The Distribution of Platinum Complexes in Biological Systems

The toxicity of platinum anticancer drugs presents a major obstacle in the effective treatment of tumours. Much of the toxicity stems from a lack of specificity of the drugs for the sites at which they are able to exert maximum anticancer activity. An improved understanding of the behaviour of the drugs in the tumour environment may assist in the rational design of future platinum anticancer agents with enhanced specificity and reduced toxicity. In the work presented herein, the specificity of two classes of platinum anticancer agents was assessed (platinum(IV) cisplatin analogues and platinum(II) anthraquinone complexes). The interaction of the platinum(IV) agents with DNA, believed to be their main cellular target, was examined using XANES spectroscopy. This experiment was designed to assess the ability of the drugs to interact with DNA and thus exert their anticancer activity. It was shown that the platinum(IV) complexes were not reduced by DNA during 48 hr incubation. It was not possible to conclusively determine whether the interaction of the complexes with DNA was direct or platinum(II) catalysed, or whether interaction had occurred at all. The distribution of platinum(II) anthraquinone complexes and their corresponding anthraquinone ligands in tumour cells (A2780 ovarian and DLD-1 colon cancer cell lines) was investigated. The cytotoxicity of the compounds in DLD-1 cells was also assessed. It was found that the compounds were efficiently taken up into the cells and entered the lysosomal compartments almost exclusively. This suggested that the cytotoxicity of the drugs was caused by lysosomal disruption, or that the platinum complexes were degraded, leaving a platinum species to enter the cell nuclei and interact with DNA. Alternatively, the complexes may bind to proteins and transport into the nuclei of the cells, though with their fluorescence quenched by the protein. The penetration and distribution of platinum(IV) complexes was assessed in DLD-1 multicellular tumour spheroids (established models of solid tumours) using a number of synchrotron techniques, including micro-tomography, micro-SRIXE, and micro-XANES. The complexes were found to be capable of penetrating throughout the entire volume of the spheroids. Micro-XANES indicated that in central and peripheral spheroidal regions, bound platinum species were present largely as platinum(II)

Doctor of Philosophy

dissertationHospital-acquired pressure injuries (PI) are localized areas of damage to the skin, underlying tissue, or both, as a result of pressure. Critical-care patients represent a highly specialized patient population, and currently available risk-assessment scales, such as the Braden scale, tend to identify most critical-care patients as being "at risk" for pressure injuries, and therefore are of limited clinical utility. The purpose of this dissertation was to (a) conduct a systematic review of the literature to identify independent risk factors for pressure injuries, (b) use longitudinal analysis to identify the hazards of developing a pressure injury based on changing Braden Scale total and subscale scores, and (c) develop a PI prediction model. We conducted our systematic review based on standardized criteria and developed a tool for quality assessment based on a literature search and input from experts. Mobility/activity, age, and vasopressor infusion emerged as important risk factors, whereas results from other risk categories were mixed. For the Braden scale analysis and the predictive model we used electronic health record cases (N=6,376). We employed time-dependent Cox regression to determine the hazards of developing a pressure injuries based on the Braden scale subscale scores. With the exception of the friction and shear subscales, patients of all ages with midrange Braden scale scores were more likely to develop pressure injuries than their counterparts with higher risk scores. We developed a predictive model using random forest analysis. The model, an ensemble classifier, was composed of 500 decision trees, each using a random subset of 4 of 20 clinical features. The area under the receiver operating characteristic curve was 0.9 for the outcome >category 1 pressure injuries and 0.87 for the outcome >category 2 pressure injuries. The most important variables in our model in descending order based on the mean decrease in accuracy were longer surgical duration, lower hemoglobin, higher creatinine, older age, higher glucose, lower body mass index, lower albumin, and higher lactate. Due to our model's relatively strong performance, it may be useful for directing preventive interventions that are not feasible for every patient due to cost

Risk Factors for Pressure Injuries Among Critical Care Patients: A Systematic Review

Objective: To identify risk factors independently predictive of pressure injury (also known as pressure ulcer) development among critical-care patients. Design: We undertook a systematic review of primary research based on standardized criteria set forth by the Institute of Medicine. Data sources: We searched the following databases: CINAHL (EBSCOhost), the Cochrane Library (Wilson), Dissertations & Theses Global (ProQuest), PubMed (National Library of Medicine), and Scopus. There was no language restriction. Method: A research librarian coordinated the search strategy. Articles that potentially met inclusion criteria were screened by two investigators. Among the articles that met selection criteria, one investigator extracted data and a second investigator reviewed the data for accuracy. Based on a literature search, we developed a tool for assessing study quality using a combination of currently available tools and expert input. We used the method developed by Coleman et al. in 2014 to generate evidence tables and a summary narrative synthesis by domain and subdomain. Results: Of 1753 abstracts reviewed, 158 were identified as potentially eligible and 18 fulfilled eligibility criteria. Five studies were classified as high quality, two were moderate quality, nine were low quality, and two were of very low quality. Age, mobility/activity, perfusion, and vasopressor infusion emerged as important risk factors for pressure injury development, whereas results for risk categories that are theoretically important, including nutrition, and skin/pressure injury status, were mixed. Methodological limitations across studies limited the generalizability of the results, and future research is needed, particularly to evaluate risk conferred by altered nutrition and skin/pressure injury status, and to further elucidate the effects of perfusion-related variables. Conclusions: Results underscore the importance of avoiding overinterpretation of a single study, and the importance of taking study quality into consideration when reviewing risk factors. Maximal pressure injury prevention efforts are particularly important among critical-care patients who are older, have altered mobility, experience poor perfusion, or who are receiving a vasopressor infusion

WHS Guidelines for the Treatment of Pressure Ulcers: 2023 Update

The major populations at risk for developing pressure ulcers are older adults who have multiple risk factors that increase their vulnerability, people who are critically ill and those with spinal cord injury/disease. The reported prevalence of pressure ulcers in the United States is 2.5 million. However, this estimate is derived from acute care facilities and does not include people who are living at home or in nursing facilities. Despite the implementation of hospital and facility-based preventive measures, the incidence of pressure ulcers has not decreased in decades. In addition to the burden of pain, infection and death, it is estimated that hospital-acquired pressure ulcers cost the health system $26.8 billion annually with over 50% of the cost attributed to treating Stage 3 and 4 pressure injuries. Thus, it is critical to examine the literature and develop guidelines that will improve the outcomes of this complex and costly condition. This guideline update is a compendium of the best available evidence for the treatment of Pressure Ulcers published since the last update in 2015 and includes a new section based on changing demographics entitled ‘Palliative wound care for seriously ill patients with pressure ulcers’. The overall goal of the Wound Healing Society Guideline project is to present clear, concise and commercial free guidelines that clinicians can use to guide care, that researchers can use to develop studies that will improve treatment and that both clinicians and researchers can use to understand the gaps in our knowledge base

Leaving the Past (Self) Behind: Non-Reporting Rape Survivors' Narratives of Self and Action

Using a symbolic interactionist framework, this study considers the narratives of non-reporting rape survivors. We use interviews to examine the complex processes that inform a survivor’s decision not to report. Rape is not interpreted as an isolated event; it is something that is seen as caused by, connected to, and affecting the survivor’s sense of self and agency. Rape forces the survivor to reconstruct a sense of agency in the aftermath of the traumatic attack. Rather than report the rape, the survivors constructed narratives that direct blame and accountability toward the “old self”. This less visible, yet still agentic strategy, allows the survivors to regain a sense of agency and control. As a result, a more positive, optimistic self can be constructed, while pursuing legal justice would force them to reenact an “old” self that cannot be disentangled from the rape