[ Back to EurekAlert! ] Public release date: 22-Apr-2008
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Journal of Clinical Investigation

JCI table of contents: April 22, 2008

EDITOR'S PICK: Two types of image are better than one for analyzing tumors

Doctors treating individuals with cancer would find a noninvasive method to determine the amount of oxygen in a tumor very useful, because low levels of oxygen in a tumor have been linked to a poor outcome. A new method to do this and to image the surrounding organs and tissues at the same time has been developed and used to image tumors in mice by Murali Krishna and colleagues, at the National Institutes of Health, Bethesda. The importance of this technical advance for furthering our understanding of tumor development in pre-clinical studies is discussed in an accompanying commentary by Mark Dewhirst and colleagues, at Duke University, Durham. As are some of the challenges that need to be overcome to develop the approach for use in the clinic, where it could be used diagnostically to determine the best treatment approach for tumors and other diseases as well as to monitor responses to treatment.

TITLE: Low-field paramagnetic resonance imaging of tumor oxygenation and glycolytic activity in mice

AUTHOR CONTACT:
Murali C. Krishna
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-7511, Fax: (301) 480-2238, E-mail: murali@helix.nih.gov

View the PDF of this article at: https://www.the-jci.org/article.php?id=34928

ACCOMPANYING COMMENTARY
TITLE: One-stop-shop tumor imaging: buy hypoxia, get lactate free

AUTHOR CONTACT:
Mark W. Dewhirst
Duke University, Durham, North Carolina, USA.
Phone: (919) 684-4180; Fax: (919) 684-8718; Email: dewhi001@mc.duke.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35543


TRANSPLANTATION: One reason why curative transplants might fail in type 1 diabetics

Individuals with autoimmune type 1 diabetes, which is caused by immune cells known as T cells attacking the body’s own insulin-producing pancreatic islet cells, need daily injections with insulin to control their blood sugar levels. This dependence on insulin injections can be circumvented by transplantation with islet cells. However, transplant recipients must be treated with a drug regimen, known as the Edmonton protocol, that decreases their number of T cells in an attempt to prevent the transplanted islet cells from being attacked by T cells that recognize the new islet cells as being from another human and from the same T cells that attacked the body’s original islet cells. Despite the drug regimen, islet cell transplants eventually fail in most recipients. New data, generated by Ezio Bonifacio and colleagues, at Dresden University of Technology, Germany, have indicated that the T cells that attacked the body’s original islet cells increase in number following treatment with the Edmonton protocol, leading them to suggest that this contributes to transplant failure.

In the study, the T cell loss caused by the Edmonton protocol was shown to be associated with the production of soluble factors that stimulate T cell proliferation as well as an increase in the number of T cells that recognize a protein (GAD65) expressed by islet cells. In two transplant recipients studied, two of the drugs in the Edmonton protocol (FK506 and rapamycin) were replaced with an alternative (micophenolate mofetil). No increase in the number of T cells that recognize GAD65 was observed in these individuals, leading the authors to suggest that drug regimens that do not promote the expansion of T cells might improve the outcome of islet cell transplantation. The importance of these observations for the ongoing development of new protocols for ensuring islet cell transplant survival is discussed in an accompanying commentary by Tom Van Belle and Matthias von Herrath, at the La Jolla Institute for Allergy and Immunology.

TITLE: Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells

AUTHOR CONTACT:
Ezio Bonifacio
Dresden University of Technology, Dresden, Germany.
Phone: 49-0-351-463-40092; Fax: 49-0-351-463-40090; E-mail: ezio.bonifacio@crt-dresden.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35197

ACCOMPANYING COMMENTARY
TITLE: Immunosuppression in islet transplantation

AUTHOR CONTACT:
Matthias von Herrath
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Phone: (858) 752-6817; Fax: (858) 752-6993; E-mail: matthias@liai.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35639


NEUROBIOLOGY: One protein, opposite effects on a characteristic of some neurodegenerative disorders

One of the characteristics of the brain of people with Alzheimer disease (AD) is the presence of tangles, insoluble twisted fibers that build up inside the nerve cells of the brain resulting in malfunctions in communication between nerves and later in their death. As these tangles are due to abnormal aggregation of the tau protein, AD is classified as a tauopathy. Other tauopathies include the neurodegenerative disease frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Although the tau protein in individuals with AD is not mutated, mice carrying the mutated forms of tau found in individuals with FTDP-17 are often used as mouse models of AD. However, Kun Ping Lu and colleagues, at Harvard Medical School, Boston, have now determined that nonmutated tau protein and the most frequent form of mutant tau in individuals with FTDP-17 (P301L tau) are regulated differently by the protein Pin1, meaning that mice carrying mutated forms of tau are not likely to model AD very faithfully.

