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Targeting endothelial cell integrins has been pursued as a means to inhibit tumor angiogenesis. In this issue, Andrew Reynolds and his coworkers (p 392) reveal a potential pitfall to this strategy: low doses of αvα3/αvα5 integrin inhibitors lead to increased tumor angiogenesis and growth in mice. These effects may stem from increased recycling of the vascular endothelial growth factor receptor, VEGFR2, to the plasma membrane of endothelial cells. The cover image shows VEGFR2 staining (green) within vesicular structures in a tumor blood vessel in mice (laminin, red; nuclei, blue).
A recent US Supreme Court ruling places responsibility for the wording of drug labels on pharmaceutical companies. But the task of improving the communication of drug risks does not rest with the pharmaceutical industry alone.
Agnès Saint Raymond has long advocated for children's health and worked with members of the European Parliament to draft and pass new legislation in 2006 to promote drug development in this area. She spoke with Genevive Bjorn about the future of medicines designed for youngsters.
An indigestion drug blamed for a debilitating illness that affected thousands of people in the 1950s has been resurrected as a potential treatment for Alzheimer's disease. But not everyone is cheering for the drug, clioquinol, to make a comeback. Lauren Cahoon reports.
Growth factors used to accelerate engraftment after hematopoietic cell transplantation can increase the severity of graft-versus-host disease. Experiments with mice examine how irradiation, used to prepare recipients for transplants, contributes to this problem (pages 436–441).
Experiments in two mouse models of thromboinflammatory disease show how neutrophils stick to red blood cells and platelets—leading to reduced blood flow and damage to the microcirculation. Polarized expression of αMβ2 integrins on neutrophils helps set the process in motion (pages 384–391).
Toll-like receptors on lung epithelia recognize allergens and help provoke asthma. The findings put new emphasis on innate immunity as a driver of allergic responses (pages 410–416).
Experiments in rodents identify a factor that causes the release of multipotent cells into the circulation after injury. These cells contribute to tissue repair (pages 425–435).
Type 2 diabetes is often viewed as a disorder of glucose metabolism. But many factors come into play in this condition, with obesity a prime risk factor and cardiovascular disease a major result. In Bedside to Bench, Babak Razani and Clay Semenkovich examine the linkages between diabetes and cardiovascular disease. They call for new research approaches in the wake of clinical trials showing that lowering glucose levels does not decrease cardiovascular events in people with type 2 diabetes. In Bench to Bedside, Steven Shoelson and Allison Goldfine examine how type 2 diabetes and other disorders can stem from obesity—and its effect on inflammation. These authors take a look at two recent studies showing how obesity perturbs inflammatory gene networks.
The neurotoxic Aβ peptide is produced after traumatic brain injury. Mark P. Burns and his colleagues show that inhibiting the enzymes involved in Aβ production can block the neuron death and neurological dysfunction that occurs after traumatic brain injury.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome that is often difficult to treat. Hiroshi Watanabe and coworkers now show that flecainide, an approved drug known to inhibit sodium channels, is able to target the underlying cause of CPVT by inhibiting calcium release through the ryanodine receptor. Flecainide prevented arrhythmia in a mouse model of CPVT and was also effective when tested in two individuals with CPVT.
Signaling between endothelial and blood cell types controls inflammatory and thrombotic responses. Andrés Hidalgo and his coworkers now uncover a signaling mechanism by which the endothelium, acting on adherent leukocytes, promotes the capture of platelets or red blood cells by those leukocytes, contributing to pathology in mouse models of two very different types of disease—transfusion-related acute lung injury and sickle cell disease(pages 364–366).
Inhibitors of αvβ3 and αvβ5 integrins have previously been shown to inhibit tumor angiogenesis and growth and have entered human clinical trials. Andrew Reynolds and his coworkers now show that low (nanomolar) concentrations of these inhibitors can unexpectedly promote VEGF-dependent tumor angiogenesis and growth in vivo. Such effects could compromise the anticancer efficacy of these agents in humans.
Bali Pulendran and his colleagues explore ways that signaling through different pathogen receptors can program dendritic cells (DCs) to orchestrate inflammatory or tolerogenic immune responses. The yeast component zymosan triggers signaling through both Toll-like receptor 2 (TLR2) and the C-type lectin dectin-1. In the absence of TLR2, zymosan induces proinflammatory responses through dectin-1. But TLR2 triggering induces DCs to form the vitamin A–metabolizing enzyme Raldh2. The DCs can then form retinoic acid that acts in an autocrine manner on the DCs, programming them for the induction of regulatory T cell responses.
House dust mite allergen (HDM) is a potent trigger of airway inflammation. Dendritic cells (DCs) and lung epithelial cells both express the pathogen receptor TLR4, which senses lipopolysaccharide contaminating the allergen. Bart Lambrecht and his colleagues show that TLR4 on the epithelial cells, not the DCs, is the primary sensor of HDM. TLR4 on these lung structural cells is required for recruitment of DCs and the induction of allergic inflammation in response to HDM (pages 366–367).
Kurt Redlich and his colleagues show that estrogen deficiency results in increased numbers of preosteoclast progenitor cells in the bones of mice. But they also find that lack of CCR2 in these future bone-resorbing cells prevents their maturation and thus protects the mice from osteoporosis, suggesting a future target for therapy in humans.
New factors in wound healing are sorely needed. Here Youngsook Son and colleagues identify substance P, a small neuropeptide, as one such factor that seems to work by mobilizing stromal-like cells to the site of wounding, accelerating the healing process (pages 367–369).
Granulocyte colony-stimulating factor (G-CSF) is used to accelerate neutrophil engraftment in bone marrow transplant (BMT) recipients to reduce bacterial infections but may also enhance the risk of graft-versus-host disease (GVHD). Morris et al. now show that total body irradiation increases the expression of the G-CSF receptor on recipient dendritic cells, resulting in the activation of donor natural killer T cells and enhanced GVHD when G-CSF is administered shortly after BMT (pages 363–364).
One way to reduce obesity is to alter fat absorption from the diet. Here Robert Farese, Jr. and his colleagues identify MGAT2 as a potential therapeutic target for doing so. The enzyme is mostly expressed in the gut of humans and mice, and its genetic deletion in mice results in slower kinetics of fat absorption—more of the fat is burned and less is stored, offering protection from diet-induced obesity.
Viral-mediated gene therapy presents many challenges in the clinic, including the potential for physiological effects that overshoot the intended goals. In a new report by Matthew During and his colleagues, the authors devise a scheme by which packaging of a microRNA into the virus, expressed under the control of a physiological response induced by the viral transgene, allows coordinated dampening of the transgene expression when the therapeutic response achieves a certain threshold.
The leukocyte enzyme myeloperoxidase (MPO) is key to normal host defense mechanisms. Dysregulated MPO, however, is linked to acute and chronic inflammatory conditions, such as atherosclerosis and cancer. The authors describe a luminol-based bioluminescence imaging system that provides an optical readout of physiological levels of MPO activity in vivo. The system is demonstrated in animal models of acute dermatitis, focal arthritis and spontaneous large granular lymphocytic tumors.