Cleavage of amyloid precursor protein (APP) by β- and γ-secretases into neurotoxic β-amyloid peptides is believed to play a leading role in the development of Alzheimer’s disease, although clinical proof of this hypothesis remains elusive. Researchers at Genentech and the Salk Institute have now discovered a new pathway by which APP could contribute to the development of Alzheimer’s disease. The researchers propose that interaction of an N-terminal extracellular domain of APP (N-APP) with death receptor 6 (DR6) triggers widespread caspase-mediated neuronal destruction and axonal pruning. DR6 is expressed by developing neurons and, together with APP, plays a key role in remodelling the embryonic brain during development by triggering apoptosis in neurons and pruning axons that fail to make productive connections. Axonal pruning was found to require caspase 6 whereas cell body apoptosis requires caspase 3.

Although the team has yet to demonstrate that N-APP causes Alzheimer’s disease and the mechanism underlying reactivation of the pruning process in adults is, as yet, unknown, the discovery identifies several new potential targets for the treatment of Alzheimer’s disease. The study does not rule out a role for β-amyloid peptides in the pathogenesis of Alzheimer’s disease but suggests that blocking the action of N-APP on DR6, either directly or via downstream pathways, may also provide benefit.

The study is published in the February 19^th advanced online issue of the journal Nature.

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β₂-Adrenergic receptor agonists, which act directly on smooth muscle in the airways causing dilation and increased air flow, are standard therapy for treating bronchospasm in asthmatics. Both short- and long-acting agonists are used in the management of asthma, although there are increasing concerns that chronic use of β₂-agonists is associated with loss of disease control and may increase mortality in asthmatics. A study published in the journal PNAS has now shown that β₂-adrenergic receptor inverse agonists reduce symptoms in an allergen-driven mouse model of asthma.

Although acute inhibition of β₂-adrenergic receptor signalling narrows the airways, long term administration of a β₂-inverse agonist caused similar improvements in asthma symptoms to genetic knock-out of the receptor. The researchers also found that chronic administration of alprenolol, a β-blocker without inverse agonist properties, did not reduce the symptoms, suggesting that basal signalling by empty receptors, rather than agonist-induced signalling, causes asthma. Whereas chronic exposure to β₂-agonists leads to receptor down-regulation and worsening of asthma control, chronic blockade of the receptors may result in up-regulation and better control. Small scale clinical trials are being carried out to assess the effect of chronic dosing with the non-selective β-blocker, nadolol, in asthmatic patients.

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Organ transplants save many lives annually, but transplant patients must take immunosuppressive drugs to prevent rejection of the new organ or cells. Two reports now provide new insights into the mechanisms of rejection. Researchers at the University of North Carolina at Chapel Hill School of Medicine and the UNC Lineberger Comprehensive Cancer Center looked at the mechanism of graft-versus-host disease (GVHD), a common but serious complication of bone marrow transplantation in which functional immune cells in the transplanted marrow mount an attack on organs of the recipient, most often the skin, gastrointestinal tract and liver. Interferons had initially been thought to be involved in triggering GVHD, but several studies showed that blocking the action of interferons actually exacerbated the disease. The authors of the present study, which is published in the journal Blood, showed that blocking the action of interferons resulted in a large increase in the number of a specific subset of T-lymphocytes, TH17 cells. When purified TH17 cells were transplanted into mice, they caused a GVHD-like response, with the most severe damage to the lungs and skin. The researchers went on to link the skin damage to production of IL17 and other cytokines and that of other tissues to production of TNF-α. The authors hope that their findings will allow the development of new treatments for GVHD which do not have the harmful side effects of traditional immunosuppressive therapy.

A second report, by scientists at the Johns Hopkins University School of Medicine adds to the mounting evidence linking the activity of blood platelets to organ rejection. When transplants are rejected, platelets line up in the interior of the blood vessels supplying the transplanted tissue and then recruit and activate immune cells to attack the transplanted organ. Treatments aimed at subduing platelet activity could play a role in managing chronic rejection – a major complication for which there is little treatment at present. Craig Morrell, from Johns Hopkins, is author of a comprehensive review of platelets and transplant biology published in the American Journal of Transplantation.

