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PUBLIC RELEASE DATE:
22-May-2008

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Contact: Karen Honey
press_releases@thje-jci.org
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Journal of Clinical Investigation
@jclinicalinvest

JCI table of contents: May 22, 2008

EDITOR'S PICK: Anti-HIV drugs reduce the cause of some forms of vision loss

A potential new therapeutic use for anti-HIV drugs known as protease inhibitors has been suggested by a team of researchers from Harvard Medical School, Boston, and Inserm U848, France, as a result of their work in a mouse model of retinal detachment.

An important cause of vision loss in many diseases of the eye is the death (by a process known as apoptosis) of nerve cells in the eye (known as photoreceptors) after retinal detachment. In the study, administration of HIV protease inhibitors by mouth markedly decreased photoreceptor apoptosis in the mouse model of retinal detachment. Mechanistic analysis in mouse retinal cell cultures and in mice expressing decreased amounts of specific proteins established that the HIV protease inhibitors disrupted two molecular pathways that cause apoptotic cell death, both of which affect the cell compartments known as mitochondria. As the same apoptotic cell death-inducing pathways were shown to be activated in human retinas after retinal detachment, the authors suggest that although the HIV protease inhibitors cannot reattach the retina, they might be of clinical benefit through their ability to prevent the photoreceptor apoptosis that has a central role in vision loss after retinal detachment.

TITLE: HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice

AUTHOR CONTACT:
Joan W. Miller
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 573-3526; Fax: (617) 573-3364; E-mail joan_miller@meei.harvard.edu.

Guido Kroemer
INSERM U848, Villejuif (Paris), France.
Phone: 33-1-42-11-60-46; Fax: 33-1-42-11-60-47; E-mail kroemer@igr.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34267


EDITOR'S PICK: What identifies cancer cells causing relapse and metastasis? Not CD133

New data, generated by Shahin Rafii and colleagues, at Weill Medical College of Cornell University, New York, through analysis of human colon cancer cells and mice, have shed doubt on the recently proposed designation of the protein CD133 as a marker of colon cancer stem cells -- a term given to the small number of cells within a colon cancer that are thought to be able to give rise to a new tumor and that therefore are responsible for tumor recurrence and metastasis.

In the study, mice were engineered such that they expressed a reporter protein everywhere that CD133 is normally expressed. In contrast to previous studies in which CD133 expression had been shown to be expressed by very few cells in the colon, this reporter protein was detected in many cells in the colon, including non-stem cells. A similarly broad expression of CD133 in the colon of both mice and humans was observed using antibodies that bind CD133. Analysis of human and spontaneous mouse primary colon tumors indicated that CD133 was expressed by most cells. Conversely, not all human colon cancer cells that had metastasized to the liver expressed CD133. Further, both the CD133+ and CD133- cells generated tumors when transplanted into immunocompromised mice. Some of the reasons why this study and previous investigations reached such distinct conclusions as to whether or not CD133 is a marker of colon cancer stem cells are noted by the authors and discussed in detail in an accompanying commentary by Mark LaBarge and Mina Bissell, at Lawrence Berkeley National Laboratory, Berkeley.

TITLE: CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors

AUTHOR CONTACT:
Shahin Rafii
Weill Medical College of Cornell University, New York, New York, USA.
Phone: (212) 746-2070; Fax: (212) 746-2286; E-mail: srafii@med.cornell.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34401

ACCOMPANYING COMMENTARY
TITLE: Is CD133 a marker of metastatic colon cancer stem cells?

AUTHOR CONTACT:
Mina J. Bissell
Lawrence Berkeley National Laboratory, Berkeley, California, USA.
Phone: (510) 486-4365; Fax: (510) 486-5586; E-mail: MJBissell@lbl.gov.

