Approaches for improving the safety and efficacy of adenoviral gene therapy

Cancer is a devastating disease with poor prognosis and no curative treatment, when widely metastatic. Conventional therapies, such as chemotherapy and radiotherapy, have efficacy but are not curative and systemic toxicity can be considerable. Almost all cancers are caused due to changes in the genetic material of the transformed cells. Cancer gene therapy has emerged as a new treatment option, and past decades brought new insights in developing new therapeutic drugs for curing cancer. Oncolytic viruses constitute a novel therapeutic approach given their capacity to replicate in and kill specifically tumor cells as well as reaching tumor distant metastasis. Adenoviral gene therapy has been suggested to cause liver toxicity. This study shows that new developed adenoviruses, in particular Ad5/19p-HIT, can be redirected towards kidney while adenovirus uptake by liver is minimal. Moreover, low liver transduction resulted in a favorable tumor to liver ratio of virus load. Further, we established a new immunocompetent animal model Syrian hamsters. Wild type adenovirus 5 was found to replicate in Hap-T1 hamster tumors and normal tissues. There are no antiviral drugs available to inhibit adenovirus replication. In our study, chlorpromazine and cidofovir efficiently abrogated virus replication in vitro and showed significant reduction in vivo in tumors and liver. Once safety concerns were addressed together with the new given antiviral treatment options, we further improved oncolytic adenoviruses for better tumor penetration, local amplification and host system modulation. Further, we created Ad5/3-9HIF-Δ24-VEGFR-1-Ig, oncolytic adenovirus for improved infectivity and antiangiogenic effect for treatment of renal cancer. This virus exhibited increased anti-tumor effect and specific replication in kidney cancer cells. The key player for good efficacy of oncolytic virotherapy is the host immune response. Thus, we engineered a triple targeted adenovirus Ad5/3-hTERT-E1A-hCD40L, which would lead to tumor elimination due to tumor-specific oncolysis and apoptosis together with an anti-tumor immune response prompted by the immunomodulatory molecule. In conclusion, the results presented in this thesis constitute advances in our understanding of oncolytic virotherapy by successful tumor targeting, antiviral treatment options as a safety switch in case of replication associated side-effects, and modulation of the host immune system towards tumor elimination.  

Microvascular reconstruction in extremity soft tissue sarcoma surgery

Soft tissue sarcomas (STS) are rare tumors of soft tissue occurring most frequently in the extremities. Modern treatment of extremity STS is based on limb-sparing surgery combined with radiotherapy. To prevent local recurrence, a healthy tissue margin of 2.5 cm around the resected tumor is required. This results in large defects of soft tissue and bone, necessitating the use of reconstructive surgery to achieve wound closure. When local or pedicled soft tissue flaps are unavailable, reconstruction with free flaps is used. Free flaps are elevated at a distant site, and have their blood flow restored at the recipient site through microvascular anastomosis. When limb-sparing surgery is made impossible, amputation is the only option. Proximal amputation such as forequarter amputation (FQA) causes considerable morbidity, but is nevertheless warranted for carefully selected patients for cure or palliation. 116 patients treated in 1985 - 2006 were included in the study. Of these, 93 patients treated with limb-sparing surgery and microvascular reconstructive surgery after resection of extremity STS. 25 patients who underwent FQA were also included. Patients were identified and their medical records retrospectively reviewed. In all, 105 free flap procedures were performed for 103 patients. A total of 95 curatively treated STS patients were included in survival analysis. The latissimus dorsi, used in 56% of cases, was the most frequently used free flap. Free flap success rate was 96%. There were 9% microvascular anastomosis complications and 15% wound complications. For curatively treated STS patients, local recurrence-free survival at 5 years was 73.1%, metastasis-free survival 58.3%, and overall disease-specific survival 68.9%. Functional results were good, with 75% of patients regaining normal or near-normal function after lower extremity, and 55% after upper extremity STS resection. Among curatively treated forequarter amputees, 5-year disease-free survival was 44%. In the palliatively treated group median time until disease death was 14 months. Microvascular reconstruction after extremity soft tissue sarcoma resection is safe and reliable, and produces well-healing wounds allowing early oncological treatment. Oncological outcome after these procedures is comparable to that of other extremity sarcoma patients. Functional results are generally good. Forequarter amputation is a useful treatment option for soft tissue tumors of the shoulder girdle and proximal upper extremity. When free flap coverage of extended forequarter amputation is required, the preferable flap is a fillet flap from the amputated extremity. Acceptable oncological outcome is achieved for curatively treated FQA patients. In the palliatively treated patient considerable periods of increased quality of life can be achieved.

