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  • Open Access
    Authors: 
    K. Kiiveri; Daniel Gruen; Alexis Finoguenov; Thomas Erben; L. van Waerbeke; Eli S. Rykoff; Lance Miller; Steffen Hagstotz; R. A. Dupke; J. Patrick Henry; +12 more
    Publisher: Oxford University Press (OUP)
    Countries: Finland, France, Italy

    The COnstrain Dark Energy with X-ray clusters (CODEX) sample contains the largest flux limited sample of X-ray clusters at $0.35 < z < 0.65$. It was selected from ROSAT data in the 10,000 square degrees of overlap with BOSS, mapping a total number of 2770 high-z galaxy clusters. We present here the full results of the CFHT CODEX program on cluster mass measurement, including a reanalysis of CFHTLS Wide data, with 25 individual lensing-constrained cluster masses. We employ $lensfit$ shape measurement and perform a conservative colour-space selection and weighting of background galaxies. Using the combination of shape noise and an analytic covariance for intrinsic variations of cluster profiles at fixed mass due to large scale structure, miscentring, and variations in concentration and ellipticity, we determine the likelihood of the observed shear signal as a function of true mass for each cluster. We combine 25 individual cluster mass likelihoods in a Bayesian hierarchical scheme with the inclusion of optical and X-ray selection functions to derive constraints on the slope $��$, normalization $��$, and scatter $��_{\ln ��| ��}$ of our richness-mass scaling relation model in log-space: $\left = ����+ ��$, with $��= \ln (M_{200c}/M_{\mathrm{piv}})$, and $M_{\mathrm{piv}} = 10^{14.81} M_{\odot}$. We find a slope $��= 0.49^{+0.20}_{-0.15}$, normalization $ \exp(��) = 84.0^{+9.2}_{-14.8}$ and $��_{\ln ��| ��} = 0.17^{+0.13}_{-0.09}$ using CFHT richness estimates. In comparison to other weak lensing richness-mass relations, we find the normalization of the richness statistically agreeing with the normalization of other scaling relations from a broad redshift range ($0.0 37 pages, 12 figures

  • Open Access
    Authors: 
    Imen Ben-Cheikh; Roberto Beneduce; Jaswant Guzder; Sushrut Jadhav; Azaad Kassam; Myrna Lashley; Malika Mansouri; Marie Rose Moro; Don Quang Tran;
    Publisher: SAGE Publications
    Country: Italy
  • Open Access
    Authors: 
    Augustin Mortier; Jonas Gliß; Michael Schulz; Wenche Aas; Elisabeth Andrews; Huisheng Bian; Mian Chin; Paul Ginoux; Jenny L. Hand; Brent N. Holben; +12 more
    Publisher: Copernicus GmbH
    Countries: Norway, Switzerland
    Project: EC | CRESCENDO (641816), EC | FORCeS (821205), NSF | The Management and Operat... (1852977)

    This study presents a multiparameter analysis of aerosol trends over the last 2 decades at regional and global scales. Regional time series have been computed for a set of nine optical, chemical-composition and mass aerosol properties by using the observations from several ground-based networks. From these regional time series the aerosol trends have been derived for the different regions of the world. Most of the properties related to aerosol loading exhibit negative trends, both at the surface and in the total atmospheric column. Significant decreases in aerosol optical depth (AOD) are found in Europe, North America, South America, North Africa and Asia, ranging from −1.2 % yr−1 to −3.1 % yr−1. An error and representativity analysis of the spatially and temporally limited observational data has been performed using model data subsets in order to investigate how much the observed trends represent the actual trends happening in the regions over the full study period from 2000 to 2014. This analysis reveals that significant uncertainty is associated with some of the regional trends due to time and space sampling deficiencies. The set of observed regional trends has then been used for the evaluation of 10 models (6 AeroCom phase III models and 4 CMIP6 models) and the CAMS reanalysis dataset and of their skills in reproducing the aerosol trends. Model performance is found to vary depending on the parameters and the regions of the world. The models tend to capture trends in AOD, the column Ångström exponent, sulfate and particulate matter well (except in North Africa), but they show larger discrepancies for coarse-mode AOD. The rather good agreement of the trends, across different aerosol parameters between models and observations, when co-locating them in time and space, implies that global model trends, including those in poorly monitored regions, are likely correct. The models can help to provide a global picture of the aerosol trends by filling the gaps in regions not covered by observations. The calculation of aerosol trends at a global scale reveals a different picture from that depicted by solely relying on ground-based observations. Using a model with complete diagnostics (NorESM2), we find a global increase in AOD of about 0.2 % yr−1 between 2000 and 2014, primarily caused by an increase in the loads of organic aerosols, sulfate and black carbon.

