37 results on '"Jacob Shreve"'
Search Results
2. 1266 Utilizing predictive modeling to risk stratify patients to low versus high grade immune checkpoint inhibitor therapy-related pneumonitis
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Svetomir Markovic, Antonious Hazim, Jacob Shreve, Irene Riestra Guiance, Damian McGlothlin, Gordon Ruan, Keith Mcconn, Robert Haemmerle, Konstantinos Leventakos, and Ashley Egan
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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3. P812: PREDICTING HIGH-RISK DISEASE BIOLOGY USING ARTIFICIAL INTELLIGENCE BASED FDG PET/CT RADIOMICS IN NEWLY DIAGNOSED MULTIPLE MYELOMA
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Jacob Shreve, Charalampos Charalampous, Taxiarchis Kourelis, Josh Pritchett, Yi Hwa, Jonas Paludo, Wilson Gonsalves, Yi Lin, Mithun Shah, Miriam Hobbs, Joselle Cook, Martha Lacy, Angela Dispenzieri, Stephen Broski, Vincent Rajkumar, Shaji Kumar, and Moritz Binder
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. P921: ARTIFICIAL INTELLIGENCE BASED FDG PET/CT RADIOMICS FOR RISK STRATIFICATION IN NEWLY DIAGNOSED MULTIPLE MYELOMA
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Jacob Shreve, Charalampos Charalampous, Rahma Warsame, Josh Pritchett, Prashant Kapoor, Francis Buadi, Jonas Paludo, David Dingli, Mithun Shah, Amie Fonder, Suzanne Hayman, Nelson Leung, Morie Gertz, Robert Kyle, Stephen Broski, Vincent Rajkumar, Shaji Kumar, and Moritz Binder
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. P1152: DEPTH OF METABOLIC RESPONSE AT INTERIM PET AND SURVIVAL OUTCOMES AMONG PATIENTS WITH PRIMARY REFRACTORY OR EARLY RELAPSING DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)
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Allison Bock, Raphael Mwangi, Fatemeh Ataei, Matthew Thorpe, Matthew Maurer, Josh Pritchett, Jacob Shreve, Jonas Paludo, James Cerhan, Arushi Khurana, Thomas Witzig, Thomas Habermann, Yucai Wang, Grzegorz S. Nowakowski, and Jason Young
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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6. A machine learning model of response to hypomethylating agents in myelodysplastic syndromes
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Nathan Radakovich, David A. Sallman, Rena Buckstein, Andrew Brunner, Amy Dezern, Sudipto Mukerjee, Rami Komrokji, Najla Al-Ali, Jacob Shreve, Yazan Rouphail, Anne Parmentier, Alexandre Mamedov, Mohammed Siddiqui, Yihong Guan, Teodora Kuzmanovic, Metis Hasipek, Babal Jha, Jaroslaw P. Maciejewski, Mikkael A. Sekeres, and Aziz Nazha
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Drugs ,cancer ,artificial intelligence ,Science - Abstract
Summary: Hypomethylating agents (HMA) prolong survival and improve cytopenias in individuals with higher-risk myelodysplastic syndrome (MDS). Only 30-40% of patients, however, respond to HMAs, and responses may not occur for more than 6 months after HMA initiation. We developed a model to more rapidly assess HMA response by analyzing early changes in patients’ blood counts. Three institutions’ data were used to develop a model that assessed patients’ response to therapy 90 days after the initiation using serial blood counts. The model was developed with a training cohort of 424 patients from 2 institutions and validated on an independent cohort of 90 patients. The final model achieved an area under the receiver operating characteristic curve (AUROC) of 0.79 in the train/test group and 0.84 in the validation group. The model provides cohort-wide and individual-level explanations for model predictions, and model certainty can be interrogated to gauge the reliability of a given prediction.
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- 2022
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7. Personalized Prediction of Hospital Mortality in COVID-19–Positive Patients
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Daniel Rozenbaum, MD, Jacob Shreve, MD, MS, Nathan Radakovich, MD, Abhijit Duggal, MD, MPH, MSc, Lara Jehi, MD, MHCDS, and Aziz Nazha, MD
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Medicine (General) ,R5-920 - Abstract
Objective: To develop predictive models for in-hospital mortality and length of stay (LOS) for coronavirus disease 2019 (COVID-19)–positive patients. Patients and Methods: We performed a multicenter retrospective cohort study of hospitalized COVID-19–positive patients. A total of 764 patients admitted to 14 different hospitals within the Cleveland Clinic from March 9, 2020, to May 20, 2020, who had reverse transcriptase-polymerase chain reaction–proven coronavirus infection were included. We used LightGBM, a machine learning algorithm, to predict in-hospital mortality at different time points (after 7, 14, and 30 days of hospitalization) and in-hospital LOS. Our final cohort was composed of 764 patients admitted to 14 different hospitals within our system. Results: The median LOS was 5 (range, 1-44) days for patients admitted to the regular nursing floor and 10 (range, 1-38) days for patients admitted to the intensive care unit. Patients who died during hospitalization were older, initially admitted to the intensive care unit, and more likely to be white and have worse organ dysfunction compared with patients who survived their hospitalization. Using the 10 most important variables only, the final model’s area under the receiver operating characteristics curve was 0.86 for 7-day, 0.88 for 14-day, and 0.85 for 30-day mortality in the validation cohort. Conclusion: We developed a decision tool that can provide explainable and patient-specific prediction of in-hospital mortality and LOS for COVID-19–positive patients. The model can aid health care systems in bed allocation and distribution of vital resources.
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- 2021
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8. Expression profiles of cell-wall related genes vary broadly between two common maize inbreds during stem development
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Bryan W. Penning, Tânia M. Shiga, John F. Klimek, Philip J. SanMiguel, Jacob Shreve, Jyothi Thimmapuram, Robert W. Sykes, Mark F. Davis, Maureen C. McCann, and Nicholas C. Carpita
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Zea mays (maize) ,Stem development ,Cell-wall biosynthesis ,Gene expression ,Transcript profiling ,Lignocellulosic biomass ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background The cellular machinery for cell wall synthesis and metabolism is encoded by members of large multi-gene families. Maize is both a genetic model for grass species and a potential source of lignocellulosic biomass from crop residues. Genetic improvement of maize for its utility as a bioenergy feedstock depends on identification of the specific gene family members expressed during secondary wall development in stems. Results High-throughput sequencing of transcripts expressed in developing rind tissues of stem internodes provided a comprehensive inventory of cell wall-related genes in maize (Zea mays, cultivar B73). Of 1239 of these genes, 854 were expressed among the internodes at ≥95 reads per 20 M, and 693 of them at ≥500 reads per 20 M. Grasses have cell wall compositions distinct from non-commelinid species; only one-quarter of maize cell wall-related genes expressed in stems were putatively orthologous with those of the eudicot Arabidopsis. Using a slope-metric algorithm, five distinct patterns for sub-sets of co-expressed genes were defined across a time course of stem development. For the subset of genes associated with secondary wall formation, fifteen sequence motifs were found in promoter regions. The same members of gene families were often expressed in two maize inbreds, B73 and Mo17, but levels of gene expression between them varied, with 30% of all genes exhibiting at least a 5-fold difference at any stage. Although presence-absence and copy-number variation might account for much of these differences, fold-changes of expression of a CADa and a FLA11 gene were attributed to polymorphisms in promoter response elements. Conclusions Large genetic variation in maize as a species precludes the extrapolation of cell wall-related gene expression networks even from one common inbred line to another. Elucidation of genotype-specific expression patterns and their regulatory controls will be needed for association panels of inbreds and landraces to fully exploit genetic variation in maize and other bioenergy grass species.
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- 2019
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9. The Evolving Landscape of Myelodysplastic Syndrome Prognostication
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Jacob Shreve and Aziz Nazha
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Acute myeloid leukemia (AML) ,Myelodysplastic syndromes (MDS) ,Prognostic model ,Machine learning ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Myelodysplastic syndromes (MDSs) are potentially devastating monoclonal deviations of hematopoiesis that lead to bone marrow dysplasia and variable cytopenias. Predicting severity of disease progression and likelihood to undergo acute myeloid leukemia transformation is the basis of treatment strategy. Some patients belong to a low-risk cohort best managed with conservative supportive care, whereas others are included in a high-risk cohort that requires decisive therapy with hematopoietic cell transplantation or hypomethylating agent administration. Risk scoring systems for MDS prognostication were traditionally based on karyotype characteristics and clinical factors readily available from chart review, and validation was typically conducted on de novo MDS patients. However, retrospective analysis found a large subset of patients incorrectly risk-stratified. In this review, the most commonly used scoring systems are evaluated, and pitfalls therein are identified. Emerging technologies such as personal genomics and machine learning are then explored for efficacy in MDS risk modeling. Barriers to clinical adoption of artificial intelligence-derived models are discussed, with focus on approaches meant to increase model interpretability and clinical relevance. Finally, a guiding set of recommendations is proposed for best designing an accurate and universally applicable prognostic model for MDS, which is supported by more than 20 years of observation of traditional scoring system performance, as well as modern efforts in creating hybrid genomic-clinical scoring systems.
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- 2020
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10. Coordination of MicroRNAs, PhasiRNAs, and NB-LRR Genes in Response to a Plant Pathogen: Insights from Analyses of a Set of Soybean Rps Gene Near-Isogenic Lines
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Meixia Zhao, Chunmei Cai, Jixian Zhai, Feng Lin, Linghong Li, Jacob Shreve, Jyothi Thimmapuram, Teresa J. Hughes, Blake C. Meyers, and Jianxin Ma
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Plant culture ,SB1-1110 ,Genetics ,QH426-470 - Abstract
Disease-related genes, particularly the nucleotide binding site (NB)–leucine-rich repeat (LRR) class of plant genes can be triggered by microRNAs (miRNAs) to generate phased small interfering RNAs (phasiRNAs), which could reduce the transcript levels of their targets. However, how global changes in transcript levels coordinate with changes in miRNA and phasiRNA levels in defense responses remains largely unknown. Here, we investigated changes in the relative abundance of small RNAs (sRNAs), with a focus on miRNAs and phasiRNAs and their potential targets in response to the pathogen in the susceptible soybean [Glycine max (L.) Merr.] ‘Williams’ and nine resistant near-isogenic lines (NILs), each carrying a unique () gene. In total, 369 distinct miRNAs, including 78 new ones, were identified in the 10 soybean lines. The majority of miRNAs were downregulated by the pathogen. Of the 525 genes found in the soybean reference genome, 257 were predicted to be the targets of eight abundant miRNA families and 126 (dubbed or ) were predicted to have produced phasiRNAs. Upregulation of 15 was associated with downregulation of their corresponding phasiRNAs in the NILs; these phasiRNAs were predicted to regulate 75 additional s in . In addition, we identified putative 24-nucleotide (nt) phasiRNAs from transposons, possibly representing a novel general epigenetic mechanism for regulation of transposon activity under biotic stresses. Together, these observations suggest that miRNAs and phasiRNAs play an important role in response to plant pathogens through complex, multiple layers of post-transcriptional regulation.
