137 results on '"Donghui Cheng"'
Search Results
2. Epinephrine promotes tumor progression and M2 polarization of tumor-associated macrophages by regulating the TRIM2- NF-κB pathway in colorectal cancer cells
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Zhengyi Liu, Chenxing Jian, Wenzheng Yuan, Guiqing jia, Donghui cheng, Yanzhuo Liu, Yanling Zhang, Bin Zhang, Zili Zhou, and Gaoping Zhao
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Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Published
- 2024
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3. Estimation of groundwater evapotranspiration rate in the loess phreaticaquifer by removing the barometric effect
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Donghui CHENG, Jing YUAN, and Lijun QI
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groundwater evapotranspiration ,barometric effect ,water table fluctuation method ,loessphreatic aquifer ,Geology ,QE1-996.5 - Abstract
Groundwater evapotranspiration (ETg) is the most important dischargeway of shallow groundwater in arid and semi-arid areas, and also is a significant component of the water budget in groundwater systems. When groundwater levelsare interfered with barometric effect, the traditional water table fluctuation method for estimation of the ETg rate cannot be directly employed.This paper proposes a hydrographical method for removing the barometric effect on the ETg rateestimation using water-table fluctuations based on the changes ingroundwater levels and barometric pressure.The results illustrate that thechangesin barometric pressure usually reach the peak before midnight, generally between 22:00 and 24:00 when the barometric effect can be ignored, and the evapotranspiration rate is the minimum and therefore thegroundwater level changes rate at this time interval is equivalent to the net recharge rate. Furthermore, the second time period between 0:00 and 4:00 when the ETg rate is negligible and the barometric pressure is generally in a continuous decline, is then selected to estimate the barometric efficiency. On the basis of these analyses, the ETg rate can be readily estimated by the groundwater level balance method and the water table fluctuation method. The data required in theproposed methodare easy to obtain and the estimated ETg ratesare relatively accurate.
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- 2021
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4. Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy
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Yan-Ruide Li, Yang Zhou, Yu Jeong Kim, Yanni Zhu, Feiyang Ma, Jiaji Yu, Yu-Chen Wang, Xianhui Chen, Zhe Li, Samuel Zeng, Xi Wang, Derek Lee, Josh Ku, Tasha Tsao, Christian Hardoy, Jie Huang, Donghui Cheng, Amélie Montel-Hagen, Christopher S. Seet, Gay M. Crooks, Sarah M. Larson, Joshua P. Sasine, Xiaoyan Wang, Matteo Pellegrini, Antoni Ribas, Donald B. Kohn, Owen Witte, Pin Wang, and Lili Yang
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hematopoietic stem cell ,invariant natural killer T cells ,cancer immunotherapy ,allogeneic off-the-shelf cell therapy ,chimeric antigen receptor ,allogeneic HSC-engineered iNKT cells ,Medicine (General) ,R5-920 - Abstract
Summary: Cell-based immunotherapy has become the new-generation cancer medicine, and “off-the-shelf” cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. Here, by combining hematopoietic stem cell (HSC) gene engineering and in vitro differentiation, we generate human allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of AlloHSC-iNKT cell products and lay a foundation for their translational and clinical development.
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- 2021
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5. Identification of Bacterial Communities and Tick-Borne Pathogens in Haemaphysalis spp. Collected from Shanghai, China
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Wenbo Zeng, Zhongqiu Li, Tiange Jiang, Donghui Cheng, Limin Yang, Tian Hang, Lei Duan, Dan Zhu, Yuan Fang, and Yi Zhang
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Ixodidae ,bacteria ,TBPs ,metagenomics ,PCR ,China ,Medicine - Abstract
Ticks can carry and transmit a large number of pathogens, including bacteria, viruses and protozoa, posing a huge threat to human health and animal husbandry. Previous investigations have shown that the dominant species of ticks in Shanghai are Haemaphysalis flava and Haemaphysalis longicornis. However, no relevant investigations and research have been carried out in recent decades. Therefore, we investigated the bacterial communities and tick-borne pathogens (TBPs) in Haemaphysalis spp. from Shanghai, China. Ixodid ticks were collected from 18 sites in Shanghai, China, and identified using morphological and molecular methods. The V3–V4 hypervariable regions of the bacterial 16S rRNA gene were amplified from the pooled tick DNA samples and subject to metagenomic analysis. The microbial diversity in the tick samples was estimated using the alpha diversity that includes the observed species index and Shannon index. The Unifrac distance matrix as determined using the QIIME software was used for unweighted Unifrac Principal coordinates analysis (PCoA). Individual tick DNA samples were screened with genus-specific or group-specific nested polymerase chain reaction (PCR) for these TBPs and combined with a sequencing assay to confirm the results of the V3–V4 hypervariable regions of the bacterial 16S rRNA gene. We found H. flava and H. longicornis to be the dominant species of ticks in Shanghai in this study. Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria are the main bacterial communities of Haemaphysalis spp. The total species abundances of Proteobacteria, Firmicutes and Bacteroidetes, are 48.8%, 20.8% and 18.1%, respectively. At the level of genus analysis, H. longicornis and H. flava carried at least 946 genera of bacteria. The bacteria with high abundance include Lactobacillus, Coxiella, Rickettsia and Muribaculaceae. Additionally, Rickettsia rickettsii, Rickettsia japonica, Candidatus Rickettsia jingxinensis, Anaplasma bovis, Ehrlichia ewingii, Ehrlichia chaffeensis, Coxiella spp. and Coxiella-like endosymbiont were detected in Haemaphysalis spp. from Shanghai, China. This study is the first report of bacterial communities and the prevalence of some main pathogens in Haemaphysalis spp. from Shanghai, China, and may provide insights and evidence for bacterial communities and the prevalence of the main pathogen in ticks. This study also indicates that people and other animals in Shanghai, China, are exposed to several TBPs.
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- 2022
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6. Experimental Research on Mechanical Properties of Carbon Fiber-Reinforced Reactive Powder Concrete after Exposure to Cryogenic Temperatures
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Li Wang, Donghui Cheng, and Xiaoting Wang
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reactive powder concrete ,carbon fiber ,cryogenic temperature ,mechanical properties ,stress–strain relationship ,Technology ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Microscopy ,QH201-278.5 ,Descriptive and experimental mechanics ,QC120-168.85 - Abstract
This study aims to evaluate the mechanical properties of carbon fiber-reinforced reactive powder concrete (CFRPC) after exposure to cryogenic temperature. The mechanical properties of plain RPC and CFRPC with carbon fiber volume contents of 0, 0.5%, 1.0%, and 1.5% were examined after exposure to 20 °C, −5 °C, −15 °C, and −25 °C for 72 h. The effect of fiber contents and exposure temperatures on the cubic and axial compressive strength, splitting tensile strength, elastic modulus, and peak strain were systematically reported and analyzed. The results showed adding carbon fiber to RPC could significantly enhance the strength and slightly improve ductility performance. Additionally, CFRPC with 1.0% fiber content showed the best mechanical properties. The maximum increases in cubic and axial compressive strength and tensile strength were 26.0%, 25.7%, and 21.8%, the elastic modulus was 13.2%, and the peak strain was 13.0% over the plain RPC. Additionally, all mechanical properties continued to degrade with decreasing temperature. After exposure to −25 °C, the cubic, axial compressive strength, and tensile strength of CFRPC degraded to 82.2–84.9%, 80.7–87.5%, and 72.7–73.7% of the normal temperature strength, respectively. In addition, the linear relationship equation between the discount factor of each mechanical property and the temperature was established. Finally, the equation for the stress–strain ascending curve of CFRPC described by a quadratic polynomial was proposed, which fitted well with the experimental results.
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- 2022
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7. Calculation of Additional Internal Forces in Post-Tensioned Prestressed Concrete Frame Columns Based on Equivalent Lateral Stiffness
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Li Wang, Donghui Cheng, Enxiang Qu, Daoming Zhang, and Chun Lv
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post-tensioned prestressed frame structure ,frame column ,equivalent lateral stiffness ,third shear ,third bending moment ,finite element analysis ,Building construction ,TH1-9745 - Abstract
The additional internal forces in vertical members caused by prestressed tendons are typically overlooked in the design of post-tensioned prestressed concrete. A calculation method for additional internal forces in single-story multi-span prestressed concrete frame columns based on equivalent lateral stiffness is proposed in this paper. The slope-deflection equation for the bar element was presented using Timoshenko beam assumptions, taking into account the influence of shear and bending deformations. Subsequently, the concept of equivalent lateral stiffness and calculation equations were proposed. On this basis, the equations of the third shear and third bending moment for single-story multi-span prestressed frame columns were established. Furthermore, applying engineering examples, the method in this study was verified by ABAQUS software and previous methods. The results show that theoretical values and FEA results are in good agreement. Compared to previous methods, the method in this paper is more accurate and widely applicable. In addition, the stretching plan has a significant path effect and time-varying effect on the interlayer distribution of the third moment. It should be considered at the building stage to check the calculation of the frame column.
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- 2022
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8. Sensitive Detection and Analysis of Neoantigen-Specific T Cell Populations from Tumors and Blood
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Songming Peng, Jesse M. Zaretsky, Alphonsus H.C. Ng, William Chour, Michael T. Bethune, Jongchan Choi, Alice Hsu, Elizabeth Holman, Xiaozhe Ding, Katherine Guo, Jungwoo Kim, Alexander M. Xu, John E. Heath, Won Jun Noh, Jing Zhou, Yapeng Su, Yue Lu, Jami McLaughlin, Donghui Cheng, Owen N. Witte, David Baltimore, Antoni Ribas, and James R. Heath
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Biology (General) ,QH301-705.5 - Abstract
Summary: Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanoparticles that present neoantigen-loaded major histocompatibility complex (MHC) tetramers at high avidity by barcoded DNA linkers. The magnetic particles provide a convenient handle to isolate the desired cell populations, and the barcoded DNA enables multiplexed analysis. The method exhibits superior recovery of antigen-specific T cell populations relative to literature approaches. We applied the method to profile neoantigen-specific T cell populations in the tumor and blood of patients with metastatic melanoma over the course of anti-PD1 checkpoint inhibitor therapy. We show that the method has value for monitoring clinical responses to cancer immunotherapy and might help guide the development of personalized mutational neoantigen-specific T cell therapies and cancer vaccines. : Peng et al. report a sensitive method to detect tumor-associated neoantigen-specific T cells. Neoantigens and fluorescent DNA barcodes, presented on nanoparticle scaffolds, permit multiplex capture and analysis of specific T cell populations from blood or tumor. Neoantigen-specific T cell numbers track tumor volume in a melanoma patient responding to immunotherapy. Keywords: neoantigens, cancer immunotherapy, nanotechnology, microfluidics, T cell receptor
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- 2019
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9. Domain-swapped T cell receptors improve the safety of TCR gene therapy
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Michael T Bethune, Marvin H Gee, Mario Bunse, Mark S Lee, Eric H Gschweng, Meghana S Pagadala, Jing Zhou, Donghui Cheng, James R Heath, Donald B Kohn, Michael S Kuhns, Wolfgang Uckert, and David Baltimore
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receptor biogenesis ,cancer immunotherapy ,protein engineering ,autoimmunity ,T cell ,T cell receptor ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the α and β chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of αβ TCR domains with corresponding γδ TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy.