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Although the use of embryonic stem cells is controversial and hotly debated from both sides, many researchers believe that these cells offer the promise of revolutionary treatments for a wide variety of diseases and injuries, including spinal cord injuries and degenerative diseases.

Embryonic stem cells are derived from the inner cell mass of an early stage embryo and are pluripotent, meaning that they are able to differentiate into any of the more than 200 cell types that make up the human body. For their full potential to be realised, it is important to maintain this pluripotency whilst growing them in cell culture. Glycogen synthase kinase 3 (GSK-3) had previously been implicated as a regulator of both self-renewal and differentiation, and a study published in the journal Chemistry and Biology now clarifies the role of GSK-3 in murine embryonic stem cell development by showing that inhibitors of GSK-3 enhance self-renewal in the presence of serum and leukaemia inhibitory factor. The authors propose that, by inhibiting GSK-3 activity in the appropriate cell culture environment, it will be possible to more easily obtain large numbers of undifferentiated, pluripotent, cells for medical use. Once the inhibitor is removed from the cell culture medium, it is possible to induce the stem cells to differentiate into the chosen type of specialised cells.

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Traditionally, prescribing has been on a one-size-fits-all basis, with standardised doses of medicines given to all patients. Personalised medicine offers the promise of more effective therapy with fewer side effects by better understanding the genetic causes of disease and different individual reactions to drug treatment. Genetic variants in the genes encoding the cytochrome p450 enzymes, which activate or degrade many commonly used drugs, are increasingly being linked to variations in response to medicines. Separate reports by Collet et al, Mega et al and Simon et al highlight the importance of CYP2C19 polymorphisms in responsiveness to clopidogrel, an oral antiplatelet agent that is commonly prescribed after heart attacks to reduce the likelihood of subsequent cardiovascular events. Clopidogrel is a pro-drug that is inactive until it is metabolised in the liver by cytochrome P450 enzymes, including CYP2C19. All studies found that individuals with loss-of-function variants of CYP2C19 were more likely to die or experience major adverse cardiovascular events than individuals with fully functional CYP2C19.

The FDA and the International Serious Adverse Events Consortium have also recently released the first data on the genetics associated with serious drug-induced skin rashes, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Understanding which patients are likely to suffer severe reactions to commonly prescribed drugs should reduce the incidence of these life-threatening conditions.

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Inappropriate activation of PKC isozymes has been implicated in many forms of cancer and researchers at the Mayo Clinic, Florida Campus, have been elucidating the roles of the isozymes in colon carcinoma using transgenic mice. Their earlier studies, reported in the January 15^th issue of Cancer Research, demonstrated a requirement for PKC-βII in the initiation of colon cancer in mice exposed to a carcinogen. The same study also showed that PKC-ι/λ was required for cancer progression.

Now the scientists have shown that daily administration of the selective PKC-β inhibitor, Enzastaurin, provides a degree of protection to mice administered a carcinogen known to cause colon tumours. Since colon cancer develops over a 10-15 year period in humans, there is a large window of opportunity for the use of chemopreventative drugs. The authors suggest that Enzastaurin could represent a good candidate for clinical study in this setting because it has few side-effects.

Enzastaurin is currently in Phase III clinical trials for the treatment of B-cell lymphoma and high-grade brain gliomas. Although Enzastaurin is selective for PKC-β, it also significantly inhibits other PKC isozymes.

The full study with Enzastaurin is published in the February 15^th issue of Cancer Research.

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Membrane proteins, which make up around one third of the proteome, perform a wide variety of biological functions and are important drug targets, but crystallisation and structural and functional analysis have so far proved challenging. A study published in the journal PNAS which describes the use of amphipathic polymers (“amphipols”) to replace the lipid membrane may provide a generalised method of stabilising and immobilising membrane proteins in their native state. The amphipol can be used to attach the functional protein to almost any type of solid support, including chips and beads. Amphipols are short soluble polymers with many hydrophobic side chains by means of which they are able to associate with the transmembrane domain of proteins, thereby maintaining water solubility without the use of detergents. Although non-covalent, the association is irreversible unless another surfactant is added.

