Dual Role of Sp3 Transcription Factor as an Inducer of Apoptosis and a Marker of Tumour Aggressiveness

International audienceBACKGROUND: The ambiguous role of transcription factor Sp3 for tumour progression is still debated since it was described as a transcriptional repressor or activator. Here we tried to decipher the molecular mechanisms implicated in Sp3 accumulation observed in aggressive tumours. METHODOLOGY: We generated normal and tumour cell lines conditionally expressing Sp3. Cell growth was analyzed in vitro and after inoculation in nude mice. Apoptosis was assessed by pan- caspase activity assays, by counting fragmented nuclei and by determination of caspase 9 cleavage. Gene expression was determined by quantitative PCR. Cleavage by different caspases was performed after in vitro translation of the Sp3 cDNA in the presence of [S(35)] labelled methionine. Different tumour cell lines and head and neck tumour samples were tested for the presence of Sp3 by western blots. Correlation between Sp3 expression and overall survival has been statistically determined. PRINCIPAL FINDINGS: Conditional over-expression of Sp3 induces apoptosis and modifies expression of genes implicated in the regulation of cell cycle and pro and anti apoptotic genes. Sp3 over-expression strongly reduces the development of tumours in nude mice confirming its pro-apoptotic potential in vivo. However, cells can survive to apoptosis through selective Sp3 cleavage by caspase. Sp3 induction in established tumours resulted in transient regression then progression. Progression coincides with re-accumulation of the full length form of Sp3. Sp3 is over-expressed in tumour cell lines of different origins. The presence of high levels of the full-length form of Sp3 indicates a poor prognosis for overall survival of patients with head and neck tumours. CONCLUSIONS: Full length Sp3 accumulation highlights bypass of tumour cell apoptotic capacities and is indicative of head and neck tumours aggressiveness

Breakthrough infections due to SARS-CoV-2 Delta variant: relation to humoral and cellular vaccine responses

IntroductionCOVID-19 vaccines are expected to provide effective protection. However, emerging strains can cause breakthrough infection in vaccinated individuals. The immune response of vaccinated individuals who have experienced breakthrough infection is still poorly understood.MethodsHere, we studied the humoral and cellular immune responses of fully vaccinated individuals who subsequently experienced breakthrough infection due to the Delta variant of SARS-CoV-2 and correlated them with the severity of the disease.ResultsIn this study, an effective humoral response alone was not sufficient to induce effective immune protection against severe breakthrough infection, which also required effective cell-mediated immunity to SARS-CoV-2. Patients who did not require oxygen had significantly higher specific (p=0.021) and nonspecific (p=0.004) cellular responses to SARS-CoV-2 at the onset of infection than those who progressed to a severe form.DiscussionKnowing both humoral and cellular immune response could allow to adapt preventive strategy, by better selecting patients who would benefit from additional vaccine boosters.Trial registration numbershttps://clinicaltrials.gov, identifier NCT04355351; https://clinicaltrials.gov, identifier NCT04429594

Oral and oropharyngeal cancer surgery with free-flap reconstruction in the elderly: Factors associated with long-term quality of life, patient needs and concerns. A GETTEC cross-sectional study

Objectives: To assess the factors associated with long-term quality of life (QoL) and patient concerns in elderly oral or oropharyngeal cancer (OOPC) patients after oncologic surgery and free-flap reconstruction. Methods: Patients aged over 70 years who were still alive and disease-free at least 1 year after surgery were enrolled in this cross-sectional multicentric study. Patients completed the EORTC QLQ-C30, -H&N35 and -ELD14 QoL questionnaires, and the Hospital Anxiety and Depression Scale (HADS). Patient needs were evaluated using the Patient Concerns Inventory (PCI). Factors associated with these clinical outcomes were determined in univariate and multivariate analysis. Results: Sixty-four patients were included in this study. Long-term QoL, functioning scales and patient autonomy were well-preserved. Main persistent symptoms were fatigue, constipation and oral function-related disorders. Salivary and mastication/swallowing problems were the main patient concerns. The mean number of patient concerns increased with the deterioration of their QoL. Psychological distress (HADS score ≥ 15) and patient frailty (G8 score < 15) were significantly associated with poor QoL outcomes. Conclusions: We found a negative correlation between the number of patient concerns and QoL. Dental rehabilitation and psychological and nutritional supportive measures are of critical importance in the multidisciplinary management of elderly OOPC patients

