Transplantation of human embryonic stem cell-derived alveolar epithelial type II cells abrogates acute lung injury in mice.

Respiratory diseases are a major cause of mortality and morbidity worldwide. Current treatments offer no prospect of cure or disease reversal. Transplantation of pulmonary progenitor cells derived from human embryonic stem cells (hESCs) may provide a novel approach to regenerate endogenous lung cells destroyed by injury and disease. Here, we examine the therapeutic potential of alveolar type II epithelial cells derived from hESCs (hES-ATIICs) in a mouse model of acute lung injury. When transplanted into lungs of mice subjected to bleomycin (BLM)-induced acute lung injury, hES-ATIICs behaved as normal primary ATIICs, differentiating into cells expressing phenotypic markers of alveolar type I epithelial cells. Without experiencing tumorigenic side effects, lung injury was abrogated in mice transplanted with hES-ATIICs, demonstrated by recovery of body weight and arterial blood oxygen saturation, decreased collagen deposition, and increased survival. Therefore, transplantation of hES-ATIICs shows promise as an effective therapeutic to treat acute lung injury.

A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells.

Alveolar epithelial type II (ATII) cells are small, cuboidal cells that constitute approximately 60% of the pulmonary alveolar epithelium. These cells are crucial for repair of the injured alveolus by differentiating into alveolar epithelial type I cells. ATII cells derived from human ES (hES) cells are a promising source of cells that could be used therapeutically to treat distal lung diseases. We have developed a reliable transfection and culture procedure, which facilitates, via genetic selection, the differentiation of hES cells into an essentially pure (>99%) population of ATII cells (hES-ATII). Purity, as well as biological features and morphological characteristics of normal ATII cells, was demonstrated for the hES-ATII cells, including lamellar body formation, expression of surfactant proteins A, B, and C, alpha-1-antitrypsin, and the cystic fibrosis transmembrane conductance receptor, as well as the synthesis and secretion of complement proteins C3 and C5. Collectively, these data document the successful generation of a pure population of ATII cells derived from hES cells, providing a practical source of ATII cells to explore in disease models their potential in the regeneration and repair of the injured alveolus and in the therapeutic treatment of genetic diseases affecting the lung.

Development of a Bayesian Joint Logistic Model to Better Study the Association between Haplotypes and Disease

In 2011, there will be an estimated 1,596,670 new cancer cases and 571,950 cancer-related deaths in the US. With the ever-increasing applications of cancer genetics in epidemiology, there is great potential to identify genetic risk factors that would help identify individuals with increased genetic susceptibility to cancer, which could be used to develop interventions or targeted therapies that could hopefully reduce cancer risk and mortality. In this dissertation, I propose to develop a new statistical method to evaluate the role of haplotypes in cancer susceptibility and development. This model will be flexible enough to handle not only haplotypes of any size, but also a variety of covariates. I will then apply this method to three cancer-related data sets (Hodgkin Disease, Glioma, and Lung Cancer). I hypothesize that there is substantial improvement in the estimation of association between haplotypes and disease, with the use of a Bayesian mathematical method to infer haplotypes that uses prior information from known genetics sources. Analysis based on haplotypes using information from publically available genetic sources generally show increased odds ratios and smaller p-values in both the Hodgkin, Glioma, and Lung data sets. For instance, the Bayesian Joint Logistic Model (BJLM) inferred haplotype TC had a substantially higher estimated effect size (OR=12.16, 95% CI = 2.47-90.1 vs. 9.24, 95% CI = 1.81-47.2) and more significant p-value (0.00044 vs. 0.008) for Hodgkin Disease compared to a traditional logistic regression approach. Also, the effect sizes of haplotypes modeled with recessive genetic effects were higher (and had more significant p-values) when analyzed with the BJLM. Full genetic models with haplotype information developed with the BJLM resulted in significantly higher discriminatory power and a significantly higher Net Reclassification Index compared to those developed with haplo.stats for lung cancer. Future analysis for this work could be to incorporate the 1000 Genomes project, which offers a larger selection of SNPs can be incorporated into the information from known genetic sources as well. Other future analysis include testing non-binary outcomes, like the levels of biomarkers that are present in lung cancer (NNK), and extending this analysis to full GWAS studies.

