La prévisibilité en droit des contrats

La prévisibilité est une notion omniprésente en droit des contrats. La loi et la jurisprudence y font parfois référence de manière explicite (prévisibilité du dommage, imprévisibilité du cas de force majeure), mais elle est plus souvent mise en œuvre par le biais de mécanismes qui lui servent, en quelque sorte, de « prête-noms » (devoir de loyauté, principe de sécurité juridique, contrôle des clauses abusives, etc…). Pourtant, la nature même du mécanisme contractuel, que l’on définit souvent comme un acte de prévision, incline à penser que la prévisibilité a vocation à jouer un rôle bien plus important que celui qui lui est actuellement reconnu dans le droit positif. La réforme du droit des contrats par l’ordonnance n°2016-131 du 10 février 2016 a d’ailleurs fortement accentué ce rôle, en conférant à la notion une fonction réellement normative des comportements contractuels (introduction des actions interrogatoires, consécration d’un devoir général d’information, encadrement des négociations sous l’égide du principe de bonne foi, etc.). L’étude de ces diverses manifestations et de l’évolution d’ensemble du droit positif au cours des dernières décennies, sous l’influence du droit de l’Union européenne et des instruments d’harmonisation internationale du droit des contrats, conduit donc à s’interroger sur le caractère opportun d’une élévation de la notion au rang de principe directeur à part entière de la matière. Cela permettrait de proposer un nouvel équilibre entre les rôles respectifs du droit positif et de la convention dans le rapport au risque, et une responsabilisation accrue des contractants dans la gestion de celui-ci.Predictability is an omnipresent concept in contract law. Law and jurisprudence sometimes explicitly refer to it (foreseeability of damage, unpredictability of the case of force majeure), but it is more often implemented by mechanisms which are sorts of screens (Loyalty, Legal security, control of unfair terms, etc ...). However, Contract is often defined as an act of forecast. It suggests that predictability is in position to play a greater role than is currently recognized in positive law. The reform of Contract law by the ordinance n ° 2016-131 of February 10th, 2016 has accentuated this role: the notion henceforth really regulates contractual behaviors (interrogatory actions, consecration of a general duty of information, affirmation of the principle of good faith, etc.). The study of these various events and of the evolution of law in recent decades, under the influence of European Union law and instruments of international harmonization of contract law, is a good reason to think it would be expedient of elevating the notion to the rank of a real principle. This would provide a new balance between the respective roles of Law and Contract in confrontation to risk, and increased accountability of contractors in the management of this

A joint physics and radiobiology DREAM team vision - Towards better response prediction models to advance radiotherapy.

Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines

Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy

<p>Abstract</p> <p>Background</p> <p>Tumor hypoxia is marked by enhanced expression of hypoxia-inducible factor-α (HIF-1α) and glucose transporter-1 (Glut-1). Hypoxic conditions have also been associated with overexpression of angiogenic factors, such as leptin. The aim of our study was to analyze the relationships between hypoxia markers HIF-1α, Glut-1, leptin, leptin receptor (ObR) and other breast cancer biomarkers in primary and metastatic breast cancer in patients treated or untreated with preoperative chemotherapy.</p> <p>Methods</p> <p>The expression of different biomarkers was examined by immunohistochemistry in 116 primary breast cancers and 65 lymph node metastases. Forty five of these samples were obtained form patients who received preoperative chemotherapy and 71 from untreated patients.</p> <p>Results</p> <p>In primary tumors without preoperative chemotherapy, HIF-1α and Glut-1 were positively correlated (p = 0.02, r = 0.437). HIF-1α in primary and metastatic tumors without preoperative therapy positively correlated with leptin (p < 0.0001, r = 0.532; p = 0.013, r = 0.533, respectively) and ObR (p = 0.002, r = 0.319; p = 0.083, r = 0.387, respectively). Hypoxia markers HIF-1α and Glut-1 were negatively associated with estrogen receptor alpha (ERα) and positively correlated with estrogen receptor beta (ERβ). In this group of tumors, a positive correlation between Glut-1 and proliferation marker Ki-67 (p = 0.017, r = 0.433) was noted. The associations between HIF-1α and Glut-1, HIF-1α and leptin, HIF-1α and ERα as well as Glut-1 and ERβ were lost following preoperative chemotherapy.</p> <p>Conclusions</p> <p>Intratumoral hypoxia in breast cancer is marked by coordinated expression of such markers as HIF-1α, Glut-1, leptin and ObR. The relationships among these proteins can be altered by preoperative chemotherapy.</p

