Volume 18 Issue 4, April 2012

Since inception of the Malaria Vaccine Initiative (MVI) in 1999, the Washington, DC–based initiative has played an instrumental part in advancing a number of leading vaccine candidates, including RTS,S, the first to show clinical efficacy in a major phase 3 trial. Steering the ship in the next phase of the journey is David Kaslow, who spoke with Roxanne Khamsi about how his experience in the public and private sectors will help inform his decisions in the nonprofit world.

The long wars in Afghanistan and Iraq have created greater awareness of post-traumatic stress disorder, a condition in which people relive the agony of past events over and over again. Preliminary evidence has hinted that medicines currently used to treat high blood pressure or to terminate pregnancy might help treat PTSD by erasing painful memories. Cassandra Willyard looks at whether repurposing these drugs will work or whether experimental compounds being tested in rats might offer a more promising solution.

In the US, states anxious to establish genetic rights are acting in the absence of clear, informed leadership. The result is specious legislative language and conflicting proposals that create confusion and disrupt genetic research and healthcare activities. It's time to look beyond our state and national borders for guidance.

Vitamin E is commonly taken as a dietary supplement because it has been shown to have cardioprotective effects. However, its effects on bone metabolism are unknown. A new study in mice shows that α-tocopherol, the main isoform of vitamin E, stimulates bone osteoclast fusion independently of its antioxidant activity, resulting in increased bone resorption (pages 589–594).

Changes in gut microbial composition have been linked to inflammatory bowel disease, obesity and allergies in humans. A new study shows that pattern recognition of commensal bacteria by B cells reduces allergic inflammation in mice, adding to the mounting evidence for the 'hygiene hypothesis' (pages 538–546).

Cancer genome sequencing projects focus exclusively on the discovery of somatic changes. A new study shows that germline alterations in the proapoptotic protein BIM can have a crucial role in how a tumor responds to treatment (pages 521–528).

A recent study provides new insights into the central control of energy balance and obesity, showing that feeding behavior in mice can be modulated by local dendritic translation of a key protein in neuronal plasticity brain-derived neurotrophic factor (pages 564–571).

Liver injury promotes the outgrowth of cell types that are relatively rare in healthy livers, including progenitors and stromal cells. A new study shows that the type of injury influences the cellular composition of the liver progenitor niche, which then seems to direct the fate of progenitors during regeneration (pages 572–579).

Addiction to drugs of abuse, such as cocaine, remains a clinical and social problem, in part owing to the lack of effective treatment. The challenges of coping with addiction extend to the bench, pulling researchers to continue exploring the origins of addiction and the molecular and structural changes in the brain driving lack of self-control and impulsivity in people suffering from addiction or relapses. But what triggers these brain alterations has not been fully elucidated, and addiction animal models showing disparate outcomes have puzzled researchers. An assumed paradigm poses that brain changes during addiction result from chronic drug use. In 'Bedside to Bench,' Peter W. Kalivas and Kathleen Brady examine a clinical study that counters this model, suggesting that pathological brain alterations involved in cocaine addiction may also be inherited, contributing to addiction vulnerability. The implications for future preclinical studies and clinical care are numerous. But the controversy surrounding addiction also reaches the molecular level. In 'Bench to Bedside,' Marisela Morales and Antonello Bonci peruse a study in mice showing that activation of brain cannabinoid receptor 2—thought to have no effect on addiction owing to its scarcity in the brain—attenuates effects of cocaine use, including rewarding and locomotor stimulation. This may open the door to the development of selective drugs to treat cocaine addiction.

Intrinsic resistance to tyrosine kinase inhibitor (TKI) drugs is limiting the progress of targeted cancer therapies. The efficacy of TKIs relies on their inhibition of oncogenic signaling but also on the induction of apoptosis in cancer cells, driven by activation of pro-apoptotic BIM proteins. The authors identify a germline BIM polymorphism common in East Asian individuals that switches BIM splicing, eliminating the BH3 domain responsible for apoptosis induction. The polymorphism provides resistance to TKIs, such as BCR-ABL inhibitors in chronic myeloid leukemia and EGFR inhibitors in non–small-cell lung cancer samples, and drug sensitivity can be reinstated by addition of BH3-mimetic drugs. The polymorphism predicts treatment responses and outcome in East Asian patients with leukemia and lung cancer and could provide useful guidance for therapeutic implementation.

