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7. Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells

Author

Jones, Courtney L., Stevens, Brett M., Pollyea, Daniel A., Culp-Hill, Rachel, Reisz, Julie A., Nemkov, Travis, Gehrke, Sarah, Gamboni, Fabia, Krug, Anna, Winters, Amanda, Pei, Shanshan, Gustafson, Annika, Ye, Haobin, Inguva, Anagha, Amaya, Maria, Minhajuddin, Mohammad, Abbott, Diana, Becker, Michael W., DeGregori, James, Smith, Clayton A., D’Alessandro, Angelo, and Jordan, Craig T.

Published
2020
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12. Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia

Author

Winters, Amanda C., Gutman, Jonathan A., Purev, Enkhtsetseg, Nakic, Molly, Tobin, Jennifer, Chase, Stephanie, Kaiser, Jeff, Lyle, Lindsey, Boggs, Chelsey, Halsema, Keri, Schowinsky, Jeffrey T., Rosser, Julie, Ewalt, Mark D., Siegele, Bradford, Rana, Vishal, Schuster, Steven, Abbott, Diana, Stevens, Brett M., Jordan, Craig T., Smith, Clayton, and Pollyea, Daniel A.

Published
2019
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14. Sequential azacitidine and lenalidomide for patients with relapsed and refractory acute myeloid leukemia: Clinical results and predictive modeling using computational analysis

Author

Stevens, Brett, Winters, Amanda, Gutman, Jonathan A., Fullerton, Aaron, Hemenway, Gregory, Schatz, Derek, Miltgen, Nicholas, Wei, Qi, Abbasi, Taher, Vali, Shireen, Singh, Neeraj K., Drusbosky, Leylah, Cogle, Christopher R., Hammes, Andrew, Abbott, Diana, Jordan, Craig T., Smith, Clayton, and Pollyea, Daniel A.

Published
2019
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16. The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells

Author

Adane, Biniam, Ye, Haobin, Khan, Nabilah, Pei, Shanshan, Minhajuddin, Mohammad, Stevens, Brett M., Jones, Courtney L., D’Alessandro, Angelo, Reisz, Julie A., Zaberezhnyy, Vadym, Gasparetto, Maura, Ho, Tzu-Chieh, Kelly, Kathleen K., Myers, Jason R., Ashton, John M., Siegenthaler, Julie, Kume, Tsutomu, Campbell, Eric L., Pollyea, Daniel A., Becker, Michael W., and Jordan, Craig T.

Published
2019
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17. Linked data for libraries: benefits of a conceptual shift from library-specific record structures to RDF-based data models

Author

Alemu, Getaneh, Stevens, Brett, Ross, Penny, and Chandler, Jane

Subjects
IA. Cataloging, bibliographic control., IF. Information transfer: protocols, formats, techniques., IG. Information presentation: hypertext, hypermedia., LC. Internet, including WWW., LR. OPAC systems.
Abstract

Contemporary metadata principles and standards tended to result in document-centric rather than data-centric; human-readable rather than machine-processable metadata. In order for libraries to create and harness shareable, mashable and re-usable metadata, a conceptual shift can be achieved by adjusting current library models such as Resource Description and Access (RDA) and Functional Requirements for Bibliographic Records (FRBR) to models based on Linked Data principles. In relation to technical formats, libraries can leapfrog to Linked Data technical formats such as the Resource Description Framework (RDF), without disrupting current library metadata operations. This paper provides six key recommendations for libraries and standards agencies. These include rising to the challenges and embracing the opportunities presented by current technological trends, adopting minimal requirements of Linked Data principles, developing ontologies, deciding on what needs to be retained from current library models, becoming part of the Linked Data cloud, and developing mixed-metadata (standards-based and socially-constructed) approaches. Finally, the paper concludes by identifying and discussing five major benefits of such metadata re-conceptualisation. The benefits include metadata openness and sharing, serendipitous discovery of information resources, identification of zeitgeist and emergent metadata, facet-based navigation and metadata enriched with links.

