150 results on '"Mark J. Koury"'
Search Results
2. EpoR stimulates rapid cycling and larger red cells during mouse and human erythropoiesis
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Daniel Hidalgo, Jacob Bejder, Ramona Pop, Kyle Gellatly, Yung Hwang, S. Maxwell Scalf, Anna E. Eastman, Jane-Jane Chen, Lihua Julie Zhu, Jules A. A. C. Heuberger, Shangqin Guo, Mark J. Koury, Nikolai Baastrup Nordsborg, and Merav Socolovsky more...
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Science - Abstract
Maturing erythroblasts become smaller with every cell division. Here, the authors show that Epo stimulation promotes cell division and also generates larger red cells, and that this occurs in mouse and human cells, suggesting that red cell size could be a diagnostic marker for hypoxic stress. more...
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- 2021
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Catalog
3. A Hybrid Computation Model to Describe the Progression of Multiple Myeloma and Its Intra-Clonal Heterogeneity
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Anass Bouchnita, Fatima-Ezzahra Belmaati, Rajae Aboulaich, Mark J. Koury, and Vitaly Volpert
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multiple myeloma ,intra-clonal heterogeneity ,hybrid model ,Electronic computers. Computer science ,QA75.5-76.95 - Abstract
Multiplemyeloma(MM)isageneticallycomplexhematologicalcancerthatischaracterized by proliferation of malignant plasma cells in the bone marrow. MM evolves from the clonal premalignant disorder monoclonal gammopathy of unknown significance (MGUS) by sequential genetic changes involving many different genes, resulting in dysregulated growth of multiple clones of plasma cells. The migration, survival, and proliferation of these clones require the direct and indirect interactions with the non-hematopoietic cells of the bone marrow. We develop a hybrid discrete-continuous model of MM development from the MGUS stage. The discrete aspect of the modelisobservedatthecellularlevel: cellsarerepresentedasindividualobjectswhichmove,interact, divide, and die by apoptosis. Each of these actions is regulated by intracellular and extracellular processes as described by continuous models. The hybrid model consists of the following submodels that have been simplified from the much more complex state of evolving MM: cell motion due to chemotaxis, intracellular regulation of plasma cells, extracellular regulation in the bone marrow, and acquisition of mutations upon cell division. By extending a previous, simpler model in which the extracellular matrix was considered to be uniformly distributed, the new hybrid model provides a more accurate description in which cytokines are produced by the marrow microenvironment and consumed by the myeloma cells. The complex multiple genetic changes in MM cells and the numerous cell-cell and cytokine-mediated interactions between myeloma cells and their marrow microenviroment are simplified in the model such that four related but evolving MM clones can be studied as they compete for dominance in the setting of intraclonal heterogeneity. more...
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- 2017
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4. Regulation of LMO2 mRNA and protein expression in erythroid differentiation
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Stephen J. Brandt and Mark J. Koury
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2009
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5. Red blood cell production and kinetics
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Mark J. Koury and Lionel Blanc
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- 2022
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6. Vadadustat for treatment of anemia in patients with dialysis-dependent chronic kidney disease receiving peritoneal dialysis
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Mark J Sarnak, Rajiv Agarwal, Neil Boudville, Pradip C P Chowdhury, Kai-Uwe Eckardt, Carlos R Gonzalez, Laura A Kooienga, Mark J Koury, Kwabena A Ntoso, Wenli Luo, Patrick S Parfrey, Dennis L Vargo, Wolfgang C Winkelmayer, Zhiqun Zhang, and Glenn M Chertow more...
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Transplantation ,Nephrology - Abstract
Background Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. Methods We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary efficacy period (weeks 24–36). Results Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups (hazard ratio 1.10; 95% CI 0.62, 1.93). In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was −0.10 g/dL (95% CI −0.33, 0.12) in the primary efficacy period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. Conclusions In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa. more...
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- 2023
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7. Vadadustat in Patients with Anemia and Non–Dialysis-Dependent CKD
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Youssef M.K. Farag, Kimberly A. Walters, Gabriel Bako, Wolfgang C. Winkelmayer, Kai-Uwe Eckardt, Prabir Roy-Chaudhury, Dennis Vargo, Rajiv Agarwal, Amit Sharma, Mark J. Sarnak, Kunihiro Matsushita, Mark J. Koury, Bruce Spinowitz, Glenn M. Chertow, Wenli Luo, Patrick S. Parfrey, Zeeshan Khawaja, Susan Arnold, Eldrin F. Lewis, Steven K. Burke, Fausto P. Castillo, Alan G. Jardine, Carol Tseng, Bradley J. Maroni, Pablo E. Pergola, Peter A. McCullough, Janet Wittes, Tim Lin, Geoffrey A. Block, and James A. Tumlin more...
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Anemia ,business.industry ,Vadadustat ,General Medicine ,Meth ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Multicenter study ,chemistry ,Non dialysis dependent ,Erythropoietin ,medicine ,In patient ,030212 general & internal medicine ,business ,medicine.drug - Abstract
Background Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. Meth...
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- 2021
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8. Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease
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Mark J. Koury, Rajiv Agarwal, Glenn M. Chertow, Kai‐Uwe Eckardt, Steven Fishbane, Tomas Ganz, Volker H. Haase, Mark R. Hanudel, Patrick S. Parfrey, Pablo E. Pergola, Prabir Roy‐Chaudhury, James A. Tumlin, Robert Anders, Youssef M. K. Farag, Wenli Luo, Todd Minga, Christine Solinsky, Dennis L. Vargo, and Wolfgang C. Winkelmayer more...
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Iron ,Glycine ,Hemoglobins ,Hepcidins ,Urologi och njurmedicin ,vadadustat ,Humans ,Urology and Nephrology ,HIF ,Darbepoetin alfa ,Erythropoiesis ,iron metabolism ,Hematologi ,Renal Insufficiency, Chronic ,Picolinic Acids ,Erythropoietin ,Randomized Controlled Trials as Topic ,hypoxia ,Klinisk medicin ,Anemia ,Hematology ,anemia ,Clinical Trials, Phase III as Topic ,Ferritins ,Hematinics ,Transferrins ,Clinical Medicine ,chronic kidney disease - Abstract
Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation. more...
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- 2022
9. MO541HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH NON--DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE
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Mark J. Koury, Prabir Roy-Chaudhury, Wolfgang C. Winkelmayer, Dennis Vargo, Wenli Luo, Pablo E. Pergola, and Youssef M.K. Farag
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Transplantation ,medicine.medical_specialty ,Hematology ,business.industry ,Anemia ,Surrogate endpoint ,Vadadustat ,medicine.disease ,Nephrology ,Non dialysis dependent ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,In patient ,business ,Kidney disease - Abstract
Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylases under development to treat anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two phase 3, randomized trials (the PRO2TECT trials) in adult patients with non–dialysis-dependent (NDD) CKD and anemia, in which vadadustat met prespecified noninferiority criteria compared to darbepoetin alfa, with respect to hematologic efficacy (correction/maintenance of hemoglobin [Hb] target concentrations). Method The mean screening Hb level for the ESA-untreated NDD-CKD trial (NCT02648347) had to be Results A total of 3,476 patients (1751 ESA-untreated and 1725 ESA-treated) were randomized 1:1 to vadadustat or darbepoetin alfa. In both trials, vadadustat was noninferior to darbepoetin alfa with regard to the difference of mean change in Hb concentrations between baseline and PEP, as well as between baseline and SEP. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 50.4% versus 50.2% and 43.1% versus 43.5% in the ESA-untreated trial and 60.1% versus 60.7% and 50.7% versus 49.0% in the ESA-treated trial. The proportion of patients (vadadustat vs darbepoetin alfa) who achieved an Hb increase >1.0 g/dL from baseline to week 52 was assessed only for the ESA-untreated trial and was 87.7% (95% CI: 85.4%, 89.8%) for vadadustat versus 88.0% (95% CI: 85.6%, 90.0%) for darbepoetin alfa. Hematologic parameters at time points within the PEP and SEP are presented in Table 1. In both the ESA-untreated and ESA-treated trials, the reticulocyte count trended up from baseline through week 52 for vadadustat and trended down from baseline for darbepoetin alfa. Trends in erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb were largely unremarkable by week 52 in both treatment groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of adults with anemia in CKD not on dialysis, whether ESA-untreated or ESA-treated at study entry. more...
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- 2021
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10. MO539HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH KIDNEY FAILURE ON DIALYSIS
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Wenli Luo, James A. Tumlin, Steven Fishbane, Dennis Vargo, Wolfgang C. Winkelmayer, Mark J. Koury, and Youssef M.K. Farag
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Transplantation ,medicine.medical_specialty ,Kidney ,Anemia ,business.industry ,medicine.medical_treatment ,Vadadustat ,medicine.disease ,medicine.anatomical_structure ,Nephrology ,Reticulocyte count ,Internal medicine ,medicine ,In patient ,business ,Dialysis - Abstract
Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase being developed for treatment of anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two of the four phase 3, randomized, open-label, sponsor-blind trials (the INNO2VATE trials) in adult patients with dialysis-dependent (DD) CKD and anemia, where vadadustat met prespecified noninferiority criteria compared with darbepoetin alfa with respect to cardiovascular safety and correction/maintenance of hemoglobin (Hb) target concentrations. Method The mean screening Hb range for the incident DD-CKD trial (NCT02865850) was 8.0-11.0 g/dL; for the prevalent DD-CKD trial (NCT02892149), it was 8.0-11.0 g/dL in the United States (US) and 9.0-12.0 g/dL for non-US. Patients in the incident and prevalent DD-CKD trials had initiated dialysis within 12 weeks with established ESA treatment prior to screening, respectively. Vadadustat starting dose was 300 mg/day for all patients, whereas initial darbepoetin alfa dose depended on each patient’s prior dose or product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) during the primary evaluation period (PEP; weeks 24-36) and the secondary evaluation period (SEP; weeks 40-52). Herein, we present topline results from PEP and SEP endpoints, as well as other, more detailed hematologic erythrocyte parameters. Results A total of 3923 patients (369 with incident DD-CKD and 3554 with prevalent DD-CKD) were randomized 1:1 to vadadustat or darbepoetin alfa. Vadadustat was noninferior to darbepoetin alfa in achieving target-range Hb concentrations (primary efficacy endpoint) among patients who were new to, or established on, dialysis. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 43.6% versus 56.9% and 39.8% versus 41.0% in the incident trial and 49.2% versus 53.2% and 44.3% versus 50.9% in the prevalent dialysis trial. The proportion of patients who achieved an Hb increase >1.0 g/dL from baseline to week 52 was assessed only for the incident trial and was 84.0% (95% CI: 77.8%, 89.0%) for vadadustat versus 89.9% (95% CI: 84.7%, 93.8%) for darbepoetin alfa. Hematologic erythrocyte parameters at time points within the PEP and SEP are presented in Table 1. In the incident trial, reticulocyte count was slightly increased from baseline at 28 and 52 weeks for vadadustat, whereas for darbepoetin alfa, reticulocyte count was slightly decreased or unchanged in both trials. Erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb showed increases by week 52 for both groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of anemia associated with CKD in adults in both incident dialysis and prevalent dialysis settings. more...
