News Release

JCI table of contents: Aug. 23, 2007

Peer-Reviewed Publication

JCI Journals

EDITOR'S PICK: New weapon to fight leukemia

In a new study, Danilo Perrotti and colleagues from Ohio State University, Columbus, show that treatment with a drug known as FTY720 prevents disease in a mouse model of many leukemias caused by the cancer protein BCR-ABL (nearly all cases of blast crisis chronic myeloid leukemia [CML-BC] and some cases of acute lymphocytic leukemia [ALL]). As the drug also induced cell lines from humans with these leukemias to die in vitro the authors suggest that FTY720 should be considered by researchers and clinicians developing new approaches to treat CML-BC and ALL patients.

FTY720 was chosen for these studies because it does not directly target the BCR-ABL kinase, which in individuals with CML-BC and ALL is resistant to kinase inhibitors such as imatinib (Gleevec). Instead, FTY720 activates protein phosphatase 2A (PP2A), which is a tumor suppressor that is inactivated by signals induced by BCR-ABL. The pharmacologic doses of FTYY720 used to suppress leukemogenesis in the mice had no adverse effects and FTY720 has thus far shown no adverse effects in clinical trials testing its potential as a therapeutic for the treatment of multiple sclerosis. The authors therefore believe their data provide strong support for the use of FTY720 as a novel therapeutic for CML-BC and ALL patients that are not responsive to treatment with kinase inhibitors.

TITLE: FTY720, a new and alternative strategy for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia

AUTHOR CONTACT:
Danilo Perrotti
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
Phone: (614) 293-5739; Fax: (614) 293-5952; E-mail: danilo.perrotti@osumc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31095


EDITOR'S PICK: Inhaling helps heal liver transplant recipients

A new report from a team of researchers at the University of Washington, Seattle, and the University of Alabama at Birmingham indicates that one of the main complications of liver transplantation can be treated very simply by allowing the transplant recipients to inhale nitric oxide (NO) during the operation in which they received their new liver. Inhalation of NO decreased the length of time the patients had to stay in hospital and increased the rate at which the function of the transplanted liver was restored, leading the authors to suggest that inhalation of NO is a valuable preemptive approach to enhancing liver function after transplantation.

The authors chose to investigate the potential benefits of NO inhalation to liver transplant recipients because ischemia/reperfusion damage, which is one of the main causes of liver dysfunction and failure after transplantation, is associated with decreased NO production by the liver. The study was prospective, blinded, and placebo-controlled and clearly showed that inhaling NO was beneficial to the transplant recipients. Further analysis indicated that the beneficial effects of inhaled NO were probably mediated through increased levels of nitrite in the circulation. Although these results are extremely promising, the authors caution that further studies using a larger number of patients are needed before a final conclusion about the benefits of inhaling NO can be reached.

TITLE: Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation

AUTHOR CONTACT:

John D. Lang
University of Washington, Seattle, Washington, USA.
Phone: (206) 764-2854; Fax: (206) 764-2914; E-mail:jdlang@u.washington.edu.

Rakesh P. Patel
University of Alabama at Birmingham, Birmingham, Alabama, USA.
Phone: (205) 975-9225; Fax: (205) 934-7447; E-mail: rakeshp@.uab.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31892


METABOLIC DISEASE: Being fat needn't be all bad news

Many individuals become type 2 diabetics because the cells of their body no longer respond to insulin. It is thought that one reason over eating causes insulin resistance is that fat is deposited in organs of the body, such as the liver, rather than in the fat tissue. This idea is now supported by the work of Phillip Scherer and colleagues at Albert Einstein College of Medicine, New York, who have shown that insulin resistance in mice is not determined by how fat they are but rather where the fat is stored.

Mice that are obese because they lack leptin (ob/ob mice) become insulin resistant. In the new study, researchers show that if ob/ob mice are engineered to express adiponectin they do not become insulin resistant. However, these mice were morbidly obese and the mass of their fat tissues was much increased compared with normal ob/ob mice. The authors therefore suggest that an inability to maintain high levels of adiponectin might be what causes insulin resistance in individuals who over eat because it would mean that the excess food they consume is stored in regions of the body other than the fat tissues.

