Abstract 1905: Defining a therapeutic classification of breast cancer by actionable targets

Breast cancer remains a frequent cause of female cancer death despite the great strides in elucidation of biological subtypes and their reported clinical and prognostic significance. We have defined a general cohort of breast cancers in terms of putative actionable targets, involving growth and proliferative factors, the cell cycle, and apoptotic pathways, both as single biomarkers across a general cohort and within intrinsic molecular subtypes.

We identified 293 patients treated with adjuvant chemotherapy. Additional hormonal therapy and trastuzumab was administered depending on hormonal and HER2 status respectively. We performed immunohistochemistry for ER, PR, HER2, MM1, CK5/6, p53, TOP2A, EGFR, IGF1R, PTEN, p-mTOR and e-cadherin. The cohort was classified into luminal (62%) and non-luminal (38%) tumors as well as luminal A (27%), luminal B HER2 negative (22%) and positive (12%), HER2 enriched (14%) and triple negative (25%). Patients with luminal tumors and co-overexpression of TOP2A or IGF1R loss displayed worse overall survival (p=0.0251 and p=0.0008 respectively). Non-luminal tumors had much greater heterogeneous expression profiles with no individual markers of prognostic significance. Non-luminal tumors were characterised by EGFR and TOP2A overexpression, IGF1R, PTEN and p-mTOR negativity and extreme p53 expression.

Our results indicate that only a minority of intrinsic subtype tumors purely express single novel actionable targets. This lack of pure biomarker expression is particular prevalent in the triple negative subgroup and may allude to the mechanism of targeted therapy inaction and myriad disappointing trial results. Utilising a combinatorial biomarker approach may enhance studies of targeted therapies providing additional information during design and patient selection while also helping decipher negative trial results.

Reasoning Rights: Comparative judicial engagement

This edited book is about comparative reasoning in human rights cases, exploring the questions: How is it that notionally universal norms are reasoned by courts in such dramatically different ways? What is the shape of this reasoning? What techniques are common across the transnational jurisprudence? What techniques are diverse? With contributions by a team of world-leading human rights scholars, the book moves beyond simply addressing the institutional questions concerning courts and human rights, which too often dominate discussions of this kind. Instead, it seeks a deeper examination of the similarities and divergence in the content of reasons being developed by different courts when addressing comparable human rights questions. These differences, while partly influenced by institutional issues, cannot be attributable to them alone. The book explores the diverse and rich underlying spectrum of human rights reasoning, as a distinctive and particular form of legal reasoning, evident in the case studies across the selected jurisdictions. It is a fascinating study for all those interested in human rights law and legal reasoning.

Using Comparative Reasoning in Human Rights Adjudication:The Court of Justice of the European Union and the European Court of Human Rights Compared

This article examines the relationship between the methods that the European Court of Human Rights (ECtHR) and the Court of Justice of the European Union (CJEU) use to decide disputes that involve ‘human’ or ‘fundamental’ rights claims, and the substantive outcomes that result from the use of these particular methods. It has a limited aim: in attempting to understand the interrelationship between human rights methodology and human rights outcomes, it considers primarily the use of ‘comparative reasoning’ in ‘human’ and ‘fundamental’ rights claims by these courts. It is not primarily concerned with examining the extent to which the use of comparative reasoning is based on an appropriate methodology or whether there is a persuasive normative theory underpinning the use of comparative reasoning. The issues considered in this chapter do some of the groundwork, however, that is necessary in order to address these methodological and normative questions.

Kinect and Episodic Reasoning for Human Action Recognition

This paper presents a method for rational behaviour recognition that combines vision-based pose estimation with knowledge modeling and reasoning. The proposed method consists of two stages. First, RGB-D images are used in the estimation of the body postures. Then, estimated actions are evaluated to verify that they make sense. This method requires rational behaviour to be exhibited. To comply with this requirement, this work proposes a rational RGB-D dataset with two types of sequences, some for training and some for testing. Preliminary results show the addition of knowledge modeling and reasoning leads to a significant increase of recognition accuracy when compared to a system based only on computer vision.

Abstract: Psychometric properties of two self-report clinical competence scales for nursing students.

Abstract: Psychometric properties of two self-report clinical competence scales for nursing students.
Background: It is important to assess the clinical competence of nursing students to gauge their professional development and educational needs. This can be measured by self-assessment tools. Anema and McCoy (2010) contended that the currently available measures need further psychometric testing.
Aim: To test the psychometric properties of Nursing Competencies Questionnaire (NCQ) and Self-Efficacy in Clinical Performance (SECP) clinical competence scales.

Method: A non-randomly selected sample of n=248 2nd year nursing students completed NCQ, SECP and demographic questionnaires (June and September 2013). Mokken Scaling Analysis (MSA) was used to test the structural validity and scale properties, convergent and discriminant validity and reliability were subsequently tested.

