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International audience; Objective: To assess the impact of global physician empathy and its three subdimensions (establishing rapport, emotional and cognitive processes) on the severity of postoperative complications in a sample of cancer patients.Methods: We retrospectively analyzed data on 256 patients with esogastric cancer from the French national FREGAT database. Empathy and its subdimensions were assessed using the patient-reported CARE scale and the severity of medical and surgical complications was reported with the Clavien-Dindo classification system. The usual covariates were included in multinomial logistic regression analyses.Results: Physician empathy predicted the odds of reporting major complications. When patients perceived high empathy, they were less likely to report major complications compared to no complications (OR = .95, 95% CI = [.91-.99], p = .029). Among the three dimensions, only "establishing rapport" (OR = .84, 95% CI = [.73-.98], p = .019) and the "emotional process" (OR = .85, 95% CI = [.74-.98], p = .022) predicted major complications.Conclusions: Physician empathy is essential before surgery. Further research is needed to understand the mechanisms associating empathy with health outcomes in cancer. Physicians should be trained to establish good rapport with patients, especially in the preoperative period.

Additional file 2: Fig. S1. Hydrodynamic diameter (nm) of TiO2- and CB-NPs measured by DLS in DMEM/F12 at 37 °C. Diameter (nm) of aggregates of TiO2 and CB nanoparticles was measured by DLS following sonication of NPs, dilution in DMEM/F12, and centrifugation for 2 sec at 2000 g to remove large aggregates. At 10, 25 and 50 µg ml−1, TiO2-NPs displayed an average diameter of 130 nm (Polydispersity Index-PDI = 0.21), 206 nm (PDI = 0.53), and 375 nm (PDI = 0.22), respectively, and CB-NPs 171 nm (PDI = 0.13), 188 nm (PDI = 0.15), and 327 nm (PDI = 0.52), respectively. The experiments were performed in triplicates.

Additional file 3: Fig. S2. TiO2 and CB nanoparticles provoke TACE depletion and TNFR1 accumulation at the plasma membrane of serotonergic 1C115-HT neuronal cells in a PDK1-dependent manner. TNFR1 a and TACE b immunostaining at the cell surface of 1C115-HT neuronal cells exposed for 4 h to TiO2- or CB-NPs (1 µg cm−2) in the presence or not of the PDK1 inhibitor BX912 (1 µM) and related quantification histograms. Representative images of three experiments performed in triplicates are shown. Values are means ± SEM. * denotes p < 0.05 and **p < 0.01 versus unexposed cells.

Additional file 1: Table S1. Hydrodynamic diameter (nm) of TiO2- and CB-NPs in PBS at 22 °C measured by DLS. Diameter (nm) of aggregates of TiO2 and CB nanoparticles (5 up to 80 µg ml−1) measured by DLS after NP sonication, dilution in PBS, and centrifugation for 2 sec at 2000 g to remove large aggregates. The hydrodynamic diameter could not be measured for the 5 µg ml−1 NP concentration. The experiments were performed in triplicates.

Additional file 5: Fig. S4. Corruption of PrPC-coupled signaling pathways by TiO2- and CB-NPs in neuronal cells: toward a pro-Alzheimer effect of some TiO2 and CB nanoparticles. Cellular prion protein PrPC is a plasma membrane receptor recognized by TiO2- and CB-NPs in neuronal cells. The interaction between full-length PrPC and NPs mobilizes PrPC-coupled signaling pathways, leading to (i) the activation of NADPH oxidase and the production of ROS, and (ii) the activation of PDK1 that promotes the internalization of TACE α-secretase and thereby down-regulates TACE shedding activity at the root of plasma membrane TNFR1 accumulation and rise in Aβ40/42 production. Such NP interferences with the PrPC signaling network triggers molecular signs of Alzheimer’s disease: modification of cell redox equilibrium, neuronal priming to TNFα inflammatory stress, and accumulation of neurotoxic Aβ40/42 peptides (Image drawn using Servier medical art).

