Lung cancer is the most common cause of cancer deaths worldwide. Hope is considered essential to life and has been positively associated with coping. The purpose of this study was to describe the level of hope in patients receiving medical treatment for lung cancer. The study was guided by Dufault and Martocchio's multidimensional theoretical model of hope. A total of 167 patients were recruited for this cross sectional descriptive study from oncology clinics in the Southeast United States. Each participant completed a nine-item demographic self-survey questionnaire and a twelve-item, four point Likert-type Herth Hope Index (possible scores 12-48, higher score = higher hope) to measure the level of hope. Clinical information included lung cancer type, stage of lung cancer, and time since diagnosis. The overall total mean hope score was 41.48 (SD = 5.10). This finding suggests that although lung cancer patients may be at risk for lower hope scores, this study demonstrated that lung cancer patients continue to hope throughout their disease trajectory. The other major findings demonstrated that widow/widowers (n = 14, 8%), were more hopeful (M = 42.57) than divorced (n = 36, 22%), (M = 39.29) and Blacks/African Americans (n = 22, 13.2%) had higher levels of hope (M = 43.22) than Whites/Caucasians (n = 140, 83%) (M = 41.26). Participants undergoing second line of chemotherapy treatment n = 30 (18%), were more hopeful 43.63(4.99) compared to all others. Future studies may include measuring hope at the time of diagnosis and throughout the disease trajectory, as well as at multiple data points during different lines of chemotherapy treatment.

The long-term success of lung transplantation has been challenged by chronic graft dysfunction, which is manifested as obliterative bronchiolitis (OB). We demonstrated that allograft airway fibrosis is a dynamic process of tissue remodelling, in which cellular and matrix components dynamically change before or after complete obliteration of the airway lumen. This dynamic process was associated with changes in expression and activity of matrix metalloproteinases (MMPs). The early inflammatory phase was associated with MMP-dependent migration of blood-borne fibrocytes, which highly express MMP-9 and MMP-12. ‘Established’ fibrosis was associated with MMP-2 and MMP-14 expressed by myofibroblasts in both human OB lesions and their animal models. In established allograft airway fibrosis, general MMP inhibition resulted in apoptosis of myofibroblasts in vivo and in vitro, while low-doses of MMP-inhibitor treatment induced upregulation of MMP-2, increased collagenolytic activity, and significantly decreased myofibroblasts and collagen. The dynamic process of tissue remodelling in established allograft airway fibrosis was supported by underlying continuous alloimmune responses, in particular, direct T-cell-myofibroblast contact. iii Modulation of tissue remodelling using a low-dose MMP inhibitor in combination with cyclosporine induced partial regression of fibrosis after its establishment. We further demonstrated the mechanism of alloimmune responses unique to the lung. Human and animal studies demonstrated that bronchioles develop de novo lymphoid tissue characterized by formation of high endothelial venules and homing of effector memory T-cells. A following study demonstrated the important role of local immunological memory maintained by the intrapulmonary lymphoid tissue in exerting effector function in allograft rejection. Collectively, the present studies support the hypothesis that tissue remodelling is an important mechanism of allograft airway fibrosis. Regulation of tissue remodelling and underlying tissue injury is important not only to arrest aberrant remodelling of allograft airways but likely to reverse aberrant remodelling and to regenerate normal tissue architecture in airways after lung transplantation.

Inflammation is believed to play a pivotal role in the development of cancer and in particular lung cancer through both intrinsic and extrinsic pathways. This thesis aimed through 4 manuscripts to determine the role of lung-specific inflammation-related exposures as well as genetic variants (Single Nucleotide Polymorphism (SNPs)) in genes related to inflammation pathways in lung cancer risk. Risk factors of particular interest were lung diseases including emphysema, chronic bronchitis, pneumonia and tuberculosis. Data were collected from a Toronto-based case-control study and combined with data from the International Lung Cancer Consortium (17 studies for the non-genetic analyses and 6 studies for the genetic analyses). For non-genetic data, methods included, but were not limited to, unconditional logistic regression within single studies, Cox proportional hazards regression, meta-analytic techniques and pooled analyses techniques. For genetic data, additive models of association across 7,650 SNPs (selected based on role in inflammation) were pooled across studies and hierarchical modeling iv (HM) was used to incorporate prior functional information from various sources concerning the SNPs of interest. Within the Toronto study (manuscript 1) associations with increased lung cancer risk were observed for occupational exposures, previous lung diseases and a family history of cancer. The meta-analysis (manuscript 2) and pooled analysis (manuscript 3) showed relatively consistent associations between previous lung diseases and lung cancer risk across histology, gender and smoking categories. Results persisted when examining lung disease diagnoses made >10 or >20 years before cancer diagnosis. Our pathway-based analysis of inflammation-related variants and lung cancer risk using HM (manuscript 4) showed that HM is applicable to SNP analysis using pooled designs where heterogeneity can be incorporated into SNP priors. After HM a previously observed variant (rs2736100) and novel variant (rs2741354) were observed to be associated with lung cancer risk at corrected levels and replicated in an independent population. Taken together these results provide further evidence of both intrinsic and extrinsic factors affecting risk of lung cancer through inflammation.

