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ABSTRACT: Acquired drug resistance represents a major obstacle to using sunitinib for the treatment of solid tumors. Here, we examined the cellular and molecular alterations in tumors that are associated with acquired brain tumor resistance to sunitinib by using an in vivo model. U87MG tumors obtained from nude mice that received sunitinib (40 mg/kg/day) for 30 days were classified into sunitinib-sensitive and -resistant groups based on tumor volume and underwent targeted gene microarray and protein array analyses. The expression of several angiogenesis-associated genes was significantly modulated in sunitinib-treated tumors compared with those in control tumors (p < 0.05), whereas no significant differences were observed between sunitinib-sensitive and -resistant tumors (p > 0.05). Tumor vasculature based on microvessel density, neurogenin 2 chondroitin sulfate proteoglycan density, and α-smooth muscle actin density was also similar in sunitinib-treatment groups (p > 0.05). The moderate increase in unbound sunitinib tumor-to-plasma area-under-the-curve ratio in sunitinib-resistant mice was accompanied by up-regulated ATP-binding cassette G2 expression in tumor. The most profound difference between the sunitinib-sensitive and -resistant groups was found in the expression of several phosphorylated proteins involved in intracellular signaling. In particular, phospholipase C-γ1 phosphorylation in sunitinib-resistant tumors was up-regulated by 2.6-fold compared with that in sunitinib-sensitive tumors (p < 0.05). In conclusion, acquired sunitinib resistance in U87MG tumors is not associated with revascularization in tumors, but rather with the activation of alternate prosurvival pathways involved in an escape mechanism facilitating tumor growth and possibly insufficient drug uptake in tumor cells caused by an up-regulated membrane efflux transporter.
Journal of Pharmacology and Experimental Therapeutics 08/2012; 343(2):509-19. · 3.83 Impact Factor
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Amin R Mazloom,
Ruth Dannenfelser,
Neil R Clark,
Arsen V Grigoryan,
Kathryn M Linder,
Timothy J Cardozo,
Julia C Bond,
Aislyn D W Boran,
Ravi Iyengar,
Anna Malovannaya,
Rainer B Lanz,
Avi Ma'ayan
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ABSTRACT: Coregulator proteins (CoRegs) are part of multi-protein complexes that transiently assemble with transcription factors and chromatin modifiers to regulate gene expression. In this study we analyzed data from 3,290 immuno-precipitations (IP) followed by mass spectrometry (MS) applied to human cell lines aimed at identifying CoRegs complexes. Using the semi-quantitative spectral counts, we scored binary protein-protein and domain-domain associations with several equations. Unlike previous applications, our methods scored prey-prey protein-protein interactions regardless of the baits used. We also predicted domain-domain interactions underlying predicted protein-protein interactions. The quality of predicted protein-protein and domain-domain interactions was evaluated using known binary interactions from the literature, whereas one protein-protein interaction, between STRN and CTTNBP2NL, was validated experimentally; and one domain-domain interaction, between the HEAT domain of PPP2R1A and the Pkinase domain of STK25, was validated using molecular docking simulations. The scoring schemes presented here recovered known, and predicted many new, complexes, protein-protein, and domain-domain interactions. The networks that resulted from the predictions are provided as a web-based interactive application at http://maayanlab.net/HT-IP-MS-2-PPI-DDI/.
PLoS Computational Biology 12/2011; 7(12):e1002319. · 5.22 Impact Factor
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ABSTRACT: Experiments such as ChIP-chip, ChIP-seq, ChIP-PET and DamID (the four methods referred herein as ChIP-X) are used to profile the binding of transcription factors to DNA at a genome-wide scale. Such experiments provide hundreds to thousands of potential binding sites for a given transcription factor in proximity to gene coding regions.
