Publications

2022

Sex and Circadian Timing Modulate Oxaliplatin Hematological and Hematopoietic Toxicities

Dulong, Sandrine, Souza, Lucas, Machowiak, Jean, Peuteman, Benoit, Duvallet, Gaelle, Boyenval, Déborah, Roth, Elise, Asgarova, Afag, Chang, Yunhua, Li, Xiao-Mei, Foudi, Adlen, and Ballesta, Annabelle

Pharmaceutics, vol. 14, pp. 2465, Nov, 2022

[Abs] [PDF] [DOI]

Oxaliplatin was nearly twice as hematotoxic, with optimal circadian timing differing by 6 h, in women as compared to men with colorectal cancers. Hence, we investigated sex- and timing related determinants of oxaliplatin hematopoietic toxicities in mice. Body weight loss (BWL), blood cell counts, bone marrow cellularity (BMC) and seven flow-cytometry-monitored hematopoietic progenitor populations were evaluated 72 h after oxaliplatin chronotherapy administration (5 mg/kg). In control animals, circadian rhythms of circulating white blood cells showed a peak at ZT5 in both sexes, whereas BMC was maximum at ZT20 in males and ZT13h40 in females. All BM progenitor counts presented robust rhythms with phases around ZT3h30 in females, whereas only three of them rhythmically cycled in males with a ≈ −6 h phase shift. In treated females, chronotoxicity rhythms occurred in BWL, WBC, BMC and all BM progenitors with the best timing at ZT15, ZT21, ZT15h15 and ZT14h45, respectively. In males, almost no endpoints showed circadian rhythms, BWL and WBC toxicity being minimal, albeit with a substantial drop in BM progenitors. Increasing dose (10 mg/kg) in males induced circadian rhythms in BWL and WBC but not in BM endpoints. Our results suggest complex and sex-specific clock-controlled regulation of the hematopoietic system and its response to oxaliplatin.
Formal modelling of cyclic biological behaviours with checkpoints: the cell cycle regulation (in French)

Boyenval, Déborah

PhD thesis, Université Côte d’Azur (Computer Science), Dec, 2022

[Abs] [Bib] [PDF] [Slides]

The cell cycle is a series of events by which a cell reproduces itself while maintaining the integrity of its genome. This property is ensured by a set of regulatory mechanisms called checkpoints. Their ability to stop the cell cycle in response to DNA damage has motivated numerous studies in the field of biomedicine. This thesis argues that the phenomenon of cell cycle arrest, which is observed in the context of perturbation, is a consequence of more fundamental properties such as the temporal separation of phases and the irreversibility of phase transitions. In this context, a phase describes a particular aspect of a proliferating cell, for example the phase of genome replication (S-phase) or that of cell division (M-phase). The fundamental properties of checkpoints have never been formalized, mainly due to the fact that phase modelling itself has never been tackled before. The thesis presents a discrete model of the regulation of the cell cycle and proposes a methodology for formalizing a phase. The latter is firstly characterized by a finite multi-set of discrete events which occur from an initial state. By opting for René Thomas’ modelling framework, the genetically modified Hoare logic can be applied to compute the set of sequences of events, exhibited by the initial multiset, that are consistent with a certain set of parameterizations of a regulation graph. The set of event sequences that characterizes a phase temporally insulates it from the others if there is a parameterization such that any event that can complete a phase is required before any event that can trigger the next phase. This problem has been specified using a Prolog predicate. The irreversibility property of phase transitions is formalized using a temporal logic and model-checking identifies the parameterizations of a cell cycle model that satisfy this property. We show that this method for formalizing and verifying the fundamental properties of checkpoints allows us to target the inconsistencies of a regulatory graph while getting rid of certain arbitrary choices found in most cell cycle modeling studies.
```
@phdthesis{myphe,
  author = {Boyenval, Déborah},
  title = {Formal modelling of cyclic biological behaviours with checkpoints: the cell cycle regulation (in French)},
  school = {Université Côte d'Azur (Computer Science)},
  month = dec,
  year = {2022},
}
```

2020

What is a cell cycle checkpoint? The ToTemBioNet answer

Boyenval, Déborah, Bernot, Gilles, Collavizza, Hélène, and Comet, Jean-Paul

18th International Conference on Computational Methods in Systems Biology (CMSB 2020), Sep, 2020

[Abs] [Bib] [PDF] [Slides] [DOI]

TotemBioNet is a new software platform to assist the design of qualitative regulatory network models by combining “genetically modified Hoare logic”, temporal logic model checking and optimized enumeration techniques. TotemBioNet is particularly efficient to manage parameter identification, the most critical step of formal modelling. It is also remarkably flexible and efficient to check properties in order to explore biological assumptions. To illustrate this efficacy, we address the classical example of the cell cycle, where the passage from one phase to the next one, called checkpoint, is crucial but is usually a rather fuzzy informal concept. The cyclic behaviour of the cell cycle is specified by temporal logic and the order of individual events inside each phase is explored thanks to quantifiers introduced in Hoare logic. This way, TotemBioNet rapidly suggests a sensible formalization of checkpoints
```
@article{cmsb2020,
  author = {Boyenval, Déborah and Bernot, Gilles and Collavizza, Hélène and Comet, Jean-Paul},
  title = {What is a cell cycle checkpoint? The ToTemBioNet answer},
  journal = {18th International Conference on Computational Methods in Systems Biology (CMSB 2020)},
  month = sep,
  year = {2020},
  doi = {10.1007/978-3-030-60327-4_21},
}
```

2018

Mathematical modeling of sex-specific chronotoxicity of an anticancer drug: Irinotecan (in French)

Boyenval, Déborah

Dec, 2018

[Abs] [PDF]

The circadian system is a complex and highly integrated physiologic system that daily coordinates most of physiological and behavioural functions in mammals. This temporal organization results in variations in the toxicity of many anticancer drugs according to the time of administration. Irinotecan is a cytotoxic drugs commonly used to treat digestives cancers. Although it demonstrates a significant antitumor efficacy, it is often responsible for intestinal and hematologic toxicity, which can be life threatening. Preclinical and clinical results showed that irinotecan toxicities highly varies according to the time of drug administration. Indeed, cancer chronotherapy, that is administering anticancer drugs according to the patient’s biological rhythms over the 24h span can reduce by up to 5-fold the occurrence of severe toxicities in both colon and bone marrow with regards to irinotecan. Furthermore, recent findings indicate that irinotecan’s optimal timing critically depends on patient’s sex. Based on existing modelling works, a model of irinotecan chronopharmacokinetics-pharmacodynamics (chronoPK-PD) in male and female mice has been designed. Subsequently, parameters has been estimated for both male and female mice according to available in vitro and mouse experimental datasets. Using these sex-specific models, an in silico experiment was achieved and focused on modelling drug toxicities in the intestine and the bone marrow. In terms of global perspective, male and female chronotoxicities modelling in colon and bone marrow will be used at the aim of identifying circadian biomarkers which are the determinants of irinotecan tolerability circadian rhythms for both sexes. Next, the scaling of the mice chronoPK-PD model for humans will be initiated in view of set up personalized cancer chronotherapy firstly based on patient’s sex.