Overcoming Resistance to Targeted Therapies in Cancer

The recent discovery of oncogenic drivers and subsequent development of novel targeted strategies has significantly added to the therapeutic armamentarium of anti-cancer therapies. Targeting BCR-ABL in chronic myeloid leukemia (CML) or HER2 in breast cancer has led to practice-changing clinical benefits, while promising therapeutic responses have been achieved by precision medicine approaches in EGFR mutant lung cancer, colorectal cancer and BRAF mutant melanoma. However, although initial therapeutic responses to targeted therapies can be substantial, many patients will develop disease progression within 6-12 months. An increasing application of powerful omics-based approaches and improving preclinical models have enabled the rapid identification of secondary resistance mechanisms. Herein, we discuss how this knowledge has translated into rational, novel treatment strategies for relapsed patients in genomically selected cancer populations.

A Hybrid Imperialist Approach in Solving University Timetabling Problems. Information Sciences. Vol. 283, 1-21

Generating timetables for an institution is a challenging and time consuming task due to different demands on the overall structure of the timetable. In this paper, a new hybrid method which is a combination of a great deluge and artificial bee colony algorithm (INMGD-ABC) is proposed to address the university timetabling problem. Artificial bee colony algorithm (ABC) is a population based method that has been introduced in recent years and has proven successful in solving various optimization problems effectively. However, as with many search based approaches, there exist weaknesses in the exploration and exploitation abilities which tend to induce slow convergence of the overall search process. Therefore, hybridization is proposed to compensate for the identified weaknesses of the ABC. Also, inspired from imperialist competitive algorithms, an assimilation policy is implemented in order to improve the global exploration ability of the ABC algorithm. In addition, Nelder–Mead simplex search method is incorporated within the great deluge algorithm (NMGD) with the aim of enhancing the exploitation ability of the hybrid method in fine-tuning the problem search region. The proposed method is tested on two differing benchmark datasets i.e. examination and course timetabling datasets. A statistical analysis t-test has been conducted and shows the performance of the proposed approach as significantly better than basic ABC algorithm. Finally, the experimental results are compared against state-of-the art methods in the literature, with results obtained that are competitive and in certain cases achieving some of the current best results to those in the literature.

A hybrid training method for B-spline neural networks

Current and past research has brought up new views related to the optimization of neural networks. For a fixed structure, second order methods are seen as the most promising. From previous works we have shown how second order methods are of easy applicability to a neural network. Namely, we have proved how the Levenberg-Marquard possesses not only better convergence but how it can assure the convergence to a local minima. However, as any gradient-based method, the results obtained depend on the startup point. In this work, a reformulated Evolutionary algorithm - the Bacterial Programming for Levenberg-Marquardt is proposed, as an heuristic which can be used to determine the most suitable starting points, therefore achieving, in most cases, the global optimum.

Shape control of laminated panels using piezoelectric actuators

This paper presents a finite element formulation based on the classical laminated plate theory for laminated structures with integrated piezoelectric layers or patches, acting as actuators.The finite element model is a single layer trinaguular nonconforming plate/shell element with 18 degrees of fredom for the generalized displacements, and one electrical potential degree of freedom for each piezoelectric element elemenet layer or patch. An optimization of the patches position is perfomed to maximize the piezoelectric actuators efficiency as well as,the electric potential distribution is serach to reach the specified strusctura transverse displacement distribution is search to reach the specified structures trsnsverse displacement distribution (shape control). A gradient based algorithm is used for this purpose.Results are presented and discussed.

Design of laminated structures using piezoelectric materials

Composite structures incorporating piezoelectric sensors and actuators are increasingly becoming important due to the offer of potential benefits in a wide range of engineering applications such as vibration and noise supression, shape control and precisition positioning. This paper presents a finit element formulation based on classical laminated plate theory for laminated structures with integrated piezoelectric layers or patches, acting as actuators. The finite element model is a single layer triangular nonconforming plate/shell element with 18 degrees of freedom for the generalized displacements, and one electrical potential degree of freedom for each piezsoelectric elementlayer or patch, witch are surface bonded on the laminate. An optimization of the patches position is performed to maximize the piezoelectric actuators efficiency as well as, the electric potential distribuition is search to reach the specified structure transverse displacement distribuition (shape control). A gradient based algorithm is used for this purpose. The model is applied in the optimization of illustrative laminated plate cases, and the results are presented and discussed.

