Publications by authors named "Heng Zhu"

244 Publications

Direct Electrochemical Protonation of Metal Oxide Particles.

J Am Chem Soc 2021 Jun 8;143(24):9236-9243. Epub 2021 Jun 8.

Jiangsu Key Laboratory for Nano Technology, Eco-Materials and Renewable Energy Research Center (ERERC), Collaborative Innovation Center of Advanced Microstructures, College of Engineering and Applied Sciences, Nanjing University, No. 22 Hankou Road, Nanjing, Jiangsu 210093, People's Republic of China.

Metal oxides with surface protonation exhibit versatile physical and chemical properties suitable for use in many fields. Here, we develop an electrochemical route to directly protonize the physically assembled oxide particles, such as TiO, NbO, and WO, in a NaSO neutral electrolyte, which is a result of electrochemically induced oxygen vacancies reacting with water molecules. With no need of electric connection among particles or between particles and conductive substrate, the electrochemical protonation follows a bottom-up particle-by-particle surface protonation mechanism due to the fact that the protonation inducing high surface conductivity creates an efficient electron transfer pathway among particles. Our results show that electrochemical protonation of particles provides a chance to finely functionalize the surface of a single particle by only adjusting electrode potentials. Such a facile, cost-efficient, and green route is easy to run for a large-scale production and unlocks the potential of semiconductor oxides for various applications.
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http://dx.doi.org/10.1021/jacs.1c04631DOI Listing
June 2021

Fluorescent dissolved organic matter facilitates the phytoavailability of copper in the coastal wetlands influenced by artificial topography.

Sci Total Environ 2021 May 26;790:147855. Epub 2021 May 26.

Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, Xiamen University, Xiamen 361102, PR China; State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen 361102, PR China. Electronic address:

Dissolved organic matter (DOM) is a crucial driver in ecosystem services and a central part of the carbon transport and biological cycle in land-sea interaction. DOM exhibits characteristic environmental behavior in the coastal zone, but its sustainability is affected by expanding artificial topography (AT) construction. It requires combining analyses on AT-induced response of field fluorescent DOM (fDOM) and its quenching pattern under metal-complexation. Herein, we conducted systemic investigations into the spatiotemporal dynamics of fDOM compositions with further in-lab verification to study its Cu-binding capacity. We detected three humid-like fDOM components sensitive to AT. The total fDOM intensity was positively correlated with low molecular weight organic acid (LMWOA) extractable Cu and the Cu pools in above-ground biomass. The enriched fDOM serves as an ecological engineer by increasing the Cu mobility, confirmed by an in-lab fluorescence titration. The application of LMWOA greatly enhanced the intensity of one fDOM component, elevated its conditional stability constant, and decreased its quenched proportion, implying that LMWOA might extract part of Cu from fDOM complexation. The present work provides an "fDOM-LMWOA pump" explanation to suggest that fDOM is a novel ecological regulator on vegetation growth under the AT-induced matter accumulation.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147855DOI Listing
May 2021

Orchestrated cellular, biochemical, and biomechanical optimizations endow platelet-rich plasma-based engineered cartilage with structural and biomechanical recovery.

Bioact Mater 2021 Nov 10;6(11):3824-3838. Epub 2021 Apr 10.

Department of Orthopedics, Chinese PLA General Hospital, Haidian, Beijing, 100853, China.

Recently, biomaterials for cartilage regeneration has been intensively investigated. However, the development of scaffolds that capture regenerated cartilage with biomechanical and structural recovery has rarely been reported. To address this challenge, platelet-rich plasma (PRP)-based cartilage constructs with a well-orchestrated symphony of cellular, biochemical and biomechanical elements were prepared by simultaneously employing chondrogenic progenitor cells (CPCs) as a cell source, optimizing platelet concentration, and adding an enzyme-ion activator. It was shown that this triple-optimized PRP + CPC construct possessed increased biomechanical properties and suitable biochemical signals. The following study demonstrated that the triple-optimized PRP + CPC constructs generated cartilage-like tissue with higher expression levels of chondrogenic-specific markers, more deposition of cartilage-specific extracellular matrix (ECM), and greater biomechanical values than those of the other constructs. Twelve weeks after the construct was implanted in a cartilage defect , histological analysis, qPCR, and biomechanical tests collectively showed that the triple-optimized constructs yielded a more chondrocyte-like cell phenotype with a higher synthesis of Col-II and aggrecan. More importantly, the triple-optimized constructs facilitated cartilage regeneration with better biomechanical recovery than that of the other constructs. These results demonstrate the efficacy of the triple-optimization strategy and highlight the simplicity and potency of this PRP + CPC construct for cartilage regeneration.
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http://dx.doi.org/10.1016/j.bioactmat.2021.03.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065202PMC
November 2021

Clinical-grade human dental pulp stem cells suppressed the activation of osteoarthritic macrophages and attenuated cartilaginous damage in a rabbit osteoarthritis model.

Stem Cell Res Ther 2021 05 1;12(1):260. Epub 2021 May 1.

Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, P. R. China.

Background: Although increasing evidence has demonstrated that human dental pulp stem cells (hDPSCs) are efficacious for the clinical treatment of skeletal disorders, the underlying mechanisms remain incompletely understood. Osteoarthritis (OA) is one of the most common degenerative disorders in joints and is characterized by gradual and irreversible cartilaginous tissue damage. Notably, immune factors were newly identified to be closely related to OA development. In this study, we explored the modulatory effects of clinical-grade hDPSCs on osteoarthritic macrophages and their protective effects on cartilaginous tissues in OA joints.

Methods: The cell morphology, immunophenotype, and inflammatory factor expression of osteoarthritic macrophages were explored by phase contrast microscope, transmission electron microscopy, immunostaining, flow cytometry, quantitative polymerase chain reaction, and enzyme linked immunosorbent assay, respectively. Additionally, the factors and signaling pathways that suppressed macrophage activation by hDPSCs were determined by enzyme-linked immunosorbent assay and western-blotting. Furthermore, hDPSCs were administered to a rabbit knee OA model via intra-articular injection. Macrophage activation in vivo and cartilaginous tissue damage were also evaluated by pathological analysis.

