Curricular training report: clinical studies coordination in a clinical research organization vs an investigational site perspective

This report describes my experience of nine months as a trainee of a CRO (Eurotrials, Scientific Consultants), as well as a trainee of a clinical research site (Clinical Academic Center – Braga, Association). This document describes the European framework about clinical research and the Portuguese situation compared to similar countries. The activities developed during this internship are also described. These activities are divided in two phases. The first one occurred in Eurotrials, Scientific Consultants, a CRO specialized in clinical research and scientific advice. The first weeks were dedicated to intensive self-training needed to perform CTA tasks. These tasks included qualification, initiation and monitoring activities related to clinical trials, as well as the development of a quality management system. The second phase took place on 2CA-Braga, a clinical research center located in Hospital of Braga. Clinical studies coordination was the main focus of this second phase of my internship, as well as negotiation of clinical studies agreements. I had also the opportunity to participate in “1as Jornadas de Investigação Clínica e Inovação” (1st Clinical Investigation and Innovation Conference) organized by 2CA-Braga. Globally, this internship was a great opportunity to get knowledge and experience in the implementation and management of clinical trials, in a CRO and clinical research site perspectives. These two perspectives provided an interesting overview about the scientific needs of different players involved in clinical research. To conclude, this internship strengthened the knowledge acquired from my academic background, which make me able to face and overcome new challenges in the clinical research area.