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- 2021
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11. Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis
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Kimberly A. Walters, Kai-Uwe Eckardt, Zeeshan Khawaja, Mark J. Sarnak, Janet Wittes, Eldrin F. Lewis, Rafal Zwiech, James A. Tumlin, Geoffrey A. Block, Youssef M.K. Farag, Mark J. Koury, Ahmed Awad, Wolfgang C. Winkelmayer, Alan G. Jardine, Dennis Vargo, Bradley J. Maroni, Kunihiro Matsushita, Bruce Spinowitz, Ahmad Aswad, Steven Fishbane, Pablo E. Pergola, Glenn M. Chertow, Wenli Luo, Patrick S. Parfrey, Marcelo R. Bacci, Harold Hubert, Rajiv Agarwal, and Peter A. McCullough more...
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Male ,Anemia ,medicine.medical_treatment ,Glycine ,030204 cardiovascular system & hematology ,Endogenous erythropoietin ,Pharmacology ,03 medical and health sciences ,Hemoglobins ,0302 clinical medicine ,Renal Dialysis ,Medicine ,Humans ,In patient ,Darbepoetin alfa ,030212 general & internal medicine ,Renal Insufficiency, Chronic ,Picolinic Acids ,Dialysis ,Aged ,business.industry ,Vadadustat ,Prolyl-Hydroxylase Inhibitors ,General Medicine ,Middle Aged ,medicine.disease ,Cardiovascular Diseases ,Hematinics ,Female ,business - Abstract
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO more...
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- 2021
12. The Erythropoietin Receptor Stimulates Rapid Cycling and Formation of Larger Red Cells During Mouse and Human Erythropoiesis
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S. Maxwell Scalf, Jules Heuberger, Daniel Hidalgo, Merav Socolovsky, Anna E. Eastman, Shangqin Guo, J J Chen, Ramona Pop, Jacob Bejder, Mark J. Koury, Kyle Gellatly, Nikolai Baastrup Nordsborg, and Lihua Julie Zhu more...
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medicine.anatomical_structure ,Red Cell ,Cell growth ,Chemistry ,Cell ,medicine ,Erythropoiesis ,Bone marrow ,Cell cycle ,Developmental biology ,Cell biology ,Erythropoietin receptor - Abstract
Erythroid terminal differentiation entails cell divisions that are coupled to progressive decreases in cell size. EpoR signaling is essential for the survival of erythroid precursors, but it is unclear whether it has other functions in these cells. Here we endowed mouse precursors that lack the EpoR with survival signaling, finding that this was sufficient to support their differentiation into enucleated red cells, but that the process was abnormal. Precursors underwent fewer and slower cell cycles and yet differentiated into smaller red cells. Surprisingly, EpoR further accelerated cycling of early erythroblasts, the fastest cycling cells in the bone marrow, while simultaneously increasing their cell size. EpoR-mediated formation of larger red cells was independent of the established pathway regulating red cell size by iron through Heme-regulated eIF2α kinase (HRI). We confirmed the effect of Epo on red cell size in human volunteers, whose mean corpuscular volume (MCV) increased following Epo administration. This increase persisted after Epo declined and was not the result of increased reticulocytes. Our work reveals a unique effect of EpoR signaling on the interaction between the cell cycle and cell growth. Further, it suggests new diagnostic interpretations for increased red cell volume, as reflecting high Epo and erythropoietic stress. more...
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- 2020
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13. Cardiovascular safety and efficacy of vadadustat for the treatment of anemia in non-dialysis-dependent CKD: Design and baseline characteristics
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Kai-Uwe Eckardt, Rajiv Agarwal, Wenli Luo, Patrick S. Parfrey, Geoffrey A. Block, Peter A. McCullough, Mark J. Sarnak, Zeeshan Khawaja, Kunihiro Matsushita, Janet Wittes, Alan G. Jardine, Dennis Vargo, Wolfgang C. Winkelmayer, Glenn M. Chertow, Tim Lin, Kimberly A. Walters, Youssef M.K. Farag, Pablo E. Pergola, Eldrin F. Lewis, Mark J. Koury, and Carol Tseng more...
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Male ,medicine.medical_specialty ,Darbepoetin alfa ,Anemia ,Glycine ,Administration, Oral ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Renal Dialysis ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Renal Insufficiency, Chronic ,Picolinic Acids ,Aged ,Cardiovascular safety ,business.industry ,Vadadustat ,Middle Aged ,medicine.disease ,Clinical trial ,Treatment Outcome ,Baseline characteristics ,Female ,Hemoglobin ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug ,Kidney disease ,Follow-Up Studies - Abstract
Current clinical practice guidelines for anemia management in non–dialysis-dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PRO2TECT program comprises 2 global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (N = 1751) had hemoglobin more...
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- 2020
14. Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials
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Mark J. Koury, Dennis Vargo, Zeeshan Khawaja, Wolfgang C. Winkelmayer, Glenn M. Chertow, Wenli Luo, Youssef M.K. Farag, Geoffrey Ross, Peter A. McCullough, Patrick S. Parfrey, Mark J. Sarnak, Rajiv Agarwal, Alan G. Jardine, Kunihiro Matsushita, and Kai-Uwe Eckardt more...
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Adult ,medicine.medical_specialty ,Darbepoetin alfa ,Anemia ,medicine.medical_treatment ,Population ,030232 urology & nephrology ,Glycine ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,03 medical and health sciences ,Hemoglobins ,0302 clinical medicine ,Renal Dialysis ,Internal medicine ,hemic and lymphatic diseases ,medicine ,vadadustat ,Humans ,Renal Insufficiency, Chronic ,education ,Picolinic Acids ,AcademicSubjects/MED00340 ,Erythropoietin ,hypoxia-inducible factor ,Dialysis ,Transplantation ,education.field_of_study ,anaemia ,business.industry ,Vadadustat ,medicine.disease ,Nephrology ,Hematinics ,dialysis ,Original Article ,Hemodialysis ,business ,chronic kidney disease ,medicine.drug ,Kidney disease - Abstract
Background Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics. Methods Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0–23), maintenance (Weeks 24–52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24–36). Results A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD. Conclusions The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population. more...
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- 2020
15. TG-Interacting Factor 1 expression quantitatively impacts survival in acute myeloid leukemia
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David Wotton, Julie Means-Powell, Utpal P. Davé, Yu Shyr, John P. Greer, Stephen J. Brandt, Vladimir D. Kravtsov, Ling Yan, Mark J. Koury, Rizwan Hamid, and Danko Martincic
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Retinoic acid ,Myeloid leukemia ,Biology ,medicine.disease ,Fusion gene ,Leukemia ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,hemic and lymphatic diseases ,Knockout mouse ,Cancer research ,medicine ,Bone marrow ,Gene ,Transforming growth factor - Abstract
Applying transcriptional profiling analysis to myeloblasts from 59 adult patients with acute myeloid leukemia (AML) treated at our institution, we found that expression of the three-amino acid loop extension (TALE) homeobox gene TG-Interacting Factor 1 (TGIF1) correlated with overall and relapse-free survival, which was then confirmed in two other cohorts of patients.Moreover, TGIF1 expression correlated with survival for all cytogenetic risk groups and was an independent prognostic factor in multivariate analysis. To elucidate the mechanism, we used Tgif1 knockout mice in which acute or chronic myeloid leukemia was induced through retroviral transfer of the MLL-AF9 or BCR-ABL fusion genes into bone marrow cells. Loss of Tgif1 accelerated disease progression, shortened survival, attenuated the response to chemotherapy, and doubled the frequency of leukemia-initiating cells. RNA-based sequencing analysis showed that genes associated with transforming growth factor-β (TGF-β) and retinoic acid signaling pathways were differentially affected in Tgif1-/- compared to Tgif1+/+ leukemia cells. more...
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- 2020
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16. Epor Stimulates Rapid Cycling and Larger Red Cells during Mouse and Human Erythropoiesis
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Nikolai Baastrup Nordsborg, Yung Hwang, Mark J. Koury, Anna E. Eastman, Jacob Bejder, Kyle Gellatly, Lihua Julie Zhu, Jules Heuberger, Daniel Hidalgo, S. Maxwell Scalf, Merav Socolovsky, Shangqin Guo, Ramona Pop, and Jane-Jane Chen more...
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Male ,Erythrocytes ,Reticulocytes ,Haematopoietic system ,Erythroblasts ,General Physics and Astronomy ,Biochemistry ,Erythropoietin receptor ,Cell growth ,Rapid cycling ,hemic and lymphatic diseases ,Faculty of Science ,Receptors, Erythropoietin ,Erythropoiesis ,Multidisciplinary ,EpoR ,Chemistry ,Cell Cycle ,food and beverages ,Cell Differentiation ,Hematology ,Healthy Volunteers ,Cell biology ,Liver ,CD4 Antigens ,embryonic structures ,Female ,Cyclin-Dependent Kinase Inhibitor p27 ,Signal Transduction ,circulatory and respiratory physiology ,Adult ,Cell division ,Cell Survival ,Iron ,Science ,Immunology ,bcl-X Protein ,Protein Serine-Threonine Kinases ,Models, Biological ,Article ,General Biochemistry, Genetics and Molecular Biology ,Fetus ,Antigens, CD ,Receptors, Transferrin ,Animals ,Humans ,Erythropoietin ,Cell Size ,Cell Nucleus ,Mean corpuscular volume (MCV) ,General Chemistry ,Cell Biology ,Embryo, Mammalian ,EpoR signaling ,Mice, Inbred C57BL - Abstract
The erythroid terminal differentiation program couples sequential cell divisions with progressive reductions in cell size. The erythropoietin receptor (EpoR) is essential for erythroblast survival, but its other functions are not well characterized. Here we use Epor−/− mouse erythroblasts endowed with survival signaling to identify novel non-redundant EpoR functions. We find that, paradoxically, EpoR signaling increases red cell size while also increasing the number and speed of erythroblast cell cycles. EpoR-regulation of cell size is independent of established red cell size regulation by iron. High erythropoietin (Epo) increases red cell size in wild-type mice and in human volunteers. The increase in mean corpuscular volume (MCV) outlasts the duration of Epo treatment and is not the result of increased reticulocyte number. Our work shows that EpoR signaling alters the relationship between cycling and cell size. Further, diagnostic interpretations of increased MCV should now include high Epo levels and hypoxic stress., Maturing erythroblasts become smaller with every cell division. Here, the authors show that Epo stimulation promotes cell division and also generates larger red cells, and that this occurs in mouse and human cells, suggesting that red cell size could be a diagnostic marker for hypoxic stress. more...
