(Press-News.org) EDITOR'S PICK: What sex are you?
Sex in mammals is genetically determined. In humans, females have two X chromosomes, while males have one X and one Y chromosome. However, some individuals are born with male genitalia despite having two X chromosomes, a condition known as XX male sex reversal. A team of researchers, led by Paul Thomas, University of Adelaide, Australia, has now determined that overexpression of the Sox3 gene in mice causes frequent XX male sex reversal. The clinical relevance of this was highlighted by the discovery of genomic rearrangements in the regulatory region of the human SOX3 gene in three patients with XX male sex reversal. The authors therefore conclude that SOX3 genomic rearrangements are likely to be a significant cause of XX male sex reversal.
TITLE: Identification of SOX3 as an XX male sex reversal gene in mice and humans
AUTHOR CONTACT:
Paul Thomas
University of Adelaide, North Terrace, Adelaide, South Australia, Australia.
Phone: 61.8.8303.7047; Fax: 61.8.8303.4362; E-mail: paul.thomas@adelaide.edu.au.
View this article at: http://www.jci.org/articles/view/42580?key=d5c128baa67b2a0f7661
EDITOR'S PICK: KISSing a theory goodbye in the link between puberty and nutrition status
The timing of the onset of puberty is linked to levels of nutrition: later onset is associated with malnutrition, while earlier onset is linked to childhood obesity. A team of researchers, led by Carol Elias, at the University of Texas Southwestern Medical Center, Dallas, has now generated data in mice that run counter to current thinking about the molecular pathway by which nutrition status affects the onset of puberty. Further, the team defines a new regulatory pathway for the process, which, if confirmed in humans, could potentially lead to new approaches to treating disorders of puberty and fertility.
The hormone leptin, which is produced by fat tissue, is a key signal that lets the reproductive system know that levels of nutrition are sufficient to support puberty. Several lines of data had led researchers to believe that the permissive effects of leptin on puberty were mediated indirectly, by leptin stimulating nerve cells in a region of the brain known as the hypothalamus to produce kisspeptins, small proteins that trigger the first step in the onset of puberty. However, Elias and colleagues, found no effects on puberty in mice when expression of the molecule to which leptin binds was selectively eliminated in kisspeptin-producing nerve cells in the hypothalamus. Further analysis revealed that expression of the molecule to which leptin binds in a region of the brain known as the ventral premammillary nucleus was required for leptin to exert its effects on puberty onset.
In an accompanying commentary, Rexford Ahima, at the University of Pennsylvania, Philadelphia, notes that the comprehensive series of experiments carried out by Elias and colleagues provide important new insight into the regulation of puberty onset that could potentially have clinical ramifications.
TITLE: Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons
AUTHOR CONTACT:
Carol F. Elias
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214.648.0248; Fax: 214.648.5612. E-mail: carol.elias@utsouthwestern.edu.
View this article at: http://www.jci.org/articles/view/45106?key=0ba657de2e2d16c52134
ACCOMPANYING COMMENTARY
TITLE: No Kiss1ng by leptin during puberty?
AUTHOR CONTACT:
Rexford S. Ahima
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.573.1872; Fax: 215.898.5408; E-mail: ahima@mail.med.upenn.edu.
View this article at: http://www.jci.org/articles/view/45813?key=f4c94a8b50b5083f51a8
EDITOR'S PICK: Picking a poison for brain tumors: arsenic
Arsenic is usually thought of as a poison. Despite this, it has been used in medicine for over 2000 years, and the arsenic compound arsenic trioxide (ATO) is FDA approved for the treatment of acute promyelocytic leukemia. Now, a team of researchers, led by Aykut Üren, at Georgetown University Medical Center, Washington, has generated data using human cancer cell lines that suggest that ATO might also be of benefit to individuals with certain brain tumors or connective tissue tumors.
Certain cancers, in particular brain tumors known as medulloblastomas and connective tissue tumors known as Ewing sarcoma, are characterized by inappropriate activation of a signaling pathway known as the Hh/GLI1 signaling pathway. The team found that GLI1-dependent growth of medulloblastoma and Ewing sarcoma cell lines was suppressed by ATO, which worked by inhibiting GLI1. Furthermore, ATO prevented GLI1-dependent human Ewing sarcoma cell lines from developing tumors upon transplantation into mice and improved survival in a clinically relevant spontaneous mouse model of medulloblastoma with activated Hh pathway signaling. The authors therefore suggest that ATO should be considered as potential therapeutic for the treatment of tumors that exhibit inappropriate Hh/GLI1 pathway activation.
