EDITOR'S PICK: Identifying preterm infants at risk of life-threatening conditions
Infants born prematurely are highly susceptible to life-threatening conditions that are clinically difficult to detect. These include late-onset septicemia, a condition in which infectious microbes are present in the blood, and necrotizing enterocolitis, a condition in which portions of the intestines die. But now, Terrence Poon and colleagues, at the The Chinese University of Hong Kong, Hong Kong, have identified in the blood biomarkers of these devastating conditions. Importantly, the biomakers discovered in the initial analysis were validated in a prospective cohort study. Although the biomarkers need to be confirmed in further multicenter trials, the authors hope that their use will help diagnose preterm infants with these devastating conditions, thereby identifying those who require urgent treatment.
TITLE: Host-response biomarkers for diagnosis of late-onset septicemia and necrotizing enterocolitis in preterm infants
Terence Chuen Wai Poon
Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
Phone: 852.2632.1205; Fax: 852.2648.8842; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/40196?key=d4a5eb4e565373716d96
METABOLIC DISEASE: Childhood obesity: possible new insight from mice
Given the current 'epidemic' of obesity and its related diseases (including type 2 diabetes and heart disease), understanding how food intake, body composition, and energy expenditure are regulated has become a research priority. One soluble molecule found to regulate all these processes, and more, is leptin. Leptin causes many of its effects by acting on nerve cells in different regions of the brain, but exactly what effects each brain region mediates has not been clearly determined. However, Lori Zeltser and Laurence Ring have now generated mice in which leptin signaling is disrupted in only the hypothalamic region of the brain and shown that leptin signals in the hypothalamus are required to prevent the development of obesity up to 8 weeks of age. After 8 weeks of age, leptin signals in regions of the brain other than the hypothalamus were able to control further development of obesity, although they could not reverse obesity established prior to 8 weeks of age. The authors suggest that these data might have implications for combating childhood obesity.
TITLE: Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels
Lori M. Zeltser
Columbia University, New York, New York, USA.
Phone: 212.851.5314; Fax: 212.851.5306; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/41985?key=ee928b6505cbee5baee5
METABOLIC DISEASE: A tale of tribbles 3: understanding its role in type 2 diabetes
Type 2 diabetes is characterized by insufficient secretion of the hormone insulin, which controls glucose levels in the blood, and reduced mass of insulin-secreting pancreatic beta-cells. A team of researchers, led by Rohit Kulkarni, at Harvard Medical School, Boston, has now confirmed recent data indicating that a genetic variant of the tribbles 3 (TRB3) gene is associated with increased risk of developing type 2 diabetes and determined the reasons underlying this. Specifically, the protein generated by the genetic variant was shown to impair the release of insulin from mouse and human pancreatic beta-cells in which it was expressed and to reduce the mass of pancreatic beta-cells by decreasing their proliferation and enhancing their death. The authors therefore suggest that targeting TRB3 might help prevent two of the central characteristics of type 2 diabetes and thereby provide therapeutic benefit.
TITLE: The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse beta cells
Rohit N. Kulkarni
Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.713.3460; Fax: 617.713.3476; E-mail: Rohit.Kulkarni@joslin.harvard.edu.
View this article at: http://www.jci.org/articles/view/36849?key=53f83115ab8916a3b1e0
ONCOLOGY: Silencing genes that protect from cancer: a role for the protein hNaa10p
Tumor suppressor genes are genes that generate proteins that protect cells from becoming cancerous. Loss or reduction in their expression contributes to the onset of cancer. One mechanism by which tumor suppressor genes are silenced in cancer cells is excessive modification of their promoter (the region of the gene that drives expression) with molecules known as methyl groups. Understanding the mechanism underlying hypermethylation of tumor suppressor gene promoters might provide new approaches to cancer treatment.
In this regard, a team of researchers, led by Cheng-Wen Wu and Li-Jung Juan, at Academia Sinica, Taiwan, has now identified a role for the protein hNaa10p in mediating tumor suppressor gene silencing by promoting the function of the protein DNMT1, which transfers methyl groups to DNA. Importantly, depletion of hNaa10p impaired human lung cancer cell proliferation in vitro and upon transplantation into mice. Consistent with hNaa10p having a role in promoting lung tumor development, it was found to be overexpressed in many human lung tumor samples, and patients with the highest levels of hNaa10p expression had poor prognosis and survival. The authors therefore conclude that hNaa10P promotes tumor formation, although they caution that while this might be true for the lung, it might not be true in other tissues.
TITLE: hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Phone: 886.2.2652.3015; Fax: 886.2.2652.3075; E-mail: email@example.com.
