Background: Measurement of carbon monoxide in expired air samples (ECO) is a non-invasive, cost-effective biochemical marker for smoking. Cut points of 6. ppm-10. ppm have been established, though appropriate cut-points for pregnant woman have been debated due to metabolic changes. This study assessed whether an ECO cut-point identifying at least 90% of pregnant smokers, and misidentifying fewer than 10% of non-smokers, could be established. Methods: Pregnant women (N=167) completed a validated self-report smoking assessment, a urine drug screen for cotinine (UDS), and provided an expired air sample twice during pregnancy. Results: Half of women reported non-smoking status early (51%) and late (53%) in pregnancy, confirmed by UDS. Using a traditional 8. ppm. +. cut-point for the early pregnancy reading, only 1% of non-smokers were incorrectly identified as smokers, but only 56% of all smokers, and 67% who smoked 5. + cigarettes in the previous 24. h, were identified. However, at 4. ppm. +, only 8% of non-smokers were misclassified as smokers, and 90% of all smokers and 96% who smoked 5. + cigarettes in the previous 24. h were identified. False positives were explained by heavy second hand smoke exposure and marijuana use. Results were similar for late pregnancy ECO, with ROC analysis revealing an area under the curve of 95 for early pregnancy, and 94 for late pregnancy readings. Conclusions: A lower 4. ppm ECO cut-point may be necessary to identify pregnant smokers using expired air samples, and this cut-point appears valid throughout pregnancy. Work is ongoing to validate findings in larger samples, but it appears if an appropriate cut-point is used, ECO is a valid method for determining smoking status in pregnancy.

Background: Measurement of carbon monoxide in expired air samples (ECO) is a non-invasive, cost-effective biochemical marker for smoking. Cut points of 6. ppm-10. ppm have been established, though appropriate cut-points for pregnant woman have been debated due to metabolic changes. This study assessed whether an ECO cut-point identifying at least 90% of pregnant smokers, and misidentifying fewer than 10% of non-smokers, could be established. Methods: Pregnant women (N=167) completed a validated self-report smoking assessment, a urine drug screen for cotinine (UDS), and provided an expired air sample twice during pregnancy. Results: Half of women reported non-smoking status early (51%) and late (53%) in pregnancy, confirmed by UDS. Using a traditional 8. ppm. +. cut-point for the early pregnancy reading, only 1% of non-smokers were incorrectly identified as smokers, but only 56% of all smokers, and 67% who smoked 5. + cigarettes in the previous 24. h, were identified. However, at 4. ppm. +, only 8% of non-smokers were misclassified as smokers, and 90% of all smokers and 96% who smoked 5. + cigarettes in the previous 24. h were identified. False positives were explained by heavy second hand smoke exposure and marijuana use. Results were similar for late pregnancy ECO, with ROC analysis revealing an area under the curve of 95 for early pregnancy, and 94 for late pregnancy readings. Conclusions: A lower 4. ppm ECO cut-point may be necessary to identify pregnant smokers using expired air samples, and this cut-point appears valid throughout pregnancy. Work is ongoing to validate findings in larger samples, but it appears if an appropriate cut-point is used, ECO is a valid method for determining smoking status in pregnancy.