In an accompanying commentary, Praveen Raju, at Weill Cornell Medical College, New York, notes that the data provide rationale for considering ATO as a therapy for cancers other than acute promyelocytic leukemia. However, he cautions Ewing sarcoma and medulloblastoma are predominantly tumors of childhood and the Hh pathway is crucial for both embryonic and postnatal development, so ATO inhibition of this pathway might have severe side effects in such patients.
TITLE: Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway
AUTHOR CONTACT:
Aykut Üren
Georgetown University Medical Center, Washington, DC, USA.
Phone: 202.687.9504; Fax: 202.687.1434; E-mail: au26@georgetown.edu.
View this article at: http://www.jci.org/articles/view/42874?key=b4953e0cf3401fb57e38
ACCOMPANYING COMMENTARY
TITLE: Arsenic: a potentially useful poison for Hedgehog-driven cancers
AUTHOR CONTACT:
G. Praveen Raju
Weill Cornell Medical College, New York, New York, USA.
Phone: 212.746.1279; Fax: 212.746.4001; E-mail: prr9001@med.cornell.edu.
View this article at: http://www.jci.org/articles/view/45692?key=d168085cd96838efb43b
ONCOLOGY: Gaining access to the brain to destroy brain tumors
A major obstacle to developing new approaches to treating brain tumors is the almost impenetrable blood-brain barrier, which, as its name suggests, shelters the brain from the general blood supply to the body. However, a team of researchers, led by Renata Pasqualini and Wadih Arap, at the University of Texas M.D. Anderson Cancer Center, Houston, has now developed an approach that allowed them to deliver therapeutic cargo and molecular imaging reporters across the blood-brain barrier in an intracranial mouse model of glioblastoma, one of the most lethal of all cancers. The approach relied on expression of the protein TfR by both cells lining the blood vessels of the brain and cells of the tumor. As further analysis indicated that primary human gliomas express TfR, the authors hope that their approach can be translated to the clinic for the targeted detection and treatment of brain tumors.
In an accompanying commentary, Paul Mischel and David Nathanson, at the University of California, Los Angeles, discuss both the importance of these data for developing new approaches to treating brain tumors and the potential for this approach to be applied to the discovery of new druggable targets for other forms of cancer.
TITLE: Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma
AUTHOR CONTACT:
Renata Pasqualini
The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Phone: 713.792.3872; Fax: 713.745.2999; E-mail: rpasqual@mdanderson.org.
Wadih Arap
The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Phone: 713.792.3872; Fax: 713.745.2999; E-mail: warap@mdanderson.org.
View this article at: http://www.jci.org/articles/view/44798?key=5d899f946725c22b5f81
ACCOMPANYING COMMENTARY
TITLE: Charting the course across the blood-brain barrier
AUTHOR CONTACT:
Paul S. Mischel
David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Phone: 310.794.5223; Fax: 310.206.8290; E-mail: pmischel@mednet.ucla.edu.
View this article at: http://www.jci.org/articles/view/45758?key=7acf1d3d30e1e9039d10
ONCOLOGY: Adjuvant use of anti-cancer drug targeting the protein ETAR makes sense
Individuals who die from bladder cancer do so predominantly because their tumor has spread to (metastasized to) another site, often the lungs. The protein ET-1 has been implicated in this process. As a result, therapeutics targeting the molecule to which ET-1 binds (ETAR) are being developed and tested in the clinic. Now, a team of researchers, working primarily at the University of Virginia, Charlottesville, has determined that these agents should be tested as adjuvant therapeutic agents, rather than as initial treatment for primary or metastatic disease, if they are to succeed in the clinic. Several lines of evidence led the team, which was headed by Dan Theodorescu, to this conclusion. In particular, the observation that tumor expression of ET-1 and ETAR was necessary for human and mouse cancer cell metastasis to the mouse lung but was less important for the growth of established primary and metastatic tumors.
TITLE: Tumor endothelin-1 enhances metastatic colonization of the lung in mouse xenograft models of bladder cancer
AUTHOR CONTACT:
Dan Theodorescu
University of Colorado, Aurora, Colorado, USA.
Phone: 303.724.7135; Fax: 303.724.3162; E-mail: dan.theodorescu@ucdenver.edu.