Metastatic lung cancer in a new mouse model inheriting p53 and latent K-ras mutations

Lung cancer is a devastating disease with very poor prognosis. The design of better treatments for patients would be greatly aided by mouse models that closely resemble the human disease. The most common type of human lung cancer is adenocarcinoma with frequent metastasis. Unfortunately, current models for this tumor are inadequate due to the absence of metastasis. Based on the molecular findings in human lung cancer and metastatic potential of osteosarcomas in mutant p53 mouse models, I hypothesized that mice with both K-ras and p53 missense mutations might develop metastatic lung adenocarcinomas. Therefore, I incorporated both K-rasLA1 and p53RI72HΔg alleles into mouse lung cells to establish a more faithful model for human lung adenocarcinoma and for translational and mechanistic studies. Mice with both mutations ( K-rasLA1/+ p53R172HΔg/+) developed advanced lung adenocarcinomas with similar histopathology to human tumors. These lung adenocarcinomas were highly aggressive and metastasized to multiple intrathoracic and extrathoracic sites in a pattern similar to that seen in lung cancer patients. This mouse model also showed gender differences in cancer related death and developed pleural mesotheliomas in 23.2% of them. In a preclinical study, the new drug Erlotinib (Tarceva) decreased the number and size of lung lesions in this model. These data demonstrate that this mouse model most closely mimics human metastatic lung adenocarcinoma and provides an invaluable system for translational studies. ^ To screen for important genes for metastasis, gene expression profiles of primary lung adenocarcinomas and metastases were analyzed. Microarray data showed that these two groups were segregated in gene expression and had 79 highly differentially expressed genes (more than 2.5 fold changes and p<0.001). Microarray data of Bub1b, Vimentin and CCAM1 were validated in tumors by quantitative real-time PCR (QPCR). Bub1b , a mitotic checkpoint gene, was overexpressed in metastases and this correlated with more chromosomal abnormalities in metastatic cells. Vimentin, a marker of epithelial-mesenchymal transition (EMT), was also highly expressed in metastases. Interestingly, Twist, a key EMT inducer, was also highly upregulated in metastases by QPCR, and this significantly correlated with the overexpression of Vimentin in the same tumors. These data suggest EMT occurs in lung adenocarcinomas and is a key mechanism for the development of metastasis in K-ras LA1/+ p53R172HΔg/+ mice. Thus, this mouse model provides a unique system to further probe the molecular basis of metastatic lung cancer.^

The role of smoking status on postoperative complications and survival in lung cancer patients presenting to M.D. Anderson Cancer Center

It is estimated that 50% of all lung cancer patients continue to smoke after diagnosis. Many of these lung cancer patients who are current smokers often experience tremendous guilt and responsibility for their disease, and feel it might be too late for them to quit smoking. In addition, many oncologists may be heard to say that it is 'too late', 'it doesn't matter', 'it is too difficult', 'it is too stressful' for their patients to stop smoking, or they never identify the smoking status of the patient. Many oncologists feel unprepared to address smoking cessation as part of their clinical practice. In reality, physicians can have tremendous effects on motivating patients, particularly when patients are initially being diagnosed with cancer. More information is needed to convince patients to quit smoking and to encourage clinicians to assist patients with their smoking cessation. ^ In this current study, smoking status at time of lung cancer diagnosis was assessed to examine its impact on complications and survival, after exploring the reliability of smoking data that is self-reported. Logistic Regression was used to determine the risks of smoking prior to lung resection. In addition, survival analysis was performed to examine the impact of smoking on survival. ^ The reliability of how patients report their smoking status was high, but there was some discordance between current smokers and recent quitters. In addition, we found that cigarette pack-year history and duration of smoking cessation were directly related to the rate of a pulmonary complication. In regards to survival, we found that current smoking at time of lung cancer diagnosis was an independent predictor of early stage lung cancer. This evidence supports the idea that it is "never too late" for patients to quit smoking and health care providers should incorporate smoking status regularly into their clinical practice.^

