25 results on '"Ann T. Chen"'
Search Results
2. Betulinic acid self-assembled nanoparticles for effective treatment of glioblastoma
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Yong Li, Yixuan Wang, Lun Gao, Yinqiu Tan, Jiayang Cai, Zhang Ye, Ann T. Chen, Yang Xu, Linyao Zhao, Shiao Tong, Qian Sun, Baohui Liu, Shenqi Zhang, Daofeng Tian, Gang Deng, Jiangbing Zhou, and Qianxue Chen
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Betulinic acid ,Nanoparticles ,Proliferation ,Apoptosis ,CB1/CB2 ,Biotechnology ,TP248.13-248.65 ,Medical technology ,R855-855.5 - Abstract
Abstract Background Glioblastoma (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). Due to the existence of blood–brain barrier (BBB), most therapeutics cannot efficiently reach tumors in the brain, and as a result, they are unable to be used for effective GBM treatment. Accumulating evidence shows that delivery of therapeutics in form of nanoparticles (NPs) may allow crossing the BBB for effective GBM treatment. Methods Betulinic acid NPs (BA NPs) were synthesized by the standard emulsion approach and characterized by electron microscopy and dynamic light scattering analysis. The resulting NPs were characterized for their anti-tumor effects by cell viability assay, EdU-DNA synthesis assay, cell cycle assay, mitochondrial membrane potential, and PI-FITC apoptosis assay. Further mechanistic studies were carried out through Western Blot and immunostaining analyses. Finally, we evaluated BA NPs in vivo for their pharmacokinetics and antitumor effects in intracranial xenograft GBM mouse models. Results BA NPs were successfully prepared and formed into rod shape. BA NPs could significantly suppress glioma cell proliferation, induce apoptosis, and arrest the cell cycle in the G0/G1 phase in vitro. Furthermore, BA NPs downregulated the Akt/NFκB-p65 signaling pathway in a concentration dependent manner. We found that the observed anti-tumor effect of BA NPs was dependent on the function of CB1/CB2 receptors. Moreover, in the intracranial GBM xenograft mouse models, BA NPs could effectively cross the BBB and greatly prolong the survival time of the mice. Conclusions We successfully synthesized BA NPs, which could cross the BBB and demonstrated a strong anti-tumor effect. Therefore, BA NPs may potentially be used for effective treatment of GBM. Graphical Abstract
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- 2022
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3. Mutation-Directed Therapeutics for Neurofibromatosis Type I
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Andre Leier, David M. Bedwell, Ann T. Chen, George Dickson, Kim M. Keeling, Robert A. Kesterson, Bruce R. Korf, Tatiana T. Marquez Lago, Ulrich F. Müller, Linda Popplewell, Jiangbing Zhou, and Deeann Wallis
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Significant advances in biotechnology have led to the development of a number of different mutation-directed therapies. Some of these techniques have matured to a level that has allowed testing in clinical trials, but few have made it to approval by drug-regulatory bodies for the treatment of specific diseases. While there are still various hurdles to be overcome, recent success stories have proven the potential power of mutation-directed therapies and have fueled the hope of finding therapeutics for other genetic disorders. In this review, we summarize the state-of-the-art of various therapeutic approaches and assess their applicability to the genetic disorder neurofibromatosis type I (NF1). NF1 is caused by the loss of function of neurofibromin, a tumor suppressor and downregulator of the Ras signaling pathway. The condition is characterized by a variety of phenotypes and includes symptoms such as skin spots, nervous system tumors, skeletal dysplasia, and others. Hence, depending on the patient, therapeutics may need to target different tissues and cell types. While we also discuss the delivery of therapeutics, in particular via viral vectors and nanoparticles, our main focus is on therapeutic techniques that reconstitute functional neurofibromin, most notably cDNA replacement, CRISPR-based DNA repair, RNA repair, antisense oligonucleotide therapeutics including exon skipping, and nonsense suppression.
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- 2020
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4. Targeted Delivery of Secretory Promelittin via Novel Poly(lactone‐co‐β‐amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases
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Yu Zhou, Shenqi Zhang, Zeming Chen, Youmei Bao, Ann T. Chen, Wendy C. Sheu, Fuyao Liu, Zhaozhong Jiang, and Jiangbing Zhou
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brain metastasis ,breast cancer ,gene therapy ,melittin ,poly(lactone‐co‐β‐amino ester) ,Science - Abstract
Abstract Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an innovative gene therapy regimen is reported that is designed for effective treatment of BCBM. First, poly(lactone‐co‐β‐amino ester) nanoparticles that are capable of efficient gene delivery are synthesized and are engineered for targeted delivery to BCBM through surface conjugation of AMD3100, which interacts with CXCR4 enriched in the tumor microenvironment. Next, an artificial gene, proMel, is designed for the expression of secretory promelittin protein, which has limited toxicity on its own but releases cytolytic melittin after activation by MMP‐2 accumulated in tumors. It is demonstrated that delivery of the proMel via the AMD3100‐conjugated nanoparticles effectively inhibits tumor progression in a BCBM mouse model. This study suggests a new direction to treat BCBM through targeted delivery of promelittin‐mediated gene therapy.
