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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.

Background Retinoids have been used for the treatment of skin disorders such as acne, psoriasis, and photoaging. However, despite their beneficial effects, topical retinoids often cause severe local irritation called retinoid dermatitis. We previously developed a novel vitamin A derivative, retinyl retinoate, which induces less irritation and affords excellent tolerance. In this study, we examined whether co-treatment with topical peroxisome proliferator-activated receptor-α (PPARα) agonists (e.g. WY14643) reduce retinoid dermatitis in hairless mouse skin. Methods The effect of concomitant treatment with a PPARα agonist on retinoid dermatitis in hairless mouse epidermis was evaluated by measuring transepidermal water loss, epidermal histology, and cytokine expression. Results Retinyl retinoate induced less severe retinoid dermatitis than retinoic acid. Topical application of a PPARα agonist improved the stratum corneum structure and function, reduced mRNA expression of interleukin (IL)-1α, tumor necrosis factor-α and IL-8, and inhibited ear edema induced by retinoic acid or retinyl retinoate. Conclusions Our results indicate that PPARα agonists can potentially be used to improve retinoid dermatitis. We suggest that co-treatment with retinyl retinoate and a PPARα agonist may reduce or prevent detrimental alterations in retinoid-treated skin.

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.

To develop a novel skin depigmenting agent from natural sources, the inhibition of melanogenesis by the Chinese herb, Sterculia lynchnophera (SL), was evaluated. Treatment of B16F10 melanoma cells and melan-a cells with SL exhibited a 32.9% and 68.2% inhibition of melanin synthesis without cytotoxicity at a concentration of 200 μg/ml, respectively. This herb possessed a high free radical scavenging activity with IC50=11.02 μM. The methanol extract of SL slightly inhibited in vitro mushroom tyrosinase activity (23.4% at a concentration of 200 μg/ml) and had a significant inhibitory effect on cellular tyrosinase activivity (48.65% and 88.56% inhibition at the concentration 200 μg/ml in B16F10 cells and C57BL/6 melan-a cells, respectively). From the western blotting results, SL inhibited the expression of tyrosinase and tyrosinase related protein 1 (TRP-1). Taken together, we suggest that SL may be a safe and effective depigmentation agent.

Obesity, which is related to metabolic syndrome and is associated with liver disease, represents an epidemic problem demanding effective therapeutic strategies. Evidence shows that the Wnt/β-catenin pathway is closely associated with obesity and that small molecules regulating the Wnt/β-catenin pathway can potentially control adipogenesis related to obesity. Eleven plant extracts activating the Wnt/β-catenin pathway were screened by using HEK 293-TOP cells retaining the Wnt/β-catenin signaling reporter gene. An extract of Persicaria hydropiper (L.) Spach was found to activate Wnt/β-catenin signaling. P. hydropiper is grown worldwide in temperate climates and is found widely in Southeast Asia. The P. hydropiper extract inhibited the differentiation of adipocyte 3T3-L1 cells. Isoquercitrin and isorhamnetin, constituents of P. hydropiper, also activated Wnt/β-catenin signaling and suppressed the differentiation of 3T3-L1 cells. These results indicate that isoquercitrin in P. hydropiper suppresses the adipogenesis of 3T3-L1 cells via the inhibition of Wnt/β-catenin signaling. P. hydropiper and isoquercitrin may therefore be potential therapeutic agents for obesity and its associated disorders.

Hyaluronan, a non-sulfated glycosaminoglycan, retains water, maintains the extracellular spaces and facilitates the transport of ion solutes and nutrients. Hyaluronan is closely involved in keratinocyte proliferation, migration and differentiation. The synthesis of hyaluronan in vitro can be stimulated by several growth factors, including retinoids, dibutyryl cyclic adenosine monophosphate and peroxisome proliferator-activated receptor-alpha agonist. In this study, we examined retinyl retinoate (a novel retinol derivative) on hyaluronan expression in primary human keratinocytes and in hairless mouse epidermal skin. Histochemistry using hyaluronan-binding protein revealed that topical retinyl retinoate increased the intensity of hyaluronan staining in murine skin. Moreover, topical retinyl retinoate increased CD44 (hyaluronan receptor) expression. Using reverse transcription polymerase chain reaction, we assessed the expression level of the hyaluronan synthase 2 (HAS2) gene in primary human keratinocytes and in hairless mouse epidermal skin. We found that retinyl retinoate upregulated mouse HAS2 and human HAS2 mRNA. Application of retinyl retinoate induced increasing transepidermal water loss less than retinol, retinoic acid and retinaldehyde. Taken together, we suggest that retinyl retinoate is more effective on hyaluronan production and less of an irritant than other retinoids.