EphA2 expression is regulated by EGFR and KRAS and promotes non-small cell lung cancer progression

Lung cancer is the leading cause of cancer deaths worldwide. The development of improved systemic therapy is needed for the most common form of the disease, non-small cell lung cancer (NSCLC). This will depend on the identification of valid molecular targets. Recent studies point to the receptor tyrosine kinase EphA2 as a novel therapeutic target. Overexpression of EphA2 has been demonstrated in a number of epithelial cancers, and its expression has been associated with more severe disease. Regulation of EphA2 in cancer is poorly understood. Recently, regulation of EphA2 by EGFR and KRAS has been reported in a number of in vitro models, but no examination of this relationship has been undertaken in patient tumors. Because of the established importance of EGFR and KRAS in NSCLC, we have investigated the relationship between these mutations and EphA2 in NSCLC patient tissues and cell lines. The significance of Epha2 expression was further examined by testing for correlation with survival, metastases, histology, and smoking status in patient tissues, and tumor cell proliferation and migration in vitro. EphA2 expression was analyzed in by immunohistochemistry in tissue microarray (TMA) format utilizing surgically resected lung cancer specimens. EGFR and KRAS mutation status was determined for the majority of specimens. EphA2 expression was detected in >90% of NSCLC tumors. High EphA2 expression was associated with decreased time to recurrence and metastases, and predicted poorer progression free and overall survival. Expression of EphA2 was positively correlated with activated EGFR and with KRAS mutation. Expression of EphA2 was also positively correlated with a history of smoking. There was no association between gender or histology and EphA2 expression. In H322 cells, activation of EGFR or KRAS resulted in an increase in EphA2 protein expression. Downregulation of EphA2 resulted in decreased proliferation in a clonal growth assay, and inhibited migration in a wound healing assay, in a panel of cell lines. The decrease in proliferation correlated with a transient decrease in the levels of phospho-ERK, a downstream effector of EGFR and KRAS. Based on these data, the potential of EphA2 as a therapeutic target for NSCLC should be further investigated. ^

Transcriptional regulation of lung tumor suppressor GPRC5A in malignant and normal cells

Chronic exposure of the airways to cigarette smoke induces inflammatory response and genomic instability that play important roles in lung cancer development. Nuclear factor kappa B (NF-κB), the major intracellular mediator of inflammatory signals, is frequently activated in preneoplastic and malignant lung lesions. ^ Previously, we had shown that a lung tumor suppressor GPRC5A is frequently repressed in human non-small cell lung cancers (NSCLC) cells and lung tumor specimens. Recently, other groups have shown that human GPRC5A transcript levels are higher in bronchial samples of former than of current smokers. These results suggested that smoking represses GPRC5A expression and thus promotes the occurrence of lung cancer. We hypothesized that cigarette smoking or associated inflammatory response repressed GPRC5A expression through NF-κB signaling. ^ To determine the effect of inflammation, we examined GPRC5A protein expression in several lung cell lines following by TNF-α treatment. TNF-α significantly suppressed GPRC5A expression in normal small airway epithelial cells (SAEC) as well as in Calu-1 cells. Real-time PCR analysis indicated that TNF-α inhibits GPRC5A expression at the transcriptional level. NF-κB, the major downstream effectors of TNF-α signaling, mediates TNF-α-induced repression of GPRC5A because over-expression of NF-κB suppressed GPRC5A. To determine the region in the GPRC5A promoter through which NF-κB acts, we examined the ability of TNF-α to inhibit a series of reporter constructs with different deletions of GPRC5A promoter. The luciferase assay showed that the potential NF-κB binding sites containing region are irresponsible for TNF-α-induced suppression. Further analysis using constructs with different deletions in p65 revealed that NF-κB-mediated repression of GPRC5A is transcription-independent. Co-immunoprecipitation assays revealed that NF-κB could form a complex with RAR/RXR heterodimer. Moreover, the inhibitory effect of NF-κB has been found to be proportional to NF-κB/RAR ratio in luciferase assay. Finally, Chromatin IP demonstrated that NF-κB/p65 bound to GPRC5A promoter as well as RAR/RXR and suppressed transcription. Taken together, we propose that inflammation-induced NF-κB activation disrupts the RA signaling and suppresses GPRC5A expression and thus contributes to the oncogenesis of lung cancer. Our studies shed new light on the pathogenesis of lung cancer and potentially provide novel interventions for preventing and treating this disease. ^