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- 2016
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10. Deoxycytidine kinase augments ATM-Mediated DNA repair and contributes to radiation resistance.
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Yuri L Bunimovich, Evan Nair-Gill, Mireille Riedinger, Melissa N McCracken, Donghui Cheng, Jami McLaughlin, Caius G Radu, and Owen N Witte
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Medicine ,Science - Abstract
Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts its substrate specificity toward deoxycytidine, increases intracellular dCTP pools post IR, and enhances the rate of DNA repair. Mutation of a single serine 74 residue has profound effects on murine T and B lymphocyte development, suggesting that post-translational regulation of dCK may be important in maintaining genomic stability during hematopoiesis. Using [(18)F]-FAC, a dCK-specific positron emission tomography (PET) probe, we visualized and quantified dCK activation in tumor xenografts after IR, indicating that dCK activation could serve as a biomarker for ATM function and DNA damage response in vivo. In addition, dCK-deficient leukemia cell lines and murine embryonic fibroblasts exhibited increased sensitivity to IR, indicating that pharmacologic inhibition of dCK may be an effective radiosensitization strategy.
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- 2014
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11. Defining T cell receptor repertoires using nanovial-based binding and functional screening.
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Doyeon Koo, Zhiyuan Mao, Dimatteo, Robert, Miyako Noguchi, Tsubamoto, Natalie, McLaughlin, Jami, Tran, Wendy, Sohyung Lee, Donghui Cheng, de Rutte, Joseph, Sojo, Giselle Burton, Witte, Owen N., and Di Carlo, Dino
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T cell receptors ,MAJOR histocompatibility complex ,CELL populations ,VIRAL antigens ,T cells - Abstract
The ability to selectively bind to antigenic peptides and secrete effector molecules can define rare and low-affinity populations of cells with therapeutic potential in emerging T cell receptor (TCR) immunotherapies. We leverage cavity-containing hydrogel microparticles, called nanovials, each coated with peptide-major histocompatibility complex (pMHC) monomers to isolate antigen-reactive T cells. T cells are captured and activated by pMHCs inducing the secretion of effector molecules including IFN-γ and granzyme B that are accumulated on nanovials, allowing sorting based on both binding and function. The TCRs of sorted cells on nanovials are sequenced, recovering paired αβ-chains using microfluidic emulsion-based single-cell sequencing. By labeling nanovials having different pMHCs with unique oligonucleotide-barcodes and secretions with oligo-barcoded detection antibodies, we could accurately link TCR sequences to specific targets and rank each TCR based on the corresponding cell's secretion level. Using the technique, we identified an expanded repertoire of functional TCRs targeting viral antigens with high specificity and found rare TCRs with activity against cancer-specific splicing-enhanced epitopes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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12. Study on the Compressive Properties of RPC Restrained by CFRP Sheet under Low-Temperature Curing.
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Donghui Cheng, Ke Li, and Xiaoting Wang
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To address the problem of significant degradation of compressive properties of reactive powder concrete (RPC) after freezing during the curing period in a low-temperature environment, carbon fiber-reinforced polymer (CFRP) was used to restrain RPC specimens with carbon fiber filament content of 0 or 1 %, and axial compression tests were performed after low-temperature curing (20°C, -5°C, -15°C, and -25°C). The effects of temperature, restraint, and carbon fiber filament content on the compression properties of the RPC were analyzed. Results of the analysis showed that the mechanical properties of RPC under compression decreased with decreasing curing temperature. The use of CFRP sheets for the restraint of RPC specimens and the addition of carbon fiber filaments can both increase the ultimate load capacity of RPC specimens at each curing temperature, and the specimens were relatively intact after damage. With the addition of carbon fiber filaments, which can slow down the rate of decay of load capacity as curing temperature decreases, the degree of load capacity improvement is greater the lower the temperature. The degree of load capacity increase of the CFRP sheet decreases with decreasing temperature because of the weakening of the epoxy resin adhesive bond strength in the CFRP sheet at low temperatures. Both CFRP sheets and carbon fiber filament can increase the compressive pre-crack energy absorbed by RPC at each of the temperatures and can increase the toughness of RPC at low temperatures. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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13. Dual-inhibitory domain iCARs improve the efficiency of the AND-NOT gate CAR T strategy.
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Bangayan, Nathanael J., Liang Wang, Sojo, Giselle Burton, Noguchi, Miyako, Donghui Cheng, Lisa Ta, Donny Gunn, Zhiyuan Mao, Shiqin Liu, Qingqing Yin, Riedinger, Mireille, Keyu Li, Wu, Anna M., Stoyanova, Tanya, and Witte, Owen N.
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CHIMERIC antigen receptors ,T cells ,CYTOTOXINS ,FIREPROOFING agents - Abstract
CAR (chimeric antigen receptor) T cell therapy has shown clinical success in treating hematological malignancies, but its treatment of solid tumors has been limited. One major challenge is on-target, off-tumor toxicity, where CAR T cells also damage normal tissues that express the targeted antigen. To reduce this detrimental side-effect, Boolean-logic gates like AND-NOT gates have utilized an inhibitory CAR (iCAR) to specifically curb CAR T cell activity at selected nonmalignant tissue sites. However, the strategy seems inefficient, requiring high levels of iCAR and its target antigen for inhibition. Using a TROP2-targeting iCAR with a single PD1 inhibitory domain to inhibit a CEACAM5-targeting CAR (CEACAR), we observed that the inefficiency was due to a kinetic delay in iCAR inhibition of cytotoxicity. To improve iCAR efficiency, we modified three features of the iCAR--the avidity, the affinity, and the intracellular signaling domains. Increasing the avidity but not the affinity of the iCAR led to significant reductions in the delay. iCARs containing twelve different inhibitory signaling domains were screened for improved inhibition, and three domains (BTLA, LAIR-1, and SIGLEC-9) each suppressed CAR T function but did not enhance inhibitory kinetics. When inhibitory domains of LAIR-1 or SIGLEC-9 were combined with PD-1 into a single dual-inhibitory domain iCAR (DiCARs) and tested with the CEACAR, inhibition efficiency improved as evidenced by a significant reduction in the inhibitory delay. These data indicate that a delicate balance between CAR and iCAR signaling strength and kinetics must be achieved to regulate AND-NOT gate CAR T cell selectivity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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14. IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing
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Yang Pan, John W. Phillips, Beatrice D. Zhang, Miyako Noguchi, Eric Kutschera, Jami McLaughlin, Pavlo A. Nesterenko, Zhiyuan Mao, Nathanael J. Bangayan, Robert Wang, Wendy Tran, Harry T. Yang, Yuanyuan Wang, Yang Xu, Matthew B. Obusan, Donghui Cheng, Alex H. Lee, Kathryn E. Kadash-Edmondson, Ameya Champhekar, Cristina Puig-Saus, Antoni Ribas, Robert M. Prins, Christopher S. Seet, Gay M. Crooks, Owen N. Witte, and Yi Xing
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Male ,RNA splicing ,Mononuclear ,T cell receptors ,Vaccine Related ,Epitopes ,Clinical Research ,Neoplasms ,Receptors ,Leukocytes ,RNA Precursors ,Genetics ,Humans ,Antigens ,Cancer ,Multidisciplinary ,Human Genome ,T-Cell ,Alternative Splicing ,Good Health and Well Being ,T-Lymphocyte ,5.1 Pharmaceuticals ,Antigen ,Neoplasm ,Immunization ,immunotherapy ,Development of treatments and therapeutic interventions ,Peptides ,Biotechnology - Abstract
Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe I soform peptides from R NA splicing for I mmunotherapy target S creening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric antigen receptor T cell (CAR-T) therapies. IRIS leverages large-scale tumor and normal transcriptome data and incorporates multiple screening approaches to discover AS-derived TAs with tumor-associated or tumor-specific expression. In a proof-of-concept analysis integrating transcriptomics and immunopeptidomics data, we showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules. We applied IRIS to RNA-seq data of neuroendocrine prostate cancer (NEPC). From 2,939 NEPC-associated AS events, IRIS predicted 1,651 epitopes from 808 events as potential TCR targets for two common HLA types (A*02:01 and A*03:01). A more stringent screening test prioritized 48 epitopes from 20 events with “neoantigen-like” NEPC-specific expression. Predicted epitopes are often encoded by microexons of ≤30 nucleotides. To validate the immunogenicity and T cell recognition of IRIS-predicted TCR epitopes, we performed in vitro T cell priming in combination with single-cell TCR sequencing. Seven TCRs transduced into human peripheral blood mononuclear cells (PBMCs) showed high activity against individual IRIS-predicted epitopes, providing strong evidence of isolated TCRs reactive to AS-derived peptides. One selected TCR showed efficient cytotoxicity against target cells expressing the target peptide. Our study illustrates the contribution of AS to the TA repertoire of cancer cells and demonstrates the utility of IRIS for discovering AS-derived TAs and expanding cancer immunotherapies.
- Published
- 2023
15. Supplementary Figure 3 from Low Levels of Circulating Estrogen Sensitize PTEN-Null Endometrial Tumors to PARP Inhibition In Vivo
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Sanaz Memarzadeh, Kym Faull, Michael E. Jung, Christopher M. Ryan, Huseyin Kayadibi, Owen N. Witte, Donghui Cheng, Brian Yep, Miguel A. Rosales, Daniel Y. Paik, and Deanna M. Janzen
- Abstract
PDF file - 80K, Figure S3. Decreased levels of Cyp3A4 were detected in estrogen depleted mice.
- Published
- 2023
16. Supplementary Figure 5 from Low Levels of Circulating Estrogen Sensitize PTEN-Null Endometrial Tumors to PARP Inhibition In Vivo
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Sanaz Memarzadeh, Kym Faull, Michael E. Jung, Christopher M. Ryan, Huseyin Kayadibi, Owen N. Witte, Donghui Cheng, Brian Yep, Miguel A. Rosales, Daniel Y. Paik, and Deanna M. Janzen
- Abstract
PDF file - 322K, Figure S5. Levels of Rad51 transcript were higher in estrogen supplemented PTEN-null endometrial epithelia.
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- 2023
17. Supplementary Methods, Figure Legend, Table 1 from Low Levels of Circulating Estrogen Sensitize PTEN-Null Endometrial Tumors to PARP Inhibition In Vivo
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Sanaz Memarzadeh, Kym Faull, Michael E. Jung, Christopher M. Ryan, Huseyin Kayadibi, Owen N. Witte, Donghui Cheng, Brian Yep, Miguel A. Rosales, Daniel Y. Paik, and Deanna M. Janzen
- Abstract
PDF file - 84K, Supplementary Table S1. Antibodies used for immunostaining.
