Medicine

Budget cuts and administrative changes that have eliminated the Ministry of Science in Spain illustrate the need to safeguard science funding and policies in European countries immersed in the economic crisis.

Congress vouches for priority review of childhood disease Nature Medicine 18, 181 (2012). doi:10.1038/nm0212-181 Author: Roxanne Palmer

India mulling stricter laws to curb unethical trials Nature Medicine 18, 182 (2012). doi:10.1038/nm0212-182 Author: Killugudi Jayaraman

With bated breath, companies await approval for inhalable drugs Nature Medicine 18, 183 (2012). doi:10.1038/nm0212-183 Author: Elie Dolgin

Spain reeling from budget and staff cuts in biomedicine Nature Medicine 18, 184 (2012). doi:10.1038/nm0212-184a Author: Michele Catanzaro

New insight on bariatric surgery difficult to swallow Nature Medicine 18, 184 (2012). doi:10.1038/nm0212-184b Author: Melinda Wenner Moyer

Internet data miners strike disease detection gold Nature Medicine 18, 185 (2012). doi:10.1038/nm0212-185 Author: Rebecca Hersher

Clinicians call for greater transparency in trial recruitment Nature Medicine 18, 186 (2012). doi:10.1038/nm0212-186a Author: Rebecca Hersher

Fifth time's the charm? Nature Medicine 18, 186 (2012). doi:10.1038/nm0212-186b Author: Rebecca Hersher

Patrick Soon-Shiong has only one mode of thinking: big. The South Africa-born surgeon-scientist has founded two multi-billion-dollar pharmaceutical firms and is now setting his sights on transforming the entire US biomedical system with a modern, high-speed data network. Amber Dance sat down with Soon-Shiong to talk about how uniting physicians and scientists will surmount the most pressing challenges in biomedicine and cancer research.

Biomedical briefing Nature Medicine 18, 188 (2012). doi:10.1038/nm0212-188

Correction Nature Medicine 18, 189 (2012). doi:10.1038/nm0212-189

Suicide is the third leading cause of death in the US among people under the age of 45. Yet psychiatrists know remarkably little about what treatments can most effectively prevent people from killing themselves. For the most part, investigators have shied away from studying the problem head-on because designing intervention studies with suicidal subjects is fraught with difficulty. Elie Dolgin talks to the small group of mental health professionals who are hoping to put an end to that.

The long-term decline in the number of UK doctors who conduct research is well recognized. Although some signs of recovery have been noted in the last few years, government budget cuts and the imminent rise in the tuition fee cap may make a bad situation worse.

Smallpox: the big picture Nature Medicine 18, 195 (2012). doi:10.1038/nm.2662 Author: Amy E. Slaton

A new study shows that mice lacking tau develop parkinsonism because of intracellular iron accumulation that results in degeneration of dopamine neurons. Tau deficiency seems to impair ferroportin iron export by retention of the amyloid precursor protein, a neuronal ferroxidase partner, inside the endoplasmic reticulum (pages 291–295).

Some individuals with colorectal cancer benefit from therapies targeting the epidermal growth factor receptor (EGFR). However, resistance to EGFR blockade inevitably occurs. The characterization of a new mechanism of resistance to the EGFR-specific antibody cetuximab provides clues into how therapeutic strategies might be designed to overcome this specific resistance mechanism (pages 221–223).

Why do some influenza infections cause fatal disease and others barely a sniffle? Although viral virulence can vary, the immunological history of the host is also important. A new study in humans suggests that CD4+ T lymphocytes activated during previous infections can limit disease severity in the absence of specific antibodies (pages 274–280).

New strategies for selectively stimulating bone formation without promoting bone resorption are required, as all currently approved agents for osteoporosis act on both of these aspects of the bone remodeling process. A recent study describes an approach that specifically delivers therapeutic siRNAs to bone-forming surfaces without affecting bone resorption (pages 307–314).

A newly identified role for SMAD specific E3 ubiquitin protein ligase 2 (Smurf2) in the regulation of histone ubiquitination uncovers a broad tumor suppressor activity that helps to maintain genomic stability in mice. A recent study suggests a new mechanism underlying the role of ubiquitination in cancer (pages 227–234).

