Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle

Funding: The authors are supported by grants from the AstraZeneca SciLifeLab Research Programme, Novo Nordisk Foundation (NNF14OC0011493, and NNF17OC0030088), Swedish Diabetes Foundation (DIA2018-357), Swedish Research Council (2015-00165 and 2018-02389), the Knut and Alice Wallenberg Foundation (2018-0094), the Strategic Research Programme in Diabetes at Karolinska Institutet (2009-1068), the Stockholm County Council (SLL20170159), and the Swedish Research Council for Sport Science (P2019-0140). B.M.G. was supported by fellowships from the Novo Nordisk Foundation (NNF19OC0055072), the Wenner-Gren Foundation, an Albert Renold Travel Fellowship from the European Foundation for the Study of Diabetes, and an Eric Reid Fund for Methodology from the Biochemical Society. N.J.P. and L.S.-P. were supported by an Individual Fellowship from the Marie Skłodowska-Curie Actions (European Commission: 704978 and 675610). X.Z. and K.A.E. were supported by NIH R01AR066082. N.J.P. was supported by grants from the Sigurd och Elsa Goljes Minne and Lars Hierta Memorial Foundations (Sweden). We acknowledge the Beta Cell in-vivo Imaging/Extracellular Flux Analysis core facility supported by the Strategic Research Program in Diabetes for the usage of the Seahorse flux analyzer. Additional support was received from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation. We acknowledge the Single-Cell Omics platform at the Novo Nordisk Foundation Center for Basic Metabolic Research for technical and computational expertise and support. Schematics are created with BioRender.com.Peer reviewedPublisher PD

Prolégomènes aux principes de la peine

Traduction à paraître dans la revue Droits accompagnée d'une introduction d'environ 20 000 signesH.L.A. Hart, "Prolegomenon to the Principles of Punishment", in Punishment and Responsibility : Essays in the Philosophy of Law, 2e édition, Oxford : Oxford University Press, 2008, p. 1-2

Développement d'inhibiteurs non covalents du protéasome eucaryote (conception, criblage et évaluation biologique dans le cadre de la physiopathologie musculaire)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Noncovalent inhibition of 20S proteasome by pegylated dimerized inhibitors.

International audienceWe exploited the concept of polyvalent interactions to produce highly selective and efficient inhibitors of eukaryotic proteasome. This multicatalytic protease with the unique topography of its 6 active sites has emerged as a promising target to treat cancer with the use of the covalent inhibitor bortezomib. We used our reference noncovalent inhibitor, a selective TMC-95A tripeptide linear mimic, to design dimeric noncovalent proteasome inhibitors that target two active sites simultaneously. We synthesized pegylated monomer and dimers of the reference inhibitor and evaluated their capacity to inhibit a mammalian 20S proteasome. The inhibitory power of the dimers depended on the average length of their spacer. Lineweaver-Burk double-reciprocal plots indicated competitive inhibition. The best dimer inhibited CT-L activity 800-times more efficiently than the reference inhibitor

Management of cutaneous toxicities under amivantamab (anti MET and anti EGFR bispecific antibody) in patients with metastatic non-small cell lung cancer harboring EGFR Exon20ins: towards a proactive, multidisciplinary approach

International audienceContexte. The Epidermal Growth Factor Receptor (EGFR) is mutated in 10–15% of patients with lung adenocarcinoma. At metastatic stage EGFR tyrosine kinase inhibitors (TKIs) are used front line for patients harboring targetable mutations. Novel anti-EGFR therapies are being developed. Amivantamab is a bispecific anti-EGFR and anti-MET antibody with expected skin toxicities. Objective: We developed here guidelines for prevention and treatment of cutaneous toxicities under amivantamab according to our experience at Institut Curie. Materiel & Method: The first patients with metastatic lung cancer harboring EGFR Exon20ins mutation, included in the phase 1 CHRYSALIS trial and cured at Institute Curie from November 1st 2019 until December 31st 2021 were selected for this work. Retrospectively, all cutaneous adverse events were registered and classified according to the CTCAE 6.0 classification, and actions we implemented to minimize and treat these adverse events were collected. We then developed guidelines based on these datas. Results: A total of seven patients started amivantamab as monotherapy. The two most frequent dermatological adverse events were: acneiform rash and paronychia (100 % of patients). Other adverse events presented by the patients were reported: modification of hair growth with hypertrichosis in 50 % of men (n = 1/2) and hirsutism in 80 % of women (n = 4/5); skin abrasion of the scalp in 71 % (n = 5/7); and skin fissure in 57 % (n = 4/7). We recommend first a rigorous inspection of the skin and teguments to determine the risk rate to have dryer skin under treatment; second a prevention of paronychia/acneiform rash/and skin fissures with prophylactic tetracycline, skin moisturizing, and hygienic measures starting at least 14 days before treatment initiation; third a particular attention to the psychological impact of skin toxicities with access to psychological support. Conclusion: We propose here guidelines for the management of dermatological toxicities under amivantamab with a multidisciplinary approach for the proactive management of cutaneous toxicities with a focus on preventive actions