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- 2020
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5. Author Correction: Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids
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Shuhua Li, Wen Su, Hao Wu, Ting Yuan, Chang Yuan, Jun Liu, Gang Deng, Xingchun Gao, Zeming Chen, Youmei Bao, Fanglong Yuan, Shixin Zhou, Hongwei Tan, Yunchao Li, Xiaohong Li, Louzhen Fan, Jia Zhu, Ann T. Chen, Fuyao Liu, Yu Zhou, Miao Li, Xingchen Zhai, and Jiangbing Zhou
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Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Computer Science Applications ,Biotechnology - Published
- 2022
6. Peer Teaching as Bioinformatics Training Strategy: Incentives, Challenges, and Benefits
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Ann T. Chen, Nur-Taz Rahman, Wesley L. Cai, Razib Obaid, Durga Thakral, Caitlin Meyer, and Rolando Garcia-Milian
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Classroom management ,Motivation ,media_common.quotation_subject ,Teaching ,Professional development ,Computational Biology ,Health Informatics ,Library and Information Sciences ,Bioinformatics ,Training (civil) ,Peer Group ,Incentive ,ComputingMilieux_COMPUTERSANDEDUCATION ,Institution ,Training needs ,Personal experience ,Curriculum ,Psychology ,Peer teaching ,media_common ,Education, Medical, Undergraduate - Abstract
As biomedical research becomes more data-intensive, bioinformatics is becoming essential to understanding biological processes, systems, and diseases. In this paper we describe the use of a series of peer teaching workshops as a strategy to respond to the bioinformatics training needs at a research-intensive institution. In addition to the data collected from the workshops, we also used personal experiences of researchers who participated as peer teachers to understand the incentives, challenges, and benefits of peer teaching. Developing communication skills such as confidence in teaching, explaining complex concepts, and better understanding of the topic emerged as primary benefits that the teachers obtained from this experience. Lack of time for teaching and the struggles of classroom management were identified as two major challenges. We suggest that peer teaching can be beneficial not only to train researchers in bioinformatics, but also as a professional development opportunity for graduate students and postdoctoral trainees.
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- 2022
7. LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy
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Xingchun Gou, Chen Huang, Hongyi Zhang, Jun Liu, Ting Jiang, Jun Dou, Cong Han, Yong Zhu, Jun Ma, Jianhui Wang, Youmei Bao, Yanke Chen, Mehdi Baqri, Ann T. Chen, Hong Lei, Ranjit S. Bindra, Xintao Jing, Zhenzhen Wang, Jiangbing Zhou, Zeming Chen, and James E. Hansen
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Radiation-Sensitizing Agents ,Ku80 ,DNA Repair ,DNA repair ,DNA damage ,medicine.medical_treatment ,Mice, Nude ,Apoptosis ,Breast Neoplasms ,Ataxia Telangiectasia Mutated Proteins ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Phosphorylation ,Cell Proliferation ,030304 developmental biology ,Mice, Inbred BALB C ,0303 health sciences ,Ku70 ,Brain Neoplasms ,business.industry ,Nuclear Proteins ,Cancer ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,Cell biology ,Radiation therapy ,MutS Homolog 2 Protein ,Gamma Rays ,MSH2 ,030220 oncology & carcinogenesis ,Female ,business ,DNA Damage ,Signal Transduction ,Brain metastasis - Abstract
Breast cancer brain metastasis (BCBM) is a devastating disease. Radiation therapy remains the mainstay for treatment of this disease. Unfortunately, its efficacy is limited by the dose that can be safely applied. One promising approach to overcoming this limitation is to sensitize BCBMs to radiation by inhibiting their ability to repair DNA damage. Here, we report a DNA repair suppressor, leucine-rich repeat-containing protein 31 (LRRC31), that was identified through a genome-wide CRISPR screen. We found that overexpression of LRRC31 suppresses DNA repair and sensitizes BCBMs to radiation. Mechanistically, LRRC31 interacts with Ku70/Ku80 and the ataxia telangiectasia mutated and RAD3-related (ATR) at the protein level, resulting in inhibition of DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) recruitment and activation, and disruption of the MutS homologue 2 (MSH2)-ATR module. We demonstrate that targeted delivery of the LRRC31 gene via nanoparticles improves the survival of tumour-bearing mice after irradiation. Collectively, our study suggests LRRC31 as a major DNA repair suppressor that can be targeted for cancer radiosensitizing therapy.
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- 2020
8. Mutation-Directed Therapeutics for Neurofibromatosis Type I
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Ulrich Müller, Linda Popplewell, Tatiana T. Marquez Lago, Deeann Wallis, Ann T. Chen, Bruce R. Korf, André Leier, Robert A. Kesterson, David M. Bedwell, Kim M. Keeling, George Dickson, and Jiangbing Zhou
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0301 basic medicine ,Bioinformatics ,medicine.disease_cause ,Article ,Viral vector ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,CRISPR ,Loss function ,Neurofibromatosis type I ,Mutation ,biology ,business.industry ,lcsh:RM1-950 ,Genetic disorder ,medicine.disease ,Neurofibromin 1 ,Exon skipping ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,business - Abstract
Significant advances in biotechnology have led to the development of a number of different mutation-directed therapies. Some of these techniques have matured to a level that has allowed testing in clinical trials, but few have made it to approval by drug-regulatory bodies for the treatment of specific diseases. While there are still various hurdles to be overcome, recent success stories have proven the potential power of mutation-directed therapies and have fueled the hope of finding therapeutics for other genetic disorders. In this review, we summarize the state-of-the-art of various therapeutic approaches and assess their applicability to the genetic disorder neurofibromatosis type I (NF1). NF1 is caused by the loss of function of neurofibromin, a tumor suppressor and downregulator of the Ras signaling pathway. The condition is characterized by a variety of phenotypes and includes symptoms such as skin spots, nervous system tumors, skeletal dysplasia, and others. Hence, depending on the patient, therapeutics may need to target different tissues and cell types. While we also discuss the delivery of therapeutics, in particular via viral vectors and nanoparticles, our main focus is on therapeutic techniques that reconstitute functional neurofibromin, most notably cDNA replacement, CRISPR-based DNA repair, RNA repair, antisense oligonucleotide therapeutics including exon skipping, and nonsense suppression., Graphical Abstract, We present a comprehensive review that addresses therapeutic approaches to treating specific genetic defects that cause neurofibromatosis type I, including nanoparticle delivery, exon skipping, gene editing, mRNA trans-splicing ribozymes, and non-sense suppression therapeutics. Our multi-faceted approach can be utilized for virtually any rare disease to affect personalized medicine.
