Hypoxia in Lung Cancer Management: A Translational Approach

SIMPLE SUMMARY: Hypoxia is a common feature of lung cancers. Nonetheless, no guidelines have been established to integrate hypoxia-associated biomarkers in patient management. Here, we discuss the current knowledge and provide translational novel considerations regarding its clinical detection and targeting to improve the outcome of patients with non-small-cell lung carcinoma of all stages. ABSTRACT: Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, we expound on the main current techniques to evaluate hypoxic status in NSCLC focusing on positive emission tomography. We present existing alternative experimental approaches such as the examination of circulating markers and highlight the interest in non-invasive markers. Finally, we evaluate the relevance of investigating hypoxia in lung cancer management as a companion biomarker at various lung cancer stages. Hypoxia could support the identification of patients with higher risks of NSCLC. Moreover, the presence of hypoxia in treated tumours could help clinicians predict a worse prognosis for patients with resected NSCLC and may help identify patients who would benefit potentially from adjuvant therapies. Globally, the large quantity of translational data incites experimental and clinical studies to implement the characterisation of hypoxia in clinical NSCLC management

Phenotypic characterization in viral exacerbations and epithelial repair process in chronic obstructive pulmonary disease

Le maintien de l'intégrité de l'épithélium des voies aériennes est assuré par un mécanisme de réparation épithéliale pouvant être dérégulé dans la bronchopneumopathie chronique obstructive (BPCO). La BPCO, définie par une obstruction irréversible des débits aériens et émaillée d'épisodes d'exacerbation, présente différents phénotypes, pour lesquels l'évaluation de la sévérité tient compte de la fonction respiratoire et de données cliniques. L'objectif de cette thèse était d'étudier du point de vue phénotypique des patients BPCO lors des exacerbations virales et au cours du processus de réparation épithéliale. Nous avons étudié prospectivement 51 patients BPCO suivis mensuellement et lors des exacerbations. Virus et bactéries étaient recherchés dans l'expectoration induite par PCR et culture. Les résultats analysés en fonction des données cliniques et fonctionnelles respiratoires ont montré qu'une coinfection, présente dans 25% des exacerbations, n'était pas associée au phénotype des patients ni à la sévérité ou à la récidive de l'exacerbation. Nous avons ensuite étudié la réparation de cellules épithéliales bronchiques primaires dans un modèle de réparation de lésion. L'analyse des paramètres de fermeture de lésion (vitesse de fermeture, sécrétions, prolifération cellulaire) en fonction des données cliniques, fonctionnelles et histologiques a montré notamment que la vitesse de fermeture était associée à la sévérité de l'obstruction bronchique. Ces résultats suggèrent le rôle d'anomalies de réparation épithéliale dans la physiopathologie de la BPCO et soulignent la complexité du phénotypage des patients atteints de BPCO.The integrity of airway epithelium is provided by a complex mechanism of epithelial repair that can be dysegulated in chronic obstructive pulmonary disease (COPD). COPD is a heterogeneous condition defined by an irreversible obstructive airflow limitation with frequent acute episodes of exacerbations. COPD patients can present different phenotypes, for which severity evaluation must take into account the severity of lung function and clinical data. The aim of this thesis was to study the COPD patients in a phenotypic point of view during viral exacerbations and during the process of epithelial repair.We prospectively studied 51 COPD patients monitored monthly and during exacerbations. Induce sputum were analyzed for viruses and bacteria detection by PCR and culture. These results analyzed according to the clinical and functional respiratory data showed that co-infection was present in 25 % of exacerbations and was not associated with the phenotype of patients or the severity or recurrence of exacerbation.We then studied primary bronchial epithelial cells repair in a model of wound closure. Associations between wound closure parameters (speed of wound closure, secretions, cell proliferation) and clinical, histological and functional data were analyzed. We showed that the speed of wound closure was associated with the severity of bronchial obstruction. These results suggest the role of abnormal epithelial repair in the pathogenesis of COPD and highlight the complexity of phenotypic characterization of COPD patients

Is atopy associated with immunologic and allergologic events after a kidney transplantation?