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- 2023
18. Supplementary Figure 2 from Low Levels of Circulating Estrogen Sensitize PTEN-Null Endometrial Tumors to PARP Inhibition In Vivo
- Author
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Sanaz Memarzadeh, Kym Faull, Michael E. Jung, Christopher M. Ryan, Huseyin Kayadibi, Owen N. Witte, Donghui Cheng, Brian Yep, Miguel A. Rosales, Daniel Y. Paik, and Deanna M. Janzen
- Abstract
PDF file - 409K, Figure S2. The histology of Olaparib treated estrogen deprived PTEN-null tumors was similar to vehicle treated counterparts and resembled human endometrioid endometrial carcinoma.
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- 2023
19. Supplementary Figure 4 from Low Levels of Circulating Estrogen Sensitize PTEN-Null Endometrial Tumors to PARP Inhibition In Vivo
- Author
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Sanaz Memarzadeh, Kym Faull, Michael E. Jung, Christopher M. Ryan, Huseyin Kayadibi, Owen N. Witte, Donghui Cheng, Brian Yep, Miguel A. Rosales, Daniel Y. Paik, and Deanna M. Janzen
- Abstract
PDF file - 139K, Figure S4. Three-dimensional in vitro model for growth and treatment of PTEN-null epithelia co-cultured with WT endometrial stroma.
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- 2023
20. Data from Low Levels of Circulating Estrogen Sensitize PTEN-Null Endometrial Tumors to PARP Inhibition In Vivo
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Sanaz Memarzadeh, Kym Faull, Michael E. Jung, Christopher M. Ryan, Huseyin Kayadibi, Owen N. Witte, Donghui Cheng, Brian Yep, Miguel A. Rosales, Daniel Y. Paik, and Deanna M. Janzen
- Abstract
Earlier in vitro work demonstrated that PARP inhibition induces cell death in PTEN-null endometrial cancer cell lines, but the in vivo therapeutic efficacy of these agents against endometrial cancer remains unknown. Here, we test the efficacy of AZD2281 (olaparib), an oral PARP inhibitor, in the therapy of PTEN-null endometrial tumors in a preclinical endometrial cancer mouse model. Primary endometrial tumors were generated by epithelial loss of PTEN using an in vivo model. This model recapitulates epithelial-specific loss of PTEN seen in human tumors, and histologically resembles endometrioid carcinomas, the predominant subtype of human endometrial cancers. Olaparib was administered orally to tumor-bearing mice in two hormonal extremes: high or low estrogen. Olaparib treatment achieved a significant reduction in tumor size in a low estrogenic milieu. In striking contrast, no response to olaparib was seen in tumors exposed to high levels of estrogen. Two key observations were made when estrogen levels were dropped: (i) the serum concentration of olaparib was significantly increased, resulting in sustained PARP inhibition at the tumor bed; and (ii) the homologous recombination pathway was compromised, as evidenced by decreased Rad51 protein expression and function. These two mechanisms may account for the sensitization of PTEN-null tumors to olaparib with estrogen deprivation. Results of this preclinical trial suggest that orally administered PARP inhibitors in a low estrogenic hormonal milieu can effectively target PTEN-null endometrial tumors. Extension of this work to clinical trials could personalize the therapy of women afflicted with advanced endometrial cancer using well-tolerated orally administered therapeutic agents. Mol Cancer Ther; 12(12); 2917–28. ©2013 AACR.
- Published
- 2023
21. Supplementary Figure 1 from Low Levels of Circulating Estrogen Sensitize PTEN-Null Endometrial Tumors to PARP Inhibition In Vivo
- Author
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Sanaz Memarzadeh, Kym Faull, Michael E. Jung, Christopher M. Ryan, Huseyin Kayadibi, Owen N. Witte, Donghui Cheng, Brian Yep, Miguel A. Rosales, Daniel Y. Paik, and Deanna M. Janzen
- Abstract
PDF file - 422K, Figure S1. Despite Olaparib therapy, PTEN-null endometrial tumors persisted and resembled human endometrial endometrioid cancers.
- Published
- 2023
22. Defining T cell receptor repertoires using nanovial-based affinity and functional screening
- Author
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Doyeon Koo, Zhiyuan Mao, Robert Dimatteo, Natalie Tsubamoto, Miyako Noguchi, Jami McLaughlin, Wendy Tran, Sohyung Lee, Donghui Cheng, Joseph de Rutte, Giselle Burton Sojo, Owen N. Witte, and Dino Di Carlo
- Abstract
The ability to selectively bind to antigenic peptides and secrete cytokines can define populations of cells with therapeutic potential in emerging T cell receptor (TCR) immunotherapies. We leverage cavity-containing hydrogel microparticles, called nanovials, each coated with millions of peptide-major histocompatibility complex (pMHC) monomers to isolate antigen-reactive T cells. T cells are captured and activated by pMHCs and secrete cytokines on nanovials, allowing sorting based on both affinity and function. The TCRs of sorted cells on nanovials are sequenced, recovering paired αβ-chains using microfluidic emulsion-based single-cell sequencing. By labeling nanovials having different pMHCs with unique oligonucleotide-barcodes we could link TCR sequence to targets with 100% accuracy. We identified with high specificity an expanded repertoire of functional TCRs targeting viral antigens compared to standard techniques.One-sentence SummaryAffinity and secretion-based screening of antigen-specific T cells using nanovials defines a functional TCR repertoire
- Published
- 2023
23. The RNA-binding proteins hnRNP H and F regulate splicing of a MYC-dependent HRAS exon in prostate cancer cells.
- Author
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Xinyuan Chen, Yang, Harry Taegyun, Beatrice Zhang, Phillips, John W., Donghui Cheng, Rigo, Frank, Witte, Owen N., Yi Xing, and Black, Douglas L.
- Subjects
RNA-binding proteins ,PROSTATE cancer ,ALTERNATIVE RNA splicing ,CANCER cells ,GENE expression - Abstract
The MYC proto-oncogene contributes to the pathogenesis of more than half of human cancers. Malignant transformation by MYC transcriptionally up-regulates the core pre-mRNA splicing machinery and causes misregulation of alternative splicing. However, our understanding of how splicing changes are directed by MYC is limited. We performed a signaling pathway-guided splicing analysis to identify MYC-dependent splicing events. These included an HRAS cassette exon repressed by MYC across multiple tumor types. To molecularly dissect the regulation of this HRAS exon, we used antisense oligonucleotide tiling to identify splicing enhancers and silencers in its flanking introns. RNA-binding motif prediction indicated multiple binding sites for hnRNP H and hnRNP F within these cis-regulatory elements. Using siRNA knockdown and cDNA expression, we found that both hnRNP H and F activate the HRAS cassette exon. Mutagenesis and targeted RNA immunoprecipitation implicate two downstream G-rich elements in this splicing activation. Analyses of ENCODE RNA-seq datasets confirmed hnRNP H regulation of HRAS splicing. Analyses of RNA-seq datasets across multiple cancers showed a negative correlation of HNRNPH gene expression with MYC hallmark enrichment, consistent with the effect of hnRNP H on HRAS splicing. Interestingly, HNRNPF expression showed a positive correlation with MYC hallmarks and thus was not consistent with the observed effects of hnRNP F. Loss of hnRNP H/F altered cell cycle progression and induced apoptosis in the PC3 prostate cancer cell line. Collectively, our results reveal mechanisms for MYC-dependent regulation of splicing and point to possible therapeutic targets in prostate cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
24. The RNA binding proteins hnRNP H and F regulate splicing of a MYC dependent HRAS exon in Prostate Cancer Cells
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Xinyuan Chen, Harry Taegyun Yang, Beatrice Zhang, John W. Phillips, Donghui Cheng, Frank Rigo, Owen N. Witte, Yi Xing, and Douglas L. Black
- Abstract
The Myc proto-oncogene contributes to the pathogenesis of more than half of human cancers. Malignant transformation by Myc transcriptionally upregulates the core pre-mRNA splicing machinery and causes mis-regulation of alternative splicing. However, our understanding of how splicing changes are directed by Myc is limited. We performed a signaling pathway-guided splicing analysis to identify Myc dependent splicing events. These included an HRAS cassette exon repressed by Myc across multiple tumor types. To molecularly dissect the regulation of this HRAS exon, we used antisense oligonucleotide tiling to identify splicing enhancers and silencers in its flanking introns. RNA binding motif prediction indicated multiple binding sites for hnRNP H and hnRNP F within these cis-regulatory elements. Using siRNA knockdown and cDNA expression, we found that both hnRNP H and F activate the HRAS cassette exon.Mutagenesis and targeted RNA immunoprecipitation implicate two downstream G-rich elements in this splicing activation. Analyses of ENCODE RNA-seq datasets confirmed hnRNP H regulation of HRAS splicing. Analyses of RNA-seq datasets across multiple cancers showed a negative correlation of hnRNP H gene expression with Myc hallmark enrichment, consistent with the effect of hnRNP H on HRAS splicing. Interestingly, hnRNP F expression showed a positive correlation with Myc hallmarks and thus was not consistent with the observed effects of hnRNP F. Loss of hnRNP H/F altered cell cycle progression and induced apoptosis in the PC3 prostate cancer cell line. Collectively, our results reveal new mechanisms for Myc-dependent regulation of splicing, and point to new possible therapeutic targets in prostate cancers.SIGNIFICANCE STATMENTMyc Transformation by the proto-oncogene c-Myc causes dysregulation of the pre-mRNA splicing reaction in cancer, but it is not known how mRNA isoform changes are directed by Myc. Here, we use bioinformatics to identify a splicing event in another proto-oncogene, HRAS, that is regulated by Myc across multiple tumor types. We identify new splicing regulators, hnRNP’s H and F, that control this HRAS exon by binding to enhancer elements within its downstream intron. Additional pan-cancer bioinformatic analyses show hnRNP H expression to be anti- correlated with Myc hallmarks, consistent with the reduced splicing of the HRAS exon in Myc driven cancer. These findings uncover new mechanisms by which Myc can alter splicing in cancer cells and provide new molecular targets for potential therapeutics.
