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.
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.
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.
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.
Vladlen Z. Slepak
University of Miami Miller School of Medicine, Miami, Florida, USA.
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
Michael G. Ziegler
University of California at San Diego School of Medicine, San Diego, California, USA.
Source: Karen Honey
Journal of Clinical Investigation
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