Volume 18 Issue 7, July 2012

Since its inception ten years ago, the Surviving Sepsis Campaign has successfully developed a series of best-practice criteria—the International Guidelines on the

Management of Severe Sepsis and Septic Shock, which are currently being revised under Phillip Dellinger’s leadership—as well as engaged physicians and the general public around the world in a broad educational program to warn about the threat posed by the disease. Dellinger spoke with Roxanne Khamsi about the struggle to catalyze change in the sepsis field.

Drugs designed to protect or rescue neurons from damage wrought by stroke have repeatedly failed in clinical trials, prompting a mass flight of pharmaceutical companies from the field. A small Canadian startup is bucking the trend—and it hopes that monkey data will help the field evolve. Elie Dolgin reports.

The Recombinant DNA Advisory Committee, formed in 1974, was originally charged with advising on potential risks of recombinant technology and took on review of clinical gene therapy protocols in the late 1980s. But as gene therapy has made headway with safety, it's time to shift the committee's mission toward broader ethical and technical issues linked to the field.

MicroRNAs (miRNAs) have emerged as crucial mediators of human disease, but their roles in autoimmunity have only recently been appreciated. A new study using mouse and human tissues from various interleukin-17 (IL-17)-related autoimmune disorders now shows that miRNA-23b is a central regulator of inflammation in resident tissue cells during autoimmunity (pages 1077–1086).

A recent study highlights the potential of therapeutically modulating the endogenous miRNA pathway in a mouse model of spinal and bulbar muscular atrophy (SBMA). The overexpression of a naturally occurring miRNA led to the downregulation of the mutant androgen receptor transcript as well as the polyglutamine-containing protein it encodes, both of which may contribute to pathogenesis in SBMA (pages 1136–1141).

Acute exposure to ionizing radiation can cause lethality via severe damage to the hematopoietic system. A new study shows that infusion of the anticoagulants thrombomodulin or activated protein C reduces radiation toxicities and improves survival (pages 1123–1129).

Whereas the adaptive immune response is essential for control and clearance of hepatitis B virus infection, the importance of the early innate immune response is controversial and the players involved are poorly defined. A new study shows that activation of natural killer T cells by infected hepatocytes is crucial for the early control of this disease (pages 1060–1068).

Endometriosis occurs when estrogen-sensitive endometrial cells that are shed to distal sites manage to attach and survive in a foreign, inflammatory environment. A new study reports a unique interaction between a cleaved form of steroid receptor coactivator 1 (SRC-1) and caspase 8 that blocks apoptosis in endometriotic cells, allowing them to survive (pages 1102–1111).

The enthesis is the region at the junction between tendon and bone and has been suggested to be a key target in spondyloarthritic diseases. This zone is now shown to contain a unique population of resident T cells, which, when activated by the cytokine interleukin-23 (IL-23), can promote pathogenesis that is characteristic of spondyloarthritis (pages 1069–1076).

Several decades of scientific observations followed by years of basic and now clinical research support the notion that the metabolic power of tumor cells can provide the long-desired Achilles' heel of cancer. Yet many questions remain as to what defines the true metabolic makeup of a tumor and whether well-known factors and pathways involved in metabolic signaling act as tumor suppressors or oncogenes. In 'Bedside to Bench', Kıvanç Birsoy, David M. Sabatini and Richard Possemato discuss how retrospective studies of diabetic individuals with pancreatic cancer treated with the antidiabetic drug metformin point to a possible anticancer effect for this drug. Further research will need to discern whether this drug acts at the organismal level or by directly targeting the power plant of tumor cells. In 'Bench to Bedside', Regina M. Young and M. Celeste Simon peruse the complex function of a key metabolic factor that mediates the cell's response to low oxygen levels, often found in tumors. This hypoxia-inducible factor (HIF) comes in two flavors, which can be either tumor promoting or tumor suppressive, depending on the type of cancer. Because of this, the therapeutic use of HIF inhibitors must proceed with caution. Further defining the relationship between metabolic regulation of HIF and tumor progression may open up new diagnostic tools and treatments.

Fibrosis is a key aspect of many chronic inflammatory diseases and can affect almost every tissue in the body. This review discusses recent advances in our understanding of the mechanisms of fibrosis, focusing on the innate and adaptive immune responses. It also describes how some of these crucial pathogenic pathways are being therapeutically targeted in the clinic.

Genomic technologies are being rapidly applied to the area of prenatal diagnosis, and many genomic prenatal tests have already been transitioned to the clinic. Diana Bianchi reviews these advances in prentatal diagnosis and highlights the challenges in bringing them to the clinic. She also discusses how genomic and transcriptomic technologies might be applied to understand the pathology of fetal diseases and disorders of pregnancy and, perhaps, develop new therapies for these conditions.

