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Article ; Online: A mixture-like model for tumor-immune system interactions.

Fotso, Christian Tayou / Girel, Simon / Anjuère, Fabienne / Braud, Véronique M / Hubert, Florence / Goudon, Thierry

2024 Volume 581, Page(s) 111738

Abstract: We introduce a mathematical model based on mixture theory intended to describe the tumor-immune system interactions within the tumor microenvironment. The equations account for the geometry of the tumor expansion, and the displacement of the immune cells, ...

Abstract	We introduce a mathematical model based on mixture theory intended to describe the tumor-immune system interactions within the tumor microenvironment. The equations account for the geometry of the tumor expansion, and the displacement of the immune cells, driven by diffusion and chemotactic mechanisms. They also take into account the constraints in terms of nutrient and oxygen supply. The numerical investigations analyze the impact of the different modeling assumptions and parameters. Depending on the parameters, the model can reproduce elimination, equilibrium or escape phases and it identifies a critical role of oxygen/nutrient supply in shaping the tumor growth. In addition, antitumor immune cells are key factors in controlling tumor growth, maintaining an equilibrium while protumor cells favor escape and tumor expansion.
MeSH term(s)	Humans ; Neoplasms/pathology ; Immune System ; Mathematics ; Oxygen ; Tumor Microenvironment
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2024-01-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2972-5
ISSN	1095-8541 ; 0022-5193
ISSN (online)	1095-8541
ISSN	0022-5193
DOI	10.1016/j.jtbi.2024.111738
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Article ; Online: Tumorigenesis and axons regulation for the pancreatic cancer: A mathematical approach.

Chauvet, Sophie / Hubert, Florence / Mann, Fanny / Mezache, Mathieu

Journal of theoretical biology

2022 Volume 556, Page(s) 111301

Abstract: The nervous system is today recognized to play an important role in the development of cancer. Indeed, neurons extend long processes (axons) that grow and infiltrate tumors in order to regulate the progression of the disease in a positive or negative way, ...

Abstract	The nervous system is today recognized to play an important role in the development of cancer. Indeed, neurons extend long processes (axons) that grow and infiltrate tumors in order to regulate the progression of the disease in a positive or negative way, depending on the type of neuron considered. Mathematical modeling of this biological process allows to formalize the nerve-tumor interactions and to test hypotheses in silico to better understand this phenomenon. In this work, we introduce a system of differential equations modeling the progression of pancreatic ductal adenocarcinoma (PDAC) coupled with associated changes in axonal innervation. The study of the asymptotic behavior of the model confirms the experimental observations that PDAC development is correlated with the type and densities of axons in the tissue. We study then the identifiability and the sensitivity of the model parameters. The identifiability analysis informs on the adequacy between the parameters of the model and the experimental data and the sensitivity analysis on the most contributing factors on the development of cancer. It leads to significant insights on the main neural checkpoints and mechanisms controlling the progression of pancreatic cancer. Finally, we give an example of a simulation of the effects of partial or complete denervation that sheds lights on complex correlation between the healthy, pre-cancerous and cancerous cell densities and axons with opposite functions.
MeSH term(s)	Humans ; Pancreatic Neoplasms/pathology ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/pathology ; Axons ; Cell Transformation, Neoplastic ; Carcinogenesis ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; Pancreatic Neoplasms
Language	English
Publishing date	2022-10-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2972-5
ISSN	1095-8541 ; 0022-5193
ISSN (online)	1095-8541
ISSN	0022-5193
DOI	10.1016/j.jtbi.2022.111301
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Book ; Online: Tumorigenesis and axons regulation for the pancreatic cancer