- Published
- 2022
25. Physical and in silico immunopeptidomic profiling of a cancer antigen prostatic acid phosphatase reveals targets enabling TCR isolation
- Author
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Zhiyuan Mao, Pavlo A. Nesterenko, Jami McLaughlin, Weixian Deng, Giselle Burton Sojo, Donghui Cheng, Miyako Noguchi, William Chour, Diana C. DeLucia, Kathryn A. Finton, Yu Qin, Matthew B. Obusan, Wendy Tran, Liang Wang, Nathanael J. Bangayan, Lisa Ta, Chia-Chun Chen, Christopher S. Seet, Gay M. Crooks, John W. Phillips, James R. Heath, Roland K. Strong, John K. Lee, James A. Wohlschlegel, and Owen N. Witte
- Subjects
immunopeptidome ,Mononuclear ,Acid Phosphatase ,Receptors, Antigen, T-Cell ,Vaccine Related ,Epitopes ,Antigens, Neoplasm ,Clinical Research ,Neoplasms ,Receptors ,HLA-A2 Antigen ,Leukocytes ,Humans ,2.1 Biological and endogenous factors ,Antigens ,Aetiology ,Cancer ,Multidisciplinary ,HLA-A Antigens ,Prevention ,major histocompatibility complexes ,T-Cell ,prostate cancer ,Antigen ,Leukocytes, Mononuclear ,Neoplasm ,Immunization ,T cell receptor ,Peptides ,prostatic acid phosphatase - Abstract
Tissue-specific antigens can serve as targets for adoptive T cell transfer-based cancer immunotherapy. Recognition of tumor by T cells is mediated by interaction between peptide–major histocompatibility complexes (pMHCs) and T cell receptors (TCRs). Revealing the identity of peptides bound to MHC is critical in discovering cognate TCRs and predicting potential toxicity. We performed multimodal immunopeptidomic analyses for human prostatic acid phosphatase (PAP), a well-recognized tissue antigen. Three physical methods, including mild acid elution, coimmunoprecipitation, and secreted MHC precipitation, were used to capture a thorough signature of PAP on HLA-A*02:01. Eleven PAP peptides that are potentially A*02:01-restricted were identified, including five predicted strong binders by NetMHCpan 4.0. Peripheral blood mononuclear cells (PBMCs) from more than 20 healthy donors were screened with the PAP peptides. Seven cognate TCRs were isolated which can recognize three distinct epitopes when expressed in PBMCs. One TCR shows reactivity toward cell lines expressing both full-length PAP and HLA-A*02:01. Our results show that a combined multimodal immunopeptidomic approach is productive in revealing target peptides and defining the cloned TCR sequences reactive with prostatic acid phosphatase epitopes.
- Published
- 2022
26. Rhodium(III)-Catalyzed Alkenyl C–H Functionalization to Dienes and Allenes
- Author
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Ying Chen, Wei Wei, Donghui Cheng, Yi Lu, Yuelu Zhu, Xinyang Zhao, Jing Zhao, and Feng Chen
- Subjects
010405 organic chemistry ,Organic Chemistry ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,0104 chemical sciences ,Rhodium ,Catalysis ,chemistry ,Surface modification ,Stereoselectivity ,Physical and Theoretical Chemistry - Abstract
An oxyacetamide-directed Rh(III)-catalyzed Z-type alkenyl C-H functionalization through a rare exo-rhodacyle intermediate is described, forming multisubstituted dienes and allenes. A variety of alkenes and propargylic carbonate coupling partners are suitable for this transformation with high regio- and stereoselectivity. The synthetic utility is demonstrated by the selective late-stage modification of the Z-type natural products as well as the synthesis of the unnatural β-amino acid.
- Published
- 2020
27. HLA-A∗02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses
- Author
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Pavlo A. Nesterenko, Jami McLaughlin, Brandon L. Tsai, Giselle Burton Sojo, Donghui Cheng, Daniel Zhao, Zhiyuan Mao, Nathanael J. Bangayan, Matthew B. Obusan, Yapeng Su, Rachel H. Ng, William Chour, Jingyi Xie, Yan-Ruide Li, Derek Lee, Miyako Noguchi, Camille Carmona, John W. Phillips, Jocelyn T. Kim, Lili Yang, James R. Heath, Paul C. Boutros, and Owen N. Witte
- Subjects
Receptors, Antigen, T-Cell, alpha-beta ,viruses ,T cells ,Cell Culture Techniques ,Receptors, Antigen, T-Cell ,Epitopes, T-Lymphocyte ,CD8-Positive T-Lymphocytes ,Cross Reactions ,General Biochemistry, Genetics and Molecular Biology ,immune response ,antigen ,Report ,HLA-A2 Antigen ,Humans ,Coronavirus RNA-Dependent RNA Polymerase ,HLA-A Antigens ,SARS-CoV-2 ,Immunodominant Epitopes ,COVID-19 ,virus diseases ,CD8 ,specific ,single-cell ,Spike Glycoprotein, Coronavirus ,Leukocytes, Mononuclear ,RNA, Viral ,cell therapy ,TCR - Abstract
Cross-reactivity and direct killing of target cells remain underexplored for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific CD8+ T cells. Isolation of T cell receptors (TCRs) and overexpression in allogeneic cells allows for extensive T cell reactivity profiling. We identify SARS-CoV-2 RNA-dependent RNA polymerase (RdRp/NSP12) as highly conserved, likely due to its critical role in the virus life cycle. We perform single-cell TCRαβ sequencing in human leukocyte antigen (HLA)-A∗02:01-restricted, RdRp-specific T cells from SARS-CoV-2-unexposed individuals. Human T cells expressing these TCRαβ constructs kill target cell lines engineered to express full-length RdRp. Three TCR constructs recognize homologous epitopes from common cold coronaviruses, indicating CD8+ T cells can recognize evolutionarily diverse coronaviruses. Analysis of individual TCR clones may help define vaccine epitopes that can induce long-term immunity against SARS-CoV-2 and other coronaviruses., Graphical abstract, Nesterenko et al. identify T cell responses with potential to confer long-term immunity against SARS-CoV-2. The machinery responsible for replicating the viral genome is highly conserved and, as shown by Nesterenko et al., can be effectively targeted by CD8+ T cells.
- Published
- 2021
28. A hydrographic method to identify the groundwater net recharge, barometric effect and evapotranspiration from a complicated semidiurnal water table fluctuation
- Author
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Lijun Qi, Donghui Cheng, and Jing Yuan
- Subjects
Hydrology ,Water table ,Evapotranspiration ,Environmental science ,Groundwater recharge ,Hydrography ,Groundwater ,Water Science and Technology - Published
- 2021
29. Abstract 789: Elucidating transcriptional dynamics in neuroendocrine differentiation of advanced prostate cancer
- Author
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Chia-Chun Chen, Kai Song, Wendy Tran, Matthew Obusan, Tyler Sugimoto, Katherine Sheu, Donghui Cheng, Grigor Varuzhanyan, Liang Wang, Lisa Ta, Zhiyuan Mao, Nathanael Bangayan, Jung-Wook Park, Thomas Graerber, and Owen Witte
- Subjects
Cancer Research ,Oncology - Abstract
Small cell carcinomas of the lung, bladder, and prostate share similar transcription patterns and drug sensitivities. Due to their high cellular plasticity, these cancers often escape treatment through a trans-differentiation from adenocarcinoma to the neuroendocrine state. We previously developed a pan small cell cancer in vitro/in vivo model named PARCB that can recapitulate this transition from primary patient tissues. To understand which transcription factors may be important in this transition, we conducted bulk and single cell RNA sequencing over time. We identified a developmental trajectory that is shared among all samples and is defined by stage-specific transcription factors. We plan to interrogate the role that these transcription factors play in the PARCB transformation assay. We performed ATAC sequencing to investigate how these transcription factors regulate these transitional states. Our study will provide a basic understanding of the transcriptional changes that occur during neuroendocrine differentiation and provide new potential therapeutic targets for small cell cancers. Citation Format: Chia-Chun Chen, Kai Song, Wendy Tran, Matthew Obusan, Tyler Sugimoto, Katherine Sheu, Donghui Cheng, Grigor Varuzhanyan, Liang Wang, Lisa Ta, Zhiyuan Mao, Nathanael Bangayan, Jung-Wook Park, Thomas Graerber, Owen Witte. Elucidating transcriptional dynamics in neuroendocrine differentiation of advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 789.
- Published
- 2022
30. Abstract 2438: Determining the role of non-mutated C-Raf kinase in metastatic disease
- Author
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Lisa H. Ta, Janai R. Carr-Ascher, Weixian Deng, Brandon L. Tsai, Wendy Tran, Donny Gun, Donghui Cheng, Jihui Sha, Yeonjoo Hwang, John W. Phillips, Matthew B. Obusan, Nathanael J. Bangayan, Miyako Noguchi, Zhiyuan Mao, Chia-Chun Chen, Liang Wang, Grigor Varuzhanyan, John D. Gordon, James W. Wohlschlegel, and Owen N. Witte
- Subjects
Cancer Research ,Oncology - Abstract
Many aggressive epithelial cancers do not carry targetable driver mutations (Mendiratta et al. 2021, NCI-MATCH Clinical trial NCT02465060). Commonly altered signaling pathways highlight the propensity for tumors to depend on such pathways for growth and survival where genomic alterations may not be required for pathway activation. The Raf family kinases are crucial mediators of the Ras/Raf/MEK/ERK (MAPK) cascade, which has been shown to be upregulated in a subset of metastatic cancers and are mutated in many epithelial cancers. A recent study suggests non-mutated C-Raf can drive metastasis to the lungs, bone, and various other tissues (Faltermeir et al. 2016). Though the mechanism of C-Raf driven metastasis is likely through MAPK activation, C-Raf has been demonstrated to possess MAPK independent roles that may also contribute to this phenotype. In this study, we explored various C-Raf functions as drivers of metastasis in an intracardiac mouse model system. Using a series of Raf knock-out cell lines and mutants targeting functional residues in C-Raf, we demonstrated that C-Raf dimerization is necessary to drive metastasis. We further showed that the metastasis-promoting activity of C-Raf is dependent on co-expression of its family member, B-Raf, for an accelerated metastatic phenotype. However, overexpression of a kinase-dead C-Raf mutant was still able to produce metastases albeit with lower efficiency, suggesting C-Raf possesses non-kinase dependent functions that also contributed to metastasis. Together, these results point to the importance of Raf non-canonical roles in oncogenic processes that may be unappreciated in metastatic disease. Citation Format: Lisa H. Ta, Janai R. Carr-Ascher, Weixian Deng, Brandon L. Tsai, Wendy Tran, Donny Gun, Donghui Cheng, Jihui Sha, Yeonjoo Hwang, John W. Phillips, Matthew B. Obusan, Nathanael J. Bangayan, Miyako Noguchi, Zhiyuan Mao, Chia-Chun Chen, Liang Wang, Grigor Varuzhanyan, John D. Gordon, James W. Wohlschlegel, Owen N. Witte. Determining the role of non-mutated C-Raf kinase in metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2438.
