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3. Adeno-associated virus-based gene therapy treats inflammatory kidney disease in mice

Author

Wu, Guochao, Liu, Shuya, Hagenstein, Julia, Alawi, Malik, Hengel, Felicitas E., Schaper, Melanie, Akyuz, Nuray, Liao, Zhouning, Wanner, Nicola, Tomas, Nicola M., Failla, Antonio Virgilio, Dierlamm, Judith, Korbelin, Jakob, Lu, Shun, and Huber, Tobias B.

Subjects
Care and treatment, Physiological aspects, Usage, Health aspects, Gene therapy -- Physiological aspects, Inflammation -- Physiological aspects, Medical research, Kidney diseases -- Physiological aspects -- Care and treatment, Dependoviruses -- Usage -- Health aspects, Medicine, Experimental
Abstract

Introduction Most kidney diseases are associated with the dysfunction of the glomerular filtration barrier (GFB), which comprises 3 layers, including the glomerular endothelial cells (GEC), the glomerular basement membrane (GBM) [...], Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.

Published
2024
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4. Biallelic FRA10AC1 variants cause a neurodevelopmental disorder with growth retardation.

Author

von Elsner, Leonie, Chai, Guoliang, Schneeberger, Pauline E, Harms, Frederike L, Casar, Christian, Qi, Minyue, Alawi, Malik, Abdel-Salam, Ghada MH, Zaki, Maha S, Arndt, Florian, Yang, Xiaoxu, Stanley, Valentina, Hempel, Maja, Gleeson, Joseph G, and Kutsche, Kerstin

Subjects
Brain Disorders, Neurosciences, Clinical Research, Intellectual and Developmental Disabilities (IDD), Rare Diseases, Genetics, Aetiology, 2.1 Biological and endogenous factors, DNA-Binding Proteins, Growth Disorders, Humans, Intellectual Disability, Membrane Proteins, Microcephaly, Neurodevelopmental Disorders, Nuclear Proteins, RNA Splice Sites, RNA-Binding Proteins, Repressor Proteins, exome sequencing, homozygous, major spliceosome, splicing, intellectual disability, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5' and 3' splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction with splice sites. We identified biallelic pathogenic variants in FRA10AC1 in five individuals from three consanguineous families. The two unrelated Patients 1 and 2 with loss-of-function variants showed developmental delay, intellectual disability, and no speech, while three siblings with the c.494_496delAAG (p.Glu165del) variant had borderline to mild intellectual disability. All patients had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. FRA10AC1 transcripts and proteins were drastically reduced or absent in fibroblasts of Patients 1 and 2. In a heterologous expression system, the p.Glu165del variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localization. By co-immunoprecipitation, we found ectopically expressed HA-FRA10AC1 in complex with endogenous DGCR14, another component of the spliceosomal C complex, while the splice factors CHERP, NKAP, RED, and SF3B2 could not be co-immunoprecipitated. Using an in vitro splicing reporter assay, we did not obtain evidence for FRA10AC1 deficiency to suppress missplicing events caused by mutations in the highly conserved dinucleotides of 5' and 3' splice sites in an in vitro splicing assay in patient-derived fibroblasts. Our data highlight the importance of specific peripheral spliceosomal C complex proteins for neurodevelopment. It remains possible that FRA10AC1 may have other and/or additional cellular functions, such as coupling of transcription and splicing reactions.

Published
2022

7. Hypoimmune induced pluripotent stem cell–derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice

Author

Deuse, Tobias, Tediashvili, Grigol, Hu, Xiaomeng, Gravina, Alessia, Tamenang, Annika, Wang, Dong, Connolly, Andrew, Mueller, Christian, Mallavia, Beñat, Looney, Mark R, Alawi, Malik, Lanier, Lewis L, and Schrepfer, Sonja

Subjects
Stem Cell Research - Embryonic - Non-Human, Cardiovascular, Regenerative Medicine, Transplantation, Heart Disease, Biotechnology, Lung, Stem Cell Research, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Animals, Cardiovascular Diseases, Endothelial Cells, Heart Failure, Hindlimb, Immunocompetence, Induced Pluripotent Stem Cells, Ischemia, Lung Diseases, Mice, Inbred BALB C, Mice, Inbred C57BL, Myocytes, Cardiac, Stem Cell Transplantation, Transplantation, Homologous, alpha 1-Antitrypsin, hypoimmune stem cells, immune evasion, cell therapy
Abstract

The emerging field of regenerative cell therapy is still limited by the few cell types that can reliably be differentiated from pluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in immunocompetent, fully allogeneic recipients. Transplanted endothelial cells improved perfusion and increased the likelihood of limb preservation in mice with critical limb ischemia. Endothelial cell grafts transduced to express a transgene for alpha1-antitrypsin (A1AT) successfully restored physiologic A1AT serum levels in mice with genetic A1AT deficiency. This cell therapy prevented both structural and functional changes of emphysematous lung disease. A mixture of endothelial cells and cardiomyocytes was injected into infarcted mouse hearts, and both cell types orthotopically engrafted in the ischemic areas. Cell therapy led to an improvement in invasive hemodynamic heart failure parameters. Our study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.

Published
2021

8. The SIRPα–CD47 immune checkpoint in NK cells

Author

Deuse, Tobias, Hu, Xiaomeng, Agbor-Enoh, Sean, Jang, Moon K, Alawi, Malik, Saygi, Ceren, Gravina, Alessia, Tediashvili, Grigol, Nguyen, Vinh Q, Liu, Yuan, Valantine, Hannah, Lanier, Lewis L, and Schrepfer, Sonja

Subjects
Cancer, Vaccine Related, Prevention, Immunization, HIV/AIDS, Vaccine Related (AIDS), Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Animals, CD47 Antigen, Cells, Cultured, Cytokines, Cytotoxicity, Immunologic, Endothelial Cells, Histocompatibility Antigens Class I, Humans, Immune Checkpoint Inhibitors, Killer Cells, Natural, Macaca mulatta, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Protein Binding, Receptors, Immunologic, Species Specificity, Medical and Health Sciences, Immunology
Abstract

Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I-deficient target cells against SIRPα+ primary NK cells, but not against SIRPα- NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα-CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell-mediated killing of allogeneic and xenogeneic tissues.

Published
2021

12. Pregnancy-induced maternal microchimerism shapes neurodevelopment and behavior in mice

Author

Schepanski, Steven, Chini, Mattia, Sternemann, Veronika, Urbschat, Christopher, Thiele, Kristin, Sun, Ting, Zhao, Yu, Poburski, Mareike, Woestemeier, Anna, Thieme, Marie-Theres, Zazara, Dimitra E., Alawi, Malik, Fischer, Nicole, Heeren, Joerg, Vladimirov, Nikita, Woehler, Andrew, Puelles, Victor G., Bonn, Stefan, Gagliani, Nicola, Hanganu-Opatz, Ileana L., and Arck, Petra C.

Published
2022
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15. Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism

Author

Harms, Frederike Leonie, Girisha, Katta M, Hardigan, Andrew A, Kortüm, Fanny, Shukla, Anju, Alawi, Malik, Dalal, Ashwin, Brady, Lauren, Tarnopolsky, Mark, Bird, Lynne M, Ceulemans, Sophia, Bebin, Martina, Bowling, Kevin M, Hiatt, Susan M, Lose, Edward J, Primiano, Michelle, Chung, Wendy K, Juusola, Jane, Akdemir, Zeynep C, Bainbridge, Matthew, Charng, Wu-Lin, Drummond-Borg, Margaret, Eldomery, Mohammad K, El-Hattab, Ayman W, Saleh, Mohammed AM, Bézieau, Stéphane, Cogné, Benjamin, Isidor, Bertrand, Küry, Sébastien, Lupski, James R, Myers, Richard M, Cooper, Gregory M, and Kutsche, Kerstin

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Pediatric, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Adolescent, Adult, Amino Acid Substitution, Ataxia, Child, Child, Preschool, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, Developmental Disabilities, Exome, Face, Female, Gene Expression Regulation, Genes, Reporter, HEK293 Cells, Humans, Intellectual Disability, Language Development Disorders, Male, Models, Molecular, Mosaicism, Mutation, Neurodevelopmental Disorders, Protein Transport, Syndrome, Transcription Factors, Transcription, Genetic, EBF3, de novo mutation, developmental delay, gene regulation, intellectual disability, transcription factor, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ∼0.1% of individuals with unexplained neurodevelopmental disorders.