Urban development modifies lake food webs in the Pacific Northwest

Thesis (Master's)--University of Washington, 2015

Making way for change at the Bar: The practical implications of the new Bar Standards Board Handbook

The Legal Services Act 2007 caused a need to change professional conduct rules for lawyers in England and Wales. The Bar Standards Board Handbook brings substantial changes to the way barristers are regulated. Changes include litigation rights, reporting of professional misconduct, an increased focus on chambers, and expansion to include employees of chambers and barristers without practicing certificates (unregistered or non-practicing barristers). The approach to enforcement and supervision moves to include elements of outcome focused, principle based and risk based approaches. These changes have the potential to change the practice of different groups of barristers and the dynamics between them.

TRAILER project overview: tagging, recognition and acknowledgment of informal learning experiences

The evolution of new technology and its increasing use, have for some years been making the existence of informal learning more and more transparent, especially among young and older adults in both Higher Education and workplace contexts. However, the nature of formal and non-formal, course-based, approaches to learning has made it hard to accommodate these informal processes satisfactorily, and although technology bring us near to the solution, it has not yet achieved. TRAILER project aims to address this problem by developing a tool for the management of competences and skills acquired through informal learning experiences, both from the perspective of the user and the institution or company. This paper describes the research and development main lines of this project.

Short-term Wind Speed Forecasting using Support Vector Machines

Wind speed forecasting has been becoming an important field of research to support the electricity industry mainly due to the increasing use of distributed energy sources, largely based on renewable sources. This type of electricity generation is highly dependent on the weather conditions variability, particularly the variability of the wind speed. Therefore, accurate wind power forecasting models are required to the operation and planning of wind plants and power systems. A Support Vector Machines (SVM) model for short-term wind speed is proposed and its performance is evaluated and compared with several artificial neural network (ANN) based approaches. A case study based on a real database regarding 3 years for predicting wind speed at 5 minutes intervals is presented.

Promise for plant pest control: root-associated pseudomonads with insecticidal activities.

Insects are an important and probably the most challenging pest to control in agriculture, in particular when they feed on belowground parts of plants. The application of synthetic pesticides is problematic owing to side effects on the environment, concerns for public health and the rapid development of resistance. Entomopathogenic bacteria, notably Bacillus thuringiensis and Photorhabdus/Xenorhabdus species, are promising alternatives to chemical insecticides, for they are able to efficiently kill insects and are considered to be environmentally sound and harmless to mammals. However, they have the handicap of showing limited environmental persistence or of depending on a nematode vector for insect infection. Intriguingly, certain strains of plant root-colonizing Pseudomonas bacteria display insect pathogenicity and thus could be formulated to extend the present range of bioinsecticides for protection of plants against root-feeding insects. These entomopathogenic pseudomonads belong to a group of plant-beneficial rhizobacteria that have the remarkable ability to suppress soil-borne plant pathogens, promote plant growth, and induce systemic plant defenses. Here we review for the first time the current knowledge about the occurrence and the molecular basis of insecticidal activity in pseudomonads with an emphasis on plant-beneficial and prominent pathogenic species. We discuss how this fascinating Pseudomonas trait may be exploited for novel root-based approaches to insect control in an integrated pest management framework.