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- 2020
9. Copresentation of Tumor Antigens and Costimulatory Molecules via Biomimetic Nanoparticles for Effective Cancer Immunotherapy
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Junning Ma, Miao Li, Haijun Wang, Jun Liu, Zhiyong Zou, Ying Xie, Yuwen Zhu, Hui Xu, Youmei Bao, Wendy C. Sheu, Shenqi Zhang, Jiangbing Zhou, Longbo Zhang, Haoan Wu, Xue Zhang, Zhouqi Meng, Fuyao Liu, and Ann T. Chen
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medicine.medical_treatment ,Cell ,Bioengineering ,02 engineering and technology ,Immune system ,Cancer immunotherapy ,Antigen ,Antigens, Neoplasm ,Biomimetics ,Neoplasms ,medicine ,Humans ,General Materials Science ,Chemistry ,Mechanical Engineering ,Dendritic Cells ,General Chemistry ,Immunotherapy ,Dendritic cell ,Biomimetic nanoparticles ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,Surface coating ,medicine.anatomical_structure ,Cancer research ,Nanoparticles ,0210 nano-technology - Abstract
Nanoparticle (NP)-based cancer immunotherapy has been extensively explored. However, the efficacy of existing strategies is often limited by the lack of effective tumor-specific antigens or the inability to present costimulatory signal or both. Here, we report a novel approach to overcoming these limitations through surface coating with dendritic-tumor fusion cell membranes, which present whole repertories of tumor-associated antigens in the presence of costimulatory molecules. Because antigen-presenting and costimulatory molecules are displayed on their surface, these NPs can efficiently penetrate immune organs and activate T cells. We show that these NPs can be utilized to prevent tumor development and regress established tumors, including tumors in the brain. We demonstrate that encapsulation of immune adjuvants further improves their efficacy. Due to their significant efficacy, the whole tumor antigen-presenting costimulatory NPs have the potential to be translated into clinical applications for treatment of various cancers.
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- 2020
10. Synergistic Chemotherapy for Breast Cancer and Breast Cancer Brain Metastases via Paclitaxel-Loaded Oleanolic Acid Nanoparticles
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Gang Deng, Shenqi Zhang, Ann T. Chen, Youmei Bao, Guangyu Yao, Jiangbing Zhou, Zhiqiang Yu, Zeming Chen, Weiguo Xu, Junning Ma, and Jianjun Chen
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Drug ,Paclitaxel ,media_common.quotation_subject ,medicine.medical_treatment ,Mice, Nude ,Pharmaceutical Science ,Antineoplastic Agents ,Breast Neoplasms ,02 engineering and technology ,030226 pharmacology & pharmacy ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Oleanolic Acid ,Oleanolic acid ,media_common ,Chemotherapy ,Brain Neoplasms ,business.industry ,Brain ,Cancer ,Drug Synergism ,Combination chemotherapy ,021001 nanoscience & nanotechnology ,medicine.disease ,Regimen ,chemistry ,Cancer research ,Nanoparticles ,Molecular Medicine ,Female ,0210 nano-technology ,business - Abstract
Breast cancer is the most common type of cancer in women. About 12% of all women in the United States will be diagnosed with breast cancer over their lifetimes. At the same time, incidences of brain metastases (BMs) are increasing and represent an emerging health threat. However, there is no effective chemotherapy for breast cancer brain metastases (BCBMs), which is largely due to lack of efficient delivery of antitumor drugs or drug combinations to the brain. In this study, oleanolic acid (OA), a natural pentacyclic triterpenoid compound with excellent antitumor activity, was found to form nanoparticles (NPs) and efficiently penetrate the brain for BCBMs treatment. On the basis of these findings, we developed a synergistic combinatorial chemotherapeutic regimen by formulating paclitaxel (PTX) into OA NPs and demonstrated that the resulting PTX-OA NPs effectively inhibited primary breast cancer and BCBMs in mouse xenografts. Collectively, this study introduces a new direction to treat primary breast cancer and BCBMs through noninvasive combination chemotherapy.