Published
2012

18. Semantic Metadata Interoperability in Digital Libraries: A Constructivist Grounded Theory Approach

Author

Alemu, Getaneh, Stevens, Brett, Ross, Penny, Freund, Luanne, Rasmussen, Edie, and Sugiyama, Kazunari

Subjects
A. Theoretical and general aspects of libraries and information., LR. OPAC systems.
Abstract

This paper highlights problems of semantic metadata interoperability in digital libraries. The prevalence of a plethora of standards and a lack of semantic interoperability can partly be attributed to the absence of theoretical foundations to underpin current metadata approaches and solutions. Contemporary metadata standards and interoperability approaches are mainly top-down and hierarchical, and, hence, fail to take into account the diversity of cultural, linguistic and local perspectives that abound. To overcome this, it is proposed that a social constructivist approach should be adopted by libraries and other cultural heritage institutions when archiving information objects that need to be enriched with metadata, thereby reflecting the diversity of views and perspectives that can be held by their users. Following on Charmaz [1], a constructivist grounded theory method is employed to investigate how library professionals and library users view metadata standards, collaborative metadata approaches and semantic web technologies in relation to semantic metadata interoperability. This method allows an active interplay between the researcher and the participants who can be either Library and Information Science researchers, librarians or library users. Following the completion first phase of data collection, preliminary reflections are presented, with emphasis on how Library and Information Science professionals view current metadata practices, especially as used in academic library contexts. However, as the study is ongoing one, it is too early to generate theoretical categories and conclusions.

Published
2011

19. Machine Learning–Based Exploratory Clinical Decision Support for Newly Diagnosed Patients With Acute Myeloid Leukemia Treated With 7 + 3 Type Chemotherapy or Venetoclax/Azacitidine

Author

Islam, Nazmul, Reuben, Jamie S., Dale, Justin, Gutman, Jon, McMahon, Christine M., Amaya, Maria, Goodman, Bruce, Toninato, Joseph, Gasparetto, Maura, Stevens, Brett, Pei, Shanshan, Gillen, Austin, Staggs, Sarah, Engel, Krysta, Davis, Sarah, Hull, Madelyne, Burke, Elizabeth, Larchick, Lenny, Zane, Richard, Weller, Grant, Jordan, Craig, and Smith, Clay

Published
2022
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22. Intermittent Search, Not Strict Lévy Flight, Evolves under Relaxed Foraging Distribution Constraints.

Author

Campeau, Winston, Simons, Andrew M., and Stevens, Brett

Subjects
LEVY processes, RANDOM walks, FORAGING behavior, EVOLUTIONARY models, EVOLUTIONARY algorithms
Abstract

The survival of an animal depends on its success as a forager, and understanding the adaptations that result in successful foraging strategies is an enduring endeavour of behavioral ecology. Random walks are one of the primary mathematical descriptions of foraging behavior. Power law distributions are often used to model random walks, as they can characterize a wide range of behaviors, including Lévy walks. Empirical evidence indicates the prevalence and efficiency of Lévy walks as a foraging strategy, and theoretical work suggests an evolutionary origin. However, previous evolutionary models have assumed a priori that move lengths are drawn from a power law or other families of distributions. Here, we remove this restriction with a model that allows for the evolution of any distribution. Instead of Lévy walks, our model unfailingly results in the evolution of intermittent search, a random walk composed of two disjoint modes—frequent localized walks and infrequent extensive moves—that consistently outcompeted Lévy walks. We also demonstrate that foraging using intermittent search may resemble a Lévy walk because of interactions with the resources within an environment. These extrinsically generated Lévy-like walks belie an underlying behavior and may explain the prevalence of Lévy walks reported in the literature. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia

Author

Pollyea, Daniel A., Stevens, Brett M., Jones, Courtney L., Winters, Amanda, Pei, Shanshan, Minhajuddin, Mohammad, D’Alessandro, Angelo, Culp-Hill, Rachel, Riemondy, Kent A., Gillen, Austin E., Hesselberth, Jay R., Abbott, Diana, Schatz, Derek, Gutman, Jonathan A., Purev, Enkhtsetseg, Smith, Clayton, and Jordan, Craig T.

Published
2018
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34. CD46–ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts.

Author

VanWyngarden, Michael J., Walker, Zachary J., Su, Yang, Perez de Acha, Olivia, Stevens, Brett M., Forsberg, Peter A., Mark, Tomer M., Matsui, William, Liu, Bin, and Sherbenou, Daniel W.