  • Open Access
    Authors: 
    Michael D. Parkes; Arezu Aliabadi; Martin Cadeiras; María G. Crespo-Leiro; Mario C. Deng; Eugene C. DePasquale; J. Goekler; Daniel Kim; Jon A. Kobashigawa; Alexandre Loupy; +4 more
    Publisher: Elsevier BV
    Countries: Australia, Spain

    © 2019 International Society for Heart and Lung Transplantation BACKGROUND: We previously reported a microarray-based diagnostic system for heart transplant endomyocardial biopsies (EMBs), using either 3-archetype (3AA)or 4-archetype (4AA)unsupervised algorithms to estimate rejection. In the present study we examined the stability of machine-learning algorithms in new biopsies, compared 3AA vs 4AA algorithms, assessed supervised binary classifiers trained on histologic or molecular diagnoses, created a report combining many scores into an ensemble of estimates, and examined possible automated sign-outs. METHODS: We studied 889 EMBs from 454 transplant recipients at 8 centers: the initial cohort (N = 331)and a new cohort (N = 558). Published 3AA algorithms derived in Cohort 331 were tested in Cohort 558, the 3AA and 4AA models were compared, and supervised binary classifiers were created. RESULTS: A‘lgorithms derived in Cohort 331 performed similarly in new biopsies despite differences in case mix. In the combined cohort, the 4AA model, including a parenchymal injury score, retained correlations with histologic rejection and DSA similar to the 3AA model. Supervised molecular classifiers predicted molecular rejection (areas under the curve [AUCs]>0.87)better than histologic rejection (AUCs <0.78), even when trained on histology diagnoses. A report incorporating many AA and binary classifier scores interpreted by 1 expert showed highly significant agreement with histology (p < 0.001), but with many discrepancies, as expected from the known noise in histology. An automated random forest score closely predicted expert diagnoses, confirming potential for automated signouts. CONCLUSIONS: Molecular algorithms are stable in new populations and can be assembled into an ensemble that combines many supervised and unsupervised estimates of the molecular disease states.

  • Open Access
    Authors: 
    Mélanie Bruchard; François Ghiringhelli;
    Publisher: Frontiers Media SA

    Cancer is a complex disease and the role played by innate lymphoid cells (ILCs) in cancer development has begun to be uncovered over recent years. We aim to provide an exhaustive summary of the knowledge acquired on the role of ILCs in cancer. ILCs are classified into 3 different categories, ILC1s, ILC2s, and ILC3s, each encompassing specific and unique functions. ILC1s exhibit NK cells characteristics and can exert anti-tumor functions, but surprisingly their IFNγ production is not associated with a better immune response. In response to TGF-β or IL-12, ILC1s were shown to exert pro-tumor functions and to favor tumor growth. ILC2s role in cancer immune response is dependent on cytokine context. The production of IL-13 by ILC2s is associated with a negative outcome in cancer. ILC2s can also produce IL-5, leading to eosinophil activation and an increased anti-tumor immune response in lung cancer. ILC3s produce IL-22, which could promote tumor growth. In contrast, ILC3s recognize tumor cells and facilitate leukocyte tumor entry, increasing anti-tumor immunity. In some contexts, ILC3s were found at the edge of tertiary lymphoid structures, associated with a good prognostic. We are at the dawn of our understanding of ILCs role in cancer. This review aims to thoroughly analyze existing data and to provide a comprehensive overview of our present knowledge on the impact of ILCs in cancer.

