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Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.

The promyelocytic leukemia (PML) gene is a tumor suppressor gene. It was first identified in acute promyelocytic leukemia, in which it is fused to retinoic acid receptor α by the (15;17) chromosomal translocation. The function of the PML protein is frequently lost or aberrant in human solid tumors. In human ovarian carcinoma tissue, PML detected by immunohistochemistry was highly expressed. A PML-silencing vector, pSRG-shPml, was constructed and used to transfect human ovarian cancer cells. Cells were cultured and selected with puromycin for 10-15 days, and then the PML mRNA expression levels were detected by RT-qPCR and immunofluorescence. Proliferation and clone number of PML-depleted cells were detected using MTT assay and colony-forming assay. The protein expression associated with DNA damage and apoptosis was assessed in PML-depleted cells using western blot analysis and immunofluorescence. The results showed that PML was highly expressed in human ovarian tissue. The proliferation and colony formation of ovarian cancer cells were significantly inhibited after PML was depleted. Western blot analysis and immunofluorescence revealed that p-H2AX and cleaved caspase-3 expression significantly increased after PML silencing. PML was located in the nucleus, and it formed foci after X-ray irradiation. PML foci increased significantly with increasing irradiation doses.

Background The death-domain-associated protein (DAXX) was originally identified as a protein that binds to the transmembrane death receptor FAS and enhances both FAS-induced and transforming growth factor-β-dependent apoptosis. In a previous study, we found that nude mice injected with DAXX-overexpressing cells (ES-2-DAXX) accumulated large concentrations of first-generation ascites cells (I ascites cells). The role of DAXX in the development of ascites is unknown. The aim of this study was to analyze the effect of DAXX on proliferation and migration of ascites cells in ovarian cancer in vitro and in vivo. Methods Nude mice were housed in cages with a 14:10 h light:dark cycle; water and food were provided ad libitum. ES-2-DAXX cells (1×106) were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, I ascites cells were collected. The I ascites cells were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, II ascites cells were collected and cultured. Ascites cell survival, migration, and colony formation were measured using colony formation and cell growth assays. Immunofluorescent staining revealed the co-localization of DAXX and promyelocytic leukemia protein (PML) in ascites cell nuclei. Western blotting and immunohistochemistry showed that extracellular signal-related kinase (p-ERK) 1/2 and CEBP-β were highly expressed in tumor tissues formed by II ascites cells. Through immunoprecipitation, we also found that DAXX can interact with CEBP-β. Results DAXX enhanced ascites cell survival, migration, and colony formation. DAXX and PML nuclear foci dramatically increased in a passage-dependent manner in ascites cells, DAXX promoted the tumor growth of ascites cells in vivo, increased ascites cell proliferation in vivo, and enhanced ascites cell survival and migration by activating the ERK signalling pathway and integrating with CEBP-β. Conclusions DAXX can interact with CEBP-β. DAXX can induce ovarian cancer ascites formation by activating the ERK signal pathway and binding to CEBP-β.

Tet methylcytosine dioxygenases (TETs) catalyze the oxidative reactions of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). However, TET1 roles in ovarian cancer cell growth are unknown. Here, we show that ectopic expression of TET1 increased 5hmC levels, and inhibited proliferation and colony formation in ovarian cancer cell lines. Furthermore, in vitro and in vivo functional studies demonstrated that TET1 overexpression is necessary for the suppression of ovarian cancer growth, whereas depletion of TET1 expression had the opposite effect. Furthermore, the results of RNA-seq and qRT-PCR analyses identified a tumor suppressor, Ras association domain family member 5 (RASSF5), as the key downstream target of TET1. TET1 promotes RASSF5 expression by demethylating a CpG site within RASSF5 promoter. Up-regulated RASSF5 expression leads to the suppression of ovarian cancer cells growth. Additionally, we demonstrated that inhibition of CUL4-DDB1 ubiquitin ligase complex decrease 5hmC levels in ovarian cancer cells. These results provide new insights into the understanding of how ovarian cancers develop and grow, and identify TET1 as a key player in this process.

In order to study the shear resistance and design method of hybrid fiber (steel fiber and polypropylene fiber) reinforced high performance concrete deep beams, the shear tests were conducted according to the orthogonal experimental design. The contributory factors such as the characteristic parameters of steel fiber (types, volume fraction, aspect ratio), the volume fraction of polypropylene fiber, the ratio of web horizontal reinforcement and the ratio of web vertical reinforcement were analyzed. Results illuminate that shear failure mode of hybrid fiber reinforced HPC deep beams are splitting failure and diagonal compression failure. Hybrid fiber can notably increase the diagonal cracking strength and shear strength of HPC deep beams. The diagonal cracking strength is increased by 5.6%~83.8% while the shear strength is increased by15.6%~35.2%. A formula to calculate the shear resistance of hybrid fiber reinforced HPC deep beams is put forward based on spatial strut-and-tie mode and splitting failure. Meantime test verification is carried out and the calculated results are satisfied.