- Published
- 2022
31. Droplet-based mRNA sequencing of fixed and permeabilized cells by CLInt-seq allows for antigen-specific TCR cloning
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Zhiyuan Mao, John W. Phillips, Matthew B. Obusan, Donghui Cheng, Jami McLaughlin, Pavlo A Nesterenko, Nathanael J Bangayan, Christopher S. Seet, Yu Qin, Owen N. Witte, and Giselle Burton Sojo
- Subjects
0301 basic medicine ,Epstein-Barr Virus Infections ,T-Lymphocytes ,Messenger ,Cytomegalovirus ,CD8-Positive T-Lymphocytes ,Epitopes ,0302 clinical medicine ,Receptors ,2.1 Biological and endogenous factors ,RNA-Seq ,Aetiology ,Multidisciplinary ,Chemistry ,Forkhead Transcription Factors ,Regulatory ,Cell biology ,Infectious Diseases ,030220 oncology & carcinogenesis ,Antigen ,HIV/AIDS ,Single-Cell Analysis ,Intracellular ,TCR ,Human ,Biotechnology ,1.1 Normal biological development and functioning ,T cells ,mRNA sequencing ,single-cell sequencing ,Vaccine Related ,03 medical and health sciences ,Interferon-gamma ,Underpinning research ,Genetics ,Humans ,Transcription factor ,Cloning ,Messenger RNA ,Tumor Necrosis Factor-alpha ,Prevention ,Inflammatory and immune system ,T-cell receptor ,Human Genome ,Herpesvirus 4 ,Molecular ,T-Cell ,V(D)J Recombination ,030104 developmental biology ,MRNA Sequencing ,Single cell sequencing ,RNA ,T cell receptor - Abstract
T cell receptors (TCRs) are generated by somatic recombination of V/D/J segments to produce up to 1015 unique sequences. Highly sensitive and specific techniques are required to isolate and identify the rare TCR sequences that respond to antigens of interest. Here, we describe the use of mRNA sequencing via cross-linker regulated intracellular phenotype (CLInt-Seq) for efficient recovery of antigen-specific TCRs in cells stained for combinations of intracellular proteins such as cytokines or transcription factors. This method enables high-throughput identification and isolation of low-frequency TCRs specific for any antigen. As a proof of principle, intracellular staining for TNFα and IFNγ identified cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-reactive TCRs with efficiencies similar to state-of-the-art peptide-MHC multimer methodology. In a separate experiment, regulatory T cells were profiled based on intracellular FOXP3 staining, demonstrating the ability to examine phenotypes based on transcription factors. We further optimized the intracellular staining conditions to use a chemically cleavable primary amine cross-linker compatible with current single-cell sequencing technology. CLInt-Seq for TNFα and IFNγ performed similarly to isolation with multimer staining for EBV-reactive TCRs. We anticipate CLInt-Seq will enable droplet-based single-cell mRNA analysis from any tissue where minor populations need to be isolated by intracellular markers.
- Published
- 2021
32. Ras Homolog Family Member F, Filopodia Associated Promotes Hepatocellular Carcinoma Metastasis by Altering the Metabolic Status of Cancer Cells Through RAB3D
- Author
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Yu Liu, Shi Li, Jianling Xia, Mengwan Wu, Donghui Cheng, Yifeng Bai, and Min Chen
- Subjects
0301 basic medicine ,rho GTP-Binding Proteins ,Carcinoma, Hepatocellular ,Epithelial-Mesenchymal Transition ,rab3 GTP-Binding Proteins ,Biology ,AMP-Activated Protein Kinases ,Cell morphology ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Stress, Physiological ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Neoplasm Invasiveness ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,Phosphorylation ,Neoplasm Staging ,Hepatology ,Oncogene ,Liver Neoplasms ,AMPK ,Cell migration ,medicine.disease ,Prognosis ,Warburg effect ,digestive system diseases ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cancer cell ,Cancer research ,030211 gastroenterology & hepatology - Abstract
Background and aims The mechanism by which tumor cells resist metabolic stress remains unclear, but many oncogenes are known to regulate this process. Accordingly, metabolic stress is closely associated with tumor metastasis. In this study, gene chip technology showed that Ras homolog family member F, filopodia associated (RHOF), a member of the Rho guanosine triphosphatase family, is an oncogene that is significantly related to hepatocellular carcinoma (HCC) metastasis; however, it has rarely been reported in tumors. Our aim was to determine the clinicopathological significance and role of RHOF in HCC progression and investigate the associated mechanisms. Approach and results The results showed that compared to expression in adjacent noncancerous tissues, RHOF was frequently up-regulated in HCC tumor samples and elevated under conditions of glucose deprivation. RHOF expression was associated with tumor-node-metastasis stage, T grade, metastasis status, recurrence, and survival in HCC. RHOF also affected cell morphology and promoted migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cell lines. Analysis of the underlying mechanism showed that RHOF promoted the Warburg effect by up-regulating the expression and function of several glycolytic enzymes in HCC cells. This metabolic shift enhanced HCC cell migration and invasion. Specifically, RHOF exerted a tumor-promoting effect by directly interacting with AMP-activated protein kinase (AMPK) and increasing the phosphorylation of AMPK. This subsequently affected RAB3D mRNA stability and led to elevated RAB3D expression, thereby amplifying the Warburg effect and malignant biological behaviors of HCC cells. Conclusions RHOF helps tumor cells resist metabolic stress through modulating the Warburg effect and plays a critical role in promoting HCC cell migration, invasion, and EMT, highlighting its important role in remodeling the metastatic microenvironment and regulating tumor metastasis. RHOF shows potential as a therapeutic target and prognostic biomarker for HCC.
- Published
- 2020
33. Pathway-guided analysis identifies Myc-dependent alternative pre-mRNA splicing in aggressive prostate cancers
- Author
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Yida Zhang, Harry Taegyun Yang, Brandon L. Tsai, Qiang Hu, Donghui Cheng, Yang Pan, Douglas L. Black, Song Liu, Zhijie Xie, Owen N. Witte, Wen Xiao, Yi Xing, Levon Demirdjian, Chia Ho Lin, and John W. Phillips
- Subjects
Male ,Lung Neoplasms ,rMATS ,RNA Splicing ,Datasets as Topic ,RNA-binding protein ,Breast Neoplasms ,Computational biology ,Myc ,Biology ,Adenocarcinoma ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Exon ,Prostate cancer ,alternative splicing ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,RNA Precursors ,Humans ,Computer Simulation ,RNA-Seq ,Frameshift Mutation ,Gene ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Alternative splicing ,PEGASAS ,Cancer ,Prostatic Neoplasms ,Exons ,Biological Sciences ,medicine.disease ,prostate cancer ,Stop codon ,3. Good health ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,RNA splicing ,Codon, Terminator ,Female ,Applied Biological Sciences ,Software ,Signal Transduction - Abstract
Significance Alternative pre-mRNA splicing is a regulated process that greatly diversifies gene products by changing the exons incorporated into mRNA. This process is dysregulated in cancers. Here, we studied exon usage in aggressive prostate cancers and linked exon incorporation decisions to cancer driver genes. Through computational and experimental studies, we found that a strong cancer driver gene, Myc, was linked to exon changes in genes that themselves regulate alternative splicing. These exons often encoded premature stop codons that would decrease gene expression, suggestive of a Myc-driven autoregulatory loop to help control levels of splicing regulatory proteins., We sought to define the landscape of alternative pre-mRNA splicing in prostate cancers and the relationship of exon choice to known cancer driver alterations. To do so, we compiled a metadataset composed of 876 RNA-sequencing (RNA-Seq) samples from five publicly available sources representing a range of prostate phenotypes from normal tissue to drug-resistant metastases. We subjected these samples to exon-level analysis with rMATS-turbo, purpose-built software designed for large-scale analyses of splicing, and identified 13,149 high-confidence cassette exon events with variable incorporation across samples. We then developed a computational framework, pathway enrichment-guided activity study of alternative splicing (PEGASAS), to correlate transcriptional signatures of 50 different cancer driver pathways with these alternative splicing events. We discovered that Myc signaling was correlated with incorporation of a set of 1,039 cassette exons enriched in genes encoding RNA binding proteins. Using a human prostate epithelial transformation assay, we confirmed the Myc regulation of 147 of these exons, many of which introduced frameshifts or encoded premature stop codons. Our results connect changes in alternative pre-mRNA splicing to oncogenic alterations common in prostate and many other cancers. We also establish a role for Myc in regulating RNA splicing by controlling the incorporation of nonsense-mediated decay-determinant exons in genes encoding RNA binding proteins.
- Published
- 2020
34. Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer
- Author
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Sitao Wu, Yan Chang, Kefeng Lei, Jiaoti Huang, Yanjing Li, Qianben Wang, Yiping He, Qing Yang, Suzette Farber-Katz, Allen C. Gao, Qingfu Zhang, Hailiang Hu, John K. Lee, Donghui Cheng, Tyler Landrith, Qing Cheng, Yinglu Zhou, Shannon J. McCall, Matthew Rettig, Vickie Hsuan, Jung-Wook Park, Andrew S. Goldstein, Owen N. Witte, Rachid Karam, Bryan A. Smith, Xufeng Chen, Andrew J. Armstrong, Bing Li, Hong Zhang, Daniel G. Taylor, Melissa Flowers, Lingfan Xu, and William Butler
- Subjects
Male ,Aging ,Nude ,Drug Resistance ,Medical and Health Sciences ,Receptors, Interleukin-8B ,Chemokine receptor ,Prostate cancer ,Mice ,Receptors ,Tumor Microenvironment ,2.1 Biological and endogenous factors ,CXC chemokine receptors ,Molecular Targeted Therapy ,Aetiology ,Receptor ,Cancer ,Tumor ,Neovascularization, Pathologic ,Prostate Cancer ,General Medicine ,Biological Sciences ,Neuroendocrine Tumors ,Phenotype ,5.1 Pharmaceuticals ,Disease Progression ,Neoplastic Stem Cells ,Adenocarcinoma ,Hormonal therapy ,Development of treatments and therapeutic interventions ,Signal Transduction ,Urologic Diseases ,Mice, Nude ,Article ,Cell Line ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Interleukin-8B ,Neovascularization ,Pathologic ,Tumor microenvironment ,business.industry ,Cell Membrane ,Prostatic Neoplasms ,medicine.disease ,Neurosecretory Systems ,Androgen receptor ,Drug Resistance, Neoplasm ,Cancer research ,Neoplasm ,Neoplasm Grading ,business ,Biomarkers - Abstract
Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR(+) luminal tumor cells and AR(−) neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR(+) luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
- Published
- 2019
35. 18F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis
- Author
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John S. Van Arnam, Jessica R. Salas, Alicia Wong, Peter M. Clark, Owen N. Witte, Bao Ying Chen, and Donghui Cheng
- Subjects
CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Chronic Liver Disease and Cirrhosis ,Clinical Sciences ,PET imaging ,autoimmune disease ,Inflammation ,Autoimmune hepatitis ,CD8-Positive T-Lymphocytes ,Diagnostic Radiology ,Hepatitis ,Mice ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Immune system ,Infection/Inflammation ,Positron Emission Tomography Computed Tomography ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Inbred BALB C ,Autoimmune disease ,medicine.diagnostic_test ,Animal ,Liver Disease ,Cytarabine ,medicine.disease ,Nuclear Medicine & Medical Imaging ,Good Health and Well Being ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,030220 oncology & carcinogenesis ,Liver biopsy ,Hepatocyte ,Disease Models ,Biomedical Imaging ,hepatocytes ,medicine.symptom ,Digestive Diseases ,Viral hepatitis ,Autoimmune - Abstract
Immune cell–mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation ((18)F-FDG and (18)F-1-(2′-deoxy-2′-fluoro-arabinofuranosyl)cytosine [(18)F-FAC]) and hepatocyte biology ((18)F-2-deoxy-2-fluoroarabinose [(18)F-DFA]) can visualize and quantify liver-infiltrating immune cells and hepatocyte inflammation, respectively, in a preclinical model of autoimmune hepatitis. Methods: Mice treated with concanavalin A (ConA) to induce a model of autoimmune hepatitis or vehicle were imaged with (18)F-FDG, (18)F-FAC, and (18)F-DFA PET. Immunohistochemistry, digital autoradiography, and ex vivo accumulation assays were used to localize areas of altered radiotracer accumulation in the liver. For comparison, mice treated with an adenovirus to induce a viral hepatitis were imaged with (18)F-FDG, (18)F-FAC, and (18)F-DFA PET. (18)F-FAC PET was performed on mice treated with ConA and vehicle or with ConA and dexamethasone. Biopsy samples of patients with autoimmune hepatitis were immunostained for deoxycytidine kinase. Results: Hepatic accumulation of (18)F-FDG and (18)F-FAC was 173% and 61% higher, respectively, and hepatic accumulation of (18)F-DFA was 41% lower, in a mouse model of autoimmune hepatitis than in control mice. Increased hepatic (18)F-FDG accumulation was localized to infiltrating leukocytes and inflamed sinusoidal endothelial cells, increased hepatic (18)F-FAC accumulation was concentrated in infiltrating CD4 and CD8 cells, and decreased hepatic (18)F-DFA accumulation was apparent in hepatocytes throughout the liver. In contrast, viral hepatitis increased hepatic (18)F-FDG accumulation by 109% and decreased hepatic (18)F-DFA accumulation by 20% but had no effect on hepatic (18)F-FAC accumulation (nonsignificant 2% decrease). (18)F-FAC PET provided a noninvasive biomarker of the efficacy of dexamethasone for treating the autoimmune hepatitis model. Infiltrating leukocytes in liver biopsy samples from patients with autoimmune hepatitis express high levels of deoxycytidine kinase, a rate-limiting enzyme in the accumulation of (18)F-FAC. Conclusion: Our data suggest that PET can be used to noninvasively visualize activated leukocytes and inflamed hepatocytes in a mouse model of autoimmune hepatitis.
