HAL Université de Tours
Not a member yet
55851 research outputs found
Sort by
Anti-cathepsin D antibody-drug conjugates for the targeted delivery of monomethyl auristatin F and E elicit potent anticancer activity in breast cancer
No full textInternational audienceBreast cancer (BC) is the leading cause of cancer deaths in women. Patients with estrogen receptor-positive (ER + ) and human epidermal growth factor receptor 2-negative or low (HER2 -; HER2 low ) BC exhibit a late recurrence pattern and resistance to endocrine therapy. Antibody-drug conjugates (ADCs) are new anticancer agents that currently show a remarkable acceleration in preclinical and clinical development. The aspartic protease cathepsin D (cath-D), a poor prognosis marker in BC, is a tumor cell-associated protein with pro-tumor activity that is highly and specifically secreted by BC cells. We recently showed using the human anti-cath-D antibody F1M1 that cath-D is a potent target for antibody-based therapy in BC. Here, we asked whether cath-D is a suitable target for ADC-based therapy in non-amplified ER + /HER2 low BC. To this aim, we bioconjugated F1M1 to the cytotoxic payload monomethyl auristatin F (MMAF) via a non-cleavable linker (for the release of a non-cell permeable MMAF metabolite) and to its cell permeable derivative monomethyl auristatin E (MMAE) via a protease-sensitive cleavable linker, to form the ADCs F1M1-MMAF and F1M1-MMAE respectively, with a drugto-antibody ratio close to four. These F1M1-based ADCs were specifically internalized and showed cytotoxic activity in the nanomolar range in the ER + /HER2 low MCF-7 and endocrine therapy-resistant ER + /HER2 low MCF-7/LCC2 BC cell lines. In vivo, three injections of F1M1-based ADCs led to long-lasting tumor growth inhibition in mice harboring MCF-7/LCC2 cell xenografts. In conclusion, we showed for the first time that cath-D is a potent target for ADC in BC
Operating financial sustainability in the German car industry: a new approach
No full textInternational audienc
Revisiting 15 years of unusual transatlantic monetary policies
No full textInternational audienceThe European Central Bank and the Federal Reserve introduced new policy instruments and made changes to their operational frameworks to address the global financial crisis (2008) and the Covid-19 pandemic (2020). We study the macroeconomic effects of these monetary policy evolutions on both sides of the Atlantic Ocean by developing and estimating a tractable two-country dynamic stochastic general equilibrium model. We show that the euro area and the United States faced shocks of different natures, explaining some asynchronous monetary policy measures between 2008 and 2023. However, counterfactual exercises highlight that all conventional and unconventional policies implemented since 2008 have appropriately (i) supported economic growth and (ii) maintained inflation on track in both areas. The exception is the delayed reaction to the inflationary surge during 2021–2022. Furthermore, exchange rate shocks played a significant role in shaping the overall monetary conditions of the two economies
Auditory Change Detection in autism during aging: An ERP Study
No full textInternational audienceAutistic individuals are often thought to exhibit reduced tolerance for change, which may stem from atypicalities in sensory processing, particularly in the detection of environmental changes. Within the predictive coding framework, this intolerance may reflect altered generation and updating internal predictions in response to sensory input, leading to increased prediction errors. Mismatch Negativity and the P3a component, event-related potential markers of automatic auditory change detection and involuntary attention shifts, index these processes. While studied in autistic children and young adults, little is known about how these components evolve during aging, an important gap as 21 million autistic adults over 60 are expected by 2050. This study examined mismatch negativity and P3a responses in 43 autistic adults (aged 21–64) and 60 non-autistic adults (aged 20–69) using a passive auditory oddball paradigm with standard (1000 Hz) and deviant (1100 Hz; p = 0.15) tones. Electroencephalography recording revealed no significant differences between autistic and non-autistic individuals on mismatch negativity and P3a amplitude or latency. However, mismatch negativity amplitude decreased with age over frontal site, similarly across both groups. No age-related effects were found for mismatch negativity latency or P3a measures in either group. These findings suggest that, from adulthood onward, the neural mechanisms underlying automatic change detection and pre-attentional processes are similar in both autistic and non-autistic adults, and that their overall time course of aging appears comparable, supporting the parallel aging hypothesis. Nonetheless, future research should explore how these preserved neural responses relate to behavioral reactivity to change in autism