18 different groups of hybrid fiber (steel fiber and polypropylene fiber) reinforced HPC deep beams and 2 groups of HPC deep beams without fiber were made. The shear tests under the static load and the numerical simulation by ABAQUS were conducted. Good agreement are found between test results and simulation results.The results of finite element analysis indicate that with the increment of reinforcement ratio, the shear capacity of hybrid fiber reinforced HPC deep beams increases, but quite limited. The variation of shear capacity of hybrid fiber reinforced HPC deep beams is not obvious as the shear-span ratio changes (when ) . The increment of span-depth ratio can improve the shear capacity of hybrid fiber reinforced HPC deep beams, but only with small amplitude. All these regularities are similar to those of ordinary reinforced concrete deep beams.

The shear behavior of 18 different groups of hybrid fiber (steel fiber and polypropylene fiber) reinforced HPC deep beams and 2 groups of HPC deep beams without fiber were discussed through experimental study and nonlinear finite element analysis. The shear tests were made under the static load and the finite element analysis software ABAQUS was used in numerical simulation. Results illuminate that hybrid fiber can significantly increase the diagonal cracking load and the ultimate shear load of deep beams although it can not change the brittleness of shear damage. Good agreement are found between test results and simulative results, including failure mode of hybrid fiber reinforced HPC deep beams, load-displacement curves, stress distribution of steel bars and concrete, etc.

The shear tests were made on 18 different groups of deep beams with steel fiber and polypropylene fiber according to the orthogonal experimental design. For comparison, 2 groups of high performance concrete deep beams without fiber were conducted. Shear ductility and deformation performance of deep beams were analyzed quantitatively. Results illuminate that failure mode of high performance concrete shear deep beam is splitting failure, while hybrid fiber reinforced HPC shear deep beam has two failure modes (splitting failure and diagonal compression failure). The mixing of hybrid fiber makes rigidity of HPC deep beam increase obviously, the strain of web horizontal reinforcement and web vertical reinforcement decrease significantly. The catastrophe of strain of cracked concrete is also obviously smaller and the descending step of loaddeflection curve is flatter when adding hybrid fiber. Hybrid fiber can greatly increase shear ductility of deep beams and shear ductility is at the most increased by 40.7% whereas it can not change the brittleness of shear damage radically. The volume fraction of steel fiber plays the most important role in shear ductility whereas the shape of steel fiber has minimum effect among analyzed six factors.

In order to investigate the effect of steel fiber and polypropylene fiber on shear behavior of HPC deep beams, the shear tests were conducted on 18 different groups of deep beams with steel fiber and polypropylene fiber and 2 groups of HPC deep beams without fiber according to the orthogonal experiment. 6 factors, including the shape of steel fiber, the volume fraction of steel fiber, the aspect ratio of steel fiber, the volume fraction of polypropylene fiber, the ratio of web horizontal reinforcement and the ratio of web vertical reinforcement, were compared by direct-viewing analysis. Results illuminate that hybrid fibers greatly increase the diagonal cracking strength and shear strength of HPC deep beams. The aspect ratio of steel fiber plays the most important role in diagonal cracking strength whereas the ratio of web vertical reinforcement has minimum effect. Meanwhile the ratio of web horizontal reinforcement plays the most important role in shear strength whereas the volume fraction of polypropylene fiber has minimum effect. An anti-cracking capacity for inclined section calculation formula and a shear bearing capacity calculation formula for hybrid fiber reinforced HPC deep beams are put forward based on current code. Meantime test verification is carried out and the calculated results are satisfied.

To determine the efficacy of pyridoxine in treating seizures, 90 infants and children with recurrent convulsions primarily due to acute infectious diseases were enrolled in the present study. Forty patients were treated with high-dose pyridoxine (30 or 50 mg/kg/day) by intravenous infusion, and 50 subjects served as controls. Antiepileptic drugs and other therapies were similar in the two groups except for pyridoxine. Clinical efficacy criteria were based on the frequency of convulsions per day and on the duration of individual seizures after therapy was initiated. The results indicated that total response rates in the pyridoxine group and control group were 92.5% and 64%, respectively (chi-square = 14.68, P < .001). After initiation of therapy, seizures resolved after 2.4 +/- 1.4 days in the pyridoxine group and after 3.7 +/- 2.0 days in the control group (t = 3.67, P < .001). No adverse effects of pyridoxine were apparent during the observation period. We conclude that pyridoxine is an effective, safe, well-tolerated, and relatively inexpensive adjunct to routine antiepileptic drugs for treatment of recurrent seizures in children.