November 2002
From Journal of Clinical Investigation
JCI Table of Contents, November 18, 2002 Find below two highlighted articles and the full Table of Contents for the November 18, 2002 issue.**************************************************** Targeting bone metastasis and hypercalcemia Most cancer patients are not killed by their primary tumors but succumb to metastatic disease. The most common human cancers--lung, breast, and prostate--frequently spread to bone, causing suffering and morbidity through pain, fractures, and nerve compression syndromes. Tumor cells enter bones through blood and lymphatic vessels. In order to establish bone metastases, they have to influence bone metabolism. Most breast cancers that spread to bone express high levels of parathyroid hormone related protein, or PTHrP, a molecule that promotes bone breakdown. Scientists believe that the bone breakdown caused by PTHrP starts a vicious cycle: cross-talk between the tumor cells and the osteoclasts, cells that specialize in breaking down bone, ultimately leads to more and more bone loss and more and more aggressive growth of the tumor. Consistent with this scenario, inhibition of osteoclast activity not only decreases bone lesions but also reduces tumor burden in animals. Preliminary results from human patients treated with bisphosphonates, a group of drugs also used to prevent and treat osteoporosis, suggest that the same might be true in humans. An article in the November 18 issue of the Journal of Clinical Investigation focuses on direct inhibition of PTHrP, the molecule that is believed to play a critical role in starting the vicious cycle in most breast cancers that metastasize to bone. Wolfgang Gallwitz and colleagues (of Osteoscreen Ltd in San Antonio, Texas) identified two compounds that inhibit PTHrP production in human breast cancer cells. In animal models, the compounds did reduce metastatic bone breakdown, and compared favorably with bisphoshonates. The mode of action of the two classes of drugs is different--the new compounds inhibit PTHrP production and secretion by the tumor cells whereas bisphosphonates inhibit osteoclasts--which suggests that the two drugs might have synergistic effects when used in combination. In an accompanying Commentary, T. John Martin, of St. Vincent's Institute of Medical Research in Melbourne, Australia, discusses the findings in the context of our understanding of bone metabolism and comments on potential therapeutic benefits and risks of PTHrP inhibitors in cancer. PTHrP secretion by tumor cells frequently causes another complication in cancer patients, namely elevated calcium levels. The excess calcium comes on the one hand from increased breakdown of bone, and on the other from increased retention of calcium by the kidney. Hypercalcemia occurs in an estimated 10-20% of cancer patients and is the most common life-threatening metabolic abnormality associated with neoplastic disease. Mouse studies performed by Gallwitz and colleagues suggest that their PTHrP inhibitors have potential in the treatment of hypercalcemia as well. CONTACT:
Wolfgang E. Gallwitz
OsteoScreen, Inc.
Suite 201
2040 Babcock Road
San Antonio, TX 78229
USA
Phone 1: 210-614-0770
Fax 1: 210-614-0797
E-mail: gallwitz@osteoscreen.com View the PDF of this article at: https://www.the-jci.org/press/11936.pdf ACCOMPANYING COMMENTARY: Manipulating the environment of cancer cells in bone: a novel therapeutic approach CONTACT:
T. John Martin
St. Vincent's Institute of Medical Research
9 Princes Street
Fitzroy, Melbourne, Victoria 3065
AUSTRALIA
PHONE: 61-3-9288-2480
FAX: 61-3-9416-2676
E-mail: j.martin@medicine.unimelb.edu.au View the PDF of this commentary at: https://www.the-jci.org/press/17124.pdf **************************************************** The growing Staphylococcus aureus arsenal Staphylococcus aureus is an opportunistic pathogen with a diverse battery of virulence factors, each of which can act alone or in concert in the development of persistent and sometimes lethal infections such as sepsis, toxic shock syndrome, food poisoning and severe skin diseases. Staphylococcal infections begin when the organism gains access to host tissues or the adjoining blood supply through breaches in the skin. More than 20% of healthy humans are natural carriers of S. aureus, 10%-20% of these carriers harbor multidrug-resistant strains, and the frequencies of both community-acquired and hospital-acquired staphylococcal infections continue to increase. Disturbingly, our stockpile of antibiotics is not evolving at a rate capable of quelling the uprising of resistance. Determining whether an infection is contained or succeeds in spreading is a complex battle between defensive cells of the patient's immune system and the onslaught of the array of enzymes, toxins and other injurious factors released by the bacterium. During early stages of infection the S. aureus expresses proteins that enable its binding to, and colonization of, host tissue. Following establishment within the host, other toxins and enzymes help the staphylococci spread to nearby tissue and begin the process of colonization over and over again. In the November 18 issue of the Journal of Clinical Investigation Eric Brown and colleagues from the Texas A&M University Health Science Center further investigate the role of another interesting member of the S. aureus artillery. The MHC class II Analog Protein (known as Map) was shown to interfere with the function of T cells, a patient's most specific defense against foreign intruders, which appeared to promote the persistence and survival of S. aureus in infected mice. CONTACT:
