Algal-derived dissolved organic matter accelerates mercury methylation under cyanobacterial blooms in the sediment of eutrophic lakes.

Mercury (Hg), especially in the form of methylmercury (MeHg), poses a significant threat to both organisms and the environment due to its extreme toxicity. While methylation process of Hg in sediments has been extensively studied, recognition of its associated risks and mechanisms during cyanobacterial blooms remains limited. This study investigated the distribution characteristics of Hg and MeHg in sediments of Taihu Lake, China. The concentration of Hg and MeHg varied within the range of 96.0-212.0 ng g-1 and 0.1-0.5 ng g-1, respectively. Higher ecological risks of Hg were found in algal-dominated regions compared to macrophyte areas. The significant correlations observed between Hg, MeHg, and algal-derived dissolved organic matter (ADOM) components C1 and C2 in algal-dominated regions indicate a close association between ADOM components and the Hg methylation process. These components are involved in the absorption or complexation of Hg, participate in redox reactions, and modulate microbial activity. The dsrB gene in sulfate-reducing bacteria (SRB) was found to accelerate the metabolic pathways of Hg methylation. These findings indicate that ADOM could enhance the methylation process of Hg during cyanobacterial blooms, which warrants attention.

Arteannuin B Enhances the Effectiveness of Cisplatin in Non-Small Cell Lung Cancer by Regulating Connexin 43 and MAPK Pathway.

Cisplatin (DDP)-based chemotherapy is the first-line regimen for advanced non-small cell lung cancer (NSCLC) patients. However, advanced NSCLC patients may have innate resistance to DDP or develop resistance during DDP treatment. We investigated a natural compound, arteannuin B (Art B), for its potential effects on DDP resistance in NSCLC. Art B was isolated from Artemisia annua by chromatographic purification and spectral elucidation. The activities of Art B on DDP-mediated effects were examined using in vitro and in vivo assays. We observed significant correlations in T stage, clinical stage, chemotherapy resistance and poor survival of NSCLC patients with low Cx43 expression. Art B enhanced the effectiveness of cisplatin by increasing Cx43 expression in normal and DDP-resistant NSCLC cells. Art B also increased DDP uptake through up-regulating Cx43. The combination of DDP and Art B showed better therapeutic effect than individual treatments both in vitro and in vivo. Art B increased intracellular Fe[Formula: see text] level, promoted calcium influx, and activated gap junction and MAPK pathways, which might contribute to Art B-mediated effects. Art B may serve as a new drug candidate to enhance the antitumor effect of DDP on NSCLC.

Identification of multi-target anti-cancer agents from TCM formula by in silico prediction and in vitro validation.

Cancer is a complex disease associated with multiple gene mutations and malignant phenotypes, and multi-target drugs provide a promising therapy idea for the treatment of cancer. Natural products with abundant chemical structure types and rich pharmacological characteristics could be ideal sources for screening multi-target antineoplastic drugs. In this paper, 50 tumor-related targets were collected by searching the Therapeutic Target Database and Thomson Reuters Integrity database, and a multi-target anti-cancer prediction system based on mt-QSAR models was constructed by using naïve Bayesian and recursive partitioning algorithm for the first time. Through the multi-target anti-cancer prediction system, some dominant fragments that act on multiple tumor-related targets were analyzed, which could be helpful in designing multi-target anti-cancer drugs. Anti-cancer traditional Chinese medicine (TCM) and its natural products were collected to form a TCM formula-based natural products library, and the potential targets of the natural products in the library were predicted by multi-target anti-cancer prediction system. As a result, alkaloids, flavonoids and terpenoids were predicted to act on multiple tumor-related targets. The predicted targets of some representative compounds were verified according to literature review and most of the selected natural compounds were found to exert certain anti-cancer activity in vitro biological experiments. In conclusion, the multi-target anti-cancer prediction system is very effective and reliable, and it could be further used for elucidating the functional mechanism of anti-cancer TCM formula and screening for multi-target anti-cancer drugs. The anti-cancer natural compounds found in this paper will lay important information for further study.