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- 2015
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11. The Evolving Landscape of Myelodysplastic Syndrome Prognostication
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Aziz Nazha and Jacob Shreve
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medicine.medical_specialty ,lcsh:Medicine ,02 engineering and technology ,Article ,Machine learning ,0202 electrical engineering, electronic engineering, information engineering ,medicine ,Acute myeloid leukemia (AML) ,0501 psychology and cognitive sciences ,Clinical significance ,Myelodysplastic syndromes (MDS) ,Intensive care medicine ,050107 human factors ,Interpretability ,business.industry ,Myelodysplastic syndromes ,05 social sciences ,lcsh:R ,020207 software engineering ,medicine.disease ,Transplantation ,Hypomethylating agent ,Cohort ,Prognostic model ,business ,Personal genomics - Abstract
Myelodysplastic syndromes (MDSs) are potentially devastating monoclonal deviations of hematopoiesis that lead to bone marrow dysplasia and variable cytopenias. Predicting severity of disease progression and likelihood to undergo acute myeloid leukemia transformation is the basis of treatment strategy. Some patients belong to a low-risk cohort best managed with conservative supportive care, whereas others are included in a high-risk cohort that requires decisive therapy with hematopoietic cell transplantation or hypomethylating agent administration. Risk scoring systems for MDS prognostication were traditionally based on karyotype characteristics and clinical factors readily available from chart review, and validation was typically conducted on de novo MDS patients. However, retrospective analysis found a large subset of patients incorrectly risk-stratified. In this review, the most commonly used scoring systems are evaluated, and pitfalls therein are identified. Emerging technologies such as personal genomics and machine learning are then explored for efficacy in MDS risk modeling. Barriers to clinical adoption of artificial intelligence-derived models are discussed, with focus on approaches meant to increase model interpretability and clinical relevance. Finally, a guiding set of recommendations is proposed for best designing an accurate and universally applicable prognostic model for MDS, which is supported by more than 20 years of observation of traditional scoring system performance, as well as modern efforts in creating hybrid genomic-clinical scoring systems.
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- 2020
12. Expression profiles of cell-wall related genes vary broadly between two common maize inbreds during stem development
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Mark F. Davis, Jacob Shreve, Nicholas C. Carpita, Bryan W. Penning, Robert W. Sykes, John F. Klimek, Philip J. SanMiguel, Tânia M. Shiga, Jyothi Thimmapuram, and Maureen C. McCann
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lcsh:QH426-470 ,lcsh:Biotechnology ,Arabidopsis ,Biology ,Lignin ,Zea mays ,Zea mays (maize) ,Inbred strain ,Cell Wall ,lcsh:TP248.13-248.65 ,Genetic variation ,Genetic model ,Gene expression ,Genetics ,Gene family ,Cellulose ,Promoter Regions, Genetic ,Gene ,Plant Stems ,food and beverages ,Stem development ,Promoter ,Lignocellulosic biomass ,Plant Breeding ,lcsh:Genetics ,Transcript profiling ,Cell-wall biosynthesis ,Multigene Family ,Xylans ,DNA microarray ,Transcriptome ,Research Article ,Biotechnology - Abstract
BackgroundThe cellular machinery for cell wall synthesis and metabolism is encoded by members of large multi-gene families. Maize is both a genetic model for grass species and a potential source of lignocellulosic biomass from crop residues. Genetic improvement of maize for its utility as a bioenergy feedstock depends on identification of the specific gene family members expressed during secondary wall development in stems.ResultsHigh-throughput sequencing of transcripts expressed in developing rind tissues of stem internodes provided a comprehensive inventory of cell wall-related genes in maize (Zea mays, cultivar B73). Of 1239 of these genes, 854 were expressed among the internodes at ≥95 reads per 20 M, and 693 of them at ≥500 reads per 20 M. Grasses have cell wall compositions distinct from non-commelinid species; only one-quarter of maize cell wall-related genes expressed in stems were putatively orthologous with those of the eudicot Arabidopsis. Using a slope-metric algorithm, five distinct patterns for sub-sets of co-expressed genes were defined across a time course of stem development. For the subset of genes associated with secondary wall formation, fifteen sequence motifs were found in promoter regions. The same members of gene families were often expressed in two maize inbreds, B73 and Mo17, but levels of gene expression between them varied, with 30% of all genes exhibiting at least a 5-fold difference at any stage. Although presence-absence and copy-number variation might account for much of these differences, fold-changes of expression of aCADaand aFLA11gene were attributed to polymorphisms in promoter response elements.ConclusionsLarge genetic variation in maize as a species precludes the extrapolation of cell wall-related gene expression networks even from one common inbred line to another. Elucidation of genotype-specific expression patterns and their regulatory controls will be needed for association panels of inbreds and landraces to fully exploit genetic variation in maize and other bioenergy grass species.
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- 2019
13. Personalized Prediction Model to Risk Stratify Patients With Myelodysplastic Syndromes
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Amy E. DeZern, Yasunubo Nagata, Harry P. Erba, Manja Meggendorfer, Aziz Nazha, Teodora Kuzmanovic, Gail J. Roboz, Najla Al Ali, Torsten Haferlach, Xuefei Jia, Betty K. Hamilton, Wencke Walter, Eric Padron, Nathan Radakovich, Guillermo Garcia-Manero, Vera Adema, C. Beau Hilton, Rami S. Komrokji, Mikkael A. Sekeres, Stephan Hutter, David P. Steensma, Cassandra M Kerr, Claudia Haferlach, Sudipto Mukherjee, David A. Sallman, Jaroslaw P. Maciejewski, and Jacob Shreve
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,MEDLINE ,Young Adult ,Clinical Trials, Phase II as Topic ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Prospective Studies ,Aged ,Aged, 80 and over ,Models, Statistical ,business.industry ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,ORIGINAL REPORTS ,Genomics ,Middle Aged ,medicine.disease ,Prognosis ,Survival Rate ,Cell Transformation, Neoplastic ,Analytics ,Myelodysplastic Syndromes ,Mutation ,Disease Progression ,Female ,business ,Algorithms ,Follow-Up Studies - Abstract
PURPOSE Patients with myelodysplastic syndromes (MDS) have a survival that can range from months to decades. Prognostic systems that incorporate advanced analytics of clinical, pathologic, and molecular data have the potential to more accurately and dynamically predict survival in patients receiving various therapies. METHODS A total of 1,471 MDS patients with comprehensively annotated clinical and molecular data were included in a training cohort and analyzed using machine learning techniques. A random survival algorithm was used to build a prognostic model, which was then validated in external cohorts. The accuracy of the proposed model, compared with other established models, was assessed using a concordance (c)index. RESULTS The median age for the training cohort was 71 years. Commonly mutated genes included SF3B1, TET2, and ASXL1. The algorithm identified chromosomal karyotype, platelet, hemoglobin levels, bone marrow blast percentage, age, other clinical variables, seven discrete gene mutations, and mutation number as having prognostic impact on overall and leukemia-free survivals. The model was validated in an independent external cohort of 465 patients, a cohort of patients with MDS treated in a prospective clinical trial, a cohort of patients with paired samples at different time points during the disease course, and a cohort of patients who underwent hematopoietic stem-cell transplantation. CONCLUSION A personalized prediction model on the basis of clinical and genomic data outperformed established prognostic models in MDS. The new model was dynamic, predicting survival and leukemia transformation probabilities at different time points that are unique for a given patient, and can upstage and downstage patients into more appropriate risk categories.
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- 2021
14. A Personalized Clinical-Decision Tool to Improve the Diagnostic Accuracy of Myelodysplastic Syndromes
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Nathan Radakovich, Manja Meggendorfer, Luca Malcovati, Mikkael A. Sekeres, Jacob Shreve, Cameron Beau Hilton, Yazan Rouphail, Wencke Walter, Stephan Hutter, Sudipto Mukherjee, Cassandra M. Kerr, Babal K. Jha, Anna Gallì, Sarah Pozzi, Aaron T. Gerds, Cassandra M Kerr, Claudia Haferlach, Jaroslaw P. Maciejewski, Torsten Haferlach, and Aziz Nazha
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Cytopenia ,medicine.medical_specialty ,business.industry ,Essential thrombocythemia ,Myelodysplastic syndromes ,Immunology ,Chronic myelomonocytic leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,hemic and lymphatic diseases ,Internal medicine ,Cohort ,medicine ,Data monitoring committee ,business ,Myelofibrosis ,Myeloproliferative neoplasm - Abstract
Background While histo- and cytomorphological examinations are central to the diagnosis of myelodysplastic syndromes (MDS), significant inter-observer variability exists. The diagnosis can be challenging in pancytopenic patients (pts) without evidence of dysplasia and is contingent on observer expertise. We developed and externally validated a geno-clinical model that uses mutational data and peripheral blood counts/clinical variables to distinguish MDS from other myeloid malignancies. Methods Clinical and genomic data, including commercially available next-generation sequencing panels, were obtained for patients (pts) treated at the Cleveland Clinic (CC; 652 pts), Munich Leukemia Laboratory (MLL; 1509 pts), and the University of Pavia in Italy (UP, 536 pts). All patients had carried a diagnosis of MDS, chronic myelomonocytic leukemia (CMML), MDS/myeloproliferative neoplasm overlap (MDS/MPN), myeloproliferative neoplasm (MPN; either polycythemia vera, essential thrombocythemia, or myelofibrosis), clonal cytopenia of undetermined significance (CCUS), or idiopathic cytopenia of undetermined significance (ICUS). All diagnoses were established with bone marrow aspiration and according to World Health Organization 2017 criteria. The training cohort included data from CC and UP and randomly divided into learner (80%) and test (20%) cohorts. The final model was independently validated in the MLL cohort. A machine learning algorithm was used to build the model; multiple extraction algorithms were used to extract genomic/clinical variables on both the cohort and individual levels. Performance was evaluated according to the area under the curve of the receiver operating characteristic (ROC-AUC) and accuracy matrices. Results Among the 2697 pts included from all sites, the median age was 70 years [36 - 86]. Median hemoglobin (Hb) was 10.4g/dl [6.9 - 15.7], median platelet count (PLT) was 132 k/dL [14 - 722], median WBC count was 5.3 k/dL [1.4 - 49.9], median ANC was 2.8 k/dL [0.3 - 27.7], median monocyte count was 0.3 k/dL [0 - 9.9], and median lymphocyte count (ALC) was 1.1 k/dL [0.1 - 5.4], and median peripheral blast percentage 0% [0 - 8]. The most commonly mutated genes in all patients were (list top 5 genes) and among pts with MDS were SF3B1 (27%), TET2 (25%), ASXL1 (19%), SRSF2 (16%), and DNMT3A (11%); among patients with MDS-MPN/CMML, the most commonly mutated genes were MDS-MPN/CMML (TET2 46%, ASXL1 34%, SRSF2 29%, RUNX1 13%, CBL 12%) ; among patients with MPNs, the most commonly mutated genes were (JAK2 64%, ASXL1 27%, TET2 14%, DNMT3A 8%, U2AF1 7%); among patients with CCUS the most commonly mutated genes were (TET2 41%, DNMT3A 27%, ASXL1 19%, SRSF2 17%, ZRSR2 10%). The most important features for model predictions (ranked from the most to the least important) included: number of mutations detected/sample, peripheral blast percentage, AMC, JAK2 status, Hb, basophil count, age, eosinophil count, ALC, WBC, EZH2 mutation status, ANC, mutation status of KRAS and SF3B1, platelets, and gender. The final model achieved an average AUROC of 0.95 (95% CI 0.93-0.96) when applied to the test cohort and 0.93 (95% CI 0.91 - 0.94) when it was applied to the MLL cohort. The model also provides individual-level explanations for predictions, providing top differential diagnoses and individual-level explanations of how features influence a putative diagnosis (Figure 1b). Conclusions We developed and externally validated a highly accurate and interpretable model that can distinguish MDS from other myeloid malignancies using clinical and mutational data from a large international cohort. The model can provide personalized interpretations of its outcome and can aid physicians and hematopathologists in recognizing MDS with high accuracy when encountering pts with pancytopenia and with a suspected diagnosis of MDS. Disclosures Sekeres: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy. Gerds:Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Apexx Oncology: Consultancy; Celgene: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy; Gilead Sciences: Research Funding; Pfizer: Research Funding. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Nazha:Jazz: Research Funding; Incyte: Speakers Bureau; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee.
