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  1. Article ; Online: Collateral responses to classical cytotoxic chemotherapies are heterogeneous and sensitivities are sparse

    Simona Dalin / Beatrice Grauman-Boss / Douglas A. Lauffenburger / Michael T. Hemann

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 14

    Abstract: Abstract Chemotherapy resistance is a major obstacle to curing cancer patients. Combination drug regimens have shown promise as a method to overcome resistance; however, to date only some cancers have been cured with this method. Collateral sensitivity— ... ...

    Abstract Abstract Chemotherapy resistance is a major obstacle to curing cancer patients. Combination drug regimens have shown promise as a method to overcome resistance; however, to date only some cancers have been cured with this method. Collateral sensitivity—the phenomenon whereby resistance to one drug is co-occurrent with sensitivity to a second drug—has been gaining traction as a promising new concept to guide rational design of combination regimens. Here we evolved over 100 subclones of the Eµ-Myc; p19ARF−/− cell line to be resistant to one of four classical chemotherapy agents: doxorubicin, vincristine, paclitaxel, and cisplatin. We then surveyed collateral responses to acquisition of resistance to these agents. Although numerous collateral sensitivities have been documented for antibiotics and targeted cancer therapies, we observed only one collateral sensitivity: half of cell lines that acquired resistance to paclitaxel also acquired a collateral sensitivity to verapamil. However, we found that the mechanism of this collateral sensitivity was unrelated to the mechanism of paclitaxel resistance. Interestingly, we observed heterogeneity in the phenotypic response to acquisition of resistance to most of the drugs we tested, most notably for paclitaxel, suggesting the existence of multiple different states of resistance. Surprisingly, this phenotypic heterogeneity in paclitaxel resistant cell lines was unrelated to transcriptomic heterogeneity among those cell lines. These features of phenotypic and transcriptomic heterogeneity must be taken into account in future studies of treated tumor subclones and in design of chemotherapy combinations.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Artificial neural networks enable genome-scale simulations of intracellular signaling

    Avlant Nilsson / Joshua M. Peters / Nikolaos Meimetis / Bryan Bryson / Douglas A. Lauffenburger

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 16

    Abstract: Many diseases are caused by disruptions to the network of biochemical reactions that allow cells to respond to external signals. Here Nilsson et al develop a method to simulate cellular signaling using artificial neural networks to predict cellular ... ...

    Abstract Many diseases are caused by disruptions to the network of biochemical reactions that allow cells to respond to external signals. Here Nilsson et al develop a method to simulate cellular signaling using artificial neural networks to predict cellular responses and activities of signaling molecules.
    Keywords Science ; Q
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article: In vivo systems biology approaches to chronic immune/inflammatory pathophysiology

    Starchenko, Alina / Douglas A Lauffenburger

    Current opinion in biotechnology. 2018 Aug., v. 52

    2018  

    Abstract: Systems biology offers an emphasis on integrative computational analysis of complex multi-component processes to enhance capability for predictive insights concerning operation of those processes. The immune system represents a prominent arena in which ... ...

    Abstract Systems biology offers an emphasis on integrative computational analysis of complex multi-component processes to enhance capability for predictive insights concerning operation of those processes. The immune system represents a prominent arena in which such processes are manifested for vital roles in physiology and pathology, encompassing dozens of cell types and hundreds of reciprocal interactions. Chronic, debilitating pathologies involving immune system dysregulation have become recognized as increasing in incidence over recent decades. While clinical consequences of immune dysregulation in such pathologies are well characterized, treatment options remain limited and focus on ameliorating symptoms. Because it is difficult to recapitulate more than a severely limited facet of the immune system in vitro, application of systems biology approaches to autoimmune and inflammatory pathophysiology in vivo has opened a new door toward discerning disease sub-groups and developing associated stratification strategies for patient treatment. In particular, early instances of these approaches have demonstrated advances in uncovering previously under-appreciated dysregulation of signaling networks between immune system and tissue cells, raising promise for improving upon current therapeutic approaches.
    Keywords immune system ; pathophysiology ; patients ; physiology
    Language English
    Dates of publication 2018-08
    Size p. 9-16.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 1052045-4
    ISSN 1879-0429 ; 0958-1669
    ISSN (online) 1879-0429
    ISSN 0958-1669
    DOI 10.1016/j.copbio.2018.02.006
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: Beta-spike-containing boosters induce robust and functional antibody responses to SARS-CoV-2 in macaques primed with distinct vaccines

    Yixiang Deng / Caroline Atyeo / Dansu Yuan / Taras M. Chicz / Timothy Tibbitts / Matthew Gorman / Sabian Taylor / Valerie Lecouturier / Douglas A. Lauffenburger / Roman M. Chicz / Galit Alter / Ryan P. McNamara

    Cell Reports, Vol 42, Iss 11, Pp 113292- (2023)

    2023  

    Abstract: Summary: The reduced effectiveness of COVID-19 vaccines due to the emergence of variants of concern (VOCs) necessitated the use of vaccine boosters to bolster protection against disease. However, it remains unclear how boosting expands protective breadth ...