LncRNA ARAP1-AS1 Promotes Bladder Cancer Development by Regulating the miR-3918/KIF20A Axis.

This study is to clarify the effect of the long non-coding RNA ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 1-antisense RNA 1 (ARAP1-AS1)/microRNA (miR)-3918/kinesin family member 20A (KIF20A) on bladder cancer cell function. ARAP1-AS1, miR-3918, and KIF20A expression levels in bladder cancer cells were determined using quantitative reverse transcription-polymerase chain reaction. The effects of ARAP1-AS1, miR-3918, and KIF20A on bladder cell activity, proliferation, apoptosis, and in vivo growth were examined using the cell counting kit-8, colony formation, caspase-3 activity, and xenograft tumor growth assays, respectively, in nude mice. The binding relationships among ARAP1-AS1, miR-3918, and KIF20A were analyzed using luciferase and RNA immunoprecipitation assays. ARAP1-AS1 and KIF20A were overexpressed in bladder cancer, while miR-3918 was underexpressed. The downregulation of ARAP1-AS1 or KIF20A expression significantly inhibited the viability and proliferation of cancer cells and promoted apoptosis, whereas low expression of miR-3918 or high expression of ARAP1-AS1/KIF20A showed the opposite effect. miR-3918 was sponged by ARAP1-AS1, and targeted KIF20A. In addition, miR-3918 expression was inversely correlated with ARAP1-AS1 and KIF20a expression levels in bladder cancer tissues. In addition, the rescue experiment showed that interference with miR-3918 could reverse the effect of low ARAP1-AS1 or KIF20A expression on bladder cancer cell malignancy. ARAP1-AS1 facilitates the malignant behavior of bladder cancer cells via the regulation of KIF20A expression by sponging miR-3918.

Long non-coding RNA-PCGEM1 contributes to prostate cancer progression by sponging microRNA miR-129-5p to enhance chromatin licensing and DNA replication factor 1 expression.

PCGEM1 facilitates prostate cancer (PCa) progression. This study aimed to elucidate the mechanism of action of PCGEM1 in PCa. The expression of PCGEM1, microRNA miR-129-5p, chromatin licensing, and DNA replication factor 1 (CDT1) was detected by quantitative reverse transcription-PCR (qRT-PCR). A series of function experiments including cell counting kit-8 (CCK-8), caspase-3 activity, and cell cycle assays were performed to evaluate the influence of PCGEM1, miR-129-5p, and CDT1 on the biological processes of PCa cells. CyclinD1, cyclin dependent kinase 4 (CDK4), Bax, and Bcl-2 protein levels were measured by western blotting. Subcellular isolation revealed the distribution of PCa cells. The connections between PCGEM1, miR-129-5p, and CDT1 were evaluated by luciferase, RIP assay, and Pearson correlation analysis. Both PCGEM1 and CDT1 were upregulated in PCa, while miR-129-5p was downregulated and negatively correlated with PCGEM1 and CDT1. Downregulation of PCGEM1 or CDT1 inhibited the viability, promoted apoptosis and cycle arrest of PCa cells in vitro, and controlled tumor growth in vivo. PCGEM1 plays a crucial role in the progression of PCa by sponging miR-129-5p as a ceRNA of CDT1. PCGEM1 is a CDT1-dependent PCa promoter site that absorbs miR-129-5p.

DL0410 ameliorates cognitive disorder in SAMP8 mice by promoting mitochondrial dynamics and the NMDAR-CREB-BDNF pathway.