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- 2020
15. Personalized Prediction of Hospital Mortality in COVID-19-Positive Patients
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Nathan Radakovich, Daniel Rozenbaum, Aziz Nazha, Lara Jehi, Jacob Shreve, and Abhijit Douggal
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medicine.medical_specialty ,Medicine (General) ,030204 cardiovascular system & hematology ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,R5-920 ,Personalized prediction ,law ,medicine ,ROC AUC, Area under the Receiver Operating Characteristics curve ,030212 general & internal medicine ,LOS, Length of stay ,COVID-19, Coronavirus disease 2019 ,Receiver operating characteristic ,medicine.diagnostic_test ,business.industry ,Organ dysfunction ,COVID-19 ,Retrospective cohort study ,mortality ,Intensive care unit ,ICU, Intensive care unit ,Quartile ,Emergency medicine ,Absolute neutrophil count ,medicine.symptom ,Chest radiograph ,business ,Body mass index - Abstract
Objective: To develop predictive models for in-hospital mortality and length of stay (LOS) for COVID-19 positive patients. Patients and Methods: We performed a multicenter retrospective cohort study of hospitalized COVID-19 positive patients. A total of 764 patients admitted to 14 different hospitals within the Cleveland Clinic from 03/09/2020 to 05/20/2020 who had reverse transcriptase-polymerase chain reaction proven coronavirus infection were included. We used LightGBM, a machine learning algorithm, to predict in-hospital mortality at different time points (after 7 days, 14 days, and 30 days of hospitalization) and in-hospital LOS. Results: Among 764 patients, 116 (15%) either died (n = 87) or were transitioned to hospice care (n = 29) during their hospitalization. The median LOS was 5 days (range 1 - 44 days) for patients admitted to the regular nursing floor and 10 days (range 1-38 days) for patients admitted to the intensive care unit (ICU). Patients who died during hospitalization were older, initially admitted to the ICU, more likely to be white and to have worse organ dysfunction compared to patients who survived their hospitalization. Using the 10 most important variables only, the final model's area under the Receiver Operating Characteristics curve was 0.86 for 7-day, 0.88 for 14-day, and 0.85 for 30-day mortality in the validation cohort. Conclusions: We developed a decision tool that can provide explainable and patient-specific prediction of in-hospital mortality and LOS for COVID-19 positive patients. The model can aid healthcare systems in bed allocation and distribution of vital resources.
- Published
- 2021
16. Genome Sequence of the Virulent Model Herpes Simplex Virus 1 Strain McKrae Demonstrates the Presence of at Least Two Widely Used Variant Strains
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Esteban A. Engel, Lynn W. Enquist, Daniel W. Renner, Lance Parsons, Colleen A. Mangold, Chad V. Kuny, Jacob Shreve, Moriah L. Szpara, and Donna M. Neumann
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Whole genome sequencing ,Genetics ,0303 health sciences ,Key genes ,030306 microbiology ,Strain (biology) ,viruses ,Genome Sequences ,Virulence ,Biology ,medicine.disease_cause ,Genome ,03 medical and health sciences ,Herpes simplex virus ,Immunology and Microbiology (miscellaneous) ,medicine ,Molecular Biology ,030304 developmental biology - Abstract
Herpes simplex virus 1 (HSV-1) strain McKrae was isolated in 1965 and has been utilized by many laboratories. Three HSV-1 strain McKrae stocks have been sequenced previously, revealing discrepancies in key genes. We sequenced the genome of HSV-1 strain McKrae from James Hill, to better understand the genetic differences between isolates., Herpes simplex virus 1 (HSV-1) strain McKrae was isolated in 1965 and has been utilized by many laboratories. Three HSV-1 strain McKrae stocks have been sequenced previously, revealing discrepancies in key genes. We sequenced the genome of HSV-1 strain McKrae from the laboratory of James M. Hill to better understand the genetic differences between isolates.
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- 2021
17. Novel Prognostic Models for Myelodysplastic Syndromes
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Jacob Shreve and Aziz Nazha
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medicine.medical_specialty ,Poor prognosis ,Genomic data ,Disease ,Models, Biological ,Risk Assessment ,03 medical and health sciences ,Genetic Heterogeneity ,0302 clinical medicine ,medicine ,Humans ,Intensive care medicine ,Prognostic models ,business.industry ,Myelodysplastic syndromes ,Computational Biology ,Disease Management ,Hematology ,Therapeutic decision making ,DNA Methylation ,medicine.disease ,Prognosis ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Mutation ,Myelopoiesis ,Bone marrow ,Disease Susceptibility ,business ,030215 immunology - Abstract
Myelodysplastic syndromes are disorders of clonal myelopoiesis having a range of clinical manifestations, from benign and indolent to aggressive with very poor prognosis. Classifying the likely trajectory of disease within a patient largely guides therapeutic decision making and therefore survival. Traditional methods of risk-stratification systems rely on clinical features: simple blood tests, peripheral smears, bone marrow biopsies, and cytogenetics, but do not adequately predict disease severity for a substantial proportion of patients. This article reviews the state of stratification at use in the clinic, describes emerging systems that leverage large-scale genomic data, and summarizes efforts toward truly personalized prediction models.
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- 2020
18. Genotype-Phenotype Correlations in Patients with Myeloid Malignancies Using Explainable Artificial Intelligence
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Stephan Hutter, Manja Meggendorfer, Aziz Nazha, Luca Malcovati, Torsten Haferlach, Babal K. Jha, Mikkael A. Sekeres, Jacob Shreve, Yazan Rouphail, Sarah Pozzi, Claudia Haferlach, Cassandra M Kerr, Nathan Radakovich, Anna Gallì, Jaroslaw P. Maciejewski, Sudipto Mukherjee, Wencke Walter, Aaron T. Gerds, and Cameron Beau Hilton
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Chromosome 7 (human) ,Oncology ,medicine.medical_specialty ,Cytopenia ,Myeloid ,Essential thrombocythemia ,business.industry ,Myelodysplastic syndromes ,Immunology ,Chronic myelomonocytic leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chromosome 17 (human) ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business ,Myelofibrosis - Abstract
Background: Myelodysplastic syndromes (MDS) and related myeloid malignancies are highly variable in both their clinical manifestations and underlying genetic abnormalities. While few mutations in myeloid malignancies are considered disease-defining, significant and complex associations between these genes exist and can influence the clinical characteristics and disease phenotype. Here, we took advantage of a large, international cohort of patients with myeloid malignancies to define genotype-phenotype relationships using state of the art machine learning models. Methods Data were collected for patients (pts) from the Cleveland Clinic (CC; 652 pts), Munich Leukemia Laboratory (MLL; 1509 pts), and the University of Pavia in Italy (UP; 536 patients). Clinical data including CBC at time of diagnosis and a genomic panel of 20 commonly mutated genes in myeloid malignancies were analyzed. Gene-gene correlations within disease subtypes, individual genes' co-occurrence or exclusivity within disease subtypes, and the co-occurrence or exclusivity of individual genes with clinically meaningful features including karyotypic abnormalities and severe cytopenias (defined as hemoglobin < 8 g/dL, platelets < 50k/dL, and ANC < 1k/dL) were evaluated using multiple machine learning/correlation/feature extraction algorithms. Results 2697 pts were included, 1630 (60%) with MDS, 399 (15%) with chronic myelomonocytic leukemia (CMML), 142 (5%) with idiopathic cytopenia of undetermined significance (ICUS), 129 (5%) with MDS-MPN overlap syndromes (MDS-MPN), 95 (4%) with primary myelofibrosis (PMF), 93 (3%) with clonal cytopenia of undetermined significance (CCUS), 52 (2%) with essential thrombocythemia (ET), 41 (2%) with polycythemia vera (PV), and 26 (1%) with other myeloproliferative neoplasms (MPNs). The median age at diagnosis for the entire cohort was 70 years [36 - 86]. Of patients with karyotype data available, 1091 pts (50%) had a normal karyotype, 17 (1%) had chromosome 17 abnormalities, 96 (4%) had chromosome 7 abnormalities, 145 (7%) had chromosome 5 abnormalities, and 123 (6%) had a complex karyotype. The most commonly mutated genes were: TET2 (28%), ASXL1 (22%), SF3B1 (22%), SRSF2 (19), JAK2 (11%), DNMT3A (9%), RUNX1 (9%), and U2AF1 (6%) SF3B1 mutations were associated with normal karyotype (NK), age 1 k/dL, platelets (plts) >50 k/dL, marrow blasts (MB) Clinical characteristics were also associated with specific genomic alterations (Figure 1). For example, NK correlated with the presence of SF3B1, ZRSR2, DNMT3A, a higher number of mutations, and absence of TP53, ASXL1, or KRAS; chromosome 5, 7, and 17 abnormalities were associated with a lower mutation number and the presence of TP53 mutations; complex karyotype correlated with the absence of TET2 and SF3B1 and the presence of TP53; age < 65 was associated with the presence of NRAS and JAK2 mutations and the absence of TET2, SF3B1, and SRSF2 mutations; hemoglobin < 8 g/dL positively correlated with mutation number and SF3B1 mutations and negatively correlated with TET2 mutations; ANC < 1 negatively correlated with JAK2, SF3B1, and DNMT3A mutations; platelets < 50k/dL negatively correlated with SF3B1 and JAK2 mutations, and positively correlated with the number of mutations; and MB Conclusions We applied machine learning techniques to reveal the complex relationships between mutational data and the clinical characteristics of several myeloid malignancies using a large, international patient cohort. In addition to correctly identifying previously described genotype-phenotype relationships, we identified several other intriguing relationships such as the relationship of particular mutations to the development of different cytopenias, demonstrating the potential utility for machine learning approaches in interrogating genomic data. Disclosures Sekeres: BMS: Consultancy; Pfizer: Consultancy; Takeda/Millenium: Consultancy. Gerds:Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Pfizer: Research Funding; Sierra Oncology: Research Funding; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Apexx Oncology: Consultancy; Celgene: Consultancy, Research Funding; Roche/Genentech: Research Funding. Mukherjee:Aplastic Anemia and MDS International Foundation: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squib: Honoraria; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Nazha:Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Jazz: Research Funding; Incyte: Speakers Bureau.