  • Open Access
    Authors: 
    Denisa Hathazi; Dan Cox; Adele D'Amico; Giorgio Tasca; Richard Charlton; Robert-Yves Carlier; Jennifer Baumann; Laxmikanth Kollipara; René P. Zahedi; Ingo Feldmann; +18 more
    Publisher: Oxford University Press (OUP)
    Countries: United Kingdom, France, Germany, Italy
    Project: CIHR , UKRI | Exosomal protein deficien... (MR/N025431/1)

    Abstract Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

  • Open Access
    Authors: 
    Ricardo A. Scrosati; Janelle K. Holt;
    Publisher: Frontiers Media SA
    Project: NSERC
  • Open Access
    Authors: 
    Dominique Perrin; Christophe Reutenauer;
    Publisher: Elsevier BV
    Country: France
    Project: NSERC

    International audience; We show how the use of graded alphabets allows one to provide simpler proofs of some results on free monoids and free Lie algebras. We first generalize to graded alphabets the characterization of the length distributions of circular codes. We also show that the existence of a circular code with a given distribution of degrees is equivalent to the existence of an embedding of Lie algebras. We finally give a generalization to graded alphabets of the famous result of Eastman on comma free codes of odd degree.

  • Open Access
    Authors: 
    K. Abe; C. Bronner; Yoshinari Hayato; M. Ikeda; K. Iyogi; J. Kameda; Y. Kato; Yasuhiro Kishimoto; Ll. Marti; M. Miura; +153 more
    Publisher: American Astronomical Society
    Countries: United Kingdom, United Kingdom, Italy, France, Italy
    Project: EC | SKPLUS (641540), NSERC

    We report the results of a neutrino search in Super-Kamiokande for coincident signals with the first detected gravitational wave produced by a binary neutron star merger, GW170817, which was followed by a short gamma-ray burst, GRB170817A, and a kilonova/macronova. We searched for coincident neutrino events in the range from 3.5 MeV to $\sim$100 PeV, in a time window $\pm$500 seconds around the gravitational wave detection time, as well as during a 14-day period after the detection. No significant neutrino signal was observed for either time window. We calculated 90% confidence level upper limits on the neutrino fluence for GW170817. From the upward-going-muon events in the energy region above 1.6 GeV, the neutrino fluence limit is $16.0^{+0.7}_{-0.6}$ ($21.3^{+1.1}_{-0.8}$) cm$^{-2}$ for muon neutrinos (muon antineutrinos), with an error range of $\pm5^{\circ}$ around the zenith angle of NGC4993, and the energy spectrum is under the assumption of an index of $-2$. The fluence limit for neutrino energies less than 100 MeV, for which the emission mechanism would be different than for higher-energy neutrinos, is also calculated. It is $6.6 \times 10^7$ cm$^{-2}$ for anti-electron neutrinos under the assumption of a Fermi-Dirac spectrum with average energy of 20 MeV. 8 pages, 4 figures

  • Open Access
    Authors: 
    Bradley J. Monk; Nicoletta Colombo; Amit M. Oza; Keiichi Fujiwara; Michael J. Birrer; Leslie M Randall; Elena Poddubskaya; Giovanni Scambia; Yaroslav Shparyk; Myong Cheol Lim; +8 more
    Publisher: Elsevier BV
    Country: Italy

