Novel protein kinase cAMP-Activated Catalytic Subunit Alpha (PRKACA) inhibitor shows anti-tumor activity in a fibrolamellar hepatocellular carcinoma model.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is known as a highly aggressive liver cancer that typically affects young adults without virus infection. Since this type of cancer does not respond to chemotherapy, surgery is the only known effective therapeutic option. Most FL-HCC patients express the fusion gene DNAJB1-PRKACA, which has been recognized as the signature of FL-HCC. It has also been reported that PRKACA kinase activity is essential for its oncogenic activity, suggesting that PRKACA kinase inhibition could be considered as an useful therapeutic target. In this study, we established an evaluation system for PRKACA kinase inhibitors and synthesized DS89002333, a novel PRKACA inhibitor. DS89002333 showed potent PRKACA inhibitory activity and inhibited fusion protein-dependent cell growth both in vitro and in vivo. Furthermore, this compound showed anti-tumor activity in an FL-HCC patient-derived xenograft model expressing the DNAJB1-PRKACA fusion gene. Our data suggest that DS89002333 could be considered as a potential therapeutic agent for FL-HCC.

Relationship between the three-dimensional structure of the human plantar epidermis and the dermoscopic patterns seen in melanocytic nevi.

OBJECTIVE: Our aim was to investigate the relationship between the distribution of the dermoscopic patterns seen in plantar melanocytic nevi and the 3-dimensional structures of the epidermis. METHODS: The precise locations of 69 melanocytic nevi on the sole and the border areas were investigated, with attention paid to each dermoscopic pattern. In addition, the basal surfaces of the plantar epidermis from 14 anatomical areas were observed by scanning electron microscopy (SEM). RESULTS: In the weight-bearing area, melanocytic nevi with a fibrillar pattern were preferentially observed. Those with a lattice-like pattern were observed in the arch area, whereas those with a crista reticulated pattern were seen in the border area. On SEM observations, transverse ridges formed a couple of parallel lamellae on the crista profunda limitans (limiting ridges). Between the limiting ridges and the crista profunda intermedia (intermediate ridges), the transverse ridges had different shapes according to the anatomical location of the sole. CONCLUSION: These results suggest that the characteristic dermoscopic patterns seen in plantar melanocytic nevi simulate the arrangement of transverse ridges.

Correspondence between dermoscopic features and epidermal structures revealed by scanning electron microscope.

It is already known that some typical dermoscopic patterns seen in melanocytic nevi on the sole have their own favorite site. In the weight-bearing area, melanocytic nevi with a parallel furrow pattern were preferentially observed. Those with a lattice-like pattern were observed in the arch area, whereas those with a crista reticulated pattern were seen in the border area. To investigate the relationship between the distribution of the dermoscopic patterns seen in plantar melanocytic nevi and the 3-D structures of the epidermis, the basal surfaces of the plantar epidermis from 14 skin lesions were observed by scanning electron microscopy (SEM). Our SEM observations revealed that transverse ridges formed a couple of parallel lamellae on the crista profunda limitans (limiting ridges). Between the limiting ridges and the crista profunda intermedia (intermediate ridges), the transverse ridges had different shapes according to the anatomical location of the sole. From these results, it was suggested that the characteristic dermoscopic patterns seen in acquired and junctional melanocytic nevi on the sole simulate the arrangement of transverse ridges.