STAT5-and hypoxia-dependent upregulation of AXL

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones

Michel Strogoff. Marche triomphale : [pour piano] / musique de Alexandre Artus, ... ; [ill. par] P. Borie

Titre uniforme : Artus, Alexandre (1821-1911). Compositeur. [Michel Strogoff. Piano ou orchestre. Marche triomphale

Rothomago-fanfare : pas redoublé : piano / Alexandre Artus, ...

Titre uniforme : Artus, Alexandre (1821-1911). Compositeur. [Rothomago-fanfare. Piano ou orchestre

Marche des trompettes : exécutée au Théâtre du Châtelet dans "Madame Thérèse" : piano / [musique de] Alexandre Artus, ...

Titre uniforme : Artus, Alexandre (1821-1911). Compositeur. [Madame Thérèse. Piano. Marche des trompettes

ICM conversion to epiblast by FGF/ERK inhibition is limited in time and requires transcription and protein degradation

Abstract Inner cell Mass (ICM) specification into epiblast (Epi) and primitive endoderm (PrE) is an asynchronous and progressive process taking place between E3.0 to E3.75 under the control of the Fibroblast Growth Factor (FGF)/Extracellular signal-Regulated Kinase (ERK) signaling pathway. Here, we have analyzed in details the kinetics of specification and found that ICM cell responsiveness to the up and down regulation of FGF signaling activity are temporally distinct. We also showed that PrE progenitors are generated later than Epi progenitors. We further demonstrated that, during this late phase of specification, a 4 hours period of FGF/ERK inhibition prior E3.75 is sufficient to convert ICM cells into Epi. Finally, we showed that ICM conversion into Epi in response to inhibition during this short time window requires both transcription and proteasome degradation. Collectively, our data give new insights into the timing and mechanisms involved in the process of ICM specification

Efficacy and safety of the new TightRail™ mechanical sheath for transvenous lead extraction: Results of a French multicenter study

Abstract Introduction The aim of this study was to assess the safety and efficacy of the TightRail™ sheath for pacemaker/defibrillator transvenous lead extraction (TLE). Methods Multicenter observational study including patients who underwent a TLE with the TightRail™ sheath in five French university hospitals from September 2014 to January 2020. Results Two hundred and twenty‐five patients (76% males, 71 ± 12 years) underwent a TLE procedure with the TightRail™. A total of 438 leads were extracted using the TightRail™, and the mean age of the extracted leads was 128 ± 85 months; of these, 344 (79%) were pacing leads and 94 (21%) were implantable cardioverter defibrillator leads. The overall clinical success of the extraction procedures was 93%. Overall, 410 of the 438 leads (95%) were extracted (complete or incomplete removal). After multilevel mixed‐effects logistic regression model, we found that lead age (odds ratio [OR], 95% confidence interval [CI] for a 1 year increase: 1.11 [1.07–1.15], p < .001) and number of leads extracted (OR, 95% CI: 2.09 [1.50–2.96], p < .001) were the two independent factors associated with complete lead removal failure. Finally, there were 7 (3%) cases of major complications but no per‐procedural death. Conclusion This is the first large‐scale survey assessing the efficacy and safety profile of the Tightrail™ mechanical sheath. The clinical success rate was 93%, and the lead removal failure was dependent on the age and number of leads. We show a satisfactory safety profile in this cohort of patients from primarily low‐volume centers with older leads

Detection of Myocardial Infarction by Cardiac Magnetic Resonance in Embolic Stroke Related to First Diagnosed Atrial Fibrillation

International audienc

Acute myocarditis with autoimmune features: one-year follow-up with CMR

International audienc

Adherence to Treatment Guidelines and Associated Survival in Older Patients with Prostate Cancer: A Prospective Multicentre Cohort Study

International audienceThe guidelines on prostate cancer treatment in older men recommend evaluating the patient’s underlying health status before treatment selection. We aimed to evaluate the frequency of a guideline–discordant treatment (GDT), identify factors associated with GDT, and assess the relationship between GDT and overall survival. We studied patients with prostate cancer aged 70 or older included in the ELCAPA cohort between 2010 and 2019. Multivariable logistic regression assessed GDT-associated factors. The restricted mean survival time (RMST) assessed the 24- and 36-month OS using stabilized inverse probability of treatment weighting of propensity scores. We included 356 patients (median age: 81 years), and 164 (46%) received a GDT (95% confidence interval (CI) = (41–51%)). Patients with metastases were less likely to receive a GDT (adjusted odds ratio (95% CI) = 0.34 (0.17–0.69); p = 0.003). After weighting, the RMST at 24 months was shorter in the GDT group (13.9 months, vs. 17 months for compliant treatments; difference (95% CI): −3.1 months (−5.3, −1.0); p = 0.004). RMST at 36 months was 18.5 months, vs. 21.8 months (difference: −3.3 months (−6.7, 0.0); p = 0.053). GDT is common in older patients with prostate cancer and especially those with non-metastatic disease. GDT was associated with worse survival, independently of health status and tumour characteristics

Nephron-sparing surgery for renal tumors measuring more than 7 cm: morbidity, and functional and oncological outcomes

International audienceBACKGROUND: The purpose of this study was to evaluate morbidity, functional, and oncological outcomes after NSS in renal tumors \textgreater 7 cm. MATERIALS AND METHODS: We retrospectively analyzed data from 168 patients with tumors \textgreater 7 cm who were treated using NSS between 1998 and 2012. RESULTS: Imperative and elective indications accounted for 76 (45.2%) and 92 (54.8%) patients, respectively. Major perioperative complications and renal function deterioration occurred in 33 (19.6%) and 51 patients (30.4%), respectively. In multivariate analysis, age older than 60 years (P = .001; hazard ratio [HR], 5) and tumor malignancy (P = .014; HR, 6.7) were prognostic factors for renal function deterioration whereas imperative indication was a risk factor for major postoperative complications (P = .0019; HR, 2.7). In 126 (75%) patients with malignant tumors, after a median follow-up of 30 months (range, 1-254 months), 25 patients (20.2%) died. In multivariate analysis, imperative indication (P = .023; HR, 4.2), positive surgical margin (P = .021; HR, 3.3), and Fuhrman grade \textgreater II (P = .013; HR, 3.7) were prognostic indicators for cancer-free survival (CFS). Imperative indication (P = .04; HR, 8.5) and Fuhrman grade \textgreater II (P = .04; HR, 3.9) were predictive factors of cancer-specific survival (CSS). In case of elective indication, positive surgical margin, local recurrence, and cancer-related death occurred in 4 (7.6%), 1 (1.1%), and 1 (1.1%) cases, respectively. For elective indication, 5-year estimates of CFS, CSS, and overall survival rates were: 85.7%, 98%, and 93.9%, respectively. CONCLUSION: In this selected population, imperative vs. elective indication status seems to play a critical role in oncologic outcomes. Oncologic results for elective indications are close to those reported with radical nephrectomy