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
View this article at: http://www.jci.org/articles/view/59227?key=ea2a2976eda990b97f6f
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. 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
View this article at: http://www.jci.org/articles/view/58815?key=c0fbf3396c0256802880
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 toxin-associated hemolytic uremic syndrome in humans and mice
View this article at: http://www.jci.org/articles/view/57313?key=94d0ea84d0b2f1f1dbba
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
View this article at: http://www.jci.org/articles/view/46116?key=a448a96779e4cb2bc80a
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