JCI Table of Contents, March 1, 2005

02/03/05

The very unexpected life and death of a leukemic cell

B cell chronic lymphocytic leukemia (CLL) is an incurable disease in which cells in the bone marrow grow and survive to the point where they become abnormal and malignant (leukemic). The progression of the disease is slow and there has been a lack of information regarding the rate of production of CLL cells, and the time-course of their death.

For years, doctors and scientists believed that CLL was a static disease of long-lived lymphocytes -- that the leukemia cells were both immortal and born at a slow rate, causing the slow rise in cell count over time. But researchers had been unable to find any problems with the programmed cell death machinery in CLL cells. This was a hint that perhaps the leukemia cells were not immortal, a hypothesis tested by Nicholas Chiorazzi and colleagues in a paper appearing online on February 10 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation. This new study shows that leukemia cells are born at a fast rate and do indeed die. The slow rise in the cell count over time can be attributed to the difference between the birth and death rates of the cells, according to the study.

The researchers at the Institute for Medical Research at North Shore-LIJ analyzed the kinetics of CLL cells in vivo by employing a non-radioactive labeling technique – using "heavy water" to track cell production. Heavy water is made using a form of hydrogen that has twice its normal mass, making the water molecule "heavier" than normal. The special hydrogen serves as a tag that enables researchers to track the utilization of water in the body. The hydrogen incorporates into glucose and the tagged glucose eventually makes its way into the cell's DNA.

Researchers gave 19 individuals with CLL a small dose of heavy water every day for 84 days, and the tagged water was incorporated into the DNA of the leukemia cells. This provided the researchers a way to track the cell division, or "birth" of new leukemia cells. Chiorazzi and his team calculated birth and death rates of the leukemic cells and found that, contrary to expectations, production and destruction of CLL cells is highly variable, and does not exhibit a steady birth and death rate as previously thought.

The data also reveal that a correlation exists between the rate at which CLL cells are born and the clinical activity or progression of the disease in a patient. The disease activity may vary over time and this may be the result of fluctuations in birth and/or death rates of the CLL cells.

This challenges the dogma that CLL is a purely accumulative disorder where leukemic cells accumulate because they cannot die. Clearly CLL is a disease in which there is a dynamic interplay between rates of cell division and cell death. The data could enable physicians to predict disease progression.

TITLE: In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells

AUTHOR CONTACT: Chiorazzi, Nicholas
Institute for Medical Research at North Shore-LIJ Manhasset, NY, USA
Phone: (516) 562-1232; Fax: (516) 562-1683; E-mail: nchizzi@nshs.edu

View the PDF of this article at: https://www.the-jci.org/press/23409.pdf

From 5:00PM USA EST Thursday February 3, 2005 a PDF of this article will be available at: http://www.jci.org/papbyrecent.shtml

Preventing a bruised heart from becoming a broken one

Acute myocardial infarction (MI) affects 1.5 million people each year and could lead to cardiac rupture, or tear in the cardiac muscle. Since cardiac rupture accounts for a percentage of deaths, it is imperative to learn more about the mechanisms underlying it. After MI, there is an increased expression of matrix metalloproteinase-2 (MMP-2) but it was not clear why. Appearing online on February 10 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation, Yasunori Okada and colleagues from Keio University show that MMP-2 plays a central role in remodeling infarcted myocardium. The authors induce MI in MMP-2 knockout mice and also in normal mice given an oral MMP-2 inhibitor or placebo for a week after MI. Targeted deletion of MMP-2 gene or drug-induced inhibition of MMP-2 activity protected against cardiac rupture by delaying remodeling of the heart and reducing infiltration of harmful cells. Thus, administration of MMP inhibitors may be potentially useful for patients at risk of cardiac rupture after MI.

TITLE: Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice

AUTHOR CONTACT: Yasunori Okada
Keio Univeristy, Tokyo, Japan
Phone: 81-3-5363-3763; Fax: 81-3-3353-3290; E-mail: okada@sc.itc.keio.ac.jp

View the PDF of this article at: https://www.the-jci.org/press/22304.pdf

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Siderocalin eases liver diseases

Liver injury in mice causes upregulation of a protein called siderocalin –a protein that binds and transports iron. Why this upregulation occurred was not known. Appearing online on February 10 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation, Jonathan Barasch and colleagues from Columbia University describe the expression of siderocalin in kidney diseases of the mouse and human and show that upregulation of the protein protects kidney cells and accelerates their recovery from damage. Human kidney biopsies show extensive expression in the proximal tubule of kidneys damaged by ischemia and toxins. When a single dose of siderocalin was administered to the proximal tubule in the early stages of kidney disease, it blocked tissue damage, normalized kidney enzyme levels, inhibited degradation of the proximal tubule, increased protective enzymes, and suppressed cell death. The work will be of interest in the field of kidney diseases and therapeutics.