Eric Brown
Texas A&M University System Health Science Center
Albert B. Alkek Institute of Biosciences and Technology
2121 W. Holcombe Blvd.
Suite 603
Houston, TX 77030-7552
USA
Phone 1: 713-677-7572
Fax 1: 713-677-7576
E-mail: ebrown@ibt.tamu.edu View the PDF of this article at: https://www.the-jci.org/press/16318.pdf **************************************************** Table of Contents **************************************************** Resident lung antigen-presenting cells have the capacity to promote Th2 T cell differentiation in situ Why do inhaled antigens frequently trigger allergic reactions? Or, in immunology-speak, why does antigen exposure via airway epithelia often result in a Th2-type response? On pages 1441-1448, Stephanie Constant and colleagues suggest some answers. They identify a resident population of antigen-presenting cells that take up the majority of intranasally-delivered antigens and present them to antigen-specific naive T cells, predominantly locally in the pulmonary tract. In response to antigen uptake, these resident antigen-presenting cells secrete Th2-promoting cytokines, including IL-10 and IL-6. Codelivery of LPS induced the expression of IL-12, but IL-10 and IL-6 levels stayed the same, as did the bias towards a Th2-type response. CONTACT:
Stephanie Constant
George Washington University
MTM, Ross Hall, Rm. 738
2300 Eye Street NW
Washington D.C., DC 20037
USA
Phone 1: 202-994-1138
Fax 1: 202-994-2913
E-mail: mtmslc@gwumc.edu View the PDF of this article at: https://www.the-jci.org/press/16109.pdf **************************************************** Osteoclasts are essential for TNF-alpha-mediated joint destruction Rheumatoid arthritis (RA) is associated with joint inflammation and progressive joint destruction. Both cartilage and bone tissues are destroyed. The latter, not seen in most other inflammatory joint diseases, is a major contributor to the debilitating symptoms of the disease. Indirect evidence suggested that bone destruction in RA--as in normal bone turnover--is mediated by osteoclasts. Georg Schett and colleagues now show (pages 1419-1427) that this is indeed the case. Transgenic mice that express human tumor necrosis factor develop severe and destructive arthritis. Mice lacking c-fos (a factor essential for osteoclast differentiation) and carrying the transgene also develop arthritis, with comparable levels of synovial inflammation and cartilage destruction, but showed no sign of bone erosion. This suggests that RA patients would benefit from therapeutic inhibition of osteoclasts. CONTACT:
Georg Schett
University of Vienna
Department of Internal Medicine III
Division of Rheumatology
Wahringer Gurtel 18-20
A-1090 Vienna, AUSTRIA PHONE: 43-1-40400-4300
FAX: 43-1-40400-4306
E-mail: georg.schett@akh-wien.ac.at View the PDF of this article at: https://www.the-jci.org/press/15582.pdf **************************************************** Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver PI 3-kinase is thought to act downstream of insulin signaling, but results from targeted disruption in mice of PI 3-kinase function--both globally or in specific tissues --have failed to yield a clear picture of when and where PI 3-kinase is required to mediate insulin's function. Taking advantage of the fact that systemic administration of adenovirus leads to accumulation of virus in the liver, Wataru Ogawa and colleagues have used an adenoviral vector carrying a dominant-negative mutant of P1 3-kinase to abolish the function of the enzyme specifically in the liver. Mice infused with the virus exhibited dyslipidemia and hyperinsulinemia, as well as a marked increase in blood glucose levels in response to glucose intake (pages 1483-1491). These results provide evidence that PI 3-kinase activity in the liver is required for normal carbohydrate and lipid metabolism in vivo. CONTACT:
