105 results on '"Junyan Lu"'
Search Results
2. Subgroup-specific gene expression profiles and mixed epistasis in chronic lymphocytic leukemia
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Almut Lütge, Junyan Lu, Jennifer Hüllein, Tatjana Walther, Leopold Sellner, Bian Wu, Richard Rosenquist, Christopher C. Oakes, Sascha Dietrich, Wolfgang Huber, and Thorsten Zenz
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Hematology - Abstract
Understanding the molecular and phenotypic heterogeneity of cancer is a prerequisite for effective treatment. For chronic lymphocytic leukemia (CLL), recurrent genetic driver events have been extensively cataloged, but this does not suffice to explain the disease’s diverse course. Here, we performed RNA-sequencing on 184 CLL patient samples. Unsupervised analysis revealed two major, orthogonal axes of gene expression variation: the first one represented the mutational status of the immunoglobulin heavy variable (IGHV) genes, and concomitantly, the three-group stratification of CLL by global DNA methylation. The second axis aligned with trisomy 12 status and affected chemokine, MAPK and mTOR signaling. We discovered nonadditive effects (epistasis) of IGHV mutation status and trisomy 12 on multiple phenotypes, including the expression of 893 genes. Multiple types of epistasis were observed, including synergy, buffering, suppression and inversion, suggesting that molecular understanding of disease heterogeneity requires studying such genetic events not only individually but in combination. We detected strong differentially expressed gene signatures associated with major gene mutations and copy-number aberrations including SF3B1, BRAF and TP53, as well as del(17)(p13), del(13)(q14) and del(11)(q22.3) beyond dosage effect. Our study reveals previously underappreciated gene expression signatures for the major molecular subtypes in CLL and the presence of epistasis between them.
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- 2023
3. A Comprehensive DNA Methylome Analysis of Stereotyped and Non-Stereotyped CLL Reveals an Epigenetic Signature with Strong Clinical Impact Encompassing IGHV Status, Stereotypes and IGLV3-21R110
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Martí Duran-Ferrer, Larry Mansouri, Ferran Nadeu, Guillem Clot, Sujata Bhoi, Lesley Ann Sutton, Panagiotis Baliakas, Sara Ek, Venera Kuci Emruli, Karla Plevova, Zadie Davis, Hanna Goransson-Kultima, Anders Isaksson, Karin E. Smedby, Gianluca Gaidano, Anton W. Langerak, Frederic Davi, Davide Rossi, David Oscier, Sarka Pospisilova, Maria Karypidou, Andreas Agathangelidis, Wolfgang Huber, Junyan Lu, Thorsten Zenz, Julio Delgado, Armando Lopez-Guillermo, Paolo Ghia, Elías Campo, Kostas Stamatopoulos, Richard Rosenquist, and José I. Martín-Subero
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
4. Table S1 from MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma
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Thorsten Zenz, Wolfgang Huber, Ulrich Keller, Markus Kreuz, Reiner Siebert, Marc Zapatka, Benedikt Brors, Michael Hummel, Lorenz H. Trümper, Markus Löffler, Birgit Burkhardt, Stephan Stilgenbauer, Christiane Pott, Wolfram Klapper, Ralf Küppers, Donato Tedesco, Kyle Bonneau, René Scholtysik, Hanne Helfrich, Olena Yavorska, Marina Lukas, Zhiqin Huang, Rabea Wagener, Sebastian Scheinost, Junyan Lu, Roma Kurilov, Katarzyna Tomska, Stefan Habringer, Alexander Jethwa, Maciej Rosolowski, Mikołaj Słabicki, and Jennifer Hüllein
- Abstract
Generanks for differential shRNA effects from GENE-E class comparison analysis
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- 2023
5. Supplementary figures from PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells
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Chang Chen, Cheng Luo, Hualiang Jiang, Jia Liu, Junyan Lu, Panpan Zhang, Hong Ding, Yingying Zhao, Xinhua Qiao, Lunfeng Zhang, Dan Zhao, Zhen Gao, and Jiangmei Li
- Abstract
Suppl. Fig. 1 First-round screening of PI4KIIα inhibitors;Suppl. Fig. 2 Second-round screening of PI4KIIα inhibitors;Suppl. Fig.3. Direct interaction between PI-273 analogs and PI4KIIα;Suppl. Fig. 4. PI-273 resistance screens using CRISPR-Cas9;Suppl. Fig.5. Generate and identify PI4KIIα knock out MCF-7 cells;Suppl. Fig. 6. Effects of PI-273 and its analogs on PI4KIIα downstream signaling pathways;Suppl. Fig. 7. PI4KIIα is required for the regulation of PI-273 on signaling transduction in breast cancer cells;Suppl. Fig. 8. PI-273 inhibits the proliferation of breast cancer cells.;Suppl. Fig. 9 Anti-tumor effect of PI-273 in an MCF-7-induced xenograft model;Suppl. Fig. 10 Inhibitory effect of 100 μM PIK inhibitors on PI4KIIα.
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- 2023
6. Table S6 from MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma
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Thorsten Zenz, Wolfgang Huber, Ulrich Keller, Markus Kreuz, Reiner Siebert, Marc Zapatka, Benedikt Brors, Michael Hummel, Lorenz H. Trümper, Markus Löffler, Birgit Burkhardt, Stephan Stilgenbauer, Christiane Pott, Wolfram Klapper, Ralf Küppers, Donato Tedesco, Kyle Bonneau, René Scholtysik, Hanne Helfrich, Olena Yavorska, Marina Lukas, Zhiqin Huang, Rabea Wagener, Sebastian Scheinost, Junyan Lu, Roma Kurilov, Katarzyna Tomska, Stefan Habringer, Alexander Jethwa, Maciej Rosolowski, Mikołaj Słabicki, and Jennifer Hüllein
- Abstract
Generanks for differential shRNA effects from GENE-E class comparison analysis for Achilles Project cell lines
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- 2023
7. Table S3 from MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma
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Thorsten Zenz, Wolfgang Huber, Ulrich Keller, Markus Kreuz, Reiner Siebert, Marc Zapatka, Benedikt Brors, Michael Hummel, Lorenz H. Trümper, Markus Löffler, Birgit Burkhardt, Stephan Stilgenbauer, Christiane Pott, Wolfram Klapper, Ralf Küppers, Donato Tedesco, Kyle Bonneau, René Scholtysik, Hanne Helfrich, Olena Yavorska, Marina Lukas, Zhiqin Huang, Rabea Wagener, Sebastian Scheinost, Junyan Lu, Roma Kurilov, Katarzyna Tomska, Stefan Habringer, Alexander Jethwa, Maciej Rosolowski, Mikołaj Słabicki, and Jennifer Hüllein
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Gene expression fold-changes from microarray analysis
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- 2023
8. Table S2, Table S4, Table S6, Figure S1, Figure S2, Figure S3, Figure S4, Figure S5, Figure S6, Supplementary Methods from MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma
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Thorsten Zenz, Wolfgang Huber, Ulrich Keller, Markus Kreuz, Reiner Siebert, Marc Zapatka, Benedikt Brors, Michael Hummel, Lorenz H. Trümper, Markus Löffler, Birgit Burkhardt, Stephan Stilgenbauer, Christiane Pott, Wolfram Klapper, Ralf Küppers, Donato Tedesco, Kyle Bonneau, René Scholtysik, Hanne Helfrich, Olena Yavorska, Marina Lukas, Zhiqin Huang, Rabea Wagener, Sebastian Scheinost, Junyan Lu, Roma Kurilov, Katarzyna Tomska, Stefan Habringer, Alexander Jethwa, Maciej Rosolowski, Mikołaj Słabicki, and Jennifer Hüllein
- Abstract
Table S2. Genetic characterization of BL cell lines; Table S4. Genetic aberrations in aggressive B-NHL patients from the MMML consortium; Table S5. Annotation of TP53 mutation and MDM4 gain in cell lines from the Achilles project; Figure S1. RNAi screen identifies common and context-specific essential genes; Figure S2. Genes essential in the context of TP53 mutation; Figure S3. p53 reactivation causes cytotoxic effect; Figure S4. Molecular impact of MDM2 or MDM4 knock-down; Figure S5. Genetic profile in TP53wt and TP53mut aggressive B-NHL patients; Figure S6. Basal MDM4 mRNA in aggressive lymphomas stratified by TP53 mutation and 1q status.
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- 2023
9. Data from PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells
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Chang Chen, Cheng Luo, Hualiang Jiang, Jia Liu, Junyan Lu, Panpan Zhang, Hong Ding, Yingying Zhao, Xinhua Qiao, Lunfeng Zhang, Dan Zhao, Zhen Gao, and Jiangmei Li
- Abstract
While phosphatidylinositol 4-kinase (PI4KIIα) has been identified as a potential target for antitumor therapy, the clinical applications of PI4KIIα are limited by a lack of specific inhibitors. Here we report the first small-molecule inhibitor (SMI) of human PI4KIIα. Docking-based and ligand-based virtual screening strategies were first employed to identify promising hits, followed by two rounds of kinase activity inhibition validation. 2-(3-(4-Chlorobenzoyl)thioureido)-4-ethyl-5-methylthiophene-3-carboxamide (PI-273) exhibited the greatest inhibitory effect on PI4KIIα kinase activity (IC50 = 0.47 μmol/L) and suppressed cell proliferation. Surface plasmon resonance and thermal shift assays indicated that PI-273 interacted directly with PI4KIIα. Kinetic analysis identified PI-273 as a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI), which contrasted with most other PI kinase inhibitors that bind the ATP binding site. PI-273 reduced PI4P content, cell viability, and AKT signaling in wild-type MCF-7 cells, but not in PI4KIIα knockout MCF-7 cells, indicating that PI-273 is highly selective for PI4KIIα. Mutant analysis revealed a role of palmitoylation insertion in the selectivity of PI-273 for PI4KIIα. In addition, PI-273 treatment retarded cell proliferation by blocking cells in G2–M, inducing cell apoptosis and suppressing colony-forming ability. Importantly, PI-273 significantly inhibited MCF-7 cell-induced breast tumor growth without toxicity. PI-273 is the first substrate-competitive, subtype-specific inhibitor of PI4KIIα, the use of which will facilitate evaluations of PI4KIIα as a cancer therapeutic target. Cancer Res; 77(22); 6253–66. ©2017 AACR.
