Publications by authors named "Lirong Sun"

62 Publications

Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial.

Lancet Oncol 2021 09 27;22(9):1322-1332. Epub 2021 Jul 27.

Department of Hematology/Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, China.

Background: Vincristine plus dexamethasone pulses are generally used throughout maintenance treatment for childhood acute lymphoblastic leukaemia. However, previous studies remain inconclusive about the benefit of this maintenance therapy and the absence of randomised, controlled trials in patients with low-risk or high-risk acute lymphoblastic leukaemia provides uncertainty. We therefore aimed to determine if this therapy could be safely omitted beyond 1 year of treatment without leading to an inferior outcome in any risk subgroup of childhood acute lymphoblastic leukaemia.

Methods: This open-label, multicentre, randomised, phase 3, non-inferiority trial involved 20 major medical centres across China. We enrolled patients who were aged 0-18 years with newly diagnosed acute lymphoblastic leukaemia that was subsequently in continuous remission for 1 year after initial treatment. Patients with secondary malignancy or primary immunodeficiency were excluded. Eligible patients were classified as having low-risk, intermediate-risk, or high-risk acute lymphoblastic leukaemia based on minimal residual disease and immunophenotypic and genetic features of leukaemic cells. Randomisation and analyses were done separately for the low-risk and intermediate-to-high-risk cohorts. Randomisation was generated by the study biostatistician with a block size of six. Stratification factors included participating centre, sex, and age at diagnosis; the low-risk cohort was additionally stratified for ETV6-RUNX1 status, and the intermediate-to-high-risk cohort for cell lineage. Patients in each risk cohort were randomly assigned (1:1) to either receive (ie, the control group) or not receive (ie, the experimental group) seven pulses of intravenous vincristine (1·5 mg/m) plus oral dexamethasone (6 mg/m per day for 7 days) during the second year of treatment. The primary endpoint was difference in 5-year event-free survival between the experimental group and the control group for both the low-risk and intermediate-to-high-risk cohorts, with a non-inferiority margin of 0·05 (5%). The analysis was by intention to treat. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-14005706.

Findings: Between Jan 1, 2015, and Feb 20, 2020, 6141 paediatric patients with newly diagnosed acute lymphoblastic leukaemia were registered to this study. Approximately 1 year after diagnosis and treatment, 5054 patients in continuous remission were randomly assigned, including 2923 (1442 in the control group and 1481 in the experimental group) with low-risk acute lymphoblastic leukaemia and 2131 (1071 control, 1060 experimental) with intermediate-to-high risk acute lymphoblastic leukaemia. Median follow-up for patients who were alive at the time of analysis was 3·7 years (IQR 2·8-4·7). Among patients with low-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (90·3% [95% CI 88·4-92·2] vs 90·2% [88·2-92·2]; p=0·90). The one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·024, establishing non-inferiority. Among patients with intermediate-to-high-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (82·8% [95% CI 80·0-85·7] vs 80·8% [77·7-84·0]; p=0·90), but the one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·055, giving a borderline inferior result for those in the experimental group. In the low-risk cohort, we found no differences in the rates of infections, symptomatic osteonecrosis, or other complications during the second year of maintenance treatment between patients in the control and experimental groups. Patients with intermediate-to-high-risk acute lymphoblastic leukaemia in the control group were more likely to develop grade 3-4 pneumonia (26 [2·4%] of 1071 vs ten [0·9%] of 1060) and vincristine-related peripheral neuropathy (17 [1·6%] vs six [0·6%]) compared with the experimental group. Incidence of grade 5 fatal infection was similar between the control group and the experimental group in both the low-risk cohort (two [0·1%] of 1442 vs five [0·3%] of 1481) and intermediate-to-high risk cohort (six [0·6%] of 1071 vs five [0·5%] of 1060).

Interpretation: Vincristine plus dexamethasone pulses might be omitted beyond 1 year of treatment for children with low-risk acute lymphoblastic leukaemia. Additional studies are needed for intermediate-to-high-risk acute lymphoblastic leukaemia.

Funding: VIVA China Children's Cancer Foundation, the National Natural Science Foundation of China, the China fourth round of Three-Year Public Health Action Plan (2015-2017), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00328-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416799PMC
September 2021

Arsenic Combined With All-Trans Retinoic Acid for Pediatric Acute Promyelocytic Leukemia: Report From the CCLG-APL2016 Protocol Study.

J Clin Oncol 2021 Jun 2:JCO2003096. Epub 2021 Jun 2.

Anhui Provincial Children's Hospital, Hefei, China.

Purpose: Arsenic combined with all-trans retinoic acid (ATRA) is the standard of care for adult acute promyelocytic leukemia (APL). However, the safety and effectiveness of this treatment in pediatric patients with APL have not been reported on the basis of larger sample sizes.

Methods: We conducted a multicenter trial at 38 hospitals in China. Patients with newly diagnosed APL were stratified into two risk groups according to baseline WBC count and mutation. ATRA plus arsenic trioxide or oral arsenic without chemotherapy were administered to the standard-risk group, whereas ATRA, arsenic trioxide, or oral arsenic plus reduced-dose anthracycline were administered to the high-risk group. Primary end points were event-free survival and overall survival at 2 years.

Results: We enrolled 193 patients with APL. After a median follow-up of 28.9 months, the 2-year overall survival rate was 99% (95% CI, 97 to 100) in the standard-risk group and 95% (95% CI, 90 to 100) in the high-risk group ( = .088). The 2-year event-free survival was 97% (95% CI, 93 to 100) in the standard-risk group and 90% (95% CI, 83 to 96) in the high-risk group ( = .252). The plasma levels of arsenic were significantly elevated after treatment, with a stable effective level ranging from 42.9 to 63.2 ng/mL during treatment. In addition, plasma, urine, hair, and nail arsenic levels rapidly decreased to normal 6 months after the end of treatment.

Conclusion: Arsenic combined with ATRA is effective and safe in pediatric patients with APL, although long-term follow-up is still needed.
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http://dx.doi.org/10.1200/JCO.20.03096DOI Listing
June 2021

miRNA-34a-5p regulates progression of neuroblastoma via modulating the Wnt/β-catenin signaling pathway by targeting SOX4.

Medicine (Baltimore) 2021 May;100(20):e25827

The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, P.R. China.

