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JCI early table of contents for May 8, 2012
Date:5/8/2012

INFECTIOUS DISEASE

Creating a new weapon in the fight against malaria

Over 200 million people contract malaria each year, and according to the World Health Organization, an estimated 655,000 people died from malaria in 2010. Malaria is caused by the parasite Plasmodium, which is transmitted to humans through mosquito bites. More effective control of malaria will require the development of new tools to prevent new infections. Wesley Van Voorhis at the University of Washington in Seattle and Oliver Billker at the Wellcome Trust Sanger Institute in Cambridge, England assembled an international research team to tackle the challenge of finding new ways to combat malaria. Their unique approach was to uncover a pathway that could block transmission of Plasmodium from humans to mosquitos, which represents a new strategy for controlling the spread of malaria. They discovered a new class of malaria transmission-blocking compounds that work by inhibiting a protein known as bumped kinase I. Bumped kinase I is required for Plasmodium to transition to sporozoites stage, the stage in its life cycle when it is infectious to mammals. In mosquitoes that fed on blood treated with the bumped kinase inhibitor, Plasmodium sporozoite formation was blocked. The research team showed preclinical data in mice indicating that bumped kinase inhibitors are safe and well tolerated. Their results show that bumped kinase inhibitors target a new life cycle stage in Plasmodium, and suggest that these compounds merit further development as a new therapy for malaria control.

TITLE:

Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors

AUTHOR CONTACT:

Kayode K. Ojo

University of Washington, Seattle, , USA

Phone: 206 543 0821; E-mail: ojo67kk@u.washington.edu

View this article at: http://www.jci.org/articles/view/61822?key=bd73a892f008d6fa9cae


VASCULAR BIOLOGY

Genetic variation contributes to high blood pressure

High blood pressure, or hypertension, is a pervasive problem that increases risk for a number of diseases including stroke, heart attack, peripheral arterial disease and chronic kidney disease. Many molecular pathways contribute to the development of hypertension, including nitric oxide signaling. Nitric oxide relaxes smooth muscles in the vascular system and regulates blood flow. Dr. Emmanuel Buys and colleagues at the Harvard Medical School in Boston wanted to better understand how multiple pathways contribute to high blood pressure. Mice with a deletion in a nitric oxide receptor gene known as the soluable guanulate cyclase α1 are prone to hypertension in some strains, but not in all. This suggests that additional genetic difference between strains contribute to hypertension. The Buys research team examined these different strains and mapped the region that contributes to hypertension in the genes that encode for renin. They further showed that renin pathway activity was elevated in mice with high blood pressure and that inhibiting this activity returned blood pressure to normal levels. Their data illustrates how complex interactions between different genes can contribute to hypertension.

TITLE:

Genetic modifiers of hypertension in soluble guanylate cyclase α1-deficient mice

AUTHOR CONTACT:

Emmanuel Buys

Massachusetts General Hospital, Boston, MA, USA

Phone: 617-643-3493; Fax: 617-724-7768; E-mail: ebuys@partners.org

View this article at: http://www.jci.org/articles/view/60119?key=ec002899ed923b1a2d38


NEUROLOGICAL DISEASE

Scratch that itch: TLR3 is critical for itch sensitivity

Itching, also known as pruritus, is a common symptom of several skin ailments, and can be difficult to treat. Dr. Ru-Rong Ji at the Harvard Medical School in Boston and colleagues sought to better understand the molecular mechanisms that contribute to itching. They suspected that a member of the toll-like receptor (TLR) family might be involved. TLR signaling is known to control aspects of pain sensations and inflammation, but its role in pruritus was not known. The Ji team found that treatment with an activator of TLR3 caused itching in normal mice, but not in mice that lack the Tlr3 gene. They showed that TLR3 was expressed in specialized neuron cells in the spinal cord. They went on to elegantly demonstrate that synaptic transmission in the spinal cord was reduced in mice without the Tlr3 gene in response to itch-inducing agents such as capsaicin and histamine. Cumulatively, their results indicate that TLR3 signaling is a key component of itch sensation, and suggest that blocking this pathway could lead to effective therapies for pruritus.

TITLE:

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

AUTHOR CONTACT:

Ru-Rong JI

Duke University Medical Center, Durham, NC, USA

Phone: 919-634-9687; E-mail: ru-rong.ji@duke.edu

View this article at: http://www.jci.org/articles/view/45414?key=3f9ef13e7d7d649b5580


ONCOLOGY

Like sirens at sea, tumors attract and kill immune defenses

For cancer to progress, tumor cells must evade detection and clearance by the body's defense mechanisms in the immune system. Dr. Leonid Metelitsa and colleagues at the Baylor College of Medicine in Houston, Texas wanted to better understand how immune cells known as Natural Killer T cells (NKTs) detect tumors and what tumors do to neutralize NKTs. Using a mouse model system, they found specialized cells in tumors known as tumor-associated macrophages secretes molecules that first attract NKTs, but then inhibit NKT cell function and viability. They further demonstrated that increasing expression of a gene called Il15 in NKTs enhanced the activity of NKTs and reduced the spread of cancer in mice. Their findings reveal how tumors can trap and evade the body's immune cells and suggest that the development of therapies that increase IL15 in NKTs merits further exploration.