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- 2021
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17. Epo reprograms the epigenome of erythroid cells
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Andrea A. Perreault, Stephen J. Brandt, Mark J. Koury, Mary Lauren Benton, and Bryan J. Venters
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Epigenomics ,0301 basic medicine ,Cancer Research ,Kruppel-Like Transcription Factors ,KLF1 ,Biology ,Article ,Epigenesis, Genetic ,Mice ,03 medical and health sciences ,Erythroid Cells ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Basic Helix-Loop-Helix Transcription Factors ,STAT5 Transcription Factor ,Genetics ,medicine ,Animals ,Erythropoiesis ,GATA1 Transcription Factor ,Epigenetics ,Enhancer ,Erythropoietin ,Molecular Biology ,T-Cell Acute Lymphocytic Leukemia Protein 1 ,Mice, Inbred BALB C ,Nuclear Proteins ,GATA1 ,Cell Biology ,Hematology ,Epigenome ,Cellular Reprogramming ,Chromatin ,DNA-Binding Proteins ,Repressor Proteins ,MicroRNAs ,030104 developmental biology ,Cancer research ,Female ,Carrier Proteins ,Signal Transduction ,medicine.drug - Abstract
The hormone erythropoietin (Epo) is required for erythropoiesis, yet its molecular mechanism of action remains poorly understood, particularly with respect to chromatin dynamics. To investigate how Epo modulates the erythroid epigenome, we performed epigenetic profiling using an ex vivo murine cell system that undergoes synchronous erythroid maturation in response to Epo stimulation. Our findings define the repertoire of Epo-modulated enhancers, illuminating a new facet of Epo signaling. First, a large number of enhancers rapidly responded to Epo stimulation, revealing a cis-regulatory network of Epo-responsive enhancers. In contrast, most of the other identified enhancers remained in an active acetylated state during Epo signaling, suggesting that most erythroid enhancers are established at an earlier precursor stage. Second, we identified several hundred super-enhancers that were linked to key erythroid genes, such as Tal1, Bcl11a, and Mir144/451. Third, experimental and computational validation revealed that many predicted enhancer regions were occupied by TAL1 and enriched with DNA-binding motifs for GATA1, KLF1, TAL1/E-box, and STAT5. Additionally, many of these cis-regulatory regions were conserved evolutionarily and displayed correlated enhancer:promoter acetylation. Together, these findings define a cis-regulatory enhancer network for Epo signaling during erythropoiesis, and provide the framework for future studies involving the interplay of epigenetics and Epo signaling. more...
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- 2017
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18. The safety of achieved iron stores and their effect on IV iron and ESA use: post-hoc results from a randomized trial of ferric citrate as a phosphate binder in dialysis
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Lawrence G. Hunsicker, Molly McFadden, Jamie P. Dwyer, Julia B. Lewis, Mark J. Koury, Kausik Umanath, Diana Jalal, Robert Niecestro, Mohammed Sika, Tom Greene, and Barbara A. Greco
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Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Anemia ,medicine.medical_treatment ,Population ,030232 urology & nephrology ,Ferric Compounds ,Gastroenterology ,Phosphates ,03 medical and health sciences ,0302 clinical medicine ,Renal Dialysis ,Internal medicine ,Multicenter trial ,medicine ,Humans ,Erythropoiesis ,030212 general & internal medicine ,education ,Dialysis ,Aged ,education.field_of_study ,biology ,business.industry ,Transferrin saturation ,Hazard ratio ,General Medicine ,Middle Aged ,medicine.disease ,Phosphate binder ,Ferritin ,Nephrology ,Ferritins ,Hematinics ,biology.protein ,Administration, Intravenous ,Female ,business - Abstract
Iron stores assuring optimal efficacy/safety for erythropoiesis are unknown in the dialysis population. Using multicenter trial data, we related safety profiles, erythropoiesis-stimulating agent (ESA), and intravenous iron dosing to achieved iron stores in 441 subjects randomized 2 : 1 to ferric citrate or active control as their phosphate binder over 52 weeks. Intravenous iron was given at each site's discretion if ferritin ≤ 1,000 ng/mL and transferrin saturation ≤ 30%. Multivariable time-dependent Cox regression jointly related the primary safety outcome (composite of cardiac, infection, gastrointestinal, and hepatobiliary serious adverse events) to moving averages of ferritin and transferrin saturation over the preceding 90 days with covariate adjustment. Multivariable generalized estimating equations related elevated ESA and intravenous iron doses to trailing 90-day averages of ferritin and transferrin saturation with covariate adjustment. The adjusted hazard ratio for the safety composite per 10% increase in transferrin saturation was 0.84 (95% confidence interval 0.68 - 1.02, p = 0.08) and 1.09 (0.86 - 1.35, p = 0.48) per 400 ng/mL increase in ferritin. The adjusted hazard ratio for the safety composite was 0.50 (0.29 - 0.88, p = 0.016) for the highest transferrin saturation tertile vs. the lowest. Adjusted odds ratios for higher intravenous iron dose were lower in the highest (0.23 [0.16 - 0.35], p 0.001) and middle transferrin saturation tertile (0.42 [0.31 - 0.57], p 0.001) vs. lowest. Incidence of elevated ESA dose was lower in the highest transferrin saturation tertile (p = 0.01). Ferritin did not predict clinical events or ESA dose. Transferrin saturation may be a better marker than serum ferritin to judge optimal iron stores in dialysis patients. Transferrin saturations 34% are safe and provide maximal efficacy. . more...
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- 2017
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19. Transition to 37°C reveals importance of NADPH in mitigating oxidative stress in stored RBCs
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Cacang Suarna, Nicholas J. Magon, Sophie Claire Waldvogel, Mark J. Koury, Jessica Maire, Aline Roch, Beat A. Imhof, Roland Stocker, Anita Ayer, and Marc Schapira
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Adult ,Male ,0301 basic medicine ,Erythrocytes ,Hot Temperature ,Cold storage ,Oxidative phosphorylation ,Pentose phosphate pathway ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pyruvic Acid ,medicine ,Humans ,Human body temperature ,Chemistry ,General Medicine ,Metabolism ,Middle Aged ,Inosine ,Oxidative Stress ,030104 developmental biology ,030220 oncology & carcinogenesis ,Carboxyhemoglobin ,Biophysics ,Female ,Hemoglobin ,NADP ,Oxidative stress ,Research Article - Abstract
The RBC storage lesion is a multiparametric response that occurs during storage at 4°C, but its impact on transfused patients remains unclear. In studies of the RBC storage lesion, the temperature transition from cold storage to normal body temperature that occurs during transfusion has received limited attention. We hypothesized that multiple deleterious events might occur in this period of increasing temperature. We show dramatic alterations in several properties of therapeutic blood units stored at 4°C after warming them to normal body temperature (37°C), as well as febrile temperature (40°C). In particular, the intracellular content and redox state of NADP(H) were directly affected by post-storage incubation at 37°C, as well as by pro-oxidant storage conditions. Modulation of the NADPH-producing pentose phosphate pathway, but not the prevention of hemoglobin autoxidation by conversion of oxyhemoglobin to carboxyhemoglobin, provided protection against storage-induced alterations in RBCs, demonstrating the central role of NADPH in mitigating increased susceptibility of stored RBCs to oxidative stress. We propose that assessing RBC oxidative status after restoration of body temperature constitutes a sensitive method for detecting storage-related alterations that has the potential to improve the quality of stored RBCs for transfusion. more...
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- 2019
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20. A multiscale model to design therapeutic strategies that overcome drug resistance to tyrosine kinase inhibitors in multiple myeloma
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Vitaly Volpert, Andreas Hellander, Mark J. Koury, Anass Bouchnita, Uppsala University, Ecole Centrale Casablanca, Institut Camille Jordan (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Modélisation multi-échelle des dynamiques cellulaires : application à l'hématopoïese (DRACULA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-Inria Lyon, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Modélisation mathématique, calcul scientifique (MMCS), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut Camille Jordan [Villeurbanne] (ICJ), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Multi-scale modelling of cell dynamics : application to hematopoiesis (DRACULA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS) more...
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0301 basic medicine ,Statistics and Probability ,medicine.drug_class ,medicine.medical_treatment ,Context (language use) ,Antineoplastic Agents ,Drug resistance ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Tyrosine-kinase inhibitor ,Targeted therapy ,Pentose Phosphate Pathway ,03 medical and health sciences ,0302 clinical medicine ,Gefitinib ,Medicine ,[MATH.MATH-AP]Mathematics [math]/Analysis of PDEs [math.AP] ,Humans ,Enzyme Inhibitors ,Protein Kinase Inhibitors ,General Immunology and Microbiology ,business.industry ,Applied Mathematics ,Cancer ,General Medicine ,Protein-Tyrosine Kinases ,medicine.disease ,3. Good health ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Modeling and Simulation ,Cancer cell ,Cancer research ,General Agricultural and Biological Sciences ,business ,Multiple Myeloma ,Tyrosine kinase ,medicine.drug - Abstract
International audience; Drug resistance (DR) is a phenomenon characterized by the tolerance of a disease to pharmaceutical treatment. In cancer patients, DR is one of the main challenges that limit the therapeutic potential of the existing treatments. Therefore, overcoming DR by restoring the sensitivity of cancer cells would be greatly beneficial. In this context, mathematical modeling can be used to provide novel therapeutic strategies that maximize the efficiency of anti-cancer agents and potentially overcome DR. In this paper, we present a new multiscale model devoted to the interaction of potential treatments with multiple myeloma (MM) development. In this model, MM cells are represented as individual objects that move, divide, and die by apoptosis. The fate of each cell depends on intracellular and extracellular regulation, as well as the administered treatment. The model is used to explore the combined effects of a tyrosine-kinase inhibitor (TKI) with a pentose phosphate pathway (PPP) inhibitor. We use numerical simulations to tailor effective and safe treatment regimens that may eradicate the MM tumors. The model suggests that an interval for the daily dose of the PPP inhibitor can maximize the responsiveness of MM cells to the treatment with TKIs. Then, it demonstrates that the combination of high-dose pulsatile TKI treatment with high-dose daily PPP inhibitor therapy can potentially eradicate the tumor.The predictions of numerical simulations using such a model can be considered as testable hypotheses in future pre-clinical experiments and clinical studies. more...
