المؤلفون: Zook, Justin M, Hansen, Nancy F, Olson, Nathan D, Chapman, Lesley, Mullikin, James C, Xiao, Chunlin, Sherry, Stephen, Koren, Sergey, Phillippy, Adam M, Boutros, Paul C, Sahraeian, Sayed Mohammad E, Huang, Vincent, Rouette, Alexandre, Alexander, Noah, Mason, Christopher E, Hajirasouliha, Iman, Ricketts, Camir, Lee, Joyce, Tearle, Rick, Fiddes, Ian T, Barrio, Alvaro Martinez, Wala, Jeremiah, Carroll, Andrew, Ghaffari, Noushin, Rodriguez, Oscar L, Bashir, Ali, Jackman, Shaun, Farrell, John J, Wenger, Aaron M, Alkan, Can, Soylev, Arda, Schatz, Michael C, Garg, Shilpa, Church, George, Marschall, Tobias, Chen, Ken, Fan, Xian, English, Adam C, Rosenfeld, Jeffrey A, Zhou, Weichen, Mills, Ryan E, Sage, Jay M, Davis, Jennifer R, Kaiser, Michael D, Oliver, John S, Catalano, Anthony P, Chaisson, Mark JP, Spies, Noah, Sedlazeck, Fritz J, Salit, Marc

المصدر: Nature Biotechnology. 38(11)

مصطلحات موضوعية: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Diploidy, Genomic Structural Variation, Germ-Line Mutation, Humans, INDEL Mutation, Molecular Sequence Annotation, Sequence Analysis, DNA

الوصف: New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution and comprehensiveness. To help translate these methods to routine research and clinical practice, we developed a sequence-resolved benchmark set for identification of both false-negative and false-positive germline large insertions and deletions. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle Consortium integrated 19 sequence-resolved variant calling methods from diverse technologies. The final benchmark set contains 12,745 isolated, sequence-resolved insertion (7,281) and deletion (5,464) calls ≥50 base pairs (bp). The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.51 Gbp and 5,262 insertions and 4,095 deletions supported by ≥1 diploid assembly. We demonstrate that the benchmark set reliably identifies false negatives and false positives in high-quality SV callsets from short-, linked- and long-read sequencing and optical mapping.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/83j0h3wsTest

المؤلفون: Zook, Justin M, Hansen, Nancy F, Olson, Nathan D, Chapman, Lesley, Mullikin, James C, Xiao, Chunlin, Sherry, Stephen, Koren, Sergey, Phillippy, Adam M, Boutros, Paul C, Sahraeian, Sayed Mohammad E, Huang, Vincent, Rouette, Alexandre, Alexander, Noah, Mason, Christopher E, Hajirasouliha, Iman, Ricketts, Camir, Lee, Joyce, Tearle, Rick, Fiddes, Ian T, Barrio, Alvaro Martinez, Wala, Jeremiah, Carroll, Andrew, Ghaffari, Noushin, Rodriguez, Oscar L, Bashir, Ali, Jackman, Shaun, Farrell, John J, Wenger, Aaron M, Alkan, Can, Soylev, Arda, Schatz, Michael C, Garg, Shilpa, Church, George, Marschall, Tobias, Chen, Ken, Fan, Xian, English, Adam C, Rosenfeld, Jeffrey A, Zhou, Weichen, Mills, Ryan E, Sage, Jay M, Davis, Jennifer R, Kaiser, Michael D, Oliver, John S, Catalano, Anthony P, Chaisson, Mark JP, Spies, Noah, Sedlazeck, Fritz J, Salit, Marc

المصدر: Nature Biotechnology. 38(11)

