Thèse dirigée en co-tutelle par Robert Descimon (EHESS) et Claire Dolan (Université Laval, Québec), devant un jury composé de Pierre Bonin (Université Paris 1 Panthéon-Sorbonne), Fanny Cosandey ...(EHESS), Michel De Waele (Université Laval, Québec) et Sylvie Perrier (Université d’Ottawa). Résumé : Ce travail prend appui sur une source jusqu’ici largement sous-exploitée et qui appartient à la communauté des procureurs au parlement de Paris sous l’Ancien Régime. Source aux apparences familières en...
Expatriation for work presents various challenges before departure, during expatriation, and upon return to one’s home country. These challenges are why learning to manage cultural differences is a ...vital skill for expatriate managers and professionals, and hiring managers. Cultural intelligence (CQ) has been the subject of much research over the last decade. The present systematic review contributes to the literature on expatriate worker CQ by collecting and analyzing 97 empirical articles on the subject. Findings point to five core elements associated with CQ and five avenues for future research. Ultimately, the study results show that CQ positively affects many outcomes during expatriation.
Despite being the primary homeland of Quebec's Inuit people, Nunavik's health care is typically planned and provided by non‐Inuit newcomers. This retrospective case study investigates the effects of ...ethical leadership on the Westernized local Nunavik health care system's cultural sensitivity to its disproportionately Inuit populations. An integrative framework is developed that considers the dimensions of ethical leadership and the omnibus and discrete dimensions of context. This study shows that some Nunavik health care managers seek to improve and adapt the system to the needs of their Inuit populations, while others do not. Unfortunately, the context restricts the former managers' ability to act consistently with their moral responsibilities and beliefs. Specifically, the findings show various institutional barriers to providing respectful and sensitive health care to Inuit. This study contributes to the scientific literature on ethical leadership by proposing an integrative conceptual framework. This framework illustrates how ethical leadership is inseparable from organizational context, identifying 16 contextual factors influencing managers' ethical behavior. Finally, three practical recommendations are proposed to highlight the omnibus and discrete context elements.
The PD-L1 (CD274) immune-checkpoint ligand is often upregulated in cancers to inhibit T cells and elicit immunosuppression. Independent of this activity, PD-L1 has recently been shown to also exert a ...cancer cell-intrinsic function promoting tumorigenesis. Here, we establish this tumor-intrinsic role of PD-L1 in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Using FACS-assisted shRNA screens, we identified the cell-surface adhesion receptor CD44 as a key positive regulator of PD-L1 expression in these cancers. Mechanistically, CD44 activated
transcription in part through its cleaved intracytoplasmic domain (ICD), which bound to a regulatory region of the
locus containing a consensus CD44-ICD binding site. Supporting this genetic interaction, CD44 positively correlated with PD-L1 expression at the mRNA and protein levels in primary tumor samples of TNBC and NSCLC patients. These data provide a novel basis for CD44 as a critical therapeutic target to suppress PD-L1 tumor-intrinsic function. SIGNIFICANCE: CD44 is a potential target to suppress PD-L1 function in TNBC. This finding has the potential to open a new area of therapy for TNBC.
Abstract
Rocaglates are a class of eukaryotic translation initiation inhibitors that are being explored as chemotherapeutic agents. They function by targeting eukaryotic initiation factor (eIF) 4A, ...an RNA helicase critical for recruitment of the 40S ribosome (and associated factors) to mRNA templates. Rocaglates perturb eIF4A activity by imparting a gain-of-function activity to eIF4A and mediating clamping to RNA. To appreciate how rocaglates could best be enabled in the clinic, an understanding of resistance mechanisms is important, as this could inform on strategies to bypass such events as well as identify responsive tumor types. Here, we report on the results of a positive selection, ORFeome screen aimed at identifying cDNAs capable of conferring resistance to rocaglates. Two of the most potent modifiers of rocaglate response identified were the transcription factors
FOXP3
and
NR1I3
, both of which have been implicated in
ABCB1
regulation—the gene encoding P-glycoprotein (Pgp). Pgp has previously been implicated in conferring resistance to silvestrol, a naturally occurring rocaglate, and we show here that this extends to additional synthetic rocaglate derivatives. In addition,
FOXP3
and
NR1I3
impart a multi-drug resistant phenotype that is reversed upon inhibition of Pgp, suggesting a potential therapeutic combination strategy.