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- 2020
19. Personalized Transcriptomic Analyses Identify Unique Signatures That Correlate with Genomic Subtypes in Acute Myeloid Leukemia (AML) Using Explainable Artificial Intelligence
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Nathan Radakovich, Aziz Nazha, Yazan Rouphail, Babal K. Jha, Jaroslaw P. Maciejewski, Sudipto Mukherjee, Mikkael A. Sekeres, and Jacob Shreve
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MEG3 ,NPM1 ,Immunology ,Cell Biology ,Hematology ,Computational biology ,Biology ,Biochemistry ,Phenotype ,Deep sequencing ,Transcriptome ,Genotype ,Gene ,Exome sequencing - Abstract
Background Multi-omic analysis can identify unique signatures that correlate with cancer subtypes. While clinically meaningful molecular subtypes of AML have been defined based on the status of single genes such as NPM1 and FLT3, such categories remain heterogeneous and further work is needed to characterize their genetic and transcriptomic diversity on a truly individualized basis. Further, patients (pts) with NPM1+/FLT3-ITD- AML have a better overall survival compared to patients with NPM1-/FLT3-ITD+, suggesting that these pts could have different transcriptomic signature that impact phenotype, pathophysiology, and outcomes. Many current transcriptome analytic techniques use clustering analysis to aggregate samples and look at relationships on a cohort-wide basis to build transcriptomic signatures that correlate with phenotype or outcome. Such approaches can undermine the heterogeneity of the gene expression in pts with the same signatures. In this study, we took advantage of state of the art machine learning algorithms to identify unique transcriptomic signatures that correlate with AML genomic phenotype. Methods Genomic (whole exome sequencing and targeted deep sequencing) and transcriptomic data from 451 AML pts included in the Beat AML study (publicly available data) were used to build transcriptomic signatures that are specific for AML patients with NPM1+/FLT3-ITD+ compared to NPM1+/FLT3-ITD, and NPM1-/FLT3-ITD-. We chose these AML phenotypes as they have been described extensively and they correlate with clinical outcomes. Results A total of 242 patients (54%) had NPM1-/FLT3-, 35 (8%) were NPM1+/FLT3-, and 47 (10%) were NPM1+/FLT3+. Our algorithm identified 20 genes that are highly specific for NPM1/FLT3ITD phenotype: HOXB-AS3, SCRN1, LMX1B, PCBD1, DNAJC15, HOXA3, NPTXq, RP11-1055B8, ABDH128, HOXB8, SOCS2, HOXB3, HOXB9, MIR503HG, FAM221B, NRP1, NDUFAF3, MEG3, CCDC136, and HIST1H2BC. Interestingly, several of those genes were overexpressed or underexpressed in specific phenotypes. For example, SCRN1, LMX1B, RP11-1055B8, ABDH128, HOXB8, MIR503HG, NRP1 are only overexpressed or underexpressed in patients with NPM1-/FLT3-, while PCBD1, NDUFAF3, FAM221B are overexpressed or underexpressed in pts with NPM1+/FLT3+. These genes affect several important pathways that regulate cell differentiation, proliferation, mitochondrial oxidative phosphorylation, histone modification and lipid metabolism. All these genes had previously been reported as having altered expression in genomic studies of AML, confirming our approach's ability to identify biologically meaningful relationships. Further, our algorithm can provide a personalized explanation of overexpressed and underexpressed genes specific for a given patient, thus identifying targetable pathways for each pt. Figure 1 below shows three pts with the same genotype (NPM1+/FLT3-ITD+) but demonstrate different transcriptomic patterns of overexpression or underexpression that affect different biological pathways. Conclusions We describe the use of a state of the art explainable machine learning approach to define transcriptomic signatures that are specific for individual pts. In addition to correctly distinguishing AML subtype based on specific transcriptomic signatures, our model was able to accurately identify upregulated and downregulated genes that affecte several important biological pathways in AML and can summarize these pathways at an individual level. Such an approach can be used to provide personalized treatment options that can target the activated pathways at an individual level. Disclosures Mukherjee: Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squib: Honoraria; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Sekeres:BMS: Consultancy; Takeda/Millenium: Consultancy; Pfizer: Consultancy. Nazha:Jazz: Research Funding; Incyte: Speakers Bureau; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee.
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- 2020
20. 587 MACHINE LEARNING MODEL CORRECTLY IDENTIFIES PATIENTS WITH ADVANCED LIVER FIBROSIS WHICH ARE INDETERMINATE BY FIB-4 INDEX IN NON-ALCOHOLIC FATTY LIVER DISEASE
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Manik Aggarwal, Jacob Shreve, and Arthur J. McCullough
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medicine.medical_specialty ,Hepatology ,business.industry ,Liver fibrosis ,Fatty liver ,Gastroenterology ,Non alcoholic ,Disease ,Fib 4 index ,medicine.disease ,Internal medicine ,medicine ,Indeterminate ,business - Published
- 2021
21. Fibrinolysis in Trauma: 'Myth,' 'Reality,' or 'Something in Between'
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Andres S. Piscoya, Julie A. Wegner, John Bryant, Patrick Davis, Forest R. Sheppard, Victoria A. Ploplis, Hunter B. Moore, James Lantry, Scott G. Thomas, Anton Crepinsek, Tim Pohlman, Daniel Hake, Mark Walsh, Francis J. Castellino, Jacob Shreve, and Ernest E. Moore
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congenital, hereditary, and neonatal diseases and abnormalities ,Antifibrinolytic ,Psychotherapist ,medicine.drug_class ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Fibrinolysis ,medicine ,Humans ,Fibrin split products ,medicine.diagnostic_test ,business.industry ,030208 emergency & critical care medicine ,Hematology ,Mythology ,medicine.disease ,Hyperfibrinolysis ,Thromboelastography ,nervous system diseases ,body regions ,Thromboelastometry ,Wounds and Injuries ,Narrative review ,Medical emergency ,Cardiology and Cardiovascular Medicine ,business ,human activities - Abstract
The emphasis on fibrinolysis as an important contributor to trauma-induced coagulopathy (TIC) has led to a debate regarding the relative clinical significance of fibrinolysis in the setting of trauma. The debate has centered on two camps. The one camp defines fibrinolysis in trauma by standard coagulation tests as well as fibrin split products, D-dimers, and plasmin/antiplasmin levels. This camp favors a more liberal use of tranexamic acid and attributes more significance to hyperfibrinolysis in TIC. The other camp favors a definition of fibrinolysis based on the viscoelastic tests (VET), rotational thromboelastometry (ROTEM), and thromboelastography (TEG). These whole blood assays define hyperfibrinolysis at a higher threshold than plasma-based tests. Therefore, this VET camp reserves antifibrinolytic treatment for patients who demonstrate severe coagulopathy associated with hyperfibrinolysis. This bimodal attribution of the clinical relevance of fibrinolysis in trauma suggests that there may be an underlying "Myth" of the concept of TIC that was historically defined by plasma-based tests and a future "Reality" of the concept of TIC that is grounded on an understanding of TIC based on a VET-defined "fibrinolytic spectrum" of TIC. This narrative review explores this "Myth" and "Reality" of fibrinolysis in TIC and proposes a direction that will allow a "Future" interpretation of TIC that incorporates both the past "Myth" and present "Reality" of fibrinolysis TIC.
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- 2017
22. Viral forensic genomics reveals the relatedness of classic herpes simplex virus strains KOS, KOS63, and KOS79
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Yolanda R. Tafuri, Richard D. Dix, Daniel W. Renner, Kimberly M. Payne, Derek Gatherer, Christopher D. Bowen, Paul R. Kinchington, Jacob Shreve, and Moriah L. Szpara
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Adult ,Forensic Genetics ,0301 basic medicine ,Asia ,viruses ,Genomics ,Genome, Viral ,Herpesvirus 1, Human ,Biology ,medicine.disease_cause ,Genome ,Article ,Cell Line ,03 medical and health sciences ,Fetus ,Phylogenetics ,Virology ,Genetic variation ,medicine ,Humans ,Phylogeny ,Genetics ,Strain (biology) ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Herpes Simplex ,Fibroblasts ,Europe ,Phylogeography ,030104 developmental biology ,Herpes simplex virus ,Genetic distance ,DNA, Viral ,North America ,Restriction fragment length polymorphism - Abstract
Herpes simplex virus 1 (HSV-1) is a widespread global pathogen, of which the strain KOS is one of the most extensively studied. Previous sequence studies revealed that KOS does not cluster with other strains of North American geographic origin, but instead clustered with Asian strains. We sequenced a historical isolate of the original KOS strain, called KOS63, along with a separately isolated strain attributed to the same source individual, termed KOS79. Genomic analyses revealed that KOS63 closely resembled other recently sequenced isolates of KOS and was of Asian origin, but that KOS79 was a genetically unrelated strain that clustered in genetic distance analyses with HSV-1 strains of North American/European origin. These data suggest that the human source of KOS63 and KOS79 could have been infected with two genetically unrelated strains of disparate geographic origins. A PCR RFLP test was developed for rapid identification of these strains.
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- 2016
23. A personalized prediction model for hospital readmission risk for cancer patients
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Alberto J. Montero, James P. Stevenson, Jacob Shreve, Rachel Benish Shirley, Sarah Lee, Nathan Radakovich, Aziz Nazha, Christina Felix, and Cameron Beau Hilton
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Cancer Research ,Hospital readmission ,medicine.medical_specialty ,Oncology ,business.industry ,Emergency medicine ,medicine ,Cancer ,medicine.disease ,business - Abstract
7057 Background: Cancer patients (pts) are at high risk of unplanned hospital readmissions. Predicting which cancer patients are at higher risk of readmission would improve post-discharge follow-up/navigation, decrease cost, and improve pt outcomes. Methods: We conducted a retrospective cohort study of non-surgical cancer pts hospitalized at our center between 12/2014 to 7/2018. A machine learning algorithm was trained on 348 medical, sociodemographic and cancer-specific variables with a total of 1,801,944 data points. The cohort was randomly divided into training (80%) and validation (20%) subsets. Prediction performance was measured by area under the receiver operator characteristic curve (AUC). Results: A total of 5,178 hospitalizations were included, of which 45.1% were women, and 27.6% experienced an unplanned readmission within 30 days. The most frequently represented cancers were hematologic malignancies (30.5%), followed by GI (18.1%), lung (13.7%), and GU (10.9%). Significant variables that impacted the algorithm decision are ranked from the most to the least important, including: days from last admission; planned index chemotherapy admission; number of vascular access lines, drains, and airways in use; length of stay; cancer diagnosis; total ED visits in past 6 months; age; discharge lab values (sodium, albumin, alkaline phosphatase, bilirubin, platelets); number of prior admissions; and discharge disposition. The AUC for the validation subset was 0.80. To ease the translation of this model into the clinic, we developed a web application whereby users can supply the aforementioned variables to the model and receive a personalized prediction that highlights those variables most affecting a subject’s readmission risk status: www.Cancer-Readmission.com. Conclusions: A cancer-specific readmission risk model with high AUC for 30-days unplanned readmission has been developed. The model is embedded in a freely available web application that provides personalized, patient-specific predictions. Programs that integrate this model can identify cancer patients with a greater risk for unplanned hospital readmission, thus providing a personalized approach to prevent future unplanned readmissions.