Chauvet, Sophie / Hubert, Florence / Mann, Fanny / Mezache, Mathieu

a mathematical approach

2022

Abstract	The nervous system is today recognized to play an important role in the development of cancer. Indeed, neurons extend long processes (axons) that grow and infiltrate tumors in order to regulate the progression of the disease in a positive or negative way, depending on the type of neuron considered. Mathematical modelling of this biological process allows to formalize the nerve-tumor interactions and to test hypotheses in silico to better understand this phenomenon. In this work, we introduce a system of differential equations modelling the progression of pancreatic ductal adenocarcinoma (PDAC) coupled with associated changes in axonal innervation. The study of the asymptotic behavior of the model confirms the experimental observations that PDAC development is correlated with the type and densities of axons in the tissue. In addition, we study the identifiability of the model parameters. This informs on the adequacy between the parameters of the model and the experimental data. It leads to significant insights such that the transdifferentiation phenomenon accelerates during the development process of PDAC cells. Finally, we give an example of a simulation of the effects of partial or complete denervation that sheds lights on complex correlation between the cell populations and axons with opposite functions.
Keywords	Mathematics - Dynamical Systems ; Statistics - Applications
Subject code	612
Publishing date	2022-05-24
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Growth-Fragmentation Approach for Modeling Microtubule Dynamic Instability.

Honoré, Stéphane / Hubert, Florence / Tournus, Magali / White, Diana

Bulletin of mathematical biology

2018 Volume 81, Issue 3, Page(s) 722–758

Abstract: Microtubules (MTs) are protein filaments found in all eukaryotic cells which are crucial for many cellular processes including cell movement, cell differentiation, and cell division. Due to their role in cell division, they are often used as targets for ... ...

Abstract	Microtubules (MTs) are protein filaments found in all eukaryotic cells which are crucial for many cellular processes including cell movement, cell differentiation, and cell division. Due to their role in cell division, they are often used as targets for chemotherapy drugs used in cancer treatment. Experimental studies of MT dynamics have played an important role in the development and administration of many novel cancer drugs; however, a complete description of MT dynamics is lacking. Here, we propose a new mathematical model for MT dynamics, that can be used to study the effects of chemotherapy drugs on MT dynamics. Our model consists of a growth-fragmentation equation describing the dynamics of a length distribution of MTs, coupled with two ODEs that describe the dynamics of free GTP- and GDP-tubulin concentrations (the individual dimers that comprise of MTs). Here, we prove the well-posedness of our system and perform a numerical exploration of the influence of certain model parameters on the systems dynamics. In particular, we focus on a qualitative description for how a certain class of destabilizing drugs, the vinca alkaloids, alter MT dynamics. Through variation of certain model parameters which we know are altered by these drugs, we make comparisons between simulation results and what is observed in in vitro studies.
MeSH term(s)	Animals ; Computer Simulation ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; Humans ; Mathematical Concepts ; Microtubule Proteins/chemistry ; Microtubule Proteins/metabolism ; Microtubules/drug effects ; Microtubules/metabolism ; Models, Biological ; Protein Stability/drug effects ; Tubulin/chemistry ; Tubulin/metabolism ; Tubulin Modulators/pharmacology ; Vinblastine/pharmacology
Chemical Substances	Microtubule Proteins ; Tubulin ; Tubulin Modulators ; Guanosine Diphosphate (146-91-8) ; Vinblastine (5V9KLZ54CY) ; Guanosine Triphosphate (86-01-1)
Language	English
Publishing date	2018-11-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	184905-0
ISSN	1522-9602 ; 0007-4985 ; 0092-8240
ISSN (online)	1522-9602
ISSN	0007-4985 ; 0092-8240
DOI	10.1007/s11538-018-0531-2
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Article ; Online: Exploring the effect of end-binding proteins and microtubule targeting chemotherapy drugs on microtubule dynamic instability.

White, Diana / Honoré, Stéphane / Hubert, Florence

Journal of theoretical biology

2017 Volume 429, Page(s) 18–34

Abstract: Microtubules (MTs) play a key role in normal cell development and are a primary target for many cancer chemotherapy MT targeting agents (MTAs). As such, understanding MT dynamics in the presence of such agents, as well as other proteins that alter MT ... ...

