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Knowledge gaps in the exposure parameters for recreational water activities make quantitative risk assessment related to water recreation difficult. Therefore, the annual exposure frequency and single exposure duration for the recreational water activities of residents from ten cities in the North and South of China were investigated. Questionnaire interviews were carried on recreational water activities comprising swimming (SW), boating (BA), playing in interactive fountains (PF), and watching fountains (WF). Quantitative microbial risk assessment for the exposure of urban residents to Cryptosporidium and Giardia was also performed. For the four recreational water activities, the participation rates of urban residents in SW and WF were higher than the others. For SW and BA, the mean annual exposure frequency and single exposure duration for males were significantly higher than those for females. PF and WF showed the opposite. The annual exposure frequency for above 35-year-old residents was higher than that for young residents (18–35 years). However, the single exposure duration for young residents was highest in SW, BA, and PF. The mean annual exposure frequency and single exposure duration for North China residents were higher than those for South China residents in all recreational water activities, except for SW. Overall, the annual exposure frequency and single exposure duration in recreational water activities for all urban residents followed a lognormal distribution. In the four recreational water activities, the total annual infection risk of male exposure to Cryptosporidium was 1.0 × 10-2, with the confidence intervals between 95 and 5% of [4.3 × 10-4, 3.7 × 10-2], whereas that for females was 6.8 × 10-3 and [4.2 × 10-4, 2.4 × 10-2]. Also, the annual infection risk of males to Giardia was 8.8 × 10-3 and [5.1×10-4, 3.2×10-2], and that of females was 5.3 × 10-3 and [4.0 × 10-4, 1.8 × 10-2]. These results demonstrated that SW and PF made the highest contribution to the total annual infection risk. Sensitivity analysis highlighted that the characterization of exposure parameters plays a critical role in health risk assessment, which may provide a scientific basis for recreational water quality standards formulation.

To observe the efficacy of chimeric antigen receptor T cell (CAR-T) in the treatment of children with refractory/recurrent B acute lymphocytic leukemia (B-ALL).Thirty-two patients with r/r B-ALL were treated by CAR-T, the recurrence and death respectively were the end point events to evaluate the efficacy and safety of CAR-T.The median age of the patients was 7.5 (2-17.5) years old; 40 times CAR-T were received in all patients and the median number of CAR-T was 0.9×107/kg; efficacy evaluation showed that 2 cases died before the first evaluation. Thirty patients showed that 3, 6, and 9-moth RFS was (96.3±3.6)%, (81.4±8.6)% and (65.3±12.5)%, respectively, while 3, 6, and 9-month OS was all 100%, and 12, 24-month OS was (94.7±5.1)% and (76±12.8)%. BM blasts≥36% before reinfusion and ferritin peak≥2 500 ng/ml within two weeks of CAR-T cell reinfusion were associated with recurrence. Adverse reactions mainly included cytokine release syndrome (CRS) and CART-cell-related encephalopathy syndrome (CRES), CRS appeared in 26 patients within a week of CAR-T cell reinfusion. CRES reaction was detected in 12 patients. Eighteen patients received intravenous drip of tocilizumab, among them, 12 combined with glucocorticoid. CRS and CRES reactions were relieved within one week after treatment. Hormone dosage was related to the duration of remission in patients, and the cumulative dose of methylprednisolone≥8 mg/kg showed a poor prognosis.CAR-T is a safe and effective treatment for r/r B-ALL, most CRS and CRES reactions are reversible. BM blasts ≥36% before reinfusion and cumulative dose of methylprednisolone ≥8 mg/kg after reinfusion both affect the therapeutic effect. Ferritin≥2 500 ng/ml within two weeks after reinfusion is related to disease recurrence and is an independent prognostic risk factor.嵌合抗原受体T细胞治疗儿童难治/复发急性B淋巴细胞白血病的疗效.观察嵌合抗原受体（CAR）T细胞治疗儿童难治/复发急性B淋巴细胞白血病（r/r B-ALL）的疗效及不良反应.回顾性分析32例r/r B-ALL患儿行CAR-T细胞治疗的临床资料，分别以复发、死亡为终点事件，评估CAR-T细胞治疗r/r B-ALL的疗效及安全性.2017年7月至2020年1月，共32例r/r B-ALL患儿接受CAR-T细胞治疗，中位年龄7.5（2-17.5）岁。32例患儿共回输CAR-T细胞40次，回输中位CAR-T细胞总量0.9×107/kg（患儿体重）。结果显示，2例患儿在评估前死亡，其余30例患儿3、6、9个月RFS分别为（96.3±3.6）%、（81.4±8.6）%和（65.3±12.5）%；3、6、9个月OS均为100%，12个月OS（94.7±5.1）%，24个月OS（76±12.8）%。回输前骨髓肿瘤负荷≥36%、CAR-T细胞回输2周内铁蛋白峰值≥2 500 ng/ml与复发相关。不良反应主要为细胞因子释放综合征（CRS）和CAR-T治疗相关脑病综合征（CRES），26例在CAR-T细胞回输1周内出现CRS反应，12例出现CRES反应。18例给予托珠单抗静滴，其中12例联合糖皮质激素，CRS反应及CRES反应经治疗后大多1周内缓解。激素使用剂量与患儿持续缓解时间相关，甲泼尼龙累积剂量≥8 mg/kg预后不佳.CAR-T细胞治疗儿童r/r B-ALL有效且安全，CRS及CRES反应经治疗后均可缓解；回输前骨髓肿瘤负荷≥36%、回输后甲泼尼龙累积剂量≥8 mg/kg预后不佳；回输后两周内铁蛋白峰值≥2 500 ng/ml与疾病复发相关，且为独立预后危险因素.

