C-myc causes hormones to lose control in recurrent prostate cancer
Current treatment for progressed prostate cancer is withdrawal of the hormone androgen. While initially effective, this treatment is unable to completely and permanently eliminate all prostate cancer cells. It is not uncommon, that after a patient shows an initial response to treatment, there is a relapse as the cancer progresses to an androgen-independent stage. A major goal of researchers has been to identify the molecular mechanisms involved in the progression of prostate cancer from androgen dependence to independence.
David Bernard and colleagues from University College London studied the ability of c-myc to confer androgen-independent prostate cancer cell growth. In the December 4 issue of the Journal of Clinical Investigation these authors report that ectopic expression of c-myc allowed human androgen-dependent prostate cancer cells to grow without androgen stimulation and to keep their tumorigenic activity in androgen-depleted conditions. Analysis of signaling pathways showed that c-myc is regulated by the androgen receptor, is required for androgen-dependent growth and, following ectopic expression, can induce androgen-independent growth. In addition, c-myc downregulation slowed the growth of androgen-independent tumor cell lines. These results suggest a physiological role for c-myc in prostate cancer and a possible target for therapeutic intervention.
TITLE: Myc confers androgen-independent prostate cancer cell growth
AUTHOR CONTACT:
David H. Beach
University College London, London, United Kingdom
Phone: 0032-2555-6016
Fax: 0032-2555-6257
E-mail: dhbeach@btinternet.com
View a PDF of this article at: https://www.the-jci.org/press/19035.pdf
Regulatory T cells keep graft-versus-host disease in check
Bone marrow transplantation offers the hope of a complete cure for patients suffering from certain forms of cancer, such as leukemia or other immune deficiency diseases. However, there is a risk that transplanted cells may recognize the recipient patient's tissues as foreign and begin to attack them. This reaction, known as graft-versus-host disease (GVHD), can be lethal if it continues unchecked. It has recently been shown in mice that the use of large numbers of immunoregulatory CD4+CD25+ T cells can induce tolerance to donor tissue following allogeneic hematopoietic stem cell transplantation and therefore control the development of GVHD. The challenge however has been to obtain enough freshly purified CD4+CD25+ regulatory T cells from a single donor patient to achieve this therapeutic effect in a clinical setting.
In the December 4 issue of the Journal of Clinical Investigation José Cohen and colleagues from Centre National de la Recherche Scientifique in Paris describe a protocol to circumvent this difficulty. The authors performed regulatory T cell expansion ex vivo by stimulation with allogeneic antigen-presenting cells, which has the additional effect of producing alloantigen-specific regulatory T cells. Regulatory T cells specific for recipient-type alloantigens, but not irrelevant regulatory T cells, controlled GVHD while favoring immune reconstitution. Preferential survival of specific regulatory T cells was observed in the grafted animals. The results will be extremely useful in the design of future clinical trials that rely on the use of CD4+CD25+ regulatory T cells to control GVHD.
TITLE: Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia
AUTHOR CONTACT:
José L. Cohen
Centre National de la Recherche Scientifique, Paris, France
Phone: 33-1-42-17-74-61
Fax: 33-1-42-17-74-62
E-mail: jose.cohen@chups.jussieu.fr
View the PDF of this article at: https://www.the-jci.org/press/17702.pdf
Mast cells to blame for allergic diarrhea
While exposure to food allergens is often associated with diarrhea in humans, knowledge of the cell types and mediators involved in the process is still limited. A report from Marc Rothenberg and colleagues from Cincinnati Children's Hospital Medical Center, Ohio, in the December 4 issue of the Journal of Clinical Investigation describes the use of a murine model of oral allergen–induced intestinal inflammation accompanied by strong Th2-associated humoral and cellular responses. Mice had dose-dependent acute diarrhea associated with increased intestinal permeability, and an increase in granular white blood cells (eosinophilia) and mast cells (mastocytosis). Depletion of mast cells completely abrogated intestinal mastocytosis and blocked the allergic diarrhea.