Subjects
THERAPEUTIC use of monoclonal antibodies, IN vitro studies, FLOW cytometry, DRUG efficacy, STATISTICS, XENOGRAFTS, IN vivo studies, ANALYSIS of variance, ALDEHYDE dehydrogenase, T-test (Statistics), ENZYME-linked immunosorbent assay, DESCRIPTIVE statistics, RESEARCH funding, MULTIPLE myeloma, TUMOR antigens, CELL lines, HEMATOPOIETIC stem cells, DATA analysis software, DATA analysis, ANTIGENS, PHENOTYPES, MICE
Abstract

Simple Summary: Multiple myeloma (MM) is incurable, implying that the disease cells are inherently resistant to current agents and inevitably lead to relapse. One strategy to improve the treatment paradigm is to pursue novel drug targets that are associated with relapsed disease. Towards this end, we developed a novel antibody–drug conjugate (ADC) that targets the cell surface complement inhibitor CD46. Here, we study the potential of this new agent to affect disease initiation. The gene encoding for CD46 is amplified on chromosome 1q in the majority of relapsed myeloma patients, as well as cells containing stem-like aldehyde dehydrogenase activity. We demonstrate the curative potential of CD46–ADC via its ability to abrogate disease engraftment of primary MM cell xenografts. In combination with a recent clinical trial, this study supports the continued study of CD46 as a therapeutic target in MM. An antibody–drug conjugate (ADC) targeting CD46 conjugated to monomethyl auristatin has a potent anti-myeloma effect in cell lines in vitro and in vivo, and patient samples treated ex vivo. Here, we tested if CD46–ADC may have the potential to target MM-initiating cells (MM-ICs). CD46 expression was measured on primary MM cells with a stem-like phenotype. A patient-derived xenograft (PDX) model was implemented utilizing implanted fetal bone fragments to provide a humanized microenvironment. Engraftment was monitored via serum human light chain ELISA, and at sacrifice via bone marrow and bone fragment flow cytometry. We then tested MM regeneration in PDX by treating mice with CD46–ADC or the nonbinding control–ADC. MM progenitor cells from patients that exhibit high aldehyde dehydrogenase activity also have a high expression of CD46. In PDX, newly diagnosed MM patient samples engrafted significantly more compared to relapsed/refractory samples. In mice transplanted with newly diagnosed samples, CD46–ADC treatment showed significantly decreased engraftment compared to control–ADC treatment. Our data further support the targeting of CD46 in MM. To our knowledge, this is the first study to show preclinical drug efficacy in a PDX model of MM. This is an important area for future study, as patient samples but not cell lines accurately represent intratumoral heterogeneity. [ABSTRACT FROM AUTHOR]

Published
2023
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36. MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia

Author

Riedel, Simone S., Haladyna, Jessica N., Bezzant, Matthew, Stevens, Brett, Pollyea, Daniel A., Sinha, Amit U., Armstrong, Scott A., Wei, Qi, Pollock, Roy M., Daigle, Scott R., Jordan, Craig T., Ernst, Patricia, Neff, Tobias, and Bernt, Kathrin M.

Subjects
Observations, Development and progression, Innovations, Genetic aspects, Properties, Methyltransferases -- Properties, Molecular targeted therapy -- Innovations, Gene expression -- Observations, Acute myelocytic leukemia -- Genetic aspects -- Development and progression
Abstract

Introduction The meningioma-1 (MN1) gene is frequently overexpressed in acute myeloid leukemia (AML) and is associated with a poor prognosis (1-5). High MN1 expression occurs across multiple cytogenetic and molecular [...], Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meisl as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either Mill or Dotll in MN1-expressing cells abrogated the cell of origin-derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mill or Dotll impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical [MN1.sup.hi] leukemia, and human [MN1.sup.hi]/[HOXA9.sup.hi] leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in [MN1.sup.hi] AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML.