Mark A. LaBarge
Lawrence Berkeley National Laboratory, Berkeley, California, USA.
Phone: (510) 486-4365; Fax: (510) 486-5586; E-mail: MALabarge@lbl.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36046


EDITOR'S PICK: It's not an AKT: genetic variation affects brain region dysfunctional in schizophrenia

New data, generated by Daniel Weinberger and colleagues, at the National Institutes of Health, Bethesda, have indicated that in healthy individuals, variation in a gene known as AKT1 affects the structure and function of part of the brain that is dysfunctional in individuals with schizophrenia. Specifically, in healthy individuals, one particular AKT1 variant was associated with impaired cognition (an impaired ability to process information), something that is markedly affected in individuals with schizophrenia. In addition, the same AKT1 variant was associated with decreased grey-matter volume in the frontostriatal region of the brain, which is dysfunctional in individuals with schizophrenia. Further analysis indicated that the AKT1 variant was associated with an increased risk of schizophrenia and the therapeutic implications of this, as well as the other results of the study, are discussed in an accompanying commentary by Alexander Arguello and Joseph Gogos, at Columbia University College of Physicians and Surgeons, New York.

TITLE: Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans

AUTHOR CONTACT:
Daniel R. Weinberger
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 402-7564; Fax: (301) 480-7795; E-mail: weinberd@mail.nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34725

ACCOMPANYING COMMENTARY
TITLE: A signaling pathway AKTing up in schizophrenia

AUTHOR CONTACT:
Joseph A. Gogos
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 305-0744; Fax: (212) 342-1801; Email: jag90@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35931


OPHTHALMOLOGY: Looking from a new perspective at drugs to correct one cause of vision loss

A frequent complication in individuals with long-term diabetes is diabetic retinopathy, an eye condition that is the leading cause of blindness in adults of working age. One factor that contributes to vision loss is the accumulation of fluid in the retina of the eye because blood vessels in the retina have become more permeable. New data, suggesting that a family of drugs known as vasoinhibins might provide a new approach to decreasing the permeability in the blood vessels of the eye of individuals with diabetic retinopathy, has been generated in rats by Carmen Clapp and colleagues, from the Universidad Nacional Autónoma de México.

Vasoinhibins antagonize a molecule known as VEGF, which is an important initiator of increased blood vessel permeability in the retina of individuals with diabetic retinopathy. In the study, injection of vasoinhibins into the eye was found to block increases in blood vessel permeability in the eye of diabetic rats and to block increases in blood vessel permeability in the eye of normal rats injected (into the eye) with either VEGF or the fluid from the eye of an individual with diabetic retinopathy. Mechanistically the vasoinhibins were shown to work by activating a protein known as PP2A, which, in turn, inactivated a protein known as eNOS.

TITLE: Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A-dependent eNOS inactivation

AUTHOR CONTACT:
Carmen Clapp
Universidad Nacional Autónoma de México, Querétaro, Mexico.
Phone: (52-442) 238-1028; Fax: (52-442) 238-1005; E-mail: clapp@servidor.unam.mx.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34508


IMMUNOLOGY: A new target for tumor immunotherapy on dendritic cells?

Many researchers are interested in developing approaches to induce antitumor immune responses carried out by immune cells known as CTLs. In mice, one way to do this is to target tumor proteins to a subset of immune cells known as dendritic cells (DCs) that express the protein CD8-alpha. This is because DCs expressing CD8-alpha are able to efficiently direct CTLs to attack any proteins that are targeted to them. A new way to target tumor proteins to DCs expressing CD8-alpha has been uncovered by Caetano Reis e Sousa and colleagues, at Cancer Research UK, United Kingdom, who have identified a molecule whose expression is restricted in mice to DCs expressing CD8-alpha and another subset of DC known as plasmacytoid DCs.

Functional studies indicated that the molecule, which was named dendritic cell NK lectin group receptor-1 (DNGR-1), was an endocytic receptor and that if an antibody that recognizes DNGR-1 was linked to a peptide it delivered the peptide specifically to DCs expressing CD8-alpha. CTL responses directed to the peptide were induced in mice vaccinated with the peptide-linked DNGR-1-specific antibody and an adjuvant. Directing these CTL responses toward melanoma cells by linking the DNGR-1-specific antibody to peptides from proteins overexpressed by a melanoma cell line eradicated melanoma in a therapeutic mouse model. Further, as expression of DNGR-1 in humans was found to be restricted to a subset of DCs with characteristics similar to mouse DCs expressing CD8-alpha, the authors suggested that targeting DCs via DNGR-1 might provide a new approach to tumor immunotherapy.