Published
2017

16. Oxidation of sulfur, hydrogen, and iron by metabolically versatile Hydrogenovibrio from deep sea hydrothermal vents

Author

Laufer-Meiser, Katja, Alawi, Malik, Böhnke, Stefanie, Solterbeck, Claus-Henning, Schloesser, Jana, Schippers, Axel, Dirksen, Philipp, Brüser, Thomas, Henkel, Susann, Fuss, Janina, Perner, Mirjam, Laufer-Meiser, Katja, Alawi, Malik, Böhnke, Stefanie, Solterbeck, Claus-Henning, Schloesser, Jana, Schippers, Axel, Dirksen, Philipp, Brüser, Thomas, Henkel, Susann, Fuss, Janina, and Perner, Mirjam

Abstract

Chemolithoautotrophic Hydrogenovibrio are ubiquitous and abundant at hydrothermal vents. They can oxidize sulfur, hydrogen or iron, but none are known to use all three energy sources. This ability though would be advantageous in vents hallmarked by highly dynamic environmental conditions. We isolated three Hydrogenovibrio strains from vents along the Indian Ridge, which grow on all three electron donors. We present transcriptomic data from strains grown on iron, hydrogen or thiosulfate with respective oxidation and autotrophic CO2 fixation rates, RubisCO activity, SEM, and EDX. Maximum estimates of one strain’s oxidation potential were 10, 24, and 952 mmol for iron, hydrogen and thiosulfate oxidation and 0.3, 1, and 84 mmol CO2 fixation, respectively, per vent per hour indicating their relevance for element cycling in-situ. Several genes were up- or downregulated depending on the inorganic electron donor provided. Although no known genes of iron-oxidation were detected, upregulated transcripts suggested iron-acquisition and so far unknown iron-oxidation-pathways.

Published
2024
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17. Intestinal Epithelia and Myeloid Immune Cells Shape Colitis Severity and Colorectal Carcinogenesis via High-mobility Group Box Protein 1.

Author

Foelsch, Katharina, Pelczar, Penelope, Zierz, Elisabeth, Kondratowicz, Stephanie, Qi, Minyue, Mueller, Christian, Alawi, Malik, Huebener, Sina, Clauditz, Till, Gagliani, Nicola, Huber, Samuel, and Huebener, Peter

Abstract

Background High-mobility group box protein 1 [HMGB1] is a ubiquitous nucleoprotein with immune-regulatory properties following cellular secretion or release in sterile and in infectious inflammation. Stool and serum HMGB1 levels correlate with colitis severity and colorectal cancer [CRC] progression, yet recent reports indicate that HMGB1 mainly operates as an intracellular determinant of enterocyte fate during colitis, and investigations into the roles of HMGB1 in CRC are lacking. Methods Using mice with conditional HMGB1-knockout in enterocytes [ Hmgb1 ΔIEC] and myeloid cells [ Hmgb1 ΔLysM], respectively, we explored functions of HMGB1 in pathogenetically diverse contexts of colitis and colitis-associated CRC. Results HMGB1 is overexpressed in human inflammatory bowel disease and gastrointestinal cancers, and HMGB1 protein localises in enterocytes and stromal cells in colitis and CRC specimens from humans and rodents. As previously described, enterocyte HMGB1 deficiency aggravates severe chemical-induced intestinal injury, but not Citrobacter rodentium or T cell transfer colitis in mice. HMGB1 - deficient enterocytes and organoids do not exhibit deviant apoptotic or autophagic activity, altered proliferative or migratory capacity, abnormal intestinal permeability, or aberrant DSS-induced organoid inflammation in vitro. Instead, we observed altered in vivo reprogramming of both intestinal epithelia and infiltrating myeloid cells in Hmgb1 ΔIEC early during colitis, suggesting HMGB1-mediated paracrine injury signalling. Hmgb1 ΔIEC had higher CRC burden than wild types in the Apc +/min model, whereas inflammatory CRC was attenuated in Hmgb1 ΔLysM. Cellular and molecular phenotyping of Hmgb1 ΔIEC and Hmgb1 ΔLysM cancers indicates context-dependent transcriptional modulation of immune signalling and extracellular matrix remodelling via HMGB1. Conclusion Enterocytes and myeloid cells context-dependently regulate host responses to severe colitis and maladaptive intestinal wound healing via HMGB1. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Glioma escape signature and clonal development under immune pressure

Author

Maire, Cecile L., Mohme, Malte, Bockmayr, Michael, Fita, Krystian D., Riecken, Kristoffer, Bornigen, Daniela, Alawi, Malik, Failla, Antonio, Kolbe, Katharina, Zapf, Svenja, Holz, Mareike, Neumann, Katrin, Duhrsen, Lasse, Lange, Tobias, Fehse, Boris, Westphal, Manfred, and Lamszus, Katrin

Subjects
Gliomas -- Genetic aspects, B cells -- Genetic aspects, Genes -- Genetic aspects, Immunotherapy, Palladium, Health care industry
Abstract

Immunotherapeutic strategies are increasingly important in neuro-oncology, and the elucidation of escape mechanisms that lead to treatment resistance is crucial. We investigated the impact of immune pressure on the clonal dynamics and immune escape signature by comparing glioma growth in immunocompetent versus immunodeficient mice. Glioma-bearing WT and [Pd-1.sup.-/-] mice survived significantly longer than immunodeficient [Pfp.sup.-/-] [Rag2.sup.-/-] mice. While tumors in [Pfp.sup.-/-] [Rag2.sup.-/-] mice were highly polyclonal, immunoedited tumors in WT and [Pd-1.sup.-/-] mice displayed reduced clonality with emergence of immune escape clones. Tumor cells in WT mice were distinguished by an IFN-[gamma]-mediated response signature with upregulation of genes involved in immunosuppression. Tumor-infiltrating stromal cells, which include macrophages/microglia, contributed even more strongly to the immunosuppressive signature than the actual tumor cells. The identified murine immune escape signature was reflected in human patients and correlated with poor survival. In conclusion, immune pressure profoundly shapes the clonal composition and gene regulation in malignant gliomas., Introduction Glioblastoma represents the most frequent aggressive intrinsic brain tumor, and patient outcome remains uniformly fatal despite improved treatment options (1). The current era of glioblastoma therapy is being redefined [...]