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- 2023
10. Supplementary tables from PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells
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Chang Chen, Cheng Luo, Hualiang Jiang, Jia Liu, Junyan Lu, Panpan Zhang, Hong Ding, Yingying Zhao, Xinhua Qiao, Lunfeng Zhang, Dan Zhao, Zhen Gao, and Jiangmei Li
- Abstract
suppl. table 1chemical structures and activity of representative PI-93 analogues;suppl.table 2. activity and Tm of the PI4KIIα inhibitors;Suppl. Fig.3. Direct interaction between PI-273 analogs and PI4KIIα;Suppl. Fig. 4. PI-273 resistance screens using CRISPR-Cas9;Suppl. Fig.5. Generate and identify PI4KIIα knock out MCF-7 cells;Suppl. Fig. 6. Effects of PI-273 and its analogs on PI4KIIα downstream signaling pathways;Suppl. Fig. 7. PI4KIIα is required for the regulation of PI-273 on signaling transduction in breast cancer cells;Suppl. Fig. 8. PI-273 inhibits the proliferation of breast cancer cells.;Suppl. Fig. 9 Anti-tumor effect of PI-273 in an MCF-7-induced xenograft model;Suppl. Fig. 10 Inhibitory effect of 100 μM PIK inhibitors on PI4KIIα.
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- 2023
11. Supplementary methods from PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KIIα, Inhibits the Growth of Breast Cancer Cells
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Chang Chen, Cheng Luo, Hualiang Jiang, Jia Liu, Junyan Lu, Panpan Zhang, Hong Ding, Yingying Zhao, Xinhua Qiao, Lunfeng Zhang, Dan Zhao, Zhen Gao, and Jiangmei Li
- Abstract
informations for experiments
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- 2023
12. Data from MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma
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Thorsten Zenz, Wolfgang Huber, Ulrich Keller, Markus Kreuz, Reiner Siebert, Marc Zapatka, Benedikt Brors, Michael Hummel, Lorenz H. Trümper, Markus Löffler, Birgit Burkhardt, Stephan Stilgenbauer, Christiane Pott, Wolfram Klapper, Ralf Küppers, Donato Tedesco, Kyle Bonneau, René Scholtysik, Hanne Helfrich, Olena Yavorska, Marina Lukas, Zhiqin Huang, Rabea Wagener, Sebastian Scheinost, Junyan Lu, Roma Kurilov, Katarzyna Tomska, Stefan Habringer, Alexander Jethwa, Maciej Rosolowski, Mikołaj Słabicki, and Jennifer Hüllein
- Abstract
Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-function screening in eight Burkitt lymphoma cell lines and integrated non-Burkitt lymphoma RNAi screens and genetic data. We identified 76 genes essential to Burkitt lymphoma, including genes associated with hematopoietic cell differentiation (FLI1, BCL11A) or B-cell development and activation (PAX5, CDKN1B, JAK2, CARD11) and found a number of context-specific dependencies including oncogene addiction in cell lines with TCF3/ID3 or MYD88 mutation. The strongest genotype–phenotype association was seen for TP53. MDM4, a negative regulator of TP53, was essential in TP53 wild-type (TP53wt) Burkitt lymphoma cell lines. MDM4 knockdown activated p53, induced cell-cycle arrest, and decreased tumor growth in a xenograft model in a p53-dependent manner. Small molecule inhibition of the MDM4–p53 interaction was effective only in TP53wt Burkitt lymphoma cell lines. Moreover, primary TP53wt Burkitt lymphoma samples frequently acquired gains of chromosome 1q, which includes the MDM4 locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and MDM4 was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles Project. Our findings highlight the critical role of p53 as a tumor suppressor in Burkitt lymphoma and identify MDM4 as a functional target of 1q gain in a wide range of cancers that is therapeutically targetable.Significance:Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.
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- 2023
13. Trends of the Global Burden of Disease Attributable to Cannabis Use Disorder in 204 Countries and Territories, 1990–2019: Results from the Disease Burden Study 2019
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Heng Shao, Heyue Du, Quan Gan, Dequan Ye, Zhuangfei Chen, Yanqing Zhu, Shasha Zhu, Lang Qu, Junyan Lu, Yutong Li, Jing Duan, Yingqi Gu, and Meiling Chen
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Psychiatry and Mental health - Abstract
Cannabis is the fourth psychoactive substance to be legalized which are of far-reaching significance to the world. We analyzed data from the 2019 Global Burden of Disease Study (GBD) to estimate the incidence and prevalence of cannabis use disorder (CUD) and calculated the disease burden of CUD in 204 countries and territories and 21 regions over the past three decades. We reported disease burden due to CUD in terms of disability-adjusted life years (DALYs), age-standardized rate (ASR), estimated annual percentage change (EAPC), and analyzed associations between the burden of CUD and sociodemographic index (SDI) quintiles. Globally, the number of incidence cases of CUD was estimated to be increasing by 32.3% from 1990 to 2019 and males are nearly double higher than that of female. DALYs increase 38.6% from 1990. Young people aged 20–24 years old with cannabis use disorder have the highest DALYs in 2019, followed by those younger than 20 years old. India, Canada, USA, Qatar, Kenya, and high SDI quintile areas showed a high burden of disease. Nearly 200 million individuals are cannabis users worldwide, and CUD is a notable condition of GBD. The global cultivation of cannabis, rooted in different cultures, diversified access to cannabis, legalization in controversy, the promotion of medical cannabis, and many other factors promote the global cannabis industry is constantly updated and upgraded. It deserves more discussion in the future in terms of pathophysiological mechanisms, socioeconomics, law, and policy improvement.
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- 2023
14. Semantic Joint Monocular Remote Sensing Image Digital Surface Model Reconstruction Based on Feature Multiplexing and Inpainting
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Junyan Lu and Qinglei Hu
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General Earth and Planetary Sciences ,Electrical and Electronic Engineering - Published
- 2022
15. Negative feedback regulation of MAPK signaling is an important driver of CLL progression
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Veronika Ecker, Lisa Brandmeier, Martina Stumpf, Piero Giansanti, Aida Varela Moreira, Lisa Pfeuffer, Marcel Fens, Junyan Lu, Bernhard Küster, Thomas Engleitner, Simon Heidegger, Ingo Ringshausen, Thorsten Zenz, Clemens Wendtner, Markus Müschen, Jürgen Ruland, and Maike Buchner
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Despite several potent targeted treatments for chronic lymphocytic leukemia (CLL), the clinical challenge of treating drug-resistant disease is emerging. In this study, we discovered that the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate Mitogen-activated protein kinases (MAPK) and thus counterbalance excessive MAPK activity to prevent apoptosis in CLL. We show that DUSP1 and DUSP6 are widely expressed in CLL and high expression of DUSP6 in CLL correlates with a poor clinical prognosis, which may reflect high levels of MAPK activity. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small molecule are toxic for CLL cells in vitro and in vivo. Analyzing downstream effects using global phospho-proteome approaches, we observed that acute activation of MAPK signaling by DUSP1/6 inhibition induces DNA damage response and thereby apoptotic cell death in CLL cells. This cell death is mediated by CHK kinases and can function independent of p53 and ATM, both effectors of DNA damage response, which are frequently deleted in CLL. Finally, we observed that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising novel treatment concept to eliminate drug-resistant CLL cells.
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- 2023
16. Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein
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Zhifeng Chen, Bing Zhou, Cheng Luo, Junchi Hu, Chinatsu Otomo, Xie Yuli, Yongjun Dang, Liyan Yue, Yuanyuan Zhang, Lianchun Li, Naixia Zhang, Wei Wan, Junyan Lu, Hualiang Jiang, Takanori Otomo, Yi Wen, Quanfu Li, Lin Tingting, Hongru Tao, Zhiyi Yao, Hong Ding, Pan Xu, Mingrui Zhu, Bidong Zhang, Minjia Tan, Kaixian Chen, and Shijie Fan
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Models, Molecular ,Molecular Structure ,biology ,Chemistry ,Autophagy ,Lipid-anchored protein ,General Medicine ,General Chemistry ,biology.organism_classification ,Small molecule ,Article ,Catalysis ,Cell biology ,Small Molecule Libraries ,HeLa ,Covalent bond ,Acetylation ,Proteome ,Humans ,Receptor ,Microtubule-Associated Proteins ,HeLa Cells - Abstract
The autophagic ubiquitin-like protein LC3 functions through interactions with LC3-interaction regions (LIRs) of other autophagy proteins, including autophagy receptors, which stands out as a promising protein-protein interaction (PPI) target for the intervention of autophagy. Post-translational modifications like acetylation of Lys49 on the LIR-interacting surface could disrupt the interaction, offering an opportunity to design covalent small molecules interfering with the interface. Through screening covalent compounds, we discovered a small molecule modulator of LC3A/B that covalently modifies LC3A/B protein at Lys49. Activity-based protein profiling (ABPP) based evaluations reveal that a derivative molecule DC-LC3in-D5 exhibits a potent covalent reactivity and selectivity to LC3A/B in HeLa cells. DC-LC3in-D5 compromises LC3B lipidation in vitro and in HeLa cells, leading to deficiency in the formation of autophagic structures and autophagic substrate degradation. DC-LC3in-D5 could serve as a powerful tool for autophagy research as well as for therapeutic interventions.
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- 2021
17. Association between triglyceride-glucose index and worsening renal function in the elderly
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Li, Lei, Hongbin, Liang, Yali, Qu, Qianhong, Zhong, Qiuxia, Zhang, Lei, Dai, Junyan, Lu, Min, Xiao, Zhimeng, Zhao, Fengyun, Zhou, Yun, Li, Guifang, Hu, Jiancheng, Xiu, and Xinlu, Zhang
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Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism ,Food Science - Abstract
BackgroundTriglyceride-glucose (TyG) index is a simple marker of insulin resistance. However, insufficient data is available on whether the TyG index is associated with worsening renal function (WRF) in the elderly. Therefore, this study was designed to explore the association between the TyG index and WRF based on a community elderly cohort.MethodsIn this study, 7,822 elderly (aged ≥ 65 years) adults from southern China were enrolled and divided into four groups according to the TyG index quartiles. The primary endpoint was incident chronic kidney disease (CKD), defined as incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Additional endpoints included a decline in eGFR of 30% and 40% during the follow-up period.ResultsDuring the median 2.04 year follow-up period, 1,541 (19.7%) participants developed CKD. After adjusting for confounding factors, multivariable Cox regression models revealed significant associations between TyG index and incident CKD (HR per SD increase, 1.21; 95% CI: 1.14–1.29), a decline in eGFR of 30% (HR per SD increase, 1.38; 95% CI: 1.26–1.50), and decline in eGFR of 40% (HR per SD increase, 1.42; 95% CI: 1.24–1.63). Furthermore, compared with those in Q1, participants in Q4 demonstrated a higher risk of developing CKD (HR, 1.59; 95% CI: 1.35–1.88). These positive associations remained consistent across different subgroup populations.ConclusionOur study suggests a positive and independent association between the TyG index and WRF in the elderly.