Alzheimer's disease (AD) is a worldwide problem and there are no effective drugs for AD treatment. Previous studies show that DL0410 is a multi-target, anti-AD agent. In this study, we investigated the therapeutic effect of DL0410 and its action mechanism in SAMP8 mice. DL0410 (1-10 mg·kg-1·d-1) was orally administered to 8-month-old SAMP mice (SAMP8) for 8 weeks. We showed that DL0410 administration effectively ameliorated the cognitive deficits in the Morris water maze test, novel object recognition test, and nest building test. We revealed that DL0410 dose-dependently increased the expression levels of the mitochondrial proteins (PGC-1α, Mitofusin 2, OPA1, and Drp1), and subsequently ameliorated the processes of mitochondrial biosynthesis, fusion, and fission in the cortex and hippocampus of SAMP8 mice. Furthermore, DL0410 administration promoted the expression of synaptic proteins (synaptophysin and PSD95) in the brain of SAMP8 mice, and upregulated the protein phosphorylation in NMDAR-CAMKII/CAMKIV-CREB pathway responsible for the synaptic plasticity. DL0410 administration dose-dependently increased the expression of BDNF and TrkB, and the neurotrophic effect was mediated via the ERK1/2 and PI3K-AKT-GSK-3ß pathways. DL0410 administration upregulated Bcl-2, increased the Bcl-2/Bax ratio and the level of caspase 3 and PARP-1, alleviating neuronal apoptosis. We proposed that the NMDAR-CREB-BDNF pathway might establish a positive feedback loop between synaptic plasticity and neurotrophy, with CREB at the center. In summary, DL0410 promotes synaptic function and neuronal survival, thus ameliorating cognitive deficits in SAMP8 mice via improved mitochondrial dynamics and increased activity of the NMDAR-CREB-BDNF pathway. DL0410 is a promising candidate to treat aging-related AD, and deserves more research and development in future.

Prediction, management, and prognosis of mixed chimerism after hematopoietic stem cell transplantation in transfusion-dependent pediatric thalassemia patients.

BACKGROUND: Early-onset mixed chimerism (MC) with a high proportion of residual host cells is considered a signal of graft rejection in patients undergoing allogenic hematopoietic stem cell transplantation for transfusion-dependent thalassemia. In order to prevent graft rejection and minimize the risk of treatment-related graft-versus-host disease (GVHD), we established a hierarchical management system based on chimerism analysis. METHOD: This retrospective study provides a comprehensive review of the characteristics, interventions, and outcomes of the 38 patients who developed MC after transplantation among the 144 pediatric thalassemia patients between July 2007 and January 2019 at our center. RESULTS: A sibling donor, a blood type-matched donor, conditioning regimens without fludarabine, and transplants containing <10 × 108 total nucleated cells/kg were identified to be associated with the development of MC. Among the 38 patients developing MC, only four patients rejected the grafts. The response rate to donor lymphocyte infusion (DLI, only for patients receiving sibling donor transplantation) and cytokine immunomodulation without DLI was 70.6% and 42.9%, respectively. Patients that developed GVHD after DLI or cytokine therapy had a more significant increase in donor cell chimerism (16%, range 0%-35%) than those without (8.5%, range -21% to 40%, P = .049). However, even when treatment-related GVHD was included, patients with MC had a lower cumulative incidence of total acute GVHD than patients with complete donor chimerism (29.2% vs 48.0%, P = .030). CONCLUSIONS: Interventions based on chimerism analysis were effective in preventing graft rejection and did not increase treatment-related GVHD in thalassemia patients with MC.

DCK is an Unfavorable Prognostic Biomarker and Correlated With Immune Infiltrates in Liver Cancer.