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- 2019
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21. Multi-scale Modelling of Erythropoiesis and Hemoglobin Production
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Eric Fanchon, Vitaly Volpert, Mark J. Koury, Alexandre Rocca, Jean-Marc Moulis, Anass Bouchnita, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Université Mohammed V de Rabat [Agdal] (UM5), Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Vanderbilt University [Nashville], Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Multi-scale modelling of cell dynamics : application to hematopoiesis (DRACULA), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Camille Jordan (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Modélisation mathématique, calcul scientifique (MMCS), Institut Camille Jordan (ICJ), Université Mohammed V de Rabat [Agdal], Institut Camille Jordan [Villeurbanne] (ICJ), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS) more...
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0301 basic medicine ,Kidney ,Polymers and Plastics ,Chemistry ,Anemia ,[SDV]Life Sciences [q-bio] ,Hypoxia (medical) ,medicine.disease ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Erythropoietin ,hemic and lymphatic diseases ,Materials Chemistry ,medicine ,[CHIM]Chemical Sciences ,Macrophage ,Erythropoiesis ,[INFO]Computer Science [cs] ,Bone marrow ,Hemoglobin ,medicine.symptom ,ComputingMilieux_MISCELLANEOUS ,medicine.drug - Abstract
The paper is devoted to multi-scale modelling of erythropoiesis and hemoglobin production. Red blood cells, which carry oxygen from the lungs to the other body tissues, are produced in the bone marrow of adult humans in cell units called erythroblastic islands. Erythroblastic islands are composed by a central macrophage surrounded by erythroid cells in different stages of maturation. Immature cells, the colony-forming units-erythroid, make a choice between self-renewal, differentiation and apoptosis determined by the intracellular proteins and extracellular substances. Moreover, this choice is regulated by erythropoietin and other hormones. Erythropoietin is produced in the kidney in response to hypoxia from decreased numbers of red blood cells, and it is delivered in the plasma to the bone marrow. Erythropoietin stimulates differentiation of erythroid cells and increases their proliferation by downregulating apoptosis. The rate of erythropoietin production depends on the level of hemoglobin in blood which is function of the number of circulating red blood cells. Hemoglobin is produced in the erythroid cells within the bone marrow in the process of their terminal differentiation. Thus, there is a feedback between production of red blood cells by the bone marrow, the level of hemoglobin contained in these cells and the level of erythropoietin. The multi-scale model developed in this work includes erythroid cells in the bone marrow, their intracellular and extracellular regulations, hemoglobin production, and the feedback by erythropoietin. This model describes normal functioning of erythropoiesis and its response to anemia resulting from the loss of red blood cells. more...
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- 2016
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22. Stress reticulocytes lose transferrin receptors by an extrinsic process involving spleen and macrophages
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Mark J. Koury, Stephen T. Koury, James O. Price, Prapaporn Kopsombut, Catherine E. Alford, and Melissa Rhodes
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0301 basic medicine ,chemistry.chemical_classification ,education.field_of_study ,Population ,Spleen ,Transferrin receptor ,Hematology ,Exosome ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Transferrin ,hemic and lymphatic diseases ,medicine ,Macrophage ,Erythropoiesis ,education ,Receptor - Abstract
As they mature into erythrocytes during normal erythropoiesis, reticulocytes lose surface transferrin receptors before or concurrently with reticulin. Exosome release accounts for most of the loss of transferrin receptors from reticulocytes. During erythropoietic stress, reticulocytes are released early from hematopoietic tissues and have increased reticulin staining and transferrin receptors. Flow cytometry of dually stained erythrocytes of mice recovering from phlebotomy demonstrated delayed loss of reticulin and transferrin receptors during in vitro maturation compared to in vivo maturation, indicating that an in vivo process extrinsic to the reticulocytes facilitates their maturation. Splenectomy or macrophage depletion by liposomal clodronate inhibited in vivo maturation of reticulocytes and increased the numbers of reticulin-negative, transferrin receptor-positive cells during and after recovery from phlebotomy. This reticulin-negative, transferrin receptor-positive population was rarely found in normal mice. Transmission electron microscopy demonstrated that the reticulin-negative, transferrin receptor-positive cells were elongated and discoid erythrocytes, but they had intracellular and surface structures that appeared to be partially degraded organelles. The results indicate that maturation of circulating stress reticulocytes is enhanced by an extrinsic process that occurs in the spleen and involves macrophage activity. Complete loss of reticulin with incomplete loss of surface transferrin receptors in this process produces a reticulin-negative, transferrin receptor-positive erythrocyte population that has potential utility for detecting prior erythropoietic stresses including bleeding, hemolysis and erythropoietin administration, even after recovery has been completed. Am. J. Hematol. 91:875-882, 2016. © 2016 Wiley Periodicals, Inc. more...
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- 2016
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23. Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis
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Mark J. Koury, Nathalie Eymard, Anass Bouchnita, Vitaly Volpert, and Tamara K. Moyo
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Chemotherapy ,Anemia ,business.industry ,Bortezomib ,medicine.medical_treatment ,Hematology ,medicine.disease ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,hemic and lymphatic diseases ,medicine ,Erythropoiesis ,Bone marrow ,business ,Infiltration (medical) ,Multiple myeloma ,Lenalidomide ,medicine.drug - Abstract
Multiple myeloma (MM) infiltrates bone marrow and causes anemia by disrupting erythropoiesis, but the effects of marrow infiltration on anemia are difficult to quantify. Marrow biopsies of newly diagnosed MM patients were analyzed before and after four 28-day cycles of non-erythrotoxic remission induction chemotherapy. Complete blood cell counts and serum paraprotein concentrations were measured at diagnosis and before each chemotherapy cycle. At diagnosis, marrow area infiltrated by myeloma correlated negatively with hemoglobin, erythrocytes, and marrow erythroid cells. After successful chemotherapy, patients with less than 30% myeloma infiltration at diagnosis had no change in these parameters, whereas patients with more than 30% myeloma infiltration at diagnosis increased all three parameters. Clinical data were used to develop mathematical models of the effects of myeloma infiltration on the marrow niches of terminal erythropoiesis, the erythroblastic islands (EBIs). A hybrid discrete-continuous model of erythropoiesis based on EBI structure/function was extended to sections of marrow containing multiple EBIs. In the model, myeloma cells can kill erythroid cells by physically destroying EBIs and by producing proapoptotic cytokines. Following chemotherapy, changes in serum paraproteins as measures of myeloma cells and changes in erythrocyte numbers as measures of marrow erythroid cells allowed modeling of myeloma cell death and erythroid cell recovery, respectively. Simulations of marrow infiltration by myeloma and treatment with non-erythrotoxic chemotherapy demonstrate that myeloma-mediated destruction and subsequent reestablishment of EBIs and expansion of erythroid cell populations in EBIs following chemotherapy provide explanations for anemia development and its therapy-mediated recovery in MM patients. more...
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- 2016
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24. 3085 – THE EPOR STIMULATES RAPID CYCLING AND FORMATION OF LARGER RED CELLS DURING MOUSE AND HUMAN ERYTHROPOIESIS
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Jacob Bejder, Nikolai Baastrup Nordsborg, Kyle Gellatly, Ramona Pop, Mark J. Koury, Daniel Hidalgo, Jules Heuberger, Lihua Julie Zhu, Jane-Jane Chen, and Merav Socolovsky
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Cancer Research ,Red Cell ,Cell ,food and beverages ,Cell Biology ,Hematology ,Cell cycle ,Biology ,Cell biology ,Erythropoietin receptor ,medicine.anatomical_structure ,Reticulocyte ,Apoptosis ,embryonic structures ,Genetics ,medicine ,Erythropoiesis ,Progenitor cell ,Molecular Biology - Abstract
EpoR signaling is essential for the survival of erythroid precursors during terminal differentiation, when these cells undergo 3-5 cell divisions that are coupled to a rapid loss in cell size. The absolute dependence of erythroblasts on EpoR signaling for survival makes it challenging to identify other essential functions of EpoR in these cells. Key open questions include a role for EpoR in cell cycle regulation; and a potential role for EpoR in the induction of erythroid genes. To address these gaps, we developed a genetic system that allowed us to examine essential non-survival functions of EpoR signaling in erythroid differentiation. We rescued mouse Epor-/- fetal liver erythroid progenitors from apoptosis by transduction with the anti-apoptotic protein bcl-xL, comparing their ensuing differentiation with that of Epor-/- progenitors that were rescued by re-introduction of the EpoR. We found that the bcl-xL survival signal, in the absence of any EpoR signaling, was sufficient to allow erythroid terminal differentiation and formation of anucleated red cells. However, key features were abnormal. First, erythroblasts underwent slower and fewer cell cycles, generating fewer than half the number of red cells, showing an essential role for EpoR signaling in the regulation of cell cycle speed and number. Second, we found that EpoR signaling unexpectedly increased red cell size, in spite of the concurrent increase in the number of cell divisions. Using mice doubly deleted for both EpoR and HRI, we found that EpoR regulation of red cell size is independent of the well-described red cell size regulation by iron and heme. Healthy human volunteers that were administered Epo showed an increase in mean corpuscular volume (MCV) that persisted long after Epo and reticulocyte levels returned to baseline, supporting a role for the regulation of red cell size by Epo and suggesting new diagnostic interpretations for this common clinical test. Together, our findings reveal novel functions for the EpoR in erythroid differentiation including an unexpected role in the regulation of red cell size. more...
