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  • Springer Science and Business Media LLC  (43)
  • 1
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    Online Resource
    Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors
    Springer Science and Business Media LLC ; 2020
    In:  Nature Communications Vol. 11, No. 1 ( 2020-05-05)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-05-05)
    Abstract: Compared to adult carcinomas, there is a paucity of targeted treatments for solid tumors in children, adolescents, and young adults (C-AYA). The impact of germline genomic signatures has implications for heritability, but its impact on targeted therapies has not been fully appreciated. Performing variant-prioritization analysis on germline DNA of 1,507 C-AYA patients with solid tumors, we show 12% of these patients carrying germline pathogenic and/or likely pathogenic variants (P/LP) in known cancer-predisposing genes (KCPG). An additional 61% have germline pathogenic variants in non-KCPG genes, including PRKN , SMARCAL1 , SMAD7 , which we refer to as candidate genes. Despite germline variants in a broad gene spectrum, pathway analysis leads to top networks centering around p53. Our drug-target analysis shows 1/3 of patients with germline P/LP variants have at least one druggable alteration, while more than half of them are from our candidate gene group, which would otherwise go unidentified in routine clinical care.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-020-16067-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2553671-0
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  • 2
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    Artificial intelligence framework identifies candidate targets for drug repurposing in Alzheimer’s disease
    Springer Science and Business Media LLC ; 2022
    In:  Alzheimer's Research & Therapy Vol. 14, No. 1 ( 2022-12)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2022-12)
    Abstract: Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer’s disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. Methods To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein–protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human protein–protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Results Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861–0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862–0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. Conclusions In summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.
    Type of Medium: Online Resource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-021-00951-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2506521-X
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  • 3
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    AlzGPS: a genome-wide positioning systems platform to catalyze multi-omics for Alzheimer’s drug discovery
    Springer Science and Business Media LLC ; 2021
    In:  Alzheimer's Research & Therapy Vol. 13, No. 1 ( 2021-12)
    Details
    In: Alzheimer's Research & Therapy, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2021-12)
    Abstract: Recent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, yet there is still a lack of disease-modifying treatments for AD. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor. Methods In this study, we developed AlzGPS ( G enome-wide P ositioning S ystems platform for Alz heimer’s Drug Discovery, https://alzgps.lerner.ccf.org ), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and development of effective prevention and treatment for AD. Results Via AlzGPS: (1) we curated more than 100 AD multi-omics data sets capturing DNA, RNA, protein, and small molecule profiles underlying AD pathogenesis (e.g., early vs. late stage and tau or amyloid endophenotype); (2) we constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks; (3) we provided possible treatment information from ~ 3000 FDA approved/investigational drugs for AD using state-of-the-art network proximity analyses; (4) we curated nearly 300 literature references for high-confidence drug candidates; (5) we included information from over 1000 AD clinical trials noting drug’s mechanisms-of-action and primary drug targets, and linking them to our integrated multi-omics view for targets and network analysis results for the drugs; (6) we implemented a highly interactive web interface for database browsing and network visualization. Conclusions Network visualization enabled by AlzGPS includes brain-specific neighborhood networks for genes-of-interest, endophenotype disease module networks for omics-of-interest, and mechanism-of-action networks for drugs targeting disease modules. By virtue of combining systems pharmacology and network-based integrative analysis of multi-omics data, AlzGPS offers actionable systems biology tools for accelerating therapeutic development in AD.
    Type of Medium: Online Resource
    ISSN: 1758-9193
    URL: Article
    DOI: 10.1186/s13195-020-00760-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2506521-X
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  • 4
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    Accurate prediction of molecular properties and drug targets using a self-supervised image representation learning framework
    Springer Science and Business Media LLC ; 2022
    In:  Nature Machine Intelligence Vol. 4, No. 11 ( 2022-11-17), p. 1004-1016
    Details
    In: Nature Machine Intelligence, Springer Science and Business Media LLC, Vol. 4, No. 11 ( 2022-11-17), p. 1004-1016
    Type of Medium: Online Resource
    ISSN: 2522-5839
    URL: Article
    DOI: 10.1038/s42256-022-00557-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2933875-X
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  • 5
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    A Bayesian framework that integrates multi-omics data and gene networks predicts risk genes from schizophrenia GWAS data
    Springer Science and Business Media LLC ; 2019
    In:  Nature Neuroscience Vol. 22, No. 5 ( 2019-5), p. 691-699
    Details
    In: Nature Neuroscience, Springer Science and Business Media LLC, Vol. 22, No. 5 ( 2019-5), p. 691-699
    Type of Medium: Online Resource
    ISSN: 1097-6256 , 1546-1726
    URL: Article
    DOI: 10.1038/s41593-019-0382-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 1494955-6
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  • 6
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    A network-based approach to uncover microRNA-mediated disease comorbidities and potential pathobiological implications
    Springer Science and Business Media LLC ; 2019
    In:  npj Systems Biology and Applications Vol. 5, No. 1 ( 2019-11-13)
    Details
    In: npj Systems Biology and Applications, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2019-11-13)
    Abstract: Disease–disease relationships (e.g., disease comorbidities) play crucial roles in pathobiological manifestations of diseases and personalized approaches to managing those conditions. In this study, we develop a network-based methodology, termed meta-path-based Disease Network (mpDisNet) capturing algorithm, to infer disease–disease relationships by assembling four biological networks: disease–miRNA, miRNA–gene, disease–gene, and the human protein–protein interactome. mpDisNet is a meta-path-based random walk to reconstruct the heterogeneous neighbors of a given node. mpDisNet uses a heterogeneous skip-gram model to solve the network representation of the nodes. We find that mpDisNet reveals high performance in inferring clinically reported disease–disease relationships, outperforming that of traditional gene/miRNA-overlap approaches. In addition, mpDisNet identifies network-based comorbidities for pulmonary diseases driven by underlying miRNA-mediated pathobiological pathways (i.e., hsa-let-7a- or hsa-let-7b-mediated airway epithelial apoptosis and pro-inflammatory cytokine pathways) as derived from the human interactome network analysis. The mpDisNet offers a powerful tool for network-based identification of disease–disease relationships with miRNA-mediated pathobiological pathways.
