutic can be determined.
TITLE: SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model
John F. Engelhardt
Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Phone: (319) 335-7744; Fax: (319) 335-6581; E-mail: firstname.lastname@example.org.
Health Science Relations, University of Iowa, Iowa City, Iowa, USA.
Phone: (319) 335-9917; Fax: (319) 384-4638; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34060
ACCOMPANYING COMMENTARY TITLE: Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1
Don W. Cleveland
University of California at San Diego, La Jolla, California, USA.
Phone: (858) 534-7811; Fax: (858) 534-7659; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34613
NEUROBIOLOGY: Genetic link to one form of a very common pediatric illness inflammation of the middle ear
Inflammation of the middle ear (otitis media) is one of the most common pediatric ailments. Young children are particularly prone to otitis media as their Eustachian tubes, which regulate the pressure in the middle ear, have not yet fully developed. In many instances it is accompanied by an acute ear infection and can be resolved by a course of antibiotics. However, other forms of the disease, e.g, otitis media with effusion, which occurs when fluid accumulates in the middle-ear cavity in the absence of an acute ear infection, are linked to auditory or eustachian tube dysfunction. This, in turn, is influenced by poorly understood factors, including genetics.
In a new study, J. G. Seidman and colleagues at Harvard Medical School in Boston, found that removing the Eya4 gene in mice caused malformation of the Eustachian tube as well as otitis media with effusion. The authors therefore suggested that EYA4 mutations might predispose individuals to otitis media with effusion. As discussed in an accompanying commentary by Evelyn Lazaridis and James Saunders at the University of Pennsylvania, Philadelphia, this description of a genetic model of otitis media with effusion should aid in the development of therapeutics for this condition, frequent recurrence of which is accompanied by an increased risk for sustained conductive hearing loss, with the potential for speech, language, and learning problems.
TITLE: Eya4-deficient mice are a model for heritable otitis media
J. G. Seidman
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 432-7830; Fax: (617) 432-7832; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32899
ACCOMPANYING COMMENTARY TITLE: Can you hear me now? A genetic model of otitis media with effusion
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-7504; Fax: (215) 898-7504; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33716
OPHTHALMOLOGY: I can see clearly now Epo has come and gone
Erythropoietin (Epo) is a hormone that stimulates red blood cell production and that is used to treat individuals who are anemic, including individuals who are anemic and have diseases of the eye caused by pathologic new blood vessel growth in the retina, such as diabetic retinopathy (DR) and retinopathy of prematurity. However, high levels of Epo have been found in the eye of individuals who are not anemic but who have DR, meaning that the relationship between Epo and retinopathies is not well defined. A new study by Lois Smith and her colleagues at Childrens Hospital, Boston, has now revealed a highly timing-dependent role for Epo in this disease process in mice.
Retinopathy occurs in two phases that are characterized by blood vessel loss and growth, respectively. In this study, Epo deficiency during early retinopathy was shown to contribute to retinal blood vessel loss in mice, and Epo treatment reduced this loss. In contrast, late Epo treatment exacerbated retinal disease by enhancing blood vessel growth. The authors have therefore recommended careful monitoring of Epo therapy in patients at risk for retinopathy, particularly diabetics. As early treatment with Epo also protected mice from retinal nerve cell death, Maria Grant and colleagues suggested in an accompanying commentary that Epo might prove a novel treatment for neurovascular damage, but they caution that its timing must be carefully regulated to prevent adverse effects.
TITLE: Erythropoietin deficiency decreases vascular stability in mice
Lois E. H. Smith
Childrens Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 355-8531; Fax: (617) 730-0328; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=33813
ACCOMPANYING COMMENTARY TITLE: Erythropoietin: when liability becomes asset in neurovascular repair
Maria B. Grant
University of Florida, Gainesville, Florida, USA.
Phone: (352) 846-0978; Fax: (352) 392-9696; Email: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34643
|Contact: Karen Honey|
Journal of Clinical Investigation