Profiling Prostate Cancer
Determining proper treatment for individuals diagnosed with prostate cancer suffers because of the current unreliability of methods to predict the clinical course of the disease. Existing procedures for patient stratification include a series of clinical, biochemical, and histopathological examinations, such as prostate specific antigen (PSA) levels, tumor stage, Gleason score, and genetic approaches that look for specific oncogenic alterations. Used together, these tools still have only limited classification capability. Recent studies utilizing cDNA microarray technology have indicated that specific genetic markers may be useful as potential prostate cancer markers. In the March 15 issue of the Journal of Clinical Investigation, Gennadi Glinsky and colleagues, from the Sydney Kimmel Cancer Center, San Diego, CA, present a highly accurate gene-expression-based prostate cancer recurrence predictor algorithm. The authors used a microarray-based gene-expression profiling method to determine molecular signatures that could distinguish subgroups of patients with different disease outcomes. The algorithm was developed utilizing an analysis that assessed expression profiles of over 12,000 genes from 100 different tumors. Five highly discriminating gene-expression clusters were assigned from this analysis and then tested on a new set of 79 patients. Of those patients who ultimately had recurrence of prostate cancer, the algorithm correctly classified 88% of these patients into the poor-prognosis group. This study provides a significant advance in our ability to properly classify the clinical outcome of prostate cancer patients for use in determining appropriate treatment.
In an accompanying commentary, Mitchell Benson and James McKiernan of Columbia University, place this study in context with other methods for predicting clinical outcome, and how combination of these methods with that presented here should enhance our ability to stratify patient populations and better manage disease treatment.
TITLE: Gene expression profiling predicts clinical outcome of prostate cancer
Gennadi V. Glinsky
Sidney Kimmel Cancer Center, San Diego, California, USA.
View the PDF of this article at: https://www.the-jci.org/press/20032.pdf
ACCOMPANYING COMMENTARY: Predicting the clinical course of prostate cancer
Mitchell C. Benson
Columbia University College of Physicians and Surgeons, New York, New York, USA.
View the PDF of this commentary at: https://www.the-jci.org/press/21310.pdf
The Bare Bones of Cutting the Fat
Osteoporosis affects over 10 million individuals in the United States. The overall level of bone mass in an individual is known to be controlled primarily by the balance between the two cell types involved in bone remodeling: osteoblasts, which regenerate bone tissue, and osteoclasts, which degrade it. Osteoblasts come from mesenchymal progenitor cells, which can also give rise to fat cells, called adipocytes. An intriguing fact is that in aging individuals while osteoblast development declines, there is an increase in the presence of adipocytes in the bone marrow. In the March 15 issue of the Journal of Clinical Investigation, Hiroshi Kawaguchi and colleagues, from the University of Tokyo, investigate the relationship between the generation of bone-building cells and fat-storage cells, by looking at the effect of the loss of a protein called PPAR-gamma, a key regulator in adipocyte development, in mesenchymal cell differentiation into bone or fat cells. Mice that were deficient in one of their PPAR-gamma genes had increased bone mass and a higher generation of osteoblasts. Furthermore, mouse embryonic stem (ES) cells that had no PPAR-gamma gene completely failed to differentiate into adipocytes, but spontaneously formed osteoblasts. These and other data indicate an intriguing reciprocal relationship between bone and fat development, and may provide a new avenue for osteoporosis therapies.
In an accompanying commentary, Peter Tontonoz and Liming Pei, from the University of California in Los Angeles, discuss the findings of this study in the broader context PPAR-gamma's role in fat development as well as the strengths and limitations of likely use of the pathway for novel osteoporosis therapy.
TITLE: PPAR-gamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors
The University of Tokyo, Tokyo, Japan.
Phone: 81-3-3815-5411 ext. 30473 or 33376
View the PDF of this article at: https://www.the-jci.org/press/19900.pdf
ACCOMPANYING COMMENTARY: Fat's loss is bone's gain
University of California Los Angeles, Los Angeles, California, USA.
View the PDF of this commentary at: https://www.the-jci.org/press/21311.pdf
The Catch 22 of Immune Response to AIDs Viral Infection
A strong antigen-specific T-cell response to HIV infection is important for controlling virus replication; however, because HIV selectively infects and replicates in CD4 T cells, increased number of these cells in response to viral infection may also be detrimental as these cells provide fuel for the infection to grow. In the March 15 issue of the Journal of Clinical Investigation, Mark Feinberg and colleagues, of Emory University Vaccine Center, analyze the specific parameters of T-cell activation that may be harmful or helpful in fighting HIV infection by looking at simian immunodeficiency viral (SIV) replication in rhesus macaques where they have blocked CD4 and CD8 T-cell co-stimulation pathways. The study provides clear evidence for an important role in the immune activation level directly affects the initial peak of virus in the blood stream. They further show that the steady-state viral levels in chronic infection are directly related to the generation of a primary immune response. Evidence in this study also indicates, indirectly, that immunological response may indeed be harmful by providing increased numbers of target cells for infection. The work here presents the first set of data to differentiate between helpful and harmful effects of the immune response to HIV, and may therefore contribute to new strategies for combating this disease.