TITLE: Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

AUTHOR CONTACT: Barasch, Jonathan
Columbia University, New York, NY USA
Phone : (212) 305-1890; Fax: (212) 305-3475; E-mail: jmb4@columbia.edu

View the PDF of this article at: https://www.the-jci.org/press/23056.pdf

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Watch what you eat

A new paper appearing online on February 10 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation, describes the interactions of two circulating hormones that control food intake and body weight – leptin and cholecystokinin. Michael Schwartz and colleagues from the University of Washington used rats that develop severe obesity due to genetic absence of leptin receptors. The rats consume increased amounts of food and have reduced satiety. Thus, leptin signaling appears to be required for normal responses to internal signals that tell the body to stop eating. To determine whether a specific area of the brain called the hypothalamic arcuate nucleus contributes to these actions of leptin, the authors used gene therapy to introduce functional leptin receptors into this brain area. Restoration of leptin signaling selectively to the arcuate nucleus of these rats reduced meal size, and enhanced satiety. These findings shed new light on the mechanisms of food intake during individual meals and provide strong evidence for a hypothalamic action of leptin in modulating satiety signaling.

TITLE: Leptin Action in the Forebrain Regulates the Hindbrain Response to Satiety Signals

AUTHOR CONTACT: Michael W. Schwartz
University of Washington, Seattle, Washington, USA
Phone: (206) 341-5288; Fax: (206) 341-5293; E-mail: mschwart@u.washington.edu

View the PDF of this article at: https://www.the-jci.org/press/22081.pdf

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Removing IRS: good for taxes, bad for diabetes

Insulin resistance in the liver contributes to the development of type 2 diabetes, and diabetics have reduced hepatic levels of insulin receptor substrate proteins IRS-1 and IRS-2. Whether decreased IRS proteins simply correlate with or are causative of insulin resistance has been difficult to determine since global IRS-1 and IRS-2 knockout mice have no obvious phenotype and compound knockouts die in utero.

Appearing online on February 10 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation, C. Ronald Kahn and colleagues from Harvard University report a novel approach to interfere with translation of IRS-1 and IRS-2 specifically in the liver in order to determine the roles of these molecules in the metabolism of normal mice. Knockdown of both IRS-1 and IRS-2 led to symptoms of the metabolic syndrome, including insulin resistance, glucose intolerance, and fatty liver. The authors also discovered that IRS-1 and IRS-2 play unique roles in regulating gene expression in the liver; upon removal of IRS-1, the expression of genes involved in glucose metabolism was altered while decreased IRS-2 levels were more closely linked to changes in the expression of lipid metabolism–related genes.

The authors conclude that IRS-1 and IRS-2 are complementary in the regulation of overall liver metabolism but with differential effects on gluconeogenesis and lipogenesis. This study provides new insights into the physiological role of IRS proteins and their involvement in diabetes. Clearly, decreasing liver IRS expression has a direct causative role in the pathogenesis of diabetes and is not merely a correlative observation.

TITLE: Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism

AUTHOR CONTACT: C. Ronald Kahn
Joslin Diabetes Center, Boston, Massachusetts, USA
Phone: (617) 732-2635; Fax: (617) 732-2593; E-mail: c.ronald.kahn@joslin.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/23187.pdf

From 5:00PM USA EST Thursday February 3, 2005 a PDF of this article will be available at: http://www.jci.org/papbyrecent.shtml

Allergy and asthma take a dip in the gene pool

Genetic factors play a role in susceptibility to allergy and asthma. In particular, IL-13 is a gene associated with allergy and is known to be naturally present in different forms. Appearing online on February 10 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation, Donata Vercelli and colleagues from the University of Arizona study this natural genetic variation. The authors show that, in cells, distinct genetic variants of IL-13 differentially promote the mechanisms that lead to allergic inflammation. This is because the variants bind cellular proteins differently and have altered functions inside the cell. The work adds to our understanding of how genetic variation contributes to the pathogenesis of complex diseases.

TITLE: IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

AUTHOR CONTACT: Donata Vercelli
University of Arizona, Tucson, Arizona USA
Phone: (520) 626-6387; Fax: (520) 626-6623; E-mail: donata@arc.arizona.edu

View the PDF of this article at: https://www.the-jci.org/press/22818.pdf

From 5:00PM USA EST Thursday February 3, 2005 a PDF of this article will be available at: http://www.jci.org/papbyrecent.shtml

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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