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- 2022
18. A transformer–CNN for deep image inpainting forensics
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Xinshan Zhu, Junyan Lu, Honghao Ren, Hongquan Wang, and Biao Sun
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Computer Vision and Pattern Recognition ,Computer Graphics and Computer-Aided Design ,Software - Published
- 2022
19. Drug‐microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in <scp>CLL</scp>
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Peter‐Martin Bruch, Holly AR Giles, Carolin Kolb, Sophie A Herbst, Tina Becirovic, Tobias Roider, Junyan Lu, Sebastian Scheinost, Lena Wagner, Jennifer Huellein, Ivan Berest, Mark Kriegsmann, Katharina Kriegsmann, Christiane Zgorzelski, Peter Dreger, Judith B Zaugg, Carsten Müller‐Tidow, Thorsten Zenz, Wolfgang Huber, and Sascha Dietrich
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General Immunology and Microbiology ,Applied Mathematics ,Nuclear Proteins ,Trisomy ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,General Biochemistry, Genetics and Molecular Biology ,Computational Theory and Mathematics ,Disease Progression ,Tumor Microenvironment ,Humans ,Interleukin-4 ,General Agricultural and Biological Sciences ,Transcription Factors ,Information Systems - Abstract
The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll-like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL-infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell-extrinsic mechanisms of drug resistance and disease progression.
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- 2022
20. Functional Anti-Apoptotic Protein Dependence and Its Relation to Genomic Prognostic Markers and Response to Treatment in Chronic Lymphocytic Leukemia
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Stephen Jun Fei Chong, Junyan Lu, Rebecca Valentin, Timothy Z. Lehmberg, Mary C Collins, Charles Herbaux, Carsten Utoft Niemann, Wolfgang Huber, Thorsten Zenz, and Matthew S. Davids
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
21. Development of a Novel Chromatin Activation Score As a Powerful Independent Prognostic Factor in Chronic Lymphocytic Leukemia
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Vicente Chapaprieta, Alba Maiques-Diaz, Guillem Clot, Ferran Nadeu, Judith Mateos-Jaimez, Anna Vidal, Stella Charalampopoulou, Martí Duran-Ferrer, Romina Royo, Junyan Lu, Thorsten Zenz, Julio Delgado, Armando Lopez-Guillermo, Elías Campo, and José I. Martín-Subero
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
22. Data management plan for the trans-European ERA PerMed consortium CLL-CLUE: Tailoring the targeted treatment of chronic lymphocytic leukemia
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Sigrid S. Skånland, Tero Aittokallio, Barbara Eichhorst, Laszlo Lorenzovici, Junyan Lu, Carsten U. Niemann, and Thorsten Zenz
- Abstract
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Europe and remains incurable. Targeted therapies have revolutionized the treatment of CLL, but many patients develop resistance, have severe side effects or relapse during treatment. In order to prevent ineffective treatment and toxic effects, there is an unmet clinical need for tailoring optimal therapy for each patient. The ERA PerMed project CLL-CLUE will identify novel biomarkers and implement artificial intelligence-based clinical decision support systems to guide treatment decisions. We expect that this will lead to significantly increased treatment efficacy, individualization of therapy and reduced drug use and side effects. In addition, reduced consumption of drugs and cost-effective outcomes will lower financial stress that the health care providers and patients experience. The proposed project will be carried out as a collaborative effort including leading clinical and molecular research groups in CLL in Europe, together with key competence in development of artificial intelligence-based decision support system for blood cancer patients and health economic evaluation in Europe. Here we present the Data Management Plan for the CLL-CLUE consortium. Data sharing between the trans-European project partners is governed by the General Data Protection Regulation (GDPR) and the Data Access Agreement (DAA) between the partners.
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- 2022
23. Immunoprognostic model of lung adenocarcinoma and screening of sensitive drugs
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Pengchen, Liang, Jin, Li, Jianguo, Chen, Junyan, Lu, Zezhou, Hao, Junfeng, Shi, Qing, Chang, and Zeng, Zeng
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Male ,Lung Neoplasms ,Multidisciplinary ,Phenoxybenzamine ,Histocompatibility Antigens Class I ,Membrane Proteins ,Adenocarcinoma ,Methotrexate ,Resveratrol ,Tumor Microenvironment ,Humans ,RNA, Long Noncoding ,RNA, Messenger ,Carrier Proteins ,Lung - Abstract
Screening of mRNAs and lncRNAs associated with prognosis and immunity of lung adenocarcinoma (LUAD) and used to construct a prognostic risk scoring model (PRS-model) for LUAD. To analyze the differences in tumor immune microenvironment between distinct risk groups of LUAD based on the model classification. The CMap database was also used to screen potential therapeutic compounds for LUAD based on the differential genes between distinct risk groups. he data from the Cancer Genome Atlas (TCGA) database. We divided the transcriptome data into a mRNA subset and a lncRNA subset, and use multiple methods to extract mRNAs and lncRNAs associated with immunity and prognosis. We further integrated the mRNA and lncRNA subsets and the corresponding clinical information, randomly divided them into training and test set according to the ratio of 5:5. Then, we performed the Cox risk proportional analysis and cross-validation on the training set to construct a LUAD risk scoring model. Based on the risk scoring model, patients were divided into distinct risk group. Moreover, we evaluate the prognostic performance of the model from the aspects of Area Under Curve (AUC) analysis, survival difference analysis, and independent prognostic analysis. We analyzed the differences in the expression of immune cells between the distinct risk groups, and also discuss the connection between immune cells and patient survival. Finally, we screened the potential therapeutic compounds of LUAD in the Connectivity Map (CMap) database based on differential gene expression profiles, and verified the compound activity by cytostatic assays. We extracted 26 mRNAs and 74 lncRNAs related to prognosis and immunity by using different screening methods. Two mRNAs (i.e., KLRC3 and RAET1E) and two lncRNAs (i.e., AL590226.1 and LINC00941) and their risk coefficients were finally used to construct the PRS-model. The risk score positions of the training and test set were 1.01056590 and 1.00925190, respectively. The expression of mRNAs involved in model construction differed significantly between the distinct risk population. The one-year ROC areas on the training and test sets were 0.735 and 0.681. There was a significant difference in the survival rate of the two groups of patients. The PRS-model had independent predictive capabilities in both training and test sets. Among them, in the group with low expression of M1 macrophages and resting NK cells, LUAD patients survived longer. In contrast, the monocyte expression up-regulated group survived longer. In the CMap drug screening, three LUAD therapeutic compounds, such as resveratrol, methotrexate, and phenoxybenzamine, scored the highest. In addition, these compounds had significant inhibitory effects on the LUAD A549 cell lines. The LUAD risk score model constructed using the expression of KLRC3, RAET1E, AL590226.1, LINC00941 and their risk coefficients had a good independent prognostic power. The optimal LUAD therapeutic compounds screened in the CMap database: resveratrol, methotrexate and phenoxybenzamine, all showed significant inhibitory effects on LUAD A549 cell lines.
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- 2022
24. Inferring tumor-specific cancer dependencies through integrating ex vivo drug response assays and drug-protein profiling
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Alina Batzilla, Junyan Lu, Jarno Kivioja, Kerstin Putzker, Joe Lewis, Thorsten Zenz, Wolfgang Huber, University of Zurich, Lu, Junyan, Zenz, Thorsten, and Huber, Wolfgang
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Ecology ,2804 Cellular and Molecular Neuroscience ,Receptors, Antigen, B-Cell ,610 Medicine & health ,Leukemia, Lymphocytic, Chronic, B-Cell ,Cellular and Molecular Neuroscience ,Leukemia, Myeloid, Acute ,1105 Ecology, Evolution, Behavior and Systematics ,1311 Genetics ,Computational Theory and Mathematics ,Modeling and Simulation ,Cell Line, Tumor ,10032 Clinic for Oncology and Hematology ,Mutation ,1312 Molecular Biology ,Genetics ,Humans ,Precision Medicine ,2303 Ecology ,Molecular Biology ,Protein Kinase Inhibitors ,Protein Kinases ,Ecology, Evolution, Behavior and Systematics ,2611 Modeling and Simulation ,1703 Computational Theory and Mathematics - Abstract
The development of cancer therapies may be improved by the discovery of tumor-specific molecular dependencies. The requisite tools include genetic and chemical perturbations, each with its strengths and limitations. Chemical perturbations can be readily applied to primary cancer samples at large scale, but mechanistic understanding of hits and further pharmaceutical development is often complicated by the fact that a chemical compound has affinities to multiple proteins. To computationally infer specific molecular dependencies of individual cancers from their ex vivo drug sensitivity profiles, we developed a mathematical model that deconvolutes these data using measurements of protein-drug affinity profiles. Through integrating a drug-kinase profiling dataset and several drug response datasets, our method, DepInfeR, correctly identified known protein kinase dependencies, including the EGFR dependence of HER2+ breast cancer cell lines, the FLT3 dependence of acute myeloid leukemia (AML) with FLT3-ITD mutations and the differential dependencies on the B-cell receptor pathway in the two major subtypes of chronic lymphocytic leukemia (CLL). Furthermore, our method uncovered new subgroup-specific dependencies, including a previously unreported dependence of high-risk CLL on Checkpoint kinase 1 (CHEK1). The method also produced a detailed map of the kinase dependencies in a heterogeneous set of 117 CLL samples. The ability to deconvolute polypharmacological phenotypes into underlying causal molecular dependencies should increase the utility of high-throughput drug response assays for functional precision oncology.
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- 2022
25. Impact of the caFFR-Guided Functional SYNTAX Score on Ventricular Tachycardia/Fibrillation Development in Patients With Acute Myocardial Infarction
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Jiazhi, Pan, Qiuxia, Zhang, Li, Lei, Yaode, Chen, Guodong, Li, Hongbin, Liang, Junyan, Lu, Xinlu, Zhang, Yongzhen, Tang, Jun, Pu, Yining, Yang, Dapeng, Mo, and Jiancheng, Xiu
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Cardiology and Cardiovascular Medicine - Abstract
AimsTo explore the relationship between the severity of coronary artery disease (CAD) and the occurrence of ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with acute myocardial infarction (AMI).MethodsWe retrospectively enrolled 705 patients with AMI, who were hospitalized and underwent percutaneous coronary intervention (PCI), in Nanfang Hospital from July 2017 to July 2020. Logistic regression analysis and backward stepwise approach were taken to select the correlation factors. The left and the receiver operating characteristic curves (ROC) analysis were plotted to observe the discriminative power of the SYNTAX score (SS)/caFFR-guided functional SS (FSScaFFR) on the incident VT/VF.ResultsAbout 58 (8.2%) patients experienced life-threatening VT/VF. The FSScaFFR (OR: 1.155; 95% CI: 1.047 to 1.273; p = 0.004) was an independent predictor of VT/VF after AMI. The ROC analysis showed that the discriminative power of FSScaFFR on the incident VT/VF was significantly better than SS (0.759 vs.0.695, p < 0.0001). Patients with VT/VF were categorized into 2 groups according to the interval between the onset of AMI and the VT/VF. The logistic regression analysis revealed that FSScaFFR was a significant independent correlation of early- and late-VT/VF.ConclusionThe incident VT/VF in patients with AMI is closely associated with the severity of CAD evaluated by SS and FSScaFFR. Compared to SS, FSScaFFR has a higher correlation with VT/VF, and FSScaFFR was demonstrated to be an independent correlation factor of incident VT/VF after AMI.