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- 2020
11. Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids
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Gang Deng, Youmei Bao, Fuyao Liu, Xiaohong Li, Wen Su, Shixin Zhou, Jiangbing Zhou, Ann T. Chen, Hongwei Tan, Louzhen Fan, Chang Yuan, Yunchao Li, Jun Liu, Xingchen Zhai, Gao Xingchun, Shuhua Li, Fanglong Yuan, Ting Yuan, Jia Zhu, Miao Li, Zeming Chen, Hao Wu, and Yu Zhou
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0301 basic medicine ,Medicine (miscellaneous) ,Mice, Nude ,Bioengineering ,Large Neutral Amino Acid-Transporter 1 ,Theranostic Nanomedicine ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Drug Delivery Systems ,Downregulation and upregulation ,Cell Line, Tumor ,Animals ,Humans ,Amino Acids ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Brain Neoplasms ,Quantum dots ,Fluorescence ,Carbon ,Computer Science Applications ,Amino acid ,030104 developmental biology ,chemistry ,Cell culture ,Quantum dot ,Drug delivery ,Cancer cell ,Biophysics ,Female ,Biomedical engineering ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Strategies for selectively imaging and delivering drugs to tumours typically leverage differentially upregulated surface molecules on cancer cells. Here, we show that intravenously injected carbon quantum dots, functionalized with multiple paired α-carboxyl and amino groups that bind to the large neutral amino acid transporter 1 (which is expressed in most tumours), selectively accumulate in human tumour xenografts in mice and in an orthotopic mouse model of human glioma. The functionalized quantum dots, which structurally mimic large amino acids and can be loaded with aromatic drugs through π–π stacking interactions, enabled—in the absence of detectable toxicity—near-infrared fluorescence and photoacoustic imaging of the tumours and a reduction in tumour burden after the targeted delivery of chemotherapeutics to the tumours. The versatility of functionalization and high tumour selectivity of the quantum dots make them broadly suitable for tumour-specific imaging and drug delivery., Intravenously injected functionalized carbon quantum dots that bind to the large neutral amino acid transporter 1 and that structurally mimic large amino acids selectively accumulate in human tumours in mice, facilitating targeted theranostics.
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- 2020
12. Targeted Therapeutics for Rare Disorders
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Kim M. Keeling, Andre Leier, David M. Bedwell, Ann T. Chen, Robert A. Kesterson, Tatiana T. Marquez Lago, Ulrich F. Müller, Jiangbing Zhou, Linda Popplewell, and Deeann Wallis
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- 2022
13. Cross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion
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Ann T Chen, Yang Xiao, Xiangjun Tang, Mehdi Baqri, Xingchun Gao, Melanie Reschke, Wendy C Sheu, Gretchen Long, Yu Zhou, Gang Deng, Shenqi Zhang, Yanxiang Deng, Zhiliang Bai, Dongjoo Kim, Anita Huttner, Russell Kunes, Murat Günel, Jennifer Moliterno, W Mark Saltzman, Rong Fan, and Jiangbing Zhou
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
Background Improved treatment of glioblastoma (GBM) needs to address tumor invasion, a hallmark of the disease that remains poorly understood. In this study, we profiled GBM invasion through integrative analysis of histological and single-cell RNA sequencing (scRNA-seq) data from 10 patients. Methods Human histology samples, patient-derived xenograft mouse histology samples, and scRNA-seq data were collected from 10 GBM patients. Tumor invasion was characterized and quantified at the phenotypic level using hematoxylin and eosin and Ki-67 histology stains. Crystallin alpha B (CRYAB) and CD44 were identified as regulators of tumor invasion from scRNA-seq transcriptomic data and validated in vitro, in vivo, and in a mouse GBM resection model. Results At the cellular level, we found that invasive GBM are less dense and proliferative than their non-invasive counterparts. At the molecular level, we identified unique transcriptomic features that significantly contribute to GBM invasion. Specifically, we found that CRYAB significantly contributes to postoperative recurrence and is highly co-expressed with CD44 in invasive GBM samples. Conclusions Collectively, our analysis identifies differentially expressed features between invasive and nodular GBM, and describes a novel relationship between CRYAB and CD44 that contributes to tumor invasiveness, establishing a cellular and molecular landscape of GBM invasion.
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- 2021
14. Vessel-Targeting Nanoclovers Enable Noninvasive Delivery of Magnetic Hyperthermia-Chemotherapy Combination for Brain Cancer Treatment
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Stefania Bellone, Bin Peng, Haoan Wu, Pan Zou, Alessandro D. Santin, Fuyao Liu, Shenqi Zhang, Jiangbing Zhou, Dongfang Li, Gang Deng, Ann T. Chen, Junning Ma, Jennifer Moliterno, and Jun Liu
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medicine.medical_treatment ,Bioengineering ,Tumor cells ,Tumor vasculature ,Brain cancer ,Cell Line, Tumor ,Medicine ,Humans ,General Materials Science ,Hyperthermia ,Magnetite Nanoparticles ,Chemotherapy ,business.industry ,Systemic chemotherapy ,Brain Neoplasms ,Mechanical Engineering ,Magnetic Phenomena ,Magnetic field exposure ,General Chemistry ,Hyperthermia, Induced ,equipment and supplies ,Condensed Matter Physics ,Magnetic hyperthermia ,Drug delivery ,Cancer research ,business ,human activities - Abstract
Despite being promising, the clinical application of magnetic hyperthermia for brain cancer treatment is limited by the requirement of highly invasive intracranial injections. To overcome this limitation, here we report the development of gallic acid-coated magnetic nanoclovers (GA-MNCs), which allow not only for noninvasive delivery of magnetic hyperthermia but also for targeted delivery of systemic chemotherapy to brain tumors. GA-MNCs are composed of clover-shaped MNCs in the core, which can induce magnetic heat in high efficiency, and polymerized GA on the shell, which enables tumor vessel-targeting. We demonstrate that intravenous administration of GA-MNCs following alternating magnetic field exposure effectively inhibited brain cancer development and preferentially disrupted tumor vasculature, making it possible to efficiently deliver systemic chemotherapy for further improved efficacy. Due to the noninvasive nature and high efficiency in killing tumor cells and enhancing systemic drug delivery, GA-MNCs have the potential to be translated for improved treatment of brain cancer.