Méthodologie des essais de phase précose en cancérologie (évolution des schémas et apport de la pharmacologie)

En cancérologie, les objectifs des études de phase 1 sont l estimation de la toxicité afin de définir la Dose Maximale Tolérée et la Dose Recommandée ainsi que l étude de la pharmacologie de la molécule testée. L'évolution des traitements anticancéreux, de la pharmacologie et des biostatistiques ont modifié l'approche méthodologique de ces études. On peut désormais regrouper ces études sous le terme générique de phase précoce représentée par : - les essais de phase 1, - les essais de phase 0 visant à étudier très précocement la molécule, - les essais de phase 1/2 mettant en évidence la dose maximisant l efficacité sous des conditions restrictives de toxicité. L'objectif de ce travail est dans une première partie, de faire le point sur l'évolution des schémas et l'apport de la pharmacologie dans les essais de phase précoce en cancérologie. Nous montrons que la méthodologie de ces études n'a cessée de s'adapter aux innovations thérapeutiques. On présente les schémas traditionnels encore très employés de nos jours. L'évolution de ces schémas par l'emploi de modèles statistiques adaptés, par l'utilisation de la pharmacologie ou pour répondre aux spécificités des thérapies ciblées. On décrit les approches récentes comme les essais de phase 0 ou les essais hybrides de phase 1/2. Pour finir par les schémas d'association de molécules dont la complexité est loin d'être résolue. La seconde partie de ce travail illustre ces considérations théoriques par une série d'études de phase précoce publiées par notre équipe ou en cours de développement. Au total, 6 études sont présentées, elles se veulent représentatives d'une partie des schémas exposés dans la partie théorique.In cancer research, the objectives of phase 1 studies are the estimation of the toxicity to define the Maximal Tolerated Dose and the Recommended Dose as well as the study of the pharmacology of the tested molecule. The evolution of anticancer treatments, the pharmacology and the progress of the biostatistics modified the methodological approach of these studies. We can include these studies under the generic name of early-phase clinical trial represented by: - phase 1 studies, - phase 0 studies, to study very prematurely molecules, - phase 1/2 studies which bring to light the dose maximizing the efficacy under restrictive toxicity conditions. The objective of our work is in a first part, to review the methodological evolution and the contribution of the pharmacology in the early-phase clinical trial in cancer research. We show that the methodology of the early-phase clinical trial evolved with the therapeutic innovations. We present the various traditional designs still very used nowadays. The evolution of these designs by the use of adapted statistical models, by the better use of the pharmacology or to answer the specific methodological requirements of the targeted therapies. We also describe the recent approaches as the phase 0 trial or the hybrid phase 1/2 trial. To finish by designs of molecules combination, the complexity of which is far from being resolved. The second part of this work illustrates these theoretical considerations by a series of studies of early-phase clinical trial published previously by our team or in the course of development. Six studies are presented. They seem to be representative of a part of design exposed in the theoretical part.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Accuracy of Segmented Le Fort I Osteotomy with Virtual Planning in Orthognathic Surgery Using Patient-Specific Implants: A Case Series