TITLE: Obesity-associated improvements in metabolic profile through expansion of adipose tissue

AUTHOR CONTACT:

Philipp E. Scherer
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-8715; Fax: (214) 648-8720; E-mail: philipp.scherer@utsouthwestern.edu.

Amanda Siegfried
Office of News & Publications
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-3404; Fax: (214) 648-9119; E-mail: amanda.siegfried@utsouthwestern.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=31021


ONCOLOGY: DNA provides clues to outcome in patients with liver cancer

The main causes of liver cancer (also known as hepatocellular carcinoma [HCC]), which is the fifth most common cancer in the world, are well defined. However, the molecular pathways activated by the triggers of liver cancer are not well characterized. In a new study, Snorri Thorgeirsson and colleagues from the National Institutes of Health, Bethesda, shed some light on this, showing that the extent to which the genome of a person's liver cancer cells is modified by a process known as methylation correlates with clinical outcome. They therefore suggest that preventing aberrant methylation or targeting the genes whose expression is altered by the aberrant methylation might provide new targets for the treatment of liver cancer.

Detailed analysis of the methylation status of the genome of human liver cells revealed that tumor cells could be identified from healthy cells by genome-wide hypomethylation and CpG hypermethylation. Furthermore, greater genome-wide hypomethylation and CpG hypermethylation correlated with shorter survival. In addition, these changes in methylation were associated with selective inactivation of a number of genes, including inhibitors of Ras and some inhibitors of angiogenesis. The authors therefore suggest that in individuals with liver cancer, analyzing the methylation status of the genome of their tumor cells might have prognostic value and that either modifying genome methylation or targeting the Ras pathway might have therapeutic value.

TITLE: Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinma

AUTHOR CONTACT:
Snorri S. Thorgeirsson
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-1935; Fax: (301) 496-0734; E-mail: snorri_thorgeirsson@nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31457


ONCOLOGY: System overload: infusion of IgG helps clear therapeutic and imaging antibodies from the circulation

The use of monoclonal IgG antibodies attached to toxins or radioactive substances for treating and imaging cancer is currently limited by the ability of IgG to remain in the blood for a long time because this decreases the tumor-to-background contrast and increases normal tissue toxicity. Now, David Scheinberg and colleagues at Memorial Sloan-Kettering Cancer Center, New York, have found a way to decrease the length of time IgG stays in the blood of both mice and humans such that tumor targeting is not compromised but the negative side effects of radiolabeled IgG are substantially diminished.

IgG hangs around in the blood for a long time because it is protected from degradation by the neonatal Fc receptor (FcRn). Infusing mice and humans with large amounts of polyclonal IgG after they had received a radiolabeled monoclonal antibody increased the rate of clearance of the radiolabeled monoclonal antibody from the blood. For both mice and humans, uptake of the radiolabeled monoclonal antibody by the tumor was the same with or without IgG infusion. However, the contrast between the labeled tumor and blood was much better with IgG infusion. Further analysis in mice also showed that IgG infusion decreased the normal tissue toxicity caused by the radiolabeled monoclonal antibody. The authors therefore suggest that polycloncal IgG infusion provides a new way to enhance the therapeutic and imaging efficacy of radiolabeled and toxin-conjugated monoclonal antibodies.

TITLE: Improved tumor imaging and therapy via i.v. Ig-mediated time-sequential modulation of neonatal Fc receptor

AUTHOR CONTACT:
David A. Scheinberg
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: (646) 888-2190; Fax: (646) 422-0296; E-mail: d-scheinberg@ski.mskcc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32226


ONCOLOGY: Uncovering the molecules behind B cell lymphomagenesis

New data produced by Andrei Thomas-Tikhonenko and colleagues at the University of Pennsylvania, Philadelphia, provides a molecular mechanism by which a protein known as PAX5 promotes the growth of a number of types of lymphoma.

Overexpression of PAX5 in mouse B cell lymphoma cell lines increased tumor growth when these cells were transplanted into mice. Conversely, knocking down expression of PAX5 in these cell lines decreased tumor growth when the cells were transplanted into mice. Further analysis revealed that PAX5 promoted B cell lymphomagenesis by increasing the level of expression of molecules involved in B cell receptor signaling and decreasing the level of expression of molecules that inhibit B cell receptor signaling. Inhibitors of the BCR signaling pathway blocked tumor growth further highlighting the importance of BCR signaling in PAX5-driven growth of B cell lymphomas.

