Volume 17 Issue 4, April 2011

It was announced last month that Seth Berkley, who founded and heads the International AIDS Vaccine Initiative (IAVI), will take over the helm of the GAVI Alliance in August. Berkley, an epidemiologist who previously held jobs with the Rockefeller Foundation, the Carter Center and the US Centers for Disease Control and Prevention, has witnessed ups and downs in the vaccination field, from the disappointing STEP trial in 2007 to the more recent good news from the 2009 Thai study, which reported as much as 31% protection against HIV. Roxanne Khamsi spoke with Berkley about what he has learned in his quest for a preventative shot against AIDS.

Genetic mutations are usually the source of debilitating disease. But, for a number of rare inherited blood and skin disorders, spontaneous DNA changes can repair and even reverse disease symptoms. Mike May explores the therapeutic potential of this 'natural gene therapy'.

A surprising percentage of people with autism also suffer from seizures, but doctors have been baffled by this overlap for decades. Now, various groups of scientists have begun exploring how the same genetic risk factors and aberrations in nerve signaling in early brain development might underlie both these disorders. Marissa Miley reports on how solving this riddle could point to better treatments for epilepsy and autism.

The do-it-yourself biology movement has exploded in recent years, culminating in the formation of the world's first community laboratory, opened late last year. As this grassroots effort continues to grow, professional biomedical researchers stand to benefit from partnering with the legions of garage biotechnology enthusiasts.

Alum is the most widely used vaccine adjuvant, but its mechanism of action remains largely unknown. A recent study shows that alum interacts directly with membrane lipids on the surface of dendritic cells, triggering signaling cascades that promote CD4⁺ T cell activation and humoral immune responses (pages 479–487).

A new study shows how SRC, a nonmembrane tyrosine kinase, is a common signaling node in trastuzumab resistance caused by different mechanisms in HER2-positive breast cancers (pages 461–469). A SRC inhibitor restored trastuzumab sensitivity in vitro and in mouse tumor models, suggesting a new way to tackle drug resistance in breast tumors.

By the time diabetes is diagnosed, irreversible pathology is typically present, challenging therapeutic intervention. A reliable test for predicting diabetes risk could allow earlier implementation of intervention measures. Increased blood concentrations of amino acids are now suggested to predict risk of diabetes (pages 448–453), and amino acid profiling might also provide mechanistic insights into this disease.

Retinoic acid receptors inhibit chondrogenesis, but their ability to block the cartilaginous scaffold of heterotopic endochondral ossification has not been explored. A study in mice shows that agonists of retinoic acid receptor-γ potently inhibit heterotopic endochondral ossification, suggesting therapeutic potential in people with this condition (pages 454–460).

A new potential breast cancer oncogene, ZNF703, has been identified in the chromosomal region 8p12 in humans, which is commonly amplified in an aggressive subtype of breast cancer. ZNF703 is a transcriptional repressor and regulates many genes that are involved in multiple aspects of the cancer phenotype, such as increased proliferation, invasion and an altered balance of progenitor stem cells.

Axonal damage causes neurological defects in multiple sclerosis. In vivo imaging in mouse models of multiple sclerosis now shows a reversible and sequential process of focal axonal degeneration (FAD) (pages 495–499), suggesting the use of neuroregenerative as well as neuroprotective drugs as potential therapies for multiple sclerosis.

A new study shows that a candidate schizophrenia pathway, neuregulin-1–ErbB4 signaling, inhibits Src-mediated enhancement of synaptic N-methyl-D-aspartate receptor (NMDAR) function (pages 470–478). These results suggest that Src can have a pivotal role in NMDAR hypofunction in schizophrenia and thus might have potential therapeutic implications for this complex neuropsychiatric disorder.

Bone is an endocrine organ that reaches out to other tissues, orchestrating responses that may have a role in pathology and physiology at distant sites. In 'Bench to Bedside', L. Darryl Quarles discusses recent studies showing how a feedback loop between the bone hormone FGF-23 and renal phosphate excretion and vitamin D metabolism is integrated with the classical PTH–vitamin D axis in chronic kidney disease (CKD). This new paradigm may change the diagnosis and treatment of disordered mineral homeostasis of people with CKD. A recent epidemiological study argues a mechanistic link between bone loss and atherosclerosis, maladies usually linked to aging. In 'Bedside to Bench', Sundeep Khosla discusses how this clinical study underpins research showing that mediators of inflammation and oxidative stress share common mechanisms that may lead to this calcium shift during aging.

