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Background and aims Transarterial chemoembolization (TACE) is a standard locoregional therapy for patients with hepatocellular carcinoma (HCC) patients with a variable overall response in efficacy. We aimed to identify key molecular signatures and related pathways leading to HCC resistance to TACE, with the hope of developing effective approaches in preselecting patients with survival benefit from TACE. Approach and results Four independent HCC cohorts with 680 patients were used. MicroRNA (miRNA) transcriptome analysis in patients with HCC revealed a 41-miRNA signature related to HCC recurrence after adjuvant TACE, and miR-125b was the top reduced miRNA in patients with HCC recurrence. Consistently, patients with HCC with low miR-125b expression in tumor had significantly shorter time to recurrence following adjuvant TACE in two independent cohorts. Loss of miR-125b in HCC noticeably activated the hypoxia inducible factor 1 alpha subunit (HIF1α)/pAKT loop in vitro and in vivo. miR-125b directly attenuated HIF1α translation through binding to HIF1A internal ribosome entry site region and targeting YB-1, and blocked an autocrine HIF1α/platelet-derived growth factor β (PDGFβ)/pAKT/HIF1α loop of HIF1α translation by targeting the PDGFβ receptor. The miR-125b-loss/HIF1α axis induced the expression of CD24 and erythropoietin (EPO) and enriched a TACE-resistant CD24-positive cancer stem cell population. Consistently, patients with high CD24 or EPO in HCC had poor prognosis following adjuvant TACE therapy. Additionally, in patients with HCC having TACE as their first-line therapy, high EPO in blood before TACE was also noticeably related to poor response to TACE. Conclusions MiR-125b loss activated the HIF1α/pAKT loop, contributing to HCC resistance to TACE and the key nodes in this axis hold the potential in assisting patients with HCC to choose TACE therapy.

ObjectsThe incidence of hepatocellular carcinoma (HCC) shows an obvious male dominance in rodents and humans. We aimed to identify the key autosomal liver-specific sex-related genes and investigate their roles in hepatocarcinogenesis.DesignTwo HCC cohorts (n=551) with available transcriptome and metabolome data were used. Class comparisons of omics data and ingenuity pathway analysis were performed to explore sex-related molecules and their associated functions. Functional assays were employed to investigate roles of the key candidates, including cellular assays, molecular assays and multiple orthotopic HCC mouse models.ResultsA global comparison of multiple omics data revealed 861 sex-related molecules in non-tumour liver tissues between female and male HCC patients, which denoted a significant suppression of cancer-related diseases and functions in female liver than male. A member of cytochrome P450 family, CYP39A1, was one of the top liver-specific candidates with significantly higher levels in female vs male liver. In HCC tumours, CYP39A1 expression was dramatically reduced in over 90% HCC patients. Exogenous CYP39A1 significantly blocked tumour formation in both female and male mice and partially reduced the sex disparity of hepatocarcinogenesis. The HCC suppressor role of CYP39A1 did not rely on its known P450 enzyme activity but its C-terminal region, by which CYP39A1 impeded the transcriptional activation activity of c-Myc, leading to a significant inhibition of hepatocarcinogenesis.ConclusionsThe liver-specific CYP39A1 with female-preferential expression was a strong suppressor of HCC development. Strategies to up-regulate CYP39A1 might be promising methods for HCC treatment in both women and men in future.

In the tensioning construction of continuous box girder bridge strengthened by a stay cable system, local stress concentration of steel joist and bracket is easy to be caused. This paper studies the stress and deformation of key section of steel joist and bracket by combining with real bridge test. The results show that the maximum stress of steel joist and bracket is less than the allowable stress. When the tensioning force value is 2.66 times of the completion cable force, the bottom plate first reaches the yield strength, and the stress change law of the bracket is not strong. The mid-span deformation of the steel joist in the early period of tensioning is gentle, and the change in the later period is large. When the tensioning force reaches the completion cable force, the value is about 1/400 of the span. In the early tensioning period, the relative displacement between the steel bracket and the girder is large, but the change in the later tensioning period is not large.

Aim: Type VI secretion systems (T6SS) play key roles in bacterial pathogenesis, but their evolutionary features remain largely unclear. In this study, we conducted systematic comparisons among the documented T6SSs in Salmonella and determined their structural diversity, phylogenetic distribution and lineage-specific properties. Materials & methods: We screened 295 Salmonella genomes for 13 T6SS core components by hidden Markov models and identified 363 T6SS clusters covering types i1, i2, i3 and i4a. Results: Type i3 and i4a T6SSs were restricted to Salmonella enterica subspecies enterica and Salmonella bongori, respectively. whereas type i2 T6SSs were conserved between S. enterica subspecies, arizonae and diarizonae. S. enterica subspecies salamae, indica and houtenae harbored only type i1 T6SSs, which had wide distribution and high sequence diversity. Conclusion: The diverse Salmonella T6SSs have undergone purifying selection pressures during the bacterial evolution and may be involved in host adaptation.

The Dongming Yellow River Highway Bridge (75+7×120+75 m), is a large span prestressed concrete rigid frame and continuous combination beam bridge, which was the first bridge strengthened by cable-stayed system in China. Using towers and stay cable system, the main bridge was transformed to provide vertical support with superstructure. For the foundation reconstruction, bored piles were constructed as new pile foundations on both sides of the original pile foundations. After cofferdam pumping, to ensure the positioning of the protective tubes, the reinforcing bars, concrete cover and concrete piles left in the river bed were removed by using brush drilling rigs, long arm digging machines and frogmen, while the "U-tube" method was used to grout at the bottom of the piles. The diamond wire saw cutting technology was adopted to complete the transformation of the old caps and insert shear nails. Using the post-pouring strip temporary shields, the new caps and old caps were connected until the tensioning of the cables was finished. To ascertain the arrangement of the reinforcement on the floor and the prestressed reinforcement, and then stick the positioning plates on the floors, bonded rebars holes were drilled utilizing the hydraulic core drill that was made. The joists and the brackets are manufactured by the factory and assembled in the construction site. Gantry cranes and angle fine-tuning devices were used to install the joists and brackets, and then the connecting bolts were inserted. Concurrently, material was transported through the hole in the roof of the middle-span, and the steel supports within the box were installed. From the middle towers to the side towers, from the short cables to the long cables, cables were tensioned by batches and levels with constant monitoring throughout the whole process of this tensioning construction. Finally, the external prestressed strands inside the box were adjusted and the bridge deck construction was completed.