Hormone therapy and physical activity as predictors of lung cancer risk and survival: The California Teachers Study

Cigarette smoking is responsible for the majority of lung cancer cases worldwide; however, a proportion of never smokers still develop lung cancer over their lifetime, prompting investigation into additional factors that may modify lung cancer incidence, as well as mortality. Although hormone therapy (HT), physical activity (PA), and lung cancer have been previously examined, the associations remain unclear. This study investigated exposure to HT and PA that may modulate underlying mechanisms of lung cancer etiology and progression among women by using existing, de-identified data from the California Teachers Study (CTS).^ The CTS cohort, established in 1995–1996, has 133,479 active and retired female teachers and administrators, recruited through the California State Teachers Retirement System, and followed annually for cancer diagnosis, death, and change of address. Each woman enrolled in the CTS returned a questionnaire covering a wide variety of issues related to cancer risk and women's health, including recent and past HT use and physical activity, as well as active and environmental cigarette smoke exposure. Complete data to assess the associations between HT and lung cancer risk and survival were available for 60,592 postmenopausal women. Between 1995 and 2007, 727 of these women were diagnosed with invasive lung cancer; 441 of these died. Complete data to assess the associations between PA and lung cancer risk and survival were available for 118,513 women. Between 1995 and 2007, 853 of these women were diagnosed with invasive lung cancer; 516 of these died.^ After careful adjustment for smoking habits and other potential confounders, no measure of HT use was associated with lung cancer risk; however, any HT use (vs. no use) was associated with a decrease in lung-cancer-specific mortality. Specifically, among women who only used estrogen (E-only), decreases in lung cancer mortality were seen for recent use, but not for former use; no association was observed for estrogen plus progestin (E+P). Furthermore, among former users of HT, a statistically significant decrease in lung cancer mortality was observed for E-only use within 5 years prior to baseline, but not for E-only use >5 years prior to baseline. Neither long-term recreational PA nor recent recreational PA alone were associated with lung cancer risk; however, among women with a BMI<25 and ever smokers, high long-term moderate+strenuous PA was associated with a decrease in lung cancer risk. Women with non-local disease showed a decrease in lung cancer mortality associated with increasing duration of strenuous long-term activity, and 1.50-3.00 h/wk/y of recent moderate or recent strenuous PA. Long-term moderate PA was associated with decreased lung cancer mortality in never smokers, whereas recent moderate PA was associated with increased lung cancer mortality in current smokers. ^ Placing our findings in the context of the current literature, HT does not appear to be associated with lung cancer risk and previous studies reporting a protective effect of HT use on lung cancer risk may be subject to residual confounding by smoking. Looking at our findings regarding PA overall, the evidence still remains inconclusive regarding whether or not physical activity influence lung cancer risk or mortality. Our results suggest that recreational PA may associated with decreased lung cancer risk among women with BMI<25 and ever smoking-women; however, residual confounding by smoking should be strongly considered. To our knowledge, this is the first study to investigate lifetime recreational PA and lung cancer mortality among women. Our results contribute to the growing body of knowledge regarding non-smoking-related risk factors for lung cancer incidence and mortality among women. Given the potential clinical and interventional significance, further study and validation of these findings is warranted.^