Background: When maxillary transversal expansion is needed, two protocols of treatment can be used: a maxillary orthodontic expansion followed by a classical bimaxillary osteotomy or a bimaxillary osteotomy with maxillary segmentation. The aim of this study was to assess the accuracy of segmented Le Fort I osteotomy using computer-aided orthognathic surgery and patient-specific titanium plates in patients who underwent a bimaxillary osteotomy for occlusal trouble with maxillary transversal insufficiencies. Methods: A virtual simulation of a Le Fort I osteotomy with maxillary segmentation, a sagittal split ramus osteotomy, and genioplasty (if needed) was conducted on a preoperative three-dimensional (3D) model of each patient’s skull using ProPlan CMF 3.0 software (Materialise, Leuven, Belgium). Computer-assisted osteotomy saw-and-drill guides and patient-specific implants (PSIs, titanium plates) were produced and used during the surgery. We chose to focus on the maxillary repositioning accuracy by comparing the preoperative virtual surgical planning and the postoperative 3D outcome skulls using surface superimpositions and 13 standard dental and bone landmarks. Errors between these preoperative and postoperative landmarks were calculated and compared to discover if segmental maxillary repositioning using PSIs was accurate enough to be safely used to treat transversal insufficiencies. Results: A total of 22 consecutive patients—15 females and 7 males, with a mean age of 27.4 years—who underwent bimaxillary computer-assisted orthognathic surgery with maxillary segmentation were enrolled in the study. All patients presented with occlusion trouble, 13 with Class III malocclusions (59%) and 9 (41%) with Class II malocclusions. A quantitative analysis revealed that, overall, the mean absolute discrepancies for the x-axis (transversal dimension), y-axis (anterior–posterior dimensions), and z-axis (vertical dimension) were 0.59 mm, 0.74 mm, and 0.56 mm, respectively. The total error rate of maxillary repositioning was 0.62 mm between the postoperative cone-beam computed tomography (CBCT) and the preoperatively planned 3D skull. According to the literature, precision in maxilla repositioning is defined by an error rate (clinically relevant) at each landmark of <2 mm and a total error of <2 mm for each patient. Conclusions: A high degree of accuracy between the virtual plan and the postoperative result was observed

Summary of the population and the surgical procedures.

<p>Summary of the population and the surgical procedures.</p

Evolution des patients présentant une maladie des emboles de cholestérol traités par dialyse péritonéale : étude rétrospective à partir du registre du RDPLF

Cholesterol crystal embolisms disease (CED) is a systemic disease characterized by tissue ischemia and microinflammation related to occlusion of arterioles by microemboli from ulcerated atheromatous plaques. The kidney is one of the most affected organs, often requiring dialysis. Our study examines the outcomes of a cohort of patients with CED treated with peritoneal dialysis (PD). As anticoagulants can favor emboli, peritoneal dialysis may theoretically have an advantage. From the database of the French Language Peritoneal Dialysis Registry (RDPLF), between January 1, 1995, and December 31, 2021, we selected patients treated with PD for &gt;90 days and with an age &gt;18 years. On the basis of the variables of patient autonomy, diabetes, BMI, modified Charlson index, age, sex, pre-PD treatment, causes of death, causes of transfer to hemodialysis, and peritonitis, three types of survival were estimated (patient, technical, and composite). After adjustment by propensity scores and taking into account competitive risks, 2 groups of patients were constituted on the basis of baseline nephropathy: emboli group vs. control group. Patient survival and strict technical survival are not associated with the type of nephropathy (CED versus others). Composite technical survival (uncensored for deaths and transfers to hemodialysis) was only associated with cholesterol emboli nephropathy in the multivariate analysis adjusted for diabetes, autonomy, and age of the patient at the start of the dialysis treatment (p=0.011; 95% CI [0.736 [0.581-0.931]]). Our study from the RDPLF database shows no difference in technical and patient survival in a cohort of patients with CED vs. a control group. It also confirms that PD may represent an adequate choice in this pathology.La maladie des emboles de cholestérol (MEC) est une maladie systémique, caractérisée par une ischémie tissulaire et une micro-inflammation, liée à l’occlusion des artérioles par des micro-emboles en provenance de plaques athéromateuses ulcérées. Le rein est parmi les organes les plus touchés avec souvent nécessité de recours à la dialyse. Les anticoagulants augmentant le risque d’emboles, la dialyse péritonéale peut avoir théoriquement un avantage. Notre étude examine le devenir d’une cohorte de patients avec MEC traités par dialyse péritonéale (DP). A partir de la base de données du Registre de Dialyse Péritonéale de Langue Française (RDPLF), entre le 1/1/1995 et le 31/12/2021, nous avons sélectionné les patients traités par DP depuis &gt;90jours et ayant un âge &gt;18 ans. Sur la base des variables suivantes&nbsp;: autonomie des patients, diabète, IMC, indice de Charlson modifié, âge, sexe, traitement avant DP, causes de décès, causes de transferts en hémodialyse et péritonite, trois types de survie ont été estimées (patient, technique stricte et technique composite). Après ajustement par les scores de propension et prise en compte des risques compétitifs, 2 groupes de patients ont été constitués sur la base de la néphropathie de base&nbsp;: groupe emboles vs groupe autres. La survie patient et la survie technique stricte ne sont pas associées au type de néphropathie (MEC versus autres). La survie technique composite (non censurée pour les décès et transferts en hémodialyse) &nbsp;n’est associée à la néphropathie par emboles de cholestérol que dans l’analyse multivariée ajustée sur le diabète, l’autonomie et l’âge du patients au début de la dialyse (p=0.011&nbsp;; IC95% [0.736 [0.581-0.931]]). &nbsp; Notre étude à partir de la base de données du RDPLF montre l’absence de différence de survie technique et patient dans une cohorte de patients avec MEC vs un groupe contrôle. Elle &nbsp;confirme aussi que la DP peut représenter un choix adéquat au cours de cette pathologie

