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      Cysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

      1 , 2 , 3 , 4 , 5 , 2 , 6 , 7 , 7 , 1 , 1 , 1 , 4 , 5 , 8 , 9 , 10 , 5 , 4 , 9 , 7 , 2 , 6 , 5 , 2 , 3 , 1 , 1 ,
      EMBO Molecular Medicine
      John Wiley and Sons Inc.
      alpha‐ketoglutarate, Bicalutamide combination therapy, cysteamine, cystinosis, renal Fanconi syndrome, Genetics, Gene Therapy & Genetic Disease, , Urogenital System

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          Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha‐ketoglutarate as a potential metabolite to bridge cystinosin loss to autophagy, apoptosis and kidney proximal tubule impairment in cystinosis. This insight combined with a drug screen revealed a bicalutamide–cysteamine combination treatment as a novel dual‐target pharmacological approach for the phenotypical correction of cystinotic kidney proximal tubule cells, patient‐derived kidney tubuloids and cystinotic zebrafish.


          Nephropathic cystinosis is a severe genetic disorder caused by mutations in the lysosomal cystine transporter, cystinosin. Although several cellular defects have been associated with cystinosis, the mechanism linking cystinosin loss, and epithelial dysfunction remains largely unknown.

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          Genome engineering using the CRISPR-Cas9 system.

          Targeted nucleases are powerful tools for mediating genome alteration with high precision. The RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate efficient genome engineering in eukaryotic cells by simply specifying a 20-nt targeting sequence within its guide RNA. Here we describe a set of tools for Cas9-mediated genome editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in mammalian cells, as well as generation of modified cell lines for downstream functional studies. To minimize off-target cleavage, we further describe a double-nicking strategy using the Cas9 nickase mutant with paired guide RNAs. This protocol provides experimentally derived guidelines for the selection of target sites, evaluation of cleavage efficiency and analysis of off-target activity. Beginning with target design, gene modifications can be achieved within as little as 1-2 weeks, and modified clonal cell lines can be derived within 2-3 weeks.
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            The Perseus computational platform for comprehensive analysis of (prote)omics data.

            A main bottleneck in proteomics is the downstream biological analysis of highly multivariate quantitative protein abundance data generated using mass-spectrometry-based analysis. We developed the Perseus software platform (http://www.perseus-framework.org) to support biological and biomedical researchers in interpreting protein quantification, interaction and post-translational modification data. Perseus contains a comprehensive portfolio of statistical tools for high-dimensional omics data analysis covering normalization, pattern recognition, time-series analysis, cross-omics comparisons and multiple-hypothesis testing. A machine learning module supports the classification and validation of patient groups for diagnosis and prognosis, and it also detects predictive protein signatures. Central to Perseus is a user-friendly, interactive workflow environment that provides complete documentation of computational methods used in a publication. All activities in Perseus are realized as plugins, and users can extend the software by programming their own, which can be shared through a plugin store. We anticipate that Perseus's arsenal of algorithms and its intuitive usability will empower interdisciplinary analysis of complex large data sets.
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              Monitoring and Measuring Autophagy

              Autophagy is a cytoplasmic degradation system, which is important for starvation adaptation and cellular quality control. Recent advances in understanding autophagy highlight its importance under physiological and pathological conditions. However, methods for monitoring autophagic activity are complicated and the results are sometimes misinterpreted. Here, we review the methods used to identify autophagic structures, and to measure autophagic flux in cultured cells and animals. We will also describe the existing autophagy reporter mice that are useful for autophagy studies and drug testing. Lastly, we will consider the attempts to monitor autophagy in samples derived from humans.

                Author and article information

                EMBO Mol Med
                EMBO Mol Med
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                24 June 2021
                07 July 2021
                : 13
                : 7 ( doiID: 10.1002/emmm.v13.7 )
                [ 1 ] Division of Pharmacology Department of Pharmaceutical Sciences Faculty of Science Utrecht University Utrecht The Netherlands
                [ 2 ] Biomolecular Mass Spectrometry and Proteomics Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht The Netherlands
                [ 3 ] Netherlands Proteomics Center Utrecht The Netherlands
                [ 4 ] Hubrecht Institute‐Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht Utrecht The Netherlands
                [ 5 ] Department of Nephrology and Hypertension University Medical Center Utrecht Utrecht The Netherlands
                [ 6 ] Division of Cell Biology, Cancer & Metabolism Department of Biomolecular Health Sciences Faculty of Veterinary Medicine Utrecht University Utrecht The Netherlands
                [ 7 ] Department of Pediatric Nephrology & Growth and Regeneration University Hospitals Leuven & KU Leuven Leuven Belgium
                [ 8 ] Renal Diseases Research Unit, Genetics and Rare Diseases Research Area Bambino Gesù Children’s Hospital IRCCS Rome Italy
                [ 9 ] Section Cell Biology Center for Molecular Medicine University Medical Center Utrecht Utrecht University Utrecht The Netherlands
                [ 10 ] Department of Pediatric Nephrology Wilhelmina Children’s Hospital University Medical Centre Utrecht Utrecht The Netherlands
                Author notes
                [*] [* ] Corresponding author. Tel: +31 30 2531599; E‐mail: m.j.janssen1@ 123456uu.nl


                These authors contributed equally to this work.

                © 2021 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 14, Tables: 2, Pages: 20, Words: 14399
                Funded by: Nierstichting (Dutch Kidney Foundation) , open-funder-registry 10.13039/501100002997;
                Award ID: 150KG19
                Funded by: E‐rare 2‐joint call 2014, Zon‐MW
                Award ID: 113301402
                Funded by: Health Holland, TopSector Life Sciences & Health
                Award ID: RegMed XB
                Funded by: Netherlands Organization for Scientific Research, Graviation program
                Award ID: 024.003.013
                Custom metadata
                07 July 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:07.07.2021

                Molecular medicine
                alpha‐ketoglutarate,bicalutamide combination therapy,cysteamine,cystinosis,renal fanconi syndrome,genetics, gene therapy & genetic disease,urogenital system


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