366 Combined exploratory immunophenotyping and transcriptomic tumor analysis in patients treated with OSE2101 vaccine in HLA-A2+ advanced non-small cell lung cancer (NSCLC) from the ATALANTE-1 trial

BackgroundOSE2101 (Tedopi®) is an anticancer vaccine with HLA-A2+ restricted modified epitopes targeting five tumor-associated antigens (TAAs) frequently expressed in lung cancer (CEA, HER2, MAGE2, MAGE3, P53). Step-1 results of the phase III, randomized, open-label ATALANTE-1 study comparing Tedopi® vs standard treatment (SoC) showed a favorable benefit/risk of Tedopi® over SoC (HR 0.71 for overall survival OS) in HLA-A2+ NSCLC patients in 2nd or 3rd line treatment after progression on immune checkpoint blockers (ICB).1 We analyze available tumor biopsies at initial diagnosis from some patients treated with Tedopi® to determine the expression of the 5 TAAs and to identify other tumor factors associated with long-term survival.MethodsTumor biopsies were available for 8 HLA-A2+ (blood test) stage IV NSCLC patients included in the trial. Primary (<12 weeks) and secondary (≥ 12 weeks) resistance to ICB were observed in 3 (38%) and 5 (62%) of patients. Best response to Tedopi® and OS were: 1 partial response (PR) (OS of 33 months), 3 stable disease (SD) (OS of 22, 26 and 41 mo.) and 4 disease progression (PD) (OS of 3, 4, 30 and 31 mo.). HLA-class I, PD-L1, CD8 T-cells, HER2, CEA and P53 tumor expression were evaluated by immunohistochemistry (IHC). NanoString gene expression profiling was performed using the Pan Cancer Immune gene set.ResultsHLA-class I was expressed in all tumor samples. IHC analysis revealed that P53, CEA and HER2 were expressed in 6/7, 5/7 and 0/7 patients, respectively. P53, CEA, HER2, MAGE2, and MAGE3 were detected at RNA level in 5/5 tested patients (table 1). IMMUNOSCORE® IC CD8/PDL1 analysis showed High/High, High/Low and Low/Low scores for 1/7, 1/7 and 5/7 patients, respectively. The High/High IMMUNOSCORE® with a pronounced CD8+ T-cell tumor infiltration was observed in the patient with PR. High percentage of tumor cells expressing P53 (69%–97%) and overexpression of genes associated with activated macrophages (TREM2, MARCO, SLC11A1, CHIT1, SERPINB2) were observed in the PR and SD patients. High IFN-gamma and Expanded Immune Gene Signature scores were observed in long-term survivor patients with secondary resistance to ICB, even after progressive disease.Abstract 366 Table 1Summary of clinical and translational dataCEACarcinoembryonic antigen; HER2: Human Epidermal Growth Factor Receptor-2; ICB: Immune checkpoint blocker; IHC: Immunohistochemistry; ND: Not determined; OS: Overall Survival; Patient ID: Patient identification; PDL1: Programmed death-ligand 1; PFS: Progression-free survival; ssGSEA: Single-sample Gene Set Enrichment Analysis. Blue bars = Length of overall survival; Green bars = Gene Signature upregulation; Red bars = Gene Signature downregulationConclusionsThis study shows that all HLA-A2+ patients (blood test), expressed HLA class I in the tumors at initial diagnosis. Transcriptomic data in the patients that benefited from Tedopi® showed activated macrophage pathway, high IFN-gamma and Expanded Immune Gene Signatures scores. These data will be validated on larger number of patients treated with Tedopi® after the step 2 analysis.AcknowledgementsWe thank Julie Le Boulicaut, François Montestruc and Constant Josse (eXYSTAT, Malakoff, France) for the statistical analysis, and HalioDx for the IHC and NanoString analysis.Trial RegistrationEudraCT number2015-003183-36; NCT number: NCT02654587ReferenceGiaccone, et al. Activity of OSE-2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (ICI): step 1 results of phase III ATALANTE-1 randomised trial. ESMO meeting 2020, abstract #1260MO.Ethics ApprovalThe study protocol and its related documents (including the patient information and informed consent form) received approval from the Institutional Review Board (IRB), and the Competent Authority prior to study initiation.ConsentEach patient gave his/her written informed consent prior to study enrolment

Unraveling the morphological diversity of P(VDF-ter-TrFE-ter-CTFE) semi-crystalline terpolymers via combined AFM and SAXS experiments

