Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Bridging that gap : occupational therapist experiences of client-centred practice

Although client-centred practice has become an essential part of Canadian occupational therapy practice in the last twenty years (Law, 1998; Sumsion & Smyth, 2000), many authors have indicated that therapists do not practice in a client-centred manner (Law, Baptiste & Mills, 1995; Toomey, Nicholson & Carswell, 1995; Hammell, 1998a). Some authors have focused on how therapists are responsible for problems implementing client-centred practice, because they are unwilling to give up power (Sumsion, 1999c; Gage, 1999; Hammell, 1998a; Law, Polatajko, Pollock, McColl, Carswell, & Baptiste, 1994). As power has been identified as an important construct in the literature on client-centred practice, I have conducted an exploratory, qualitative study of occupational therapists' experiences of client-centred practice using standpoint theory and Foucault's work on power to frame the study. Based on a thematic analysis of in-depth ethnographic interviews of nine therapists from acute care and homecare settings three main themes were identified. "Bridging that gap: ideal versus real conceptions of client-centred practice" reveals the tensions that therapists experience between the discourse and practice of occupational therapy. "Related to the service environment: the importance of setting" focuses on how institutional factors shape practice. The final theme "a bit of tension: problems with the client-therapist relationship" describes the client-therapist interaction, which is influenced by discursive and institutional factors. The thesis concludes with a discussion of the theoretical implications, practical applications, limitations and significance of these research findings.Medicine, Faculty ofGraduat

Exploring the impact of wheelchairs on individuals in residential care : a two-phase, mixed-methods study

Wheelchairs are the primary means of mobility for most of the older adults living in residential care. Despite their intuitive benefits, little research has explored the outcomes of wheelchair use for facility residents. Therefore, a two-phase, mixed-methods project was undertaken. Phase 1: Exploratory Ethnographic Study. Objectives. 1. To explore the perceptions and experiences of facility life among residents who use wheelchairs as their primary means of mobility and to examine how wheelchairs are used in these settings. 2. To identify nondemographic factors that enable or curtail the mobility, participation and life satisfaction of these residents. Method. Sixteen residents from two facilities took part in participant observations, and these residents or surrogate family members completed a series of in-depth interviews. Results. We drew upon the work of Pierre Bourdieu to understand how wheelchairs and other forms of capital could either enable or curtail the things residents did and the places that they went. These findings emphasize the critical role that the facility environment plays in the lives of residents. This study identified a wide range of potential wheelchair-related, environmental, and personal factors related to resident’s mobility, participation, and life satisfaction. Phase 2: Quantitative Cross-sectional Study. Objective. To identify the predictors of mobility, participation and life satisfaction of residents who use wheelchairs as their primary means of mobility. Method. We conducted a cross-sectional study with 268 residents from 11 facilities. To measure independent and dependent study variables we administered standardized personal, wheelchair-related and environmental tools and collected socio-demographic and wheelchair equipment data. Results. Wheelchair skills (including the capacity to engage brakes and manoeuvre) were the most important independent predictors of mobility. Depression was the most important independent predictor of life satisfaction among self-responding and proxy subjects and of participation for self-responding subjects. For proxy subjects, mobility was the most important independent predictor of participation; and depression approached significance. Significance. The study findings emphasize the pivotal role that wheelchairs play in the lives of residents, reveal institutional practices that may curtail their mobility and participation, suggest potential policy and practice changes, and lay the groundwork for future research.Medicine, Faculty ofGraduat