Abstract: Neuroblastoma is an embryonal tumor of the autonomic nervous system with poor prognosis in children. In present study, we demonstrated the relationship of miRNA-34a-5p in the regulating of the Wnt/β-catenin signaling pathway by targeting SRY-related HMG-box (SOX4)Reverse transcription-quantitative PCR was used to detect the expression levels of miRNA-34a-5p and SoX4. Western blotting was performed to assess the protein expression levels of SoX4, Wnt, MMP9, Bax, and Bcl-2. The proliferation, apoptosis, migration and invasion of neuroblastoma cells were determined using MTT, flow cytometry and Transwell assays.In this study, we sought to investigate the role of miRNA-34a-5p on neuroblastoma and the possible molecular mechanism. We had performed in-vitro and in-vivo experiments to evaluate the effects of miRNA-34a-5p on neuroblastoma cell proliferation and invasion by altering its expression level via cell transfection. On the basis of our study, miRNA-34a-5p showed decreased expression levels in neuroblastoma. Subsequently, we manipulated miRNA-34a-5p expression through cell transfection and observed abnormal expression of β-catenin as well as the downstream targets of the Wnt/β-catenin pathway in neuroblastoma cells. With all these evidences, we determined that miRNA-34a-5p regulated Wnt/β-catenin pathway by targeting SOX4.In conclusion, our study demonstrates that miRNA-34a-5p can inhibit the over-activation of the Wnt/β-catenin signaling pathway via targeting SOX4 and further regulate proliferation, invasion of neuroblastoma cells.
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http://dx.doi.org/10.1097/MD.0000000000025827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137035PMC
May 2021

Clinical characteristics of tumor lysis syndrome in childhood acute lymphoblastic leukemia.

Sci Rep 2021 May 6;11(1):9656. Epub 2021 May 6.

Department of Hematology and Oncology, Children's Hospital of Nanjing Medical University, Nanjing, China.

Tumor lysis syndrome (TLS) is a common and fatal complication of childhood hematologic malignancies, especially acute lymphoblastic leukemia (ALL). The clinical features, therapeutic regimens, and outcomes of TLS have not been comprehensively analyzed in Chinese children with ALL. A total of 5537 children with ALL were recruited from the Chinese Children's Cancer Group, including 79 diagnosed with TLS. The clinical characteristics, treatment regimens, and survival of TLS patients were analyzed. Age distribution of children with TLS was remarkably different from those without TLS. White blood cells (WBC) count ≥ 50 × 10/L was associated with a higher risk of TLS [odds ratio (OR) = 2.6, 95% CI = 1.6-4.5]. The incidence of T-ALL in TLS children was significantly higher than that in non-TLS controls (OR = 4.7, 95% CI = 2.6-8.8). Hyperphosphatemia and hypocalcemia were more common in TLS children with hyperleukocytosis (OR = 2.6, 95% CI = 1.0-6.9 and OR = 5.4, 95% CI = 2.0-14.2, respectively). Significant differences in levels of potassium (P = 0.004), calcium (P < 0.001), phosphorus (P < 0.001) and uric acid (P < 0.001) were observed between groups of TLS patients with and without increased creatinine. Laboratory analysis showed that older age was associated with a higher level of creatinine. Calcium level was notably lower in males. WBC count, lactate dehydrogenase, and creatinine levels were significantly higher in T-ALL subgroup, whereas procalcitonin level was higher in B-ALL children. Older age, infant, a higher level of WBC and T-ALL were risk factors TLS occurrence. Hyperleukocytosis has an impact on the severity of TLS, while renal injury may be an important feature in the process of TLS.
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http://dx.doi.org/10.1038/s41598-021-88912-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102476PMC
May 2021

Prognostic factors for CNS control in children with acute lymphoblastic leukemia treated without cranial irradiation.

Blood 2021 Jul;138(4):331-343

Departments of Oncology, Global Pediatric Medicine, Biostatistics and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN.

To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).
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http://dx.doi.org/10.1182/blood.2020010438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323972PMC
July 2021

2 × 2 anisotropic transfer matrix approach for optical propagation in uniaxial transmission filter structures.

Opt Express 2020 Nov;28(24):35761-35783

Multi-layered metamaterial structures show promise in a wide variety of optical applications such as superlenses, electromagnetic cloaking, tunable filters, sensors, and spatial light modulators. Optical transmission analysis of multilayer metallo-dielectric stacks with overall thickness less than the wavelength of light can be modeled using effective medium theory and the Berreman matrix method. For multilayer anisotropic stacks of arbitrary thickness, a rigorous 4 × 4 transfer matrix embodiment is typically used. In this work, a 2 × 2 anisotropic transfer matrix method is developed to analyze optical propagation through multilayer uniaxial stacks of arbitrary thicknesses. Optical transmission of a multilayer silver-zinc oxide stack deposited on a quartz substrate is modeled with this 2 × 2 anisotropic transfer matrix method and reconciled with experimental observations. Results indicate that this numerical approach is applicable to in situ assessment of the complex refractive indices of constituent metal and dielectric layers. Additionally, the anisotropic 2 × 2 transfer matrix method enables the possibility of modeling the transmission of the same metallo-dielectric structure deposited on an electro-optic, uniaxial substrate. Simulation results predict that adjusting the bias field across the substrate results in an electrically tunable transmission filter.
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http://dx.doi.org/10.1364/OE.408803DOI Listing
November 2020

Versatile Roles of Aquaporins in Plant Growth and Development.

Int J Mol Sci 2020 Dec 13;21(24). Epub 2020 Dec 13.

State Key Laboratory of Cotton Biology, Henan Key Laboratory of Plant Stress Biology, School of Life Sciences, Henan University, Kaifeng 475004, China.

Aquaporins (AQPs) are universal membrane integrated water channel proteins that selectively and reversibly facilitate the movement of water, gases, metalloids, and other small neutral solutes across cellular membranes in living organisms. Compared with other organisms, plants have the largest number of AQP members with diverse characteristics, subcellular localizations and substrate permeabilities. AQPs play important roles in plant water relations, cell turgor pressure maintenance, the hydraulic regulation of roots and leaves, and in leaf transpiration, root water uptake, and plant responses to multiple biotic and abiotic stresses. They are also required for plant growth and development. In this review, we comprehensively summarize the expression and roles of diverse AQPs in the growth and development of various vegetative and reproductive organs in plants. The functions of AQPs in the intracellular translocation of hydrogen peroxide are also discussed.
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http://dx.doi.org/10.3390/ijms21249485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763978PMC
December 2020

Associations of urinary phenolic environmental estrogens exposure with blood glucose levels and gestational diabetes mellitus in Chinese pregnant women.