The chemokine receptor CXCR7 is an atypical CXCL12 receptor that, as opposed to the classical CXCL12 receptor CXCR4, signals preferentially via the β-arrestin pathway and does not mediate chemotaxis. ...We previously reported that the cyclic peptide TC14012, a potent CXCR4 antagonist, also engaged CXCR7, albeit with lower potency. Surprisingly, the compound activated the CXCR7–arrestin pathway. The reason underlying the opposite effects of TC14012 on CXCR4 and CXCR7, and the mode of binding of TC14012 to CXCR7, remained unclear. The mode of binding of TC14012 to CXCR4 is known from cocrystallization of its analogue CVX15 with CXCR4. We here report the the mode of binding of TC14012 to CXCR7 by combining the use of compound analogues, receptor mutants, and molecular modeling. We find that the mode of binding of TC14012 to CXCR7 is indeed similar to that of CVX15 to CXCR4, with compound positions Arg2 and Arg14 engaging CXCR7 key residues D1794.60 (on the tip of transmembrane domain 4) and D2756.58 (on the tip of transmembrane domain 6), respectively. Interestingly, the TC14012 parent compound T140 is not a CXCR7 agonist, because of conformational constraints in its pharmacophore, which in TC14012 are relieved through C-terminal amidation. However, an engineered salt bridge between the CXCR7 ECL2 substitution R197D and compound residue Arg1 permitted T140 agonism by repositioning the compound in the binding pocket. In conclusion, our results show that the opposite effect of TC14012 on CXCR4 and CXCR7 is not explained by different binding modes. Rather, engagement of the interface between transmembrane domains and extracellular loops readily triggers CXCR7, but not CXCR4, activation.
In budding yeast, the most abundantly spliced pre-mRNAs encode ribosomal proteins (RPs). To investigate the contribution of splicing to ribosome production and function, we systematically eliminated ...introns from all RP genes to evaluate their impact on RNA expression, pre-rRNA processing, cell growth, and response to stress. The majority of introns were required for optimal cell fitness or growth under stress. Most introns are found in duplicated RP genes, and surprisingly, in the majority of cases, deleting the intron from one gene copy affected the expression of the other in a nonreciprocal manner. Consistently, 70% of all duplicated genes were asymmetrically expressed, and both introns and gene deletions displayed copy-specific phenotypic effects. Together, our results indicate that splicing in yeast RP genes mediates intergene regulation and implicate the expression ratio of duplicated RP genes in modulating ribosome function.
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► Duplicated ribosomal protein genes are asymmetrically expressed and regulated ► Introns mediate copy-specific expression of duplicated ribosomal protein genes ► Introns of ribosomal protein genes modulate the processing of pre-rRNA ► Introns regulate the function of yeast ribosomes
Many yeast ribosomal proteins are encoded by two paralogous genes. An intron within one paralog modulates the expression of the other paralog to affect the composition of translating ribosomes.
Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little is known regarding the generality of these changes ...and whether specific therapies elicit unique metabolic alterations. Using a combination of metabolomics, transcriptomics, and functional genomics, we show that two anthracyclines, doxorubicin and epirubicin, elicit distinct primary metabolic vulnerabilities in human breast cancer cells. Doxorubicin-resistant cells rely on glutamine to drive oxidative phosphorylation and de novo glutathione synthesis, while epirubicin-resistant cells display markedly increased bioenergetic capacity and mitochondrial ATP production. The dependence on these distinct metabolic adaptations is revealed by the increased sensitivity of doxorubicin-resistant cells and tumor xenografts to buthionine sulfoximine (BSO), a drug that interferes with glutathione synthesis, compared with epirubicin-resistant counterparts that are more sensitive to the biguanide phenformin. Overall, our work reveals that metabolic adaptations can vary with therapeutics and that these metabolic dependencies can be exploited as a targeted approach to treat chemotherapy-resistant breast cancer.
Abstract
Study Objectives
Concomitant patterns of sleep aid use may provide insight for understanding the transition to chronic sleep medication use. Therefore, we sought to characterize the ...trajectories of concomitant natural product (NP), over-the-counter (OTC), and prescribed (Rx) sleep aid use in a population-based sample over 12-months.
Methods
Self-reported data on the use of NP, OTC, and Rx sleep aids were extracted from a Canadian longitudinal study on the natural history of insomnia (N = 3416, M age = 49.7 ± 14.7 years old; 62% women) at baseline, 6-month, and 12-month. Latent class growth modeling was used to identify latent class trajectories using MPlus Version 7. Participants completed a battery of clinical measures: Ford Insomnia Response to Stress Test, abbreviated Dysfunctional Beliefs and Attitudes about Sleep Scale, Beck Depression Inventory, Insomnia Severity Index and, the Pittsburgh Sleep Quality Index. Associations between class membership and baseline covariates were evaluated.
Results
Concurrent sleep aid use fell into six distinct latent class trajectories over a 12-month period: Minimal Use (74.5%), Rx-Dominant (11.3%), NP-Dominant (6.3%), OTC-Dominant (4.3%), Rx-NP-Dominant (2.4%), and Rx-OTC-Dominant (1.1%). The three latent classes with prominent prescribed agent use predicted greater incidence of healthcare professional consultations for their sleep (p < 0.05), poorer sleep quality (p < 0.001), elevated dysfunctional sleep beliefs (p < 0.001), and sleep reactivity (p < 0.001). Compared to the other four latent classes, clinical profiles of Rx-NP-dominant and Rx-OTC-dominant groups endorsed greater severity across measures.
