Characterization of Chromatin Dysregulation in Cancer Through Analysis of Fresh and Archival Human Samples

In the past several years, advances in high-throughput DNA sequencing have enabled massive tumor genome sequencing studies to identify recurrent mutations across many different cancer types and thousands of patients. These mutational surveys have reinforced the paradigm that cancer is a disease of the genome through the identification of inactivating mutations in well studied tumor-suppressors and activating mutations in well studied oncogenes, particularly in adult cancers. A new class of recurrent mutations has emerged as well, inactivating genes that encode chromatin regulators; these are disproportionately prevalent in pediatric and hematological malignancies. The molecular consequences of chromatin regulator mutations on a genome-wide scale, and moreover, how other genetic insults drive chromatin dysregulation and potentially enhance tumorigenesis, were until now completely unknown. In the chapters that follow, we show that a translocation-derived transcription factor chimera in Ewing Sarcoma acquired chromatin modifying activity such that it acts as a pioneer factor, altering chromatin configuration and inducing transcriptional dysregulation. We also demonstrate how alterations in chromatin link aberrancies in transcript processing with histone methyltransferase loss in clear cell Renal Cell Carcinoma through functional studies of chromatin accessibility and RNA processing in primary human tumors. Lastly, we describe how simple modifications to our experimental assay of chromatin accessibility permit the usage of archival (FFPE) human specimens. Together, in addition to contributing a greater understanding of chromatin biology and dysregulation in human cancers, this work will enable large-scale studies of the causes and roles of chromatin dysregulation in other models of human disease. It has also led to the initiation of high-throughput screens for compounds that affect chromatin accessibility, and subsequently tumor cell proliferation. Future work will utilize chromatin accessibility information as a novel clinical diagnostic and prognostic to guide and enhance patient treatment.Doctor of Philosoph

The use of social networking technologies for home-based online businesses: The case of Saudi Arabian female entrepreneurs

Over the years, many Saudi Arabian female entrepreneurs have adopted social networking technologies, also called social networking sites, to overcome certain cultural challenges and to manage their home-based online businesses. The effectiveness of adopting social networking technologies to produce business benefits is an area that has received significant attention. However, most of the previous studies focus on ‘what social networking technologies do’ rather than ‘what impact social networking technologies have’. The purpose of this study is to better understand how Saudi Arabian female entrepreneurs -- a group about which little is known -- use social networking technologies to derive benefits from their utilisation and to enhance their home-based online businesses. It employs a qualitative approach to explore the opportunities and challenges that they experience when they use these technologies to run their businesses. The research questions centre around the business benefits derived from the use of social networking technologies in a home-based context, the motivations that drove the adaptation of these platforms, and the most critical issues women face when using these platforms for business activities. Interviewees in this study describe how they negotiate between entrepreneurship and technology values, in light of their cultural roles. They discuss how the available technology enables their personal growth and allows them to create jobs for themselves and to enter the labour market without physically leaving their homes. The study reveals that the use of social networking technologies by Saudi female entrepreneurs achieves multiple objectives, including building their business brand, organising networks, and extending their customer base beyond family circles. The motivations of these female entrepreneurs are largely driven by personal desire, a need for professional growth and personal development, and a desire to serve their communities. The use of these technologies helps to create job opportunities and to achieve financial security, but the entrepreneurs also face a range of challenges. These include determining the most appropriate social networking technology to use for their specific business objectives, an initial lack of online marketing and management skills, and the need for additional resources to help them manage their online presence. In examining how social networking technologies are employed by Saudi female entrepreneurs, this study contributes to the extant literature on home-based entrepreneurship by focusing on a group about which minimal knowledge exists

Change blindness: eradication of gestalt strategies

Arrays of eight, texture-defined rectangles were used as stimuli in a one-shot change blindness (CB) task where there was a 50% chance that one rectangle would change orientation between two successive presentations separated by an interval. CB was eliminated by cueing the target rectangle in the first stimulus, reduced by cueing in the interval and unaffected by cueing in the second presentation. This supports the idea that a representation was formed that persisted through the interval before being 'overwritten' by the second presentation (Landman et al, 2003 Vision Research 43149–164]. Another possibility is that participants used some kind of grouping or Gestalt strategy. To test this we changed the spatial position of the rectangles in the second presentation by shifting them along imaginary spokes (by ±1 degree) emanating from the central fixation point. There was no significant difference seen in performance between this and the standard task [F(1,4)=2.565, p=0.185]. This may suggest two things: (i) Gestalt grouping is not used as a strategy in these tasks, and (ii) it gives further weight to the argument that objects may be stored and retrieved from a pre-attentional store during this task

Targets in Gene Therapy

This book aims at providing an up-to-date report to cover key aspects of existing problems in the emerging field of targets in gene therapy. With the contributions in various disciplines of gene therapy, the book brings together major approaches: Target Strategy in Gene Therapy, Gene Therapy of Cancer and Gene Therapy of Other Diseases. This source enables clinicians and researchers to select and effectively utilize new translational approaches in gene therapy and analyze the developments in target strategy in gene therapy