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- 2021
15. Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles
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Kevin N. Sheth, Haitian Zhao, Yiyun Huang, Jun Liu, Pan Zou, Ann T. Chen, Zeming Chen, Yang Xin, W. Taylor Kimberly, Jonathan Avery, Jiangbing Zhou, Daniel Holden, Fuyao Liu, Keunpoong Lim, Songye Li, Chao Ma, Richard E. Carson, Shenqi Zhang, Gang Deng, J. Marc Simard, Qianxue Chen, and Fengyi Du
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Male ,antioxidant ,Antioxidant ,Combination therapy ,medicine.medical_treatment ,Drug delivery to the brain ,Medicine (miscellaneous) ,Brain Edema ,Pharmacology ,Antioxidants ,combination therapy ,Rats, Sprague-Dawley ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Delivery Systems ,0302 clinical medicine ,Pharmacotherapy ,betulinic acid ,Positron Emission Tomography Computed Tomography ,Edema ,Betulinic acid ,Glyburide ,ischemic stroke ,Animals ,Humans ,Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Stroke ,030304 developmental biology ,0303 health sciences ,business.industry ,Eucommiaceae ,medicine.disease ,Triterpenes ,Rats ,3. Good health ,Mice, Inbred C57BL ,chemistry ,Ischemic stroke ,Nanoparticles ,Drug Therapy, Combination ,medicine.symptom ,Pentacyclic Triterpenes ,business ,030217 neurology & neurosurgery ,Drugs, Chinese Herbal ,Research Paper - Abstract
Stroke is a deadly disease without effective pharmacotherapies, which is due to two major reasons. First, most therapeutics cannot efficiently penetrate the brain. Second, single agent pharmacotherapy may be insufficient and effective treatment of stroke requires targeting multiple complementary targets. Here, we set to develop single component, multifunctional nanoparticles (NPs) for targeted delivery of glyburide to the brain for stroke treatment. Methods: To characterize the brain penetrability, we radiolabeled glyburide, intravenously administered it to stroke- bearing mice, and determined its accumulation in the brain using positron emission tomography-computed tomography (PET/CT). To identify functional nanomaterials to improve drug delivery to the brain, we developed a chemical extraction approach and tested it for isolation of nanomaterials from E. ulmoides, a medicinal herb. To assess the therapeutic benefits, we synthesized glyburide-loaded NPs and evaluated them in stroke- bearing mice. Results: We found that glyburide has a limited ability to penetrate the ischemic brain. We identified betulinic acid (BA) capable of forming NPs, which, after intravenous administration, efficiently penetrate the brain and significantly reduce ischemia-induced infarction as an antioxidant agent. We demonstrated that BA NPs enhance delivery of glyburide, leading to therapeutic benefits significantly greater than those achieved by either glyburide or BA NPs. Conclusion: This study suggests a new direction to identify functional nanomaterials and a simple approach to achieving anti-edema and antioxidant combination therapy. The resulting glyburide- loaded BA NPs may be translated into clinical applications to improve clinical management of stroke.
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- 2019
16. ZNF117 regulates glioblastoma stem cell differentiation towards oligodendroglial lineage
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Jun Liu, Xiaoying Wang, Ann T. Chen, Xingchun Gao, Benjamin T. Himes, Hongyi Zhang, Zeming Chen, Jianhui Wang, Wendy C. Sheu, Gang Deng, Yang Xiao, Pan Zou, Shenqi Zhang, Fuyao Liu, Yong Zhu, Rong Fan, Toral R. Patel, W. Mark Saltzman, and Jiangbing Zhou
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endocrine system ,Multidisciplinary ,Brain Neoplasms ,Cell Line, Tumor ,fungi ,Neoplastic Stem Cells ,General Physics and Astronomy ,Humans ,Cell Differentiation ,General Chemistry ,Glioblastoma ,General Biochemistry, Genetics and Molecular Biology - Abstract
Glioblastoma (GBM) is a deadly disease without effective treatment. Because glioblastoma stem cells (GSCs) contribute to tumor resistance and recurrence, improved treatment of GBM can be achieved by eliminating GSCs through inducing their differentiation. Prior efforts have been focused on studying GSC differentiation towards the astroglial lineage. However, regulation of GSC differentiation towards the neuronal and oligodendroglial lineages is largely unknown. To identify genes that control GSC differentiation to all three lineages, we performed an image-based genome-wide RNAi screen, in combination with single-cell RNA sequencing, and identified ZNF117 as a major regulator of GSC differentiation. Using patient-derived GSC cultures, we show that ZNF117 controls GSC differentiation towards the oligodendroglial lineage via the Notch pathway. We demonstrate that ZNF117 is a promising target for GSC differentiation therapy through targeted delivery of CRISPR/Cas9 gene-editing nanoparticles. Our study suggests a direction to improve GBM treatment through differentiation of GSCs towards various lineages.
