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JCI online early table of contents: Jan. 9, 2012

EDITOR'S PICK: Genetic and mechanistic basis for rotor syndrome uncovered

The main symptom of Rotor syndrome is jaundice caused by a buildup of a substance known as conjugated bilirubin. Bilirubin is a yellow substance generated in large quantities when the body recycles red blood cells. It is conjugated in the liver to make it soluble in water so that it can be cleared from the body. Although Rotor syndrome is known to be a genetic disorder, it is not known which genes are involved. However, a team of researchers led by Alfred Schinkel, at The Netherlands Cancer Institute, The Netherlands; and Milan Jirsa, at the Institute for Clinical and Experimental Medicine, Czech Republic has now linked genetic mutations predicted to cause complete and simultaneous deficiencies of the proteins OATP1B1 and OATP1B3 to Rotor syndrome in 8 families. Detailed analysis in mice identified the underlying mechanism involved. Moreover, further screening of Rotor syndrome families suggested that although complete lack of either OATP1B1 or OATP1B3 alone does not cause Rotor syndrome, it could cause hypersensitivity to certain drugs.

TITLE: Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver

Alfred H. Schinkel
The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Phone: 31-20-5122046; Fax: 31-20-6961383; E-mail:

Milan Jirsa,
Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Phone: 420-261362773; Fax: 420-241721666; E-mail:

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EDITOR'S PICK: New gene, new mechanism for neuron loss in hereditary spastic paraplegias

Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterized by progressive weakness and spasticity (stiffness) of the legs. Mutations in more than 30 genes have been linked to HSPs. A team of researchers led by Stephan Zchner, at the University of Miami Miller School of Medicine, Miami; Evan Reid, at the University of Cambridge, United Kingdom; and Antonio Orlacchio, at the Centro Europeo di Ricerca sul CervelloIstituto di Ricovero e Cura a Carattere Scientifico Santa Lucia, Italy has now associated mutations in the gene reticulon 2 with hereditary spastic paraplegia type 12. In addition to identifying a new HSP-associated gene, the team was able to uncover how the mutations in reticulon 2 are likely to cause neurodegeneration, providing new insight into this diverse group of inherited disorders.

TITLE: Mutations in the ER-shaping protein cause the axon-degenerative disorder hereditary spastic paraplegia type 12

Stephan Zchner
University of Miami Miller School of Medicine, Miami, Florida, USA.
Phone: 305-243-2281; Fax: 305-243-2703; E-mail:

Evan Reid
University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom.
Phone: 44-1223-762602; Fax: 44-1223-762640; E-mail:

Antonio Orlacchio
Centro Europeo di Ricerca sul CervelloIstituto di Ricovero e Cura a Carattere Scientifico Santa Lucia, Rome, Italy.
Phone: 39-06-501703308; Fax: 39-06-501703312; E-mail:

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ONCOLOGY: KRAS provides maintenance for pancreatic cancer

The outlook for individuals diagnosed with the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDA), is very poor; the average time of survival after diagnosis is less than 6 months. New therapeutic approaches are therefore much needed. By developing and studying two new mouse models of pancreatic cancer, a team of researchers led by Marina Pasca di Magliano, at the University of Michigan, Ann Arbor, has now identified potential new targets for treating individuals with this terminal condition.

Mutations in the KRAS gene are detectable in the majority of pancreatic cancers. However, the relative importance of these mutations in promoting the formation of and maintaining the presence of pancreatic cancers is not completely understood. Pasca di Magliano and colleagues have now generated data that indicate that KRAS mutations drive the formation of pancreatic tumors in mice and are essential for the maintenance of these tumors. They therefore suggest that inhibiting the constitutively active form of KRAS templated by mutated KRAS genes and/or molecules activated by the mutant KRAS could provide much needed new approaches for the treatment of pancreatic cancer.

TITLE: Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice

Marina Pasca di Magliano
University of Michigan, Ann Arbor, Michigan, USA.
Phone: 734-615-7424; Fax: 734-647-9654; E-mail:

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HEMATOLOGY: Potential new therapeutic target for chronic myelogenous leukemia?

