Articles in 2011

The future of imaging is the integration of function and anatomy. Hongki Yoo et al. have successfully done just that by combining two existing intravascular imaging techniques into a single catheter-based system. Their dual-modality intra-arterial catheter uses a combination of optical frequency domain imaging and near-infrared fluorescence imaging to simultaneously provide molecular information in the context of the surrounding three-dimensional microanatomy of the artery wall.

Makoto Mitsunaga et al. have developed a new form of molecular-targeted cancer therapy that provides an alternative to current photodynamic approaches where damage to surrounding healthy cells and tissues can be a problem. They use a target-specific photosensitizer based on a near-infrared phthalocyanine dye, which is conjugated to monoclonal antibodies targeting human epidermal growth factor receptors (HER1 and HER2). Selective treatment using this approach was shown in vivo in subcutaneous cancer xenografts in mice.

Osteoarthritis, the breakdown of cartilage in synovial joints, has long been viewed as the result of 'wear and tear', but this report shows that dysregulation of the complement system has an active role in the pathogenesis of this disease.

The complexity of the brain adds another level of difficulty to our understanding of how the brain develops, matures and functions. Both structural and molecular components define brain functional connectivity, and its alteration may result in developmental, behavioral and social deficits. Uncovering the roots and mechanisms behind neurodevelopmental disorders, such as fragile X syndrome or autism, is the goal of several lines of research. Despite the challenges associated with studying these diseases, new advances are linking pathological genetic changes with mechanisms in the brain. In Bench to Bedside, Guoping Feng and Jonathan Ting peruse a study that uncovers how fragile X syndrome–causing gene mutations unleash a translation break that finally leads to overexpression of synaptic proteins that alter the proper transmission of signals at the synapse. Furthermore, changes in the brain during the development of a person can also provide information about when and where the diseased brain loses functional connectivity. In Bedside to Bench, Jeffrey Neul proposes that studying the functional networks in people with autism and other neurodevelopmental disorders, and correlating changes with functional connectivity in animal models of these diseases, will uncover the mechanisms of normal and abnormal development and suggest possible treatment strategies.

A burst of research into the genetics of autism has given scientists insight into the basis for the disorder. Now, some companies aim to capitalize on these findings by developing DNA screens that might one day provide a diagnosis at birth. Hannah Waters examines the genetic tests and explores what parents—and their autistic children—have to gain.

Ovarian tumors preferentially metastasize to the omentum, a peritoneal fat layer. This report proposes that the reasons for this predilection stem from the growth advantage conferred by adipocytes on ovarian cancer cells. Adipocytes seem to promote homing of cancer cells through adipokine secretion, and direct contact of the two cell types promotes metabolic changes that result in lipid transfer from adipocytes to tumor cells. Environmental-driven metabolic adaptations could be exploited to target omental metastasis.

Helga Ellingsgaard et al. show that secretion of interleukin-6 by muscle in response to exercise, or injection of recombinant protein, increases the expression of the incretin GLP-1 by both intestinal cells and by pancreatic alpha cells, thus potentiating insulin release and improving glycemic control. These results identify a new endocrine loop linking energy demands to homeostatic control while also suggesting further targets for type 2 diabetes therapy.

Fahumiya Samad and her colleagues have shown that the serine protease tissue factor, a key regulator of coagulation, has a role in obesity and metabolic disease. They find that tissue factor signaling in adipocytes promotes obesity, whereas its signaling in adipose tissue macrophages promotes local inflammation and insulin resistance.

By implementing the conditions for orthotopic implantation of different types of human breast tumors, the authors have created a publicly available bank of new mouse models that more faithfully recreate individual tumor properties and provide individualized information about tumor behavior and prognosis.

The holy grail in the bone field is the identification of a pharmacological compound that promotes bone growth during osteoporosis. Hiroshi Takayanagi and his colleagues take a step forward in that direction by showing that osteoclast-mediated expression of semaphorin D inhibits osteoblast differentiation and that, by inhibiting this pathway with a blocking antibody, they could prevent bone loss in a mouse model of osteoporosis.

Séverine Coulon et al. identify a new mechanism regulating red blood cell production through transferrin receptor engagement. By binding this receptor on erythroblasts, the polymeric form of immunoglobin A1 (pIgA1) or iron-loaded transferrin acts in conjunction with erythropoietin to promote erythroblast maturation. Administration of either pIgA1 or iron-loaded transferrin accelerated recovery from anemia in mice, suggesting that these findings may have therapeutic implications.

Spinocerebellar ataxia 1 is a neurodegenerative disease caused by a CAG trinucleotide expansion in the ATXN1 gene encoding the protein ataxin-1. Puneet Opal and his colleagues find that ataxin-1 represses the expression of the angiogenic and neurotrophic factor vascular endothelial growth factor (VEGF) and that VEGF levels are decreased in animals with motor impairment. Overexpression or infusion of VEGF improves motor performance and pathology, suggesting VEGF may have therapeutic potential in this disease.

Jan Brosens and his colleagues have found that deregulation of a single kinase—SGK1, a kinase involved in fluid balance—in two distinct cellular compartments of the endometrium is linked to two different forms of reproductive failure in humans. Using gain- and loss-of-function approaches in mice, the group confirmed the importance of these expression changes in such pathologies.

Ron Evans and his colleagues have shown that excess thyroid hormone receptor signaling during embryonic development in mice impairs the differentiation of type I pneumocytes, a key lung cell type needed for proper gas exchange. They also show that treatment with antithyroid drugs during this stage of development rescues the defect in lung maturation, suggesting a possible therapy for some children born with respiratory distress syndrome.