In this article, the diverse morphologies observed after annealing or crystallization from the melt in P(VDF-ter-TrFE-ter-CTFE) terpolymers with varying CTFE amounts were explained through a combination of AFM and SAXS experiments. The very significant and, so far, unexplained evolution of the SAXS spectra after annealing above the Curie transition was interpreted by the formation, during annealing, of semi-crystalline domains without a significant evolution of the crystalline lamellar period. The morphologies obtained after crystallization from the melt were also explained and the coexistence of two periodic stacks (with period around 30–40 nm and 14–18 nm) was shown. Low cooling rates and CTFE amounts create long and thick semi-crystalline domains with a well-defined orientation, while high cooling rates and CTFE amounts create thinner and shorter domains without a predominant orientation. The AFM images showed that the periodic organization of the crystalline lamellae with a period, LP, around 15 nm is maintained, regardless of the crystallization process used (solvent cast, annealed, or melt-crystallized). The combined AFM/SAXS method used in this study can be applied to other semi-crystalline polymers.ANR FETA Chaire Arkema/CNRS-ENSAM-Cna

Enhanced Electrocaloric Response of Vinylidene Fluoride–Based Polymers via One‐Step Molecular Engineering

Electrocaloric refrigeration is one of the most promising environmentally-friendly technologies to replace current cooling platforms—if a notable electrocaloric effect (ECE) is realized around room temperature where the highest need is. Here, a straight-forward, one-pot chemical modification of P(VDF-ter-TrFE-ter-CTFE) is reported through the controlled introduction of small fractions of double bonds within the backbone that, very uniquely, decreases the lamellar crystalline thickness while, simultaneously, enlarging the crystalline coherence along the a-b plane. This increases the polarizability and polarization without affecting the degree of crystallinity or amending the crystal unit cell—undesirable effects observed with other approaches. Specifically, the permittivity increases by >35%, from 52 to 71 at 1 kHz, and ECE improves by >60% at moderate electric fields. At 40 °C, an adiabatic temperature change >2 K is realized at 60 MV m−1 (>5.5 K at 192 MV m−1), compared to ≈1.3 K for pristine P(VDF-ter-TrFE-ter-CTFE), highlighting the promise of a simple, versatile approach that allows direct film deposition without requiring any post-treatment such as mechanical stretching or high-temperature annealing for achieving the desired performance

Influenza and associated co-infections in critically ill immunosuppressed patients

Abstract Background It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. Methods Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. Results Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P < 0.001). Patients with influenza plus co-infection had the highest rates of intubation and longest ICU LOS. On crude analysis, influenza infection status was associated with ICU mortality (P < 0.001) but not hospital mortality (P = 0.09). Patients with influenza plus co-infection and patients with non-influenza infection alone had similar ICU mortality (41% and 37% respectively) that was higher than patients with influenza alone or those without infection (33% and 26% respectively). A propensity score-matched analysis did not show a difference in hospital mortality attributable to influenza infection (OR = 1.01, 95%CI 0.90–1.13, P = 0.85). Age, severity scores, ARDS, and performance status were all associated with ICU, hospital, and 90-day mortality. Conclusions Category of infectious etiology of respiratory failure (influenza, non-influenza, influenza plus co-infection, and non-infectious) was associated with ICU but not hospital mortality. In a propensity score-matched analysis, influenza infection was not associated with the primary outcome of hospital mortality. Overall, influenza infection alone may not be an independent risk factor for hospital mortality in immunosuppressed patients

