Publications by authors named "Lingyu Zeng"

116 Publications

A novel strategy for isolation of mice bone marrow endothelial cells (BMECs).

Stem Cell Res Ther 2021 May 3;12(1):267. Epub 2021 May 3.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China.

Background: In the bone marrow microenvironment (BM), endothelial cells are individual cells that form part of the sinusoidal blood vessels called the "bone marrow endothelial-vascular niche." They account for less than 2% of the bone marrow cells. They play essential functions by generating growth and inhibitory factors that promote the hematopoietic stem cells (HSCs) regulation. In response to inflammatory stimuli, the BMECs increase in proliferation to maintain the blood vessels' integrity within the BM. The inflammatory response releases cytokines such as tumor necrosis factor-alpha (TNF-α) that promote vascular endothelial cells' expansion and upregulation of adhesion molecules (ICAM-1 and VCAM-1, respectively) in the BM. However, the evaluation of mouse BMECs in the bone marrow microenvironment is scared by a lack of mouse bone marrow endothelial cell primary culture METHODS: Two steps approach for isolation of bone marrow endothelial cells (BMECs) from mice. In brief, the bone marrow cells extracted from the mice long bones were cultured overnight with Dulbecco's modified Eagle's medium (DMEM) supplemented with 20% fetal bovine serum (FBS) and antibiotics to separate between marrow-derived adherent and non-adherent cells. The floating cells were discarded, and the adhered section detached with accutase and BMECs selected using CD31 microbeads. The isolated BMECs were cultured in a dish pre-coated with rat-tail collagen type 1 with endothelial cells medium supplement with growth factors. The cells were verified by confocal microscopy for morphology and tube formation by matrigel assay. We validate the cells' purity by flow cytometry, RT-qPCR, immunofluorescence staining, and immunoblotting by established BMEC markers, PECAM-1, VE-cadherin, vascular endothelial cell growth factor receptor-2 (VEGFR2), CD45, E-selectin, and endothelial selectin adhesion molecule (ESAM). Lastly, we characterize BMEC activation with recombinant TNF-α.

Results: Our method clearly defined the cells isolated have the characteristics of BMECs with the expression of CD31, VE-cadherin, E-selectin, VEGFR-2, and ESAM. The cells' response to TNF-α indicates its inflammatory function by increasing proliferation and upregulation of adhesion molecules.

Conclusions: This study outline a simple new technique of isolating mouse BMEC primary culture and a suitable method to evaluate the function and dysregulation of BMEC in in vitro studies using mouse models.
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http://dx.doi.org/10.1186/s13287-021-02352-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091666PMC
May 2021

Combination of Mesenchymal Stem Cell and Endothelial Progenitor Cell Infusion Accelerates Injured Intestinal Repair by Regulating Gut Microbiota after Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 Feb 13;27(2):152.e1-152.e9. Epub 2020 Dec 13.

Institute of Blood Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Key Laboratory of Bone Marrow Stem Cells, Xuzhou Medical University, Xuzhou, Jiangsu, China; School of Medical Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China. Electronic address:

Mesenchymal stem cells (MSC) have been widely applied for repairing intestinal barrier function and restoring immune homeostasis for pretransplantation conditioning, yet the repair process is often impaired or delayed owing to a lack of vascularity. How combined therapy with MSC and endothelial progenitor cells (EPC) for the intestinal microenvironment and repair remain unclear. In this study, BALB/c mice received syngeneic bone marrow transplantation with or without MSC or EPC infusion. The findings show that the MSC+EPC mice had greater blood capillary distribution and higher expression of tight junction protein (occludin) in the small intestinal tract. Meanwhile, the MSC+EPC cotreatment increased IL-17A levels and decreased IFN-γ levels at the early stage after transplantation. Furthermore, the MSC+EPC treatment motivated p38 mitogen-activated protein kinase (MAPK) and enhanced heat shock protein 27 (HSP27) activation, which subsequently promoted intestinal epithelial cell proliferation and down-regulated apoptosis-related molecule caspase 3 expression. Finally, the high-throughput sequencing of gut microbiota (16S) showed that the MSC+EPC treatment can inhibit the Enterococcus population (<0.5%) and stabilize the Akkermansia population (~15%), with the Akkermansia population showing significant positive correlations with p38 MAPK/phos-p38, HSP27/phos-HSP27, IL-17A, and occludin. Taken together, our results show that MSC+EPC combined therapy is beneficial for the repair of injured intestine and drives gut microbial community stability by regulating the intestinal microenvironment.
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http://dx.doi.org/10.1016/j.jtct.2020.10.013DOI Listing
February 2021

FeO hollow nanospheres on graphene oxide as an efficient heterogeneous photo-Fenton catalyst for the advanced treatment of biotreated papermaking effluent.

Environ Sci Pollut Res Int 2021 Mar 22. Epub 2021 Mar 22.

Guangxi Key Laboratory of Clean Pulp and Papermaking and Pollution Control, Light Industry and Food Engineering College, Guangxi University, Nanning, 530004, China.

This study focused on the feasibility of using FeO/graphene oxide (FGO) nanocomposites as heterogeneous catalysts for the advanced treatment of real industrial wastewater. FGO nanocomposites with different graphene oxide (GO) ratios were synthesized by coprecipitating iron salts onto GO sheets in basic solution. The characterization of the resulting material structures and functionalities was performed using a range of analytical techniques. A low GO loading afforded a good FeO nanoparticle dispersibility and resulted in a higher Brunauer-Emmett-Teller surface area and pore volume. The FGO nanocomposites and pure FeO were used to treat papermaking wastewater in a heterogeneous photo-Fenton process. The results suggested that the nanocomposite designated FGO1 (GO loading of 25 mg) exhibits a higher photocatalytic efficiency than other FGO nanocomposites and pure FeO. A maximum chemical oxygen demand degradation efficiency of 89.6% was achieved in 80 min with 1.5 g L FGO1 at pH 3. The degradation of different pollutants present in wastewater was evaluated with the aid of gas chromatography-mass spectrometry and 3D excitation-emission-matrix analysis. Inductively coupled plasma atomic emission spectroscopy and magnetic measurements confirmed that the FGO1 nanocomposites possess a low iron leachability and a high reusability. Thus, a comprehensive advanced treatment of real industrial wastewater using a magnetic FGO catalyst is demonstrated.
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http://dx.doi.org/10.1007/s11356-021-13458-9DOI Listing
March 2021

Caspase-1 inhibition ameliorates murine acute graft versus host disease by modulating the Th1/Th17/Treg balance.