TITLE:

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

AUTHOR CONTACT:

Leonid Metelitsa

Baylor College of Medicine, Houston, TX, USA

Phone: 832-824-4395; E-mail: lsmeteli@txch.org

View this article at: http://www.jci.org/articles/view/59535?key=d4bb63659b4c9888cd11


ONCOLOGY

NUPR1 regulates pancreatic cancer development in mice

Pancreatic cancer is fourth most deadly cancer type worldwide. Patients typically have very few symptoms at early stages, frequently leading to detection at late, advanced stages with a poor prognosis. At the cellular level, pancreatic cancer cells show a remarkable resistance to cellular stress, which may account for such high resistance to treatment. Dr. Juan Lucio Iovanna and colleagues at the Mayo Clinic in Rochester, Minnesota wanted to better understand the molecular basis for this resistance to cellular stress. The Iovanna team specifically examined the role of Nuclear protein 1 (NUPR1), which is elevated in pancreatic cancer. Using a mouse model of pancreatic cancer, they found that loss of NUPR1 reduces the appearance of cancerous lesions and triggers a cell death. Further, they showed that higher levels of NUPR1 in pancreatic cancer patients correlated with decreased survival time. Their result suggest that the development of therapeutics targeting NUPR1 might be provide an effective target for treating pancreatic cancer.

TITLE:

Nupr1 regulates RelB-dependent events necessary for pancreatic cancer development in mice

AUTHOR CONTACT:

Juan Lucio Iovanna

Institut National de la Sant et de la Recherche Mdicale (INSERM), Marseille, UNK, FRA

Phone: 33 4 91 82 88 03; E-mail: juan.iovanna@inserm.fr

View this article at: http://www.jci.org/articles/view/60144?key=723af014f0e1b35f03a5


GASTROENTEROLOGY

Breaking down barriers

The gastrointestinal tract must balance the need to form a barrier against foreign pathogens and the need to uptake nutrients from the intestinal lumen. A complex interplay between intestinal epithelial cells and the body's immune cells give rise to the intestinal barrier. Specialized immune system tissue, known as Peyer's patches, functions to monitor the microorganisms in the gut, helping to establish tolerance to beneficial organisms and mount a defense against pathogens. Researchers at the Universit Paris-Diderot in France discovered how one pathogen, Yersinia pseudotuberculosis, exploits molecular pathways in Peyer's patches to disrupt the intestinal barrier function. Led by Frdrick Barreau, the research team discovered Y. pseudotuberculos is disrupted the normal transport systems in Peyer's patches to break through the intestinal barrier. Moreover, once inside the Peyer's patches, the bacteria infected immune cells and triggered the production of a signaling molecule called IL-1β by activating TLR-2 in immune cells. This immune cell activity triggers a counter response in the intestinal epithelial cells that led to the opening of epithelial tight junctions and increased permeability. Their results highlight the intricate interactions between epithelial cells and immune cells during infection and demonstate how Y. pseudotuberculosis subverts these molecular pathways.

TITLE:

Yersinia pseudotuberculosis disrupts intestinal barrier integrity through hematopoietic TLR-2 signaling

AUTHOR CONTACT:

Frdrick Barreau

INSERM, U843, Universit Paris 7, Hpital Robert Debr, Paris, , FRA

Phone: 33 1 57 27 73 27; E-mail: frederick.barreau@inserm.fr

View this article at: http://www.jci.org/articles/view/58147?key=df106eb6bfee3153ced7


HEMATOLOGY

Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents

Protein disulfide isomerase (PDI) is an oxidoreductase that has recently been shown to participate in thrombus formation. While currently available antithrombotic agents inhibit either platelet aggregation or fibrin generation, inhibition of secreted PDI blocks the earliest stages of thrombus formation, suppressing both pathways. Since thrombosis and its sequelae remain a leading cause of morbidity and mortality and recurrent thrombosis is common despite current optimal therapy, we explored extracellular PDI as an alternative target of antithrombotic therapy. A high throughput screen identified quercetin-3-rutinoside as an inhibitor of PDI reductase activity in vitro. Inhibition of PDI was selective, as quercetin-3-rutinoside failed to inhibit the reductase activity of several other thiol isomerases found in the vasculature. Using intravital microscopy, we demonstrated that quercetin-3-rutinoside blocks thrombus formation in vivo by inhibiting PDI. Infusion of recombinant PDI reversed the antithrombotic effect of quercetin-3-rutinoside. Thus, PDI is a viable target for small molecule inhibition of thrombus formation, and its inhibition may prove a useful adjunct in refractory thrombotic diseases not controlled with conventional antithrombotic agents.

TITLE:

Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents

AUTHOR CONTACT:

Robert Flaumenhaft

Beth Israel Deaconess Medical Center, Boston, MA, USA

Phone: 617-735-4005; Fax: 617-735-4000; E-mail: rflaumen@bidmc.harvard.edu

View this article at: http://www.jci.org/articles/view/61228?key=656937ff864f2e691a72


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Contact: Sarah Jackson
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Journal of Clinical Investigation
Source:Eurekalert

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