Publications by authors named "Wenyi Lu"

32 Publications

Infection Temperature Affects the Phenotype and Function of Chimeric Antigen Receptor T Cells Produced Lentiviral Technology.

Front Immunol 2021 19;12:638907. Epub 2021 Apr 19.

Nankai University School of Medicine, Tianjin, China.

Chimeric antigen receptor (CAR)-T cell therapy has become an important method for the treatment of hematological tumors. Lentiviruses are commonly used gene transfer vectors for preparing CAR-T cells, and the conditions for preparing CAR-T cells vary greatly. This study reported for the first time the influence of differences in infection temperature on the phenotype and function of produced CAR-T cells. Our results show that infection at 4 degrees produces the highest CAR-positive rate of T cells, infection at 37 degrees produces the fastest proliferation in CAR-T cells, and infection at 32 degrees produces CAR-T cells with the greatest proportion of naive cells and the lowest expression of immune checkpoints. Therefore, infection at 32 degrees is recommended to prepare CAR-T cells. CAR-T cells derived from infection at 32 degrees seem to have a balance between function and phenotype. Importantly, they have increased oncolytic ability. This research will help optimize the generation of CAR-T cells and improve the quality of CAR-T cell products.
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http://dx.doi.org/10.3389/fimmu.2021.638907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089475PMC
April 2021

CD19 CAR-T cell treatment conferred sustained remission in B-ALL patients with minimal residual disease.

Cancer Immunol Immunother 2021 Apr 25. Epub 2021 Apr 25.

Department of Hematology, Tianjin First Central Hospital, No. 24 Fu Kang Road, Tianjin, 300192, People's Republic of China.

The persistence or recurrence of minimal residual disease (MRD) after chemotherapy predicts relapse of B-cell acute lymphoblastic leukemia (B-ALL). CD19-directed chimeric antigen receptor T (CD19 CAR-T) cells have shown promising responses in B-ALL. However, their role in chemotherapy-refractory MRD-positive B-ALL remains unclear. Here we aimed to assess the effectiveness and safety of CD19 CAR-T cells in MRD-positive B-ALL patients. From January 2018, a total of 14 MRD-positive B-ALL patients received one or more infusions of autogenous CD19 CAR-T cells. Among them, 12 patients achieved MRD-negative remission after one cycle of CAR-T infusion. At a median follow-up time of 647 days (range 172-945 days), the 2-year event-free survival rate in MRD-positive patients was 61.2% ± 14.0% and the 2-year overall survival was 78.6 ± 11.0%, which were significantly higher than patients with active disease (blasts ≥ 5% or with extramedullary disease). Moreover, patients with MRD had a lower grade of cytokine release syndrome (CRS) than patients with active disease. However, the peak expansion of CAR-T cells in MRD positive patients showed no statistical difference compared to patients with active disease. Five patients received two or more CAR-T cell infusions and these patients showed a decreased peak expansion of CAR-T cell in subsequent infusions. In conclusion, pre-emptive CD19 CAR-T cell treatment is an effective and safe approach and may confer sustained remission in B-ALL patients with chemotherapy-refractory MRD. The trials were registered at www.chictr.org.cn as ChiCTR-ONN-16009862 (November 14, 2016) and ChiCTR1800015164 (March 11, 2018).
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http://dx.doi.org/10.1007/s00262-021-02941-4DOI Listing
April 2021

Corrigendum: Targeting Bcl-2 Proteins in Acute Myeloid Leukemia.

Front Oncol 2020 17;10:632775. Epub 2020 Dec 17.

Department of Hematology, Tianjin First Central Hospital, Tianjin, China.

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http://dx.doi.org/10.3389/fonc.2020.632775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774455PMC
December 2020

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

Targeting Bcl-2 Proteins in Acute Myeloid Leukemia.

Front Oncol 2020 5;10:584974. Epub 2020 Nov 5.

Department of Hematology, Tianjin First Central Hospital, Tianjin, China.

B cell lymphoma 2 (BCL-2) family proteins play an important role in intrinsic apoptosis. Overexpression of BCL-2 proteins in acute myeloid leukemia can circumvent resistance to apoptosis and chemotherapy. Considering this effect, the exploration of anti-apoptotic BCL-2 inhibitors is considered to have tremendous potential for the discovery of novel pharmacological modulators in cancer. This review outlines the impact of BCL-2 family proteins on intrinsic apoptosis and the development of acute myeloid leukemia (AML). Furthermore, we will also review the new combination therapy with venetoclax that overcomes resistance to venetoclax and discuss biomarkers of treatment response identified in early-phase clinical trials.
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http://dx.doi.org/10.3389/fonc.2020.584974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674767PMC
November 2020

Acute Graft-Versus-Host Disease After Humanized Anti-CD19-CAR T Therapy in Relapsed B-ALL Patients After Allogeneic Hematopoietic Stem Cell Transplant.