The assembly of different types of materials like metals and ceramics forms a structure called sandwich structure, which need advanced techniques to joint it together like the thermo compression. However, the rise of residual stress caused by the discontinuity of nature of this type of sandwich material, like incompatibility of the characteristics, which creates a risk of rupture of the structure and limited the using range of these types of materials. In this paper, we study the bonding of ceramic and metal and we will focus on the role played by the ceramic element in the stress state of ceramic/ metal interface and the stresses evaluation by Finite Element when the structure is subjected to thermo-Mechanical loading.

An industrial fibreglass winding process is employed to apply graphene based sizing (0.2 wt% graphene concentration) on fibreglass surface. Both SEM and Raman spectroscopy characterization have proved that the coating of graphene on fibreglass surface is homogeneous and that the roughness of the fibreglass surface was improved. Long fiberglass-graphene reinforced PA66 pellets are successfully prepared through a pultrusion process. LGF-graphene-PA66 composites are produced following an injection molding process. Thermal conductivity was found to increase from 0.23 W/m · K−1 to 0.67 W/m · K−1 when compared with samples without graphene coating. The tensile strength of LGF-graphene-PA66 is 196 MPa while that of LGF-PA66 is 173 MPa. Tensile modulus is also found to increase to 13.5 GPa from 10.6 GPa after graphene coating. This new graphene coating process is a good method to produce high performance composites.

Neuroblastoma is the most common extracranial solid childhood tumor. Despite the availability of advanced multimodal therapy, high-risk patients still have low survival rates. p21-activated kinase 4 (PAK4) has been shown to regulate many cellular processes in cancer cells, including migration, polarization and proliferation. However, the role of PAK4 in neuroblastoma remains unclear. In the present study, we demonstrated that PAK4 was overexpressed in neuroblastoma tissues and was correlated with tumor malignance and prognosis. To investigate the function of PAK4 in neuroblastoma, we used a small-molecule inhibitor that targets PAK4, that is, PF-3758309. Our results showed that PF-3758309 significantly induced cell cycle arrest at the G1 phase and apoptosis in neuroblastoma cell lines. Meanwhile, the inhibition of PAK4 by PF-3758309 increased the expression of CDKN1A, BAD and BAK1 and decreased the expression of Bcl-2 and Bax. In addition, we screened the target genes of PAK4 by PCR array and found that 23 genes were upregulated (including TP53I3, TBX3, EEF1A2, CDKN1A, IFNB1 and MAPK8IP2) and 20 genes were downregulated (including TNFSF8, Bcl2-A1, Bcl2L1, SOCS3, BIRC3 and NFKB1) after PAK4 inhibition by PF-3758309. Moreover, PAK4 was found to regulate the cell cycle and apoptosis via the ERK signaling pathway. In conclusion, the present study demonstrated, for the first time, the expression and function of PAK4 in neuroblastomas and the inhibitory effect of PF-3758309, which deserves further investigation as an alternative strategy for neuroblastoma treatment.

