Therapeutics bioconjugates: evaluation of iminoboronates as payload delivery system for cancer

The advent of bioconjugation impacted deeply the world of sciences and technology. New biomolecules were found, biological processes were understood, and novel methodologies were formed due to the fast expansion of this area. The possibility of creating new effective therapies for diseases like cancer is one of big applications of this now big area of study. Off target toxicity was always the problem of potent small molecules with high activity towards specific tumour targets. However, chemotherapy is now selective due to powerful linkers that connect targeting molecules with affinity to interesting biological receptors and cytotoxic drugs. This linkers must have very specific properties, such as high stability in plasma, no toxicity, no interference with ligand affinity nor drug potency, and at the same time, be able to lyse once inside the target molecule to release the therapeutic warhead. Bipolar environments between tumour intracellular and extracellular medias are usually exploited by this linkers in order to complete this goal. The work done in this thesis explores a new model for that same task, specific cancer drug delivery. Iminoboronates were studied due to its remarkable selective stability towards a wide pH range and endogenous molecules. A fluorescence probe was design to validate this model by creating an Off/On system and determine the payload release location in situ. A process was optimized to synthetize the probe 8-(1-aminoethyl)-7-hydroxy-coumarin (1) through a reductive amination reaction in a microwave reactor with 61 % yield. A method to conjugate this probe to ABBA was also optimized, obtaining the iminoboronate in good yields in mild conditions. The iminoboronate model was studied regarding its stability in several simulated biological environments and each half-life time was determined, showing the conjugate is stable most of the cases except in tumour intracellular systems. The construction of folate-ABBA-coumarin bioconjugate have been made to complete this evaluation. The ability to be uptaken by a cancer cell through endocytosis process and the conjugation delivery of coumarin fluorescence payload are two features to hope for in this construct.

Using active learning for monitoring networks design: The example of wind power plants sites evaluation

Locating new wind farms is of crucial importance for energy policies of the next decade. To select the new location, an accurate picture of the wind fields is necessary. However, characterizing wind fields is a difficult task, since the phenomenon is highly nonlinear and related to complex topographical features. In this paper, we propose both a nonparametric model to estimate wind speed at different time instants and a procedure to discover underrepresented topographic conditions, where new measuring stations could be added. Compared to space filling techniques, this last approach privileges optimization of the output space, thus locating new potential measuring sites through the uncertainty of the model itself.

In situ evaluation of single-cell lysis by cytosol extraction observation through fluorescence decay and dielectrophoretic trapping time

We present a new method for lysis of single cells in continuous flow, where cells are sequentially trapped, lysed and released in an automatic process. Using optimized frequencies, dielectrophoretic trapping allows exposing cells in a reproducible way to high electrical fields for long durations, thereby giving good control on the lysis parameters. In situ evaluation of cytosol extraction on single cells has been studied for Chinese hamster ovary (CHO) cells through out-diffusion of fluorescent molecules for different voltage amplitudes. A diffusion model is proposed to correlate this out-diffusion to the total area of the created pores, which is dependent on the potential drop across the cell membrane and enables evaluation of the total pore area in the membrane. The dielectrophoretic trapping is no longer effective after lysis because of the reduced conductivity inside the cells, leading to cell release. The trapping time is linked to the time required for cytosol extraction and can thus provide additional validation of the effective cytosol extraction for non-fluorescent cells. Furthermore, the application of one single voltage for both trapping and lysis provides a fully automatic process including cell trapping, lysis, and release, allowing operating the device in continuous flow without human intervention.

Gastric supply manipulation to modulate ghrelin production and enhance vascularization to the cardia: proof of the concept in a porcine model.