Published
2020
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25. Impact of Multiple Minor Histocompatibility Antigen Differences on Graft-Versus-Host Disease and Relapse Risk in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients

Author

Mueller, Christian, primary, Alawi, Malik, additional, Loeffler, Juergen, additional, Bonin, Michael, additional, Schreiber, Andreas, additional, Kreyenberg, Hermann, additional, Wiegering, Verena, additional, Woelfl, Matthias, additional, Caruana, Ignazio, additional, Schlegel, Paul G., additional, and Eyrich, Matthias, additional

Published
2023
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27. Stenotrophomonas maltophilia affects the gene expression profiles of the major pathogens Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro multispecies biofilm model

Author

Alio, Ifey, primary, Moll, Raphael, additional, Hoffmann, Tim, additional, Mamat, Uwe, additional, Schaible, Ulrich E., additional, Pappenfort, Kai, additional, Alawi, Malik, additional, Schie, Marcel, additional, Thünauer, Roland, additional, Stamm, Johanna, additional, Rohde, Holger, additional, and Streit, Wolfgang R., additional

Published
2023
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28. Preeclampsia-induced cardiovascular diseases: identification of specific immune markers using Infinity Flow

Author

Humke, Charlotte, primary, Thiele, Kristin, additional, Pagenkemper, Mirja, additional, Maaß, Laura M., additional, Tallarek, Ann-Christin, additional, Hansen, Gudula, additional, Alawi, Malik, additional, Qi, Minyue, additional, Zeller, Tanja, additional, Nikolaev, Viacheslav, additional, Hecher, Kurt, additional, Arck, Petra C., additional, and Diemert, Anke, additional

Published
2023
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30. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients

Author

Renner, Sina, Schüler, Helke, Alawi, Malik, Kolbe, Verena, Rybczynski, Meike, Woitschach, Rixa, Sheikhzadeh, Sara, Stark, Veronika C., Olfe, Jakob, Roser, Elke, Seggewies, Friederike Sophia, Mahlmann, Adrian, Hempel, Maja, Hartmann, Melanie J., Hillebrand, Mathias, Wieczorek, Dagmar, Volk, Alexander Erich, Kloth, Katja, Koch-Hogrebe, Margarete, Abou Jamra, Rami, Mitter, Diana, Altmüller, Janine, Wey-Fabrizius, Alexandra, Petersen, Christine, Rau, Isabella, Borck, Guntram, Kubisch, Christian, Mir, Thomas S., von Kodolitsch, Yskert, Kutsche, Kerstin, and Rosenberger, Georg

Published
2019
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31. Cellular Importin-α3 Expression Dynamics in the Lung Regulate Antiviral Response Pathways against Influenza A Virus Infection

Author

Thiele, Swantje, Stanelle-Bertram, Stephanie, Beck, Sebastian, Kouassi, Nancy Mounogou, Zickler, Martin, Müller, Martin, Tuku, Berfin, Resa-Infante, Patricia, van Riel, Debby, Alawi, Malik, Günther, Thomas, Rother, Franziska, Hügel, Stefanie, Reimering, Susanne, McHardy, Alice, Grundhoff, Adam, Brune, Wolfram, Osterhaus, Albert, Bader, Michael, Hartmann, Enno, and Gabriel, Gülsah

Published
2024
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32. Impact of AKT1 on cell invasion and radiosensitivity in a triple negative breast cancer cell line developing brain metastasis

Author

Kempska, Joanna, primary, Oliveira-Ferrer, Leticia, additional, Grottke, Astrid, additional, Qi, Minyue, additional, Alawi, Malik, additional, Meyer, Felix, additional, Borgmann, Kerstin, additional, Hamester, Fabienne, additional, Eylmann, Kathrin, additional, Rossberg, Maila, additional, Smit, Daniel J., additional, Jücker, Manfred, additional, Laakmann, Elena, additional, Witzel, Isabell, additional, Schmalfeldt, Barbara, additional, Müller, Volkmar, additional, and Legler, Karen, additional

Published
2023
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37. Preclinical patient‐derived modeling of castration‐resistant prostate cancer facilitates individualized assessment of homologous recombination repair deficient disease

Author

Elsesy, Mohamed E., primary, Oh‐Hohenhorst, Su Jung, additional, Oing, Christoph, additional, Eckhardt, Alicia, additional, Burdak‐Rothkamm, Susanne, additional, Alawi, Malik, additional, Müller, Christian, additional, Schüller, Ulrich, additional, Maurer, Tobias, additional, von Amsberg, Gunhild, additional, Petersen, Cordula, additional, Rothkamm, Kai, additional, and Mansour, Wael Y., additional

Published
2023
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38. Impact of AKT1 on cell invasion and radiosensitivity in a triple negative breast cancer cell line developing brain metastasis

Author

Kempska, Joanna, Oliveira-Ferrer, Leticia, Grottke, Astrid, Qi, Minyue, Alawi, Malik; https://orcid.org/0000-0002-5993-7709, Meyer, Felix, Borgmann, Kerstin, Hamester, Fabienne, Eylmann, Kathrin, Rossberg, Maila, Smit, Daniel J, Jücker, Manfred, Laakmann, Elena, Witzel, Isabell; https://orcid.org/0000-0002-8734-4521, Schmalfeldt, Barbara; https://orcid.org/0000-0001-7785-6403, Müller, Volkmar, Legler, Karen, Kempska, Joanna, Oliveira-Ferrer, Leticia, Grottke, Astrid, Qi, Minyue, Alawi, Malik; https://orcid.org/0000-0002-5993-7709, Meyer, Felix, Borgmann, Kerstin, Hamester, Fabienne, Eylmann, Kathrin, Rossberg, Maila, Smit, Daniel J, Jücker, Manfred, Laakmann, Elena, Witzel, Isabell; https://orcid.org/0000-0002-8734-4521, Schmalfeldt, Barbara; https://orcid.org/0000-0001-7785-6403, Müller, Volkmar, and Legler, Karen

Abstract

Introduction: The PI3K/AKT pathway is activated in 43-70% of breast cancer (BC)-patients and promotes the metastatic potential of BC cells by increasing cell proliferation, invasion and radioresistance. Therefore, AKT1-inhibition in combination with radiotherapy might be an effective treatment option for triple-negative breast cancer (TNBC)-patients with brain metastases. Methods: The impact of AKT1-knockout (AKT1_KO) and AKT-inhibition using Ipatasertib on MDA-MB-231 BR cells was assessed using in vitro cell proliferation and migration assays. AKT1-knockout in MDA-MB-231BR cells was performed using CRISPR/Cas9. The effect of AKT1-knockout on radiosensitivity of MDA-MB-231BR cell lines was determined via colony formation assays after cell irradiation. To detect genomic variants in AKT1_KO MDA-MB-231BR cells, whole-genome sequencing (WGS) was performed. Results: Pharmacological inhibition of AKT with the pan-AKT inhibitor Ipatasertib led to a significant reduction of cell viability but did not impact cell migration. Moreover, only MDA-MB-231BR cells were sensitized following Ipatasertib-treatment. Furthermore, specific AKT1-knockout in MDA-MB-231BR showed reduced cell viability in comparison to control cells, with significant effect in one of two analyzed clones. Unexpectedly, AKT1 knockout led to increased cell migration and clonogenic potential in both AKT1_KO clones. RNAseq-analysis revealed the deregulation of CTSO, CYBB, GPR68, CEBPA, ID1, ID4, METTL15, PBX1 and PTGFRN leading to the increased cell migration, higher clonogenic survival and decreased radiosensitivity as a consequence of the AKT1 knockout in MDA-MB-231BR. Discussion; Collectively, our results demonstrate that Ipatasertib leads to radiosensitization and reduced cell proliferation of MDA-MB-231BR. AKT1-inhibition showed altered gene expression profile leading to modified cell migration, clonogenic survival and radioresistance in MDA-MB-231BR. We conclude, that AKT1-inhibition in combination with rad

Published
2023

40. A transplant “immunome” screening platform defines a targetable epitope fingerprint of multiple myeloma

Author

Schieferdecker, Aneta, Oberle, Anna, Thiele, Benjamin, Hofmann, Fabian, Göthel, Markus, Miethe, Sebastian, Hust, Michael, Braig, Friederike, Voigt, Mareike, von Pein, Ute-Marie, Koch-Nolte, Friedrich, Haag, Friedrich, Alawi, Malik, Indenbirken, Daniela, Grundhoff, Adam, Bokemeyer, Carsten, Bacher, Ulrike, Kröger, Nicolaus, and Binder, Mascha

Published
2016
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43. Homozygous synonymous FAM111Avariant underlies an autosomal recessive form of Kenny-Caffey syndrome