TITLE: B cell activator PAX5 promotes lymphomagenesis through stimulation of B cell receptor signaling

AUTHOR CONTACT:
Andrei Thomas-Tikhonenko
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-5138; Fax: (215) 746-0380; E-mail: andreit@mail.vet.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30842


PHYSIOLOGY: Building muscle requires Foxo1

The mechanisms by which Foxo proteins regulate metabolism are relatively well characterized. However, little was known about the mechanisms by which these same proteins regulate cellular differentiation. New data generated by Domenico Accili and colleagues at Columbia University, New York, now indicates that Foxo1 cooperates with Notch to control muscle cell differentiation in vitro.

Overexpression of either a constitutively active form of Foxo1 or a constitutively active form of Notch was found to inhibit the in vitro differentiation of a mouse myoblast cell line. Further analysis revealed that Foxo1 binds to the effector of Notch signaling Csl and that this is required for Notch activation of its target gene Hes1, which suppresses the expression of the myoblast differentiation factor MyoD. Consistent with this, mice lacking Foxo1 in skeletal muscle cells have more MyoD-containing muscle fibers. The authors therefore suggest that Notch and Foxo1 cooperation might allow environmental and metabolic cues, respectively, to be integrated into the muscle cell differentiation decision.

TITLE: A Foxo/Notch pathway controls myogenic differentiation and fiber type specification

AUTHOR CONTACT:
Domenico Accili
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 851-5332; Fax: (212) 851-5331; E-mail: da230@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32054


HEMATOLOGY: Making blood cells requires tescalcin

The recently identified protein tescalcin is known to be highly expressed in hematopoietic cells, but its function in these cells had not been determined. In a new study, Konstantin Levay and Vladlen Slepak at the University of Miami now show that tescalcin has a central role in the in vitro differentiation of megakaryocytes, the cells responsible for producing platelets.

The expression of tescalcin was found to dramatically increase when a hematopoietic progenitor cell line was induced to differentiate into megakaryocytes and overexpression of tescalcin in this cell line induced the spontaneous initiation of megakaryocyte differentiation. Conversely knockdown of tescalin expression in this cell line and in primary hematopoietic progenitors inhibited the induction of megakaryocyte differentiation. Further analysis showed that tescalcin couples the ERK signaling cascade with the expression of Ets family transcription factors. This study therefore identifies a cellular and molecular function for tescalcin in terminal differentiation in the hematopioetic system.

TITLE: Tescalcin is an essential factor in megakaryocytic differentiation associated with Ets family gene expression

AUTHOR CONTACT:

Konstantin Levay
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone: (305) 243-3431; Fax: (305) 243-4555; E-mail: k.levay@miami.edu.

Vladlen Z. Slepak
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone: (305) 243-3430; Fax: (305) 243-4555; E-mail: v.slepak@miami.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=27465


GENETICS: Risk factor for heart disease: Just say NO

Nitric oxide (NO) acts as a biological mediator throughout the body; for example, if the pressure in a blood vessel increases, the cells that line the blood vessel produce NO, which causes the surrounding smooth muscle cells to relax so that the blood vessels dilate and the pressure in the vessel drops. In a new study, Daniel O'Connor and colleagues from UCSD School of Medicine, San Diego, show that in humans a common variant of the GCH1 gene predicts NO excretion in the urine, which they used as a correlate for NO production in the body. The same GCH1 genetic variant was associated with increased blood pressure, a risk factor for developing heart disease. This study led the authors to suggest that "the NO pathway is centrally involved in the early pathogenesis of cardiac diseases" and that "treatments targeting the pathway might be beneficial in preventing later cardiac diseases if administered to subjects at specific genetic risk."

TITLE: Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing NO, autonomic activity, and cardiovascular risk

AUTHOR CONTACT:

Daniel T. O'Connor
University of California at San Diego School of Medicine, San Diego, California, USA.
Phone: (858) 534-0661; Fax: (858) 534-0626; E-mail: doconnor@ucsd.edu.

Michael G. Ziegler
University of California at San Diego School of Medicine, San Diego, California, USA.
Phone: (858) 534-0661; Fax: (858) 534-0626; mziegler@ucsd.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=31093

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