Sci Total Environ 2021 Feb 31;754:142085. Epub 2020 Aug 31.

Department of Occupational and Environmental Health, Tianjin Key Laboratory of Environment, Nutrition and Public Health, School of Public Health, Tianjin Medical University, Tianjin, China.

Background: Endocrine-disrupting chemicals (EDCs) are considered to be related to diabetes, but studies of the association between phenolic EDCs and gestational diabetes mellitus (GDM) are limited.

Objectives: To assess associations of maternal urinary bisphenol A (BPA), nonylphenol (NP), and 2-tert-octylphenol (2-t-OP) with GDM occurrence.

Methods: A cross-sectional study was performed among 390 Chinese women at 24-28 weeks of gestation. GDM was diagnosed with a 2-h 75-g oral glucose tolerance test (OGTT). BPA, NP, and 2-t-OP concentrations were determined in urine samples. Linear and logistic regression tests evaluated associations of BPA, NP, and 2-t-OP with blood glucose levels and GDM prevalence.

Results: The 2-t-OP concentrations in GDM patients were significantly higher than in non-GDM women with median values of 2.23 μg/g Cr and 1.79 μg/g Cr, respectively. No significant difference was observed in BPA and NP. Urinary 2-t-OP was positively associated with blood glucose levels after adjustment for several confounding factors and urinary BPA and NP. Higher 2-t-OP levels were associated with higher odds of GDM (OR: 5.78; 95% CI: 2.04, 16.37), whereas higher NP levels were associated with lower odds (OR: 0.22; 95% CI: 0.05, 0.85) in the adjusted models. In addition, compared to the first quartile of 2-t-OP, the adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for GDM in the second, third, and fourth quartiles were 2.81 (1.23, 6.42), 3.01 (1.30, 6.93), and 5.49 (2.24, 13.46), respectively.

Conclusion: Our study indicates that, for the first time to our knowledge, exposure to 2-t-OP is associated with a higher risk of GDM. However, higher NP exposure is associated with lower GDM risk. Further studies are necessary to affirm the associations of 2-t-OP and NP with GDM, and to elucidate the causality of these findings.
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http://dx.doi.org/10.1016/j.scitotenv.2020.142085DOI Listing
February 2021

INNO-406 inhibits the growth of chronic myeloid leukemia and promotes its apoptosis via targeting PTEN.

Hum Cell 2020 Oct 29;33(4):1112-1119. Epub 2020 Aug 29.

Department of Pediatric Hematology, Affiliated Hospital of Qingdao University, Huangdao District, 1677 Wutaishan Road, Qingdao, 266555, Shandong, China.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. INNO-406 is a novel tyrosine kinase inhibitor (TKI) that possess specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. The present study aimed to confirm the anti-tumor effect of INNO-406 on CML cells, and elucidate the underlying molecular mechanism. CML cells were treated by INNO-406 at the concentration of 5, 25, 50, 100 μM at the indicated time. Cell proliferation was measured by MTT. Cell apoptosis were detected by Western blot and flow cytometry, respectively. As suggested by the findings, INNO-406 significantly inhibited the proliferation and induced apoptosis of CML cells. In addition, INNO-406 promoted the expression level of PTEN. Rescue experiment revealed that PTEN knockdown reversed the effect of INNO-406 which indicated the correlation between INNO-406 and PTEN. Further study determined that PTEN inhibited the phosphorylation of AKT and 4EBP1 and subsequently altered the expression of apoptotic proteins including bax, cytoplasmic cytochrome c (cyto-c), cleaved caspase3 and bcl-2. In vivo study further confirmed that INNO-406 inhibited the growth of CML cells by targeting PTEN. Based on the above findings, this work extended our understanding of INNO-406 in the therapy of CML and its molecular mechanism.
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http://dx.doi.org/10.1007/s13577-020-00413-yDOI Listing
October 2020

Neuroprotection Against Parkinson's Disease Through the Activation of Akt/GSK3β Signaling Pathway by Tovophyllin A.

Front Neurosci 2020 9;14:723. Epub 2020 Jul 9.

Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

Parkinson's disease (PD) is one of the most prevalent and life-threatening neurodegenerative disease and mainly characterized by lack of sufficient dopaminergic neurons in the substantia nigra pars compacta (SNc). Although current treatments help to alleviate clinical symptoms, effective therapies preventing neuronal loss remain scarce. Tovophyllin A (TA), one of the xanthones extracted from L. (GM), has recently been reported to play a beneficial role in the therapy of neurodegenerative diseases. In our research, we explored whether TA has protective effects on dopaminergic neurons in PD models. We found that TA significantly reduced apoptotic cell death in primary cortical neurons treated with 1-methyl-4-phenyl pyridinium (MPP) or paraquat (PQ) in the PD model. In an acute PD model induced by 1-methyl4-phenyl-1,2,3,5-tetrahydropyridine (MPTP) treatment, TA also attenuated the resulting behavioral dysfunctions and dopaminergic neuron loss. In the collected brain tissues, TA increased the phosphorylation of Akt and GSK-3β, which may be related to TA-mediated dopaminergic neuronal protective effects. In summary, our results illustrated that TA is a powerful cytoprotective agent for dopaminergic neurons in the MPTP-induced PD model, suggesting TA as a possible therapeutic candidate for PD.
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http://dx.doi.org/10.3389/fnins.2020.00723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364155PMC
July 2020

Regional difference in the susceptibility of non-alcoholic fatty liver disease in China.

BMJ Open Diabetes Res Care 2020 06;8(1)

Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan Institute of Metabolic Disease, Fudan University, Shanghai, China

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a global health problem with high geographic heterogeneity. We aimed to investigate regional-specific concomitant rate of NAFLD and quantitative relationship between liver fat content (LFC) and glucose metabolism parameters in representative clinical populations from six provinces/municipalities of China.

Research Design And Methods: A total of 2420 eligible Han Chinese were enrolled consecutively from 10 clinics of obesity, diabetes and metabolic diseases located at six provinces/municipalities of China, and divided into North (Tianjin, Shandong and Heilongjiang) and South (Shanghai, Jiangsu and Henan) groups according to their geographical latitude and proximity of NAFLD concomitant rate. LFC was assessed by a quantitative ultrasound method. Multivariate regression models and analysis of covariance were used to assess the regional difference in the risk of NAFLD.