Front Oncol 2020 29;10:573822. Epub 2020 Sep 29.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

We studied the acute graft-versus-host disease (GVHD) after humanized anti-CD19-CAR T therapy in relapsed B-acute lymphoblastic leukemia (ALL) patients after allogeneic hematopoietic stem cell transplant (allo-HSCT). Fifteen B-ALL patients were enrolled in our study. Thirteen patients (86.67%) achieved a complete response (CR) or CR with incomplete count recovery. The donor chimerism of the 13 patients reached 99.86 ± 0.21%. The development of aGVHD was observed in 10 patients (66.67%). Six patients developed grade I-II of aGVHD, while the other four patients developed grade III-IV of aGVHD. The notable adverse events were grade 1-2 cytokine release syndrome (CRS) in 10 patients and grade 3-4 CRS in five patients. Two patients died of infection, while another patient died of sudden cardiac arrest. The anti-CD19-CAR T cells were not eliminated in peripheral blood when the patients developed aGVHD. However, we did not observe their expansion peaks again in the process of aGVHD. During the aGVHD, the peaks of IL-6 and TNF-a were correlated with aGVHD levels. By May 31, 2020, the rates of leukemia-free survival (LFS) and overall survival (OS) at 180 days were 53.846 and 61.638%, respectively. All the patients who survived to date experienced aGVHD after humanized anti-CD19-CAR T cell therapy. The patients were enrolled in clinical trials of and .
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http://dx.doi.org/10.3389/fonc.2020.573822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551306PMC
September 2020

Synergistic effect of programmed death-1 inhibitor and programmed death-1 ligand-1 inhibitor combined with chemotherapeutic drugs on DLBCL cell lines and .

Am J Cancer Res 2020 1;10(9):2800-2812. Epub 2020 Sep 1.

The First Central Clinical College of Tianjin Medical University Tianjin, China.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). Chemotherapy is one of the main treatments for cancer, but the antitumor effect of chemotherapeutic drugs is affected by the patient's immune status. The programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis is an important central checkpoint in tumor progression. The present study demonstrated a significant synergistic effect of PD-1 inhibitor and oxaliplatin, cisplatin, etoposide, cytarabine, ifosfamide and carboplatin. There was no difference in cytotoxicity between the groups with or without PD-L1 inhibitor. It was also observed that cytotoxicity of T cells combined with PD-1 inhibitor against DLBCL cells was inhibited by dexamethasone addition to the culture system at 24, 48 and 72 h. There was no difference in cytotoxicity between the group of dexamethasone added at 96 h and the group without dexamethasone at 96 h. Then, we selected a PD-1 inhibitor combined with a chemotherapeutic regimen in a Pfeiffer cell mouse xenograft model. At 21 days, the reduction in tumor size was more obvious in the DHAP combined with PD-1 inhibitor group (dexamethasone after 96 h of PD-1) compared with that in the DHAP (=0.007), the PD-1 inhibitor (=0.001) and the DHAP combined with PD-1 inhibitor (dexamethasone after 24 h of PD-1) (=0.005) groups. However, the reduction in tumor size was more obvious in the GemOx combined with PD-1 inhibitor group compared with that in the GemOx group (=0.037). Therefore, the present study demonstrated the synergistic effects of PD-1 inhibitor combined with chemotherapeutic regimens in DLBCL.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539778PMC
September 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

Umbilical cord blood-derived mesenchymal stromal cells promote myeloid-derived suppressor cell proliferation by secreting HLA-G to reduce acute graft-versus-host disease after hematopoietic stem cell transplantation.

Cytotherapy 2020 12 15;22(12):718-733. Epub 2020 Aug 15.

Department of Hematology, Tianjin First Central Hospital, Tianjin, China. Electronic address:

Background Aims: Mesenchymal stem cells (MSCs) use multiple mechanisms to constrain both innate and adaptive immune responses to prevent graft-versus-host disease (GVHD). Myeloid-derived suppressor cells (MDSCs), as a heterogeneous population of early myeloid progenitor cells originating from bone marrow, are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses, indicating their potential for GVHD therapy. There is accumulating evidence that MSCs and MDSCs do not act independently, but rather establish crosstalk. However, the role of MSCs in MDSC expansion and activation in GVHD remains unexplored.

Methods: In vitro experiments included 2 groups: peripheral blood mononuclear cells (PBMCs) after mobilization and human umbilical cord blood-derived MSCs (UCB-MSCs) co-cultured with PBMCs. The number and functional difference of MDSCs in PBMCs were determined by flow cytometry. The culture supernatants of co-cultured cells were analyzed to identify cytokines involved in MDSC proliferation. The relationship between MSCs and MDSCs was clarified in GVHD and graft-versus-leukemia (GVL) animal models.