Abstract	Microtubules (MTs) play a key role in normal cell development and are a primary target for many cancer chemotherapy MT targeting agents (MTAs). As such, understanding MT dynamics in the presence of such agents, as well as other proteins that alter MT dynamics, is extremely important. In general, MTs grow relatively slowly and shorten very fast (almost instantaneously), an event referred to as a catastrophe. These dynamics, referred to as dynamic instability, have been studied in both experimental and theoretical settings. In the presence of MTAs, it is well known that such agents work by suppressing MT dynamics, either by promoting MT polymerization or promoting MT depolymerization. However, recent in vitro experiments show that in the presence of end-binding proteins (EBs), low doses of MTAs can increase MT dynamic instability, rather than suppress it. Here, we develop a novel mathematical model, to describe MT and EB dynamics, something which has not been done in a theoretical setting. Our MT model is based on previous modeling efforts, and consists of a pair of partial differential equations to describe length distributions for growing and shortening MT populations, and an ordinary differential equation (ODE) system to describe the time evolution for concentrations of GTP- and GDP-bound tubulin. A new extension of our approach is the use of an integral term, rather than an advection term, to describe very fast MT shortening events. Further, we introduce an ODE system to describe the binding and unbinding of EBs with MTs. To compare simulation results with experiment, we define novel mathematical expressions for time- and distance-based catastrophe frequencies. These quantities help to define MT dynamics in in vivo and in vitro settings. Simulation results show that increasing concentrations of EBs work to increase time-based catastrophe while distance-based catastrophe is less affected by changes in EB concentration, a result that is consistent with experiment. We further describe how EBs and MTAs alter MT dynamics. In the context of this modeling framework, we show that it is likely that MTAs and EBs do not work independently from one another. Thus, we propose a mechanism for how EBs can work synergistically with MTAs to promote MT dynamic instability at low MTA dose.
MeSH term(s)	Animals ; Carrier Proteins/pharmacology ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Microtubule-Associated Proteins ; Microtubules/chemistry ; Microtubules/drug effects ; Models, Biological ; Models, Theoretical ; Polymerization/drug effects ; Protein Stability/drug effects
Chemical Substances	Carrier Proteins ; Microtubule-Associated Proteins
Language	English
Publishing date	2017-06-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2972-5
ISSN	1095-8541 ; 0022-5193
ISSN (online)	1095-8541
ISSN	0022-5193
DOI	10.1016/j.jtbi.2017.06.014
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Book ; Online: Fiscal incentives, European integration and the location of foreign direct investment

Hubert, Florence / Pain, Nigel

(Discussion paper / National Institute of Economic and Social Research ; 195)

2002

Institution	National Institute of Economic and Social Research
Author's details	Florence Hubert
Series title	Discussion paper / National Institute of Economic and Social Research ; 195
Keywords	Auslandsinvestition ; Deutsch ; Investitionspolitik ; Betrieblicher Standort ; EU-Staaten
Language	English
Size	Online-Ressource, 33 p., text
Edition	[Elektronische Ressource]
Publisher	National Inst. of Economic and Social Research
Publishing place	London
Document type	Book ; Online
Note	IMD-Felder maschinell generiert
Database	ECONomics Information System

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Book ; Online: Fiscal incentives, European integration and the location of foreign direct investment

Hubert, Florence / Pain, Nigel

(Research paper / Leverhulme Centre for Research on Globalisation and Economic Policy ; 2001,34 : Internationalisation of economic policy programme)

2001

Author's details	by F. Hubert
Series title	Research paper / Leverhulme Centre for Research on Globalisation and Economic Policy ; 2001,34 : Internationalisation of economic policy programme
Keywords	Auslandsinvestition ; Deutsch ; Investitionspolitik ; Betrieblicher Standort ; EU-Staaten
Language	English
Size	Online-Ressource, [40] p., text
Edition	[Elektronische Ressource]
Publisher	Leverhulme Centre for Research on Globalisation and Economic Policy
Publishing place	Nottingham
Document type	Book ; Online
Note	IMD-Felder maschinell generiert
Database	ECONomics Information System

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Article ; Online: Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer.

Nature communications

2022 Volume 13, Issue 1, Page(s) 1985

Abstract: Neuronal nerve processes in the tumor microenvironment were highlighted recently. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via conventional histological ... ...