Wataru Ogawa
Division of Diabetes and Digestive and Kidney Diseases
Kobe University
7-5-1 Kusunoki-cho, Chuo-ku
Kobe, UNK 650-0017 JAPAN
Phone 1: 81-78-382-5861
Fax 1: 81-78-382-2080
E-mail: ogawa@med.kobe-u.ac.jp View the PDF of this article at: https://www.the-jci.org/press/15880.pdf **************************************************** Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS T-cell mediated immune responses play a major role in hepatitis-induced liver injury. Studies investigating concanavalin A-induced (Con A-induced) hepatitis have revealed the involvement of multiple cells and cytokines; however, the mechanisms underlying these interactions are not completely understood. Bin Gao and colleagues (pages 1503-1513) investigated the roles of IFN-g, IL-6, and members of the JAK-STAT and SOCS families of proteins in Con A-induced hepatitis by studying disease development and progression in various mutant mouse strains. Their results lead to a model in which disease is controlled, on one hand, by IFN-g-activated STAT1 which stimulates immune cells and promotes liver cell death and, on the other hand by IL-6-activated STAT3 which suppresses IFN-g signaling and induces anti-apoptotic factors --on the other. The two pathways negatively regulate each other through the induction of SOCS. Elevated levels of IL-6 and IFN-g are also observed in several human liver disorders, suggesting that modulation of the mutual antagonism between STAT 1 and STAT 3 may help to limit T cell-mediated liver damage in patients. CONTACT:
Bin Gao
NIAAA/NIH
Section of Liver Biology
Park Bldg., Room 120
12420 Parklawn Drive, MSC 8115
Bethesda, MD 20892
USA
Phone 1: 301-443-3998
Fax 1: 301-480-0257
E-mail: bgao@mail.nih.gov View the PDF of this article at: https://www.the-jci.org/press/15841.pdf **************************************************** Modulation of tumor growth by inhibitory Fc-gamma receptor expressed by human melanoma cells CONTACT:
Catherine Sautes-Fridman
INSERM U255
Centre de Recherches Biomedicales des Cordeliers
15 rue de l'Ecole de Medecine
75006 Paris, FRANCE
Phone 1: 331-5310-0403
Fax 1: 331-4051-0420
E-mail: catherine.fridman@u255.bhdc.jussieu.fr View the PDF of this article at: https://www.the-jci.org/press/15454.pdf **************************************************** IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism CONTACT:
Rolf Kiessling
Karolinska Institute
Cancer Center Karolinska, R8:01
Karolinska Hospital
S-17176 Stockholm, SWEDEN
Phone 1: 46-8-51776857
Fax 1: 46-8-309195
E-mail: rolf.kiessling@mtc.ki.se View the PDF of this article at: https://www.the-jci.org/press/15564.pdf ACCOMPANYING COMMENTARY: IFN-gamma suspends the killing license of anti-tumor CTLs CONTACT:
Aron E. Lukacher
Contact: Lukacher, Aron E
Woodruff Memorial Research
Dept. of Pathology
1639 Pierce Dr.
Atlanta, GA 30322
USA
PHONE: 404-727-1896
FAX: 404-727-5764
E-mail: alukach@emory.edu View the PDF of this commentary at: https://www.the-jci.org/press/17209.pdf **************************************************** Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies CONTACT:
Philipp J. Kahle
Ludwig Maximilians University of Munich
Adolf Butenandt Institute
Dept. Biochem.