Prostate Cancer Cell Lines under Hypoxia Exhibit Greater Stem-Like Properties

Hypoxia is an important environmental change in many cancers. Hypoxic niches can be occupied by cancer stem/progenitor-like cells that are associated with tumor progression and resistance to radiotherapy and chemotherapy. However, it has not yet been fully elucidated how hypoxia influences the stem-like properties of prostate cancer cells. In this report, we investigated the effects of hypoxia on human prostate cancer cell lines, PC-3 and DU145. In comparison to normoxia (20% O2), 7% O2 induced higher expressions of HIF-1α and HIF-2α, which were associated with upregulation of Oct3/4 and Nanog; 1% O2 induced even greater levels of these factors. The upregulated NANOG mRNA expression in hypoxia was confirmed to be predominantly retrogene NANOGP8. Similar growth rates were observed for cells cultivated under hypoxic and normoxic conditions for 48 hours; however, the colony formation assay revealed that 48 hours of hypoxic pretreatment resulted in the formation of more colonies. Treatment with 1% O2 also extended the G0/G1 stage, resulting in more side population cells, and induced CD44 and ABCG2 expressions. Hypoxia also increased the number of cells positive for ABCG2 expression, which were predominantly found to be CD44bright cells. Correspondingly, the sorted CD44bright cells expressed higher levels of ABCG2, Oct3/4, and Nanog than CD44dim cells, and hypoxic pretreatment significantly increased the expressions of these factors. CD44bright cells under normoxia formed significantly more colonies and spheres compared with the CD44dim cells, and hypoxic pretreatment even increased this effect. Our data indicate that prostate cancer cells under hypoxia possess greater stem-like properties

A joint physics and radiobiology DREAM team vision - towards better response prediction models to advance radiotherapy

Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines. [Abstract copyright: Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

Exploiting the cancer niche: Tumor-associated macrophages and hypoxia as promising synergistic targets for nano-based therapy

The tumor microenvironment has been widely exploited as an active participant in tumor progression. Extensive reports have defined the dual role of tumor-associated macrophages (TAMs) in tumor development. The protumoral effect exerted by the M2 phenotype has been correlated with a negative outcome in most solid tumors. The high infiltration of immune cells in the hypoxic cores of advanced solid tumors leads to a chain reaction of stimuli that enhances the expression of protumoral genes, thrives tumor malignancy, and leads to the emergence of drug resistance. Many studies have shown therapeutic targeting systems, solely to TAMs or tumor hypoxia, however, novel therapeutics that target both features are still warranted. In the present review, we discuss the role of hypoxia in tumor development and the clinical outcome of hypoxia-targeted therapeutics, such as hypoxia-inducible factor (HIF-1) inhibitors and hypoxia-activated prodrugs. Furthermore, we review the state-of-the-art of macrophage-based cancer therapy. We thoroughly discuss the development of novel therapeutics that simultaneously target TAMs and tumor hypoxia. Nano-based systems have been highlighted as interesting strategies for dual modality treatments, with somewhat improved tissue extravasation. Such approach could be seen as a promising strategy to overcome drug resistance and enhance the efficacy of chemotherapy in advanced solid and metastatic tumors, especially when exploiting cell-based nanotherapies. Finally, we provide an in-depth opinion on the importance of exploiting the tumor microenvironment in cancer therapy, and how this could be translated to clinical practice

A promising hypoxia-inducible suicide gene therapy strategy for prostate cancer

THESIS 8342Gene therapy targeted to hypoxic tumour cells may allow selective killing of malignant cells. The induction of gene expression under hypoxic conditions is governed by the activation of hypoxia-inducible factor 1 and its subsequent binding to hypoxia response elements. The HREs of a number of oxygen- responsive genes, including vascular endothelial growth factor (VEGF) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were cloned upstream of the cytosine deaminase (CD) gene. These constructs will drive the expression of this prodrug activation enzyme, which converts inactive 5- fluorocytosine (5-FC) to active 5-fluorouracil (5-FU), allowing selective killing of vector containing cells. 5-FU is also a radiosensitising agent, so specific expression of this agent in prostate cancer cells can also potentiate radiotherapy approaches in prostate cancer