Introduction: Genetic rearrangements in Ewing sarcoma, prostate, and leukemia cells result in activation of oncogenic ETS transcription factor fusions. Mithramycin (MTM) has been identified as an inhibitor of EWS-FLI1 transcription factor, a gene fusion product responsible for oncogenesis in Ewing sarcoma. Despite preclinical success, a phase I/II clinical trial testing MTM therapy in refractory Ewing sarcoma was terminated. Liver and blood toxicities resulted in dose de-escalation and sub-therapeutic exposures. However, the promise of selectively targeting oncogenic ETS transcription factors like EWS-FLI1 prompted us to undertake the discovery of more selective, less toxic analogues of MTM. MTM is a potent inhibitor of ubiquitous SP1 transcription factor, likely inducing non-specific toxicity. In collaboration with two medicinal chemistry groups, two semi-synthetic efforts were implemented to develop novel analogues of MTM. The first effort utilized the biosynthetic product mithramycin SA (MTMSA) to modify C3-side chain. The second effort utilized an oxime linker directly formed on MTM’s C3-side chain (MTM-oxime; MTMox). Here I present the pharmacological assessment of over 75 novel MTM analogues towards selectively targeting oncogenic ETS transcription factors, like EWS-FLI1, over ubiquitous transcription factors, like SP1. Methods: Novel MTM analogues were evaluated for selective cytotoxicity against ETS fusion-dependent cell lines. Selectively cytotoxic analogues were evaluated for inhibitory effects on several gene promoters in TC-32 reporter cell lines, a Ewing sarcoma cell line dependent on EWS-FLI1, transfected with luciferase reporter vector. Cloned reporter vectors incorporated NR0B1 (EWS-FLI1 binding), β-actin (SP1 binding) and CMV (non-specific) gene promoters. Furthermore, gene (mRNA) and protein expression changes of EWS-FLI1 and SP1, as well as regulated target genes, namely NR0B1, VEGFA and BCL-2 were evaluated with MTM analogue treatments. The MTM analogues with most selective activity in vitro were administered to mice by intravenous bolus dose for pharmacokinetic analysis. The MTM analogues with highest systemic exposure from each semi-synthetic effort, namely MTMSA-Trp-A10 and MTMox-24, were further evaluated. Metabolic stabilities in whole blood, plasma, and tumor cell matrices, and across multiple species were compared with MTM. Moreover, intrinsic hepatic clearances were estimated using mouse liver microsomes. Tumor and liver distributions were estimated in tumor bearing mice. Additionally, the effect of organic anionic transporter polypeptides (OATP) on distribution of MTM was investigated. Maximum tolerated doses were evaluated for lead MTM analogues, having both selective activities in vitro and high systemic exposure, compared to MTM. Complete blood cell counts and plasma alanine aminotransferase activity were measured to evaluate dose-dependent blood and liver toxicities, respectively. ETS fusion-dependent and non-dependent cell lines were implanted subcutaneously into immunocompromised mice for efficacy studies. Average tumor volumes and survival were tracked for mice receiving treatment, compared to MTM and vehicle treatment. Results: Evaluation of MTM analogues from both semi-synthetic efforts revealed that conjugation of MTM C3-side chain with tryptophan (Trp) and/or phenylalanine (Phe) improved selective cytotoxicity against ETS fusion-dependent cell lines. This was highlighted by MTMSA-Trp-A2 (also refer to as MTMSA-Phe-Trp) and MTMSA-Trp-A10 (also refer to as MTMSA-Trp-Trp), with selective indices of 19.1 and 15.6, respectively, compared to MTM (1.5). Similarly, MTMox-23 (also refer to as MTMox-Phe-Trp) and MTMox-20 (also refer to as MTMox-Trp) had selectivity indices of 4.6 and 4.5, respectively. These selectively cytotoxic MTM analogues inhibited EWS-FLI1-mediated transcription 10-fold more effectively than both non-specific CMV-mediated and SP1-mediated (via β-actin promoter) transcription in TC-32 reporter cell lines. Moreover, gene (mRNA) and protein expression of EWS-FLI1 and regulated gene, NR0B1, were inhibited with MTM analogue treatment (GI50, 6-hour) in TC-32 cells. Similarly, SP1 and target genes, VEGFA and BCL-2, gene (mRNA) and protein expressions were also inhibited with MTM analogue treatment (GI50, 