Volume 17 Issue 7, July 2011

The US-Russian Scientific Forum, established two years ago by a bilateral presidential commission, hopes to bring improvements by facilitating public-private research in biomedicine and innovative drugs. Valery Danilenko, who is helping to spearhead the effort and also leads the biotechnology division at the Vavilov Institute of General Genetics in Moscow, spoke with Gary Peach about his hopes for the Forum.

A group of scientists and dedicated women are participating in rigorous research to uncover secrets of a less-high-profile part of the microbiome. The goal: to learn more about a vaginal disease that most people have never heard of but affects millions of women each year with potentially life-threatening consequences to their unborn children. Alison McCook reports on the unique challenges of developing treatments for a condition with a feminine mystique.

Countless technologies aim to give scientists accurate readouts of the key components of biological samples from patients. But what if it's better to listen to a sample than to look at it? Elie Dolgin visits one company that's adapting a vibration detector developed for telecommunication satellites to make what could be the most sensitive commercial biosensor ever built.

With an eye to tackling the growing problem of antimicrobial drug resistance, US lawmakers last month proposed new incentives to jump-start the ailing antibiotic industry. But the legislation as written is not likely to have the intended consequences, as it fails to adequately shield companies from competition with generic drugs. To truly entice investment and research from the drug industry, the bill needs to simplify the path to regulatory approval, provide greater protection from generic competition and aid drug companies with intellectual property extensions, tax relief and guaranteed market commitments.

To repair the immune-mediated demyelination that occurs in people with multiple sclerosis, strategies to enhance remyelination are being considered as a possible therapy. A new study shows that inhibition of death receptor 6 (DR6) signaling increases the maturation and survival of oligodendrocytes, thus promoting remyelination in rodent models of demyelination (pages 816–821). Blocking DR6 might provide new therapeutic opportunities for the treatment of demyelinating diseases.

A recent study challenges the view that radiation-induced apoptosis is beneficial in tumor therapy by showing that caspase 3–mediated apoptosis in response to ionizing radiation activates a growth signaling cascade in tumor cells, thereby stimulating tumor repopulation (pages 860–866). These results may have important implications for the clinical use of radiotherapy or chemotherapy to induce apoptosis in tumors.

Obesity and high blood pressure are commonly associated. A study in mice now shows that hypothalamic inflammatory pathways may be the link connecting these two disorders and a potential target to uncouple obesity-related hypertension from weight gain (pages 883–887).

A new combinatorial approach harnesses the power of immuno- and virotherapy in a vesicular stomatitis virus (VSV) vector carrying a cDNA library that expresses normal human prostate antigens, thus providing proof of principle that this vaccine can induce prostate tumor rejection in mice (pages 854–859). This strategy might bypass many of the issues associated with conventional cancer immuno- or virotherapy.

Despite intensive study, the mechanisms of pathogenesis in inflammatory bowel diseases (IBDs) remain poorly understood. An innate T helper type 17 (T_H17) response that requires nucleotide oligomerization domain (Nod)-like receptors and is primed by commensal bacteria is now shown to be crucial for controlling intestinal bacterial pathogens in a mouse model (pages 837–844). Thus, dysregulation of this protective immune response may be important in IBD development.

Atherosclerotic lesions can result in fatal cardiovascular disease, but what triggers the formation of the atheroma plaques and their progression still begs further investigation. In 'Bench to Bedside', Göran K Hansson and Lars Klareskog peruse how the NLRP3 inflammasome can be activated by cholesterol crystals and worsen atherosclerosis by triggering inflammation through the release of IL-1β from macrophages. But these cells can also die at the lesion site, forming a necrotic core in the atheroma by building up apoptotic cells and debris. In 'Bedside to Bench', Ira Tabas discusses a human study showing that lesional necrosis along with thinning of the fibrotic cap are predictive of culprit lesions involved in fatal disease. Understanding the molecular underpinnings of these two morphological features may lead to new therapies to prevent or decrease the risk for major cardiovascular disease.

Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.

Snakebite toxins need to be transported through the lymphatic system before gaining access to the blood. By interfering with lymphatic system function, Megan Saul et al. found that nitric oxide donors delay the fatal effects of snake venom in rats. By giving snakebite victims more time to obtain medical care, this approach may be useful for the first-aid treatment of snakebites.

The transcription factor CREB-H has been found to regulate the expression of a suite of genes in mice that are involved in triglyceride metabolism, according to a new study by Ann-Hwee Lee and her colleagues. They also find loss-of-function mutations in the human gene for CREB-H that are associated with highly elevated levels of triglycerides, suggesting a similar role for the protein in humans.