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- 2022
26. The Association Between Visceral Adiposity Index and Worsening Renal Function in the Elderly
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Li, Lei, Lei, Dai, Qiuxia, Zhang, Junyan, Lu, Yongzhen, Tang, Min, Xiao, Guodong, Li, Shaohua, Yan, Xiaobo, Li, Yejia, Chen, Yaode, Chen, Yun, Li, Shengli, An, and Jiancheng, Xiu
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Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism ,Food Science - Abstract
BackgroundVisceral adiposity index (VAI) is an indicator of visceral fat accumulation and dysfunction. However, little is known about whether VAI is associated with worsening renal function (WRF) in the elderly. Therefore, our study aimed to explore the association between VAI and WRF among the elderly population.MethodsIn total, 5,583 elderly participants (aged ≥ 65 years) who participated in the annual health checkups at least twice between January 2017 and July 2021 were enrolled and divided into four groups according to the VAI quartiles. The primary endpoint was incident chronic kidney disease (CKD), defined as incident estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. The secondary endpoint was rapid kidney function decline (RKFD), defined as decline in eGFR of 40%. To evaluate the association between VAI and WRF, three Cox regression models were conducted, where VAI was treated as a continuous variable and a categorical variable (Q1 as reference), respectively. Subgroup analysis in participants with different baseline characteristics was also performed.ResultsDuring a median of 2.46 year follow-up, 931 (16.68%) participants developed CKD. After fully adjusting for confounding factors, VAI was significantly associated with incident CKD (HR, 1.052; 95% CI: 1.029–1.076, p < 0.001), and RKFD (HR, 1.077; 95% CI: 1.041–1.114, p < 0.001). Moreover, compared to those with the lowest VAI quartiles, subjects with the highest quartiles had a higher risk of incident CKD (HR, 1.286; 95% CI: 1.033–1.601, p = 0.024), and RKFD (HR, 1.895; 95% CI: 1.086–3.307, p = 0.025). The risk of incident CKD also tended to increase with elevated VAI quartiles (all p-values for trend ConclusionIn our study, elevated VAI was associated with increased risk of incident CKD and RKFD in the elderly population.
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- 2022
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27. PhD and postdoc training outcomes at EMBL: changing career paths for life scientists in Europe
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Junyan Lu, Britta Velten, Bernd Klaus, Mauricio Ramm, Wolfgang Huber, and Rachel Coulthard-Graf
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The life sciences are training growing numbers of PhDs and postdocs, who increasingly engage in collaborative research. The impact of these changes on the careers of researchers is, however, unclear. Here, we report an analysis of the training outcomes for 2284 researchers who completed a PhD or postdoc at the European Molecular Biology Laboratory (EMBL) between 1997 and 2020. This is the first such study published from a European institute and first time-resolved analysis globally. The most common career outcomes were in academic research, service and teaching (1263 alumni, 55%), including 636 principal investigators (PIs). A broad spectrum of other career paths was also represented, including in industry research (332, 15%) and science-related professions (349, 15%). Our analysis indicates that, although there is increased competition for PI roles, life scientists continue to enter and excel in careers that drive research and innovation.
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- 2022
28. Proteogenomics refines the molecular classification of chronic lymphocytic leukemia
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Sophie A. Herbst, Mattias Vesterlund, Alexander J. Helmboldt, Rozbeh Jafari, Ioannis Siavelis, Matthias Stahl, Eva C. Schitter, Nora Liebers, Berit J. Brinkmann, Felix Czernilofsky, Tobias Roider, Peter-Martin Bruch, Murat Iskar, Adam Kittai, Ying Huang, Junyan Lu, Sarah Richter, Georgios Mermelekas, Husen Muhammad Umer, Mareike Knoll, Carolin Kolb, Angela Lenze, Xiaofang Cao, Cecilia Österholm, Linus Wahnschaffe, Carmen Herling, Sebastian Scheinost, Matthias Ganzinger, Larry Mansouri, Katharina Kriegsmann, Mark Kriegsmann, Simon Anders, Marc Zapatka, Giovanni Del Poeta, Antonella Zucchetto, Riccardo Bomben, Valter Gattei, Peter Dreger, Jennifer Woyach, Marco Herling, Carsten Müller-Tidow, Richard Rosenquist, Stephan Stilgenbauer, Thorsten Zenz, Wolfgang Huber, Eugen Tausch, Janne Lehtiö, and Sascha Dietrich
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Proteomics ,Multidisciplinary ,Proteome ,hemic and lymphatic diseases ,Mutation ,General Physics and Astronomy ,Humans ,Receptors, Antigen, B-Cell ,General Chemistry ,Leukemia, Lymphocytic, Chronic, B-Cell ,General Biochemistry, Genetics and Molecular Biology ,Proteogenomics - Abstract
SummaryCancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterized the proteome and transcriptome in-depth alongside genetic and ex-vivo drug response profiling in a clinically well annotated CLL discovery cohort (n= 68). Unsupervised clustering of the proteome data revealed six subgroups. Five of these proteomic groups were associated with genetic features, while one group was only detectable at the proteome level. This new group was characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). We developed classifiers to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n= 165, n= 169) and confirmed that ASB-CLL comprises about 20 % of CLL patients. The inferior overall survival observed in ASB-CLL was independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling.Single sentence summaryWe performed the largest proteogenomic analysis of CLL, linked proteomic profiles to clinical outcomes, and discovered a new poor outcome subgroup (ASB-CLL).
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- 2022
29. Nomogram to predict rapid kidney function decline in population at risk of cardiovascular disease
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Yaode Chen, Li Lei, Jiazhi Pan, Qiuxia Zhang, Yun Li, Jingyi Zhang, Jiancheng Xiu, Xiangqi Lu, Junyan Lu, Xinxin Lin, Xinlu Zhang, Xiaobo Li, Hongbin Liang, Shengli An, Yejia Chen, Shiyu Zhou, and Guodong Li
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Oncology ,Male ,medicine.medical_specialty ,Population ,Renal function ,Blood Pressure ,Disease ,Decision Support Techniques ,Diabetes Complications ,Hemoglobins ,Risk Factors ,Internal medicine ,Medicine ,Humans ,Renal Insufficiency ,Rapid kidney function decline ,education ,Aged ,Retrospective Studies ,education.field_of_study ,business.industry ,Age Factors ,Reproducibility of Results ,Nomogram ,Cardiovascular disease ,Diseases of the genitourinary system. Urology ,Nomograms ,Cardiovascular Diseases ,Nephrology ,Female ,RC870-923 ,business ,Risk prediction model ,Glomerular Filtration Rate - Abstract
Background To develop a reliable model to predict rapid kidney function decline (RKFD) among population at risk of cardiovascular disease. Methods In this retrospective study, key monitoring residents including the elderly, and patients with hypertension or diabetes of China National Basic Public Health Service who underwent community annual physical examinations from January 2015 to December 2020 were included. Healthy records were extracted from regional chronic disease management platform. RKFD was defined as the reduction of estimated glomerular filtration rate (eGFR) ≥ 40% during follow-up period. The entire cohort were randomly assigned to a development cohort and a validation cohort in a 2:1 ratio. Cox regression analysis was used to identify the independent predictors. A nomogram was established based on the development cohort. The concordance index (C-index) and calibration plots were calculated. Decision curve analysis was applied to evaluate the clinical utility. Results A total of 8455 subjects were included. During the median follow-up period of 3.72 years, the incidence of RKFD was 11.96% (n = 1011), 11.98% (n = 676) and 11.92% (n = 335) in the entire cohort, development cohort and validation cohort, respectively. Age, eGFR, hemoglobin, systolic blood pressure, and diabetes were identified as predictors for RKFD. Good discriminating performance was observed in both the development (C-index, 0.73) and the validation (C-index, 0.71) cohorts, and the AUCs for predicting 5-years RKFD was 0.763 and 0.740 in the development and the validation cohort, respectively. Decision curve analysis further confirmed the clinical utility of the nomogram. Conclusions Our nomogram based on five readily accessible variables (age, eGFR, hemoglobin, systolic blood pressure, and diabetes) is a useful tool to identify high risk patients for RKFD among population at risk of cardiovascular disease in primary care. Whereas, further external validations are needed before clinical generalization.
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- 2022
30. Survey of ex vivo drug combination effects in chronic lymphocytic leukemia reveals synergistic drug effects and genetic dependencies
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Bian Wu, Tatjana Walther, Lena Wagner, Leopold Sellner, Wolfgang Huber, Thorsten Zenz, Junyan Lu, Hanibal Bohnenberger, Carolin Muley, Sascha Dietrich, Britta Velten, Alexander Jethwa, Marina Lukas, Katarzyna Tomska, Małgorzata Oleś, Jennifer Huellein, University of Zurich, and Huber, Wolfgang
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Drug ,Chronic lymphocytic leukaemia ,Cancer Research ,Afatinib ,media_common.quotation_subject ,Chronic lymphocytic leukemia ,2720 Hematology ,Primary Cell Culture ,Drug Evaluation, Preclinical ,Receptors, Antigen, B-Cell ,Syk ,610 Medicine & health ,Antineoplastic Agents ,Drug resistance ,Article ,Cell Line, Tumor ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Bruton's tyrosine kinase ,1306 Cancer Research ,Protein Kinase Inhibitors ,media_common ,Dose-Response Relationship, Drug ,biology ,business.industry ,breakpoint cluster region ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,Drug Synergism ,Hematology ,Translational research ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,ddc ,Combination drug therapy ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Drug Resistance, Neoplasm ,Preclinical research ,10032 Clinic for Oncology and Hematology ,Cancer research ,biology.protein ,2730 Oncology ,business ,IGHV@ ,medicine.drug - Abstract
Drug combinations that target critical pathways are a mainstay of cancer care. To improve current approaches to combination treatment of chronic lymphocytic leukemia (CLL) and gain insights into the underlying biology, we studied the effect of 352 drug combination pairs in multiple concentrations by analysing ex vivo drug response of 52 primary CLL samples, which were characterized by “omics” profiling. Known synergistic interactions were confirmed for B-cell receptor (BCR) inhibitors with Bcl-2 inhibitors and with chemotherapeutic drugs, suggesting that this approach can identify clinically useful combinations. Moreover, we uncovered synergistic interactions between BCR inhibitors and afatinib, which we attribute to BCR activation by afatinib through BLK upstream of BTK and PI3K. Combinations of multiple inhibitors of BCR components (e.g., BTK, PI3K, SYK) had effects similar to the single agents. While PI3K and BTK inhibitors produced overall similar effects in combinations with other drugs, we uncovered a larger response heterogeneity of combinations including PI3K inhibitors, predominantly in CLL with mutated IGHV, which we attribute to the target’s position within the BCR-signaling pathway. Taken together, our study shows that drug combination effects can be effectively queried in primary cancer cells, which could aid discovery, triage and clinical development of drug combinations.