An exploratory study for the discovery of non-invasive hepatocellular carcinoma biomarkers among high-risk hepatitis C virus infected patients

Hepatocellular Carcinoma (HCC) is a major healthcare problem, representing the third most common cause of cancer-related mortality worldwide. Chronic infections with Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) are the major risk factors for the development of HCC. The incidence of HBV -associated HCC is in decline as a result of an effective HBV vaccine; however, since an equally effective HCV vaccine has not yet been developed, there are 130 million HCV infected patients worldwide who are at a high-risk for developing HCC. Because reliable parameters and/or tools for the early detection of HCC among high-risk individuals are severely lacking, HCC patients are always diagnosed at a late stage where surgical solutions or effective treatment are not possible. Using urine as a non-invasive sample source, two different approaches (proteomic-based and genomic-based approaches) were pursued with the common goal of discovering potential biomarker candidates for the early detection of HCC among high-risk chronic HCV infected patients. Urine was collected from 106 HCV infected Egyptian patients, 32 of whom had already developed HCC and 74 patients who were diagnosed as HCC-free at the time of initial sample collection. In addition to these patients, urine samples were also collected from 12 healthy control individuals. Total urinary proteins, Trans-renal nucleic acid (Tr-NA) and microRNA (miRNA) were isolated from urine using novel methodologies and silicon carbide-loaded spin columns. In the first, "proteomic-based", approach, liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to identify potential candidates from pooled urine samples. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR (qRT-PCR). This approach revealed that significant over-expression of three proteins: DJ-1, Chromatin Assembly Factor-1 (CAF-1) and 11 Moemen Abdalla HCC Biomarkers Heat Shock Protein 60 (HSP60), were characteristic events among HCC-post HCV infected patients. As a single-based HCC biomarker, CAF-1 over-expression identified HCC among HCV infected patients with a specificity of 90%, sensitivity of 66% and with an overall diagnostic accuracy of 78%. Moreover, the CAF-lIHSP60 tandem identified HCC among HCV infected patients with a specificity of 92%, sensitivity of 61 % and with an overall diagnostic accuracy of 77%. In the second genomic-based approach, two different approaches were processed. The first approach was the miRNA-based approach. The expression levels of miRNAs isolated from urine were studied using the Illumina MicroRNA Expression Profiling Assay. This was followed by qRT-PCR-based validation of deregulated expression of identified miRNA candidates among all the patients. This approach shed the light on the deregulated expression of a number of miRNAs, which may have a role in either the development of HCC among HCV infected patients (i.e. miR-640, miR-765, miR-200a, miR-521 and miR-520) or may allow for a better understanding of the viral-host interaction (miR-152, miR-486, miR-219, miR452, miR-425, miR-154 and miR-31). Moreover, the deregulated expression of both miR-618 and miR-650 appeared to be a common event among HCC-post HCV infected patients. The results of the search for putative targets of these two miRNA suggested that miR-618 may be a potent oncogene, as it targets the tumor-suppressor gene Low density lipoprotein-related protein 12 (LPR12), while miR-650 may be a potent tumor-suppressor gene, as it is supposed to downregulate the TNF receptor-associated factor-4 (TRAF4) oncogene. The specificity of miR-618 and miR-650 deregulated expression patterns for the early detection of HCC among HCV infected patients was 68% and 58%, respectively, whereas the sensitivity was 64% and 72%, respectively. When the deregulated expression of both miRNAs was combined as a tandem biomarker, the specificity and the sensitivity were 75% and 58% respectively. 111 Moemen Abdalla HCC Biomarkers In the second, "Trans-renal nucleic acid-based", approach, the urinary apoptotic nucleic acid (uaNA) levels of 70ng/mL or more were found to be a good predictor of HCC among chronic HCV infected patients. The specificity and the sensitivity of this diagnostic approach were 76% and 86%, respectively, with an overall diagnostic value of 81 %. The uaNA levels positively correlated to HCC disease progression as monitored by epigenetic changes of a panel of eight tumor-suppressor genes (TSGs) using methylation-sensitive PCR. Moreover, the pairing of high uaNA levels (:::: 70 ng/mL) and CAF-1 over-expreSSIOn produced a highly specific (l 00%) multiple-based HCC biomarker with an acceptable sensitivity of 64%, and with a diagnostic accuracy of 82%. In comparison to the previous pairing, the uaNA levels (:::: 70 ng/mL) in tandem with HSP60 over-expression was less specific (89%) but highly sensitive (72%), resulting in a diagnostic accuracy of 64%. The specificities of miR-650 deregulated expression in combination with either high uaNA content or HSP 60 over-expression were 82% and 79%, respectively, whereas, the sensitivities of these combinations were 64% and 58%, respectively. The potential biomarkers identified in this study compare favorably with the diagnostic accuracy of the a-fetoprotein levels test, which has a specificity of 75%, sensitivity of 68% and an overall diagnostic accuracy of 70%. Here we present an intriguing study which shows the significance of using urine as a noninvasive sample source for the identification of promising HCC biomarkers. We have also introduced new techniques for the isolation of different urinary macromolecules, especially miRNA, from urine. Furthermore, we strongly recommend the potential biomarkers indentified in this study as focal points of any future research on HCC diagnosis. A larger testing pool will determine if their use is practical for mass population screening. This explorative study identified potential targets that merit further investigation for the development of diagnostically accurate biomarkers isolated from 1-2 mL urine samples that were acquired in a non-invasive manner.