Results: We found that hDPSCs markedly inhibited osteoarthritic macrophage activation in vitro. The cell morphology, immunophenotype, and inflammatory factor expression of osteoarthritic macrophages changed into less inflammatory status in the presence of hDPSCs. Mechanistically, we observed that hDPSC-derived hepatocyte growth factor and transforming growth factor β1 mediated the suppressive effects on osteoarthritic macrophages. Moreover, phosphorylation of MAPK pathway proteins contributed to osteoarthritic macrophage activation, and hDPSCs suppressed their activation by partially inactivating those pathways. Most importantly, injected hDPSCs inhibited macrophage activation in osteochondral tissues in a rabbit knee OA model in vivo. Further histological analysis showed that hDPSCs alleviated cartilaginous damage to knee joints.

Conclusions: In summary, our findings reveal a novel function for hDPSCs in suppressing osteoarthritic macrophages and suggest that macrophages are efficient cellular targets of hDPSCs for alleviation of cartilaginous damage in OA. hDPSCs treat OA via an osteoarthritic macrophages-dependent mechanisms. hDPSCs suppress the activation of osteoarthritic macrophages in vitro and in vivo and alleviate cartilaginous lesions in OA models.
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http://dx.doi.org/10.1186/s13287-021-02353-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088312PMC
May 2021

[Research Advances in Plasticity of Biological Characteristics of Mesenchymal Stem Cells--Review].

Authors:
Pei-Lin Li Heng Zhu

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2021 Apr;29(2):629-632

Beijing Institute of Radiation Medicine, Beijing 100850, China,E-mail:

Mesenchymal stem cells (MSC) are capable of supporting hematopoiesis, regulating immune responses, promoting tissue regeneration and homing to damaged tissues, but their efficacy cannot completely exploit due to various factors. Studies in recent years have shown that the biological characteristics of mesenchymal stem cells have plasticity. Researchers can enhance the biological performance of MSC by pretreatment with hypoxia, bioactive molecules, genetic modification, and mechanical stimulation, as well as adjusting MSC transplantation strategies, which has great significance for promoting the transformation of MSC. Therefore, in this review, the recent research advances in the plasticity of the biological characteristics of MSC are summarized briefly.
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http://dx.doi.org/10.19746/j.cnki.issn.1009-2137.2021.02.051DOI Listing
April 2021

Extraction and purification of cis/trans asarone from Acorus tatarinowii Schott: Accelerated solvent extraction and silver ion coordination high-speed counter-current chromatography.

J Chromatogr A 2021 Apr 18;1643:462080. Epub 2021 Mar 18.

School of Pharmaceutical Sciences and Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China. Electronic address:

Acorus tatarinowii Schott is a traditional Chinese medicine used to treat memory and cognitive dysfunction. Because of their efficacy and lower toxic effects, research on α- and β-asarone, the phytoconstituents, has attracted attention owing to their remarkable pharmacological activities. Silver ion coordination complexation high-speed counter-current chromatography was used to separate these isomers from A. tatarinowii extract, coupled with accelerated solvent extraction. Accelerated solvent extraction parameters were investigated with single-factor and orthogonal testing. A two-phase solvent system composed of n-hexane-ethyl acetate-ethanol-water (2:1:2:1, v/v) with 0.50 mol/L silver ions was selected for separation. From 2.0 g crude extract, 1.4 g of β-asarone and 0.09 g of α-asarone were obtained with purities over 98% by sequential sample loading in 20 h. The isolated compounds were identified by electrospray ionization mass spectrometry, H and C NMR. Silver ions significantly increased the separation factor and retention of the stationary phase. The chromatographic behavior indicated that cis-configuration was more strongly complexed with the silver ion. This was further demonstrated with the help of computational analysis. In conclusion, the established method could be employed to separate other cis-trans or E/Z isomers that form coordination complexes.
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http://dx.doi.org/10.1016/j.chroma.2021.462080DOI Listing
April 2021

Ferulic acid promotes bone defect repair after radiation by maintaining the stemness of skeletal stem cells.

Stem Cells Transl Med 2021 Aug 22;10(8):1217-1231. Epub 2021 Mar 22.

Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.

The reconstruction of irradiated bone defects after settlement of skeletal tumors remains a significant challenge in clinical applications. In this study, we explored radiation-induced skeletal stem cell (SSC) stemness impairments and rescuing effects of ferulic acid (FA) on SSCs in vitro and in vivo. The immunophenotype, cell renewal, cell proliferation, and differentiation of SSCs in vitro after irradiation were investigated. Mechanistically, the changes in tissue regeneration-associated gene expression and MAPK pathway activation in irradiated SSCs were evaluated. The regenerative capacity of SSCs in the presence of FA in an irradiated bone defect mouse model was also investigated. We found that irradiation reduced CD140a- and CD105-positive cells in skeletal tissues and mouse-derived SSCs. Additionally, irradiation suppressed cell proliferation, colony formation, and osteogenic differentiation of SSCs. The RNA-Seq results showed that tissue regeneration-associated gene expression decreased, and the Western blotting results demonstrated the suppression of phosphorylated p38/MAPK and ERK/MAPK in irradiated SSCs. Notably, FA significantly rescued the radiation-induced impairment of SSCs by activating the p38/MAPK and ERK/MAPK pathways. Moreover, the results of imaging and pathological analyses demonstrated that FA enhanced the bone repair effects of SSCs in an irradiated bone defect mouse model substantially. Importantly, inhibition of the p38/MAPK and ERK/MAPK pathways in SSCs by specific chemical inhibitors partially abolished the promotive effect of FA on SSC-mediated bone regeneration. In summary, our findings reveal a novel function of FA in repairing irradiated bone defects by maintaining SSC stemness and suggest that the p38/MAPK and ERK/MAPK pathways contribute to SSC-mediated tissue regeneration postradiation.
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http://dx.doi.org/10.1002/sctm.20-0536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284777PMC
August 2021

An Integrated Systems Biology Approach Identifies the Proteasome as A Critical Host Machinery for ZIKV and DENV Replication.