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- 2021
17. Liposome-Templated Hydrogel Nanoparticles for Targeted Delivery of CRISPR/Cas9 to Brain Tumors
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Zeming Chen, Jiangbing Zhou, and Ann T. Chen
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Liposome ,Chemistry ,Biophysics ,CRISPR ,Nanoparticle - Published
- 2020
18. Autocatalytic Delivery of Brain Tumor-targeting, Size-shrinkable Nanoparticles for Treatment of Breast Cancer Brain Metastases
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Ann T. Chen, Jiangbing Zhou, Jun Liu, Bin Peng, Shenqi Zhang, Zeming Chen, Qianxue Chen, Junning Ma, Fengyi Du, Tang Xiangjun, Youmei Bao, Fuyao Liu, and Gang Deng
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Materials science ,medicine.medical_treatment ,Brain tumor ,02 engineering and technology ,010402 general chemistry ,Blood–brain barrier ,01 natural sciences ,CXCR4 ,Article ,Biomaterials ,Breast cancer ,Electrochemistry ,medicine ,Doxorubicin ,Tumor microenvironment ,Chemotherapy ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,medicine.disease ,0104 chemical sciences ,Electronic, Optical and Magnetic Materials ,medicine.anatomical_structure ,Cancer research ,0210 nano-technology ,medicine.drug ,Brain metastasis - Abstract
Breast cancer brain metastases (BCBMs) represent a major cause of morbidity and mortality among patients with breast cancer. Chemotherapy, which is widely used to treat tumors outside of the brain, is often ineffective on BCBMs due to its inability to efficiently cross the blood-brain barrier (BBB). Although the BBB is partially disrupted in tumor lesions, it remains intact enough to prevent most therapeutics from entering the brain. Here, we report a nanotechnology approach that can overcome the BBB through synthesis of lexiscan-loaded, AMD3100-conjugated, shrinkable NPs, or LANPs. LANPs respond to neutrophil elastase-enriched tumor microenvironment by shrinking in size and disrupt the BBB in tumors through lexiscan-mediated modulation. LANPs recognize tumor cells through the interaction between AMD3100 and CXCR4, which are expressed in metastatic tumor cells. We demonstrate that the integration of tumor responsiveness, tumor targeting, and BBB penetration enables LANPs to penetrate metastatic lesions in the brain with high efficiency, and, when doxorubicin was encapsulated, LANPs effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. Due to their high efficiency in penetrating the BBB for BCBMs treatment, LANPs have the potential to be translated into clinical applications for improved treatment of patients with BCBMs.
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- 2020
19. Targeted disruption of tumor vasculature via polyphenol nanoparticles to improve brain cancer treatment
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Fuyao Liu, Bin Peng, Miao Li, Junning Ma, Gang Deng, Shenqi Zhang, Wendy C. Sheu, Pan Zou, Haoan Wu, Jun Liu, Ann T. Chen, Farrah S. Mohammed, and Jiangbing Zhou
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General Energy ,General Engineering ,General Physics and Astronomy ,General Materials Science ,General Chemistry - Abstract
Despite being effective for many other solid tumors, traditional anti-angiogenic therapy has been shown to be insufficient for the treatment of malignant glioma. Here, we report the development of polyphenol nanoparticles (NPs), which not only inhibit the formation of new vessels but also enable targeted disruption of the existing tumor vasculature. The NPs are synthesized through a combinatory iron-coordination and polymer-stabilization approach, which allows for high drug loading and intrinsic tumor vessel targeting. We study a lead NP consisting of quercetin and find that the NP after intravenous administration preferentially binds to VEGFR2, which is overexpressed in tumor vasculature. We demonstrate that the binding is mediated by quercetin, and the interaction of NPs with VEGFR2 leads to disruption of the existing tumor vasculature and inhibition of new vessel development. As a result, systemic treatment with the NPs effectively inhibits tumor growth and increases drug delivery to tumors.
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- 2022
20. Thrombin-Responsive, Brain-Targeting Nanoparticles for Improved Stroke Therapy
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Xing Guo, Pan Zou, Jiangbing Zhou, Kevin N. Sheth, Liang Han, Qianxue Chen, Rui Hu, Gang Deng, Shenqi Zhang, Jie Liu, Fengyi Du, Zhishu Tang, Xingchun Gou, Miao Li, Jun O. Liu, Fuyao Liu, and Ann T. Chen
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Male ,0301 basic medicine ,Proteases ,Surface Properties ,General Physics and Astronomy ,Nanoparticle ,02 engineering and technology ,Matrix (biology) ,Pharmacology ,CXCR4 ,Brain Ischemia ,Mice ,03 medical and health sciences ,Drug Delivery Systems ,Thrombin ,Glyburide ,medicine ,Animals ,Hypoglycemic Agents ,General Materials Science ,Particle Size ,Stroke ,Chemistry ,General Engineering ,021001 nanoscience & nanotechnology ,medicine.disease ,Mice, Inbred C57BL ,Brain targeting ,030104 developmental biology ,Drug delivery ,Nanoparticles ,0210 nano-technology ,medicine.drug - Abstract
Current treatments for ischemic stroke are insufficient. The lack of effective pharmacological approaches can be mainly attributed to the difficulty in overcoming the blood-brain barrier. Here, we report a simple strategy to synthesize protease-responsive, brain-targeting nanoparticles for the improved treatment of stroke. The resulting nanoparticles respond to proteases enriched in the ischemic microenvironment, including thrombin or matrix metalloproteinase-9, by shrinking or expanding their size. Targeted delivery was achieved using surface conjugation of ligands that bind to proteins that were identified to enrich in the ischemic brain using protein arrays. By screening a variety of formulations, we found that AMD3100-conjugated, size-shrinkable nanoparticles (ASNPs) exhibited the greatest delivery efficiency. The brain targeting effect is mainly mediated by AMD3100, which interacts with CXCR4 that is enriched in the ischemic brain tissue. We showed that ASNPs significantly enhanced the efficacy of glyburide, a promising stroke therapeutic drug whose efficacy is limited by its toxicity. Due to their high efficiency in penetrating the ischemic brain and low toxicity, we anticipate that ASNPs have the potential to be translated into clinical applications for the improved treatment of stroke patients.
