JCI online early table of contents: April 12, 2010

April 12, 2010

EDITOR'S PICK: Stress hormones accelerate tumor growth

Chronic stress has recently been implicated as a factor that may accelerate the growth of tumors. However, the mechanisms underlying this effect have not been determined. But now, Anil Sood and colleagues, at the University of Texas MD Anderson Cancer Center, Houston, have generated data using human ovarian cancer cell lines and tumor specimens that indicate that stress hormones, especially norepinephrine and epinephrine, can contribute to tumor progression in patients with ovarian cancer. They therefore suggest that targeting stress hormones and the signaling pathways that they activate might be of benefit to individuals with cancer.

Anoikis is the process by which cells are triggered to die when separated from their surrounding matrix and neighboring cells. Tumor cells that spread to other sites somehow escape anoikis. In the study, exposure of human ovarian cancer cells lines to either of the stress hormones norepinephrine or epinephrine protected them from anoikis. Similarly, in a mouse model of ovarian cancer, restraint stress and the associated increases in norepinephrine and epinephrine protected the tumor cells from anoikis and promoted their growth. This effect was associated with activation of the protein FAK. The clinical significance of these data was highlighted by the observation that in human ovarian cancer patients, behavioral states related to greater stress hormone activity were associated with higher levels of activated FAK, which was in turn linked to substantially accelerated mortality.

TITLE: Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis

AUTHOR CONTACT:
Anil K. Sood
University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: 713.745.5266; Fax: 713.792.7586; E-mail: asood@mdanderson.org.

View this article at: http://www.jci.org/articles/view/40802?key=2596f6813536fc72a7f8




EDITOR'S PICK: Clinical trial drug exacerbates tuberculosis in mice

Type I IFNs are immune molecules that have a central role in antiviral host defense. They have been shown to be of clinical benefit in the treatment of a number of viral infections and cancers, and molecules such as Poly-ICLC that potently induce long-lived type I IFN responses are in clinical trials. However, data generated by Lis Antonelli and colleagues, at the National Institutes of Health, Bethesda, indicate that Poly-ICLC exacerbates lung damage and bacterial load in mice infected with the bacterium that causes tuberculosis, Mycobacterium tuberculosis, leading them to suggest that such agents should be used with caution in individuals in which M. tuberculosis is dormant.

In the study, the marked increase in lung bacterial load and widespread lung damage observed in Poly-ICLC-treated M. tuberculosis-infected mice, which was absent in mice lacking the receptor for type I IFNs, was accompanied by a dramatic increase in the number of myeloid immune cells characterized as CD11b+F4/80+Gr1int in the lungs. These cells, which were recruited to the lungs by the chemoattractant CCL2 induced by Poly-ICLC, preferentially supported bacterial growth, providing a mechanistic explanation as to why Poly-ICLC exacerbates lung damage and bacterial load in M. tuberculosis-infected mice.

TITLE: Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population

AUTHOR CONTACT:
Lis R.V. Antonelli
Centro de Pesquisas René Rachou - FIOCRUZ, Minas Gerais, Brazil.
Phone: 55.31.3379.7766; Fax: 55.31.3349.7835; E-mail: lisantonelli@cpqrr.fiocruz.br.

View this article at: http://www.jci.org/articles/view/40817?key=81fba50158c3ecb117a8




EDITOR'S PICK: Immune molecules target swine- and avian-origin influenza

Antibodies are immune molecules that have a key role in protecting against infection with influenza virus. The target of the protective antibodies is the influenza protein HA, which varies so dramatically among influenza viruses that it is used to classify them into subtypes (H1-H16). It is thought that the antibodies generated by an individual's immune system protect against only a few closely related influenza viruses. However, Antonio Lanzavecchia and colleagues, at the Institute for Research in Biomedicine, Switzerland, have now found that some individuals vaccinated with seasonal influenza vaccine containing H1 and H3 influenza viruses produce antibodies that can target H5 HA, the form of HA used by the deadly H5N1 avian influenza virus. Although these antibodies protected mice from a recent swine-origin pandemic H1N1 influenza virus and several H5N1 influenza viruses, the authors note that more work needs to be done to determine whether individuals produce these antibodies at high enough levels to provide them with protection from infection by different influenza virus subtypes and how vaccination might promote their high level production.

TITLE: Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine

AUTHOR CONTACT:
Antonio Lanzavecchia
Institute for Research in Biomedicine, Bellinzona, Switzerland.
Phone: 41.91.8200310; Fax: 41.91.8200312; E-mail: lanzavecchia@irb.unisi.ch.

View this article at: http://www.jci.org/articles/view/41902?key=10140cb74438512dec4a




ONCOLOGY: Loss of the breast cancer gene BRCA1 in the absence of genetic mutations is controlled by the protein HOXA9

Women with BRCA1 genetic mutations that prevent their BRCA1 protein from being expressed or functioning properly are predisposed to develop breast and ovarian cancers. BRCA1 expression is also often reduced in breast tumors from women who do not have predisposing genetic mutations and the reason for this is not known. However, Valerie Weaver and colleagues, at the University of California, San Francisco, have now generated data that provide an explanation for the loss of BRCA1 expression in sporadic human breast tumors in the absence of BRCA1 genetic modifications by analyzing human breast cancer tissue and cell lines. Specifically, they generate several lines of evidence to indicate that the protein HOXA9 restricts breast tumor aggression by inducing BRCA1 expression and infer that the frequently observed downregulation of the HOXA9 gene in sporadic human breast cancers leads to loss of BRCA1 expression in the absence of BRCA1 genetic modifications.