BRONCHOALVEOLAR LAVAGE AND GALLIUM-67 LUNG SCANNING IN THE EVALUATION OF ASBESTOS-EXPOSED INDIVIDUALS

In this study, an attempt is made to evaluate certain parameters that might indicate the beginning of a certain fibrogenic activity in the lung parenchyma, even before such changes become visible on the chest x-ray. The hypothesis is that studies such as certain bronchoalveolar immunological characteristics and Gallium-67 lung scans may be more sensitive indicators of parenchymal lung damage in response to asbestos inhalation than conventional radiographic criteria. If so, then in those cases where the criteria for the diagnosis of asbestosis lack the presence of parenchymal changes, it would be unwise to deny the diagnosis unless further investigations, such as the bronchoalveolar lavage fluid analysis and the Gallium-67 lung scan techniques, are made available.^ Four groups of individuals have been included in this study. The volunteer group showing no history of asbestos exposure with normal chest x-rays has been used as a normal healthy comparison group. The other three groups are all asbestos-exposed but differ as to their findings in the chest radiographs. One has parenchymal changes (0/1 or more, ILO Classification), the second has no parenchymal but pleural changes, and the third has neither.^ The most significant laboratory parameter for bronchoalveolar lavage, in this study, is that of Neutrophils (PMNs). All three asbestos-exposed groups showed no differences when compared with each other, while such differences were statistically significant when such groups were separately compared with the normal comparison group. A similar finding existed also when the Helper: Suppressor T-Cell ratios were compared, and found to be higher in all the asbestos-exposed groups.^ Another sensitive test is that of Gallium-67 lung scan. This was found to be positive in some patients where parenchymal changes were absent. Even in some of those who showed neither parenchymal nor pleural changes in their chest x-ray showed positive test results. Such changes indicate a state of an underlying pathogenic process that is still undetectable by conventional radiography. This highly recommends the future application of such tests for the early detection of active pulmonary disease, especially in those who show no parenchymal changes in their chest x-rays. (Abstract shortened with permission of author.) ^