Introduction. Selective embolization of the left-gastric artery (LGA) reduces levels of ghrelin and achieves significant short-term weight loss. However, embolization of the LGA would prevent the performance of bariatric procedures because the high-risk leakage area (gastroesophageal junction [GEJ]) would be devascularized. Aim. To assess an alternative vascular approach to the modulation of ghrelin levels and generate a blood flow manipulation, consequently increasing the vascular supply to the GEJ. Materials and methods. A total of 6 pigs underwent a laparoscopic clipping of the left gastroepiploic artery. Preoperative and postoperative CT angiographies were performed. Ghrelin levels were assessed perioperatively and then once per week for 3 weeks. Reactive oxygen species (ROS; expressed as ROS/mg of dry weight [DW]), mitochondria respiratory rate, and capillary lactates were assessed before and 1 hour after clipping (T0 and T1) and after 3 weeks of survival (T2), on seromuscular biopsies. A celiac trunk angiography was performed at 3 weeks. Results. Mean (±standard deviation) ghrelin levels were significantly reduced 1 hour after clipping (1902 ± 307.8 pg/mL vs 1084 ± 680.0; P = .04) and at 3 weeks (954.5 ± 473.2 pg/mL; P = .01). Mean ROS levels were statistically significantly decreased at the cardia at T2 when compared with T0 (0.018 ± 0.006 mg/DW vs 0.02957 ± 0.0096 mg/DW; P = .01) and T1 (0.0376 ± 0.008mg/DW; P = .007). Capillary lactates were significantly decreased after 3 weeks, and the mitochondria respiratory rate remained constant over time at the cardia and pylorus, showing significant regional differences. Conclusions. Manipulation of the gastric flow targeting the gastroepiploic arcade induces ghrelin reduction. An endovascular approach is currently under evaluation.

Augmentation cystoplasty using pedicled and de-epithelialized gastric patches in the mini-pig model.

PURPOSE: The most common methods of bladder augmentation are gastrocystoplasty and enterocystoplasty. Gastrocystoplasty is advantageous due to minimal mucous secretion and a well developed muscular wall as well as good urodynamic properties of the patch. However, the permanent contact of urine with the gastric mucosa is not free of complications. We report the urodynamic, macroscopic and histological outcomes of a pedicled de-epithelialized gastric patch incorporated in the bladder. We compared the results to those of our previous study, which sought to analyze these techniques of patch coverage using sigmoid patches. MATERIALS AND METHODS: We performed 20 augmentation cystoplasties in the mini-pig model using a pedicled de-epithelialized gastric patch and 5 techniques of patch coverage. RESULTS: Three months after surgery all bladders had an increase in volume except those in which the auto-augmentation technique was used. However, all gastric patches were smaller compared to preoperative size. Many had irregular fibrosed inner surfaces and histological evaluation revealed a fibrosed newly formed submucosal layer with a complete urothelial coverage in every patch. No gastric mucosal remnant was found. CONCLUSIONS: De-epithelialized gastrocystoplasty is an attractive procedure that can increase bladder capacity as well as provide a complete urothelial lining without mucosal remnants. However, the success of this procedure seems to be limited by increased morbidity and fibrotic changes, and decreased surface of the patch.

Physicians' estimates of the 10 year cardiovascular risk in hypertensive patients: an evaluation in primary care physicians in training.

To evaluate how young physicians in training perceive their patients' cardiovascular risk based on the medical charts and their clinical judgment. Cross sectional observational study. University outpatient clinic, Lausanne, Switzerland. Two hundred hypertensive patients and 50 non-hypertensive patients with at least one cardiovascular risk factor. Comparison of the absolute 10-year cardiovascular risk calculated by a computer program based on the Framingham score and adapted for physicians by the WHO/ISH with the perceived risk as assessed clinically by the physicians. Physicians underestimated the 10-year cardiovascular risk of their patients compared to that calculated with the Framingham score. Concordance between methods was 39% for hypertensive patients and 30% for non-hypertensive patients. Underestimation of cardiovascular risks for hypertensive patients was related to the fact they had a stabilized systolic blood pressure under 140 mm Hg (OR = 2.1 [1.1; 4.1]). These data show that young physicians in training often have an incorrect perception of the cardiovascular risk of their patients with a tendency to underestimate the risk. However, the calculated risk could also be slightly overestimated when applying the Framingham Heart Study model to a Swiss population. To implement a systematic evaluation of risk factors in primary care a greater emphasis should be placed on the teaching of cardiovascular risk evaluation and on the implementation of quality improvement programs.