Protein 4.1B Contributes to the Organization of Peripheral Myelinated Axons

Neurons are characterized by extremely long axons. This exceptional cell shape is likely to depend on multiple factors including interactions between the cytoskeleton and membrane proteins. In many cell types, members of the protein 4.1 family play an important role in tethering the cortical actin-spectrin cytoskeleton to the plasma membrane. Protein 4.1B is localized in myelinated axons, enriched in paranodal and juxtaparanodal regions, and also all along the internodes, but not at nodes of Ranvier where are localized the voltage-dependent sodium channels responsible for action potential propagation. To shed light on the role of protein 4.1B in the general organization of myelinated peripheral axons, we studied 4.1B knockout mice. These mice displayed a mildly impaired gait and motility. Whereas nodes were unaffected, the distribution of Caspr/paranodin, which anchors 4.1B to the membrane, was disorganized in paranodal regions and its levels were decreased. In juxtaparanodes, the enrichment of Caspr2, which also interacts with 4.1B, and of the associated TAG-1 and Kv1.1, was absent in mutant mice, whereas their levels were unaltered. Ultrastructural abnormalities were observed both at paranodes and juxtaparanodes. Axon calibers were slightly diminished in phrenic nerves and preterminal motor axons were dysmorphic in skeletal muscle. βII spectrin enrichment was decreased along the axolemma. Electrophysiological recordings at 3 post-natal weeks showed the occurrence of spontaneous and evoked repetitive activity indicating neuronal hyperexcitability, without change in conduction velocity. Thus, our results show that in myelinated axons 4.1B contributes to the stabilization of membrane proteins at paranodes, to the clustering of juxtaparanodal proteins, and to the regulation of the internodal axon caliber

Modélisation de la méthanisation des effluents concentrés

Fiche techniqueLa méthanisation ou digestion anaérobie est un procédé de traitement biologique et de valorisation des effluents organiques. Elle conduit, à partir de matière organique, à la production d’un biogaz riche en méthane et s’applique à la plupart des déchets organiques : effluents d’élevage (lisiers,…), boues de stations d’épuration, déchets d’agro-industries, etc. La dégradation de la matière organique est assurée par une chaîne trophique au cours de laquelle des molécules complexes (celluloses, protéines, …) sont successivement transformées pour finalement aboutir au méthane et au dioxyde de carbone. Elle comporte principalement quatre étapes réalisées par des biomasses spécifiques

PREUVES D'EGALITE, D'APPARTENANCE A UN INTERVALLE ET LEURS APPLICATIONS

CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

Modélisation de la méthanisation des effluents concentrés

Fiche techniqueLa méthanisation ou digestion anaérobie est un procédé de traitement biologique et de valorisation des effluents organiques. Elle conduit, à partir de matière organique, à la production d’un biogaz riche en méthane et s’applique à la plupart des déchets organiques : effluents d’élevage (lisiers,…), boues de stations d’épuration, déchets d’agro-industries, etc. La dégradation de la matière organique est assurée par une chaîne trophique au cours de laquelle des molécules complexes (celluloses, protéines, …) sont successivement transformées pour finalement aboutir au méthane et au dioxyde de carbone. Elle comporte principalement quatre étapes réalisées par des biomasses spécifiques

Modelling of the effect of HRT on anaerobic CSTR performance based on a specific characterisation of wastes from agro-industry

International audienceThe aim of this article is to investigate the effect of the Hydraulic Retention Time (HRT) on the anaerobic CSTR digester performance in term of methane production using modelling combined with a specific characterization of wastes. Hence, a recently developed methodology (“anaerobic respirometry”) has been applied to define input state variable set for the “Anaerobic Digestion Model n°1” (ADM1) adapted to each substrate including also hydrolysis rates. Then, ADM1 was used to simulate CSTRs with different HRT for each substrate. The results obtained for 12 common organic wastes from agro-industries (slaughterhouses and meat industry) are significantly different in function of the considered substrates. As an example, an HRT of 7 days is sufficient to reach 80% of the maximal methane production for bovine blood whereas HRT values of 32 and 78 days are required for waste activated sludge and rumen content, respectively, to reach the same yield. These results highlight the interest in the adaptation of the reactor design according to the composition of the reactor feed

Modelling of the effect of HRT on anaerobic CSTR performance based on a specific characterisation of wastes from agro-industry

International audienceThe aim of this article is to investigate the effect of the Hydraulic Retention Time (HRT) on the anaerobic CSTR digester performance in term of methane production using modelling combined with a specific characterization of wastes. Hence, a recently developed methodology (“anaerobic respirometry”) has been applied to define input state variable set for the “Anaerobic Digestion Model n°1” (ADM1) adapted to each substrate including also hydrolysis rates. Then, ADM1 was used to simulate CSTRs with different HRT for each substrate. The results obtained for 12 common organic wastes from agro-industries (slaughterhouses and meat industry) are significantly different in function of the considered substrates. As an example, an HRT of 7 days is sufficient to reach 80% of the maximal methane production for bovine blood whereas HRT values of 32 and 78 days are required for waste activated sludge and rumen content, respectively, to reach the same yield. These results highlight the interest in the adaptation of the reactor design according to the composition of the reactor feed