TITLE: HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype

AUTHOR CONTACT:
Valerie M. Weaver
University of California at San Francisco, San Francisco, California, USA.
Phone: 415.476.3826; Fax: 415.476.3985; E-mail: Valerie.Weaver@ucsfmedctr.org

View this article at: http://www.jci.org/articles/view/39534?key=6ad6988347b5b448e987




IMMUNOLOGY: A NOD(1) to antibacterial host defense via type I IFNs

Type I IFNs are immune molecules that have a central role in antiviral host defense. New research, performed by a team of researchers at the National Institutes of Health, Bethesda, and Kyoto University Graduate School of Medicine, Japan, has now shown that their production can be triggered by stimulation of the protein NOD1 and that this contributes to protection against the bacterium Helicobacter pylori in mice.

The protein NOD1 is found inside the epithelial cells that line the various body cavities, including the intestines and stomach. It functions to sense specific microbial components, responding by triggering an inflammatory immune response. In this study, which was led by Warren Strober and Tomohiro Watanabe, stimulating NOD1 in human epithelial cells was unexpectedly found to activate a signaling pathway that leads to the production of type I IFNs. While detailed analysis uncovered the molecules in the pathway, the physiologic significance of this pathway was revealed by the observation that mice lacking the receptor for type I IFNs and mice in which the signaling pathway was inhibited showed increased susceptibility to H. pylori infection. These data expand our knowledge of the role of both NOD1 and type I IFNs in host defense.

TITLE: NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway

AUTHOR CONTACT:
Warren Strober
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Phone: 301.496.6810; Fax: 301.402.2240; E-mail: wstrober@niaid.nih.gov.

Tomohiro Watanabe
Kyoto University Graduate School of Medicine, Kyoto, Japan.
Phone: 81.75.751.4319; Fax: 81.75.751.4303; E-mail: tmhrwtnb@kuhp.kyoto-u.ac.jp.

View this article at: http://www.jci.org/articles/view/39481?key=6779a8120d4e09720822




HEMATOLOGY: Setting the story straight: HDL does not regulate blood clotting

HDL cholesterol is considered good cholesterol and its levels in the blood correlate inversely with hardening of the arteries, a condition that is a major cause of heart attack and stroke. Previous studies have indicated a role for HDL as a regulator of blood clotting (blood coagulation). Specifically, it was found that HDL helped the anticoagulant protein APC degrade the blood clotting protein FVa. However, a team of researchers, led by Björn Dahlbäck, at Lund University, Sweden, has now isolated HDL from human plasma using a different purification technique and found that HDL does not have the ability to perform this function, rather this property of HDL is instead caused by contaminating negatively charged phospholipid membranes.

TITLE: Reevaluation of the role of HDL in the anticoagulant activated protein C system in humans

AUTHOR CONTACT:
Björn Dahlbäck
Lund University, University Hospital, Malmö, Sweden.
Phone: 46.40.331501; Fax: 46.40.337044; E-mail: bjorn.dahlback@med.lu.se.

View this article at: http://www.jci.org/articles/view/42260?key=771e08f814204d3a06a8




HEMATOLOGY: Linking Treg immune cells to graft-versus-host-disease

Treatment for a number of leukemias, lymphomas, and other medical conditions is transplantation with bone marrow cells that can generate all blood cells from a genetically nonidentical individual (a process known as allogeneic hematopoietic stem cell transplantation [HSCT]). Despite treatment with immunosuppressive drugs, some patients go on to develop graft-versus-host-disease (GVHD), a condition in which immune cells derived from the transplanted cells attack and destroy the recipient's body. This is one of the most common and clinically important problems affecting long-term HSCT survivors and it is associated with a relative deficiency in immune cells known as Tregs in the blood. Jerome Ritz and colleagues, at the Dana-Farber Cancer Institute, Boston, have now determined that Treg deficiency occurs in patients in which the number of immune cells known as CD4+ T cells takes a long time to rebound following HSCT.

TITLE: Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

AUTHOR CONTACT:
Jerome Ritz
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Phone: 617.632.3465; Fax: 617.632.5167; E-mail: Jerome_Ritz@dfci.harvard.edu.

View this article at: http://www.jci.org/articles/view/41072?key=9d016343ada0f07a21a1




NEPHROLOGY: New player in salt retention by the kidney

It is important that the amount of salt we consume is matched by the amount released by our kidneys into the urine. This is because the amount of salt in our body determines how much fluid is retained, and too much salt in our body means excess fluid is retained and blood pressure rises. One cause of high blood pressure is abnormal retention of sodium, the component of salt responsible for regulating fluid levels, by the kidney. Drugs that block sodium transport systems in the kidney are used to treat disease states such as high blood pressure caused by abnormal renal sodium retention. Although drugs known as thiazides have been used to treat high blood pressure for many years, data indicate that not all the sodium transport mechanisms in the kidney targeted by thiazides have been identified. However, Dominique Eladari and colleagues, at INSERM U872, France, have now determined in mice that thiazides target the protein SLC4A8 and that this is an ion exchanger that mediates thiazide-sensitive sodium retention in a region of the kidney known as the cortical collecting ducts.

TITLE: The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice

AUTHOR CONTACT:
Dominique Eladari
INSERM U872, Paris, France.
Phone: 33.144413718; Fax: 33.144413717; E-mail: dominique.eladari@crc.jussieu.fr.

View this article at: http://www.jci.org/articles/view/40145?key=b7de7c1ecc1ace9366ba
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