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- 2018
21. Single small molecule-assembled nanoparticles mediate efficient oral drug delivery
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Kangkang Zhi, Jing Wang, Jiangbing Zhou, Zeming Chen, Haitian Zhao, Chao Ma, Fuyao Liu, Ningbo Gong, Gang Deng, Xiaobin Gao, Rongbin Xie, Ann T. Chen, Pengjian Zuo, Lei Yao, Jiacheng Wang, Yang Xin, Louzhen Fan, and Jun Liu
- Subjects
Chemistry ,Single component ,technology, industry, and agriculture ,Nanoparticle ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,01 natural sciences ,Combinatorial chemistry ,Small molecule ,Atomic and Molecular Physics, and Optics ,Article ,0104 chemical sciences ,Dehydrotrametenolic acid ,Drug encapsulation ,General Materials Science ,Electrical and Electronic Engineering ,0210 nano-technology ,Bile acid transporter ,Disease treatment ,Oral retinoid - Abstract
Oral drug delivery, which requires surviving the harsh environment in the gastrointestinal (GI) tract and penetrating the intestinal epithelium, has not been achieved using simple formulation nanoparticles (NPs). Medicinal natural products (MNPs) have been widely used in traditional medicine for disease management through oral consumption. However, most pharmacologically active compounds within MNPs do not have the properties suitable for oral applications. We hypothesize that some MNPs contain natural nanomaterials that can convert those compounds into oral formulations by forming NPs. After screening 66 MNPs, we identified five classes of small molecules that form NPs, many of which are capable of efficient drug encapsulation and GI penetration. We show that one of them, dehydrotrametenolic acid (DTA), is capable of mediating oral delivery for effective disease treatment. We determined that DTA NPs assemble through hydrogen bonding and penetrate the GI tract via apical sodium-dependent bile acid transporter. Our study reveals a novel class of single component, small molecule-assembled NPs for oral drug delivery, and suggests a novel approach to modernizing MNPs through nanomaterial discovery.
- Published
- 2019
22. Targeted Drug Delivery to Stroke via Chemotactic Recruitment of Nanoparticles Coated with Membrane of Engineered Neural Stem Cells
- Author
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Jonathan Avery, Shenqi Zhang, Junning Ma, Jun Liu, Kevin N. Sheth, Jiangbing Zhou, Ann T. Chen, Youmei Bao, Fuyao Liu, Haijun Wang, Gang Deng, Miao Li, Fenyi Du, Peng Wu, Yu Zhou, and Hee-Won Suh
- Subjects
Receptors, CXCR4 ,Drug delivery to the brain ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,CXCR4 ,Biomaterials ,Cell membrane ,Mice ,Drug Delivery Systems ,Neural Stem Cells ,Glyburide ,medicine ,Animals ,Humans ,General Materials Science ,Chemistry ,Chemotaxis ,Cell Membrane ,General Chemistry ,021001 nanoscience & nanotechnology ,Neural stem cell ,Chemokine CXCL12 ,0104 chemical sciences ,Cell biology ,Stroke ,Surface coating ,medicine.anatomical_structure ,Membrane ,Targeted drug delivery ,Drug delivery ,Nanoparticles ,0210 nano-technology ,Biotechnology - Abstract
Cell membrane coating has recently emerged as a promising biomimetic approach to engineering nanoparticles (NPs) for targeted drug delivery. However, simple cell membrane coating may not meet the need for efficient drug delivery to the brain. Here, a novel molecular engineering strategy to modify the surface of NPs with a cell membrane coating for enhanced brain penetration is reported. By using poly(lactic-co-glycolic) acid NPs as a model, it is shown that delivery of NPs to the ischemic brain is enhanced through surface coating with the membrane of neural stem cells (NSCs), and the delivery efficiency can be further increased using membrane isolated from NSCs engineered for overexpression of CXCR4. It is found that this enhancement is mediated by the chemotactic interaction of CXCR4 with SDF-1, which is enriched in the ischemic microenvironment. It is demonstrated that the resulting CXCR4-overexpressing membrane-coated NPs, termed CMNPs, significantly augment the efficacy of glyburide, an anti-edema agent, for stroke treatment. The study suggests a new approach to improving drug delivery to the ischemic brain and establishes a novel formulation of glyburide that can be potentially translated into clinical applications to improve management of human patients with stroke.
