Author
Grace P. McDonald-Smith
Bio: Grace P. McDonald-Smith is an academic researcher from Harvard University. The author has contributed to research in topics: Poison control & Proteome. The author has an hindex of 13, co-authored 18 publications receiving 3923 citations.
Topics: Poison control, Proteome, Biomarker discovery, CD28, Cell
Papers
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Stanford University1, Harvard University2, University of Florida3, University of Washington4, University of Texas Medical Branch5, University of Colorado Denver6, University of Texas Southwestern Medical Center7, University of Rochester8, University of Pittsburgh9, University of Toronto10, University of California, San Francisco11, Loyola University Chicago12, Washington University in St. Louis13, Rutgers University14
TL;DR: This study shows that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another.
Abstract: A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.
2,438 citations
Stanford University1, Harvard University2, University of Washington3, University of Florida4, Boston University5, University of Colorado Denver6, University of Texas Southwestern Medical Center7, University of Rochester8, University of Pittsburgh9, University of Toronto10, University of California, San Francisco11, Washington University in St. Louis12, University of Texas Medical Branch13, Loyola University Chicago14, Rutgers University15, Princeton University16
TL;DR: It is shown that critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes that alter the status of these genes in the immune system.
Abstract: Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected “genomic storm.” In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of this genomic reprioritization. The similarities in gene expression patterns between different injuries reveal an apparently fundamental human response to severe inflammatory stress, with genomic signatures that are surprisingly far more common than different. Based on these transcriptional data, we propose a new paradigm for the human immunological response to severe injury.
958 citations
TL;DR: The findings suggest that for statistical or analytical purposes the ISS or NISS should not be considered a continuous variable, particularly if ISS/NISS is treated as a continuous Variable for correlation with an outcome measure.
Abstract: Objective—The research was undertaken to describe the injury severity score (ISS) and the new injury severity score (NISS) and to illustrate their statistical properties.
Design—Descriptive analysis and assessment of the distribution of these scales.
Methods—Three data sources—the National Pediatric Trauma Registry; the Massachusetts Uniform Hospital Discharge Data Set; and a trauma registry from an urban level I trauma center in Massachusetts—were used to describe the distribution of the ISS and NISS among injured patients.
Results—The ISS/NISS was found to have a positively skewed distribution and transformation did not improve their skewness.
Conclusion—The findings suggest that for statistical or analytical purposes the ISS/NISS should not be considered a continuous variable, particularly if ISS/NISS is treated as a continuous variable for correlation with an outcome measure.
383 citations
TL;DR: This study established an extensive reference protein database for trauma patients that provides a foundation for future high throughput quantitative plasma proteomic studies designed to elucidate the mechanisms that underlie systemic inflammatory responses.
150 citations
University of Rochester1, Stanford University2, Ingenuity Systems3, University of Florida4, University of Washington5, Washington University in St. Louis6, Rutgers University7, Harvard University8, University of Pittsburgh9, Pacific Northwest National Laboratory10, University of Texas Medical Branch11, University of Alabama at Birmingham12, Loyola University Chicago13, University of Louisville14, University of Texas Southwestern Medical Center15, University of Colorado Denver16, University of Texas Health Science Center at Houston17, University of Toronto18, Boston University19, Northwestern University20
TL;DR: Genome-wide expression analysis of highly enriched circulating leukocyte subpopulations, combined with cell-specific pathway analyses, offers an opportunity to discover leukocytes regulatory networks in critically injured patients.
Abstract: Monitoring genome-wide, cell-specific responses to human disease, although challenging, holds great promise for the future of medicine. Patients with injuries severe enough to develop multiple organ dysfunction syndrome have multiple immune derangements, including T cell apoptosis and anergy combined with depressed monocyte antigen presentation. Genome-wide expression analysis of highly enriched circulating leukocyte subpopulations, combined with cell-specific pathway analyses, offers an opportunity to discover leukocyte regulatory networks in critically injured patients. Severe injury induced significant changes in T cell (5,693 genes), monocyte (2,801 genes), and total leukocyte (3,437 genes) transcriptomes, with only 911 of these genes common to all three cell populations (12%). T cell-specific pathway analyses identified increased gene expression of several inhibitory receptors (PD-1, CD152, NRP-1, and Lag3) and concomitant decreases in stimulatory receptors (CD28, CD4, and IL-2Rα). Functional analysis of T cells and monocytes confirmed reduced T cell proliferation and increased cell surface expression of negative signaling receptors paired with decreased monocyte costimulation ligands. Thus, genome-wide expression from highly enriched cell populations combined with knowledge-based pathway analyses leads to the identification of regulatory networks differentially expressed in injured patients. Importantly, application of cell separation, genome-wide expression, and cell-specific pathway analyses can be used to discover pathway alterations in human disease.