Int Immunopharmacol 2021 May 26;94:107503. Epub 2021 Feb 26.

Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China; Jiangsu Key Laboratory of Bone Marrow Stem Cells, Xuzhou Medical University, Xuzhou, Jiangsu, China. Electronic address:

Our previous studies have implicated Caspase-1 signaling in driving the proinflammatory state of acute graft versus host disease (aGVHD). Therefore, we aimed to elucidate the mechanism of Caspase-1 in in murine models of aGVHD through specific inhibition of its activity with the decoy peptide Ac-YVAD-CMK. We transplanted bone marrow from donor C57BL/6 (H-2b) mice into recipient BALB/c (H-2Kd) mice and randomized the recipients into the following treatment cohorts: (1) allogeneic hematopoietic stem cell transplantation and splenic cell infusion control (PBS group); (2) low dose Ac-YVAD-CMK (AC low group); (3) and high dose Ac-YVAD-CMK (AC high group). Indeed, we observed that Caspase-1 inhibition by Ac-YVAD-CMK ameliorated pathological damage and inflammation in the liver, lungs, and colon elicited by aGVHD. This was associated with reduced mortality secondary to aGVHD. Mechanistically, we found that Caspase-1 inhibition modulated donor T cell expansion, restored the balance of Th1/Th17/Treg subsets, and markedly decreased serum levels and aGVHD target organ mRNA expression of IL-1β, IL-18, and HMGB1. Thus, we demonstrate that inhibition of Caspase-1 by Ac-YVAD-CMK mitigates murine aGVHD by regulating Th1/Th17/Treg balance and attenuating its characteristic proinflammatory state.
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http://dx.doi.org/10.1016/j.intimp.2021.107503DOI Listing
May 2021

The effects of myeloablative or non-myeloablative total body irradiations on intestinal tract in mice.

Biosci Rep 2021 Mar;41(3)

Institute of Blood Diseases, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China.

Acute radiation injury caused by high-dose radiation exposure severely impedes the application of radiotherapy in cancer management. To deeply understand the side effects of radiation on intestinal tract, an irradiation murine model was applied and evaluated. C57BL/6 mice were given 4 Gy non-myeloablative irradiation, 8 Gy myeloablative irradiation and non-irradiation (control), respectively. Results demonstrated that the 8 Gy myeloablative irradiations significantly damaged the gut barrier along with decreasing MECA32 and ZO-1. However, a slight increase in MECA32 and ZO-1 was detected in the 4 Gy non-myeloablative irradiations treatment from day 5 to day 10. Further, the irradiations affected the expression of P38 and JNK mitogen-activated protein kinase (MAPK) but not ERK1/2 MAPK signal pathway. Moreover, irradiation had adverse effects on hematopoietic system, altered the numbers and percentages of intestinal inflammatory cells. The IL-17/AhR had big increase in the gut of 4 Gy irradiation mice at day 10 compared with other groups. Both 8 Gy myeloablative and 4 Gy non-myeloablative irradiation disturbed the levels of short-chain fatty acids (SCFAs) in intestine. Meanwhile, high dosage of irradiation decreased the intestinal bacterial diversity and altered the community composition. Importantly, the fatty acids generating bacteria Bacteroidaceae and Ruminococcaceae played key roles in community distribution and SCFAs metabolism after irradiation. Collectively, the irradiation induced gut barrier damage with dosages dependent that led to the decreased p38 MAPK and increased JNK MAPK, unbalanced the mononuclear cells (MNCs) of gut, disturbed intestinal bacterial community and SCFAs level.
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http://dx.doi.org/10.1042/BSR20202993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926181PMC
March 2021

EHMT2 inhibitor BIX-01294 induces endoplasmic reticulum stress mediated apoptosis and autophagy in diffuse large B-cell lymphoma cells.

J Cancer 2021 1;12(4):1011-1022. Epub 2021 Jan 1.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Despite advancement in the treatment of diffuse large B-cell lymphoma (DLBCL), many patients tend to relapse or become refractory after initial therapy. Therefore, it is essential to identify novel therapeutic targets and drugs, understand the molecular pathogenesis mechanism of DLBCL, and find ways to prevent and treat relapsed or refractory DLBCL. BIX-01294 is a small molecule compound that specifically inhibits EHMT2 activity. In this study, we demonstrate that BIX-01294 triggered the inhibition of human DLBCL cell proliferation, lead to G phase arrest via increasing level and reducing level. BIX-01294 also induced apoptosis via endogenous and exogenous apoptotic pathways. Moreover, BIX-01294 triggered autophagy and activated ER stress in human DLBCL cells. Furthermore, we showed that both key components of ER stress, ATF3, and ATF4, are required for BIX-01294-induced apoptosis and autophagy. Hence, this study provides new evidence that EHMT2 may be a new therapeutic target, and BIX-01294 may be a potential therapeutic drug for treating DLBCL.
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http://dx.doi.org/10.7150/jca.48310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797660PMC
January 2021

Clodronate-liposomes aggravate irradiation-induced myelosuppression by promoting myeloid differentiation.

Int J Radiat Biol 2021 11;97(2):240-248. Epub 2021 Jan 11.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.

Purpose: Clodronate-liposomes (Clod-Lip) is an effective candidate drug for treating chronic myelomonocytic leukemia, autoimmune hemolytic anemia and immune thrombocytopenic purpura in mice experiments. But its role in hematopoietic recovery after acute myelosuppression is still unknown. We aim to explore the function and underlining mechanisms of Clod-Lip on hematopoietic reconstitution after sublethal dose irradiation in mice.

Materials And Methods: Mice at 8-10 weeks received a total-body sublethal dose γ-irradiation (TBI) and injected with Clod-Lip or PBS-Liposomes (PBS-Lip) every 4 days after TBI. The survival rate of each group was recorded. Flow cytometry was used to analyze changes in hematopoietic stem cells and their progenies in bone marrow. ELISA and RT-qPCR were used for the analysis of hematopoietic regulatory factors. Regarding IL-1β inhibition, 25 mg/kg diacerein or an equal volume of DMSO was intraperitoneally injected into mice every day after TBI.