Author

Bonde, Loisa Dana, Abdelrazek, Ibrahim M., Seif, Lara, Alawi, Malik, Matrawy, Khaled, Nabil, Karim, Abdalla, Ebtesam, Kutsche, Kerstin, and Harms, Frederike Leonie

Abstract

FAM111A (family with sequence similarity 111 member A) is a serine protease and removes covalent DNA-protein cross-links during DNA replication. Heterozygous gain-of-function variants in FAM111Acause skeletal dysplasias, such as the perinatal lethal osteocraniostenosis and the milder Kenny-Caffey syndrome (KCS). We report two siblings born to consanguineous parents with dysmorphic craniofacial features, postnatal growth retardation, ophthalmologic manifestations, hair and nail anomalies, and skeletal abnormalities such as thickened cortex and stenosis of the medullary cavity of the long bones suggestive of KCS. Using exome sequencing, a homozygous synonymous FAM111Avariant, NM_001312909.2:c.81 G > A; p.Pro27=, that affects the last base of the exon and is predicted to alter FAM111Apre-mRNA splicing, was identified in both siblings. We identified aberrantly spliced FAM111Atranscripts, reduced FAM111AmRNA levels, and near-complete absence of FAM111A protein in fibroblasts of both patients. After treatment of patient and control fibroblasts with different concentrations of camptothecin that induces covalent DNA-protein cross-links, we observed a tendency towards a reduced proportion of metabolically active cells in patient compared to control fibroblasts. However, under these culture conditions, we did not find consistent and statistically significant differences in cell cycle progression and apoptotic cell death between patient and control cells. Our findings show that FAM111A deficiency underlies an autosomal recessive form of FAM111A-related KCS. Based on our results and published data, we hypothesize that loss of FAM111A and FAM111A protease hyperactivity, as observed for gain-of-function patient-variant proteins, may converge on a similar pathomechanism underlying skeletal dysplasias.

Published
2024
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46. Murine scald models characterize the role of neutrophils and neutrophil extracellular traps in severe burns

Author

Elrod, Julia, primary, Lenz, Moritz, additional, Kiwit, Antonia, additional, Armbrust, Lina, additional, Schönfeld, Lavinia, additional, Reinshagen, Konrad, additional, Pagerols Raluy, Laia, additional, Mohr, Christoph, additional, Saygi, Ceren, additional, Alawi, Malik, additional, Rohde, Holger, additional, Herrmann, Martin, additional, and Boettcher, Michael, additional

Published
2023
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47. Midgut Volvulus Adds a Murine, Neutrophil-Driven Model of Septic Condition to the Experimental Toolbox

Author

Elrod, Julia, primary, Kiwit, Antonia, additional, Lenz, Moritz, additional, Rohde, Holger, additional, Börnigen, Daniela, additional, Alawi, Malik, additional, Mohr, Christoph, additional, Pagerols Raluy, Laia, additional, Trochimiuk, Magdalena, additional, Knopf, Jasmin, additional, Reinshagen, Konrad, additional, Herrmann, Martin, additional, and Boettcher, Michael, additional

Published
2023
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49. A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns