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- 2020
31. Do English noun phrases tend to minimize dependency distance?
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Junyan Lu and Haitao Liu
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050101 languages & linguistics ,Linguistics and Language ,Dependency (UML) ,Computer science ,Working memory ,05 social sciences ,Language and Linguistics ,Noun phrase ,Linguistics ,Constraint (information theory) ,030507 speech-language pathology & audiology ,03 medical and health sciences ,0501 psychology and cognitive sciences ,0305 other medical science - Abstract
Many studies have shown that, owing to the constraint of working memory capacity, language users prefer shorter dependency distances. However, these studies, which are all based on dependency dista...
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- 2020
32. SAR: Single-Stage Anchor-Free Rotating Object Detection
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Jingyu Ma, Tie Li, Hongguang Jia, Junyan Lu, and Li Zhuqiang
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General Computer Science ,representation ,Computer science ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,0211 other engineering and technologies ,02 engineering and technology ,Convolutional neural network ,Robustness (computer science) ,0202 electrical engineering, electronic engineering, information engineering ,General Materials Science ,Computer vision ,Aerial image ,021101 geological & geomatics engineering ,Single stage ,business.industry ,circle cut horizontal ,General Engineering ,Rotating object detection ,Object detection ,single-stage ,020201 artificial intelligence & image processing ,lcsh:Electrical engineering. Electronics. Nuclear engineering ,Artificial intelligence ,business ,lcsh:TK1-9971 ,anchor-free - Abstract
As object detection is widely adopted in aerial images, scene texts and other fields, rotating object detection plays an important role and draws attention since it can provide highly accurate orientation and scale information. In this article, we propose a novel and simple baseline to effectively conduct rotating object detection. First, we design a brand-new representation for rotating objects by using a circle cut horizontal rectangle (CCH). The CCH ensures that the regression parameters will not exceed the defined domain and avoids vertex sorting, thus solving some problems in current common representations, including the boundary problem and order problem, and improving the robustness. Second, we design a lightweight head based on the CCH to add the rotating regression to classic benchmark in an almost cost-free manner and propose a single-stage anchor-free rotating (SAR) object detection convolutional neural network. Finally, we demonstrate the details of our method by applying it to data sets with different scenarios. The experiments confirm that our method achieves competitive accuracy and state-of-the-art speed in aerial image and scene text detection.
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- 2020
33. The Association Between the Frequency of Annual Health Checks Participation and the Control of Cardiovascular Risk Factors
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Li Lei, Yongzhen Tang, Qiuxia Zhang, Min Xiao, Lei Dai, Junyan Lu, Xinxin Lin, Xiangqi Lu, Wei Luo, Jiazhi Pan, Xiaoyu Xin, Shifeng Qiu, Yun Li, Shengli An, and Jiancheng Xiu
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Cardiology and Cardiovascular Medicine - Abstract
BackgroundGeneral health checks can help in controlling cardiovascular risk factors. However, few studies have investigated whether regular participation in annual health checks could further improve the control of cardiovascular risk factors compared with intermittent participation. Therefore, our study aimed to explore the association between the frequency of annual health check participation and the control of cardiovascular risk factors.MethodsResidents aged ≥ 65 years or having chronic diseases (hypertension or diabetes) from 37 communities of Guangzhou, Guangdong, who participated in the Basic Public Health Service project between January 2015 and December 2019, were enrolled and divided into 3 groups (“Sometimes,” “Usually,” and “Always”) according to their frequencies of annual health check participation. Multivariable linear regression models were performed to assess the association between the frequency of annual health check participation and the control of cardiovascular risk factors. A subgroup analysis stratified by gender was also conducted.ResultsIn total, 9,102 participants were finally included. Significant differences were identified between groups in systolic blood pressure (SBP), diastolic blood pressure (DBP), weight, fasting glucose, total cholesterol, high-density lipoprotein cholesterol, and serum creatinine. After fully adjusting for confounding factors, residents who always participated in the annual health check tended to have lower SBP (β = −4.36, 95% CI: −5.46; −3.26, p < 0.001), fasting glucose (β = −0.27, 95% CI: −0.38; −0.15, p < 0.001), and total cholesterol (β = −0.19, 95% CI: −0.26; −0.13, p < 0.001), compared with those who attended sometimes. Furthermore, gender did not alter these associations.ConclusionA higher frequency of annual health check participation was associated with lower SBP, fasting glucose, and total cholesterol.
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- 2022
34. A Cqd/Cds/G-C3n4 Photocatalyst for Dye and Antibiotic Degradation: Dual Carrier Driving Force and Tunable Electron Transfer Pathway
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Jianfei Li, Bin Zhang, Junyan Lu, Zihao Guo, Mingxia Zhang, Degang Li, Zengdian Zhao, Shasha Song, Yan Liu, and Luchang Qin
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History ,Polymers and Plastics ,Filtration and Separation ,Business and International Management ,Industrial and Manufacturing Engineering ,Analytical Chemistry - Published
- 2022
35. A gene expression assay based on chronic lymphocytic leukemia activation in the microenvironment to predict progression
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Pau Abrisqueta, Daniel Medina, Guillermo Villacampa, Junyan Lu, Miguel Alcoceba, Julia Carabia, Joan Boix, Barbara Tazón-Vega, Gloria Iacoboni, Sabela Bobillo, Ana Marín-Niebla, Marcos González, Thorsten Zenz, Marta Crespo, Francesc Bosch, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Junta de Castilla y León, Fundació La Marató de TV3, Institut Català de la Salut, [Abrisqueta P, Tazón-Vega B, Iacoboni G, Bobillo S, Marín-Niebla A, Bosch F] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Medina D, Carabia J, Boix J, Crespo M] Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Villacampa G] Oncology Data Science (OdysSey) Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Lu J] European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. [Alcoceba M, González M] Department of Hematology, University Hospital of Salamanca (HUS/IBSAL), CIBERONC and Center for Cancer Research-IBMCC (USAL-CSIC), Salamanca, Spain. [Zenz T] Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland, Vall d'Hebron Barcelona Hospital Campus, and University of Zurich
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Otros calificadores::Otros calificadores::/genética [Otros calificadores] ,Cell Physiological Phenomena::Cellular Microenvironment::Tumor Microenvironment [PHENOMENA AND PROCESSES] ,Marcadors tumorals ,fenómenos fisiológicos celulares::microambiente celular::microambiente tumoral [FENÓMENOS Y PROCESOS] ,610 Medicine & health ,Genetic Phenomena::Gene Expression [PHENOMENA AND PROCESSES] ,Hematology ,Prognosis ,Expressió gènica ,Leukemia, Lymphocytic, Chronic, B-Cell ,Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Leukemia, B-Cell::Leukemia, Lymphocytic, Chronic, B-Cell [DISEASES] ,10032 Clinic for Oncology and Hematology ,Mutation ,Other subheadings::Other subheadings::/genetics [Other subheadings] ,Tumor Microenvironment ,Humans ,Leucèmia limfocítica crònica ,Diagnosis::Prognosis [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Transcriptome ,diagnóstico::pronóstico [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,fenómenos genéticos::expresión génica [FENÓMENOS Y PROCESOS] ,neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia de células B::leucemia linfocítica crónica de células B [ENFERMEDADES] ,Proportional Hazards Models - Abstract
Several gene expression profiles with a strong correlation with patient outcomes have been previously described in chronic lymphocytic leukemia (CLL), although their applicability as biomarkers in clinical practice has been particularly limited. Here we describe the training and validation of a gene expression signature for predicting early progression in patients with CLL based on the analysis of 200 genes related to microenvironment signaling on the NanoString platform. In the training cohort (n = 154), the CLL15 assay containing a 15-gene signature was associated with the time to first treatment (TtFT) (hazard ratio [HR], 2.83; 95% CI, 2.17-3.68; P < .001). The prognostic value of the CLL15 score (HR, 1.71; 95% CI, 1.15-2.52; P = .007) was further confirmed in an external independent validation cohort (n = 112). Notably, the CLL15 score improved the prognostic capacity over IGHV mutational status and the International Prognostic Score for asymptomatic early-stage (IPS-E) CLL. In multivariate analysis, the CLL15 score (HR, 1.83; 95% CI, 1.32-2.56; P < .001) and the IPS-E CLL (HR, 2.23; 95% CI, 1.59-3.12; P < .001) were independently associated with TtFT. The newly developed and validated CLL15 assay successfully translated previous gene signatures such as the microenvironment signaling into a new gene expression–based assay with prognostic implications in CLL., This work was supported by research funding from the Asociacion Espa ´ nola Contra el C ˜ ancer grant [5U01CA157581- 05, ECRIN-M3 - A29370] and in part by the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias [PI17/00950, M.C., PI17/00943, F.B, PI18/01392, P.A.], and the Spanish Ministry of Economy and Competitiveness [CIBERONC-CB16/12/00233], the Education Council or Health Council of the Junta de Castilla y Leon [GRS 2036/A/19], and Gilead Sciences [GLD15/00348]. ´ This work was supported by research funding from the Asociacion´ Espanola Contra el C ˜ ancer grant [5U01CA157581-05, ECRIN-M3 ´ - A29370] and in part by the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias [PI17/00950, M.C., PI17/00943, F.B, PI18/01392, P.A.], and the Spanish Ministry of Economy and Competitiveness [CIBERONC-CB16/12/00233], the Education Council or Health Council of the Junta de Castilla y Leon [GRS ´ 2036/A/19], Gilead Sciences [GLD15/00348] and Gilead Fellowships [GLD16/00144, GLD18/00047, F.B.], and Fundacio la ´Marato de TV3 [201905-30-31 F.B]. All Spanish funding was ´ cosponsored by the European Union FEDER program “Una manera de hacer Europa”. M.C. holds a contract from Ministerio de Ciencia, Innovacion y Universidades [RYC-2012-2018].