Brain injury, subarachnoid hemorrhage and the subsequent delayed ischemic stroke show spreading depolarization of neurons in the tissue at risk, where it leads to spreading ischemia, vasoconstriction and brain electrical silencing, exacerbating damage and thwarting recovery. Jens Dreier reviews the underlying molecular mechanisms and the potential use for clinical diagnosis and therapies aimed at blocking spreading depolarization and boosting vasodilation to treat neurological disease.

Amino acid profiles could aid in diabetes risk assessment, as a five-amino-acid signature had highly significant associations with the development of future diabetes in two large, independent cohorts.

Heterotopic ossification is the conversion of soft tissue into bone, usually after surgery or trauma but also as a result of the genetic disease fibrodysplasia ossificans progressiva. Masahiro Iwamoto and his colleagues have now shown that retinoic receptor-γ agonists ameliorate this condition in mouse models.

This report uncovers that activation of Src lies downstream of multiple trastuzumab-resistance–driving pathways. The authors show that Src, a major mediator of PI3K and IGFR resistance pathways, also drives resistance caused by PTEN loss, revealing that Src is directly dephosphorylated by PTEN. Src inhibition can overcome de novo and acquired trastuzumab resistance, suggesting a potential therapeutic strategy broadly applicable in breast cancer.

Schizophrenia has been associated with overactive neuregulin signaling and with glutamatergic synaptic hypoactivity. Now, in brain slice culture experiments, Michael Salter and his colleagues show that neuregulin signaling interferes with Src-induced activation of glutamatergic synaptic activity.

Alum has long been used as a vaccine adjuvant, yet the mechanisms by which it increases antigen-specific immune responses remain unclear. Flach et al. now report that alum interacts with lipids in the plasma membrane of dendritic cells, resulting in nonphagocytic uptake of antigen and increased association with CD4⁺ T cells. These results suggest that, at least for dendritic cells, lipids rather than proteins may sense alum and trigger downstream signaling events that lead to enhanced T cell responses.

Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that is involved in retinal development and neural tube closure. Toshihide Yamashita and colleagues describe a previously unrecognized role for RGMa in the immune system. Blockade of RGMa attenuates clinical symptoms of experimental autoimmune encephalomyelitis and reduces T cell proliferation and cytokine release. These results suggest a possible new therapeutic target for multiple sclerosis.

Axonal degeneration is a hallmark of multiple sclerosis, but it remains unclear what triggers degeneration. By monitoring the development of axonal damage in a mouse model of multiple sclerosis, Ivana Nikić et al. describe a new variant of axonal degeneration. Axonal damage is present in myelinated axons and is reversible using scavengers of reactive oxygen and nitrogen species, thereby suggesting that early stages of degeneration may be amenable to therapeutic intervention.

This report describes the identification of three molecularly distinct subtypes of pancreatic ductal adenocarninoma (PDA). The classical, quasimesenchymal and exocrine subtypes can further stratify tumors with the same genetic alterations, and could be useful to improve prognosis and predict treatment response.

Kristoffer Weber et al. describe a new lentiviral vector-mediated RGB (red, green and blue) multicolor cell marking technique for analyzing clonal cell fates in vitro and in vivo. Here they use RGB marking to assess clonality after regeneration of injured livers by transplanted primary hepatocytes, to mark hematopoietic stem/progenitor cells and to assess the clonality of tumor cells. The approach can potentially be adapted to various cell types and other vector systems.

Noninvasive testing for Down's syndrome (trisomy 21) would greatly reduce the risks associated with the more invasive techniques used currently. Earlier identification of differentially methylated regions between fetal DNA and maternal peripheral blood has now enabled Elisavet Papageorgiou and her colleagues to develop a strategy involving methylated DNA immunoprecipitation in combination with real-time quantitative PCR that discriminates normal from trisomy 21 cases in maternal peripheral blood with high sensitivity.