BACKGROUND: The biological function of deoxycytidine kinase in tumor is not yet clear, and there are a few studies relating to the correlation of deoxycytidine kinase gene with the occurrence and development of liver cancer. METHODS: The messenger RNA expression of deoxycytidine kinase was analyzed with the use of the UALCAN and GEPIA database. Moreover, we assessed the function of deoxycytidine kinase on clinical prognosis with Kaplan-Meier plotter database. The relationship between deoxycytidine kinase and cancer immune infiltrates was investigated via Tumor Immune Estimation Resource site. Furthermore, Tumor Immune Estimation Resource was also used to evaluate the correlations between the expression of deoxycytidine kinase and gene marker sets of immune infiltrates. RESULTS: The deoxycytidine kinase messenger RNA level significantly upregulated in patients with liver cancer compared to normal liver samples. Moreover, the increased expression of deoxycytidine kinase messenger RNA was closely associated with reduced overall survival and disease-free survival in all liver cancers. In addition, deoxycytidine kinase expression displayed a strong correlation with infiltrating levels of macrophages, neutrophils, and dendritic cells in liver cancer, and deoxycytidine kinase expression was positively correlated with diverse immune marker sets in liver cancer. CONCLUSIONS: All the above findings suggested that increased expression of deoxycytidine kinase was significantly related to unfavorable prognosis in patients with liver cancer. And deoxycytidine kinase is correlated with immune infiltrating levels, including those of B cells, macrophages, neutrophils, and dendritic cells in patients with liver cancer. These findings suggest that deoxycytidine kinase can be used as a prognostic biomarker for determining prognosis and immune infiltration in liver cancer. And deoxycytidine kinase is a potential target for liver cancer therapy, and these preliminary findings require further study to determine whether deoxycytidine kinase-targeting reagents might be developed for clinical application in liver cancer.

[Preliminary Study of Chidamide Combined with Hematopoietic Stem Cell Transplantation in the Treatment of Childhood Acute T-Lymphoblastic Leukemia].

OBJECTIVE: To investigate the efficacy and safety of combination chidamide and hematopoietic stem cell transplantation (HSCT) in the treatment of childhood acute T lymphoblastic leukemia (T-ALL). METHODS: Seven children with acute T lymphoblastic leukemia received hematopoietic stem cell transplantation in SUN Yat-Sen Memorial Hospital of SUN Yat-Sen University were selected. 7 cases of T-ALL were divided into 2 groups: HSCT plus chidamide-treated group (4 cases) and traditional HSCT-treated group (3 cases) as control. The incidence of GVHD and other related complications, as well as implantation, recurrence and survival were compared between the two groups, and the side effects of chidamide were observed. All the patients were follow-up until January 2019. RESULTS: All the 7 patients were alive and, there was no difference in the incidence of acute GVHD between the HSCT plus chidamides treated group and the traditional HSCT-treated group. The implantation rate of HSCT was 100%, and there were no recurrence occurred. During the application of chidamide, 3 cases showed adverse reactions, of which 2 cases had adverse reactions of grade 3 or higher, and 2 cases were hematological adverse reactions (neutropenia, thrombocytopenia), other adverse reactions were non-hematologic adverse reactions (transaminase elevation, fatigue, nausea, vomiting), there were no serious adverse reactions occurred. In the HSCT plus chidamide-treated group, 2 cases were found that mature lymphocytes were not expressed by tumors, during examing for minimal redidaul disease (MRD). Compared with the immunophenotype and TCR rearrangement at first diagnosis, the results did not support the source of residual T-ALL tumor cells. During the review of MRD, it was found that the abnormal T cells showed an increasing trend, indicating that chidamide might induce leukemia cell differentiation through some pathways. CONCLUSION: Hematopoietic stem cell transplantation is still an effective method to cure children's T-ALL. In some cases, abnormal T-cell nonclonal amplification occurs during the application of chidamide, and the children with T-ALL can tolerable adverse reactions of chidamide.

[Efficacy of BMMSCs on aGVHD and Its Correlation with SerumInflammatory Cytokines in Pediatric Patients with Severe Refractory Acute Graft-Versus-Host Disease].