Furthermore, allergic diarrhea was dependent upon synergistic signaling induced by serotonin and platelet-activating factor (PAF), but not histamine. Additional experiments indicated that the numerous eosinophils present in the intestines did not contribute to the diarrhea. These results demonstrate that oral allergen–induced diarrhea associated with experimental Th2 intestinal inflammation is largely mast cell, serotonin, and PAF dependent. The identified mechanism also suggests that agents such as anti-IgE, recently approved for the treatment of human asthma, and the c-kit inhibitor imatinib mesilate, recently approved for the treatment of various malignancies, may also have therapeutic utility for gastrointestinal allergy.
TITLE: Mast cells are required for experimental oral allergen–induced diarrhea
AUTHOR CONTACT:
Marc E. Rothenberg
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Phone: 513-636-7210
Fax: 513-636-3310
E-mail: Rothenberg@cchmc.org
View the PDF of this article at: https://www.the-jci.org/press/19785.pdf
ONLINE FIRST ARTICLE
Disruption of autophagy gene beclin 1 promotes tumor cell growth
Autophagy is a regulated pathway whereby long-lived cellular proteins are degraded. Tumor cells often display defects in autophagy however little is known about the role of autophagy in cancer biology. The beclin 1 autophagy gene is monoallelically deleted in 40-70% of cases of human sporadic breast, ovarian, and prostate cancer. In the December 4 issue of the Journal of Clinical Investigation Beth Levine and colleagues at Columbia University College of Physicians and Surgeons in New York studied a mouse model with a heterozygous deletion of beclin 1 and observed an increase in cellular proliferation and the frequency of spontaneous malignancies, and reduced autophagy. The report demonstrates that the autophagy gene beclin 1 has a tumor suppressor function and indicates the importance of autophagy in the regulation of cell growth and tumorigenesis.
TITLE: Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
AUTHOR CONTACT:
Beth Levine
Columbia University College of Physicians and Surgeons, New York, New York, USA
Phone: 212-305-7312
Fax: 212-305-7290
E-mail: levine@cancercenter.columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/20039.pdf
Do variants of the SLC6A14 gene determine if we are fat or thin?
Diabetes is arguably the world's most prevalent nutritional disorder and a substantial contributor to morbidity and early mortality. While known to have a strong genetic component, the specific influential genes in human obesity remain largely unknown. In the December 4 issue of the Journal of Clinical Investigation Päivi Pajukanta and colleagues from the University of California examined a Finnish population and found a genetic variant, solute carrier family 6 member 14 (SLC6A14) that appears to cause some people to be fatter or thinner than others. The SLC6A14 gene is a likely candidate gene for obesity, as it is related to serotonin and serotonin receptor mechanisms that have been implicated in the control of appetite and body weight.
In an accompanying commentary, Hemant Tiwari and David Allison from the University of Alabama at Birmingham consider the strength of the evidence in support of this finding and discuss additional research questions that should be addressed in further evaluations of this genetic variant as a putative contributor to human obesity.
TITLE: The SLC6A14 gene shows evidence of association with obesity
AUTHOR CONTACT:
Päivi Pajukanta
University of California School of Medicine, Los Angeles, California, USA
Phone: 310-794-9802
Fax: 310-794-5446
E-mail: ppajukanta@mednet.ucla.edu
View the PDF of this article at: https://www.the-jci.org/press/17491.pdf
ACCOMPANYING COMMENTARY:
Do allelic variants of SLC6A14 predispose to obesity?
AUTHOR CONTACT:
David B. Allison
University of Alabama at Birmingham, Birmingham, Alabama, USA
Phone: 205-975-9169
Fax: 205-975-2540
E-mail: Dallison@UAB.edu
View the PDF of this commentary at: https://www.the-jci.org/press/20448.pdf
Therapeutic protects the liver from excess bile during toxic cholestasis
During cholestasis – the stoppage or slowing of the flow of bile – the failure to rid hepatocytes of bile constituents results in toxicity. It follows that treatments that enhance the ability of cells to rid themselves of these products will decrease toxicity. In the December 4 issue of the Journal of Clinical Investigation Stacey Jones and colleagues from GlaxoSmithKline describe a hepatoprotective effect by a potent and selective agonist of the farnesoid X receptor (FXR) in two rat models of cholestasis.