Reading Instruction and Instructors’ Perceptions of Learners’ Needs in LINC Level 1-3 Classes

This study investigates instructors’ perceptions of reading instruction and difficulties among Language Instruction for Newcomers to Canada (LINC) Level 1-3 learners. Statistics Canada reports that 60% of immigrants possess inadequate literacy skills. Newcomers are placed in classes using the Canadian Language Benchmarks but large, mixed-level classes create little opportunity for individualized instruction, leading some clients to demonstrate little change in their reading benchmarks. Data were collected (via demographic questionnaires, semi-structured interviews, teaching plans, and field study notes) to create a case study of five LINC instructors’ perceptions of why some clients do not progress through the LINC reading levels as expected and how their previous experiences relate to those within the LINC program. Qualitative analyses of the data revealed three primary themes: client/instructor background and classroom needs, reading, strategies, methods and challenges, and assessment expectations and progress, each containing a number of subthemes. A comparison between the themes and literature demonstrated six areas for discussion: (a) some clients, specifically refugees, require more time to progress to higher benchmarks; (b) clients’ level of prior education can be indicative of their literacy skills; (c) clients with literacy needs should be separated and placed into literacy-specific classes; (d) evidence-based approaches to reading instruction were not always evident in participants’ responses, demonstrating a lack of knowledge about these approaches; (e) first language literacy influences second language reading acquisition through a transfer of skills; and (f) collaboration in the classroom supports learning by extending clients’ capabilities. These points form the basis of recommendations about how reading instruction might be improved for such clients.

Social Opportunities and Individual Responsibility: The Capability Approach and the Third Way

The fashionable widespreading of Sen’s ideas coincides with a new mood in the shaping of public policies in affluent societies. In Europe indeed, an “opportunity”-based approach to social security has been implemented through the European Employment Strategy. Public action tends to rely on a procedural concern with individual opportunities or potentialities in the labour market. The underlying ethics is that individuals are then responsible to use these background opportunities in order to lead the kind of life they value most. More broadly, the discourse and practice of the so-called “Third Way” shares with the capability approach an appeal for a procedural and enabling depiction of the role of the State. The paper intends to clarify the relation between procedural and opportunity-based approaches to social justice, among them the capability approach, and these new patterns of public action. Our vision goes in the way of a yet renewed, but deeper action of the welfare state, where social agency is envisaged as the very condition of individual agency. Drawing on the various critics of mainstream equality of opportunity, two opposed approaches to responsibility are identified: on the one hand, responsibility is conceived of as i) a “luck vs. choice” fixed starting point, ii) a backward-looking conception and iii) a highly individualistic framework. On the other hand, responsibility is envisaged as i) an outcome of public policies rather than a starting point, ii) a forward-looking conception, and iii) a combined institutional-individual framework. We situate here Sen’s capability approach, as well as critics of the luck egalitarianism path. The Third Way rhetoric is assessed against both these perspectives. The issue eventually boils down to an ethical reflection on the articulation of responsibilities, and to a pragmatic and substantial concern for the content of what providing security should mean in practice.

Who has responsibility for access to essential medical drugs in the developing world?