In order to integrate data from such studies and utilize it for further biological discovery, we collected interactions from such experiments to construct a mammalian ChIP-X database. The database contains 189,933 interactions, manually extracted from 87 publications, describing the binding of 92 transcription factors to 31,932 target genes. We used the database to analyze mRNA expression data where we perform gene-list enrichment analysis using the ChIP-X database as the prior biological knowledge gene-list library. The system is delivered as a web-based interactive application called ChIP Enrichment Analysis (ChEA). With ChEA, users can input lists of mammalian gene symbols for which the program computes over-representation of transcription factor targets from the ChIP-X database. The ChEA database allowed us to reconstruct an initial network of transcription factors connected based on shared overlapping targets and binding site proximity. To demonstrate the utility of ChEA we present three case studies. We show how by combining the Connectivity Map (CMAP) with ChEA, we can rank pairs of compounds to be used to target specific transcription factor activity in cancer cells.
The ChEA software and ChIP-X database is freely available online at: http://amp.pharm.mssm.edu/lib/chea.jsp.
Bioinformatics 10/2010; 26(19):2438-44. · 5.47 Impact Factor
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ABSTRACT: The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
Nature 08/2010; 466(7308):829-34. · 36.28 Impact Factor
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ABSTRACT: Beside their contribution in DNA packaging, histone-core particles modulate the transcription machinery access to the DNA through dynamic chromatin structure. Chromatin remodeling complexes perturb such modulations through diverse mechanisms. SWI/SNF is a well-studied highly conserved chromatin remodeling complex that is ubiquitous across eukaryotes. Rigorous study of experimental observations suggests randomness in dynamics of SWI/SNF in cis chromatin remodeling process. In this work we propose a stochastic computational model that captures such fluctuations. We incorporate the physiological properties of the process through parametric microevents. Each microevent is then associated with a stochastic model that couples its random temporal and spatial dynamics with the energy landscape of the remodeling process. We further show that DNA sequence stacks and friction force have negligible effect on chromatin remodeling. Our approach shows a promising approximation to the force impinged on the DNA by the SWI/SNF complex. We validate our model predictions with several experimental data sets. The proposed model suggest that the in cis translocation rate of histone-core particle follows a Gamma distribution. By carefully analyzing the simulation results we conjecture that SWI/SNF chromatin remodeling has low energy efficiency (<0.30). We use our model to recapitulate the dynamics of the parallel remodeling processes that occur in close proximity across a typical eukaryotic genome. Our results suggest that the orchestrated chromatin remodeling makes few kilobase-pairs of the DNA accessible to the transcription machinery in a timely manner.
Bio Systems 11/2009; · 1.27 Impact Factor
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Complex Sciences, First International Conference, Complex 2009, Shanghai, China, February 23-25, 2009. Revised Papers, Part 1; 01/2009
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Bioinformatics Research and Applications, Third International Symposium, ISBRA 2007, Atlanta, GA, USA, May 7-10, 2007, Proceedings; 01/2007
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Proceedings of the 2006 IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology, CIBCB 2006, Renaissance Hotel Downtown, Toronto, Ontario, Canada, September 28-29, 2006; 01/2006
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ABSTRACT: Electrical-to-optical domain conversions and vice versa (denoted by O/E/O conversions) for each hop in optical core transport networks impose considerable capital and financial overhead on the providers. In this paper, we propose a full-mesh topology driven core network with a central scheduler that handles the task of signaling and coordination among slot transmissions for every hop to eliminate such O/E/O conversions. We introduce the concept of a container as a macro data unit that forms a separate layer in the protocol stack above the optical layer. A FAST centralized scheduling algorithm is proposed based on a preemptive scheduling technique that can ensure that there are no collisions between the containers. We also analyze the complexity of this algorithm. Next we design the logical architecture for the core and edge switches following the de facto policy of moving the complexity to the edge. We also designed a hierarchical architecture for the edge switch and provide the respective block diagrams. To get a more concrete design prototype, we further proposed a generic (vendor independent) physical architecture for a single port of the switch considering SONET/SDH on the access side. Moreover, we develop a concise delay model for the containers to analyze the packet arrival process and derive the optimal container size, based on the link speed. Finally, we present some simulation results to study the performance of the algorithms and models proposed in our work.
Computer Networks.