Results: The concomitant rate of NAFLD was 23.3%, 44.0% and 55.3% in individuals with normal glucose tolerance (NGT), pre-diabetes and diabetes, respectively. A higher concomitant rate of NAFLD was found in the participants from the North comparing with the South group, regardless of glucose metabolism status (34.7% vs 16.2% in NGT, 61.5% vs 34.7% in pre-diabetes and 67.1% vs 48.1% in diabetes). This regional difference remained significant after adjustment for age, gender, alcohol drinking, cigarette smoking, confounding metabolic parameters and liver enzymes. For any given blood glucose, participants from the North had higher LFC than those from the South group.

Conclusions: Half of Han Chinese with pre-diabetes/type 2 diabetes had NAFLD, and the individuals from the North cities were more susceptible to NAFLD.
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http://dx.doi.org/10.1136/bmjdrc-2020-001311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287499PMC
June 2020

Redox Components: Key Regulators of Epigenetic Modifications in Plants.

Int J Mol Sci 2020 Feb 19;21(4). Epub 2020 Feb 19.

State Key Laboratory of Cotton Biology, Key Laboratory of Plant Stress Biology, School of Life Sciences, Henan University, Kaifeng 475004, China.

Epigenetic modifications including DNA methylation, histone modifications, and chromatin remodeling are crucial regulators of chromatin architecture and gene expression in plants. Their dynamics are significantly influenced by oxidants, such as reactive oxygen species (ROS) and nitric oxide (NO), and antioxidants, like pyridine nucleotides and glutathione in plants. These redox intermediates regulate the activities and expression of many enzymes involved in DNA methylation, histone methylation and acetylation, and chromatin remodeling, consequently controlling plant growth and development, and responses to diverse environmental stresses. In recent years, much progress has been made in understanding the functional mechanisms of epigenetic modifications and the roles of redox mediators in controlling gene expression in plants. However, the integrated view of the mechanisms for redox regulation of the epigenetic marks is limited. In this review, we summarize recent advances on the roles and mechanisms of redox components in regulating multiple epigenetic modifications, with a focus of the functions of ROS, NO, and multiple antioxidants in plants.
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http://dx.doi.org/10.3390/ijms21041419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073030PMC
February 2020

Diagnostic Values of Inflammatory and Angiogenic Factors for Acute Joint Bleeding in Patients With Severe Hemophilia A.

Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029619892683

Department of Pediatrics, The Affiliated Hospital of Qingdao University, Qingdao, China.

This study was conducted to assess the levels of inflammatory factors and angiogenic factors in patients with severe hemophilia A and evaluate their diagnostic values for acute joint bleeding. This study included a total of 144 patients with severe hemophilia A. Of them, 66 had acute joint bleeding. Ninety healthy volunteers were recruited as control. The levels of leukocytes, monocytes, platelets, hemoglobin, phagocyte migration inhibitory factor (MIF), plasminogen, fibrin/fibrinogen degradation products, d-dimer, and α2 antifibrinolytic enzyme were measured using hematology analyzer. Thrombomodulin, endostatin, intercellular adhesion molecule 1, and vascular endothelial growth factor (VEGF) were assessed using enzyme-linked immunosorbent assay. Logistic regression analysis was performed to analyze the factors affecting acute joint bleeding. Compared with healthy volunteers, the levels of leukocytes, C-reactive protein (CRP), MIF, and VEGF were significantly ( < .05) elevated in the patients with severe hemophilia A and were significantly higher in patients with joint bleeding than in patients with nonbleeding ( < .05). Multivariate analysis showed that CRP and VEGF were independent risk factors for acute joint bleeding ( < .05). The area under the curve, sensitivity, and specificity of CRP for the diagnosis of acute joint bleeding were 0.829, 88.43%, and 67.87%, respectively, and those of VEGF were 0.758, 82.8%, and 68.3%, respectively. The levels of inflammatory factors and angiogenesis factors are elevated in patients with severe hemophilia A and both CRP and VEGF are closely related to acute joint bleeding and may be used as potential biomarkers for predicting acute joint bleeding in patients with severe hemophilia A.
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http://dx.doi.org/10.1177/1076029619892683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098200PMC
July 2020

Septicemia after chemotherapy for childhood acute lymphoblastic leukemia in China: A multicenter study CCCG-ALL-2015.

Cancer Med 2020 03 28;9(6):2113-2121. Epub 2020 Jan 28.

Department of Paediatrics, Hong Kong Children's Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.

Background: Septicemia is an important cause of treatment-related mortality and treatment failure in pediatric acute lymphoblastic leukemia (ALL) in developing countries. A multicenter CCCG-ALL-2015 study was conducted in China and factors associated with septicemia and mortality were studied.

Methods: Patients participated in CCCG-ALL-2015 study from January 2015 to December 2017 were included. Patients with documented septicemia were identified from the Data Center and additional data were collected.

Results: A total of 4080 patients were recruited in the study and 527 patients with septicemia were identified (12.9%, 95% CI 11.9%-13.9%). The intermediate risk (IR)/high risk (HR) group had significantly higher incidence of septicemia as compared with low risk (LR) group, 17.1% vs 9.1% (OR 2.07, 95% CI 1.71-2.49, P < .001). Induction phase was the period with majority of septicemia episodes happened, 66.8% in LR and 56.1% in IR/HR groups. Gram-positive bacteria accounted for 54.1%, gram-negative bacteria 44.5%, and fungus 1.4% of positive cultures. Multidrug-resistant organisms were detected in 20.5% of all organisms. The mortality rate after septicemia was 3.4% (95% CI 1.9%-4.9%). Multiple logistic regression identified female gender, comorbid complications, and fungal infection as risk factors associated with mortality. Gram-negative septicemia was associated with higher mortality, 4.9% vs 1.4% (OR 0.28, 95% CI 0.09-0.88, P = .02). There was marked variation in the incidence of septicemia among the 18 centers, from 4.8% to 29.1%.

Conclusion: Overall the incidence and pattern of septicemia in this multicenter study in China was similar to the reports of western countries. The septicemia-related mortality rate was low. There was marked variation in the incidence of septicemia among the centers.
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http://dx.doi.org/10.1002/cam4.2889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064088PMC
March 2020

Genome-wide identification and expression analysis of NADPH oxidase genes in response to ABA and abiotic stresses, and in fibre formation in .

PeerJ 2020 17;8:e8404. Epub 2020 Jan 17.

State Key Laboratory of Cotton Biology, Henan Key Laboratory of Plant Stress Biology, School of Life Sciences, Henan University, Kaifeng, Henan, China.