Introduction : Le profil immunitaire Th1/Th2 des patients transplantés rénaux pourrait être associé à leur profil évolutif post-transplantation. L objectif de cette étude rétrospective était de déterminer si le profil de sensibilisation allergénique pré-transplantation rénale était associé à la survenue d évènements immunoallergiques dans une population de patients transplantés rénaux du CHU de Reims. Méthodes : Les relations entre les résultats des tests cutanés et des dosages d IgE spécifiques pré-transplantation et les évènements en post-transplantation allergiques et immunologiques (rejet, allo-immunisation), infections opportunistes et cancer étaient analysés. Résultats : Quatre vingt huit patients étaient étudiés, d âge moyen 54 ans. Vingt cinq pourcent des patients étaient sensibilisés. Soixante huit évènements immunologiques étaient décrits, comprenant 22 rejets, 30 de novo anticorps anti-HLA, 9 infections opportunistes et 7 cancers. Un patient a développé une allergie alimentaire. Les patients sensibilisés et non sensibilisés n étaient pas différents en termes de survenue d évènements allergologiques (5% vs. 0%), de rejets (25% vs. 21%), d apparition d un nouvel anticorps anti-HLA (41% vs. 36%), du taux des sous population lymphocytaire CD4 +, CD8 +, CD19 +, du nombre d infections opportunistes (9% vs. 11%) et de cancer (0% vs. 11%). Conclusion : Le profil de sensibilisation allergénique pré-transplantation n est pas associé aux évènements en post-transplantation dans notre étude. Les explorations allergologiques en pré-transplantation doivent être adaptées à l'interrogatoire et aux antécédents allergiques de ces patients.REIMS-BU Santé (514542104) / SudocSudocFranceF

Etude de prévalence des infections bactériennes et virales au cours des exacerbations de la bronchopneumopathie chronique obstructive

REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Prévalence des allergies respiratoire dans les vignes chez les travailleurs du vignoble champenois. A propos d'une étude descriprive chez des ouvriers viticulteurs rémois

REIMS-BU Santé (514542104) / SudocSudocFranceF

CiliOPD: a ciliopathy-associated COPD endotype

International audienceThe pathophysiology of chronic obstructive pulmonary disease (COPD) relies on airway remodelling and inflammation. Alterations of mucociliary clearance are a major hallmark of COPD caused by structural and functional cilia abnormalities. Using transcriptomic databases of whole lung tissues and isolated small airway epithelial cells (SAEC), we comparatively analysed cilia-associated and ciliopathy-associated gene signatures from a set of 495 genes in 7 datasets including 538 non-COPD and 508 COPD patients. This bio-informatics approach unveils yet undescribed cilia and ciliopathy genes associated with COPD including NEK6 and PROM2 that may contribute to the pathology, and suggests a COPD endotype exhibiting ciliopathy features (CiliOPD)

Is antihistaminergic H2 really useful in prevention of hypersensitivity induced by paclitaxel?

International audienceNo abstract availabl

Nicotinic receptors as SARS-CoV-2 spike co-receptors?

International audienceNicotinic acetylcholine receptors (nAChRs) play an important role in homeostasis and respiratory diseases. Controversies regarding the association between COVID-19 hospitalizations and smoking suggest that nAChRs may contribute to SARS-CoV-2 respiratory syndrome. We recently detailed the expression and localization of all nAChR subunits in the human lung. Since virus association with nAChRs has been shown in the past, we hypothesize that nAChR subunits act as SARS-CoV-2 Spike co-receptors. Based on sequence alignment analysis, we report domains of high molecular similarities in nAChRs with the binding domain of hACE2 for SARS-CoV-2 Spike protein. This hypothesis supported by in silico pilot data provides a rational for the modelling and the in vitro experimental validation of the interaction between SARS-CoV-2 and the nAChRs

Whole-Exome Sequencing of Bronchial Epithelial Cells Reveals a Genetic Print of Airway Remodelling in COPD

International audienceThe remodelling of the airways is a hallmark of chronic obstructive pulmonary disease, but it is highly heterogeneous and erratically distributed in the airways. To assess the genetic print of remodelling in chronic obstructive pulmonary disease (COPD), we performed a comparative whole-exome sequencing analysis on microdissected bronchial epithelia. Lung resections from four non-COPD and three COPD subjects (ex-smokers and current smokers) were formalin-fixed paraffin-embedded (FFPE). Non-remodelled and remodelled bronchial epithelia were isolated by laser microdissection. Genomic DNA was captured and sequenced. The comparative quantitative analysis identified a list of 109 genes as having variants in remodelled epithelia and 160 genes as having copy number alterations in remodelled epithelia, mainly in COPD patients. The functional analysis highlighted cilia-associated processes. Therefore, bronchial-remodelled epithelia appeared genetically more altered than non-remodelled epithelia. Characterizing the unique molecular print of airway remodelling in respiratory diseases may help uncover additional factors contributing to epithelial dysfunctions, ultimately providing additional targetable proteins to correct epithelial remodelling and improve lung function