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- 2020
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25. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD
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Mark J. Koury, Kausik Umanath, Efrain Reisin, Khe Ni Ma, John Manley, Diana Jalal, Ebele M. Umeukeje, Jamie P. Dwyer, Mohammed Sika, Samuel S. Blumenthal, Julia B. Lewis, Barbara A. Greco, Dana G. Negoi, Robert Niecestro, Anand N. Hiremath, Tom Greene, and Steven Zeig more...
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Male ,medicine.medical_specialty ,Anemia ,medicine.drug_class ,Iron ,Sevelamer ,Ferric Compounds ,Gastroenterology ,Clinical Research ,Interquartile range ,Up Front Matters ,Internal medicine ,Humans ,Medicine ,biology ,business.industry ,Transferrin saturation ,General Medicine ,Middle Aged ,medicine.disease ,Surgery ,Phosphate binder ,Ferritin ,Nephrology ,Erythropoietin ,Hematinics ,biology.protein ,Kidney Failure, Chronic ,Administration, Intravenous ,Drug Therapy, Combination ,Female ,Hemoglobin ,business ,medicine.drug - Abstract
Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P more...
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- 2015
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26. A Hybrid Computation Model to Describe the Progression of Multiple Myeloma and Its Intra-Clonal Heterogeneity
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Fatima-Ezzahra Belmaati, Vitaly Volpert, Anass Bouchnita, Mark J. Koury, Rajae Aboulaich, Multi-scale modelling of cell dynamics : application to hematopoiesis (DRACULA), Institut Camille Jordan [Villeurbanne] (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Modélisation mathématique, calcul scientifique (MMCS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Mohammadia School of Engineering, Université Mohamed V, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Camille Jordan (ICJ), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), and Institut Camille Jordan (ICJ) more...
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0301 basic medicine ,General Computer Science ,Cell division ,hybrid model ,Biology ,multiple myeloma ,intra-clonal heterogeneity ,lcsh:QA75.5-76.95 ,Theoretical Computer Science ,Extracellular matrix ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Extracellular ,[MATH.MATH-AP]Mathematics [math]/Analysis of PDEs [math.AP] ,Multiple myeloma ,Applied Mathematics ,Chemotaxis ,medicine.disease ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Apoptosis ,030220 oncology & carcinogenesis ,Modeling and Simulation ,Immunology ,lcsh:Electronic computers. Computer science ,Bone marrow ,Intracellular - Abstract
International audience; Multiple myeloma (MM) is a genetically complex hematological cancer that is characterized by proliferation of malignant plasma cells in the bone marrow. MM evolves from the clonal premalignant disorder monoclonal gammopathy of unknown significance (MGUS) by sequential genetic changes involving many different genes, resulting in dysregulated growth of multiple clones of plasma cells. The migration, survival, and proliferation of these clones require the direct and indirect interactions with the non-hematopoietic cells of the bone marrow. We develop a hybrid discrete-continuous model of MM development from the MGUS stage. The discrete aspect of the model is observed at the cellular level: cells are represented as individual objects which move, interact, divide, and die by apoptosis. Each of these actions is regulated by intracellular and extracellular processes as described by continuous models. The hybrid model consists of the following submodels that have been simplified from the much more complex state of evolving MM: cell motion due to chemotaxis, intracellular regulation of plasma cells, extracellular regulation in the bone marrow, and acquisition of mutations upon cell division. By extending a previous, simpler model in which the extracellular matrix was considered to be uniformly distributed, the new hybrid model provides a more accurate description in which cytokines are produced by the marrow microenvironment and consumed by the myeloma cells. The complex multiple genetic changes in MM cells and the numerous cell-cell and cytokine-mediated interactions between myeloma cells and their marrow microenviroment are simplified in the model such that four related but evolving MM clones can be studied as they compete for dominance in the setting of intraclonal heterogeneity. more...
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- 2017
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27. The role of spatial organization of cells in erythropoiesis
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Vitaly Volpert, Nathalie Eymard, Mark J. Koury, N. Bessonov, Olivier Gandrillon, Modélisation mathématique, calcul scientifique (MMCS), Institut Camille Jordan [Villeurbanne] (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Institute of Mechanical Engineering Problems [St. Petersburg] (IPME), Russian Academy of Sciences [Moscow] (RAS), Multi-scale modelling of cell dynamics : application to hematopoiesis (DRACULA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut Camille Jordan (ICJ), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, and Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Camille Jordan (ICJ) more...
- Subjects
Fas Ligand Protein ,Erythroblasts ,Cellular differentiation ,Immunology ,Cell ,Apoptosis ,Hemorrhage ,Biology ,Models, Biological ,Biochemistry ,Mice ,Erythroblast ,hemic and lymphatic diseases ,Extracellular ,medicine ,Animals ,Humans ,[MATH.MATH-AP]Mathematics [math]/Analysis of PDEs [math.AP] ,Macrophage ,Erythropoiesis ,Cells, Cultured ,Cell Proliferation ,Erythroid Precursor Cells ,Cell growth ,Macrophages ,Applied Mathematics ,Cell Differentiation ,Mathematical Concepts ,Cell Biology ,Hematology ,Agricultural and Biological Sciences (miscellaneous) ,In vitro ,Cell biology ,Red blood cell ,medicine.anatomical_structure ,Hematocrit ,Erythropoietin ,Modeling and Simulation ,Bone marrow ,Intracellular ,medicine.drug - Abstract
The functional unit of definitive mammalian erythropoiesis, the erythroblastic island, consists of a central macrophage surrounded by adherent erythroid progenitor cells at the colony-forming unit/proerythroblast (CFU-E/Pro-EB) stages of differentiation and their differentiating progeny, the erythroblasts. Central macrophages display on their surface or secrete various growth or inhibitory factors that influence the fate of the surrounding erythroid cells. CFU-E/Pro-EBs have three possible fates: a) expansion of their numbers without differentiation, b) differentiation through the erythroblast stages into reticulocytes that are released into the blood, c) death by apoptosis. CFU-E/Pro-EB fate is under the control of a complex intracellular molecular network that is highly dependent upon environmental conditions in the erythroblastic island. Direct examination of erythroblastic island function in vivo has been limited in mice and unfeasible in humans. In order to assess the functional role of spatial organization coupled with the complex network behavior in erythroblastic islands, we developed hybrid discrete-continuous models of erythropoiesis. A mathematical model was developed in which the cells of the erythroblastic island are considered as individual physical objects, intracellular regulatory networks are modeled with ordinary differential equations, and extracellular concentrations of cytokines or hormones are modeled by partial differential equations. The concentrations of the cytokines Fas-ligand and bone morphogenetic protein-4, which are produced locally in the erythroblastic island, and the hormones erythropoietin and glucocorticosteroid hormone, which are produced at remote locations in the body, are included in the model. We used the model in simulations that investigated the impact of an important difference between humans and mice in which mature late-stage erythroblasts produce the most Fas-ligand in humans, and early-stage erythroblasts produce the most Fas-ligand in mice. Although the global behaviors of the erythroblastic islands in both species were similar, differences were found, including a relatively slower recovery time of hematocrits and erythrocyte numbers to their baselines following the development of acute anemia in humans as compared to mice. These simulation results with the model were consistent with the more rapid recovery to baseline in mice that were bled to about one-half of their normal hematocrit compared to two patients who had acute blood loss to about one-half of their respective baseline hematocrits and recovered without erythrocyte transfusions. Our modeling approach was also very consistent with the previously reported results of in vitro cultures, where the central macrophages in reconstituted erythroblastic islands of mice had a strong impact on the dynamics of erythroid cell proliferation. The spatial organization of cells in erythroblastic islands is important for the normal, stable functioning of mammalian erythropoiesis, both in vitro and in vivo. Our model of a simplified molecular network controlling erythroid progenitor cell decision and fate provides a realistic functional unit of mammalian erythropoiesis that integrates factors within the microenvironment of the erythroblastic island with those of circulating regulators of erythropoiesis. Our model highlights the need for proper inclusion of the spatial relationships of erythropoietic cells and allowing decisions to be made at the level of individual erythroid cells in the modeling process. Disclosures: Koury: Keryx Biopharmaceuticals, Inc.: Consultancy; TG Therapeutics, Inc.: Consultancy. more...
- Published
- 2014
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28. Dose-Response and Efficacy of Ferric Citrate to Treat Hyperphosphatemia in Hemodialysis Patients: A Short-term Randomized Trial
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Jamie P, Dwyer, Mohammed, Sika, Gerald, Schulman, Ingrid J, Chang, Michael, Anger, Mark, Smith, Mark, Kaplan, Steven, Zeig, Mark J, Koury, Samuel S, Blumenthal, Julia B, Lewis, and S, Blumenthal
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Male ,medicine.medical_specialty ,Time Factors ,medicine.drug_class ,medicine.medical_treatment ,Administration, Oral ,chemistry.chemical_element ,Ferric Compounds ,Gastroenterology ,law.invention ,Hyperphosphatemia ,Randomized controlled trial ,Renal Dialysis ,law ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Adverse effect ,Dose-Response Relationship, Drug ,business.industry ,Phosphorus ,Middle Aged ,medicine.disease ,Phosphate binder ,Surgery ,Clinical trial ,Treatment Outcome ,Tolerability ,chemistry ,Nephrology ,Hematinics ,Kidney Failure, Chronic ,Female ,Hemodialysis ,business ,Follow-Up Studies - Abstract
Most dialysis patients require phosphate binders to control hyperphosphatemia. Ferric citrate has been tested in phase 2 trials as a phosphate binder. This trial was designed as a dose-response and efficacy trial.Prospective, phase 3, multicenter, open-label, randomized clinical trial.151 participants with hyperphosphatemia on maintenance hemodialysis therapy.Fixed dose of ferric citrate taken orally as a phosphate binder for up to 28 days (1, 6, or 8 g/d in 51, 52, and 48 participants, respectively).Primary outcome is dose-response of ferric citrate on serum phosphorus level; secondary outcomes are safety and tolerability.Serum chemistry tests including phosphorus, safety data.151 participants received at least one dose of ferric citrate. Mean baseline phosphorus levels were 7.3 ± 1.7 (SD) mg/dL in the 1-g/d group, 7.6 ± 1.7 mg/dL in the 6-g/d group, and 7.5 ± 1.6 mg/dL in the 8-g/d group. Phosphorus levels decreased in a dose-dependent manner (mean change at end of treatment, -0.1 ± 1.3 mg/dL in the 1-g/d group, -1.9 ± 1.7 mg/dL in the 6-g/d group, and -2.1 ± 2.0 mg/dL in the 8-g/d group). The mean difference in reduction in phosphorus levels between the 6- and 1-g/d groups was 1.3 mg/dL (95% CI, 0.69 to 1.9; P0.001), between the 8- and 1-g/d groups was 1.5 mg/dL (95% CI, 0.86 to 2.1; P0.001), and between the 8- and 6-g/d groups was 0.21 mg/dL (95% CI, -0.39 to 0.81; P = 0.5). The most common adverse event was stool discoloration.Sample size and duration confirm efficacy, but limit our ability to confirm safety.Ferric citrate is efficacious as a phosphate binder in a dose-dependent manner. A phase 3 trial is ongoing to confirm safety and efficacy. more...