Soft tissue sarcoma: biology and therapeutic correlates

Soft tissue sarcomas (STS) comprise a heterogenenous group of greater than 50 malignancies of putative mesenchymal cell origin and as such they may arise in diverse tissue types in various anatomical locations throughout the whole body. Collectively they account for approximately 1% of all human malignancies yet have a spectrum of aggressive behaviours amongst their subtypes. They thus pose a particular challenge to manage and remain an under investigated group of cancers with no generally applicable new therapies in the past 40 years and an overall 5-year survival rate that remains stagnant at around 50%. From September 2000 to July 2006 I undertook a full time post-doctoral level research fellowship at the MD Anderson Cancer Center, Houston, Texas, USA in the department of Surgical Oncology to investigate the biology of soft tissue sarcoma and test novel anti- sarcoma adenovirus-based therapy in the preclinical nude rat model of isolated limb perfusion against human sarcoma xenografts. This work, in collaboration with colleagues as indicated herein, led to a number of publications in the scientific literature furthering our understanding of the malignant phenotype of sarcoma and reported preclinical studies with wild-type p53, in a replication deficient adenovirus vector, and oncolytic adenoviruses administered by isolated limb perfusion. Additional collaborative and pioneering preclinical studies reported the molecular imaging of sarcoma response to systemically delivered therapeutic phage RGD-4c AAVP. Doxorubicin chemotherapy is the single most active broadly applicable anti-sarcoma chemotherapeutic yet only has an approximate 30% overall response rate with additional breakthrough tumour progression and recurrence after initial chemo-responsiveness further problematic features in STS management. Doxorubicin is a substrate for the multi- drug resistance (mdr) gene product p-glycoprotein drug efflux pump and exerts its main mode of action by induction of DNA double-strand breaks during the S-phase of the cell cycle. Two papers in my thesis characterise different aspects of chemoresistance in sarcoma. The first shows that wild-type p53 suppresses Protein Kinase Calpha (PKCα) phosphorylation (and activation) of p-glycoprotein by transcriptional repression of PKCα through a Sp-1 transcription factor binding site in its -244/-234 promoter region. The second paper demonstrates that Rad51 (a central mediator of homologous recombination repair of double strand breaks) has elevated levels in sarcoma and particularly in the S- G2 phase of the cell cycle. Suppression of Rad51 with small interfering RNA in sarcoma cell culture led to doxorubicin chemosensitisation. Reintroduction of wild-type p53 into STS cell lines resulted in decreased Rad51 protein and mRNA expression via transcriptional repression of the Rad51 promoter through increased AP-2 binding. In light of poor response rates to chemotherapy, escape from local control portends a poor prognosis for patients with sarcoma. Two papers in my thesis characterise aspects of sarcoma angiogenesis, invasion and metastasis. Human sarcoma samples were found to have high levels of matrix metalloproteinase-9 (MMP-9) with expression levels that correlated with p53 mutational status. MMP-9 is known to degrade extracellular collagen, contribute to the control of the angiogenic switch necessary in primary tumour progression and facilitate invasion and metastasis. Reconstitution of wild-type p53 function led to decreased levels of MMP-9 protein and mRNA as well as zymography-assessed MMP-9 proteolytic activity and decreased tumour cell invasiveness. Reintroduction of wild-type p53 into human sarcoma xenografts in-vivo decreased tumour growth and MMP-9 protein expression. Wild-type p53 was found to suppress mmp-9 transcription via decreased binding of NF-κB to its -607/-595 mmp-9 promoter element. Studies on the role of the VEGF165 in sarcoma found that sarcoma cells stably transfected with VEGF165 formed more aggressive xenografted tumours with increased vascularity, growth rate, metastasis, and resistance to chemotherapy. Use of the anti-VEGFR2 antibody DC101 enhanced doxorubicin sensitivity at sub-conventional dosing, inhibited tumour growth, decreased development of metastases, and reduced tumour micro-vessel density while increasing the vessel maturation index. These effects were explained primarily through effects on endothelial cells (e.c.s), rather than the tumour cells per se, where DC101 induced e.c. sensitivity to doxorubicin and suppressed e.c. production of MMPs. The p53 tumour suppressor pathway is the most frequently mutated pathway in sarcoma. Recapitulation of wild-type p53 function in sarcoma exerts a number of anti-cancer outcomes such as growth arrest, resensitisation to chemotherapy, suppression of invasion, and attenuation of angiogenesis. Using a modified nude rat-human sarcoma xenograft model for isolated limb perfusion (ILP) delivery of wild-type p53 in a replication deficient adenovirus vector I showed that functionally competent wild-type p53 could be delivered to and detected in human leiomyosarcoma xenografts confirming preclinical feasibility - although not efficacious due to low transgene expression. Viral fibre modification to express the RGD tripeptide motif led to greater viral uptake by sarcoma cells in vitro (transductional targeting) and changing the transgene promoter to a response element active in cells with active telomerase expression restricted the transgene expression to the tumour intracellular environment (transcriptional targeting). Delivery of the fibre-modified, selectively replication proficient oncolytic adenovirus Ad.hTC.GFP/ E1a.RGD by ILP demonstrated a more robust, and tumour-restricted, transgene expression with evidence of anti-sarcoma effect confirmed microscopically. Collaborative studies using the fibre modified phage RGD-4C AAVP confirmed that systemic delivery specifically, efficiently, and repeatedly targets human sarcoma xenografts, binds to αv integrins in tumours, and demonstrates a durable, though heterogeneous, transgene expression of 1-4 weeks. Incorporation of the Herpes Simplex Virus thymidine kinase (HSVtk) transgene into RGD-4C AAVP permitted CT-PET spatial and temporal molecular imaging in vivo of transgene expression and allowed quantification of tumour metabolic activity both before and after interval administration of a systemic cytotoxic with predictable and measurable response to treatment before becoming apparent clinically. These papers further the medical and scientific community’s understanding of the biology of soft tissue sarcoma and report preclinical studies with novel and promising anti- sarcoma therapeutics.

Sparse Signal Representation in Digital and Biological Systems

Theories of sparse signal representation, wherein a signal is decomposed as the sum of a small number of constituent elements, play increasing roles in both mathematical signal processing and neuroscience. This happens despite the differences between signal models in the two domains. After reviewing preliminary material on sparse signal models, I use work on compressed sensing for the electron tomography of biological structures as a target for exploring the efficacy of sparse signal reconstruction in a challenging application domain. My research in this area addresses a topic of keen interest to the biological microscopy community, and has resulted in the development of tomographic reconstruction software which is competitive with the state of the art in its field. Moving from the linear signal domain into the nonlinear dynamics of neural encoding, I explain the sparse coding hypothesis in neuroscience and its relationship with olfaction in locusts. I implement a numerical ODE model of the activity of neural populations responsible for sparse odor coding in locusts as part of a project involving offset spiking in the Kenyon cells. I also explain the validation procedures we have devised to help assess the model's similarity to the biology. The thesis concludes with the development of a new, simplified model of locust olfactory network activity, which seeks with some success to explain statistical properties of the sparse coding processes carried out in the network.