An accompanying commentary by Bruce Walker (Harvard Medical School) and Steven Deeks (University of California, San Francisco) provides a detailed discussion of the different components of the findings and how these results aid in picking apart this complex interplay between HIV infection and our immune response.
TITLE: Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication
Emory University Vaccine Center, Atlanta, Georgia, USA.
View the PDF of this article at: https://www.the-jci.org/press/19442.pdf
ACCOMPANYING COMMENTARY: The immune response to AIDS virus infection: good, bad, or both?
Bruce D. Walker
Harvard Medical School, Boston, Massachusetts, USA.
View the PDF of this commentary at: https://www.the-jci.org/press/21318.pdf
Patching Up Skin Cancer
Mutations in the tumor suppressor gene patched (Ptch) are responsible for most basal cell carcinomas (BCCs). Mice deficient in one of their Ptch genes (Ptc1+/–) provide a good model for the study of BCCs, since their skin appears normal until exposure to radiation accelerates the induction of BCCs. Ornithine decarboxylase (ODC) catalyzes conversion of ornithine to putrescine and is induced by solar ultraviolet B (UVB) rays. This enzymatic reaction leads to the production of higher levels of polyamines, which are critical for normal and neoplastic cell growth. As ODC activity is higher in BCCs than in normal human skin, Mohammad Athar and colleagues, from Columbia University, sought to evaluate the potential for ODC inhibition as a therapeutic target for these tumors in the March 15 issue of the Journal of Clinical Investigation. They generated Ptc1+/– mice that constitutively expressed ODC in the skin and observed an even greater acceleration of BCC induction. To block ODC activity in Ptc1+/– mice, the group generated mice that overexpress antizyme, which controls ODC by posttranslational modifications and suppresses ODC activity. These mice were less susceptible to UVB-induced photocarcinogenesis and had fewer visible BCCs and reduced tumor volume. In addition, administration of a suicidal ODC inhibitor to Ptc1+/– mice diminished BCC-like lesions by more than 80%. This article indicates that ODC inhibitors might be useful for the chemoprevention of BCCs.
TITLE: Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice
Columbia University College of Physicians and Surgeons, New York, New York, USA.
View the PDF of this article at: https://www.the-jci.org/press/20732.pdf
Beneficial Expectations for Rheumatoid Arthritis Unexpectedly Detrimental
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting approximately 1–2% of the population, and is caused by the body's immune system mistakenly attacks the lining of the joints and in some cases the lining of blood vessels, the heart and the lungs. The underlying molecular mechanisms for the disease are not well understood. In the March 15 issue of the Journal of Clinical Investigation, Seema Ahuja and colleagues, of the University of Texas Health Science Center at San Antonio, investigate the effect of deleting one of the CC chemokine receptors, CCR2. The use of agents that block CCR2 action in RA mouse models partially reduces relevant RA symptoms, indicating this receptor may play a role in advancement of the disease. Completely unexpected results, however, resulted in two different mouse models for RA that had the CCR2 gene deleted: in both cases, instead of an amelioration of RA, the mice had far worse RA symptoms, indicating that instead of increasing RA risk when present, CCR2 play some protective role in RA. This study indicates clearly the complexity of the molecular interactions involved in the development of RA and indicates the need for caution in choosing therapeutic targets given the potential complex effects of the chemokine system's involvement in this disorder.
TITLE: Experimental arthritis in CC chemokine receptor 2–null mice closely mimics severe human rheumatoid arthritis
Seema S. Ahuja
The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
View the PDF of this article at: https://www.the-jci.org/press/20126.pdf
Getting to the Heart of Sympathetic Nerve Formation
The cardiac sympathetic nerve heavily regulates cardiac function. Nerve development in cardiac tissue is controlled by nerve growth factor (NGF), but molecular understanding of how NGF contributes to sympathetic nerve formation and development are not well understood. In the March 15 issue of the Journal of Clinical Investigation, Keiiichi Fukuda and colleagues, from the Keio School of Medicine, carry out molecular analyses in cell culture and genetic analyses in mice and determine that the protein Endolthelin-1 (ET-1) is a key regulator of NGF expression cardiomyocytes and its role in sympathetic innervation of the heart. Given the tight control that autonomic nerve function has on cardiac function, these findings provide potential insight into the role ET-1 may play in congestive heart failure as well as other cardiac disorders.