The authors uncover a role for the tyrosine phosphatase SHP2 in the propagation and maintenance of breast cancer tumor initiating cells. This role of SHP2 contributes to the growth and metastasis of tumors in vivo and is mediated by a newly uncovered downstream pathway that, through regulation of ERK, modulates the activity of transcription factors such as ZEB1 and Myc, also affecting microRNAs such as let-7. A genetic signature of SHP2 activation is indicative of increased aggressiveness in human breast cancers.

Alterations in commensal bacteria are associated with an increased risk of allergic disease. David Artis and his colleagues now report that commensal-derived signals influence basophil development and T_H2 cytokine–dependent allergic airway inflammation by suppressing serum IgE levels. Individuals with hyper IgE syndrome also have elevated circulating basophil numbers, suggesting a mechanistic link between commensal bacteria, B cell–mediated production of IgE and basophil hematopoiesis.

IL-17 is associated with asthma, and T_HH17 cells are found in the airways of individuals with asthma. Dean Sheppard and his colleagues now report that IL-17A (but not IL-17F) directly enhances contractile responses in airway smooth muscle cells. Mice lacking T_H17 cells in the lungs exhibit reduced airway hyper-responsiveness in response to allergen challenge.

In human leprosy, a dendritic cell differentiation pathway that depends on interleukin-32 and is induced by NOD2 represents a novel mechanism of host defense against infection.

Leptin and BDNF are two protein cytokines known to inhibit food intake. Baoji Xu and colleagues have now shown that leptin-mediated inhibition of food intake is dependent on leptin binding to one set of hypothalamic neurons, which results in neuronal activation of other hypothalamic neurons to increase the dendritic expression of BDNF in those targeted neurons. These results show a new functional link between these two anorexigenic cytokines and how leptin signaling is propagated to regulate food intake.

Hepatic precursor cells (HPCs) are known to be bipotent and to give rise to both new hepatocytes and cholangiocytes upon acute liver injury. Stuart J. Forbes and his colleagues now show that interactions of HPCs with local macrophages and myofibroblasts potentiate Wnt and Notch signaling, respectively, to determine fate specification of the HPCs. Together, these mechanisms help determine proper organ regeneration after liver injury.

HIV infection is often associated with severe nephropathy, including renal fibrosis. John He and his colleagues have used a systems biology approach in a mouse model of HIV infection to identify the key factors involved in this process, thus identifying the kinase HIPK2 as one such factor. They also show that HIPK2 genetic deletion prevented renal fibrosis in two other mouse models, suggesting this kinase has a general role in the fibrotic process.

Vitamin E has long been proposed to favor bone growth owing to its antioxidant properties. This study shows instead that, by promoting osteoclast fusion, vitamin E decreases bone mass.

Individual variation in pain sensation makes pain clinical trials quite challenging to interpret. Now, Michael Salter and colleagues report that genetic variation in the P2RX7 gene affects pore formation of the protein and pain sensation in humans.

Enteric neuron death is linked to the pathogenesis of inflammatory bowel disease. Now, Brian Gulbransen and his colleagues demonstrate that P2X7 receptor–pannexin-1 signaling is responsible for enteric neuron death in mouse models of colitis.

Drugs that induce redifferentiation of cancer cells are efficient only in some subtypes of AML. The authors show that sensitivity to pro-differentiation drugs such as ATRA can be induced by co-treatment with epigenetic drugs. An inhibitor of histone demethylase, LSD1, safely used as an antidepressant in humans, reprograms AML cells and makes them sensitive to the effects of ATRA in vitro and in vivo, suggesting that epigenetic interventions can increase response to cancer treatments.

Dysregulated hepatic glucose production (HGP) is a key feature of type 2 diabetes (T2D). Masato Kasuga and his colleagues now show that under physiological conditions, the expression and activity of the protein CITED2 in the liver is altered in response to hormonal cues that regulate HGP. They also show in a mouse model of T2D that hepatic CITED2 expression is elevated and that its genetic knockdown reduces serum glucose concentrations, suggesting this protein as a possible therapeutic target in the clinic.

Building on their recent work establishing long-term cultures from Lgr5⁺ cells of the small intestine and stomach, Shiro Yui and colleagues describe a new colonic stem cell culture and expansion method generating organoids from single Lgr5⁺ stem cells. The study provides proof of principle that the cultured Lgr5⁺ cells can be used for stem cell therapy to repair superficially damaged epithelium in a dextran sulfate sodium (DSS)-induced acute colitis mouse model.

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.