Cardiovascular risk factors and mortality in children with chronic kidney disease

Background. Cardiovascular disease (CVD) begins early in children with chronic kidney disease (CKD), and its progression is determined by the presence of single or multiple cardiovascular risk factors (CVRFs).Objective. To determine the prevalence of CVRFs in children with CKD and their association with mortality in children on chronic dialysis.Methods. This comparative cross-sectional study recruited children aged 5 - 18 years with all stages of CKD. All patients had a short history taken along with a physical examination, and their blood samples were assessed for serum creatinine, urea, albumin, calcium, phosphorus, parathyroid hormone, alkaline phosphatase, total cholesterol (TC), haemoglobin and C-reactive protein. Urine samples were also assessed for proteinuria.Results. One hundred and six children who met the study criteria were recruited, 34 with CKD I, 36 with CKD II - IV and 36 with CKD V (dialysis). The overall median age was 11 years (range 8 - 14), and the male/female ratio was 2.1:1. The most common CVRF was anaemia (39.6%). The rate of anaemia was higher in the dialysis group than in the CKD II - IV and CKD I groups (77.8%, 33.3% and 5.9%, respectively). Other CVRFs detected were hypertension, proteinuria, hypercholesterolaemia and dysregulated mineral bone metabolism. Seven deaths were recorded in the dialysis group during the study period. Severe hypertension and intracranial bleeding were the most common causes of death. Modifiable risk factors such as increased TC and decreased albumin levels were more common than other CVRFs in the dialysis patients who died.Conclusions. CVRFs may be present in early CKD, even before the decline in GFR. Routine screening for CVRFs, along with timely intervention, may prevent the progression of CVD and mortality later in life.

Seismic constraints on rotation of Sun-like star and mass of exoplanet

Rotation is thought to drive cyclic magnetic activity in the Sun and Sun-like stars. Stellar dynamos, however, are poorly understood owing to the scarcity of observations of rotation and magnetic fields in stars. Here, inferences are drawn on the internal rotation of a distant Sun-like star by studying its global modes of oscillation. We report asteroseismic constraints imposed on the rotation rate and the inclination of the spin axis of the Sun-like star HD 52265, a principal target observed by the CoRoT satellite that is known to host a planetary companion. These seismic inferences are remarkably consistent with an independent spectroscopic observation (rotational line broadening) and with the observed rotation period of star spots. Furthermore, asteroseismology constrains the mass of exoplanet HD 52265b. Under the standard assumption that the stellar spin axis and the axis of the planetary orbit coincide, the minimum spectroscopic mass of the planet can be converted into a true mass of 1.85 (+0.52,-0.42) M_Jupiter, which implies that it is a planet, not a brown dwarf.Comment: Published in Proceedings of the National Academy of Sciences (5 pages, 5 figures, 3 tables). Available at http://www.pnas.org/cgi/doi/10.1073/pnas.130329111

Detection of solar-like oscillations from Kepler photometry of the open cluster NGC 6819

Asteroseismology of stars in clusters has been a long-sought goal because the assumption of a common age, distance and initial chemical composition allows strong tests of the theory of stellar evolution. We report results from the first 34 days of science data from the Kepler Mission for the open cluster NGC 6819 -- one of four clusters in the field of view. We obtain the first clear detections of solar-like oscillations in the cluster red giants and are able to measure the large frequency separation and the frequency of maximum oscillation power. We find that the asteroseismic parameters allow us to test cluster-membership of the stars, and even with the limited seismic data in hand, we can already identify four possible non-members despite their having a better than 80% membership probability from radial velocity measurements. We are also able to determine the oscillation amplitudes for stars that span about two orders of magnitude in luminosity and find good agreement with the prediction that oscillation amplitudes scale as the luminosity to the power of 0.7. These early results demonstrate the unique potential of asteroseismology of the stellar clusters observed by Kepler.Comment: 5 pages, 4 figures, accepted by ApJ (Lett.

