Doctor of Philosophy(PhD) / Over the last 20 years both asthma and obesity have increased in prevalence. What is the link? There are data to suggest that increasing obesity is a risk for the increase in prevalence of asthma. A number of mechanisms have been postulated including the effects of reduced lung volume on bronchial reactivity and mechanical changes with lower lung volumes. Other possibilities include other obesity-induced co-morbidities including gastro-oesophageal reflux. The aim of this thesis was to evaluate the link between asthma and obesity in both adult and childhood populations and to undertake experimental studies to examine the effects of changes in lung volume on bronchial reactivity. In chapter 1, the literature is reviewed. The current literature suggests that there is a link between diagnosis of asthma, new onset of asthma, symptoms of shortness of breath and wheeze. In chapter 2, data on 1997 adults in 3 population studies were analysed and the association between body mass index (BMI) and symptoms of shortness of breath and wheeze, diagnosis of asthma, medication usage for asthma, lung function and bronchial responsiveness were studied. This study showed that obesity was a risk for recent asthma (OR 2.04; 95%CI 1.02-3.76, p=0.048), symptoms of shortness of breath and wheeze (OR 2.6; 95%CI 1.46- 4.70, p=0.001), and medication usage for asthma (OR 2.53; 95%CI 1.36-4.70, p=0.003). There was a reduction in lung volume as measured by forced vital capacity (FVC), but there was no increase in bronchial hyperresponsiveness (BHR) (OR 0.87; 95% CI 0.35-2.21, p=0.78). Thus although the symptoms of asthma are increased there were no increases in BHR, despite significantly reduced lung volumes. The increase the medication usage is unlikely to have normalised the BHR, as there were ongoing symptoms suggestive of asthma. In chapter 3, data on 5993 children in 7 population studies were analysed and the association between BMI percentile and symptoms of cough, wheeze, ix diagnosis of asthma, medication usage for asthma, atopy, lung function and bronchial responsiveness was studied. After adjusting for atopy, sex, age, smoking and family history, BMI was a significant risk factor for wheeze ever (OR=1.06; 95%CI 1.01-1.10, p=0.008) and cough (OR=1.09; 95%CI 1.05-1.14, p=0.001) but not for recent asthma (OR=1.02; 95%CI 0.98-1.07 p=0.43), or bronchial hyperresponsiveness (OR=0.97; 95%CI 0.95-1.04 p=0.77). In girls, a higher BMI was significantly associated with higher prevalence of atopy (x2 trend 7.9, p=0.005), wheeze ever (x2 trend 10.4, p=0.001), and cough (x2 trend 12.3, p<0.001). These were not significant in boys. With increasing BMI in children, there was no reduction in lung volume, no increase in airway obstruction and no increase in bronchial responsiveness. In chapter 4, the hypothesis that obesity per se is associated with bronchial responsiveness was tested. Six obese women without asthma were compared to 6 non-obese women without asthma with high dose methacholine challenges to assess the bronchial responsiveness. There was no increase in bronchial responsiveness, and no difference in the position or shape of the high dose methacholine curve despite the fact that these women had reduced lung volumes associated with their obesity. In chapter 5, the hypothesis whether reduced lung volume per se would cause a change in greater mechanical effect, ie more marked airway narrowing in both non-asthmatic and asthmatic subjects was tested. Lung volumes and methacholine challenges were undertaken in the supine and erect position on different days. As expected in normal subjects there was a small reduction in lung volume on lying down, this was associated with an increase in the measure of bronchial reactivity DRR. In contrast, in asthmatics, there was no acute fall in lung volume and there were variable changes in the index of reactivity suggesting non-homogeneity in the lung function abnormality. This suggests changes in bronchial reactivity can occur without any relationship to lung volume change. These negative results suggest that lung volume changes that may occur in obesity are unlikely contributors to the apparent increase in asthma symptoms. In chapter 6, the hypothesis that the supposed increase in asthma symptoms in the obese were due to the effects of gastro-oesophageal reflux were assessed in 147 obese subjects graded for gastro-oesophageal reflux severity using manometry and gastroscopy. This study showed that subjects with increased gastro-oesophageal reflux did not have subjective increases in asthma prevalence, obstructive sleep apnoea, or snoring however they had a clear worsening of gas transfer as measured by carbon monoxide transfer suggesting a greater level of parenchymal disease. The overall results are that there is an increase of diagnosis of asthma, increase in symptoms of asthma and medication usage for the treatment of asthma in the obese. Objectively despite reductions in lung volume, there is no increase in bronchial responsiveness in this group suggesting that these symptoms are not related to true asthma, but to alternative co-morbidities associated with obesity such as gastro-oesophageal reflux. Notably gastrooesophageal reflux was not associated with increased asthma prevalence or airway obstruction. However it was associated with reduced gas transfer suggesting parenchymal disease. This suggests that the increase in symptoms of wheeze and shortness of breath in the obese should not be attributed to asthma in the absence of variable airflow limitation that is reversible spontaneously or with treatment, or with an increase in the existing bronchial hyperresponsiveness (BHR) to a variety of stimuli.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Virginia, 1997. / Includes bibliographical references (152-164). Also available online through Digital Dissertations.

