115 results found
Quiroga-Campano AL, Panoskaltsis N, Mantalaris A, 2018, Energy-based culture medium design for biomanufacturing optimization: A case study in monoclonal antibody production by GS-NS0 cells., Metab Eng, Vol: 47, Pages: 21-30
Demand for high-value biologics, a rapidly growing pipeline, and pressure from competition, time-to-market and regulators, necessitate novel biomanufacturing approaches, including Quality by Design (QbD) principles and Process Analytical Technologies (PAT), to facilitate accelerated, efficient and effective process development platforms that ensure consistent product quality and reduced lot-to-lot variability. Herein, QbD and PAT principles were incorporated within an innovative in vitro-in silico integrated framework for upstream process development (UPD). The central component of the UPD framework is a mathematical model that predicts dynamic nutrient uptake and average intracellular ATP content, based on biochemical reaction networks, to quantify and characterize energy metabolism and its adaptive response, metabolic shifts, to maintain ATP homeostasis. The accuracy and flexibility of the model depends on critical cell type/product/clone-specific parameters, which are experimentally estimated. The integrated in vitro-in silico platform and the model's predictive capacity reduced burden, time and expense of experimentation resulting in optimal medium design compared to commercially available culture media (80% amino acid reduction) and a fed-batch feeding strategy that increased productivity by 129%. The framework represents a flexible and efficient tool that transforms, improves and accelerates conventional process development in biomanufacturing with wide applications, including stem cell-based therapies.
Allenby MC, Misener R, Panoskaltsis N, et al., 2017, A Quantitative Three-Dimensional Image Analysis Tool for Maximal Acquisition of Spatial Heterogeneity Data, TISSUE ENGINEERING PART C-METHODS, Vol: 23, Pages: 108-117, ISSN: 1937-3384
Gyorgy R, Klontzas ME, Kostoglou M, et al., 2017, An Integrated Experimental-Modelling Approach of Mesenchymal Stem Cell Bioprocess towards Osteogenic Differentiation, IFAC PAPERSONLINE, Vol: 50, Pages: 9877-9882, ISSN: 2405-8963
Győrgy R, Klontzas ME, Kostoglou M, et al., 2017, A Population Balance Model for Stem Cell Differentiation Bioprocesses, Computer Aided Chemical Engineering, Pages: 2761-2766
© 2017 Elsevier B.V. Embryonic stem cells (ESCs) are capable of differentiation into a wide variety of cell types. Their use for cell therapy and regenerative medicine applications necessitates the expansion of cell numbers in bioreactors. Herein, we compare an ordinary differential equation (ODE) model of ESC expansion in a batch bioreactor with a novel mathematical model using population balance equations (PBM). Even though both models similarly describe cell expansion during the undifferentiated culture phase, the PBM captures fine oscillations in the total cell population introduced by the initiation of the differentiation process.
Misener R, Allenby, Fuentes-Gari M, et al., 2017, Stem Cell Biomanufacturing under Uncertainty: A Case Study in Optimizing Red Blood Cell Production, AIChE Journal, ISSN: 0001-1541
As breakthrough cellular therapy discoveries are translated into reliable, commercializable applications, effective stem cell biomanufacturing requires systematically developing and optimizing bioprocess design and operation. This manuscript proposes a rigorous computational framework for stem cell biomanufacturing under uncertainty. Our mathematical tool kit incorporates: high-fidelity modeling; single- and multivariate sensitivity analysis; global topological superstructure optimization; robust optimization. We quantitatively demonstrate the advantages of the proposed bioprocess optimization framework using, as a case study, a dual hollow fiber bioreactor producing red blood cells from progenitor cells. The optimization phase reduces the cost by a factor of 4 and the price of insuring process performance against uncertainty is approximately 15% over the nominal optimal solution. Mathematical modeling and optimization can guide decision making; we quantitatively evaluate the possible commercial impact of this cellular therapy using the disruptive technology paradigm.