Schillerstrasse 44
Munich, NULL 80336
GERMANY
Phone 1: 49-89-5996-480
Fax 1: 49-89-5996-415
E-mail: pkahle@pbm.med.uni-muenchen.de View the PDF of this article at: https://www.the-jci.org/press/15777.pdf ACCOMPANYING COMMENTARY: Misfolded, protease-resistant proteins in animal models and human neurodegenerative disease CONTACT:
Dennis Dickson
Mayo Clinic
4500 San Pablo Rd.
Jacksonville, FL 32224
USA
PHONE: 904-953-2439
FAX: 904-953-7117
E-mail: dickson.dennis@mayo.edu View the PDF of this commentary at: https://www.the-jci.org/press/17164.pdf **************************************************** Target organ localization of memory CD4+ T cells in patients with chronic beryllium disease CONTACT:
Andrew P. Fontenot
University of Colorado Health Sciences Center
Division of Clinical Immunology (B-164)
4200 East Ninth Avenue
Denver, CO 80262
USA
Phone 1: 303-315-7601
Fax 1: 303-315-7642
E-mail: andrew.fontenot@uchsc.edu View the PDF of this article at: https://www.the-jci.org/press/15846.pdf **************************************************** The mouse mahoganoid coat color mutation disrupts a novel C3HC4 RING domain protein CONTACT:
Rudolph L. Leibel
Columbia University
Russ Berrie Pavilion
Room 620
1150 St. Nicholas Ave.
New York, NY 10032
USA
Phone 1: 212-851-5257
Phone 2: 212-751-6794
Fax 1: 212-851-5306
E-mail: rl232@columbia.edu View the PDF of this article at: https://www.the-jci.org/press/16131.pdf **************************************************** Arginine deficiency affects early B cell maturation and lymphoid organ development in transgenic mice CONTACT:
Wouter H. Lamers
University of Amsterdam
Department of Anatomy and Embryology
Academic Medical Center
Meibergdreef 15
Amsterdam, 1105 AZ
THE NETHERLANDS
Phone 1: 31-20-566-5405
Fax 1: 31-20-697-617
E-mail: w.h.lamers@amc.uva.nl View the PDF of this article at: https://www.the-jci.org/press/16143.pdf ACCOMPANYING COMMENTARY: Arginine: an unusual dietary requirement of pre-B lymphocytes? CONTACT:
Tucker W. LeBien
Dept. Laboratory Medcine & Pathology
University Of Minnesota
MMC 806
Minneapolis, MN 55455-0392
USA
PHONE: 612-626-1422
FAX: 612-626-7059
E-mail: lebie001@maroon.tc.umn.edu View the PDF of this commentary at: https://www.the-jci.org/press/17210.pdf **************************************************** Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy CONTACT:
Youhua Liu
University of Pittsburgh School of Medicine
Department of Pathology
S-405 Biomedical Science Tower
200 Lothrop Street
Pittsburgh, PA 15261
USA
Phone 1: 412-648-8253
Fax 1: 412-648-1916
E-mail: liuy@msx.upmc.edu View the PDF of this article at: https://www.the-jci.org/press/16219.pdf **************************************************** Rescue of CD8 T cell-mediated antimicrobial immunity with a nonspecific inflammatory stimulus CONTACT:
Eric G. Pamer
Memorial-Sloan Kettering Institute
1275 York Avenue
Infectious Disease Service
New York, NY 10021
USA
Phone 1: 212-639-7809
Fax 1: 212-717-3021
E-mail: pamere@mskcc.org View the PDF of this article at: https://www.the-jci.org/press/16356.pdf ACCOMPANYING COMMENTARY: Adoptive therapy with CD8+ T cells: it may get by with a little help from its friends CONTACT:
Philip D. Greenberg
Dept. Medicine & Immunology
Univ. of Washington School of Med.
Health Science Bldg. Room BB 1325
Box 356527
Seattle, WA 98195-6527
USA
PHONE 1: 206-543-8306
PHONE 2: 206-543-8556
FAX: 206-685-3128
E-mail: pgreen@u.washington.edu
View the PDF of this commentary at: https://www.the-jci.org/press/17214.pdf **Please mention the Journal of Clinical Investigation as the source of these articles** | 