Genomics Proteomics Bioinformatics 2021 Feb 18. Epub 2021 Feb 18.

Department of Pharmacology & Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address:

The zika virus (ZIKV) and dengue virus (DENV) flaviviruses exhibit similar replicative processes but have distinct clinical outcomes. A systematic understanding of virus-host protein-protein interaction networks can reveal cellular pathways critical to viral replication and disease pathogenesis. Here we employed three independent systems biology approaches toward this goal. First, protein array analysis of direct interactions between individual ZIKV/DENV viral proteins and 20,240 human proteins revealed multiple conserved cellular pathways and protein complexes, including proteasome complexes. Second, an RNAi screen of 10,415 druggable genes identified the host proteins required for ZIKV infection and uncovered that proteasome proteins were crucial in this process. Third, high-throughput screening of 6016 bioactive compounds for ZIKV inhibition yielded 134 effective compounds, including six proteasome inhibitors that suppress both ZIKV and DENV replication. Integrative analyses of these orthogonal datasets pinpoint proteasomes as critical host machinery for ZIKV/DENV replication. Our study provides multi-omics datasets for further studies of flavivirus-host interactions, disease pathogenesis, and new drug targets.
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http://dx.doi.org/10.1016/j.gpb.2020.06.016DOI Listing
February 2021

Identification of Novel Serological Autoantibodies in Takayasu Arteritis Patients Using HuProt Arrays.

Mol Cell Proteomics 2021 Feb 3;20:100036. Epub 2021 Feb 3.

Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China. Electronic address:

To identify novel autoantibodies of Takayasu arteritis (TAK) using HuProt array-based approach, a two-phase approach was adopted. In Phase I, serum samples collected from 40 TAK patients, 15 autoimmune disease patients, and 20 healthy subjects were screened to identify TAK-specific autoantibodies using human protein (HuProt) arrays. In phase II, the identified candidate autoantibodies were validated with TAK-focused arrays using an additional cohort comprised of 109 TAK patients, 110 autoimmune disease patients, and 96 healthy subjects. Subsequently, the TAK-specific autoantibodies validated in phase II were further confirmed using western blot analysis. We identified and validated eight autoantibodies as potential TAK-specific diagnostic biomarkers, including anti-SPATA7, -QDPR, -SLC25A2, -PRH2, -DIXDC1, -IL17RB, -ZFAND4, and -NOLC1 antibodies, with AUC of 0.803, 0.801, 0.780, 0.696, 0.695, 0.678, 0.635, and 0.613, respectively. SPATA7 could distinguish TAK from healthy and disease controls with 73.4% sensitivity at 85.4% specificity, while QDPR showed 71.6% sensitivity at 86.4% specificity. SLC25A22 showed the highest sensitivity of 80.7%, but at lower specificity of 67.0%. In addition, PRH2, IL17RB, and NOLC1 showed good specificities of 88.3%, 85.9%, and 86.9%, respectively, but at lower sensitivities (<50%). Finally, DIXDC1 and ZFAND4 showed moderate performance as compared with the other autoantibodies. Using a decision tree model, we could reach a specificity of 94.2% with AUC of 0.843, a significantly improved performance as compared with that by each individual biomarker. The performances of three autoantibodies, namely anti-SPATA7, -QDPR, and -PRH2, were successfully confirmed with western blot analysis. Using this two-phase strategy, we identified and validated eight novel autoantibodies as TAK-specific biomarker candidates, three of which could be readily adopted in a clinical setting.
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http://dx.doi.org/10.1074/mcp.RA120.002119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995655PMC
February 2021

An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine.

Nat Commun 2021 02 4;12(1):795. Epub 2021 Feb 4.

Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Epigenetic modifications of DNA play important roles in many biological processes. Identifying readers of these epigenetic marks is a critical step towards understanding the underlying mechanisms. Here, we present an all-to-all approach, dubbed digital affinity profiling via proximity ligation (DAPPL), to simultaneously profile human TF-DNA interactions using mixtures of random DNA libraries carrying different epigenetic modifications (i.e., 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine) on CpG dinucleotides. Many proteins that recognize consensus sequences carrying these modifications in symmetric and/or hemi-modified forms are identified. We further demonstrate that the modifications in different sequence contexts could either enhance or suppress TF binding activity. Moreover, many modifications can affect TF binding specificity. Furthermore, symmetric modifications show a stronger effect in either enhancing or suppressing TF-DNA interactions than hemi-modifications. Finally, in vivo evidence suggests that USF1 and USF2 might regulate transcription via hydroxymethylcytosine-binding activity in weak enhancers in human embryonic stem cells.
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http://dx.doi.org/10.1038/s41467-021-20950-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862700PMC
February 2021

Dissecting human embryonic skeletal stem cell ontogeny by single-cell transcriptomic and functional analyses.

Cell Res 2021 Jul 20;31(7):742-757. Epub 2021 Jan 20.

Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Human skeletal stem cells (SSCs) have been discovered in fetal and adult long bones. However, the spatiotemporal ontogeny of human embryonic SSCs during early skeletogenesis remains elusive. Here we map the transcriptional landscape of human limb buds and embryonic long bones at single-cell resolution to address this fundamental question. We found remarkable heterogeneity within human limb bud mesenchyme and epithelium, and aligned them along the proximal-distal and anterior-posterior axes using known marker genes. Osteo-chondrogenic progenitors first appeared in the core limb bud mesenchyme, which give rise to multiple populations of stem/progenitor cells in embryonic long bones undergoing endochondral ossification. Importantly, a perichondrial embryonic skeletal stem/progenitor cell (eSSPC) subset was identified, which could self-renew and generate the osteochondral lineage cells, but not adipocytes or hematopoietic stroma. eSSPCs are marked by the adhesion molecule CADM1 and highly enriched with FOXP1/2 transcriptional network. Interestingly, neural crest-derived cells with similar phenotypic markers and transcriptional networks were also found in the sagittal suture of human embryonic calvaria. Taken together, this study revealed the cellular heterogeneity and lineage hierarchy during human embryonic skeletogenesis, and identified distinct skeletal stem/progenitor cells that orchestrate endochondral and intramembranous ossification.
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http://dx.doi.org/10.1038/s41422-021-00467-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249634PMC
July 2021

Radial extracorporeal shockwave promotes subchondral bone stem/progenitor cell self-renewal by activating YAP/TAZ and facilitates cartilage repair in vivo.