Modulation of growth by aromatase inhibitor treatment in boys: Efficacy and safety

Without estrogen action, the fusion of the growth plates is postponed and statural growth continues for an exceptionally long time. Aromatase inhibitors, blockers of estrogen biosynthesis, have therefore emerged as a new potential option for the treatment of children with short stature. We investigated the efficacy of the aromatase inhibitor letrozole in the treatment of boys with idiopathic short stature (ISS) using a randomised, placebo-controlled, double-blind research setting. A total of 30 boys completed the two-year treatment. By decreasing estrogen-mediated central negative feedback, letrozole increased gonadotrophin and testosterone secretion in pubertal boys, whereas the pubertal increase in IGF-I was inhibited. Treatment with letrozole effectively delayed bone maturation and increased predicted adult height by 5.9 cm (P0.001), while placebo had no effect on either parameter. The effect of letrozole treatment on near-final height was studied in another population, in boys with constitutional delay of puberty, who received letrozole (n=9) or placebo (n=8) for one year, in combination with low-dose testosterone for six months during adolescence. The mean near-final height of boys randomised to receive testosterone and letrozole was significantly greater than that of boys who received testosterone and placebo (175.8 vs. 169.1 cm, P=0.04). As regards safety, treatment effects on bone health, lipid metabolism, insulin sensitivity, and body composition were monitored in boys with ISS. During treatment, no differences in bone mass accrual were evident between the treatment groups, as evaluated by dual-energy x-ray absorptiometry measurements of the lumbar spine and femoral neck. Bone turnover and cortical bone growth, however, were affected by letrozole treatment. As indicated by differences in markers of bone resorption (U-INTP) and formation (S-PINP and S-ALP), the long-term rate of bone turnover was lower in letrozole-treated boys, despite their more rapid advancement in puberty. Letrozole stimulated cortical bone growth in those who progressed in puberty: the metacarpal index (MCI), a measure of cortical bone thickness, increased more in letrozole-treated pubertal boys than in placebo-treated pubertal boys (25% vs. 9%, P=0.007). The change in MCI correlated positively with the mean testosterone-to-estradiol ratio. In post-treatment radiographic evaluation of the spine, a high rate of vertebral deformities - mild anterior wedging and mild compression deformities - were found in both placebo and letrozole groups. In pubertal boys with ISS treated with letrozole, stimulated testosterone secretion was associated with a decrease in the percentage of fat mass and in HDL-cholesterol, while LDL-cholesterol and triglycerides remained unchanged. Insulin sensitivity, as evaluated by HOMA-IR, was not significantly affected by the treatment. In summary, treatment with the aromatase inhibitor letrozole effectively delayed bone maturation and increased predicted adult height in boys with ISS. Long-term follow-up data of boys with constitutional delay of puberty, treated with letrozole for one year during adolescence, suggest that the achieved gain in predicted adult height also results in increased adult height. However, until the safety of aromatase inhibitor treatment in children and adolescents is confirmed, such treatment should be considered experimental.

Scattering and Refraction as Contrast Mechanisms in X-Ray Imaging

Differentiation of various types of soft tissues is of high importance in medical imaging, because changes in soft tissue structure are often associated with pathologies, such as cancer. However, the densities of different soft tissues may be very similar, making it difficult to distinguish them in absorption images. This is especially true when the consideration of patient dose limits the available signal-to-noise ratio. Refraction is more sensitive than absorption to changes in the density, and small angle x-ray scattering on the other hand contains information about the macromolecular structure of the tissues. Both of these can be used as potential sources of contrast when soft tissues are imaged, but little is known about the visibility of the signals in realistic imaging situations. In this work the visibility of small-angle scattering and refraction in the context of medical imaging has been studied using computational methods. The work focuses on the study of analyzer based imaging, where the information about the sample is recorded in the rocking curve of the analyzer crystal. Computational phantoms based on simple geometrical shapes with differing material properties are used. The objects have realistic dimensions and attenuation properties that could be encountered in real imaging situations. The scattering properties mimic various features of measured small-angle scattering curves. Ray-tracing methods are used to calculate the refraction and attenuation of the beam, and a scattering halo is accumulated, including the effect of multiple scattering. The changes in the shape of the rocking curve are analyzed with different methods, including diffraction enhanced imaging (DEI), extended DEI (E-DEI) and multiple image radiography (MIR). A wide angle DEI, called W-DEI, is introduced and its performance is compared with that of the established methods. The results indicate that the differences in scattered intensities from healthy and malignant breast tissues are distinguishable to some extent with reasonable dose. Especially the fraction of total scattering has large enough differences that it can serve as a useful source of contrast. The peaks related to the macromolecular structure come to angles that are rather large, and have intensities that are only a small fraction of the total scattered intensity. It is found that such peaks seem to have only limited usefulness in medical imaging. It is also found that W-DEI performs rather well when most of the intensity remains in the direct beam, indicating that dark field imaging methods may produce the best results when scattering is weak. Altogether, it is found that the analysis of scattered intensity is a viable option even in medical imaging where the patient dose is the limiting factor.