مصطلحات موضوعية: Control Engineering, Mechatronics and Robotics, Engineering

الوصف: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

الوصول الحر: https://escholarship.org/uc/item/03j114w5Test

المؤلفون: Rodriguez-Martin, Bernardo, Alvarez, Eva G, Baez-Ortega, Adrian, Zamora, Jorge, Supek, Fran, Demeulemeester, Jonas, Santamarina, Martin, Ju, Young Seok, Temes, Javier, Garcia-Souto, Daniel, Detering, Harald, Li, Yilong, Rodriguez-Castro, Jorge, Dueso-Barroso, Ana, Bruzos, Alicia L, Dentro, Stefan C, Blanco, Miguel G, Contino, Gianmarco, Ardeljan, Daniel, Tojo, Marta, Roberts, Nicola D, Zumalave, Sonia, Edwards, Paul A, Weischenfeldt, Joachim, Puiggròs, Montserrat, Chong, Zechen, Chen, Ken, Lee, Eunjung Alice, Wala, Jeremiah A, Raine, Keiran M, Butler, Adam, Waszak, Sebastian M, Navarro, Fabio CP, Schumacher, Steven E, Monlong, Jean, Maura, Francesco, Bolli, Niccolo, Bourque, Guillaume, Gerstein, Mark, Park, Peter J, Wedge, David C, Beroukhim, Rameen, Torrents, David, Korbel, Jan O, Martincorena, Iñigo, Fitzgerald, Rebecca C, Van Loo, Peter, Kazazian, Haig H, Burns, Kathleen H, PCAWG Structural Variation Working Group, Campbell, Peter J, Tubio, Jose MC, PCAWG Consortium

المصدر: Nature genetics. 52(3)

مصطلحات موضوعية: PCAWG Structural Variation Working Group, PCAWG Consortium, Humans, Neoplasms, Retroelements, Gene Rearrangement, Long Interspersed Nucleotide Elements, Genome, Human, Carcinogenesis, Genetics, Digestive Diseases, Human Genome, Cancer, Rare Diseases, Biological Sciences, Medical and Health Sciences, Developmental Biology

الوصف: About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/41m0s50zTest

المؤلفون: Li, Yilong, Roberts, Nicola D, Wala, Jeremiah A, Shapira, Ofer, Schumacher, Steven E, Kumar, Kiran, Khurana, Ekta, Waszak, Sebastian, Korbel, Jan O, Haber, James E, Imielinski, Marcin, Weischenfeldt, Joachim, Beroukhim, Rameen, Campbell, Peter J

المصدر: Nature. 578(7793)

مصطلحات موضوعية: Cancer, Human Genome, Genetics, Biotechnology, Gene Rearrangement, Genetic Variation, Genome, Human, Genomics, Humans, Mutagenesis, Insertional, Neoplasms, Telomerase, PCAWG Structural Variation Working Group, PCAWG Consortium, General Science & Technology

الوصف: A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes1-7. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types8. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions-as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2-7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and-in liver cancer-frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/55j9g5qrTest

المؤلفون: Rheinbay, Esther, Nielsen, Morten Muhlig, Abascal, Federico, Wala, Jeremiah A, Shapira, Ofer, Tiao, Grace, Hornshøj, Henrik, Hess, Julian M, Juul, Randi Istrup, Lin, Ziao, Feuerbach, Lars, Sabarinathan, Radhakrishnan, Madsen, Tobias, Kim, Jaegil, Mularoni, Loris, Shuai, Shimin, Lanzós, Andrés, Herrmann, Carl, Maruvka, Yosef E, Shen, Ciyue, Amin, Samirkumar B, Bandopadhayay, Pratiti, Bertl, Johanna, Boroevich, Keith A, Busanovich, John, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Craft, David, Dhingra, Priyanka, Diamanti, Klev, Fonseca, Nuno A, Gonzalez-Perez, Abel, Guo, Qianyun, Hamilton, Mark P, Haradhvala, Nicholas J, Hong, Chen, Isaev, Keren, Johnson, Todd A, Juul, Malene, Kahles, Andre, Kahraman, Abdullah, Kim, Youngwook, Komorowski, Jan, Kumar, Kiran, Kumar, Sushant, Lee, Donghoon, Lehmann, Kjong-Van, Li, Yilong, Liu, Eric Minwei, Lochovsky, Lucas, Park, Keunchil, Pich, Oriol, Roberts, Nicola D, Saksena, Gordon, Schumacher, Steven E, Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stewart, Chip, Tamborero, David, Tubio, Jose MC, Umer, Husen M, Uusküla-Reimand, Liis, Wadelius, Claes, Wadi, Lina, Yao, Xiaotong, Zhang, Cheng-Zhong, Zhang, Jing, Haber, James E, Hobolth, Asger, Imielinski, Marcin, Kellis, Manolis, Lawrence, Michael S, von Mering, Christian, Nakagawa, Hidewaki, Raphael, Benjamin J, Rubin, Mark A, Sander, Chris, Stein, Lincoln D, Stuart, Joshua M, Tsunoda, Tatsuhiko, Wheeler, David A, Johnson, Rory, Reimand, Jüri, Gerstein, Mark, Khurana, Ekta, Campbell, Peter J, López-Bigas, Núria, PCAWG Drivers and Functional Interpretation Working Group, PCAWG Structural Variation Working Group, Weischenfeldt, Joachim, Beroukhim, Rameen, Martincorena, Iñigo, Pedersen, Jakob Skou, Getz, Gad, PCAWG Consortium

