Gene expression profiling of normal and malignant CD34-derived megakaryocytic cells

Abstract Gene expression profiles of bone marrow (BM) CD34-derived megakaryocytic cells (MKs) were compared in patients with essential thrombocythemia (ET) and healthy subjects using oligonucleotide microarray analysis to identify differentially expressed genes and disease-specific transcripts. We found that proapoptotic genes such as BAX, BNIP3, and BNIP3L were down-regulated in ET MKs together with genes that are components of the mitochondrial permeability transition pore complex, a system with a pivotal role in apoptosis. Conversely, antiapoptotic genes such as IGF1-R and CFLAR were up-regulated in the malignant cells, as was the SDF1 gene, which favors cell survival. On the basis of the array results, we characterized apoptosis of normal and ET MKs by time-course evaluation of annexin-V and sub-G1 peak DNA stainings of immature and mature MKs after culture in serum-free medium with an optimal thrombopoietin concentration, and annexin-V–positive MKs only, with decreasing thrombopoietin concentrations. ET MKs were more resistant to apoptosis than their normal counterparts. We conclude that imbalance between proliferation and apoptosis seems to be an important step in malignant ET megakaryocytopoiesis.

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Bayesian approach for predicting responses to therapy from high-dimensional time-course gene expression profiles

BMC Bioinformatics ◽

10.1186/s12859-021-04052-4 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Arika Fukushima ◽

Masahiro Sugimoto ◽

Satoru Hiwa ◽

Tomoyuki Hiroyasu

Keyword(s):

Gene Expression ◽

Time Course ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Response To Therapy ◽

Hcv Infection ◽

Entire Treatment Period ◽

Time Points ◽

Time Course Data ◽

Conventional Methods

Abstract Background Historical and updated information provided by time-course data collected during an entire treatment period proves to be more useful than information provided by single-point data. Accurate predictions made using time-course data on multiple biomarkers that indicate a patient’s response to therapy contribute positively to the decision-making process associated with designing effective treatment programs for various diseases. Therefore, the development of prediction methods incorporating time-course data on multiple markers is necessary. Results We proposed new methods that may be used for prediction and gene selection via time-course gene expression profiles. Our prediction method consolidated multiple probabilities calculated using gene expression profiles collected over a series of time points to predict therapy response. Using two data sets collected from patients with hepatitis C virus (HCV) infection and multiple sclerosis (MS), we performed numerical experiments that predicted response to therapy and evaluated their accuracies. Our methods were more accurate than conventional methods and successfully selected genes, the functions of which were associated with the pathology of HCV infection and MS. Conclusions The proposed method accurately predicted response to therapy using data at multiple time points. It showed higher accuracies at early time points compared to those of conventional methods. Furthermore, this method successfully selected genes that were directly associated with diseases.

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Inference of gene regulatory networks and compound mode of action from time course gene expression profiles

Bioinformatics ◽

10.1093/bioinformatics/btl003 ◽

2006 ◽

Vol 22 (7) ◽

pp. 815-822 ◽

Cited By ~ 254

Author(s):

M. Bansal ◽

G. D. Gatta ◽

D. di Bernardo

Keyword(s):

Gene Expression ◽

Gene Regulatory Networks ◽

Mode Of Action ◽

Regulatory Networks ◽

Time Course ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Gene Regulatory

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Abstract 17188: Cryoem Analysis in Cardiac Isolated Mitochondria Reveals New Insights for CsA and mPTP Activation

Circulation ◽

10.1161/circ.138.suppl_1.17188 ◽

2018 ◽

Vol 138 (Suppl_1) ◽

Author(s):

Jasiel O Strubbe ◽

Jason Schrad ◽

James F Conway ◽

Kristin N Parent ◽

Jason N Bazil

Keyword(s):

Time Course ◽

Mitochondrial Permeability Transition ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Myocardial Necrosis ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Granule Formation ◽

Membrane Rupture ◽

Mptp Opening

Excessive Ca 2+ accumulation is the main source of cardiac tissue and cell death during myocardial ischemia-reperfusion injury (IR injury) and myocardial infarction. Calcium dysregulation and overload leads to mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, catastrophic energy failure, and opening of the cyclosporine A-sensitive mitochondrial permeability transition pore (mPTP). Mitochondrial Ca 2+ accumulation also results in the formation of amorphous Ca 2+ -phosphate granules localized in the mitochondrial matrix. These amorphous electron-dense granules are main components of the mitochondrial Ca 2+ sequestration and buffering system by mechanisms not yet well understood. The two aims of the present study are to test the relationship of Ca 2+ -phosphate granule size and number in cardiac mitochondria 1) exposed to a bolus calcium sufficient to elicit permeabilization and 2) whether CsA-treated mitochondria alters granule formation and size. A time course series of CryoEM images was analyzed to follow the permeabilization process. CryoEM results showed that mitochondrial incubated for longer time-courses have increased number of small granules (40 - 110 nm), swelling, membrane rupture and induction of mPTP opening. Conversely, shorter incubation time resulted in less granules per mitochondrion yet of similar size (35 - 90 nm). CsA- treated mitochondria, on the other hand, showed bigger phosphate granules (120 - 160 nm), and both lower granules per mitochondria and mPTP opening susceptibility. These results suggest a novel mechanism for CsA in which Ca 2+ -phosphate granule sizes are enhanced while maintaining fewer per mitochondrion. This effect may explain why CsA-treated mitochondria have higher calcium tolerance, delayed Ca 2+ -dependent opening of the mPTP, and protects against reperfusion-induced myocardial necrosis.

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