Relatório de estágio de qualificação profissional

Relatório EPE - Relatório de estágio em Educação Pré-Escolar: O presente relatório de estágio foi elaborado no âmbito da unidade curricular de Prática Pedagógica Supervisionada, integrada no Mestrado em Educação Pré – Escolar e Ensino do 1º Ciclo do Ensino Básico da Escola Superior de Educação do Instituto Politécnico do Porto. O estágio realizou-se no Jardim de Infância Gaia 13 que abarca crianças desde os 3 aos 6 anos de idade. A interação com a instituição e com o grupo de crianças e equipa educativa foi feita de modo progressivo, de modo a que as atividades planificadas e o projeto curricular de grupo construído, fossem ao encontro das características do contexto e do grupo de crianças. Desde o início da prática pedagógica que se construíram planificações semanais, que tinham como pressuposto a identificação das necessidades de desenvolvimento das crianças, bem como os seus interesses, os objetivos, os resultados de aprendizagem e os recursos pedagógicos, integrados no plano de ação. O trabalho desenvolvido teve por base a metodologia de investigação–ação, através de uma articulação entre a teoria e a prática, com a intenção de proporcionar competências profissionais na mestranda tais como: ser capaz de mobilizar vários saberes científicos e pedagógicos correspondentes à educação pré – escolar; ser capaz de desenvolver estratégias pedagógicas diferenciadas; construir uma atitude reflexiva de caráter indagador. Todo este processo contribuiu para a idealização de uma identidade profissional, em construção permanente, numa expectativa de aprendizagem ao longo da vida.

Existence and weak-strong uniqueness for the Navier-Stokes-Smoluchowski system over moving domains

This dissertation concerns the well-posedness of the Navier-Stokes-Smoluchowski system. The system models a mixture of fluid and particles in the so-called bubbling regime. The compressible Navier-Stokes equations governing the evolution of the fluid are coupled to the Smoluchowski equation for the particle density at a continuum level. First, working on fixed domains, the existence of weak solutions is established using a three-level approximation scheme and based largely on the Lions-Feireisl theory of compressible fluids. The system is then posed over a moving domain. By utilizing a Brinkman-type penalization as well as penalization of the viscosity, the existence of weak solutions of the Navier-Stokes-Smoluchowski system is proved over moving domains. As a corollary the convergence of the Brinkman penalization is proved. Finally, a suitable relative entropy is defined. This relative entropy is used to establish a weak-strong uniqueness result for the Navier-Stokes-Smoluchowski system over moving domains, ensuring that strong solutions are unique in the class of weak solutions.