Formation of structure in dark energy cosmologies

Acceleration of the universe has been established but not explained. During the past few years precise cosmological experiments have confirmed the standard big bang scenario of a flat universe undergoing an inflationary expansion in its earliest stages, where the perturbations are generated that eventually form into galaxies and other structure in matter, most of which is non-baryonic dark matter. Curiously, the universe has presently entered into another period of acceleration. Such a result is inferred from observations of extra-galactic supernovae and is independently supported by the cosmic microwave background radiation and large scale structure data. It seems there is a positive cosmological constant speeding up the universal expansion of space. Then the vacuum energy density the constant describes should be about a dozen times the present energy density in visible matter, but particle physics scales are enormously larger than that. This is the cosmological constant problem, perhaps the greatest mystery of contemporary cosmology. In this thesis we will explore alternative agents of the acceleration. Generically, such are called dark energy. If some symmetry turns off vacuum energy, its value is not a problem but one needs some dark energy. Such could be a scalar field dynamically evolving in its potential, or some other exotic constituent exhibiting negative pressure. Another option is to assume that gravity at cosmological scales is not well described by general relativity. In a modified theory of gravity one might find the expansion rate increasing in a universe filled by just dark matter and baryons. Such possibilities are taken here under investigation. The main goal is to uncover observational consequences of different models of dark energy, the emphasis being on their implications for the formation of large-scale structure of the universe. Possible properties of dark energy are investigated using phenomenological paramaterizations, but several specific models are also considered in detail. Difficulties in unifying dark matter and dark energy into a single concept are pointed out. Considerable attention is on modifications of gravity resulting in second order field equations. It is shown that in a general class of such models the viable ones represent effectively the cosmological constant, while from another class one might find interesting modifications of the standard cosmological scenario yet allowed by observations. The thesis consists of seven research papers preceded by an introductory discussion.

Modeling of Surface UV Radiation Using Satellite Data

Solar UV radiation is harmful for life on planet Earth, but fortunately the atmospheric oxygen and ozone absorb almost entirely the most energetic UVC radiation photons. However, part of the UVB radiation and much of the UVA radiation reaches the surface of the Earth, and affect human health, environment, materials and drive atmospheric and aquatic photochemical processes. In order to quantify these effects and processes there is a need for ground-based UV measurements and radiative transfer modeling to estimate the amounts of UV radiation reaching the biosphere. Satellite measurements with their near-global spatial coverage and long-term data conti-nuity offer an attractive option for estimation of the surface UV radiation. This work focuses on radiative transfer theory based methods used for estimation of the UV radiation reaching the surface of the Earth. The objectives of the thesis were to implement the surface UV algorithm originally developed at NASA Goddard Space Flight Center for estimation of the surface UV irradiance from the meas-urements of the Dutch-Finnish built Ozone Monitoring Instrument (OMI), to improve the original surface UV algorithm especially in relation with snow cover, to validate the OMI-derived daily surface UV doses against ground-based measurements, and to demonstrate how the satellite-derived surface UV data can be used to study the effects of the UV radiation. The thesis consists of seven original papers and a summary. The summary includes an introduction of the OMI instrument, a review of the methods used for modeling of the surface UV using satellite data as well as the con-clusions of the main results of the original papers. The first two papers describe the algorithm used for estimation of the surface UV amounts from the OMI measurements as well as the unique Very Fast Delivery processing system developed for processing of the OMI data received at the Sodankylä satellite data centre. The third and the fourth papers present algorithm improvements related to the surface UV albedo of the snow-covered land. Fifth paper presents the results of the comparison of the OMI-derived daily erythemal doses with those calculated from the ground-based measurement data. It gives an estimate of the expected accuracy of the OMI-derived sur-face UV doses for various atmospheric and other conditions, and discusses the causes of the differences between the satellite-derived and ground-based data. The last two papers demonstrate the use of the satellite-derived sur-face UV data. Sixth paper presents an assessment of the photochemical decomposition rates in aquatic environment. Seventh paper presents use of satellite-derived daily surface UV doses for planning of the outdoor material weathering tests.