In both models, rats that received the agonist showed significant reductions in serum markers of liver damage accompanied by improvements in liver histology. Treatment with the FXR agonist increased expression of the bile transporters, bile salt export pumps, and multidrug resistance–related protein 2 and repressed key genes involved in bile acid biosynthesis. FXR agonists may provide hepatoprotection in conditions of cholestasis both by increasing the capacity for bile excretion from the hepatoctye and decreasing bile acid biosynthesis.
TITLE: Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis
AUTHOR CONTACT:
Stacey A. Jones
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, USA
Phone: 919-483-1395
Fax: 919-315-6720
E-mail: stacey.a.jones@gsk.com
View the PDF of this article at: https://www.the-jci.org/press/18945.pdf
A congenital mutation in a novel gene, LCCR8, disrupts B cell development and causes agammaglobulinemia
Mutations in a variety of genes can cause congenital agammaglobulinemia and failure of B cell development. The disorder is caused by mutations in a cytoplasmic tyrosine kinase, Btk. Btk is required for the transition of pro-B cells to pre-B cells. In the December 4 issue of the Journal of Clinical Investigation Junichi Hara and colleagues from Osaka University describe an individual with agammaglobulinemia and markedly reduced numbers of B cells. The authors found a translocation of a novel gene, leucine-rich repeat–containing 8 (LRRC8), normally encoded on chromosome 9, which resulted in a truncated protein product. The authors found that the mutation had a dominant-suppressor effect on B cell development, inhibiting the differentiation of pro- to pre-B cells.
In an accompanying commentary, Mary Ellen Conley from St. Jude's Children's Research Hospital, Memphis, discusses several mechanisms that may explain how the mutation in LCCR8 is responsible for the B cell deficiency observed in the patient. She states "Finding an abnormal gene in a patient with immunodeficiency is only the first exciting step. The next steps should tell us how LRRC8 functions in the normal immune system."
TITLE: A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans
AUTHOR CONTACT:
Junichi Hara
Osaka University Graduate School of Medicine, Osaka, Japan
Phone: 81-6-6879-3932
Fax: 81-6-6879-3939
E-mail: junhara@ped.med.osaka-u.ac.jp
View the PDF of this article at:
https://www.the-jci.org/press/18937.pdf
ACCOMPANYING COMMENTARY:
Genes required for B cell development
AUTHOR CONTACT:
Mary Ellen Conley
St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Phone: 901-495-2576
Fax 1: 901-495-3977
E-mail: maryellen.conley@stjude.org
View the PDF of this commentary at: https://www.the-jci.org/press/20408.pdf
Inhibition of Notch signaling prolongs graft survival following transplantation
The cell surface receptor, Notch, has been shown to play a fundamental role in the proliferation, differentiation, and death of cells of many lineages. Notch receptors and their ligands are also expressed on the surface of many mature cells of the immune system, however the effects of Notch signaling on the peripheral immune system remain poorly defined.
In the December 4 issue of the Journal of Clinical Investigation Margaret Dallman and colleagues from Imperial College, London, investigated the role of Notch signaling in promoting allograft survival in a murine cardiac transplant model. The authors show that fibroblasts expressing allogeneic MHC class I molecules as well as a Notch ligand from the Delta-like family may be used to repress the recipient anti-alloantigen response and prolong graft survival following transplantation. Furthermore, the authors determine that this phenomenon is dependent on the presence of CD8+ cells at the time of antigen challenge.
The data implicate Notch signaling in the regulation of peripheral immunity. The ability to induce antigen-specific unresponsiveness without nonspecific immunosuppression is highly desirable and will be beneficial in the context of not only bone marrow and organ transplantation, but also in the context of diseases of autoimmune or allergic nature.
TITLE: Notch ligation by Delta1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell–dependent mechanism
AUTHOR CONTACT:
Maggie Dallman
Imperial College of Science, Technology & Medicine, London, United Kingdom
Phone 1: 44-20-7594-5406
Fax: 44-20-7584-9075
E-mail:
m.dallman@imperial.ac.uk
View the PDF of this article at: https://www.the-jci.org/press/18020.pdf
Neutrophils know how to kill and not be killed
Neutrophils and related leukocytes ingest invading microorganisms and kill them via the generation of reactive oxygen species (ROS). However, inappropriate and/or excessive production of ROS can also exacerbate the inflammatory process and cause tissue damage.