Additional file 4: Fig. S3. TiO2 and CB nanoparticles enhance Aβ40 production in 1C11 precursors and 1C115-HT neuronal cells. a ELISA-based quantification of Aβ40 peptides in 1C11 and 1C115-HT neuronal cells exposed to TiO2- or CB-NPs (1 µg cm−2) up to 24 h. b APP and BACE1 expression level as assessed by RT-qPCR and Western-blotting in 1C11 cells exposed to TiO2- or CB-NPs (1 µg cm−2) for 4 h. c ELISA-based quantification of Aβ40 peptides in 1C115-HT neuronal cells exposed to TiO2- or CB-NPs (1 µg cm−2) for 4 h in the presence or not of a siRNA toward PrPC (siPrP) or the PDK1 inhibitor, BX912 (1 µM). The experiments were performed three times in triplicates. Values are means ± SEM. * denotes p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 versus unexposed cells.

Corruption of cellular prion protein (PrPC) function(s) at the plasma membrane of neurons is at the root of prion diseases, such as Creutzfeldt-Jakob disease and its variant in humans, and Bovine Spongiform Encephalopathies, better known as mad cow disease, in cattle. The roles exerted by PrPC, however, remain poorly elucidated. With the perspective to grasp the molecular pathways of neurodegeneration occurring in prion diseases, and to identify therapeutic targets, achieving a better understanding of PrPC roles is a priority. Based on global approaches that compare the proteome and metabolome of the PrPC expressing 1C11 neuronal stem cell line to those of PrPnull-1C11 cells stably repressed for PrPC expression, we here unravel that PrPC contributes to the regulation of the energetic metabolism by orienting cells towards mitochondrial oxidative degradation of glucose. Through its coupling to cAMP/protein kinase A signaling, PrPC tones down the expression of the pyruvate dehydrogenase kinase 4 (PDK4). Such an event favors the transfer of pyruvate into mitochondria and its conversion into acetyl-CoA by the pyruvate dehydrogenase complex and, thereby, limits fatty acids β-oxidation and subsequent onset of oxidative stress conditions. The corruption of PrPC metabolic role by pathogenic prions PrPSc causes in the mouse hippocampus an imbalance between glucose oxidative degradation and fatty acids β-oxidation in a PDK4-dependent manner. The inhibition of PDK4 extends the survival of prion-infected mice, supporting that PrPSc-induced deregulation of PDK4 activity and subsequent metabolic derangements contribute to prion diseases. Our study posits PDK4 as a potential therapeutic target to fight against prion diseases., Author summary Transmissible Spongiform Encephalopathies (TSEs), commonly named prion diseases, are caused by pathogenic prions PrPSc that trigger degeneration of neurons in the brain. Although PrPSc exerts its neurotoxicity by corrupting the function(s) of normal cellular prion protein (PrPC), our understanding of the mechanisms involved in prion diseases remains limited. There is still to date no medicine to fight against TSEs. The current study demonstrates that the deregulation of PrPC regulatory function towards glucose metabolism contributes to neurodegeneration in prion diseases. In the brain of prion-infected mice, PrPSc-induced overactivation of pyruvate dehydrogenase kinase 4 (PDK4) and downstream reduction in mitochondria pyruvate dehydrogenase (PDH) activity promote a metabolic shift from glucose oxidative degradation to pro-oxidant fatty acids β-oxidation contributing to prion pathogenesis. The pharmacological inhibition of PDK4 extends the lifespan of prion-infected mice by rescuing normal glucose metabolism. This study opens up new avenues to design PDK4-based therapeutic strategies to combat TSEs.

International audience; Amyloid-based neurodegenerative diseases such as prion, Alzheimer's, and Parkinson's diseases have distinct etiologies and clinical manifestations, but they share common pathological events. These diseases are caused by abnormally folded proteins (pathogenic prions PrP Sc in prion diseases, β-amyloids/Aβ and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease) that display β-sheet-enriched structures, propagate and accumulate in the nervous central system, and trigger neuronal death. In prion diseases, PrP Sc -induced corruption of the physiological functions exerted by normal cellular prion proteins (PrP C ) present at the cell surface of neurons is at the root of neuronal death. For a decade, PrP C emerges as a common cell surface receptor for other amyloids such as Aβ and α-synuclein, which relays, at least in part, their toxicity. In lipid-rafts of the plasma membrane, PrP C exerts a signaling function and controls a set of effectors involved in neuronal homeostasis, among which are the RhoA-associated coiled-coil containing kinases (ROCKs). Here we review (i) how PrP C controls ROCKs, (ii) how PrP C -ROCK coupling contributes to neuronal homeostasis, and (iii) how the deregulation of the PrP C -ROCK connection in amyloid-based neurodegenerative diseases triggers a loss of neuronal polarity, affects neurotransmitter-associated functions, contributes to the endoplasmic reticulum stress cascade, renders diseased neurons highly sensitive to neuroinflammation, and amplifies the production of neurotoxic amyloids.