OBJECTIVE: To investigate the efficacy of bone marrow mesenchymal stem cells (BMMSC) on children with refractory graft-versus-host disease (GVHD) and to judge the efficacy of BMMSC by dynamically monitoring the changes of cytokines in children with GVHD before and after infusion of BMMSC, so as to provide a theoretical basis for clarifying the mechanism of BMMSC. METHODS: 17 children with refractory aGVHD including 7 of grade II, 6 cases of grade III and 4 cases of grade IV after allo-HSCT were enrolled. All the children with aGVHD, who received routine immunosuppressive therapy, but the state of disease not improved, were treated with immunosuppressive drugs combined with BMMSC infusion. Study endpoints included safety of BMMSC infusion, response to BMMSC, and overall response of aGVHD. The serum levels of IL-2α, IL-6, IL-10, IL-8 and TNF-α in aGVHD patients were measured by chemiluminescence before infusion of BMMSCs and Day 7, Day 14 after infusion of BMMSCs. RESULTS: The cumulative median dose of BMMSCs was 5.5 (3.4-11.1) × 106/kg for average of 3.7 times, and the median time of 16.5 (4-95) days for the first infusion of MSCs. In 17 cases of refractory GVHD, 14 responded to treatment, whereas 3 patients failed. The total effective rate was 82.4% and no adverse reactions occurred. Of the 14 survived cases (82.4%), the median follow-up time was 944 (559-1245) days from the first infusion of MSCs. The levels of TNF-α in children with grade II, III and IV GVHD before treatment were 9.5±4.3 pg/ml, 16.3±10.9 pg/ml and 35.8±21.2 pg/ml respectively. The difference between grade II and IV, III and IV was statistically significant (P<0.05). Compared with the ineffective group of BMMSC infusion, the serum TNF-αlevel in the BMMSCs treatment effective group was 10.8±5.6 pg/ml vs 40.6±14.8 pg/ml (t=-3.901, P<0.05) before treatment. In the effective group of BMMSCs infusion, IL-10 20±17.4 pg/ml of day 14 was significantly higher than that 7.3±3.1 pg/ml before the treatment (t=-2.850, P<0.05), while , the serum levels of IL-2α, IL-6, IL-8, TNF-α were not statistically significantly different (P＞0.05). CONCLUSION: The infusion of BMMSC is safe and effective in the treatment of refractory GVHD in children. TNF-αlevel relates with the severity of GVHD. BMMSC may play an anti-GVHD role by up regulating the level of cytokine IL-10 in vivo.

Bioassay of ferulic acid derivatives as influenza neuraminidase inhibitors.

Four series of ferulic acid derivatives were designed, synthesized, and evaluated for their neuraminidase (NA) inhibitory activities against influenza virus H1N1 in vitro. The pharmacological results showed that the majority of the target compounds exhibited moderate influenza NA inhibitory activity, which was also better than that of ferulic acid. The two most potent compounds were 1m and 4a with IC50 values of 12.77 ± 0.47 and 12.96 ± 1.34 µg/ml, respectively. On the basis of the biological results, a preliminary structure-activity relationship (SAR) was derived and discussed. Besides, molecular docking was performed to study the possible interactions of compounds 1p, 2d, 3b, and 4a with the active site of NA. It was found that the 4-OH-3-OMe group and the amide group (CON) of ferulic acid amide derivatives were two key pharmacophores for NA inhibitory activity. It is meaningful to further modify the natural product ferulic acid to improve its influenza NA inhibitory activity.

DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission and reducing neuronal loss.

At present, few available drugs can be used to either improve pathological features or prevent the progression of Alzheimer's disease (AD). DL0410 ((1,1'-([1,1'-biphenyl]-4,4'-diyl) bis (3-(piperidin-1-yl) propan-1-one) dihydrochloride) is a multiple-target small molecule that has been found to reverse cognitive impairment in different animal models of AD. In this study we evaluated the cognition-improving effects of DL0410 in APP/PS1 transgenic mice and explored the underlying mechanisms. APP/PS1 transgenic mice were administered DL0410 (3, 10, 30 mg· kg-1· d-1, ig) for 2 months. We found that DL0410 administration significantly ameliorated cognitive deficits in both the nest-building and Morris water maze tests. In electrophysiological analysis of hippocampal slices, we showed that DL0410 administration significantly enhanced the field EPSP slope and HFS-induced LTP in CA1 area. Furthermore, we revealed that DL0410 administration significantly increased the phosphorylation of AKT and the activity of GSK-3ß in the hippocampus and cortex. Moreover, DL0410 administration dose-dependently increased the expression level of phosphorylated ERK1/2 in the hippocampus and cortex. In addition, DL0410 dose-dependently decreased the neuronal loss by decreasing the production of Aß deposition, inhibited glial overactivation, and the production of inflammatory cytokines such as TNF-α, IL-1ß, and IL-6. We conclude that DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission via activating the AKT/GSK-3ß and MAPK/ERK signaling pathway and reducing neuronal loss. DL0410 may be an effective agent for AD treatment in the future.