On the efficient evaluation of ruin probabilities for completely monotone claim size distributions

In this paper we propose a highly accurate approximation procedure for ruin probabilities in the classical collective risk model, which is based on a quadrature/rational approximation procedure proposed in [2]. For a certain class of claim size distributions (which contains the completely monotone distributions) we give a theoretical justification for the method. We also show that under weaker assumptions on the claim size distribution, the method may still perform reasonably well in some cases. This in particular provides an efficient alternative to a related method proposed in [3]. A number of numerical illustrations for the performance of this procedure is provided for both completely monotone and other types of random variables.

Cost evaluation and comparison of three decision strategies for cardiac revascularization : results of the suspected CAD protocol of the European CMR registry

Background: The public health burden of coronary artery disease (CAD) is important. Perfusion cardiac magnetic resonance (CMR) is generally accepted to detect and monitor CAD. Few studies have so far addressed its costs and costeffectiveness. Objectives: To compare in a large CMR registry the costs of a CMR-guided strategy vs two hypothetical invasive strategies for the diagnosis and the treatment of patients with suspected CAD. Methods: In 3'647 patients with suspected CAD included prospectively in the EuroCMR Registry (59 centers; 18 countries) costs were calculated for diagnostic examinations, revascularizations as well as for complication management over a 1-year follow-up. Patients with ischemia-positive CMR underwent an invasive X-ray coronary angiography (CXA) and revascularization at the discretion of the treating physician (=CMR+CXA strategy). Ischemia was found in 20.9% of patients and 17.4% of them were revascularized. In ischemia-negative patients by CMR, cardiac death and non-fatal myocardial infarctions occurred in 0.38%/y. In a hypothetical invasive arm the costs were calculated for an initial CXA followed by FFR testing in vessels with ≥50% diameter stenoses (=CXA+FFR strategy). To model this hypothetical arm, the same proportion of ischemic patients and outcome was assumed as for the CMR+CXA strategy. The coronary stenosis - FFR relationship reported in the literature was used to derive the proportion of patients with ≥50% diameter stenoses (Psten) in the study cohort. The costs of a CXA-only strategy were also calculated. Calculations were performed from a third payer perspective for the German, UK, Swiss, and US healthcare systems.

An exploration of transformation theory and the western tradition: a critical evaluation of a graduate studies class

This qualitative study is an exploration of transformation theory, the Western tradition, and a critical evaluation of a graduate studies class at a university. It is an exploration of assumptions that are embedded in experience, that influence the experience and provide meaning about the experience. An attempt has been made to identify assumptions that are embedded in Western experience and connect them with assumptions that shape the graduate class experience. The focus is on assumptions that facilitate and impede large group discussions. Jungian psychology of personality type and archetype and developmental psychology is used to analyze the group experience. The pragmatic problem solving model, developed by Knoop, is used to guide thinking about the Western tradition. It is used to guide the analysis, synthesis and writing of the experience of the graduate studies class members. A search through Western history, philosophy. and science revealed assumptions about the nature of truth, reality, and the self. Assumptions embedded in Western thinking about the subject-object relationship, unity and diversity are made explicit. An attempt is made to identify Western tradition assumptions underlying transformation theory. The critical evaluation of the graduate studies class experience focuses upon issues associated with group process, self-directed learning, the educator-learner transaction and the definition of adult education. The advantages of making implicit assumptions explicit is explored.

