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  • 1
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    Autologous Sarcoma Cell Vaccines (2015)
    The American Association for Cancer Research (AACR)
    Details
    Publication Date: 2015-07-16
    Description: Purpose: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviral-mediated gene transfer to secrete granulocyte–macrophage colony-stimulating factor (GM-CSF). Experimental Design: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. Results: Vaccines were successfully manufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1–2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell–mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)–positive CD8 + T cells in association with PD ligand-1 (PD-L1)–expressing sarcoma cells. No tumor regressions were observed. Conclusions: Vaccination with irradiated, GM-CSF–secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1–negative regulatory pathway might intensify immune-mediated tumor destruction. Clin Cancer Res; 21(14); 3178–86. ©2015 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 2
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    The Molecular Chaperone DnaK Is a Source of Mutational Robustness (2016)
    Oxford University Press
    Details
    Publication Date: 2016-10-08
    Description: Molecular chaperones, also known as heat-shock proteins, refold misfolded proteins and help other proteins reach their native conformation. Thanks to these abilities, some chaperones, such as the Hsp90 protein or the chaperonin GroEL, can buffer the deleterious phenotypic effects of mutations that alter protein structure and function. Hsp70 chaperones use a chaperoning mechanism different from that of Hsp90 and GroEL, and it is not known whether they can also buffer mutations. Here, we show that they can. To this end, we performed a mutation accumulation experiment in Escherichia coli , followed by whole-genome resequencing. Overexpression of the Hsp70 chaperone DnaK helps cells cope with mutational load and completely avoid the extinctions we observe in lineages evolving without chaperone overproduction. Additionally, our sequence data show that DnaK overexpression increases mutational robustness, the tolerance of its clients to nonsynonymous nucleotide substitutions. We also show that this elevated mutational buffering translates into differences in evolutionary rates on intermediate and long evolutionary time scales. Specifically, we studied the evolutionary rates of DnaK clients using the genomes of E. coli , Salmonella enterica , and 83 other gamma-proteobacteria. We find that clients that interact strongly with DnaK evolve faster than weakly interacting clients. Our results imply that all three major chaperone classes can buffer mutations and affect protein evolution. They illustrate how an individual protein like a chaperone can have a disproportionate effect on the evolution of a proteome.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    GenVisR: Genomic Visualizations in R (2016)
    Oxford University Press
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    Publication Date: 2016-10-04
    Description: : Visualizing and summarizing data from genomic studies continues to be a challenge. Here, we introduce the GenVisR package to addresses this challenge by providing highly customizable, publication-quality graphics focused on cohort level genome analyses. GenVisR provides a rapid and easy-to-use suite of genomic visualization tools, while maintaining a high degree of flexibility by leveraging the abilities of ggplot2 and Bioconductor. Availability and Implementation: GenVisR is an R package available via Bioconductor ( https://bioconductor.org/packages/GenVisR ) under GPLv3. Support is available via GitHub ( https://github.com/griffithlab/GenVisR/issues ) and the Bioconductor support website. Contacts: obigriffith@wustl.edu or mgriffit@wustl.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 4
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    High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer (2018)
    The American Association for Cancer Research (AACR)
    Details
    Publication Date: 2018-04-04
    Description: Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer. Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: ( 1 ) intellectual disability and/or congenital anomalies, ( 2 ) multiple malignancies, ( 3 ) family history of cancer, or ( 4 ) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome. Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 ( n = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy ( EP300 -based Rubinstein–Taybi syndrome, ARID1A -based Coffin–Siris syndrome, ACTB -based Baraitser–Winter syndrome, and EZH2 -based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2 , which are possibly involved in genetic cancer predisposition. Conclusions: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. Clin Cancer Res; 24(7); 1594–603. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 5
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    Fitness Trade-Offs Determine the Role of the Molecular Chaperonin GroEL in Buffering Mutations (2015)