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- 2020
24. Molecular dissection of normal karyotype acute myeloid leukemia
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Aziz Nazha, Mikkael A. Sekeres, Wencke Walter, Nathan Radakovich, Stephan Hutter, Yihong Guan, Metis Hasipek, Torsten Haferlach, Teodora Kuzmanovic, Sudipto Mukherjee, Claudia Haferlach, Yasunobu Nagata, Manja Meggendorfer, Cassandra M Kerr, Hassan Awada, Jaroslaw P. Maciejewski, Babal K. Jha, Jacob Shreve, and Ahed Makhoul
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Cancer Research ,Dissection ,Conventional cytogenetics ,Oncology ,business.industry ,Normal karyotype acute myeloid leukemia ,Cancer research ,Myeloid leukemia ,Medicine ,Karyotype ,business - Abstract
7534 Background: Conventional cytogenetics remain one of the most important prognostic factors in acute myeloid leukemia (AML), though 50-60% of patients (pts) have normal karyotype (NK), conventionally classified as intermediate-risk, and have very heterogeneous outcomes. A fraction of mutations such as NPM1, FLT3-ITD, and CEBPa can improve risk stratification for some pts but underestimate the molecular complexity and interactions between these genes and others. Methods: Genomic and clinical data of 2,793 primary AML (pAML) pts were analyzed. A panel of 35 genes that are commonly mutated in AML and myeloid malignancies and have shown to impact OS was included. Correlation of each mutation with others and their impact on OS were evaluated. OS was calculated from the date of diagnosis to date of death or last follow-up. Results: Of 2,793 pts with pAML, 1,352 (48%) had NK and were included in the final analysis. The median age was 55 years (range, 18-93). The median number of mutations/sample was 3 (range, 0-7). The most commonly mutated genes were: NPM1 (49%), DNMT3A (37%), FLT3-ITD (24%), CEBPa (19%), TET2 (17%), IDH2 (17%), and RUNX1 (15%). In univariate Cox regression analysis, mutations in NPM1 (HR 0.81, p =0.008), and CEBPa (single mutant, HR 0.8, double mutant, HR 0.69, p< 0.001, respectively) were associated with longer OS, while mutations in DNMT3a (HR 1.26, p =0.003), FLT3-ITD (HR 1.49, p< 0.001), TET2 (HR 1.26, p =0.02), RUNX1 (HR 1.36, p =0.003), SRSF2 (HR 1.58, p Mut/ DNMT3AWT/FLT3-ITDWT was 99.1 months(m), NMP1Mut/DNMT3AMut /FLT3-ITDWT 54.8m, NMP1Mu t/DNMT3AWT/FLT3-ITDMut 42.3m, NMP1Mut/DNMT3AMut/FLT3-ITDMut 13.4m, NMP1WT/DNMT3AMut/FLT3-ITDMut 13.1m, and NMP1WT/DNMT3AWT/FLT3-ITDWT (triple negative) 32.7m. The median OS for pts with 0-2 mutations/sample was 59.3m, compared to 34.1m for pts with 3-4 mutations, and 16.1m for pts with > 5 mutations ( p< 0.001). Conclusions: We propose a simplified and robust approach to risk stratify AML pts with NK based on the mutational status of NPM1, DNMT3A, FLT3-ITD (alone or in combination with each other), CEBPa, and the number of mutations/sample.
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- 2020
25. Predicting Response to Hypomethylating Agents in Patients with Myelodysplastic Syndromes (MDS) Using Artificial Intelligence (AI)
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Hassan Awada, Yasunobu Nagata, Metis Hasipek, Teodora Kuzmanovic, Sudipto Mukherjee, Jaroslaw P. Maciejewski, Cameron Beau Hilton, Yazan Rouphail, Vera Adema, Rachel Benish Shirley, Nathan Radakovich, Jacob Shreve, Mikkael A. Sekeres, Yihong Guan, Anjali S. Advani, Cassandra M Kerr, Babal K. Jha, and Aziz Nazha
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Myelodysplastic syndromes ,Immunology ,Area under the curve ,Complete blood count ,Context (language use) ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,International Prognostic Scoring System ,Sample size determination ,Internal medicine ,Cohort ,medicine ,Data monitoring committee ,business - Abstract
Introduction While the hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) improve cytopenias and prolong survival in MDS patients (pts), response is not guaranteed. Timely identification of non-responders could prevent prolonged exposure to ineffective therapy, thereby reducing toxicities and costs. Currently no widely accepted clinical or genomic models exist to predict response or resistance to HMAs. We developed a clinical model to predict response or resistance to HMA after 90 days of initiating therapy based on changes in blood counts using time series analysis technology similar to the kind used in Apple's Siri or Google Assistant. In the setting of voice recognition, the sequence and context of words determines the meaning of a sentence; similarly, we hypothesized that the pattern of changes in MDS pts' blood counts would predict response or resistance early during treatment. Methods We screened a cohort of 107 pts with MDS (per 2016 WHO criteria) who received HMAs at our institution between February 2005 and July 2013 and had regular CBCs drawn during treatment. Mutations from a panel of 60 genes commonly mutated in myeloid malignancy were included. Responses were assessed after 6 months of therapy per International Working Group (IWG) 2006 criteria. Pts were divided randomly into training (80%) and validation (20%) cohorts. To address the potential for bias due to a small sample size, an oversampling algorithm was used to cluster similar pts based on their CBC data, Revised International Prognostic Scoring System (IPSS-R) score, and % bone marrow blasts at the time of diagnosis. CBC data from the first 90 days of treatment were fed into deep neural network (recurrent neural network) and decision tree algorithms, which were trained to predict whether pts would achieve a response (defined as complete remission (CR), partial remission (PR), or hematologic Improvement (HI)). Area under the curve (AUC) was used to assess model performance. Important features that impact the algorithm's predictions were extracted and plotted. Results 20747 unique data points were used, including CBC, clinical and genomic data. Among 107 pts, 61 (57.0%) received AZA only, 19 (17.8%) DAC only, 4 (3.7%) received both DAC and AZA, and 23 (21.5%) received HMA with an additional agent. Median age was 69 years (range: 37-100 years), and 27 (26.4%) were female. Forty pts (37.4%) were very low/low risk, 32 (29.9%) intermediate, 19 (17.8%) high, and 16 (14.9%) very high risk per IPSS-R. Responses included 23 (22.5%) CR, 2 (1.9%) marrow CR, 4 (3.9%) PR, and 20 (19.6%) HI. The most commonly mutated genes were ASXL1 (17.6%), TET2 (16.7%), SRSF2 (15.7%), SF3B1 (11.8%), RUNX1 (10.8%), STAG2(10.8%), and DNMT3A (10.8%). The median number of mutations per sample was 1 (range, 0-11), and 40 pts (39.2%) had > 3 mutations per sample. When trained using absolute values and changes in CBC values, the model's AUC was 0.95 in the training cohort and 0.83 in the validation cohort. When the cohort was oversampled to 1000 pts, the validation cohort AUC increased to 0.89. Feature extraction algorithms identified increases in MCV and RDW during weeks 2-8 of treatment, increased proportion of lymphocytes, decreased proportion of monocytes, and increased platelet counts during weeks 6-8 as factors favoring response to HMA. The model provides personalized, patient-specific predictions that correlate with blood counts (Figure 1). Conclusions We describe a machine learning model that monitors changes in blood counts during therapy with HMA to predict response or resistance to HMA in MDS pts. Such a model can be used to develop novel trial designs wherein pts predicted to not respond after 90 days of HMA treatment could be assigned to an investigational agent. Conversely, it would help inform the decision to continue HMA therapy in pts predicted to respond. Increasing sample size with oversampling dramatically increased model accuracy; a larger cohort of pts treated at different institutions is currently under development. Disclosures Sekeres: Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; McGraw Hill Hematology Oncology Board Review: Other: Editor; Bristol-Myers Squibb: Speakers Bureau. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Nazha:Novartis: Speakers Bureau; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; MEI: Other: Data monitoring Committee.