Cloning and Expression Profile of Glyceraldehyde-3-Phosphate Dehydrogenase in Haemaphysalis flava (Acari: Ixodidae).

Haemaphysalis flava (Acari: Ixodidae) harbors pathogenic microorganisms and transfers these to hosts during blood feeding. Proteomic analysis in the midgut contents of H. flava detected glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and contig 1683 was retrieved as a GAPDH gene fragment by searching our previous transcriptomic library. In the study, the 5' and 3' ends of contig 1683 were cloned by rapid amplification of cDNA ends (RACE) and a full length, 1340 bp cDNA of Hf-GAPDH was obtained. The open-reading frame had 999 bp and coded for 333 amino acids. Hf-GAPDH was predicted to have an N-terminal NAD binding domain and a C-terminal glyceraldehyde dehydrogenase catalytic domain. The molecular structure of Hf-GAPDH was analyzed and the evolutionary relationship also established. The GAPDH protein sequence was conserved among ticks. The expression pattern of Hf-GAPDH, analyzed by real-time PCR, significantly differed among life phases, feeding stages, and tissues. As the ticks grew, the expression level of Hf-GAPDH was up-regulated. The expression levels of Hf-GAPDH in salivary glands and midguts from half-engorged ticks were lower than the same tissues from engorged ticks. This study will provide reference data for the follow-up verification of the GAPDH-related function and the feasibility as a potential anti-tick vaccine.

Effect of Aspergillus flavus Fungal Elicitor on the Production of Terpenoid Indole Alkaloids in Catharanthus roseus Cambial Meristematic Cells.

This study reported the inducing effect of Aspergillus flavus fungal elicitor on biosynthesis of terpenoid indole alkaloids (TIAs) in Catharanthus roseus cambial meristematic cells (CMCs) and its inducing mechanism. According to the results determined by HPLC and HPLC-MS/MS, the optimal condition of the A. flavus elicitor was as follows: after suspension culture of C. roseus CMCs for 6 day, 25 mg/L A. flavus mycelium elicitor were added, and the CMC suspensions were further cultured for another 48 h. In this condition, the contents of vindoline, catharanthine, and ajmaline were 1.45-, 3.29-, and 2.14-times as high as those of the control group, respectively. Transcriptome analysis showed that D4H, G10H, GES, IRS, LAMT, SGD, STR, TDC, and ORCA3 were involved in the regulation of this induction process. The results of qRT-PCR indicated that the increasing accumulations of vindoline, catharanthine, and ajmaline in C. roseus CMCs were correlated with the increasing expression of the above genes. Therefore, A. flavus fungal elicitor could enhance the TIA production of C. roseus CMCs, which might be used as an alternative biotechnological resource for obtaining bioactive alkaloids.

Anti-influenza effect and action mechanisms of the chemical constituent gallocatechin-7-gallate from Pithecellobium clypearia Benth.

Host cdc2-like kinase 1 (CLK1) is responsible for the alternative splicing of the influenza virus M2 gene during influenza virus infection and replication that has been recognized as a potential anti-influenza virus target. In this study, we showed that gallocatechin-7-gallate (J10688), a novel CLK1 inhibitor isolated from Pithecellobium clypearia Benth, exerted potent anti-influenza virus activity in vivo and in vitro. ICR mice were intranasally infected with a lethal dose of H1N1. Administration of J10688 (30 mg·kg-1·d-1, iv, for 5 days) significantly increased the survival rate of the H1N1-infected mice to 91.67% and prolong their mean survival time from 5.83 ± 1.74 days to 13.66 ± 1.15 days. J10688 administration also slowed down body weight loss, significantly alleviated influenza-induced acute lung injury, reduced lung virus titer, elevated the spleen and thymus indexes, and enhanced the immunological function. We further explored its anti-influenza mechanisms in the H1N1-infected A549 cells: as a novel CLK1 inhibitor, J10688 (3, 10, 30 µmol/L) dose-dependently impaired synthesis of the viral proteins NP and M2, and significantly downregulated the phosphorylation of splicing factors SF2/ASF and SC35, which regulate virus M2 gene alternative splicing. As a novel CLK1 inhibitor with potent anti-influenza activity in vitro and in vivo, J10688 could be a promising antiviral drug for the therapy of influenza A virus infection.

