Volume 15 Issue 7, July 2009

Mauro Ferrari has Texas-size aspirations for using nanotechnology to treat illness. This past June, Ferrari became professor and chairman of the newly established Department of Nanomedicine and Biomedical Engineering (nBME) at the University of Texas Health Science Center at Houston. Ferrari met with Jon Evans to discuss nanomedicine, the importance of matching technology to therapeutic need and becoming a medical student in his mid-40s.

In the late 1990s the drug gefitinib became a new tool in treating the most common type of lung cancer, called non–small cell lung cancer. But doctors found that even with continued gefitinib treatment, some patients experienced a cancer relapse within a year. For the past several years, researchers have been working to uncover why these patients lost sensitivity to gefitinib and seeking how to overcome resistance to the drug. Kirsten Dorans reports on the strategies scientists are developing to outpace continually evolving cancer.

Two receptors have now been identified for the virus behind severe hand, foot and mouth disease (pages 794–797 and 798–801).

To maintain skeletal integrity and prevent fractures, degradation and rebuilding of bone must occur in synchrony. Transforming growth factor-β1 is now found to coordinate this restructuring process: the molecule is released during bone degradation and stimulates bone rebuilding (pages 757–765).

Manipulation of cell renewal pathways creates T memory stem cells that can generate a sustained and targeted immune response. These findings have broad implications for vaccine development and immunotherapy (pages 808–813).

A monoclonal antibody directed against lymphotoxin-α (LT-α) expressed by pathogenic T cells can prompt the clearance of these cells from the body (pages 766–773). The findings bring us one step closer to targeting only the cell populations that cause harm in autoimmune diseases while leaving beneficial arms of the immune system largely intact.

People with damage to the central nervous system often undergo rehabilitation therapy. James Fawcett and Armin Curt examine how such therapy might work in conjunction with experimental approaches that increase the ability of neurons to form new connections. They discuss how animal studies raise questions about how to test such approaches in people in a field where firm data are already hard to come by. Phillip Popovich and Dana McTigue take a look at a specific type of nervous system damage—spinal cord injury—and argue that the role of the immune system is underappreciated. They also suggest that one common therapy, application of glucocorticoids, might actually exacerbate the condition.

It has been a long-held belief that the hormone ghrelin is activated when an animal is hungry, inducing the brain to increase food intake. Now, Matthias Tschöp and his colleagues show in vivo that it is not the deficiency of calories per se that activates ghrelin, but rather the presence of energy-rich medium-chain dietary fats.

Immunosuppressive regimens used to prevent rejection of transplanted organs are associated with many adverse side effects. Weaver et al. report that by combining the use of a CD2-targeting reagent (alefacept) with a co-stimulation blockade–based protocol, they can prolong survival of kidney allografts in macaques while avoiding the use of standard immunosuppressive agents.

Ewing's sarcoma family tumors are dependent on an oncogenic fusion protein, most commonly EWS-FLI1, which interacts with RNA helicase A (RHA) in transcriptional complexes. Erkizan et al. have identified a small molecule that inhibits the interaction of RHA with EWS-FLI1 and impairs the growth of Ewing's sarcoma xenografts in mice. The findings provide evidence that targeting tumor-specific transcription factors may be a feasible approach to treating cancer.

Bone is a dynamic tissue and requires the precise coordination of formation with loss. Here, Xu Cao and his colleagues show that the bone-chewing activity of osteoclasts results in the local release of active TGF-β1 from the surface of the bone, inducing the migration of nearby bone-forming osteoblastic progenitor cells to this resorbed region. In this manner, proper matching of the localized rates of bone loss and bone creation is ensured (pages 729–731).

B cell–depleting antibodies have therapeutic efficacy against arthritis. Here Jane Grogan and her colleagues report a new approach to depleting pathogenic T cells. They show that lymphotoxin-α is upregulated on the surface of activated T_H1 and T_H17 CD4⁺ cells, which have a pathogenic role in several autoimmune diseases, and a monoclonal antibody targeted to lymphotoxin-a can inhibit collagen-induced arthritis and EAE in mice (pages 732–733).

TLR4 has a key role in driving inflammation in mouse models of arthritis and may also have a role in the human disease. The extracellular matrix protein tenascin-C is upregulated in the joints of individuals with rheumatoid arthritis. Here Kim Midwood and her colleagues show that tenascin-C is an endogenous activator of TLR4 and that it contributes to the maintenance of arthritis in mice.

Christopher Kirk and his colleagues have developed the first specific inhibitor of the immunoproteasome. They find that the immunoproteasome has a major role in regulating cytokine production, as well as antigen presentation, and their inhibitor has good efficacy in animal models of arthritis.

Modulating the entry of inflammatory T cells into the brain could be one way to treat the autoimmune disease multiple sclerosis. Now, Frauke Zipp and colleagues demonstrate that activation of kinin receptor B1 can block autoimmune T cell migration into the brain and can therefore inhibit experimental autoimmune encephalomyelitis in mice.

Enterovirus 71 (EV71) causes hand, foot and mouth disease, a mild infectious disease that can, however, occasionally lead to severe neurological impairments. These two studies, by Nishimura et al. and Yamayoshi et al., independently identify two different receptors for EV71—P-selectin glycoprotein ligand-1 ((PSGL-1) and scavenger receptor class B, member 2 (SCARB2) (pages 728–729) and (pages 798–801).

Enterovirus 71 (EV71) causes hand, foot and mouth disease, a mild infectious disease that can, however, occasionally lead to severe neurological impairments. These two studies, by Nishimura et al. and Yamayoshi et al., independently identify two different receptors for EV71—P-selectin glycoprotein ligand-1 ((PSGL-1) and scavenger receptor class B, member 2 (SCARB2) (pages 728–729) and (pages 794–797).

Pain is one of the many debilitating side effects of cancer. Now, Rohini Kuner and her colleagues show that blocking hematopoietic colony-stimulating factor signaling on neurons can inhibit pain caused by bone cancer.

The Wnt pathway has a central role in stem cell regulation. Gattinoni et al. now show that activation of the Wnt signaling cascade in naive CD8⁺ T cells blocks their differentiation into effector T cells and triggers instead a memory stem cell–like phenotype. These T memory stem cells show enhanced antitumor efficacy in mice compared with other T cell subsets, arguing for their further evaluation in adoptive immunotherapies (pages 731–732).