6-hour) in TC-32 cells. Conjugation of Trp and/or Phe to C3-side chain of MTM increased systemic exposure in vivo. Most impressively, the addition of two Trp residues, namely MTMSA-Trp-A10 and MTMox-24 (also refer to as MTMox-Trp-Trp), resulted in systemic exposure increases of 218- and 42-fold, respectively, after intravenous (IV) bolus dose. Metabolically, tryptophan/phenylalanine conjugated MTM analogues are liable to esterase activity on carboxy-methyl functional group. Very rapid de-methylation in biological matrix was observed with MTMox-24, compared to MTMSA-Trp-A10, suggesting a regiospecific effect. However, esterase activity was limited to rodent matrices and demethylation occurred at significantly diminished rates in non-human primate and human plasma. MTM analogues were not susceptible to p450-mediated metabolism, with negligible loss in mouse liver microsome assay compared to verapamil control. MTM (1mg/kg) and MTMox-24 (6mg/kg) were detected in subcutaneously implanted (flank) LL2 tumors and liver homogenates after IV bolus dose. Interestingly, MTMSA-Trp-A10 (2mg/kg) was not. Despite a 3-fold increase in systemic exposure with rifampin oral pretreatment, an OATP inhibitor, exposure of MTM was unaffected in Oatp knockout mouse model. Exposure of MTM in liver tissue was 8.4-fold higher compared to tumor tissue with low tissue clearance. This agrees with the lack of metabolism observed in liver microsomes and may provide a mechanism for clinically observed liver toxicity. MTMSATrp-A10 had a single maximum tolerated dose (MTD) of 0.75mg/kg, compared to 1mg/kg for MTM, administered by IV bolus. In contrast, MTM-oxime analogues (MTMox-20, -23, -24 and -25) had single maximum tolerated doses of 20 – 25mg/kg. These increased tolerances are the result of additive differences in whole blood stability, cytotoxicity and systemic exposure. At a dose of 0.75mg/kg, administered every 3 days, MTMSA-Trp-A10 did not result in an efficacious result in tumor xenograft studies. These studies remain under further investigation, but the result may indicate high plasma protein binding of MTMSA-Trp-A10 and lack of free fraction available within tumor. The most selective MTM-oxime analogue in vitro, MTMox-23, significantly inhibited TC-32 (EWS-FLI1+) tumor xenograft growth (p=0.0025, day 16, one-way ANOVA multiple comparisons test) compared to MTM (p=0.1174, day 16) and extending survival for 17 days out of 48 days on study (p=0.0003, Log Rank (Mantel-Cox) single comparison test) with treatment at MTD every 3 days, compared to vehicle. Additionally, the MTM-oxime analogue with highest systemic exposure, MTMox-24, also significantly inhibited TC-32 (EWS-FLI1+) tumor xenograft growth (p=0.0003, day 21, one-way ANOVA multiple comparisons test) compared to MTM (p=0.032, day 21) and extending survival for 12 days out of 37 days on study (p=0.0004, Log Rank (Mantel-Cox) single comparison test) with treatment, compared to vehicle. Conclusion: These studies in whole highlight the importance of exposure (pharmacokinetics; PK), toxicity and efficacy (pharmacodynamics; PD) relationships. The cytotoxicity and high systemic exposure of MTMSA-Trp-A10 directly contributes to its lower tolerated dose. However, despite a similar tolerated dose to MTM, systemic exposure remains 163-fold higher at the MTD. High systemic exposure may be attributed to high plasma protein binding, but also reduces the exposure of free MTMSA-Trp-A10 within the tumor tissue, which drives the efficacious response. In contrast, the less cytotoxic and rapidly de-methylated MTM-oxime analogues allow for 25-fold higher tolerances in mice. This unique metabolism and clearance may prevent exposures required to induced systemic blood and liver toxicities induced by MTM. Moreover, at these highly tolerated doses, the initial systemic exposure at MTD is highest among analogues tested, which resulted in an efficacious response with MTMox-23 and MTMox-24 treatment in tumor xenograft models. It remains to be determined if these PK/PD relationships can be reproduced in additional animal models, including human, without inducing toxicity. Nonetheless, these initial studies in mice demonstrate that a more selective, more tolerated analogue of MTM has potential for clinical success in treating ETS fusion-dependent tumors.