Results: In sublethal dose-irradiated mice, Clod-Lip reduced the survival rate, the total number of bone marrow and hematopoietic stem cells, delayed peripheral blood recovery of red blood cells and platelets. However, it could increase the number of CMP, MEP and myeloid cells, which suggested that Clod-Lip could induce HSC to myeloid differentiation in vivo. We further verified that Clod-Lip may induce myeloid differentiation by bone marrow microenvironmental factor IL-1β.

Conclusions: In summary, this study suggested that Clod-Lip may aggravate inhibitor effect of hematopoietic function and promote myeloid differentiation in myelosuppression mice model.
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http://dx.doi.org/10.1080/09553002.2021.1857452DOI Listing
January 2021

Comparative mitochondrial genomics of five Dermestid beetles (Coleoptera: Dermestidae) and its implications for phylogeny.

Genomics 2021 Jan 22;113(1 Pt 2):927-934. Epub 2020 Oct 22.

Department of Entomology, MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing 100193, China. Electronic address:

Dermestid beetles (Coleoptera: Dermestidae) are important pests of various stored products, posing potential threats to international trade. Their detailed characterization on molecular basis is a pre-requisite for proper identification and for understanding of their phylogenetic relationships. In this work, the whole mitochondrial genomes (mitogenomes) of Trogoderma granarium, Dermestes lardarius, D. ater, Attagenus augustatus augustatus and Attagenus unicolor japonicus were firstly sequenced to update the database using the next-generation sequencing technique. Based on the selected model species, a comparative analysis of four Dermestidae genera was performed. The mitochondrial genomes of these five species above showed high similarity in nucleotide composition, base composition and gene order, including 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs) and a non-coding control region, which was similar to most of Coleoptera species. The phylogenetic analysis based on the PCGs and two rRNAs indicated that the relationships within Dermestidae were reconstructed as (((Trogoderma + Anthrenus) + Attagenus) + Dermestes) using both Maximum Likelihood (ML) and Bayesian Inference (BI) analysis. However, more mitogenomes should be sequenced to obtain a more holistic view of the whole family. This study not only showed the mitogenomes of five Dermestidae species and their high conservativeness, but also discussed its implications for reconstructing a more comprehensive phylogeny of dermestids.
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http://dx.doi.org/10.1016/j.ygeno.2020.10.026DOI Listing
January 2021

Role of T cell immune response cDNA 7 on the pathology of acute graft-versus-host disease.

Oncol Lett 2020 Dec 28;20(6):300. Epub 2020 Sep 28.

Blood Disease Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China.

Activation of T lymphocytes is the initiating factor of the occurrence of acute graft-versus-host disease (aGVHD), and cytotoxic T lymphocyte antigen-4 (CTLA-4) is the inhibitory receptor for activating T cells. T cell immune response cDNA 7 (TIRC7) is considered an upstream regulator of CTLA-4; however, little is understood regarding the effects of TIRC7 on the regulation of CTLA-4 in aGVHD. The purpose of the present study was to evaluate the regulatory effects of TIRC7 on aGVHD, mainly in the pathology. Recipient mice were exposed to a preconditioning dose of 7.5 Gy irradiation on the day of the transplantation and were divided into the following groups: Blank control group, bone marrow transplantation control group, total body irradiation group, mild-moderate aGVHD group and severe aGVHD group. According to the different administration of CTLA-4 and TIRC7 monoclonal antibodies, the mild-moderate and severe aGVHD groups were randomly divided into the hematopoietic stem cell transplantation (HSCT) and HSCT + CTLA-4/TIRC7 groups. Recipient mice were sacrificed at different time points post-HSCT for histopathological analysis by hematoxylin and eosin staining. Compared with the control and other experimental groups, the mice in the combined CTLA-4 and TIRC7 group exhibited ameliorated pathological injury, and lower pathology scores of the liver, lung and intestine. These data revealed that intraperitoneal injection of anti-TIRC7 and/or anti-CTLA-4 monoclonal antibody into mice could effectively alleviate the severity of aGVHD.
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http://dx.doi.org/10.3892/ol.2020.12163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577082PMC
December 2020

PEDF promotes the repair of bone marrow endothelial cell injury and accelerates hematopoietic reconstruction after bone marrow transplantation.

J Biomed Sci 2020 Sep 1;27(1):91. Epub 2020 Sep 1.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.

Background: Preconditioning before bone marrow transplantation such as irradiation causes vascular endothelial cells damage and promoting the repair of damaged endothelial cells is beneficial for hematopoietic reconstitution. Pigment epithelium-derived factor (PEDF) regulates vascular permeability. However, PEDF's role in the repair of damaged endothelial cells during preconditioning remains unclear. The purpose of our study is to investigate PEDF's effect on preconditioning-induced damage of endothelial cells and hematopoietic reconstitution.

Methods: Damaged endothelial cells induced by irradiation was co-cultured with hematopoietic stem cells (HSC) in the absence or presence of PEDF followed by analysis of HSC number, cell cycle, colony formation and differentiation. In addition, PEDF was injected into mice model of bone marrow transplantation followed by analysis of bone marrow injury, HSC number and peripheral hematopoietic reconstitution as well as the secretion of cytokines (SCF, TGF-β, IL-6 and TNF-α). Comparisons between two groups were performed by student t-test and multiple groups by one-way or two-way ANOVA.

Results: Damaged endothelial cells reduced HSC expansion and colony formation, induced HSC cell cycle arrest and apoptosis and promoted HSC differentiation as well as decreased PEDF expression. Addition of PEDF increased CD144 expression in damaged endothelial cells and inhibited the increase of endothelial permeability, which were abolished after addition of PEDF receptor inhibitor Atglistatin. Additionally, PEDF ameliorated the inhibitory effect of damaged endothelial cells on HSC expansion in vitro. Finally, PEDF accelerated hematopoietic reconstitution after bone marrow transplantation in mice and promoted the secretion of SCF, TGF-β and IL-6.

Conclusions: PEDF inhibits the increased endothelial permeability induced by irradiation and reverse the inhibitory effect of injured endothelial cells on hematopoietic stem cells and promote hematopoietic reconstruction.
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http://dx.doi.org/10.1186/s12929-020-00685-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466818PMC
September 2020

Tacrolimus ameliorates thrombocytopenia in an ITP mouse model.

Ann Hematol 2020 Oct 29;99(10):2315-2322. Epub 2020 Jul 29.