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- 2019
26. Geno-Clinical Model for the Diagnosis of Bone Marrow Myeloid Neoplasms
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Mikkael A. Sekeres, Nathan Radakovich, Brianna N Smith, Babal K. Jha, Aziz Nazha, Yazan Rouphail, Sudipto Mukherjee, Manja Meggendorfer, Michael R. Savona, Rami S. Komrokji, Eric Padron, Stephan Hutter, Wencke Walter, Claudia Haferlach, Yasunobu Nagata, Jacob Shreve, Cassandra M. Hirsch, Torsten Haferlach, Jaroslaw P. Maciejewski, Aaron T. Gerds, and Cameron Beau Hilton
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Cytopenia ,Pathology ,medicine.medical_specialty ,Myeloid ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Pancytopenia ,Leukemia ,medicine.anatomical_structure ,Polycythemia vera ,Dysplasia ,Medicine ,Bone marrow ,business ,Myelofibrosis - Abstract
Background Myelodysplastic syndromes (MDS) and other myeloid neoplasms are mainly diagnosed based on morphological changes in the bone marrow. Diagnosis can be challenging in patients (pts) with pancytopenia with minimal dysplasia, and is subject to inter-observer variability, with up to 40% disagreement in diagnosis (Zhang, ASH 2018). Somatic mutations can be identified in all myeloid neoplasms, but no gene or set of genes are diagnostic for each disease phenotype. We developed a geno-clinical model that uses mutational data, peripheral blood values, and clinical variables to distinguish among several bone marrow disorders that include: MDS, idiopathic cytopenia of undetermined significance (ICUS), clonal cytopenia of undetermined significance (CCUS), MDS/myeloproliferative neoplasm (MPN) overlaps including chronic myelomonocytic leukemia (CMML), and MPNs such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (PMF). Methods We combined genomic and clinical data from 2471 pts treated at our institution (684) and the Munich Leukemia Laboratory (1787). Pts were diagnosed with MDS, ICUS, CCUS, CMML, MDS/MPN, PV, ET, and PMF according to 2016 WHO criteria. Diagnoses were confirmed by independent hematopathologists not associated with the study. A panel of 60 genes commonly mutated in myeloid malignancies was included. The cohort was randomly divided into learner (80%) and validation (20%) cohorts. Machine learning algorithms were applied to predict the phenotype. Feature extraction algorithms were used to extract genomic/clinical variables that impacted the algorithm decision and to visualize the impact of each variable on phenotype. Prediction performance was evaluated according to the area under the curve of the receiver operator characteristic (ROC-AUC). Results Of 2471 pts, 1306 had MDS, 223 had ICUS, 107 had CCUS, 478 had CMML, 89 had MDS/MPN, 79 had PV, 90 had ET, and 99 had PMF. The median age for the entire cohort was 71 years (range, 9-102); 38% were female. The median white blood cell count (WBC) was 3.2x10^9/L (range, 0.00-179), absolute monocyte count (AMC) 0.21x10^9/L (range, 0-96), absolute lymphocyte count (ALC) 0.88x10^9/L (range, 0-357), absolute neutrophil count (ANC) 0.60x10^9/L (range, 0-170), and hemoglobin (Hgb) 10.50 g/dL (range, 3.9-24.0). The most commonly mutated genes in all pts were: TET2 (28%), ASXL1 (23%), SF3B1 (15%). In MDS, they were: TET2 (26%), SF3B1 (24%), ASXL1 (21%). In CCUS: TET2 (46%), SRSF2 (24%), ASXL1 (23%). In CMML, TET2 (51%), ASXL1 (43 %), SRSF2 (25%). In MDS/MPN: SF3B1 (39%), JAK2 (37%), TET2 (20%). In PV, JAK2 (94%), TET2 (22%), DNMT3A (8%). In ET: JAK2 (44%), TET2 (13%), DNMT3A (8%). In PMF: JAK2 (67%), ASXL1 (43%), SRSF2 (17%). 71 genomic/clinical variables were evaluated. Feature extraction algorithms were used to identify the variables with the most significant impacts on prediction. The top variables are shown in the Figure 1. Overall, the most important variables were: age, AMC, ANC, Hgb, Plt, ALC, total number of mutations, JAK2, ASXL1, TET2, U2AF1, SRSF2, SF3B1, BCOR, EZH2, and DNMT3A. The top variables for each disease were different, see Figure. When applying the model to the validation cohort, AUC performance was as follows (a perfect predictor has an AUC of 1, and AUC ≥ 0.90 are generally considered excellent): MDS: 0.95 +/- 0.04, ICUS: 0.96 +/- 0.05, CCUS: 0.95 +/- 0.05, CMML: 0.95 +/- 0.05, MDS/MPN: 0.95 +/- 0.05, PV: 0.95 +/- 0.05, ET: 0.96 +/- 0.05, PMF: 0.95 +/- 0.05. When the analysis was restricted to MDS, ICUS, and CCUS, the AUC remained high, 0.95 +/- 0.4. The model can also provide personalized explanations of the variables supporting the prediction and the impact of each variable on the outcome (Figure). Conclusions We propose a new approach using interpretable, individualized modeling to predict myeloid neoplasm phenotypes based on genomic and clinical data without bone marrow biopsy data. This approach can aid clinicians and hematopathologists when encountering pts with cytopenias and suspicion for these disorders. The model also provides feature attributions that allow for quantitative understanding of the complex interplay among genotypes, clinical variables, and phenotypes. A web application to facilitate the translation of this model into the clinic is under development and will be presented at the meeting. Figure 1 Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Walter:MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Savona:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Gerds:Incyte: Consultancy, Research Funding; Roche: Research Funding; Imago Biosciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Pfizer: Consultancy; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding. Mukherjee:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Pfizer: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy.
- Published
- 2019
27. A Personalized Prediction Model to Risk Stratify Patients with Acute Myeloid Leukemia (AML) Using Artificial Intelligence
- Author
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Vera Adema, Nathan Radakovich, Wencke Walter, Torsten Haferlach, Jaroslaw P. Maciejewski, Manja Meggendorfer, Yazan Rouphail, Sudipto Mukherjee, Ahed Makhoul, Hassan Awada, Bhumika J. Patel, Jacob Shreve, Yasunobu Nagata, Aziz Nazha, Cassandra M Kerr, Teodora Kuzmanovic, Mikkael A. Sekeres, Stephan Hutter, Cameron Beau Hilton, and Claudia Haferlach
- Subjects
0301 basic medicine ,Oncology ,Neuroblastoma RAS viral oncogene homolog ,NPM1 ,medicine.medical_specialty ,Immunology ,Cell Biology ,Hematology ,Gene mutation ,medicine.disease ,Biochemistry ,Transplantation ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,Cohort ,CEBPA ,medicine ,Data monitoring committee ,030215 immunology - Abstract
Background AML is a heterogeneous clonal disorder that is characterized by the accumulation of complex genomic alterations that affect disease biology and outcomes. Despite significant advances in our understanding of the impact of these mutations on overall survival (OS), established AML risk stratification guidelines are based primarily on cytogenetic analyses and a limited number of genes, don't take into account the complexity and the interaction between these mutations, and how particular constellations of genomic and clinical risk factors affect patient (pt) outcome. We developed a novel prognostic model that incorporates clinical, cytogenetic, and mutational data to determine personalized outcomes specific to a particular pt. Method A total of 792,779 genomic and clinical data points from 3,421 pts were analyzed. The cohort was comprised of five independent datasets: 443 pts from the Beat AML Master Trial (Tyner et al, Nature, 2018), 855 pts from Cleveland Clinic, 414 pts from Munich Leukemia Laboratory (MLL), 1,509 pts from the German-Austrian Study Group (Papaemmanuil et al, NEJM, 2016), and 200 pts from The Cancer Genome Atlas (NEJM, 2013). A panel of 44 gene mutations commonly implicated in AML was used in the analysis, along with numerous cytogenetic and clinical variables such age, white blood cell count WBC) at diagnosis, and AML subtype (primary vs. secondary vs. therapy-related. A machine learning algorithm capable of accounting for survival (XGBOOST) was used to build the new model, in which clinical and molecular variables were randomly selected for inclusion in determining OS. Feature extraction algorithms were used to isolate the most important variables that impacted decision making within the model. The algorithm can also plot the important features that are specific for a given pt and show the impact of each feature on the outcome (positive vs. negative). The C-index was used to evaluate the accuracy of the new model compared to 2017 ELN risk classification. Results The median age of the cohort was 56 years (range, 18-100); 1,122 pts (32.8%) had favorable risk cytogenetics per ELN criteria, 956 (27.9%) intermediate (INT), and 1,343 (39.3%) adverse. The most commonly mutated genes were: NPM1 (24%), FLT3 (23%), DNMT3A (20%), NRAS (13%), IDH2 (11%), RUNX1 (10%) and TET2 (10%). Mutations occurred in different frequencies in each cytogenetic risk group. The most commonly mutated genes in the favorable risk group were: NRAS (30%), KIT (23%), FLT3 (17%), and KRAS (8%). The most commonly mutated genes in the INT risk group were: NPM1 (28%), FLT3 (26%), DNMT3A (22%), IDH2 (12%), TET2 (11%), NRAS (11%), and RUNX1 (11%). The most commonly mutated genes in pts with adverse cytogenetics included: TP53 (34%), DNMT3A (13%), NRAS (11%), RUNX1 (10%), PTPN11 (8%), IDH2 (7%), U2AF1 (6%) and FLT3 (6%). All genomic-clinical variables were included in the machine learning algorithm. Variable importance analyses (the most important variables that contributed to the outcome) and multiple backward elimination analyses (identifying the least number of variables that can provide the least error rate) identified the following variables that impacted OS: age, transplant (yes vs. no), WBC, bone marrow blast %, cytogenetics, ASXL1, CEBPA, DNMT3A, FLT3, KDM6A, KIT, KRAS, NPM1, NRAS, PHF6, PTPN11, RUNX1, TET2, and TP53. The clinical and mutational variables that impacted each pt outcome can be visualized in a highly personalized manner, Figure 1. The C-index for the new model was 0.80 which significantly outperformed ELN classification (0.59). When applying the new model to each of the five patient cohorts, the c-indices remained high and were as follows: Beat AML (0.81), Cleveland Clinic (0.85), MLL (0.83), Papaemmanuil E, et al (0.79), and TCGA (0.80). Conclusions Genomic alterations have a differential impact on OS in each cytogenetic risk group, highlighting the complexity of incorporating these mutations into risk stratification. A personalized prediction model based on clinical-genomic data can accurately provide survival unique to each individual pt and can significantly outperform ELN classifications or any currently available models. To ease the translation of this model into the clinic, a web application is currently under development and will be publicly available for use. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor. Walter:MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Nazha:Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; MEI: Other: Data monitoring Committee.
- Published
- 2019
28. A Massive Expansion of Effector Genes Underlies Gall-Formation in the Wheat Pest Mayetiola destructor
- Author
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Brandon J. Schemerhorn, Mehwish Javaid, Kerstin P. Blankenburg, Marion O. Harris, Lora Perales, Lucio Navarro Escalante, Chaoyang Zhao, J. J. Stuart, Mustapha El-Bouhssini, Jacob Shreve, Doina Caragea, Marcus Coyle, Panagiotis Ioannidis, Subhashree Subramanyam, Martin Andersson, Kun Xue, David A. Wheeler, Ming-Shun Chen, DeNard Simmons, Christer Löfstedt, Swapnil Nagar, Geoffrey Okwuonu, Fiona Ongeri, Susan J. Brown, Nicolae Herndon, Xuming Liu, Dianhui Zhu, Richard H. Shukle, Sanjay Chellapilla, Tony Grace, George M. Weissenberger, Alisha J. Johnson, Shalini N. Jhangiani, Evgeny M. Zdobnov, Christopher B. Williams, Donna M. Muzny, Robert M. Waterhouse, Yiming Zhu, Lynne V. Nazareth, Rebecca Thornton, LaRonda Jackson, Steven E. Scherer, Cornelis J. P. Grimmelikhuijzen, Robert Mata, Liezl Francisco, Matthew Batterton, Riyue Bao, Divya Kalra, Sandra L. Lee, Markus Friedrich, Yi Han, Stephen Richards, Thiago R Benatti, Fremiet Lara, Viktoriya Korchina, John H. Werren, Navdeep Gill, Christie Kovar, Hang Chen, M. Holder, James C. Carolan, Kim C. Worley, Susanta K. Behura, Tittu Mathew, Ling Pu, Jiaxin Qu, Hugh M. Robertson, Frank Hauser, Brittany F. Peterson, Waterhouse, Robert, Ioannidis, Panagiotis, and Zdobnov, Evgeny
- Subjects
0106 biological sciences ,Ubiquitin-Protein Ligases ,Molecular Sequence Data ,Adaptation, Biological ,Plant Tumors ,Sequence Homology ,01 natural sciences ,Genome ,Chromosomes ,General Biochemistry, Genetics and Molecular Biology ,Sexual Behavior, Animal ,03 medical and health sciences ,Two-Hybrid System Techniques ,Animals ,Gene family ,Gall ,ddc:576.5 ,Amino Acid Sequence ,Mayetiola destructor ,Gene ,Phylogeny ,Triticum ,030304 developmental biology ,2. Zero hunger ,Genetics ,0303 health sciences ,Base Sequence ,Models, Genetic ,Agricultural and Biological Sciences(all) ,biology ,Biochemistry, Genetics and Molecular Biology(all) ,Effector ,Diptera ,fungi ,food and beverages ,Sequence Analysis, DNA ,biology.organism_classification ,Cecidomyiidae ,Larva ,Multigene Family ,General Agricultural and Biological Sciences ,010606 plant biology & botany - Abstract
SummaryGall-forming arthropods are highly specialized herbivores that, in combination with their hosts, produce extended phenotypes with unique morphologies [1]. Many are economically important, and others have improved our understanding of ecology and adaptive radiation [2]. However, the mechanisms that these arthropods use to induce plant galls are poorly understood. We sequenced the genome of the Hessian fly (Mayetiola destructor; Diptera: Cecidomyiidae), a plant parasitic gall midge and a pest of wheat (Triticum spp.), with the aim of identifying genic modifications that contribute to its plant-parasitic lifestyle. Among several adaptive modifications, we discovered an expansive reservoir of potential effector proteins. Nearly 5% of the 20,163 predicted gene models matched putative effector gene transcripts present in the M. destructor larval salivary gland. Another 466 putative effectors were discovered among the genes that have no sequence similarities in other organisms. The largest known arthropod gene family (family SSGP-71) was also discovered within the effector reservoir. SSGP-71 proteins lack sequence homologies to other proteins, but their structures resemble both ubiquitin E3 ligases in plants and E3-ligase-mimicking effectors in plant pathogenic bacteria. SSGP-71 proteins and wheat Skp proteins interact in vivo. Mutations in different SSGP-71 genes avoid the effector-triggered immunity that is directed by the wheat resistance genes H6 and H9. Results point to effectors as the agents responsible for arthropod-induced plant gall formation.