L’accès aux traitements de base est un enjeu crucial pour la santé, la pauvreté et le développement. La responsabilité en matière d’accès est alors une question essentielle. Le huitième Objectif du Millénaire pour le Développement postule qu’en coopération avec les firmes pharmaceutiques, l’accès aux traitements essentiels doit être assuré. Les principales parties prenantes qui doivent engager leur responsabilité pour l’accès aux médicaments sont (1) l’industrie pharmaceutique, (2) les gouvernements, (3) la société au sens large, et (4) les individus (qu’ils soient ou non malades). Quatre approches permettent d’appréhender la responsabilité: (a) l’approche déontologique; (b) l’utilitarisme; (c) l’égalitarisme; (b) l’approche basée sur les droits de l’homme. Ces quatre arguments peuvent être utilisés pour assigner une responsabilité aux gouvernements dans l’accès aux médicaments. Le papier conclut qu’il est parfois difficile de distinguer entre ces quatre approches et qu’un « glissement-d’échelle » de la responsabilité est une voie utile pour appréhender les rôles des quatre principales parties prenantes dans l’accès aux médicaments, dépendant du pays ou de la région et de son environnement interne.

Routage adaptatif et qualité de service dans les réseaux optiques à commutation de rafales

Les réseaux optiques à commutation de rafales (OBS) sont des candidats pour jouer un rôle important dans le cadre des réseaux optiques de nouvelle génération. Dans cette thèse, nous nous intéressons au routage adaptatif et au provisionnement de la qualité de service dans ce type de réseaux. Dans une première partie de la thèse, nous nous intéressons à la capacité du routage multi-chemins et du routage alternatif (par déflection) à améliorer les performances des réseaux OBS, pro-activement pour le premier et ré-activement pour le second. Dans ce contexte, nous proposons une approche basée sur l’apprentissage par renforcement où des agents placés dans tous les nœuds du réseau coopèrent pour apprendre, continuellement, les chemins du routage et les chemins alternatifs optimaux selon l’état actuel du réseau. Les résultats numériques montrent que cette approche améliore les performances des réseaux OBS comparativement aux solutions proposées dans la littérature. Dans la deuxième partie de cette thèse, nous nous intéressons au provisionnement absolu de la qualité de service où les performances pire-cas des classes de trafic de priorité élevée sont garanties quantitativement. Plus spécifiquement, notre objectif est de garantir la transmission sans pertes des rafales de priorité élevée à l’intérieur du réseau OBS tout en préservant le multiplexage statistique et l’utilisation efficace des ressources qui caractérisent les réseaux OBS. Aussi, nous considérons l’amélioration des performances du trafic best effort. Ainsi, nous proposons deux approches : une approche basée sur les nœuds et une approche basée sur les chemins. Dans l’approche basée sur les nœuds, un ensemble de longueurs d’onde est assigné à chaque nœud du bord du réseau OBS pour qu’il puisse envoyer son trafic garanti. Cette assignation prend en considération les distances physiques entre les nœuds du bord. En outre, nous proposons un algorithme de sélection des longueurs d’onde pour améliorer les performances des rafales best effort. Dans l’approche basée sur les chemins, le provisionnement absolu de la qualité de service est fourni au niveau des chemins entre les nœuds du bord du réseau OBS. À cette fin, nous proposons une approche de routage et d’assignation des longueurs d’onde qui a pour but la réduction du nombre requis de longueurs d’onde pour établir des chemins sans contentions. Néanmoins, si cet objectif ne peut pas être atteint à cause du nombre limité de longueurs d’onde, nous proposons de synchroniser les chemins en conflit sans le besoin pour des équipements additionnels. Là aussi, nous proposons un algorithme de sélection des longueurs d’onde pour les rafales best effort. Les résultats numériques montrent que l’approche basée sur les nœuds et l’approche basée sur les chemins fournissent le provisionnement absolu de la qualité de service pour le trafic garanti et améliorent les performances du trafic best effort. En outre, quand le nombre de longueurs d’ondes est suffisant, l’approche basée sur les chemins peut accommoder plus de trafic garanti et améliorer les performances du trafic best effort par rapport à l’approche basée sur les nœuds.