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5. Soluble Immune Checkpoints Are Dysregulated in COVID-19 and Heavy Alcohol Users With HIV Infection

Author

Li, Wei, Syed, Fahim, Yu, Richard, Yang, Jing, Xia, Ying, Relich, Ryan F, Russell, Patrick M, Zhang, Shanxiang, Khalili, Mandana, Huang, Laurence, Kacena, Melissa A, Zheng, Xiaoqun, and Yu, Qigui

Subjects
Biomedical and Clinical Sciences, Immunology, Clinical Research, Infectious Diseases, Emerging Infectious Diseases, Alcoholism, Alcohol Use and Health, Substance Misuse, Prevention, HIV/AIDS, Aetiology, 2.1 Biological and endogenous factors, Infection, Inflammatory and immune system, Cancer, Good Health and Well Being, Alcoholism, Biomarkers, COVID-19, HIV Infections, HIV-1, Humans, Immune Checkpoint Proteins, Neoplasms, SARS-CoV-2, Severity of Illness Index, immune checkpoint, soluble immune checkpoint, HIV, heavy alcohol user, alcohol-associated liver disease, inflammation, Medical Microbiology, Biochemistry and cell biology, Genetics
Abstract

Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the world's most serious public health challenges. A "storm" of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol misuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol misuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease.

Published
2022

12. The genetic evolution of metastatic uveal melanoma

Author

Shain, A Hunter, Bagger, Mette M, Yu, Richard, Chang, Darwin, Liu, Shanshan, Vemula, Swapna, Weier, Jingly F, Wadt, Karin, Heegaard, Steffen, Bastian, Boris C, and Kiilgaard, Jens F

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Eye Disease and Disorders of Vision, Cancer, Genetic Testing, Human Genome, Biotechnology, Rare Diseases, Biomarkers, Tumor, Case-Control Studies, DNA Copy Number Variations, Evolution, Molecular, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Humans, Liver Neoplasms, Melanoma, Mutation, Phylogeny, Retrospective Studies, Uveal Neoplasms, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Uveal melanoma is a clinically distinct and particularly lethal subtype of melanoma originating from melanocytes in the eye. Here, we performed multi-region DNA sequencing of primary uveal melanomas and their matched metastases from 35 patients. We observed previously unknown driver mutations and established the order in which these and known driver mutations undergo selection. Metastases had genomic alterations distinct from their primary tumors; metastatic dissemination sometimes occurred early during the development of the primary tumor. Our study offers new insights into the genetics and evolution of this melanoma subtype, providing potential biomarkers for progression and therapy.

Published
2019

19. Computing Resource Allocation in Three-Tier IoT Fog Networks: a Joint Optimization Approach Combining Stackelberg Game and Matching

Author

Zhang, Huaqing, Xiao, Yong, Bu, Shengrong, Niyato, Dusit, Yu, Richard, and Han, Zhu

Subjects
Computer Science - Computer Science and Game Theory, Computer Science - Distributed, Parallel, and Cluster Computing
Abstract

Fog computing is a promising architecture to provide economic and low latency data services for future Internet of things (IoT)-based network systems. It relies on a set of low-power fog nodes that are close to the end users to offload the services originally targeting at cloud data centers. In this paper, we consider a specific fog computing network consisting of a set of data service operators (DSOs) each of which controls a set of fog nodes to provide the required data service to a set of data service subscribers (DSSs). How to allocate the limited computing resources of fog nodes (FNs) to all the DSSs to achieve an optimal and stable performance is an important problem. In this paper, we propose a joint optimization framework for all FNs, DSOs and DSSs to achieve the optimal resource allocation schemes in a distributed fashion. In the framework, we first formulate a Stackelberg game to analyze the pricing problem for the DSOs as well as the resource allocation problem for the DSSs. Under the scenarios that the DSOs can know the expected amount of resource purchased by the DSSs, a many-to-many matching game is applied to investigate the pairing problem between DSOs and FNs. Finally, within the same DSO, we apply another layer of many-to-many matching between each of the paired FNs and serving DSSs to solve the FN-DSS pairing problem. Simulation results show that our proposed framework can significantly improve the performance of the IoT-based network systems.