Spectral Frame Analysis and Learning through Graph Structure

This dissertation investigates the connection between spectral analysis and frame theory. When considering the spectral properties of a frame, we present a few novel results relating to the spectral decomposition. We first show that scalable frames have the property that the inner product of the scaling coefficients and the eigenvectors must equal the inverse eigenvalues. From this, we prove a similar result when an approximate scaling is obtained. We then focus on the optimization problems inherent to the scalable frames by first showing that there is an equivalence between scaling a frame and optimization problems with a non-restrictive objective function. Various objective functions are considered, and an analysis of the solution type is presented. For linear objectives, we can encourage sparse scalings, and with barrier objective functions, we force dense solutions. We further consider frames in high dimensions, and derive various solution techniques. From here, we restrict ourselves to various frame classes, to add more specificity to the results. Using frames generated from distributions allows for the placement of probabilistic bounds on scalability. For discrete distributions (Bernoulli and Rademacher), we bound the probability of encountering an ONB, and for continuous symmetric distributions (Uniform and Gaussian), we show that symmetry is retained in the transformed domain. We also prove several hyperplane-separation results. With the theory developed, we discuss graph applications of the scalability framework. We make a connection with graph conditioning, and show the in-feasibility of the problem in the general case. After a modification, we show that any complete graph can be conditioned. We then present a modification of standard PCA (robust PCA) developed by Cand\`es, and give some background into Electron Energy-Loss Spectroscopy (EELS). We design a novel scheme for the processing of EELS through robust PCA and least-squares regression, and test this scheme on biological samples. Finally, we take the idea of robust PCA and apply the technique of kernel PCA to perform robust manifold learning. We derive the problem and present an algorithm for its solution. There is also discussion of the differences with RPCA that make theoretical guarantees difficult.

Methods matter: computational modelling in public health policy and planning

This work is aimed at understanding and unifying information on epidemiological modelling methods and how those methods relate to public policy addressing human health, specifically in the context of infectious disease prevention, pandemic planning, and health behaviour change. This thesis employs multiple qualitative and quantitative methods, and presents as a manuscript of several individual, data-driven projects that are combined in a narrative arc. The first chapter introduces the scope and complexity of this interdisciplinary undertaking, describing several topical intersections of importance. The second chapter begins the presentation of original data, and describes in detail two exercises in computational epidemiological modelling pertinent to pandemic influenza planning and policy, and progresses in the next chapter to present additional original data on how the confidence of the public in modelling methodology may have an effect on their planned health behaviour change as recommended in public health policy. The thesis narrative continues in the final data-driven chapter to describe how health policymakers use modelling methods and scientific evidence to inform and construct health policies for the prevention of infectious diseases, and concludes with a narrative chapter that evaluates the breadth of this data and recommends strategies for the optimal use of modelling methodologies when informing public health policy in applied public health scenarios.

Spatial and temporal measurements using polyoxometalate, enzymatic and biofilm layers on a CMOS 0.35 μm 64 X 64-pixel I.S.F.E.T. array sensor

This thesis presents the achievements and scientific work conducted using a previously designed and fabricated 64 x 64-pixel ion camera with the use of a 0.35 μm CMOS technology. We used an array of Ion Sensitive Field Effect Transistors (ISFETs) to monitor and measure chemical and biochemical reactions in real time. The area of our observation was a 4.2 x 4.3 mm silicon chip while the actual ISFET array covered an area of 715.8 x 715.8 μm consisting of 4096 ISFET pixels in total with a 1 μm separation space among them. The ion sensitive layer, the locus where all reactions took place was a silicon nitride layer, the final top layer of the austriamicrosystems 0.35 μm CMOS technology used. Our final measurements presented an average sensitivity of 30 mV/pH. With the addition of extra layers we were able to monitor a 65 mV voltage difference during our experiments with glucose and hexokinase, whereas a difference of 85 mV was detected for a similar glucose reaction mentioned in literature, and a 55 mV voltage difference while performing photosynthesis experiments with a biofilm made from cyanobacteria, whereas a voltage difference of 33.7 mV was detected as presented in literature for a similar cyanobacterial species using voltamemtric methods for detection. To monitor our experiments PXIe-6358 measurement cards were used and measurements were controlled by LabVIEW software. The chip was packaged and encapsulated using a PGA-100 chip carrier and a two-component commercial epoxy. Printed circuit board (PCB) has also been previously designed to provide interface between the chip and the measurement cards.