    Abstract Summary: The reduced effectiveness of COVID-19 vaccines due to the emergence of variants of concern (VOCs) necessitated the use of vaccine boosters to bolster protection against disease. However, it remains unclear how boosting expands protective breadth when primary vaccine platforms are distinct and how boosters containing VOC spike(s) broaden humoral responses. Here, we report that boosters composed of recombinant spike antigens of ancestral (prototype) and Beta VOCs elicit a robust, pan-VOC, and multi-functional humoral response in non-human primates largely independent of the primary vaccine series platform. Interestingly, Beta-spike-containing boosters stimulate immunoglobulin A (IgA) with a greater breadth of recognition in protein-primed recipients when administered with adjuvant system 03 (AS03). Our results highlight the utility of a component-based booster strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for broad humoral recognition, independent of primary vaccine series. This is of high global health importance given the heterogeneity of primary vaccination platforms distributed.
    Keywords CP: Immunology ; Biology (General) ; QH301-705.5
    Subject code 006
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Computational Interspecies Translation Between Alzheimer’s Disease Mouse Models and Human Subjects Identifies Innate Immune Complement, TYROBP, and TAM Receptor Agonist Signatures, Distinct From Influences of Aging

    Meelim J. Lee / Chuangqi Wang / Molly J. Carroll / Douglas K. Brubaker / Bradley T. Hyman / Douglas A. Lauffenburger

    Frontiers in Neuroscience, Vol

    2021  Volume 15

    Abstract: Mouse models are vital for preclinical research on Alzheimer’s disease (AD) pathobiology. Many traditional models are driven by autosomal dominant mutations identified from early onset AD genetics whereas late onset and sporadic forms of the disease are ... ...

    Abstract Mouse models are vital for preclinical research on Alzheimer’s disease (AD) pathobiology. Many traditional models are driven by autosomal dominant mutations identified from early onset AD genetics whereas late onset and sporadic forms of the disease are predominant among human patients. Alongside ongoing experimental efforts to improve fidelity of mouse model representation of late onset AD, a computational framework termed Translatable Components Regression (TransComp-R) offers a complementary approach to leverage human and mouse datasets concurrently to enhance translation capabilities. We employ TransComp-R to integratively analyze transcriptomic data from human postmortem and traditional amyloid mouse model hippocampi to identify pathway-level signatures present in human patient samples yet predictive of mouse model disease status. This method allows concomitant evaluation of datasets across different species beyond observational seeking of direct commonalities between the species. Additional linear modeling focuses on decoupling disease signatures from effects of aging. Our results elucidated mouse-to-human translatable signatures associated with disease: excitatory synapses, inflammatory cytokine signaling, and complement cascade- and TYROBP-based innate immune activity; these signatures all find validation in previous literature. Additionally, we identified agonists of the Tyro3 / Axl / MerTK (TAM) receptor family as significant contributors to the cross-species innate immune signature; the mechanistic roles of the TAM receptor family in AD merit further dedicated study. We have demonstrated that TransComp-R can enhance translational understanding of relationships between AD mouse model data and human data, thus aiding generation of biological hypotheses concerning AD progression and holding promise for improved preclinical evaluation of therapies.
    Keywords Alzheimer’s disease ; transcriptomics ; systems biology ; cross-species analysis ; TAM receptor agonists ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571
    Subject code 616 ; 006
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Computational translation of genomic responses from experimental model systems to humans.

    Douglas K Brubaker / Elizabeth A Proctor / Kevin M Haigis / Douglas A Lauffenburger

    PLoS Computational Biology, Vol 15, Iss 1, p e

    2019  Volume 1006286

    Abstract: The high failure rate of therapeutics showing promise in mouse models to translate to patients is a pressing challenge in biomedical science. Though retrospective studies have examined the fidelity of mouse models to their respective human conditions, ... ...