Biovalta, toiseus ja naisten toimijuus hedelmöityshoidoissa

Biopower, Otherness and Women's Agency in Assisted Reproduction. This sociological study analyses how, why and with what kind of consequences assisted reproductive technologies (ART) have become the primary technology for governing infertility in Finland both on the level of individuals and society. The phenomenon is construed as one the strategies of the Focaultian biopower since ART are political techniques of the beginning of life par excellence, as they are used to prepare the bodies of certain types of women to create certain kind of life, i.e. certain kind of children. Moreover, ART are interpreted to be gendered control techniques with which the pure, and at the same time prevailing, social order symbolised by a female body is maintained by naming and excluding otherness, unsuitable mother candidates and children. Finally, it is considered how the agency, subjectivity, of women experiencing infertility and seeking treatment appears in the prevailing context of ART. The introduction of IVF-based reproductive technologies to Finland and the treatment practices of the early 1990s have been studied on the basis of a clinic questionnaire, medical doctor interviews and articles of the Medical Journal Duodecim from 1969 to 2000. Opinions on the method of the treatment providers were studied by conducting a theme interview with fertilisation doctors in 1993. Experiences of women who have received treatment or experienced infertility were studied by means of a survey in 1994 and by analysing the content of messages in an online discussion forum in 2000. On the basis of the medical doctor interviews, significant criterion for choosing mother candidates turned out to be her vitality and her mental and physical health, which are considered prerequisites for a vitality of the child to be born. The hierarchies concerning children became evident. While people normally make their children on their own, this is what people experiencing infertility are trying to do as well. In the era of ART, the primary child is genetically the parents' own child, a secondary option for Finnish parents is a genetically Finnish child conceived by donated Finnish gametes or embryos and the last option is an adopted child of foreign origin. Women's agency mainly appears in their way of using ART as a technology of the self for self-control on one's own nature, which helps them to prepare their bodies in order to become pregnant in co-operation with a fertilisation doctor. Women's creative free agency exceeding governance appeared as a distinctive use of language with which they created shared meaning for their infertility experience, their own individual and group identity and distinctive reality. ART are very political techniques as they have a possibility to change the methods of having children and to shape life. Therefore, further sociological research on them is important and needed. Key words: practises of assisted reproduction, women's agency, biopower, vital politics of the beginning of life, otherness

Studies on Binary Time Series Models with Applications to Empirical Macroeconomics and Finance

This thesis studies binary time series models and their applications in empirical macroeconomics and finance. In addition to previously suggested models, new dynamic extensions are proposed to the static probit model commonly used in the previous literature. In particular, we are interested in probit models with an autoregressive model structure. In Chapter 2, the main objective is to compare the predictive performance of the static and dynamic probit models in forecasting the U.S. and German business cycle recession periods. Financial variables, such as interest rates and stock market returns, are used as predictive variables. The empirical results suggest that the recession periods are predictable and dynamic probit models, especially models with the autoregressive structure, outperform the static model. Chapter 3 proposes a Lagrange Multiplier (LM) test for the usefulness of the autoregressive structure of the probit model. The finite sample properties of the LM test are considered with simulation experiments. Results indicate that the two alternative LM test statistics have reasonable size and power in large samples. In small samples, a parametric bootstrap method is suggested to obtain approximately correct size. In Chapter 4, the predictive power of dynamic probit models in predicting the direction of stock market returns are examined. The novel idea is to use recession forecast (see Chapter 2) as a predictor of the stock return sign. The evidence suggests that the signs of the U.S. excess stock returns over the risk-free return are predictable both in and out of sample. The new "error correction" probit model yields the best forecasts and it also outperforms other predictive models, such as ARMAX models, in terms of statistical and economic goodness-of-fit measures. Chapter 5 generalizes the analysis of univariate models considered in Chapters 2 4 to the case of a bivariate model. A new bivariate autoregressive probit model is applied to predict the current state of the U.S. business cycle and growth rate cycle periods. Evidence of predictability of both cycle indicators is obtained and the bivariate model is found to outperform the univariate models in terms of predictive power.

