SUMMARY We performed integrated genomic, transcriptomic and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1 and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1 and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

Disrupted-in-schizophrenia 1 (DISC1) has emerged as a schizophrenia-susceptibility gene affecting various neuronal functions. In this study, we characterized Mitofilin, a mitochondrial inner membrane protein, as a mediator of the mitochondrial function of DISC1. A fraction of DISC1 was localized to the inside of mitochondria and directly interacts with Mitofilin. A reduction in DISC1 function induced mitochondrial dysfunction, evidenced by decreased mitochondrial NADH dehydrogenase activities, reduced cellular ATP contents, and perturbed mitochondrial Ca 2+ dynamics. In addition, deficiencies in DISC1 and Mitofilin induced a reduction in mitochondrial monoamine oxidase-A activity. The mitochondrial dysfunctions evoked by the deficiency of DISC1 were partially phenocopied by an overexpression of truncated DISC1 that is associated with schizophrenia in human. DISC1 deficiencies induced the ubiquitination of Mitofilin, suggesting that DISC1 is critical for the stability of Mitofilin. Finally, the mitochondrial dysfunction induced by DISC1 deficiency was partially reversed by coexpression of Mitofilin, confirming a functional link between DISC1 and Mitofilin for the normal mitochondrial function. According to these results, we propose that DISC1 plays essential roles for mitochondrial function in collaboration with a mitochondrial interacting partner, Mitofilin.IMMT | mitochondrial dysfunctions | hyperdopaminergia | calcium buffering | psychiatric disorders

Preoperative CA19-9 level was a valuable clinical factor for predicting histopathologic invasiveness as well as clinical outcome. An adequate resection margin was the only modifiable factor by a surgeon during hepatic resection for ICC.

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Laser treatment using low fluence for melasma was previously introduced to overcome postinflammatory hypermelanosis after Q-switched laser therapy. However, research on the mechanism of this treatment is very limited. In this study, a collimated low fluence 1064 nm Q-switched Nd:YAG laser with a pulse width of <7 ns was applied using top-hat beam mode. The aim of this study was to investigate the mode of action of this laser treatment through electron microscopy. The effectiveness of this treatment was confirmed by clinical photos, melasma area and severity index and spectrophotometer. To understand the mode of action, the three-dimensional structure of melanocytes in the epidermis was analyzed using serial images acquired by a 3VIEW surface block face scanning electron microscope. In the epidermis, after laser treatment, fewer dendrites in the melanocytes were observed compared with pretreatment. In addition, ultrastructural changes in the melanosome were studied using transmission electron microscopy, which showed that laser treatment caused selective photothermolysis on Stage IV melanosome. Therefore, this treatment should be regarded as an effective method for treating melasma through subcellular-selective photothermolysis.