Pancreatic ductal adenocarcinoma with acinar-to-ductal metaplasia-like cancer cells shows increased cellular proliferation.

BACKGROUND/OBJECTIVES: Acinar-to-ductal metaplasia (ADM) has been shown to contribute to the development of pancreatic ductal adenocarcinoma (PDAC) in genetically engineered mouse models, but little is known about whether acinar cell plasticity contributes to carcinogenesis in human PDAC. We aimed to assess whether cancer cells that stain positive for amylase and CK19 (ADM-like cancer cells) are present in human resected PDAC and to investigate their role in tumor progression. METHODS: We immunohistochemically investigated the presence of ADM-like cancer cells, and compared the clinical and histological parameters of PDAC patients with and without ADM-like cancer cells. RESULTS: ADM-like cancer cells were detected in 16 of 60 (26.7%) PDAC specimens. Positive staining for anterior gradient protein 2 (AGR2) was observed in 14 of 16 (87.5%) PDAC specimens with ADM-like cancer cells. On the other hand, the intensity of AGR2 expression (negative, low/moderate or high) was lower in PDAC with ADM-like cancer cells (9/7) than in PDAC without these cells (11/33) (P = 0.032). The presence of ADM-like cancer cells was significantly correlated with increased cell proliferation (P = 0.012) and tended to be associated with MUC1 expression (P = 0.067). CONCLUSIONS: These results indicated that acinar cells may act as the origin of human PDAC, and that their presence may be useful for the stratification of human PDAC to predict prognosis.

Magnetochiral Dichroism in a Collinear Antiferromagnet with No Magnetization.

We show the directional dichroism in a collinear antiferromagnet MnTiO_{3}. The dichroism between two distinctive antiferromagnetic states with opposite signs of staggered magnetic moments can be regarded as magnetochiral dichroism in the absence of external fields. Electric-field reversal of antiferromagnetic domain causes a change in the absorption intensity of unpolarized light around 2.15 eV. The difference in optical absorption between two antiferromagnetic states is reversed for the light propagating in the opposite direction. The absorption coefficient displays a hysteretic behavior for a cycle of sweeping the external electric or magnetic field.

Ir-Catalyzed Synthesis of Substituted Tribenzosilepins by Dehydrogenative C-H/Si-H Coupling.

The Ir-catalyzed intramolecular reaction of 2',6'-diaryl-2-(hydrosilyl)biphenyls gave substituted tribenzosilepins by direct dehydrogenative C-H/Si-H coupling. This is the first example of catalytic construction of the tribenzosilepin skeleton. Enantiomerically pure tribenzosilepin was prepared by optical resolution using chiral HPLC, and its inversion barrier was calculated by measurement of rate of racemization using the Eyring kinetic equation under heating conditions.

Catalytic and Enantioselective Synthesis of Chiral Multisubstituted Tribenzothiepins by Intermolecular Cycloadditions.

The first catalytic and highly enantioselective synthesis of tribenzothiepin derivatives was achieved. Two types of intermolecular cycloadditions using either diphenyl-sulfide-tethered diynes or 2-phenyl sulfanylbenzene-tethered diynes with a monoalkyne successfully gave chiral multisubstituted tribenzothiepins in good to excellent ee values under mild conditions. The inversion energy of this saddle-shaped molecule was calculated by measurement of the racemization rate of chiral tribenzothiepins using the Eyring kinetic equation under heating conditions. The present protocol could also be used to prepare a chiral tribenzoselenepin.

Inhibition of Distinct Proline- or N-Acetylglucosamine-Induced Hyphal Formation Pathways by Proline Analogs in Candida albicans.

Candida albicans undergoes a yeast-to-hyphal transition that has been recognized as a virulence property as well as a turning point leading to biofilm formation associated with candidiasis. It is known that yeast-to-hyphal transition is induced under complex environmental conditions including temperature (above 35°C), pH (greater than 6.5), CO2, N-acetylglucosamine (GlcNAc), amino acids, RPMI-1640 synthetic culture medium, and blood serum. To identify the hyphal induction factor in the RPMI-1640 medium, we examined each component of RPMI-1640 and established a simple hyphal induction condition, that is, incubation in L-proline solution at 37°C. Incubation in GlcNAc solution alone, which is not contained in RPMI-1640, without any other materials was also identified as another simple hyphal induction condition. To inhibit hyphal formation, proline and GlcNAc analogs were examined. Among the proline analogs used, L-azetidine-2-carboxylic acid (AZC) inhibited hyphal induction under both induction conditions, but L-4-thiazolidinecarboxylic acid (T4C) specifically inhibited proline-induced hyphal formation only, while α-N-methyl-L-proline (mPro) selectively inhibited GlcNAc-induced hyphal formation. Hyphal formation in fetal bovine serum was also inhibited by AZC or T4C together with mPro without affecting the proliferation of yeast form. These results indicate that these proline analogs are ideal inhibitors of yeast-to-hyphal transition in C. albicans.

Farnesol, a morphogenetic autoregulatory substance in the dimorphic fungus Candida albicans, inhibits hyphae growth through suppression of a mitogen-activated protein kinase cascade.

Candida albicans grew in hyphal form in RPMI1640, however, addition of farnesol inhibited the formation. Farnesol did not affect the expression of mRNAs related to cAMP-EFG1 pathways. The mRNAs (HST7 and CPH1) in mitogen activated protein kinase (MAP) cascades were decreased in farnesol-treated cells, but CST20 was not. Furthermore, expression of general amino acid permease 1 (GAP1) was decreased by farnesol. We concluded that farnesol inhibits a MAP kinase cascades, and the suppression is a cause of interruption of hyphae formation.

Role of Ca2+/calmodulin signaling pathway on morphological development of Candida albicans.

A human fungal pathogen, Candida albicans, varies from the yeast form to the hyphal form due to various external signals. This morphogenetic transformation has been implicated in the development of pathogenicity. In this report, we show that calmodulin inhibitors (TFP and W-7) and an adenylatecyclase inhibitor (MDL-12-330A) suppressed the hyphae formation of C. albicans. Furthermore, the expression of hyphae-specific mRNAs located downstream from the RAS1-cAMP pathway was inhibited by these inhibitors. Suppression of hyphae formation by TFP or W-7 was not inhibited by the addition of cAMP, and these inhibitors did not affect the amount of cAMP in C. albicans. These results suggest that the Ca2+/calmodulin pathway contributes to hyphae formation and is related to the RAS1-cAMP pathway.