A NOVEL MECHANISM OF ACTION FOR LEAD ANTI-TUMOR AGENT
Anti-angiogenic agents have been successful in the clinic for blocking the growth of solid tumors. However, these agents used in combination with chemotherapy have improved the survival of patients with cancers by only several months. Therefore, identification of unrecognized angiogenic pathways that selectively support tumor neo-vessel assembly will increase the efficacy of anti-angiogenic or anti-vascular therapy.
The prototypical vascular targeting agent combretastatin A4 phosphate (CA4P) exerts its anti-angiogenic effect by targeting unstable budding tumor neo-vessels. CA4P is currently being studied in clinical trials in oncology.
In a paper appearing online on October 6 in advance of print publication of the November issue of the Journal of Clinical Investigation, Shahin Rafii and colleagues from Cornell University provide important mechanistic data demonstrating how CA4P has anti-tumor and anti-angiogenic activity.
The authors find that CA4P selectively targets endothelial cells (flat-shaped cells that make up the inside of blood vessels) but not smooth muscle cells (cells which surround most blood vessels), and induces regression of unstable, newly formed vessels by disruption of Vascular Endothelial-cadherin (VE-cadherin) signaling. VE-cadherin is a protein found at the junctions of overlapping regions of endothelial cells and plays a key role in many aspects of vascular function including, endothelial cell survival, cell migration, cell proliferation and assembly into vessel-like structures.
Dissecting the mechanism whereby CA4P exerts its anti-vascular effect will open up new avenues of research to selectively target tumor neo-vessels and increase the therapeutic window of anti-angiogenic agents.
TITLE: Combretastatin A4 phosphate disrupts tumor vasculature and growth by interfering with vascular endothelial-cadherin signaling
Weill Cornell Medical School, New York, NY USA
Phone: 212 746-2070; Fax: 212 746-8866; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=24586
A NEW MUTATION PUTS SCID ON THE SKIDS
Patients with severe combined immunodeficiency disease (SCID) have an absence or severe lack of immune cells (T cells and B cells). Because of this, these patients cannot produce antibodies and appropriate immune responses.
In a paper appearing online on October 6 in advance of print publication of the November issue of the Journal of Clinical Investigation, Stephan Ehl and colleagues from the University of Freiburg describe the first patient with a clinical and molecular diagnosis of SCID, but who was able to produce specific antibodies to some vaccines, infections and self-antigens.
The patient had severely reduced T cells expressing the alpha/beta T cell receptor (TCR), but normal numbers of T cells expressing the gamma/delta TCR. This represents a new type of primary immunodeficiency due to a mutation in the RAG1 gene.
TITLE: A variant of severe combined immunodeficiency with specific immune responses and predominance of gamma/delta T cells
University of Freiburg, Freiburg, Germany
Phone: +49-761-270-4301; Fax: +49-761-270-4481; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25221
IN Treg BIOLOGY, WHAT IS TRUE IN MICE DOES NOT STAND UP IN MAN
Proper regulation of the immune system depends on special T cells known at Tregs. In a paper appearing online on October 6 in advance of print publication of the November issue of the Journal of Clinical Investigation, Megan Levings and colleagues from the University of British Columbia investigated the capacity of FOXP3 and a previously uncharacterized isoform (FOXP3Delta2), to drive the development of human CD4+CD25+ Treg cells. FOXP3 was known to drive the generation of CD4+CD25+ Treg cells in mice but its role in humans was unclear.
The authors show that expression of FOXP3 may be necessary but is not sufficient for the generation of CD4+CD25+ Treg cells in humans, unlike in mice. This manuscript offers new insight into the role of FOXP3 in the generation and function of human CD4+CD25+ Tregs.
TITLE: The role of two FOXP3 isoforms in the generation of human CD4+ T regulatory cells
University of British Columbia, Vancouver, BC Canada
Phone: 604-875-4111 x66742; Fax: 604-875-4497; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=24685
THE ANSWER TO SKIN BLISTERING DISEASES POPS UP
Patients with pemphigus vulgaris and pemphigus foliaceus have skin blistering diseases that occur because the patients form antibodies against proteins in the skin that hold the skin tightly together. The cellular basis of pathogenesis in pemphigus is still poorly understood. It has been hypothesized that antibody binding to the desmoglein proteins could directly induce blistering by steric hindrance, but other evidence suggests that cytoplasmic events involving intracellular signaling may be involved.
In a paper appearing online on October 6 in advance of print publication of the November issue of the Journal of Clinical Investigation, Jens Waschke and colleagues from University of Wurzburg answer this question using atomic force microscopy and laser tweezers. They demonstrate that antibodies from patients suffering from these autoimmune skin diseases induce blisters not by blocking desmoglein transinteraction by steric hindrance, but require cell-dependent mechanisms. This work answers a long-standing question in this field.
TITLE: Pemphigus foliaceus IgG cause dissociation of desmoglein 1–containing junctions without blocking desmoglein 1 transinteraction
University of Wurzburg, Wurzburg, Germany
Phone: 0049-931-31-2384; Fax: 0049-931-31-2712; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=23475
TLR2 TAKES A TOLL ON ATHEROSCLEROSIS
Atherosclerosis is a major cause of morbidity in Western societies. Despite its prevalence, the inflammatory signals that cause atherosclerosis are still controversial. There is evidence that a link exists between atherosclerosis and a family of proteins called toll-like receptors (TLR), which recognize components of microbes as well as some endogenous proteins. In particular, the roll of TLR-2 in atherosclerosis has been hard to pin down.
In a paper appearing online on October 6 in advance of print publication of the November issue of the Journal of Clinical Investigation, Adam Mullick and colleagues from Scripps provide evidence for a role of TLR2 in atherosclerosis. Using atherosclerosis-prone mice on a high-fat diet, the authors demonstrate the atheroprotective effect of deletion of TLR2. With bone marrow transplant studies, they show cells not of bone marrow origin mediate this effect. With TLR2 agonist injections, the researchers observe a profound increase in lesion severity in these mice fed a high-fat diet. This effect is abolished in animals that do not express TLR2 in bone marrow-derived cells. These data suggest a key role of TLR2 in atherosclerosis.
TITLE: Modulation of atherosclerosis in mice by Toll-like receptor 2
The Scripps Research Institute, La Jolla, CA USA
Phone: (858) 784-8130; Fax: (858) 784-9144; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=25482
LOOKING AT LUPUS B CELLS AND FINDING WHAT AILS THEM
Systemic lupus erythomatosus (SLE) is an autoimmune disease with a wide range of symptoms. In a paper appearing online on October 6 in advance of print publication of the November issue of the Journal of Clinical Investigation, Inaki Sanz and colleagues from University of Rochester provide the first description of a specific checkpoint in the regulation of autoreactive B-cells whose function is defective in human SLE.
The authors also directly analyze germinal center B-cells in human SLE and demonstrate the feasibility of using tonsil biopsies for the analysis of secondary lymphoid tissue in human autoimmune diseases. Ready availability of such tissue has been a long-standing hurdle for the study of these diseases. This work contributes to our understanding of the events leading to the activation of autoreactive B cells in patients with SLE.
TITLE: Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus
University of Rochester, Rochester, NY USA
Phone: (585) 275-2891; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24179
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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