    Background: Although most patients with epithelial ovarian cancer respond to frontline platinum-based chemotherapy, around 70% will relapse within 3 years. The phase 3 JAVELIN Ovarian 100 trial compared avelumab (anti-PD-L1 monoclonal antibody) in combination with chemotherapy followed by avelumab maintenance, or chemotherapy followed by avelumab maintenance, versus chemotherapy alone in patients with treatment-naive epithelial ovarian cancer. Methods: JAVELIN Ovarian 100 was a global, open-label, three-arm, parallel, randomised, phase 3 trial run at 159 hospitals and cancer treatment centres in 25 countries. Eligible women were aged 18 years and older with stage III–IV epithelial ovarian, fallopian tube, or peritoneal cancer (following debulking surgery, or candidates for neoadjuvant chemotherapy), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to receive chemotherapy (six cycles; carboplatin dosed at an area under the serum-concentration-time curve of 5 or 6 intravenously every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks or 80 mg/m2 once a week [investigators' choice]) followed by avelumab maintenance (10 mg/kg intravenously every 2 weeks; avelumab maintenance group); chemotherapy plus avelumab (10 mg/kg intravenously every 3 weeks) followed by avelumab maintenance (avelumab combination group); or chemotherapy followed by observation (control group). Randomisation was in permuted blocks of size six and stratified by paclitaxel regimen and resection status. Patients and investigators were masked to assignment to the two chemotherapy groups without avelumab at the time of randomisation until completion of the chemotherapy phase. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomly assigned patients (analysed by intention to treat). Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02718417. The trial was fully enrolled and terminated at interim analysis due to futility, and efficacy is no longer being assessed. Findings: Between May 19, 2016 and Jan 23, 2018, 998 patients were randomly assigned (avelumab maintenance n=332, avelumab combination n=331, and control n=335). At the planned interim analysis (data cutoff Sept 7, 2018), prespecified futility boundaries were crossed for the progression-free survival analysis, and the trial was stopped as recommended by the independent data monitoring committee and endorsed by the protocol steering committee. Median follow-up for progression-free survival for all patients was 10·8 months (IQR 7·1–14·9); 11·1 months (7·0–15·3) for the avelumab maintenance group, 11·0 months (7·4–14·5) for the avelumab combination group, and 10·2 months (6·7–14·0) for the control group. Median progression-free survival was 16·8 months (95% CI 13·5–not estimable [NE]) with avelumab maintenance, 18·1 months (14·8–NE) with avelumab combination treatment, and NE (18·2 months–NE) with control treatment. The stratified hazard ratio for progression-free survival was 1·43 (95% CI 1·05–1·95; one-sided p=0·99) with the avelumab maintenance regimen and 1·14 (0·83–1·56; one-sided p=0·79) with the avelumab combination regimen, versus control treatment. The most common grade 3–4 adverse events were anaemia (69 [21%] patients in the avelumab maintenance group, 63 [19%] in the avelumab combination group, and 53 [16%] in the control group), neutropenia (91 [28%], 99 [30%], and 88 [26%]), and neutrophil count decrease (49 [15%], 45 [14%], and 59 [18%]). Serious adverse events of any grade occurred in 92 (28%) patients in the avelumab maintenance group, 118 (36%) in the avelumab combination group, and 64 (19%) in the control group. Treatment-related deaths occurred in one (<1%) patient in the avelumab maintenance group (due to atrial fibrillation) and one (<1%) patient in the avelumab combination group (due to disease progression). Interpretation: Although no new safety signals were observed, results do not support the use of avelumab in the frontline treatment setting. Alternative treatment regimens are needed to improve outcomes in patients with advanced epithelial ovarian cancer. Funding: Pfizer and Merck KGaA, Darmstadt, Germany.

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Include:
The following results are related to Canada. Are you interested to view more results? Visit OpenAIRE - Explore.
30,331 Research products, page 1 of 3,034
  • Open Access
    Authors: 
    K. Kiiveri; Daniel Gruen; Alexis Finoguenov; Thomas Erben; L. van Waerbeke; Eli S. Rykoff; Lance Miller; Steffen Hagstotz; R. A. Dupke; J. Patrick Henry; +12 more
    Publisher: Oxford University Press (OUP)
    Countries: Finland, France, Italy

    The COnstrain Dark Energy with X-ray clusters (CODEX) sample contains the largest flux limited sample of X-ray clusters at $0.35 < z < 0.65$. It was selected from ROSAT data in the 10,000 square degrees of overlap with BOSS, mapping a total number of 2770 high-z galaxy clusters. We present here the full results of the CFHT CODEX program on cluster mass measurement, including a reanalysis of CFHTLS Wide data, with 25 individual lensing-constrained cluster masses. We employ $lensfit$ shape measurement and perform a conservative colour-space selection and weighting of background galaxies. Using the combination of shape noise and an analytic covariance for intrinsic variations of cluster profiles at fixed mass due to large scale structure, miscentring, and variations in concentration and ellipticity, we determine the likelihood of the observed shear signal as a function of true mass for each cluster. We combine 25 individual cluster mass likelihoods in a Bayesian hierarchical scheme with the inclusion of optical and X-ray selection functions to derive constraints on the slope $��$, normalization $��$, and scatter $��_{\ln ��| ��}$ of our richness-mass scaling relation model in log-space: $\left = ����+ ��$, with $��= \ln (M_{200c}/M_{\mathrm{piv}})$, and $M_{\mathrm{piv}} = 10^{14.81} M_{\odot}$. We find a slope $��= 0.49^{+0.20}_{-0.15}$, normalization $ \exp(��) = 84.0^{+9.2}_{-14.8}$ and $��_{\ln ��| ��} = 0.17^{+0.13}_{-0.09}$ using CFHT richness estimates. In comparison to other weak lensing richness-mass relations, we find the normalization of the richness statistically agreeing with the normalization of other scaling relations from a broad redshift range ($0.0 37 pages, 12 figures