Author

Jiao, Wei, Atwal, Gurnit, Polak, Paz, Karlic, Rosa, Cuppen, Edwin, Al-Shahrour, Fatima, Bailey, Peter J, Biankin, Andrew V, Boutros, Paul C, Campbell, Peter J, Chang, David K, Cooke, Susanna L, Deshpande, Vikram, Faltas, Bishoy M, Faquin, William C, Garraway, Levi, Getz, Gad, Grimmond, Sean M, Haider, Syed, Hoadley, Katherine A, Kaiser, Vera B, Kato, Mamoru, Kübler, Kirsten, Lazar, Alexander J, Li, Constance H, Louis, David N, Margolin, Adam, Martin, Sancha, Nahal-Bose, Hardeep K, Nielsen, G Petur, Nik-Zainal, Serena, Omberg, Larsson, P’ng, Christine, Perry, Marc D, Rheinbay, Esther, Rubin, Mark A, Semple, Colin A, Sgroi, Dennis C, Shibata, Tatsuhiro, Siebert, Reiner, Smith, Jaclyn, Stein, Lincoln D, Stobbe, Miranda D, Sun, Ren X, Thai, Kevin, Wright, Derek W, Wu, Chin-Lee, Yuan, Ke, Zhang, Junjun, Danyi, Alexandra, de Ridder, Jeroen, van Herpen, Carla, Lolkema, Martijn P, Steeghs, Neeltje, Morris, Quaid D, Aaltonen, Lauri A, Abascal, Federico, Abeshouse, Adam, Aburatani, Hiroyuki, Adams, David J, Agrawal, Nishant, Ahn, Keun Soo, Ahn, Sung-Min, Aikata, Hiroshi, Akbani, Rehan, Akdemir, Kadir C, Al-Ahmadie, Hikmat, Al-Sedairy, Sultan T, Alawi, Malik, Albert, Monique, Aldape, Kenneth, Alexandrov, Ludmil B, Ally, Adrian, Alsop, Kathryn, Alvarez, Eva G, Amary, Fernanda, Amin, Samirkumar B, Aminou, Brice, Ammerpohl, Ole, Anderson, Matthew J, Ang, Yeng, Antonello, Davide, Anur, Pavana, Aparicio, Samuel, Appelbaum, Elizabeth L, Arai, Yasuhito, Aretz, Axel, Arihiro, Koji, Ariizumi, Shun-ichi, Armenia, Joshua, Arnould, Laurent, Asa, Sylvia, Assenov, Yassen, Aukema, Sietse, Auman, J Todd, Aure, Miriam RR, Awadalla, Philip, Aymerich, Marta, Bader, Gary D, Baez-Ortega, Adrian, Bailey, Matthew H, Balasundaram, Miruna, Balu, Saianand, Bandopadhayay, Pratiti, Banks, Rosamonde E, Barbi, Stefano, Barbour, Andrew P, Barenboim, Jonathan, Barnholtz-Sloan, Jill, Barr, Hugh, Barrera, Elisabet, Bartlett, John, Bartolome, Javier, Bassi, Claudio, Bathe, Oliver F, Baumhoer, Daniel, Bavi, Prashant, Baylin, Stephen B, Bazant, Wojciech, Beardsmore, Duncan, Beck, Timothy A, Behjati, Sam, Behren, Andreas, Niu, Beifang, Bell, Cindy, Beltran, Sergi, Benz, Christopher, Berchuck, Andrew, Bergmann, Anke K, Bergstrom, Erik N, Berman, Benjamin P, Berney, Daniel M, Bernhart, Stephan H, Beroukhim, Rameen, Berrios, Mario, Bersani, Samantha, Bertl, Johanna, Betancourt, Miguel, Bhandari, Vinayak, Bhosle, Shriram G, Bieg, Matthias, Bigner, Darell, Binder, Hans, Birney, Ewan, Birrer, Michael, Biswas, Nidhan K, Bjerkehagen, Bodil, Bodenheimer, Tom, Boice, Lori, Bonizzato, Giada, De Bono, Johann S, Boot, Arnoud, Bootwalla, Moiz S, Borg, Ake, Borkhardt, Arndt, Boroevich, Keith A, Borozan, Ivan, Borst, Christoph, Bosenberg, Marcus, Bosio, Mattia, Boultwood, Jacqueline, Bourque, Guillaume, Bova, G Steven, Bowen, David T, Bowlby, Reanne, Bowtell, David DL, Boyault, Sandrine, Boyce, Rich, Boyd, Jeffrey, Brazma, Alvis, Brennan, Paul, Brewer, Daniel S, Brinkman, Arie B, Bristow, Robert G, Broaddus, Russell R, Brock, Jane E, Brock, Malcolm, Broeks, Annegien, Brooks, Angela N, Brooks, Denise, Brors, Benedikt, Brunak, Søren, Bruxner, Timothy JC, Bruzos, Alicia L, Buchanan, Alex, Buchhalter, Ivo, Buchholz, Christiane, Bullman, Susan, Burke, Hazel, Burkhardt, Birgit, Burns, Kathleen H, Busanovich, John, Bustamante, Carlos D, Butler, Adam P, Butte, Atul J, Byrne, Niall J, Børresen-Dale, Anne-Lise, Caesar-Johnson, Samantha J, Cafferkey, Andy, Cahill, Declan, Calabrese, Claudia, Caldas, Carlos, Calvo, Fabien, Camacho, Niedzica, Campo, Elias, Cantù, Cinzia, Cao, Shaolong, Carey, Thomas E, Carlevaro-Fita, Joana, Carlsen, Rebecca, Cataldo, Ivana, Cazzola, Mario, Cebon, Jonathan, Cerfolio, Robert, Chadwick, Dianne E, Chakravarty, Dimple, Chalmers, Don, Chan, Calvin Wing Yiu, Chan, Kin, Chan-Seng-Yue, Michelle, Chandan, Vishal S, Chanock, Stephen J, Chantrill, Lorraine A, Chateigner, Aurélien, Chatterjee, Nilanjan, Chayama, Kazuaki, Chen, Hsiao-Wei, Chen, Jieming, Chen, Ken, Chen, Yiwen, Chen, Zhaohong, Cherniack, Andrew D, Chien, Jeremy, Chiew, Yoke-Eng, Chin, Suet-Feung, Cho, Juok, Cho, Sunghoon, Choi, Jung Kyoon, Choi, Wan, Chomienne, Christine, Chong, Zechen, Choo, Su Pin, Chou, Angela, Christ, Angelika N, Christie, Elizabeth L, Chuah, Eric, Cibulskis, Carrie, Cibulskis, Kristian, Cingarlini, Sara, Clapham, Peter, Claviez, Alexander, Cleary, Sean, Cloonan, Nicole, Cmero, Marek, Collins, Colin C, Connor, Ashton A, Cooper, Colin S, Cope, Leslie, Corbo, Vincenzo, Cordes, Matthew G, Cordner, Stephen M, Cortés-Ciriano, Isidro, Covington, Kyle, Cowin, Prue A, Craft, Brian, Craft, David, Creighton, Chad J, Cun, Yupeng, Curley, Erin, Cutcutache, Ioana, Czajka, Karolina, Czerniak, Bogdan, Dagg, Rebecca A, Danilova, Ludmila, Davi, Maria Vittoria, Davidson, Natalie R, Davies, Helen, Davis, Ian J, Davis-Dusenbery, Brandi N, Dawson, Kevin J, De La Vega, Francisco M, De Paoli-Iseppi, Ricardo, Defreitas, Timothy, Dei Tos, Angelo P, Delaneau, Olivier, Demchok, John A, Demeulemeester, Jonas, Demidov, German M, Demircioğlu, Deniz, Dennis, Nening M, Denroche, Robert E, Dentro, Stefan C, Desai, Nikita, Deshwar, Amit G, Desmedt, Christine, Deu-Pons, Jordi, Dhalla, Noreen, Dhani, Neesha C, Dhingra, Priyanka, Dhir, Rajiv, DiBiase, Anthony, Diamanti, Klev, Ding, Li, Ding, Shuai, Dinh, Huy Q, Dirix, Luc, Doddapaneni, HarshaVardhan, Donmez, Nilgun, Dow, Michelle T, Drapkin, Ronny, Drechsel, Oliver, Drews, Ruben M, Serge, Serge, Dudderidge, Tim, Dueso-Barroso, Ana, Dunford, Andrew J, Dunn, Michael, Dursi, Lewis Jonathan, Duthie, Fraser R, Dutton-Regester, Ken, Eagles, Jenna, Easton, Douglas F, Edmonds, Stuart, Edwards, Paul A, Edwards, Sandra E, Eeles, Rosalind A, Ehinger, Anna, Eils, Juergen, Eils, Roland, El-Naggar, Adel, Eldridge, Matthew, Ellrott, Kyle, Erkek, Serap, Escaramis, Georgia, Espiritu, Shadrielle MG, Estivill, Xavier, Etemadmoghadam, Dariush, Eyfjord, Jorunn E, Fan, Daiming, Fan, Yu, Farcas, Claudiu, Fassan, Matteo, Fatima, Aquila, Favero, Francesco, Fayzullaev, Nodirjon, Felau, Ina, Fereday, Sian, Ferguson, Martin