- Published
- 2015
29. The value of cold storage whole blood platelets in trauma resuscitation is like real estate: a function of 'location, location, location'
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Scott G. Thomas, Mark Walsh, and Jacob Shreve
- Subjects
Blood Platelets ,Cryopreservation ,Resuscitation ,business.industry ,Blood preservation ,Cold storage ,030208 emergency & critical care medicine ,Real estate ,Hematology ,030204 cardiovascular system & hematology ,medicine.disease ,Cold Temperature ,03 medical and health sciences ,0302 clinical medicine ,Blood Preservation ,medicine ,Humans ,Medical emergency ,business ,Trauma resuscitation ,Whole blood - Published
- 2017
30. Genetic Determinants for Enzymatic Digestion of Lignocellulosic Biomass Are Independent of Those for Lignin Abundance in a Maize Recombinant Inbred Population
- Author
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Michael A. Held, Bryan W. Penning, Jyothi Thimmapuram, Geoffrey B. Turner, Robert W. Sykes, Nathan S. Mosier, Christopher K. Dugard, Maureen C. McCann, Matthew Fowler, John F. Klimek, Stephen R. Decker, Angela Ziebell, Clifford F. Weil, Nicholas C. Babcock, Mark F. Davis, Nathan M. Springer, Jacob Shreve, and Nicholas C. Carpita
- Subjects
Candidate gene ,Physiology ,Population ,Biomass ,Lignocellulosic biomass ,macromolecular substances ,Plant Science ,Biology ,Quantitative trait locus ,Xylose ,complex mixtures ,chemistry.chemical_compound ,Engineering ,Enzymatic hydrolysis ,Genetic variation ,Botany ,Medicine and Health Sciences ,Physical Sciences and Mathematics ,Genetics ,education ,education.field_of_study ,technology, industry, and agriculture ,Life Sciences ,food and beverages ,Articles ,chemistry - Abstract
Biotechnological approaches to reduce or modify lignin in biomass crops are predicated on the assumption that it is the principal determinant of the recalcitrance of biomass to enzymatic digestion for biofuels production. We defined quantitative trait loci (QTL) in the Intermated B73 × Mo17 recombinant inbred maize (Zea mays) population using pyrolysis molecular-beam mass spectrometry to establish stem lignin content and an enzymatic hydrolysis assay to measure glucose and xylose yield. Among five multiyear QTL for lignin abundance, two for 4-vinylphenol abundance, and four for glucose and/or xylose yield, not a single QTL for aromatic abundance and sugar yield was shared. A genome-wide association study for lignin abundance and sugar yield of the 282-member maize association panel provided candidate genes in the 11 QTL of the B73 and Mo17 parents but showed that many other alleles impacting these traits exist among this broader pool of maize genetic diversity. B73 and Mo17 genotypes exhibited large differences in gene expression in developing stem tissues independent of allelic variation. Combining these complementary genetic approaches provides a narrowed list of candidate genes. A cluster of SCARECROW-LIKE9 and SCARECROW-LIKE14 transcription factor genes provides exceptionally strong candidate genes emerging from the genome-wide association study. In addition to these and genes associated with cell wall metabolism, candidates include several other transcription factors associated with vascularization and fiber formation and components of cellular signaling pathways. These results provide new insights and strategies beyond the modification of lignin to enhance yields of biofuels from genetically modified biomass.
- Published
- 2014
31. Tranexamic Acid for Trauma Resuscitation in the United States of America
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Patrick Davis, Andres S. Piscoya, Nathan D. Nielsen, Daniel Hake, John Bryant, Anton Crepinsek, Michael Son, Julie A. Wegner, Alberto Grassetto, Mark Walsh, Scott G. Thomas, Jacob Shreve, Ernest E. Moore, Tim Pohlman, Hunter B. Moore, and Francis J. Castellino
- Subjects
medicine.medical_specialty ,Antifibrinolytic ,Randomization ,medicine.drug_class ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Fibrinolysis ,medicine ,Humans ,Intensive care medicine ,business.industry ,030208 emergency & critical care medicine ,Hematology ,United States ,Surgery ,Survival benefit ,Tranexamic Acid ,Wounds and Injuries ,Narrative review ,Cardiology and Cardiovascular Medicine ,Trauma resuscitation ,business ,Tranexamic acid ,medicine.drug - Abstract
The utilization of tranexamic acid (TXA) for the management of bleeding trauma patients has been a subject of much debate on both sides of the Atlantic and in Australia. As a result of the large randomized controlled study called the Clinical Randomization of an Antifibrinolytic in Severe Hemorrhage (CRASH-2), there was an initial enthusiasm for the use of TXA to treat bleeding patients. However, the adoption of TXA in the United States was delayed by concerns of “knowledge and evidence gaps” of the CRASH-2 study and because of a lack of mechanistic rationale that would explain the survival benefit noted in the study. Subsequent nonrandomized controlled trials questioned the liberal use of TXA in trauma patients. This narrative review explores the historical as well as clinical and theoretical grounds for the more measured use of TXA in the United States and proposes a clinical and point-of-care guided utilization of TXA, blood components, and adjunctive hemostatic agents in bleeding trauma patients.
- Published
- 2016
32. A genome-wide survey of small interfering RNA and microRNA pathway genes in a galling insect
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Jeffrey J. Stuart, Jacob Shreve, Alisha J. Johnson, Christopher B. Williams, Richard H. Shukle, Subhashree Subramanyam, and Brandon J. Schemerhorn
- Subjects
Genetics ,Small interfering RNA ,biology ,Physiology ,Diptera ,Genome, Insect ,fungi ,RNA ,Piwi-interacting RNA ,Argonaute ,biology.organism_classification ,Genome ,MicroRNAs ,RNA interference ,Insect Science ,Animals ,Insect Proteins ,RNA Interference ,RNA, Small Interfering ,Mayetiola destructor ,Gene ,Phylogeny - Abstract
Deployment of resistance (R) genes is the most effective control for Hessian fly, Mayetiola destructor (Say); however, deployment of R genes results in an increased frequency of pest genotypes that display virulence to them. RNA interference (RNAi) is a useful reverse genetics tool for studying such insect virulence pathways, but requires a systemic phenotype, which is not found in all species. In an effort to correlate our observed weak RNAi phenotype in M. destructor with a genetic basis, we have aggregated and compared RNAi related genes across M. destructor, three other insect species, and the nematode Caenorhabditis elegans. We report here the annotation of the core genes in the small interfering RNA (siRNA) and microRNA (miRNA) pathways in M. destructor. While most of the miRNA pathway genes were highly conserved across the species studied, the siRNA pathway genes showed increased relative variability in comparison to the miRNA pathway. In particular, the Piwi/Argonaute/Zwille (PAZ) domain of Dicer-2 (DCR-2) had the least amount of sequence similarity of any domain among species surveyed, with a trend of increased conservation in those species with amenable systemic RNAi. A homolog of the systemic interference defective-1 (Sid-1) gene of C. elegans was also not annotated in the M. destructor genome. Indeed, it is of interest that a Sid-1 homolog has not been detected in any dipteran species to date. We hypothesize the sequence architecture of the PAZ domain in the M. destructor DCR-2 protein is related to reduced efficacy of this enzyme and this taken together with the lack of a Sid-1 homolog may account for the weak RNAi response observed to date in this species as well as other dipteran species.
- Published
- 2013
33. Identification of a plastidial phenylalanine exporter that influences flux distribution through the phenylalanine biosynthetic network
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Rohit Jaini, Longyun Guo, Funmilayo Adebesin, Natalia Dudareva, David Rhodes, Heejin Yoo, Jacob Shreve, Joseph H. Lynch, Jyothi Thimmapuram, Rachel M. McCoy, Michael Gutensohn, John A. Morgan, Joshua R. Widhalm, and Yichun Qian
- Subjects
Phenylalanine ,General Physics and Astronomy ,Biology ,Real-Time Polymerase Chain Reaction ,Article ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,Metabolic flux analysis ,Escherichia coli ,Aromatic amino acids ,Plastids ,Tyrosine ,Plastid ,Plant Proteins ,chemistry.chemical_classification ,Volatile Organic Compounds ,Multidisciplinary ,Reverse Transcriptase Polymerase Chain Reaction ,Sequence Analysis, RNA ,General Chemistry ,Plants, Genetically Modified ,Metabolic Flux Analysis ,Biosynthetic Pathways ,Amino acid ,Petunia ,Metabolic pathway ,chemistry ,Biochemistry ,Amino Acid Transport Systems, Basic ,RNA Interference ,Flux (metabolism) - Abstract
In addition to proteins, L-phenylalanine is a versatile precursor for thousands of plant metabolites. Production of phenylalanine-derived compounds is a complex multi-compartmental process using phenylalanine synthesized predominantly in plastids as precursor. The transporter(s) exporting phenylalanine from plastids, however, remains unknown. Here, a gene encoding a Petunia hybrida plastidial cationic amino-acid transporter (PhpCAT) functioning in plastidial phenylalanine export is identified based on homology to an Escherichia coli phenylalanine transporter and co-expression with phenylalanine metabolic genes. Radiolabel transport assays show that PhpCAT exports all three aromatic amino acids. PhpCAT downregulation and overexpression result in decreased and increased levels, respectively, of phenylalanine-derived volatiles, as well as phenylalanine, tyrosine and their biosynthetic intermediates. Metabolic flux analysis reveals that flux through the plastidial phenylalanine biosynthetic pathway is reduced in PhpCAT RNAi lines, suggesting that the rate of phenylalanine export from plastids contributes to regulating flux through the aromatic amino-acid network., Phenylalanine is synthesized in plant chloroplasts and is then exported to the cytosol, where it is a precursor for various secondary metabolites. Here, the authors identify PhpCAT as a plastid phenylalanine transporter required to maintain metabolic flux in petunia.