View this article at: http://www.jci.org/articles/view/42912?key=2683fab420b3d4fa6359
VIROLOGY: Predicting who will not respond to treatment for hepatitis C virus
Most people who become infected with hepatitis C virus (HCV) fail to clear the virus from their body and become chronically infected. Current treatment for chronic HCV infection is effective in only about half of those that receive it. Recent data indicate that high levels of the molecule CXCL10, which helps attract immune cells to sites of infection, in the blood of an HCV-infected patient forecast a poor response to treatment. The work of a team of researchers, led by Matthew Albert, at the Institut Pasteur, France, has now provided an explanation for this. Specifically, the team found that CXCL10 in the blood of patients chronically infected with HCV was shorter than normal CXCL10 and could not attract immune cells. Further analysis revealed that this antagonist form of CXCL10 was generated in the blood by cleavage by the protein DPP4. As discussed by Lynn Dustin and Edgar Charles, at The Rockefeller University, New York, in an accompanying commentary, if these data can be successfully validated in larger cohorts of patients it should be possible to identify those patients who will not respond to anti-HCV treatment and spare them from a therapy that has severe side effects.
TITLE: Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV
AUTHOR CONTACT:
Matthew L. Albert
Institut Pasteur, Paris, France.
Phone: 33.0.1.45.68.85.45; Fax: 33.0.1.45.68.85.48; E-mail: albertm@pasteur.fr.
View this article at: http://www.jci.org/articles/view/40594?key=48a115adfcdd54a3517b
ACCOMPANYING COMMENTARY
TITLE: Chemokine antagonism in chronic hepatitis C virus infection
AUTHOR CONTACT:
Lynn B. Dustin
The Rockefeller University, New York, New York, USA.
Phone: 212.327.7067; Fax: 212.327.7048; E-mail: dustinl@rockefeller.edu.
View this article at: http://www.jci.org/articles/view/45610?key=382c2266e619a5edac5c
IMMUNOLOGY: Two genetic hits and you are down with autoimmune lymphoproliferative syndrome
Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disease that affects the immune system. The most common cause of ALPS is mutations in the TNFRSF6 (also known as FAS) gene. If a person inherits two mutant TNFRSF6 genes they develop severe ALPS early in life. However, people who inherit only one mutant TNFRSF6 gene develop disease of variable severity, with some individuals showing no clinical sign of disease. A team of researchers, led by Frédéric Rieux-Laucat, at INSERM U768, Hôpital Necker-Enfants Malades, France, has now provided an explanation as to why individuals with only one mutant TNFRSF6 gene develop disease with varying characteristics — individuals that develop more severe disease acquire, after birth, a mutation in their second TNFRSF6 gene. Importantly, this second genetic event was detectable only in a population of immune cells known as double negative T cells, which are normally rare but accumulate in individuals with ALPS. Thus, a second genetic hit can lead to severe disease onset.
In an accompanying commentary, Michael Lenardo and Bernice Lo, at the National Institutes of Health, Bethesda, discuss how these data expand the paradigm of two genetic hits causing disease, which is well known to oncologists, to the immunology setting.
TITLE: Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation
AUTHOR CONTACT:
Frédéric Rieux-Laucat
INSERM U768, Hôpital Necker-Enfants Malades, Paris, France.
Phone: 33.0.144.495.082; Fax: 33.0.142.730.640; E-mail: frederic.rieux-laucat@inserm.fr.
View this article at: http://www.jci.org/articles/view/43752?key=69dee108c522c61cbb09
ACCOMPANYING COMMENTARY
TITLE: Gene defects in the soma: some get it and some don't!
AUTHOR CONTACT:
Michael J. Lenardo
National Institute of Allergy and Infectious Disease, NIH, Bethesda, Maryland, USA.
Phone: 301.496.6753; Fax: 301.402.8530; E-mail: lenardo@nih.gov.
View this article at: http://www.jci.org/articles/view/45664?key=02e333e4c3644d7801d4
VACCINES: Boosting anti-vaccine immune responses
Vaccines are one of the most cost-effective ways to prevent disease. It is believed that vaccines that induce potent responses by immune cells known as CD8+ T cells are required if diseases such as malaria, tuberculosis, and HIV/AIDS are to be successfully targeted. A team of researchers, led by Shahram Salek-Ardakani and Michael Croft, at La Jolla Institute for Allergy and Immunology, La Jolla, has now generated data in mice that should help in the future design of vaccines capable of inducing potent CD8+ T cell responses.
Many human vaccine strategies use poxvirus vectors to deliver the immunizing proteins. For safety reasons, such strategies mostly use attenuated poxviruses, but these often induce poor CD8+ T cell responses and do not provide optimal protection. The team sought to understand how virulent viruses induce more potent immune responses than do attenuated viruses by immunizing mice with vaccinia virus strains of differing virulence. The most virulent vectors, which provided the mice with protection from subsequent lethal challenge with vaccina virus, generated potent CD8+ T cell responses as a result of stimulation of OX40 and CD27 proteins on the cell surface of the CD8+ T cells. Consistent with this, low virulence vectors engendered protection only when administered to the mice with a molecule that stimulated OX40.