No description available.

Policymakers' action of mitigating and slowing down the continued increase of carbon emission is a significant global priority. One way to internalise the negative externality of pollution is to put a price on greenhouse gases and use the market-based approach of emission trading systems. On the other hand, according to economic reasoning, pollution is an essential tool for economic development. This paper aims to investigate the economic effects of introducing the first international emission trading system of greenhouse gases, the EU emission trading system, by observing the economic growth and gross fixed capital formation. Mankiw, Romer, and Wiel's (1992) theory is utilised in this study and based on cross-country and cross-state panel data between 1999-2012, an empirical analysis using the fixed effects model was followed. The finding shows that the EU emission trading system has a negative effect on the growth of real gross domestic product per capita compared to states and countries not participating in an emission trading system. In addition, the first phase results having a positive effect and the second phase has a negative effect on the economic growth compared to states and countries not participating in an emission trading system. There is no statistical evidence of the effect on gross fixed capital formation as a percentage share of GDP. Organisations can use the findings to decide whether developing countries can afford the consequence of an implemented emission trading system since it tends to slow down growth. However, further research needs to consider the effect of the financial crisis of 2008 and the interpretation of the EU emission trading scheme.

Carbene ligands over these years have become a heavily utilizes and effective ligand for catalysis. The diamino carbene class of ligands are slightly less understood. The effects of bis(carbene) ligand structures of palladium (II) catalysts were investigated using the ETS-NOCV method. The results showed that the amount of π-backbonding played a major role in the rate of the reaction for these NHC complexes. The amount of pi acceptance from the ligand increased in correlation to the length of the methylene linkage in the ligand back bone resulting in increased catalytic activity. The ETS-NOCV method was used to determine the deformation densities that had a contribution to this interaction based on visual interpretation. The percent contribution of pi interactions provided a linear correlation to the natural log of the initial reaction rate, indicating that π-backbonding plays a crucial role in the overall catalytic activity of the palladium complexes. Gold (I) bis acyclic diamino carbenes (ADCs) were investigated for the possibility to be strong hydrogen bond catalysts. The ligand motif of the gold (I) bisADCs were found to be analogous thiourea compounds. Based on NBO analysis there were some improvements to hydrogen bond donicity in comparison to thioureas with the same functional group. The complexes were analyzed for hydrogen bond interactions and polarizations interactions between simple nitroolefin substrate and the catalyst using ETS-NOCV. Results showed that the compounds can form a stable hydrogen bonding system and activate the substrate. This capability is tunable by changing the electron withdrawing properties of the ligase motif, providing the idea that gold (I) bisADCs have potential to be good hydrogen bond catalysts. New thiourea-like gold (I) catalysts utilizing the acyclic diamino carbene motif that were hypothesized were synthesized using a one pot synthesis approach utilizing a metal templated synthesis method. The synthesis, characterization, and application prove these complexes with their cationic centers and bisADCs ligand motif can be utilized for Friedel-Crafts alkylation of indoles, resulting in the production of three new compounds to literature. This research also provided a new application for this specific ligand class and further proved the robustness of ADC ligands.

This thesis investigates the market rules of the European carbon market (EU ETS) during 2005-2007. We provide theoretical and empirical analyses of banking and borrowing provisions, price drivers and risk hedging strategies attached to tradable quotas, which were introduced to cover the CO2 emissions of around 10,600 installations in Europe.In Chapter 1, we outline the economic and environmental effects of banking and borrowing on tradable permits markets. More specifically, we examine the banking and borrowing provisions adopted in the EU ETS, and the effects of banning banking between Phases I and II on CO2 price changes. We show statistically that the low levels of CO2 prices recorded until the end of Phase I may be explained by the restriction on the inter-period tranfer of allowances, besides the main explanations that were identified by market observers.In Chapter 2, we identify the carbon price drivers since the launch of the EU ETS on January 1, 2005. We emphasize the central role played by the 2005 yearly compliance event imposed by the European Commission in revealing the net short/long position at the installation level in terms of allowances allocated with respect to verified emissions. The main result of this study features that price drivers of CO2 allowances linked to energy market prices and unanticipated weather events vary around institutional events. Moreover, we show the influence of the variation of industrial production in three sectors covered by the EU ETS on CO2 price changes by applying a disentangling analysis, that has also been extended at the country-level.In Chapter 3, we focus on the risk hedging strategies linked to holding CO2 allowances. By using a methodology applied on stock markets, we recover the changes in investors' average risk aversion. This study shows that, during the time period considered, risk aversion has been higher on the carbon market than on the stock market, and that the risk is linked to an increasing price structure after the 2006 compliance event. With reference to Chapter 1, we finally evaluate how banking may be used as a risk management tool in order to cope with political uncertainty on a tradable permits market. We detail an optimal risk-sharing rule, and discuss the possibility of pooling the risk linked to allowance trading between agents.Overall, this thesis highlights the inefficiencies following the creation of the European carbon market that prevented the emergence of a price signal leading to effective emissions reductions by industrials. However, in a changing institutional environment, these inefficiencies do not seem to have been transfered to the period 2008-2012.

