Few researchers have examined the relationship between earlier stages of breast cancer and its effect on staging of the disease process and the co-occurring coping and communication patterns between mothers and their children. The purposes of this qualitative study with a multiple case study design were to examine (a) coping mechanisms that mothers used to manage the uncertainty of their breast cancer status and (b) the impact of early-stage breast cancer on communication patterns between mothers and their children. The Lazarus and Folkman theory of psychological coping and the McMaster family systems communication theory informed the conceptual framework for the data analysis. The instrument for data gathering was a researcher-designed, semistructured interview guide. The sample consisted of 20 maternal breast cancer survivors and their children. Qualitative data analysis involved member checking and content analysis to confirm the frequency of similarities and differences occurring among participant responses. Key findings were that participants: (a) adapted to their diagnosis while refining their preexisting coping mechanisms, (b) found motherhood to be a source of emotional strength throughout the duration of their cancer process, and (c) managed changes in communication with their children during each phase of cancer treatment by using combinations of communication styles. Oncology social workers can use the findings of this study as an opportunity to develop models of best practices that are effective in helping patients cope with early stage breast cancer. The findings of this study impact social change by informing clinical social work with an effective paradigm that helps mothers and their children cope with the different phases of breast cancer.

No description available.

Radiofrequency ablation (RFA) is an established treatment option for patients with inoperable liver tumours and is now being investigated for the treatment of lung and other solid tumours. The aim of this thesis was to investigate the use RFA to decrease blood loss during liver resection, for the treatment of the liver resection edge and to investigate the safety and efficacy of brain RFA. Blood loss is an important factor affecting both the morbidity and mortality following liver resection. The use of a novel in line RF probe to ablate the transection plane prior to liver resection resulted in decreased blood loss with easier resection. This has potential in the treatment of liver tumors in cirrhotic livers and also in other vascular organs. The other important prognostic factor affecting long-term survival in patients undergoing liver resection for liver tumors is the surgical margins. Positive margins which cannot be treated with repeat resection may be treated with cryotherapy. The use of a novel probe to ablate the resection edge with RFA was found to be equally effective as cryotherapy and superior to argon beam coagulation or diathermy in an ex-vivo model. The radiofrequency ablation of the brain was found to be safe with no hemorrhage or damage to the surrounding brain parenchyma. There was no rise in intra-cranial pressure in the animals treated with RFA. The brain RFA was found to be effective and has potential for the treatment of brain tumours. Dispersive pad site burns was a significant problem in patients treated with radiofrequency ablation for lung and liver tumours occurring in 5% of patients. Pad tissue temperature of 45oC was found to be the threshold temperature above which burns occurred. Monitoring of pad-tissue temperatures with thermocouples and application of ice packs in addition to increasing the number of pads may help decrease this complication.

Introduction: Objectives were to describe time intervals between presentation to a tertiary care center, diagnosis and treatment in pediatric acute lymphoblastic leukemia (ALL) and Hodgkin disease (HD), and measure their impact on overall survival (OS) and event-free survival (EFS). Methods: Children in POGONIS (Pediatric Oncology group of Ontario Networked Information System) with ALL or HD from 1997-2007 were eligible. Time intervals were dichotomized at clinically defined cut-points. OS and EFS were examined with univariate and multivariable Cox proportional hazards (CPH) models. Results: In ALL, in multivariable analysis, those with treatment > 3 days after diagnosis had inferior OS (adjHR=2.49; 95%CI 1.4-4.43;p=0.002), and inferior EFS (adjHR=1.73; 95%CI 1.01-2.96;p=0.047). In HD, in multivariable analysis, those with treatment > 7 days after diagnosis had superior EFS (adjHR=0.37; 95%CI 0.18-0.77;p=0.008). Conclusions: Time to treatment is associated with survival in ALL and HD. Future research will further delineate the relationship between time to treatment and outcome.

BACKGROUND: The incidence of liver metastases from colorectal cancer (CLM) is on the rise. Older cancer patients are frequently subject to under-treatment. METHODS: A Markov decision model was built to examine the effect on life expectancy (LE) and quality-adjusted life expectancy (QALE) of four strategies – best supportive care (BSC), systemic chemotherapy (SC), radiofrequency ablation (RFA), and hepatic resection (HR). The model was designed to account for both age and comorbidities. RESULTS: In the base case analysis, BSC, SC, RFA, and HR yielded LEs of 11.9, 23.1, 34.8, and 37.0 months, respectively, and QALEs of 7.8, 13.2, 22.0, and 25.0 months, respectively. Model results were sensitive to several variables including age, comorbidity status, and length of model simulation. CONCLUSION: Hepatic resection may be the optimal treatment strategy for healthy older patients with CLM. Treatment decisions in older cancer patients should be individualized and account for patient age, comorbidities, and values.