Cancers causes a disruption in the lives of patients and their caregivers. They must assume new responsibilities that can lead to health problems, altered quality of life, and adjustment difficulties (e.g., impaired emotional, physical, social, and professional functioning, somatic symptoms, emotional distress). Thus, caregivers need support from health professionals to cope with their role but they frequently report unmet supportive care needs. This thesis work is a part of a more global research program and aims to better understand the supportive care needs of caregivers of cancer patients and their determinants, in particular through emotional processes. The first study of this work validated the French version of a scale assessing the unmet supportive care needs of caregivers of cancer patients. The second study identified profiles of caregivers at higher risk of having at least one moderate or high unmet supportive care need from intrapersonal factors (i.e. emotional distress) and socio-demographic and medical variables (e.g., age of patients and caregivers, metastatic cancer). Finally, the third study tested the theoretical model of the thesis work, already validated for cancer patients, which considers that the emotional competence of caregivers can reduce their unmet supportive care needs by reducing their anxiety and depression symptoms. The results highlight the importance of identifying and addressing the unmet supportive care needs of caregivers, especially related to cancer care, information, and psychological and emotional support. Some profiles of caregivers may represent a population at higher risk of having difficulties and requiring more attention from professionals. Finally, taking into account emotional processes, including emotional competence and anxiety and depression symptoms, may be essential in the supportive care of caregivers.; Le diagnostic de cancer et les traitements associés vont entrainer un bouleversement de la vie du patient mais aussi de son entourage, et en particulier des proches-aidants. Ces derniers devenant « aidant » doivent assumer de nouvelles responsabilités qui peuvent entrainer des problèmes de santé, une altération de leur qualité de vie et ainsi de manière générale des difficultés d’ajustement face à la maladie (e.g., altération du fonctionnement émotionnel, physique, social et professionnel, symptômes somatiques, détresse émotionnelle). Les proches-aidants ont ainsi besoin du soutien des professionnels de santé pour faire face à leur rôle d’aidant mais ils rapportent souvent des besoins en soins de support insatisfaits. Ce travail de thèse, inscrit dans un programme de recherche plus global, vise ainsi à mieux appréhender les besoins en soins de support des proches-aidants de patients atteints d’un cancer et leurs déterminants, à travers notamment l’implication des processus émotionnels. La première étude de ce travail a consisté à valider en français une échelle évaluant les besoins en soins de support des proches-aidants de patients atteints d’un cancer. La deuxième étude visait à déterminer des profils de proches-aidants plus à risques d’avoir au moins un besoin en soins de support insatisfait moyen ou fort selon des facteurs intrapersonnels (i.e., symptômes anxieux-dépressifs) et sociodémographiques et médicales (e.g., âge des patients et des proches-aidants, cancer métastatique ou non). Enfin, la troisième étude visait à tester le modèle théorique, validé en amont auprès des patients, selon lequel les compétences émotionnelles des proches-aidants auraient un effet bénéfique sur leurs besoins en soins de support insatisfaits via moins de symptômes anxieux-dépressifs. Ces résultats montrent l’importance de dépister et prendre en charge les besoins en soins de support des proches-aidants, surtout liés à la prise en charge du patient, à l’information et au soutien psychologique et émotionnel. Certains profils de proches-aidants pourraient représenter une population particulièrement à risques de difficultés qui nécessiteraient une attention particulière des professionnels de santé. Enfin, tenir compte des processus émotionnels, notamment des compétences émotionnelles et des symptômes anxieux-dépressifs, parait important pour la prise en charge en soins de support des proches-aidants.