Conclusions
Patterns of sleep aid use may provide insight for identifying individuals who may be vulnerable to inappropriate self-medicating practices.
Loop ileostomy closure is a common procedure in colorectal surgery. Often seen as a simple operation associated with a low complication rate, it still leads to lengthy hospitalizations. Reducing ...postoperative complications and ileus rates could lead to a shorter length of stay and even ambulatory surgery.
This study aimed to assess the safety and feasibility of ileostomy closure performed in a 23-hour hospitalization setting using a standardized enhanced recovery pathway.
Randomized controlled trial.
Two high-volume colorectal surgery centers.
Healthy adults undergoing elective ileostomy closure from July 2019 to January 2022.
All patients were enrolled in a standardized enhanced recovery pathway specific to ileostomy closure, including daily irrigation of efferent limb with a nutritional formula for 7 days before surgery. Patients were randomly allocated to either conventional hospitalization (n = 23) or a 23-hour stay (n = 24).
Primary outcome was total length of stay and secondary outcomes were 30-day rates of readmission, postoperative ileus, surgical site infections, and postoperative morbidity and mortality.
A total of 47 patients were ultimately randomly allocated. Patients in the 23-hour hospitalization arm had a shorter median length of stay (1 vs 2 days, p = 0.02) and similar rates of readmission (4% vs 13%, p = 0.35), postoperative ileus (none in both arms), surgical site infection (0% vs 4%, p = 0.49), postoperative morbidity (21% vs 22%, p = 1.00), and mortality (none in both arms).
Due to coronavirus disease 2019, access to surgical beds was greatly limited, leading to a shift toward ambulatory surgery for ileostomy closure. The study was terminated early, which affected its statistical power.
Loop ileostomy closures as 23-hour stay procedures are feasible and safe. Ileus rate might be reduced by preoperative intestinal stimulation with nutritional formula through the stoma's efferent limb, although specific randomized controlled trials are needed to confirm this association. See Video Abstract .
ANTECEDENTES:El cierre de la ileostomía en asa es un procedimiento común en la cirugía colorrectal. A menudo vista como una operación simple asociada con bajas tasas de complicaciones, aún conduce a largas hospitalizaciones. La reducción de las complicaciones postoperatorias y las tasas de íleo podría conducir a una estadía hospitalaria más corta o incluso a una cirugía ambulatoria.OBJETIVOS:El presente estudio pretende evaluar la seguridad y la viabilidad del cierre de ileostomía realizadas en un entorno de hospitalización de 23 horas utilizando una vía de recuperación mejorada y estandarizada.DISEÑO:Estudio aleatorio controladoAJUSTES:Dos centros de cirugía colorrectal de gran volúmenPACIENTES:Adultos sanos sometidos a cierre electivo de ileostomía, desde Julio de 2019 hasta Enero de 2022.INTERVENCIÓN:Todos los pacientes fueron inscritos en una vía de recuperación mejorada y estandarizada específica para el cierre de la ileostomía, incluyendo la irrigación diaria de la extremidad eferente del intestino asociada a una fórmula nutricional durante 7 días previos a la cirugía. Los pacientes fueron asignados aleatoriamente en hospitalización convencional (n = 23) o a una estadía de 23 horas (n = 24).PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la duración total de la estadía hospitalaria y los resultados secundarios fueron las tasas de reingreso a los 30 días, el íleo postoperatorio, las infecciones de la herida quirúrgica, la morbilidad y mortalidad postoperatorias.RESULTADOS:Finalmente fueron randomizados un total de 47 pacientes. Aquellos que se encontraban en el grupo de hospitalización de 23 horas tuvieron una estadía media más corta (1 día versus 2 días, p = 0,02) y tasas similares de reingreso (4% vs 13%, p = 0,35), de íleo postoperatorio (ninguno en ambos brazos), de infección del sitio quirúrgico (0 vs 4%, p = 0,49), de morbilidad postoperatoria (21% vs 22%, p > 0,99) y de mortalidad (ninguna en ambos brazos).LIMITACIONES:Debido a la pandemia SARS CoV-2, el acceso a las camas quirúrgicas fue muy limitado, lo que llevó a un cambio hacia la cirugía ambulatoria para el cierre de ileostomías. El estudio finalizó anticipadamente, lo que afectó su poder estadístico.CONCLUSIÓN:Los cierres de ileostomía en asa como procedimientos de estadía de 23 horas son factibles y seguros. La tasa de íleo podría reducirse mediante la estimulación intestinal preoperatoria a través de la rama eferente del estoma asociada a fórmulas nutricionales, por lo que se necesitan estudios randomizados específicos para confirmar esta asociación. (Traducción-Dr. Xavier Delgadillo ).
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