Ischemic heart disease remains the primary cause of morbidity and mortality in the Western world. Current therapeutic strategies are aimed at relieving the ischemia by opening blocked arteries; however, no current therapies can directly protect the heart and ensure ongoing heart function. Faced with this challenge, Walter J. Koch and fellow researchers at Duke University Medical Center, North Carolina, have developed a strategy whereby delivery of erythropoietin (EPO), shortly after ischemic injury, was shown to enhance heart function and prevent subsequent smaller attacks by inhibiting cardiac myocyte cell death.
These results, reported in the October 1 issue of the Journal of Clinical Investigation, demonstrate that a therapeutic window of opportunity may exist in which a single dose of EPO following myocardial infarct, cardiac surgery or other acute coronary syndromes may offer acute protection as well as long term preservation of the ischemic and infarcted heart.
TITLE: A novel protective effect of erythropoietin in the infarcted heart
AUTHOR CONTACT:
Walter J. Koch
Jefferson Medical College, Philadelphia, Pennsylvania, USA.
Phone: 215-955-9982
Fax: 215-955-1690
E-mail: walter.koch@jefferson.edu
View the PDF of this article at: https://www.the-jci.org/press/18200.pdf
A dangerous duo: heart disease and diabetes
The prevalence of obesity and diabetes is increasing worldwide and diabetes currently represents the leading cause of blindness, renal failure, and amputation in the USA. However, these conditions can be slowed or prevented by controlling glucose levels within the body. Interestingly, individuals with diabetes have a two to four-fold higher risk of developing heart disease. However, to date, scientists have been unable to determine how high levels of glucose lead to excess cardiovascular risk. Surprisingly, the treatment of hyperglycemia, exclusive of other heart disease intervention protocols, is currently inadequate to reverse or reduce heart disease. In the October 1 issue of the Journal of Clinical Investigation, a study by Michael A. Brownlee and colleagues from Albert Einstein College of Medicine in New York, reveals a new target – an enzyme called PARP – that is dysregulated by high glucose levels, resulting in increased oxidative stress, which effects endothelial cells lining the heart and blood vessels. The authors demonstrated that inhibition of PARP activation blocked all the known pathways of hyperglycemia-induced vascular damage, suggesting that PARP inhibitors might have unique clinical efficacy in preventing the development and progression of diabetic complications of the cardiovascular system.
In an accompanying commentary, Jane Reusch from the University of Colorado Health Sciences Center comments "with the incidence of diabetes and its complications on the rise, these results offer hope for new treatments in the foreseeable future".
TITLE: Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells
AUTHOR CONTACT:
Michael A. Brownlee
Albert Einstein College of Medicine, New York, New York, USA.
Phone: 718-430-3636
Fax: 718-430-8570
Email: brownlee@aecom.yu.edu
View the PDF of this article at: https://www.the-jci.org/press/18127.pdf
ACCOMPANYING COMMENTARY:
Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose?
AUTHOR CONTACT:
Jane E. B. Reusch
Veterans Affairs Medical Center, Denver, Colorado, USA.
Phone: 303-399-8020 ext. 2775
Fax: 303-393-5271
Email: jane.reusch@uchsc.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19902.pdf
A spoon full of sugar helps inflammation go down
Immune responses in the skin are mediated by effector T cells migrating to the inflamed and injured area. Inhibition of this migration has long been an attractive, though challenging, basis for anti-inflammatory treatment strategies. The migration is regulated, in part, by the proteins E-selectin and P-selectin present within endothelial cells of the skin. In a new study, Charles Dimitroff and colleagues from Harvard Medical School introduce a new strategy for the inhibition of selectin ligand production, which blocks E-selectin ligand expression and therefore ultimately prevents the development of contact hypersensitivity (CHS) responses. Most interestingly, the agent used – a novel fluorosugar compound, 4-F-GlcNAc -– inhibited CHS responses with higher efficacy than glucocorticoids or calcineurin inhibitors currently available for the treatment of allergic skin reactions such as psoriasis and atopic dermatitis. The authors indicate that while a novel drug may still be some way off in terms of an available treatment, inhibition of selectin ligand activity has the potential for efficacy in both preventative and therapeutic applications. In an accompanying commentary, Thomas Zollner and Khusru Asadullah from Schering AG in Berlin, Germany, discuss the underlying mechanisms of this approach and potential therapeutic applications.
TITLE: Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen
AUTHOR CONTACT:
Charles J. Dimitroff
Harvard Institutes of Medicine, Boston, Massachusetts, USA.