Computer-assisted teaching of bilateral sagittal split osteotomy: Learning curve for condylar positioning

<div><p>Bilateral sagittal split osteotomy (BSSO) is a widely-performed procedure in orthognathic surgery for the correction of dentofacial deformity. Condylar positioning is a critical step during BSSO to maximize functional and morphological results. The unsuitable positioning of condyles represents one of the causative mechanisms that may induce temporomandibular joint noxious effects after BSSO. Repositioning devices can assist surgeons in maintaining the preoperative condylar position; however, empirical repositioning methods based on experience gained are still commonly used. Trainee learning curves are difficult to assess. The aim of this study was to evaluate the relevance of computer-assisted surgery in the acquisition of condylar positioning skills. Forty-eight patients underwent BSSO performed by six maxillofacial trainees (four junior residents and two senior experienced residents). A condyle positioning system (CPS) was used by a senior surgeon to record a condylar position score during the procedure. Firstly, scores were recorded when the trainee manually positioned the condyle without access to the CPS score (phase 1) and then when the trainee positioned the condyle and performed osteosynthesis with visual access to the CPS score (phase 2). Six parameters describing condylar three-dimensional motions were assessed: translational motion from top to bottom (TB), back to front (BF), and left to right (LR), axial rotation (AR), sagittal rotation (SR), frontal rotation (FR), and a total score (TS). There were no significant differences between junior and senior residents in condyle positioning without access to the CPS. Condyles were significantly better positioned during phase 2 with access to the CPS (<i>p</i><0.001). Over time, use of the CPS (phase 2) produced significantly quicker improvements in scores (<i>p</i> = 0.042). For those teaching surgeries to trainees, computer-assisted devices can potentially result in more rapid learning curves than traditional “observations-imitation” models. Use of a CPS by trainees facilitated condylar repositioning that resulted in an accurate occlusal result and avoidance of adverse effects on the temporomandibular joint.</p></div

Infrared reflectors fixed on the orbital rim.

<p>Infrared reflectors fixed on the orbital rim.</p

Tracking of condylar displacement (rotational and translational motions) on the computer screen.

<p>green: condylar fixed reference position, blue: mobilized bone segment by trainee (trainee position).</p