Central SELENOT deficiency impairs gonadotrope axis function, sexual behavior and fertility in male and female mice
No full textInternational audienceReproductive disorders can result from a defective action of the neuropeptide gonadotropin-releasing hormone (GnRH), the master regulator of reproduction. We have previously shown that SELENOT, a newly-described thioredoxin-like selenoprotein highly expressed in endocrine and neuroendocrine cells, plays a role in hormone secretion and neuroprotection. However, whether SELENOT is involved in neuro-endocrine regulations in vivo is totally unknown. We found that SELENOT deficiency in the brain impaired sexual behavior, leading to a decline in fertility in both male and female mice. Biochemical and histological analyses of the gonadotrope axis of these mice revealed a higher expression of GnRH, which is associated with circulating luteinizing hormone (LH) excess, and elevated steroid hormones in males and a polycystic ovary syndrome (PCOS)-like phenotype in females. In addition, SELENOT deficiency impaired LH pulse secretion in both male and female mice. These alterations are reverted after administration of a GnRH antagonist. Together, our data demonstrate for the first time the role of a selenoprotein in the central control of sexual behavior and reproduction, and identify a new redox effector of GnRH neuron activity impacting both male and female reproductive function
Understanding the Equity-Corporate Bond Nexus: A Framework for Risk Decomposition and Interest Rate Hedging
No full textInternational audienceThis study explores the complex dynamics between equity and corporate bond markets, focusing on their correlation’s decomposition into credit risk and interest rate sensitivity components. By utilizing equity-credit default swap and equity-sovereign bond correlations, this research identifies macroeconomic factors—such as growth and inflation uncertainties—that influence these interactions across different credit qualities and market regimes. Empirical findings reveal significant variations in the equity-corporate bond correlation during periods of market stress and rising interest rates. Additionally, we propose two novel dynamic hedging strategies, leveraging adaptive hedge ratios to isolate credit risk while mitigating interest rate exposure. The results demonstrate that these strategies outperform traditional approaches, offering robust tools for portfolio management amidst fluctuating economic conditions
HBK-15 bypasses BDNF via ERK1/2-biased 5-HT1A receptor signaling to deliver a rapid antidepressant-like effect
No full textAbstract Rapid-onset antidepressants hold transformative potential for treating affective and cognitive symptoms of depression, yet their mechanisms remain incompletely understood. Serotonin receptors orchestrate emotional and cognitive regulation, but current treatments poorly target their intracellular signaling. Here, we characterize HBK-15, a multi-target aminergic ligand, as a functionally selective compound that biases intracellular signaling at 5-HT 1A and 5-HT 7 receptors. HBK-15 acts as a partial agonist at the ERK1/2 arm of the 5-HT 1A receptor while blocking β-arrestin recruitment, cAMP inhibition, and calcium mobilization; at 5-HT 7 receptors, it preserves cAMP signaling but blocks β-arrestin recruitment. A single dose of HBK-15 reversed depressive- and cognitive-like deficits in two mouse strains subjected to chronic stress, engaging ERK1/2-linked kinases and plasticity-related signaling in the prefrontal cortex. Pharmacological blockade experiments showed that ERK1/2, but not PKA, signaling in the medial prefrontal cortex is required for HBK-15’s behavioral effects. Notably, HBK-15 retained antidepressant-like efficacy in mice carrying the human BDNF Val66Met polymorphism, a translational model characterized by impaired activity-dependent BDNF release, increased depression vulnerability, and reduced treatment responsiveness. The absence of cognitive rescue in this context uncovers a layered mechanism: ERK1/2 signaling is required for both behavioral domains, but BDNF-dependent pathways appear critical for cognitive restoration. These findings position HBK-15 as a mechanistically distinct compound with rapid behavioral efficacy, offering a prototype for signaling-driven strategies in next-generation antidepressant development
