Chemoprevention of Lung Carcinogenesis: Aerosol Administration and Deposition in the Mouse Lung

INTRODUCTION Chemoprevention is the use of natural or synthetic agents to inhibit either the initial development or the further progression of early lesions. Chemoprevention of lung cancer aims to decrease lung cancer morbidity and mortality, especially for former smokers. Many synthetic and natural compounds have been investigated for their potential chemopreventive efficacy. Conventional administration of these compounds: especially oral administration) is convenient, but may potentially result in adverse side effects. Aerosol delivery, on the other hand, offers many advantages over conventional routes of administration for diseases of the respiratory tract and the lungs. These advantages include the extensive pulmonary surface area available for drug deposition, the avoidance of first-pass metabolic degradation by the liver and/or intestines, the noninvasive nature of administration, and the localized effect of low doses of drugs, all of which lead to a rapid response with fewer systemic side effects. The efficacy of a given drug via aerosol administration depends on many factors such as particle size distribution, total particle mass concentration, and the physiochemical properties of drug particles. Genetically-engineered mice play an important role in drug screening and preclinical studies. However, because mice have much smaller lungs than those of human beings, the lung deposition data attained for humans cannot be applied to the mouse. Hence few studies have focused on particle deposition in the mouse lung. It is thus necessary to measure the mass deposition of particles in the mouse lung. METHOD A spray-drying process was used to study the inhibitory effects of potential chemopreventive agents on carcinogen-induced tumors in the A/J mouse. The carcinogen in the studies was benzo[a]pyrene, unless otherwise specified. Synthetic and natural compounds were investigated individually or in combination. The compounds were aerosolized with a custom-built Collison atomizer. The resultant drug aerosols were delivered to the mice that were retained in a nose-only exposure chamber. Four small molecular inhibitors: gefitinib, erlotinib, lapatinib and wortmannin), and four natural agents: resveratrol, caffeine, anthocyanins, and protocatechuic acid), were considered as examples of single agents. Gefitinib and erlotinib were delivered in an aerosol form to reduce the cutaneous side effects. Lapatinib and wortmannin were each administered both via aerosol and oral gavage to compare the efficacy and toxicity as they were administered via different routes. Resveratrol was evaluated in two models with either vinyl carbamate or benzo[a]pyrene as the carcinogen. It was delivered via aerosol to avoid fast clearance in the blood before it reached the lung. Caffeine was delivered in aerosol to assess only its inhibitory effects and to avoid its negative effects on body weight. Anthocyanins were delivered via aerosol due to their poor bioavailability. Protocatechuic acid is a metabolite of anthocyanins and was also delivered via aerosol for comparison with anthocyanins. The combinations of aerosolized budesonide: a synthetic glucocorticoid) and dietary polyphenon E: a well-defined mixture of green tea extract) was discussed as one example of the combinational treatment. In addition to the bioassays, drug deposition in the mouse lung was evaluated for both polydispersed and monodispersed drug particles for a better understanding of the delivery process and for future applications. Gefitinib was selected as the model agent. Polydispersed gefitinib particles were generated with the Collison atomizer used in the animal studies. Monodispersed particles were generated using the single-capillary electrospray technique. Lung and blood samples were harvested immediately after the aerosol treatment. The lung and plasma levels of gefitinib were measured with varied solution concentrations, exposure durations, and particle sizes. The aerial mass concentration in the chamber was also measured to estimate the doses. RESULTS Aerosolized erlotinib: 5 mg/ml) did not inhibit tumor multiplicity but reduced tumor load by 63.8%: P \u3c 0.05). Aerosolized gefitinib in three separate doses: 5, 10, and 15 mg/ml) inhibited tumor multiplicity by ~30% for all three doses when the tumors were induced by one dose of benzo[a]pyrene: 100 mg/kg body weight), but the results were not statistically significant. Aerosolized gefitinib showed consistent inhibitory effects on tumor load, and the inhibition rate increased as the dose increased. The tumor load was reduced by 39.0%, 46.2%, and 56.4%: P \u3c 0.05) for 5, 10, and 15 mg/ml gefitinib