TITLE: Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin

AUTHOR CONTACT:
Caetano Reis e Sousa
Cancer Research UK, London, United Kingdom.
Phone: 44-20-7269-2832; Fax: 44-20-7269-2833; E-mail: caetano@cancer.org.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34584


NEUROBIOLOGY: To protect against or to promote, that is the question about the role of the cellular process autophagy in Alzheimer disease

All neurodegenerative disorders (e.g. Alzheimer disease [AD], Parkinson disease, and Huntington disease) are characterized by the presence of protein aggregates in the brain and nerve cell death. Recent data have implicated a cellular process known as autophagy (whereby cells can degrade long-lived proteins and compartments to remodel their interiors and/or survive stressful situations) in neurodegeneration, but whether it protects against or promotes neurodegeneration remains controversial. New data, generated by Tony Wyss-Coray and colleagues, at Stanford University, have indicated that decreased autophagy in nerve cells can increase neurodegeneration in a mouse model of AD.

In the study, mice lacking one of their Becn1 genes, which carry the information required to make the key autophagy protein beclin 1, were found to exhibit decreased nerve cell autophagy and this was associated with increased neurodegeneration. When a mouse model of AD was similarly engineered to lack one Becn1 gene, an increased amount of neurodegeneration and protein accumulation in the brain was observed. Conversely, if the mouse model of AD was engineered to express increased amounts of beclin 1, decreased protein accumulation in the brain was observed. The authors therefore suggest that increasing levels of beclin 1 might be of benefit to individuals with AD.

In an accompanying commentary, Jin-A Lee and Fen-Biao Gao, at the University of California at San Francisco, note that although modulating beclin 1 levels might be an attractive approach for treating individuals with AD, further studies in other animal models are required to verify the viability of this strategy.

TITLE: The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid-beta accumulation in mice

AUTHOR CONTACT:
Tony Wyss-Coray
Stanford University, Stanford, California, USA.
Phone: (650) 852-3220; Fax: (650) 849-0434; E-mail: twc@stanford.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33585

ACCOMPANYING COMMENTARY
TITLE: Regulation of A-beta pathology by beclin 1: a protective role for autophagy?

AUTHOR CONTACT:
Fen-Biao Gao
University of California at San Francisco, San Francisco, California, USA.
Phone: (415) 734-2514; Fax: (415) 355-0824; E-mail: fgao@gladstone.ucsf.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35662


INFLAMMATION: Round and round we go: proinflammatory positive feedback loop identified in the intestines of individuals with Crohn disease

Although Crohn disease (CD) and ulcerative colitits (UC) are both types of inflammatory bowel disease (IBD), the mechanisms underlying these two diseases are different. New insight into the inflammatory cell disturbances in the intestines of individuals with CD has been provided by Toshifumi Hibi and colleagues, at Keio University School of Medicine, Japan, who have suggested that these changes might contribute to the development of disease.

Most immune cells known as macrophages that live in the intestine do not express the molecule CD14 and this characteristic is associated with a lack of production of proinflammatory factors known as cytokines. In the study, an increased number of macrophages expressing CD14 (as well as other molecules not usually expressed by intestinal macrophages) were detected in the intestines of individuals with CD compared with the intestines of healthy individuals and those with UC. These cells produced large amounts of the proinflammatory cytokines IL-23 and TNF-alpha, which caused other immune cells in the area to produce another proinflammatory cytokine, IFN-gamma. As the IFN-gamma was found to cause a further increase in the number of macrophages expressing CD14 and producing IL-23, the authors suggest that IL-23 and IFN-gamma form a positive feedback loop that promotes inflammation in the intestine of individuals with CD.