Results: In vitro experiments confirmed that UCB-MSCs secreted HLA-G protein to promote and maintain the proliferation of MDSCs in peripheral blood after granulocyte colony-stimulating factor mobilization, and UCB-MSCs mediated the function of MDSCs to inhibit the proliferation of T cells and promote the proliferation of regulatory T cells. UCB-MSCs overexpressing HLA-G induced MDSC production in recipient mice, improved the ability of MDSCs to suppress T cells and further reduced acute GVHD (aGVHD) symptoms and survival time without influencing GVL effects.

Conclusions: UCB-MSCs expanded MDSCs via HLA-G/Ig-like transcript 4, reducing the severity of aGVHD without affecting GVL. The immunosuppressive potential of MSCs for the treatment of aGVHD significantly affects the development of MDSCs, thereby consolidating the position of MSCs in the prevention and treatment of aGVHD.
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http://dx.doi.org/10.1016/j.jcyt.2020.07.008DOI Listing
December 2020

Study on the effect of sodium-nanoparticle in rice root development.

Plant Signal Behav 2020 06 30;15(6):1759954. Epub 2020 Apr 30.

Jiangsu Key Laboratory of Crop Genetics and Physiology/Co-Innovation Center for Modern Production Technology of Grain Crops/Joint International Research Laboratory of Agriculture &agri-product Safety, Yangzhou University , Yangzhou, China.

Micro-nanoparticles can enter the root tissue of plant cells along with the multiple lanes, and then accumulate in the tissue. But the plant physiological effect is still less studied. In this study, rice seedlings at germination stage were treated with 100 µM NaBiF and BiF. We found that exogenous application of NaBiF treatment inhibited the elongation of rice roots and promoted the generation of adventitious roots, but treated BiF did not mediate obvious phenotype. Further analysis of the peroxidase activity in related tissues showed that NaBiF induced the activity of SOD and CAT decreased, and POD increased, while BiF only induced the activity of SOD to reduced, but the activity of CAT and POD were no changed. Further analysis of the sodium element and potassium element concentration in tissues showed that only the NaBiF treatment reduced content of potassium, but not sodium. Finally, stress-related genes , and were analyzed by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). These results showed that NaBiF induced the expression of decreased, and increased. However, BiF only induced expression of increased. These results provide a physiological basis for further analysis of the effects of sodium salt-nanoparticles in crop plants.
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http://dx.doi.org/10.1080/15592324.2020.1759954DOI 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

Novel insights into the effect of drought stress on the development of root and caryopsis in barley.

PeerJ 2020 31;8:e8469. Epub 2020 Jan 31.

Jiangsu Key Laboratory of Crop Genetics and Physiology/Joint International Research Laboratory of Agriculture & Agri-Product Safety of the Ministry of Education/College of Biological Sciences and Technology, Yangzhou University, Yangzhou, China.

Drought is a common natural disaster in barley production, which restricts the growth and development of barley roots and caryopses seriously, thereby decreasing yield and debasing grain quality. However, mechanisms for how drought stress affects barley caryopses and roots development under drought stress are unclear. In this paper, Suluomai1 was treated with drought from flowering to caryopses mature stage. The morphological and structural changes in roots growth and caryopses development of barley were investigated. Drought stress increased root/shoot ratio and eventually led to the 20.16% reduction of ear weight and 7.75% reduction of 1,000-grain weight by affecting the biomass accumulation of roots and caryopses. The barley roots under drought had more lateral roots while the vessel number and volume of roots decreased. Meanwhile, drought stress accelerated the maturation of caryopses, resulting in a decrease in the accumulation of starch but a significant increase of protein accumulation in barley endosperm. There was a significantly positive correlation (0.76) between the area of root vessel and the relative area of protein in endosperm cells under normal condition and drought increased the correlation coefficient (0.81). Transcriptome analysis indicated that drought induced differential expressions of genes in caryopses were mainly involved in encoding storage proteins and protein synthesis pathways. In general, drought caused changes in the morphology and structure of barley roots, and the roots conveyed stress signals to caryopses, inducing differential expression of genes related to protein biosynthesis, ultimately leading to the increase in the accumulation of endosperm protein. The results not only deepen the study on drought mechanism of barley, but also provide theoretical basis for molecular breeding, high-yield cultivation and quality improvement in barley.
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http://dx.doi.org/10.7717/peerj.8469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996498PMC
January 2020

Comparison of outcomes of haploidentical donor hematopoietic stem cell transplantation supported by third-party cord blood with HLA-matched unrelated donor transplantation.

Leuk Lymphoma 2020 04 28;61(4):840-847. Epub 2019 Nov 28.

Department of Hematology, Tianjin First Center Hospital, Tianjin, PR China.

