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Search Results: 1 - 10 of 44830 matches for " Michael Nebozhyn "
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Molecular Insights into the Pathogenesis of Alzheimer's Disease and Its Relationship to Normal Aging
Alexei A. Podtelezhnikov, Keith Q. Tanis, Michael Nebozhyn, William J. Ray, David J. Stone, Andrey P. Loboda
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0029610
Abstract: Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression.
cDNA targets improve whole blood gene expression profiling and enhance detection of pharmocodynamic biomarkers: a quantitative platform analysis
Mark L Parrish, Chris Wright, Yarek Rivers, David Argilla, Heather Collins, Brendan Leeson, Andrey Loboda, Michael Nebozhyn, Matthew J Marton, Serguei Lejnine
Journal of Translational Medicine , 2010, DOI: 10.1186/1479-5876-8-87
Abstract: To compare and quantify the impact of different mitigation technologies, we used a globin transcript spike-in strategy to synthetically generate a globin-induced signature and then mitigate it with the three different technologies. Biological differences, in globin transcript spiked samples, were modeled by supplementing with either 1% of liver or 1% brain total RNA. In order to demonstrate the biological utility of a robust globin artifact mitigation strategy in biomarker discovery, we treated whole blood ex vivo with suberoylanilide hydroxamic acid (SAHA) and compared the overlap between the obtained signatures and signatures of a known biomarker derived from SAHA-treated cell lines and PBMCs of SAHA-treated patients.We found cDNA hybridization targets detect at least 20 times more specific differentially expressed signatures (2597) between 1% liver and 1% brain in globin-supplemented samples than the PNA (117) or no treatment (97) method at FDR = 10% and p-value < 3x10-3. In addition, we found that the ex vivo derived gene expression profile was highly concordant with that of the previously identified SAHA pharmacodynamic biomarkers.We conclude that an amplification method for gene expression profiling employing cDNA targets effectively mitigates the negative impact on data of abundant globin transcripts and greatly improves the ability to identify relevant gene expression based pharmacodynamic biomarkers from whole blood.Whole blood is a complex mixture of cell types that are exquisitely acute sensors of the body's physiological state [1-8]. It has long been the source tissue used in numerous tests for the identification of disease and the monitoring of disease progression. Peripheral blood is easily accessed and the available analytical techniques are well-established with a focus on the quantification of various chemical analytes (proteins, lipids, etc). Yet, gene expression profiling of peripheral whole blood has yet to be employed broadly. With the prolifera
A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors
Andrey Loboda, Michael Nebozhyn, Rich Klinghoffer, Jason Frazier, Michael Chastain, William Arthur, Brian Roberts, Theresa Zhang, Melissa Chenard, Brian Haines, Jannik Andersen, Kumiko Nagashima, Cloud Paweletz, Bethany Lynch, Igor Feldman, Hongyue Dai, Pearl Huang, James Watters
BMC Medical Genomics , 2010, DOI: 10.1186/1755-8794-3-26
Abstract: We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets.The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer.These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.Signal transduction in response to growth factor receptor activation in tumors is a complex process that involves downstream signaling through the RAS (reviewed in [1]) and PI3K (reviewed in [2]) signaling pathways. These pathways are among the best characterized in cancer biology, involve a network of protein and lipid kinases working in concert to regulate diverse biolo
EMT is the dominant program in human colon cancer
Andre Loboda, Michael V Nebozhyn, James W Watters, Carolyne A Buser, Peter Shaw, Pearl S Huang, Laura Van't Veer, Rob AEM Tollenaar, David B Jackson, Deepak Agrawal, Hongyue Dai, Timothy J Yeatman
BMC Medical Genomics , 2011, DOI: 10.1186/1755-8794-4-9
Abstract: We performed an unsupervised analysis of microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 deciphered two primary, intrinsic molecular subtypes of colon cancer that predicted disease progression and recurrence.Here we report that the most dominant pattern of intrinsic gene expression in colon cancer (PC1) was tightly correlated (Pearson R = 0.92, P < 10-135) with the EMT signature-- both in gene identity and directionality. In a global micro-RNA screen, we further identified the most anti-correlated microRNA with PC1 as MiR200, known to regulate EMT.These data demonstrate that the biology underpinning the native, molecular classification of human colon cancer--previously thought to be highly heterogeneous-- was clarified through the lens of comprehensive transcriptome analysis.Colon cancer has long been postulated to be a molecularly heterogeneous disease. This heterogeneity has been proposed as the reason why it has been difficult to identify unifying molecular hypotheses explaining the biology and behavior of the disease. Molecular profiling of colon cancer has been a relatively effective approach for identifying prognosis of early and intermediate stage disease. We and others have identified biologically complex signatures that affect multiple programs such as adhesion, invasion, and angiogenesis and correlate well with cancer progression and recurrence. These signatures appear to support Weinberg's hypothesis [1] of multiple programs leading to cancer development and progression. These signatures have generally been developed using supervised machine learning techniques that train their models on pre-determined good vs. poor prognosis patient populations [2-6]. Colon cancer, unlike breast cancer where luminal and basal "intrinsic" subtypes have been identified [7-13], or bladder cancer where intrinsic signatures of recurrence have been established [14,15], has yet to be classified by uns
