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Leveraging nature's tool kit

Adrian Woolfson
2019 Science  
BIOENGINEERING By Adrian Woolfson Leveraging nature's tool kit The reviewer is the executive vice president of research and development at Sangamo Therapeutics, San Francisco, CA.  ... 
doi:10.1126/science.aaw9433 fatcat:ktmndi2x7bgbxp24fmupeeifti

Profiling CD antigens on leukaemias with an antibody microarray

Nicole Barber, Swetlana Gez, Larissa Belov, Stephen P. Mulligan, Adrian Woolfson, Richard I. Christopherson
2009 FEBS Letters  
Edited by Miguel De la Rosa Keywords: Leukaemia Lymphoma Cluster of differentiation antigen Microarray a b s t r a c t Cluster of differentiation (CD) antigens are defined when a surface molecule found on some members of a standard panel of human cells reacts with at least one novel antibody, and there is good accompanying molecular data. Monoclonal antibodies to surface CD antigens on leukocytes have been used for flow cytometry, and more recently to construct microarrays that capture live
more » ... s. These DotScan TM microarrays enable the rapid and highly parallel characterization of repertoires of CD antigens whose expression patterns may be correlated with discrete leukaemia subtypes, or used to define biomarker 'signatures' for non-hematological diseases. DotScan TM with fluorescence multiplexing enables profiling of CD antigens for minor subsets of cells, such as colorectal cancer cells and tumour-infiltrating lymphocytes from a surgical sample.
doi:10.1016/j.febslet.2009.03.018 pmid:19298816 fatcat:2uolfqz375f3fapqfkwguhjnyy

Structural Capacitance in Protein Evolution and Human Diseases [article]

Chen Li, Liah VT Clark, Rory Zhang, Benjamin T Porebski, Julia M McCoey, Natalie A Borg, Geoffrey I Webb, Itamar Kass, Malcolm Buckle, Jiangning Song, Adrian Woolfson, Ashley M Buckle
2018 bioRxiv   pre-print
Canonical mechanisms of protein evolution include the duplication and diversification of pre-existing folds through genetic alterations that include point mutations, insertions, deletions, and copy number amplifications, as well as post-translational modifications that modify processes such as folding efficiency and cellular localization. Following a survey of the human mutation database, we have identified an additional mechanism, that we term 'structural capacitance', which results in the de
more » ... ovo generation of microstructure in previously disordered regions. We suggest that the potential for structural capacitance confers select proteins with the capacity to evolve over rapid timescales, facilitating saltatory evolution as opoposed to exclusively canonical Darwinian mechanisms. Our results implicate the elements of protein microstructure generated by this distinct mechanism in the pathogenesis of a wide variety of human diseases. The benefits of rapidly furnishing the potential for evolutionary change conferred by structural capacitance are consequently counterbalanced by this accompanying risk, with the extent of this determined by the host immune system. The phenomenon of structural capacitance has implications ranging from the ancestral diversification of protein folds to the engineering of synthetic proteins with enhanced evolvability.
doi:10.1101/269613 fatcat:262odgy2vvbwxp3724bhef5nc4

Selective JAK2/ABL dual inhibition therapy effectively eliminates TKI-insensitive CML stem/progenitor cells

Hanyang Lin, Min Chen, Katharina Rothe, Matthew V. Lorenzi, Adrian Woolfson, Xiaoyan Jiang
2014 OncoTarget  
Imatinib Mesylate (IM) and other tyrosine kinase inhibitor (TKI) therapies have had a major impact on the treatment of chronic myeloid leukemia (CML). However, TKI monotherapy is not curative, with relapse and persistence of leukemic stem cells (LSCs) remaining a challenge. We have recently identified an AHI-1-BCR-ABL-JAK2 protein complex that contributes to the transforming activity of BCR-ABL and IMresistance in CML stem/progenitor cells. JAK2 thus emerges as an attractive target for improved
more » ... therapies, but off-target effects of newly developed JAK2 inhibitors on normal hematopoietic cells remain a concern. We have examined the biological effects of a highly selective, orally bioavailable JAK2 inhibitor, BMS-911543, in combination with TKIs on CD34 + treatment-naïve IM-nonresponder cells. Combination therapy reduces JAK2/STAT5 and CRKL activities, induces apoptosis, inhibits proliferation and colony growth, and eliminates CML LSCs in vitro. Importantly, BMS-911543 selectively targets CML stem/progenitor cells while sparing healthy stem/progenitor cells. Oral BMS-911543 combined with the potent TKI dasatinib more effectively eliminates infiltrated leukemic cells in hematopoietic tissues than TKI monotherapy and enhances survival of leukemic mice. Dual targeting BCR-ABL and JAK2 activities in CML stem/ progenitor cells may consequently lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.
doi:10.18632/oncotarget.2353 pmid:25226617 pmcid:PMC4226710 fatcat:xdg7gwerhnc33isrgcciiiwo4i