    Type of Medium: Online Resource
    ISSN: 2056-7189
    URL: Article
    DOI: 10.1038/s41540-019-0115-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2841868-2
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  • 7
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    Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2
    Springer Science and Business Media LLC ; 2020
    In:  Cell Discovery Vol. 6, No. 1 ( 2020-03-16)
    Details
    In: Cell Discovery, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2020-03-16)
    Abstract: Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV–host interactome and drug targets in the human protein–protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV–host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the “ Complementary Exposure ” pattern: the targets of the drugs both hit the HCoV–host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.
    Type of Medium: Online Resource
    ISSN: 2056-5968
    URL: Article
    DOI: 10.1038/s41421-020-0153-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2842548-0
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  • 8
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    Multimodal single-cell omics analysis identifies epithelium–immune cell interactions and immune vulnerability associated with sex differences in COVID-19
    Springer Science and Business Media LLC ; 2021
    In:  Signal Transduction and Targeted Therapy Vol. 6, No. 1 ( 2021-07-30)
    Details
    In: Signal Transduction and Targeted Therapy, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2021-07-30)
    Abstract: Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial, and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied. Here we inspected sex differences in SARS-CoV-2 infection, hospitalization, admission to the intensive care unit (ICU), sera inflammatory biomarker profiling, and single-cell RNA-sequencing (scRNA-seq) profiles across nasal, bronchoalveolar lavage fluid (BALF), and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with varying degrees of disease severities. Our propensity score-matching observations revealed that male individuals have a 29% elevated likelihood of SARS-CoV-2 positivity, with a hazard ratio (HR) 1.32 (95% confidence interval [CI] 1.18–1.48) for hospitalization and HR 1.51 (95% CI 1.24–1.84) for admission to ICU. Sera from male patients at hospital admission had elevated neutrophil–lymphocy te ratio and elevated expression of inflammatory markers (C-reactive protein and procalcitonin). We found that SARS-CoV-2 entry factors, including ACE2 , TMPRSS2 , FURIN , and NRP1 , have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19. We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples, which offers potential molecular mechanism for sex-biased susceptibility to viral infection. Cell–cell interaction network analysis reveals potential epithelium–immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19. Mechanistically, monocyte-elevated expression of Toll-like receptor 7 ( TLR7 ) and Bruton tyrosine kinase ( BTK ) is associated with severe outcomes in males with COVID-19. In summary, these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.
    Type of Medium: Online Resource
    ISSN: 2059-3635
    URL: Article
    DOI: 10.1038/s41392-021-00709-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2886872-9
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  • 9
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    GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity
    Springer Science and Business Media LLC ; 2023
    In:  Nature Cancer Vol. 4, No. 5 ( 2023-05-11), p. 648-664
    Details
    In: Nature Cancer, Springer Science and Business Media LLC, Vol. 4, No. 5 ( 2023-05-11), p. 648-664
    Abstract: The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host–tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development.
    Type of Medium: Online Resource
    ISSN: 2662-1347
    URL: Article
    DOI: 10.1038/s43018-023-00556-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 3005299-3
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  • 10
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    Pharmacophore modeling of human adenosine receptor A2A antagonists
    Springer Science and Business Media LLC ; 2010
    In:  Journal of Molecular Modeling Vol. 16, No. 12 ( 2010-12), p. 1867-1876
    Details
    In: Journal of Molecular Modeling, Springer Science and Business Media LLC, Vol. 16, No. 12 ( 2010-12), p. 1867-1876
    Type of Medium: Online Resource
    ISSN: 1610-2940 , 0948-5023
    URL: Article
    DOI: 10.1007/s00894-010-0690-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 1284729-X
    SSG: 12
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