Diurnal variation of the human adipose transcriptome and the link to metabolic disease
Andrey Loboda, Walter K Kraft, Bernard Fine, Jeffrey Joseph, Michael Nebozhyn, Chunsheng Zhang, Yudong He, Xia Yang, Christopher Wright, Mark Morris, Ira Chalikonda, Mark Ferguson, Valur Emilsson, Amy Leonardson, John Lamb, Hongyue Dai, Eric Schadt, Howard E Greenberg, Pek Lum
BMC Medical Genomics , 2009, DOI: 10.1186/1755-8794-2-7
Abstract: The present study examines the effect of diurnal rhythm on gene expression in the subcutaneous adipose tissue of overweight to mildly obese, healthy individuals. In this well-controlled clinical study, adipose biopsies were taken in the morning, afternoon and evening from individuals in three study arms: treatment with the weight loss drug sibutramine/fasted, placebo/fed and placebo/fasted.The results indicated that diurnal rhythm was the most significant driver of gene expression variation in the human adipose tissue, with at least 25% of the genes having had significant changes in their expression levels during the course of the day. The mRNA expression levels of core clock genes at a specific time of day were consistent across multiple subjects on different days in all three arms, indicating robust diurnal regulation irrespective of potential confounding factors. The genes essential for energy metabolism and tissue physiology were part of the diurnal signature. We hypothesize that the diurnal transition of the expression of energy metabolism genes reflects the shift in the adipose tissue from an energy-expending state in the morning to an energy-storing state in the evening. Consistent with this hypothesis, the diurnal transition was delayed by fasting and treatment with sibutramine. Finally, an in silico comparison of the diurnal signature with data from the publicly-available Connectivity Map demonstrated a significant association with transcripts that were repressed by mTOR inhibitors, suggesting a possible link between mTOR signaling, diurnal gene expression and metabolic regulation.Diurnal rhythm plays an important role in the physiology and regulation of energy metabolism in the adipose tissue and should be considered in the selection of novel targets for the treatment of obesity and other metabolic disorders.Circadian (diurnal) rhythms are part of the daily lives of many living organisms, from photosynthetic prokaryotes to higher eukaryotes [1,2]. These os
Does Child Maltreatment Mediate Family Environment and Psychological Well-Being?  [PDF]
Michael Galea
Psychology (PSYCH) , 2010, DOI: 10.4236/psych.2010.12019
Abstract: This study tried to establish if childhood maltreatment mediates the established relationship between family environ-ment and psychological well-being, in a sample of Maltese university students (N = 312). However, our analysis sug-gested partial mediation only. Moreover, results indicated that abusive families are less loving, socially integrated, organized, and more conflicted. Family environment contributed positively, albeit limited, to cognitive well-being after controlling for child abuse history. In particular, cohesion, do add unique variance to subjective well-being, after controlling for child abuse. This study replicates classic research on the important role that family environment plays in children’s holistic development.
Blended Change Management: Concept and Empirical Investigation of Blending Patterns  [PDF]
Michael REISS
iBusiness (IB) , 2009, DOI: 10.4236/ib.2009.12008
Abstract: In coping with the challenges of revolutionary or evolutionary change processes, change managers do not rely on single tools but on toolboxes containing several domains of tools. The impact of toolboxes on change performance depends both on the complementary inter-domain mix and the intra-domain blending of tools. The patterns of blending are investigated both conceptually and empirically with respect to scope, diversity and coupling of tools. Survey results indicate that blending practices are predominantly determined by rational tool evaluation and by task context.
Single Wire Electrical System  [PDF]
Michael Bank
Engineering (ENG) , 2012, DOI: 10.4236/eng.2012.411092
Abstract: The purpose of this article is to remind of the past and present problems of creating single wire electrical systems. This article presents a new one wire electrical transmission system named B-Line which uses one line only and does not use ground as a second line. The proposed method is to work on all frequencies and on all communication systems including DC systems. It also proposes to work on the concept of the single-pole signal source and single-pole signal load. It illustrates the possibility of cutting the cost of electrical lines and several other advantages in the fields of high frequency communication lines and antennas.
Relationship of nine constants  [PDF]
Michael Snyder
Natural Science (NS) , 2013, DOI: 10.4236/ns.2013.59117
Abstract:

Through the process of trial and error, four unitless equations made up of nine constants have been found with exact answers. The related constants are the Speed of Light [1], the Planck constant [2], Wien’s displacement constant [3], Avogadro’s number [4], the universal Gravity constant [5], the Ampere constant [6], the Faraday constant [7], the Gas constant [8] and Apery’s constant [9].

The Counterfeit Electronics Problem  [PDF]
Michael Pecht
Open Journal of Social Sciences (JSS) , 2013, DOI: 10.4236/jss.2013.17003
Abstract:

Counterfeit electronics have been reported in a wide range of products, including computers, telecommunications equipment, automobiles, avionics and military systems. Counterfeit electronic products include everything from very inexpensive capacitors and resistors to costly microprocessors to servers. This paper describes the counterfeit electronic products problem, and discusses the implication of counterfeit electronics on the electronic supply chain. We then present counterfeit detection and prevention techniques for electronics.

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