Exploiting Mitochondrial Dysfunction for Effective Elimination of Imatinib-Resistant Leukemic Cells

Challenges today concern chronic myeloid leukemia (CML) patients resistant to imatinib. There is growing evidence that imatinib-resistant leukemic cells present abnormal glucose metabolism but the impact on mitochondria has been neglected. Our work aimed to better understand and exploit the metabolic alterations of imatinib-resistant leukemic cells. Imatinib-resistant cells presented high glycolysis as compared to sensitive cells. Consistently, expression of key glycolytic enzymes, at least partly mediated by HIF-1α, was modified in imatinib-resistant cells suggesting that imatinib-resistant cells uncouple glycolytic flux from pyruvate oxidation. Interestingly, mitochondria of imatinib-resistant cells exhibited accumulation of TCA cycle intermediates, increased NADH and low oxygen consumption. These mitochondrial alterations due to the partial failure of ETC were further confirmed in leukemic cells isolated from some imatinib-resistant CML patients. As a consequence, mitochondria generated more ROS than those of imatinib-sensitive cells. This, in turn, resulted in increased death of imatinib-resistant leukemic cells following in vitro or in vivo treatment with the pro-oxidants, PEITC and Trisenox, in a syngeneic mouse tumor model. Conversely, inhibition of glycolysis caused derepression of respiration leading to lower cellular ROS. In conclusion, these findings indicate that imatinib-resistant leukemic cells have an unexpected mitochondrial dysfunction that could be exploited for selective therapeutic intervention

Arguments en faveur de l'existence d'une activité pro-apoptotique des lamellarines vis-à-vis des cellules tumorales par ciblage mitochondrial