Genetic Predictors of Clinical Outcomes in Non-Small Cell Lung Cancer Patients

Lung cancer is the leading cause of cancer-related mortality in the US. Emerging evidence has shown that host genetic factors can interact with environmental exposures to influence patient susceptibility to the diseases as well as clinical outcomes, such as survival and recurrence. We aimed to identify genetic prognostic markers for non-small cell lung cancer (NSCLC), a major (85%) subtype of lung cancer, and also in other subgroups. With the fast evolution of genotyping technology, genetic association studies have went through candidate gene approach, to pathway-based approach, to the genome wide association study (GWAS). Even in the era of GWAS, pathway-based approach has its own advantages on studying cancer clinical outcomes: it is cost-effective, requiring a smaller sample size than GWAS easier to identify a validation population and explore gene-gene interactions. In the current study, we adopted pathway-based approach focusing on two critical pathways - miRNA and inflammation pathways. MicroRNAs (miRNA) post-transcriptionally regulate around 30% of human genes. Polymorphisms within miRNA processing pathways and binding sites may influence patients’ prognosis through altered gene regulation. Inflammation plays an important role in cancer initiation and progression, and also has shown to impact patients’ clinical outcomes. We first evaluated 240 single nucleotide polymorphisms (SNPs) in miRNA biogenesis genes and predicted binding sites in NSCLC patients to determine associations with clinical outcomes in early-stage (stage I and II) and late-stage (stage III and IV) lung cancer patients, respectively. First, in 535 early-stage patients, after correcting multiple comparisons, FZD4:rs713065 (hazard ratio [HR]:0.46, 95% confidence interval [CI]:0.32-0.65) showed a significant inverse association with survival in early stage surgery-only patients. SP1:rs17695156 (HR:2.22, 95% CI:1.44-3.41) and DROSHA:rs6886834 (HR:6.38, 95% CI:2.49-16.31) conferred increased risk of progression in the all patients and surgery-only populations, respectively. FAS:rs2234978 was significantly associated with improved survival in all patients (HR:0.59, 95% CI:0.44-0.77) and in the surgery plus chemotherapy populations (HR:0.19, 95% CI:0.07-0.46).. Functional genomics analysis demonstrated that this variant creates a miR-651 binding site resulting in altered miRNA regulation of FAS, providing biological plausibility for the observed association. We then analyzed these associations in 598 late-stage patients. After multiple comparison corrections, no SNPs remained significant in the late stage group, while the top SNP NAT1:rs15561 (HR=1.98, 96%CI=1.32-2.94) conferred a significantly increased risk of death in the chemotherapy subgroup. To test the hypothesis that genetic variants in the inflammation-related pathways may be associated with survival in NSCLC patients, we first conducted a three-stage study. In the discovery phase, we investigated a comprehensive panel of 11,930 inflammation-related SNPs in three independent lung cancer populations. A missense SNP (rs2071554) in HLA-DOB was significantly associated with poor survival in the discovery population (HR: 1.46, 95% CI: 1.02-2.09), internal validation population (HR: 1.51, 95% CI: 1.02-2.25), and external validation (HR: 1.52, 95% CI: 1.01-2.29) population. Rs2900420 in KLRK1 was significantly associated with a reduced risk for death in the discovery (HR: 0.76, 95% CI: 0.60-0.96) and internal validation (HR: 0.77, 95% CI: 0.61-0.99) populations, and the association reached borderline significance in the external validation population (HR: 0.80, 95% CI: 0.63-1.02). We also evaluated these inflammation-related SNPs in NSCLC patients in never smokers. Lung cancer in never smokers has been increasingly recognized as distinct disease from that in ever-smokers. A two-stage study was performed using a discovery population from MD Anderson (411 patients) and a validation population from Mayo Clinic (311 patients). Three SNPs (IL17RA:rs879576, BMP8A:rs698141, and STK:rs290229) that were significantly associated with survival were validated (pCD74:rs1056400 and CD38:rs10805347) were borderline significant (p=0.08) in the Mayo Clinic population. In the combined analysis, IL17RA:rs879576 resulted in a 40% reduction in the risk for death (p=4.1 × 10-5 [p=0.61, heterogeneity test]). We also validated a survival tree created in MD Anderson population in the Mayo Clinic population. In conclusion, our results provided strong evidence that genetic variations in specific pathways that examined (miRNA and inflammation pathways) influenced clinical outcomes in NSCLC patients, and with further functional studies, the novel loci have potential to be translated into clinical use.

Detecting genetic and nutritional lung cancer risk factors related to folate metabolism using Bayesian generalized linear models

Complex diseases, such as cancer, are caused by various genetic and environmental factors, and their interactions. Joint analysis of these factors and their interactions would increase the power to detect risk factors but is statistically. Bayesian generalized linear models using student-t prior distributions on coefficients, is a novel method to simultaneously analyze genetic factors, environmental factors, and interactions. I performed simulation studies using three different disease models and demonstrated that the variable selection performance of Bayesian generalized linear models is comparable to that of Bayesian stochastic search variable selection, an improved method for variable selection when compared to standard methods. I further evaluated the variable selection performance of Bayesian generalized linear models using different numbers of candidate covariates and different sample sizes, and provided a guideline for required sample size to achieve a high power of variable selection using Bayesian generalize linear models, considering different scales of number of candidate covariates. ^ Polymorphisms in folate metabolism genes and nutritional factors have been previously associated with lung cancer risk. In this study, I simultaneously analyzed 115 tag SNPs in folate metabolism genes, 14 nutritional factors, and all possible genetic-nutritional interactions from 1239 lung cancer cases and 1692 controls using Bayesian generalized linear models stratified by never, former, and current smoking status. SNPs in MTRR were significantly associated with lung cancer risk across never, former, and current smokers. In never smokers, three SNPs in TYMS and three gene-nutrient interactions, including an interaction between SHMT1 and vitamin B12, an interaction between MTRR and total fat intake, and an interaction between MTR and alcohol use, were also identified as associated with lung cancer risk. These lung cancer risk factors are worthy of further investigation.^