المصدر: Nature. 578(7793)

مصطلحات موضوعية: PCAWG Drivers and Functional Interpretation Working Group, PCAWG Structural Variation Working Group, PCAWG Consortium, Humans, Neoplasms, Gene Expression Regulation, Neoplastic, Mutation, Genome, Human, Databases, Genetic, DNA Breaks, INDEL Mutation, Genome-Wide Association Study, Gene Expression Regulation, Neoplastic, Genome, Human, Databases, Genetic, General Science & Technology

الوصف: The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6b64z06zTest

المؤلفون: Rheinbay, Esther, Nielsen, Morten Muhlig, Abascal, Federico, Wala, Jeremiah A, Shapira, Ofer, Tiao, Grace, Hornshøj, Henrik, Hess, Julian M, Juul, Randi Istrup, Lin, Ziao, Feuerbach, Lars, Sabarinathan, Radhakrishnan, Madsen, Tobias, Kim, Jaegil, Mularoni, Loris, Shuai, Shimin, Lanzos, Andrés, Herrmann, Carl, Maruvka, Yosef E, Shen, Ciyue, Amin, Samirkumar B, Bandopadhayay, Pratiti, Bertl, Johanna, Boroevich, Keith A, Busanovich, John, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Craft, David, Dhingra, Priyanka, Diamanti, Klev, Fonseca, Nuno A, Gonzalez-Perez, Abel, Guo, Qianyun, Hamilton, Mark P, Haradhvala, Nicholas J, Hong, Chen, Isaev, Keren, Johnson, Todd A, Juul, Malene, Kahles, Andre, Kahraman, Abdullah, Kim, Youngwook, Komorowski, Jan, Kumar, Kiran, Kumar, Sushant, Lee, Donghoon, Lehmann, Kjong-Van, Li, Yilong, Liu, Eric Minwei, Lochovsky, Lucas, Park, Keunchil, Pich, Oriol, Roberts, Nicola D, Saksena, Gordon, Schumacher, Steven E, Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stewart, Chip, Tamborero, David, Tubio, Jose M C, Umer, Husen M, Uusküla-Reimand, Liis, Wadelius, Claes, Wadi, Lina, Yao, Xiaotong, Zhang, Cheng-Zhong, Zhang, Jing, Haber, James E, Hobolth, Asger, Imielinski, Marcin, Kellis, Manolis, Lawrence, Michael S, von Mering, Christian, Nakagawa, Hidewaki, Raphael, Benjamin J, Rubin, Mark, Sander, Chris, Stein, Lincoln D, Stuart, Joshua M, Tsunoda, Tatsuhiko, Wheeler, David A, Johnson, Rory, Reimand, Jüri, Gerstein, Mark, Khurana, Ekta, Campbell, Peter J, López-Bigas, Núria, Weischenfeldt, Joachim, Beroukhim, Rameen, Martincorena, Iñigo, Pedersen, Jakob Skou, Getz, Gad

المصدر: Rheinbay, Esther; Nielsen, Morten Muhlig; Abascal, Federico; Wala, Jeremiah A; Shapira, Ofer; Tiao, Grace; Hornshøj, Henrik; Hess, Julian M; Juul, Randi Istrup; Lin, Ziao; Feuerbach, Lars; Sabarinathan, Radhakrishnan; Madsen, Tobias; Kim, Jaegil; Mularoni, Loris; Shuai, Shimin; Lanzos, Andrés; Herrmann, Carl; Maruvka, Yosef E; Shen, Ciyue; . (2023). Author Correction: Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Nature, 614(7948), E40. Springer Nature 10.1038/s41586-022-05599-9