Blood Diseases Institute, Xuzhou Medical University, 84 West Huaihai Rd, Quanshan District, Xuzhou, 221002, Jiangsu, China.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by lower platelet count resulting from immune cells-mediated platelet clearance. Tacrolimus is an immunosuppressive agent which selectively inhibits T cell activation. Whether tacrolimus plays a role in ITP remains unclear. This study aimed to investigate the effect of tacrolimus on ITP in mice. An ITP mouse model was established by injection of rat anti-mouse integrin GPIIb/CD41 immunoglobulin and treated with tacrolimus followed by isolation of peripheral blood mononuclear cells and plasma. The mRNA expression of T-bet, GATA3, and Foxp3 was measured by RT-PCR, and level of IFN-γ, IL-12p70, IL-4, IL-13, and TGF-β in plasma was measured by ELISA. Tacrolimus inhibited antiplatelet antibody-mediated platelet clearance in ITP mouse model. Meanwhile, tacrolimus-treated ITP mice displayed a significant decrease in the mRNA expression of T-bet and plasma level of IFN-γ and IL-12p70 compared with ITP mice but without differences when compared with normal mice. Furthermore, the expression of GATA3, Foxp3, and plasma level of IL-4 and TGF-β were upregulated in tacrolimus-treated ITP mice without significant differences to normal mice (except TGF-β). Tacrolimus prevents antiplatelet antibody-mediated thrombocytopenia in ITP mice possibly through regulating T cell differentiations, suggesting it might be a novel approach for preventing ITP.
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http://dx.doi.org/10.1007/s00277-020-04203-2DOI Listing
October 2020

Cladribine Induces ATF4 Mediated Apoptosis and Synergizes with SAHA in Diffuse Large B-Cell Lymphoma Cells.

Int J Med Sci 2020 30;17(10):1375-1384. Epub 2020 May 30.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Cladribine is a purine nucleoside analog used to treat B-cell chronic lymphocytic leukemia and hairy cell leukemia, also functions as an inhibitor of DNA synthesis to block the repair of the damaged DNA. The therapeutic role of cladribine against diffuse large B-cell lymphoma cells (DLBCL) is still undefined. In the present study, we demonstrated that cladribine inhibited cell proliferation and induced G phase arrest in human DLBCL cells. Furthermore, we showed that cladribine induced apoptosis by decreasing the expression of c-FLIP and increasing the expression of DR4 and the cleaved form of caspase8. Cladribine also upregulated the expression of Bax, and downregulated the expression of Mcl-1 and Bcl-2 in a dose-dependent manner. It also activated endoplasmic reticulum (ER) stress, and ATF4 expression was required for cladribine induced apoptosis. Also, we showed that suberoylanilide hydroxamic acid (SAHA) enhanced the pro-apoptotic role of cladribine. Collectively, cladribine activated extrinsic and intrinsic apoptotic signaling pathways via stimulating ER stress signaling pathway and eliciting synergistic effect with SAHA in DLBCL cells.
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http://dx.doi.org/10.7150/ijms.41793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330656PMC
March 2021

Phase II trial of co-administration of CD19- and CD20-targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma.

Cancer Med 2020 08 1;9(16):5827-5838. Epub 2020 Jul 1.

Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.

Purpose: Anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy for refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL). However, this therapy failed in nearly 25% patients mainly due to antigen loss. The authors performed a phase Ⅱ trial by coadministration of anti-CD19 and anti-CD20 CAR-T cells treatment for R/R DLBCL and evaluated its efficacy and toxicity.

Methods: Totally 21 patients with DLBCL were enrolled in this study. The patients were conditioned with fludarabine and cyclophosphamide before the infusion of anti-CD19 and anti-CD20 CAR-T cells. Treatment response, toxicity, and persistence were monitored continuously.

Results: Of the 21 patients received the treatment, the objective response rate (ORR) is 81.0% (95% confidence interval [CI], 58.1%-94.6%) with four cases of bulk (4/5) and one case of testis involvement; 52.4% (95% CI, 29.8%-74.3%) had a complete response (CR). Peak levels of anti-CD19 and anti-CD20 CAR cells were associated with response (P = .007 and .002). Grade 3-4 cytokine release syndrome (CRS) and neurologic events occurred in 28.5% and 9.5% patients, respectively. Median overall survival (OS) and progression-free survival (PFS) were 8.1 and 5.0 months, respectively. The maximum standard uptake value (SUVmax) of CD4/CD8 ratio before and after infusion were associated with responses, and the total lesion glycolysis (TLG) before infusion correlates with cytokines level.

Conclusions: Coadministration of anti-CD19 and CD20 CAR-T cells therapy for DLBCL is feasible with manageable toxicity. Cytokine markers are related to toxicity and SUVmax could predict efficacy. This trial was registered at www.clinicaltrials.gov as NCT03207178.
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http://dx.doi.org/10.1002/cam4.3259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433814PMC
August 2020

p47phox deficiency impairs platelet function and protects mice against arterial and venous thrombosis.

Redox Biol 2020 07 11;34:101569. Epub 2020 May 11.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China. Electronic address:

NADPH oxidase-derived reactive oxygen species (ROS) regulates platelet function and thrombosis. It remains controversial regarding NOX2's role in platelet function. As a regulatory subunit for NOX2, whether p47phox regulates platelet function remains unclear. Our study intends to evaluate p47phox's role in platelet function. Platelets were isolated from wild-type or p47phox mice followed by analysis of platelet aggregation, granule secretion, surface receptors expression, spreading, clot retraction and ROS generation. Additionally, in vivo hemostasis, arterial and venous thrombosis was assessed. Moreover, human platelets were treated with PR-39 to inhibit p47phox activity followed by analysis of platelet function. p47phox deficiency significantly prolonged tail-bleeding time, delayed arterial and venous thrombus formation in vivo as well as reduced platelet aggregation, ATP release and αIIbβ3 activation. In addition, p47phox platelets presented impaired spreading on fibrinogen or collagen and defective clot retraction concomitant with decreased phosphorylation of Syk and PLCγ2. Moreover, CRP or thrombin-stimulated p47phox platelets displayed reduced intracellular ROS generation which was further decreased after inhibition of NOX1. Meanwhile, p47phox deficiency increased VASP phosphorylation and decreased phosphorylation of ERK1/2, p38, ERK5 and JNK without affecting AKT and c-PLA2 phosphorylation. Furthermore, p47phox translocates to membrane to interact with both NOX1 and NOX2 after stimulation with CRP or thrombin. Finally, inhibition of p47phox activity by PR-39 reduced ROS generation, platelet aggregation and clot retraction in human platelets. In conclusion, p47phox regulates platelet function, arterial and venous thrombus formation and ROS generation, indicating that p47phox might be a novel therapeutic target for treating thrombotic or cardiovascular diseases.
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http://dx.doi.org/10.1016/j.redox.2020.101569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231845PMC
July 2020

The oxidation of hydrocarbons by diverse heterotrophic and mixotrophic bacteria that inhabit deep-sea hydrothermal ecosystems.