Stem Cell Res Ther 2021 01 7;12(1):19. Epub 2021 Jan 7.

Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Medical School, No. 28 Fuxing Road, Haidian District, Beijing, 100853, China.

Background: Radial extracorporeal shockwave (r-ESW), an innovative and noninvasive technique, is gaining increasing attention in regenerative medicine due to its mechanobiological effects. Subchondral bone stem/progenitor cells (SCB-SPCs), originating from the pivotal zone of the osteochondral unit, have been shown to have multipotency and self-renewal properties. However, thus far, little information is available regarding the influences of r-ESW on the biological properties of SCB-SPCs and their therapeutic effects in tissue regeneration.

Methods: SCB-SPCs were isolated from human knee plateau osteochondral specimens and treated with gradient doses of r-ESW in a suspension stimulation system. The optimized parameters for SCB-SPC self-renewal were screened out by colony-forming unit fibroblast assay (CFU-F). Then, the effects of r-ESW on the proliferation, apoptosis, and multipotency of SCB-SPCs were evaluated. Moreover, the repair efficiency of radial shockwave-preconditioned SCB-SPCs was evaluated in vivo via an osteochondral defect model. Potential mechanisms were explored by western blotting, confocal laser scanning, and high-throughput sequencing.

Results: The CFU-F data indicate that r-ESW could augment the self-renewal of SCB-SPCs in a dose-dependent manner. The CCK-8 and flow cytometry results showed that the optimized shockwave markedly promoted SCB-SPC proliferation but had no significant influence on cell apoptosis. Radial shockwave exerted no significant influence on osteogenic capacity but strongly suppressed adipogenic ability in the current study. For chondrogenic potentiality, the treated SCB-SPCs were mildly enhanced, while the change was not significant. Importantly, the macroscopic scores and further histological analysis strongly demonstrated that the in vivo therapeutic effects of SCB-SPCs were markedly improved post r-ESW treatment. Further analysis showed that the cartilage-related markers collagen II and proteoglycan were expressed at higher levels compared to their counterpart group. Mechanistic studies suggested that r-ESW treatment strongly increased the expression of YAP and promoted YAP nuclear translocation in SCB-SPCs. More importantly, self-renewal was partially blocked by the YAP-specific inhibitor verteporfin. Moreover, the high-throughput sequencing data indicated that other self-renewal-associated pathways may also be involved in this process.

Conclusion: We found that r-ESW is capable of promoting the self-renewal of SCB-SPCs in vitro by targeting YAP activity and strengthening its repair efficiency in vivo, indicating promising application prospects.
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http://dx.doi.org/10.1186/s13287-020-02076-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792202PMC
January 2021

Surface polaron states on single-crystal rutile TiO nanorod arrays enhancing charge separation and transfer.

Dalton Trans 2020 Nov;49(42):15054-15060

Eco-Materials and Renewable Energy Research Center (ERERC), Collaborative Innovation Center of Advanced Microstructures, College of Engineering and Applied Sciences, Nanjing University, No. 22, Hankou Road, Nanjing, Jiangsu 210093, P. R. China.

Polaron states on TiO2 photoanodes provide an important electron transfer pathway at the electrode-electrolyte interface. Here, we electrochemically doped single-crystal rutile TiO2 nanorod arrays with exposed (110) facets to produce surface polaron states, Ti3+-OH, which greatly contributed to charge separation and transfer. Our results experimentally clarified the previously confused understanding of the origin of improved photoelectrochemical (PEC) water splitting performance and verified that the enhanced PEC effects mainly arise from surface polaron states instead of grain boundary passivation.
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http://dx.doi.org/10.1039/d0dt03068fDOI Listing
November 2020

Polaron States as a Massive Electron-Transfer Pathway at Heterojunction Interface.

J Phys Chem Lett 2020 Nov 15;11(21):9184-9194. Epub 2020 Oct 15.

Eco-Materials and Renewable Energy Research Center (ERERC), Collaborative Innovation Center of Advanced Microstructures, College of Engineering and Applied Sciences, Nanjing University, No. 22 Hankou Road, Nanjing, Jiangsu 210093, P.R. China.

For heterojunction semiconductor photoelectrodes, efficient charge separation is localized in the junction-induced electric field region and charge transfer follows a band-to-band charge-transfer pathway. Here, we found that polaron states at the heterojunction interface have a function of storing and transferring electrons. As a successful demonstration, we verified that the polaron states (TiOH) on TiO are not passivated when used to create a CdS/TiO heterojunction and function as an efficient pathway for massively capturing, storing, and transferring the electrons from conduction bands of both TiO and CdS, thus effectively enhancing the charge separation efficiency of the heterojunction photoanode. The electron throughput of polaron states remains a positive correlation with polaron state density. Interfacial electron transfer through the TiO surface polaron states has great potential application in the development of high-performance heterojunction devices based on TiO.
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http://dx.doi.org/10.1021/acs.jpclett.0c02291DOI Listing
November 2020

A study of human leukocyte antigen-haploidentical hematopoietic stem cells transplantation combined with allogenic mesenchymal stem cell infusion for treatment of severe aplastic anemia in pediatric and adolescent patients.

Stem Cells Transl Med 2021 Feb 25;10(2):291-302. Epub 2020 Sep 25.

Department of Experimental Hematology & Biochemistry, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.