- Published
- 2015
34. Rapid Genome Assembly and Comparison Decode Intrastrain Variation in Human Alphaherpesviruses
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Lance Parsons, Lynn W. Enquist, Jacob Shreve, Moriah L. Szpara, Mackenzie M. Shipley, Christopher D. Bowen, and Yolanda R. Tafuri
- Subjects
Adult ,viruses ,Molecular Sequence Data ,Sequence assembly ,Genome, Viral ,Herpesvirus 1, Human ,Biology ,medicine.disease_cause ,Microbiology ,Genome ,Virus ,Virology ,Genetic variation ,medicine ,Humans ,Pathogen ,Comparative genomics ,Genetics ,Computational Biology ,Genetic Variation ,Sequence Analysis, DNA ,Phenotype ,QR1-502 ,3. Good health ,Herpes simplex virus ,Mutation ,Research Article - Abstract
Herpes simplex virus (HSV) is a widespread pathogen that causes epithelial lesions with recurrent disease that manifests over a lifetime. The lifelong aspect of infection results from latent viral infection of neurons, a reservoir from which the virus reactivates periodically. Recent work has demonstrated the breadth of genetic variation in globally distributed HSV strains. However, the amount of variation or capacity for mutation within one strain has not been well studied. Here we developed and applied a streamlined new approach for assembly and comparison of large DNA viral genomes such as HSV-1. This viral genome assembly (VirGA) workflow incorporates a combination of de novo assembly, alignment, and annotation strategies to automate the generation of draft genomes for large viruses. We applied this approach to quantify the amount of variation between clonal derivatives of a common parental virus stock. In addition, we examined the genetic basis for syncytial plaque phenotypes displayed by a subset of these strains. In each of the syncytial strains, we found an identical DNA change, affecting one residue in the gB (UL27) fusion protein. Since these identical mutations could have appeared after extensive in vitro passaging, we applied the VirGA sequencing and comparison approach to two clinical HSV-1 strains isolated from the same patient. One of these strains was syncytial upon first culturing; its sequence revealed the same gB mutation. These data provide insight into the extent and origin of genome-wide intrastrain HSV-1 variation and present useful methods for expansion to in vivo patient infection studies., IMPORTANCE Herpes simplex virus (HSV) infects more than 70% of adults worldwide, causing epithelial lesions and recurrent disease that manifests over a lifetime. Prior work has demonstrated that HSV strains vary from country to country and between individuals. However, the amount of variation within one strain has not been well studied. To address this, we developed a new approach for viral genome assembly (VirGA) and analysis. We used this approach to quantify the amount of variation between sister clones of a common parental virus stock and to determine the basis of a unique fusion phenotype displayed by several variants. These data revealed that while sister clones of one HSV stock are more than 98% identical, these variants harbor enough genetic differences to change their observed characteristics. Comparative genomics approaches will allow us to explore the impacts of viral inter- and intrastrain diversity on drug and vaccine efficacy.
- Published
- 2015
35. Coordination of MicroRNAs, PhasiRNAs, and NB-LRR Genes in Response to a Plant Pathogen: Insights from Analyses of a Set of Soybean Rps Gene Near-Isogenic Lines
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Jianxin Ma, Meixia Zhao, Feng Lin, Jacob Shreve, Chunmei Cai, Blake C. Meyers, Teresa J. Hughes, Jixian Zhai, Linghong Li, and Jyothi Thimmapuram
- Subjects
Genetics ,Transposable element ,biology ,lcsh:QH426-470 ,fungi ,food and beverages ,Plant Science ,lcsh:Plant culture ,biology.organism_classification ,lcsh:Genetics ,Downregulation and upregulation ,microRNA ,Phytophthora sojae ,lcsh:SB1-1110 ,Binding site ,Agronomy and Crop Science ,Gene ,Pathogen ,Reference genome - Abstract
Disease-related genes, particularly the nucleotide binding site (NB)–leucine-rich repeat (LRR) class of R plant genes can be triggered by microRNAs (miRNAs) to generate phased small interfering RNAs (phasiRNAs), which could reduce the transcript levels of their targets. However, how global changes in NB-LRR transcript levels coordinate with changes in miRNA and phasiRNA levels in defense responses remains largely unknown. Here, we investigated changes in the relative abundance of small RNAs (sRNAs), with a focus on miRNAs and phasiRNAs and their potential targets in response to the pathogen Phytophthora sojae in the susceptible soybean [Glycine max (L.) Merr.] ‘Williams’ and nine resistant near-isogenic lines (NILs), each carrying a unique resistance to P. sojae (Rps) gene. In total, 369 distinct miRNAs, including 78 new ones, were identified in the 10 soybean lines. The majority of miRNAs were downregulated by the pathogen. Of the 525 NB-LRR genes found in the soybean reference genome, 257 were predicted to be the targets of eight abundant miRNA families and 126 (dubbed phasi-NB-LRRs or pNLs) were predicted to have produced phasiRNAs. Upregulation of 15 phasi-NB-LRRs was associated with downregulation of their corresponding phasiRNAs in the NILs; these phasiRNAs were predicted to regulate 75 additional NB-LRRs in trans. In addition, we identified putative 24-nucleotide (nt) phasiRNAs from transposons, possibly representing a novel general epigenetic mechanism for regulation of transposon activity under biotic stresses. Together, these observations suggest that miRNAs and phasiRNAs play an important role in response to plant pathogens through complex, multiple layers of post-transcriptional regulation.
- Published
- 2015
36. Metatranscriptomic profiles of Eastern subterranean termites, Reticulitermes flavipes (Kollar) fed on second generation feedstocks
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Michael E. Scharf, Jyothi Thimmapuram, Ketaki Bhide, Jacob Shreve, and Swapna Priya Rajarapu
- Subjects
Soybean residue ,Lignocellulase ,Cellulase ,Isoptera ,010402 general chemistry ,01 natural sciences ,7. Clean energy ,Lignin ,Zea mays ,03 medical and health sciences ,Reticulitermes ,chemistry.chemical_compound ,Termite ,Botany ,Genetics ,Animals ,Cellulose ,Corn stover ,Gene ,030304 developmental biology ,2. Zero hunger ,chemistry.chemical_classification ,0303 health sciences ,biology ,Protists ,biology.organism_classification ,0104 chemical sciences ,Enzyme ,chemistry ,Microbial population biology ,Gene Expression Regulation ,biology.protein ,Soybeans ,RNA-seq ,Transcriptome ,Entomology ,Biotechnology ,Research Article - Abstract
Background Second generation lignocellulosic feedstocks are being considered as an alternative to first generation biofuels that are derived from grain starches and sugars. However, the current pre-treatment methods for second generation biofuel production are inefficient and expensive due to the recalcitrant nature of lignocellulose. In this study, we used the lower termite Reticulitermes flavipes (Kollar), as a model to identify potential pretreatment genes/enzymes specifically adapted for use against agricultural feedstocks. Results Metatranscriptomic profiling was performed on worker termite guts after feeding on corn stover (CS), soybean residue (SR), or 98% pure cellulose (paper) to identify (i) microbial community, (ii) pathway level and (iii) gene-level responses. Microbial community profiles after CS and SR feeding were different from the paper feeding profile, and protist symbiont abundance decreased significantly in termites feeding on SR and CS relative to paper. Functional profiles after CS feeding were similar to paper and SR; whereas paper and SR showed different profiles. Amino acid and carbohydrate metabolism pathways were downregulated in termites feeding on SR relative to paper and CS. Gene expression analyses showed more significant down regulation of genes after SR feeding relative to paper and CS. Stereotypical lignocellulase genes/enzymes were not differentially expressed, but rather were among the most abundant/constitutively-expressed genes. Conclusions These results suggest that the effect of CS and SR feeding on termite gut lignocellulase composition is minimal and thus, the most abundantly expressed enzymes appear to encode the best candidate catalysts for use in saccharification of these and related second-generation feedstocks. Further, based on these findings we hypothesize that the most abundantly expressed lignocellulases, rather than those that are differentially expressed have the best potential as pretreatment enzymes for CS and SR feedstocks. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1502-8) contains supplementary material, which is available to authorized users.
- Published
- 2015
37. MED18 interaction with distinct transcription factors regulates multiple plant functions
- Author
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Tesfaye Mengiste, Sang Yeol Lee, Jyothi Thimmapuram, Ketaki Bhide, Craig Schluttenhofer, Dae-Jin Yun, Zhibing Lai, and Jacob Shreve
- Subjects
Arabidopsis ,General Physics and Astronomy ,Plant Immunity ,Flowers ,Flowering time ,General Biochemistry, Genetics and Molecular Biology ,Mediator ,Plant Growth Regulators ,Gene Expression Regulation, Plant ,Transcription factor ,YY1 Transcription Factor ,Multidisciplinary ,Mediator Complex ,biology ,Arabidopsis Proteins ,fungi ,food and beverages ,Membrane Transport Proteins ,General Chemistry ,biology.organism_classification ,Cell biology ,Trans-Activators ,RNA Polymerase II ,Function (biology) ,Hormone ,Transcription Factors - Abstract
Mediator is an evolutionarily conserved transcriptional regulatory complex. Mechanisms of Mediator function are poorly understood. Here we show that Arabidopsis MED18 is a multifunctional protein regulating plant immunity, flowering time and responses to hormones through interactions with distinct transcription factors. MED18 interacts with YIN YANG1 to suppress disease susceptibility genes glutaredoxins GRX480, GRXS13 and thioredoxin TRX-h5. Consequently, yy1 and med18 mutants exhibit deregulated expression of these genes and enhanced susceptibility to fungal infection. In addition, MED18 interacts with ABA INSENSITIVE 4 and SUPPRESSOR OF FRIGIDA4 to regulate abscisic acid responses and flowering time, respectively. MED18 associates with the promoter, coding and terminator regions of target genes suggesting its function in transcription initiation, elongation and termination. Notably, RNA polymerase II occupancy and histone H3 lysine tri-methylation of target genes are affected in the med18 mutant, reinforcing MED18 function in different mechanisms of transcriptional control. Overall, MED18 conveys distinct cues to engender transcription underpinning plant responses.
- Published
- 2013
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