- Published
- 2018
36. Design method for concrete columns strengthened with prestressed CFRP sheets
- Author
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Donghui Cheng and Yanhong Yang
- Subjects
Carbon fiber reinforced polymer ,Ultimate load ,Bearing (mechanical) ,Materials science ,business.industry ,0211 other engineering and technologies ,020101 civil engineering ,02 engineering and technology ,Building and Construction ,Structural engineering ,Compression (physics) ,0201 civil engineering ,law.invention ,Stress (mechanics) ,Compressive strength ,law ,021105 building & construction ,Ultimate tensile strength ,General Materials Science ,Bearing capacity ,Composite material ,business ,Civil and Structural Engineering - Abstract
To improve upon the bearing capacities of short circular concrete columns strengthened with carbon fiber reinforced polymer (CFRP) sheets, this paper conducted experimental and numerical investigations to study the influencing factors on the compressive strength of CFRP-strengthened concrete columns, including the preloading of columns, the prestressing applied to CFRP sheets and the number of layers of CFRP sheets. The test columns consisted of an un-strengthened control column in addition to 10 preloaded and non-preloaded columns strengthened in compression with one or two CFRP layers at prestress levels of either 300 MPa or 600 MPa. These columns were tested under an axial load. The failure modes, stress changes, bearing capacities and load–longitudinal displacement behaviors of the tested specimens were recorded and discussed. Furthermore, the finite element models (FEM) of 10 strengthened columns were developed and validated by comparing the load–longitudinal displacement curves obtained through finite element analysis (FEA) with those retrieved experimentally. A parametric study was subsequently performed using the validated FEM to investigate the effects of preloading, prestressing and the number of CFRP layers. The parametric study demonstrated that the strain lag caused by preloading was negatively related to the compressive strength of the CFRP-strengthened columns. In addition, prestressing could reduce the negative effects of preloading and could improve on the utilization of CFRP tensile strength. Furthermore, the yield load of CFRP-strengthened concrete columns was improved correlative with an increment of the number of layers and the prestress levels of the CFRP sheets. Conversely, whereas the ultimate load only improved with an increment of the number of layers of CFRP sheets, it had no obvious relationship with the prestress levels of the CFRP sheets and was instead related to their ultimate tensile strength. Based on the test data, the bearing capacity formulas for preloaded and non-preloaded short circular concrete columns strengthened with prestressed CFRP sheets were proposed. Subsequently, the presented formulas were confirmed to be reasonably accurate by comparing the bearing capacities calculated numerically with those measured experimentally.
- Published
- 2017
37. Characteristics of inverted saturated zone under unclogged streams
- Author
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Donghui Cheng, Jie Li, Dawei Cheng, and Hongbin Zhan
- Subjects
010504 meteorology & atmospheric sciences ,Water table ,Flow (psychology) ,0207 environmental engineering ,Flux ,02 engineering and technology ,Mechanics ,Infiltration (HVAC) ,01 natural sciences ,Hydraulic head ,Hydraulic conductivity ,Free surface ,020701 environmental engineering ,Saturation (chemistry) ,Geology ,0105 earth and related environmental sciences ,Water Science and Technology - Abstract
Unclogged streams are widespread in nature and can generate dynamic inverted saturated zones (ISZ) underneath the streams above the regional water tables. This study is devoted to investigating the evolutional process of such an ISZ and its frontal movement. It defines a uniform saturation zone by moving the boundary of saturation flow from the inverted water table (IWT) to the end of the capillary saturation zone. Consequently, the conventional concept of specific yield, infiltration rate and governing equation at the ISZ frontal surface (IFS) must be revisited. Two new ISZ models are developed and quantified with great details with infiltration rate being constant and variable. The equations of hydraulic head profile development and the IFS are obtained. This study indicates that classical free surface equations, locating at IWT, is not self-consistent. The water balance requirement is not satisfied at IFS in the Green and Ampt (1911) model or the Polubarinova-Kochina (1962) model, causing physically unrealistic spatial variables. The increase of the IFS with time exhibits three different modes depending on the infiltration rate and the saturated hydraulic conductivity. The maximum depth of an IFS (corresponding to a depth with infiltration rate being stable) is linearly correlated with stream stage and air-entry head. The streambed infiltration flux decreases with time and appears to exhibit three modes similar to the IFS evolution. The findings of this study reconstruct the theoretical basis of the dynamic evolution process of stream-aquifer system and can help for better understanding of physical connotation of free surface equations and basic characteristics of ISZ evolution.
- Published
- 2021
38. Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL
- Author
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Joseph R. Boyd, Linn M Eggesbø, Hilde Schjerven, Jami McLaughlin, Eugene Park, Jessica L. Heath, Ida Lindeman, Stephen T. Smale, Etapong Fonabei Ayongaba, Donghui Cheng, Markus Müschen, Owen N. Witte, Ali Aghajanirefah, Seth Frietze, and Huimin Geng
- Subjects
0301 basic medicine ,Tumor suppressor gene ,Immunology ,Fusion Proteins, bcr-abl ,Antigens, CD34 ,Biology ,Article ,law.invention ,Ikaros Transcription Factor ,Mice ,03 medical and health sciences ,law ,Cell Line, Tumor ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,hemic and lymphatic diseases ,Transcriptional regulation ,Animals ,Humans ,Immunology and Allergy ,Research Articles ,Regulation of gene expression ,Genetics ,Leukosialin ,Gene Expression Regulation, Leukemic ,Tumor Suppressor Proteins ,Cell Cycle ,Cell cycle ,3. Good health ,Chromatin ,Cell biology ,Mice, Inbred C57BL ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,Suppressor - Abstract
Schjerven et al. compare mouse and human models of pre–B ALL to define conserved target genes and pathways of the tumor suppressor Ikaros, revealing CTNND1 and the early hematopoietic cell-surface receptors SPN (CD43) and CD34 as novel Ikaros targets that each confer oncogenic growth advantage., Inactivation of the tumor suppressor gene encoding the transcriptional regulator Ikaros (IKZF1) is a hallmark of BCR-ABL1+ precursor B cell acute lymphoblastic leukemia (pre–B ALL). However, the mechanisms by which Ikaros functions as a tumor suppressor in pre–B ALL remain poorly understood. Here, we analyzed a mouse model of BCR-ABL1+ pre–B ALL together with a new model of inducible expression of wild-type Ikaros in IKZF1 mutant human BCR-ABL1+ pre–B ALL. We performed integrated genome-wide chromatin and expression analyses and identified Ikaros target genes in mouse and human BCR-ABL1+ pre–B ALL, revealing novel conserved gene pathways associated with Ikaros tumor suppressor function. Notably, genetic depletion of different Ikaros targets, including CTNND1 and the early hematopoietic cell surface marker CD34, resulted in reduced leukemic growth. Our results suggest that Ikaros mediates tumor suppressor function by enforcing proper developmental stage–specific expression of multiple genes through chromatin compaction at its target genes.
- Published
- 2017
39. Groundwater evapotranspiration under psammophilous vegetation covers in the Mu Us Sandy Land, northern China
- Author
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Donghui Cheng, Jibo Duan, Kang Qian, Hong Bin Yang, Lijun Qi, and Xunhong Chen
- Subjects
Hydrology ,geography ,geography.geographical_feature_category ,010504 meteorology & atmospheric sciences ,Water table ,0208 environmental biotechnology ,Aquifer ,02 engineering and technology ,Vegetation ,Management, Monitoring, Policy and Law ,01 natural sciences ,Arid ,020801 environmental engineering ,Evapotranspiration ,Environmental science ,Drainage ,Water cycle ,Groundwater ,0105 earth and related environmental sciences ,Earth-Surface Processes ,Water Science and Technology - Abstract
Groundwater is a significant component of the hydrological cycle in arid and semi-arid areas. Its evapotranspiration is an important part of the water budget because many plants are groundwater-dependent. To restore the degraded ecosystems, the need is pressing to further our understanding of the groundwater evapotranspiration (ETg) in arid and semi-arid areas. This study employed the White method to estimate ETg at four sites in the Mu Us Sandy Land in northern China, and the four sites are covered by Salix psammophila (SP site), Artemisia ordosica (AO site), Poplar alba (PA site), and Carex enervis (CE site), respectively. The depth of groundwater table and the duration of drainage were taken into account in calculating the specific yield (Sy) to improve the accuracy of the ETg estimats. Our results showed that from late May to early November 2013 the ETg were 361.87 (SP site), 372.53 (AO site), 597.86 (PA site) and 700.76 mm (CE site), respectively. The estimated ETg rate was also species-dependent and the descending order of the ETg rate for the four vegetation was: C. enervis, P. alba, A. ordosica, and S. psammophila. In addition, the depth of groundwater table has an obvious effect on the ETg rate and the effect varied with the vegetation types. Furthermore, the evapotranspiration for the vegetation solely relying on the water supply from unsaturated layers above the groundwater table was much less than that for the vegetation heavily relying on the water supply from shallow aquifers.