An accompanying commentary by Barbara Hempstead, of Weill Medical College of Cornell University, provides an overview of the sympathetic innervation of organs and information on how the ET-1 findings may relate to clinical analyses and treatments of cardiac disease.
TITLE: Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression
Keio University School of Medicine, Tokyo, Japan.
View the PDF of this article at: https://www.the-jci.org/press/19480.pdf
ACCOMPANYING COMMENTARY: Sculpting organ innervation
Barbara L. Hempstead
Weill Medical College of Cornell University, New York, New York, USA.
View the PDF of this commentary at: https://www.the-jci.org/press/21309.pdf
Defining the Ergotope in T-cell Vaccination
T-cell vaccination (TCV) is a potential new treatment for individuals suffering from an autoimmune disease, and has already been tested in a limited number of people suffering from multiple sclerosis with promising results. The rational behind TCV is analogous to classical vaccination methods, whereby exposure to an attenuated form of the pathogen results in the immune system learning to recognize and attack that pathogen. Likewise, TCV introduces an attenuated form of the autoimmune T cell, resulting in the immune system in some way eliminating or reducing the effect of the autoreactive T cell. The mechanisms underlying this response remain unclear, but have led the way to a new understanding of the immune system and a recognition that, counter to previous understanding, autoimmune T cells are a normal part of the immune system, not an unexpected aberrancy, and that the immune system has built-in systems that keep these autoreactive T cells under control. This built-in system relies on a relatively unknown interaction of a newly defined type of T cell that involves a protein or peptide associated with the autoreactive T cell acting as an ergotope that induces anti-ergotypic T cells that in turn affect the autoreactive T cells. In the March 15 issue of the Journal of Clinical Investigation, Irum Cohen and colleagues, from The Weizmann Institute of Science, Rehovot, Israel, provide new insight into the specific mechanics of the effects of TCV. Previous studies have shown that antibodies against the IL-2 receptor (CD25) are clinically ably to result in immunosuppression. Here, the authors use vaccination with the complete CD25 DNA, and show that such vaccination protects rats from adjuvant arthritis (AA), an autoimmune disorder. Analysis of the changes in T-cell state and activity provided novel information on the nature of the ergotope, indicating that CD25 may be a target ergotope in TCV. This work has important implications for understanding the nature of the ergotope and the role of anti-ergotypic T cells in immune regulation, which should aid in defining methods for use of TCV in treatment of autoimmune disorders.
TITLE: DNA vaccination with CD25 protects rats from adjuvant arthritis and induces an antiergotypic response
Irum R. Cohen
The Weizmann Institute of Science, Rehovot, Israel.
View the PDF of this article at: https://www.the-jci.org/press/17772.pdf
Linking Cystic Diseases
Maturity-onset diabetes of the young type 5 (MODY5) and autosomal recessive polycystic kidney disease (ARPKD) are caused by mutations in two distinct genes, HNF1-beta and PKHD1, respectively. Both diseases affect the kidney and result in renal cystogenesis. In the March 15 issue of the Journal of Clinical Investigation, Peter Igarashi and colleagues, from the University of Texas Southwestern, have determined a link between these genetic diseases by identifying an evolutionarily conserved HNF1-beta binding site on the proximal promoter of PKHD1. In vitro studies demonstrated that wild-type HNF1-beta activated transcription of the PKHD1 promoter, whereas a dominant negative form could not. Moreover, specific mutations and deletions of the binding site on the PKHD1 promoter abolished promoter activity as assayed by a gene reporter system. To relay this information in vivo, the authors generated transgenic mice expressing a dominant negative form of HNF1-beta. As expected, PKHD1 gene expression was decreased in the kidneys of transgenic mice. Examination of renal histology revealed renal cysts in these mice. Finding a commonality in the mechanism of these diseases may enable shared treatment strategies for renal cyst diseases.
TITLE: Mutation of hepatocyte nuclear factor–1b inhibits Pkhd1 gene expression and produces renal cysts in mice
University of Texas Southwestern, Dallas, Texas, USA.