A social-cognitive model of monitoring and its relationship to behaviour in a naturalistic observation : development and individual differences

years 8 months) and 24 older (M == 7 years 4 months) children. A Monitoring Process Model (MPM) was developed and tested in order to ascertain at which component process ofthe MPM age differences would emerge. The MPM had four components: (1) assessment; (2) evaluation; (3) planning; and (4) behavioural control. The MPM was assessed directly using a referential communication task in which the children were asked to make a series of five Lego buildings (a baseline condition and one building for each MPM component). Children listened to instructions from one experimenter while a second experimenter in the room (a confederate) intetjected varying levels ofverbal feedback in order to assist the children and control the component ofthe MPM. This design allowed us to determine at which "stage" ofprocessing children would most likely have difficulty monitoring themselves in this social-cognitive task. Developmental differences were obselVed for the evaluation, planning and behavioural control components suggesting that older children were able to be more successful with the more explicit metacomponents. Interestingly, however, there was no age difference in terms ofLego task success in the baseline condition suggesting that without the intelVention ofthe confederate younger children monitored the task about as well as older children. This pattern ofresults indicates that the younger children were disrupted by the feedback rather than helped. On the other hand, the older children were able to incorporate the feedback offered by the confederate into a plan ofaction. Another aim ofthis study was to assess similar processing components to those investigated by the MPM Lego task in a more naturalistic observation. Together the use ofthe Lego Task ( a social cognitive task) and the naturalistic social interaction allowed for the appraisal of cross-domain continuities and discontinuities in monitoring behaviours. In this vein, analyses were undertaken in order to ascertain whether or not successful performance in the MPM Lego Task would predict cross-domain competence in the more naturalistic social interchange. Indeed, success in the two latter components ofthe MPM (planning and behavioural control) was related to overall competence in the naturalistic task. However, this cross-domain prediction was not evident for all levels ofthe naturalistic interchange suggesting that the nature ofthe feedback a child receives is an important determinant ofresponse competency. Individual difference measures reflecting the children's general cognitive capacity (Working Memory and Digit Span) and verbal ability (vocabulary) were also taken in an effort to account for more variance in the prediction oftask success. However, these individual difference measures did not serve to enhance the prediction oftask performance in either the Lego Task or the naturalistic task. Similarly, parental responses to questionnaires pertaining to their child's temperament and social experience also failed to increase prediction oftask performance. On-line measures ofthe children's engagement, positive affect and anxiety also failed to predict competence ratings.

Clinician-Perceived Bridges and Barriers to Parental Implementation of Picture Exchange Communication System (PECS): An evaluation.

Picture Exchange Communication System (PECS) is an augmentative and alternative communicative system that improves communication and decreases problem behaviors in children with Developmental Disabilities and Autism. The mediator model is a validated approach that clinicians use to train parents to perform evidence-based interventions. Parental non-adherence to treatment recommendations is a documented problem. This qualitative study investigated clinician-perceived factors that influence parental adherence to PECS recommendations. Three focus groups (n=8) were conducted with Speech Language Pathologists and Behavior Therapists experienced in providing parents with PECS recommendations. Constant comparison analysis was used. In general, clinicians believed that PECS was complex to implement. Thirty-one bridges were identified to overcome complexity. Twenty-two barriers and 6 other factors also impacted parental adherence. Strategies to address these factors were proposed based on a review of the literature. Future research will be performed to validate these findings using parents and a larger sample size.