Most anticancer treatments induce apoptosis of tumor cells in vitro and in vivo. The common anticancer agents act on primitive cellular targets, mainly localized in nucleus, and active subsequently different apoptotic pathways leading ultimately to cell death. Therefore, resistance to apoptosis induction by classical chemotherapeutic compounds is a crucial problem. Thus targeting others subcellular structures different from nucleus may be useful to bypass in part phenomenon of apoptosis resistance. The mitochondria appear an interesting target localized on crossroad of the different apoptotic pathways. Thus, new drugs targeting the mitochondria have been identified. From them, our lab interested on the Lamellarins, marine hexacyclic pyrrolic alkaloids. In addition to their inhibitor effects on nuclear topoisomerases-I, Lamellarins also act on mitochondria of cancer cells. My work consisted 1) on evaluating advantages of the Lamellarins in treatment of resistant cancer cell lines with inefficient apoptotic pathways (non small carcinoma lung cancer cells, NSCLC) and 2) on elucidating the apoptotic pathways activated by the Lamellarins. Thereby, we tested effects of two potential anticancer agents from Lamellarins class on a highly apoptosis-resistant NSCLC cell line. Both the Lamellarin-D (Lam-D) and its synthetic amino derivative PM031379, act directly on mitochondria inducing the Bax activation, the mitochondrial release of cytochrome-c and AIF, as well as the activation of caspase-3. However the PM031379 only triggered cell death coupled to the nuclear translocation of AIF. Furthermore, this lethal effect needs the generation of mitochondrial reactive oxygen species (ROS). These results allowed understanding the mechanisms useful to restore apoptosis in chemoresistant cells. 2) The second part of this work consisted on characterizing the apoptotic pathways activated by the Lam-D by evaluating precisely the nuclear and mitochondrial contributions on its pro-apoptotic effects. The Lam-D displays high potent cytotoxicity against a large panel of tumors. In the micromolar range, Lam-D promoted nuclear apoptosis in leukemia cells without prominent cell cycle arrest. Signals transmitted by Lam-D initiated apoptosis via the mitochondrial intrinsic apoptotic pathway, activating Bax and reducing the levels of anti-apoptotic proteins Bcl-2 and cIAP2 in association with activation of caspases-9 and -3. Our results indicate that cell death induced by Lam-D was independent of the extrinsic apoptotic pathway. Lam-D also exerted a topoisomerase I-mediated DNA damage response resulting in phosphorylation of H2AX, upregulation of the repair protein Rad51 and of p53. However, using several cancer cell lines, we have shown that the mechanism of apoptosis induced by Lam-D is independent of the p53 status of the tumor cells. Furthermore sensitivity to Lam-D was abrogated in enucleated cells (cytoplasts). Altogether these results demonstrate that the Lam-D exerts its cytotoxic effects by inducing mitochondrial apoptosis and that these effects can be initiated independently of nuclear signaling. The mitochondria are the fundamental target responsible of its pro-apoptotic effect. Thus the Lam-D and its synthetic derivative, by an original action mechanism targeting directly mitochondria, are able to induce apoptosis of cancer cells resistant to conventional chemotherapies (NSCLC, melanoma).La plupart des traitements anticancéreux induisent l'apoptose des cellules tumorales in vitro comme in vivo. Les agents anticancéreux classiques agissent au niveau de cibles primitives, principalement localisées au niveau nucléaire, et activent consécutivement les différentes voies apoptotiques conduisant au stade ultime à la mort des cellules. Cependant, la résistance à l'induction de l'apoptose par les agents chimiothérapeutiques classiques reste un problème crucial. De nouvelles approches ont été développées pour dépasser la résistance à l'apoptose. Parmi elles, le ciblage de la mitochondrie apparaît comme une stratégie prometteuse pour tuer les cellules cancéreuses résistantes. Ainsi, de nouvelles molécules ciblant la mitochondrie ont été identifiées. Parmi celles-ci, notre laboratoire s'est intéressé aux Lamellarines, alcaloïdes pyrroliques hexacycliques d'origine marine. Outre leur effet inhibiteur des topoisomérases-I nucléaires, elles agissent également sur les mitochondries des cellules cancéreuses. Mon travail a consisté 1) à évaluer l'avantage des Lamellarines dans le traitement de lignées de cellules cancéreuses résistantes, défaillantes dans les voies apoptotiques (cas des carcinomes pulmonaires non à petites cellules, NSCLC) et 2) à décrypter les voies apoptotiques déclenchées par les Lamellarines. Ainsi, 1) sur les cellules NSCLC hautement résistantes à l'apoptose induite par les chimiothérapies classiques, nous avons évalué deux agents anticancéreux potentiels de la famille des Lamellarines. La Lamellarine-D (Lam-D) et son dérivé de synthèse PM031379 agissent directement sur la mitochondrie, induisant l'activation de Bax, la libération mitochondriale de cytochrome-c et d'AIF, et l'activation de la caspase-3. Cependant, seul le PM031379 induit la mort cellulaire qui s'accompagne de la translocation nucléaire d'AIF. De plus, cet effet létal nécessite la production d'espèces réactives de l'oxygène (ROS) d'origine exclusivement mitochondriale. Ces résultats ont permis de comprendre les mécanismes permettant de restaurer l'apoptose des cellules chimiorésistantes. 2) La seconde partie de ce travail a consisté à caractériser les voies apoptotiques déclenchées par la Lam-D en évaluant précisément le rôle du noyau et des mitochondries dans son effet pro-apoptotique. La Lam-D exerce une remarquable cytotoxicité envers un large panel de tumeurs. A des concentrations de l'ordre du micromolaire, elle provoque l'apoptose nucléaire dans les cellules leucémiques sans blocage du cycle cellulaire. Les signaux transmis par la Lam-D initient l'apoptose via la voie apoptotique intrinsèque mitochondriale, activant Bax et réduisant les taux des protéines anti-apoptotiques Bcl-2 et cIAP2, en association avec l'activation des caspases-9 et -3. Nos résultats ont également permis d'évincer l'implication de la voie apoptotique extrinsèque dans la mort cellulaire induite par la Lam-D. Par ailleurs, la Lam-D engendre une réponse aux dommages à l'ADN générés par son effet inhibiteur de topoisomérase-I, résultant en la phosphorylation de l'histone H2AXγ, l'expression de la protéine de réparation Rad51 et de p53. Grâce à diverses lignées de cellules cancéreuses, nous avons également démontré que les mécanismes apoptotiques induits par la Lam-D sont indépendants du statut p53 des cellules tumorales. De plus, des cellules dépourvues de noyau (cytoplastes) subissent aussi l'apoptose induite par la Lam-D. L'ensemble de ces résultats démontre que la Lam-D ne nécessite pas la signalisation nucléaire pour promouvoir la mort des cellules cancéreuses et que la mitochondrie est la cible primordiale responsable de son effet pro-apoptotique. Ainsi, la Lamellarine-D et ses dérivés de synthèses, de part leur mécanisme d'action original ciblant directement les mitochondries, sont capables d'induire l'apoptose de cellules tumorales y compris résistantes aux chimiothérapies classiques (NSCLC, mélanomes)

Arguments en faveur de l'existence d'une activité pro-apoptotique des lamellarines vis-à-vis des cellules tumorales par ciblage mitochondrial