Reassessment of the Risk-stratified GD-2008 ALL Protocol.

OBJECTIVE: To explore the clinical features and outcomes of relapsed childhood acute lymphoblastic leukemia (ALL) at our center, achieve the early detection of risk factors for recurrence and assess the risk-stratified Guangdong (GD)-2008 ALL protocol. MATERIALS AND METHODS: In total, 59 Chinese childhood ALL patients treated with the GD-2008 ALL protocol who relapsed between July 2008 and March 2015 were enrolled in this study. Their clinical features and outcomes were retrospectively analyzed and compared with those of 218 patients who achieved continuous complete remission. RESULTS: Of the 285 study participants, 8 died of treatment-related infections or other complications before remission, 218 achieved continuous complete remission, and 59 patients relapsed, yielding a relapse rate of 20.7%. The number of relapsed patients in the standard-risk, intermediate-risk, and high-risk groups were 15 (17.0%), 27 (19.7%), and 17 (32.7%), respectively. Risk factors included age 10 years and above at first diagnosis, white blood cell (WBC) count ≥50×10/L, poor prednisone response, failure to achieve bone marrow complete remission at day 15 of induction chemotherapy. High-risk stratification and a high level (≥0.1%) of minimal residual disease at day 33 were the risk factors for relapse. Multivariate analysis showed that a high WBC at first diagnosis was an independent risk factor for relapse (P=0.000). CONCLUSION: For the GD-2008 ALL risk stratification based on age and initial WBC, 10 years of age and WBC 50×10/L can be used as cut-offs. Patients at high risk benefited from the GD-2008 ALL protocol. In addition, the impact of minimal residual disease on prognosis should be considered.

Network pharmacology-based analysis of Chinese herbal Naodesheng formula for application to Alzheimer's disease.

Naodesheng (NDS) formula, which consists of Rhizoma Chuanxiong, Lobed Kudzuvine, Carthamus tinctorius, Radix Notoginseng, and Crataegus pinnatifida, is widely applied for the treatment of cardio/cerebrovascular ischemic diseases, ischemic stroke, and sequelae of cerebral hemorrhage, etc. At present, the studies on NDS formula for Alzheimer's disease (AD) only focus on single component of this prescription, and there is no report about the synergistic mechanism of the constituents in NDS formula for the potential treatment of dementia. Therefore, the present study aimed to predict the potential targets and uncover the mechanisms of NDS formula for the treatment of AD. Firstly, we collected the constituents in NDS formula and key targets toward AD. Then, drug-likeness, oral bioavailability, and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for treatment of central nervous system diseases. By combining the advantages of machine learning, molecular docking, and pharmacophore mapping, we attempted to predict the targets of constituents and find potential multi-target compounds from NDS formula. Finally, we built constituent-target network, constituent-target-target network and target-biological pathway network to study the network pharmacology of the constituents in NDS formula. To the best of our knowledge, this represented the first to study the mechanism of NDS formula for potential efficacy for AD treatment by means of the virtual screening and network pharmacology methods.

Analysis of Treatment of 3 Patients with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is an acute liver decompensation that occurs within 4 weeks on the basis of chronic liver disease. At present, the treatments of ACLF include general supportive treatment, etiological treatment, prevention and treatment of complications, artificial liver treatment, and liver transplantation. Many studies suggest that stem cell therapy may become a new treatment for patients with ACLF. Our department has also tried the application of this treatment. Now, there are three cases of stem cell therapy for patients with ACLF by our department which will be briefly reported.

