Commentary
Abstract
Transcriptional profiling of patient tumors is a much-heralded advancement in cancer therapy, as it provides the opportunity to identify patients who would benefit from more or less aggressive therapy and thus allows the development of individualized treatment. However, translation of this promise into patient benefit has proven challenging. In this issue of the JCI, Glinsky and colleagues used human and murine models to identify a potential stem cell mRNA signature, based on the hypothesis that tumors with stem cell–like characteristics are likely to have a poor prognosis. Remarkably, an 11-gene “expression signature” associated with “stem cell–ness” separated patients with different cancers into good- and poor-prognosis groups. Such a “magic marker” would, if validated, have a major impact on patient care. However, there remain challenges incumbent with creating and validating such signatures.
Authors
John P. Lahad, Gordon B. Mills, Kevin R. Coombes
Abstract
Adoptive transfer of autologous or allogenic T cells to patients is being used with increased frequency as a therapy for infectious diseases and cancer. However, many questions remain with regard to defining optimized procedures for preparation and selection of T cell populations for transfer. In a new study in this issue of the JCI, Gattinoni and colleagues used a TCR transgenic mouse model to examine in vitro–generated tumor antigen–specific CD8+ T cells at various stages of differentiation for their efficacy in adoptive immunotherapy against transplantable melanoma. The results confirm that CD8+ T cells progressively lose immunocompetence with prolonged in vitro cultivation and suggest that effector CD8+ T cells alone may be considerably less potent at protecting hosts with advanced tumors than are less differentiated T cells.
Authors
Daniel E. Speiser, Pedro Romero
Abstract
A vast excess of α-globin production and inadequate γ-globin compensation lead to the development of severe anemia in human β-thalassemia. Newly identified modifiers of α- and γ-globin synthesis and insights into the mechanisms of globin regulation provide the tools for potential new approaches to treating this and other red blood cell disorders. In the study by Han and colleagues in this issue of the JCI, the activity of a heme-regulated protein, HRI, is shown to modulate the accumulation of excess α-globin chains in murine β-thalassemia and to decrease the severity of the disease.
Authors
Arthur Bank
Abstract
Lipoxins are potent antiinflammatory lipid mediators that restrain and promote the resolution of a wide variety of inflammatory processes. Recent studies implicating deficient lipoxin production in the pathogenesis of diverse inflammatory diseases, along with numerous reports of the beneficial effects of lipoxin analog administration in animal models of inflammatory pathology, have suggested that harnessing the pleiotropic activities of the lipoxins is a strategy with considerable therapeutic promise. In this issue of the JCI, Bafica et al. address the other side of the coin, reporting that endogenous lipoxins compromise immune-mediated control of Mycobacterium tuberculosis infection in mice. In addition to providing novel insight into the mechanisms that interfere with the development of protective immune responses to M. tuberculosis, the study raises the possibility that pharmacological inhibition of lipoxin synthesis may provide a method of augmenting inefficient immune responses in TB and other important chronic infectious diseases.
Authors
Christopher L. Karp, Andrea M. Cooper
Abstract
Anorexia is one of several abnormalities characterizing chronic kidney disease (CKD) that cause cachexia, the loss of muscle and adipose stores. It has been attributed to mechanisms ranging from accumulation of toxic “middle molecules” to psychological problems. In this issue of the JCI, Cheung and coworkers used elegant techniques to demonstrate that CKD-associated anorexia is caused by defective hypothalamic regulation of appetite. They attributed the defect to an alteration in the hypothalamus’s response to leptin and inflammation. Since similar hypothalamic defects suppress appetite in inflammatory states and in cancer, it is possible that anorexia in several cachexia-inducing conditions results from a common set of hypothalamic abnormalities. The development of small molecules capable of preventing these regulatory abnormalities holds the promise of eliminating the contribution of anorexia to the development of cachexia.