Interestingly, neutrophil adherence to extracellular matrix proteins, such as fibronectin, results in an initial delay in ROS formation, followed by enhanced ROS formation. This process is an important mechanism used by the body to avoid inflammatory tissue damage during leukocyte trafficking.
In the December 4 issue of the Journal of Clinical Investigation Gary Bokoch and colleagues from Scripps Research Institute investigated the mechanism of adhesion-induced suppression of human leukocyte NADPH oxidase activity. The authors demonstrate that fibronectin attachment prevents activation and membrane association of Rac2 via integrin signaling. The integrins cause suppression of the activation of Rac GTPase by the membrane-localized regulatory exchange factor, Vav1.
The authors propose that they have defined a novel inhibitory pathway initiated by adhesion in human neutrophils that regulates the generation of ROS, and thus inflammation. This data is of broad significance to our understanding of the innate immune response and its normal regulation.
TITLE: The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils
AUTHOR CONTACT:
Gary M. Bokoch
The Scripps Research Institute, La Jolla, California, USA
Phone: 858-784-8217
Fax: 858-784-8217
E-mail: bokoch@scripps.edu
View the PDF of this article at: https://www.the-jci.org/press/19108.pdf
Selectins regulate T cell trafficking to grafted tissue
The homing of T cells to the sites of injury and inflammation is a critical step in the adaptive immune response. An unresolved issue in the field of transplantation rejection is how alloreactive T cells recognize donor vasculature. In a report in the December 4 issue of the Journal of Clinical Investigation Christian Larsen and colleagues from Emory University use intravital fluorescence videomicroscopy to directly observe the patterns of naïve and donor-specific T cell trafficking during the rejection of a skin allograft. The authors found that P- and E-selectin expressed within blood vessels play overlapping roles in the recruitment of activated T cells to the graft site. Naïve T cells are recruited via L-selectin and L-selectin ligand upregulation on vasculature rejecting the allograft. The study indicates that a specific collection of molecules is upregulated during the rejection response and therefore represents potential therapeutic targets.
TITLE: Intravital microscopy identifies selectins that regulate T cell traffic into allografts
AUTHOR CONTACT:
Christian P. Larsen
Emory University School of Medicine, Atlanta, Georgia, USA
Phone: 404-727-8465
Fax: 404-727-3660
E-mail: clarsen@emory.org
View the PDF of this article at: https://www.the-jci.org/press/19391.pdf
Mutant vasopressin causes neurohypophyseal diabetes
Familial neurohypophyseal diabetes insipidus (FNDI) in humans is an autosomal dominant disorder caused by a variety of mutations in the arginine vasopressin (AVP) precursor. AVP is synthesized in the hypothalamus by distinct neurons and then either stored or secreted into the circulation. In the December 4 issue of the Journal of Clinical Investigation J. Larry Jameson and colleagues from Northwestern University used mice in which a mutant AVP allele had been "knocked-in" in order to determine how specific mutations in AVP cause FNDI. The authors found that the mice developed progressive FNDI due to retention of AVP precursors in the hypothalamus, which causes cellular toxicity and progressive loss of AVP-producing neurons.
In an accompanying commentary, John A. Philips III from Vanderbilt University discusses FNDI and other endocrine disorders that may be caused by similar dominant-negative mutations.
