DanaFarber Cancer Institute

Boston, MA, United States

DanaFarber Cancer Institute

Boston, MA, United States
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Drewry D.H.,University of North Carolina at Chapel Hill | Wells C.I.,University of North Carolina at Chapel Hill | Andrews D.M.,Astrazeneca | Angell R.,University College London | And 21 more authors.
PLoS ONE | Year: 2017

Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases. © 2017 Drewry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Mcmillin D.W.,DanaFarber Cancer Institute | Mcmillin D.W.,Harvard University | Negri J.M.,Harvard University | Mitsiades C.S.,DanaFarber Cancer Institute | Mitsiades C.S.,Harvard University
Nature Reviews Drug Discovery | Year: 2013

The role of stromal cells and the tumour microenvironment in general in modulating tumour sensitivity is increasingly becoming a key consideration for the development of active anticancer therapeutics. Here, we discuss how these tumour-stromal interactions affect tumour cell signalling, survival, proliferation and drug sensitivity. Particular emphasis is placed on the ability of stromal cells to confer-to tumour cells-resistance or sensitization to different classes of therapeutics, depending on the specific microenvironmental context. The mechanistic understanding of these microenvironmental interactions can influence the evaluation and selection of candidate agents for various cancers, in both the primary site as well as the metastatic setting. Progress in in vitro screening platforms as well as orthotopic and 'orthometastatic' xenograft mouse models has enabled comprehensive characterization of the impact of the tumour microenvironment on therapeutic efficacy. These recent advances can hopefully bridge the gap between preclinical studies and clinical trials of anticancer agents. Copyright © 2013 Macmillan Publishers Limited.

Yue Y.,Brigham and Women's Hospital | Yue Y.,DanaFarber Cancer Institute | Yue Y.,Harvard University | Aristophanous M.,Brigham and Women's Hospital | And 8 more authors.
Medical Physics | Year: 2010

Purpose: Fiducials can be used to aid organ localization during RapidArc delivery. Specifically, the 3‐D tumor position may be found through the tracking of fiducials during beam delivery. A promising technique is the detection of fiducials in 2‐D EPID images, and then reconstruction of the 3‐D position using limited views. Methods and Materials: The CIRS dynamic thorax phantom with a custom tumor model is used in the study. Two fiducials are placed on the surface of the tumor at clinically relevant distances apart from each other. Clinical RapidArc plans are delivered to the phantom based on a single 360° arc. The fiducial detection algorithms are developed based on an image block matching filter and anisotropic diffusion techniques. A wavelet‐based block matching filter is developed to suppress the noise and texture of images while preserving the edges of fiducials. Furthermore, the anisotropic diffusion technique removes redundant edges and trivial structures of the results of the previous filtering. Experiments show that the algorithms are robust to image contrast and aperture variations during the RapidArc delivery. With detected 2‐D locations, 3‐D spatial locations of fiducials are reconstructed using the inverse 3‐D rotation matrix. Results: The position accuracy in 2D EPID is 0.77+0.58 mm by comparing with the manual outlines. The 3D fiducial positions are reconstructed using the 2D EPID images. The displacement from the references in the 3D CBCT image is within one millimeter. Conclusion: Novel filtering and detection algorithms are developed to identify the fiducials in 2D EPID images. The results show that limited angles of full rotation can rigorously reconstruct the locations of each of fiducials in 3D to within one millimeter. Conflict of Interest: Varian Medical Systems, Inc. © 2010, American Association of Physicists in Medicine. All rights reserved.

Helander S.,Linköping University | Montecchio M.,Linköping University | Lemak A.,University of Toronto | Fares C.,University of Toronto | And 9 more authors.
Biochemical and Biophysical Research Communications | Year: 2014

In this paper, we describe the structure of a N-terminal domain motif in nuclear-localized FKBP251-73, a member of the FKBP family, together with the structure of a sequence-related subdomain of the E3 ubiquitin ligase HectD1 that we show belongs to the same fold. This motif adopts a compact 5-helix bundle which we name the Basic Tilted Helix Bundle (BTHB) domain. A positively charged surface patch, structurally centered around the tilted helix H4, is present in both FKBP25 and HectD1 and is conserved in both proteins, suggesting a conserved functional role. We provide detailed comparative analysis of the structures of the two proteins and their sequence similarities, and analysis of the interaction of the proposed FKBP25 binding protein YY1. We suggest that the basic motif in BTHB is involved in the observed DNA binding of FKBP25, and that the function of this domain can be affected by regulatory YY1 binding and/or interactions with adjacent domains. ©2014 Elsevier Inc. All rights reserved.