Authors
William E. Mitch
Abstract
An emerging body of evidence implicates peripheral and central endocannabinoid pathways in the regulation of feeding behavior and body weight. A report in this issue of the JCI demonstrates the presence of a common endocannabinoid-regulated molecular pathway for peripheral lipogenic and central appetitive regulation. This pathway involves the activation of the transcription factor SREBP-1c and its associated enzymes, acetyl-CoA carboxylase-1 and fatty acid synthase, in the liver and hypothalamus. Activation of cannabinoid receptor 1 (CB1) in liver plays a key role in increased serum lipid production, fatty liver, and possibly diet-induced obesity. Conversely, stimulation of these receptors in the hypothalamus may lead to an increase in food consumption. Thus, targeting both of these pathways with CB1 antagonists could promote sustained weight loss and favorable serum lipid profiles in obese patients.
Authors
Aron H. Lichtman, Benjamin F. Cravatt
Abstract
Angiogenesis may be an important factor in the development of fibrotic lung disease. Prior studies have strongly suggested a role for angiogenic vascular remodeling in pulmonary fibrosis, and emerging evidence indicates that new vessel formation is critical in airway fibrosis. Bronchiolitis obliterans syndrome is a fibrotic occlusion of distal airways that is largely responsible for the morbidity and mortality of patients after lung transplantation. In this issue, Belperio et al. demonstrate a role for CXC chemokine receptor 2 in the regulation of angiogenesis-mediated airway fibroproliferation. By integrating an understanding of neovascularization into the study of events that occur between inflammation and fibrosis, it becomes increasingly possible to rationally design therapies that can halt conditions of maladaptive fibrosis.
Authors
Ivor S. Douglas, Mark R. Nicolls
Abstract
The inability of insulin to suppress hepatic glucose production (HGP) is a key defect found in type 2 diabetes. Insulin inhibits HGP through both direct and indirect means, the latter of which include inhibition of glucagon secretion, reduction in plasma nonesterified fatty acid level, decrease in the load of gluconeogenic substrates reaching the liver, and change in neural signaling to the liver. Two studies in this issue of the JCI demonstrate that selective changes in the expression of insulin receptors in mouse liver do not have a detectable effect on the ability of insulin to inhibit HGP (see the related articles beginning on pages 1306 and 1314). These provocative data suggest that the indirect effects of insulin on the liver are the primary determinant of HGP in mice.
Authors
Alan D. Cherrington
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a component of the metabolic syndrome, with a clinical spectrum ranging from simple fatty liver to steatohepatitis, cirrhosis, and hepatocellular carcinoma. The primary event of NAFLD is the accumulation of triacylglycerols (TAGs) in hepatocytes. In this issue of the JCI, Donnelly et al. report on their use of stable isotope methodology to show that fatty acids stored in adipose tissue and fatty acids newly made within the liver through de novo lipogenesis are the major sources of TAGs in the liver and are secreted as lipoproteins in NAFLD.
Authors
Shinji Tamura, Iichiro Shimomura
Abstract
Infantile cortical hyperostosis (also known as Caffey disease) is characterized by hyperirritability, acute inflammation of soft tissues, and profound alterations of the shape and structure of the underlying bones, particularly the long bones, mandible, clavicles, or ribs. In this issue of the JCI, Gensure et al. undertook fine mapping of the genetic locus for this disease in a large kindred of individuals with the autosomal dominant form of the condition. The authors found a novel missense mutation in COL1A1, the gene encoding the α1 chain of type I collagen, in all affected individuals in 3 discrete pedigrees. This is a surprising finding, as all other reported mutations affecting the synthesis of type I collagen lead to conditions such as osteogenesis imperfecta and Ehlers-Danlos syndrome, in which quantitative or qualitative defects in type I collagen synthesis give rise to bone fragility and/or connective tissue hyperextensibility. The deleterious effect of the mutation on collagen fibril morphology is demonstrated; however, the precise functional link between the reported missense mutation and the localized inflammation and hyperostosis seen in Caffey disease awaits future studies.
Authors
Francis H. Glorieux
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