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- 2022
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36. Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia
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Sascha Dietrich, Brian Giacopelli, Jennifer Hüllein, Christopher C. Oakes, Bernd Bodenmiller, Lena Wagner, Almut Lütge, Ferran Nadeu, Ester Cannizzaro, Julio Delgado, Wolfgang Huber, Fabienne Meier-Abt, Thorsten Zenz, Sebastian Scheinost, Dimitrios Mougiakakos, Maurizio Mangolini, Andrea Jacobs, Junyan Lu, Holly A. R. Giles, Elias Campo, Peter-Martin Bruch, Martin Böttcher, Ingo Ringshausen, University of Zurich, Zenz, Thorsten, and Huber, Wolfgang
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Proteomics ,Cancer Research ,Chronic lymphocytic leukemia ,Lymphocyte ,Cell ,610 Medicine & health ,Biology ,Oxidative Phosphorylation ,Article ,Transcriptome ,hemic and lymphatic diseases ,medicine ,Humans ,Doubling time ,Clinical significance ,1306 Cancer Research ,PI3K/AKT/mTOR pathway ,TOR Serine-Threonine Kinases ,DNA Methylation ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,medicine.anatomical_structure ,Oncology ,DNA methylation ,10032 Clinic for Oncology and Hematology ,Cancer research ,2730 Oncology ,11493 Department of Quantitative Biomedicine - Abstract
Chronic Lymphocytic Leukemia (CLL) has a complex pattern of driver mutations and much of its clinical diversity remains unexplained. We devised a method for simultaneous subgroup discovery across multiple data types and applied it to genomic, transcriptomic, DNA methylation and ex-vivo drug response data from 217 Chronic Lymphocytic Leukemia (CLL) cases. We uncovered a biological axis of heterogeneity strongly associated with clinical behavior and orthogonal to the known biomarkers. We validated its presence and clinical relevance in four independent cohorts (n=547 patients). We find that this axis captures the proliferative drive (PD) of CLL cells, as it associates with lymphocyte doubling rate, global hypomethylation, accumulation of driver aberrations and response to pro-proliferative stimuli. CLL-PD was linked to the activation of mTOR-MYC-oxidative phosphorylation (OXPHOS) through transcriptomic, proteomic and single cell resolution analysis. CLL-PD is a key determinant of disease outcome in CLL. Our multi-table integration approach may be applicable to other tumors whose inter-individual differences are currently unexplained.
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- 2021
37. Combinatorial drug-microenvironment interaction mapping reveals cell-extrinsic drug resistance mechanisms and clinically relevant patient subgroups in CLL
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Carolin Kolb, Sophie A. Herbst, Lena Wagner, Sebastian Scheinost, Peter-Martin Bruch, Peter Dreger, Tobias Roider, Carsten Müller-Tidow, Mark Kriegsmann, Ivan Berest, Jennifer Huellein, Sascha Dietrich, Holly A. R. Giles, Christiane Zgorzelski, Katharina Kriegsmann, Tina Becirovic, Junyan Lu, Judith B. Zaugg, Wolfgang Huber, and Thorsten Zenz
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B-cell receptor ,medicine ,Cancer research ,breakpoint cluster region ,Cancer ,Drug resistance ,Copy-number variation ,Biology ,IGHV@ ,medicine.disease ,Trisomy ,Fludarabine ,medicine.drug - Abstract
The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited to small scale studies and systematic analyses are lacking. We chose Chronic Lymphocytic Leukaemia (CLL), the most common leukaemia in adults, as a model disease to study this complex interplay systematically. We performed a combinatorial assay using 12 drugs individually co-applied with each of 17 microenvironmental stimuli in 192 primary CLL samples, generating a comprehensive map of drug-microenvironment interactions in CLL. This data was combined with whole-exome sequencing, DNA-methylation, RNA-sequencing and copy number variant annotation. Our assay identified four distinct CLL subgroups that differed in their responses to the panel of microenvironmental stimuli. These subgroups were characterized by distinct clinical outcomes independently of known prognostic markers. We investigated the effect of CLL- specific recurrent genetic alterations on microenvironmental responses and identified trisomy 12 as an amplifier of multiple microenvironmental stimuli. We further quantified the impact of microenvironmental stimuli on drug response, confirmed known interactions such as Interleukin (IL) 4 mediated resistance to B cell receptor (BCR) inhibitors, and identified new interactions such as Interferon-γ induced resistance to BCR inhibitors. Finally, we identified interactions which were limited to genetic subgroups. Resistance to chemotherapeutics, such as Fludarabine, induced by Toll-Like Receptor (TLR) agonists could be observed in IGHV unmutated patient samples and IGHV mutated samples with trisomy 12. In-vivo relevance was investigated in CLL-infiltrated lymph nodes, which showed increased IL4 and TLR signalling activity compared to healthy samples (pWe provide a publicly available resource (www.dietrichlab.de/CLL_Microenvironment/) which uncovers tumour cell extrinsic influences on drug response and disease progression in CLL, and how these interactions are modulated by cell intrinsic molecular features.
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- 2021
38. SAMHD1 mutations in mantle cell lymphoma are recurrent and confer in vitro resistance to nucleoside analogues
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Tharshika Thavayogarajah, Holger Moch, Junyan Lu, Ewerton Marques Maggio, Sebastian Scheinost, Eugenia Haralambieva, Ferran Nadeu, Eva Giné, Elias Campo, Thorsten Zenz, Manfred Hensel, Damien Roos-Weil, Olivier A. Bernard, Marco M Bühler, Sílvia Beà, Markus G. Manz, Wolfgang Huber, University of Zurich, and Zenz, Thorsten
- Subjects
Cancer Research ,2720 Hematology ,Antineoplastic Agents ,610 Medicine & health ,Lymphoma, Mantle-Cell ,Biology ,medicine.disease_cause ,SAM Domain and HD Domain-Containing Protein 1 ,03 medical and health sciences ,0302 clinical medicine ,Cyclin D1 ,Recurrence ,hemic and lymphatic diseases ,10049 Institute of Pathology and Molecular Pathology ,medicine ,Humans ,1306 Cancer Research ,neoplasms ,Gene ,Mutation ,Nucleosides ,Hematology ,medicine.disease ,Lymphoma ,Fludarabine ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,10032 Clinic for Oncology and Hematology ,Cytarabine ,Cancer research ,Mantle cell lymphoma ,2730 Oncology ,030215 immunology ,medicine.drug ,SAMHD1 - Abstract
The genomic landscape of mantle cell lymphoma (MCL) includes frequent alterations of TP53, ATM, CCND1 and KMT2D. Thus far, the mutational landscape provides little information for treatment stratification. We characterized a cohort of MCL by targeted next generation sequencing and discovered SAMHD1 as a novel recurrently mutated gene (8.5% of investigated cases, 4/47 samples). Furthermore, we provide evidence of in vitro resistance of SAMHD1 mutated patient-derived MCL cells to cytarabine and fludarabine.
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- 2021
39. Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia
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Junyan Lu, Melissa C. Larson, William G. Wierda, Kanti R. Rai, Laura Z. Rassenti, Kari G. Rabe, Lynne V. Abruzzo, Madelyn M. Gerber, James S. Blachly, Thomas J. Kipps, Kerry A. Rogers, Brian Giacopelli, Kevin R. Coombes, Yue Zhong Wu, Akwasi Agyeman, Qiuhong Zhao, Amy S. Ruppert, Thorsten Zenz, Jennifer A. Woyach, Christopher C. Oakes, Michael J. Keating, Christoph Weigel, Tait D. Shanafelt, Jennifer R. Brown, John C. Byrd, Neil E. Kay, University of Zurich, and Oakes, Christopher C
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1303 Biochemistry ,Chronic lymphocytic leukemia ,2720 Hematology ,Immunology ,610 Medicine & health ,Biology ,Biochemistry ,Epigenesis, Genetic ,1307 Cell Biology ,chemistry.chemical_compound ,Chemoimmunotherapy ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Testing ,Epigenetics ,2403 Immunology ,Lymphoid Neoplasia ,ZAP70 ,Cancer ,Cell Biology ,Hematology ,DNA Methylation ,Prognosis ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,chemistry ,Genetic Loci ,Ibrutinib ,10032 Clinic for Oncology and Hematology ,DNA methylation ,Disease Progression ,Cancer research - Abstract
Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.
- Published
- 2019
40. MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma
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Sebastian Scheinost, Jennifer Hüllein, Benedikt Brors, Markus W. Löffler, Alexander Jethwa, Wolfram Klapper, Hanne Helfrich, Rabea Wagener, Junyan Lu, Stefan Habringer, Ulrich Keller, Kyle Bonneau, Lorenz Trümper, Markus Kreuz, Zhiqin Huang, Stephan Stilgenbauer, Olena Yavorska, Marc Zapatka, Donato Tedesco, Ralf Küppers, Christiane Pott, Maciej Rosolowski, Roma Kurilov, Wolfgang Huber, Thorsten Zenz, René Scholtysik, Mikolaj Slabicki, Michael Hummel, Birgit Burkhardt, Katarzyna Tomska, Marina Lukas, and Reiner Siebert
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0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,Medizin ,Apoptosis ,Cell Cycle Proteins ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,RNA interference ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Cell Proliferation ,Chromosome Aberrations ,Cell growth ,Cell Cycle Checkpoints ,medicine.disease ,Oncogene Addiction ,Burkitt Lymphoma ,Xenograft Model Antitumor Assays ,3. Good health ,Lymphoma ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Chromosomes, Human, Pair 1 ,030220 oncology & carcinogenesis ,FLI1 ,Mutation ,Cancer research ,PAX5 ,CDKN1B ,Tumor Suppressor Protein p53 - Abstract
Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-function screening in eight Burkitt lymphoma cell lines and integrated non-Burkitt lymphoma RNAi screens and genetic data. We identified 76 genes essential to Burkitt lymphoma, including genes associated with hematopoietic cell differentiation (FLI1, BCL11A) or B-cell development and activation (PAX5, CDKN1B, JAK2, CARD11) and found a number of context-specific dependencies including oncogene addiction in cell lines with TCF3/ID3 or MYD88 mutation. The strongest genotype–phenotype association was seen for TP53. MDM4, a negative regulator of TP53, was essential in TP53 wild-type (TP53wt) Burkitt lymphoma cell lines. MDM4 knockdown activated p53, induced cell-cycle arrest, and decreased tumor growth in a xenograft model in a p53-dependent manner. Small molecule inhibition of the MDM4–p53 interaction was effective only in TP53wt Burkitt lymphoma cell lines. Moreover, primary TP53wt Burkitt lymphoma samples frequently acquired gains of chromosome 1q, which includes the MDM4 locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and MDM4 was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles Project. Our findings highlight the critical role of p53 as a tumor suppressor in Burkitt lymphoma and identify MDM4 as a functional target of 1q gain in a wide range of cancers that is therapeutically targetable. Significance: Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.