Previous study indicated that co-infusion of cord blood cells may potentially improve the outcome of haploidentical donor (HID) transplantation. In this study, we analyzed the outcomes of patients who underwent HID transplantation supported by cord blood when compared with HLA-matched unrelated donor (URD) transplantation. Starting in 2015, 40 patients with hematopoietic malignancies underwent HID transplantation and 26 patients underwent URD transplantation. Hematopoietic recovery, the incidences of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD was comparable in the two groups. At two year, the relapse risk in HID group was significantly lower than in URD group (RR 4.630; 95%CI, 1.081-19.839;  = .039). Moreover, HID group have prolonged PFS (RR 2.642; 95%CI, 1.046-6.672;  = .040). In conclusion, HID transplantation supported by cord blood results in better outcomes compared with URD transplantation and it might be a favorable alternative to a HLA-matched URD transplantation.
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http://dx.doi.org/10.1080/10428194.2019.1695053DOI Listing
April 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

Anti-CD19 Chimeric Antigen Receptor T Cells in Combination With Nivolumab Are Safe and Effective Against Relapsed/Refractory B-Cell Non-hodgkin Lymphoma.

Front Oncol 2019 19;9:767. Epub 2019 Aug 19.

Department of Hematology, Tianjin First Central Hospital, Tianjin, China.

Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment for patients with refractory/relapsed B-cell non-Hodgkin lymphoma (B-NHL), and combination with PD1 inhibitors may further improve the efficacy of anti-CD19 CAR (CD19 CAR)-T cells in the treatment of lymphomas. In a single-center study, we evaluated the safety and efficacy of a combination therapy with CD19 CAR-T cells and an anti-PD-1 antibody (nivolumab) in patients with relapsed/refractory B-NHL. A total of 11 patients with refractory/relapsed B-NHL were recruited and subsequently received CD19 CAR-T cells and nivolumab. The primary end points were safety and feasibility. The infusions were safe, and no dose-limiting toxicities occurred. Grade 1 or 2 cytokine release syndrome (CRS) was observed in 25% (3/11) and 50% (6/11) of the patients, respectively, and only one patient (1/11) experienced neurotoxicity. The objective response rate (ORR) and complete response (CR) rate were 81.81% (9/11) and 45.45% (5/11), respectively. The median follow-up time was 6 (1~15) months. The median progression-free survival (PFS) time was 6 months (1~14 months), and 3 patients continued to have a response at the time of this writing. Our study demonstrated that the combination of CD19 CAR-T cells and nivolumab was feasible and safe and mediated potent anti-lymphoma activity, which should be examined further in prospective clinical trials in refractory/relapsed B-NHL.
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http://dx.doi.org/10.3389/fonc.2019.00767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709654PMC
August 2019

Association between trimester-specific gestational weight gain and childhood obesity at 5 years of age: results from Shanghai obesity cohort.

BMC Pediatr 2019 05 2;19(1):139. Epub 2019 May 2.

Department of Clinical Nutrition, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.

Background: It is still unclear if and at which trimester gestational weight gain is related to childhood adiposity. Thus we aimed to evaluate the association between trimester-specific gestational weight gain and body-fat compositions in Chinese children.

Methods: Maternal gestational weight were measured by trained nurses every 2 to 4 weeks from the first prenatal care, and body-fat compositions of 407 children from the Shanghai Obesity Cohort at 5 years of age were measured by nutritionist through bioelectrical impedance analysis. Overweight/obesity of children was defined according to the criteria of International Obesity Task Force. Logistic and linear regression models adjusted for potential confounders were conducted to evaluate the associations of gestational weight gains with childhood obesity and body-fat compositions. Two-sided P-value < 0.05 was considered statistically significant.

Results: Greater gestational weight gain in the 1-trimester was significantly associated with a higher risk of childhood overweight/obesity [OR: 1.40 (95% CI: 1.06, 1.86)], fat mass index [β: 0.25 (95% CI: 0.12, 0.38)], body fat percentage [β: 1.04 (95% CI: 0.43, 1.65)], and waist-to-height ratio [β: 0.005 (95% CI: 0.002, 0.008)]. A positive but nonsignificant association was found between greater 3-trimester gestational weight gain and a higher risk of offspring overweight/obesity, and we speculated that the association between 2-trimester gestational weight gain and offspring overweight/obesity is the "U" type.

Conclusions: Weight gain in the first trimester gestation is positively correlated with the risk of childhood overweight/obesity and with body adiposity distributions of children at 5 years of age. Weight gain should be well controlled and monitored from early pregnancy.
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http://dx.doi.org/10.1186/s12887-019-1517-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495507PMC
May 2019

Prenatal exposure to perfluorobutanesulfonic acid and childhood adiposity: A prospective birth cohort study in Shanghai, China.

Chemosphere 2019 Jul 19;226:17-23. Epub 2019 Mar 19.