In an accompanying commentary, Stuart Isaacs, at the University of Pennsylvania, discusses some of the questions that need to be answered before it can be determined if these data will translate into effective human vaccine design and development.
TITLE: The TNFR family members OX40 and CD27 link viral virulence to protective T cell vaccines in mice
AUTHOR CONTACT:
Shahram Salek-Ardakani
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Phone: 858.752.6752; Fax: 858.752.6985; E-mail: ssalek@liai.org.
Michael Croft
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Phone: 858.752.6752; Fax: 858.752.6985; E-mail: mick@liai.org.
View this article at: http://www.jci.org/articles/view/42056?key=5097f4ccc796cf805ed2
ACCOMPANYING COMMENTARY
TITLE: A stimulating way to improve T cell responses to poxvirus-vectored vaccines
AUTHOR CONTACT:
Stuart N. Isaacs
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.662.2150; Fax: 215.349.5111; E-mail: isaacs@mail.med.upenn.edu.
View this article at: http://www.jci.org/articles/view/45726?key=9f291f3dbddc87be69b3
HEMATOLOGY: What happens when Fanconi anemia cells overcome checkpoint arrest
The rare genetic disorder Fanconi anemia is associated with depletion of bone marrow cells, which leads to bone marrow failure, and a strong predisposition to cancer. The main cause of death for individuals with Fanconi anemia is bone marrow failure. However, a small proportion of individuals do not develop severe bone marrow failure and they live longer than others. A team of researchers, led by Jean Soulier, at Saint-Louis Hospital, France, has now identified a mechanism by which some patients become clinically stable.
In individuals with Fanconi anemia, the bone marrow cells become depleted because DNA damage causes cells to stop dividing, getting stuck at a point in cell division known as G2. The team found that in some individuals with Fanconi anemia, a few cells develop the ability to overcome the cell division arrest in G2. These cells prevented the dramatic loss of bone marrow cells and enabled the patients to reach adulthood. However, the cost of this improved clinical outcome was increased risk of developing leukemia. The authors therefore suggest that better understanding of disease in this unusual subset of patients might enable the development of strategies that can predict a patient's clinical course and guide treatment choices.
In an accompanying commentary, Monica Bessler and Philip Mason, at Children's Hospital of Philadelphia, Philadelphia, discuss the importance of this work and how it fits with other recent papers on cell division defects in Fanconi anemia cells.
TITLE: Spontaneous abrogation of the G2 DNA damage checkpoint has clinical benefits but promotes leukemogenesis in Fanconi anemia patients
AUTHOR CONTACT:
Jean Soulier
INSERM U944 and CNRS UMR7212, Institute of Hematology, Saint-Louis Hospital, Paris, France.
Phone: 33.1.4249.9891; Fax: 33.1.4249.4027; E-mail: jean.soulier@sls.aphp.fr.
View this article at: http://www.jci.org/articles/view/43836?key=431c96bdf2f3b6a7c786
ACCOMPANYING COMMENTARY
TITLE: Cytokinesis failure and attenuation: new findings in Fanconi anemia
AUTHOR CONTACT:
Philip J. Mason
The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Phone: 267.426.9327; Fax: 215.590.4834; E-mail: masonp@email.chop.edu.
View this article at: http://www.jci.org/articles/view/45619?key=8cf67728ef433652bea9
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JCI table of contents: Dec. 22, 2010
2010-12-23
ELSE PRESS RELEASES FROM THIS DATE:
Mortality rates are an unreliable metric for assessing hospital quality, study finds
2010-12-23
BOSTON (December 22, 2010) -- Is quality in the eye of the beholder?
Researchers at Harvard Medical School and Massachusetts General Hospital have found wide disparities among four common measures of hospital-wide mortality rates, with competing methods yielding both higher- and lower-than-expected rates for the same Massachusetts hospitals during the same year.
The findings, published Dec. 23 in a special article in the New England Journal of Medicine, stoke a simmering debate over the value of hospital-wide mortality rates as a yardstick for health care quality. ...
Genome of extinct Siberian human sheds new light on modern human origins
2010-12-23
BOSTON, Mass. (December 22, 2010) — The sequencing of the nuclear genome from an ancient finger bone found in a Siberian cave shows that the cave dwellers were neither Neandertals nor modern humans.