TITLE: A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons
AUTHOR CONTACT:
J. Larry Jameson
Northwestern University, Chicago, Illinois, USA
Phone: 312-926-9436
Fax: 312-926-7260
E-mail: ljameson@northwestern.edu
View the PDF of this article at: https://www.the-jci.org/press/18616.pdf
ACCOMPANYING COMMENTARY:
Dominant-negative diabetes insipidus and other endocrinopathies
AUTHOR CONTACT:
John A. Philips III
Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Phone: 615-322-7601
Fax: 615-343-9951
E-mail: john.a.phillips@vanderbilt.edu
View the PDF of this commentary at: https://www.the-jci.org/press/20441.pdf
Not just angiogenesis: a role for VEGF in transplantation immunity
Vascular endothelial growth factor (VEGF) plays an established role in new blood vessel formation (angiogenesis). Transplant recipients also expresses VEGF in grafted tissue undergoing rejection, however the function of VEGF in the rejection process has not been defined. In the December 4 issue of the Journal of Clinical Investigation David Briscoe and colleagues from Children's Hospital, Boston, elucidate the role of VEGF in two animal transplantation models. The authors found that in vitro, VEGF enhanced endothelial expression of monocyte chemoattractant protein-1 and IL-8, and in combination with IFN-gamma VEGF synergistically induced endothelial production of the T cell chemoattractant IFN-inducible protein–10 (IP-10). These reactions induced the trafficking of T cells into skin grafts in mice. Furthermore, the administration of anti-VEGF to mice receiving fully mismatched donor hearts inhibited T cell infiltration of allografts and acute rejection of the transplanted organ. Thus, VEGF appears to be functional in acute allograft rejection via its effects on leukocyte trafficking. These observations provide mechanistic insight into the proinflammatory function of VEGF in immunity.
TITLE: Proinflammatory functions of vascular endothelial growth factor in alloimmunity
AUTHOR CONTACT:
David M. Briscoe
Children's Hospital, Boston, Massachusetts, USA
Phone: 617-355-6129
Fax: 617-232-4315
E-mail: david.briscoe@tch.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/17712.pdf
Complement system on the attack in autoimmunity
The antiphospholipid syndrome is characterized by fetal loss, thrombosis, and the presence of autoantibodies to lipid-binding proteins. In the December 4 issue of the Journal of Clinical Investigation Jane Salmon and colleagues from Cornell University developed a model of this procoagulant condition in which these antibodies were injected into pregnant mice. The authors demonstrated that fetal loss could be prevented by blocking complement activation. Specifically, interaction of complement component 5a with its receptor is necessary for thrombosis of the placental vasculature. The report suggests that inhibition of complement activation may have a therapeutic role in this disease.
In an accompanying commentary John Atkinson from Washington University discusses the mechanisms of complement activation that mediate tissue injury and the potential utility of complement inhibitors in treating the antiphospholipid syndrome and other autoimmune diseases such as rheumatoid arthritis.
TITLE: Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome
AUTHOR CONTACT:
Jane E. Salmon
Cornell University Medical College, New York, New York, USA
Phone: 212-606-1422
Fax: 212-717-1192
E-mail: salmonj@hss.edu
View the PDF of this article at: https://www.the-jci.org/press/18817.pdf
ACCOMPANYING COMMENTARY:
Complement system on the attack in autoimmunity
AUTHOR CONTACT:
John P. Atkinson
Washington University School of Medicine, St. Louis, Missouri, USA
Phone: 314-362-8391
Fax: 314-362-1366
E-mail: jatkinso@im.wustl.edu
View the PDF of this commentary at: https://www.the-jci.org/press/20309.pdf
Researchers determine how fusion proteins cause leukemia
The pathogenesis of acute myeloid leukemias (AMLs) is associated with the appearance of oncogenic fusion proteins generated following specific chromosome translocations. These fusion proteins function as aberrant transcriptional regulators and interfere in the process of myeloid differentiation. The identification and analysis of common and specific target genes regulated by AML fusion proteins should help the implementation of disease-specific drug design. In the December 4 issue of the Journal of Clinical Investigation Myriam Alcalay and colleagues from the European Institute of Experimental Oncology in Milan use DNA microarrays to assess gene expression changes induced by AML fusion oncoproteins. The authors found 1,555 genes regulated by at least two fusion proteins. These genes were involved in the maintenance of stem cell phenotype and repression of DNA repair genes. Functional studies confirmed that expression of these fusion proteins activates pathways leading to increased stem cell renewal and provokes accumulation of DNA damage. These pathways are critical to the ability of AML-associated fusion proteins to induce leukemia.
TITLE: Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair
AUTHOR CONTACT:
Myriam Alcalay
IFOM, Milan, Italy
Phone: 39-02-57430-3266
Fax: 39-02-57430-3244
E-mail: alcalay@ifom-firc.it
View the PDF of this article at: https://www.the-jci.org/press/17595.pdf
Journal
Journal of Clinical Investigation