This thesis investigates the regulatory impact of the EU ETS and CBAM regulations on supplier selection processes for procuring iron ore pellets, lime, and ferromanganese from 2025 to 2035. The study is set within the context of evolving EU environmental regulations, emphasizing the importance of understanding their effects on procurement practices in the steel industry. Employing quantitative multi-criteria decision-making (MCDM) through a TOPSIS analysis, the study evaluates suppliers over the specified timeframe based on market price, emissions, shipping cost, and regulatory cost. Additionally, a comprehensive review of current literature within the research area is provided. The methodology section details the research approach, design, data collection, and research quality. A case study conducted at H2 Green Steel, including company background and project execution, is also outlined. The results indicate potential changes over time due to the regulatory effects of the EU ETS and CBAM, with a sensitivity analysis exploring various weight scenarios of TOPSIS results to understand the relationship between the selected criteria. The analysis highlights advantages in integrating sustainability into procurement practices, driven by regulatory incentives. These findings suggest significant implications for procurement managers, emphasizing the importance of considering regulatory costs in supplier selection and adopting long-term monitoring of regulatory changes in the EU ETS and CBAM regulations. The study's implications are discussed in terms of validity, reliability, practical application, and future research directions.

This thesis analyzes how the EU Emissions Trading System (ETS) evolved in response to the European Green Deal, with a particular focus on climate justice. In previous trading periods, the ETS faced extensive criticism from researchers and international environmental organizations, who argued that the system exacerbated social and economic inequalities. However, as part of the Green Deal, the ETS underwent reforms with stricter regulations, clearer targets, and the inclusion of more sectors. The aim of this thesis is to analyze these changes and assess whether the system could now be considered just. The analysis is conducted using a critical approach and an ideal-type analysis, evaluating the ETS according to two justice-based criteria: effectiveness and the equitable distribution of climate change responsibilities. The results indicates that the current form of the emission trading system fails to meet the standards of fairness on both criteria.

Im Jahr 2005 wurde als Reaktion auf die Unterzeichnung des Kyoto-Protokolls und der damit verbundenen Verpflichtung zur Reduktion von Treibhausgasemissionen der europäische Emissionshandel eingeführt. Versuche der Standardsetter für IFRS und US GAAP zu einer einheitlichen Bilanzierungsregel für Emissionsrechte scheiterten. Seitdem stehen den beteiligten Unternehmen speziell bei Ansatz und Bewertung von Emissionsrechten sowie der Verbindlichkeit für verursachte Emissionen Wahlrechte zur Verfügung. Da unterschiedliche Bilanzierungsansätze zu verschiedenen Resultaten beispielsweise in der Gewinn- und Verlustrechnung führen können, schränkt die Regelungslücke die Vergleichbarkeit zwischen Unternehmen mit unterschiedlichen Bilanzierungsansätzen ein. Dabei wird zudem deutlich, wie wichtig die Offenlegung des gewählten Bilanzierungsansatzes ist. Diese Arbeit beschreibt mit Hilfe einer ausführlichen Literaturrecherche den Diskurs in der Forschung und fasst die theoretisch möglichen Ansätze zusammen. Dem schließt sich eine Analyse aller im STOXX Europe 600 gelisteten Unternehmen an. Untersucht wird, inwieweit die Unternehmen am Emissionshandel beteiligt sind, welchen Ansatz zur Bilanzierung von Emissionsrechten sie wählen und in welcher Vollständigkeit sie den gewählten Ansatz im Geschäftsbericht offenlegen. Insgesamt 70 Unternehmen im STOXX Europe 600 geben eine Beteiligung am europäischen Emissionshandel an, 68 davon erhalten Emissionsrechte kostenfrei von einer staatlichen Stelle zugeteilt. Davon wiederum können 31 Unternehmen sicher einem Bilanzierungsansatz zugeordnet werden; bei den übrigen Unternehmen werden nicht alle relevanten Bilanzierungsentscheidungen offengelegt. Die große Mehrheit dieser 31 Unternehmen wendet den Netto-Ansatz an, bei welchem die zugeteilten Emissionsrechte zu Anschaffungskosten (üblicherweise Null) angesetzt werden. Nur zwei Unternehmen bilanzieren Emissionsrechte nach der 2005 zurückgenommenen, aber weiterhin gültigen Interpretation IFRIC 3. Insgesamt gibt es bezüglich der Bilanzierung von Emissionsrechten in europäischen Unternehmen in Theorie und Praxis Unterschiede, welche die Vergleichbarkeit einschränken. Dies wird durch die häufig unvollständige Offenlegung der Bilanzierungsentscheidung verstärkt. Diese Kritikpunkte sollten aus Sicht der Standardsetter IASB und FASB ausreichend Anlass geben, eine einheitliche Regelung zur Bilanzierung von Emissionsrechten zu entwickeln.