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Formation Of Gold-Astatine Bonds in N-Heterocyclic Carbene Complexes
No full textInternational audienceWith the purpose of exploring alternatives to the poorly stable astatoaryl bond found in most 211At‐labeled radiopharmaceuticals, the coordination between astatine and metal‐NHC (NHC = N‐heterocyclic carbene) complexes was investigated. To orient this work, relativistic DFT calculations were performed, highlighting a superiority of gold(I) over rhodium(I) and iridium(I), both regarding the strength of the metal‐astatine bond and the metal’s preference for astatine over other halogens. The DFT calculations also revealed a more stable metal‐astatine bond with electron withdrawing NHCs. Accordingly, two Au(I) complexes, [AuCl(IPr)] (IPr = N,N’‐bis[2,6‐(di‐isopropyl)phenyl]imidazol‐2‐ylidene) and [AuCl(IAd)] (IAd = N,N’‐bis[adamantyl]imidazol‐2‐ylidene) were radiolabelled by halide exchange in excellent radiochemical yields with iodine‐125 and astatine‐211 in a water/acetonitrile mixture with a reducing agent. While the adamantyl substituted complex was not investigated further due to its lack of solubility in aqueous or semi aqueous media, the stability of [Au211At(IPr)] in presence of phosphate buffered saline was evaluated and proved excellent (96% after two half‐lives) encouraging further studies with relevant cancer targeting vectors
Stereotactic body radiotherapy for lung oligometastatic prostate cancer: An international retrospective multicenter study
No full textInternational audienceBackground: Management of prostate cancer (PCa) patients with lung oligometastases remains unclear in the absence of published data.Objective: The aim of this study was to evaluate the efficacy of Stereotactic Body Radiotherapy (SBRT) in this setting.Design setting and participants: We conducted a multicenter retrospective study that included 35 PCa patients treated with SBRT for lung oligometastases in 7 centers across 3 countries.Outcome measurements and statistical analysis: The efficacy was evaluated by the progression free-survival (PFS), defined as pre-SBRT PSA + 25 % or nadir PSA + 25 % and + 2 ng/mL or radiological progression if it occurred before biochemical progression. The local recurrence free-survival (LRFS), distant metastases free-survival (DMFS), Overall Survival (OS) and Androgen Deprivation Therapy free-survival were also assessed. Survival was estimated using the Kaplan Meier method.Results: 35 patients were included with lung oligometastases staged with PET-CT for 97 % and histologically biopsy confirmed for 51 %. 77 % had an oligorecurrent metastatic disease. The median pre SBRT PSA was at 1.7 ng/mL [0.8, 3.0] and the median follow-up after SBRT was 28.7 months. The median PFS was 21.6 months [95 %CI: 21.6; NA] and the median DMFS was 32.4 months [95 %CI: 22.2-NA]. No parameters were significantly associated with PFS on the univariate and multivariate models.For patients who did not start ADT before or concomitantly with SBRT (n = 18), the 1-year ADT free-survival rate was estimated at 87.2 % [71.9;100].Conclusions: SBRT for PCa lung oligometastases offers good oncological outcomes, comparable to those reported for bone and/or lymph node metastases SBRT. Our results encourage the inclusion of patients with lung oligometastatic disease in clinical trials designed to assess the value of SBRT.Patient summary: SBRT for prostate cancer lung oligometastases shows promising results, similar to treatments for bone or lymph node oligometastases
Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden: A Real-World Observational Study From the French National Healthcare System Database
No full textInternational audiencePurpose: To assess the incidence (all lesions) of bladder cancer (BC) in France, describe patient characteristics and healthcare pathways during the first year after diagnosis, and estimate medical costs.Methods: All adult patients with an initial BC diagnosis (ICD-10 codes: C67, D09.0, D41.4) in 2017 were selected from the French National Healthcare System Database. Patients were classified according to the most invasive surgical procedure they underwent. Treatments included cystectomy, transurethral resection of bladder tumor (TURBT), intravesical therapy, chemotherapy, and radiotherapy. Healthcare pathways were analyzed as sequences and grouped using hierarchical clustering. Medical costs during the first year of the disease were estimated for each cluster.Results: Out of 24,737 incident BC patients selected, the median age at diagnosis was 72 years, and 80.2% were men. Nearly 20% had received treatment for a cancer other than BC in the previous year. The majority (n = 9501, 38.4%) underwent TURBT only with a mean medical cost of €4435 [95% CI: 4322; 4548]. A total of 3037 patients (12.3%) underwent cystectomy as their initial treatment. The estimated costs for the group receiving intravesical instillations following a single TURBT (€6129 [5994; 6264]) were lower than those for the group with repeated TURBT (€9357 [9086; 9628]). Costs for patients who received systemic treatment after cystectomy were the highest at €25,636 [24,519; 26,752].Conclusion: Our study estimates the incidence of BC in France, describes healthcare pathways at the national level, and analyses the associated economic burden
Early development and co‐evolution of microstructural and functional brain connectomes: A multi‐modal MRI study in preterm and full‐Term Infants