Introduction: Objectives were to describe time intervals between presentation to a tertiary care center, diagnosis and treatment in pediatric acute lymphoblastic leukemia (ALL) and Hodgkin disease (HD), and measure their impact on overall survival (OS) and event-free survival (EFS). Methods: Children in POGONIS (Pediatric Oncology group of Ontario Networked Information System) with ALL or HD from 1997-2007 were eligible. Time intervals were dichotomized at clinically defined cut-points. OS and EFS were examined with univariate and multivariable Cox proportional hazards (CPH) models. Results: In ALL, in multivariable analysis, those with treatment > 3 days after diagnosis had inferior OS (adjHR=2.49; 95%CI 1.4-4.43;p=0.002), and inferior EFS (adjHR=1.73; 95%CI 1.01-2.96;p=0.047). In HD, in multivariable analysis, those with treatment > 7 days after diagnosis had superior EFS (adjHR=0.37; 95%CI 0.18-0.77;p=0.008). Conclusions: Time to treatment is associated with survival in ALL and HD. Future research will further delineate the relationship between time to treatment and outcome.

BACKGROUND: The incidence of liver metastases from colorectal cancer (CLM) is on the rise. Older cancer patients are frequently subject to under-treatment. METHODS: A Markov decision model was built to examine the effect on life expectancy (LE) and quality-adjusted life expectancy (QALE) of four strategies – best supportive care (BSC), systemic chemotherapy (SC), radiofrequency ablation (RFA), and hepatic resection (HR). The model was designed to account for both age and comorbidities. RESULTS: In the base case analysis, BSC, SC, RFA, and HR yielded LEs of 11.9, 23.1, 34.8, and 37.0 months, respectively, and QALEs of 7.8, 13.2, 22.0, and 25.0 months, respectively. Model results were sensitive to several variables including age, comorbidity status, and length of model simulation. CONCLUSION: Hepatic resection may be the optimal treatment strategy for healthy older patients with CLM. Treatment decisions in older cancer patients should be individualized and account for patient age, comorbidities, and values.

Radiation dermatitis is a common side effect of external beam radiation therapy. The purpose of this study was to evaluate the effectiveness of applying an aloe vera based skin gel to the target area skin in preventing the development of radiation dermatitis to postlumpectomy/ mastectomy patients receiving external beam radiation therapy in an ambulatory radiation-oncology clinic in the southeastern region of the United States. In this descriptive correlational study, a convenience sample of willing participants (n=18) was followed from initial treatment through the one-month follow-up examination to assess the intensity of their skin reaction. Five research questions were examined pertaining to the relationship between prognostic indicators and the development of radiation dermatitis when RadiacareR gel was used before and throughout external beam radiation therapy post-mastectomy or post-lumpectomy. The prognostic indicators used in this study were: Breast size > C-cup, prior chemotherapeutic exposure, length of incision, age of client, and weight changes since diagnosis. Analysis of Variance (ANOVA) and Pearson's Correlation Coefficients were used in the data analysis with a confidence of p=0.05. This study indicated that breast size and weight changes were the most prognostic of the factors studied. The small sample size and lack of randomization or control group limit the generalizability of these findings to clinical practice; however, it does support the need for continued research in this area. Recommendations for future studies include comparing Body Mass Index (BMI) to incidence and determining a relationship between gel use and treatment breaks and if there is a difference in the length of time until the skin is restored to baseline upon completion of therapy.

<p><p>Pin1 specifically binds to and catalyzes the <i>cis-trans</i> isomerization of phosphorylated-Ser/Thr-Pro motifs, which modulate the stability, localization, and function of numerous Pin1 substrates involved in cell cycle and tumorigenesis. During cell cycle progression, the timely synthesis and degradation of key regulatory proteins is required to maintain genomic integrity. Previously, we determined that Pin1 binds to and promotes the degradation of the oncoprotein c-Myc. Pin1 and the SCF^Cdc4 ubiquitin ligase recognize a &ldquo;phosphodegron&rdquo; sequence in c-Myc, which leads to its ubiquitination and degradation by the 26 S proteasome. Since cyclin E is another oncoprotein regulated by SCF^Cdc4, we hypothesized that Pin1 may also bind to and facilitate cyclin E turnover. Here we show that Pin1 binds to the cyclin E-Cdk2 complex in a manner that requires Ser384 of cyclin E, which is phosphorylated by Cdk2. The absence of Pin1 in mouse embryonic fibroblasts (MEFs) results in stabilization of cyclin E, and impairment of G1-S phase progression. Furthermore, deregulated cyclin E and c-Myc levels correlate with accelerated genomic instability in <i>Pin1^-/-</i> MEFs, which results in sensitization of these cells to more aggressive Ras-dependent transformation and tumorigenesis.</p></p><p><p>However, the role of Pin1 in cancer is controversial as it has been proposed to conditionally promote or suppress tumorigenesis depending on the genetic context. In human cancer, Pin1 protein levels are frequently altered in several cancers. Interestingly, the PIN1 gene is located on chromosome 19p13.2, which is a region subject to loss of heterozygosity in several tumors. Since Pin1 protein is frequently under-expressed in kidney cancer, we tested the hypothesis that it may have a tumor suppressive role in human clear cell renal cell carcinoma (ccRCC). Here we show evidence for PIN1 gene deletion and mRNA under-expression as a mechanism of Pin1 reduction in ccRCC tumors. We demonstrate that restoration of Pin1 in cell lines found to be deficient in Pin1 protein expression can attenuate the growth of ccRCC cells in soft agar and a xenograft tumor model. Moreover, this ability of Pin1 to negatively influence tumor growth in ccRCC cells may be dependent on the presence of functional p53, which is infrequently mutated in ccRCC. These observations suggest Pin1 may function as a conditional tumor suppressor.</p></p> / Dissertation