  • Open Access
    Authors: 
    Imen Ben-Cheikh; Roberto Beneduce; Jaswant Guzder; Sushrut Jadhav; Azaad Kassam; Myrna Lashley; Malika Mansouri; Marie Rose Moro; Don Quang Tran;
    Publisher: SAGE Publications
    Country: Italy
  • Open Access
    Authors: 
    Augustin Mortier; Jonas Gliß; Michael Schulz; Wenche Aas; Elisabeth Andrews; Huisheng Bian; Mian Chin; Paul Ginoux; Jenny L. Hand; Brent N. Holben; +12 more
    Publisher: Copernicus GmbH
    Countries: Norway, Switzerland
    Project: EC | CRESCENDO (641816), EC | FORCeS (821205), NSF | The Management and Operat... (1852977)

    This study presents a multiparameter analysis of aerosol trends over the last 2 decades at regional and global scales. Regional time series have been computed for a set of nine optical, chemical-composition and mass aerosol properties by using the observations from several ground-based networks. From these regional time series the aerosol trends have been derived for the different regions of the world. Most of the properties related to aerosol loading exhibit negative trends, both at the surface and in the total atmospheric column. Significant decreases in aerosol optical depth (AOD) are found in Europe, North America, South America, North Africa and Asia, ranging from −1.2 % yr−1 to −3.1 % yr−1. An error and representativity analysis of the spatially and temporally limited observational data has been performed using model data subsets in order to investigate how much the observed trends represent the actual trends happening in the regions over the full study period from 2000 to 2014. This analysis reveals that significant uncertainty is associated with some of the regional trends due to time and space sampling deficiencies. The set of observed regional trends has then been used for the evaluation of 10 models (6 AeroCom phase III models and 4 CMIP6 models) and the CAMS reanalysis dataset and of their skills in reproducing the aerosol trends. Model performance is found to vary depending on the parameters and the regions of the world. The models tend to capture trends in AOD, the column Ångström exponent, sulfate and particulate matter well (except in North Africa), but they show larger discrepancies for coarse-mode AOD. The rather good agreement of the trends, across different aerosol parameters between models and observations, when co-locating them in time and space, implies that global model trends, including those in poorly monitored regions, are likely correct. The models can help to provide a global picture of the aerosol trends by filling the gaps in regions not covered by observations. The calculation of aerosol trends at a global scale reveals a different picture from that depicted by solely relying on ground-based observations. Using a model with complete diagnostics (NorESM2), we find a global increase in AOD of about 0.2 % yr−1 between 2000 and 2014, primarily caused by an increase in the loads of organic aerosols, sulfate and black carbon.

  • Open Access
    Authors: 
    Michael D. Parkes; Arezu Aliabadi; Martin Cadeiras; María G. Crespo-Leiro; Mario C. Deng; Eugene C. DePasquale; J. Goekler; Daniel Kim; Jon A. Kobashigawa; Alexandre Loupy; +4 more
    Publisher: Elsevier BV
    Countries: Australia, Spain

    © 2019 International Society for Heart and Lung Transplantation BACKGROUND: We previously reported a microarray-based diagnostic system for heart transplant endomyocardial biopsies (EMBs), using either 3-archetype (3AA)or 4-archetype (4AA)unsupervised algorithms to estimate rejection. In the present study we examined the stability of machine-learning algorithms in new biopsies, compared 3AA vs 4AA algorithms, assessed supervised binary classifiers trained on histologic or molecular diagnoses, created a report combining many scores into an ensemble of estimates, and examined possible automated sign-outs. METHODS: We studied 889 EMBs from 454 transplant recipients at 8 centers: the initial cohort (N = 331)and a new cohort (N = 558). Published 3AA algorithms derived in Cohort 331 were tested in Cohort 558, the 3AA and 4AA models were compared, and supervised binary classifiers were created. RESULTS: A‘lgorithms derived in Cohort 331 performed similarly in new biopsies despite differences in case mix. In the combined cohort, the 4AA model, including a parenchymal injury score, retained correlations with histologic rejection and DSA similar to the 3AA model. Supervised molecular classifiers predicted molecular rejection (areas under the curve [AUCs]>0.87)better than histologic rejection (AUCs <0.78), even when trained on histology diagnoses. A report incorporating many AA and binary classifier scores interpreted by 1 expert showed highly significant agreement with histology (p < 0.001), but with many discrepancies, as expected from the known noise in histology. An automated random forest score closely predicted expert diagnoses, confirming potential for automated signouts. CONCLUSIONS: Molecular algorithms are stable in new populations and can be assembled into an ensemble that combines many supervised and unsupervised estimates of the molecular disease states.