solutions, respectively. The highest dose: 15 mg/ml) of gefitinib was repeated in mice whose tumors were induced by two doses of benzo[a]pyerene: 100 mg/kg body weight, one week apart) and it inhibited both tumor multiplicity: by 49.8%, P \u3c 0.001) and tumor load: by 57.0%, P \u3c 0.001). No visible skin alteration was observed in mice treated with aerosolized gefitinib or erlotinib. Both aerosolized lapatinib: 50 mg/ml) and orally-administered lapatinib: 100 mg/kg body weight) showed inhibitory effects. Aerosolized lapatinib reduced tumor multiplicity by 39.6%: P \u3c 0.05) and tumor load by 41.7%: P \u3c 0.05). Orally-dosed lapatinib reduced tumor multiplicity by 37.6%: not significant) and tumor load by 42.4%: P \u3c 0.05). At the current doses of lapatinib, no adverse side effect was observed in either the aerosol group or the orally-dosed group. Wortmannin showed striking inhibitory effects via aerosol inhalation and per os. Oral wortmannin: 1.0 mg/kg body weight) inhibited tumor multiplicity by 85.5%: P \u3c 0.001) and tumor load by 77.9%: P \u3c 0.05). In the same model, aerosolized wortmannin: 2.0 mg/ml) inhibited tumor multiplicity by 50.8%: P \u3c 0.05) and tumor load by 79.7%: P \u3c 0.05). Despite the efficacy of oral wortmannin, the accompanying systemic adverse effects were not negligible. Reduced body weight and death were observed in the orally-dosed mice, but not in the aerosol treated mice. Thus, aerosolized wortmannin was evaluated a second time in the bioassay with two doses of benzo[a]pyrene, and it was found to reduce tumor multiplicity and tumor load by 66.7%: P \u3c 0.001) and 80.4%: P \u3c 0.0001), respectively, with a slight decrease in body weight. Resveratrol inhibited the proliferation of cells in the human lung cancer cell lines A549 and H1129, which indicates that resveratrol could possibly be an effective inhibitor of human lung cancer. Aerosolized resveratrol was shown to inhibit the tumor load in both vinyl carbamate- and benzo[a]pyrene-induced models. The decrease in tumor load was 26.3%: P \u3c 0.05) and 36.0%: P \u3c 0.01) for 7.5 and 15 mg/ml solutions, respectively, in the vinyl carbamate-induced model. In the benzo[a]pyrene-induced model, aerosolized resveratrol: 15 mg/ml) significantly reduced tumor multiplicity by 37.1%: P \u3c 0.05) and tumor load by 72.0%: P \u3c 0.01). Pharmacokinetic studies showed that more resveratrol was delivered to the lung by aerosol inhalation than by oral gavage. Aerosolized caffeine: 10 mg/ml) inhibited tumor multiplicity by 31.9%: P \u3c 0.05) and tumor load by 44.3%: P \u3c 0.05) without causing a reduction in the body weight gain, in contrast to the orally-administered caffeine, which did cause body weight loss. Aerosolized protocatechuic acid: 12 mg/ml) reduced tumor multiplicity by 47.8%: P \u3c 0.05) and tumor load by 44.9%: P \u3c 0.05). However, the inhibitory effects of anthocyanins: 5 mg/ml, extracted from black raspberries) were marginal: 14.5% on the tumor multiplicity and 30.4% on the tumor load, not significant). The particle deposition in the mouse lung was estimated using gefitinib as the model compound. For the Collison atomizer, the aerosol mass concentration in the exposure chamber increased linearly from 12.3 to 179.8 μg/L as the solution concentration increased from 1 to 50 mg/ml. The lung and plasma levels of gefitinib increased monotonically with increased solution concentration and exposure time, and the concentration in the lung was much higher than that in the plasma. The deposition efficiency is defined as the ratio of the mass deposited in the lung to the dose, and it is a function of particle size. In general, monodispersed particles have a higher delivery efficiency than polydispersed particles. For polydispersed particles, the 2.5 mg/ml solution: with a mass mean aerodynamic diameter, MMAD, at 120 nm) had the highest efficiency. For monodispersed particles, 100 nm particles showed the highest deposition efficiency. CONCLUSIONS Aerosol delivery is a promising approach for the chemoprevention of lung cancer. Many natural and synthetic compounds showed inhibitory effects on benzo[a]pyrene-induced lung tumorigenesis in A/J when they are delivered via aerosol inhalation. In contrast to oral administration, aerosol delivery of the agents mitigated systemic toxicities with comparable inhibitory effects and improved the efficacy of some agents by increasing their bioavailability in the lung. The current aerosol delivery system was characterized and the mass deposition in the mouse lung was positively correlated with both the solution concentration and the exposure time. Aerosols with an MMAD around 100 nm may have the highest delivery efficiency, for both polydispersed and monodispersed distributions