Department of Pediatrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. Electronic address:

Background: Several per- and polyfluoroalkyl substances (PFAS) have been phased out due to their adverse effects, and replaced by the short-chain perfluorobutanesulfonic acid (PFBS). However, the long-term impacts of PFBS on human health are unknown.

Objective: We aimed to investigate the association between prenatal exposure to PFAS, especially PFBS and childhood adiposity at 5 years of age.

Methods: We conducted a prospective birth cohort study involving 1,140 pregnant women from 2012 to 2017 in Shanghai. Fetal umbilical cord blood was collected at birth. A total of 404 children (196 girls) completed the adiposity measurements using a bioelectrical impedance analysis method and cord plasma PFAS measurements using LC-MS/MS. Multivariable linear models after adjustment for potential confounders were used to evaluate the associations between PFAS and childhood adiposity.

Results: The median concentration of PFAS in the cord plasma ranged from 0.05 (PFBS) to 6.74 ng/mL (PFOA). Results of multivariable linear regression found that in girls, PFBS had a significant positive association with waist circumference and waist to height ratio (P-values < 0.05). Girls in the highest tertile of PFBS concentrations had more fat mass, as well as higher body fat percentage, waist circumference, and waist to height ratio compared to those in the lowest tertile. However, girls in the second tertile of PFDoA had lower body fat percentage, waist circumference and fat mass.

Conclusions: Adiposity at 5 years of age shows a positive association with prenatal exposure to PFBS in girls. These findings need to be further verified in larger prospective studies.
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http://dx.doi.org/10.1016/j.chemosphere.2019.03.095DOI Listing
July 2019

Human Bone Marrow Mesenchymal Stem Cells Rescue Endothelial Cells Experiencing Chemotherapy Stress by Mitochondrial Transfer Via Tunneling Nanotubes.

Stem Cells Dev 2019 05 24;28(10):674-682. Epub 2019 Apr 24.

1 Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation, Institute of Haematology, Peking University People's Hospital, Beijing, China.

Tunneling nanotubes (TNTs) are newly discovered tubular structures between two distant cells that facilitate the intercellular exchange of signals and components. Recent reports show that mesenchymal stem cells (MSCs) can rescue injured target cells and promote recovery from a variety of stresses via TNT-mediated mitochondrial transfer. In this study, we explored how TNTs form between bone marrow MSCs and endothelial cells (ECs) by using a human umbilical cord vein endothelial cell (HUVEC) model. TNT formation between MSCs and HUVECs could be induced by treating HUVECs with cytarabine (Ara-C), and human bone marrow mesenchymal stem cells (hBMMSCs) could transfer mitochondria to injured HUVECs through TNTs. Mitochondrial transfer from hBMMSCs to HUVECs via TNTs rescued the injured HUVECs by reducing apoptosis, promoting proliferation and restoring the transmembrane migration ability as well as the capillary angiogenic capacity of HUVECs. This study provides novel insights into the cell-cell communication between MSCs and ECs and supports the results of prior studies indicating that ECs promote hematopoietic regeneration. An improved understanding of MSC-EC cross-talk will promote the development of MSC-directed strategies for improving EC function and hematopoietic system regeneration following myelosuppressive and myeloablative injuries.
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http://dx.doi.org/10.1089/scd.2018.0248DOI Listing
May 2019

Dye-sensitized upconversion nanocomposites for ratiometric semi-quantitative detection of hypochlorite in vivo.

Nanoscale 2019 Feb;11(6):2959-2965

Department of Chemistry & State Key Laboratory of Molecular Engineering of Polymers & Collaborative Innovation Center of Chemistry for Energy Material, Fudan University, Shanghai, 200433, P. R. China.

Ratiometric fluorescent sensors, which can provide a built-in correction for environmental effects, have attracted significant attention for analytical sensing and optical imaging with the potential to provide a precise and quantitative analysis. Herein, we report a strategy based on dye-sensitized upconversion for the design of dual-excitation upconverion ratiometric probes possessing same emission peaks under a large separation in the excitation spectra (980 nm and 808 nm). Specifically, effective enhancement of upconversion luminescence could be attributed to Cy787 dyes present on the surface of nanoparticles, and it subsequently decreased upon the addition of ClO- under an 808 nm irradiation, whereas the signal under 980 nm excitation remained essentially constant, thus allowing for quantitative ratiometric monitoring of ClO-. The rationally designed dye-sensitized upconverion nanosystem exhibits excellent sensitivity for ClO- with a quantification limit of 3.6 nM in aqueous solutions. We have also demonstrated that the designed nanoprobe is a promising material for semi-quantitative detection of ClO- in an arthritis mouse model.
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http://dx.doi.org/10.1039/c8nr09531kDOI Listing
February 2019

Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice.

Haematologica 2018 10 14;103(10):1627-1634. Epub 2018 Jun 14.