Two bracketing schemes for the Penn Treebank

The trees in the Penn Treebank have a standard representation that involves complete balanced bracketing. In this article, an alternative for this standard representation of the tree bank is proposed. The proposed representation for the trees is loss-less, but it reduces the total number of brackets by 28%. This is possible by omitting the redundant pairs of special brackets that encode initial and final embedding, using a technique proposed by Krauwer and des Tombe (1981). In terms of the paired brackets, the maximum nesting depth in sentences decreases by 78%. The 99.9% coverage is achieved with only five non-top levels of paired brackets. The observed shallowness of the reduced bracketing suggests that finite-state based methods for parsing and searching could be a feasible option for tree bank processing.

Two bracketing schemes for the Penn Treebank

The trees in the Penn Treebank have a standard representation that involves complete balanced bracketing. In this article, an alternative for this standard representation of the tree bank is proposed. The proposed representation for the trees is loss-less, but it reduces the total number of brackets by 28%. This is possible by omitting the redundant pairs of special brackets that encode initial and final embedding, using a technique proposed by Krauwer and des Tombe (1981). In terms of the paired brackets, the maximum nesting depth in sentences decreases by 78%. The 99.9% coverage is achieved with only five non-top levels of paired brackets. The observed shallowness of the reduced bracketing suggests that finite-state based methods for parsing and searching could be a feasible option for tree bank processing.

A Cointegration Approach to Topics in Empirical Macroeconomics (summary section only)

Mikael Juselius’ doctoral dissertation covers a range of significant issues in modern macroeconomics by empirically testing a number of important theoretical hypotheses. The first essay presents indirect evidence within the framework of the cointegrated VAR model on the elasticity of substitution between capital and labor by using Finnish manufacturing data. Instead of estimating the elasticity of substitution by using the first order conditions, he develops a new approach that utilizes a CES production function in a model with a 3-stage decision process: investment in the long run, wage bargaining in the medium run and price and employment decisions in the short run. He estimates the elasticity of substitution to be below one. The second essay tests the restrictions implied by the core equations of the New Keynesian Model (NKM) in a vector autoregressive model (VAR) by using both Euro area and U.S. data. Both the new Keynesian Phillips curve and the aggregate demand curve are estimated and tested. The restrictions implied by the core equations of the NKM are rejected on both U.S. and Euro area data. These results are important for further research. The third essay is methodologically similar to essay 2, but it concentrates on Finnish macro data by adopting a theoretical framework of an open economy. Juselius’ results suggests that the open economy NKM framework is too stylized to provide an adequate explanation for Finnish inflation. The final essay provides a macroeconometric model of Finnish inflation and associated explanatory variables and it estimates the relative importance of different inflation theories. His main finding is that Finnish inflation is primarily determined by excess demand in the product market and by changes in the long-term interest rate. This study is part of the research agenda carried out by the Research Unit of Economic Structure and Growth (RUESG). The aim of RUESG it to conduct theoretical and empirical research with respect to important issues in industrial economics, real option theory, game theory, organization theory, theory of financial systems as well as to study problems in labor markets, macroeconomics, natural resources, taxation and time series econometrics. RUESG was established at the beginning of 1995 and is one of the National Centers of Excellence in research selected by the Academy of Finland. It is financed jointly by the Academy of Finland, the University of Helsinki, the Yrjö Jahnsson Foundation, Bank of Finland and the Nokia Group. This support is gratefully acknowledged.