The clinical applications of human leukocyte antigen (HLA) haploidentical hematopoietic stem cells transplantation (haplo-HSCT) have offered most of the young severe aplastic anemia (SAA) patients an opportunity to accept curative therapy at the early stage of bone marrow lesions. However, the outcome of juvenile SAA patients received haplo-HSCT remain to be improved due to high incidence of graft failure and graft vs host disease (GVHD). Mesenchymal stem cells (MSCs) have been characterized by their hematopoiesis-supporting and immunomodulatory properties. In the current study, we designed a combination of haplo-HSCT with allogenic MSC for treatment of SAA in pediatric and adolescent patients and evaluated its effects. Juvenile patients (<18 years) with SAA (n = 103) were given HLA-haploidentical HSC combined with allogenic MSC after a conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin and an intensive GVHD prophylaxis, including cyclosporine, short-term methotrexate, mycophenolate mofetil, and basiliximab. Neutrophil engraftment was achieved in 102 of 103 patients in a median time of 14.3 days (range 9-25 days). The median time of platelet engraftment was 25.42 days (range 8-93 days). The cumulative incidence of II-IV acute GVHD at day +100 was 26.32% ± 0.19% and III-IV acute GVHD was 6.79% ± 0.06% at day +100, respectively. The cumulative incidence of chronic GVHD was 25.56% ± 0.26%. The overall survival was 87.15% ± 3.3% at a median follow-up of 40 (1.3-98) months. Our data suggest that cotransplantation of HLA-haploidentical HSC and allogenic mesenchymal stem cell may provide an effective and safe treatment for children and adolescents with SAA who lack matched donors.
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http://dx.doi.org/10.1002/sctm.20-0345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848315PMC
February 2021

Virion Display: A High-Throughput Method to Express Functional Membrane Proteins.

Curr Protoc Mol Biol 2020 09;132(1):e126

Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Transmembrane proteins are responsible for many critical cellular functions and represent one of the largest families of drug targets. However, these proteins, especially multipass transmembrane proteins, are difficult to study because they must be embedded in a lipid bilayer to maintain their native conformations. The development of the virion display (VirD) technology enables transmembrane proteins to be integrated into the viral envelope of herpes simplex virus 1 (HSV-1). Combining high-throughput cloning, expression, and purification techniques, VirD technology has been applied to the largest set of human transmembrane proteins, namely G-protein-coupled receptors, and has allowed the identification of interactions that are both specific and functional. This article describes the procedures to integrate an open reading frame for any transmembrane protein into the HSV-1 genome and produce recombinant HSV-1 virus to ultimately generate pure VirD virions for biological and pharmaceutical studies. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Gateway cloning of transmembrane proteins Support Protocol 1: Ethanol precipitation of bacterial artificial chromosomal DNA Support Protocol 2: Preparation of competent cells Basic Protocol 2: Production of recombinant HSV-1 virions.
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http://dx.doi.org/10.1002/cpmb.126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699820PMC
September 2020

Identification and characterization of isocitrate dehydrogenase 1 (IDH1) as a functional target of marine natural product grincamycin B.

Acta Pharmacol Sin 2021 May 14;42(5):801-813. Epub 2020 Aug 14.

Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

Grincamycins (GCNs) are a class of angucycline glycosides isolated from actinomycete Streptomyces strains that have potent antitumor activities, but their antitumor mechanisms remain unknown. In this study, we tried to identify the cellular target of grincamycin B (GCN B), one of most dominant and active secondary metabolites, using a combined strategy. We showed that GCN B-selective-induced apoptosis of human acute promyelocytic leukemia (APL) cell line NB4 through increase of ER stress and intracellular reactive oxygen species (ROS) accumulation. Using a strategy of combining phenotype, transcriptomics and protein microarray approaches, we identified that isocitrate dehydrogenase 1(IDH1) was the putative target of GCN B, and confirmed that GCNs were a subset of selective inhibitors targeting both wild-type and mutant IDH1 in vitro. It is well-known that IDH1 converts isocitrate to 2-oxoglutarate (2-OG), maintaining intracellular 2-OG homeostasis. IDH1 and its mutant as the target of GCN B were validated in NB4 cells and zebrafish model. Knockdown of IDH1 in NB4 cells caused the similar phenotype as GCN B treatment, and supplementation of N-acetylcysteine partially rescued the apoptosis caused by IDH1 interference in NB4 cells. In zebrafish model, GCN B effectively restored myeloid abnormality caused by overexpression of mutant IDH1(R132C). Taken together, we demonstrate that IDH1 is one of the antitumor targets of GCNs, suggesting wild-type IDH1 may be a potential target for hematological malignancies intervention in the future.
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http://dx.doi.org/10.1038/s41401-020-0491-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115265PMC
May 2021

Analysis of chemical consistency and the anti-tumor activity of Huangqi-Ezhu (HQ-EZ) concentrated-granules and decoction.

Ann Palliat Med 2020 Jul 18;9(4):1648-1659. Epub 2020 Jun 18.

Beijing Institute of Radiation Medicine, Beijing, China.

Background: Traditional Chinese medicine decoction and modern concentrated-granules are two kinds of Chinese herbal medicine forms used in clinic at present. The former is extracted by traditional boiling method of a pre-mixed multi-herbal medicine according to the doctor's prescription. The latter is a mixture of extract active ingredients from a single variety of herbs by modern technology. It is not clear whether there is a difference in the content and efficacy of the active components between the two methods.

Methods: The effective components of Huangqi-Ezhu (HQ-EZ) traditional decoction and concentratedgranules were determined by HPLC, and the subcutaneous transplanted tumor model of tumor-bearing mice was established to compare the anti-tumor effect. HQ-EZ traditional decoction and concentrated-granules were given respectively by continuous intragastric administration for 15 days. After the last administration the tumor tissue, liver and kidney were removed completely, and the corresponding indexes were detected.

Results: Active components of concentrated-granules and traditional decoction are basically the same. Both of TCM forms have great anti-tumor effect against lung cancer, without toxify to liver and kidney.

