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Background Pembrolizumab has shown promising results for patients with programmed cell death ligand-1 (PD-L1)-positive solid tumors. However, data on immunotherapy for biliary tract cancers are limited, and biomarkers to identify appropriate candidates for immunotherapy needs to be defined. Methods A total of 153 patients with advanced biliary tract cancers were included (gallbladder n = 48, distal bile duct n = 17, perihilar bile duct n = 32, intrahepatic bile duct n = 49, and ampulla of vater n = 7). Patients were screened for PD-L1 expression by a prototype immunohistochemistry assay (PharmDx). Of PD-L1-positive patients, 12 patients were treated with pembrolizumab. Treatment response was evaluated and correlated with PD-L1 immunohistochemistry, microsatellite instability (MSI) status, tumor-infiltrating lymphocytes (TIL), and CD8+ T cells density. Results 74% (113 of 153) of patients showed tumoral PD-L1 positivity at 1% cut off, and 8.5% (13 of 153) patients showed high PD-L1 expression (tumor proportion score ≧ 50). Of 122 patients with MSI status, only one patient had MSI-H tumor. Twelve patients were treated with pembrolizumab, and all treated patients received prior standard chemotherapy. Two (16.7%) patients had dramatic treatment response, and the rest showed no response. Both two responders had high PD-L1 expression (tumor proportion score ≧ 50), and high PD-L1 expression was associated with treatment response (P = 0.045) None of treated patients was MSI-H. Of two responders, one showed the highest TIL and CD8+ cells density. However, TIL and CD8+ positive cells densities were not significantly associated with treatment response. Conclusions Approximately 10% of patients with advanced biliary tract cancers revealed high PD-L1 expression, and high PD-L1 expression was associated with treatment response of pembrolizumab. MSI-H was rare in biliary tract cancers. We suggest that PD-L1 expression need to be evaluated to identify patients who would benefit from immunotherapy for advanced biliary tract cancers. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

We investigated the inhibitory effects of hesperidin on melanogenesis. To find melanosome transport inhibitor from natural products, we collected the structural information of natural products from Korea Food and Drug Administration (KFDA) and performed pharmacophore-based in silico screening for Rab27A and melanophilin (MLPH). Hesperidin did not inhibit melanin production in B16F10 murine melanoma cells stimulated with α-melanocyte stimulating hormone (α-MSH), and also did not affect the catalytic activity of tyrosinase. But, hesperidin inhibited melanosome transport in melanocyte and showed skin lightening effect in pigmented reconstructed epidermis model. Therefore, we suggest that hesperidin is a useful inhibitor of melanosome transport and it might be applied to whitening agent.

This study investigates the effect of roll surface profile on the centerline segregation of the molten metal (bloom) being solidified in the soft reduction process, where the molten metal (bloom) thickness is reduced consecutively by a set of rolls. The roll surface profiles are convex and flat. Finite element analysis was performed to examine the variations in solidus line contour, the phase state across the bloom cross-section and stress state of the bloom in the mushy zone to the casting direction when high carbon bloom (400 mm in thickness and 500 mm in width) was solidified and plastically deformed at the same time. To verify the finite element analysis results, soft reduction test with an actual bloom caster was also carried out. Results reveal that a convex roll surface profile is much more effective than a flat roll surface profile in decreasing the centerline segregation and the internal cracks in the bloom. The convex roll surface profile compresses the mushy zone from both directions (bloom thickness and width) and subsequently compensates efficiently the solidification shrinkage of molten metal. In addition, the convex roll can save energy required in deforming the bloom in the soft reduction process.

Hot cracking behavior of Fe-Ni alloys was investigated by using a high-speed camera to observe hot cracking in samples that were temperature-gradient heated and tensile deformed. The susceptibility to hot cracking was reliably evaluated based on critical strain and crack propagation length as functions of Ni content and cool side temperature. Grain size and shape in the brittle temperature region depended on liquid boundary migration due to solute diffusion within the liquid boundary under temperature gradient. High susceptibility to hot cracking of Fe-Ni alloys could be explained by the high sulfur segregation near the grain boundary and the large grain size within the solid/liquid coexisting region due to the rapid migration of the liquid boundary.

In this study, the surface crack sensitivities in samples of a Nb-bearing steel and a high Ni grade steel from continuous casting slabs have been examined by simple compression tests at various temperatures between 700-1 100°C using a metallography method to evaluate the severity of surface cracks, and corresponding microstructure in the two grades of steel has been investigated. The results show that most specimen have cracks on the hoop surface after 50% compression in height in the temperature range of interest, and the critical hoop strain obtained from the metallography examination gives a clear cracking tendency for the two grades of steel. Microstructure observation revealed that the static precipitation of TNb(CN) before deformation and thin ferrite film along grain boundaries are important for controlling surface crack sensitivity for the Nb-bearing steel, while coarse grains with flat boundaries, and grain-boundary precipitation of Cu 2 S and flake-like T(CN) at lower temperature, is responsible for the high crack sensitivity in high Ni steel between 700-1 100°C, which implies Cu, S, Ti and N content should be kept as low as possible in this grade of steel, and surface temperatures of continuous casting slabs at the straightening point should be above 970°C for Nb-bearing steel while 980°C for high Ni steel to avoid transverse cracking.