Decreased autophagy is accompanied by the development of a myeloproliferative state or acute myeloid leukemia (AML). AML cells are often sensitive to autophagy‑inducing stimuli, prompting the idea that targeting autophagy can be useful in AML cytotoxic therapy. AML NB4 cells overexpressing microtubule-associated protein 1 light chain 3-green fluorescent protein were screened with 69 inhibitors to analyze autophagy activity. AML cells were treated with the polo-like kinase 1 (PLK1) inhibitors RO3280 and BI2536 before autophagy analysis. Cleaved LC3 (LC3-II) and the phosphorylation of mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase, and Unc-51-like kinase 1 during autophagy was detected with western blotting. Autophagosomes were detected using transmission electron microscopy. Several inhibitors had promising autophagy inducer effects: BI2536, MLN0905, SK1-I, SBE13 HCL and RO3280. Moreover, these inhibitors all targeted PLK1. Autophagy activity was increased in the NB4 cells treated with RO3280 and BI2536. Inhibition of PLK1 expression in NB4, K562 and HL-60 leukemia cells with RNA interference increased LC3-II and autophagy activity. The phosphorylation of mTOR was reduced significantly in NB4 cells treated with RO3280 and BI2536, and was also reduced significantly when PLK1 expression was downregulated in the NB4, K562 and HL-60 cells. We demonstrate that PLK1 inhibition induces AML cell autophagy and that it results in mTOR dephosphorylation. These results may provide new insights into the molecular mechanism of PLK1 in regulating autophagy.

Ground subsidence induced by internal erosion around defective sewer pipes commonly occurs in urban areas of many cities over the world, which has caused substantial socioeconomic loss. Professional pipe design, inspection and maintenance demand a comprehensive understanding of the internal erosion mechanism due to defective pipes. This paper conducts a series of experimental, theoretical and numerical analyses aiming to propose a new method quantifying the erosion process around defective pipes. In this study, a laboratory experimental test of internal erosion was conducted using gap-graded soils, followed by the derivation of a nonlinear incremental governing equation for quantifying the erosion rate of soil on the basis of experimental results. After that, a new type of element was established to incorporate the proposed governing equation of erosion into Mohr-Coulomb constitutive soil model. Finally, this new element was adopted in a 2D soil-fluid coupled finite element analysis of soil erosion due to pipe defect. Results indicate that (1) the hydraulic head greatly affects cavity formation and soil loss, whereas the defect types have a little effect on eroded region, (2) visual images during test show that the soil erosion gradually slows down and eventually stabilizes along with the forming of soil skeleton, (3) the numerical results match well with the experimental results, demonstrating the effectiveness of both the theoretical method and numerical tool for the analysis of soil erosion around defective pipes.

In recent years, the cave-in on roads frequently occurs in urban area to threaten the city safety, which is usually initiated by the ground cavity due to internal erosion around defective buried pipelines. In order to study the mechanism of internal erosion inducing cavity, the model tests are performed using gap grading soil samples. The effects of soil saturation, hydraulic head, initial soil grading and defect size of the pipeline on the internal erosion are studied with eight model tests. The erosion is characterized in terms of the erosion area and cavity formation during erosion. The test results show that the erosion can get stable due to the support of coarse particle skeleton in gap grading soil. The erosion areas can be classified into three forms of gravel area, flow area and cavity according to erosion state. Furthermore, the erosion area especially the cavity in saturated soil is more extensive than that in unsaturated soil. Besides, no hidden cavity forms in unsaturated soil, but the surface settlement. The higher hydraulic head induces bigger erosion area and cavity forms at the water table. More initial fine-sand content means more sand loss, leading to more significant soil deformation. While bigger defect size may cause a little more erosion amount, the effects on cavity is not significant. Finally, the mechanism of internal erosion and cavity formation are interpreted from the microscopic and macroscopic aspects.

This work is part of an ambitious project aiming to manufacture epoxy-glass leaf spring by microwave processing. Physical properties of final products to be manufactured, in particular the mechanical properties, are directly dependent on uniform repartition of microwave source heating during the treatment. The major problem in microwave processing, however, is attenuation of microwave source. We propose Dielectric Effect of Attenuation Inversion of the Electromagnetic Waves (DEAI) as a new way for uniform treatment of epoxy glassmicrowave energy. This solution utilizes dielectric properties of the mold to control the microwave heat source attenuation into the composite to be treated. Electromagnetic modelling of microwave process was carried out and validated by experimental results. The results show that microwave source heating attenuation can be controlled and inversed. We demonstrated uniform treatment on epoxy-glass parts ca. 100 cm long by means of compensation of microwave source attenuation.

In all process based in powder and in particular in the rotational moulding process, the major physical phenomenon during the flow of the powders is the sintering and grains growth. The sintering is the formation of only one particle starting from two or many particles under the effect of the temperature and the forces of surface tension. We interest in this study in particular at the mechanism of Polyvinylidene fluoride (PVDF) sintering. The results of this study can enable us to maximize our knowledge about sintering mechanism and enable us to determine parameters such as the speed of sintering for the optimization of the process.