By digital profiling of residual breast tumors after neoadjuvant therapy, the authors identify gene expression patterns that correspond with a higher risk of metastasis and recurrence. Activation of the Ras-ERK pathway through loss of DUSP4 confers therapy resistance that can be overcome by combined treatment with MEK inhibitors.

Hepatitis B virus (HBV) infection is known to be controlled by T and B cell responses, but the role of natural killer T (NKT) cells is less clear. Richard Blumberg and his colleagues now show that NKT cells are activated immediately after HBV infection by presentation of an HBV-altered repertoire of lysophospholipids on infected hepatocytes and are necessary for the induction of optimal T and B cell responses and rapid viral control.

Spondyloarthropathies are characterized by a distinct pattern of inflammation at distinct anatomical sites and are associated with elevated expression of interleukin 23 (IL-23). Daniel Cua and his colleagues identify an IL-23–responsive CD4⁻CD8⁻ T cell population located within entheses. Systemic overexpression of IL-23 activates these cells and recapitulates aspects of the human disease in mice, and neutralization of IL-17 and IL-22 decreases pathology, suggesting new therapeutic targets for these disorders.

Several microRNAs have been identified that affect lymphocyte effector function and contribute to autoimmune inflammatory disease. Here Youcun Qian and his colleagues find that interleukin-17 (IL-17) suppresses miR-23b expression in nonimmune cells present in inflammatory lesions from individuals with rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis and in the respective mouse models. MiR-23b targets several signaling molecules downstream of IL-17, TNF-α and IL-1β signaling, thereby suppressing proinflammatory cytokine expression and inhibitng autoimmune pathogenesis in vivo.

Temporal lobe epilepsy (TLE) is linked to neuron death in the hippocampus. Now David Henshall and colleagues show that miR-134 is upregulated in humans with TLE and in an experimental epilepsy model in mice. Decreasing miR-134 before induction of epilepsy in mice reduces neuron death and the generation of spontaneous seizures.

Bone remodeling involves a coupled balance between bone resorption and bone formation. Xu Cao and his colleagues have shown before that mesenchymal stem cells (MSCs) are recruited to the surface of the bone during this process. They now show that insulin-like growth factor 1 (IGF-1) is released from the bone surface during bone resorption, where it signals the recruited MSCs to differentiate into osteoblasts. In this way, bone resorption is linked to bone formation, and IGF-1 as a target of bone therapy is suggested.

Endometriosis afflicts ~15% of women of reproductive age, causing pelvic pain, and is often associated with infertility. In a new study, Bert O'Malley and his colleagues now show that in response to TNF-α signaling, a unique isoform of SRC-1, an estrogen receptor coactivator, is elevated in endometriotic tissue, preventing the normal apoptosis of these cells. These results could explain the proliferation of these cells, while also further suggesting the antibody to TNF-α etanercept as a therapy for this condition.

Activation of the epithelial Na⁺ channel ENaC in mouse endometrium triggers Ca²⁺ influx and upregulation of cyclooxygenase 2, an enzyme key for prostaglandin production and for embryo implantation.

This report identifies upregulation of HGF as an autocrine growth pathway in several subsets of AML. Ligand-dependent activation of MET represents a new oncogenic stimulus, and the dynamic regulation of HGF can overcome the effects of MET inhibition. These results suggest that combination treatments may be needed to disrupt this autocrine signaling loop and quell the growth of AML.

Using an unbiased genetic screen in mice, Hartmut Geiger et al. found that the thrombomodulin–activated protein C pathway, which controls blood coagulation among other functions, also protects from radiation damage. Administration of a recombinant variant of thrombomodulin or of recombinant activated protein C protected mice from total body irradiation, pointing to potential therapeutic applications.

Pelizaeus-Merzbacher disease (PMD) is a neurological disease caused by loss of myelin. Now, Gesine Saher et al. show that a cholesterol-enriched diet can ameliorate disease in a mouse model of PMD.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by aggregation of the androgen receptor (AR) protein. Here Gen Sobue and colleagues show that upregulation of miR-196a can reduce expression of AR mRNA and ameliorate disease symptoms in mouse models of SBMA.

Nadia Dominici and her colleagues have developed a multidirectional robotic neurorehabilitation system that is capable of operating as a propulsive or postural neuroprosthesis and overcomes some of the limitations of existing systems. The robotic interface allows for the independent assessment and restoration of motor function in rats with mild to severe neuromotor disorders and is validated in various models of spinal cord injury and stroke.

In the past, small-diameter, synthetic vascular prostheses have been made in vitro either entirely from cells or by inoculating cells onto scaffolds. Wei Wu and colleagues have taken a cell-free approach where biodegradable elastomeric grafts are rapidly degraded, producing neoarteries that were almost free of foreign materials 90 days after grafting in a rat abdominal aorta. Grafts were rapidly remodeled by the host and produced compliance and burst pressure values similar to those of native aorta.