Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer's disease in a southern Chinese population

In this case-controlled study, we tested susceptible genetic variants for Alzheimer's disease (AD) in CR1, CLU and PICALM from genome-wide association studies (GWAS) in a southern Chinese population. Eight hundred twelve participants consisting of 462 late-onset Alzheimer's disease (LOAD) patients and 350 nondemented control subjects were recruited. We found by multivariate logistic regression analysis, that single nucleotide polymorphisms (SNPs) in CR1 (rs6656401 adjusted allelic p = 0.035; adjusted genotypic p = 0.043) and CLU (rs2279590 adjusted allelic p = 0.035; adjusted genotypic p = 0.006; rs11136000 adjusted allelic p = 0.038; adjusted genotypic p = 0.009) were significantly different between LOAD patients and nondemented controls. For PICALM, LOAD association was found only in the APOE ε4 (-) subgroup (rs3851179 adjusted allelic p = 0.028; adjusted genotypic p = 0.013). Our findings showed evidence of CR1, CLU, and PICALM and LOAD susceptibility in an independent southern Chinese population, which provides additional evidence for LOAD association apart from prior genome-wide association studies in Caucasian populations. © 2012 Elsevier Inc.postprin

Knocking down 10-formyltetrahydrofolate dehydrogenase increased oxidative stress and impeded zebrafish embryogenesis by obstructing morphogenetic movement

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Fusion dual-tracer SPECT-based hepatic dosimetry predicts outcome after radioembolization for a wide range of tumour cell types

Purpose Fusion dual-tracer SPECT imaging enables physiological rather than morphological voxel-based partitioning and dosimetry for Y-90 hepatic radioembolization (RE). We evaluated its prognostic value in a large heterogeneous cohort of patients with extensive hepatic malignancy. Methods A total of 122 patients with primary or secondary liver malignancy (18 different cell types) underwent SPECT imaging after intraarterial injection of Tc-99m macroaggregated albumin (TcMAA) as a simulation of subsequent Y-90 microsphere distribution, followed by administration of an excess of intravenous Tc-99m-labelled sulphur colloid (TcSC) as a biomarker for functional liver, and a second SPECT scan. TcMAA distribution was used to estimate Y-90 radiation absorbed dose in tumour (D (T)) and in functional liver. Laboratory and clinical follow-up were recorded for 12 weeks after RE, and radiographic responses according to (m)RECIST were evaluated at 3 and 6 months. Dose-response relationships were determined for efficacy and toxicity. Results Patients were treated with a median of 1.73 GBq activity of resin microspheres (98 patients) or glass microspheres (24 patients), in a whole-liver approach (97 patients) or a lobar approach (25 patients). The objective response rate was 41 % at 3 months and 48 % at 6 months. Response was correlated with D (T) (P <0.01). Median overall survival was 10.1 months (95 % confidence interval 7.4 - 12.8 months). Responders lived for 36.0 months compared to 8.7 months for nonresponders (P <0.01). Stratified for tumour cell type, D (T) was independently associated with survival (P <0.01). Absorbed dose in functional liver was correlated with toxicity grade change (P <0.05) and RE-induced liver disease (P <0.05). Conclusion Fusion dual-tracer SPECT imaging offers a physiology-based functional imaging tool to predict efficacy and toxicity of RE. This technique can be refined to define dosing thresholds for specific tumour types and treatments, but appears generally predictive even in a heterogeneous cohort

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Anti-Arthritic Effects of Magnolol in Human Interleukin 1β-Stimulated Fibroblast-Like Synoviocytes and in a Rat Arthritis Model