- Published
- 2016
40. Sensitive Detection and Analysis of Neoantigen-Specific T Cell Populations from Tumors and Blood
- Author
-
John E. Heath, Alphonsus H. C. Ng, Songming Peng, Won Jun Noh, Jami McLaughlin, William Chour, Xiaozhe Ding, Michael T. Bethune, Antoni Ribas, Katherine Guo, Jongchan Choi, Yapeng Su, Alice Hsu, Jungwoo Kim, David Baltimore, Donghui Cheng, Elizabeth Holman, Jesse M. Zaretsky, Jing Zhou, James R. Heath, Yue Lu, Alexander M. Xu, and Owen N. Witte
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Biopsy ,T-Lymphocytes ,Cell ,Medical Physiology ,Programmed Cell Death 1 Receptor ,Major Histocompatibility Complex ,Jurkat Cells ,0302 clinical medicine ,Cancer immunotherapy ,Nucleic Acids ,Receptors ,Lymphocytes ,Magnetite Nanoparticles ,lcsh:QH301-705.5 ,Tomography ,Melanoma ,Cancer ,nanotechnology ,integumentary system ,3. Good health ,X-Ray Computed ,medicine.anatomical_structure ,Antigen ,Immunotherapy ,T cell ,microfluidics ,Receptors, Antigen, T-Cell ,Biology ,Major histocompatibility complex ,General Biochemistry, Genetics and Molecular Biology ,Article ,Vaccine Related ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,Antigens, Neoplasm ,medicine ,Genetics ,Humans ,Tumor-Infiltrating ,Antigens ,cancer immunotherapy ,T-cell receptor ,Reproducibility of Results ,medicine.disease ,T-Cell ,Kinetics ,030104 developmental biology ,Good Health and Well Being ,HEK293 Cells ,lcsh:Biology (General) ,biology.protein ,Cancer research ,Neoplasm ,Immunization ,Biochemistry and Cell Biology ,T cell receptor ,Tomography, X-Ray Computed ,030217 neurology & neurosurgery ,CD8 ,neoantigens - Abstract
SUMMARY Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanoparticles that present neoantigen-loaded major histocompatibility complex (MHC) tetramers at high avidity by barcoded DNA linkers. The magnetic particles provide a convenient handle to isolate the desired cell populations, and the barcoded DNA enables multiplexed analysis. The method exhibits superior recovery of antigen-specific T cell populations relative to literature approaches. We applied the method to profile neoantigen-specific T cell populations in the tumor and blood of patients with metastatic melanoma over the course of anti-PD1 checkpoint inhibitor therapy. We show that the method has value for monitoring clinical responses to cancer immunotherapy and might help guide the development of personalized mutational neoantigen-specific T cell therapies and cancer vaccines., Graphical Abstract, In Brief Peng et al. report a sensitive method to detect tumor-associated neoantigen-specific T cells. Neoantigens and fluorescent DNA barcodes, presented on nanoparticle scaffolds, permit multiplex capture and analysis of specific T cell populations from blood or tumor. Neoantigen-specific T cell numbers track tumor volume in a melanoma patient responding to immunotherapy.
- Published
- 2019
41. Development of Hematopoietic Stem Cell-Engineered Invariant Natural Killer T Cell Therapy for Cancer
- Author
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Yanni Zhu, Drake J. Smith, Yang Zhou, Yan-Ruide Li, Jiaji Yu, Derek Lee, Yu-Chen Wang, Stefano Di Biase, Xi Wang, Christian Hardoy, Josh Ku, Tasha Tsao, Levina J. Lin, Alexander T. Pham, Heesung Moon, Jami McLaughlin, Donghui Cheng, Roger P. Hollis, Beatriz Campo-Fernandez, Fabrizia Urbinati, Liu Wei, Larry Pang, Valerie Rezek, Beata Berent-Maoz, Mignonette H. Macabali, David Gjertson, Xiaoyan Wang, Zoran Galic, Scott G. Kitchen, Dong Sung An, Siwen Hu-Lieskovan, Paula J. Kaplan-Lefko, Satiro N. De Oliveira, Christopher S. Seet, Sarah M. Larson, Stephen J. Forman, James R. Heath, Jerome A. Zack, Gay M. Crooks, Caius G. Radu, Antoni Ribas, Donald B. Kohn, Owen N. Witte, and Lili Yang
- Subjects
invariant natural killer T cell ,medicine.medical_treatment ,Genetic enhancement ,Adoptive ,Mice, SCID ,HSC ,Regenerative Medicine ,stem cell therapy ,Medical and Health Sciences ,Immunotherapy, Adoptive ,sr39TK suicide gene ,Cell therapy ,Mice ,0302 clinical medicine ,Cancer immunotherapy ,Stem Cell Research - Nonembryonic - Human ,Neoplasms ,Receptors ,Cells, Cultured ,Cancer ,0303 health sciences ,Cultured ,Hematopoietic stem cell ,Stem-cell therapy ,Hematology ,Gene Therapy ,Biological Sciences ,Haematopoiesis ,medicine.anatomical_structure ,5.1 Pharmaceuticals ,Antigen ,iNKT ,HSCT ,Molecular Medicine ,Stem Cell Research - Nonembryonic - Non-Human ,Immunotherapy ,Development of treatments and therapeutic interventions ,Genetic Engineering ,TCR ,Biotechnology ,Cells ,Receptors, Antigen, T-Cell ,Biology ,SCID ,Article ,03 medical and health sciences ,Immune system ,medicine ,Genetics ,Animals ,Humans ,030304 developmental biology ,cancer immunotherapy ,5.2 Cellular and gene therapies ,Cell Biology ,medicine.disease ,T-Cell ,Stem Cell Research ,Hematopoietic Stem Cells ,Xenograft Model Antitumor Assays ,HSC transfer ,Cancer research ,Natural Killer T-Cells ,hematopoietic stem cell ,T cell receptor ,cell therapy ,preclinical development ,030217 neurology & neurosurgery ,Stem Cell Transplantation ,Developmental Biology - Abstract
Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been greatly hindered by their extremely low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells for a patient’s lifetime. Using a human HSC engrafted mouse model and a human iNKT TCR gene engineering approach, we demonstrated the efficient and long-term generation of HSC-iNKT cells in vivo. These HSC-iNKT cells closely resembled endogenous human iNKT cells, could deploy multiple mechanisms to attack tumor cells, and effectively suppressed tumor growth in vivo in multiple human tumor xenograft mouse models. Preclinical safety studies showed no toxicity or tumorigenicity of the intended HSC-iNKT cell therapy. Collectively, these results demonstrated the feasibility, safety, and cancer therapy potential of the proposed HSC-iNKT cell therapy and laid a foundation for future clinical development.
- Published
- 2019
42. Isolation and characterization of NY-ESO-1-specific T cell receptors restricted on various MHC molecules
- Author
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Lili Yang, Jonathan Cebon, Jiaji Yu, Michael T. Bethune, Colleen Mathis, Xiao-Hua Li, Cristina Puig-Saus, Antoni Ribas, Stephanie Wong, David Baltimore, Donghui Cheng, Jami McLaughlin, Siwen Hu-Lieskovan, Katherine Woods, Angel Garcia-Diaz, Owen N. Witte, Blanca Homet Moreno, and Ashley Knights
- Subjects
0301 basic medicine ,Medical Sciences ,Genetic enhancement ,Receptors, Antigen, T-Cell ,T cell receptor gene therapy ,Immune Targeting ,chemical and pharmacologic phenomena ,Major histocompatibility complex ,Epitope ,Major Histocompatibility Complex ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Clinical Research ,MHC class I ,Receptors ,Genetics ,Animals ,Humans ,NY-ESO-1 ,Cloning, Molecular ,Cancer ,Homeodomain Proteins ,Multidisciplinary ,biology ,5.2 Cellular and gene therapies ,Inflammatory and immune system ,T-cell receptor ,Molecular ,Gene Therapy ,Biological Sciences ,T-Cell ,3. Good health ,030104 developmental biology ,PNAS Plus ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,immunotherapy ,Development of treatments and therapeutic interventions ,MHC ,TCR ,Cloning - Abstract
Significance T immune cells can be engineered to express tumor-specific T cell receptor (TCR) genes and thereby kill cancer cells. This approach—termed TCR gene therapy—is effective but can cause serious adverse events if the target is also expressed in healthy, noncancerous tissue. NY-ESO-1 is a tumor-specific antigen that has been targeted successfully and safely through TCR gene therapies for melanoma, synovial sarcoma, and myeloma. However, trials to date have focused exclusively on a single NY-ESO-1–derived epitope presented on HLA-A*02:01, limiting application to patients expressing that allele. In this work, we isolate TCRs that collectively recognize multiple NY-ESO-1–derived epitopes presented by multiple MHC alleles. We thereby outline a general approach for expanding targeted immunotherapies to more diverse MHC haplotypes., Tumor-specific T cell receptor (TCR) gene transfer enables specific and potent immune targeting of tumor antigens. Due to the prevalence of the HLA-A2 MHC class I supertype in most human populations, the majority of TCR gene therapy trials targeting public antigens have employed HLA-A2–restricted TCRs, limiting this approach to those patients expressing this allele. For these patients, TCR gene therapy trials have resulted in both tantalizing successes and lethal adverse events, underscoring the need for careful selection of antigenic targets. Broad and safe application of public antigen-targeted TCR gene therapies will require (i) selecting public antigens that are highly tumor-specific and (ii) targeting multiple epitopes derived from these antigens by obtaining an assortment of TCRs restricted by multiple common MHC alleles. The canonical cancer-testis antigen, NY-ESO-1, is not expressed in normal tissues but is aberrantly expressed across a broad array of cancer types. It has also been targeted with A2-restricted TCR gene therapy without adverse events or notable side effects. To enable the targeting of NY-ESO-1 in a broader array of HLA haplotypes, we isolated TCRs specific for NY-ESO-1 epitopes presented by four MHC molecules: HLA-A2, -B07, -B18, and -C03. Using these TCRs, we pilot an approach to extend TCR gene therapies targeting NY-ESO-1 to patient populations beyond those expressing HLA-A2.