مصطلحات موضوعية: 610 Medicine & health

وصف الملف: application/pdf

العلاقة: https://boris.unibe.ch/177916Test/

الإتاحة: https://doi.org/10.1038/s41586-022-05599-9Test
https://boris.unibe.ch/177916/1/s41586-022-05599-9.pdfTest
https://boris.unibe.ch/177916Test/

المؤلفون: Rheinbay, Esther, Nielsen, Morten Muhlig, Abascal, Federico, Wala, Jeremiah A, Shapira, Ofer, Tiao, Grace, Hornshøj, Henrik, Hess, Julian M, Juul, Randi Istrup, Lin, Ziao, Feuerbach, Lars, Sabarinathan, Radhakrishnan, Madsen, Tobias, Kim, Jaegil, Mularoni, Loris, Shuai, Shimin, Lanzós, Andrés, Herrmann, Carl, Maruvka, Yosef E, Shen, Ciyue, Amin, Samirkumar B, Bandopadhayay, Pratiti, Bertl, Johanna, Boroevich, Keith A

المصدر: Rheinbay , E , Nielsen , M M , Abascal , F , Wala , J A , Shapira , O , Tiao , G , Hornshøj , H , Hess , J M , Juul , R I , Lin , Z , Feuerbach , L , Sabarinathan , R , Madsen , T , Kim , J , Mularoni , L , Shuai , S , Lanzós , A , Herrmann , C , Maruvka , Y E , Shen , C , Amin , S B , Bandopadhayay , P , Bertl , J , Boroevich ....

العلاقة: https://pure.au.dk/portal/en/publications/f3690d87-ab44-4a91-b003-27d295c05ec2Test

الإتاحة: https://doi.org/10.1038/s41586-022-05599-9Test
https://pure.au.dk/portal/en/publications/f3690d87-ab44-4a91-b003-27d295c05ec2Test
http://www.scopus.com/inward/record.url?scp=85148250763&partnerID=8YFLogxKTest

المؤلفون: Rodriguez-Martin, Bernardo, Alvarez, Eva G., Baez-Ortega, Adrian, Zamora, Jorge, Supek, Fran, Demeulemeester, Jonas, Santamarina, Martin, Ju, Young Seok, Temes, Javier, Garcia-Souto, Daniel, Detering, Harald, Li, Yilong, Rodriguez-Castro, Jorge, Dueso-Barroso, Ana, Bruzos, Alicia L., Dentro, Stefan C., Blanco, Miguel G., Contino, Gianmarco, Ardeljan, Daniel, Tojo, Marta, Roberts, Nicola D., Zumalave, Sonia, Edwards, Paul A., Weischenfeldt, Joachim, Puiggròs, Montserrat, Chong, Zechen, Chen, Ken, Lee, Eunjung Alice, Wala, Jeremiah A., Raine, Keiran M., Butler, Adam, Waszak, Sebastian M., Navarro, Fabio C. P., Schumacher, Steven E., Monlong, Jean, Maura, Francesco, Bolli, Niccolo, Bourque, Guillaume, Gerstein, Mark, Park, Peter J., Wedge, David C., Beroukhim, Rameen, Torrents, David, Korbel, Jan O., Martincorena, Iñigo, Fitzgerald, Rebecca C., Van Loo, Peter, Kazazian, Haig H., Burns, Kathleen H., Akdemir, Kadir C.

المصدر: Nature Genetics ; volume 55, issue 6, page 1080-1080 ; ISSN 1061-4036 1546-1718

مصطلحات موضوعية: Genetics

الإتاحة: https://doi.org/10.1038/s41588-023-01319-9Test
https://www.nature.com/articles/s41588-023-01319-9.pdfTest
https://www.nature.com/articles/s41588-023-01319-9Test

المؤلفون: Li, Yilong, Roberts, Nicola D., Wala, Jeremiah A., Shapira, Ofer, Schumacher, Steven E., Kumar, Kiran, Khurana, Ekta, Waszak, Sebastian, Korbel, Jan O., Haber, James E., Imielinski, Marcin, Akdemir, Kadir C., Alvarez, Eva G., Baez-Ortega, Adrian, Beroukhim, Rameen, Boutros, Paul C., Bowtell, David D. L., Brors, Benedikt, Burns, Kathleen H., Campbell, Peter J., Chan, Kin, Chen, Ken, Cortés-Ciriano, Isidro, Dueso-Barroso, Ana, Dunford, Andrew J., Edwards, Paul A., Estivill, Xavier, Etemadmoghadam, Dariush, Feuerbach, Lars, Fink, J. Lynn, Frenkel-Morgenstern, Milana, Garsed, Dale W., Gerstein, Mark, Gordenin, Dmitry A., Haan, David, Hess, Julian M., Hutter, Barbara, Jones, David T. W., Ju, Young Seok, Kazanov, Marat D., Klimczak, Leszek J., Koh, Youngil, Lee, Eunjung Alice, Lee, Jake June-Koo, Lynch, Andy G.

المصدر: Nature ; ISSN 0028-0836 1476-4687

مصطلحات موضوعية: Multidisciplinary

الإتاحة: https://doi.org/10.1038/s41586-022-05597-xTest
https://www.nature.com/articles/s41586-022-05597-x.pdfTest
https://www.nature.com/articles/s41586-022-05597-xTest

المؤلفون: Dubois, Frank, Shapira, Ofer, Greenwald, Noah, Zack, Travis, Wala, Jeremiah, Tsai, Jessica, Crane, Alexander, Baguette, Audrey, Hadjadj, Djihad, Harutyunyan, Ashot, Kumar, Kiran, Blattner-Johnson, Mirjam, Vogelzang, Jayne, Sousa, Cecilia, Kang, Kyung Shin, Sinai, Claire, Wang, Dayle, Khadka, Prasidda, Malkin, Hayley, Ho, Patricia, O'Rourke, Ryan, Zhang, Shu, Gold, Rose, Deng, Davy, Serrano, Jonathan, Snuderl, Matija, Jones, Chris, Wright, Karen, Chi, Susan, Grill, Jacques, Kleinman, Claudia, Goumnerova, Liliana, Jabado, Nada, Jones, David, Kieran, Mark, Ligon, Keith, Beroukhim, Rameen, Bandopadhayay, Pratiti

المصدر: Neuro-Oncology ; volume 24, issue Supplement_1, page i75-i76 ; ISSN 1522-8517 1523-5866

مصطلحات موضوعية: Cancer Research, Neurology (clinical), Oncology

الوصف: Pediatric high-grade gliomas (pHGGs), encompassing hemispheric and diffuse midline gliomas (DMGs), remain a devastating disease. The last decade has revealed oncogenic drivers including single nucleotide variants (SNVs) in histones. However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored due to limitations in early SV analysis approaches. Using SV algorithms, we recently created, we analyzed SVs in whole-genome sequences of 179 pHGGs including a novel cohort of treatment naïve samples–the largest WGS cohort assembled in adult or pediatric glioma. The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases, including a novel SV amplifying a MYC enhancer in the lncRNA CCDC26 in 12% of DMGs and revealing a more central role for MYC in these cancers than previously known. Applying de novo SV signature discovery, we identified five signatures including three (SVsig1-3) involving primarily simple SVs, and two (SVsig4-5) involving complex, clustered SVs. These SV signatures associated with genetic variants that differed from what was observed for SV signatures in other cancers, suggesting different links to underlying biology. Tumors with simple SV signatures were TP53 wild-type but were enriched with alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A, and RB1 early in tumor evolution, and with extrachromosomal amplicons that likely occurred later. All pHGGs exhibited at least one simple SV signature but complex SV signatures were primarily restricted to subsets of H3.3K27M DMGs and hemispheric pHGGs. Importantly, DMGs with the complex SV signatures SVsig4-5 were associated with shorter overall survival independent of histone type and TP53 status. These data inform the role and impact of SVs in gliomagenesis and mechanisms that shape them.

الإتاحة: https://doi.org/10.1093/neuonc/noac079.275Test
https://academic.oup.com/neuro-oncology/article-pdf/24/Supplement_1/i75/43945374/noac079.275.pdfTest