Consistent with previous studies, it was found that elimination of Pin1 in mice enhanced the stability of nonmutated tau protein, whereas overexpression of Pin1 decreased the stability of the protein and suppressed tauopathy in mice engineered to express nonmutated human tau. By contrast, elimination of Pin1 in mice decreased the stability of P301L tau and suppressed tauopathy in mice engineered to express P301L tau, whereas overexpression of Pin1 enhanced tauopathy in P301L tau mice. The authors therefore suggest that therapeutics inducing Pin1 up-regulation might be beneficial for individuals with AD, whereas Pin1 inhibition might be helpful for patients with FTDP-17 due to P301L tau.

TITLE: Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy

AUTHOR CONTACT:
Kun Ping Lu
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 667-4143; Fax: (617) 667-0610; E-mail: klu@caregroup.harvard.edu.

MEDIA CONTACT:
Bonnie Prescott
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 667-7306; E-mail: bprescot@bidmc.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34308


VIROLOGY: Uncovering the secret ways of HIV: the HIV protein Nef impairs blood cell development

The generation and function of all types of blood cell are impaired in individuals infected with HIV. HIV is thought to cause this problem by disrupting the function of cells that are the precursors of all blood cells; these cells are known as hematopoietic progenitor cells. Exactly how HIV affects hematopoietic progenitor cells has not been determined, although it seems to be an indirect effect as the cells are not themselves infected with HIV. New data, generated by Stéphane Prost and colleagues, at the Institute of Emerging Disease and Innovative Therapies, CEA, France, have now indicated that the HIV protein Nef disrupts the function of hematopoietic progenitor cells.

In the study, production of the protein Nef was shown to be essential for the monkey form of HIV (SIV) to disrupt hematopoietic progenitor cell function in vivo and ex vivo. The ability of both SIV and HIV Nef to cause this problem was dependent on the hematopoietic progenitor cells expressing the protein PPAR-gamma. Further, when PPAR-gamma agonists were administered to macaques they impaired hematopoietic progenitor cell function. Disruption of hematopoietic progenitor cell function by both PPAR-gamma agonists and SIV and HIV Nef was associated with downregulation of the signaling molecules STAT5A and STAT5B, indicating that Nef is likely to impair blood cell development by targeting a PPAR-gamma/STAT5 signaling pathway. The authors have therefore suggested that PPAR-gamma antagonists might be of benefit to both individuals infected with HIV and those with blood cell–deficiency disorders. As noted by the authors and, in an accompany commentary, Frank Kirchhoff and Guido Silvestri, these data also have implications for PPAR-gamma agonists, which are currently used to treat individuals with type 2 diabetes.

TITLE: Human and simian immunodeficiency viruses deregulate early hematopoiesis through a Nef/PPAR-gamma/STAT5 signaling pathway in macaques

AUTHOR CONTACT:
Stéphane Prost
Institute of Emerging Disease and Innovative Therapies, CEA, Fontenay-aux-Roses, France.
Phone: 33-1-46-54-94-69; Fax: 33-1-46-54-77-26; E-mail: stephane.prost@cea.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33037

ACCOMPANYING COMMENTARY
TITLE: Is Nef the elusive cause of HIV-associated hematopoietic dysfunction?

AUTHOR CONTACT:
Frank Kirchhoff
University of Ulm, Ulm, Germany.
Phone: 49-731-50065109; Fax: 49-731-50065131; E-mail: frank.kirchhoff@uniklinik-ulm.de.

Guido Silvestri
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-5363; Fax: (215) 573-5366; E-mail: gsilvest@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35487


ONCOLOGY: Downfall of some tumor cells is their reliance on just one of three cyclin D proteins

Unlike normal cells, which have three cyclin D proteins that can each cover for the others, the cells of many types of cancer, especially blood cancers such as multiple myeloma, express only one cyclin D protein. This has led to the suggestion that targeting individual cyclin D proteins might provide a good approach to treating individuals with cancers characterized by a reliance on just one cyclin D protein. Evidence to support this idea has now been generated in preclinical models by Keith Stewart and colleagues, at the Mayo Clinic in Scottsdale, Arizona.