The big four skills: Teachers’ assumptions on measurement of non-native students cognition

The four-skills on tests for young native speakers commonly do not generate correlation incongruency concerning the cognitive strategies frequently reported. Considering the non-native speakers there are parse evidence to determine which tasks are important to assess properly the cognitive and academic language proficiency (Cummins, 1980; 2012). Research questions: It is of high probability that young students with origin in immigration significantly differ on their communication strategies and skills in a second language processing context (1); attached to this first assumption, it is supposed that teachers significantly differ depending on their scientific area and previous training (2). Purpose: This study intends to examine whether school teachers (K-12) as having different origin in scientific domain of teaching and training perceive differently an adapted four-skills scale, in European Portuguese. Research methods: 77 teachers of five areas scientific areas, mean of teaching year service = 32 (SD= 2,7), 57 males and 46 females (from basic and high school levels). Main findings: ANOVA (Effect size and Post-hoc Tukey tests) and linear regression analysis (stepwise method) revealed statistically significant differences among teachers of different areas, mainly between language teachers and science teachers. Language teachers perceive more accurately tasks in a multiple manner to the broad skills that require to be measured in non-native students. Conclusion: If teachers perceive differently the importance of the big-four tasks, there would be incongruence on skills measurement that teachers select for immigrant puppils. Non-balanced tasks and the teachers’ perceptions on evaluation and toward competence of students would likely determine limitations for academic and cognitive development of non-native students. Furthermore, results showed sufficient evidence to conclude that tasks are perceived differently by teachers toward importance of specific skills subareas. Reading skills are best considered compared to oral comphreension skills in non-native students.

Development of business processes and sales reporting - Case recovered paper

The purpose of this research is to discover development points for business processes and sales reporting in the recovered paper sourcing organization. The processes under development are both sales and sourcing processes that were determined by the commissioning company. All of these processes have in common that there are used sales orders to organize the money flows correctly. Although the main objective is to source only recovered paper, the sourcing also brings by-products that cannot be utilized and are thus sold. As the purpose of the sales function is to only support the sourcing strategy, it should be organized as efficiently as possible. Investigating the current status of the processes and finding development points help in building proposals for enhanced process descriptions. In order that sales function could be analyzed, should the sales reporting be accurate and present the needed key figures. The current status of the processes as well as the possible problems and development ideas were researched with the help of interviews. Best practices could also be brought from other business lines in the commissioning company. The theory part was build according to relevant literature and scientific articles. The research indicates, that processes have shaped differently in sourcing organization’s business units. Local infrastructure and legislation sets certain limitations to the sourcing of recovered paper, and these circumstances cannot be changed. Customer-supplier power relations also affect to the formulation of business processes. In order to steer the processes, there has to be more internal controls. Still, the enterprise resource planning system also sets boundaries how the processes can be made more efficient.

CHARACTERISTICS OF PRIVATE HIGH SCHOOLS FOR STUDENTS WITH EMOTIONAL DISABILITIES AND PERCEPTIONS OF THEIR PUBLIC SCHOOL CASE MANAGERS

Placement of students with disabilities in private special-education schools remains costly and controversial. This is particularly concerning, given the lack of research on the characteristics and quality of these restrictive settings. The purpose of this study was to identify the academic and vocational course offerings and behavioral supports provided in private special-education schools the serve high school students with emotional disabilities (ED). Second, the research examined the perceptions of the quality of services in these setting from the perspectives of public school case managers. Using a mixed-method design to collect data, 9 administrative heads of private special-education schools were surveyed, and 7 public school case managers were interviewed. Results indicated that (a) private special-education schools offer the basic academic core courses needed to meet graduation requirements, (b) vocational options for students enrolled in these schools are quite limited, (c) these schools provide a variety of behavioral interventions and supports, and (d) case managers are concerned with the lack of academic rigor and inconsistent programming at these schools but applauded the notion that students with ED are exiting with a high school diploma. Findings from this study may have policy implications for improving and developing programming options for high school students with ED.

Summit between West Chester University, Pennsylvania, USA and Universidad Nacional, Heredia Costa Rica. Global Library Literacy Initiative: An Intercultural Learning Experience

 This document describes the experience of academic cooperation between professionals in the field of library science, both from West Chester University (WCU), and the National University (UNA) of Costa Rica. The event took place at West Chester University during the week May 4th to May 8th, 2009. The objectives of this revolved around the exchange of ideas and interests in the academic and cultural relations between the two universities. In addition, it unveiled several services and procedures in the handling of information and highlighted the importance of promoting the exchange of students from both institutions. Finally, this article highlights the schedule of activities to integrate international and intercultural perspective in various areas related to the teaching-learning process, the contribution of university libraries on student success and techniques of information dissemination.