Conclusions: The two preparation methods have their own advantages in effective components, and the compatibility of HQ-EZ can inhibit the tumor growth of tumor-bearing mice, and has no liver and kidney toxicity.
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http://dx.doi.org/10.21037/apm-19-592DOI Listing
July 2020

Method to examine how geometry affects the release and retention of alpine touring boot-binding systems.

J Sci Med Sport 2020 May 26. Epub 2020 May 26.

Department of Mechanical Engineering, University of Washington, USA.

Objectives: Develop a method to examine the effects of component geometry and force-deflection on the release process of Tech/Pin alpine touring (AT) ski boots and bindings.

Design And Methods: For seven AT boots, we measured the critical geometric dimensions of the metal inserts at the toe region of the boots. Binding geometry (including the pins and rocker arms) and the force-angular deflection curves of typical AT bindings were measured. A kinematic model was derived to predict the contact force between the metal inserts of the AT boots and the pins of the AT bindings, dependent on angular displacement of the binding rocker arms. By combining the kinematic model, the force-angular deflection curves, and moment equilibrium, we determined the force and binding rotation angle needed to release the AT boot in a direction normal to the ski.

Results: The metal AT boot insert geometry and AT binding pin geometry and dimensions can affect significantly the contact states and kinematics of release. Two load-deflection curves of similar peak loads can result in significantly different maximal forces and angles to release the binding, even when the geometry and dimensions of the binding pins and boot inserts remain unchanged.

Conclusions: The geometry and dimensions of the binding (pins and rocker arm) and the boot inserts define the kinematics of the binding release. The model can be used to test the effects of varying parameters on the release and retention characteristics of Tech/Pin boot-binding systems to optimize the release and retention characteristics.
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http://dx.doi.org/10.1016/j.jsams.2020.05.020DOI Listing
May 2020

Posterior full-endoscopic cervical discectomy in cervical radiculopathy: A prospective cohort study.

Clin Neurol Neurosurg 2020 08 22;195:105948. Epub 2020 May 22.

Clinical Medical School, Yangzhou University, Northern Jiangsu People's Hospital, China. Electronic address:

Objectives: This study was conducted to assess the clinical outcomes of using the posterior full-endoscopic cervical discectomy (PECD) in comparison with the conventional anterior cervical decompression and fusion (ACDF) in treating patients with cervical radiculopathy.

Patients And Methods: From May 2015 to January 2018, patients with single cervical radiculopathy were enrolled in this study. The operative time, blood loss, hospital stay, and perioperative complications were recorded. The Visual Analog Scale (VAS) for neck and arm pain, the Neck Disability Index (NDI), and the modified MacNab criteria were used to quantify the postoperative outcomes.

Results: A total of 84 patients were initially enrolled in this study, while three patients were lost during the follow-up. The remaining 81 patients were divided into two groups. Thirty-eight patients underwent conventional ACDF, and the rest 43 patients were treated by PECD procedure. The patients in the ACDF group were slightly older than those in the PECD group (51.4 ± 8.2 VS 46.6 ± 8.8 years old, p = 0.012*). The blood loss and hospital stay were significantly less in patients treated with PECD compared with those undergoing ACDF (p < 0.05*). There were no significant differences in the VAS scores, the NDI, and the modified MacNab criteria between the two groups. The patients in the ACDF group obtained a better Cobb angle and had less operative time compared with those in the PECD group (p < 0.05*). Only mild complications were observed in both groups, with no significant difference (p = 0.28).

Conclusion: PECD could significantly relieve pain and disability with no severe complication, and the majority of patients were satisfied with this technique. Thus, it is safe and effective to use this procedure in managing patients with cervical radiculopathy as an alternative procedure to ACDF.
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http://dx.doi.org/10.1016/j.clineuro.2020.105948DOI Listing
August 2020

Flavonoid epimers from custard apple leaves, a rapid screening and separation by HSCCC and their antioxidant and hypoglycaemic activities evaluation.

Sci Rep 2020 06 1;10(1):8819. Epub 2020 Jun 1.

Key Laboratory of TCM Quality Control, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250014, China.

Leaves of custard apple are widely used in many places as a popular dietary supplement for the treatment of diabetes. Flavonoids are known to have anti-diabetic activity. In this study, the main flavonoid epimers were separated. The crude extract was first screened by HPLC-DAD before and after incubation with DPPH method to evaluate the antioxidants. An efficient extraction method was employed to remove non-flavonoid components. Subsequently, five main flavonoids with two pairs of epimers including quercetin-3-O-robinobioside, rutin, quercetin-3-O-β-D-glucoside, kaempferol-3-O-robinobioside, and kaempferol-3-O-rutinoside were successfully separated by high-speed counter-current chromatography with ethyl acetate/n-butanol/water (4:1:5, v/v) coupled with online-storage inner-recycling mode. The structures of the separated compounds were identified by spectral techniques. The purity of the separated flavonoid glycosides was over 98%, as determined by HPLC. The separated pure constituents were found to possess the antioxidant capacities following DPPH radical scavenging protocol. The compounds (1-3) exhibited better antioxidant activity. Furthermore, the glucose uptake of crude flavonoid extract had better results than the crude ethanol extract. The present study demonstrates that the efficacy of custard apple leaves in lowering glucose level, and antioxidant capacities of separated pure compounds probably appear to be predominantly responsible for hypoglycaemic properties on HepG2 cells.
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http://dx.doi.org/10.1038/s41598-020-65769-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264225PMC
June 2020

Preparation of Flame-Retardant Rigid Polyurethane Foams by Combining Modified Melamine-Formaldehyde Resin and Phosphorus Flame Retardants.

Authors:
Heng Zhu Shiai Xu

ACS Omega 2020 May 22;5(17):9658-9667. Epub 2020 Apr 22.

Shanghai Key Laboratory of Advanced Polymeric Materials, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.