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- 2013
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29. Red blood cell production and kinetics
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Mark J. Koury
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medicine.medical_specialty ,Microcytic anemia ,Kinetics ,Iron deficiency ,Biology ,medicine.disease ,Red blood cell ,Endocrinology ,medicine.anatomical_structure ,Hypoxia-inducible factors ,Erythropoietin ,Internal medicine ,medicine ,Erythropoiesis ,Macrocytic anemia ,medicine.drug - Published
- 2016
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30. Clinical Implications of Novel Regulatory Mechanisms for Production of Platelets, Neutrophils, and Erythrocytes
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Mark J. Koury
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Chemistry ,Platelet ,Cell biology - Published
- 2016
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31. How to approach chronic anemia
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Mark J. Koury and Melissa Rhodes
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hemic and lymphatic diseases ,Hematology - Abstract
We present herein an approach to diagnosing the cause of chronic anemia based on a patient's history and complete blood cell count (CBC). Four patterns that are encountered frequently in CBCs associated with chronic anemias are considered: (1) anemia with abnormal platelet and/or leukocyte counts, (2) anemia with increased reticulocyte counts, (3) life-long history of chronic anemia, and (4) anemia with inappropriately low reticulocytes. The pathophysiologic bases for some chronic anemias with low reticulocyte production are reviewed in terms of the bone marrow (BM) events that reduce normal rates of erythropoiesis. These events include: apoptosis of erythroid progenitor and precursor cells by intrinsic and extrinsic factors, development of macrocytosis when erythroblast DNA replication is impaired, and development of microcytosis due to heme-regulated eIF2α kinase inhibition of protein synthesis in iron-deficient or thalassemic erythroblasts. more...
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- 2012
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32. The Safety and Tolerability of Ferric Citrate as a Phosphate Binder in Dialysis Patients
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Mohammed Sika, Tom Greene, Warren Shapiro, Marvin Sinsakul, Julia B. Lewis, Stephen M. Korbet, Mark J. Koury, Mark T. Smith, and Jamie P. Dwyer
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Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Iron ,medicine.medical_treatment ,Color ,Ferric Compounds ,Gastroenterology ,Feces ,Renal Dialysis ,Surveys and Questionnaires ,Internal medicine ,Humans ,Medicine ,Adverse effect ,Chelating Agents ,Chronic Kidney Disease-Mineral and Bone Disorder ,medicine.diagnostic_test ,biology ,Transferrin saturation ,business.industry ,Complete blood count ,Phosphorus ,General Medicine ,Middle Aged ,Phosphate binder ,Ferritin ,Tolerability ,Nephrology ,Ferritins ,biology.protein ,Kidney Failure, Chronic ,Ferric ,Female ,Hemodialysis ,business ,Constipation ,medicine.drug - Abstract
Background: A phase II open-label study was conducted in hemodialysis patients evaluating the short-term safety, tolerability, and iron absorption with ferric citrate when used as a phosphate binder. Methods: Enrollment occurred in two periods. Period 1 recruited patients taking 6–15 pills/day of binder with phosphorus of ≥2.5 mg/dl. Period 2 recruited patients taking ≥12 pills/day of binder with phosphorus of ≥3.5 mg/dl. Participants with ferritin ≥1,000 µg/l or transferrin iron saturation (TSAT) ≥50% at screening were excluded. Subjects discontinued their previous binders and started 4.5 g/day of ferric citrate (period 1) or 6 g/day (period 2) and were titrated for 4 weeks to maintain a phosphorus of 3.5–5.5 mg/dl. Chemistries and complete blood count were obtained weekly and a gastrointestinal questionnaire was administered at drug initiation and final visit. Iron therapy was permitted if the ferritin was Results: Fifty-five subjects were enrolled. Four serious adverse events were reported; none were related to the study drug. Findings from the gastrointestinal questionnaire included stool discoloration (69%), constipation (15%), and bloating (7%). Mean iron parameters at the beginning of the study were ferritin 554 ± 296 µg/l, iron 68 ± 21 µg/dl, and iron saturation 30 ± 7.8%. At the end of study, mean ferritin was 609 ± 340 µg/l (p = 0.02), iron 75 ± 27 µg/dl (p = 0.04), and TSAT was 35 ± 13% (p = 0.001). Mean phosphorus and calcium levels were unchanged from baseline at the end of study. Conclusion: Ferric citrate was well tolerated by patients after 4 weeks with no significant clinical or biochemical adverse events related to exposure. more...
- Published
- 2012
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33. Rationale and study design of a three-period, 58-week trial of ferric citrate as a phosphate binder in patients with ESRD on dialysis
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Mohammed Sika, Robert Niecestro, Carolyn Connelly, Gerald Schulman, Julia B. Lewis, Jamie P. Dwyer, Mark J. Koury, and Kausik Umanath
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medicine.medical_specialty ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Hematology ,medicine.disease ,Placebo ,Gastroenterology ,Surgery ,Peritoneal dialysis ,law.invention ,Phosphate binder ,Clinical trial ,Randomized controlled trial ,Nephrology ,law ,Internal medicine ,medicine ,Hemodialysis ,business ,Dialysis ,Kidney disease - Abstract
Chronic kidney disease associated mineral and bone disorders arise as a result of aberrant bone mineral metabolism in patients with advancing levels of renal dysfunction and end-stage renal disease. One of the cornerstones of treatment is the use of phosphate-binding agents. We describe the rationale and study design for a clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder. This trial is a three-period, international, multicenter, randomized, controlled clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder, consisting of a 2-week washout period, a 52-week safety assessment period in which subjects are randomized to ferric citrate or active control, and a 4-week efficacy assessment period in which subjects randomized to ferric citrate in the safety assessment period are randomized to ferric citrate or placebo. Eligible subjects include end-stage renal disease patients who have been treated with thrice-weekly hemodialysis or peritoneal dialysis for at least 3 months in dialysis clinics in the United States and Israel. Primary outcome measure will be the effect of ferric citrate vs. placebo on the change in serum phosphorus. Safety assessments will be performed by monitoring adverse events, concomitant medication use, and sequential blood chemistries (including iron parameters, phosphorus, and calcium). This three-period trial will assess the efficacy of ferric citrate as a phosphate binder. If proven safe and efficacious, ferric citrate will likely provide an additional phosphate binder to treat chronic kidney disease associated mineral and bone disorders. more...
- Published
- 2012
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34. Eto2/MTG16 and MTGR1 are heteromeric corepressors of the TAL1/SCL transcription factor in murine erythroid progenitors
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Mark J. Koury, Zhixiong Xu, Jingping Xie, Stephen J. Brandt, Amy-Joan L. Ham, Scott W. Hiebert, and Ying Cai
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Biophysics ,Biology ,Biochemistry ,Article ,Mice ,Cell Line, Tumor ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Molecular Biology ,Transcription factor ,T-Cell Acute Lymphocytic Leukemia Protein 1 ,Erythroid Precursor Cells ,Nuclear Proteins ,Promoter ,Cell Biology ,Fusion protein ,Molecular biology ,Chromatin ,Repressor Proteins ,Corepressor ,Chromatin immunoprecipitation ,Transcription Factors ,TAL1 - Abstract
The TAL1 (or SCL) gene, originally discovered through its involvement by a chromosomal translocation in T-cell acute lymphoblastic leukemia, encodes a basic helix-loop-helix (bHLH) transcription factor essential for hematopoietic and vascular development. To identify its interaction partners, we expressed a tandem epitope-tagged protein in murine erythroleukemia (MEL) cells and characterized affinity-purified Tal1-containing complexes by liquid chromatography-tandem mass spectrometry analysis. In addition to known interacting proteins, two proteins related to the Eight-Twenty-One (ETO) corepressor, Eto2/Mtg16 and Mtgr1, were identified from the peptide fragments analyzed. Tal1 interaction with Eto2 and Mtgr1 was verified by coimmunoprecipitation analysis in Tal1, Eto2-, and Mtgr1-transfected COS-7 cells, MEL cells expressing V5 epitope-tagged Tal1 protein, and non-transfected MEL cells. Mapping analysis with Gal4 fusion proteins demonstrated a requirement for the bHLH domain of Tal1 and TAF110 domain of Eto2 for their interaction, and transient transfection and glutathione S-transferase pull-down analysis showed that Mtgr1 and Eto2 enhanced the other’s association with Tal1. Enforced expression of Eto2 in differentiating MEL cells inhibited the promoter of the Protein 4.2 (P4.2) gene, a direct target of TAL1 in erythroid progenitors, and transduction of Eto2 and Mtgr1 augmented Tal1-mediated gene repression. Finally, chromatin immunoprecipitation analysis revealed that Eto2 occupancy of the P4.2 promoter in MEL cells decreased with differentiation, in parallel with a decline in Eto2 protein abundance. These results identify Eto2 and Mtgr1 as authentic interaction partners of Tal1 and suggest they act as heteromeric corepressors of this bHLH transcription factor during erythroid differentiation. more...
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- 2009
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35. S-Adenosylhomocysteine—a better indicator of vascular disease than homocysteine?