Phone: 617-525-5602
Fax: 617-525-5571
Email: cdimitroff@rics.bwh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/19220.pdf
ACCOMPANYING COMMENTARY:
Selectin and selectin ligand binding: a bittersweet attraction
AUTHOR CONTACT:
Thomas M. Zollner
Schering AG, Berlin, Germany.
Phone: 49-30-468-17235
Fax: 49-30-468-97235
Email: Thomas.Zollner@schering.de
View the PDF of this commentary at: https://www.the-jci.org/press/19962.pdf
The two faces of TGF-beta in breast cancer progression
The growth factor TGF-beta plays a complex role in the progression of breast cancer. It has long been believed that during the early stages of breast cancer, TGF-beta acts as a tumor suppressor, but as a pro-oncogenic factor in later stages of the disease. In common with many epithelial cancers, human breast cancers frequently show decreased expression and sensitivity of type II TGF-beta receptors. Lalage Wakefield and colleagues at the National Cancer Institute in Bethesda, Maryland, have used a model of breast cancer progression to analyze the consequences of decreased epithelial cell responsiveness to TGF-beta at different stages of breast cancer progression.
The authors found that a decrease in the expression of TGF-beta receptors, and therefore a decreased response to TGF-beta, observed in 30-50% of human breast cancers, plays a causal role in promoting cancer progression up to the stage of histologically aggressive but nonmetastatic disease. At the point when the disease spreads to additional tissue types and organs, TGF-beta appears to switch from a tumor suppressor to a pro-oncogenic factor. These data have important implications for understanding epithelial carcinogenesis and for the design of new approaches to the prevention and treatment of breast cancer.
TITLE: TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression
AUTHOR CONTACT:
Lalage Wakefield
National Cancer Institute, Bethesda, Maryland, USA.
Phone: 301-496-8351
Fax: 301-496-8395
Email: wakefiel@dce41.nci.nih.gov
View the PDF of this article at: https://www.the-jci.org/press/18899.pdf
Mutant gene accounts for some cases of congenital heart disease
Sick sinus syndrome (SSS) was first described in 1967 and is characterized by arrhythmia, palpitations, and fainting. Although frequently associated with heart disease and seen most often in the elderly, SSS may occur in the fetus, infant or child without apparent cause. In these cases, it is presumed to be congenital. D. Woodrow Benson and colleagues at Children's Hospital Medical Center in Cincinnati, Ohio, screened 10 pediatric SSS patients from 7 families for mutations in the alpha subunit of the cardiac sodium channel gene (SCN5A) – a gene previously associated with cardiac rhythm disorders -– and found that 5 individuals carrying mutations in this gene demonstrated a loss of sodium channel function, predicted to reduce excitability of the heart. This study reveals that congenital SSS, in some families, is a recessive disorder of the cardiac sodium channel.
TITLE: Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)
AUTHOR CONTACT:
D. Woodrow Benson
Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: 513-636-7716
Fax: 513-636-5958
Email: woody.benson@cchmc.org
View the PDF of this article at: https://www.the-jci.org/press/18062.pdf
Cryptococcus neoformans: the fungus among us
Infection by Cryptococcus neoformans occurs following inhalation of fungal cells that travel from the lung to the brain. The first line of defense includes recruited alveolar macrophages (AMs), which engulf and kill fungal cells -– a process called phagocytosis. Maurizio Del Poeta and colleagues from the Medical University of South Carolina, identified a novel cryptococcal factor, antiphagocytic protein 1 (App1), whose expression is regulated by the enzyme inositol phosphoryl ceramide synthase 1 (Ipc1). The authors found that App1 is secreted by C. neoformans and regulates the internalization of the organism by AMs. The authors also observed that the impact of the Ipc1-App1 pathway on pathogenicity had different outcomes depending on the immunocompetency of the host. This study identifies App1 as a novel regulator of phagocytosis and virulence and may set novel criteria for antifungal drug development.
TITLE: Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans
AUTHOR CONTACT:
Maurizio Del Poeta
Medical University of South Carolina, Charleston, South Carolina, USA.
Phone: 843-792-8381
Fax: 843-792-8565
E-mail: delpoeta@musc.edu
View the PDF of this article at: https://www.the-jci.org/press/18309.pdf
Protect the liver: Stat!
Stat3 is one of the most important molecules involved in initiating liver development and regeneration. Michitaka Ozaki and colleagues from the National Research Institute for Child Health and Development in Tokyo, Japan, have shown that Stat3 protects against Fas-mediated liver damage via two specific mechanisms.
