Synergic PDE3 and PDE4 control intracellular cAMP and cardiac excitation-contraction coupling in a porcine model

International audienc

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response

Mise en évidence d’une transition endothéliale/mésenchymateuse dans les lésions vasculaires pulmonaires d’hypertension artérielle pulmonaire par microscopie corrélative

National audienceL'hypertension artérielle pulmonaire résulte de l'obturation des artères pulmonaires de diamètre inférieur à 500 μm. Par microscopie corrélative, nous avons pu démontrer que cette obturation était la conséquence d'une trans-différenciation des cellules endothéliales en cellules mésenchymateuses

Basic Hemodynamic Monitoring Using Ultrasound or Electrical Cardiometry During Transportation of Neonates and Infants

OBJECTIVES: Electrical cardiometry and heart ultrasound might allow hemodynamic evaluation during transportation of critically ill patients. Our aims were 1) to test feasibility of stroke volume monitoring using electrical cardiometry or ultrasound during transportation and 2) to investigate if transportation impacts on electrical cardiometry and ultrasound reliability. DESIGN: Prospective, pragmatic, feasibility cohort study. SETTING: Mobile ICUs specialized for neonatal and pediatric transportation. PATIENTS: Thirty hemodynamically stable neonates and infants. INTERVENTIONS: Patients enrolled underwent paired stroke volume measurements (180 before/after and 180 during the transfer) by electrical cardiometry (SVEC) and ultrasound (SVUS). MEASUREMENTS AND MAIN RESULTS: No problems or malfunctioning occurred neither with electrical cardiometry nor with ultrasound. Ultrasound lasted on average 90 (10) seconds, while 45 (15) seconds were needed to instigate electrical cardiometry monitoring. Coefficient of variation was higher for SVUS (before/after: 0.57; during: 0.66) than for SVEC (before/after: 0.38; during: 0.36). Correlations between SVEC and SVUS before/after and during the transfer were r equal to 0.57 and r equal to 0.8, respectively (p always \textless 0.001). Bland-Altman analysis showed that stroke volume tends to be higher if measured by electrical cardiometry. SVEC measured before (5.5 [2.4] mL), during (5.4 [2.4] mL), and after the transfer (5.4 [2.3] mL) are similar (p = 0.955); same applies for SVUS before (2.6 [1.5] mL), during (2.4 [2] mL), and after (2.9 [2] mL) the transfer (p = 0.268). CONCLUSIONS: Basic hemodynamic monitoring is feasible during pediatric and neonatal transportation both with electrical cardiometry and ultrasound. These two techniques show comparable reliability, although stroke volume was higher if measured by electrical cardiometry. The transportation itself does not affect the reliability of stroke volume measurements

Red Noise in Steady-State Multiphase Flow in Porous Media

Understanding the interaction between competing fluids in the pore space of rocks is key for predicting subsurface flow and trapping, such as with CO2 in a saline aquifer. These processes occur over a large span of timescales (from seconds to thousands of years), and length scales (from microns to kilometers). Understanding the link between these temporal and spatial scales will enable us to interpolate between observations made at different resolutions. In this work we explore the temporal scales present during macroscopically steady-state multiphase flow in a porous carbonate rock using differential pressure measurements acquired over a period of 60 min. Nitrogen and brine were injected simultaneously into a sample 5 mm in diameter and 21 mm in length. We observe a cascade of timescales in the pressure differential that is, a continuous range of frequencies, with lower frequencies having greater amplitudes. We demonstrate a scaling of the spectral density with frequency of S ∼ 1/f2, or red noise, to describe the dynamics. This scaling is independent of the flow rate of the fluids or the fraction of the flow taken by water. This red, or Brownian, noise indicates a stochastic process where pressure fluctuations are seen throughout the pore space, resulting in intermittent filling of pores over a wide range of time-scales, from seconds to minutes in these experiments. The presence of red noise suggests self-organized critically, with no characteristic time or length scale.</p

Ca 2+ handling remodeling and STIM1L/Orai1/TRPC1/TRPC4 upregulation in monocrotaline-induced right ventricular hypertrophy

International audienceBackground Right ventricular (RV) function is the most important prognostic factor for pulmonary arterial hypertension (PAH) patients. The progressive increase of pulmonary vascular resistance induces RV hypertrophy (RVH) and at term RV failure (RVF). However, the molecular mechanisms of RVH and RVF remain understudied. In this study, we gained insights into cytosolic Ca 2+ signaling remodeling in ventricular cardiomyocytes during the pathogenesis of severe pulmonary hypertension (PH) induced in rats by monocrotaline (MCT) exposure, and we further identified molecular candidates responsible for this Ca 2+ remodeling. Methods and Results After PH induction, hypertrophied RV myocytes presented longer action potential duration, higher and faster [Ca 2+ ]i transients and increased sarcoplasmic reticulum (SR) Ca 2+ content, whereas no changes in these parameters were detected in left ventricular (LV) myocytes. These modifications were associated with increased P-Ser 16-phospholamban pentamer expression without altering SERCA2a (Sarco/Endoplasmic Reticulum Ca 2+-ATPase) pump abundance. Moreover, after PH induction, Ca 2+ sparks frequency were higher in hypertrophied RV cells, while total RyR2 (Ryanodine Receptor) expression and phosphorylation were unaffected. Together with cellular hypertrophy, the T-tubules network was disorganized. Hypertrophied RV cardiomyocytes from MCT-exposed rats showed decreased expression of classical STIM1 (Stromal Interaction molecule) associated with increased expression of muscle-specific STIM1 Long isoform, glycosylated-Orai1 channel form, and TRPC1 and TRPC4 channels, which was correlated with an enhanced Ca 2+-release-activated Ca 2+ (CRAC)like current. Pharmacological inhibition of TRPCs/Orai1 channels in hypertrophied RV cardiomyocytes normalized [Ca 2+ ]i transients amplitude, the SR Ca 2+ content and cell contractility to control levels. Finally, we showed that most of these changes did not appear in LV cardiomyocytes. Conclusions These new findings demonstrate RV-specific cellular Ca 2+ cycling remodeling in PH rats with maladaptive RVH and that the STIM1L/Orai1/TRPC1/C4-dependent Ca 2+ current participates in this Ca 2+ remodeling in RVH secondary to PH

Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension

International audienceObjective: We aimed to assess the mitochondrial respiratory capacities in the right ventricle in the setting of ventricular remodeling induced by pressure overload.Methods: Chronic thromboembolic pulmonary hypertension was induced in 8 piglets over a 12-week period (chronic thromboembolic pulmonary hypertension model). Right ventricular remodeling, right ventricular function, and mitochondrial respiratory function were assessed at 3, 6, and 12 weeks after induction of pulmonary hypertension and were compared with sham animals (n = 5). Right ventricular cardiomyocytes and mitochondrial structure were studied in transmission electronic microscopy after 12 weeks.Results: As of 3 weeks, chronic pressure overload induced right ventricular dilatation, right ventricular hypertrophy, and right ventricular dysfunction. Maladaptive remodeling in the chronic thromboembolic pulmonary hypertension model was confirmed by the decrease of right ventricular pulmonary artery coupling and right fractional area change. Mitochondrial functional assays in permeabilized right ventricular myocardial fibers revealed that oxidative phosphorylation capacities (complex I, complex II, and IV of the mitochondrial respiratory chain) were degraded. Furthermore, no change in substrate preference of mitochondria was found in the overloaded right ventricle. There was a good correlation between maximal mitochondrial oxygen consumption rate and right ventricular pulmonary artery coupling (Pearson coefficient r = 0.83). Transmission electronic microscopy analysis showed that the composition of cardiomyocytes was no different between the chronic thromboembolic pulmonary hypertension group and the sham group. However, mitochondrial structure anomalies were significantly increased in the chronic thromboembolic pulmonary hypertension group.Conclusions: Mitochondrial respiratory function impairment is involved early in the development of right ventricular dysfunction in a piglet model of chronic thromboembolic pulmonary hypertension. Underlying mechanisms remain to be elucidated

Occurrence of minimal change nephrotic syndrome in classical Hodgkin lymphoma is closely related to the induction of c-mip in Hodgkin-Reed Sternberg cells and podocytes.

International audienceIt is currently considered that idiopathic minimal change nephrotic syndrome is an immune-mediated glomerular disease. Its association with classical Hodgkin lymphoma minimal change nephrotic syndrome (cHL-MCNS) suggests a molecular link, which remains to be elucidated. We analyzed the expression of cmaf inducing protein (c-mip) in lymphomatous tissues and kidney biopsy samples of patients with cHL-MCNS (n = 8) and in lymphomatous tissues of patients with isolated cHL (n = 9). Because c-mip affects the regulatory loop involving Fyn, we investigated possible structural defects in this signaling pathway, using laser capture microdissection, reverse transcription polymerase chain reaction, and Western blotting. We found that c-mip was selectively expressed in Hodgkin and Reed-Sternberg (HRS) cells and podocytes of patients with cHL-MCNS but is undetectable in patients with isolated cHL. We demonstrated that c-mip was specifically involved in the negative regulation of early proximal signaling through its interaction with phosphoprotein associated with glycosphingolipid-enriched microdomains and Fyn. We showed that the up-regulation of c-mip in cHL-MCNS was associated with a possible Fyn defect in HRS cells and podocytes. Moreover, we showed that c-mip was up-regulated in Fyn-deficient podocytes. c-mip may be a useful marker of cHL-MCNS and its induction reflects the dysregulation of proximal signaling

Concise Review: Pluripotent Stem Cell-Derived Cardiac Cells, A Promisingă Cell Source for Therapy of Heart Failure: Where Do We Stand?

International audienceHeart failure is still a major cause of hospitalization and mortality ină developed countries. Many clinical trials have tested the use ofă multipotent stem cells as a cardiac regenerative medicine. The benefită for the patients of this therapeutic intervention has remained limited.ă Herein, we review the pluripotent stem cells as a cell source foră cardiac regeneration. We more specifically address the variousă challenges of this cell therapy approach. We question the cell deliveryă systems, the immune tolerance of allogenic cells, the potentială proarrhythmic effects, various drug mediated interventions to facilitateă cell grafting and, finally, we describe the pathological conditions thată may benefit from such an innovative approach. As members of aă transatlantic consortium of excellence of basic science researchers andă clinicians, we propose some guidelines to be applied to cell types andă modes of delivery in order to translate pluripotent stem cell cardiacă derivatives into safe and effective clinical trials