Proposal for the creation of a Center for Learning Resources (CRA) in the School of San Lorenzo de Tarrazu

Education is the basis for economic and social development, but there are great inequalities in education and access to documentary resources, audiovisual and technology, a situation that affects school performance. The Organization of the United Nations Educational and Scientific Organization (UNESCO) found a correlation between levels of inequality in a country and performance: the greater the inequality, the worse the performance. Investment in education affects human development and benefit is obtained for the individual and society, which is necessary to ensure social equity, so that there is quality education for all. One of the fundamental purposes of the educational process is to train Costa Rican human thinking, analytical and critical of their environment. The purpose of that is acquired through various methods of academic achievement, learning, participation and constant communication of knowledge between the administrative staff, faculty and students. It is appropriate for schools and colleges have a school library or Resource Center for Learning, it is the gathering, analysis and work of the educational community, working with the intellectual growth of students, faculty, staff and community through access to different services and learning resources provided by the library or CRA.

Friendships of High-Achieving African American Adolescents: Relation to Ethnic Identity and Achievement Values

The academic achievement of African American adolescents is a national concern for educators and researchers especially since current reports depict the underachievement of African American students as continuing to lag behind their European American peers. Determining what factors within the school environment that contributes to the achievement gap and how it can be reduced remains an important issue in alleviating disparities seen in educational achievement and attainment. This study examined the relation between characteristics of the close friendships of high-achieving African American adolescents and students’ identity development and motivation in school. Data were collected from 217 high-achieving African American students within 10th to 12th grade from 5 public and private high schools. Each student self-reported on their ethnicity, gender, parents’ education level, grade, FARMs, GPA, perceived teacher support (emotional, academic, and instrumental support), their perception of their ethnic identity, and their perception of their achievement values. Through the use of nomination procedures, students also identified their close friends and responded to questions concerning how supportive (emotional, academic, and instrumental support) they each were. Results from multiple regression analyses showed that the provision of instrumental support from close friends related to the exploration process of the high-achieving students’ ethnic identity. In addition, there was a strong relation between the ethnic identity of close friends and that of the individual. Furthermore, although friend support was not a significant predictor of achievement values, demographic (mother’s education level, grade, and FARMS) and control (teacher support) variables predicted students’ importance and utility of school respectively. These findings add to the literature on age and socioeconomic status as they relate to student’s motivation to achieve. Overall, this study provides some evidence highlighting ways in which close friendships might relate to the self-development of high-achieving African American adolescents. This study provides a starting point for additional ways in which to explore how peer processes relate to the academic behaviors of high-achieving African American adolescents.

The dynamics of Brazilian protozoology over the past century

Brazilian scientists have been contributing to the protozoology field for more than 100 years with important discoveries of new species such as Trypanosoma cruzi and Leishmania spp. In this work, we used a Brazilian thesis database (Coordination for the Improvement of Higher Education Personnel) covering the period from 1987-2011 to identify researchers who contributed substantially to protozoology. We selected 248 advisors by filtering to obtain researchers who supervised at least 10 theses. Based on a computational analysis of the thesis databases, we found students who were supervised by these scientists. A computational procedure was developed to determine the advisors’ scientific ancestors using the Lattes Platform. These analyses provided a list of 1,997 researchers who were inspected through Lattes CV examination and allowed the identification of the pioneers of Brazilian protozoology. Moreover, we investigated the areas in which researchers who earned PhDs in protozoology are now working. We found that 68.4% of them are still in protozoology, while 16.7% have migrated to other fields. We observed that support for protozoology by national or international agencies is clearly correlated with the increase of scientists in the field. Finally, we described the academic genealogy of Brazilian protozoology by formalising the “forest” of Brazilian scientists involved in the study of protozoa and their vectors over the past century.