A new hybrid, retinyl retinoate 1, was synthesized with a condensing reaction between retinol and retinoic acid to improve the photo-stability, and the in vitro biological activity of the hybrid was analyzed. This retinol derivative had enhanced thermal stability and decreased photosensitivity, and exhibited decreased cell toxicity compared to that of retinol. In addition, RAR activity analysis showed that retinyl retinoate 1 had higher inhibitory activity against c-Jun than retinol and showed superior effects on collagen synthesis compared to retinol. Thus, retinyl retinoate 1 may have the potential to be conveniently used as an additive in cosmetics for prevention and improvement of skin aging and medicines for the treatment of skin troubles due to its excellent stability under severe and accelerated conditions.

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.

We synthesized a novel derivative of a well-known skin-lightening compound niacinamide, N-nicotinoyl dopamine (NND). NND did not show inhibitory effects of tyrosinase and melanin synthesis in B16F10 mouse melanoma cells. However, NND retains high antioxidant activity without affecting viability of cells. In a reconstructed skin model, topical applications of 0.05% and 0.1% NND induced skin lightening and decreased melanin production without affecting the viability and morphology of melanocytes and overall tissue histology. Moreover, no evidence for skin irritation or sensitization was observed when 0.1% NND emulsion was applied onto the skin of 52 volunteers. The effect of NND on skin lightening was further revealed by pigmented spot analyses of human clinical trial. Overall, NND treatment may be a useful trial for skin lightening and treating pigmentary disorders.

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.

Effects of centerline macrosegregation on necking was examined by the stretching experiment for cold rolled P-added extra low carbon steel sheets. The centerline macrosegregated zone containing high concentration of Mn and P was elongated in the rolling process. The elongated macrosegregated zone induced instability in the strain state when the sheet was stretched, thus resulted in the waved sheet surface. The formability of cold rolled steel sheet was deteriorated due to the wave formed by the macrosegregation. The waved surface was thought to be caused by the higher hardness in the macrosegregated zone compared to the segregation free zone. The experiments on the stretching of sheet including macrosegregation showed that the macrosegregation was the important source of instability in that of the cold rolled steel sheets. A 3D FEM analysis was carried out for the quantitative evaluation of waved surface. It was confirmed that the main source of the waved surface was the macrosegregation. Stretching in the transverse direction under the plane strain condition made the cold rolled steel sheet more inhomogeneous than stretching in any other strain condition. The thickness difference in the stretched sheet was linearly increased when the ratio of hardness in the macrosegregated zone to that of the segregation free zone was increased. The macrosegregation formed in the internal crack close to the surface was more harmful to the formability in the cold rolled steel sheet than the centerline macrosegregation.

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.

Obesity, which is related to metabolic syndrome and is associated with liver disease, represents an epidemic problem demanding effective therapeutic strategies. Evidence shows that the Wnt/β-catenin pathway is closely associated with obesity and that small molecules regulating the Wnt/β-catenin pathway can potentially control adipogenesis related to obesity. Eleven plant extracts activating the Wnt/β-catenin pathway were screened by using HEK 293-TOP cells retaining the Wnt/β-catenin signaling reporter gene. An extract of Persicaria hydropiper (L.) Spach was found to activate Wnt/β-catenin signaling. P. hydropiper is grown worldwide in temperate climates and is found widely in Southeast Asia. The P. hydropiper extract inhibited the differentiation of adipocyte 3T3-L1 cells. Isoquercitrin and isorhamnetin, constituents of P. hydropiper, also activated Wnt/β-catenin signaling and suppressed the differentiation of 3T3-L1 cells. These results indicate that isoquercitrin in P. hydropiper suppresses the adipogenesis of 3T3-L1 cells via the inhibition of Wnt/β-catenin signaling. P. hydropiper and isoquercitrin may therefore be potential therapeutic agents for obesity and its associated disorders.

Hyaluronan, a non-sulfated glycosaminoglycan, retains water, maintains the extracellular spaces and facilitates the transport of ion solutes and nutrients. Hyaluronan is closely involved in keratinocyte proliferation, migration and differentiation. The synthesis of hyaluronan in vitro can be stimulated by several growth factors, including retinoids, dibutyryl cyclic adenosine monophosphate and peroxisome proliferator-activated receptor-alpha agonist. In this study, we examined retinyl retinoate (a novel retinol derivative) on hyaluronan expression in primary human keratinocytes and in hairless mouse epidermal skin. Histochemistry using hyaluronan-binding protein revealed that topical retinyl retinoate increased the intensity of hyaluronan staining in murine skin. Moreover, topical retinyl retinoate increased CD44 (hyaluronan receptor) expression. Using reverse transcription polymerase chain reaction, we assessed the expression level of the hyaluronan synthase 2 (HAS2) gene in primary human keratinocytes and in hairless mouse epidermal skin. We found that retinyl retinoate upregulated mouse HAS2 and human HAS2 mRNA. Application of retinyl retinoate induced increasing transepidermal water loss less than retinol, retinoic acid and retinaldehyde. Taken together, we suggest that retinyl retinoate is more effective on hyaluronan production and less of an irritant than other retinoids.

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.