A non-invasive method for measuring beta cell mass during diabetes
Diabetes results from a reduction in the number of islet beta cells in the pancreas, which leads to insufficient insulin secretion and high blood glucose levels (hyperglycemia). Currently, insulin secretion is used as a surrogate measure of beta cell mass. However serum insulin concentrations provide an imprecise measure of beta cell mass, and no reliable non-invasive measure of beta cell mass has been available, until now. In a study appearing online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation, Paul Harris and colleagues from Columbia University in New York report that positron emission tomography (PET)-based quantitation of pancreatic radiolabeled VMAT2 receptors in diabetic rats is a reliable and non-invasive way to measure beta cell mass.
The authors exploited the finding that type 2 vesicular monoamine transporters (VMAT2) are expressed in human islet beta cells within the pancreas, as well as in tissues of the central nervous system. As the radioligand [11C]Dihydrotetrabenazine (DTBZ) binds specifically to VMAT2 and is currently used in clinical imaging of the brain, the authors were able to use DTBZ to estimate beta cell mass in rats with type 1 diabetes. In longitudinal PET studies, the authors saw a significant decline in pancreatic uptake of DTBZ that preceded the loss of glycemic control in the diabetic rat. These studies suggest that PET-based quantitation of VMAT2 receptors could provide a non-invasive measurement of beta cell mass that could be used to study the pathogenesis of diabetes and to monitor therapeutic interventions.
TITLE: Longitudinal noninvasive PET-based beta cell mass estimates in a spontaneous diabetes rat model
Press Office, Columbia University Medical Center, New York, New York, USA.
Phone: (212) 305-0820; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27645
How the body recognizes a fungus among us
The fungus Candida albicans can cause a wide variety of infections, ranging from mucosal infections in generally healthy individuals to life-threatening infections in persons with impaired immunity. Beating this infection requires mononuclear immune cells such as neutrophils and macrophages to recognize the fungus, ingest it, and kill it by releasing proinflammatory cytokines that activate the immune response. In a study appearing online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation, Mihai Netea and colleagues from Radboud University Nijmegen Medical Center, The Netherlands, show how mononuclear cells recognize the cell surface of C. albicans. They reveal that this process involves multiple recognition systems that recognize various components within the layers of the fungal cell wall.
The authors examined mutant strains of C. albicans that had specific defects in the mannosylation of cell wall proteins. They demonstrated that 3 components of the fungal cell wall are involved in the recognition by monocytes/macrophages and for the subsequent activation of proinflammatory cytokine release: (i) N-linked mannans; (ii) O-linked mannans; and (iii) beta-glucans. The N-linked and O-linked mannosyl groups of glycoproteins of the outer surface of the cell wall were responsible for most of the cytokine-stimulating activity of the fungal cell. This was achieved by specific interaction of the N-linked mannosyl residues with the mannose receptor, and of the O-linked mannosyl residues with Toll-like receptor 4. Residual cytokine production was mediated by beta-glucans interacting with a protein called dectin-1, and most likely in cooperation with Toll-like receptor 2. This study will serve as a model for future studies of how the immune system recognizes other microorganisms.
TITLE: Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors
Mihai G. Netea
Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Phone: 31-24-3618819; Fax: 31-24-3541734; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27114
Gene expression signature acts as a prognostic indicator for liver cancer
The identification of cancer-specific gene expression patterns or "signatures" is a fast growing area of cancer research. Aberrant activation of the Met signaling pathway is frequently associated with tumor growth and tumor spread to other organs. In order to define the Met-dependent gene expression signature, Snorri Thorgeirsson and colleagues from the National Cancer Institute examined the gene expression signatures from healthy as well as Met-deficient mouse liver cells. They identified 730 genes that were targets of the Met pathway, many of which were involved in the regulation of oxidative stress responses as well as cell motility, cellular organization, and blood vessel growth. To determine the importance of this Met-regulated gene expression signature, the authors examined 242 human liver carcinomas and 7 metastatic liver lesions. Analysis revealed that a subset of human liver cancers and all liver metastases shared the Met-induced gene expression signature. Furthermore, the presence of the Met signature significantly correlated with a decreased mean survival time of liver cancer patients. This signature should help researchers learn more about how cancer develops, and also to identify clinically relevant subgroups of human cancers. The study appears online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation.
TITLE: Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype
Snorri S. Thorgeirsson
National Cancer Institute, Bethesda, Maryland, USA.