    Abstract The high failure rate of therapeutics showing promise in mouse models to translate to patients is a pressing challenge in biomedical science. Though retrospective studies have examined the fidelity of mouse models to their respective human conditions, approaches for prospective translation of insights from mouse models to patients remain relatively unexplored. Here, we develop a semi-supervised learning approach for inference of disease-associated human differentially expressed genes and pathways from mouse model experiments. We examined 36 transcriptomic case studies where comparable phenotypes were available for mouse and human inflammatory diseases and assessed multiple computational approaches for inferring human biology from mouse datasets. We found that semi-supervised training of a neural network identified significantly more true human biological associations than interpreting mouse experiments directly. Evaluating the experimental design of mouse experiments where our model was most successful revealed principles of experimental design that may improve translational performance. Our study shows that when prospectively evaluating biological associations in mouse studies, semi-supervised learning approaches, combining mouse and human data for biological inference, provide the most accurate assessment of human in vivo disease processes. Finally, we proffer a delineation of four categories of model system-to-human "Translation Problems" defined by the resolution and coverage of the datasets available for molecular insight translation and suggest that the task of translating insights from model systems to human disease contexts may be better accomplished by a combination of translation-minded experimental design and computational approaches.
    Keywords Biology (General) ; QH301-705.5
    Subject code 006
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis

    Rocky Lai / Diana N. Gong / Travis Williams / Abiola F. Ogunsola / Kelly Cavallo / Cecilia S. Lindestam Arlehamn / Sarah Acolatse / Gillian L. Beamer / Martin T. Ferris / Christopher M. Sassetti / Douglas A. Lauffenburger / Samuel M. Behar

    The Journal of Clinical Investigation, Vol 133, Iss

    2023  Volume 13

    Abstract: Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin–induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique ... ...

    Abstract Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin–induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG and challenged with aerosolized M. tuberculosis. Since BCG protects only half of the CC strains tested, we concluded that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to tuberculosis (TB). T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after M. tuberculosis infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.
    Keywords Infectious disease ; Vaccines ; Medicine ; R
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Selective transfer of maternal antibodies in preterm and fullterm children

    Sepideh Dolatshahi / Audrey L. Butler / Christian Pou / Ewa Henckel / Anna Karin Bernhardsson / Anna Gustafsson / Kajsa Bohlin / Sally A. Shin / Douglas A. Lauffenburger / Petter Brodin / Galit Alter

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 16

    Abstract: Abstract Preterm newborns are more likely to suffer from infectious diseases at birth compared to children delivered at term. Whether this is due to compromised cellular, humoral, or organ-specific development remains unclear. To begin to define whether ... ...

    Abstract Abstract Preterm newborns are more likely to suffer from infectious diseases at birth compared to children delivered at term. Whether this is due to compromised cellular, humoral, or organ-specific development remains unclear. To begin to define whether maternal–fetal antibody transfer profiles differ across preterm (PT) and fullterm (FT) infants, the overall quantity and functional quality of an array of 24 vaccine-, endemic pathogen-, and common antigen-specific antibodies were assessed across a cohort of 11 PT and 12 term-delivered maternal:infant pairs from birth through week 12. While total IgG levels to influenza, pneumo, measles, rubella, EBV, and RSV were higher in FT newborns, selective Fc-receptor binding antibodies was noted in PT newborns. In fact, near equivalent antibody-effector functions were observed across PT and FT infants, despite significant quantitative differences in transferred antibody levels. Moreover, temporal transfer analysis revealed the selective early transfer of FcRn, FcγR2, and FcγR3 binding antibodies, pointing to differential placental sieving mechanisms across gestation. These data point to selectivity in placental transfer at distinct gestational ages, to ensure that children are endowed with the most robust humoral immunity even if born preterm.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2022-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition

    Lauren E. Stopfer / Joshua M. Mesfin / Brian A. Joughin / Douglas A. Lauffenburger / Forest M. White

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: Immunopeptidomics allows identifying the cellular repertoire of MHC-bound peptides, but quantifying them remains challenging. Here, the authors present a method to efficiently generate internal peptide MHC standards and calibration curves, facilitating ... ...

    Abstract Immunopeptidomics allows identifying the cellular repertoire of MHC-bound peptides, but quantifying them remains challenging. Here, the authors present a method to efficiently generate internal peptide MHC standards and calibration curves, facilitating relative and absolute quantitative immunopeptidomics.
    Keywords Science ; Q
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Multiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition

    Lauren E. Stopfer / Joshua M. Mesfin / Brian A. Joughin / Douglas A. Lauffenburger / Forest M. White

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: Immunopeptidomics allows identifying the cellular repertoire of MHC-bound peptides, but quantifying them remains challenging. Here, the authors present a method to efficiently generate internal peptide MHC standards and calibration curves, facilitating ... ...

    Abstract Immunopeptidomics allows identifying the cellular repertoire of MHC-bound peptides, but quantifying them remains challenging. Here, the authors present a method to efficiently generate internal peptide MHC standards and calibration curves, facilitating relative and absolute quantitative immunopeptidomics.
    Keywords Science ; Q
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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