Published
2016
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37. Some complementary Gray codes

Author

Hoyt, Adam and Stevens, Brett

Subjects
94B25, 05C45, Mathematics - Combinatorics, G.2.1
Abstract

A complementary Gray code for binary n-tuples is one that, when all the tuples are complemented, is identical to itself; this is equivalent to the complement of the first half of the code being identical to the second half. We generalize the notion of complementary to q-ary n-tuples, fixed size combinations of an n-set and permutations and, in each case, construct complementary Gray codes. We relax, as weakly as possible, the notions of complementary to cases where necessary conditions for existence are violated and construct Gray codes within the weakened definitions: these include binary n-tuples when n is odd and Lee metric q-ary n-tuples when n is odd and q is even. Finally a lemma used in the construction for permutations offers the first known cyclic Gray code for the permutations of a particular family of multisets., Comment: 22 pages, 14 Tables

Published
2022

38. Sets of mutually orthogoval projective and affine planes

Author

Colbourn, Charles J., Ingalls, Colin, Jedwab, Jonathan, Saaltink, Mark, Smith, Ken W., and Stevens, Brett

Subjects
FOS: Computer and information sciences, Discrete Mathematics (cs.DM), FOS: Mathematics, Mathematics - Combinatorics, Combinatorics (math.CO), Computer Science - Discrete Mathematics, 51E15, 51E21, 05B25 (Primary) 05B15, 05B40 (Secondary)
Abstract

A pair of planes, both projective or both affine, of the same order and on the same pointset are orthogoval if each line of one plane intersects each line of the other plane in at most two points. In this paper we prove new constructions for sets of mutually orthogoval planes, both projective and affine, and review known results that are equivalent to sets of more than two mutually orthogoval planes. We also discuss the connection between sets of mutually orthogoval planes and covering arrays., 20 pages

Published
2022

40. Difference Methods for Double Change Covering Designs

Author

Chafee, Amanda Lynn and Stevens, Brett

Subjects
05B10, 05B40, 05C70, FOS: Mathematics, Mathematics - Combinatorics, Combinatorics (math.CO)
Abstract

A \textbf{double change covering design} is a $v$-set $X$ and an ordered list $\mathcal{L}$ of $b$ blocks of size $k$ where every $t$-set must occur in at least one block. Each pair of consecutive blocks differs by exactly two elements. A double change covering design is circular when the first and last blocks also differ by two elements. We give a recursive construction that uses 1-factorizations and expansion sets to increase $v$ by $\frac{v+k-2}{k-2}$. We construct ${\rm CDCCD}(2k-2,k,k-1)$ and ${\rm CDCCD}(2k-1,k,k-2)$ from single change covering designs. We use difference methods to construct tight ${\rm CDCCD(4k-5,k,4k-5)$, five infinite families for any $k\geq 3$, minimum ${\rm CDCCD}(c(4k-6)+1,k,c^2(4k-6)+c)$ when $c\leq 5$ and ${\rm CDCCD}(61,4,366)$. Finally, from these, we use the recursion to construct twelve additional minimum CDCCD., 17 pages, 8 tables, 5 figures

Published
2022

41. Ordered Covering Arrays and Upper Bounds on Covering Codes in NRT spaces

Author

Castoldi, André Guerino, Carmelo, Emerson L. Monte, Moura, Lucia, Panario, Daniel, and Stevens, Brett

Subjects
FOS: Computer and information sciences, Information Theory (cs.IT), Computer Science - Information Theory, FOS: Mathematics, Mathematics - Combinatorics, Combinatorics (math.CO)
Abstract

This work shows several direct and recursive constructions of ordered covering arrays using projection, fusion, column augmentation, derivation, concatenation and cartesian product. Upper bounds on covering codes in NRT spaces are also obtained by improving a general upper bound. We explore the connection between ordered covering arrays and covering codes in NRT spaces, which generalize similar results for the Hamming metric. Combining the new upper bounds for covering codes in NRT spaces and ordered covering arrays, we improve upper bounds on covering codes in NRT spaces for larger alphabets. We give tables comparing the new upper bounds for covering codes to existing ones., 27 pages