Phone: (301) 496-5688; Fax: (301) 496-0734; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27236
Epimorphin: epithelial master regulator
The normal development (morphogenesis) and maintenance of many organs and tissues, including intestine, skin, mammary gland, lung, gallbladder, and liver, are dependent on interaction between mesenchymal and epithelial cells. Epimorphin has been identified as a mesenchymal molecule with recognized morphogenic effects. In a study appearing online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation, Deborah Rubin and colleagues from Washington University School of Medicine examined epimorphin-null mice and show that epimorphin is required for the regulation of epithelia in many tissues, including during testicular development and normal spermatogenesis. In the gut, epimorphin was found to act as a negative regulator of gut epithelial cell proliferation, and epimorphin deficiency provided protection in an experimental model of colitis. These data suggest that modulation of epimorphin expression could be used therapeutically to increase mucosal regeneration following injury to the gut in inflammatory bowel disease, ischemia, or following surgical intestinal resection.
TITLE: Epimorphin-/- mice have increased intestinal growth, decreased susceptibility to dextran sodium sulfate colitis, and impaired spermatogenesis
Deborah C. Rubin
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-8935; Fax: (314) 362-8959; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=25442
Organ development: A place for everything and everything in its place
During development, organ formation is controlled by a strictly coordinated developmental program. Yet at times, these mechanisms do not function properly and can result in an organ of other structure being positioned abnormally within the body (a condition known as ectopia). In a study appearing online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation, Yoshiya Kawaguchi and colleagues from Kyoto University, Japan, present insights into the molecular mechanisms that control organ development, particularly of the pancreas, in the fore-midgut area.
By employing cell lineage studies in transgenic mice, the authors provide convincing evidence that Notch signaling, mediated by the protein Hes1, blocks ectopic pancreas formation through inhibition of Ptf1a expression. In the event that this signaling pathway is disrupted, the ectopic pancreas can form in stomach, the common bile duct
and in the papillary entrance of the pancreas to the duodenum. These mouse studies provide a possible explanation for ectopic pancreas formation in humans.
TITLE: Ectopic pancreas formation in Hes1-knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas.
Kyoto University, Kyoto, Japan.
Phone: 81-75-751-3444; Fax: 81-75-751-4390; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27704
PAR-1 proves integral in acute lung injury
It has been previously shown that activation of TGF-beta by the alphavbeta6 integrin plays a central role in animal models of several common diseases, including pulmonary fibrosis, emphysema, and acute lung injury. While it was known that the expression of alphavbeta6 is not by itself sufficient to activate TGF-beta and that signals induced by tissue injury must induce activation, the mechanisms by which this pathway is regulated have remained completely unknown. In a study appearing online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation, Dean Sheppard and colleagues from the University of California, San Francisco, show that thrombin, which is known to be activated at sites of injury and also to activate protease-activated receptor-1 (PAR-1), is a potent inducer of alphavbeta6 integrin–dependent TGF-beta activation in 2 different animal models of acute lung injury. As such, PAR-1 and the alphavbeta6 integrin may be potential therapeutic targets in acute lung injury.
TITLE: Ligation of protease-activated receptor 1 enhances alphavbeta6 integrin–dependent TGF-beta activation and promotes acute lung injury
University of California, San Francisco, California, USA.
Phone: (415) 514-4175; Fax: (415) 514-4278; E-mail: dean.Sheppard@ucsf.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27183
Mast cells regulate adverse effects in the lung in asthma
In a study appearing online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation, Stephen Galli and colleagues from Stanford University developed a mouse model of asthma that more closely mimics human disease than standard asthma models, in order to demonstrate that mast cells are key drivers of the most important inflammatory, structural, and functional changes observed within the lungs in chronic asthma.
The authors examined wild-type mice as well as mast cell–deficient mice reconstituted with normal or Fc gamma receptor–deficient mast cells in order to assess the role of mast cell Fc gamma receptors during chronic asthma. They demonstrate that mast cells are required for the development of airway hyperresponsiveness and airway inflammation. The critical novel finding was that allergen inhalation drives an expansion of mast cells in the airways of wild-type and reconstituted mice, which is associated with increased lung expression of the Fc receptor common gamma chain. Their studies reveal that Fc gamma receptor signaling is critical for this allergen-driven mast cell expansion, airway hyperresponsiveness, and the induction of airway inflammation. As such, the activation of mast cells via Fc gamma receptor-dependent mechanisms represents an attractive therapeutic target in asthma.