L, Ferretti, Vincent, Feuerbach, Lars, Field, Matthew A, Fink, J Lynn, Finocchiaro, Gaetano, Fisher, Cyril, Fittall, Matthew W, Fitzgerald, Anna, Fitzgerald, Rebecca C, Flanagan, Adrienne M, Fleshner, Neil E, Flicek, Paul, Foekens, John A, Fong, Kwun M, Fonseca, Nuno A, Foster, Christopher S, Fox, Natalie S, Fraser, Michael, Frazer, Scott, Frenkel-Morgenstern, Milana, Friedman, William, Frigola, Joan, Fronick, Catrina C, Fujimoto, Akihiro, Fujita, Masashi, Fukayama, Masashi, Fulton, Lucinda A, Fulton, Robert S, Furuta, Mayuko, Futreal, P Andrew, Füllgrabe, Anja, Gabriel, Stacey B, Gallinger, Steven, Gambacorti-Passerini, Carlo, Gao, Jianjiong, Gao, Shengjie, Garred, Øystein, Garrison, Erik, Garsed, Dale W, Gehlenborg, Nils, Gelpi, Josep LL, George, Joshy, Gerhard, Daniela S, Gerhauser, Clarissa, Gershenwald, Jeffrey E, Gerstein, Mark, Gerstung, Moritz, Ghori, Mohammed, Ghossein, Ronald, Giama, Nasra H, Gibbs, Richard A, Gibson, Bob, Gill, Anthony J, Gill, Pelvender, Giri, Dilip D, Glodzik, Dominik, Gnanapragasam, Vincent J, Goebler, Maria Elisabeth, Goldman, Mary J, Gomez, Carmen, Gonzalez, Santiago, Gonzalez-Perez, Abel, Gordenin, Dmitry A, Gossage, James, Gotoh, Kunihito, Govindan, Ramaswamy, Grabau, Dorthe, Graham, Janet S, Grant, Robert C, Green, Anthony R, Green, Eric, Greger, Liliana, Grehan, Nicola, Grimaldi, Sonia, Grossman, Robert L, Grundhoff, Adam, Gundem, Gunes, Guo, Qianyun, Gupta, Manaswi, Gupta, Shailja, Gut, Ivo G, Gut, Marta, Göke, Jonathan, Ha, Gavin, Haake, Andrea, Haan, David, Haas, Siegfried, Haase, Kerstin, Haber, James E, Habermann, Nina, Hach, Faraz, Hama, Natsuko, Hamdy, Freddie C, Hamilton, Anne, Hamilton, Mark P, Han, Leng, Hanna, George B, Hansmann, Martin, Haradhvala, Nicholas J, Harismendy, Olivier, Harliwong, Ivon, Harmanci, Arif O, Harrington, Eoghan, Hasegawa, Takanori, Haussler, David, Hawkins, Steve, Hayami, Shinya, Hayashi, Shuto, Hayes, D Neil, Hayes, Stephen J, Hayward, Nicholas K, Hazell, Steven, He, Yao, Heath, Allison P, Heath, Simon C, Hedley, David, Hegde, Apurva M, Heiman, David I, Heinold, Michael C, Heins, Zachary, Heisler, Lawrence E, Hellstrom-Lindberg, Eva, Helmy, Mohamed, Heo, Seong Gu, Hepperla, Austin J, Heredia-Genestar, José María, Herrmann, Carl, Hersey, Peter, Hess, Julian M, Hilmarsdottir, Holmfridur, Hinton, Jonathan, Hirano, Satoshi, Hiraoka, Nobuyoshi, Hobolth, Asger, Hodzic, Ermin, Hoell, Jessica I, Hoffmann, Steve, Hofmann, Oliver, Holbrook, Andrea, Holik, Aliaksei Z, Hollingsworth, Michael A, Holmes, Oliver, Holt, Robert A, Hong, Chen, Hong, Eun Pyo, Hong, Jongwhi H, Hooijer, Gerrit K, Hornshøj, Henrik, Hosoda, Fumie, Hou, Yong, Hovestadt, Volker, Howat, William, Hoyle, Alan P, Hruban, Ralph H, Hu, Jianhong, Hu, Taobo, Hua, Xing, Huang, Kuan-lin, Huang, Mei, Huang, Mi Ni, Huang, Vincent, Huang, Yi, Huber, Wolfgang, Hudson, Thomas J, Hummel, Michael, Hung, Jillian A, Huntsman, David, Hupp, Ted R, Huse, Jason, Huska, Matthew R, Hutter, Barbara, Hutter, Carolyn M, Hübschmann, Daniel, Iacobuzio-Donahue, Christine A, Imbusch, Charles David, Imielinski, Marcin, Imoto, Seiya, Isaacs, William B, Isaev, Keren, Ishikawa, Shumpei, Iskar, Murat, Islam, SM Ashiqul, Ittmann, Michael, Ivkovic, Sinisa, Izarzugaza, Jose MG, Jacquemier, Jocelyne, Jakrot, Valerie, Jamieson, Nigel B, Jang, Gun Ho, Jang, Se Jin, Jayaseelan, Joy C, Jayasinghe, Reyka, Jefferys, Stuart R, Jegalian, Karine, Jennings, Jennifer L, Jeon, Seung-Hyup, Jerman, Lara, Ji, Yuan, Johansson, Peter A, Johns, Amber L, Johns, Jeremy, Johnson, Rory, Johnson, Todd A, Jolly, Clemency, Joly, Yann, Jonasson, Jon G, Jones, Corbin D, Jones, David R, Jones, David TW, Jones, Nic, Jones, Steven JM, Jonkers, Jos, Ju, Young Seok, Juhl, Hartmut, Jung, Jongsun, Juul, Malene, Juul, Randi Istrup, Juul, Sissel, Jäger, Natalie, Kabbe, Rolf, Kahles, Andre, Kahraman, Abdullah, Kakavand, Hojabr, Kalimuthu, Sangeetha, von Kalle, Christof, Kang, Koo Jeong, Karaszi, Katalin, Karlan, Beth, Karlić, Rosa, Karsch, Dennis, Kasaian, Katayoon, Kassahn, Karin S, Katai, Hitoshi, Katoh, Hiroto, Kawakami, Yoshiiku, Kay, Jonathan D, Kazakoff, Stephen H, Kazanov, Marat D, Keays, Maria, Kebebew, Electron, Kefford, Richard F, Kellis, Manolis, Kench, James G, Kennedy, Catherine J, Kerssemakers, Jules NA, Khoo, David, Khoo, Vincent, Khuntikeo, Narong, Khurana, Ekta, Kilpinen, Helena, Kim, Hark Kyun, Kim, Hyung-Lae, Kim, Hyung-Yong, Kim, Hyunghwan, Kim, Jaegil, Kim, Jihoon, Kim, Jong K, Kim, Youngwook, King, Tari A, Klapper, Wolfram, Kleinheinz, Kortine, Klimczak, Leszek J, Knappskog, Stian, Kneba, Michael, Knoppers, Bartha M, Koh, Youngil, Komorowski, Jan, Komura, Daisuke, Komura, Mitsuhiro, Kong, Gu, Kool, Marcel, Korbel, Jan O, Korchina, Viktoriya, Korshunov, Andrey, Koscher, Michael, Koster, Roelof, Kote-Jarai, Zsofia, Koures, Antonios, Kovacevic, Milena, Kremeyer, Barbara, Kretzmer, Helene, Kreuz, Markus, Krishnamurthy, Savitri, Kube, Dieter, Kumar, Kiran, Kumar, Pardeep, Kumar, Sushant, Kumar, Yogesh, Kundra, Ritika, Küppers, Ralf, Lagergren, Jesper, Lai, Phillip H, Laird, Peter W, Lakhani, Sunil R, Lalansingh, Christopher M, Lalonde, Emilie, Lamaze, Fabien C, Lambert, Adam, Lander, Eric, Landgraf, Pablo, Landoni, Luca, Langerød, Anita, Lanzós, Andrés, Larsimont, Denis, Larsson, Erik, Lathrop, Mark, Lau, Loretta MS, Lawerenz, Chris, Lawlor, Rita T, Lawrence, Michael S, Lazic, Ana Mijalkovic, Le, Xuan, Lee, Darlene, Lee, Donghoon, Lee, Eunjung Alice, Lee, Hee Jin, Lee, Jake June-Koo, Lee, Jeong-Yeon, Lee, Juhee, Lee, Ming Ta Michael, Lee-Six, Henry, Lehmann, Kjong-Van, Lehrach, Hans, Lenze, Dido, Leonard, Conrad R, Leongamornlert, Daniel A, Leshchiner, Ignaty, Letourneau, Louis, Letunic, Ivica, Levine, Douglas A, Lewis, Lora, Ley, Tim, Li, Chang, Li, Haiyan Irene, Li, Jun, Li, Lin, Li, Shantao, Li, Siliang, Li, Xiaobo, Li, Xiaotong, Li, Xinyue, Li, Yilong, Liang, Han, Liang, Sheng-Ben, Lichter, Peter, Lin, Pei, Lin, Ziao, Linehan, WM, Lingjærde, Ole