Plasma membrane NADPH oxidases, also named respiratory burst oxidase homologues (Rbohs), play pivotal roles in many aspects of growth and development, as well as in responses to hormone signalings and various biotic and abiotic stresses. Although Rbohs family members have been identified in several plants, little is known about Rbohs in . In this report, we characterized 13, 13, 26 and 19 Rbohs in , , and , respectively. These Rbohs were conservative in physical properties, structures of genes and motifs. The expansion and evolution of the Rbohs dominantly depended on segmental duplication, and were under the purifying selection. Transcription analyses showed that were expressed in various tissues, and most were highly expressed in flowers. Moreover, different had very diverse expression patterns in response to ABA, high salinity, osmotic stress and heat stress. Some were preferentially and specifically expressed during ovule growth and fiber formation. These results suggest that GhRbohs may serve highly differential roles in mediating ABA signaling, in acclimation to environmental stimuli, and in fiber growth and development. Our findings are valuable for further elucidating the functions and regulation mechanisms of the Rbohs in adaptation to diverse stresses, and in growth and development in .
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http://dx.doi.org/10.7717/peerj.8404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970565PMC
January 2020

Identification of Xanthones from the Mangosteen Pericarp that Inhibit the Growth of .

ACS Omega 2020 Jan 27;5(1):334-343. Epub 2019 Dec 27.

Key Laboratory of Agro-Environment in the Tropics, Ministry of Agriculture and Rural Affairs; Guangdong Provincial Key Laboratory of Eco-Circular Agriculture; Guangdong Engineering Research Centre for Modern Eco-Agriculture; College of Natural Resources and Environment, South China Agricultural University, Guangzhou 510642, People's Republic of China.

Bacterial wilt caused by is one of the most destructive bacterial diseases in agriculture. There is no effective control method, although chemical pesticides are used to prevent this disease, but they may lead to serious problems of environmental pollution. Natural products from plants can be rich and environmentally friendly sources for a broad spectrum biological control of bacteria. This study focuses on the pericarp of mangosteen () using bioactivity-guided analysis of different fractions and liquid chromatography-mass spectrometry combined with multivariate analysis to determine markers of active fractions. Six prenyl xanthones, including two new xanthones, garcimangosxanthones H and I, were isolated and identified by NMR and HRESIMS. The biomarker γ-mangostin displayed significant activity against the phytopathogen with an IC of 34.7 ± 1.5 μg/mL; γ-mangostin affected the bacterial morphology at a concentration of 16.0 μg/mL as seen with a scanning electron microscope image, and it significantly repressed the virulence-associated genes , , and of . γ-Mangostin also reduced the symptoms of bacterial wilt disease effectively that is caused by in tomato and tobacco seedlings in vitro. These results suggested that the use of γ-mangostin from the mangosteen pericarp against may be used as a natural bacteriostatic agent in agriculture.
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http://dx.doi.org/10.1021/acsomega.9b02746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964269PMC
January 2020

Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

JAMA Oncol 2020 03;6(3):358-366

State Key Laboratory of Experimental Hematology and Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin, China.

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation.

Design, Setting, And Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019.

Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy.

Main Outcomes And Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival.

Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups.

Conclusions And Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation.

Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.
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http://dx.doi.org/10.1001/jamaoncol.2019.5868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990720PMC
March 2020

Proinflammatory-factors-carrying-microvesicles from monocytes induced by high glucose enhance the activation of HIF/VEGF pathway in human renal mesangial cells.

Int J Clin Exp Pathol 2019 1;12(8):2967-2971. Epub 2019 Aug 1.

NHC Key Laboratory of Hormone and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Department of Diabetes and Gout, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology Tianjin, P. R. China.

Objectives: Renal mesangial expansion has been identified as a major factor contributing to glomerulosclerosis, a typical symptom of diabetic nephropathy. It is unclear whether microvesicles, known as a mediator for cross-talk between cells and organs, are involved in a profibrotic process. In this study, we are the first to investigate the effect of monocyte-derived microvesicles induced by high glucose on renal mesangial cells.

Methods: THP1 cells were evoked by high glucose to generate microvesicles, quantified by ELISA. Glucose uptake by THP1 cells was measured using fluorescently-labeled deoxyglucose analog 2-NBDG as a probe. The contents of inflammatory cytokines in microvesicles were detected by western blot. The expressions of HIF-1α and VEGF in human renal mesangial cells after treatment with THP1-derived microvesicles were examined by western blot.

Results: The glucose uptake by THP1 cells was significantly increased after high glucose treatment. High glucose significantly evoked MV generation, which contained increased protein level of IL-6, 8 and MCP-1. The expressions of HIF-1α and VEGF in HRMC were augmented by microvesicles.

Conclusions: Our study indicates that monocyte-derived MVs induced by high glucose can carry proinflammatory factors, and enhance the expression of the HIF/VEGF pathway in human renal mesangial cells. Our findings may provide a novel potential mechanism in the progression of diabetic nephropathy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949718PMC
August 2019

Comparison between clinical features and prognosis of malignancy- and non-malignancy-associated pediatric hemophagocytic lymphohistiocytosis.

BMC Pediatr 2019 11 29;19(1):468. Epub 2019 Nov 29.

Department of Paediatric Hematology, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, Shandong, China.

Background: The differences between the clinical characteristics and survival time in malignancy- and non-malignancy-associated secondary hemophagocytic lymphohistiocytosis (HLH) are unclear. Here, we describe the clinical characteristics, prognostic factors, and survival outcomes of malignancy-associated HLH compared to that of non-malignancy-associated HLH.

Methods: We retrospectively analyzed 91 pediatric patients with HLH (age < 14 years) at the Affiliated Hospital of Qingdao University Pediatric Department between January 2005 and October 2016. The patients were divided into the malignancy-associated group (n = 22) and non-malignancy-associated group (n = 69, also considered the control group). The clinical features were compared using the Mann-Whitney U and χ tests. The overall survival time was compared using log rank and Mann-Whitney U tests.