108 citations
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TL;DR: A review of the basis, diagnosis, and current treatment of Sepsis in patients with this disorder is examined.
Abstract: Morbidity and mortality from sepsis remains unacceptably high. Large variability in clinical practice, plus the increasing awareness that certain processes of care associated with improved critical...
2,927 citations
Stanford University1, Harvard University2, University of Florida3, University of Washington4, University of Texas Medical Branch5, University of Colorado Denver6, University of Texas Southwestern Medical Center7, University of Rochester8, University of Pittsburgh9, University of Toronto10, University of California, San Francisco11, Loyola University Chicago12, Washington University in St. Louis13, Rutgers University14
TL;DR: This study shows that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another.
Abstract: A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.
2,438 citations
TL;DR: Biomarker-guided immunotherapy that is administered to patients at the proper immune phase of sepsis is potentially a major advance in the treatment of septicaemia and in the field of infectious disease.
Abstract: Sepsis - which is a severe life-threatening infection with organ dysfunction - initiates a complex interplay of host pro-inflammatory and anti-inflammatory processes. Sepsis can be considered a race to the death between the pathogens and the host immune system, and it is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses provides a novel approach for treating this highly lethal condition. Biomarker-guided immunotherapy that is administered to patients at the proper immune phase of sepsis is potentially a major advance in the treatment of sepsis and in the field of infectious disease.
1,719 citations
Pennsylvania State University1, University of California, San Diego2, Stanford University3, University of Washington4, University of Michigan5, Florida State University6, New College of Florida7, Cold Spring Harbor Laboratory8, California Institute of Technology9, University of Vienna10, Emory University11, Fred Hutchinson Cancer Research Center12, Massachusetts Institute of Technology13, Broad Institute14, University of California, Irvine15, University of California, Santa Cruz16, University of California, San Francisco17, Yale University18, University of Florida19, Johns Hopkins University20, University College London21, University of Oxford22, Cornell University23, Memorial Sloan Kettering Cancer Center24, Harvard University25, University of Iowa26, Yeshiva University27, University of Pennsylvania28, Washington University in St. Louis29, National Institutes of Health30, University of North Carolina at Chapel Hill31
TL;DR: The mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types as mentioned in this paper.
Abstract: The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases
1,335 citations
TL;DR: It is hypothesised that immunoadjuvant therapy represents the next major advance in sepsis, and explains why many previous sepsi trials which were directed at blocking inflammatory mediators or pathogen recognition signalling pathways failed.
Abstract: Summary Failures of highly touted trials have caused experts to call for re-evaluation of the current approach toward sepsis. New research has revealed key pathogenic mechanisms; autopsy results have shown that most patients admitted to intensive care units for treatment of sepsis had unresolved septic foci at post mortem, suggesting that patients were unable to eradicate invading pathogens and were more susceptible to nosocomial organisms, or both. These results suggest that therapies that improve host immunity might increase survival. Additional work showed that cytokine production by splenocytes taken post mortem from patients who died of sepsis is profoundly suppressed, possibly because of so-called T-cell exhaustion—a newly recognised immunosuppressive mechanism that occurs with chronic antigenic stimulation. Results from two clinical trials of biomarker-guided therapeutic drugs that boosted immunity showed promising findings in sepsis. Collectively, these studies emphasise the degree of immunosuppression that occurs in sepsis, and explain why many previous sepsis trials which were directed at blocking inflammatory mediators or pathogen recognition signalling pathways failed. Finally, highly encouraging results from use of the new immunomodulatory molecules interleukin 7 and anti-programmed cell death 1 in infectious disease point the way for possible use in sepsis. We hypothesise that immunoadjuvant therapy represents the next major advance in sepsis.
1,109 citations