No full textInternational audienceFunctional networks characterized by coherent neural activity across distributed brain regions have been observed to emerge early in neurodevelopment. Synchronized maturation across regions that relate to functional connectivity (FC) could be partially reflected in the developmental changes in underlying microstructure. Nevertheless, covariation of regional microstructural properties, termed “microstructural connectivity” (MC), and its relationship to the emergence of functional specialization during the early neurodevelopmental period remain poorly understood. We investigated the evolution of MC and FC postnatally across a set of cortical and subcortical regions, focusing on 45 preterm infants scanned longitudinally, and compared to 45 matched full‐term neonates as part of the developing Human Connectome Project (dHCP) using direct comparisons of grey‐matter connectivity strengths as well as network‐based analyses. Our findings revealed a global strengthening of both MC and FC with age, with connection‐specific variability influenced by the connection maturational stage. Prematurity at term‐equivalent age was associated with significant connectivity disruptions, particularly in FC. During the preterm period, direct comparisons of MC and FC strength showed a positive linear relationship, which seemed to weaken with development. On the other hand, overlaps between MC‐ and FC‐derived networks (estimated with Mutual Information) increased with age, suggesting a potential convergence towards a shared underlying network structure that may support the co‐evolution of microstructural and functional systems. Our study offers novel insights into the dynamic interplay between microstructural and functional brain development and highlights the potential of MC as a complementary descriptor for characterizing brain network development and alterations due to perinatal insults such as premature birth
Efficacy of Irbesartan in Celiprolol-Treated Patients With Vascular Ehlers-Danlos Syndrome
No full textInternational audienceBACKGROUND: Vascular Ehlers-Danlos syndrome is a rare genetic disorder characterized by defective type III collagen and a high risk of arterial morbidity and mortality. Several cardiovascular drugs are used for treatment, including celiprolol, but no controlled trial in this condition has been conducted to date. We hypothesized the benefit of the addition of an angiotensin II receptor blocker. METHODS: A multicenter, randomized, placebo-controlled trial was conducted to assess the efficacy and safety of the angiotensin II receptor blocker irbesartan in adults with vascular Ehlers-Danlos syndrome on stable background celiprolol therapy. Patients were randomized 1:1 to receive irbesartan (150 mg/day titrated to 300 mg/day) or placebo for 2 years. The composite primary outcome was defined as any vascular Ehlers-Danlos syndrome–related fatal or nonfatal arterial event or any new or worsening arterial lesions detected by systematic head-to-pelvis computed tomography angiography or peripheral arterial duplex ultrasound at different time points, using a time-to-first-event analysis. RESULTS: Twenty-nine participants (62% female; 40.3±11.3 years of age) were randomized to irbesartan, and 28 (64% female; 40.7±11.0 years of age) were randomized to placebo. The composite primary outcome occurred in 8 of 29 patients (27.6%) receiving irbesartan versus 15 of 28 patients (53.6%) receiving placebo (hazard ratio, 0.42 [95% CI, 0.17, 0.99]; P <0.05). The risk of recurrent symptomatic or nonsymptomatic arterial events was lower with irbesartan than with placebo (risk ratio, 0.37 [95% CI, 0.19, 0.68]; P =0.002). A reduction of progression of arterial lesions was observed at all sites. Irbesartan significantly reduced systolic blood pressure compared with placebo (baseline-adjusted difference of 5.4 mm Hg [ P <0.001]), but no relation was observed with the reduction of the primary composite outcome. Eleven episodes of irbesartan-related hypotension were recorded, leading to a downtitration in 4 patients. CONCLUSIONS: Compared with placebo, irbesartan reduced the risk of severe symptomatic and asymptomatic arterial events in patients with vascular Ehlers-Danlos syndrome on background celiprolol therapy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02597361
Acne-induced Post-inflammatory Hyperpigmentation: From Grading to Treatment
No full textInternational audienceAcne-induced post-inflammatory hyperpigmentation (AI-PIH) can occur without any visible clinical evidence of significant inflammation, even in patients with mild to moderate acne. Currently, visual assessment is the main criterion for evaluating the severity of PIH, including that of AI-PIH in daily clinical practice. Treatment indications are lacking. This work provides an easy-to-use AI-PIH severity grading tool for daily clinical practice as well as indications on how to prevent and treat AI-PIH using currently available treatment options. Five experts in acne provided a short overview concerning the epidemiology and physiopathology of AI-PIH, developed an AI-PIH severity grading tool, and proposed preventive measures as well as an AI-PIH treatment algorithm. Only a small number of epidemiological data on AI-PIH are available, confirming that the condition is mainly observed in patients with Phototypes IV to VI. The physiopathology of AI-PIH is still not completely understood. Innate immunity, Cutibacterium acnes, and external factors such as UV radiation, visible light, and air pollution play a role in its development. An easy-to-use AI-PIH severity grading tool (Acne PIgmentation Grading) allows quick assessment of acne severity during the consultation, and, in addition to proposed preventive measures, a treatment algorithm is proposed according to AI-PH severity. Patient education remains key. Providing an AI-PIH severity assessment tool as well as preventive and treatment recommendations may help to manage AI-PIH more efficiently