An international team of researchers led by Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig (Germany) has sequenced the nuclear genome from a finger bone of an extinct hominin that is at least 30,000 years old and was excavated by archaeologists from the Russian Academy of Sciences in Denisova Cave in southern Siberia, Russia, in 2008. A ...
Placebos work -- even without deception
2010-12-23
For most of us, the "placebo effect" is synonymous with the power of positive thinking; it works because you believe you're taking a real drug. But a new study rattles this assumption.
Researchers at Harvard Medical School's Osher Research Center and Beth Israel Deaconess Medical Center (BIDMC) have found that placebos work even when administered without the seemingly requisite deception.
The study published on December 22 in PLoS ONE.
Placebos—or dummy pills—are typically used in clinical trials as controls for potential new medications. Even though they contain ...
Designer probiotics could reduce obesity
2010-12-23
Specially designed probiotics can modulate the physiology of host fat cells say scientists writing in Microbiology. The findings could lead to specialised probiotics that have a role in the prevention or treatment of conditions such as obesity.
Scientists from the Alimentary Pharmabiotic Centre (APC), Cork, University College Cork and Teagasc, in Ireland engineered a strain of Lactobacillus to produce a version of a molecule called conjugated linoleic acid (CLA). When this engineered bacterial strain was fed to mice, the researchers found that the composition of the mice's ...
Scientists reveal how biological activity is regulated in fruit fly and roundworm genomes
2010-12-23
Scientists today published catalogs of the fruit fly and roundworm's functional genomic elements: DNA sequences in the genome that carry the instructions and determine which genes are turned on and off at various times in different cells.
Initially sequenced as part of the Human Genome Project, the genomes of the fruit fly, Drosophila melanogaster, and the roundworm, Caenorhabditis elegans, are powerful models for understanding human biology and disease, as many functional genomic elements have been conserved across the vast evolutionary distances separating each organism. ...
Movement and threat of RNA viruses widespread in pollinator community
2010-12-23
Penn State researchers have found that native pollinators, like wild bees and wasps, are infected by the same viral diseases as honey bees and that these viruses are transmitted via pollen. Their research published on December 22nd in PLoS ONE, an online open-access journal for the communication of all peer-reviewed scientific and medical research.
This multi-institutional study provides new insights into viral infections in native pollinators, suggesting that viral diseases may be key factors impacting pollinator populations.
According to Diana Cox-Foster, co-author ...
Learning to read the genome
2010-12-23
In the past decade researchers have made astonishing progress in the rapid and accurate sequencing of genomes from all realms of life. Yet the listing of chemical base pairs has gotten far ahead of understanding how the information they contain becomes functional. Even the best-understood genomes conceal mysteries.
Genetic information carried by DNA and RNA operates together with the patterns and physical organization of chromosomes to produce a working organism. Major advances in understanding these complex relationships are published this week by the "model organism ...
UT Southwestern researchers identify site in brain where leptin may trigger puberty
2010-12-23
DALLAS – Dec. 22, 2010 – UT Southwestern Medical Center researchers have pinpointed a tiny site in the brain where the hormone leptin may help trigger the onset of puberty.
The findings in mice indicate that a site within the hypothalamus called the ventral premammillary nucleus, or PMV, is the target where the hormone leptin effectively kick starts puberty in females.
Researchers have known that puberty starts when individuals have enough energy stores or fat to meet the demands of reproduction, and that leptin – a hormone produced by fat cells – acts in the brain ...
Brain gene makes a female develop as a male
2010-12-23
Australian scientists have discovered that changes to a gene involved in brain development can lead to testis formation and male genitalia in an otherwise female embryo.
Lead Melbourne researcher Professor Andrew Sinclair, of the Murdoch Childrens Research Institute and the University of Melbourne, said the breakthrough would improve diagnosis and clinical management of patients with disorders of sex development (DSD). These conditions occur when the testes or ovaries do not develop properly in the embryo, causing genital abnormalities in one in 4500 babies.
The gene, ...
Brain gene a trigger for determining gender
2010-12-23
University of Adelaide researchers are a step closer to unraveling the mysteries of human sexual development, following genetic studies that show male mice can be created without a Y chromosome – through the activation of an ancient brain gene.
Males usually have one Y chromosome and one X chromosome, while females have two X chromosomes. A single gene on the Y, called SRY, triggers testes development in the early embryo, and once these begin to form, the rest of the embryo also becomes male.
However, Adelaide researchers have discovered a way of creating a male mouse ...