Use of brief, simple anxiety assessment tools in palliative care – yes, we can: a cross-sectional observational study of anxiety visual analog scale and numeric rating scale
No full textInternational audienceBackground: Given the high prevalence of anxiety in palliative care and its frequent underestimation by healthcare professionals, it is important to use simplified tools to facilitate the evaluation of anxiety. The State-Trait Anxiety Inventory-State scale is a reference 20-item questionnaire that has been validated in this population, but is too long for some patients. The visual analog scale (VAS) and the numeric rating scale (NRS) are two short instruments that have been validated to assess pain, but not anxiety in palliative care.Aim: This study sought to investigate the correlation between anxiety VAS and NRS and State-Trait Anxiety Inventory-State scale for assessing anxiety in palliative care patients.Methods: A single-center cross-sectional observational study was conducted over 2 years. All palliative care patients followed by the palliative care team of a French university hospital were eligible. Each patient completed the State-Trait Anxiety Inventory-State scale and rated their perceived anxiety using the NRS and VAS. Pearson's correlation test between the scales and receiver operating characteristic (ROC) curve analysis were performed to determine diagnostic cut-offs.Results: A total of 186 patients were included (89.8% with cancer), 20.4% of whom had severe or very severe anxiety. The NRS/ State-Trait Anxiety Inventory-State scale and VAS/ State-Trait Anxiety Inventory-State scale correlations were 0.62 and 0.70, respectively. The NRS and VAS showed good discrimination, with an area under the ROC curve of 0.81 and 0.88, respectively. Cut-offs of 5 (NRS) and 49 millimeters (VAS) yielded sensitivities of 89.5% and 89.2%, respectively, for the detection of severe or very severe anxiety, with specificities of 60.1% and 70.3%, respectively.Conclusion: Cut-offs of 5 for the NRS and 49 millimeters for the VAS showed excellent sensitivity for detecting anxiety in palliative care
Factors for adherence to a physical activity promotion program in the workplace: a systematic review
No full textInternational audienceIntroduction: The health benefits of physical activity (PA) are now widely accepted and proven. Promoting PA in the workplace is therefore of major public health interest, but is limited by employees' adherence.Method: A systematic review was therefore carried out to identify factors for adherence to PA promotion program in the workplace (primary outcome); health outcomes were to be regarded as secondary outcomes. Four databases, PubMed, Web of Science, Cochrane Central Register of Controlled Trials (Cochrane CRCTs) and PsycInfo were searched to find all pertinent articles published from 2000 until June 2024. Only randomized controlled trials (RCTs) and clinical trials were selected.Results: More than 9000 publications were analyzed and 91 were retrieved. Two main types of study were identified: 46 non-supervised PA programs (NSPAPs) supported by socio-cognitive theories, and 45 supervised (tailored) programs (SPAPs). Concerning the primary outcome, the main factors identified for adherence were the levels of baseline PA, health and motivation of the individual; intervention individualization at the interventional level; and work environment quality at the organizational level. This review highlighted significant health benefits in both types of study, with effect sizes ranging from small to large.Discussion: Assessing these factors for adherence emerges as an essential prerequisite before implementing a PA promotion program in the workplace. According to our results, implementing NSPAPs, supported by socio-cognitive theories, is rather complex, and such programs can be difficult to operationalize in their entirety; consequently, coach-supervised PAPs based on RCT programs tend to be more effective.Conclusion: Our results prove the short and medium-term beneficial effect on health of PAP in the workplace based on rigorous methodology such as RCTs. Management's support through work organization and the follow-up of actions in the long term are an essential factor for adherence to these programs. Finally, we suggest what this literature review contributes for future research or entrepreneurial and/or political projects. In fine, new models of working time will have to be considered