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Sun, Jing

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Jing

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Sun, Jing
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    FluKB: A Knowledge-Based System for Influenza Vaccine Target Discovery and Analysis of the Immunological Properties of Influenza Viruses
    (Hindawi Publishing Corporation, 2015) Simon, Christian; Kudahl, Ulrich J.; Sun, Jing; Olsen, Lars Rønn; Zhang, Guang Lan; Reinherz, Ellis; Brusic, Vladimir
    FluKB is a knowledge-based system focusing on data and analytical tools for influenza vaccine discovery. The main goal of FluKB is to provide access to curated influenza sequence and epitope data and enhance the analysis of influenza sequence diversity and the analysis of targets of immune responses. FluKB consists of more than 400,000 influenza protein sequences, known epitope data (357 verified T-cell epitopes, 685 HLA binders, and 16 naturally processed MHC ligands), and a collection of 28 influenza antibodies and their structurally defined B-cell epitopes. FluKB was built using a modular framework allowing the implementation of analytical workflows and includes standard search tools, such as keyword search and sequence similarity queries, as well as advanced tools for the analysis of sequence variability. The advanced analytical tools for vaccine discovery include visual mapping of T- and B-cell vaccine targets and assessment of neutralizing antibody coverage. FluKB supports the discovery of vaccine targets and the analysis of viral diversity and its implications for vaccine discovery as well as potential T-cell breadth and antibody cross neutralization involving multiple strains. FluKB is representation of a new generation of databases that integrates data, analytical tools, and analytical workflows that enable comprehensive analysis and automatic generation of analysis reports.
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    Phosphatidylinositol 3-Kinase (PI3K) δ blockade increases genomic instability in B cells
    (2017) Compagno, Mara; Wang, Qi; Pighi, Chiara; Cheong, Taek-Chin; Meng, Fei-Long; Poggio, Teresa; Yeap, Leng-Siew; Karaca, Elif; Blasco, Rafael B.; Langellotto, Fernanda; Ambrogio, Chiara; Voena, Claudia; Wiestner, Adrian; Kasar, Siddha N.; Brown, Jennifer; Sun, Jing; Wu, Catherine; Gostissa, Monica; Alt, Frederick; Chiarle, Roberto
    Activation-induced cytidine deaminase (AID) is a B-cell specific enzyme that targets immunoglobulin (Ig) genes to initiate class switch recombination (CSR) and somatic hypermutation (SHM)1. Through off-target activity, however, AID has a much broader impact on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in lymphoma development and progression2. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation3. The phosphatidylinositol 3-kinase (PI3K) δ pathway plays a key role in AID regulation by suppressing its expression in B cells4. Novel drugs for leukemia or lymphoma therapy such as idelalisib, duvelisib or ibrutinib block PI3Kδ activity directly or indirectly5–8, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation (SHM) and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both these effects were completely abrogated in AID deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumors in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IgH and AID off-target sites in human chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased SHM in AID off-targets. In summary, we show that PI3Kδ or BTK inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism, an effect that should be carefully considered as such inhibitors are administered for years to patients.
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    Large-Scale Analysis of B-Cell Epitopes on Influenza Virus Hemagglutinin – Implications for Cross-Reactivity of Neutralizing Antibodies
    (Frontiers Media S.A., 2014) Sun, Jing; Kudahl, Ulrich J.; Simon, Christian; Cao, Zhiwei; Reinherz, Ellis; Brusic, Vladimir
    Influenza viruses continue to cause substantial morbidity and mortality worldwide. Fast gene mutation on surface proteins of influenza virus result in increasing resistance to current vaccines and available antiviral drugs. Broadly neutralizing antibodies (bnAbs) represent targets for prophylactic and therapeutic treatments of influenza. We performed a systematic bioinformatics study of cross-reactivity of neutralizing antibodies (nAbs) against influenza virus surface glycoprotein hemagglutinin (HA). This study utilized the available crystal structures of HA complexed with the antibodies for the analysis of tens of thousands of HA sequences. The detailed description of B-cell epitopes, measurement of epitope area similarity among different strains, and estimation of antibody neutralizing coverage provide insights into cross-reactivity status of existing nAbs against influenza virus. We have developed a method to assess the likely cross-reactivity potential of bnAbs for influenza strains, either newly emerged or existing. Our method catalogs influenza strains by a new concept named discontinuous peptide, and then provide assessment of cross-reactivity. Potentially cross-reactive strains are those that share 100% identity with experimentally verified neutralized strains. By cataloging influenza strains and their B-cell epitopes for known bnAbs, our method provides guidance for selection of representative strains for further experimental design. The knowledge of sequences, their B-cell epitopes, and differences between historical influenza strains, we enhance our preparedness and the ability to respond to the emerging pandemic threats.