The liver is the first line of protection against damage caused by ingested agents and acute liver failure generally results following activation of one of two different pathways: (i) oxidative damage following ingestion of toxic agents; and (ii) immune-mediated damage, which occurs as a result of activation of the Fas apoptotic death pathway. A link between these two pathways has only recently been established.
Ozaki and colleagues demonstrate that Stat3 protects against Fas-mediated liver damage by caspase-dependent and redox-dependent mechanisms, demonstrating a novel mechanism of Stat3 protection against liver damage.
In an accompanying commentary, Rebecca Taub from Bristol-Myers Squibb commented, "these findings provide new insights into common mechanisms of hepatoprotection in both Fas-mediated and toxin-mediated acute liver injury and allow predictions about potential therapeutic interventions that could prove beneficial in a variety of liver insults".
TITLE: Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms
AUTHOR CONTACT:
Michitaka Ozaki
National Research Institute for Child Health and Development, Tokyo, Japan.
Phone: 81-3-3416-0181 ext. 8774
Fax: 81-3-3411-7309
Email: mozaki@nch.go.jp
View the PDF of this article at: https://www.the-jci.org/press/17970.pdf
ACCOMPANYING COMMENTARY:
Hepatoprotection via the IL-6/Stat3 pathway
AUTHOR CONTACT:
Rebecca Taub
Bristol-Myers Squibb, Wallingford, Connecticut, USA.
Phone: 203-677-6727
Fax: 203-677-7569
Email: rebecca.taub@bms.com
View the PDF of this commentary at: https://www.the-jci.org/press/19974.pdf
Finding NEMO in genetic disorders affecting skin development
NF-kappaB is a DNA binding factor that exists and accumulates in the cytoplasm of resting cells. Relocation of NF-kappaB to the cell nucleus is a crucial step in the expression of many genes fundamental to cell development, survival, and function. Jean-Laurent Casanova and colleagues report a novel human mutation in the gene encoding the protein NEMO, which negatively regulates NF-kappaB activation. This mutation gives rise to the clinical syndrome ectodermal dysplasia, characterized by the abnormal development of the skin, hair, nails, teeth, and sweat glands in addition to an increased susceptibility to infection.
In an accompanying commentary, Jordan Orange and Raif Geha from Harvard Medical School discuss how the study of human gene mutations that result in dysreguation of the NF-kappaB pathway has provided insight into the functions of individual components of NF-kappaB activation, their interrelations, and the significance of these signaling pathways to the human body.
TITLE: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency
AUTHOR CONTACT:
Jean-Laurent Casanova
Université de Paris René Descartes-INSERM 550, Paris, France.
Phone: 33-1-40-61-53-81
Fax: 33-1-40-61-56-88
E-mail: casanova@necker.fr
View the PDF of this article at: https://www.the-jci.org/press/18714.pdf
ACCOMPANYING COMMENTARY:
Finding NEMO: genetic disorders of NF-kappaB activation
AUTHOR CONTACT:
Raif S. Geha
Children's Hospital, Boston, Massachusetts, USA.
Phone: 617-355-7603
Fax: 617-730-0528
E-mail: Raif.Geha@TCH.Harvard.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19960.pdf
Researchers itching to find treatment for atopic dermatitis
Interested in the role of IL-10 in inflammatory skin disease, particularly atopic dermatitis (AD), Raif Geha and colleagues from the Children's Hospital, Boston, studied a mouse model of AD and found that in the absence of IL-10, the immune reaction in skin cells was substantially diminished. Interventions directed at downregulating IL-10 production in atopic individuals at the time of allergen exposure may provide a novel therapeutic modality for the prevention of allergic diseases.
TITLE: IL-10 is critical for Th2 responses in a murine model of allergic dermatitis
AUTHOR CONTACT:
Raif S. Geha
Harvard-Children's Hospital, Boston, Massachusetts, USA.
Phone: 617-355-7602
Fax: 617-739-3145
Email: raif.geha@tch.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/18246.pdf
Enzyme inhibition may prevent heart failure
Classic characteristics of the failing heart include desensitization and reduction in the number of beta-adrenergic receptors (betaARs) expressed by heart cells. The enzyme PI3K is also involved in the regulation of cardiac contractility. However, it was previously unknown whether PI3K played a role in the development of heart failure through its interaction with betaARs. In a mouse model of heart failure, Howard Rockman and colleagues at Duke University Medical Center demonstrated that abnormalities in betaAR are directly linked to the development of heart failure.
The authors demonstrated that cardiac-targeted overexpression of inactive PI3K prevented betaAR downregulation and desensitization and improved the development of cardiac dysfunction under conditions of chronic pressure overload. The authors demonstrate that the effect on betaAR function was specific to the disruption of a complex of the enzyme betaARK1 and PI3K, as mice lacking PI3K still demonstrate similar betaAR downregulation and desensitization.