Exposure to nonsteroidal anti-inflammatory drugs and weight loss and hospitalization in non-small cell lung cancer patients

Background. Cancer cachexia is a common syndrome complex in cancer, occurring in nearly 80% of patients with advanced cancer and responsible for at least 20% of all cancer deaths. Cachexia is due to increased resting energy expenditure, increased production of inflammatory mediators, and changes in lipid and protein metabolism. Non-steroidal anti-inflammatory drugs (NSAIDs), by virtue of their anti-inflammatory properties, are possibly protective against cancer-related cachexia. Since cachexia is also associated with increased hospitalizations, this outcome may also show improvement with NSAID exposure. ^ Design. In this retrospective study, computerized records from 700 non-small cell lung cancer patients (NSCLC) were reviewed, and 487 (69.57%) were included in the final analyses. Exclusion criteria were severe chronic obstructive pulmonary disease, significant peripheral edema, class III or IV congestive heart failure, liver failure, other reasons for weight loss, or use of research or anabolic medications. Information on medication history, body weight and hospitalizations was collected from one year pre-diagnosis until three years post-diagnosis. Exposure to NSAIDs was defined if a patient had a history of being treated with NSAIDs for at least 50% of any given year in the observation period. We used t-test and chi-square tests for statistical analyses. ^ Results. Neither the proportion of patients with cachexia (p=0.27) nor the number of hospitalizations (p=0.74) differed among those with a history of NSAID use (n=92) and those without (n=395). ^ Conclusions. In this study, NSAID exposure was not significantly associated with weight loss or hospital admissions in patients with NSCLC. Further studies may be needed to confirm these observations.^

Using spatial linear models with SAR and CAR structure to examine Texas lung cancer incidence rates

Scholars have found that socioeconomic status was one of the key factors that influenced early-stage lung cancer incidence rates in a variety of regions. This thesis examined the association between median household income and lung cancer incidence rates in Texas counties. A total of 254 individual counties in Texas with corresponding lung cancer incidence rates from 2004 to 2008 and median household incomes in 2006 were collected from the National Cancer Institute Surveillance System. A simple linear model and spatial linear models with two structures, Simultaneous Autoregressive Structure (SAR) and Conditional Autoregressive Structure (CAR), were used to link median household income and lung cancer incidence rates in Texas. The residuals of the spatial linear models were analyzed with Moran's I and Geary's C statistics, and the statistical results were used to detect similar lung cancer incidence rate clusters and disease patterns in Texas.^

Epidemiology of Acute Lung Injury and Acute Respiratory Distress Syndrome in children in Vietnam

Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) are life- threatening disorders that can result from many severe conditions and diseases. Since the American European Consensus Conference established the internationally accepted definition of ALI and ARDS, the epidemiology of pediatric ALI/ARDS has been described in some developed countries. In the developing world, however, there are very few data available regarding the burden, etiologies, management, outcome, and factors associated with outcomes of ALI/ARDS in children. ^ Therefore, we conducted this observational, clinical study to estimate the prevalence and case mortality rate of ALI/ARDS among a cohort of patients admitted to the pediatric intensive care unit (PICU) of the National Hospital of Pediatrics in Hanoi, the largest children's hospital in Vietnam. Etiologies and predisposing factors, and management strategies for pediatric ALI/ARDS were described. In addition, we determined the prevalence of HIV infection among children with ALI/ARDS in Vietnam. We also identified the causes of mortality and predictors of mortality and prolonged mechanical ventilation of children with ALI/ARDS. ^ A total of 1,051 patients consecutively admitted to the pediatric intensive care unit from January 2011 to January 2012 were screened daily for development of ALI/ARDS using the American-European Consensus Conference Guidelines. All identified patients with ALI/ARDS were followed until hospital discharge or death in the hospital. Patients' demographic and clinical data were collected. Multivariable logistic regression models were developed to identify independent predictors of mortality and other adverse outcome of ALI/ARDS. ^ Prevalence of ALI and ARDS was 9.6% (95% confidence interval, 7.8% to 11.4%) and 8.8% (95% confidence interval, 7.0% to 10.5%) of total PICU admissions, respectively. Infectious pneumonia and sepsis were the most common causes of ALI/ARDS accounting for 60.4% and 26.7% of cases, respectively. Prevalence of HIV infection among children with ALI/ARDS was 3.0%. The case fatality rate of ALI/ARDS was 63.4% (95% confidence interval, 53.8% to 72.9%). Multiple organ failure and refractory hypoxemia were the main causes of death. Independent predictors of mortality and prolonged mechanical ventilation were male gender, duration of intensive care stay prior to ALI/ARDS diagnosis, level of oxygenation defect measured by PaO2/FiO2 ratio at ALI/ARDS diagnosis, presence of non-pulmonary organ dysfunction at day one and day three after ALI/ARDS diagnosis, and presence of hospital acquired infection. ^ The results of this study demonstrated that ALI/ARDS was a common and severe condition in children in Vietnam. The level of both pulmonary and non-pulmonary organ damage influenced survival of patients with ALI/ARDS. Strategies for preventing ALI/ARDS and for clinical management of the disease are necessary to reduce the associated risks.^

INTERACTION OF BACILLUS ANTHRACIS EXOSPORIUM PROTEIN BCLA WITH COMPLEMENT FACTOR H AND SPORE PERSISTENCE IN THE LUNG

Anthrax outbreaks in the United States and Europe and its potential use as a bioweapon have made Bacillus anthracis an interest of study. Anthrax infections are caused by the entry of B. anthracis spores into the host via the respiratory system, the gastrointestinal tract, cuts or wounds in the skin, and injection. Among these four forms, inhalational anthrax has the highest lethality rate and persistence of spores in the lungs of animals following pulmonary exposure has been noted for decades. However, details or mechanisms of spore persistence were not known. In this study, we investigated spore persistence in a mouse model. The results suggest that B. anthracis spores have special properties that promote persistence in the lung, and that there may be multiple mechanisms contributing to spore persistence. Moreover, recent discoveries from our laboratory suggest that spores evolved a sophisticated mechanism to interact with the host complement system. The complement system is a crucial part of the host defense mechanism against foreign microorganisms. Knowledge of the specific interactions that occur between the complement system and B. anthracis was limited. Studies performed in our laboratory have suggested that spores of B. anthracis can target specific proteins, such as Factor H (fH) of the complement system. Spores of B. anthracis are enclosed by an exosporium, which consists of a basal layer surrounded by a nap of hair-like filaments. The major structural component of the filaments is called Bacillus collagen-like protein of anthracis (BclA), which comprises a central collagen-like region and a globular C-terminal domain. BclA is the first point of contact with the innate system of an infected host. In this study, we investigated the molecular details of BclA-fH interaction with respect to the specific binding mechanism and the functional significance of this interaction in a murine model of anthrax infection. We hypothesized that the recruitment of fH to the spore surface by BclA limits the extent of complement activation and promotes pathogen survival and persistence in the infected host. Findings from this study are significant to understanding how to treat post-exposure prophylaxis and improve our knowledge of spores with the host immune system.