In this work, ethylene glycol-modified melamine-formaldehyde resin (EMF) was synthesized from ethylene glycol, paraformaldehyde, and melamine, and then rigid polyurethane foams (RPUFs) were prepared using EMF, polyols and polyisocyanate. The effects of ammonium polyphosphate (APP) and dimethyl methylphosphonate (DMMP) on the flame retardancy, mechanical properties, thermal stability, and morphology of the prepared RPUFs were studied. It is shown that the flame-retardant performance of EMF-filled RPUFs can be enhanced by the addition of APP and DMMP. Thus, APP and DMMP can synergistically improve the flame retardancy of RPUFs. APP has good smoke suppression, while DMMP can increase the total smoke production and CO/CO weight ratio during the combustion of RPUFs.
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http://dx.doi.org/10.1021/acsomega.9b03659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203688PMC
May 2020

Efficacy of Using Platelet-Rich Plasma in Spinal Fusion Surgery-A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Compliant Meta-Analysis.

World Neurosurg 2020 07 18;139:e517-e525. Epub 2020 Apr 18.

Neurosurgery Department, The Second Affiliated Hospital of Soochow University, Suzhou, China; Neurosurgery Department, Northern Jiangsu People's Hospital, Yangzhou City, China. Electronic address:

Background: Platelet-rich plasma (PRP) has been frequently used to enhance bone regeneration. A meta-analysis was conducted to systematically assess the fusion rate and pain relief of applying PRP during spinal fusion surgery.

Methods: Studies investigating spinal fusion surgery combined with PRP were retrieved from Medline and the Web of Science in accordance with the inclusion and exclusion criteria. A quality evaluation was conducted using the Cochrane collaboration tool for randomized controlled trials and the Newcastle-Ottawa scale quality assessment for cohort trials. Statistical analysis was performed using RevMan, version 5.3.

Results: A total of 12 studies, including 3 randomized controlled trials and 9 cohort studies, with 661 patients, were included in the present meta-analysis. The mean age was 52.3 ± 8.0 years. Overall, the pooled results demonstrated that the differences in the fusion rates between the PRP and non-PRP treatment groups were not statistically significant. The risk ratio was 1.01 (95% confidence interval, 0.95-1.06; P = 0.83). Also, no significant difference in pain relief measured using the visual analog scale was found between the 2 groups. The mean difference was -0.08 (95% confidence interval, -0.26 to 0.11; P = 0.42).

Conclusions: Adding PRP did not increase the fusion rates from spinal fusion surgery. In addition, no significant difference was found in pain relief between the PRP and non-PRP treatment groups.
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http://dx.doi.org/10.1016/j.wneu.2020.04.047DOI Listing
July 2020

Developments and Applications of Functional Protein Microarrays.

Mol Cell Proteomics 2020 06 17;19(6):916-927. Epub 2020 Apr 17.

Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Viral Oncology Program, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231. Electronic address:

Protein microarrays are crucial tools in the study of proteins in an unbiased, high-throughput manner, as they allow for characterization of up to thousands of individually purified proteins in parallel. The adaptability of this technology has enabled its use in a wide variety of applications, including the study of proteome-wide molecular interactions, analysis of post-translational modifications, identification of novel drug targets, and examination of pathogen-host interactions. In addition, the technology has also been shown to be useful in profiling antibody specificity, as well as in the discovery of novel biomarkers, especially for autoimmune diseases and cancers. In this review, we will summarize the developments that have been made in protein microarray technology in both in basic and translational research over the past decade. We will also introduce a novel membrane protein array, the GPCR-VirD array, and discuss the future directions of functional protein microarrays.
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http://dx.doi.org/10.1074/mcp.R120.001936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261817PMC
June 2020

Biological potential alterations of migratory chondrogenic progenitor cells during knee osteoarthritic progression.

Arthritis Res Ther 2020 03 27;22(1):62. Epub 2020 Mar 27.

Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.

Background: Although increasing studies have demonstrated that chondrogenic progenitor cells (CPCs) remain present in human osteoarthritic cartilage, the biological alterations of the CPCs from the less diseased lateral tibial condyle and the more diseased medial condyle of same patient remain to be investigated.

Methods: CPCs were isolated from paired grade 1-2 and grade 3-4 osteoarthritic cartilage by virtue of cell migratory capacities. The cell morphology, immunophenotype, self-renewal, multi-differentiation, and cell migration of these CPCs were evaluated. Additionally, the distributions of CD105/CD271 cells in OA osteochondral specimen were determined. Furthermore, a high-throughput mRNA sequencing was performed.

Results: Migratory CPCs (mCPCs) robustly outgrew from mildly collagenases-digested osteoarthritic cartilages. The mCPCs from grade 3-4 cartilages (mCPCs, grades 3-4) harbored morphological characteristics, cell proliferation, and colony formation capacity that were similar to those of the mCPCs from the grade 1-2 OA cartilages (mCPCs, grades 1-2). However, the mCPCs (grades 3-4) highly expressed CD271. In addition, the mCPCs (grades 3-4) showed enhanced osteo-adipogenic activities and decreased chondrogenic capacity. Furthermore, the mCPCs (grades 3-4) exhibited stronger cell migration in response to osteoarthritis synovial fluids. More CD105/CD271 cells resided in grade 3-4 articular cartilages. Moreover, the results of mRNA sequencing showed that mCPCs (grades 3-4) expressed higher migratory molecules.

Conclusions: Our data suggest that more mCPCs (grades 3-4) migrate to injured articular cartilages but with enhanced osteo-adipogenic and decreased chondrogenic capacity, which might explain the pathological changes of mCPCs during the progression of OA from early to late stages. Thus, these dysfunctional mCPCs might be optional cell targets for OA therapies.
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http://dx.doi.org/10.1186/s13075-020-2144-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099802PMC
March 2020

Tumor necrosis factor α in aGVHD patients contributed to the impairment of recipient bone marrow MSC stemness and deficiency of their hematopoiesis-promotion capacity.

Stem Cell Res Ther 2020 03 17;11(1):119. Epub 2020 Mar 17.