Essays on Stock Options, Incentives, and Managerial Action

Executive compensation and managerial behavior have received an increasing amount of attention in the financial economics literature since the mid 1970s. The purpose of this thesis is to extend our understanding of managerial compensation, especially how stock option compensation is linked to the actions undertaken by the management. Furthermore, managerial compensation is continuously and heatedly debated in the media and an emerging consensus from this discussion seems to be that there still exists gaps in our knowledge of optimal contracting. In Finland, the first executive stock options were introduced in the 1980s and throughout the last 15 years it has become increasingly popular for Finnish listed firms to use this type of managerial compensation. The empirical work in the thesis is conducted using data from Finland, in contrast to most previous studies that predominantly use U.S. data. Using Finnish data provides insight of how market conditions affect compensation and managerial action and provides an opportunity to explore what parts of the U.S. evidence can be generalized to other markets. The thesis consists of four essays. The first essay investigates the exercise policy of the executive stock option holders in Finland. In summary, Essay 1 contributes to our understanding of the exercise policies by examining both the determinants of the exercise decision and the markets reaction to the actual exercises. The second essay analyzes the factors driving stock option grants using data for Finnish publicly listed firms. Several agency theory based variables are found to have have explanatory power on the likelihood of a stock option grant. Essay 2 also contributes to our understanding of behavioral factors, such as prior stock return, as determinants of stock option compensation. The third essay investigates the tax and stock option motives for share repurchases and dividend distributions. We document strong support for the tax motive for share repurchases. Furthermore, we also analyze the dividend distribution decision in companies with stock options and find a significant difference between companies with and without dividend protected options. We thus document that the cutting of dividends found in previous U.S. studies can be avoided by dividend protection. In the fourth essay we approach the puzzle of negative skewness in stock returns from an altogether different angle than in previous studies. We suggest that negative skewness in stock returns is generated by management disclosure practices and find proof for this. More specifically, we find that negative skewness in daily returns is induced by returns for days when non-scheduled firm specific news is disclosed.

From Creative Ideas to New Emerging Ventures: Entrepreneurial Processes among Finnish Design Entrepreneurs

This study focuses on self-employed industrial designers and how they emerge new venture ideas. More specifically, this study strives to determine what design entrepreneurs do when they create new venture ideas, how venture ideas are nurtured into being, and how the processes are organized to bring such ideas to the market in the given industrial context. In contemporary times when the concern for the creative class is peaking, the research and business communities need more insight of the kind that this study provides, namely how professionals may contribute to their entrepreneurial processes and other agents’ business processes. On the one hand, the interviews underlying this study suggest that design entrepreneurs may act as reactive service providers who are appointed by producers or marketing parties to generate product-related ideas on their behalf. On the other hand, the interviews suggest that proactive behaviour that aims on generating own venture ideas, may force design entrepreneurs to take considerable responsibility in organizing their entrepreneurial processes. Another option is that they strive to bring venture ideas to the market in collaboration, or by passing these to other agents’ product development processes. Design entrepreneurs’ venture ideas typically emerge from design related starting points and observations. Product developers are mainly engaged with creating their own ideas, whereas service providers refer mainly to the development of other agents’ venture ideas. In contrast with design entrepreneurs, external actors commonly emphasize customer demand as their primary source for new venture ideas, as well as development of these in close interaction with available means of production and marketing. Consequently, design entrepreneurs need to address market demand since without sales their venture ideas may as well be classified as art. In case, they want to experiment with creative ideas, then there should be another source of income to support this typically uncertain and extensive process. Currently, it appears like a lot of good venture ideas and resources are being wasted, when venture ideas do not suite available production or business procedures. Sufficient communication between design entrepreneurs and other agents would assist all parties in developing production efficient and distributable venture ideas. Overall, the findings suggest that design entrepreneurs are often involved simultaneously in several processes that aim at emerging new product related ventures. Consequently, design entrepreneurship is conceptualized in this study as a dual process. This implies that design entrepreneurs can simultaneously be in charge of their entrepreneurial processes, as they operate as resources in other agents’ business processes. The interconnection between activities and agents suggests that these kinds of processes tend to be both complex and multifaceted to their nature.

Optimal Risk Adoption: A Real Options Approach

This study develops a real options approach for analyzing the optimal risk adoption policy in an environment where the adoption means a switch from one stochastic flow representation into another. We establish that increased volatility needs not decelerate investment, as predicted by the standard literature on real options, once the underlying volatility of the state is made endogenous. We prove that for a decision maker with a convex (concave) objective function, increased post-adoption volatility increases (decreases) the expected cumulative present value of the post-adoption profit flow, which consequently decreases (increases) the option value of waiting and, therefore, accelerates (decelerates) current investment.

Hedging Options with Different Time Units in the Pricing Models

This study examined the effects of the Greeks of the options and the trading results of delta hedging strategies, with three different time units or option-pricing models. These time units were calendar time, trading time and continuous time using discrete approximation (CTDA) time. The CTDA time model is a pricing model, that among others accounts for intraday and weekend, patterns in volatility. For the CTDA time model some additional theta measures, which were believed to be usable in trading, were developed. The study appears to verify that there were differences in the Greeks with different time units. It also revealed that these differences influence the delta hedging of options or portfolios. Although it is difficult to say anything about which is the most usable of the different time models, as this much depends on the traders view of the passing of time, different market conditions and different portfolios, the CTDA time model can be viewed as an attractive alternative.