Problems in Mathematical Finance Related to Time-inconsistency and Mean Field Games

This thesis consists of two problems on time inconsistency and one problem on mean field games, all featuring the study of equilibrium and applications in economics and finance. In Chapter II, we deal with time inconsistency in the infinite horizon mean- variance stopping problem under discrete time setting. In order to determine a proper time-consistent plan, we investigate subgame perfect Nash equilibria among three different types of strategies, pure stopping times, randomized stopping times and liquidation strategies. We show that equilibria among pure stopping times or randomized stopping times may not exist, while an equilibrium liquidation strategy always exists. Furthermore, we argue that the mean-standard deviation variant of this problem makes more sense for this type of strategies in terms of time consistency. The existence and uniqueness of optimal equilibrium liquidation strategies are also analyzed. In Chapter III, we delve into equilibrium concepts for time inconsistent stopping problems in continuous time. We point out that the two existing notions of equi- librium in the literature, which we call mild equilibrium and weak equilibrium, are inadequate to capture the idea of subgame perfect Nash equilibrium. To characterize it more accurately, we introduce a new notion, strong equilibrium. It is proved that an optimal mild equilibrium is always a strong equilibrium. Moreover, we provide a new iteration method that can directly construct an optimal mild equilibrium and thus also guarantees its existence. xi In Chapter IV, we adopt a mean field game (MFG) approach to analyze a costly job search model with incomplete credit and insurance markets. The MFG approach enables us to quantify the impact of a class of countercyclical unemployment benefit policies on labor supply in general equilibrium. Our model provides two interesting predictions. First, the difference between unemployment rates under a countercyclical policy and an acyclical policy is positive and increases rapidly with the size of the aggregate shock. Second, compared with a baseline policy without means test, a means-tested policy which is targeted to provide more generous benefits to liquidity constrained individuals turns out to provide improved consumption insurance to all individuals as well as results in a lower equilibrium unemployment rate relative to a comparable non-targeted policy.PHDApplied and Interdisciplinary MathematicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/169644/1/jingjiez_1.pd

Equilibrium concepts for time-inconsistent stopping problems in continuous time

A \emph{new} notion of equilibrium, which we call \emph{strong equilibrium}, is introduced for time-inconsistent stopping problems in continuous time. Compared to the existing notions introduced in ArXiv: 1502.03998 and ArXiv: 1709.05181, which in this paper are called \emph{mild equilibrium} and \emph{weak equilibrium} respectively, a strong equilibrium captures the idea of subgame perfect Nash equilibrium more accurately. When the state process is a continuous-time Markov chain and the discount function is log sub-additive, we show that an optimal mild equilibrium is always a strong equilibrium. Moreover, we provide a new iteration method that can directly construct an optimal mild equilibrium and thus also prove its existence.Comment: Final version. To appear in Mathematical Finance. Keywords:Time-inconsistency, optimal stopping, strong equilibria, weak equilibria, mild equilibria, non-exponential discounting, subgame perfect Nash equilibriu

Students on the move - interregional migration aspirations of higher education institution graduate candidates in Central China

China is an important and interesting case to examine for interregional migration research. The interregional migration of higher education institution graduates is high on the policy agenda because of concerns about brain drain from Central China to the Eastern coastal regions. For several decades specific policies have been enacted to retain graduates in the inland regions. Whilst the academic literature on migration is predominantly based on Western theoretical approaches, premised on a market-oriented context, Chinese higher education is still closely regulated by ‘state-prescribed admission policies, quota and assignment systems’ after China’s 1978 reform and opening up campaign. For this reason, the characteristics of graduate migration within China are likely to diverge from patterns observed in previous research based in Western countries. A priori, therefore, it is unclear how well the established theoretical canon fits the case of China. This mixed methods research has been designed and applied to understand the direction and drivers of the migration intentions/aspirations of prospective graduates in Central China. By combining a substantial survey (n=975) of final year undergraduates with structured interviews, this research has found that a chronological perspective on investigating potential migrants’ decision-making process is important in the migration research field. Life experiences play an important role in the value shaping process of graduates, which forms the inner reasons for how students value different factors in the migration decision-making process. Also, the influence of latent factors (in this research, cultural and social aspects) has constrained or reinforced graduates’ migration aspirations. Some elements of the special Chinese context, such as the education system and economic geography, were also found to be important for Chinese graduates in multiple aspects. This research offers a new perspective on interregional migration research and reveals gaps that further investigation could help to fill

Neuroprotective effects of electro-acupuncture in spinal cord injury rats via up-regulation of DUSP14

Purpose: To study the effect and mechanism of action of electro-acupuncture (EA) on nerve regeneration by analyzing the behavior, inflammation and cell death in spinal cord injury (SCI) rat model. Methods: SCI model was established according to Allen’s falling strike method. Electroacupuncture was performed on Jiaji (EX-B2)/Mingmen (GV4) acupoint with a 1 mA current intermittent wave at a frequency of 2Hz for 20 min daily. Interleukin (IL-6) and tumor necrosis factor-α (TNF-α) levels were measured using ELISA kits. Apoptosis-induced DNA strand breaks were evaluated by TUNEL assay while relative mRNA expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels were measured by western blot. Results: Relative mRNA and protein expressions of DUSP14 decreased in SCI rats with time but increased by EA treatment. Further, partial locomotor functional recovery was presented in SCI rats by EA treatment. Moreover, intraspinal injection of DUSP14 over-expression viral supernatants/EA treatment ameliorated inflammation and apoptosis in SCI rats. Meanwhile, the protein levels of NF-κB p65 (nucleus) and phosphorylated TGF-activated kinase 1 (p-TAK1) increased in SCI rats following EA treatment but were decreased by EA treatment and intraspinal injection of DUSP14 over-expression viral supernatants. Conclusion: EA acupoint treatment exerts neuroprotective effects in SCI rats via the reduction of inflammation and apoptosis, and induction of DUSP14