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Phone: 886.2.2787.1234; Fax: 866.2.2789.8811; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/42275?key=9cf8b56f73f4f7952258
ONCOLOGY: TGF-beta a DAB(2) hand at tumor promotion
The soluble factor TGF-beta has a complex role in tumor formation and progression. It seems to suppress tumor formation and early development but promote later tumor progression. A team of researchers, led by Gareth Inman, at The Beatson Institute for Cancer Research, United Kingdom, has now identified a mechanism by which TGF-beta switches from being a suppressor of tumor development to a promoter of tumor progression by studying human squamous cell carcinoma (the second most common type of skin cancer) cells in vitro and in vivo in mice. Specifically, they found that downregulation of the protein DAB2, which they determined occurs in human squamous cell carcinomas and predicted poor prognosis, abrogated the tumor suppressor function of TGF-beta. The authors suggest that determining whether or not DAB2 is downregulated might provide a way to stratify patients with advanced squamous cell carcinoma to identify those that might benefit from antiTGF-beta therapies.
TITLE: Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter
Gareth J. Inman
Biomedical Research Institute, University of Dundee, Dundee, United Kingdom.
Phone: +44.1382.496696; Fax: +44.1382.669993; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/36125?key=9ba8f92e6a5c850ecf45
CARDIOVASCULAR DISEASE: Zebrafish help us understand human blood vessel disease in the brain
Cerebral cavernous malformation is a common human disease of the small blood vessels in the brain that often results in stroke, seizure, and brain hemorrhage. It is caused by genetic mutations that result in loss of function of any one of three proteins (CCM1, CCM2, and CCM3). These proteins cooperate during blood vessel development in mice and zebrafish, but the downstream molecules involved in this process have not been determined. A team of researchers, led by Mark Kahn, at the University of Pennsylvania, Philadelphia, has now determined that proteins known as STKs act downstream of CCM3 in zebrafish development and a new zebrafish model of cerebral cavernous malformation caused by mutations in CCM3. These data suggest that the functional role of CCM3 in zebrafish parallels its role in humans and that future studies in zebrafish will provide a way to better understand the role of this protein in human cerebral cavernous malformation as well as possible way to test the efficacy of new drugs designed to treat the disease.
TITLE: CCM3 signaling through sterile 20like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations
Mark L. Kahn
Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.898.9007; Fax: 215.573.2094; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/39679?key=953594aa09229ff769cd
MUSCLE BIOLOGY: Understanding how mutant proteins cause muscular dystrophy
Limb-girdle muscular dystrophy type 2A (LGMD2A) is a genetic disease characterized by progressive muscle weakness. Most patients become confined to a wheelchair in their third decade of life. Although LGMD2A is known to be caused by mutations in the gene CAPN3, which controls the generation of the protein p94, how mutant p94 proteins lead to disease has not been determined. Now, a team of researchers, led by Hiroyuki Sorimachi, at the Tokyo Metropolitan Institute of Medical Science, Japan, has determined that in mice, mutant p94 protein that is unable to cleave other proteins (a key function of p94) causes a disease that resembles LGMD2A and is exacerbated by exercise. The exercise-induced muscle degeneration was associated with inefficient relocalization of the mutant p94 protein. The authors therefore conclude that exercise-induced dynamic redistribution of p94 is dependent on its ability to cleave other proteins and essential to protect muscle from degeneration.
TITLE: Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy
The Tokyo Metropolitan Institute of Medical Science (Rinshoken), Tokyo, Japan.
Phone: 81.3.5316.3277; Fax: 81.3.5316.3613; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/40658?key=a0e3462f9c84e525da8c
METABOLIC DISEASE: Disorder of fat absorption also affects the immune system
Abetalipoproteinemia is a rare genetic disorder caused by mutations in the gene responsible for generating the protein MTP. It is characterized by malabsorption of fats in the intestine and low levels of fat in the blood, as well as defects in liver, nerve cell, and eye function. Recently, MTP was shown to regulate the CD1 family of proteins that influence the immune system, but little is known about the function of the immune system in patients with abetalipoproteinemia. Now, a team of researchers, led by Richard Blumberg, at Brigham and Women's Hospital, Harvard Medical School, Boston, has determined that individuals with abetalipoproteinemia have immune defects. Specifically, defects in the numbers and function of immune cells known as iNKT cells, which become activated when they recognize microbial (and self) fat-containing molecules complexed with CD1 molecules. The authors therefore conclude that abetalipoproteinemia is not only a disorder that affects fat absorption, levels, and usage but also an immune disease involving CD1.
TITLE: Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function
Richard S. Blumberg
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.732.6917; Fax: 617.264.5185; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/42703?key=42c843332541236b0321
|Contact: Karen Honey|
Journal of Clinical Investigation