Maintaining and breaking symmetry in homomeric coiled-coil assemblies

Guto G. Rhys, Christopher W. Wood, Eric J. M. Lang, Adrian J. Mulholland, R. Leo Brady, Andrew R. Thomson, Derek N. Woolfson
2018 Nature Communications  
The scripts used to perform this analysis are available online through GitHub: ( Explicit-solvent constant pH-REMD.  ... 
doi:10.1038/s41467-018-06391-y pmid:30297707 pmcid:PMC6175849 fatcat:7ray7y5jk5g5rfjbo2qcabsqle

Targeting the Chronic Myeloid Leukemia Stem Cell: A Paradigm for the Curative Treatment of Human Malignancies [chapter]

Adrian Woolfson, Xiaoyan Jiang
2011 Myeloid Leukemia - Basic Mechanisms of Leukemogenesis  
Woolfson is an employee of Bristol-Myers Squibb, some of whose products are discussed in this chapter.  ...  How to reference In order to correctly reference this scholarly work, feel free to copy and paste the following: Adrian Woolfson and Xiaoyan Jiang (2011) .  ... 
doi:10.5772/29354 fatcat:6wygdzjrhff6zdxxl5tykd35dy

Structural resolution of switchable states of a de novo peptide assembly

William M. Dawson, Eric J. M. Lang, Guto G. Rhys, Kathryn L. Shelley, Christopher Williams, R. Leo Brady, Matthew P. Crump, Adrian J. Mulholland, Derek N. Woolfson
2021 Nature Communications  
AbstractDe novo protein design is advancing rapidly. However, most designs are for single states. Here we report a de novo designed peptide that forms multiple α-helical-bundle states that are accessible and interconvertible under the same conditions. Usually in such designs amphipathic α helices associate to form compact structures with consolidated hydrophobic cores. However, recent rational and computational designs have delivered open α-helical barrels with functionalisable cavities. By
more » ... ing glycine judiciously in the helical interfaces of an α-helical barrel, we obtain both open and compact states in a single protein crystal. Molecular dynamics simulations indicate a free-energy landscape with multiple and interconverting states. Together, these findings suggest a frustrated system in which steric interactions that maintain the open barrel and the hydrophobic effect that drives complete collapse are traded-off. Indeed, addition of a hydrophobic co-solvent that can bind within the barrel affects the switch between the states both in silico and experimentally.
doi:10.1038/s41467-021-21851-8 pmid:33750792 fatcat:wtvcq7zmgrcahmvcatilnyxkga

A catalytic role for methionine revealed by a combination of computation and experiments on phosphite dehydrogenase

Kara E. Ranaghan, John E. Hung, Gail J. Bartlett, Tiddo J. Mooibroek, Jeremy N. Harvey, Derek N. Woolfson, Wilfred A. van der Donk, Adrian J. Mulholland
2014 Chemical Science  
Novel role for methionine in enzyme catalysis.
doi:10.1039/c3sc53009d fatcat:xghzlaoqrrazbf7vpls5md7a3i

Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies

Yosuke Minami, Hironobu Minami, Toshihiro Miyamoto, Goichi Yoshimoto, Yukio Kobayashi, Wataru Munakata, Yasushi Onishi, Masahiro Kobayashi, Mari Ikuta, Geoffrey Chan, Adrian Woolfson, Chiho Ono (+4 others)
2017 Cancer Science  
資源タイプ Resource Type Journal Article / 学術雑誌論文 版区分 Resource Version publisher 権利 Rights
doi:10.1111/cas.13285 pmid:28556364 pmcid:PMC5543507 fatcat:753yft5bl5bafcp3drzkrkqgwq

Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers

Shaohua Peng, Chad J Creighton, Yiqun Zhang, Banibrata Sen, Tuhina Mazumdar, Jeffery N Myers, Adrian Woolfson, Matthew V Lorenzi, Diana Bell, Michelle D Williams, Faye M Johnson
2013 Journal of Translational Medicine  
The patient-derived xenograft (PDX) model is likely to reflect human tumor biology more accurately than cultured cell lines because human tumors are implanted directly into animals; maintained in an in vivo, three-dimensional environment; and never cultured on plastic. PDX models of head and neck squamous cell carcinoma (HNSCC) have been developed previously but were not well characterized at the molecular level. HNSCC is a deadly and disfiguring disease for which better systemic therapy is
more » ... erately needed. The development of new therapies and the understanding of HNSCC biology both depend upon clinically relevant animal models. We developed and characterized the patient-derived xenograft (PDX) model because it is likely to recapitulate human tumor biology. Methods: We transplanted 30 primary tumors directly into mice. The histology and stromal components were analyzed by immunohistochemistry. Gene expression analysis was conducted on patient tumors and on PDXs and cell lines derived from one PDX and from independent, human tumors. Results: Five of 30 (17%) transplanted tumors could be serially passaged. Engraftment was more frequent among HNSCC with poor differentiation and nodal disease. The tumors maintained the histologic characteristics of the parent tumor, although human stromal components were lost upon engraftment. The degree of difference in gene expression between the PDX and its parent tumor varied widely but was stable up to the tenth generation in one PDX. For genes whose expression differed between parent tumors and cell lines in culture, the PDX expression pattern was very similar to that of the parent tumor. There were also significant expression differences between the human tumors that subsequently grew in mice and those that did not, suggesting that this model enriches for cancers with distinct biological features. The PDX model was used successfully to test targeted drugs in vivo. Conclusion: The PDX model for HNSCC is feasible, recapitulates the histology of the original tumor, and generates stable gene expression patterns. Gene expression patterns and histology suggested that the PDX more closely recapitulated the parental tumor than did cells in culture. Thus, the PDX is a robust model in which to evaluate tumor biology and novel therapeutics.
doi:10.1186/1479-5876-11-198 pmid:23981300 pmcid:PMC3844397 fatcat:hcxg5zyj2jc5bae2pmqfcec77q