Published
2022

44. Linear and circular single‐change covering designs revisited.

Author

Chafee, Amanda and Stevens, Brett

Subjects
*DIFFERENCE sets
Abstract

A single‐change covering design (SCCD) is a v $v$‐set X $X$ and an ordered list ℒ ${\rm{ {\mathcal L} }}$ of b $b$ blocks of size k $k$ where every pair from X $X$ must occur in at least one block. Each pair of consecutive blocks differs by exactly one element. This is a linear single‐change covering design, or more simply, a single‐change covering design. A single‐change covering design is circular when the first and last blocks also differ by one element. A single‐change covering design is minimum if no other smaller design can be constructed for a given v,k $v,k$. In this paper, we use a new recursive construction to solve the existence of circular SCCD(v,4,b $v,4,b$) for all v $v$ and three residue classes of circular SCCD(v,5,b $v,5,b$) modulo 16. We solve the existence of three residue classes of SCCD(v,5,b) $(v,5,b)$ modulo 16. We prove the existence of circular SCCD(2c(k−1)+1,k,c2(2k−2)+c) $(2c(k-1)+1,k,{c}^{2}(2k-2)+c)$, for all c≥1,k≥2 $c\ge 1,k\ge 2$, using difference methods. [ABSTRACT FROM AUTHOR]

Published
2023
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48. Nonexistence Certificates for Ovals in a Projective Plane of Order Ten

Author

Bright, Curtis, Cheung, Kevin K. H., Stevens, Brett, Kotsireas, Ilias, and Ganesh, Vijay

Subjects
FOS: Computer and information sciences, Computer Science - Symbolic Computation, Computer Science - Logic in Computer Science, Discrete Mathematics (cs.DM), Symbolic Computation (cs.SC), Article, Logic in Computer Science (cs.LO), Satisfiability checking, Symbolic computation, Combinatorial search, FOS: Mathematics, Mathematics - Combinatorics, Combinatorics (math.CO), Computer Science - Discrete Mathematics
Abstract

In 1983, a computer search was performed for ovals in a projective plane of order ten. The search was exhaustive and negative, implying that such ovals do not exist. However, no nonexistence certificates were produced by this search, and to the best of our knowledge the search has never been independently verified. In this paper, we rerun the search for ovals in a projective plane of order ten and produce a collection of nonexistence certificates that, when taken together, imply that such ovals do not exist. Our search program uses the cube-and-conquer paradigm from the field of satisfiability (SAT) checking, coupled with a programmatic SAT solver and the nauty symbolic computation library for removing symmetries from the search., Appears in the Proceedings of the 31st International Workshop on Combinatorial Algorithms (IWOCA 2020)

Published
2020

49. Towards a conceptual framework for user-driven semantic metadata interoperability in digital libraries: A social constructivist approach

Author

Alemu, Getaneh, Stevens, Brett, and Ross, Penny

Subjects
AA. Library and information science as a field., AB. Information theory and library theory., IA. Cataloging, bibliographic control., IE. Data and metadata structures., LR. OPAC systems.
Abstract

Purpose – With the aim of developing a conceptual framework which aims to facilitate semantic metadata interoperability, this paper explores overarching conceptual issues on how traditional library information organization schemes such as Online Public Access Catalogues (OPACs), taxonomies, thesauri, and ontologies on the one hand versus Web 2.0 technologies such as social tagging (folksonomies) can be harnessed to provide users with satisfying experiences. Design/methodology/approach –This paper reviews works in relation to current metadata creation, utilization and interoperability approaches focusing on how a social constructivist philosophical perspective can be employed to underpin metadata decisions in digital libraries. Articles are retrieved from databases such as EBSCO host and Emerald and online magazines such as D-Lib and Ariadne. Books, news articles and blog posts that are deemed relevant are also used to support the arguments put forward in this paper. Findings – Current metadata approaches are deeply authoritative and metadata deployments in digital libraries tend to favour an objectivist approach with focus on metadata simplicity. It is argued that unless information objects are enriched with metadata generated through a collaborative and user-driven approach, achieving semantic metadata interoperability in digital libraries will remain difficult. Practical implications – In this paper, it is indicated that the number of metadata elements (fields) constituting a standard has a direct bearing on metadata richness, which in turn directly affects semantic interoperability. It is expected that this paper will contribute towards a better understanding of harnessing user-driven metadata. Originality/value – As suggested in this paper, a conceptual metadata framework which is underpinned by a social constructivist approach substantially contributes to semantic interoperability in digital libraries.

Published
2012

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