The study identifies a new role for PI3K in maintaining the levels of betaARs in the heart and that betaAR dysfunction may be involved in the development of heart failure. The results suggest that inhibition of betaAR-localized PI3K activity may be a novel therapeutic strategy for the restoration of betaAR function and cardiac integrity.
TITLE: Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure
AUTHOR CONTACT:
Howard A. Rockman
Duke University Medical Center, Durham, North Carolina, USA.
Phone: 919-668-2521
Fax: 919-668-2524
Email: h.rockman@duke.edu
View the PDF of this article at: https://www.the-jci.org/press/18213.pdf
Less ECM is more in asthma
Allergic asthma is characterized by eosinophilic airway inflammation and structural changes in the airway wall. The remodeled phenotype, which may be the consequence of excessive repair processes following repeated airway injury, includes increased deposition of extracellular matrix (ECM) proteins. A. Barry Kay and colleagues from Imperial College London have now shown that specific reduction of bronchial mucosal eosinophils with anti–IL-5 treatment could reduce markers of airway remodeling in asthma. Prior to airway injury, airway eosinophil infiltration and ECM protein deposition were increased in the basement membrane of asthmatics compared to nonasthmatic controls. Treatment of asthmatics with anti–IL-5 antibody, which specifically decreased airway eosinophil numbers, significantly reduced the deposition of the ECM proteins tenascin, lumican, and procollagen III. These data suggest that eosinophils may contribute to the tissue remodeling processes in asthma by regulating the deposition of ECM proteins. TITLE: Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics
AUTHOR CONTACT:
A. Barry Kay
Imperial College London, London, United Kingdom.
Phone: 44-207-351-8181
Fax: 44-201-376-3138
Email: a.b.kay@imperial.ac.uk
View the PDF of this article at: https://www.the-jci.org/press/17974.pdf
Boosting post-transplant T cell populations
Individuals receiving allogeneic hematopoietic stem cell transplants often suffer from post-transplant immune deficiency, which significantly increases morbidity and mortality due to infection. This deficiency is most pronounced in the delayed reconstitution of CD4+ T cells and the rate of reconstitution is slower in older recipients. A challenge for researchers has been the determination of a post-transplant strategy to boost T cell reconstitution that would not simultaneously induce graft-versus-host disease (GVHD).
Marcel R.M. van der Brink and colleagues from Memorial Sloan-Kettering Cancer Center in New York report that post-transplant administration of IL-7 in mice selectively promoted host T cell reconstitution -– by stimulating the proliferation of host T cells that did not react to the engrafted cells – but had no effect on reactive T cells (which would normally contribute to the development of GVHD. The study demonstrates that IL-7 administration has clinical potential to overcome delayed T cell engraftment and resulting immunodeficiency in certain transplant recipients.
TITLE: IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation
AUTHOR CONTACT:
Marcel R. M. van den Brink
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 212-639-5606
Fax: 917-432-2375
Email: vandenbm@mskcc.org
View the PDF of this article at: https://www.the-jci.org/press/17865.pdf
Revealing the mysteries of regulatory T cells in autoimmune disease
CD8+ T cells play a critical role in preventing experimental autoimmune encephalitis (EAE) and mediating resistance to EAE following T cell vaccination. On the other hand, these T cells have also been implicated in the induction of EAE. CD8+CD28– T cells have been shown to exist in humans in vitro, but have not until now been shown to exist in vivo. Samia Khoury and colleagues from Brigham and Women's Children's Hospital have now addressed the important questions of whether these cells also exist in vivo and whether they can regulate experimental autoimmunity. Adoptive transfer of CD8+CD28– T cells, but not CD8+CD28+ T cells, into CD8–/– mice resulted in significant suppression of EAE. Depletion of CD8+ T cells from CD28–/– mice rendered these resistant mice susceptible to EAE. These data indicate that regulatory CD8+ T cells play a critical role in suppressing EAE in CD28–/– mice by preventing the upregulation of molecules that stimulate an immune response and thereby control the outgrowth of reactive CD4+ T cells. CD8+CD28– T cells may represent a unique regulatory CD8+ T cell population that functions in innate immunity.
TITLE: Regulatory functions of CD8+CD28– T cells in an autoimmune disease model
AUTHOR CONTACT:
Samia J. Khoury,
Brigham and Women's Hospital, Boston, Massachusetts, USA.
Phone: 617-525-5370
Fax: 617-525-5252
E-mail: skhoury@rics.bwh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/17935.pdf
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