ISME J 2020 08 30;14(8):1994-2006. Epub 2020 Apr 30.

Key Laboratory of Marine Genetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen, China.

Hydrothermal activity can generate numerous and diverse hydrocarbon compounds. However, little is known about the influence of such hydrocarbons on deep-sea hydrothermal microbial ecology. We hypothesize that certain bacteria live on these hydrocarbons. Therefore, in this study, the distribution of hydrocarbons and their associated hydrocarbon-degrading bacteria were investigated at deep-sea hydrothermal vents at the Southern Mid-Atlantic Ridge, the Southwest Indian Ridge, and the East Pacific Rise. A variety of hydrocarbon-degrading consortia were obtained from hydrothermal samples collected at the aforementioned sites after low-temperature enrichment under high hydrostatic pressures, and the bacteria responsible for the degradation of hydrocarbons were investigated by DNA-based stable-isotope probing with uniformly C-labeled hydrocarbons. Unusually, we identified several previously recognized sulfur-oxidizing chemoautotrophs as hydrocarbon-degrading bacteria, e.g., the SAR324 group, the SUP05 clade, and Sulfurimonas, and for the first time confirmed their ability to degrade hydrocarbons. In addition, Erythrobacter, Pusillimonas, and SAR202 clade were shown to degrade polycyclic aromatic hydrocarbons for the first time. These results together with relatively high abundance in situ of most of the above-described bacteria highlight the potential influence of hydrocarbons in configuring the vent microbial community, and have made the importance of mixotrophs in hydrothermal vent ecosystems evident.
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http://dx.doi.org/10.1038/s41396-020-0662-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368058PMC
August 2020

Salidroside inhibits platelet function and thrombus formation through AKT/GSK3β signaling pathway.

Aging (Albany NY) 2020 04 30;12(9):8151-8166. Epub 2020 Apr 30.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.

Salidroside is the main bioactive component in and possesses multiple biological and pharmacological properties. However, whether salidroside affects platelet function remains unclear. Our study aims to investigate salidroside's effect on platelet function. Human or mouse platelets were treated with salidroside (0-20 μM) for 1 hour at 37°C. Platelet aggregation, granule secretion, and receptors expression were measured together with detection of platelet spreading and clot retraction. In addition, salidroside (20 mg/kg) was intraperitoneally injected into mice followed by measuring tail bleeding time, arterial and venous thrombosis. Salidroside inhibited thrombin- or CRP-induced platelet aggregation and ATP release and did not affect the expression of P-selectin, glycoprotein (GP) Ibα, GPVI and αβ. Salidroside-treated platelets presented decreased spreading on fibrinogen or collagen and reduced clot retraction with decreased phosphorylation of c-Src, Syk and PLCγ2. Additionally, salidroside significantly impaired hemostasis, arterial and venous thrombus formation in mice. Moreover, in thrombin-stimulated platelets, salidroside inhibited phosphorylation of AKT (T308/S473) and GSK3β (Ser9). Further, addition of GSK3β inhibitor reversed the inhibitory effect of salidroside on platelet aggregation and clot retraction. In conclusion, salidroside inhibits platelet function and thrombosis via AKT/GSK3β signaling, suggesting that salidroside may be a novel therapeutic drug for treating thrombotic or cardiovascular diseases.
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http://dx.doi.org/10.18632/aging.103131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244060PMC
April 2020

TIRC7 inhibits Th1 cells by upregulating the expression of CTLA‑4 and STAT3 in mice with acute graft‑versus‑host disease.

Oncol Rep 2020 Jul 21;44(1):43-54. Epub 2020 Apr 21.

Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China.

In a previous study, it was demonstrated that T‑cell immune response cDNA 7 (TIRC7) levels reflect the efficacy of treatment of patients with acute graft‑versus‑host disease (GVHD). However, the pathogenesis of TIRC7 in acute GVHD remains poorly understood. Lymphocytes from patients with acute GVHD were selected as targeT cells, and the effects of TIRC7 on cytotoxic T lymphocyte antigen‑4 (CTLA‑4), T cell activation and cytokine secretion were observed by electroporation. A mouse model of acute GVHD was established; anti‑TIRC7 and anti‑CTLA‑4 monoclonal antibodies were intraperitoneally injected into recipient mice. Then, the effects of TIRC7 and CTLA‑4 on T cell activation and acute GVHD were monitored. After TIRC7 expression was downregulated, CTLA‑4 levels were decreased and STAT3 phosphorylation was reduced; conversely, the activation capacity of T lymphocytes was elevated, and the secretion of interferon‑γ and other cytokines was increased. The mice in the TIRC7 + CTLA‑4 co‑administration group exhibited the lowest acute GVHD scores, with the longest average survival time and shortest recovery time of hematopoietic reconstitution. In conclusion, the results indicated that TIRC7 may positively regulate the function of CTLA‑4 and inhibit T cell activation, thus suppressing the development and progression of acute GVHD.
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http://dx.doi.org/10.3892/or.2020.7588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254953PMC
July 2020

Assessment of oral ciprofloxacin impaired gut barrier integrity on gut bacteria in mice.

Int Immunopharmacol 2020 Jun 2;83:106460. Epub 2020 Apr 2.