Noise-induced hearing loss is caused primarily by damage to auditory hair cells; however, humans are unable to regenerate damaged hair cells, necessitating the development of new therapeutic strategies to protect auditory hair cells. A new study suggests that the use of phosphodiesterase 5 (PDE5) inhibitors may provide a protective therapeutic route for hearing loss (pages 252–259).

A delicate balance: tweaking IL-2 immunotherapy Nature Medicine 18, 208 (2012). doi:10.1038/nm0212-208

Effective treatment for schizophrenia is still an unmet clinical need. Alleviating problems associated with cognitive impairment and finding the root of the disease remain priorities for clinicians and scientists. The incomplete understanding of the basis of this pathology has urged for research that will unravel the genetic origin of schizophrenia. But studies involving environmental exposure and social impact have also hinted at extrinsic factors as players in the pathogenesis of schizophrenia, which may be exploited to prevent the development of the disease. In 'Bench to Bedside', Patrick Sullivan proposes a model putting forward how genetic variants may confer risk by functioning together within the same pathway. This disease pathway hypothesis would imply a polygenetic variation affecting the same pathway and the alteration of a transcriptional network as a root for increasing schizophrenia risk. In 'Bedside to Bench', Andreas Meyer-Linderberg and Heike Tost discuss human-based population studies that suggest that environmental factors linked to development of schizophrenia can affect brain regions involved in the human social-emotional processing network. Genetic risk variants for schizophrenia can also influence similar regions in the brain, suggesting that environmental and intrinsic factors may converge in the same neural circuit.

Puzzling over schizophrenia: Schizophrenia, social environment and the brain Nature Medicine 18, 211 (2012). doi:10.1038/nm.2671 Authors: Heike Tost & Andreas Meyer-Lindenberg

Obesity: Is beige the new brown? Nature Medicine 18, 215 (2012). doi:10.1038/nm.2674 Author: Randy Levinson

Antimicrobials: Mycobacterial asymmetry Nature Medicine 18, 215 (2012). doi:10.1038/nm.2675 Author: Meera Swami

Inflammation: Burning up the brain Nature Medicine 18, 215 (2012). doi:10.1038/nm.2676 Author: Kevin Da Silva

Brain: Anxious about your meal? Nature Medicine 18, 215 (2012). doi:10.1038/nm.2677 Author: Carolina Pola

Pathogens have remarkable abilities to flout therapeutic intervention. This characteristic is driven by evolution, either as a direct response to intervention (for example, the evolution of antibiotic resistance) or through long-term co-evolution that generates host or parasite traits that interact with therapy in undesirable or unpredicted ways. To make progress towards successful control of infectious diseases, the concepts and techniques of evolutionary biology must be deeply integrated with traditional approaches to immunology and pathogen biology. An interdisciplinary approach can inform our strategies to control pathogens or even the treatment of infected patients, positioning us to meet the current and future challenges of controlling infectious diseases.

By modeling acquired resistance to the EGFR antibody cetuximab in metastatic colorectal cancer, the authors identify a new mutation in the ectodomain of the receptor. The mutation is present in patient tumors after cetuximab therapy, confirming that it represents a clinically-relevant mechanism for therapy resistance. Moreover, the mutation does not affect the response to other EGFR antibodies, suggesting that if independently confirmed it may be a useful indicator to tailor anti-EGFR therapy.

This report uncovers a direct link between cancer-driving inflammation and DNA methylation by showing that PGE2 regulates the expression of DNA methylases, resulting in silencing of tumor-suppressor genes. The authors suggest that DNA methylation is an important component of the pathogenic effect of inflammatory signaling in colorectal cancer.

The authors identify a new tumor suppressor role for Smurf2 that is linked to its regulation of histone modifications through RNF20. In the absence of Smurf2 in mice, and potentially also when its nuclear function is compromised in human tumors, higher levels of histone ubiquitination lead to a relaxation of chromatin structure, and alterations in DNA repair result in compromised genomic instability and increased tumorigenesis in aging mice. The findings suggest that loss of Smurf2 function may underlie tumor initiation by reshaping the epigenetic landscape of cells.

