GNAS(R201H) and Kras(G12D) cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm.

Intraductal papillary mucinous neoplasm (IPMN), the most common pancreatic cystic neoplasm, is known to progress to invasive ductal adenocarcinoma. IPMNs commonly harbor activating somatic mutations in GNAS and KRAS, primarily GNAS(R201H) and KRAS(G12D). GNAS encodes the stimulatory G-protein α subunit (Gsα) that mediates a stimulatory signal to adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP), subsequently activating cAMP-dependent protein kinase A. The GNAS(R201H) mutation results in constitutive activation of Gsα. To study the potential role of GNAS in pancreatic tumorigenesis in vivo, we generated lines of transgenic mice in which the transgene consisted of Lox-STOP-Lox (LSL)-GNAS(R201H) under the control of the CAG promoter (Tg(CAG-LSL-GNAS)). These mice were crossed with pancreatic transcription factor 1a (Ptf1a)-Cre mice (Ptf1a(Cre/+)), generating Tg(CAG-LSL-GNAS);Ptf1a(Cre/+) mice. This mouse line showed elevated cAMP levels, small dilated tubular complex formation, loss of acinar cells and fibrosis in the pancreas; however, no macroscopic tumorigenesis was apparent by 2 months of age. We then crossed Tg(CAG-LSL-GNAS);Ptf1a(Cre/+) mice with LSL-Kras(G12D) mice, generating Tg(CAG-LSL-GNAS);LSL-Kras(G12D);Ptf1a(Cre/+) mice. We used these mice to investigate a possible cooperative effect of GNAS(R201H) and Kras(G12D) in pancreatic tumorigenesis. Within 5 weeks, Tg(CAG-LSL-GNAS);LSL-Kras(G12D);Ptf1a(Cre/+) mice developed a cystic tumor consisting of marked dilated ducts lined with papillary dysplastic epithelia in the pancreas, which closely mimicked the human IPMN. Our data strongly suggest that activating mutations in GNAS and Kras cooperatively promote murine pancreatic tumorigenesis, which recapitulates IPMN. Our mouse model may serve as a unique in vivo platform to find biomarkers and effective drugs for diseases associated with GNAS mutations.

The use of Er:YAG, Nd:YAG and Ga-Al-As lasers in periapical surgery: a 3-year clinical study.

OBJECTIVES: In an attempt to increase the successful rate of endodontic surgical procedures this study proposes the use of an association of three lasers in apicectomy: Er:YAG laser, (wavelength 2.94 microm pulse mode), Nd:YAG laser (wavelength 1.064 microm, pulse mode), and Ga-Al-As laser, (wavelength of 790 nm, continuous wave). BACKGROUND DATA: Previous studies have shown the low success rate of apicectomy by conventional methods due to the presence of remaining bacteria in the surgical site. METHODS: The Er:YAG laser was used to perform osteotomy and root resection without vibration, discomfort, less contamination of the surgical site, and no smear-layer on the dentine surface. The Nd:YAG laser irradiation through a fiber performed sealing of the dentinal tubules and bacterial reduction of the cavity bone. In addition, the improvement of healing and better post-operative achieved with the Ga-Al-As laser encourages the use of those lasers in periapical surgeries. RESULTS: Three years follow-up examination of the clinical case showed radiographically significant decrease of the radiolucent periapical area and no clinical signs and symptoms. CONCLUSION: The outcome of this clinical case indicates that the use of those lasers could be considered an alternative, suitable, and useful method to perform an apicectomy.