In the study, a large number of chemicals were screened for their ability to inhibit the expression of the CCND2 gene, which is the gene that carries the information for making the cyclin D2 protein. During the screen, a chemical from plants known as kinetin riboside was shown to inhibit expression of both the CCND2 gene and the CCND1 gene. Further analysis revealed that the chemical inhibited the expression of both cyclin D1 and cyclin D2 in cells from individuals with multiple myeloma and myeloma cell lines, causing the cells to stop growing and to die. The chemical also prevented myeloma cell lines from growing when transplanted into mice. The authors have therefore suggested that these data provide a good rationale for further exploration of the ability of kinetin riboside and other drugs that target cyclin D1 and/or cyclin D2 to benefit individuals with cancers characterized by a reliance on either cyclin D1 or cyclin D2, such as many individuals with multiple myeloma.

TITLE: Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity

AUTHOR CONTACT:
A. Keith Stewart
Mayo Clinic, Scottsdale, Arizona, USA.
Phone: (480) 301 4411; Fax: (480) 301 8387; E-mail: stewart.keith@mayo.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34149


REPRODUCTIVE BIOLOGY: How is a regulator of sex hormone production regulated itself?

The production of the sex hormones testosterone, progesterone, and estrogen is controlled by two other hormones, which are known as luteinizing hormone (LH) and follicle stimulating hormone (FSH). Disturbances in the levels of either LH or FSH affect the production of sex hormones and can cause either premature or delayed puberty as well as infertility. New data, generated in mice by Jacques Baenziger and colleagues, at Washington University School of Medicine, St. Louis, have identified a new mechanism by which levels of LH in the blood are regulated.

Attached to LH are unique carbohydrate structures that end in a carbohydrate unit known as GalNAc-4-SO4. In the study, mice lacking the protein responsible for adding GalNAc-4-SO4 to the end of the carbohydrates on LH were found to have higher levels of LH in the blood than normal mice. In male mice this caused increased levels of testosterone and premature sexual development. In female mice this caused increased levels of estrogen, premature sexual development, and increased fertility. Thus, the authors concluded that the unique carbohydrate structures attached to LH have a crucial role in regulating the levels of this hormone in the blood.

TITLE: Ablation of GalNAc-4-sulfotranferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice

AUTHOR CONTACT:
Jacques U. Baenziger
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-8730; Fax: (314) 362-8888; E-mail: baenziger@wustl.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32467


ONCOLOGY: Filling in the blanks: defining a molecular pathway that promotes inflammation and tumor development in the stomach

Persistent infection with the bacterium Helicobacter pylori leads to persistent inflammation of the stomach lining and in some individuals stomach cancer, also known as gastric cancer. New insight into some of the molecules and signaling pathways that might promote inflammation and tumor development in the stomach has been provided by a team of researchers in Australia, at the Royal Melbourne Hospital and Monash University, through their analysis of a mouse model of gastric cancer. Specifically, it was shown that the soluble factor IL-11 was responsible for promoting inflammation and tumor development in these mice through activation of the signaling molecules Stat3 and, to a lesser extent, Stat1. Further, the activation of Stat3 and Stat1 was found to induce the expression of more IL-11, generating an amplification effect. The importance of these observations is discussed in detail in an accompanying commentary by Juanita Merchant, at the University of Michigan, Ann Arbor.

TITLE: STAT3 and STAT1 mediate IL-11–dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice

AUTHOR CONTACT:
Matthias Ernst
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Phone: 61-3-9341-3155; Fax: 61-3-9341-3104; E-mail: Matthias.Ernst@ludwig.edu.au.

