Relevance of pi sigma(*) states in the photoinduced processes of adenine, adenine dimer, and adenine-water complexes

Ab initio calculations and time-resolved photoionization spectroscopy were carried out to characterize the role of the lowest two pi sigma(*) excited states for the photoinduced processes in the adenine monomer, adenine dimer, and adenine-water clusters. The calculations show-with respect to the monomer-a stabilization of 0.11-0.14 eV for the pi sigma(*) states in different isomers of adenine dimer and an even bigger stabilization of 0.14-0.36 eV for isomers of adenine-(H2O)(1) and adenine-(H2O)(3). Hence, the stabilized pi sigma(*) states should play an important role in the excited-state relaxation of partially or fully solvated adenine. This conclusion is supported by experimental results: In the adenine monomer, strong n pi(*) state signals are observed. Those signals are reduced in adenine dimer and vanish in water clusters due to the competing relaxation via the pi sigma(*) states

Dicer Regulates Differentiation and Viability during Mouse Pancreatic Cancer Initiation

<div><p>miRNA levels are altered in pancreatic ductal adenocarcinoma (PDA), the most common and lethal pancreatic malignancy, and intact miRNA processing is essential for lineage specification during pancreatic development. However, the role of miRNA processing in PDA has not been explored. Here we study the role of miRNA biogenesis in PDA development by deleting the miRNA processing enzyme Dicer in a PDA mouse model driven by oncogenic Kras. We find that loss of Dicer accelerates Kras driven acinar dedifferentiation and acinar to ductal metaplasia (ADM), a process that has been shown to precede and promote the specification of PDA precursors. However, unconstrained ADM also displays high levels of apoptosis. Dicer loss does not accelerate development of Kras driven PDA precursors or PDA, but surprisingly, we observe that mouse PDA can develop without Dicer, although at the expense of proliferative capacity. Our data suggest that intact miRNA processing is involved in both constraining pro-tumorigenic changes in pancreatic differentiation as well as maintaining viability during PDA initiation.</p></div

The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN-PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN-PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN-PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets

Dicer loss promotes Kras driven loss of acinar identity and ductal reprogramming.

<p>(<b>A–D</b>) Clusterin (blue) and YFP (green) staining in 3 week old <i>Dicer^Het; YFP</i> (A), <i>Dicer^Homo; YFP</i> (B), <i>Kras; Dicer^Het; YFP</i> (C), and <i>Kras; Dicer^Homo; YFP</i> mice (D). Scale bar 100 µM (<b>E</b>) RT-PCR analysis of Dicer, miRNA-141 and 216b (left), acinar enriched genes Amylase and Mist1 (center), and duct enriched genes CK19 and Sox9 (right) of YFP+, CD49f+, CD133- cells from <i>Dicer^Het; YFP</i> (n = 4), <i>Dicer^Homo; YFP</i> (n = 4), <i>Kras; Dicer^Het; YFP</i> (n = 3), and <i>Kras; Dicer^Homo; YFP</i> (n = 3) mice. Mean ± SD. P-values are calculated from two-tailed, unpaired t-tests comparing <i>Dicer^Het</i> and <i>Dicer^Hom°</i>CK19 and Sox9 expression values.</p