Pu C.-L.,Nanjing Southeast University | Pu C.-L.,Northeastern University | Pu C.-L.,DanaFarber Cancer Institute | Zhou S.-Y.,Nanjing Southeast University | And 3 more authors.
Physica A: Statistical Mechanics and its Applications | Year: 2012

Information routing is one of the most important problems in large communication networks. In this paper we propose a novel routing strategy in which the optimal paths between all pairs of nodes are chosen according to a cost function that incorporates degrees of nodes in paths. Results on large scale-free networks demonstrate that our routing strategy is more efficient than the shortest path algorithm and the efficient routing strategy proposed by Yan et al. [Phys. Rev. E 73, 046108 (2006)]. Furthermore our routing strategy has strong robustness against cascading failure attacks on networks. © 2011 Elsevier B.V. All rights reserved.

Duke University, Sloan Kettering Institute For Cancer Research and Danafarber Cancer Institute | Date: 2013-10-28

The present invention relates, in general, to human immunodeficiency virus-1 (HIV-1), and, in particular to a vaccine for HIV-1 and to methods of making and using same. The present invention provides synthetic glycosylated HIV-1 peptides, method for their preparation and use.

Wu H.,Chinese Academy of Sciences | Wu H.,Anhui University of Science and Technology | Wang W.,Chinese Academy of Sciences | Liu F.,Chinese Academy of Sciences | And 26 more authors.
ACS Chemical Biology | Year: 2014

BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLC2 (Tyr759) with an EC50 of 318 nM. In Ramos cells QL47 induces a G1 cell cycle arrest that is associated with pronounced degradation of BTK protein. QL47 inhibits the proliferation of B-cell lymphoma cancer cell lines at submicromolar concentrations. © 2014 American Chemical Society.

Lank S.M.,University of Wisconsin - Madison | Golbach B.A.,University of Wisconsin - Madison | Creager H.M.,University of Wisconsin - Madison | Wiseman R.W.,University of Wisconsin - Madison | And 7 more authors.
BMC Genomics | Year: 2012

Background: High-resolution HLA genotyping is a critical diagnostic and research assay. Current methods rarely achieve unambiguous high-resolution typing without making population-specific frequency inferences due to a lack of locus coverage and difficulty in exon-phase matching. Achieving high-resolution typing is also becoming more challenging with traditional methods as the database of known HLA alleles increases.Results: We designed a cDNA amplicon-based pyrosequencing method to capture 94% of the HLA class I open-reading-frame with only two amplicons per sample, and an analogous method for class II HLA genes, with a primary focus on sequencing the DRB loci. We present a novel Galaxy server-based analysis workflow for determining genotype. During assay validation, we performed two GS Junior sequencing runs to determine the accuracy of the HLA class I amplicons and DRB amplicon at different levels of multiplexing. When 116 amplicons were multiplexed, we unambiguously resolved 99%of class I alleles to four- or six-digit resolution, as well as 100% unambiguous DRB calls. The second experiment, with 271 multiplexed amplicons, missed some alleles, but generated high-resolution, concordant typing for 93% of class I alleles, and 96% for DRB1 alleles. In a third, preliminary experiment we attempted to sequence novel amplicons for other class II loci with mixed success.Conclusions: The presented assay is higher-throughput and higher-resolution than existing HLA genotyping methods, and suitable for allele discovery or large cohort sampling. The validated class I and DRB primers successfully generated unambiguously high-resolution genotypes, while further work is needed to validate additional class II genotyping amplicons. © 2012 Lank et al.; licensee BioMed Central Ltd.

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