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Conrad Wagner and Mark J. Koury
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medicine.medical_specialty ,Methionine ,Methyltransferase ,Nutrition and Dietetics ,Homocysteine ,Vascular disease ,Rapid immunoassay ,Metabolite ,Medicine (miscellaneous) ,medicine.disease ,Control subjects ,S-Adenosylhomocysteine ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,medicine ,Humans ,Vascular Diseases ,Risk factor - Abstract
It is widely accepted that elevated plasma total homocysteine is an independent risk factor for vascular disease. The relation is believed to be causal, but there is no generally accepted mechanism for the pathophysiology involved. The metabolic precursor of homocysteine in all tissues is S-adenosylhomocysteine (AdoHcy). AdoHcy is present in normal human plasma at concentrations approximately 1-500th of those of homocysteine, a fact that presents difficulties in measurement. The requirement for specialized equipment, complicated time-consuming methodology, or both is a reason that measurement of plasma AdoHcy has not generally been carried out in large studies. A recently published rapid immunoassay for AdoHcy in human plasma should make measurement of this important metabolite available for general use. Advantages of the measurement of plasma AdoHcy include 1) a smaller overlap of values between control subjects and patients, and thus the possibility of observing significant differences in fewer samples, 2) an accepted mechanism of metabolic activity as an inhibitor of all S-adenosylmethionine-mediated methyltransferases, and 3) evidence (from recent studies) that a higher plasma concentration of AdoHcy is a more sensitive indicator of vascular disease than is a higher plasma concentration of homocysteine. more...
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- 2007
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36. Maturational loss of the vitamin C transporter in erythrocytes
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Zhi-chao Qu, James M. May, Huan Qiao, and Mark J. Koury
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Aging ,Erythrocytes ,Organic anion transporter 1 ,Biophysics ,Organic Anion Transporters, Sodium-Dependent ,Cell Enlargement ,Biochemistry ,Article ,Mice ,Reticulocyte ,Erythroblast ,medicine ,Animals ,Humans ,Sodium-Coupled Vitamin C Transporters ,Molecular Biology ,Cells, Cultured ,Symporters ,biology ,Developmental maturation ,Vitamin C ,Cell Biology ,medicine.anatomical_structure ,Symporter ,biology.protein ,Intracellular - Abstract
Erythrocytes have the same intracellular concentration of ascorbate as plasma, which is much lower than that of nucleated cells. To determine why erythrocytes are unable to concentrate ascorbate, we tested for the presence of ascorbate transporters in these cells. Human erythrocytes had very low rates of uptake of radiolabeled ascorbate, which was accounted for by the lack of ascorbate transporter SVCT2 in immunoblots. Using a cell culture model of Friend virus-infected mouse erythroblasts, immunoblots showed that the SVCT2 was present in the erythroblast stages, but was lost following extrusion of the nucleus in the formation of the reticulocyte stage. Rates of specific ascorbate transport correlated with the presence of the SVCT2. These results show that mature erythrocytes fail to concentrate ascorbate due to the loss of SVCT2 during maturation in the bone marrow. more...
- Published
- 2007
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37. Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis
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Anass, Bouchnita, Nathalie, Eymard, Tamara K, Moyo, Mark J, Koury, and Vitaly, Volpert
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Adult ,Erythrocyte Indices ,Male ,Anemia ,Middle Aged ,Models, Theoretical ,Dexamethasone ,Thalidomide ,Bortezomib ,Treatment Outcome ,Erythroid Cells ,Bone Marrow ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Erythropoiesis ,Female ,Multiple Myeloma ,Lenalidomide ,Biomarkers ,Aged - Abstract
Multiple myeloma (MM) infiltrates bone marrow and causes anemia by disrupting erythropoiesis, but the effects of marrow infiltration on anemia are difficult to quantify. Marrow biopsies of newly diagnosed MM patients were analyzed before and after four 28-day cycles of non-erythrotoxic remission induction chemotherapy. Complete blood cell counts and serum paraprotein concentrations were measured at diagnosis and before each chemotherapy cycle. At diagnosis, marrow area infiltrated by myeloma correlated negatively with hemoglobin, erythrocytes, and marrow erythroid cells. After successful chemotherapy, patients with less than 30% myeloma infiltration at diagnosis had no change in these parameters, whereas patients with more than 30% myeloma infiltration at diagnosis increased all three parameters. Clinical data were used to develop mathematical models of the effects of myeloma infiltration on the marrow niches of terminal erythropoiesis, the erythroblastic islands (EBIs). A hybrid discrete-continuous model of erythropoiesis based on EBI structure/function was extended to sections of marrow containing multiple EBIs. In the model, myeloma cells can kill erythroid cells by physically destroying EBIs and by producing proapoptotic cytokines. Following chemotherapy, changes in serum paraproteins as measures of myeloma cells and changes in erythrocyte numbers as measures of marrow erythroid cells allowed modeling of myeloma cell death and erythroid cell recovery, respectively. Simulations of marrow infiltration by myeloma and treatment with non-erythrotoxic chemotherapy demonstrate that myeloma-mediated destruction and subsequent reestablishment of EBIs and expansion of erythroid cell populations in EBIs following chemotherapy provide explanations for anemia development and its therapy-mediated recovery in MM patients. more...
- Published
- 2015
38. Tracking erythroid progenitor cells in times of need and times of plenty
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Mark J. Koury
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0301 basic medicine ,Cancer Research ,Cell Survival ,Cellular differentiation ,Stimulation ,Apoptosis ,03 medical and health sciences ,Cell Movement ,hemic and lymphatic diseases ,Cell Self Renewal ,Genetics ,medicine ,Animals ,Humans ,Erythropoiesis ,Molecular Biology ,Progenitor ,Cell Proliferation ,Erythroid Precursor Cells ,Cell growth ,business.industry ,Anemia ,Cell Differentiation ,Cell Biology ,Hematology ,medicine.disease ,Hemolysis ,Cell biology ,Red blood cell ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,business - Abstract
Red blood cell production rates increase rapidly following blood loss or hemolysis, but the expansion of erythropoiesis in these anemic states is tightly regulated such that rebound polycythemia does not occur. The erythroid cells that respond to erythropoietic stimulation or suppression are the progenitor stages of burst-forming units–erythroid (BFU-Es) and colony-forming units–erythroid (CFU-Es). Results from an early study of the changes in the size, location, and cell cycling status of BFU-E and CFU-E populations in mice under normal conditions, erythropoietic stimulation, and erythropoietic suppression are used as reference points to review subsequent developments related to erythroid progenitor populations and regulation of their size. The review concerns development of erythroid progenitor populations mainly in mice and humans, with a focus on the mechanisms related to the rapid but highly regulated expansion of erythropoiesis in spleens of erythropoietically stimulated mice. Current knowledge is used as a model of erythroid progenitor populations in mice under normal, erythropoietically suppressed, and erythropoietically stimulated conditions. Clinical applications of information learned from studies of erythropoietic expansion, in terms of current therapies for anemia, are reviewed. more...
- Published
- 2015
39. Anaemia in kidney disease: harnessing hypoxia responses for therapy
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Volker H. Haase and Mark J. Koury
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Inflammation ,Article ,Pathogenesis ,hemic and lymphatic diseases ,Basic Helix-Loop-Helix Transcription Factors ,Medicine ,Humans ,Erythropoiesis ,Renal Insufficiency, Chronic ,Kidney ,business.industry ,Anemia ,Hypoxia (medical) ,medicine.disease ,Cell Hypoxia ,medicine.anatomical_structure ,Nephrology ,Erythropoietin ,Immunology ,Cancer research ,Hypoxia-Inducible Factor 1 ,medicine.symptom ,Signal transduction ,business ,Kidney disease ,medicine.drug ,Signal Transduction - Abstract
Improved understanding of the oxygen-dependent regulation of erythropoiesis has provided new insights into the pathogenesis of anaemia associated with renal failure and has led to the development of novel therapeutic agents for its treatment. Hypoxia-inducible factor (HIF)-2 is a key regulator of erythropoiesis and iron metabolism. HIF-2 is activated by hypoxic conditions and controls the production of erythropoietin by renal peritubular interstitial fibroblast-like cells and hepatocytes. In anaemia associated with renal disease, erythropoiesis is suppressed due to inadequate erythropoietin production in the kidney, inflammation and iron deficiency; however, pharmacologic agents that activate the HIF axis could provide a physiologic approach to the treatment of renal anaemia by mimicking hypoxia responses that coordinate erythropoiesis with iron metabolism. This Review discusses the functional inter-relationships between erythropoietin, iron and inflammatory mediators under physiologic conditions and in relation to the pathogenesis of renal anaemia, as well as recent insights into the molecular and cellular basis of erythropoietin production in the kidney. It furthermore provides a detailed overview of current clinical experience with pharmacologic activators of HIF signalling as a novel comprehensive and physiologic approach to the treatment of anaemia. more...
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- 2015
40. The Phosphate Binder Ferric Citrate and Mineral Metabolism and Inflammatory Markers in Maintenance Dialysis Patients: Results From Prespecified Analyses of a Randomized Clinical Trial
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Shahabul S. Arfeen, Tom Greene, Mohammed Sika, Gil Chernin, Julia B. Lewis, Stephen Z. Fadem, Simin Goral, Peter N. Van Buren, Marvin Sinsakul, Mark J. Koury, Daniel E. Weiner, Kausik Umanath, Isai G. Bowline, John P. Middleton, Jamie P. Dwyer, and Josephine Abraham more...