View the PDF of this article at: https://www.the-jci.org/press/20083.pdf
Src is the Myocardial Shark
Within hours following ischemic injury, VEGF expression increases, leading to changes in the vasculature including increased permeability, blood vessel growth, and endothelial cell survival. However, in the March 15 issue of the Journal of Clinical Investigation, David Cheresh and colleagues, from the Scripps Research Center, report that, in addition to the potential positive effects VEGF may have following acute myocardial infarction (MI), VEGF also has a dark side. The authors showed that the VEGF-induced vascular permeability (VP) response led to edema and extensive cardiac tissue injury following MI. However, they demonstrated that mice deficient in pp60Src or normal mice treated with pharmacological Src inhibitors showed minimal VP, edema, and platelet microthrombi following MI. These animals exhibited not only dramatically reduced infarct volume early on, but also a decrease in fibrosis and mortality months after the injury. Importantly, a single dose of an Src inhibitor given up to 6 hours after injury still provided cardiac protection. Furthermore, the biochemical mechanism responsible for this protection is the stabilization of an endothelial cell Flk/cadherin complex, which normally dissociates upon VEGF-mediated Src signaling. These data suggest that important consideration must be exercised in the use of VEGF clinically to promote angiogenesis, and they support Src blockade as a therapy to limit tissue injury following MI and perhaps other ischemic diseases.
TITLE: Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction
The Scripps Research Institute, La Jolla, California, USA.
View the PDF of this article at: https://www.the-jci.org/press/20702.pdf
MAT1A Loss Lets Liver Down
TNF-alpha signaling can elicit multiple responses including proliferation, inflammation, or cell death. Recently, acidic sphingomyelinase (ASMase) has been shown to play a significant role in hepatocellular apoptosis and liver damage induced by TNF-alpha. In the March 15 issue of the Journal of Clinical Investigation, José Fernández-Checa and colleagues, at the Institut de Malalties Digestives in Barcelona, Spain, further these findings to show that ASMase exerts its ill effects by downregulating methionine adenosyltransferase 1A (MAT1A) levels in the liver. Generation of ceramide by human placenta ASMase decreased MAT1/III protein levels in cultured rat hepatocytes. Using an in vivo mouse model of lethal hepatitis, the authors observed depletion of S-adenosy-L-methionine (SAM), the synthesized product of MATs, before fatal liver damage ensued. However, ASMase deficient mice maintained higher levels of SAM and experienced minimal liver damage. Furthermore, SAM administration prevented lethal liver failure in mice containing ASMase. These studies identify a novel function for ASMase in TNF-alpha mediated cytotoxicity and suggest a therapeutic use for SAM in the treatment of liver diseases and liver failure.
TITLE: Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor–induced lethal hepatitis
Institut de Malalties Digestives, Hospital Clinic i Provincial, Barcelona, Spain.
View the PDF of this article at: https://www.the-jci.org/press/19852.pdf
Putting the PACAP on Bleeding
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that has a wide distribution of receptors throughout the body. It, therefore, exerts its activity on a vast array of physiological processes, including reproduction, development, growth, and cardiovascular, respiratory, and digestive function, as well as immune responses and circadian rhythms. In the March 15 issue of the Journal of Clinical Investigation, Kathleen Freson and colleagues discover a new role for PACAP in hematological processes. Analysis of two patients with partial trisomy 18p showed these patients had three copies of the PCAP gene. The patients suffered from severe mental retardation and a bleeding tendency, with mild thrombosis. The authors' research showed, investigation of these patients, use of PACAP agonists, and creation of PACAP knockout mice, that the bleeding and thrombosis activity were related to PACAP overexpression. This study provides potential new directions for prevention or treatment of bleeding disorders.
TITLE: The pituitary adenylate cyclase–activating polypeptide is a physiological inhibitor of platelet activation
University of Leuven, Leuven, Belgium.
View the PDF of this article at: https://www.the-jci.org/press/19252.pdf
Shedding LIGHT on Glomerulonephritus
Immunoglobin-A nephropathy (IgAN) is the most common type of glomerulonephritus worldwide and results from elevated serum IgA in about 50% of the patients and renal mesangial cell deposition of IgA. The exact molecular mechanisms underlying this disorder the presence of the pathogenic IgA remain uncertain. In the March 15 issue of the Journal of Clinical Investigation, Yang-Xin Fu and colleagues from the University of Chicago, present evidence that dysregulation of IgA production through the lymphotoxin -beta receptor (LTBR) signaling pathway serves as the mechanism for IgA pathogenesis. There results show that LIGHT, a ligand for LTBR, stimulated IgA overproduction, but more importantly promoted its improper transport into the gut lumen in transgenic mice. These studies indicate that improper regulation of LIGHT itself may be a major underlying factor for IgAN and focus on its production and regulation should shed more light on this disease.
TITLE: Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy
The University of Chicago, Chicago, Illinois, USA.
View the PDF of this article at: https://www.the-jci.org/press/20096.pdf
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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