Medical Center of Air Forces, PLA, Road Fucheng 30, Beijing, 100142, People's Republic of China.

Background: Though accumulated evidence has demonstrated visceral organ involvement in acute graft-versus-host disease (aGVHD), how aGVHD influences the bone marrow (BM) niche and the reconstitution of hematopoiesis post-hematopoietic stem cell transplantation remains largely unknown.

Methods: In the current study, the cell morphology, immunophenotype, multi-differentiation capacity, self-renewal capacity, and hematopoiesis promotion of the MSCs from aGVHD and non-aGVHD patients were investigated. Additionally, the stemness and hematopoiesis-promoting property of healthy donor-derived MSCs were evaluated in the presence of BM supernatant from aGVHD patients. Mechanistically, antibodies targeting inflammatory cytokines involved in aGVHD were added into the MSC culture. Furthermore, a recombinant human tumor necrosis factor (TNF-α) receptor-Ig fusion protein (rhTNFR:Fc) was used to protect healthy donor-derived MSCs. Moreover, mRNA sequencing was performed to explore the underlying mechanisms.

Results: The aGVHD MSCs exhibited morphological and immunophenotypic characteristics that were similar to those of the non-aGVHD MSCs. However, the osteogenic and adipogenic activities of the aGVHD MSCs significantly decreased. Additionally, the colony formation capacity and the expression of self-renewal-related genes remarkably decreased in aGVHD MSCs. Further, the hematopoiesis-supporting capacity of aGVHD MSCs significantly reduced. The antibody neutralization results showed that TNF-α contributed to the impairment of MSC properties. Moreover, rhTNFR:Fc exhibited notable protective effects on MSCs in the aGVHD BM supernatants. The mRNA sequencing results indicated that the TNF-α pathway and the Toll-like receptor pathway may be activated by TNF-α.

Conclusions: Thus, our data demonstrate MSCs as cellular targets of aGVHD and suggest a potential role of TNF-α blockage in maintaining the BM niche of aGVHD patients.
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http://dx.doi.org/10.1186/s13287-020-01615-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079531PMC
March 2020

PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications.

Mol Cancer 2020 03 2;19(1):49. Epub 2020 Mar 2.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Pancreatic cancer is a highly lethal disease with a poor prognosis, and existing therapies offer only limited effectiveness. Mutation gene sequencing has shown several gene associations that may account for its carcinogenesis, revealing a promising research direction. Poly (ADP-ribose) polymerase (PARP) inhibitors target tumor cells with a homologous recombination repair (HRR) deficiency based on the concept of synthetic lethality. The most prominent target gene is BRCA, in which mutations were first identified in breast cancer and ovarian cancer. PARP inhibitors can trap the PARP-1 protein at a single-stranded break/DNA lesion and disrupt its catalytic cycle, ultimately leading to replication fork progression and consequent double-strand breaks. For tumor cells with BRCA mutations, HRR loss would result in cell death. Pancreatic cancer has also been reported to have a strong relationship with BRCA gene mutations, which indicates that pancreatic cancer patients may benefit from PARP inhibitors. Several clinical trials are being conducted and have begun to yield results. For example, the POLO (Pancreatic Cancer Olaparib Ongoing) trial has demonstrated that the median progression-free survival was observably longer in the olaparib group than in the placebo group. However, PARP inhibitor resistance has partially precluded their use in clinical applications, and the major mechanism underlying this resistance is the restoration of HRR. Therefore, determining how to use PARP inhibitors in more clinical applications and how to avoid adverse effects, as well as prognosis and treatment response biomarkers, require additional research. This review elaborates on future prospects for the application of PARP inhibitors in pancreatic cancer.
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http://dx.doi.org/10.1186/s12943-020-01167-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053129PMC
March 2020

Integration of IgA and IgG Autoantigens Improves Performance of Biomarker Panels for Early Diagnosis of Lung Cancer.

Mol Cell Proteomics 2020 03 10;19(3):490-500. Epub 2020 Jan 10.

Provincial Clinical College, Fujian Medical University, Fuzhou 350001, Fujian, China; Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, Fujian, China; Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou 350001, Fujian, China. Electronic address:

Lung cancer (LC) remains the leading cause of mortality from malignant tumors worldwide. In our previous study, we surveyed both IgG and IgM-bound serological biomarkers and validated a panel of IgG-bound autoantigens for early LC diagnosis with 50% sensitivity at 90% specificity. To further improve the performance of these serological biomarkers, we surveyed HuProt arrays, comprised of 20,240 human proteins, for IgA-bound autoantigens because IgAs are a major immunoglobulin isotype in the lung. Integrating with IgG-bound autoantigens, we discovered and validated a combined biomarker panel using ELISA-format tests. Specifically, in Phase I, we obtained IgA-based autoimmune profiles of 69 early stage LC patients, 30 healthy subjects and 25 patients with lung benign lesions (LBL) on HuProt arrays and identified 28 proteins as candidate autoantigens that were significantly associated with early stage LC. In Phase II, we re-purified the autoantigens and converted them into an ELISA-format testing to profile an additional large cohort, comprised of 136 early stage LC patients, 58 healthy individuals, and 29 LBL patients. Integration of IgG autoimmune profiles allowed us to identify and validate a biomarker panel of three IgA autoantigens ( BCL7A, and TRIM33 and MTERF4) and three IgG autoantigens ( CTAG1A, DDX4 and MAGEC2) for diagnosis of early stage LC with 73.5% sensitivity at >85% specificity. In Phase III, the performance of this biomarker panel was confirmed with an independent cohort, comprised of 88 early stage LC patients, 18 LBL patients, and 36 healthy subjects. Finally, a blind test on 178 serum samples was conducted to confirm the performance of the biomarker panel. In summary, this study demonstrates for the first time that an integrated panel of IgA/IgG autoantigens can serve as valuable biomarkers to further improve the performance of early diagnosis of LC.
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http://dx.doi.org/10.1074/mcp.RA119.001905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050113PMC
March 2020