Christian, Liu, Dongbing, Liu, Eric Minwei, Liu, Fei-Fei Fei, Liu, Fenglin, Liu, Jia, Liu, Xingmin, Livingstone, Julie, Livitz, Dimitri, Livni, Naomi, Lochovsky, Lucas, Loeffler, Markus, Long, Georgina V, Lopez-Guillermo, Armando, Lou, Shaoke, Lovat, Laurence B, Lu, Yiling, Lu, Yong-Jie, Lu, Youyong, Luchini, Claudio, Lungu, Ilinca, Luo, Xuemei, Luxton, Hayley J, Lynch, Andy G, Lype, Lisa, López, Cristina, López-Otín, Carlos, Z, Eric, Ma, Yussanne, MacGrogan, Gaetan, MacRae, Shona, Macintyre, Geoff, Madsen, Tobias, Maejima, Kazuhiro, Mafficini, Andrea, Maglinte, Dennis T, Maitra, Arindam, Majumder, Partha P, Malcovati, Luca, Malikic, Salem, Malleo, Giuseppe, Mann, Graham J, Mantovani-Löffler, Luisa, Marchal, Kathleen, Marchegiani, Giovanni, Mardis, Elaine R, Margolin, Adam A, Marin, Maximillian G, Markowetz, Florian, Markowski, Julia, Marks, Jeffrey, Marques-Bonet, Tomas, Marra, Marco A, Marsden, Luke, Martens, John WM, Martin-Subero, Jose I, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Maruvka, Yosef E, Mashl, R Jay, Massie, Charlie E, Matthew, Thomas J, Matthews, Lucy, Mayer, Erik, Mayes, Simon, Mayo, Michael, Mbabaali, Faridah, McCune, Karen, McDermott, Ultan, McGillivray, Patrick D, McLellan, Michael D, McPherson, John D, McPherson, John R, McPherson, Treasa A, Meier, Samuel R, Meng, Alice, Meng, Shaowu, Menzies, Andrew, Merrett, Neil D, Merson, Sue, Meyerson, Matthew, Meyerson, William, Mieczkowski, Piotr A, Mihaiescu, George L, Mijalkovic, Sanja, Mikkelsen, Tom, Milella, Michele, Mileshkin, Linda, Miller, Christopher A, Miller, David K, Miller, Jessica K, Mills, Gordon B, Milovanovic, Ana, Minner, Sarah, Miotto, Marco, Arnau, Gisela Mir, Mirabello, Lisa, Mitchell, Chris, Mitchell, Thomas J, Miyano, Satoru, Miyoshi, Naoki, Mizuno, Shinichi, Molnár-Gábor, Fruzsina, Moore, Malcolm J, Moore, Richard A, Morganella, Sandro, Morrison, Carl, Mose, Lisle E, Moser, Catherine D, Muiños, Ferran, Mularoni, Loris, Mungall, Andrew J, Mungall, Karen, Musgrove, Elizabeth A, Mustonen, Ville, Mutch, David, Muyas, Francesc, Muzny, Donna M, Muñoz, Alfonso, Myers, Jerome, Myklebost, Ola, Möller, Peter, Nagae, Genta, Nagrial, Adnan M, Nakagama, Hitoshi, Nakagawa, Hidewaki, Nakamura, Hiromi, Nakamura, Toru, Nakano, Kaoru, Nandi, Tannistha, Nangalia, Jyoti, Nastic, Mia, Navarro, Arcadi, Navarro, Fabio CP, Neal, David E, Nettekoven, Gerd, Newell, Felicity, Newhouse, Steven J, Newton, Yulia, Ng, Alvin Wei Tian, Ng, Anthony, Nicholson, Jonathan, Nicol, David, Nie, Yongzhan, Nielsen, Morten Muhlig, Noble, Michael S, Nones, Katia, Northcott, Paul A, Notta, Faiyaz, O’Connor, Brian D, O’Donnell, Peter, O’Donovan, Maria, O’Meara, Sarah, O’Neill, Brian Patrick, O’Neill, J Robert, Ocana, David, Ochoa, Angelica, Oesper, Layla, Ogden, Christopher, Ohdan, Hideki, Ohi, Kazuhiro, Ohno-Machado, Lucila, Oien, Karin A, Ojesina, Akinyemi I, Ojima, Hidenori, Okusaka, Takuji, Ong, Choon Kiat, Ossowski, Stephan, Ott, German, Ouellette, BF Francis, Paczkowska, Marta, Paiella, Salvatore, Pairojkul, Chawalit, Pajic, Marina, Pan-Hammarström, Qiang, Papaemmanuil, Elli, Papatheodorou, Irene, Paramasivam, Nagarajan, Park, Ji Wan, Park, Joong-Won, Park, Keunchil, Park, Kiejung, Park, Peter J, Parker, Joel S, Parsons, Simon L, Pass, Harvey, Pasternack, Danielle, Pastore, Alessandro, Patch, Ann-Marie, Pauporté, Iris, Pea, Antonio, Pearson, John V, Pedamallu, Chandra Sekhar, Pedersen, Jakob Skou, Pederzoli, Paolo, Peifer, Martin, Pennell, Nathan A, Perou, Charles M, Petersen, Gloria M, Peto, Myron, Petrelli, Nicholas, Petryszak, Robert, Pfister, Stefan M, Phillips, Mark, Pich, Oriol, Pickett, Hilda A, Pihl, Todd D, Pillay, Nischalan, Pinder, Sarah, Pinese, Mark, Pinho, Andreia V, Pitkänen, Esa, Pivot, Xavier, Piñeiro-Yáñez, Elena, Planko, Laura, Plass, Christoph, Pons, Tirso, Popescu, Irinel, Potapova, Olga, Prasad, Aparna, Preston, Shaun R, Prinz, Manuel, Pritchard, Antonia L, Prokopec, Stephenie D, Provenzano, Elena, Puente, Xose S, Puig, Sonia, Puiggròs, Montserrat, Pulido-Tamayo, Sergio, Pupo, Gulietta M, Purdie, Colin A, Quinn, Michael C, Rabionet, Raquel, Rader, Janet S, Radlwimmer, Bernhard, Radovic, Petar, Raeder, Benjamin, Raine, Keiran M, Ramakrishna, Manasa, Ramakrishnan, Kamna, Ramalingam, Suresh, Raphael, Benjamin J, Rathmell, W Kimryn, Rausch, Tobias, Reifenberger, Guido, Reimand, Jüri, Reis-Filho, Jorge, Reuter, Victor, Reyes-Salazar, Iker, Reyna, Matthew A, Reynolds, Sheila M, Riazalhosseini, Yasser, Richardson, Andrea L, Richter, Julia, Ringel, Matthew, Ringnér, Markus, Rino, Yasushi, Rippe, Karsten, Roach, Jeffrey, Roberts, Lewis R, Roberts, Nicola D, Roberts, Steven A, Robertson, A Gordon, Robertson, Alan J, Rodriguez, Javier Bartolomé, Rodriguez-Martin, Bernardo, Rodríguez-González, F Germán, Roehrl, Michael HA, Rohde, Marius, Rokutan, Hirofumi, Romieu, Gilles, Rooman, Ilse, Roques, Tom, Rosebrock, Daniel, Rosenberg, Mara, Rosenstiel, Philip C, Rosenwald, Andreas, Rowe, Edward W, Royo, Romina, Rozen, Steven G, Rubanova, Yulia, Rubio-Perez, Carlota, Rudneva, Vasilisa A, Rusev, Borislav C, Ruzzenente, Andrea, Rätsch, Gunnar, Sabarinathan, Radhakrishnan, Sabelnykova, Veronica Y, Sadeghi, Sara, Sahinalp, S Cenk, Saini, Natalie, Saito-Adachi, Mihoko, Saksena, Gordon, Salcedo, Adriana, Salgado, Roberto, Salichos, Leonidas, Sallari, Richard, Saller, Charles, Salvia, Roberto, Sam, Michelle, Samra, Jaswinder S, Sanchez-Vega, Francisco, Sander, Chris, Sanders, Grant, Sarin, Rajiv, Sarrafi, Iman, Sasaki-Oku, Aya, Sauer, Torill, Sauter, Guido, Saw, Robyn PM, Scardoni, Maria, Scarlett, Christopher J, Scarpa, Aldo, Scelo, Ghislaine, Schadendorf, Dirk, Schein, Jacqueline E, Schilhabel, Markus B, Schlesner, Matthias, Schlomm, Thorsten, Schmidt, Heather K, Schramm, Sarah-Jane, Schreiber, Stefan, Schultz, Nikolaus, Schumacher, Steven E, Schwarz, Roland F, Scolyer, Richard A, Scott, David, Scully, Ralph, Seethala, Raja, Segre, Ayellet V, Selander, Iris, Senbabaoglu, Yasin, Sengupta, Subhajit, Sereni, Elisabetta, Serra, Stefano, Shackleton, Mark, Shah, Nimish