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Male ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Serum albumin ,chemistry.chemical_element ,Parathyroid hormone ,Sevelamer ,Calcium ,Acetates ,Ferric Compounds ,Article ,Peritoneal dialysis ,Phosphates ,Hyperphosphatemia ,chemistry.chemical_compound ,Renal Dialysis ,Internal medicine ,medicine ,Polyamines ,Humans ,Aged ,Chelating Agents ,biology ,business.industry ,Calcium Compounds ,Middle Aged ,medicine.disease ,Phosphate ,Phosphate binder ,Endocrinology ,chemistry ,Nephrology ,biology.protein ,Kidney Failure, Chronic ,Female ,Inflammation Mediators ,business ,medicine.drug - Abstract
Background Phosphate binders are the cornerstone of hyperphosphatemia management in dialysis patients. Ferric citrate is an iron-based oral phosphate binder that effectively lowers serum phosphorus levels. Study Design 52-week, open-label, phase 3, randomized, controlled trial for safety-profile assessment. Setting & Participants Maintenance dialysis patients with serum phosphorus levels ≥6.0mg/dL after washout of prior phosphate binders. Intervention 2:1 randomization to ferric citrate or active control (sevelamer carbonate and/or calcium acetate). Outcomes Changes in mineral bone disease, protein-energy wasting/inflammation, and occurrence of adverse events after 1 year. Measurements Serum calcium, intact parathyroid hormone, phosphorus, aluminum, white blood cell count, percentage of lymphocytes, serum urea nitrogen, and bicarbonate. Results There were 292 participants randomly assigned to ferric citrate, and 149, to active control. Groups were well matched. For mean changes from baseline, phosphorus levels decreased similarly in the ferric citrate and active control groups (−2.04±1.99 [SD] vs −2.18±2.25mg/dL, respectively; P =0.9); serum calcium levels increased similarly in the ferric citrate and active control groups (0.22±0.90 vs 0.31±0.95mg/dL; P =0.2). Hypercalcemia occurred in 4 participants receiving calcium acetate. Parathyroid hormone levels decreased similarly in the ferric citrate and active control groups (−167.1±399.8 vs −152.7±392.1pg/mL; P =0.8). Serum albumin, bicarbonate, serum urea nitrogen, white blood cell count and percentage of lymphocytes, and aluminum values were similar between ferric citrate and active control. Total and low-density lipoprotein cholesterol levels were lower in participants receiving sevelamer than those receiving ferric citrate and calcium acetate. Fewer participants randomly assigned to ferric citrate had serious adverse events compared with active control. Limitations Open-label study, few peritoneal dialysis patients. Conclusions Ferric citrate was associated with similar phosphorus control compared to active control, with similar effects on markers of bone and mineral metabolism in dialysis patients. There was no evidence of protein-energy wasting/inflammation or aluminum toxicity, and fewer participants randomly assigned to ferric citrate had serious adverse events. Ferric citrate is an effective phosphate binder with a safety profile comparable to sevelamer and calcium acetate. more...
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- 2015
41. Correlation of the Molecular and Anatomical Aspects of Renal Erythropoietin Production1
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Stanley E. Graber, Mark J. Koury, Stephen T. Koury, and Maurice C. Bondurant
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Correlation ,Erythropoietin ,business.industry ,medicine ,business ,Bioinformatics ,medicine.drug - Published
- 2015
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42. Complement Component C3b and RBCs Provide a Potential Clearance Mechanism for Damaged Plasma Proteins
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Mark J. Koury
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Chemistry ,Mechanism (biology) ,Component (UML) ,Blood proteins ,Complement (complexity) ,Cell biology - Published
- 2015
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43. Less Autophagy in Myeloid Precursors Boosts Neutrophil Counts
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Mark J. Koury
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Myeloid ,medicine.anatomical_structure ,Chemistry ,Autophagy ,Cancer research ,medicine - Published
- 2015
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44. Erythroferrone: A Missing Link in Iron Regulation
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Mark J. Koury
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Chemistry ,Computational biology ,Erythroferrone ,Link (knot theory) - Published
- 2015
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45. Can Prolyl Hydroxylase Inhibition Treat EPO-Deficient Anemia of Renal Failure With Fewer Vascular Complications Than EPO Itself?
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Mark J. Koury
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medicine.medical_specialty ,Endocrinology ,Anemia ,business.industry ,Internal medicine ,medicine ,medicine.disease ,business - Published
- 2015
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46. Too Many RBCs or Platelets Stall Blood Flow in Cerebral Capillaries
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Mark J. Koury
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business.industry ,Biophysics ,Medicine ,Stall (fluid mechanics) ,Platelet ,Blood flow ,business - Published
- 2015
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47. Ruptured Megakaryocytes Rapidly Release New Platelets in Response to Interleukin-1α
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Mark J. Koury
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medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,Interleukin 1α ,medicine ,Platelet - Published
- 2015
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48. Relationship between plasma S-adenosylhomocysteine concentration and glomerular filtration rate in children
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William D. Dupont, Kathy Jabs, Conrad Wagner, and Mark J. Koury
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medicine.medical_specialty ,Adolescent ,Homocysteine ,Endocrinology, Diabetes and Metabolism ,Renal function ,urologic and male genital diseases ,chemistry.chemical_compound ,Folic Acid ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Blood plasma ,Congenital Hypothyroidism ,medicine ,Humans ,cardiovascular diseases ,Vitamin B12 ,Child ,Creatinine ,Vascular disease ,Infant ,medicine.disease ,S-Adenosylhomocysteine ,nervous system diseases ,Congenital hypothyroidism ,Vitamin B 12 ,chemistry ,Child, Preschool ,Kidney Diseases ,Glomerular Filtration Rate - Abstract
S-Adenosylhomocysteine (SAH) is the metabolic precursor of all the homocysteine (Hcy) produced in the body. It is formed by the enzyme SAH hydrolase in a reversible reaction. In a previous study we have shown that plasma SAH is a more sensitive indicator of the risk for cardiovascular disease, and in a second study involving patients with renal disease, we also showed that it is a more sensitive indicator of renal insufficiency than plasma Hcy. However, in the latter study, the patients with renal disease were older and had a variety of other diseases such as diabetes and primary hypertension, which are associated with vascular disease and which could reduce renal function by involvement of the kidneys. Our objective was to rule out these complicating factors as the cause of the elevated SAH in renal disease and determine whether renal insufficiency alone was the cause of the elevated SAH. We therefore measured SAH, Hcy, folate, and vitamin B12 in 23 patients between the ages of 1 and 18 years with a wide range of renal function, but who had none of these complicating factors. Glomerular filtration rate (GFR) was calculated using serum creatinine according to the Schwartz formula. None of the children were deficient in folate or vitamin B12. After adjusting for age, folate, and vitamin B12, there was a modest and insignificant decrease of 0.033 micromol/L of Hcy associated with an increase of 1 mL/min of GFR (95% confidence interval, -0.066 to 0.0002). However, there was a strong and statistically significant association between log(SAH) and log(GFR): P < .0005, R2 = 0.76. This result suggests that plasma SAH rather than Hcy is the metabolite primarily affected in renal disease. We suggest that plasma Hcy elevations that have been linked to vascular disease may be due to elevated SAH resulting from renal insufficiency. more...
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- 2006
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49. Nuclear substructure reorganization during late-stage erythropoiesis is selective and does not involve caspase cleavage of major nuclear substructural proteins
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Mark J. Koury, Joel Anne Chasis, Sharon Wald Krauss, Annie J. Lo, Sarah A. Short, and Narla Mohandas
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Erythroblasts ,Red Cells ,Immunology ,Mice, Inbred Strains ,Biochemistry ,Mice ,Nuclear Matrix-Associated Proteins ,Erythroblast ,medicine ,Animals ,Erythropoiesis ,Nuclear protein ,Caspase ,Cell Nucleus ,Genetics ,Lamin Type B ,biology ,Nuclear Proteins ,DNA ,Cell Biology ,Hematology ,Nuclear matrix ,Cell Nucleus Structures ,Chromatin ,Cell biology ,Cell nucleus ,medicine.anatomical_structure ,Caspases ,biology.protein ,Keratinocyte - Abstract
Enucleation, a rare feature of mammalian differentiation, occurs in 3 cell types: erythroblasts, lens epithelium, and keratinocytes. Previous investigations suggest that caspase activation functions in lens epithelial and keratinocyte enucleation, as well as in early erythropoiesis encompassing erythroid burst-forming unit (BFU-E) differentiation to proerythroblast. To determine whether caspase activation contributes to later erythropoiesis and whether nuclear substructures other than chromatin reorganize, we analyzed distributions of nuclear subcompartment proteins and assayed for caspase-induced cleavage of subcompartmental target proteins in mouse erythroblasts. We found that patterns of lamin B in the filamentous network interacting with both the nuclear envelope and DNA, nuclear matrix protein NuMA (Nuclear mitotic apparatus), and splicing factors Sm and SC35 persisted during nuclear condensation, consistent with effective transcription of genes expressed late in differentiation. Thus, nuclear reorganization prior to enucleation is selective, allowing maintenance of critical transcriptional processes independent of extensive chromosomal reorganization. Consistent with these data, we found no evidence for caspase-induced cleavage of major nuclear subcompartment proteins during late erythropoiesis, in contrast to what has been observed in early erythropoiesis and in lens epithelial and keratinocyte differentiation. These findings imply that nuclear condensation and extrusion during terminal erythroid differentiation involve novel mechanisms that do not entail major activation of apoptotic machinery. (Blood. 2005;106:2200-2205) more...
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- 2005
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50. In vitro maturation of nascent reticulocytes to erythrocytes
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Mark J. Koury, Prapaporn Kopsombut, Stephen T. Koury, and Maurice C. Bondurant
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Erythrocytes ,Reticulocytes ,Immunology ,Population ,bcl-X Protein ,Heme ,Vacuole ,Biology ,Mitochondrion ,Biochemistry ,Mice ,Reticulocyte ,Erythroblast ,medicine ,Animals ,education ,Inner mitochondrial membrane ,Cell Shape ,Cells, Cultured ,Organelles ,education.field_of_study ,Cell Differentiation ,Cell Biology ,Hematology ,Cell biology ,In vitro maturation ,Microscopy, Electron ,Reticulin ,Red blood cell ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Ribosomes - Abstract
Most studies of mammalian reticulocyte maturation have used blood reticulocytes.Nascent reticulocytes, as found in bone marrow, have not been available in developmentally synchronized populations. Nascent murine reticulocytes formed in vitro by enucleation of Friend virus–infected erythroblasts were purified and recultured for 110 hours. At 0 hours, all recultured cells were lobulated and contained dense, centralized reticulin. By 110 hours, about 20% to 25% of the cells became biconcave erythrocytes. Most ribosomes and cellular RNAs were degraded within 20 hours, and during that period, heme synthesis declined from a rate equal to that of late erythroblasts to less than 10% of that rate. Many mitochondria appeared normal until they showed outer membrane swelling, degradation, and apparent fusion with intracellular vacuoles at 40 hours of culture. During the period of mitochondrial loss, Bcl-XL, an antiapoptotic protein that accumulates during erythroblast differentiation and maintains mitochondrial membrane integrity, demonstrated progressive decreases and changes consistent with deamidation. Nevertheless, the reticulocytes did not undergo apoptosis, because their apoptotic machinery was degraded. This experimental system that provides a developmentally synchronized population of nascent murine reticulocytes that mature into biconcave erythrocytes in vitro should be useful in further investigations of the cellular events involved in reticulocyte maturation. more...
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- 2005
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