Department of Hematology, Tianjin First Central Hospital, Tianjin, PR China

There is increasing clinical evidence to suggest a suppressive effect on hematopoiesis in myelodysplastic syndrome patients with iron overload. However, how iron overload influences hematopoiesis in myelodysplastic syndrome (MDS) remains unknown. Here, the -transduced bone marrow mononuclear cells were yielded and transplanted into lethally irradiated recipient mice together with radioprotective bone marrow cells to generate MDS mice. Eight weeks post transplantation, the recipient mice received an intraperitoneal injection of 0.2 mL iron dextran at a concentration of 25 mg/mL once every other day for a total of 8 times to establish an iron overload model. In the present study, we show that iron overload impairs the frequency and colony-forming capacity of normal hematopoietic stem and progenitor cells, especially in erythroid, in MDS mice, which is due, at least in part, to growth differentiation factor 11-induced reactive oxygen species, shortening survival of MDS mice. Given that we are the first to construct an iron overload model in MDS mice, we hope this model will be helpful for further exploring the influence and mechanism of iron overload on MDS.
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http://dx.doi.org/10.3324/haematol.2018.193128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165791PMC
October 2018

Risk factors for and diagnosis of pseudophakic cystoid macular edema after cataract surgery in diabetic patients.

J Cataract Refract Surg 2017 02;43(2):207-214

From the Department of Ophthalmology (Yang, Cai, Sun, Ye, Fan, Zhang, W. Lu, Y. Lu), Eye and ENT Hospital of Fudan University, and the Myopia Key Laboratory of Health PR China (Yang, Cai, Sun, Ye, Fan, Zhang, Y. Lu), Shanghai, China. Electronic address:

Purpose: To evaluate the risk factors and potential diagnostic criteria for pseudophakic cystoid macular edema (CME) in diabetic patients after phacoemulsification.

Setting: Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China.

Design: Prospective nonrandomized study.

Methods: Diabetic patients were followed for up to 6 months after cataract surgery and examined to evaluate their foveal thickness, macular sensitivity, and corrected distance visual acuity. Multiple statistical analyses were performed to determine risk factors and diagnostic criteria for pseudophakic CME.

Results: The duration, type of diabetes, stage of diabetic retinopathy, nuclear opalescence grading, glycosylated hemoglobin A (HbA), and ultrasound time were correlated with the change in foveal thickness and macular sensitivity after cataract surgery. Unsupervised data analysis showed 3 groups of patients as follows: nonpseudophakic CME, level 1 pseudophakic CME, and level 2 pseudophakic CME. Subclinical level 1 patients had a 30% to 40% increase in foveal thickness 1 month postoperatively, while level 2 patients had at least a 40% increase in foveal thickness and a 20% decrease in macular sensitivity. The incidence of clinical pseudophakic CME was 3.2% in diabetic patients as per the diagnostic criteria. The change in macular sensitivity was more consistent and correlated with foveal thickness.

Conclusions: The duration, severity, type of diabetes, hardness of the lens, and HbA were risks for pseudophakic CME in diabetic patients after cataract surgery. A 40% or more increase in foveal thickness and 20% or more decrease in macular sensitivity offer an objective and reliable diagnostic standard to report pseudophakic CME in diabetics.
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http://dx.doi.org/10.1016/j.jcrs.2016.11.047DOI Listing
February 2017

Rosiglitazone Promotes Bone Marrow Adipogenesis to Impair Myelopoiesis under Stress.

PLoS One 2016 19;11(2):e0149543. Epub 2016 Feb 19.

Department of Hematology, Peking University People's Hospital, Beijing, China.

Objective: The therapeutic use of thiazolidinediones (TZDs) causes unwanted hematological side effects, although the underlying mechanisms of these effects are poorly understood. This study tests the hypothesis that rosiglitazone impairs the maintenance and differentiation of hematopoietic stem/progenitor cells, which ultimately leads to hematological abnormalities.

Methods: Mice were fed a rosiglitazone-supplemented diet or a normal diet for 6 weeks. To induce hematopoietic stress, all mice were injected once with 250 mg/kg 5-fluorouracil (5-Fu) intraperitoneally. Next, hematopoietic recovery, hematopoietic stem/progenitor cells (HSPCs) subsets, and myeloid differentiation after 5-Fu treatment were evaluated. The adipogenesis induced by rosiglitazone was assessed by histopathology and oil red O staining. The effect of adipocytes on HSPCs was studied with an in vitro co-culture system.

Results: Rosiglitazone significantly enhanced bone marrow adipogenesis and delayed hematopoietic recovery after 5-Fu treatment. Moreover, rosiglitazone inhibited proliferation of a granulocyte/monocyte progenitor (GMP) cell population and granulocyte/macrophage colony-stimulating factor (GM-CSF) colonies, although the proliferation and mobilization of Lin-c-kit+Sca-1+ cells (LSK) was maintained following hematopoietic stress. These effects could be partially reversed by the selective PPARγ antagonist BADGE. Finally, we demonstrated in a co-culture system that differentiated adipocytes actively suppressed the myeloid differentiation of HSPCs.