Cidea is typically thought of as a lipid droplet–associated cytoplasmic protein in brown adipose tissue. Peng Li and colleagues now show that it is also in the nucleus, and in mammary gland epithelial cells it acts as an essential transcriptional coactivator of C/EBPβ to regulate the expression of genes involved in milk lipid secretion during lactation.

Mutations in the type I ryanodine receptor (RYR1), a calcium channel, leads to stimulus-induced pathological muscle contractions, including malignant hyperthermia. Currently there are no pharmacological agents to protect against this condition, but Susan Hamilton and her colleagues have now identified AICAR as one possible candidate compound. To date, AICAR has been thought to be an AMPK activator, but her group shows that in a mouse model of malignant hyperthermia it does not target this kinase, but rather RYR1, to prevent improper calcium leakage and pathology.

Noise-induced hearing loss (NIHL) is a prevalent problem in the industrialized world. Now, Lukas Rüttiger and colleagues show that the phosphodiesterase inhibitor vardenafil can prevent NIHL in rats and mice.

Protective T helper 2 (TH2)-type responses are induced by parasite infection and can control inflammation and induce parasite expulsion. In this issue, Chen et al. report that in a mouse model of helminth infection, TH2-type responses protect against acute lung tissue damage by both suppressing inflammation and promoting macrophage-associated wound healing.

The ability of Mycobacterium leprae to upregulate miRNA-21 provides an effective mechanism for the pathogen to escape from the vitamin D–dependent antimicrobial pathway.

The role of T cells in modulating the course of influenza infection in humans is not clear. Wilkinson et al. now report that, in the absence of strain-specific humoral immunity, preexisting cytotoxic CD4+ T cells limit the severity and duration of symptoms in humans challenged with influenza virus and suggest these CD4+ T cell responses might be harnessed in vaccine development.

The Niemann-Pick C1–like 1 cholesterol uptake receptor is an entry factor for the hepatitis C virus, according to this report. Ezetimibe, a drug that targets this receptor and is approved for use in humans, inhibits infection by the hepatitis C virus in a mouse model, highlighting the therapeutic potential of this discovery.

Using mice with an amino substitution in the kinase PKG, a key regulator of blood vessel tone, Oleksandra Prysyazhna et al. provide evidence for the physiological importance of PKG oxidation and disulfide formation in maintaining normal blood pressure. These results clarify the nature of an enigmatic vasodilatory activity termed endothelium-derived hyperpolarizing factor and suggest that vascular oxidative stress can have blood pressure-lowering effects.

Tau aggregation is associated with neurodegenerative diseases called tauopathies. Ashley Bush and colleagues now report that aged tau-deficient mice develop motor and cognitive dysfunction that is linked to elevated iron levels in the brains of the mice.

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3) by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.

Kejia Cai et al. describe a method to non-invasively detect glutamate (Glu) concentrations in the brain with MRI at high resolution. The approach is based on the pH-dependent chemical exchange saturation transfer (CEST) effect between the amino group of Glu and bulk water and offers advantages over proton magnetic resonance spectroscopy. Feasibility of GluCEST was demonstrated in rat brain after middle cerebral artery occlusion stroke and in a rat brain tumor model, as well as in healthy human brain at 7 Tesla.

Zhang and colleagues have developed a new targeted delivery system for RNA interference–based bone anabolic therapy. Using dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine (AspSerSer)6, the system provided selective enrichment of the encapsulated osteogenic siRNA in osteogenic lineage cells at the bone formation surface and the subsequent depletion of the target gene, encoding the bone formation inhibitor casein kinase-2 interacting protein-1 (PLEKHO1, also known as CKIP-1), leading to the promotion of bone formation in healthy and osteoporotic rats.

Cell-surface glycans are known to alter as Barrett's esophagus progresses to adenocarcinoma, leading to specific changes in lectin binding patterns. Bird-Lieberman and her colleagues have exploited this knowledge to develop a new endoscopic approach that uses fluorescent-labeled lectins to visualize pre-cancerous, high-grade dysplastic lesions in Barrett's esophagus that cannot be detected by conventional endoscopy. The method uses commonly available endoscopic equipment, provides a wide field of view and is shown here in ex vivo esophageal tissue.