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- 2019
41. CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness
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Katja Steiger, Anna Katharina Scherger, Ulrich Keller, Thorsten Zenz, Matthias Wirth, H. Carlo Maurer, Junyan Lu, Richard Lewis, Le Zhang, Stefan Habringer, Nikita Singh, Veronika Schulze, Markus Schick, Marion Espéli, Leticia Quintanilla-Martinez, Karl Balabanian, Irene Gonzalez-Menendez, Konstandina Isaakidis, and Roland Rad
- Subjects
Article ,B-cell lymphoma ,Cancer models ,Oncogenes ,Oncogenesis ,Male ,Cancer Research ,Receptors, CXCR4 ,Chronic lymphocytic leukemia ,Aggressive lymphoma ,Cell Cycle Proteins ,Biology ,Protein Serine-Threonine Kinases ,CXCR4 ,Pathogenesis ,Mice ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,medicine ,Animals ,Mice, Knockout ,Hyperactivation ,Gene Expression Regulation, Leukemic ,Forkhead Box Protein M1 ,Cancer ,Hematology ,medicine.disease ,Phenotype ,Leukemia, Lymphocytic, Chronic, B-Cell ,ddc ,Lymphoma ,Mice, Inbred C57BL ,Oncology ,Mutation ,Cancer research ,Disease Progression ,Female - Abstract
Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression, and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4C1013G) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic pathways. CXCR4 hyperactivation resulted in an expansion of transitional B1 lymphocytes, which represent the precursors of chronic lymphocytic leukemia (CLL). Indeed, CXCR4 hyperactivation led to a significant acceleration of disease onset and a more aggressive phenotype in the murine Eµ-TCL1 CLL model. Hyperactivated CXCR4 signaling cooperated with TCL1 to cause a distinct oncogenic transcriptional program in B cells, characterized by PLK1/FOXM1-associated pathways. In accordance, Eµ-TCL1;CXCR4C1013G B cells enriched a transcriptional signature from patients with Richter’s syndrome, an aggressive transformation of CLL. Notably, MYC activation in aggressive lymphoma was associated with increased CXCR4 expression. In line with this finding, additional hyperactive CXCR4 signaling in the Eµ-Myc mouse, a model of aggressive B-cell cancer, did not impact survival. In summary, we here identify CXCR4 hyperactivation as a co-driver of an aggressive lymphoma phenotype.
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- 2021
42. Subgroup-specific gene expression profiles and mixed epistasis in chronic lymphocytic leukemia
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Tatjana Walther, Junyan Lu, Almut Lütge, Sascha Dietrich, Wolfgang Huber, Thorsten Zenz, Christopher C. Oakes, Jennifer Hüllein, Leopold Sellner, Bin Wu, and Richard Rosenquist
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Genetics ,Mutation ,Chronic lymphocytic leukemia ,DNA methylation ,medicine ,Epistasis ,Gene mutation ,Biology ,medicine.disease ,medicine.disease_cause ,IGHV@ ,Gene ,Phenotype - Abstract
Despite the extensive catalogue of recurrent mutations in chronic lymphocytic leukaemia (CLL), the diverse molecular driving events and the resulting range of disease phenotypes remain incompletely understood. To study the molecular heterogeneity of CLL, we performed RNA-sequencing on 184 CLL patient samples. Unsupervised analysis revealed two major independent axes of gene expression variation: the first one aligned with the mutational status of the immunoglobulin heavy variable (IGHV) genes, and concomitantly, with the three-group stratification of CLL by global DNA methylation pattern, and affected biological functions including B- and T-cell receptor signaling. The second one aligned with trisomy 12 status and affected chemokine signaling. Furthermore, we searched for differentially expressed genes associated with gene mutations and copy-number aberrations and detected strong signatures for TP53, BRAF and SF3B1, as well as for del(11)(q22.3), del(17)(p13) and del(13)(q14) beyond the dosage effect. We discovered strong non-additive effects (i.e., genetic interactions, or epistasis) of IGHV mutation status and trisomy 12 on multiple phenotypes, including the expression of 893 genes. Multiple types of epistasis were observed, including synergy, buffering, suppression and inversion. Our study reveals previously underappreciated gene expression signatures for (epi)genomic variants in CLL and the presence of epistasis between them. The findings will serve as a reference for a functional resolution of CLL molecular heterogeneity.
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- 2021
43. NOTCH1 drives immune-escape mechanisms in B cell malignancies
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I. Moutsoupoulos, Chandra Sekhar Reddy Chilamakuri, Junyan Lu, Irina Mohorianu, S. Deaglio, Thorsten Zenz, José I. Martín-Subero, Anthony T. Moore, V. N. Roamio Franklin, S. Charalampopoulou, Andreas Rosenwald, Maurizio Mangolini, Ingo Ringshausen, A. Maiques-Diaz, S. Stilgenbauer, E. Gerhard-Hartmann, Clive D'Santos, and Johannes Bloehdorn
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Chronic lymphocytic leukemia ,Biology ,medicine.disease ,Lymphoma ,medicine.anatomical_structure ,hemic and lymphatic diseases ,medicine ,Cancer research ,CIITA ,Gene silencing ,Mantle cell lymphoma ,Autocrine signalling ,Gene ,B cell - Abstract
NOTCH1 is a recurrently mutated gene in Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). Functional studies to investigate its role have been hampered by the inability to genetically manipulate primary human lymphoma cells, attributed to low transduction-efficacy and procedure-associated toxicity. To overcome these limitations, we have developed a novel method to retrovirally transfer genes into malignant human B cells. We generated isogenic human tumor cells from patients with CLL and MCL, differing only in their expression of NOTCH1. Our data demonstrate that NOTCH1 facilitates immune-escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-γ signaling. In addition, NOTCH1 causes silencing of the entire HLA-class II locus via suppression of the transcriptional co-activator CIITA. These NOTCH1-mediated immune escape mechanisms are associated with the expansion of CD4+ T cells in vivo, further contributing to the poor clinical outcome of NOTCH1-mutated CLL and MCL.
- Published
- 2021
44. Control of PD-L1 expression in CLL-cells by stromal triggering of the Notch-c-Myc-EZH2 oncogenic signaling axis
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Wolfgang Huber, Andreas Mackensen, Martin Böttcher, Heiko Bruns, Junyan Lu, Dimitrios Mougiakakos, Thorsten Zenz, Elisavet Chartomatsidou, Maike Büttner-Herold, Kostas Stamatopoulos, Marco Herling, Simon Völkl, Kristin Mentz, Nikos Papakonstantinou, Paolo Ghia, Bottcher, M., Bruns, H., Volkl, S., Lu, J., Chartomatsidou, E., Papakonstantinou, N., Mentz, K., Buttner-Herold, M., Zenz, T., Herling, M., Huber, W., Ghia, P., Stamatopoulos, K., Mackensen, A., and Mougiakakos, D.
- Subjects
Cancer Research ,Chronic lymphocytic leukemia ,T-Lymphocytes ,immunomodulation ,Lymphocyte Activation ,B7-H1 Antigen ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Tumor Microenvironment ,Immunology and Allergy ,hematologic neoplasms ,RC254-282 ,Clinical/Translational Cancer Immunotherapy ,Receptors, Notch ,Gene Expression Regulation, Leukemic ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunosurveillance ,Leukemia ,Oncology ,Molecular Medicine ,Signal transduction ,Signal Transduction ,Stromal cell ,Immunology ,Mice, Transgenic ,Biology ,programmed cell death 1 receptor ,Cell Line ,Proto-Oncogene Proteins c-myc ,Downregulation and upregulation ,Paracrine Communication ,medicine ,B-lymphocytes ,tumor microenvironment ,Animals ,Humans ,Enhancer of Zeste Homolog 2 Protein ,Pharmacology ,Tumor microenvironment ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Immune checkpoint ,Coculture Techniques ,Mice, Inbred C57BL ,Case-Control Studies ,Cancer research ,Tumor Escape ,Stromal Cells - Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Emerging data suggest that CLL-cells efficiently evade immunosurveillance. T-cell deficiencies in CLL include immuno(metabolic) exhaustion that is achieved by inhibitory molecules, with programmed cell death 1/programmed cell death ligand 1 (PD-L1) signaling emerging as a major underlying mechanism. Moreover, CLL-cells are characterized by a close and recurrent interaction with their stromal niches in the bone marrow and lymph nodes. Here, they receive nurturing signals within a well-protected environment. We could previously show that the interaction of CLL-cells with stroma leads to c-Myc activation that is followed by metabolic adaptations. Recent data indicate that c-Myc also controls expression of the immune checkpoint molecule PD-L1. Therefore, we sought out to determine the role of stromal contact for the CLL-cells’ PD-L1 expression and thus their immuno-evasive phenotype.To do so, we analyzed PD-L1 expression on CLL cell (subsets) in untreated patients and on healthy donor-derived B-cells. Impact of stromal contact on PD-L1 expression on CLL-cells and the underlying signaling pathways were assessed in well-established in vitro niche models. Ex vivo and in vitro findings were validated in the Eµ-TCL1 transgenic CLL mouse model.We found increased PD-L1 expression on CLL-cells as compared with B-cells that was further enhanced in a cell-to-cell contact-dependent manner by stromal cells. In fact, circulating recent stromal-niche emigrants displayed higher PD-L1 levels than long-time circulating CLL-cells. Using our in vitro niche model, we show that a novel Notch-c-Myc-enhancer of zeste homolog 2 (EZH2) signaling axis controls PD-L1 upregulation. Ultimately, elevated PD-L1 levels conferred increased resistance towards activated autologous T-cells.In summary, our findings support the notion that the CLL microenvironment contributes to immune escape variants. In addition, several targetable molecules (eg, Notch or EZH2) could be exploited in view of improving immune responses in patients with CLL, which warrants further in-depth investigation.
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- 2021
45. The protein landscape of chronic lymphocytic leukemia
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Ruedi Aebersold, Junyan Lu, Sascha Dietrich, Ben C. Collins, Elias Campo, Ferran Nadeu, Jennifer Hüllein, Marcel F. Pohly, Laura Kunz, Sibylle Pfammatter, Wolfgang Huber, Sandra Kummer, Myriam Gwerder, Sebastian Scheinost, Michael Roiss, Ester Cannizzaro, Fabienne Meier-Abt, Thorsten Zenz, Kwang Seok Lee, Peng Xue, and University of Zurich
- Subjects
Proteome ,10039 Institute of Medical Genetics ,Chronic lymphocytic leukemia ,Immunology ,Immunoglobulin Variable Region ,610 Medicine & health ,10071 Functional Genomics Center Zurich ,Trisomy ,Biochemistry ,DEAD-box RNA Helicases ,immune system diseases ,Interferon ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Bruton's tyrosine kinase ,Humans ,STAT2 ,Protein kinase B ,biology ,Gene Expression Regulation, Leukemic ,breakpoint cluster region ,Cell Biology ,Hematology ,medicine.disease ,Phosphoproteins ,Leukemia, Lymphocytic, Chronic, B-Cell ,10032 Clinic for Oncology and Hematology ,Mutation ,biology.protein ,Cancer research ,RNA Splicing Factors ,IGHV@ ,Immunoglobulin Heavy Chains ,Transcriptome ,medicine.drug - Abstract
Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are unknown. This may be in part due to a scarcity of information on the proteome of CLL. We profiled the proteome of 117 CLL patient samples with data-independent acquisition mass spectrometry and integrated the results with genomic, transcriptomic, ex vivo drug response, and clinical outcome data. We found trisomy 12, IGHV mutational status, mutated SF3B1, trisomy 19, del(17)(p13), del(11)(q22.3), mutated DDX3X and MED12 to influence protein expression (false discovery rate [FDR] = 5%). Trisomy 12 and IGHV status were the major determinants of protein expression variation in CLL as shown by principal-component analysis (1055 and 542 differentially expressed proteins, FDR = 5%). Gene set enrichment analyses of CLL with trisomy 12 implicated B-cell receptor (BCR)/phosphatidylinositol 3-kinase (PI3K)/AKT signaling as a tumor driver. These findings were supported by analyses of protein abundance buffering and protein complex formation, which identified limited protein abundance buffering and an upregulated protein complex involved in BCR, AKT, MAPK, and PI3K signaling in trisomy 12 CLL. A survey of proteins associated with trisomy 12/IGHV-independent drug response linked STAT2 protein expression with response to kinase inhibitors, including Bruton tyrosine kinase and mitogen-activated protein kinase kinase (MEK) inhibitors. STAT2 was upregulated in unmutated IGHV CLL and trisomy 12 CLL and required for chemokine/cytokine signaling (interferon response). This study highlights the importance of protein abundance data as a nonredundant layer of information in tumor biology and provides a protein expression reference map for CLL.
