Research Spotlight

Posted April 15th 2016

PP2A methylation controls sensitivity and resistance to beta-amyloid-induced cognitive and electrophysiological impairments.

Erland Arning Ph.D.

Erland Arning, Ph.D.

Nicholls, R. E., J. M. Sontag, H. Zhang, A. Staniszewski, S. Yan, C. Y. Kim, M. Yim, C. M. Woodruff, E. Arning, B. Wasek, D. Yin, T. Bottiglieri, E. Sontag, E. R. Kandel and O. Arancio (2016). “PP2A methylation controls sensitivity and resistance to beta-amyloid-induced cognitive and electrophysiological impairments.” Proc Natl Acad Sci U S A 113(12): 3347-3352.

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Elevated levels of the beta-amyloid peptide (Abeta) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer’s disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Abeta exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Abeta-induced impairments. Neither transgene affected Abeta production or the electrophysiological response to low concentrations of Abeta, suggesting that these manipulations selectively affect the pathological response to elevated Abeta levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Abeta levels in AD patients.


Posted April 15th 2016

Understanding physical activity in the group home setting: a qualitative inquiry.

Simon Driver Ph.D.

Simon Driver, Ph.D.

Dixon-Ibarra, A., S. Driver, K. Vanderbom and K. Humphries (2016). “Understanding physical activity in the group home setting: a qualitative inquiry.” Disabil Rehabil: Mar 23:1-10. [Epub ahead of print].

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PURPOSE: Persons with intellectual disabilities have low physical activity levels and high rates of chronic disease. One predictor limitedly explored is the home environment, which could influence the type and amount of physical activity in this population. The purpose of this study is to qualitatively explore physical activity in the group home setting and determine what key stakeholders want from a physical activity programme. METHOD: This study adopted a qualitative descriptive design, using semistructured focus groups. Twenty stakeholders (i.e., residents with intellectual disability, support staff and programme coordinators) participated in one of three focus groups, separated by stakeholder status. RESULTS: A number of factors emerged that would assist rehabilitation professionals in understanding physical activity within the group home setting. The following six meta-themes were identified: nature of residents’ physical activity, facilitators to physical activity, barriers to physical activity, personal factors, organizational factors and solutions to increase physical activity. CONCLUSIONS: Findings suggest that residents with intellectual disabilities have low physical activity and opportunities for participation. Key attributes of the group home setting were identified between barriers and facilitators to activity. Consideration for the development of physical activity programmes should focus on the unique needs of the group home setting as expressed by stakeholders. Implications for rehabilitation Physical activity can improve physical fitness, function, and community participation yet physical activity remains low among adults with intellectual disabilities. Understanding physical activity within the group home setting is essential to develop targeted interventions to increase activity within that environment. Key barriers for physical activity within the group home setting include; operational priorities, limited staff, staff turnover, busy schedules, and staff attitudes towards physical activity.


Posted April 15th 2016

A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers.

Carlos Becerra M.D.

Carlos Becerra, M.D.

Coveler, A. L., A. H. Ko, D. V. Catenacci, D. Von Hoff, C. Becerra, N. C. Whiting, J. Yang and B. Wolpin (2016). “A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers.” Invest New Drugs Mar 18. [Epub ahead of print]

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Purpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.


Posted April 15th 2016

Sirt1 Is Required for Resveratrol-Mediated Chemopreventive Effects in Colorectal Cancer Cells.

Ajay Goel Ph.D.

Ajay Goel, Ph.D.

Buhrmann, C., P. Shayan, B. Popper, A. Goel and M. Shakibaei (2016). “Sirt1 Is Required for Resveratrol-Mediated Chemopreventive Effects in Colorectal Cancer Cells.” Nutrients Mar 5;8(3).

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Sirt1 is a NAD(+)-dependent protein-modifying enzyme involved in regulating gene expression, DNA damage repair, metabolism and survival, as well as acts as an important subcellular target of resveratrol. The complex mechanisms underlying Sirt1 signaling during carcinogenesis remain controversial, as it can serve both as a tumor promoter and suppressor. Whether resveratrol-mediated chemopreventive effects are mediated via Sirt1 in CRC growth and metastasis remains unclear; which was the subject of this study. We found that resveratrol suppressed proliferation and invasion of two different human CRC cells in a dose-dependent manner, and interestingly, this was accompanied with a significant decrease in Ki-67 expression. By transient transfection of CRC cells with Sirt1-ASO, we demonstrated that the anti-tumor effects of resveratrol on cells was abolished, suggesting the essential role of this enzyme in the resveratrol signaling pathway. Moreover, resveratrol downregulated nuclear localization of NF-kappaB, NF-kappaB phosphorylation and its acetylation, causing attenuation of NF-kappaB-regulated gene products (MMP-9, CXCR4) involved in tumor-invasion and metastasis. Finally, Sirt1 was found to interact directly with NF-kappaB, and resveratrol did not suppress Sirt1-ASO-induced NF-kappaB phosphorylation, acetylation and NF-kappaB-regulated gene products. Overall, our results demonstrate that resveratrol can suppress tumorigenesis, at least in part by targeting Sirt1 and suppression of NF-kappaB activation.


Posted April 15th 2016

Molecular basis for globotriaosylceramide regulation and enzyme uptake in immortalized aortic endothelial cells from Fabry mice.

Raphael Schiffmann M.D.

Raphael Schiffmann, M.D.

Meng, X. L., T. S. Day, N. McNeill, P. Ashcraft, T. Frischmuth, S. H. Cheng, Z. P. Liu, J. S. Shen and R. Schiffmann (2016). “Molecular basis for globotriaosylceramide regulation and enzyme uptake in immortalized aortic endothelial cells from Fabry mice.” J Inherit Metab Dis. Mar 10. [Epub ahead of print]

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Fabry disease is caused by deficient activity of alpha-galactosidase A and subsequent intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Vascular endothelial cells may play important roles in disease pathogenesis, and are one of the main target cell types in therapeutic interventions. In this study, we generated immortalized aortic endothelial cell lines from a mouse model of Fabry disease. These cells retained endothelial cell-specific markers and functions. Gb3 expression level in one of these clones (referred to as FMEC2) was highly susceptible to culture media, and appeared to be regulated by glucosylceramide synthase. Results also showed that Gb3 could be upregulated by hydrocortisone. FMEC2 express the mannose 6-phosphate receptor and sortilin but not the mannose receptor. Uptake studies suggested that sortilin plays a role in the binding and internalization of mammalian cell-produced alpha-galactosidase A. Moss-aGal (a plant-made enzyme) was endocytosed by FMEC2 via a receptor other than the aforementioned receptors. In conclusion, this study suggests that glucosylceramide synthase and hydrocortisone may play important roles in modulating Gb3 levels in Fabry mouse aortic endothelial cells, and that endocytosis of recombinant alpha-galactosidase A involves a combination of multiple receptors depending on the properties of the enzyme.