Morphine loses its ability to fight pain after chronic use. Now, Howard Gutstein and his colleagues report that morphine induces release of PDGF, and blockade of PDGFR signaling can reestablish morphine analgesic efficacy in rats that have become tolerant.

The authors report a new type of genetic alteration in lung adenocarcinoma. Fusions of KIF5B with RET kinase are found in 1–2% of lung cancer patients, segregate from other known alterations and can potentially be targeted using RET kinase inhibitors.

Using high-coverage targeted next-generation sequencing, this report provides a catalog of genetic alterations in colorectal and lung cancers, identifying previously unknown alterations, such as JAK2 mutations and KIF5B-RET fusions, that may represent druggable targets.

Through an integrated screening system, the authors catalog ALK and ROS1 fusions in lung cancer and identify a new class of fusions involving KIF5B and RET that may represent new therapeutic targets in adenocarcinoma.

TGF-β signaling is commonly aberrantly activated in gliomas and other tumors and can exert a pro-oncogenic function. The authors identify a new mechanism for upregulation of TGF-β signaling in cancer. The deubiquitinase USP15 is shown to be able to bind the TGF-β receptor complex, counteract its degradation and potentiate its stimulation of downstream mediators. USP15 is amplified in human glioblastoma and could represent a therapeutic target, as its downregulation impairs the growth of glioblastoma cells in vivo.

The insulin signaling pathway regulating glucose homeostasis that has been well accepted is insulin to insulin receptor to IRS proteins to PI3K to Akt to Foxo1—a pathway that does not respond properly in states of insulin resistance, including type 2 diabetes. In a new study from Morris Birnbaum and colleagues, an alternative insulin signaling pathway has been uncovered, as mice with liver-specific deletion of Akt and Foxo1 still respond normally to nutritional cues and properly regulate glucose metabolism. Although the exact nature of this alternative pathway needs to be identified, the results should open many new avenues of exploration in the field of type 2 diabetes.

In a new study, Yasuhiro Kobayashi and his colleagues show that noncanonical Wnt signaling regulates balanced osteoblast-induced osteoclastogenesis during normal physiology and that this pathway is perturbed in pathophysiological states, such as rheumatoid arthritis. These results explain further how osteoblasts cross-talk with preosteoclasts to ensure matched bone resorption with bone formation during skeletal homeostasis in the adult and also suggest a new target to treat arthritis.

BMP7 has been previously shown to protect against renal fibrosis. Raghu Kalluri and his colleagues have now identified activin-like kinase 3 (Alk3) as the key co-receptor for BMP7 in the kidney and have identified an orally available, small-peptide agonist of Alk3 that reduces established fibrosis in five animal models of kidney injury.

Antiretroviral drug combinations for the treatment of HIV-1 infection have been determined on the basis of clinical trial outcomes, but without clear insight into why certain combinations are superior to others. Robert Siliciano and his colleagues present a quantitative basis for determining efficacious antiretroviral drug combinations.

Neuromuscular disease is often marked by insufficient neural activation of muscle activity, resulting in muscle weakness. Fady Malik and colleagues have developed an orally available small molecule that sensitizes muscles to neural activity by reducing the off rate of calcium binding to troponin C. They validate the therapeutic potential of this drug in vivo in a rat model of myasthenia gravis and show that treatment improves grip strength by 50%.

Targeting mesenchymal stem cells (MSCs), progenitors of osteoblasts, to bone has been a long-standing goal but has had limited success so far. Here, Min Guan and her colleagues deliver a peptidomimetic integrin ligand against integrin α4β1 conjugated to the bone-seeking agent bisphosphonate alendronate as a means of attracting infused and/or endogenous MSCs to the bone surface to stimulate bone formation. The approach was tested in both xenotransplantation and immunocompetent mice, as well as in mouse models of trabecular bone loss induced by aging and estrogen deficiency (ovariectomy).

Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) in the majority of people with grade 2 and 3 gliomas is associated with elevated levels of 2-hydroxyglutarate (2HG) within the tumor. As harboring IDH1 or IDH2 mutations confers a considerable survival benefit in these individuals, there has been considerable interest in studying this metabolite as a potential biomarker. Here, Changho Choi et al. report the successful noninvasive detection of 2HG in 30 subjects with gliomas using a proton magnetic resonance spectroscopy approach.