Vernardis SI, Terzoudis K, Panoskaltsis N, et al., 2017, Human embryonic and induced pluripotent stem cells maintain phenotype but alter their metabolism after exposure to ROCK inhibitor, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Allenby MC, Tahlawi A, Misener R, et al., 2016, Spatiotemporal Mapping of Erythroid, Stromal, and Osteogenic Niche Formation to Support Physiologic Red Cell Production in a Three-Dimensional Hollow Fibre Perfusion Bioreactor, BLOOD, Vol: 128, ISSN: 0006-4971
Arami S, Ayto R, Parcharidou A, et al., 2016, MANTLE CELL LYMPHOMA PRESENTING WITH MARKEDLY HIGH EOSINOPHIL COUNT: A CASE REPORT, 7th International Eurasian Hematology Congress, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: S23-S23, ISSN: 0145-2126
Chaudhry MS, Gilmour KC, House IG, et al., 2016, Missense mutations in the perforin (PRF1) gene as a cause of hereditary cancer predisposition, ONCOIMMUNOLOGY, Vol: 5, ISSN: 2162-402X
Fauzi I, Panoskaltsis N, Mantalaris A, 2016, In Vitro Differentiation of Embryonic Stem Cells into Hematopoietic Lineage: Towards Erythroid Progenitor's Production., Methods Mol Biol, Vol: 1341, Pages: 217-234
Embryonic stem cells (ESCs) differentiation via embryoid body (EB) formation is an established method that generates the three germ layers. However, EB differentiation poses several problems including formation of heterogeneous cell populations. Herein, we described a differentiation protocol on enhancing mesoderm derivation from murine ESCs (mESCs) using conditioned medium (CM) from HepG2 cells. We used this technique to direct hematopoiesis by generating "embryoid-like" colonies (ELCs) from murine (m) ESCs without following standard formation of EBs. Our CM-mESCs group yielded an almost fivefold increase in ELC formation (p ≤ 0.05) and higher expression of mesoderm genes;-Brachyury-T, Goosecoid, and Flk-1 compared with control mESCs group. Hematopoietic colony formation from CM-mESCs was also enhanced by twofold at days 7 and 14 with earlier colony commitment compared to control mESCs (p ≤ 0.05). This early clonogenic capacity was confirmed morphologically by the presence of nucleated erythrocytes and macrophages as early as day 7 in culture using standard 14-day colony-forming assay. Early expression of hematopoietic primitive (ζ-globin) and definitive (β-globin) erythroid genes and proteins was also observed by day 7 in the CM-treated culture. These data indicate that hematopoietic cells more quickly differentiate from CM-treated, compared with those using standard EB approaches, and provide an efficient bioprocess platform for erythroid-specific differentiation of ESCs.
Kostoglou M, Fuentes-Gari M, Garcia-Munzer D, et al., 2016, A comprehensive mathematical analysis of a novel multistage population balance model for cell proliferation, COMPUTERS & CHEMICAL ENGINEERING, Vol: 91, Pages: 157-166, ISSN: 0098-1354
Savvopoulos S, Misener R, Panoskaltsis N, et al., 2016, A Personalized Framework for Dynamic Modeling of Disease Trajectories in Chronic Lymphocytic Leukemia, IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, Vol: 63, Pages: 2396-2404, ISSN: 0018-9294
dos Santos SB, Allenby MC, Mantalaris A, et al., 2016, Early Erythroid Development Is Enhanced with Hypoxia and Terminal Maturation with Normoxia in a 3D Ex Vivo Physiologic Eythropoiesis Model, 58th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Allenby MC, Tahlawi A, Dos Santos SB, et al., 2015, Development of a Hematopoietic Microenvironment for the Production of Red Blood Cells (RBCs) in a Novel 3D Hollow Fibre Bioreactor, TISSUE ENGINEERING PART A, Vol: 21, Pages: S15-S16, ISSN: 1937-3341
Allenby MC, Tahlawi A, dos Santos SB, et al., 2015, DEVELOPMENT OF AN EX VIVO BONE MARROW MIMICRY MICROENVIRONMENT IN A NOVEL 3D HOLLOW FIBRE BIOREACTOR, 44th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH), Publisher: ELSEVIER SCIENCE INC, Pages: S51-S51, ISSN: 0301-472X
Burnett AK, Russell N, Hills RK, et al., 2015, A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia., Leukemia, Vol: 29, Pages: 1312-1319
The development of new treatments for older patients with acute myeloid leukaemia (AML) is an active area, but has met with limited success. Sapacitabine is a novel orally administered nucleoside analogue that has shown encouraging activity in unrandomised early-stage trials. We randomised 143 untreated patients with AML or with high-risk myelodysplastic syndrome (>10% marrow blasts) between sapacitibine and low-dose ara-C (LDAC) in our 'Pick a Winner' trial design. At the planned interim analysis there was no difference between LDAC and sapacitibine in terms of remission rate (CR/CRi, 27% vs 16% hazard ratio (HR) 1.98(0.90-4.39) P=0.09), relapse-free survival (10% vs 14% at 2 years, HR 0.73(0.33-1.61) P=0.4) or overall survival (OS; 12% vs 11% at 2 years, HR 1.24(0.86-1.78) P=0.2). Sapacitibine was well tolerated, apart from more grade 3/4 diarrhoea. On the basis of these findings sapacitibine did not show sufficient evidence of benefit over LDAC for the trial to be continued.