The authors suggest that amphipol-mediated immobilisation of membrane proteins represents a significant improvement over existing methodologies and demonstrated the generality of the approach by immobilising proteins from several different sources onto supports suitable for either label-free or fluorescence-based ligand binding studies. Although the possibility of amphipol interference with ligand binding cannot be completely ruled out, it is seen as unlikely to be a serious problem in most cases.

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Sigma-1 receptors are widely distributed throughout the body, especially within some areas of the brain, and have been linked to a number of pharmacological activities. Although the endogenous ligand for the sigma-1 receptor had not been identified, synthetic agonists have been linked to beneficial effects on cognition and learning, whilst antagonists have been shown to be effective in some models of pain and to induce apoptosis in susceptible cell types.

Scientists have long been searching for naturally occurring ligands for the sigma-1 receptor and a team led by researchers at the University of Wisconsin has now identified a component of plants traditionally used in shamanic rituals in South America as a natural ligand. The active ingredient, N,N-dimethyltryptamine (DMT), is hallucinogenic and also occurs naturally in the body. Although its function is not understood, higher levels have been found in the urine of schizophrenics. Biochemical, physiological and behavioural studies proved that DMT acts as an agonist of the receptor and, although it is not known whether the sigma-1 receptor is connected to the hallucinogenic activity of DMT, the authors hope that their discovery could have implications for the treatment of drug abuse and depression. The study is published in the February 13^th issue of the journal Science.

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Available treatments for Alzheimer’s disease offer relatively small symptomatic benefits and more effective treatments are much needed. β-Amyloid has been implicated in the pathogenesis of Alzheimer’s disease and much attention has focussed on inhibiting two enzymes responsible for production of this peptide, the β- and γ-secretases. Although potent inhibitors of both enzymes have been identified, achieving robust activity in animal models and progression to clinical studies has proved more challenging. Using a high-throughput functional genomics screen, scientists at VIB and Galapagos Pharmaceuticals have now identified a constitutively expressed orphan G protein-coupled receptor, GPR3, as another modulator of β-amyloid production. GPR3 is highly expressed in areas of the brain associated with Alzheimer’s disease and levels are elevated in brain tissue from people with sporadic Alzheimer’s disease. The researchers showed that blocking GPR3 prevented accumulation of β-amyloid, both in cell culture experiments and in a mouse model of Alzheimer’s disease.

Since G protein-coupled receptors have been relatively easy to exploit as drug targets, the scientists hope that GPR3 will prove to be a promising target for the treatment of Alzheimer’s disease.

The study is published in the February 13^th issue of the journal Science.

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Although prostate cancer is one of the most common types of cancer in men, it occurs most frequently after the age of fifty and many men who have the disease will eventually die of other causes without ever being diagnosed. Prostate cancer is most often discovered by prostate specific antibody (PSA) tests but, since relatively low levels of antibody are found in some men with prostate cancer and elevated levels can be found in other prostate conditions, the use of screening is controversial. Prostate cancers are, in most cases, slow-growing and the decision whether or not to treat a localised tumour is a trade-off between the expected beneficial and harmful effects of treatment in terms of patient survival and quality of life. In men who are being treated for prostate cancer, however, PSA is invaluable as a ‘tumour marker’ to assess response to therapy and monitor progression of the disease.

Two new biomarkers have recently been described which may improve the diagnosis of prostate cancer and – importantly – distinguish more aggressive forms of the disease so that patients can make more informed decisions about treatment.

The first study, by researchers at the University of Michigan Medical School and published in the February 12^th issue of the journal Nature, showed that levels of sarcosine (N-methyl glycine) were elevated in the urine of men with prostate cancer, particularly those with more aggressive disease. In cell culture experiments, sarcosine was also found to help prostate cancer cells invade surrounding tissues. Along with sarcosine, levels of a number of other metabolites were found to be elevated dramatically during progression from benign tissue to localised cancer to metastatic disease. The team hopes that measuring levels of sarcosine alone, or with other metabolites, could provide a better indicator of likely disease progression.

The second study, described in the February issue of the journal Cancer Epidemiology, Biomarkers & Prevention shows that men with elevated levels of total – and particularly ionised – calcium in their blood have an increased risk of fatal prostate cancer.

The introduction of tests which give a better indication of which individuals will go on to develop an aggressive form of prostate cancer would allow men to make better informed decisions about when, or whether, to begin treatment.

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