Building new regional medical consortium in the model of trusting county-level hospitals to provincial-level large-scale public third-level grade-A hospitals can optimize the allocation of medical resources, promote two-way referral system and rational shunting of patients, and drive multi-sited practice of physicians. Furthermore, it can constantly improve regional medical service level, and achieve the goal of medical reform—comprehensive reform of county-level public hospitals. By introducing general situation where two county-level hospitals are trusted to Hubei Provincial People’s Hospital, this study analyses its operation performance and existing problems, and then puts forwards developmental countermeasures and recommendations for provincial-level hospitals to hold county-level hospitals in trust to build a medical consortium, including driving reorganization of medical resources, making clear roles of all the parties concerned, clarifying internal governance structure of hospitals under trust, reinforcing policy guidance, enhancing internal developmental force of trusteeship, intensifying supporting, and improving functions of medical consortium incrementally.

The direct-billing collaboration between medical institutions and commercial health insurance institutions is an internationally applied method of commercial health insurance claims. This paper discusses the reasons why the direct-billing service of medical institutions is currently limited, including the trivial size of commercial health insurance and hospitals’ concern on cost control, by taking the practice of direct-billing service in a certain hospital in Wuhan as an example. It also summarizes the problems encountered in the operation, including the refusal to medical payment, the risks in excessive medical care, the increasing costs of medical institutions and acting against the equalization principle of medical service. The author then proposes several advices on the direct-billing service operated by hospitals, in terms of strengthening the risk control, taking part into the “Big Data” health management, reforming HIS system united with commercial insurance institutions and adjusting the pricing system of direct-billing service.

Background Overexpression of cyclin D1 dependent kinases 4 and 6 (CDK4/6) is a common feature of many human cancers including leukemia. LEE011 is a novel inhibitor of both CDK4 and 6. To date, the molecular function of LEE011 in leukemia remains unclear. Methods Leukemia cell growth and apoptosis following LEE011 treatment was assessed through CCK-8 and annexin V/propidium iodide staining assays. Cell senescence was assessed by β-galactosidase staining and p16INK4a expression analysis. Gene expression profiles of LEE011 treated HL-60 cells were investigated using an Arraystar Human LncRNA array. Gene ontology and KEGG pathway analysis were then used to analyze the differentially expressed genes from the cluster analysis. Results Our studies demonstrated that LEE011 inhibited proliferation of leukemia cells and could induce apoptosis. Hoechst 33,342 staining analysis showed DNA fragmentation and distortion of nuclear structures following LEE011 treatment. Cell cycle analysis showed LEE011 significantly induced cell cycle G1 arrest in seven of eight acute leukemia cells lines, the exception being THP-1 cells. β-Galactosidase staining analysis and p16INK4a expression analysis showed that LEE011 treatment can induce cell senescence of leukemia cells. LncRNA microarray analysis showed 2083 differentially expressed mRNAs and 3224 differentially expressed lncRNAs in LEE011-treated HL-60 cells compared with controls. Molecular function analysis showed that LEE011 induced senescence in leukemia cells partially through downregulation of the transcriptional expression of MYBL2. Conclusions We demonstrate for the first time that LEE011 treatment results in inhibition of cell proliferation and induction of G1 arrest and cellular senescence in leukemia cells. LncRNA microarray analysis showed differentially expressed mRNAs and lncRNAs in LEE011-treated HL-60 cells and we demonstrated that LEE011 induces cellular senescence partially through downregulation of the expression of MYBL2. These results may open new lines of investigation regarding the molecular mechanism of LEE011 induced cellular senescence. Electronic supplementary material The online version of this article (doi:10.1186/s12935-017-0405-y) contains supplementary material, which is available to authorized users.

Sphingosine kinase 1 (SphK1) is over-expressed in many cancers and therefore serves as a biomarker for cancer prognosis. SKI-5C is a new SphK1 inhibitor, and until now its molecular function in Wilms’ tumor cells remained unknown. Here, using CCK-8 and nude mice experiments we assessed cell growth in Wilms’ tumor cell lines (SK-NEP-1 and G401) in vitro and in vivo. We demonstrated that SphK1 is highly expressed in SK-NEP-1 and G401 cells, and through annexin V/propidium iodide staining and flow cytometry analysis, we detected cell apoptosis. Treatment with SKI-5C inhibited proliferation and induced apoptosis of SK-NEP-1 and G401 cells in a dose-dependent manner. Moreover, SKI-5C treatment inhibited the growth of SK-NEP-1 xenograft tumors in nude mice, with few side effects. Our microarray analysis revealed that SKI-5C-treated SK-NEP-1 cells mostly downregulated PRKACA and significantly inhibited phosphorylation of ERK1/2 and NF-κB p65. These results imply that SKI-5C induces apoptosis of SK-NEP-1 cells through the PRKACA/MAPK/NF-κB pathway. While, further research is required to determine the underlying details, these results provide new clues for the molecular mechanism of cell death induced by SKI-5C and suggest that SKI-5C may act as new candidate drug for Wilms’ tumor.