The multiple sclerosis brain shows massive demyelination. Now, Sha Mi and colleagues show that upregulation of DR6 in multiple sclerosis brain is responsible for inhibiting remyelination and brain repair by oligodendrocytes.

Drugs that block calcium channels reduce pain, but they can cause unwanted side effects. Now, Rajesh Khanna and his colleagues show that a peptide that inhibits the interaction between a calcium channel and a protein called CRMP-2 that activates the channel can reduce pain in animals without the side effects of the channel blocker drugs.

Understanding the resistance of natural hosts of simian immunodeficiency virus (SIV)—such as sooty mangabeys—to disease progression may yield insights applicable to HIV-1. In this issue, Paiardini et al. report that CD4⁺ central memory T (T_CM) cells from sooty mangabeys do not strongly upregulate CCR5 upon activation and are more resistant to SIV infection than T_CM cells from rhesus macaques, which may contribute to proper immune control and prevention of disease in these natural hosts.

T helper type 17 (T_H17) responses are crucial for immunity to intestinal pathogens. Here, Stephen E. Girardin, Dana J. Philpott and their colleagues report that early production of IL-17A by enteric CD4⁺ T helper cells is important for host defense against Citrobacter and Salmonella infection. Induction of IL-17A is dependent on Nod-like receptors. suggesting early, innate T_H17 responses are involved in controlling enteric pathogens and may have a role in inflammatory bowel disease.

Individuals with Chuvash polycythemia have an increased red blood cell count and are prone to developing blood clots. Although mutations affecting the VHL protein are known to be causative, the underlying molecular mechanisms have been unclear. Ryan C Russell et al. now show that VHL targets the key signaling molecule JAK2 for degradation by forming a complex with the SOCS1 protein. The authors also show that JAK2 inhibition has beneficial effects in a mouse model of this disease, pointing to a new therapeutic strategy.

Cancer vaccines are frequently designed to increase the immune response toward one or more of the few known tumor-associated antigens (TAAs). Kottke et al. describe an alternate approach to enhancing anti-tumor immune responses without the need for identification of specific TAAs. They show that systemic delivery of a vesicular stomatis virus–based cDNA library derived from normal tissue induces immune responses that impede growth of tumors of the same tissue type in mice.

Cytotoxic cancer therapy can induce accelerated growth of surviving cancer cells, a phenomenon known as tumor repopulation. This report uncovers a mechanism by which caspase 3 activation in treated cells promotes growth of surviving cells, mediated by iPLA₂ and PGE₂. The level of caspase 3 activation in human tumors also correlates with risk of relapse, suggesting that this pathway may be a determinant of therapeutic effects.

Tenascin C is an extracellular matrix protein previously linked to breast cancer metastasis. Here the authors uncover how tenascin C promotes the fitness of metastasis-initiating cells by sustaining the stem and survival signaling pathways NOTCH and Wnt through specific regulation of Msi1 and Lgr5, respectively.

This report identifies Cdk1's phosphorylation of BRCA1 as an important regulator of BRCA1's DNA repair function. Cdk1 inhibition renders cancer cells sensitive to PARP inhibition, and the combination treatment can inhibit tumor growth in vivo, expanding the potential application of PARP inhibitors beyond BRCA1-deficient tumors.

Obesity is often associated with hypertension and this can lead to cardiovascular disease. Further, activation of a proinflammatory signaling pathway in the brain is known to contribute to obesity. Dongsheng Cai and his colleagues now show that activation of this same pathway in a certain population of neurons results in elevated blood pressure, but independently of obesity. They also show that inhibiting this activation in these neurons prevents hypertension even in the presence of obesity.

Acetylcholine signaling by the parasympathetic nervous system is crucial for proper insulin release. Alejandro Caicedo and his colleagues now show that such cholinergic signaling in human pancreatic islets is instead locally derived by pancreatic alpha cells—a finding that may have an impact on future drug development to treat diabetes.

Using the recently developed phosphorescent probe PtP-C343, in combination with two-photon phosphorescence lifetime microscopy, Lecoq and his colleagues offer a method for mapping oxygen levels in both microvascular and extravascular compartments with high spatial and temporal resolution. They used this set-up to make micron-scale simultaneous measurements of partial pressure of oxygen (PO₂) and blood flow in the rat olfactory bulb vasculature and neuropil.