Published
2017

20. Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation

Author

Zeng, Hanlin, Jorapur, Aparna, Shain, A Hunter, Lang, Ursula E, Torres, Rodrigo, Zhang, Yuntian, McNeal, Andrew S, Botton, Thomas, Lin, Jue, Donne, Matthew, Bastian, Ingmar N, Yu, Richard, North, Jeffrey P, Pincus, Laura, Ruben, Beth S, Joseph, Nancy M, Yeh, Iwei, Bastian, Boris C, and Judson, Robert L

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Cell Line, Tumor, Cell Movement, Cyclin-Dependent Kinase Inhibitor p16, E2F1 Transcription Factor, Female, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Loss of Heterozygosity, Lung Neoplasms, Male, Melanocytes, Melanoma, Mice, Inbred NOD, Neoplasm Invasiveness, POU Domain Factors, Point Mutation, Proto-Oncogene Proteins B-raf, Signal Transduction, Skin Neoplasms, Transcriptional Activation, BRN2, CDKN2A, CRISPR engineering, E2F1, invasion, melanocytes, melanoma, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16INK4A permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2.

Published
2018

21. Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution

Author

Shain, A Hunter, Joseph, Nancy M, Yu, Richard, Benhamida, Jamal, Liu, Shanshan, Prow, Tarl, Ruben, Beth, North, Jeffrey, Pincus, Laura, Yeh, Iwei, Judson, Robert, and Bastian, Boris C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Human Genome, Genetics, Climate-Related Exposures and Conditions, Biomarkers, Tumor, Cell Movement, Cell Transformation, Neoplastic, Chromatin Assembly and Disassembly, Computational Biology, DNA Copy Number Variations, Databases, Genetic, Disease Progression, G1 Phase Cell Cycle Checkpoints, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, MAP Kinase Signaling System, Melanoma, Mutation, Neoplasm Invasiveness, Signal Transduction, Skin Neoplasms, Transcriptome, Ultraviolet Rays, DNA-seq, RNA-seq, dysplastic nevus, genomic, melanoma, metastasis, nevus, transcriptomic, tumor evolution, tumor progression, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.

Published
2018

33. Communication and ethical considerations for fertility preservation for patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group

Author

Anderson, Richard A, Barnbrock, Anke, Beck, Joern D, Bos, Annelies M E, Calaminus, Gabriele, Constine, Louis S, Demeestere, Isabelle, Denzer, Christian, Grabow, Desiree, di Iorgi, Natascia, Hoefgen, Holly R, Jahnukainen, Kirsi, Kaatsch, Peter, Kebudi, Rejin, Lambalk, Cornelis, Langer, Thorsten, Loonen, Jacqueline, Lorenzo, Armando, Meacham, Lillian R, Meissner, Andreas, Mitchell, Rod T, Nahata, Leena, Ranft, Andreas, Dinkelman-Smit, Marij, Stern, Catharyn, Stutz-Grunder, Eveline, Tournaye, Herman, van Dorp, Wendy, van Pelt, Ans M M, de Vries, Andrica, Yu, Richard, Mulder, Renée L, Font-Gonzalez, Anna, van Dulmen-den Broeder, Eline, Quinn, Gwendolyn P, Ginsberg, Jill P, Loeffen, Erik A H, Hudson, Melissa M, Burns, Karen C, van Santen, Hanneke M, Berger, Claire, Diesch, Tamara, Dirksen, Uta, Giwercman, Aleksander, Gracia, Clarisa, Hunter, Sarah E, Kelvin, Joanne F, Klosky, James L, Laven, Joop S E, Lockart, Barbara A, Neggers, Sebastian J C M M, Peate, Michelle, Phillips, Bob, Reed, Damon R, Tinner, Eva Maria E, Byrne, Julianne, Veening, Margreet, van de Berg, Marleen, Verhaak, Chris M, Anazodo, Antoinette, Rodriguez-Wallberg, Kenny, van den Heuvel-Eibrink, Marry M, Asogwa, Ogechukwu A, Brownsdon, Alexandra, Wallace, W Hamish, Green, Daniel M, Skinner, Roderick, Haupt, Riccardo, Kenney, Lisa B, Levine, Jennifer, van de Wetering, Marianne D, Tissing, Wim J E, Paul, Norbert W, Kremer, Leontien C M, and Inthorn, Julia

Published
2021
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34. Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group