C, Shahabi, Sagedeh, Shang, Catherine A, Shang, Ping, Shapira, Ofer, Shelton, Troy, Shen, Ciyue, Shen, Hui, Shepherd, Rebecca, Shi, Ruian, Shi, Yan, Shiah, Yu-Jia, Shih, Juliann, Shimizu, Eigo, Shimizu, Kiyo, Shin, Seung Jun, Shiraishi, Yuichi, Shmaya, Tal, Shmulevich, Ilya, Shorser, Solomon I, Short, Charles, Shrestha, Raunak, Shringarpure, Suyash S, Shriver, Craig, Shuai, Shimin, Sidiropoulos, Nikos, Sieuwerts, Anieta M, Sieverling, Lina, Signoretti, Sabina, Sikora, Katarzyna O, Simbolo, Michele, Simon, Ronald, Simons, Janae V, Simpson, Jared T, Simpson, Peter T, Singer, Samuel, Sinnott-Armstrong, Nasa, Sipahimalani, Payal, Skelly, Tara J, Smid, Marcel, Smith-McCune, Karen, Socci, Nicholas D, Sofia, Heidi J, Soloway, Matthew G, Song, Lei, Sood, Anil K, Sothi, Sharmila, Sotiriou, Christos, Soulette, Cameron M, Span, Paul N, Spellman, Paul T, Sperandio, Nicola, Spillane, Andrew J, Spiro, Oliver, Spring, Jonathan, Staaf, Johan, Stadler, Peter F, Staib, Peter, Stark, Stefan G, Stebbings, Lucy, Stefánsson, Ólafur Andri, Stegle, Oliver, Stenhouse, Alasdair, Stewart, Chip, Stilgenbauer, Stephan, Stratton, Michael R, Stretch, Jonathan R, Struck, Adam J, Stuart, Joshua M, Stunnenberg, Henk G, Su, Hong, Su, Xiaoping, Sungalee, Stephanie, Susak, Hana, Suzuki, Akihiro, Sweep, Fred, Szczepanowski, Monika, Sültmann, Holger, Yugawa, Takashi, Tam, Angela, Tamborero, David, Tan, Benita Kiat Tee, Tan, Donghui, Tan, Patrick, Tanaka, Hiroko, Taniguchi, Hirokazu, Tanskanen, Tomas J, Tarabichi, Maxime, Tarnuzzer, Roy, Tarpey, Patrick, Taschuk, Morgan L, Tatsuno, Kenji, Tavaré, Simon, Taylor, Darrin F, Taylor-Weiner, Amaro, Teague, Jon W, Teh, Bin Tean, Tembe, Varsha, Temes, Javier, Thayer, Sarah P, Thiessen, Nina, Thomas, Gilles, Thomas, Sarah, Thompson, Alan, Thompson, Alastair M, Thompson, John FF, Thompson, R Houston, Thorne, Heather, Thorne, Leigh B, Thorogood, Adrian, Tiao, Grace, Tijanic, Nebojsa, Timms, Lee E, Tirabosco, Roberto, Tojo, Marta, Tommasi, Stefania, Toon, Christopher W, Toprak, Umut H, Torrents, David, Tortora, Giampaolo, Tost, Jörg, Totoki, Yasushi, Townend, David, Traficante, Nadia, Treilleux, Isabelle, Trotta, Jean-Rémi, Trümper, Lorenz HP, Tsao, Ming, Tsunoda, Tatsuhiko, MC Tubio, Jose, Tucker, Olga, Turkington, Richard, Turner, Daniel J, Tutt, Andrew, Ueno, Masaki, Ueno, Naoto T, Umbricht, Christopher, Umer, Husen M, Underwood, Timothy J, Urban, Lara, Urushidate, Tomoko, Ushiku, Tetsuo, Uusküla-Reimand, Liis, Valencia, Alfonso, Van Den Berg, David J, Van Laere, Steven, Van Loo, Peter, Van Meir, Erwin G, Van den Eynden, Gert G, Van der Kwast, Theodorus, Vasudev, Naveen, Vazquez, Miguel, Vedururu, Ravikiran, Veluvolu, Umadevi, Vembu, Shankar, Verbeke, Lieven PC, Vermeulen, Peter, Verrill, Clare, Viari, Alain, Vicente, David, Vicentini, Caterina, VijayRaghavan, K, Viksna, Juris, Vilain, Ricardo E, Villasante, Izar, Vincent-Salomon, Anne, Visakorpi, Tapio, Voet, Douglas, Vyas, Paresh, Vázquez-García, Ignacio, Waddell, Nick M, Waddell, Nicola, Wadelius, Claes, Wadi, Lina, Wagener, Rabea, Wala, Jeremiah A, Wang, Jian, Wang, Jiayin, Wang, Linghua, Wang, Qi, Wang, Wenyi, Wang, Yumeng, Wang, Zhining, Waring, Paul M, Warnatz, Hans-Jörg, Warrell, Jonathan, Warren, Anne Y, Waszak, Sebastian M, Wedge, David C, Weichenhan, Dieter, Weinberger, Paul, Weinstein, John N, Weischenfeldt, Joachim, Weisenberger, Daniel J, Welch, Ian, Wendl, Michael C, Werner, Johannes, Whalley, Justin P, Wheeler, David A, Whitaker, Hayley C, Wigle, Dennis, Wilkerson, Matthew D, Williams, Ashley, Wilmott, James S, Wilson, Gavin W, Wilson, Julie M, Wilson, Richard K, Winterhoff, Boris, Wintersinger, Jeffrey A, Wiznerowicz, Maciej, Wolf, Stephan, Wong, Bernice H, Wong, Tina, Wong, Winghing, Woo, Youngchoon, Wood, Scott, Wouters, Bradly G, Wright, Adam J, Wright, Mark H, Wu, Dai-Ying, Wu, Guanming, Wu, Jianmin, Wu, Kui, Wu, Yang, Wu, Zhenggang, Xi, Liu, Xia, Tian, Xiang, Qian, Xiao, Xiao, Xing, Rui, Xiong, Heng, Xu, Qinying, Xu, Yanxun, Xue, Hong, Yachida, Shinichi, Yakneen, Sergei, Yamaguchi, Rui, Yamaguchi, Takafumi N, Yamamoto, Masakazu, Yamamoto, Shogo, Yamaue, Hiroki, Yang, Fan, Yang, Huanming, Yang, Jean Y, Yang, Liming, Yang, Lixing, Yang, Shanlin, Yang, Tsun-Po, Yang, Yang, Yao, Xiaotong, Yaspo, Marie-Laure, Yates, Lucy, Yau, Christina, Ye, Chen, Ye, Kai, Yellapantula, Venkata D, Yoon, Christopher J, Yoon, Sung-Soo, Yousif, Fouad, Yu, Jun, Yu, Kaixian, Yu, Willie, Yu, Yingyan, Yuan, Yuan, Yuen, Denis, Yung, Christina K, Zaikova, Olga, Zamora, Jorge, Zapatka, Marc, Zenklusen, Jean C, Zenz, Thorsten, Zeps, Nikolajs, Zhang, Cheng-Zhong, Zhang, Fan, Zhang, Hailei, Zhang, Hongwei, Zhang, Hongxin, Zhang, Jiashan, Zhang, Jing, Zhang, Xiuqing, Zhang, Xuanping, Zhang, Yan, Zhang, Zemin, Zhao, Zhongming, Zheng, Liangtao, Zheng, Xiuqing, Zhou, Wanding, Zhou, Yong, Zhu, Bin, Zhu, Hongtu, Zhu, Jingchun, Zhu, Shida, Zou, Lihua, Zou, Xueqing, deFazio, Anna, van As, Nicholas, van Deurzen, Carolien HM, van de Vijver, Marc J, Veer, L van’t, and von Mering, Christian

Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

In cancer, the primary tumour’s organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.

Published
2023
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50. The landscape of viral associations in human cancers

Author

Zapatka, Marc, Borozan, Ivan, Brewer, Daniel S, Iskar, Murat, Grundhoff, Adam, Alawi, Malik, Desai, Nikita, Sültmann, Holger, Moch, Holger, PCAWG Pathogens, Cooper, Colin S, Eils, Roland, Ferretti, Vincent, Lichter, Peter, PCAWG Consortium, University of Zurich, and Lichter, Peter

Subjects
Human Biology & Physiology, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], 1311 Genetics, Ecology,Evolution & Ethology, 10049 Institute of Pathology and Molecular Pathology, 610 Medicine & health, Tumour Biology, Genetics & Genomics, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.

Published
2023

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