The long-term success of lung transplantation has been challenged by chronic graft dysfunction, which is manifested as obliterative bronchiolitis (OB). We demonstrated that allograft airway fibrosis is a dynamic process of tissue remodelling, in which cellular and matrix components dynamically change before or after complete obliteration of the airway lumen. This dynamic process was associated with changes in expression and activity of matrix metalloproteinases (MMPs). The early inflammatory phase was associated with MMP-dependent migration of blood-borne fibrocytes, which highly express MMP-9 and MMP-12. ‘Established’ fibrosis was associated with MMP-2 and MMP-14 expressed by myofibroblasts in both human OB lesions and their animal models. In established allograft airway fibrosis, general MMP inhibition resulted in apoptosis of myofibroblasts in vivo and in vitro, while low-doses of MMP-inhibitor treatment induced upregulation of MMP-2, increased collagenolytic activity, and significantly decreased myofibroblasts and collagen. The dynamic process of tissue remodelling in established allograft airway fibrosis was supported by underlying continuous alloimmune responses, in particular, direct T-cell-myofibroblast contact. iii Modulation of tissue remodelling using a low-dose MMP inhibitor in combination with cyclosporine induced partial regression of fibrosis after its establishment. We further demonstrated the mechanism of alloimmune responses unique to the lung. Human and animal studies demonstrated that bronchioles develop de novo lymphoid tissue characterized by formation of high endothelial venules and homing of effector memory T-cells. A following study demonstrated the important role of local immunological memory maintained by the intrapulmonary lymphoid tissue in exerting effector function in allograft rejection. Collectively, the present studies support the hypothesis that tissue remodelling is an important mechanism of allograft airway fibrosis. Regulation of tissue remodelling and underlying tissue injury is important not only to arrest aberrant remodelling of allograft airways but likely to reverse aberrant remodelling and to regenerate normal tissue architecture in airways after lung transplantation.

Thesis (Ph. D.)--Yale University, 1981. / Vol. 3, Plates, not photocopied. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (v. 1, leaves 294-324).

Fer is a ubiquitously expressed non-receptor protein-tyrosine kinase that regulates normal physiology through signaling in a variety of cell types. Fer signals downstream of growth factor receptors frequently activated or amplified in human cancers and Fer has been identified as a positive regulator of cancer progression in the prostate and liver. Epidermal growth factor (EGF) receptor (EGFR) is frequently activated due to gene amplification or gain-of-function mutations in non-small cell lung carcinomas (NSCLC) leading to aggressive tumours that frequently metastasize. Since EGFR activates Fer, I tested whether Fer participates in EGFR-driven NSCLC cell migration, tumour progression and metastasis. Here, I show that Fer is expressed in cell lines derived from both normal lung epithelia and NSCLC and is activated following EGF treatment of NSCLC cells. To probe Fer function we used a lentiviral shRNA system to achieve stable knock-down (KD) of Fer in H1299 cells. Compared to control cells, Fer KD cells displayed a significant reduction in EGF-induced cell migration and invasion which correlated with reduced phosphorylation of the guanine nucleotide exchange factor Vav2. Consistent with Vav2 phosphorylation promoting Rac activation, we observed reduced localization of active, GTP- bound Rac1 to the leading edge of Fer KD cells treated with EGF. Tumour xenograft experiments were performed to test the role of Fer in NSCLC tumour progression and metastasis in immune compromised mice. Growth of primary tumours was normal, despite efficient Fer silencing in vivo. Interestingly, fewer spontaneous lung metastases were observed from subcutaneous Fer KD tumours compared to control. However, no differences were observed in lung seeding efficiency in experimental metastasis assays, suggesting that Fer may play a role in early stages of metastasis. Together, this study identifies Fer as a potential new therapeutic target for the treatment of EGFR-driven lung cancer metastasis. / Thesis (Master, Biochemistry) -- Queen's University, 2012-08-31 12:29:43.856

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Inflammation is believed to play a pivotal role in the development of cancer and in particular lung cancer through both intrinsic and extrinsic pathways. This thesis aimed through 4 manuscripts to determine the role of lung-specific inflammation-related exposures as well as genetic variants (Single Nucleotide Polymorphism (SNPs)) in genes related to inflammation pathways in lung cancer risk. Risk factors of particular interest were lung diseases including emphysema, chronic bronchitis, pneumonia and tuberculosis. Data were collected from a Toronto-based case-control study and combined with data from the International Lung Cancer Consortium (17 studies for the non-genetic analyses and 6 studies for the genetic analyses). For non-genetic data, methods included, but were not limited to, unconditional logistic regression within single studies, Cox proportional hazards regression, meta-analytic techniques and pooled analyses techniques. For genetic data, additive models of association across 7,650 SNPs (selected based on role in inflammation) were pooled across studies and hierarchical modeling iv (HM) was used to incorporate prior functional information from various sources concerning the SNPs of interest. Within the Toronto study (manuscript 1) associations with increased lung cancer risk were observed for occupational exposures, previous lung diseases and a family history of cancer. The meta-analysis (manuscript 2) and pooled analysis (manuscript 3) showed relatively consistent associations between previous lung diseases and lung cancer risk across histology, gender and smoking categories. Results persisted when examining lung disease diagnoses made >10 or >20 years before cancer diagnosis. Our pathway-based analysis of inflammation-related variants and lung cancer risk using HM (manuscript 4) showed that HM is applicable to SNP analysis using pooled designs where heterogeneity can be incorporated into SNP priors. After HM a previously observed variant (rs2736100) and novel variant (rs2741354) were observed to be associated with lung cancer risk at corrected levels and replicated in an independent population. Taken together these results provide further evidence of both intrinsic and extrinsic factors affecting risk of lung cancer through inflammation.