Impact of COVID-19 on the management of patients with thoracic cancers in a tertiary referral center

International audienceIntroduction: Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has spread worldwide in 2020 leading the World Health Organization to declare a pandemic. Patients with thoracic cancers have been reported at higher risk to develop severe disease, and die from COVID-19. In this setting, clinical practice recommendations for the management of patients were published. We report here how these guidelines were implemented in a routine practice setting. Methods: We retrospectively collected the characteristics, treatment regimen and modification, as well as COVID-19 status and death for all patients with thoracic malignancies scheduled for an appointment at Institute Curie from March 23rd to April 17th 2020. Results: A total of 339 patients were included. Treatment strategy was modified for a total of 110 (32 %) patients because of COVID-19; these modifications were in accordance with guidelines for 92 % of patients. The majority of dose modifications were related to immune checkpoint inhibitors, for which switch to flat dosing every 4–6 weeks was made. A total of 5 (1.5 %) patients were diagnosed with COVID-19 disease, 1 of whom died from disease complication. Conclusion: Our study provides a unique insight in the decision making for patients with thoracic malignancies in the setting of COVID-19 outbreak, showing how guidelines were implemented in the clinic, and what may be optimized in the clinical practice of thoracic oncology in the future

Immunothérapie des cancers bronchiques non à petites cellules métastatiques, de la première ligne à la résistance et sa prise en charge

International audienceL’immunothérapie seule ou en association avec la chimiothérapie fait désormais partie intégrante du traitement du CPNPC métastatique. Ce traitement transforme la prise en charge de ces cancers, avec 20 à 30% des patients atteignant une longue survie. Cependant, la progression de la maladie sous traitement est toujours la règle pour la majorité des patients, ce qui soulève des problèmes à la fois dans la compréhension de ses mécanismes et dans la prise en charge appropriée ultérieure. Cette étude examine les options thérapeutiques actuelles et propose des solutions pour contourner la résistance à l’immunothérapie. Les mécanismes de résistance à ces traitements sont également analysés

Brief Report on Teleconsultation in Lung Cancer: Toward a Semiotic Paradigm Shift?

International audienceIntroduction: Telehealth is taking an increasingly important part of medicine. This practice change is being accelerated by the pandemic linked to coronavirus disease 2019. Oncology is a medical specialty for which this paradigm shift is particularly relevant.Methods: We developed a survey aiming at evaluating the use of teleconsultation by physicians managing patients with lung cancer in France. The survey was available online from December 15, 2020, to February 10, 2021.Results: Answers were obtained from 142 clinicians (73.9% pneumologists, 18.3% medical oncologists, and 7.7% with another specialty), 129 (90.8%) of whom had already performed teleconsultation. Among those, 123 (95.3%) started after the coronavirus disease 2019 pandemic. In addition, 72.9% had a moderate usage of this tool (<10 teleconsultations/mo). The frequency of clinicians never using teleconsultation was higher in private practices (p = 0.029). The two clinical situations for which teleconsultation was frequently used were visits during treatment without imaging assessment (53.5%) and post-treatment surveillance (80.3%). Depending on the type of treatment received, the frequency of teleconsultation was variable. Lung cancer subtype also affected the clinician's practice. Indeed, 47.2% never proposed this tool for SCLC. Teleconsultation was considered to be of no contribution, a moderate contribution, a significant contribution, or a revolution of the clinical practice for 14.1%, 66.2%, 10.6%, and 2.1% of the respondents, respectively. The participants expected to decrease, stabilize, or increase their teleconsultation activity in 18.3%, 52.8%, and 23.2% of the cases, respectively.Conclusions: Most thoracic oncologists in France are using teleconsultation, mostly as an additional tool that should not replace the doctor-patient in-person relationship

Targeted delivery of immune-stimulating bispecific RNA, inducing apoptosis and anti-tumor immunity in cancer cells

Summary: Double-stranded RNAs (dsRNA)-based strategies appeared as promising therapies to induce an inflammation in the tumor microenvironment. However, currently described systems generally lack active targeting of tissues, and their clinical translation is thus limited to intratumoral injection. Herein, we developed an antibody-siRNA-5′triphosphate conjugate with multiple modes of action, combining cell surface EphA2-specific internalization, leading to a simultaneous gene silencing and activation of the receptor retinoic acid-inducible gene I (RIG-I). Recognition of cytosolic siRNA-5′triphosphate by RIG-I triggers the expression of interferons and pro-inflammatory cytokines, inducing an inflammation of the tumor environment and activating neighboring immune cells. In addition, these RIG-I-specific effects synergized with siRNA-mediated PLK1 silencing to promote cancer cell death by apoptosis. Altogether, such immune-stimulating antibody-RNA conjugate opens a novel modality to overcome some limitations encountered by dsRNA molecules currently in clinical trials