Results: Hemoglobin (HGB; p = 0.004), alanine aminotransferase (ALT; p = 0.002), and aspartate aminotransferase (AST; p = 0.001) levels in the malignancy-associated group differed from that in the non-malignancy-associated group. The mean survival times were 26.9 ± 3.82 months (malignancy-associated HLH) and 35.03 ± 2.19 months (non-malignancy-associated HLH). The overall survival time between the two groups was not statistically significantly different (p = 0.055). Univariate analysis showed that disseminated intravascular coagulation (DIC) score > 5 (p = 0.001), albumin < 25 g/L (p = 0.000), HGB < 60 g/L (p = 0.001), and platelet count (PLT) < 30 × 10/L (p = 0.042) correlated with prognosis. Multivariate Cox analysis showed that albumin < 25 g/L (p = 0.017), HGB < 60 g/L (p = 0.027), and bone marrow hemophagocytosis (p = 0.034) correlated with worse prognosis.

Conclusions: Patients with non-malignancy-associated HLH do not have better survival, although their prognosis is relatively better in clinical practice. A higher DIC score at diagnosis and lower albumin, HGB, and PLT levels are negative prognostic factors in malignancy-associated HLH.
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http://dx.doi.org/10.1186/s12887-019-1702-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883520PMC
November 2019

Angelica polysaccharide exhibits antitumor effect in neuroblastoma cell line SH-SY5Y by up-regulation of miR-205.

Biofactors 2019 Nov 23. Epub 2019 Nov 23.

Department of Pediatric Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China.

Neuroblastoma (NB) is a serious disease with high-risk and poor prognosis in children. Survivors often have serious side effects. Angelica polysaccharide (AP) has been proved to exert antitumor function. Therefore, we explored the mechanism of this function in NB to accelerate the clinical application of AP in NB therapy. SH-SY5Y cells were transfected with miR-205 inhibitor and pretreated by AP. Cell activity, colonies number, and apoptosis were detected via Cell Counting Kit-8 assay, colony formation experiment, and flow cytometry, respectively. Targeting link between miR-205 and zinc finger E-box binding homeobox 1 (ZEB1) was measured via luciferase activity assay. Quantitative reverse transcription polymerase chain reaction and western blot was to examine levels of miR-205 and related factors. We found that AP suppressed cell activity and colony formation, whereas induced apoptosis in SH-SY5Y cells. Besides, AP also suppressed Epithelial-mesenchymal transition process and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) and extracellular signal-regulated kinase (ERK1/2) signal passageways. Additionally, miR-205 was positively regulated by AP. AP played its antitumor functions through up-regulating miR-205. Target of miR-205 was ZEB1. Our study demonstrated that AP played its antitumor role in NB through positively regulation of miR-205, whose target gene was ZEB1.
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http://dx.doi.org/10.1002/biof.1586DOI Listing
November 2019

Long noncoding RNA MIAT promotes the progression of acute myeloid leukemia by negatively regulating miR-495.

Leuk Res 2019 12 31;87:106265. Epub 2019 Oct 31.

Department of Pediatrics, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong, 266001, China. Electronic address:

Acute myeloid leukemia (AML) is a malignant myeloid hematopoietic stem and progenitor cell disease. Studies have shown that the long noncoding RNA (lncRNA) myocardial infarction associated transcript (MIAT) is abundantly expressed in multiple human solid tumors. However, the expression and role of MIAT in AML has not been explored previously. In this study, we find that MIAT is overexpressed in AML patient specimens and AML cell lines. Importantly, upregulation of MIAT is closely related with poor clinical outcome. Further investigations reveal that knockdown of MIAT inhibits the colony formation and proliferation, meanwhile, accelerates the apoptosis of AML cells in vitro. Consistently, MIAT knockdown slows AML progression in immunodeficient mice. Mechanistically, we confirm that MIAT can function as a sponge to inhibit microRNA-495 (miR-495), a tumor suppressor, in AML cells. Collectively, our results demonstrate that MIAT is involved in promoting the progression of AML, at least partly, through negative regulation of miR-495, and therefore provide a promising target for treatment of AML.
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http://dx.doi.org/10.1016/j.leukres.2019.106265DOI Listing
December 2019

Asatone and Isoasatone A Against Fab. by Acting on Cytochrome P450 Monoxygenases and Glutathione Transferases.

Molecules 2019 Oct 31;24(21). Epub 2019 Oct 31.

Key Laboratory of Agro-Environment in the Tropics, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510642, China.

Asatone and isoasatone A from Cheng were determined to be defensive compounds to some insects in a previous investigation. However, the anti-insect activity mechanisms to caterpillar are still unclear. The compounds asatone and isoasatone A from were induced by . The anti-insect activity of asatone and isoasatone A to was further tested by weight growth rate of the insect through a diet experiment. Isoasatone A showed a more significant inhibitory effect on than asatone on the second day. The concentration of asatone was higher than isoasatone A in the second instar larvae of after 12 h on the feeding test diet. Both compounds caused mid-gut structural deformation and tissue decay as determined by mid-gut histopathology of . Furthermore, some detoxification enzyme activity were measured by relative expression levels of genes using a qPCR detecting system. Asatone inhibited the gene expression of the cytochrome P450 monooxygenases (P450s) CYP6AB14. Isoasatone A inhibited the relative expression levels of CYP321B1, CYP321A7, CYP6B47, CYP6AB14, and CYP9A39. Asatone increased the relative gene expression of the glutathione transferases (GSTs) SIGSTe1 and SIGSTo1, in contrast, isoasatone A decreased the relative gene expression of SIGSTe1 by about 33 fold. Neither compound showed an effect on acetylcholinesterase SIAce1 and SIAce2. The mechanism of anti-insect activity by both compounds could be explained by the inhibition of enzymes P450s and GSTs. The results provide new insights into the function of unique secondary metabolites asatone and isoasatone A in genus , and a new understanding of why is largely free of insect pests.
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http://dx.doi.org/10.3390/molecules24213940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864857PMC
October 2019

High glucose provokes microvesicles generation from glomerular podocytes via NOX4/ROS pathway.

Biosci Rep 2019 11;39(11)

NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300134, China.

