Cooling atoms, particles and polarisable objects using dissipative dipole forces

Optical cooling methods are generally applicable to a very restricted range of species. As a means of overcoming this problem, we explore the effect of the retarded interaction of any polarisable particle (an atom, a molecule or even a micromirror) with itself, similarly to cavity-mediated cooling. We use the transfer matrix method, extended to allow us to handle moving scatterers, to explore the most general configuration of a mobile particle interacting with any 1D combination of fixed optical elements. Remarkably, this model allows a solution in closed form for the force acting on the particle, without any a priori restriction on the nature of the particle.peer-reviewe

Mitochondrial respiration - an important therapeutic target in melanoma

The importance of mitochondria as oxygen sensors as well as producers of ATP and reactive oxygen species (ROS) has recently become a focal point of cancer research. However, in the case of melanoma, little information is available to what extent cellular bioenergetics processes contribute to the progression of the disease and related to it, whether oxidative phosphorylation (OXPHOS) has a prominent role in advanced melanoma. In this study we demonstrate that compared to melanocytes, metastatic melanoma cells have elevated levels of OXPHOS. Furthermore, treating metastatic melanoma cells with the drug, Elesclomol, which induces cancer cell apoptosis through oxidative stress, we document by way of stable isotope labeling with amino acids in cell culture (SILAC) that proteins participating in OXPHOS are downregulated. We also provide evidence that melanoma cells with high levels of glycolysis are more resistant to Elesclomol. We further show that Elesclomol upregulates hypoxia inducible factor 1-α (HIF-1α), and that prolonged exposure of melanoma cells to this drug leads to selection of melanoma cells with high levels of glycolysis. Taken together, our findings suggest that molecular targeting of OXPHOS may have efficacy for advanced melanoma. © 2012 Barbi de Moura et al

Developing new antidotes for poisons with existing effective treatments: a case study of fomepizole in paracetamol poisoning

Introduction: Acetylcysteine is the only effective and licensed therapy for paracetamol poisoning. However, acetylcysteine loses efficacy if treatment is delayed 8–12 hours after paracetamol ingestion, and there is also uncertainty as to whether the dose should be increased in high-risk paracetamol ingestions. Studies have identified potential therapeutic targets, including enzymes that metabolize paracetamol; the pathways causing mitochondrial toxicity via c-Jun N-terminal kinases or superoxide generation; and other specific targets, such as nuclear factor-erythroid factor 2-dependent gene induction and autophagy. With this range of potential additional therapies, how should the speciality of clinical toxicology approach the development of new antidotes for this common poisoning? Historical background: When the first treatments for paracetamol toxicity were developed, the clinical trial and ethical basis of practice were different from today. Acetylcysteine was never subjected to placebo-controlled studies, even by the United States Food and Drug Administration, as it was presumed that the toxicity of high paracetamol concentrations was so evident that placebo-controlled studies were unethical. Thus, the absolute benefit of acetylcysteine remains unknown. In addition, no dose-ranging studies of acetylcysteine in patients were ever done. The weakness of assessing the efficacy of additional antidotes in small groups of patients with moderate poisoning is illustrated by the use of cimetidine in paracetamol poisoning. Current approaches to drug (and antidote) development: The approach required by regulatory authorities today relies on several important steps. First, a clear target for therapeutic effect is sought, normally in a laboratory model. Next, a ‘proof of principle’ study is required to demonstrate that the target is ‘druggable’. Finally, clinical studies to confirm proof of principle applies in humans, followed by a controlled trial with matched patient groups with sufficient power to demonstrate the clinical outcome being sought. Such patient studies can be expensive to conduct, and non-commercial groups suffer the risk of not being funded. Fomepizole: Fomepizole prevents paracetamol-induced hepatic toxicity in mice by inhibiting cytochrome P4502E1, thereby preventing the conversion of paracetamol to its toxic metabolite. Fomepizole also inhibits c-Jun N-terminal kinases, a key pathway in the downstream toxicity on the mitochondria. The present evidence of efficacy in humans is based on small case series with no control groups. The availability of a licensed indication has facilitated off-label use of fomepizole in an unproven indication. Conclusions: Paracetamol poisoning is common, and randomized, controlled clinical trials are possible. The benefit of fomepizole can only be shown by such a study. As clinical trials using fomepizole as an added therapy to acetylcysteine are recruiting in the United States, these should be supported by all clinical toxicologists. In the interim, the publication of small case series using fomepizole should be discouraged by journals.</p

New Formulation of Paraquat: A Step Forward but in the Wrong Direction?

The author discusses whether the new paraquat formulation introduced in Sri Lanka is a step forward in reducing deaths from paraquat self-poisoning

Solution structure of the inner DysF domain of myoferlin and implications for limb girdle muscular dystrophy type 2b

Mutations in the protein dysferlin, a member of the ferlin family, lead to limb girdle muscular dystrophy type 2B and Myoshi myopathy. The ferlins are large proteins characterised by multiple C2 domains and a single C-terminal membrane-spanning helix. However, there is sequence conservation in some of the ferlin family in regions outside the C2 domains. In one annotation of the domain structure of these proteins, an unusual internal duplication event has been noted where a putative domain is inserted in between the N- and C-terminal parts of a homologous domain. This domain is known as the DysF domain. Here, we present the solution structure of the inner DysF domain of the dysferlin paralogue myoferlin, which has a unique fold held together by stacking of arginine and tryptophans, mutations that lead to clinical disease in dysferlin

A PROTEOMIC ANALYSIS OF NEOPLASTIC PROGRESSION IN BREAST CANCER

The utilization of high-throughput -omics strategies, such as proteomics, in the analysis of breastcancer will function to define central molecular characteristics across a disease that is associatedwith a high degree of molecular heterogeneity. Data reported herein details the investigation ofkey subjects in breast cancer biology focused on the characterization of endogenous andexperimentally-induced disease biology characteristics utilizing the application of LC-MS basedproteomic analyses of both in vitro models of breast cancer as well as primary clinical samples.Results include a combined global and functional proteomic strategy to identify governingfunctional roles for mutually, differentially abundant proteins observed across three divergentcell line models of breast cancer. Further, evidence is presented which provides insights into theregulatory activity of the breast cancer-associated microRNA (miR-145) in several cell linemodels of breast cancer in which expression of this microRNA has been restored. Lastly, robustanalyses are detailed focused on the identification of differential protein characteristics indicativeof disease stage as well as of recurrent disease in breast cancer derived from proteomic analysisof formalin-fixed, paraffin embedded (FFPE) clinical samples. These studies contribute to thefield of proteomics in the form of 1) providing robust experimental workflows directed towardsinvestigation of functional themes and associated functional targets in large protein data sets 2)detailing strategies for navigating the application of proteomic analysis to microRNA targetdiscovery and 3) further development and utilization of methodologies towards the proteomicanalysis of clinical, FFPE tissue samples. Furthermore, these studies benefit the breast cancercommunity on several fronts including 1) the elucidation of provocative protein candidateswhich warrant further investigation for their role in regulating disease mechanisms underlyingvbreast cancer biology and 2) through the discovery of diagnostic markers indicative of discretesubtypes and stages of disease progression in breast cancer. The results reported herein detaildisease-specific protein abundance characteristics associated with neoplastic progression inbreast cancer that will benefit further expansion of the basic biological understanding of thisdisease and describes novel proteins for further evaluation as biomarker candidates for thediagnosis of breast cancer

Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital

Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer\u27s trial selection and disease monitoring

Blood biomarkers indicative of Alzheimer\u27s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer\u27s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments