المؤلفون: Rozowsky, Joel, Gao, Jiahao, Borsari, Beatrice, Yang, Yucheng, Galeev, Timur, Gürsoy, Gamze, Epstein, Charles, Xiong, Kun, Xu, Jinrui, Li, Tianxiao, Liu, Jason, Yu, Keyang, Berthel, Ana, Chen, Zhanlin, Navarro, Fabio, Sun, Maxwell, Wright, James, Chang, Justin, Cameron, Christopher, Shoresh, Noam, Gaskell, Elizabeth, Drenkow, Jorg, Adrian, Jessika, Aganezov, Sergey, Aguet, François, Balderrama-Gutierrez, Gabriela, Banskota, Samridhi, Corona, Guillermo, Chee, Sora, Chhetri, Surya, Cortez Martins, Gabriel, Danyko, Cassidy, Davis, Carrie, Farid, Daniel, Farrell, Nina, Gabdank, Idan, Gofin, Yoel, Gorkin, David, Gu, Mengting, Hecht, Vivian, Hitz, Benjamin, Issner, Robbyn, Jiang, Yunzhe, Kirsche, Melanie, Kong, Xiangmeng, Lam, Bonita, Li, Shantao, Li, Bian, Li, Xiqi, Lin, Khine, Luo, Ruibang, Mackiewicz, Mark, Meng, Ran, Moore, Jill, Mudge, Jonathan, Nelson, Nicholas, Nusbaum, Chad, Popov, Ioann, Pratt, Henry, Qiu, Yunjiang, Ramakrishnan, Srividya, Raymond, Joe, Salichos, Leonidas, Scavelli, Alexandra, Schreiber, Jacob, Sedlazeck, Fritz, See, Lei, Sherman, Rachel, Shi, Xu, Shi, Minyi, Sloan, Cricket, Strattan, J, Tan, Zhen, Tanaka, Forrest, Vlasova, Anna, Wang, Jun, Werner, Jonathan, Williams, Brian, Xu, Min, Yan, Chengfei, Yu, Lu, Zaleski, Christopher, Zhang, Jing, Ardlie, Kristin, Cherry, J, Mendenhall, Eric, Noble, William, Weng, Zhiping, Levine, Morgan, Dobin, Alexander, Wold, Barbara, Mortazavi, Ali, Ren, Bing, Gillis, Jesse, Myers, Richard, Choudhary, Jyoti, Milosavljevic, Aleksandar, Schatz, Michael, Bernstein, Bradley, Guigó, Roderic

المصدر: Cell. 186(7)

مصطلحات موضوعية: ENCODE, GTEx, allele-specific activity, eQTLs, functional epigenomes, functional genomics, genome annotations, personal genome, predictive models, structural variants, tissue specificity, transformer model, Epigenome, Quantitative Trait Loci, Genome-Wide Association Study, Genomics, Phenotype, Polymorphism, Single Nucleotide

الوصف: Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

وصف الملف: application/pdf

URL الوصول: https://escholarship.org/uc/item/9xg116dt

المؤلفون: Manrose Singh, Samantha Cornwell, Ariel Shaddaie, Leah Wachsmuth, Ashwin Ragupathi, Leonidas Salichos, Sandra Nissel-Horowitz, Rajasree Roy, Maria Plummer, Dong Zhang, Bhoomi Mehrotra

المصدر: Gynecologic Oncology Reports, Vol 54, Iss , Pp 101417- (2024)

مصطلحات موضوعية: SBOT, Adenocarcinoma, Müllerian, BRAF, Gynecology and obstetrics, RG1-991, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: We describe a patient diagnosed with a metastatic adenocarcinoma of Müllerian origin, harboring a BRAF V600E mutation, ten years after being treated for a serous borderline tumor (SBOT). While BRAF mutations in the setting of SBOTs are common, they have been typically associated with a low chance of transformation or recurrence. The therapeutic approach, which combined hormone inhibition with receptor tyrosine kinase inhibitors (dabrafenib and trametinib), has demonstrated notable and enduring efficacy. This is clinically evidenced through serial PET-CT scans with sustained responses and extended progression-free survival, and serologically confirmed by monitoring CA-125 levels. This case demonstrates the critical role of early next-generation sequencing in detecting actionable molecular changes in rare cancers and possible metastases. It provides valuable insights into treating uncommon Müllerian adenocarcinomas and underscores the importance of targeted therapies in achieving long-lasting treatment outcomes.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2352578924000961; https://doaj.org/toc/2352-5789

URL الوصول: https://doaj.org/article/929721362e6440d383dbd360b99865fa

المؤلفون: Salichos, Leonidas^{Aff1, Aff2, IDs41598023349592_cor1}, Warrell, Jonathan, Cevasco, Hannah, Chung, Alvin, Gerstein, Mark^{Aff1, Aff3, Aff4, Aff5, Aff6, IDs41598023349592_cor5}

المصدر: Scientific Reports. 13(1)

المؤلفون: Salichos, Leonidas, Thayavally, Rishika, Kloen, Peter, Hadjiargyrou, Michael

المصدر: In Bone June 2024 183

المؤلفون: Leonidas Salichos, Jonathan Warrell, Hannah Cevasco, Alvin Chung, Mark Gerstein

المصدر: Scientific Reports, Vol 13, Iss 1, Pp 1-17 (2023)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract For the COVID-19 pandemic, viral transmission has been documented in many historical and geographical contexts. Nevertheless, few studies have explicitly modeled the spatiotemporal flow based on genetic sequences, to develop mitigation strategies. Additionally, thousands of SARS-CoV-2 genomes have been sequenced with associated records, potentially providing a rich source for such spatiotemporal analysis, an unprecedented amount during a single outbreak. Here, in a case study of seven states, we model the first wave of the outbreak by determining regional connectivity from phylogenetic sequence information (i.e. “genetic connectivity”), in addition to traditional epidemiologic and demographic parameters. Our study shows nearly all of the initial outbreak can be traced to a few lineages, rather than disconnected outbreaks, indicative of a mostly continuous initial viral flow. While the geographic distance from hotspots is initially important in the modeling, genetic connectivity becomes increasingly significant later in the first wave. Moreover, our model predicts that isolated local strategies (e.g. relying on herd immunity) can negatively impact neighboring regions, suggesting more efficient mitigation is possible with unified, cross-border interventions. Finally, our results suggest that a few targeted interventions based on connectivity can have an effect similar to that of an overall lockdown. They also suggest that while successful lockdowns are very effective in mitigating an outbreak, less disciplined lockdowns quickly decrease in effectiveness. Our study provides a framework for combining phylodynamic and computational methods to identify targeted interventions.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2045-2322

URL الوصول: https://doaj.org/article/0a68916765484e4a875126b56157bd78

المؤلفون: Michael Hadjiargyrou, Leonidas Salichos, Peter Kloen

المصدر: Journal of Orthopaedic Translation, Vol 39, Iss , Pp 113-123 (2023)

مصطلحات موضوعية: microRNA, miRNA, Nonunion, Fracture, Callus, Hypertrophic, Diseases of the musculoskeletal system, RC925-935

الوصف: Background: Nonunions remain a challenging post-traumatic complication that often leads to a financial and health burden that affects the patient's quality of life. Despite a wealth of knowledge about fracture repair, especially gene and more recently miRNA expression, much remains unknown about the molecular differences between normal physiological repair (callus tissue) and a nonunion. To probe this lack of knowledge, we embarked on a study that sought to identify and compare the human miRNAome of normal bone to that present in a normal fracture callus and those from two different classic nonunion types, hypertrophic and oligotrophic. Methods: Normal bone and callus tissue samples were harvested during revision surgery from patients with physiological fracture repair and nonunions (hypertrophic and oligotrophic) and analyzed using histology. Also, miRNAs were isolated and screened using microarrays followed by bioinformatic analyses, including, differential expression, pathways and biological processes, as well as elucidation of target genes. Results: Out of 30,424 mature miRNAs (from 203 organisms) screened via microarrays, 635 (∼2.1%) miRNAs were found to be upregulated and 855 (∼2.8%) downregulated in the fracture callus and nonunion tissues as compared to intact bone. As our tissue samples were derived from humans, we focused on the human miRNAs and out of the 4223 human miRNAs, 86 miRNAs (∼2.0%) were upregulated and 51 (∼1.2%) were downregulated. Although there were similarities between the three experimental samples, we also found specific miRNAs that were unique to individual samples. We further identified the predicted target genes from these differentially expressed miRNAs as well as the relevant biological processes, including specific signaling pathways that are activated in all three experimental samples. Conclusion: Collectively, this is the first comprehensive study reporting on the miRNAome of intact bone as compared to fracture callus and nonunion tissues. Further, we identify specific miRNAs involved in normal physiological fracture repair as well as those of nonunions. The translational potential of this article: The data generated from this study further increase our molecular understanding of the roles of miRNAs during normal and aberrant fracture repair and this knowledge can be used in the future in the development of miRNA-based therapeutics for skeletal regeneration.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2214031X23000104; https://doaj.org/toc/2214-031X

URL الوصول: https://doaj.org/article/60b6e37776964d9da6b52895f2a214a2

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المؤلفون: Ioannis A. Vathiotis, Leonidas Salichos, Sandra Martinez-Morilla, Niki Gavrielatou, Thazin Nwe Aung, Saba Shafi, Pok Fai Wong, Shlomit Jessel, Harriet M. Kluger, Konstantinos N. Syrigos, Sarah Warren, Mark Gerstein, David L. Rimm

المصدر: npj Precision Oncology, Vol 6, Iss 1, Pp 1-8 (2022)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Treatment with immune checkpoint inhibitors has altered the course of malignant melanoma, with approximately half of the patients with advanced disease surviving for more than 5 years after diagnosis. Currently, there are no biomarker methods for predicting outcome from immunotherapy. Here, we obtained transcriptomic information from a total of 105 baseline tumor samples comprising two cohorts of patients with advanced melanoma treated with programmed cell death protein 1 (PD-1)-based immunotherapies. Gene expression profiles were correlated with progression-free survival (PFS) within consecutive clinical benefit intervals (i.e., 6, 12, 18, and 24 months). Elastic net binomial regression models with cross validation were utilized to compare the predictive value of distinct genes across time. Lasso regression was used to generate a signature predicting long-term benefit (LTB), defined as patients who remain alive and free of disease progression at 24 months post treatment initiation. We show that baseline gene expression profiles were consistently able to predict long-term immunotherapy outcomes with high accuracy. The predictive value of different genes fluctuated across consecutive clinical benefit intervals, with a distinct set of genes defining benefit at 24 months compared to earlier outcomes. A 12-gene signature was able to predict LTB following anti-PD-1 therapy with an area under the curve (AUC) equal to 0.92 and 0.74 in the training and validation set, respectively. Evaluation of LTB, via a unique signature may complement objective response classification and characterize the logistics of sustained antitumor immune responses.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2397-768X

URL الوصول: https://doaj.org/article/956f4e8b0c1545fa97bfbb01c858e7bd

المؤلفون: Hadjiargyrou, Michael, Salichos, Leonidas, Kloen, Peter

المصدر: In Journal of Orthopaedic Translation March 2023 39:113-123

المؤلفون: Rheinbay, Esther, Nielsen, Morten Muhlig, Abascal, Federico, Wala, Jeremiah A., Shapira, Ofer, Tiao, Grace, Hornshoj, Henrik, Hess, Julian M., Juul, Randi Istrup, Lin, Ziao, Feuerbach, Lars, Sabarinathan, Radhakrishnan, Madsen, Tobias, Kim, Jaegil, Mularoni, Loris, Shuai, Shimin, Lanzos, Andres, 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, 1987, 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 Muhammad, Uuskula-Reimand, Liis, Wadelius, Claes, 1955, 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, Juri, Gerstein, Mark, Khurana, Ekta, Campbell, Peter J., Lopez-Bigas, Nuria, Weischenfeldt, Joachim, Beroukhim, Rameen, Martincorena, Inigo, Pedersen, Jakob Skou, Getz, Gad, Bader, Gary D., Barenboim, Jonathan, Brunak, Soren, Chen, Ken, Choi, Jung Kyoon, Deu-Pons, Jordi, Fink, J. Lynn, Frigola, Joan, Gambacorti-Passerini, Carlo, Garsed, Dale W., Gut, Ivo G., Haan, David, Harmanci, Arif O., Helmy, Mohamed, Hodzic, Ermin, Izarzugaza, Jose M. G., Kim, Jong K., Korbel, Jan O., Larsson, Erik, Li, Shantao, Li, Xiaotong, Lou, Shaoke, Marchal, Kathleen, Martinez-Fundichely, Alexander, McGillivray, Patrick D., Meyerson, William, Muinos, Ferran, Paczkowska, Marta, Park, Kiejung, Pons, Tirso, Pulido-Tamayo, Sergio, Reyes-Salazar, Iker, Reyna, Matthew A., Rubio-Perez, Carlota, Sahinalp, S. Cenk, Salichos, Leonidas, Shackleton, Mark, Shrestha, Raunak, Valencia, Alfonso, Vazquez, Miguel, Verbeke, Lieven P. C., Wang, Jiayin, Warrell, Jonathan, Waszak, Sebastian M., Wu, Guanming, Yu, Jun, Zhang, Xuanping, Zhang, Yan, Zhao, Zhongming, Zou, Lihua, Akdemir, Kadir C., Alvarez, Eva G., Baez-Ortega, Adrian, Boutros, Paul C., Bowtell, David D. L., Brors, Benedikt, Burns, Kathleen H., Chan, Kin, CortesCiriano, Isidro, Dueso-Barroso, Ana, Dunford, Andrew J., Edwards, Paul A., Estivill, Xavier, Etemadmoghadam, Dariush, Frenkel-Morgenstern, Milana, Gordenin, Dmitry A., 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., Macintyre, Geoff, Markowetz, Florian, Meyerson, Matthew, Miyano, Satoru, Navarro, Fabio C. P., Ossowski, Stephan, Park, Peter J., Pearson, John, V, Puiggros, Montserrat, Rippe, Karsten, Roberts, Steven A., RodriguezMartin, Bernardo, Scully, Ralph, Torrents, David, Villasante, Izar, Waddell, Nicola, Yang, Lixing, Yoon, Sung-Soo, Zamora, Jorge

المصدر: Nature. 578(7793):102-111

الوصف: The discovery of drivers of cancer has traditionally focused on protein-coding genes(1-4). 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) Consortium(5) 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 drivers(6,7), 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: electronic

URL الوصول: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-412969
https://doi.org/10.1038/s41586-020-1965-x
https://uu.diva-portal.org/smash/get/diva2:1444508/FULLTEXT01.pdf