Institute of Blood Diseases, Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, China; Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province 221002, China; Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province 221002, China. Electronic address:

Gut bacteria and gut barrier plays important roles in body homeostasis. Ciprofloxacin (CPFX) is widely used to treat bacterial infections. However, whether high dosage of CPFX has side effects on gut barrier integrity is still unclear. Our results indicated that the High CPFX treatment (1 mg/ml) caused weight loss, nervousness, anorexia, and increased apoptosis cells in gut, but less influence was observed in the Low CPFX group (0.2 mg/ml). Meanwhile, the High CPFX treatment impaired tight junction molecules Ocln/ZO-1 level and down-regulated antibacterial genes expression (reg3γ, pla2g2α and defb1). Further, the High CPFX treatment increased pro-inflammatory cytokine IL-1β in intestinal tract, decreased IL-17A of duodenum but increased IL-17A of colon at day 37. In addition, the gut bacterial diversity and richness behaved significantly loss regarding CPFX treatment, especially in the High CPFX group during the experiment. Indole exhibited sharply decline in both Low and High CPFX groups at day 7, and the High CPFX mice needed longer time on restoring indole level. Meanwhile, CPFX treatment strongly decreased the concentrations of butyric acid and valeric acid at day 1. Correlation analysis indicated that the linked patterns between the key bacteria (families Bacteroidales_S247, Ruminococcaceae and Desulfovibrionaceae) and metabolites (indole and butyric acid) were disturbed via the CPFX treatment. In conclusion, the High CPFX treatment impaired the gut barrier with the evidence of reduced expression of tight junction proteins, increased apoptosis cells and inflammatory cells, decreased the bacterial diversity and composition, which suggesting a proper antibiotic-dosage use should be carefully considered in disease treatment.
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http://dx.doi.org/10.1016/j.intimp.2020.106460DOI Listing
June 2020

Reference gene selection and validation for mRNA expression analysis by RT-qPCR in murine M1- and M2-polarized macrophage.

Mol Biol Rep 2020 Apr 19;47(4):2735-2748. Epub 2020 Mar 19.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China.

Murine bone marrow-derived macrophages (M0) and M1- and M2-polarized macrophages are being widely used as a laboratory model for polarized macrophages related molecular mechanism analysis. Gene expression analysis based on reference gene normalization using RT-qPCR was a powerful way to explore the molecular mechanism. But little is known about reference genes in these cell models. So, the goal of this study was to identify reference genes in these types of macrophages. Candidate reference genes in murine bone marrow-derived and polarized macrophages were selected from microarray data using Limma linear model method and evaluated by determining the stability value using five algorithms: BestKeeper, NormFinder, GeNorm, Delta CT method, and RefFinder. Finally, the selected stable reference genes were validated by testing three important immune and inflammatory genes (NLRP1, IL-1β, and TNF-α) in the cell lines. Our study has clearly shown that Ubc followed by Eef1a1 and B2m respectively were recognized as the three ideal reference genes for gene expression analysis in murine bone marrow-derived and polarized macrophages. When three reference genes with strong different stability were used for validation, a large variation of a gene expression level of IL-1β, TNF-α and NLRP1 were obtained which provides clear evidence of the need for careful selection of reference genes for RT-qPCR analysis. Normalization of mRNA expression level with Ubc rather than Actb or Gusb by qPCR in macrophages and polarized macrophages is required to ensure the accuracy of the qPCR analysis.
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http://dx.doi.org/10.1007/s11033-020-05372-zDOI Listing
April 2020

Developing a ratiometric two-photon probe with baseline resolved emissions by through band energy transfer strategy: Tracking mitochondrial SO during neuroinflammation.

Biomaterials 2020 05 24;241:119910. Epub 2020 Feb 24.

Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, China. Electronic address:

Sulfur dioxide (SO) with the largest quantity and widest distribution in the atmosphere is closely related to many nervous system diseases via mitochondria respiration. It is of great significance to monitor this gaseous molecule during various physiological and pathological processes, but currently the task still remains challenging due to the lack of reliable tools. Through-bond energy transfer (TBET) is a relatively new strategy to fabricate ratiometric fluorescent probes, which does not need spectral overlap between the energy donor and acceptor while provides high energy-transfer efficiency. It offers strong dual fluorescence emission peaks as well as large wavelength differences between the two peaks, which increases the bioimaging resolution and reliability. Herein, we developed a TBET-based ratiometric probe (TBET-SO) with a series of superior properties for in vivo SO imaging. Excited by near-infrared pulsed laser (810 nm), the probe undergoes TBET and produces far-red emission (611 nm). It achieved significant energy-transfer efficiency (90.5%) and large spectral gap between two peaks (△λ = 118 nm). Upon reacting with SO, TBET-SO showed ~30-fold enhancement of ratiometric signal contributed by the baseline resolved emissions. A detection limit of as low as 0.09 μM was obtained. Furthermore, TBET-SO was successfully applied for visualizing the mitochondrial SO in living cells and mice brain tissue during the neuroinflammation process induced by SO pollution.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119910DOI Listing
May 2020

Quantification of ERK Kinase Activity in Biological Samples Using Differential Sensing.

ACS Chem Biol 2020 01 16;15(1):83-92. Epub 2019 Dec 16.

Division of Chemical Biology & Medicinal Chemistry, College of Pharmacy , The University of Texas at Austin , Austin , Texas 78712 , United States.

The understanding of complex biological systems requires an ability to evaluate interacting networks of genes, proteins, and cellular reactions. Enabling technologies that support the rapid quantification of these networks will facilitate the development of biological models and help to identify treatment targets and to assess treatment plans. The biochemical process of protein phosphorylation, which underlies almost all aspects of cell signaling, is typically evaluated by immunoblotting procedures (Western blot) or more recently proteomics procedures, which provide qualitative estimates of the concentration of proteins and their modifications in cells. However, protein modifications are difficult to correlate with activity, and while immunoblotting and proteomics approaches have the potential to be quantitative, they require a complex series of steps that diminish reproducibility. Here, a complementary approach is presented that allows for the rapid quantification of a protein kinase activity in cell lysates and tumor samples. Using the activity of cellular ERK (extracellular signal-regulated kinase) as a test case, an array sensing approach that utilizes a library of differential peptide-based biosensors and chemometric tools was used to rapidly quantify nanograms of active ERK in micrograms of unfractionated cell lysates and tumor extracts. This approach has the potential both for high-throughput and for quantifying the activities of multiple protein kinases in a single biological sample. The critical advantages of this differential sensing approach over others are that it removes the need for the addition of exogenous inhibitors to suppress the activities of major off-target kinases and allows us to quantitate the amount of active kinase in tested samples rather than measuring the changes in its activity upon induction or inhibition.
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http://dx.doi.org/10.1021/acschembio.9b00580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085986PMC
January 2020

Janus kinase inhibitor ruxolitinib blocks thymic regeneration after acute thymus injury.