Rev-erb-α antagonism in alveolar macrophages protects against pneumococcal infection in elderly mice
No full textInternational audienceCircadian rhythms control the diurnal nature of many physiological, metabolic, and immune processes. We hypothesized that age-related impairments in circadian rhythms are associated with high susceptibility to bacterial respiratory tract infections. Our data show that the time-of-day difference in the control of Streptococcus pneumoniae infection is altered in elderly mice. A lung circadian transcriptome analysis revealed that aging alters the daily oscillations in the expression of a specific set of genes and that some pathways that are rhythmic in young-adult mice are non-rhythmic or time shifted in elderly mice. In particular, the circadian expression of the clock component Rev-erb-α and apelin/apelin receptor was altered in elderly mice. In young-adult mice, we discovered an interaction between Rev-erb-α and the apelinergic axis that controls host defenses against S. pneumoniae via alveolar macrophages. Pharmacological repression of Rev-erb-α in elderly mice resulted in greater resistance to pneumococcal infection. These data suggest the causative role of age-associated impairments in circadian rhythms on respiratory infections and have clinical relevance
Tetraspanins affect membrane structures and the trafficking of molecular partners: what impact on extracellular vesicles?
No full textInternational audienceTetraspanins are a family of 33 proteins in mammals believed to play a crucial role in the compartmentalization of various associated proteins within cells and membranes. Recent studies have elucidated the structure of several tetraspanin members, revealing that while the four transmembrane domains typically adopt a cone-shaped configuration in crystals, other conformations are also possible. This cone-shaped structure may explain why tetraspanins are often enriched in curved and tubular cellular structures, such as microvilli, tunneling nanotubes, retraction fibers, or at the site of virus budding, and may contribute to the formation or maintenance of these structures. Tetraspanins have also been detected on midbody remnants and migrasomes, as well as on extracellular vesicles (EVs), for which CD9, CD81, and CD63 are widely used as markers. Although their impact on certain membrane structures and their ability to regulate the function and trafficking of associated proteins would suggest a potential role of tetraspanins either in EV formation or in regulating their protein composition, or both, efforts to characterize these roles have been complicated by conflicting results. In line with the interaction of certain tetraspanins with cholesterol, two recent studies have suggested that the presence or organization of oxysterols and cholesterol in EVs may be regulated by Tspan6 and CD63, respectively, paving the way for further research on the influence of tetraspanins on the lipid composition of EVs
Renin-Angiotensin System Drives Leukemia Progression by Reprogramming the Niche
No full textInternational audienceNo abstract availabl
MHC-I–Driven Antitumor Immunity Counterbalances Low Absorbed Doses of Radiopharmaceutical Therapy
No full textInternational audiencePreclinical and clinical studies increasingly show that the immune response plays a major role in radiotherapy. Here, we investigated the role of major histocompatibility complex class I (MHC-I) molecules recognized by cytotoxic CD8+ T cells in the response to radiopharmaceutical therapy (RPT). Methods: Two murine melanoma cell lines that express low and high MHC-I levels (B16F10 and B16K1, respectively) were grafted in syngeneic or athymic and nude mice, and the response to a single injection of [225Ac]Ac-DOTA-TA99 monoclonal antibodies (9.25 or 18.5 kBq) was assessed and related to dosimetry. For clinical relevance, MHC-I expression was determined in samples from patients with well-differentiated, iodine-avid metastatic thyroid cancer and well-differentiated grade 2 mid-gut neuroendocrine tumors. Results: RPT efficacy was enhanced by T-cell presence and MHC-I expression. In mice harboring B16F10 and B16K1 melanoma tumors, RPT showed a stronger antitumor effect in C57BL/6J (immunocompetent) animals than in athymic and nude (immunodeficient) animals, suggesting a crucial role of T-cell-mediated immune responses. Moreover, the response to irradiation was the same in B16K1 MHC-Ihigh tumors with a low absorbed dose of α-RPT and in B16F10 MHC-Ilow tumors with a 4 times higher absorbed dose. These results indicate that CD8+ T cells can counterbalance low tumor irradiation. Conversely, delivering high absorbed doses leads to side effects and seems to prevent immune system activation, thereby not taking advantage of these mechanisms. Our results also indicate that MHC-I can be used as a predictive biomarker of RPT response in lesions receiving low absorbed doses and that RPT treatment regimens should be reconsidered in the function of the MHC-I expression level. Conclusion: This study shows that MHC-I expression can predict RPT immunostimulatory effects. This is relevant in metastatic disease where lesions in the same patient can receive very low or very high absorbed doses