Conclusion: Taken together, our results demonstrate that rosiglitazone inhibits myeloid differentiation of HSPCs after stress partially by inducing bone marrow adipogenesis. Targeting the bone marrow microenvironment might be one mechanism by which rosiglitazone impairs stress-induced hematopoiesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149543PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760757PMC
July 2016

The efficacy of lens removal plus IOL implantation for the treatment of spherophakia with secondary glaucoma.

Br J Ophthalmol 2016 Aug 25;100(8):1087-92. Epub 2015 Nov 25.

Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China Myopia Key Laboratory of Health PR China, Shanghai, China.

Aims: To evaluate the efficacy of lens removal plus intraocular lens (IOL) implantation for spherophakia with secondary glaucoma.

Methods: A series of 19 patients (n=24 eyes) were split into two groups according to the degree of zonular abnormality as follows: group 1 (within the range of one quadrant, n=7 eyes) and group 2 (beyond the range of one quadrant, n=17 eyes). The patients in group 1 underwent phacoemulsification+capsular tension ring (CTR)+IOL, whereas patients in group 2 underwent pars plana lensectomy with scleral-fixated posterior chamber (PC) IOL implantation. The best corrected visual acuity (BCVA) (logMAR unit) and intraocular pressure (IOP) were documented at presentation and at 1 day, 7 days, 3 months, 1 year and 3 years postoperatively.

Results: The IOP in both groups significantly decreased after surgery (group 1:28.84±5.36 mm Hg at presentation, 15.86±0.79 mm Hg at the 3-year visit, t=6.34, p=0.000; group 2:26.18±12.16 mm Hg at presentation, 14.54±3.40 mm Hg at the 3-year visit, t=3.80, p=0.01). The BCVA increased from 0.79±0.36 at baseline to 0.44±0.38 at the 3-year follow-up but did not reach a significantly different level in group 1 (t=1.72, p=0.11), whereas the BCVA significantly increased from 1.15±0.75 at baseline to 0.43±0.38 at the 3-year visit in group 2 (t=3.45, p=0.02).

Conclusions: Both phacoemulsification+CTR+IOL and lensectomy with scleral-fixated PC IOL implantation are effective in lowering the IOP and enhancing the visual acuity in patients with spherophakia and secondary glaucoma.
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http://dx.doi.org/10.1136/bjophthalmol-2015-307298DOI Listing
August 2016

ROS-mediated iron overload injures the hematopoiesis of bone marrow by damaging hematopoietic stem/progenitor cells in mice.

Sci Rep 2015 May 13;5:10181. Epub 2015 May 13.

Department of Hematology, Tianjin First Central Hospital, Tianjin 300192, China.

Iron overload, caused by hereditary hemochromatosis or repeated blood transfusions in some diseases, such as beta thalassemia, bone marrow failure and myelodysplastic syndrome, can significantly induce injured bone marrow (BM) function as well as parenchyma organ dysfunctions. However, the effect of iron overload and its mechanism remain elusive. In this study, we investigated the effects of iron overload on the hematopoietic stem and progenitor cells (HSPCs) from a mouse model. Our results showed that iron overload markedly decreased the ratio and clonogenic function of murine HSPCs by the elevation of reactive oxygen species (ROS). This finding is supported by the results of NAC or DFX treatment, which reduced ROS level by inhibiting NOX4 and p38MAPK and improved the long-term and multi-lineage engrafment of iron overload HSCs after transplantation. Therefore, all of these data demonstrate that iron overload injures the hematopoiesis of BM by enhancing ROS through NOX4 and p38MAPK. This will be helpful for the treatment of iron overload in patients with hematopoietic dysfunction.
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http://dx.doi.org/10.1038/srep10181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429544PMC
May 2015

Mitochondrial reactive oxygen species regulate adipocyte differentiation of mesenchymal stem cells in hematopoietic stress induced by arabinosylcytosine.

PLoS One 2015 13;10(3):e0120629. Epub 2015 Mar 13.

Department of Hematology, Peking University People's Hospital, Beijing, China; Institute of Hematology, Peking University, Beijing, China.

Objective: The increase in adipocytes induced by chemotherapeutic drugs may play a negative role in hematopoietic recovery. However, the mechanism underlying adipocyte differentiation of mesenchymal stem cells (MSCs) in hematopoietic stress is still unknown. Hence, the involvement of reactive oxygen species (ROS) in adipocyte differentiation under hematopoietic stress was investigated in vitro and in vivo.