Biochem Pharmacol 2020 01 11;171:113712. Epub 2019 Nov 11.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China. Electronic address:

Thymic epithelial cells (TECs) are crucial for the production of T-cells. Cancer therapies including cytotoxic drugs and ionizing radiations damage TECs resulting in abnormal T-cell production and function. Fortunately, TECs can regenerate after injury. The Janus kinase (Jak) pathway is important in supporting survival of TECs. Jak inhibitors are used to treat cancer and immune disorders. The impact of Jak inhibitors on recovery of TECs is unknown. We induced acute thymus injury in mice by using ionizing radiation and evaluated the impact of ruxolitinib on thymus regeneration. We also tested if ruxolitinib affected proliferation of TECs in vitro. An increase was observed in the recovery of thymus cells after acute injury in association with up-regulation of TEC-related growth factors including keratinocyte growth factor (Kgf), epidermal growth factor (Egf), insulin-like growth factor 1 (Igf1) and receptor activator of NF-κB ligand (Rankl). Giving ruxolitinib decreased levels of receptors of these growth factors on TECs and blocked growth factor-induced recovery of thymus cells in damaged thymii. Ruxolitinib also blocked growth factors-induced proliferation of TECs in vitro. Thymus regeneration was inhibited when ruxolitinib was given immediately after thymus injury but not when it was given 1 week later. These data may have implications for how ruxolitinib is used in clinical practices.
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http://dx.doi.org/10.1016/j.bcp.2019.113712DOI Listing
January 2020

Thalidomide prevents antibody-mediated immune thrombocytopenia in mice.

Thromb Res 2019 Nov 22;183:69-75. Epub 2019 Oct 22.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221002, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou 221002, China. Electronic address:

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by immune-mediated platelet destruction, leading to lower platelet count. Thalidomide is considered as a novel immunomodulatory drug for treating several autoimmune diseases. Whether thalidomide can ameliorate ITP remains unclear. This study aims to evaluate the effect of thalidomide on ITP mouse model. ITP mouse model was established through intraperitoneal injection of rat anti-mouse integrin GPIIb/CD41 immunoglobulin. Thalidomide (10, 20 or 50 mg/kg body weight) was intraperitoneally injected into mice followed by antibody injection. Then, peripheral blood and plasma was isolated for analysis of platelet count and the level of IFN-γ and IL-17 in plasma. Meanwhile, spleen was extracted to measure the expression of CD68, a macrophage marker. In addition, macrophage cell line RAW264.7 was cultured and treated with thalidomide followed by analysis of cell viability, apoptosis as well as cell cycle. Thalidomide prevented antiplatelet antibody-mediated platelet destruction in ITP mouse model. Compared with vehicle (phosphate-buffered saline), thalidomide significantly inhibited the secretion of IFN-γ and IL-17 in ITP mouse and reduced the expression of CD68 in spleen. After thalidomide treatment, the cell viability of RAW264.7 cell was significantly reduced and the cell number in S phase was also significantly decreased. In addition, the expression of cyclin E2 was significantly reduced. In conclusion, thalidomide prevents antiplatelet antibody-mediated platelet destruction in ITP mouse possibly through reducing the number of macrophages, suggesting that it might be a novel approach for treating ITP.
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http://dx.doi.org/10.1016/j.thromres.2019.09.035DOI Listing
November 2019

Advantages of digital PCR in the detection of low abundance gene in patients with chronic myeloid leukemia.

Oncol Lett 2019 Nov 12;18(5):5139-5144. Epub 2019 Sep 12.

Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China.

Quantitative monitoring of gene using reverse transcription quantitative-PCR (RT-qPCR) is an important method for evaluating the treatment effects in patients with chronic myeloid leukemia (CML). Digital-PCR (dPCR) can be applied to detect the gene with high sensitivity. In the present study, the results of the Clarity™ dPCR system were compared with those of the RT-qPCR in order to determine whether dPCR can be applied in the clinical setting. A total of 83 patients were included in the present study, and they were divided into two groups according to the results of during ongoing monitoring. A total of 43 patients with undetectable where enrolled in group A. testing was performed using the dPCR system on the same peripheral blood samples of patients from group A, and the association between dPCR results and relapse was analyzed. The RT-qPCR platform and dPCR system were used simultaneously to detect the gene of another 40 patients who achieved either partial cytogenetic response (PCyR) or further response. Among patients with undetectable , patients with dPCR-positive disease ( >0.1%) were more likely to undergo molecular relapse (P=0.018). The results of dPCR detection of % were consistent with the RT-qPCR results (R=0.9510) in patients who achieved PCyR or further response. For samples with <1.0%, the consistency of the dPCR and RT-qPCR results was better than that of >1.0% (R=0.9488 vs. R=0.9264 for ). The detection results of the gene in patients with CML using dPCR matched well with those from the RT-qPCR. To conclude, the results of the dPCR system can be applied as a supplement to the RT-qPCR platform, particularly for those with <1.0%.
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http://dx.doi.org/10.3892/ol.2019.10861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781637PMC
November 2019

A panel of 4 biomarkers for the early diagnosis and therapeutic efficacy of aGVHD.

JCI Insight 2019 08 22;4(16). Epub 2019 Aug 22.

Medical Center of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

BACKGROUNDCytokine biomarkers have already been used to predict acute graft-versus-host disease (aGVHD) onset, nonrelapse mortality, and overall survival in human and mouse models, but the consistency of the consequences between patients and mice has not been evaluated. Furthermore, no study about any biomarker or biomarker panel for aGVHD grading or steroid sensitivity of aGVHD patients simultaneously has been reported.METHODSHere we established an aGVHD mouse model and explored the relation between aGVHD onset and variations of some cytokines. Based on the results and latest progress, we selected 16 cytokines and compared their serum variations in aGVHD patients and non-aGVHD patients after allogeneic hematopoietic stem cell transplantation. Using protein microarray, we explored the relation between the cytokine levels and aGVHD-related events (onset, grading, and steroid sensitivity).RESULTSThe increase of chemokine levels in murine aGVHD was very consistent with that of patients. We found obviously higher levels of IL-2, IL-4, Elafin, sST2, TLR4, and TNF-α, and lower levels of TGF-β in both aGVHD mouse models and aGVHD patients. In addition, patients with severe aGVHD showed increased IL-6, TLR4, TNF receptor 1 (TNFR1), and Elafin and decreased TGF-β. TLR4 and TNFR1 were significantly increased in steroid-refractory aGVHD patients compared with steroid-effective patients (P < 0.05).CONCLUSIONA combination of TLR4, TNFR1, TGF-β, and Elafin could be a new 4-biomarker panel to assist aGVHD diagnosis, grading, and evaluation of steroid sensitivity for clinical aGVHD patients.TRIAL REGISTRATIONChiCTR1900022292 "Clinical Research of Umbilical Cord-Derived Mesenchymal Stromal Cells in the Prophylaxis of Graft-Versus-Host Disease After HLA-Haploidentical Stem-Cell Transplantation."FUNDINGNational Key Research Program, National Natural Science Foundation of China, Chongqing Social Career and People's Livelihood Security Science and Technology Innovation Project, Fundamental and Frontier Research Program of Chongqing, and Foundation of Xinqiao Hospital.
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http://dx.doi.org/10.1172/jci.insight.130413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777816PMC
August 2019

All-Trans Retinoic Acid Impairs Platelet Function and Thrombus Formation and Inhibits Protein Kinase CßI/δ Phosphorylation.

