Citations

Abstract The role of the transcription factor GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the GLI1 knockout animal (GKO) with cre-dependent pancreatic activation of oncogenic KRAS concomitant with loss of the tumor suppressor TP53 (KPC). Interestingly, in this model, GLI1 played a tumor protective function, where survival of GKO/KPC mice was reduced compared to KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time-points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and leukopenia. Expression studies identified FAS and FAS ligand as potential mediators of this phenomenon. The FAS /FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation assays identified FAS and FASL as direct targets of GLI1 where GKO/KPC mice showed lower levels of this ligand compared to KPC animals. Furthermore, GLI1 overexpression and knockdown studies demonstrate a key regulatory role for GLI1 in both FAS and FASL expression. Finally, decreased levels of apoptosis were detected in the tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help the design and analysis of trials targeting GLI1-related pathways. Citation Format: Lisa D. Mills, Lizhi Zhang, Ronald J. Marler, Phyllis A. Svingen, Maite Fernandez-Barena, Maneesh Dave, William Bamlet, Robert McWilliams, William A. Faubion, Martin E. Fernandez-Zapico. Loss of GLI1 accelerates pancreatic cancer progression in the KPC mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A76.

Objectives To determine the association between multiple chronic conditions and risk of incident mild cognitive impairment ( MCI ) and dementia. Design Prospective cohort study. Setting Olmsted County, Minnesota. Participants Cognitively normal individuals (N = 2,176) enrolled in the Mayo Clinic Study of Aging ( MCSA ). Measurements Participants were randomly selected from the community, evaluated by a physician, and underwent neuropsychometric testing at baseline and at 15‐month intervals to assess diagnoses of MCI and dementia. Information on International Classification of Diseases, Ninth Revision codes for chronic conditions in the 5 years before enrollment was electronically captured using the Rochester Epidemiology Project medical records linkage system. Multimorbidity was defined as having two or more chronic conditions, and the association between multimorbidity and MCI and dementia was examined using Cox proportional hazards models. Results Of 2,176 cognitively normal participants (mean age ± standard deviation 78.5 ± 5.2; 50.6% male), 1,884 (86.6%) had multimorbidity. The risk of MCI or dementia was higher in persons with multimorbidity (hazard ratio ( HR ) = 1.38, 95% confidence interval ( CI ) = 1.05–1.82) than in those with one or no chronic condition. The HR was of greater magnitude in persons with four or more conditions ( HR = 1.61, 95% CI = 1.21–2.13) than in those with two or three conditions ( HR = 1.03, 95% CI = 0.76–1.39) and for men with multimorbidity( HR = 1.53, 95% CI = 1.01–2.31) than for women with multimorbidity ( HR = 1.20, 95% CI = 0.83–1.74), compared to those with one or no chronic condition. Conclusion In older adults, having multiple chronic conditions is associated with greater risk of MCI and dementia. This is consistent with the hypothesis that multiple etiologies may contribute to MCI and late‐life dementia. Preventing chronic diseases may be beneficial in delaying or preventing MCI and dementia.

BackgroundRecently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi‐incident Mennonite family.MethodsIn the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD).ResultsOur sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed.ConclusionOur results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

AbstractIntroductionRapid eye movement (REM) sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with differences in clinical phenotype, including dementia, autonomic loss, and gait dysfunction. The pathological basis for this remains unclear.MethodsParkinson's disease subjects in a longitudinal clinicopathologic study were screened for probable RBD with the Mayo Sleep Questionnaire. After death, semiquantitative analyses were conducted for synuclein, amyloid, neurofibrillary tangles, and cerebrovascular lesions.ResultsForty cases had probable RBD (PD+RBD), and 41 did not (PD‐RBD). Despite similar age at death (∼80 y) and disease duration (∼14.5 y), PD+RBD had increased synuclein deposition in all regions examined, with nine of 10 regions significantly different. The Lewy body 10‐region total score (scale = 0‐40) was 29.5 in PD+RBD versus 24.5 in PD‐RBD (Cohen‐d effect size = 0.79, P = 0.002). Cerebrovascular lesion burden was slightly higher in PD‐RBD.ConclusionsAlthough overlap occurs between groups, PD patients with probable RBD may have greater density and range of synuclein pathology on autopsy. © 2015 International Parkinson and Movement Disorder Society