    Oxford University Press
    Details
    Publication Date: 2015-09-22
    Description: Molecular chaperones fold many proteins and their mutated versions in a cell and can sometimes buffer the phenotypic effect of mutations that affect protein folding. Unanswered questions about this buffering include the nature of its mechanism, its influence on the genetic variation of a population, the fitness trade-offs constraining this mechanism, and its role in expediting evolution. Answering these questions is fundamental to understand the contribution of buffering to increase genetic variation and ecological diversification. Here, we performed experimental evolution, genome resequencing, and computational analyses to determine the trade-offs and evolutionary trajectories of Escherichia coli expressing high levels of the essential chaperonin GroEL. GroEL is abundantly present in bacteria, particularly in bacteria with large loads of deleterious mutations, suggesting its role in mutational buffering. We show that groEL overexpression is costly to large populations evolving in the laboratory, leading to groE expression decline within 66 generations. In contrast, populations evolving under the strong genetic drift characteristic of endosymbiotic bacteria avoid extinction or can be rescued in the presence of abundant GroEL. Genomes resequenced from cells evolved under strong genetic drift exhibited significantly higher tolerance to deleterious mutations at high GroEL levels than at native levels, revealing that GroEL is buffering mutations in these cells. GroEL buffered mutations in a highly diverse set of proteins that interact with the environment, including substrate and ion membrane transporters, hinting at its role in ecological diversification. Our results reveal the fitness trade-offs of mutational buffering and how genetic variation is maintained in populations.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Abundance and potential metabolic activity of methanogens in well-aerated forest and grassland soils of an alpine region (2016)
    Oxford University Press
    Details
    Publication Date: 2016-01-30
    Description: Although methanogens were recently discovered to occur in aerated soils, alpine regions have not been extensively studied for their presence so far. Here, the abundance of archaea and the methanogenic guilds Methanosarcinales , Methanococcales , Methanobacteriales , Methanomicrobiales and Methanocella spp . was studied at 16 coniferous forest and 14 grassland sites located at the montane and subalpine belts of the Northern Limestone Alps (calcareous) and the Austrian Central Alps (siliceous) using quantitative real-time PCR. Abundance of archaea, methanogens and the methanogenic potentials were significantly higher in grasslands than in forests. Furthermore, methanogenic potentials of calcareous soils were higher due to pH. Methanococcales , Methanomicrobiales and Methanocella spp . were detected in all collected samples, which indicates that they are autochthonous, while Methanobacteriales were absent from 4 out of 16 forest soils. Methanosarcinales were absent from 10 out of 16 forest soils and 2 out of 14 grassland soils. Nevertheless, together with Methanococcales they represented the majority of the 16S rRNA gene copies quantified from the grassland soils. Contrarily, forest soils were clearly dominated by Methanococcales . Our results indicate a higher diversity of methanogens in well-aerated soils than previously believed and that pH mainly influences their abundances and activities.
    Print ISSN: 0168-6496
    Electronic ISSN: 1574-6941
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    DGIdb 2.0: mining clinically relevant drug-gene interactions (2016)
    Oxford University Press
    Details
    Publication Date: 2016-01-07
    Description: The Drug–Gene Interaction Database (DGIdb, www.dgidb.org ) is a web resource that consolidates disparate data sources describing drug–gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug–gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug–gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Digging deeper into the Southern skies: a compact Milky Way companion discovered in first-year Dark Energy Survey data (2016)
    Luque, E., Queiroz, A., Santiago, B., Pieres, A., Balbinot, E., Bechtol, K., Drlica-Wagner, A., Neto, A. F., da Costa, L. N., Maia, M. A. G., Yanny, B., Abbott, T., Allam, S., Benoit-Levy, A., Bertin, E., Brooks, D., Buckley-Geer, E., Burke, D. L., Rosell, A. C., Kind, M. C., Carretero, J., Cunha, C. E., Desai, S., Diehl, H. T., Dietrich, J. P., Eifler, T. F., Finley, D. A., Flaugher, B., Fosalba, P., Frieman, J., Gerdes, D. W., Gruen, D., Gutierrez, G., Honscheid, K., James, D. J., Kuehn, K., Kuropatkin, N., Lahav, O., Li, T. S., March, M., Marshall, J. L., Martini, P., Miquel, R., Neilsen, E., Nichol, R. C., Nord, B., Ogando, R., Plazas, A. A., Romer, A. K., Roodman, A., Sanchez, E., Scarpine, V., Schubnell, M., Sevilla-Noarbe, I., Smith, R. C., Soares-Santos, M., Sobreira, F., Suchyta, E., Swanson, M. E. C., Tarle, G., Thaler, J., Tucker, D., Walker, A. R., Zhang, Y.