Chronic myelogenous leukemia (CML) is a slow-growing bone marrow cancer resulting in the overproduction of white blood cells. It is triggered when a specific chromosomal irregularity arises in a blood cell stem or early progenitor cell. CML has several phases the first phase, when there are few symptoms of disease, can last for years, but it eventually progresses to much more dangerous second and third phases. A team of researchers led by Adrian Ochsenbein, at University Hospital Bern, Switzerland, has now identified a role for the protein CD27 on CML stem cells in progression of disease in a mouse model of CML. Importantly, blocking CD27 delayed disease progression and prolonged survival. Ochsenbein and colleagues therefore suggest that blocking CD27 or targeting the signaling pathway downstream of its activation might provide a new therapeutic option for the treatment of individuals with CML. New treatment options are needed for this disease because even though the current first-line treatment (a drug known as imatinib [Gleevec]) is highly effective in the majority of patients, in about 10%󈝻% of patients the beneficial effects of Gleevec are very short lived.

TITLE: CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression

Adrian F. Ochsenbein
Institute for Medical Oncology, University Hospital Bern, Bern, Switzerland.
Phone: 41-31-632-4114; Fax: 41-31-632-4119; E-mail:

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ALLERGY AND ASTHMA: Integrin integral to airway narrowing

More than 10 million Americans suffer from the most common form of asthma allergic asthma. A team of researchers led by Dean Sheppard, at the University of California, San Francisco, San Francisco, has now gained new insight into the mechanisms underlying the airway narrowing that occurs during an asthma attack by studying a mouse model of allergic asthma. Specifically, the team found that the protein complex alpha-v-beta-6 integrin modulates, via its effects on the soluble protein TGF-beta, the expression of mediators of airway narrowing known as mast cell proteases. As mice lacking alpha-v-beta-6 integrin were protected from exaggerated airway narrowing in their model, Sheppard and colleagues suggest that targeting this pathway could provide a new approach to treating allergic asthma.

TITLE: The alpha-v-beta-6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells

Dean Sheppard
University of California, San Francisco, San Francisco, California, USA.
Phone: 415-514-4269, Fax: 415-514-4278; E-mail:

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BACTERIOLOGY: Making life inHUSpitable for bacterial toxins by targeting the CXCR4/SDF-1 interaction

Hemolytic uremic syndrome (HUS) is a potentially life-threatening condition. It often occurs after gastrointestinal infection with the bacterium Escherichia coli O157:H7. The bacterium releases toxins known as Shiga toxins (Stx), which cause the symptoms of HUS. A team of researchers led by Philip Marsden, at the University of Toronto, Toronto, has now defined a new molecular pathway by which Stx cause HUS. Specifically, the team identified a role for the soluble factor SDF-1 and the cell-surface proteins to which it binds (CXCR4 and CXCR7). Importantly, inhibition of the CXCR4/SDF-1 interaction decreased organ injury and improved survival in a mouse model of Stx-mediated disease, and levels of SDF-1 in the blood of children infected with Escherichia coli O157:H7 were elevated in those that developed HUS. Marsden and colleagues therefore suggest that targeting the CXCR4/CXCR7/SDF-1 pathway could provide a new approach to preventing and/or treating HUS associated with Escherichia coli O157:H7 infection.

TITLE: The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxinassociated hemolytic uremic syndrome in humans and mice

Philip A. Marsden
University of Toronto, Toronto, Ontario, Canada.
Phone: 416-847-1734; Fax: 416-864-5813; E-mail:

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LYMPHATIC SYSTEM: Role for RASA1 in regulating lymphatic vasculature growth and function

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a disorder of the blood vessel network, which is known as the vasculature. Patients have a wide array of blood vessel abnormalities. Many of these are harmless but some can be life threatening. CM-AVM is caused by mutations in the RASA1 gene, which regulates blood vessel growth. However, it is not clear why some patients also develop symptoms that suggest that they have abnormalities in their network of vessels known as the lymphatic vasculature, which carries colorless fluid known as lymph around the body. A team of researchers led by Philip King, at the University of Michigan Medical School, Ann Arbor, has now provided a potential explanation for this they find that RASA1 regulates lymphatic vasculature growth and function in mice.

TITLE: RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice

Philip D. King
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: 734-615-9073; Fax: 734-764-3562; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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