La plupart des traitements anticancéreux induisent l apoptose des cellules tumorales in vitro comme in vivo. Les agents anticancéreux classiques agissent au niveau de cibles primitives, principalement localisées au niveau nucléaire, et activent consécutivement les différentes voies apoptotiques conduisant au stade ultime à la mort des cellules. Cependant, la résistance à l induction de l apoptose par les agents chimiothérapeutiques classiques reste un problème crucial. De nouvelles approches ont été développées pour dépasser la résistance à l apoptose. Parmi elles, le ciblage de la mitochondrie apparaît comme une stratégie prometteuse pour tuer les cellules cancéreuses résistantes. Ainsi, de nouvelles molécules ciblant la mitochondrie ont été identifiées. Parmi celles-ci, notre laboratoire s est intéressé aux Lamellarines, alcaloïdes pyrroliques hexacycliques d origine marine. Outre leur effet inhibiteur des topoisomérases-I nucléaires, elles agissent également sur les mitochondries des cellules cancéreuses. Mon travail a consisté 1) à évaluer l avantage des Lamellarines dans le traitement de lignées de cellules cancéreuses résistantes, défaillantes dans les voies apoptotiques (cas des carcinomes pulmonaires non à petites cellules, NSCLC) et 2) à décrypter les voies apoptotiques déclenchées par les Lamellarines. Ainsi, 1) sur les cellules NSCLC hautement résistantes à l apoptose induite par les chimiothérapies classiques, nous avons évalué deux agents anticancéreux potentiels de la famille des Lamellarines. La Lamellarine-D (Lam-D) et son dérivé de synthèse, le PM031379, agissent directement sur la mitochondrie, induisant l activation de Bax, la libération mitochondriale de cytochrome-c et d AIF et l activation de la caspase-3. Cependant, seul le PM031379 induit la mort cellulaire qui s accompagne de la translocation nucléaire d AIF. De plus, cet effet létal nécessite la production d espèces réactives de l oxygène (ROS) d origine exclusivement mitochondriale. Ces résultats ont permis de comprendre les mécanismes permettant de restaurer l apoptose des cellules chimiorésistantes. 2) La seconde partie de ce travail a consisté à caractériser les voies apoptotiques déclenchées par la Lam-D en évaluant précisément le rôle du noyau et des mitochondries dans son effet pro-apoptotique. La Lam-D exerce une remarquable cytotoxicité envers un large panel de tumeurs. A des concentrations de l ordre du micromolaire, elle provoque l apoptose nucléaire dans les cellules leucémiques sans blocage du cycle cellulaire. Les signaux transmis par la Lam-D initient l apoptose via la voie apoptotique intrinsèque mitochondriale, activant Bax et réduisant les taux des protéines anti-apoptotiques Bcl-2 et cIAP2, en association avec l activation des caspases-9 et -3. Nos résultats ont également permis d évincer l implication de la voie apoptotique extrinsèque dans la mort cellulaire induite par la Lam-D. Par ailleurs, la Lam-D engendre une réponse aux dommages à l ADN générés par son effet inhibiteur de topoisomérase-I, résultant en la phosphorylation de l histone H2AXg, l expression de la protéine de réparation Rad51 et de p53. Grâce à diverses lignées de cellules cancéreuses, nous avons démontré que les mécanismes apoptotiques induits par la Lam-D sont indépendants du statut p53 des cellules tumorales. De plus, des cellules dépourvues de noyau (cytoplastes) subissent aussi l apoptose induite par la Lam-D. L ensemble de ces résultats démontre que la Lam-D ne nécessite pas la signalisation nucléaire pour promouvoir la mort des cellules cancéreuses et que la mitochondrie est la cible primordiale responsable de son effet pro-apoptotique. Ainsi, la Lamellarine-D et ses dérivés de synthèse, de par leur mécanisme d action original ciblant directement les mitochondries, sont capables d induire l apoptose de cellules tumorales y compris résistantes aux chimiothérapies classiques (NSCLC, mélanomes).LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Cardiovascular risk factors and mortality in children with chronic kidney disease

Background. Cardiovascular disease (CVD) begins early in children with chronic kidney disease (CKD), and its progression is determined by the presence of single or multiple cardiovascular risk factors (CVRFs). Objective. To determine the prevalence of CVRFs in children with CKD and their association with mortality in children on chronic dialysis. Methods. This comparative cross-sectional study recruited children aged 5 - 18 years with all stages of CKD. All patients had a short history taken along with a physical examination, and their blood samples were assessed for serum creatinine, urea, albumin, calcium, phosphorus, parathyroid hormone, alkaline phosphatase, total cholesterol (TC), haemoglobin and C-reactive protein. Urine samples were also assessed for proteinuria. Results. One hundred and six children who met the study criteria were recruited, 34 with CKD I, 36 with CKD II - IV and 36 with CKD V (dialysis). The overall median age was 11 years (range 8 - 14), and the male/female ratio was 2.1:1. The most common CVRF was anaemia (39.6%). The rate of anaemia was higher in the dialysis group than in the CKD II - IV and CKD I groups (77.8%, 33.3% and 5.9%, respectively). Other CVRFs detected were hypertension, proteinuria, hypercholesterolaemia and dysregulated mineral bone metabolism. Seven deaths were recorded in the dialysis group during the study period. Severe hypertension and intracranial bleeding were the most common causes of death. Modifiable risk factors such as increased TC and decreased albumin levels were more common than other CVRFs in the dialysis patients who died. Conclusions. CVRFs may be present in early CKD, even before the decline in GFR. Routine screening for CVRFs, along with timely intervention, may prevent the progression of CVD and mortality later in life