Dennis M, Russell N, Hills RK, et al., 2015, Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia, BLOOD, Vol: 125, Pages: 2923-2932, ISSN: 0006-4971
Fuentes-Gari M, Misener R, Garcia-Munzer D, et al., 2015, A mathematical model of subpopulation kinetics for the deconvolution of leukaemia heterogeneity, JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 12, ISSN: 1742-5689
Fuentes-Gari M, Misener R, Georgiadis MC, et al., 2015, Selecting a Differential Equation Cell Cycle Model for Simulating Leukemia Treatment, INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, Vol: 54, Pages: 8847-8859, ISSN: 0888-5885
Fuentes-Gari M, Misener R, Pefani E, et al., 2015, Cell cycle model selection for leukemia and its impact in chemotherapy outcomes, 12TH INTERNATIONAL SYMPOSIUM ON PROCESS SYSTEMS ENGINEERING AND 25TH EUROPEAN SYMPOSIUM ON COMPUTER AIDED PROCESS ENGINEERING, PT C, Vol: 37, Pages: 2159-2164, ISSN: 1570-7946
Fuentes-Gari M, Velliou E, Misener R, et al., 2015, A systematic framework for the design, simulation and optimization of personalized healthcare: Making and healing blood, COMPUTERS & CHEMICAL ENGINEERING, Vol: 81, Pages: 80-93, ISSN: 0098-1354
Fuentes-Gari M, Zemenides S, Misener R, et al., 2015, Use of Mathematical Modelling Indicates That Patients Treated for Acute Myeloid Leukaemia (AML) Are Undertreated When Ideal Body Weight Is Used to Dose Chemotherapy, 57th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Fuentes-Gaŕ M, Misener R, Georgiadis MC, et al., 2015, Chemotherapy optimization in Leukemia: Selecting the right mathematical models for the right biological processes, Pages: 534-539, ISSN: 1474-6670
© 2015, IFAC (International Federation of Automatic Control) Hosting by Elsevier Ltd. All rights reserved. Clinical chemotherapy dosage strategies for leukemia rely on weight/height calculations theoretically correlated to patient drug tolerance. However, over-and under-dosage still exist in clinical practice, which could be overcome by quantifying the actual fraction of cancer cells susceptible to be eradicated. In this work, we show how choosing models that are accurate enough in simulating the biological processes ultimately affecting drug efficacy is critical in order to disentangle patient to patient heterogeneity. Incorporating heterogeneity from measurable sources in such a manner brings us a step closer in our path towards the development of personalized rational therapies.
Kostoglou M, Fuentes-Gari M, Garcia-Muenzer D, et al., 2015, Mathematical analysis of multistage population balances for cell growth and death, 12TH INTERNATIONAL SYMPOSIUM ON PROCESS SYSTEMS ENGINEERING AND 25TH EUROPEAN SYMPOSIUM ON COMPUTER AIDED PROCESS ENGINEERING, PT C, Vol: 37, Pages: 2105-2110, ISSN: 1570-7946
Savvopoulos S, Misener R, Panoskaltsis N, et al., 2015, Global Sensitivity Analysis for a Model of B-Cell Chronic Lymphocytic Leukemia Disease Trajectories, 12TH INTERNATIONAL SYMPOSIUM ON PROCESS SYSTEMS ENGINEERING (PSE) AND 25TH EUROPEAN SYMPOSIUM ON COMPUTER AIDED PROCESS ENGINEERING (ESCAPE), PT A, Vol: 37, Pages: 185-190, ISSN: 1570-7946
Velliou EG, Dos Santos SB, Papathanasiou MM, et al., 2015, Towards unravelling the kinetics of an acute myeloid leukaemia model system under oxidative and starvation stress: a comparison between two- and three-dimensional cultures, BIOPROCESS AND BIOSYSTEMS ENGINEERING, Vol: 38, Pages: 1589-1600, ISSN: 1615-7591
dos Santos SB, Allenby M, Mantalaris A, et al., 2015, Effect of Oxygen and 3D Microenvironment on Physiologic Erythropoiesis, 57th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
dos Santos SB, Allenby MC, Panoskaltsis N, et al., 2015, In Vitro Physiologic Erythropoiesis in a 3D Bone Marrow Biomimicry, 4th TERMIS World Congress, Publisher: MARY ANN LIEBERT, INC, Pages: S228-S228, ISSN: 1937-3341
Fauzi I, Panoskaltsis N, Mantalaris A, 2014, Early Exposure of Murine Embryonic Stem Cells to Hematopoietic Cytokines Differentially Directs Definitive Erythropoiesis and Cardiomyogenesis in Alginate Hydrogel Three-Dimensional Cultures, STEM CELLS AND DEVELOPMENT, Vol: 23, Pages: 2720-2729, ISSN: 1547-3287
Fuentes-Gari M, Misener R, Garcia-Munzer D, et al., 2014, Development and experimental validation of a cyclin-based population balance model of the cell cycle in leukemia cell lines, JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Vol: 8, Pages: 489-489, ISSN: 1932-6254
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