  • Open Access
    Authors: 
    Mélanie Bruchard; François Ghiringhelli;
    Publisher: Frontiers Media SA

    Cancer is a complex disease and the role played by innate lymphoid cells (ILCs) in cancer development has begun to be uncovered over recent years. We aim to provide an exhaustive summary of the knowledge acquired on the role of ILCs in cancer. ILCs are classified into 3 different categories, ILC1s, ILC2s, and ILC3s, each encompassing specific and unique functions. ILC1s exhibit NK cells characteristics and can exert anti-tumor functions, but surprisingly their IFNγ production is not associated with a better immune response. In response to TGF-β or IL-12, ILC1s were shown to exert pro-tumor functions and to favor tumor growth. ILC2s role in cancer immune response is dependent on cytokine context. The production of IL-13 by ILC2s is associated with a negative outcome in cancer. ILC2s can also produce IL-5, leading to eosinophil activation and an increased anti-tumor immune response in lung cancer. ILC3s produce IL-22, which could promote tumor growth. In contrast, ILC3s recognize tumor cells and facilitate leukocyte tumor entry, increasing anti-tumor immunity. In some contexts, ILC3s were found at the edge of tertiary lymphoid structures, associated with a good prognostic. We are at the dawn of our understanding of ILCs role in cancer. This review aims to thoroughly analyze existing data and to provide a comprehensive overview of our present knowledge on the impact of ILCs in cancer.

  • Open Access
    Authors: 
    Denisa Hathazi; Dan Cox; Adele D'Amico; Giorgio Tasca; Richard Charlton; Robert-Yves Carlier; Jennifer Baumann; Laxmikanth Kollipara; René P. Zahedi; Ingo Feldmann; +18 more
    Publisher: Oxford University Press (OUP)
    Countries: United Kingdom, France, Germany, Italy
    Project: CIHR , UKRI | Exosomal protein deficien... (MR/N025431/1)

    Abstract Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

  • Open Access
    Authors: 
    Ricardo A. Scrosati; Janelle K. Holt;
    Publisher: Frontiers Media SA
    Project: NSERC
  • Open Access
    Authors: 
    Dominique Perrin; Christophe Reutenauer;
    Publisher: Elsevier BV
    Country: France
    Project: NSERC

    International audience; We show how the use of graded alphabets allows one to provide simpler proofs of some results on free monoids and free Lie algebras. We first generalize to graded alphabets the characterization of the length distributions of circular codes. We also show that the existence of a circular code with a given distribution of degrees is equivalent to the existence of an embedding of Lie algebras. We finally give a generalization to graded alphabets of the famous result of Eastman on comma free codes of odd degree.

  • Open Access
    Authors: 
    K. Abe; C. Bronner; Yoshinari Hayato; M. Ikeda; K. Iyogi; J. Kameda; Y. Kato; Yasuhiro Kishimoto; Ll. Marti; M. Miura; +153 more
    Publisher: American Astronomical Society
    Countries: United Kingdom, United Kingdom, Italy, France, Italy
    Project: EC | SKPLUS (641540), NSERC

    We report the results of a neutrino search in Super-Kamiokande for coincident signals with the first detected gravitational wave produced by a binary neutron star merger, GW170817, which was followed by a short gamma-ray burst, GRB170817A, and a kilonova/macronova. We searched for coincident neutrino events in the range from 3.5 MeV to $\sim$100 PeV, in a time window $\pm$500 seconds around the gravitational wave detection time, as well as during a 14-day period after the detection. No significant neutrino signal was observed for either time window. We calculated 90% confidence level upper limits on the neutrino fluence for GW170817. From the upward-going-muon events in the energy region above 1.6 GeV, the neutrino fluence limit is $16.0^{+0.7}_{-0.6}$ ($21.3^{+1.1}_{-0.8}$) cm$^{-2}$ for muon neutrinos (muon antineutrinos), with an error range of $\pm5^{\circ}$ around the zenith angle of NGC4993, and the energy spectrum is under the assumption of an index of $-2$. The fluence limit for neutrino energies less than 100 MeV, for which the emission mechanism would be different than for higher-energy neutrinos, is also calculated. It is $6.6 \times 10^7$ cm$^{-2}$ for anti-electron neutrinos under the assumption of a Fermi-Dirac spectrum with average energy of 20 MeV. 8 pages, 4 figures