TITLE: Mast cells can promote the development of multiple features of chronic asthma in mice
Stephen J. Galli
Stanford University, Stanford, California, USA.
Phone: (650) 723-7975; Fax: (650) 725-6902; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=25702
Mouse model reveals secrets of lung injury that can follow blood transfusions
Approximately 1 in every 600 persons who receive a transfusion of a plasma-containing blood product develops transfusion-related acute lung injury (TRALI) within 6 hours of the transfusion. As such, TRALI has emerged as the leading cause of death from a blood transfusion. The mechanisms underlying this condition are poorly understood by researchers, primarily because of the absence of a clinically relevant animal model for study. In a study appearing online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation, Mark Looney and colleagues from the University of California, San Francisco, describe a new in vivo mouse model of TRALI and provide novel insights into the role of neutrophils and Fc gammna receptors in the pathogenesis of lung injury.
The authors provide strong evidence in support of the prevailing hypothesis that donor HLA antibodies mediate TRALI. They show that neutrophil-dependent lung injury is initiated and/or primed by infusion of a monoclonal antibody directed against the MHC I antigen. They go on to show that TRALI involves changes in the permeability of alveolar epithelial cells resulting in an increased amount of water in the lung. Depletion of neutrophils protected the animals from lung injury. Similarly, mice lacking Fc gamma receptors were also resistance to lung injury. In conclusion, the new in vivo mouse model of TRALI reproduces several features of human TRALI, and the results of these studies suggest that targeting Fc gamma receptor signaling pathways may be beneficial in limiting lung injury in TRALI.
TITLE: Neutrophils and the Fc gamma receptors are essential in a mouse model of transfusion-related acute lung injury
Mark R. Looney
University of California, San Francisco, California, USA.
Phone: (415) 476-1079; Fax: (415) 502-2126; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27238
Knocking the SOCS off rheumatoid arthritis
Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of the joints and occurs when the body's tissues are mistakenly attacked by its own immune system. A study by Ian Wicks and colleagues from the Walter and Eliza Hall Research Institute, Australia, appearing online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation, is the first analysis of the function of the SOCS-3 molecule in a mouse model of inflammatory arthritis.
The authors used a conditional gene deletion strategy to delete SOCS-3 only in hematopoietic and endothelial cells of mice. Joint inflammation in these mice was particularly severe and characterized by increased numbers of neutrophils in the inflamed joints, bone marrow, blood, and spleen. Local bone breakdown and T cell production were also dramatically increased in the absence of SOCS-3. SOCS-3 appeared to be directly induced by IL-1 in macrophages. These results led to the conclusion that SOCS-3 is an important molecule implicated in arthritis and that pharmacological manipulation of SOCS-3 might be a novel therapeutic strategy to block multiple inflammatory pathways during autoimmune-mediated, inflammatory diseases.
TITLE: SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1–dependent inflammatory arthritis
Ian P. Wicks
Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
Phone: 61-3-9345-2466; Fax: 61-3-9347-0852; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=25660
Reprogramming T cells to fight persistent viral infections like HIV and hepatitis
Effective T cell responses are critical for the control of viral infections. Failure to clear persistent viral infections like HIV, and Hepatitis B and C in humans or lymphocytic choriomeningitis virus (LCMV) in rodents can be caused by early loss of T cell activity due to depletion of this cell population. Following exposure to an antigen, T cells are prompted to increase in number, and to develop certain immune functions as well as the ability to remember and recognize certain antigens. In a study appearing online on May 18 in advance of print publication in the June issue of the Journal of Clinical Investigation, David G. Brooks and colleagues from The Scripps Research Institute, La Jolla, California, show that this programming of T cells is alterable, even once the programming has begun, and is highly dependent on continuous signals from the antigen environment. In the presence of persistent viral replication, these T cell responses are rapidly altered, making T cells unresponsive and allowing for unchecked viral persistence. Brooks et al. show that deletion of immunodominant T cells and functional inactivation can be prevented in vivo in mice during persistent LCMV infection, resulting in a more diverse virus-specific T cell repertoire and the long-term preservation of cytotoxic T lymphocyte responses. The concept that T cell deletion and inactivation is neither an inevitable nor permanent consequence of persistent viral infection – that it is reversible – and that its reversal leads to control of viral infection, should have important implications for the future design of therapeutic approaches to resurrect T cell responses and treat persistent viral infections.
TITLE: Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection
David G. Brooks
The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-9461; Fax: (858) 784-9981; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=26856
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