Simultaneous measurements of arsenic and sulfide using diffusive gradients in thin films technique (DGT).

Diffusive gradients in thin films technique (DGT) is a dynamically passive sampling technique which has been applied increasingly to the environmental monitoring field. In the preliminary period, the DGT with zirconium hydroxide-silver iodide as the binding phase (ZrO-AgI DGT) has been developed for the determination of sulfide (S(II)). On this basis, this paper developed its determination method for inorganic arsenite (As(III)) to further realize the simultaneous and high-resolution measurements of labile inorganic As and S(II) in sediments. ZrO-AgI binding gel had a strong ability in adsorbing and fixing As(III), showing a linear increase in the initial 12.5 min. After saturation of S(II) on ZrO-AgI binding gel, the adsorption rate and adsorption capacity of As(III) reduced by 8 and 14%, respectively. A stable elution rate (89.1 ± 2.2%) was obtained by extraction of As(III) on the binding gel using a mixture solution of 1.0 M NaOH and 1.0 M H2O2 (1:1). The DGT capacity of As(III) determined by the ZrO-AgI DGT was 23.6 µg cm-2. DGT uptakes of As(III) were independent of pH (4.0-9.0) and ionic strength (0.01-100 mM), and they did not interfere with each other during the uptake process. Simultaneous measurements of labile As and S(II) in four sediment cores of Taihu Lake (China) with ZrO-AgI DGT showed that they had similarly vertical distributions in the top 16-mm layer in one core and in the whole profile up to the 35 mm depth in two cores. It likely reflected a simultaneous release of As and S(II) in sediments by synchronous reduction of As-hosted oxidized iron and sulfate, respectively. The simultaneous decreases of labile As and S(II) from their co-precipitation (e.g., As2S3) were not obvious in deeper sediment layer through the measurement with ZrO-AgI DGT.

Indoleamine 2,3-dioxygenase and inducible nitric oxide synthase mediate immune tolerance induced by CTLA4Ig and anti-CD154 hematopoietic stem cell transplantation in a sensitized mouse model.

Cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig) and anti-cluster of differentiation 154 (anti-CD154) are able to block B7/CD28 and CD40/CD154 co-stimulatory signals in T cells. Additionally, they promote hematopoietic stem cell transplantation (HSCT) in sensitized recipients and are able to induce immune tolerance and complete hematopoietic reconstitution. Indoleamine 2, 3-dioxygenase (IDO) and nitric oxide (NO) have been implicated in T cell immune tolerance. The aim of the present report was to study the in vivo tolerogenic mechanisms by which CTLA4Ig and anti-CD154 induce transplantation survival in mice receiving HSCT. BALB/c mice were sensitized via splenocyte transfusion and pretreated with CTLA4Ig plus anti-CD154 on day-7. IDO and inducible nitric oxide synthase (iNOS) inhibitors were applied on days-7 to 0 and the mice were divided into 4 groups (n=10) and injected with IDO every other day. The mice were sacrificed on day 0, and splenocytes were separated to identify CD11c+ antigen-presenting cells, which were subsequently assessed for IDO expression and activity. The concentration of NO was tested using a nitrate reductase kit. Following the acceptance of allogeneic HSCT, mice were tested for homing and engraftment, as well as survival rate. Application of the IDO inhibitor increased the concentration of NO, whereas a decrease in NO resulted in increased IDO activity. Immune tolerance was abrogated in the presence of both IDO and iNOS inhibitors, whereas this effect was not observed with either compound alone. CTLA4Ig and anti-CD154 may induce immune tolerance by affecting the activity of IDO and iNOS. This tolerance was abrogated in the presence of both IDO and iNOS inhibitors. A cross-regulatory pathway was observed between the IDO and NO pathways, in which the inhibition of IDO stimulated the iNOS pathway and vice versa.