  • Open Access
    Authors: 
    Bradley J. Monk; Nicoletta Colombo; Amit M. Oza; Keiichi Fujiwara; Michael J. Birrer; Leslie M Randall; Elena Poddubskaya; Giovanni Scambia; Yaroslav Shparyk; Myong Cheol Lim; +8 more
    Publisher: Elsevier BV
    Country: Italy

    Background: Although most patients with epithelial ovarian cancer respond to frontline platinum-based chemotherapy, around 70% will relapse within 3 years. The phase 3 JAVELIN Ovarian 100 trial compared avelumab (anti-PD-L1 monoclonal antibody) in combination with chemotherapy followed by avelumab maintenance, or chemotherapy followed by avelumab maintenance, versus chemotherapy alone in patients with treatment-naive epithelial ovarian cancer. Methods: JAVELIN Ovarian 100 was a global, open-label, three-arm, parallel, randomised, phase 3 trial run at 159 hospitals and cancer treatment centres in 25 countries. Eligible women were aged 18 years and older with stage III–IV epithelial ovarian, fallopian tube, or peritoneal cancer (following debulking surgery, or candidates for neoadjuvant chemotherapy), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to receive chemotherapy (six cycles; carboplatin dosed at an area under the serum-concentration-time curve of 5 or 6 intravenously every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks or 80 mg/m2 once a week [investigators' choice]) followed by avelumab maintenance (10 mg/kg intravenously every 2 weeks; avelumab maintenance group); chemotherapy plus avelumab (10 mg/kg intravenously every 3 weeks) followed by avelumab maintenance (avelumab combination group); or chemotherapy followed by observation (control group). Randomisation was in permuted blocks of size six and stratified by paclitaxel regimen and resection status. Patients and investigators were masked to assignment to the two chemotherapy groups without avelumab at the time of randomisation until completion of the chemotherapy phase. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomly assigned patients (analysed by intention to treat). Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02718417. The trial was fully enrolled and terminated at interim analysis due to futility, and efficacy is no longer being assessed. Findings: Between May 19, 2016 and Jan 23, 2018, 998 patients were randomly assigned (avelumab maintenance n=332, avelumab combination n=331, and control n=335). At the planned interim analysis (data cutoff Sept 7, 2018), prespecified futility boundaries were crossed for the progression-free survival analysis, and the trial was stopped as recommended by the independent data monitoring committee and endorsed by the protocol steering committee. Median follow-up for progression-free survival for all patients was 10·8 months (IQR 7·1–14·9); 11·1 months (7·0–15·3) for the avelumab maintenance group, 11·0 months (7·4–14·5) for the avelumab combination group, and 10·2 months (6·7–14·0) for the control group. Median progression-free survival was 16·8 months (95% CI 13·5–not estimable [NE]) with avelumab maintenance, 18·1 months (14·8–NE) with avelumab combination treatment, and NE (18·2 months–NE) with control treatment. The stratified hazard ratio for progression-free survival was 1·43 (95% CI 1·05–1·95; one-sided p=0·99) with the avelumab maintenance regimen and 1·14 (0·83–1·56; one-sided p=0·79) with the avelumab combination regimen, versus control treatment. The most common grade 3–4 adverse events were anaemia (69 [21%] patients in the avelumab maintenance group, 63 [19%] in the avelumab combination group, and 53 [16%] in the control group), neutropenia (91 [28%], 99 [30%], and 88 [26%]), and neutrophil count decrease (49 [15%], 45 [14%], and 59 [18%]). Serious adverse events of any grade occurred in 92 (28%) patients in the avelumab maintenance group, 118 (36%) in the avelumab combination group, and 64 (19%) in the control group. Treatment-related deaths occurred in one (<1%) patient in the avelumab maintenance group (due to atrial fibrillation) and one (<1%) patient in the avelumab combination group (due to disease progression). Interpretation: Although no new safety signals were observed, results do not support the use of avelumab in the frontline treatment setting. Alternative treatment regimens are needed to improve outcomes in patients with advanced epithelial ovarian cancer. Funding: Pfizer and Merck KGaA, Darmstadt, Germany.