Author

Berger, Claire, Diesch, Tamara, Giwercman, Aleksander, Grabow, Desiree, Gracia, Clarisa, Hunter, Sarah E, Inthorn, Julia, Kaatsch, Peter, Kelvin, Joanne F, Klosky, James L, Laven, Joop S E, Lockart, Barbara A, Neggers, Sebastian JCMM, Paul, Norbert W, Peate, Michelle, Phillips, Bob, Quinn, Gwendolyn P, Reed, Damon R, Tinner, Eva Maria E, van den Berg, Marleen, Verhaak, Chris, Mulder, Renée L, Font-Gonzalez, Anna, Green, Daniel M, Loeffen, Erik A H, Hudson, Melissa M, Loonen, Jacqueline, Yu, Richard, Ginsberg, Jill P, Mitchell, Rod T, Byrne, Julianne, Skinner, Roderick, Anazodo, Antoinette, Constine, Louis S, de Vries, Andrica, Jahnukainen, Kirsi, Lorenzo, Armando, Meissner, Andreas, Nahata, Leena, Dinkelman-Smit, Marij, Tournaye, Herman, Haupt, Riccardo, van den Heuvel-Eibrink, Marry M, van Santen, Hanneke M, van Pelt, Ans M M, Dirksen, Uta, den Hartogh, Jaap, van Dulmen-den Broeder, Eline, Wallace, W Hamish, Levine, Jennifer, Tissing, Wim J E, Kremer, Leontien C M, Kenney, Lisa B, and van de Wetering, Marianne D

Published
2021
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38. BigFoot: Analysis, monitoring, tracking and sharing of bio-medical features of human appendages using consumer-grade home and office based imaging devices

Author

Mavandadi, Sam, Feng, Steve, Yu, Frank, Yu, Richard, and Ozcan, Aydogan

Subjects
Computer Science - Other Computer Science
Abstract

Here we describe a system for personal and professional management and analysis of bio-medical images captured using off-the-shelf, consumer-grade imaging devices such as scanners, digital cameras, cellphones, webcams and tablet PCs. Specifically, we describe an implementation of this system for the analysis, monitoring and tracking of conditions and features of human feet using a flatbed scanner as the image capture device and a custom-designed set of algorithms and software to manage and analyze the acquired data.

Published
2012

40. 130 Low Gene Copy Numbers (GCN) of complement C4 and C4A deficiency are highly significant genetic risk factors for idiopathic inflammatory myopathies and its major subgroups

Author

Zhou, Danlei, primary, King, Emily, additional, Rothwell, Simon, additional, Kryštůfková, Olga, additional, Notarnicola, Antonella, additional, Coss, Samantha, additional, Aziz, Rabheh, additional, Miller, Katherine, additional, Dang, Amanda, additional, Yu, Richard, additional, Drew, Joanne, additional, Lundstrom, Emeli, additional, Pachman, Lauren, additional, Mamyrova, Gulnara, additional, Curiel, Rodolfo, additional, De Paepe, Boel, additional, De Bleecker, Jan, additional, Payton, Antony, additional, Ollier, William, additional, O'Hanlon, Terrance, additional, Targoff, Ira, additional, Flegel, Willy, additional, Sivaraman, Vidya, additional, Obele, Edward, additional, Akoghlanian, Shoghik, additional, Driest, Kyla, additional, Spencer, Charles, additional, Ling Wu, Yee, additional, Nagaraja, Haikady, additional, Ardoin, Stacy, additional, Chinoy, Hector, additional, Rider, Lisa, additional, Miller, Frederick, additional, Lundberg, Ingrid, additional, Padyukov, Leonid, additional, Vencovský, Jiří, additional, Lamb, Janine, additional, and Yu, Chack-Yung, additional

Published
2023
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44. MP60-02 ATP2C1 IS A CANDIDATE FOR INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME

Author

Brownstein, Catherine, primary, Estrella, Elicia, additional, Rockowitz, Shira, additional, Thorne, Marielle, additional, Smith, Pressley, additional, Petit, Jeanette, additional, Zehnder, Veronica, additional, Yu, Richard, additional, Bauer, Stuart, additional, Berde, Charles, additional, Agrawal, Pankaj, additional, Beggs, Alan, additional, Kunkel, Louis, additional, and Gharavi, Ali, additional

Published
2023
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45. ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non–Small Cell Lung Cancer (NSCLC)

Author

Cho, Byoung Chul, Kim, Dong-Wan, Bearz, Alessandra, Laurie, Scott A., McKeage, Mark, Borra, Gloria, Park, Keunchil, Kim, Sang-We, Ghosn, Marwan, Ardizzoni, Andrea, Maiello, Evaristo, Greystoke, Alastair, Yu, Richard, Osborne, Karen, Gu, Wen, Scott, Jeffrey W., Passos, Vanessa Q., Lau, Yvonne Y., and Wrona, Anna

Published
2017
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