Fibroblast-like synoviocytes (FLS) play an important role in the pathologic processes of destructive arthritis by producing a number of catabolic cytokines and metalloproteinases (MMPs). The expression of these mediators is controlled at the transcriptional level. The purposes of this study were to evaluate the anti-arthritic effects of magnolol (5,5′-Diallyl-biphenyl-2,2′-diol), the major bioactive component of the bark of Magnolia officinalis, by examining its inhibitory effects on inflammatory mediator secretion and the NF-κB and AP-1 activation pathways and to investigate its therapeutic effects on the development of arthritis in a rat model. The in vitro anti-arthritic activity of magnolol was tested on interleukin (IL)-1β-stimulated FLS by measuring levels of IL-6, cyclooxygenase-2, prostaglandin E2, and matrix metalloproteinases (MMPs) by ELISA and RT-PCR. Further studies on how magnolol inhibits IL-1β-stimulated cytokine expression were performed using Western blots, reporter gene assay, electrophoretic mobility shift assay, and confocal microscope analysis. The in vivo anti-arthritic effects of magnolol were evaluated in a Mycobacterium butyricum-induced arthritis model in rats. Magnolol markedly inhibited IL-1β (10 ng/mL)-induced cytokine expression in a concentration-dependent manner (2.5–25 µg/mL). In clarifying the mechanisms involved, magnolol was found to inhibit the IL-1β-induced activation of the IKK/IκB/NF-κB and MAPKs pathways by suppressing the nuclear translocation and DNA binding activity of both transcription factors. In the animal model, magnolol (100 mg/kg) significantly inhibited paw swelling and reduced serum cytokine levels. Our results demonstrate that magnolol inhibits the development of arthritis, suggesting that it might provide a new therapeutic approach to inflammatory arthritis diseases

Personalized predictive lung dosimetry by technetium-99m macroaggregated albumin SPECT/CT for yttrium-90 radioembolization

BACKGROUND: For yttrium-90 ((90)Y) radioembolization, the common practice of assuming a standard 1,000-g lung mass for predictive dosimetry is fundamentally incongruent with the modern philosophy of personalized medicine. We recently developed a technique of personalized predictive lung dosimetry using technetium-99m ((99m)Tc) macroaggregated albumin (MAA) single photon emission computed tomography with integrated CT (SPECT/CT) of the lung as part of our routine dosimetric protocol for (90)Y radioembolization. Its rationales are the technical superiority of SPECT/CT over planar scintigraphy, ease and convenience of lung auto-segmentation CT densitovolumetry, and dosimetric advantage of patient-specific lung parenchyma masses. METHODS: This is a retrospective study of our pulmonary clinical outcomes and comparison of lung dosimetric accuracy and precision by (99m)Tc MAA SPECT/CT versus conventional planar methodology. (90)Y resin microspheres (SIR-Spheres) were used for radioembolization. Diagnostic CT densitovolumetry was used as a reference for lung parenchyma mass. Pulmonary outcomes were based on follow-up diagnostic CT chest or X-ray. RESULTS: Thirty patients were analyzed. The mean lung parenchyma mass of our Southeast Asian cohort was 822 ± 103 g standard deviation (95% confidence interval 785 to 859 g). Patient-specific lung parenchyma mass estimation by CT densitovolumetry on (99m)Tc MAA SPECT/CT is accurate (bias −21.7 g) and moderately precise (95% limits of agreement −194.6 to +151.2 g). Lung mean radiation absorbed doses calculated by (99m)Tc MAA SPECT/CT and planar methodology are both accurate (bias <0.5 Gy), but (99m)Tc MAA SPECT/CT offers better precision over planar methodology (95% limits of agreement −1.76 to +2.40 Gy versus −3.48 to +3.31 Gy, respectively). None developed radiomicrosphere pneumonitis when treated up to a lung mean radiation absorbed dose of 18 Gy at a median follow-up of 4.4 months. CONCLUSIONS: Personalized predictive lung dosimetry by (99m)Tc MAA SPECT/CT is clinically feasible, safe, and more precise than conventional planar methodology for (90)Y radioembolization radiation planning

Variable selection for large p small n regression models with incomplete data: Mapping QTL with epistases

<p>Abstract</p> <p>Background</p> <p>Identifying quantitative trait loci (QTL) for both additive and epistatic effects raises the statistical issue of selecting variables from a large number of candidates using a small number of observations. Missing trait and/or marker values prevent one from directly applying the classical model selection criteria such as Akaike's information criterion (AIC) and Bayesian information criterion (BIC).</p> <p>Results</p> <p>We propose a two-step Bayesian variable selection method which deals with the sparse parameter space and the small sample size issues. The regression coefficient priors are flexible enough to incorporate the characteristic of "large <it>p </it>small <it>n</it>" data. Specifically, sparseness and possible asymmetry of the significant coefficients are dealt with by developing a Gibbs sampling algorithm to stochastically search through low-dimensional subspaces for significant variables. The superior performance of the approach is demonstrated via simulation study. We also applied it to real QTL mapping datasets.</p> <p>Conclusion</p> <p>The two-step procedure coupled with Bayesian classification offers flexibility in modeling "large p small n" data, especially for the sparse and asymmetric parameter space. This approach can be extended to other settings characterized by high dimension and low sample size.</p