Abstract	Neuronal nerve processes in the tumor microenvironment were highlighted recently. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via conventional histological preparations. Here, we employ three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in a murine model of pancreatic ductal adenocarcinoma (PDAC). Our results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing sympathetic nerves within tumors plus an active, localized sprouting of axon terminals into non-neoplastic lesions and tumor periphery. Ablation of the innervating sympathetic nerves increases tumor growth and spread. This effect is explained by the observation that sympathectomy increases intratumoral CD163
MeSH term(s)	Animals ; Carcinoma, Pancreatic Ductal ; Macrophages ; Mice ; Pancreatic Neoplasms ; Sympathetic Nervous System/physiology ; Tumor Microenvironment ; Pancreatic Neoplasms
Language	English
Publishing date	2022-04-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-29659-w
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Article ; Online: Study of metastatic kinetics in metastatic melanoma treated with B-RAF inhibitors: Introducing mathematical modelling of kinetics into the therapeutic decision.

Hartung, Niklas / Huynh, Cécilia T-K / Gaudy-Marqueste, Caroline / Flavian, Antonin / Malissen, Nausicaa / Richard-Lallemand, Marie-Aleth / Hubert, Florence / Grob, Jean-Jacques

PloS one

2017 Volume 12, Issue 5, Page(s) e0176080

Abstract: Background: Evolution of metastatic melanoma (MM) under B-RAF inhibitors (BRAFi) is unpredictable, but anticipation is crucial for therapeutic decision. Kinetics changes in metastatic growth are driven by molecular and immune events, and thus we ... ...

Abstract	Background: Evolution of metastatic melanoma (MM) under B-RAF inhibitors (BRAFi) is unpredictable, but anticipation is crucial for therapeutic decision. Kinetics changes in metastatic growth are driven by molecular and immune events, and thus we hypothesized that they convey relevant information for decision making. Patients and methods: We used a retrospective cohort of 37 MM patients treated by BRAFi only with at least 2 close CT-scans available before BRAFi, as a model to study kinetics of metastatic growth before, under and after BRAFi. All metastases (mets) were individually measured at each CT-scan. From these measurements, different measures of growth kinetics of each met and total tumor volume were computed at different time points. A historical cohort permitted to build a reference model for the expected spontaneous disease kinetics without BRAFi. All variables were included in Cox and multistate regression models for survival, to select best candidates for predicting overall survival. Results: Before starting BRAFi, fast kinetics and moreover a wide range of kinetics (fast and slow growing mets in a same patient) were pejorative markers. At the first assessment after BRAFi introduction, high heterogeneity of kinetics predicted short survival, and added independent information over RECIST progression in multivariate analysis. Metastatic growth rates after BRAFi discontinuation was usually not faster than before BRAFi introduction, but they were often more heterogeneous than before. Conclusions: Monitoring kinetics of different mets before and under BRAFi by repeated CT-scan provides information for predictive mathematical modelling. Disease kinetics deserves more interest.
MeSH term(s)	Aged ; Antineoplastic Agents/therapeutic use ; Female ; Humans ; Male ; Melanoma/drug therapy ; Melanoma/pathology ; Middle Aged ; Neoplasm Metastasis ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Retrospective Studies
Chemical Substances	Antineoplastic Agents ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
Language	English
Publishing date	2017-05-04
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0176080
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book ; Online: Inward investment and technical progress in the United Kingdom manufacturing sector

Hubert, Florence / Pain, Nigel

(Discussion paper / National Institute of Economic and Social Research ; 175)

2000

Institution	National Institute of Economic and Social Research
Author's details	Florence Hubert and Nigel Pain
Series title	Discussion paper / National Institute of Economic and Social Research ; 175
Keywords	Auslandsinvestition ; Multinationales Unternehmen ; Technischer Fortschritt ; Arbeitsproduktivität ; Großbritannien
Language	English
Size	Online-Ressource, 25 p., text, ill
Edition	[Elektronische Ressource]
Publisher	National Inst. of Economic and Social Research
Publishing place	London
Document type	Book ; Online
Note	IMD-Felder maschinell generiert
Database	ECONomics Information System

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