Thromb Haemost 2019 10 1;119(10):1655-1664. Epub 2019 Aug 1.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.

All-trans retinoic acid (ATRA) is widely used for induction of complete remission in patients with acute promyelocytic leukemia (APL). ATRA also regulates protein kinase C (PKC) activity. Therapeutic use of ATRA reportedly interferes with hemostatic function in APL patients, including effects on coagulation or other vascular cells, although effects of ATRA on platelets remain unclear. This study aims to investigate the effect of therapeutic-relevant doses of ATRA on platelet function. Human platelets were preincubated with ATRA (0-20 μM) for 1 hour at 37°C, followed by analysis of aggregation, granule secretion, receptor expression by flow cytometry, platelet spreading, or clot retraction. Additionally, ATRA (10 mg/kg) was injected intraperitoneally into mice and tail bleeding time and arterial thrombus formation were evaluated. ATRA inhibited platelet aggregation and adenosine triphosphate release induced by collagen (5 μg/mL) or thrombin (0.05 U/mL) in a dose-dependent manner without affecting P-selectin expression or surface levels of glycoprotein (GP) Ibα, GPVI, or αβ. ATRA-treated platelets demonstrated reduced spreading on immobilized fibrinogen or collagen and reduced thrombin-induced clot retraction together with reduced phosphorylation of Syk and PLCγ2. In addition, ATRA-treated mice displayed significantly impaired hemostasis and arterial thrombus formation in vivo. Further, in platelets stimulated with either collagen-related peptide or thrombin, ATRA selectively inhibited phosphorylation of PKCßI (Ser661) and PKCδ (Thr505), but not PKCα or PKCßII phosphorylation (Thr638/641). In conclusion, ATRA inhibits platelet function and thrombus formation, possibly involving direct or indirect inhibition of PKCßI/δ, indicating that ATRA might be beneficial for the treatment of thrombotic or cardiovascular diseases.
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http://dx.doi.org/10.1055/s-0039-1693737DOI Listing
October 2019

Humanized CD19-specific chimeric antigen-receptor T-cells in 2 adults with newly diagnosed B-cell acute lymphoblastic leukemia.

Leukemia 2019 11 15;33(11):2751-2753. Epub 2019 Jul 15.

Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, 221002, Xuzhou, China.

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http://dx.doi.org/10.1038/s41375-019-0516-7DOI Listing
November 2019

NLRP6 deficiency aggravates liver injury after allogeneic hematopoietic stem cell transplantation.

Int Immunopharmacol 2019 Sep 10;74:105740. Epub 2019 Jul 10.

Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221002, China; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; School of Medical Technology, Xuzhou Medical University, 221004, China. Electronic address:

This study aims to observe the expression and role of NLRP6 in liver injury after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Allo-HSCT model was established through infusion of 5 × 10 bone marrow mononuclear cells into whole body irradiated mice. On days 7, 14, 21 and 28 after transplantation, the peripheral blood was collected to detect liver function. The liver of the mice was obtained to assess the pathological changes of liver tissues after allo-HSCT by H&E staining and Mason staining. Meanwhile, expression of NLRP6, phosphorylated p38-MAPK and IκBα, caspase-1 and NLRP3 in liver were detected by Western blot. ELISA was used for detection of the level of interleukin (IL)-1β, IL-18, tumor necrosis factor (TNF)-α, IL-6, myeloperoxidase (MPO) and tumor growth factor (TGF)-β1. Increased expression of NLRP6, phosphorylated Iκbα, phosphorylated p38-MAPK, pro-caspase-1, and p20, in liver tissue with injury and fibrosis in mice after allo-HSCT were observed. Meanwhile, the level of IL-1β, IL-18, IL-6 and TNF-α was also increased. However, NLRP6 mice showed more severe liver damage and liver fibrosis after transplantation together with higher level of phosphorylated Iκbα, phosphorylated p38-MAPK, Pro-caspase-1, p20 expression as well as IL-1β, IL-18, IL-6, and TNF-α secretion compared with wide-type. Interestingly, the expression of NLRP3 in the liver of NLRP6 mice was significantly higher than that of wild-type. In conclusion, the expression of NLRP6 in host's liver is associated with liver injury after allo-HSCT. NLRP6 deficiency in host's liver leads to more severe liver damage, indicating a protective role of NLRP6 in host's liver to liver damage after allo-HSCT.
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http://dx.doi.org/10.1016/j.intimp.2019.105740DOI Listing
September 2019

Geometry Effects on Light-Harvesting Complex's Light Absorption and Energy Transfer in Purple Bacteria.

Photochem Photobiol 2019 11 17;95(6):1352-1359. Epub 2019 Jul 17.

State Key Laboratory of Photoelectric Materials and Technologies, School of Physics, Sun Yat-sen University, Guangzhou, China.

Light-harvesting complexes (LHC) in photosynthetic organisms perform the major function of light absorption and energy transportation. Optical spectrum of LHC provides a detailed understanding of the molecular mechanisms involved in the excitation energy transfer (EET) processes, which has been widely studied. Here, we study how the geometric property of LHC in Rhodospirillum (Rs.) molischianum would affect its spectral characteristics and energy transfer process. By adopting the effective Hamiltonian and the dipole-dipole approximation, we calculate the exciton level structures for the LH2 ring and LH1 ring and the energy transfer time between different LHCs under various structural parameters and different rotational symmetries. Our numerical results show that the LHC's absorption peaks and the energy transfer time between different LHCs can be modified by changing the geometric configurations. Our study may be beneficial to the applications in designing highly efficient photovoltaic cell and other artificial photosynthetic systems.
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http://dx.doi.org/10.1111/php.13129DOI Listing
November 2019