<p> Kaposi&rsquo;s sarcoma-associated herpesvirus (KSHV), or human herpes virus 8 (HHV8), is a ?2 lymphotropic herpesvirus and is the etiological agent of Kaposi&rsquo;s sarcoma (KS), primary effusion B-cell lymphoma (PEL), and the multicentric Castleman&rsquo;s disease (MCD). KSHV malignancies are associated with immune suppression, such as in AIDS or organ transplantation patients, and with certain African and Mediterranean populations. </p><p> In an effort to identify host factors involved in the establishment of KSHV infection, we focused on the nuclear factor E2-related factor 2 (Nrf2) a member of the Cap&rsquo;n&rsquo;Collar basic leucine zipper (bZIP) family of transcription factors. Nrf2 is induced by ROS, and has been shown to play an important role for infection by several viruses. Moreover, Nrf2 activation leads to the expression of a cohort of genes involved in apoptosis, angoigensis, metastasis, drug resistance, and the proliferative pentose pyrophosphate pathway (PPP) enzymes. Interestingly, several of these pathways are upregulated during KSHV infection through unknown mechanisms. Because KSHV infection, like other viruses that activate Nrf2, induces ROS, a powerful activator of Nrf2, <i> we hypothesized that KSHV infection of target cells activates Nrf2 in order to induce Nrf2 target genes and create a microenvironment conducive to infection and tumorigenesis.</i> To this end, we utilized cellular models to assess Nrf2 activity during <i>de novo</i> and latent KSHV infection, the mechanism of its activation, and its role in host and virus biology. </p><p> In the first part of this study, we found that Kaposi's sarcoma (KS) skin tissue exhibited elevated Nrf2 levels compared to healthy skin tissue. <i> De novo</i> infection of endothelial (HMVEC-d) cells showed that ROS were essential for Nrf2 activation during the early stages of infection, but dispensable during latency, where the COX-2/PGE2/PKC&zeta; axis played an essential role in the sustained activation. Interestingly, Nrf2 was essential for optimal COX-2 expression, a major pro-viral agent during KSHV infection, establishing a feed-forward loop between COX-2 and Nrf2 in KSHV biology. Nrf2 activation was also necessary for the KSHV-mediated induction of host Bcl-2, VEGF, and the PPP enzymes. Nrf2 colocalized with LANA-1 and the KSHV genome during latency, and played an important role in proper lytic (ORF50) and latent (ORF73) gene expression. This study demonstrated for the first time that KSHV induces Nrf2 during <i>de novo</i> infection of endothelial cells to aid with establishment of latency.</p><p> In the second part of the study, we focused on long-term-infected telomerase-immortalized endothelial cells (TIVE-LTC), which provide a model of prolonged KSHV latency. We determined that ROS did not affect Nrf2 activity in these cells. More interestingly, we identified the existence of two simultaneous Nrf2 activating pathways. The first, the non-canonical pathway, involved the autophagic protein p62-mediated sequestration of the Nrf2 inhibitor Keap1, promoting intracellular Nrf2 protein accumulation. A second activating pathway involving the COX-2/PGE2/PKC&zeta; axis further induced Nrf2 activation and phosphorylation, which was necessary for sustained expression of Nrf2 target genes, including GCS, NQO1, xCT, VEGF and IL6, all important agents in KSHV infection and oncogenesis. </p><p> In the third part of the study, we shifted our attention to KSHV latency in PEL models. We determined that histopathological tissue obtained from PEL of the stomach exhibited significant Nrf2 activation. Investigation of PEL-derived cell lines revealed that the COX-2/PGE2/PKC&zeta; axis required prostaglandin E receptor 4 (EP4) activation, which acted as the receptor used by PGE2 to activate Nrf2. Next-generation RNA sequencing (NGS) and qPCR experiments revealed that Nrf2 knockdown or inhibition with the chemical Brusatol resulted in elevated global lytic gene expression. Additionally, we identified a novel regulatory mechanism of the major lytic regulatory gene, ORF50, that involved Nrf2, viral LANA-1 and the host transcriptional repressor KAP1. We determined that Nrf2 played a crucial role in the ORF50-mediated lytic burst during early <i> de novo</i> infection, an effect that is repressed in latency by LANA-1 recruitment of KAP1 to the ORF50 promoter in an Nrf2-dependent manner. (Abstract shortened by UMI.) </p>