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    Big Data Analytics in Immunology: A Knowledge-Based Approach
    (Hindawi Publishing Corporation, 2014) Zhang, Guang Lan; Sun, Jing; Chitkushev, Lou; Brusic, Vladimir
    With the vast amount of immunological data available, immunology research is entering the big data era. These data vary in granularity, quality, and complexity and are stored in various formats, including publications, technical reports, and databases. The challenge is to make the transition from data to actionable knowledge and wisdom and bridge the knowledge gap and application gap. We report a knowledge-based approach based on a framework called KB-builder that facilitates data mining by enabling fast development and deployment of web-accessible immunological data knowledge warehouses. Immunological knowledge discovery relies heavily on both the availability of accurate, up-to-date, and well-organized data and the proper analytics tools. We propose the use of knowledge-based approaches by developing knowledgebases combining well-annotated data with specialized analytical tools and integrating them into analytical workflow. A set of well-defined workflow types with rich summarization and visualization capacity facilitates the transformation from data to critical information and knowledge. By using KB-builder, we enabled streamlining of normally time-consuming processes of database development. The knowledgebases built using KB-builder will speed up rational vaccine design by providing accurate and well-annotated data coupled with tailored computational analysis tools and workflow.
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    A systematic analysis of a broadly neutralizing antibody AR3C epitopes on Hepatitis C virus E2 envelope glycoprotein and their cross-reactivity
    (BioMed Central, 2015) Sun, Jing; Brusic, Vladimir
    Background: Hepatitis C virus (HCV) belongs to Flaviviridae family of viruses. HCV represents a major challenge to public health since its estimated global prevalence is 2.8% of the world's human population. The design and development of HCV vaccine has been hampered by rapid evolution of viral quasispecies resulting in antibody escape variants. HCV envelope glycoprotein E1 and E2 that mediate fusion and entry of the virus into host cells are primary targets of the host immune responses. Results: Structural characterization of E2 core protein and a broadly neutralizing antibody AR3C together with E1E2 sequence information enabled the analysis of B-cell epitope variability. The E2 binding site by AR3C and its surrounding area were identified from the crystal structure of E2c-AR3C complex. We clustered HCV strains using the concept of "discontinuous motif/peptide" and classified B-cell epitopes based on their similarity. Conclusions: The assessment of antibody neutralizing coverage provides insights into potential cross-reactivity of the AR3C neutralizing antibody across a large number of HCV variants.
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    Intratumoral T cell response detected after personal neoantigen vaccine in a phase Ib glioblastoma trial
    (Springer Nature) Keskin, Derin B.; Anandappa, Annabelle J.; Sun, Jing; Tirosh, Itay; Mathewson, Nathan; Li, Shuqiang; Oliveira, Giacomo; Giobbie-Hurder, Anita; Felt, Kristen; Gjini, Evisa; Shukla, Sachet A.; Hu, Zhuting; Li, Letitia; Le, Phuong M.; Allesøe, Rosa L.; Richman, Alyssa R.; Kowalczyk, Monika S.; Abdelrahman, Sara; Geduldig, Jack E.; Charbonneau, Sarah; Pelton, Kristine; Iorgulescu, Julian; Elagina, Liudmila; Zhang, Wandi; Olive, Oriol; McCluskey, Christine; Olsen, Lars R.; Stevens, Jonathan; Lane, William; Salazar, Andres M.; Daley, Heather; Wen, Patrick Y.; Chiocca, E. Antonio; Harden, Maegan; Lennon, Niall J.; Gabriel, Stacey; Getz, Gad; Lander, Eric S.; Regev, Aviv; Ritz, Jerome; Neuberg, Donna; Rodig, Scott J.; Ligon, Keith L.; Suvà, Mario L.; Wucherpfennig, Kai; Hacohen, Nir; Fritsch, Edward F.; Livak, Kenneth J.; Ott, Patrick A.; Wu, Catherine; Reardon, David A.; Keskin, Derin; Sulva, Mario
    Neoantigens, derived from tumor-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses, and can function as bona fide tumor rejection antigens. Here, we demonstrate that a strategy of multi-epitope, personalized neoantigen vaccination, previously tested only in patients with high-risk melanoma, is feasible for tumors such as glioblastoma, which typically have a relatively low mutation load and an immunologically “cold” tumor microenvironment. We immunized patients with newly diagnosed GBM using personalized neoantigen-targeting vaccines following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone, a highly potent corticosteroid frequently prescribed to glioblastoma patients for cerebral edema, generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T-cell responses that were enriched for a memory phenotype, and increased tumor-infiltrating T-cells. Utilizing single-cell T-cell receptor analysis, we provide evidence that neoantigen-specific T-cells from the peripheral blood can migrate into an intracranial glioblastoma tumor. Neoantigen-targeting vaccines thus have the potential to favorably alter the immune milieu of glioblastoma.