Visibilities and bolometric corrections for stellar oscillation modes observed by Kepler

International audienceContext.Kepler produces a large amount of data used for asteroseismological analyses, particularly of solar-like stars and red giants. The mode amplitudes observed in the Kepler spectral band have to be converted into bolometric amplitudes to be compared to models. Aims: We give a simple bolometric correction for the amplitudes of radial modes observed with Kepler, as well as the relative visibilities of non-radial modes. Methods: We numerically compute the bolometric correction cK-bol and mode visibilities for different effective temperatures Teff within the range 4000-7500 K, using a similar approach to a recent one from the literature. Results: We derive a law for the correction to bolometric values: cK - bol = 1 + a1(Teff - To) + a2(Teff - To)2, with To = 5934 K, a1 = 1.349 × 10-4 K-1, and a2 = -3.120 × 10-9 K-2 or, alternatively, as the power law cK - bol = (Teff/To)alpha with alpha = 0.80. We give tabulated values for the mode visibilities based on limb-darkening (LD), computed from ATLAS9 model atmospheres for Teff ∈ [4000,7500] K, log g ∈ [2.5,4.5] , and [M/H] ∈ [ - 1.0, + 1.0] . We show that using LD profiles already integrated over the spectral band provides quick and good approximations for visibilities. We point out the limits of these classical visibility estimations

Tumor Infiltrating Lymphocytes Signature as a New Pan-Cancer Predictive Biomarker of Anti PD-1/PD-L1 Efficacy

Tumor immune infiltrates are associated with tumor prognosis in many cancer types. However, their capacity to predict the efficacy of checkpoint inhibitors is poorly documented. We generate three signatures that evaluate in different ways these infiltrates: lymphoid- and myeloid-alone signatures, and a combined signature of both named the TIL (tumor-infiltrating lymphocyte) transcriptomic signature. We evaluate these signatures in The Cancer Genome Atlas Program (TCGA) Pan-Cancer cohort and four cohorts comprising patients with melanoma, lung, and head and neck cancer treated with anti-PD-1 or anti-CTLA-4 therapies. We observe using TCGA Pan-Cancer cohort that this TIL or lymphoid-alone signature accurately estimates prognosis in most cancer types and outperforms histological TIL evaluation or myeloid signature alone. Both TIL and lymphoid signatures are correlated with response rate to immunotherapy. Combining lymphoid signature or TIL with tumor mutational burden generates a score that is highly efficient in predicting response to immunotherapy. In different series of patients treated with checkpoint inhibitors for non-small cell lung cancer, head and neck cancer, and melanoma, we observed that TIL or lymphoid signature were associated with outcome. These data demonstrate that a simple TIL or lymphoid signature could be used as a Pan-Cancer prognostic and predictive biomarker to estimate patient survival under checkpoint inhibitors

Teaching engineering students how to design a Proof-Of-Concept: a way to experience the value of reflexive practices for engineers ?

International audienceIndustrial companies expect engineers to take an external and critical look at their activities through reflexive practices. Recognising the criticality of reflexivity, Project Based Learning approaches include assignments for students to implement reflexive approaches on their projects. However, it remains unclear in the literature whether those assignments help the students experience the value of reflexive practices or if students consider them as academic exercises. In this concept paper, we present a new teaching module that intends to make students experience the value of reflexive practices for engineers. In this module, an industrial partner asks a group of master engineering students to design and implement a Proof-of-Concept (POC) to help the company explore an innovation field. This eight-week project is mainly conducted within the company. Teachers act both as coaches through regular meetings and as experts through lectures focusing on specific engineering reasoning (statistics, modelling, simulation, design of experiments…) that are necessary to design a robust POC. At the end of the module, students present conclusions drawn from their POC to the company which explain to students the next steps envisioned from their contribution. The module is two years old : so far, the authors supervised twelve students split into four industrial projects. Feedback for both companies and students were collected, as well as the lectures and the final presentations. Based on these, we conducted a preliminary analysis that suggests that students experience the value of reflexive practices for engineering work during the module