- Published
- 2019
23. Targeted Delivery of CRISPR/Cas9-Mediated Cancer Gene Therapy via Liposome-Templated Hydrogel Nanoparticles
- Author
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Zhangyong Hong, Ann T. Chen, Gang Deng, Jiangbing Zhou, Jie Liu, Zeming Chen, Hongyi Zhang, Jun Liu, Fuyao Liu, Yanke Chen, and Xiaoying Wang
- Subjects
0301 basic medicine ,Materials science ,Cas9 ,Genetic enhancement ,Cancer ,02 engineering and technology ,Computational biology ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,medicine.disease ,PLK1 ,Molecular biology ,Article ,Electronic, Optical and Magnetic Materials ,Biomaterials ,03 medical and health sciences ,030104 developmental biology ,Lipofectamine ,Electrochemistry ,medicine ,CRISPR ,Guide RNA ,0210 nano-technology ,Gene - Abstract
Due to its simplicity, versatility, and high efficiency, the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology has emerged as one of the most promising approaches for treatment of a variety of genetic diseases, including human cancers. However, further translation of CRISPR/Cas9 for cancer gene therapy requires development of safe approaches for efficient, highly specific delivery of both Cas9 and single guide RNA to tumors. Here, novel core–shell nanostructure, liposome-templated hydrogel nanoparticles (LHNPs) that are optimized for efficient codelivery of Cas9 protein and nucleic acids is reported. It is demonstrated that, when coupled with the minicircle DNA technology, LHNPs deliver CRISPR/Cas9 with efficiency greater than commercial agent Lipofectamine 2000 in cell culture and can be engineered for targeted inhibition of genes in tumors, including tumors the brain. When CRISPR/Cas9 targeting a model therapeutic gene, polo-like kinase 1 (PLK1), is delivered, LHNPs effectively inhibit tumor growth and improve tumor-bearing mouse survival. The results suggest LHNPs as versatile CRISPR/Cas9-delivery tool that can be adapted for experimentally studying the biology of cancer as well as for clinically translating cancer gene therapy.
- Published
- 2017
24. Activatable Protein Nanoparticles for Targeted Delivery of Therapeutic Peptides
- Author
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Xiao-Long Wang, Louzhen Fan, Qianxue Chen, Jiangbing Zhou, Daofeng Tian, Xing Guo, Fengyi Du, Chao Ma, Sara M. Hashmi, Kevin N. Sheth, Liang Han, Jun Liu, Fuyao Liu, Zeming Chen, Haitian Zhao, Gang Deng, Xi Yu, Xinran Liu, Xingchun Gou, Ann T. Chen, Xudong Zhu, and Peng Wu
- Subjects
0301 basic medicine ,Proteases ,Materials science ,Lipid Bilayers ,Peptide ,02 engineering and technology ,Article ,Melittin ,Cell membrane ,03 medical and health sciences ,chemistry.chemical_compound ,Neoplasms ,medicine ,Humans ,General Materials Science ,Lipid bilayer ,chemistry.chemical_classification ,DNA synthesis ,Mechanical Engineering ,RNA ,021001 nanoscience & nanotechnology ,Melitten ,Cell biology ,Cytolysis ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Mechanics of Materials ,Nanoparticles ,Peptides ,0210 nano-technology - Abstract
Clinical translation of therapeutic peptides, particularly those that require penetration of the cell membrane or are cytolytic, is a major challenge. A novel approach based on a complementary mechanism, which has been widely used for guided synthesis of DNA or RNA nanoparticles, for de novo design of activatable protein nanoparticles (APNPs) for targeted delivery of therapeutic peptides is described. APNPs are formed through self-assembly of three independent polypeptides based on pairwise coiled-coil dimerization. They are capable of long circulation in the blood and can be engineered to target diseases. Peptides to be delivered are incorporated into APNPs and released into the disease microenvironment by locally enriched proteases. It is demonstrated that APNPs mediate efficient delivery of NR2B9c, a neuroprotective peptide that functions after cell penetration, and melittin, a cytolytic peptide that perturbs the lipid bilayer, for effective treatment of stroke and cancer, respectively. Due to their robust properties, simple design, and economic costs, APNPs have great potential to serve as a versatile platform for controlled delivery of therapeutic peptides.
- Published
- 2018
25. Single-nuclei characterization of pervasive transcriptional signatures across organs in response to COVID-19
- Author
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The COVID Tissue Atlas Consortium, Alejandro A Granados, Simon Bucher, Hanbing Song, Aditi Agrawal, Ann T Chen, Tien Peng, Norma Neff, Angela Oliveira Pisco, Franklin Huang, and Bruce Wang
- Subjects
COVID ,cell atlas ,transcriptomics ,RNA-seq ,single-cell ,transcriptional regulation ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Background: Infection by coronavirus SARS-CoV2 is a severe and often deadly disease that has implications for the respiratory system and multiple organs across the human body. While the effects in the lung have been extensively studied, less is known about the impact COVID-19 has across other organs. Methods: Here, we contribute a single-nuclei RNA-sequencing atlas comprising six human organs across 20 autopsies where we analyzed the transcriptional changes due to COVID-19 in multiple cell types. The integration of data from multiple organs enabled the identification of systemic transcriptional changes. Results: Computational cross-organ analysis for endothelial cells and macrophages identified systemic transcriptional changes in these cell types in COVID-19 samples. In addition, analysis of gene modules showed enrichment of specific signaling pathways across multiple organs in COVID-19 autopsies. Conclusions: Altogether, the COVID Tissue Atlas enables the investigation of both cell type-specific and cross-organ transcriptional responses to COVID-19, providing insights into the molecular networks affected by the disease and highlighting novel potential targets for therapies and drug development. Funding: The Chan-Zuckerberg Initiative, The Chan-Zuckerberg Biohub.
- Published
- 2023
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