Lung cancer is the leading cause of cancer death worldwide with 2.2 million new cases diagnosed and 1.8 million deaths per year. Lung squamous cell carcinoma (LSCC) is an aggressive histological subtype of non-small cell lung cancers (NSCLC), which is strongly associated with cigarette smoking and exposure to environmental pollutants. In collaboration with the Computational Biomedicine group at Boston University, we identified several putative cancer driver mutations in benign premalignant lung tumors, extracted from upper bronchial airway epithelium. The gene mutations from premalignant tumors are thought to initiate neoplasia but cannot promote malignancy independently. It is hypothesized that additional cooperating mutations will have a compounding effect on tumorigenesis if co-expressed in the same tumor cell. We used cancer genomics data from LSCC primary tumors in the Cancer Genome Atlas (TCGA) database to identify lung pre-malignancy associated genes that are significantly co-mutated. Two of the identified mutant genes, PIK3CA and NFE2L2, were shown to co-occur at a statistically significant rate in LSCC primary tumors. The PIK3CA gene encodes the PI3K lipid kinase, which regulates the AKT and mTOR kinase signaling pathways, thus promoting cell proliferation and survival. NRF2, the product of NFE2L2 gene, is a transcription factor that regulates the antioxidant response, playing a protective role against oxidizing cellular damage. NRF2 promotes the transcription of key proteins in the antioxidant response such as glutathione S transferase and NADPH oxidase. NRF2 is normally subject to ubiquitin-mediated degradation, which is regulated by the KEAP1 protein. Loss of function KEAP1 gene mutations are common in lung cancer. When cells are exposed to oxidizing agents, KEAP1 is modified by these agents, resulting in release and stabilization of NRF2, and the subsequent transcription of antioxidant response genes. Studies of PI3K and NRF2, and their downstream effectors have shown that both the PI3K/AKT/mTOR and NRF2/KEAP1 signaling pathways control autophagy, which is a catabolic process that regulates the recycling of macromolecules under conditions of nutrient deprivation. PI3K and NRF2 both control the activity of the SQSTM1/p62 protein, which plays a major role in autophagic degradation of cargo proteins. Autophagy has been implicated as a tumor suppressive mechanism. Both PI3K and NRF2 are known to inhibit autophagy in lung cancer cells. Based on the significant frequency of co-occurrence of PIK3CA and NFE2L2 gene mutations in pre-malignant LSCC lesions, we hypothesize that PI3K and NRF2 cooperate to inhibit autophagy to promote LSCC progression. To test our hypothesis, we co-expressed mutant forms of PIK3CA (E545K) and NFE2L2 (T80K) into a non-transformed Human Bronchial Epithelial Cell line (HBEC-3KT). We performed a series of Western Blots to verify PI3K and NRF2 protein expression as well as downstream AKT activation and markers of autophagy pathway activation. mTORC1 is an effector of PI3K and plays a central role in the inhibition of autophagy through the PI3K/AKT/mTOR signaling network. Therefore, we performed Western Blot analysis of samples treated with the mTORC1 inhibitor Everolimus to compare the effects of mTORC1 inhibition on autophagy activation in control, single PIK3CA, NFE2L2 and double mutant HBEC3-KT cells. We observed significant suppression of autophagy in the PI3K/NRF2 double mutant cells. Moreover, the studies also showed that the double mutant cells are more sensitive to anti-proliferative effects of Everolimus compared to control and single mutant cells. Taken together, our studies show that PIK3CA and NFE2L2 mutations cooperate to hyperactivate the AKT kinase and to suppress autophagy pathway activation. This represents a key mechanism of the malignant transformation of benign premalignant LSCC lesions. This warrants further research into the cooperation between PI3K and NRF2 in lung cancer pathogenesis. Our results have important implications both for diagnosis and treatment of LSCC. Though many important advances in the treatment of lung cancer have been made over the past few decades including the use of tyrosine kinase inhibitors (TKIs) such as Erlotinib, there is still much to understand about the biology and mechanisms of the disease.1 Blockers of the T-cell checkpoint, such as anti-PD-1 drugs are currently FDA-approved first lines of therapy for NSCLC. In addition, immunotherapy has shown some efficacy in lung cancer patients.2 Our studies provide rationale for the development of therapeutics that suppress NRF2 and PI3K activity in the treatment of LSCC.3 Since mTORC1 inhibitors cause robust inhibition of PIK3CA/NFE2L2 double mutant cell proliferation, future studies will be aimed at testing combinations of mTORC1, PI3K and NRF2 pathway inhibitors to treat LSCC.