Microvesicles (MVs) were involved in the pathogenesis of many diseases, such as cardiovascular diseases and diabetes. Oxidative stress played a key role in the development and progression of diabetic nephropathy (DN). Our aim of the present study was to investigate whether high glucose (HG) could provoke MVs generation from podocytes and its potential mechanism. Mouse podocyte clone 5 (MPC-5) was stimulated by HG. The intracellular reactive oxygen species (ROS) of podocytes were measured by fluorescence microscopy with the probe of CM-H2DCFDA and MitoSOX™. Antioxidants N-Acetyl-l-cysteine (NAC) and α lipoic acid (α-LA) were used to treat podocytes after HG stimulation. The rate of podocyte apoptosis was evaluated with Annexin V-FITC by flow cytometry. NOX4 expression was examined and siRNA were performed to explore the mechanism of MVs generation. The quantities of MVs from MPC-5 cells was significantly increased (P<0.05) by 4.6-times after 30 mM glucose stimulation, accompanied with double increased apoptosis. Cellular ROS generation was increased by HG at the peak of 48 h stimulation. HG-induced MVs were significantly decreased by 52.9% after pretreatment by antioxidant NAC. Nevertheless, mitochondrial ROS in podocytes reached a peak at 4 h stimulation, but specific antioxidant α-LA had no effect on the production of MVs (P>0.05). Levels of NOX4 mRNA and protein expression were significantly up-regulated by HG (P<0.05). Podocyte-derived MVs by HG were eliminated by NOX4 siRNA. HG can provoke MVs generation from glomerular podocytes through ROS/NOX4 pathway, not from mitochondrial pathway.
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http://dx.doi.org/10.1042/BSR20192554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863764PMC
November 2019

Genome-wide characterization and expression analysis of family members in response to ABA and osmotic stress in .

PeerJ 2019 14;7:e7105. Epub 2019 Jun 14.

State Key Laboratory of Cotton Biology, Henan Key Laboratory of Plant Stress Biology, School of Life Sciences, Henan University, Kaifeng, Henan, China.

Clade A type 2C protein phosphatases (PP2CAs), as central regulators of abscisic acid (ABA) signaling, negative control growth, development and responses to multiple stresses in plants. PP2CA gene families have been characterized at genome-wide levels in several diploid plants like and rice. However, the information about genome organization, phylogenesis and putative functions of PP2CAs in is lacking. Here, PP2CA family members were comprehensively analyzed in four species including the diploid progenitor , and the tetraploid and , and 14, 13, 27, and 23 PP2CA genes were identified in the genomic sequences of these plants, respectively. Analysis results showed that most PP2CAs were highly conserved in chromosomal locations, structures, and phylogeny among the four cotton species. Segmental duplication might play important roles in the formation of the , and most PP2CAs may be under purifying selection in during evolution. The majority of the were expressed specifically in diverse tissues, and highly expressed in flowers in . The displayed diverse expression patterns in responding to ABA and osmotic stress. Yeast-two hybrid assays revealed that many GhPP2CAs were capable of interaction with the cotton ABA receptors pyrabactin resistance1/PYR1-like/regulatory components of ABA receptors (PYR1/PYL/RCAR) GhPYL2-2D (Gh_D08G2587), GhPYL6-2A (Gh_A06G1418), and GhPYL9-2A (Gh_A11G0870) in the presence and/or absence of ABA. These results gave a comprehensive view of the PP2CAs and are valuable for further studying the functions of PP2CAs in .
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http://dx.doi.org/10.7717/peerj.7105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6573834PMC
June 2019

Transcriptome-wide analysis of pseudouridylation of mRNA and non-coding RNAs in Arabidopsis.

J Exp Bot 2019 10;70(19):5089-5600

Key Laboratory of Plant Stress Biology, State Key Laboratory of Cotton Biology, School of Life Sciences, Henan University, Kaifeng, China.

Pseudouridine (Ψ) is widely distributed in mRNA and various non-coding RNAs in yeast and mammals, and the specificity of its distribution has been determined. However, knowledge about Ψs in the RNAs of plants, particularly in mRNA, is lacking. In this study, we performed genome-wide pseudouridine-sequencing in Arabidopsis and for the first time identified hundreds of Ψ sites in mRNA and multiple Ψ sites in non-coding RNAs. Many predicted and novel Ψ sites in rRNA and tRNA were detected. mRNA was extensively pseudouridylated, but with Ψs being under-represented in 3'-untranslated regions and enriched at position 1 of triple codons. The phenylalanine codon UUC was the most frequently pseudouridylated site. Some Ψs present in chloroplast 23S, 16S, and 4.5S rRNAs in wild-type Col-0 were absent in plants with a mutation of SVR1 (Suppressor of variegation 1), a chloroplast pseudouridine synthase gene. Many plastid ribosomal proteins and photosynthesis-related proteins were significantly reduced in svr1 relative to the wild-type, indicating the roles of SVR1 in chloroplast protein biosynthesis in Arabidopsis. Our results provide new insights into the occurrence of pseudouridine in Arabidopsis RNAs and the biological functions of SVR1, and will pave the way for further exploiting the mechanisms underlying Ψ modifications in controlling gene expression and protein biosynthesis in plants.
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http://dx.doi.org/10.1093/jxb/erz273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6793436PMC
October 2019

Treatment abandonment in childhood acute lymphoblastic leukaemia in China: a retrospective cohort study of the Chinese Children's Cancer Group.

Arch Dis Child 2019 06 31;104(6):522-529. Epub 2019 Jan 31.

Department of Hematology/Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Key Lab of Pediatric Hematology and Oncology of China Ministry of Health, and National Children's Medical Center, Shanghai, China.

Objectives: Before 2003, most children with acute lymphoblastic leukaemia (ALL) abandoned treatment, with only approximately 30% treated in China. With the development of national insurance for underprivileged patients, we assessed the current frequency and causes of treatment abandonment among patients with ALL who were enrolled in the Chinese Children's Cancer Group ALL protocol between 2015 and 2016.

Methods: Demographic, clinical and laboratory data on patients who abandoned treatment, as well as economic and sociocultural data of their families were collected and analysed. General health-related statistics were retrieved from publicly accessible databanks maintained by the Chinese government.

Results: At a median follow-up of 119 weeks, 83 (3.1%, 95% CI 2.5% to 3.8%) of the 2641 patients abandoned treatment. Factors independently associated with abandonment included standard/high-risk ALL (OR 2.62, 95% CI 1.43 to 4.77), presence of minimal residual disease at the end of remission induction (OR 3.57, 95% CI 1.90 to 6.74) and low-income economic region (OR 3.7, 95% CI 1.89 to 7.05). According to the family members, economic constraints (50.6%, p=0.0001) were the main reason for treatment abandonment, followed by the belief of incurability, severe side effects and concern over late complications.

Conclusions: The rate of ALL treatment abandonment has been greatly reduced in China. Standard/high-risk ALL, residence in a low-income region and economic difficulties were associated with treatment abandonment.