- Published
- 2020
46. Full Convolution Neural Network Combined with Contextual Feature Representation for Cropland Extraction from High-Resolution Remote Sensing Images
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Zhuqiang Li, Shengbo Chen, Xiangyu Meng, Ruifei Zhu, Junyan Lu, Lisai Cao, and Peng Lu
- Subjects
ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,General Earth and Planetary Sciences ,high-resolution remote sensing image ,contextual features ,fully convolutional neural network ,cropland extraction ,morphological post-processing - Abstract
The quantity and quality of cropland are the key to ensuring the sustainable development of national agriculture. Remote sensing technology can accurately and timely detect the surface information, and objectively reflect the state and changes of the ground objects. Using high-resolution remote sensing images to accurately extract cropland is the basic task of precision agriculture. The traditional model of cropland semantic segmentation based on the deep learning network is to down-sample high-resolution feature maps to low resolution, and then restore from low-resolution feature maps to high-resolution ideas; that is, obtain low-resolution feature maps through a network, and then recover to high resolution by up-sampling or deconvolution. This will bring about the loss of features, and the segmented image will be more fragmented, without very clear and smooth boundaries. A new methodology for the effective and accurate semantic segmentation cropland of high spatial resolution remote sensing images is presented in this paper. First, a multi-temporal sub-meter cropland sample dataset is automatically constructed based on the prior result data. Then, a fully convolutional neural network combined with contextual feature representation (HRNet-CFR) is improved to complete the extraction of cropland. Finally, the initial semantic segmentation results are optimized by the morphological post-processing approach, and the broken spots are ablated to obtain the internal homogeneous cropland. The proposed method has been validated on the Jilin-1 data and Gaofen Image Dataset (GID) public datasets, and the experimental results demonstrate that it outperforms the state-of-the-art method in cropland extraction accuracy. We selected the comparison of Deeplabv3+ and UPerNet methods in GID. The overall accuracy of our approach is 92.03%, which is 3.4% higher than Deeplabv3+ and 5.12% higher than UperNet.
- Published
- 2022
47. IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms
- Author
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Junyan Lu, Rosó Mares, Thorsten Zenz, Anna Enjuanes, Ryan D. Morin, Alfredo Rivas-Delgado, Julio Delgado, Rut Mas-de-les-Valls, Peter J. Campbell, Neus Villamor, Tycho Baumann, Ferran Nadeu, Helena Suárez-Cisneros, Dolors Colomer, Alba Navarro, Elias Campo, Romina Royo, Marta Aymerich, Francesco Maura, Xose S. Puente, Silvia Martín, Sílvia Beà, Barcelona Supercomputing Center, University of Zurich, and Nadeu, Ferran
- Subjects
0301 basic medicine ,General Physics and Astronomy ,Genome ,Translocation, Genetic ,Cohort Studies ,0302 clinical medicine ,Cancer genomics ,lcsh:Science ,In Situ Hybridization, Fluorescence ,Genòmica -- Informàtica ,Sanger sequencing ,Multidisciplinary ,medicine.diagnostic_test ,Genes, Immunoglobulin ,High-Throughput Nucleotide Sequencing ,Genomics ,Immunoglobulin genes ,3100 General Physics and Astronomy ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,symbols ,Immunoglobulin Gene Rearrangement ,Algorithms ,Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC] ,Lymphoma, B-Cell ,Science ,610 Medicine & health ,1600 General Chemistry ,Computational biology ,Biology ,Immunoglobulin light chain ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,symbols.namesake ,1300 General Biochemistry, Genetics and Molecular Biology ,IgCaller ,Ig gene rearrangements ,medicine ,Immunogenetics ,Humans ,Gene ,Whole genome sequencing ,Haematological cancer ,Whole Genome Sequencing ,Genome, Human ,General Chemistry ,Oncogenes ,Immunoglobulin Class Switching ,Genòmica ,030104 developmental biology ,Cancer--Genetic aspects ,Immunoglobulin class switching ,10032 Clinic for Oncology and Hematology ,lcsh:Q ,Software ,Fluorescence in situ hybridization - Abstract
Immunoglobulin (Ig) gene rearrangements and oncogenic translocations are routinely assessed during the characterization of B cell neoplasms and stratification of patients with distinct clinical and biological features, with the assessment done using Sanger sequencing, targeted next-generation sequencing, or fluorescence in situ hybridization (FISH). Currently, a complete Ig characterization cannot be extracted from whole-genome sequencing (WGS) data due to the inherent complexity of the Ig loci. Here, we introduce IgCaller, an algorithm designed to fully characterize Ig gene rearrangements and oncogenic translocations from short-read WGS data. Using a cohort of 404 patients comprising different subtypes of B cell neoplasms, we demonstrate that IgCaller identifies both heavy and light chain rearrangements to provide additional information on their functionality, somatic mutational status, class switch recombination, and oncogenic Ig translocations. Our data thus support IgCaller to be a reliable alternative to Sanger sequencing and FISH for studying the genetic properties of the Ig loci., Immunoglobulin (Ig) rearrangement and translocation information are usually obtained by targeted sequencing of the respective loci. Here, the authors present the IgCaller algorithm, which extracts Ig heavy and light chain genetic properties from short-read whole-genome sequencing results to provide a feasible alternative to direct sequencing.
- Published
- 2020
48. SAMHD1 mutations in mantle cell lymphoma are recurrent and confer in vitro resistance to nucleoside analogues
- Author
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Wolfgang Huber, Ferran Nadeu, Damien Roos-Weil, Olivier A. Bernard, Sílvia Beà, Ewerton Marques Maggio, Eugenia Haralambieva, Markus G. Manz, Holger Moch, Marco M Bühler, Manfred Hensel, Sebastian Scheinost, Eva Giné, Tharshika Thavayogarajah, Thorsten Zenz, Elias Campo, and Junyan Lu
- Subjects
Cyclin D1 ,medicine ,Cytarabine ,Cancer research ,Mantle cell lymphoma ,Biology ,medicine.disease ,Nucleoside ,Gene ,In vitro ,Fludarabine ,medicine.drug ,SAMHD1 - Abstract
The genomic landscape of mantle cell lymphoma (MCL) includes frequent alterations of TP53, ATM, CCND1 and KMT2D. Thus far, the mutational landscape provides little information for treatment stratification. We characterized a cohort of MCL by targeted next generation sequencing and discovered SAMHD1 as a novel recurrently mutated gene (8.5% of investigated cases, 4/47 samples). Furthermore, we provide evidence of in vitro resistance of SAMHD1 mutated patient-derived MCL cells to cytarabine and fludarabine.
- Published
- 2020
49. Identification of two DNA methylation subtypes of Waldenström's macroglobulinemia with plasma and memory B cell features
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Junyan Lu, Hussein Ghamlouch, Brian Giacopelli, Camille Decaudin, Marine Armand, Thorsten Zenz, Florence Nguyen-Khac, Paresh Vyas, Christopher C. Oakes, Véronique Della-Valle, Marlen Metzner, Olivier Bernard, Magali Le Garff-Tavernier, Damien Roos-Weil, and Veronique Leblond
- Subjects
0301 basic medicine ,Mutation ,biology ,Immunology ,Waldenstrom macroglobulinemia ,Cell Biology ,Hematology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Molecular biology ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Histone ,DNA methylation ,biology.protein ,medicine ,Epigenetics ,Gene ,Reprogramming ,030215 immunology - Abstract
Epigenetic changes during B cell differentiation generates distinct DNA methylation signatures specific for B cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström's macroglobulinemia (WM) is a complex B cell malignancy uniquely comprised of a mixture of lymphocytic and plasmacytic phenotypes. Here we integrated genome-wide DNA methylation, transcriptome, mutation and other phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B cell subsets. We discovered that WM patients naturally segregate into two groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and plasma cell-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development were used to capture tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3 and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P=0.015), deletion 13q (P=0.006), splenomegaly (P=0.02) and thrombocytopenia (P=0.004), while PC-like WM harbored more deletion 6q (P=0.012), gain 6p (P=0.033), had increased frequencies of IGHV3 genes (P=0.002), CD38 surface expression (P=4.1e-5), and plasmacytic differentiation features (P=0.008). Together our findings illustrate a novel approach to subclassify WM patients using patterns of DNA methylation and reveal divergent molecular signatures among WM patients.
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- 2020
50. Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features
- Author
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Damien, Roos-Weil, Brian, Giacopelli, Marine, Armand, Véronique, Della-Valle, Hussein, Ghamlouch, Camille, Decaudin, Marlen, Metzner, Junyan, Lu, Magali, Le Garff-Tavernier, Véronique, Leblond, Paresh, Vyas, Thorsten, Zenz, Florence, Nguyen-Khac, Olivier A, Bernard, and Christopher C, Oakes
- Subjects
Plasma Cells ,B-Lymphocyte Subsets ,Humans ,DNA Methylation ,Waldenstrom Macroglobulinemia - Abstract
Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. Here, we integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development captured tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3, and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic, and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P = .015), deletion 13q (P = .006), splenomegaly (P = .02), and thrombocytopenia (P = .004), whereas PC-like WM harbored more deletion 6q (P = .012), gain 6p (P = .033), had increased frequencies of IGHV3 genes (P = .002), CD38 expression (P = 4.1e-5), and plasmacytic differentiation features (P = .008). Together, our findings illustrate a novel approach to subclassify WM patients using DNA methylation and reveal divergent molecular signatures among WM patients.
- Published
- 2020
Catalog
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