Introduction Lung cancer is the most common cause of cancer-related death in the United States (US). Tobacco smoking is a well-recognized cause of lung cancer. About 2% of the United States (US) population lives in Tennessee (TN). Nearly 21 % of TN adults are current smokers as per 2019 data, compared to 14% across the US. The percentage of smokers has historically been high in TN and its surroundings. This can be attributed to the area's socio-economic and cultural characteristics, along with large areas of tobacco farming in the region. This increases the risk of lung cancer in the TN population. Surveillance Epidemiology and End Results Program (SEER) is a collection of cancer registries across the US, covering about 35% of the US population (TN cancer registry is not a part of SEER). Our study compares lung cancer incidence and characteristics in the TN cancer registry with the SEER 18 registry. Materials and Methods Data were collected from the TN cancer registry and SEER separately for lung and bronchial cancer. Data was analyzed for different histological subtypes, age groups, gender, stage at diagnosis, and rural/urban residence. Stata and Microsoft Excel were used in data analysis. A Chi-square test was used to calculate the statistical significance. Results From 2008 to 2017, 58644 cases of lung cancer were reported in the Tennessee cancer registry. During the same period, 519112 cases were reported in the SEER registry. The most frequent histological subtype of lung cancer in TN and SEER was adenocarcinoma (frequency of 17,503 Vs. 182346), followed by squamous cell carcinoma and small cell carcinoma. Most cancers in TN and SEER were diagnosed at stage of distant metastasis (46% vs. 52% ), followed by regional metastasis, localized, and in situ (Image1). The frequency of lung cancer diagnosis was high among those older than 65 in TN and SEER (64% vs. 69%). Males had a higher incidence of lung cancer in both registries. Most lung cancers were reported in the urban area in both registries. Chronic obstructive pulmonary disease was the most commonly reported secondary diagnosis (3,099), followed by pleural effusion in the TN database; the comparable data were not available in SEER. Relative survival at 12 months and five years for lung cancer in TN were 46.6 % and 19.5 % (Vs. 46.4% and 19.9% in SEER) Discussion and Conclusion If both registries were perfect, then lung and bronchial cancer incidence will be 9241 and 6048 per million in ten years in TN and SEER, respectively. But after careful analysis, we conclude that such analysis will be erroneous. The proportion of different histological types, stage at diagnosis, age groups, and gender were in the same order in both groups. Although chi-square test values are significant for all the variables, we infer no conclusion considering the data's inherent bias. Further in-depth analysis of the data is required.

Lung cancer is the number one cause of cancer related deaths in Ontario and throughout Canada. The 5-year survival rate for those diagnosed with lung cancer in 2020 was approximately 22.2%. Poor screening techniques is the main cause of low survival rates and late detection. Recent advancements in screening for lung cancer have led researchers to look at the benefits of using low-dose CT (LDCT) scanning to screen patients at high risk for lung cancer in order to detect the cancer in its earlier stages. There is strong evidence that using this new method of testing in lung cancer screening can reduce lung cancer related mortality by increasing the chance that the disease is detected in an earlier stage and in turn improving the patient’s chance at life saving treatment. Lung cancer screening requires LDCT resources and, based on the current recommendations, there is a concern that the new demand for imaging may exceed existing capacity of the imaging centers. This research evaluates impact of the Lung Cancer Screening Pilot for People at High Risk on the imaging resources and aims to answer the question: What would be the system performance for different imaging policies assuming a fixed imaging capacity? Administrative data from the Ottawa Hospital (TOH) as well as data from other research projects were used in order to develop and populate a simulation model. The policies that were assessed include: using biannual screening for patients who receive a negative baseline scan, using annual screening for patients with a negative baseline scan with all suspicious patients returning for a follow-up scan in six months, using annual screening for patients with a negative baseline scan with all suspicious patients returning for a follow-up scan in three months, using biannual screening for patients with a negative baseline scan with all suspicious patients returning for a follow-up scan in six months and using biannual screening for patients with a negative baseline scan with all suspicious patients returning for a follow-up scan in three months. These policies were assessed by looking at wait times for patients to be screened. Possible shift between lung cancer stages was also considered. The impact of this study is to look at system performances for different screening policies that could be used assuming a fixed imaging capacity. It represents a first step for further research should the data that is needed become available.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12958号 / 論医博第2100号 / 新制||医||1011(附属図書館) / 32357 / 京都大学大学院医学研究科医学専攻 / (主査)教授 三嶋 理晃, 教授 三森 経世, 教授 浅野 雅秀 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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