- Published
- 2018
43. Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage
- Author
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Brandon L. Tsai, Thomas G. Graeber, Jung-Wook Park, John K. Lee, Owen N. Witte, Jiaoti Huang, Liang Wang, Kim Nguyen, Bryan A. Smith, Nikolas G. Balanis, Chen Cheng, Donghui Cheng, Siavash K. Kurdistani, and Katherine M. Sheu
- Subjects
0301 basic medicine ,Male ,Aging ,Lung Neoplasms ,Carcinogenesis ,Cell ,Retinoblastoma Protein ,Epithelium ,Prostate cancer ,Drug Delivery Systems ,Prostate ,2.1 Biological and endogenous factors ,Cellular Reprogramming Techniques ,Aetiology ,Lung ,Cancer ,Multidisciplinary ,Tumor ,Prostate Cancer ,Lung Cancer ,Cellular Reprogramming ,medicine.anatomical_structure ,Neuroendocrine ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Reprogramming ,Urologic Diseases ,General Science & Technology ,Biology ,Article ,Cell Line ,03 medical and health sciences ,Rare Diseases ,Cell Line, Tumor ,medicine ,Carcinoma ,Genetics ,Humans ,Cell Lineage ,Epigenetics ,Transcription factor ,Human Genome ,Prostatic Neoplasms ,Epithelial Cells ,medicine.disease ,Small Cell Lung Carcinoma ,Carcinoma, Neuroendocrine ,030104 developmental biology ,Orphan Drug ,Cancer research ,Tumor Suppressor Protein p53 - Abstract
Some (re)programming notes on cancer Epithelial cancers develop resistance to targeted therapies in a number of different ways. Several cancer types do so by undergoing phenotypic conversion to a highly aggressive cancer called small cell neuroendocrine carcinoma (SCNC). Whether distinct cancer types accomplish this “reprogramming” through the same mechanism has been unclear. Park et al. show that the same set of oncogenic factors transforms both normal lung and normal prostate epithelial cells into SCNCs that resemble clinical samples (see the Perspective by Kareta and Sage). This convergence of molecular pathways could potentially simplify the development of new therapies for SCNC, which is currently untreatable. Science , this issue p. 91 ; see also p. 30
- Published
- 2018
44. Resection vs. ablation for alpha-fetoprotein positive hepatocellular carcinoma within the Milan criteria: a propensity score analysis
- Author
-
Qiang Tao, Qi-Jiong Li, Yun Zheng, Jingxian Shen, Donghui Cheng, Wenwu Liu, Binkui Li, Guihua Chen, Ruhai Zou, Wei He, and Yunfei Yuan
- Subjects
medicine.medical_specialty ,Hepatology ,Proportional hazards model ,business.industry ,medicine.medical_treatment ,Milan criteria ,Ablation ,medicine.disease ,Gastroenterology ,Surgery ,Resection ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Internal medicine ,Propensity score matching ,medicine ,Portal hypertension ,030211 gastroenterology & hepatology ,business ,Alpha-fetoprotein - Abstract
BACKGROUND & AIMS The lack of histopathological confirmation of hepatocellular carcinoma (HCC) diagnosis for patients receiving ablation may result in misdiagnosis of benign liver nodule as HCC occasionally, contributing to false treatment efficacy. This underestimated issue is one reason why the ablation efficacy remains undetermined compared with hepatic resection. Our aim is to compare the efficacy of ablation and resection for HCC within the Milan criteria after excluding the impact of misdiagnosis. METHODS Alpha-fetoprotein > 200 ng/ml was introduced as an inclusion criterion to improve diagnosis accuracy. A total of 435 (resection, 310; ablation, 125) HCC patients within the Milan criteria and without portal hypertension were enrolled. Propensity score matching analysis identified 259 (resection, 150; ablation, 109) patients to compare treatment efficacy. RESULTS Before matching, the survival of resection group were superior to ablation group with 5-year overall survival (OS) rate of 77.6% vs. 53.8% (P < 0.001), respectively, and 5-year recurrence-free survival (RFS) rate of 57.2% vs. 29.1% (P < 0.001) respectively. After matching, the baseline was well-balanced between the two groups. The 5-year OS rates were 71.5% vs. 51.3% (P < 0.001), and 5-year RFS rates were 56.1% vs. 25.6% (P < 0.001) for the resection and ablation groups respectively. Cox regression analysis identified ablation as an independent predictor for mortality and tumour recurrence (HR: 2.123 and 2.308, respectively; both P < 0.01). CONCLUSIONS Hepatic resection provides better OS and RFS than ablation for alpha-fetoprotein positive HCC patients within the Milan criteria and without portal hypertension.
- Published
- 2016
45. Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay
- Author
-
John K. Lee, Jiaoti Huang, Jung-Wook Park, Owen N. Witte, John W. Phillips, Patrick Huang, and Donghui Cheng
- Subjects
Male ,0301 basic medicine ,Aging ,Pathology ,Cellular differentiation ,Mice, SCID ,cancer differentiation ,Cell Transformation ,Androgen ,Mice ,Prostate cancer ,Basal (phylogenetics) ,Transduction, Genetic ,Prostate ,Receptors ,2.1 Biological and endogenous factors ,Aetiology ,oragnoid culture ,Cancer ,Tumor ,Multidisciplinary ,Prostate Cancer ,Cell Differentiation ,Biological Sciences ,luminal cell ,cells of origin ,Organoids ,Prostate-specific antigen ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Receptors, Androgen ,Heterografts ,Kallikreins ,Biotechnology ,Urologic Diseases ,medicine.medical_specialty ,Acinar adenocarcinoma ,Biology ,SCID ,Cell Line ,Proto-Oncogene Proteins c-myc ,Transduction ,03 medical and health sciences ,Genetic ,Cell Line, Tumor ,Organoid ,medicine ,Animals ,Humans ,Neoplastic ,Lentivirus ,PTEN Phosphohydrolase ,Prostatic Neoplasms ,Epithelial Cells ,Prostate-Specific Antigen ,Stem Cell Research ,medicine.disease ,030104 developmental biology ,Cancer research ,human prostate cancer ,Proto-Oncogene Proteins c-akt ,Neoplasm Transplantation - Abstract
The cell of origin for prostate cancer remains a subject of debate. Genetically engineered mouse models have demonstrated that both basal and luminal cells can serve as cells of origin for prostate cancer. Using a human prostate regeneration and transformation assay, our group previously demonstrated that basal cells can serve as efficient targets for transformation. Recently, a subpopulation of multipotent human luminal cells defined by CD26 expression that retains progenitor activity in a defined organoid culture was identified. We transduced primary human prostate basal and luminal cells with lentiviruses expressing c-Myc and activated AKT1 (myristoylated AKT1 or myrAKT1) to mimic the MYC amplification and PTEN loss commonly detected in human prostate cancer. These cells were propagated in organoid culture before being transplanted into immunodeficient mice. We found that c-Myc/myrAKT1-transduced luminal xenografts exhibited histological features of well-differentiated acinar adenocarcinoma, with strong androgen receptor (AR) and prostate-specific antigen (PSA) expression. In contrast, c-Myc/myrAKT1-transduced basal xenografts were histologically more aggressive, with a loss of acinar structures and low/absent AR and PSA expression. Our findings imply that distinct subtypes of prostate cancer may arise from luminal and basal epithelial cell types subjected to the same oncogenic insults. This study provides a platform for the functional evaluation of oncogenes in basal and luminal epithelial populations of the human prostate. Tumors derived in this fashion with defined genetics can be used in the preclinical development of targeted therapeutics.
- Published
- 2016
46. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells
- Author
-
Kevan M. Shokat, Bryan A. Smith, Robert Baertsch, Jiaoti Huang, John K. Lee, Colleen Mathis, W. Clay Gustafson, Erin McCaffrey, John W. Phillips, Artem Sokolov, Joshua M. Stuart, Tanya Stoyanova, Donghui Cheng, Jung-Wook Park, Owen N. Witte, and Justin G. Meyerowitz
- Subjects
Male ,Oncology ,0301 basic medicine ,Cancer Research ,Genes, myc ,030232 urology & nephrology ,Clone (cell biology) ,AKT1 ,Mice, SCID ,medicine.disease_cause ,Human prostate ,Prostate cancer ,0302 clinical medicine ,Mice, Inbred NOD ,Transduction, Genetic ,Prostate ,Medicine ,Exome ,Proto-Oncogene Proteins c-myc ,Molecular Targeted Therapy ,Neoplasm Metastasis ,Aurora Kinase A ,Azepines ,Phenotype ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Neuroendocrine Tumors ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Neoplastic Stem Cells ,medicine.medical_specialty ,Recombinant Fusion Proteins ,Urology ,Aurora A kinase ,Antineoplastic Agents ,Laser Capture Microdissection ,Adenocarcinoma ,Article ,03 medical and health sciences ,Cell Line, Tumor ,Internal medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Protein Kinase Inhibitors ,business.industry ,Phenylurea Compounds ,Prostatic Neoplasms ,Epithelial Cells ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,Enzyme Activation ,Pyrimidines ,030104 developmental biology ,Cancer research ,business ,Carcinogenesis ,Orchiectomy ,Proto-Oncogene Proteins c-akt ,N-Myc - Abstract
MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.
- Published
- 2016
47. Study of avian Acyl-CoA Cholesterol Acyltransferase
- Author
-
Donghui Cheng
- Subjects
Biochemistry ,Chemistry ,Sterol O-acyltransferase - Published
- 2018
48. The Long Noncoding RNA HOST2 Promotes Gemcitabine Resistance in Human Pancreatic Cancer Cells
- Author
-
Donghui Cheng and Ning An
- Subjects
0301 basic medicine ,Cancer Research ,Antimetabolites, Antineoplastic ,Apoptosis ,Deoxycytidine ,Pathology and Forensic Medicine ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Humans ,Cell Proliferation ,medicine.diagnostic_test ,Cell growth ,Pancreas neoplasm ,Chemistry ,General Medicine ,medicine.disease ,Gemcitabine ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,RNA, Long Noncoding ,medicine.drug - Abstract
Our study was aimed to identify the fundamental role of lncRNA HOST2 in gemcitabine resistance regulation in human pancreatic cancer cells. The levels of HOST2 in pancreatic cancer cell lines were measured by quantitative real-time PCR (qRT-PCR). Due to high expression and strong gemcitabine resistance, Hs766T and AsPC-1 cell lines were selected to be knockdown the expression of HOST2 by transfection sh-HOST2. After manipulation of HOST2, the cell proliferation induced by gemcitabine was examined by CCK-8 assay. Next, colony formation ability of Hs766T and AsPC-1 cell lines was determined by clone-forming assay. At last, the relationship between HOST2 and cell apoptosis in Hs766T and AsPC-1 cell lines was evaluated by flow cytometry. QRT-PCR revealed that HOST2 was overexpressed in six pancreas neoplasm cell lines compared with normal cell lines HPDE6-C7. HOST2 expression levels in group resistant to gemcitabine were higher than the group sensitive to gemcitabine. Additionally, CCK-8 assay verified that cell proliferation was inhibited by sh-HOST2 with or without gemcitabine treatment. Furthermore, clone-forming assay revealed that colony formation ability was weakened by down-regulated HOST2 with or without gemcitabine treatment. Flow cytometry revealed that cell apoptosis induced by gemcitabine was promoted by sh-HOST2. In conclusion, down-regulated HOST2 inhibited proliferation and promoted apoptosis of pancreas cancer cells with or without gemcitabine treatment. Thus, HOST2 is a potential therapeutic target for gemcitabine chemoresistance in pancreatic neoplasms.
- Published
- 2018
49. Interactive comment on 'Predicting the soil water characteristic curve from the particle size distribution based on a pore space geometry containing slit-shaped spaces' by Chen-chao Chang and Dong-hui Cheng
- Author
-
Donghui Cheng
- Published
- 2018
50. author's changes in manuscript
- Author
-
Donghui Cheng
- Published
- 2018
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