Correction: Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and Histologic characteristics of human cancers

Shaohua Peng, Chad J Creighton, Yiqun Zhang, Banibrata Sen, Tuhina Mazumdar, Jeffery N Myers, Stephen Y Lai, Adrian Woolfson, Matthew V Lorenzi, Diana Bell, Michelle D Williams, Faye M Johnson
2014 Journal of Translational Medicine  
Correction We inadvertently failed to include the complete list of all coauthors for this work [1]. The full list of authors has now been added and the Authors' contributions and Competing interests section modified.
doi:10.1186/1479-5876-12-67 pmcid:PMC3975150 fatcat:hyxbqyjmszharglfrotfecduui

First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas

Ajay K Gopal, Ronald Levy, Roch Houot, Sandip P. Patel, Leslie Popplewell, Caron Jacobson, Xinmeng J Mu, Shibing Deng, Keith A Ching, Ying Chen, Craig B Davis, Bo Huang (+4 others)
2020 Clinical Cancer Research  
In this phase I study (NCT01307267), we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular lymphoma (FL) and other CD20+ non-Hodgkin lymphomas (NHL). Primary objectives were to assess treatment safety and tolerability for estimating the MTD, using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D). Sixty-seven patients
more » ... ed utomilumab (0.03-10.0 mg/kg every 4 weeks) and rituximab (375 mg/m2 weekly) in the dose-escalation groups or utomilumab (1.2 mg/kg every 4 weeks) plus rituximab in the dose-expansion cohort. No patient experienced dose-limiting toxicity. The MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg every 4 weeks. The majority of the utomilumab treatment-related adverse events (AE) were grade 1 to 2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03 to 10 mg/kg dose range. A low incidence (1.5%) of treatment-induced antidrug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI, 12.1%-33.0%) in all patients with NHL, including four complete and 10 partial responses. Analysis of paired biopsies from a relapsed/refractory FL patient with complete response showed increased T-cell infiltration and cytotoxic activity in tumors. Biomarker correlations with outcomes suggested that clinical benefit may be contingent on patient immune function. Utomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20+ NHLs.
doi:10.1158/1078-0432.ccr-19-2973 pmid:32144134 fatcat:wt4wmdrwv5gmxal6dg7wr6ewci

Page 438 of Human Resources Abstracts Vol. 41, Issue 3 [page]

2006 Human Resources Abstracts  
, Kim D., 0607 Wong, Kin Fai Ellick, 0713 Wood, John, 0780 Woolfson, Charles, 0763 Wortmann, Michael, 0757 Wright, Christopher, 0815 Wright, Gill, 0793 Wright, Patrick M., 0753, 0781 Wu, Joshua B., 0749  ...  ., 0752 Wilkinson, Adrian, 0755 Williams, Sadie, 0643 Willman, Paul, 0738 Willmott, Hugh, 0838 Wilson, John, 0897 Winchester, Nik, 0767 Wine, Byron, 0752 Winstanley, Sue, 0665 Winston, Bruce E., 0778 Witko  ... 

Page 1019 of American Anthropologist Vol. 85, Issue 4 [page]

1983 American Anthropologist  
., 204 Indians and Criminal Justice Indians A Cri Shepard Animals reviewed by Adrian Tanner, Laurence French, ed., reviewed by James E.  ...  Crawford, 741 Known as Labour Theory of Culture, The: A Re-exam ination of Engel’s Theory of Human Origins, Charles Woolfson, Philip L.  ... 

Page 112 of Endeavour Vol. 26, Issue 98 [page]

1967 Endeavour  
Woolfson.  ...  Inman iiber die Strukturgrundlagen der Spezifi- tat von Antikérpern, von Mundry iiber die Wechselwirkungen zwischen Pflan- zenviren und Wirtszellen, von Adrian Srb iiber extrachromosomale Erblichkeit in  ... 
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