    Oxford University Press
    Details
    Publication Date: 2016-03-09
    Description: We use the first-year Dark Energy Survey (DES) data down to previously unprobed photometric depths to search for stellar systems in the Galactic halo, therefore complementing the previous analysis of the same data carried out by our group earlier this year. Our search is based on a matched filter algorithm that produces stellar density maps consistent with stellar population models of various ages, metallicities, and distances over the survey area. The most conspicuous density peaks in these maps have been identified automatically and ranked according to their significance and recurrence for different input models. We report the discovery of one additional stellar system besides those previously found by several authors using the same first-year DES data. The object is compact, and consistent with being dominated by an old and metal-poor population. DES 1 is found at high significance and appears in the DES images as a compact concentration of faint blue point sources. Assuming different spatial profile parameterizations, the best-fitting heliocentric distance and total absolute magnitude in the range of 77.6–87.1 kpc and –3.00 M V  –2.21, respectively. The half-light radius of this object, r h  ~ 10 pc and total luminosity are consistent with it being a low-mass halo cluster. It is also found to have a very elongated shape ( ~ 0.57). In addition, our deeper probe of DES first-year data confirms the recently reported satellite galaxy candidate Horologium II as a significant stellar overdensity. We also infer its structural properties and compare them to those reported in the literature.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 9
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    How Archiving by Freezing Affects the Genome-Scale Diversity of Escherichia coli Populations (2016)
    Oxford University Press
    Details
    Publication Date: 2016-05-11
    Description: In the experimental evolution of microbes such as Escherichia coli , many replicate populations are evolved from a common ancestor. Freezing a population sample supplemented with the cryoprotectant glycerol permits later analysis or restarting of an evolution experiment. Typically, each evolving population, and thus each sample archived in this way, consists of many unique genotypes and phenotypes. The effect of archiving on such a heterogeneous population is unknown. Here, we identified optimal archiving conditions for E. coli. We also used genome sequencing of archived samples to study the effects that archiving has on genomic population diversity. We observed no allele substitutions and mostly small changes in allele frequency. Nevertheless, principal component analysis of genome-scale allelic diversity shows that archiving affects diversity across many loci. We showed that this change in diversity is due to selection rather than drift. In addition, ~1% of rare alleles that occurred at low frequencies were lost after treatment. Our observations imply that archived populations may be used to conduct fitness or other phenotypic assays of populations, in which the loss of a rare allele may have negligible effects. However, caution is appropriate when sequencing populations restarted from glycerol stocks, as well as when using glycerol stocks to restart or replay evolution. This is because the loss of rare alleles can alter the future evolutionary trajectory of a population if the lost alleles were strongly beneficial.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 10
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    Evaluation of Oral PF-04449913 in Solid Tumors (2015)
    The American Association for Cancer Research (AACR)
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    Publication Date: 2015-03-03
    Description: Purpose: To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced tumors. Experimental Design: A 3+3 design was used in this open-label, multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD. PF-04449913 was orally administered once daily in continuous 28-day treatment cycles. The starting dose was 80 mg. Results: A total of 23 patients were enrolled; 19 were evaluable for first-cycle dose-limiting toxicity (DLT). The first-cycle DLT rate at the 640 mg dose level was 33.3%, and the MTD was estimated to be 320 mg once daily. The recommended phase II dose was not determined. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most common treatment-related adverse events (AE) were grade 1–2 dysgeusia, fatigue, decreased appetite, nausea, dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receiving PF-04449913 640 mg once daily. No treatment-related grade 4–5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-daily dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by 〉80% downregulation of GLI1 expression in the skin of treated patients. Eight patients (34.8%) achieved stable disease; none had complete or partial response. Three patients with disease progression at enrollment had prolonged disease stabilization (≥6 months). Conclusions: The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors. Clin Cancer Res; 21(5); 1044–51. ©2014 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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