TITLE: Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis

AUTHOR CONTACT:
Toshifumi Hibi
Keio University School of Medicine, Tokyo, Japan.
Phone: 81-3-3357-6156; Fax: 81-3-3357-6156; E-mail: thibi@sc.itc.keio.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34610


VIROLOGY: CD4+ T cells really are home sweet home for the monkey relative of HIV

Many strains of monkey become naturally infected with viruses that are related to HIV. These viruses are known collectively as SIV and naturally infected monkeys do not develop AIDS. It is hoped that understanding why monkeys naturally infected with SIV do not develop AIDS might teach researchers important lessons about the mechanisms underlying the development of AIDS in humans infected with HIV and identify ways to prevent this happening. New insight into the mechanisms that control the number of virus particles in the blood of sooty mangabeys naturally infected with SIVsmm, the strain of SIV that naturally infects sooty mangabeys, has now been provided by a team of researchers from the University of Pennsylvania, Philadelphia, and Emory University, Atlanta.

HIV and SIV infect immune cells known as CD4+ T cells. So, the authors set out to determine how CD4+ T cells affected the number of virus particles in the blood of sooty mangabeys naturally infected with SIVsmm -- did they provide immune control of the number of virus particles or did they simply provide a place to live a replicate. The number of SIVsmm particles in the blood of naturally infected sooty mangabeys decreased when the monkeys were depleted of CD4+ T cells and then increased again as the number of proliferating CD4+ T cells rebounded. So, it was concluded that availability of proliferating CD4+ T cells is a key determinant of how many SIVsmm particles can be detected in the blood of naturally infected sooty mangabeys, rather than CD4+ T cells providing immune control of the virus.

TITLE: Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys

AUTHOR CONTACT:
Guido Silvestri
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-5363; Fax: (215) 573-5369; E-mail: gsilvest@mail.med.upenn.edu.

Aftab A. Ansari
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: (404) 712-2834; Fax: (404) 712-1771; E-mail: pathaaa@emory.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33814


METABOLIC DISEASE: The liver protein FoxO1 may link overindulgence with type 2 diabetes

Elevated blood levels of fats known as triglycerides and the triglyceride-rich molecule VLDL are risk factors for heart disease and diabetes. VLDL production is dependent on both the regulator of blood sugar levels insulin (it works to lower blood sugar levels) and on the liver protein MTP, although these interactions have not been well understood. In a new study, Henry Dong and his colleagues at the University of Pittsburgh School of Medicine have revealed a relationship between the liver protein FoxO1 and VLDL overproduction.

Using cultured human liver cell lines, researchers showed that FoxO1 bound to and stimulated MTP expression and inhibited insulin secretion. Consistent with this, overexpression of FoxO1 increased, and FoxO1 depletion decreased, MTP and VLDL levels in mice. Furthermore, mice with deficiencies in the breakdown of triglycerides also had elevated FoxO1 and VLDL levels. The authors therefore conclude that this relationship between FoxO1, insulin, and VLDL might account, in part, for the simultaneous increases in blood sugar and triglyceride levels seen in patients at risk for type 2 diabetes. An accompanying commentary by Janet and Charles Sparks at the University of Rochester School of Medicine further concludes that this study establishes a link between dietary overindulgence and the multiple disorders that put an individual at increased risk of developing type 2 diabetes, including high blood pressure, obesity, high levels of cholesterol, and resistance to the effects of insulin.

TITLE: FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice

AUTHOR CONTACT:
H. Henry Dong
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Tel: (412) 692-6324, Fax: (412) 692-5809, Email: dongh@pitt.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32914

ACCOMPANYING COMMENTARY
TITLE: Overindulgence and metabolic syndrome: is FoxO1 a missing link?

AUTHOR CONTACT:
Janet D. Sparks
University of Rochester Medical Center, Rochester, New York, USA.
Phone: (585) 275-7755; Fax: (585) 756-5337; E-mail: janet_sparks@urmc.rochester.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35693

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