AIR POLLUTION AND DEVELOPMENT OF NORTHERN EUROPEAN SOCIETIES 1966 – 1990

Industrialization has been one of the major influences towards the escalation of atmospheric pollutants after World War II. Metal concentrations in the atmosphere have been increased since the introduction of high-temperature processes such as fossil fuel combustion and smelting. Increased pollutants in the atmosphere have resulted in poor health and increased mortality among individuals, and degradation of the environment. This thesis characterizes aerosol concentration trends in Falsterbo, Southern Sweden, as a function of time from 1966 to 1990 and correlate the results with the meteorological data and air mass back-trajectories, including source apportionment of the elements. The analysis was divided into two parts: initial assessment of 1972 with analysis of filters from each day, and preliminary analysis of 1966 to 1990 with analysis of filters from every eighth day using Energy Dispersive X-ray Fluorescence (EDXRF). Aerosol concentrations in 1972 were analyzed using Hybrid Single-Particle Langrangian Integrated Trajectory (HYSPLIT) model to generate air mass back trajectories and determine the origin and distance of air masses entering Falsterbo, followed by Positive Matrix Factorization (PMF) analysis to determine the source apportionment of the aerosols. Concentration Weighted Trajectory (CWT) was conducted using openair function in R Studio to illustrate origin of emission. In conclusion, this study found that archived filter samples can be used for characterization of daily changes in aerosol composition in Falsterbo. Long-range air pollutants carried by air masses from Eastern and Southern Europe contribute to the local air quality. Main sources of these aerosols in 1972 were anthropogenic activities such as industrial activities, coal combustion, oil combustion, biomass burning, dust and marine aerosol. Even though various elements were present in every filter of 1972, lead (Pb) and arsenic (As) were not present in all the filters. Lastly, variation in aerosol concentration and their sources of emission can be studied in detail from 1966 to 1990 in 24-hour resolution

Design, Synthesis, and Characterization of Novel MGMT-Dependent, MMR-Independent Agents for the Treatment of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is a devastating disease afflicting over 20,000 new patients per year in the US with a 5-year survival rate of ~5%. The current standard of care treatment for GBMs consists of radiation therapy with concurrent and adjuvant chemotherapy with temozolomide (TMZ). TMZ is a prodrug that generates methyl diazonium in vivo, which in turn methylates DNA. O6-Guanine is the clinically significant site of DNA alkylation by TMZ. In healthy cells these lesions are reversed by O6-methylguanine methyltransferase (MGMT), a suicide DNA repair enzyme. However, loss of MGMT expression is common in many cancers such as grade 2/3 gliomas (50–70%), glioblastoma multiforme (GBM; 50%), colorectal (40%), and various lung cancers (25–35%). Stupp and co-workers established that loss of MGMT in GBM confers sensitivity to TMZ, and a combination of radiation therapy and TMZ increases a median overall survival by 8 months. Thus, TMZ in combination with radiotherapy has emerged as the standard-of-care in patients with MGMT– GBM.The mechanism of toxicity of TMZ is complex. O6-Methylguanine lesions themselves are relatively nontoxic (replication bypass efficiency is near 100%). However, O6-methylguanine is mispaired by thymine during replication. This mispairing triggers activation of the DNA mismatch repair (MMR) pathway, which resects the thymine residue. However, thymine is re-inserted by DNA polymerase, ultimately leading to cycles of thymine resection and insertion. These “futile cycles” lead to strand breaks and apoptosis. Thus, the toxicity of TMZ requires an intact DNA MMR pathway. Unfortunately, approximately half of all glioma patients and 15–20% of GBM patients develop acquired resistance to TMZ through mutations of MMR factors, most commonly MSH2 and MSH6. Effective treatment options for recurrent GBM are essentially non-existent as second line therapies, such as lomustine, do not possess a favorable therapeutic index and are limited by off-target toxicity. We report the design, synthesis, and evaluation of novel MGMT-dependent, MMR-independent therapeutics. Like TMZ, the novel alkylating agent, KL-50, provides a potentially clinically useful therapeutic index, but, significantly, retains activity in the setting of MMR mutations. KL-50 is active in multiple unrelated cancer cell lines with genetic and pharmacologic modeling of MGMT–/MMR– status. Structure–activity and mechanism of action studies reveal that KL-50’s activity is due to deposition of a 2-fluoroethyl adduct deposited at the O6G position of DNA. This lesion can be reversed by healthy cells that express MGMT but in the absence of MGMT this lesion converts to a highly toxic DNA interstrand cross-link. KL-50 demonstrated robust in vivo efficacy, systemic tolerability, and CNS penetrance in the treatment of both MGMT–/MMR+ and MGMT–/MMR– tumors. KL-50 is amenable to rapid derivatization of the imidazotetrazine scaffold to improve physiochemical properties, such as CNS penetration. These results position KL-50 as the first potential imidazotetrazine clinical candidate for the treatment of drug resistant gliomas

Review of \u3cem\u3eAlternatives to Social Security: An International Inquiry.\u3c/em\u3e James Midgley and Michael Sherraden. Reviewed by Eric Kingson, Boston College.

James Midgley and Michael Sherraden (Eds.), Alternatives to Social Security: An International Inquiry. Westport, CT: Auburn House, 1997. $49.95 hardcover

Reagan, Pickle and Pepper: The Benefit Reduction Versus Voluntary Approach to Encouraging Later Retirement

The degree to which benefit reduction and voluntary approaches to encouraging later retirement maximize four different and often conflicting policy objectives is assessed as are costs and benefits of these approaches to healthy and unhealthy older workers, minorities and women. While both approaches encourage later retirement, there are clear differences in the approaches in terms of meeting the goal of financing Social Security versus adequacy and social equit