Dynamic Performance Evaluation of Canadian Fixed-Income Funds using Markov Regime Switching Models

This thesis examines the performance of Canadian fixed-income mutual funds in the context of an unobservable market factor that affects mutual fund returns. We use various selection and timing models augmented with univariate and multivariate regime-switching structures. These models assume a joint distribution of an unobservable latent variable and fund returns. The fund sample comprises six Canadian value-weighted portfolios with different investing objectives from 1980 to 2011. These are the Canadian fixed-income funds, the Canadian inflation protected fixed-income funds, the Canadian long-term fixed-income funds, the Canadian money market funds, the Canadian short-term fixed-income funds and the high yield fixed-income funds. We find strong evidence that more than one state variable is necessary to explain the dynamics of the returns on Canadian fixed-income funds. For instance, Canadian fixed-income funds clearly show that there are two regimes that can be identified with a turning point during the mid-eighties. This structural break corresponds to an increase in the Canadian bond index from its low values in the early 1980s to its current high values. Other fixed-income funds results show latent state variables that mimic the behaviour of the general economic activity. Generally, we report that Canadian bond fund alphas are negative. In other words, fund managers do not add value through their selection abilities. We find evidence that Canadian fixed-income fund portfolio managers are successful market timers who shift portfolio weights between risky and riskless financial assets according to expected market conditions. Conversely, Canadian inflation protected funds, Canadian long-term fixed-income funds and Canadian money market funds have no market timing ability. We conclude that these managers generally do not have positive performance by actively managing their portfolios. We also report that the Canadian fixed-income fund portfolios perform asymmetrically under different economic regimes. In particular, these portfolio managers demonstrate poorer selection skills during recessions. Finally, we demonstrate that the multivariate regime-switching model is superior to univariate models given the dynamic market conditions and the correlation between fund portfolios.

Statistical Inference for Computable General Equilibrium Models with Application to a Model of the Moroccan Economy

We study the problem of measuring the uncertainty of CGE (or RBC)-type model simulations associated with parameter uncertainty. We describe two approaches for building confidence sets on model endogenous variables. The first one uses a standard Wald-type statistic. The second approach assumes that a confidence set (sampling or Bayesian) is available for the free parameters, from which confidence sets are derived by a projection technique. The latter has two advantages: first, confidence set validity is not affected by model nonlinearities; second, we can easily build simultaneous confidence intervals for an unlimited number of variables. We study conditions under which these confidence sets take the form of intervals and show they can be implemented using standard methods for solving CGE models. We present an application to a CGE model of the Moroccan economy to study the effects of policy-induced increases of transfers from Moroccan expatriates.

Correcting the Errors : A Note on Volatility Forecast Evaluation Based on High-Frequency Data and Realized Volatilities

This note develops general model-free adjustment procedures for the calculation of unbiased volatility loss functions based on practically feasible realized volatility benchmarks. The procedures, which exploit the recent asymptotic distributional results in Barndorff-Nielsen and Shephard (2002a), are both easy to implement and highly accurate in empirically realistic situations. On properly accounting for the measurement errors in the volatility forecast evaluations reported in Andersen, Bollerslev, Diebold and Labys (2003), the adjustments result in markedly higher estimates for the true degree of return-volatility predictability.

Intertemporal Social Evaluation

Intertemporal social-evaluation rules provide us with social criteria that can be used to assess the relative desirability of utility distributions across generations. The trade-offs between the well-being of different generations implicit in each such rule reflect the underlying ethical position on issues of intergenerational equity or justice. We employ an axiomatic approach in order to identify ethically attractive socialevaluation procedures. In particular, we explore the possibilities of using welfare information and non-welfare information in a model of intertemporal social evaluation. We focus on the individuals’ birth dates and lengths of life as the relevant non-welfare information. As usual, welfare information is given by lifetime utilities. It is assumed that this information is available for each alternative to be ranked. Various weakenings of the Pareto principle are employed in order to allow birth dates or lengths of life (or both) to matter in social evaluation. In addition, we impose standard properties such as continuity and anonymity and we examine the consequences of an intertemporal independence property. For each of the Pareto conditions employed, we characterize all social-evaluation rules satisfying it and our other axioms. The resulting rules are birth-date dependent or lifetime-dependent versions of generalized utilitarianism. Furthermore, we discuss the ethical and axiomatic foundations of geometric discounting in the context of our model.