Brendan J. Jenkins
Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Phone: 61-3-9594-7218; Fax: 61-3-9594-7211; E-mail: Brendan.Jenkins@med.monash.edu.au.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34944

ACCOMPANYING COMMENTARY
TITLE: What lurks beneath: IL-11, via Stat3, promotes inflammation-associated gastric tumorigenesis

AUTHOR CONTACT:
Juanita L. Merchant
University of Michigan, Ann Arbor, Michigan, USA.
Phone: (734) 647-2944; Fax: (734) 763-4686; E-mail: merchanj@umich.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35344


NEPHROLOGY: Connecting the dots between obesity and kidney disease

Individuals who are obese have a greater risk of developing kidney disease than those who are not obese. New data, generated by a team of researchers at the University of California at San Diego, La Jolla, and Jefferson Medical College, Philadelphia, have outlined a mechanism by which obesity can cause a clinical condition that is an indicator of kidney damage — albuminuria (the presence of the protein albumin in the urine). As noted by the authors and discussed in detail by Rexford Ahima, from the University of Pennsylvania School of Medicine, Philadelphia, in an accompanying commentary, the results have important implications for the diagnosis, prevention, and treatment of kidney disease.

Adiponectin is a soluble factor secreted by fat tissue, but the amount of adiponectin secreted decreases as an individual becomes more obese. In the study, it was shown that in a group of obese individuals at high risk of developing kidney disease levels of adiponectin in the bloodstream correlated inversely with albuminuria. Consistent with this data, mice lacking adiponectin exhibited increased albuminuria when compared with normal mice. In vitro studies indicated that adiponectin affected kidney cells known as podocytes, causing layers of these cells to become more permeable to albumin. Treating podocyte layers and mice lacking adiponectin with adiponectin reduced permeability to albumin and albuminuria, respectively. Further studies revealed that the effects of adiponectin on podocytes were mediated by AMPK activation and a subsequent reduction in Nox4 levels. The authors therefore suggested that targeting the adiponectin-AMPK-Nox4 pathway might protect against albuminuria and thereby early kidney disease.

TITLE: Adiponectin regulates albuminuria and podocyte function in mice

AUTHOR CONTACT:
Kumar Sharma
University of California at San Diego, La Jolla, California, USA.
Phone: (858) 822-0860; Fax: (858) 822-7483; E-mail: KumarSharma@ucsd.edu.

Barry J. Goldstein
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Phone: (215) 503-1272; Fax: (215) 923-7932; E-mail: Barry.Goldstein@jefferson.edu.

MEDIA CONTACT:
Debra Kain
University of California at San Diego, San Diego, California, USA.
Phone: (619) 543-6163; E-mail: ddkain@ucsd.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32691

ACCOMPANYING COMMENTARY
TITLE: Linking adiponectin to proteinuria

AUTHOR CONTACT:
Rexford S. Ahima
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-1872; Fax: (215) 573-5809; E-mail: ahima@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35655


HEMATOLOGY: A novel role for the protein CD36 in disease-causing blood clot formation

A key step in the formation of a blood clot is the activation and aggregation of cells known as platelets. If a blood clot forms in an intact blood vessel it is known as a thrombus and it can have serious consequences (such as heart disease and stroke) as it restricts, and sometimes even completely blocks, the flow of blood through the vessel. New data, generated by Roy Silverstein and colleagues, at the Cleveland Clinic, has revealed a role for the protein CD36 on platelets in thrombus formation in mice, leading to the suggestion that it might provide a useful new target for the development of anti-thrombotic drugs.

Microparticles are small particles released from cells when they become activated or undergo a form of death known as apoptosis. Physiologically, this means that they are released into the circulation when a blood vessel is injured. In the study, CD36 was shown to mediate binding of human platelets to microparticles derived in vitro from the cells that would be damaged by blood vessel injury and to microparticles isolated from healthy people. Further analysis indicated that CD36 bound a chemical known as phosphatidylserine that is found on the surface of microparticles, and that platelets exposed to microparticles were subsequently easier to activate. Importantly, under certain conditions, the formation of a thrombus in mice was delayed in the absence of CD36 and the thrombi that formed contained fewer microparticles derived from endothelial cells, which are the cells that line blood vessel walls. The rationale for the author’s suggestion that CD36 might provide a useful target for the development of therapeutics to treat individuals with thrombotic disease is supported by the observation that endothelial cell–derived microparticles are found in the blood of patients with several of these diseases.

TITLE: Platelet CD36 mediates interactions with endothelial cell–derived microparticles and contributes to thrombosis in mice

AUTHOR CONTACT:
Roy L. Silverstein
Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Phone: (216) 444-5220; Fax: (216) 444-9404; Email: silverr2@ccf.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34904

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