In order to analyze the phenomenon of mold level hunching (MLH) during thin slab casting process, the variation of the mold level and the bulging of strand were measured and analyzed using Fast Fourier Transform (FFT) spectrum analysis. Both of mold level hunching and bulging had the same frequency and the specific frequency corresponded to the main roll pitch of the thin slab caster. The unsteady bulging was found to be a main reason of mold level hunching. The unsteady bulging profile through the full range of the caster and the height of mold level hunching were calculated using a heat transfer model and a continuous beam model. The effects of process variables on mold level hunching and the process condition of reducing mold level hunching were studied. The amount of mold level hunching increased as unsteady bulging increased due to the hunching of casting speed. An aperiodic roll pitch between segments could be effective in reducing mold level hunching.

The movements of the driven rolls were measured during the continuous casting of steel and their fluctuations were compared with other signals such as the casting speed and the mold level. From the observation of large fluctuations in the movements of the driven rolls and the unevenness in the thickness of the solid shell, it is proposed that the unevenness in the thickness of the solid shell is the main reason for unsteady bulging during the casting of medium carbon steel. A two-dimensional model over the successive rolls was used to calculate the bulging profile and its changes with time, during the fluctuations in the casting speed, with the finite element method. As a result, the calculations were in good agreement with the experimental results, and, it could be concluded that the period of unsteady bulging is greatly influenced by the roll pitch, therefore, depends on the locations where different roll pitches occur, and is somewhat affected by casting speed variations. Finally, based on the calculations and the experimental results, the effect of the unsteady bulging on the mold level was discussed.

A computer-aided simulation model which can predict the temperature variation and the microstructural evolution in the process of hot rolling was developed by combining a metallurgical model and a thermal model. The developed model was utilized to analyze the variation of temperature and microstructure during hot rolling process and the mechanical properties of the final products across the transverse direction of a strip. The results of the simulation along with those of the mill trial tests indicated that the mechanical properties across the transverse direction were significantly influenced by the metallurgical inhomogeneities developed in the stage of recrystallization and grain growth during rolling as well as the stage of transformation during cooling. In addition, the effect of the edge shielding during water cooling was quantitatively estimated by the present simulation model and the edge shielding was found to be effective in achieving uniform microstructure and mechanical properties in the hot rolled steels, especially, steels with high hardenability.

A large ingot continuous caster (LICC) has been developed to increase international competitiveness in world steel markets by obtaining a higher yield and reduction of process for steelmaking industries as well as increasing quality by replacing the ingot casting process for production of an extra-large section size strand and high–alloy specialty steel. A conventional continuous caster of an extra-large section size needs a considerable amount of investment compared with a vertical semi–continuous caster such as the LICC. While the LICC is favorable for producing small lots for various steel grades, a conventional continuous caster is suitable for mass production of certain steel grades. The process of a conventional continuous caster and the process of a LICC from a ladle to a strand are similar to each other except for the withdrawer type and the standing below the LICC mold until complete solidification is achieved. At the end of the casting, the LICC bloom moves downward and stops at a certain distance below the mold, and then stands on a vertical position waiting for complete solidification. The LICC bloom is pushed horizontally to the tilter, the purpose of which is to set the bloom in a horizontal position. During the pushing stage, the bloom is separated from a well block. After a hot run of the pilot large ingot continuous caster (LICC), more than 90 heats of 12-ton liquid steel per heat for various steel grades were cast through the caster without any negative impact on the equipment or operations. From the LICC process developed by POSCO, most steel grades such as medium-carbon structural steels, stainless steels and tool steels have been cast successfully and confidently. Their surface and internal quality were found to be better than those of ingots and easily acceptable for the next process. We were able not only to design a continuous casting plant from concept design to detailed design but also to operate a new caster by ourselves. The equiaxed zone was much enlarged and its structure was found to be compactly composed of fine globular crystals. The shrinkage pipe was also greatly reduced from L to 0.23L by top heating and stirring. The casting speed, casting temperature, stirring and temperature gradient of the strand were found to be the “vital few” parameters affecting the internal quality based on investigations of the evaluation results of the macro-structure of the cast TD11 steel. The internal quality of the LICC strand for TD11 steel was much improved by using the optimum combination of these parameters, and the rolled bloom from the LICC strand has excellent internal soundness.