Methods: The roles of cellular ROS in adipogenesis were investigated in vivo through an adipocyte hyperplasia marrow model under hematopoietic stress induced by arabinosylcytosine (Ara-C) and in vitro via adipocyte differentiation of human MSCs. ROS levels were detected using the CM-H2DCFDA probe and Mito-SOX dye. Adipogenesis was evaluated by histopathology and oil red O staining, whereas detection of mRNA levels of antioxidant enzymes and adipogenesis markers was performed using quantitative real-time polymerase chain reaction analysis.

Results: ROS were found to play an important role in regulating adipocyte differentiation of MSCs by activating peroxisome proliferator-activated receptor gamma (PPARγ,) while the antioxidant N-acetyl-L-cysteine acts through ROS to inhibit adipocyte differentiation. The elevated ROS levels induced by Ara-C were caused by both over-generation of mitochondrial ROS and reduction of antioxidant enzymes (Cu/Zn Superoxide dismutase and catalase). Our findings suggest that a mitochondrial-targeted antioxidant could diminish adipocyte differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120629PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359087PMC
January 2016

[Effects and mechanism of iron overload on hematopoiesis in mice with bone marrow injury].

Zhonghua Xue Ye Xue Za Zhi 2014 Nov;35(11):1000-4

Department of Hematology and Oncology, Tianjin First Central Hospital, Tianjin 300192, China.

Objective: To explore effects of iron overload on hematopoiesis in mice with bone marrow injury and its possible mechanism (s).

Methods: C57BL/6 mice were divided into control, iron, irradiation, irradiation+iron groups. The iron-overloaded model of bone marrow injury was set up after mice were exposed to the dose of 4 Gy total body irradiation and (or) were injected iron dextran intraperitoneally. Iron overload was confirmed by observing iron deposits in mice and bone marrow labile iron pool. Additionally, the number of peripheral blood and bone marrow mononuclear cells and the frequency of erythroid cells and myeloid cells were counted and hematopoietic function was assessed.

Results: (1)Iron overload occurred by bone marrow biopsy and flow cytometry analysis. (2)Compared with control group, the number of platelets [(801.9±81.2)×10⁹/L vs (926.0±28.2)×10⁹/L] and BMMNC and the frequency of erythroid cells and myeloid cells decreased. Moreover, hematopoietic colony forming units and single-cell cloning counts decreased significantly in irradiation group (P<0.05). (3)Compared with irradiation group, the number of platelets [(619.0±60.9)×10⁹/L vs (801.9±81.2)×10⁹/L] and the frequency of erythroid cells and myeloid cells decreased; moreover, hematopoietic colony forming units and single-cell cloning counts decreased significantly in irradiation+iron group (P<0.05). (4)Compared with irradiation group, ROS level increased by 1.94 fold in BMMNC, 1.93 fold in erythroid cells and 2.70 fold in myeloid cells, respectively (P<0.05).

Conclusion: The dose of 4 Gy total body irradiation caused bone marrow damage and iron overload based on this injury model, which could damage bone marrow hematopoietic function aggravatingly. And further study found that iron overload was closely related to increased ROS level in BMMNC. The findings would be helpful to further study the injury mechanism of iron overload on the hematopoiesis of bone marrow.
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http://dx.doi.org/10.3760/cma.j.issn.0253-2727.2014.11.011DOI Listing
November 2014

Measuring the damage of heavy metal cadmium in rice seedlings by SRAP analysis combined with physiological and biochemical parameters.

J Sci Food Agric 2015 Aug 31;95(11):2292-8. Epub 2014 Oct 31.

College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310036, China.

Background: Cadmium (Cd) is one of the most poisonous pollutants, and Cd pollution has become the limiting factor of rice production and quality improvement. Therefore it is of significant importance to monitor Cd toxicity by the detection of Cd contamination in rice with biomarkers. In the present study, sequence-related amplified polymorphism (SRAP) and physiological and biochemical methods were applied to determine the toxicological effects of Cd stress on rice.

Results: With increasing Cd concentration and duration, the content of chlorophyll in the two rice varieties W7 and M63 decreased and that of malondialdehyde increased. This tendency was more apparent in M63. The antioxidant enzymes superoxide dismutase and peroxidase both increased significantly compared with controls. SRAP polymerase chain reaction results indicated significant differences between Cd treatments and controls in terms of SRAP profile, as well as genotypic differences. The genomic template stability (GTS) decreased with increasing Cd concentration and duration. Under the same treatment conditions, the GTS of W7 was higher than that of M63. Comparison analysis revealed that the changes in physiological and biochemical parameters of rice seedlings under Cd stress had a good correlation with the changes in SRAP profile. Furthermore, the changes in SRAP profile showed enhanced sensitivity in the roots of rice seedlings.

Conclusion: The SRAP profile and physiological and biochemical parameters could act as appropriate biomarkers for the measurement of Cd contamination during rice production.
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http://dx.doi.org/10.1002/jsfa.6949DOI Listing
August 2015