DanaFarber Cancer Institute

Boston, MA, United States

DanaFarber Cancer Institute

Boston, MA, United States

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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.


Patent
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.


Shyn P.B.,Harvard University | Tatli S.,Harvard University | Sainani N.I.,Harvard University | Morrison P.R.,Harvard University | And 3 more authors.
Journal of Vascular and Interventional Radiology | Year: 2011

Purpose: To validate a monitored, breath-hold positron emission tomography (PET)/computed tomography (CT) acquisition technique for the minimization of respiratory PET/CT image misregistration and lesion distortion during PET/CTguided percutaneous interventional procedures. Materials and Methods: Eleven patients referred for percutaneous biopsy or thermal ablation of tumors near the diaphragm were prospectively enrolled. Initial PET/CT scanning was performed by using a bellows device and monitored, same-level breath-holds for PET and CT acquisitions. Breath-hold PET consisted of nine 20-second breath-hold frames, yielding a 3-minute equivalent PET dataset. A second PET/CT scan was obtained without monitoring by using end-expiration breath-hold CT and free-breathing PET. PET/CT tumor misregistration and craniocaudal tumor diameter were measured on monitored and unmonitored PET/CT datasets. Data were analyzed by using nonparametric, two-sided, signed-rank statistical tests. Results: Mean PET/CT image misregistrations in the craniocaudal, anteroposterior, and transverse planes were 2.6 mm (range, 07 mm), 3.3 mm (range, 18 mm), and 2.7 mm (range, 08 mm) with monitoring and 14.7 mm (range, 049 mm), 7.6 mm (range, 124 mm), and 4.0 mm (range, 012 mm) without monitoring, respectively. Differences were significant for craniocaudal (P =.0087) and anteroposterior (P =.014) planes, but not for the transverse plane (P =.23). Mean craniocaudal target diameter was 2.5 mm (range, -2 to 9 mm) larger (ie, distorted) for unmonitored versus monitored PET (P =.061). Conclusions: Acquiring PET/CT datasets with respiratory bellows-assisted, monitored breath-holds improves PET/CT image registration versus unmonitored PET/CT and may facilitate accurate targeting during PET/CTguided interventions in anatomic regions subject to respiratory motion. © 2011 SIR.


PubMed | DanaFarber Cancer Institute
Type: Journal Article | Journal: 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.

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