Clinical Trial Registration Number: ChiCTR-IPR-14005706, pre-results.
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http://dx.doi.org/10.1136/archdischild-2018-316181DOI Listing
June 2019

Synthesis of magnetic multiwall carbon nanotubes for enantioseparation of three pesticide residues in fruits and vegetables by chiral liquid chromatography.

Chirality 2018 12 30;30(12):1321-1329. Epub 2018 Oct 30.

School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.

In this study, magnetic multiwalled carbon nanotubes (MMWCNTs) were synthesized and used as adsorbent for preconcentration of chiral pesticide residues (including epoxiconazole, tebuconazole, and metalaxyl) in lettuce, cabbage, and apple. Several parameters affecting the treatment efficiency were investigated, including extraction solvent and absorption solvent. Under the optimal conditions, all three chiral pesticides showed decent enantiomeric separation (Rs > 1.48). The linearity of each target was good with the correlation coefficient (r ) being greater than 0.9923. The average recoveries of the three spiked levels were 73.4% to 110.9% with repeatability (RSD ) less than 7.6%, and the limit of quantification of the method was 0.10 to 0.25 mg·kg . The results indicated that MMWCNTs had a good purifying effect, which can be applied as an effective pretreatment tool for the determination of residual chiral pesticides in fruits and vegetables.
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http://dx.doi.org/10.1002/chir.23029DOI Listing
December 2018

AtrbohD functions downstream of ROP2 and positively regulates waterlogging response in Arabidopsis.

Plant Signal Behav 2018 6;13(9):e1513300. Epub 2018 Sep 6.

a State Key Laboratory of Cotton Biology, Henan Key Laboratory of Plant Stress Biology, College of Life Sciences , Henan University , Kaifeng , China.

NADPH oxidase AtrbohD plays very important roles in modulating many cellular processes through production of signal molecules reactive oxygen species in Arabidopsis. However, whether it regulates the response to waterlogging stress is unclear. In this report, we showed that expression of AtrbohD was markedly induced by waterlogging stress, and mutation in AtrbohD led to clear sensitivity of Arabidopsis plants to waterlogging stress. Moreover, waterlogging-promoted increases in alcohol dehydrogenase (ADH) activity, ADH1 expression and HO accumulation were significantly attenuated in two mutant lines of AtrbohD. These results indicate that AtrbohD is required for Arabidopsis tolerance to waterlogging stress. Besides, GUS staining experiments revealed that disruption of small G protein ROP2 encoding gene evidently suppressed the increase of AtrbohD expression while defect of AtrbohD did not prominently affect the abundance enhancements of ROP2 transcripts under waterlogged conditions. Together, these data suggest that AtrbohD functions downstream of ROP2 to positively regulate the response to waterlogging stress in Arabidopsis.
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http://dx.doi.org/10.1080/15592324.2018.1513300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204828PMC
June 2019

A pilot screening of high-risk Gaucher disease children using dried blood spot methods in Shandong province of China.

Orphanet J Rare Dis 2018 04 6;13(1):48. Epub 2018 Apr 6.

Department of Pediatrics, Shengli Oilfield Central Hospital, Dongying, China.

Background: The study aim was to verify the feasibility of a diagnostic algorithm with the evaluation of beta glucocerebrosidase (GBA) activity on dried blood spots (DBS) in screening high-risk Gaucher disease (GD) children in China, and to investigate the GD prevalence in this selected population.

Methods: Children were recruited from 20 departments of pediatrics or children's hospitals in Shandong Province, China, due to splenomegaly and/or thrombocytopenia associated with one or more of the following creteria: anemia, history of bone pain, monoclonal gammopathy of unknown significance (MGUS), polyclonal gammopathy and splenectomy. GBA activity on DBS was tested, and patients with DBS GBA activity under 30 nmol/h.ml were recalled to assess enzyme assay with gold standard and molecular GBA gene analysis on leukocytes.

Results: A total of 73 children (47 boys and 26 girls) were enrolled in this study. GBA activity DBS < 30 nmol/h.ml was found in 18 (23.7%) children among which four (three boys and one girl) were diagnosed as GD with a median age 1.5 years, and the prevalence in this pediatric population was 5.5% (1.5%~ 13.4%). Three new mutations of GBA found in the four GD patients, L264I, A100Cfs*7 and D399E, have not been reported before.

Conclusions: With evaluation of GBA activity on DBS as a preliminary screening method, the diagnostic algorithm used in this study is appropriate to make early diagnosis for GD patients with mild symptoms or atypical symptoms and avoid diagnosis delay.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1186/s13023-018-0782-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889577PMC
April 2018

Angelica sinensis polysaccharide inhibits proliferation, migration, and invasion by downregulating microRNA-675 in human neuroblastoma cell line SH-SY5Y.

Cell Biol Int 2018 Jul 24;42(7):867-876. Epub 2018 Mar 24.

Department of Pediatric Hematology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.

Neuroblastoma is the most common tumor diagnosed in children and infants, with high recurrence and poor prognosis. Angelica sinensis polysaccharide (AP) whose average molecular weight is 72,900 Da possesses various bioactivities. We aimed to explore the effects of AP on neuroblastoma SH-SY5Y cells as well as the underlying mechanisms. Effects of AP on cell viability, proliferation, apoptosis, migration, invasion, and expressions of long noncoding RNA H19 (lncRNA-H19), microRNA (miR)-675, and CD44 were assessed. Then, effects of miR-675 overexpression on AP-treated cells were analyzed. Next, expression of key kinases in the PI3K/AKT and JAK/ STAT pathways was detected. The possible target gene of miR-675 was finally explored. Cell viability was reduced by 200-500 µg/mL AP. Meanwhile, AP repressed cell proliferation, migration, and invasion, but induced apoptosis. Expressions of lncRNA-H19 and miR-675 were upregulated in neuroblastoma cells, and were downregulated by AP. AP was also identified to upregulate CD44. We next found AP affected SH-SY5Y cells through downregulating miR-675. Key kinases in the PI3K/AKT and JAK/STAT pathways were downregulated by AP stimulation, while these downregulations were abrogated by miR-675 overexpression. KIF1B isoform β (KIF1Bβ) is proved to be a target of miR-675. In conclusion, AP was first identified to inhibit proliferation, migration, and invasion but induce apoptosis. Furthermore, AP might repress tumorigenesis of SH-SY5Y cells through miR-675-mediated inactivation of the PI3K/AKT and JAK/STAT pathways. Besides, KIF1Bβ might be a target of miR-675.
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http://dx.doi.org/10.1002/cbin.10954DOI Listing
July 2018
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