ASU Scholarship Showcase

The histone deacetylase (HDAC) inhibitor vorinostat has received significant attention in recent years as an ‘epigenetic’ drug used to treat solid tumors. However, its mechanisms of action are not entirely understood, particularly with regard to its interaction with the aberrations in 3D nuclear structure that accompany neoplastic progression. We investigated the impact of vorinostat on human esophageal epithelial cell lines derived from normal, metaplastic (pre-cancerous), and malignant tissue. Using a combination of novel optical computed tomography (CT)-based quantitative 3D absorption microscopy and conventional confocal fluorescence microscopy, we show that subjecting malignant cells to vorinostat preferentially alters their 3D nuclear architecture relative to non-cancerous cells. Optical CT (cell CT) imaging of fixed single cells showed that drug-treated cancer cells exhibit significant alterations in nuclear morphometry. Confocal microscopy revealed that vorinostat caused changes in the distribution of H3K9ac-marked euchromatin and H3K9me3-marked constitutive heterochromatin. Additionally, 3D immuno-FISH showed that drug-induced expression of the DNA repair gene MGMT was accompanied by spatial relocation toward the center of the nucleus in the nuclei of metaplastic but not in non-neoplastic cells. Our data suggest that vorinostat’s differential modulation of 3D nuclear architecture in normal and abnormal cells could play a functional role in its anti-cancer action.

Cellular heterogeneity plays a pivotal role in a variety of functional processes in vivo including carcinogenesis. However, our knowledge about cell-to-cell diversity and how differences in individual cells manifest in alterations at the population level remains very limited mainly due to the lack of appropriate tools enabling studies at the single-cell level. We present a study on changes in cellular heterogeneity in the context of pre-malignant progression in response to hypoxic stress. Utilizing pre-malignant progression of Barrett’s esophagus (BE) as a disease model system we studied molecular mechanisms underlying the progression from metaplastic to dysplastic (pre-cancerous) stage. We used newly developed methods enabling measurements of cell-to-cell differences in copy numbers of mitochondrial DNA, expression levels of a set of mitochondrial and nuclear genes involved in hypoxia response pathways, and mitochondrial membrane potential. In contrast to bulk cell studies reported earlier, our study shows significant differences between metaplastic and dysplastic BE cells in both average values and single-cell parameter distributions of mtDNA copy numbers, mitochondrial function, and mRNA expression levels of studied genes. Based on single-cell data analysis, we propose that mitochondria may be one of the key factors in pre-malignant progression in BE.

The principles of a new project management model have been tested for the past 20 years. This project management model utilizes expertise instead of the traditional management, direction, and control (MDC). This new project management model is a leadership-based model instead of a management model. The practice of the new model requires a change in paradigm and project management structure. Some of the practices of this new paradigm include minimizing the flow of information and communications to and from the project manager [including meetings, emails and documents], eliminating technical communications, reducing client management, direction, and control of the vendor, and the hiring of vendors or personnel to do specific tasks. A vendors is hired only after they have clearly shown that they know what they are doing by showing past performance on similar projects, that they clearly understand how to create transparency to minimize risk that they do not control, and that they can clearly outline their project plan using a detailed milestone schedule including time, cost, and tasks all communicated in the language of metrics.

For the past three decades, the Saudi construction industry (SCI) has exhibited poor performance. Many research efforts have tried to identify the problem and the potential causes but there have been few publications identifying ways to mitigate the problem and describing testing to validate the proposed solution. This paper examines the research and development (R&D) approach in the SCI. A literature research was performed identifying the impact that R&D has had on the SCI. A questionnaire was also created for surveying industry professionals and researchers. The results show evidence that the SCI practice and the academic research work exist in separate silos. This study recommends a change of mindset in both the public and private sector on their views on R&D since cooperation is required to create collaboration between the two sectors and improve the competitiveness of the country's economy.