Results: The NCQ provided evidence of a unidimensional scale which had strong scale scalability coefficients Hs =0.581; but limited evidence of item rankability HT =0.367. MSA undertaken with the SECP scale identified two potential unidimensional scales the SECP28 and SECP7, each with adequate evidence of good/reasonable scalablity psychometric properties as a summed scale but no/very limited evidence of scale rankability (SECP28: Hs = 0.55, HT=0.211; SECP7: Hs = 0.61, HT=0.049). Analysis of between cohort differences and NCQ/ SECP scale scores produced evidence of convergent and discriminant validity and good internal reliability: NCQ α = 0.93, SECP28 α = 0.96, and SECP7 α=0.89.

Discussion: The NCQ was verified to have evidence of reliability and validity; however, as the SECP findings are new, and the sample small, with reference to Straat and colleagues (2014), the SECP results should be interpreted with caution and verified on a second sample.

Conclusions: Measurement of perceived self-competence could inform the development of nursing competence and could start early in a nursing programme. Further testing of the NCQ and SECP scales with larger samples and from different years is indicated.


References:
Anema, M., G and McCoy, JK. (2010) Competency-Based Nursing Education: Guide to Achieving Outstanding Learner Outcomes. New York: Springer.
Straat, JH., van der Ark, LA and Sijtsma, K. (2014) Minimum Sample Size Requirements for Mokken Scale Analysis Educational and Psychological Measurement 74 (5), 809-822.

Abstract B64: The role of JAK1/2-STAT3 as acute resistance mechanism to MEK inhibition in BRAF mutant colorectal cancer.

Background: Oncogenic mutations in BRAF occur in 8% of patients with advanced colorectal cancer (CRC) and have been shown to correlate with poor prognosis. In contrast to BRAF mutant (MT) melanoma, where the BRAF inhibitor PLX4032 has shown significant increases in response rates and overall survival compared to standard Dacarbazine treatment, only minor responses to PLX4032 treatment have been reported in BRAFMT CRC. Clear understanding of the vulnerabilities of BRAFMT CRC is important, and identification of druggable targets uniquely required by BRAFMT CRC tumors has the potential to fill a gap in the therapeutic armamentarium of advanced CRC. The aim of this study was to identify novel resistance mechanisms to MAPK inhibition in BRAFMT CRC.

Methods: Paired BRAFMT/WT RKO and VACO432 CRC cell line models and non-isogenic BRAFMT LIM2405, WiDR and COLO205 CRC cells were used. Changes in protein expression/activity were assessed by Western Blotting. Interaction between MEK1/2 and JAK1/2 inhibition was assessed using the MTT cell viability assays and flow cytometry. Apoptosis was measured using Western blotting for PARP, cleaved caspase 3/8 and caspase 8, 3/7 activity assays.

Results: Treatment with MEK1/2 inhibitors AZD6244, GSK1120212, UO126 and PD98059 resulted in acute increases in STAT3 activity in the BRAFMT RKO and VACO432 cells but not in their BRAFWT clones and this was associated with increases in JAK2 activity. Inhibition of JAK/STAT3 activation using gene specific siRNA or small molecule inhibitors TG101348 or AZD1480, abrogated this survival response and resulted in significant increases in cell death when combined with MEK1/2 inhibitors AZD6244 or GSK1120212 in BRAFMT CRC cells. In addition, combination of MEK1/2 and JAK/STAT3 inhibition resulted in strong synergy with CI values between 0.3 and 0.7 in BRAFMT CRC cells.

Conclusions: We have identified JAK/STAT3 activation as an important escape mechanism for BRAFMT CRC following MEK1/2 inhibition. These data provide a strong rationale for further investigation of combination of MEK1/2 and JAK/STAT3 inhibition in BRAFMT in vivo models.

A atitude diagnóstica enquanto instrumento de análise de ação educativa

A investigação realizada encontra-se inserida na área das Ciências de Educação, teve como objetivo principal compreender a atitude diagnóstica no quadro das situações educativas e pedagógicas desenvolvidas pelas educadoras de alguns jardins-de-infância, do distrito de Évora e como finalidade construir uma teoria de médio alcance elaborada numa estrutura explicativa do conjunto de fenómenos em contexto. Em educação de infância, o ato de cuidar estabelece-se numa relação de ajuda à criança e orienta-se para objetivos como promover o bem-estar, o conforto e o desenvolvimento em todas as dimensões. Isto implica conhecer e compreender cada criança ou grupo de crianças e as situações educativas e pedagógicas, em contexto. Compreende um exercício prático e para o qual se projeta uma prática de diagnóstico conciliadora da compreensão dos fenómenos sociais, estruturados em comportamentos, ações e atitudes específicas. Verificam-se lacunas quanto à forma como este exercício se cumpre e evolui nas diferentes fases. Repetem-se fragilidades quanto à mobilização de saberes, atitudes e competências a cada momento do agir. Constatam-se conceitos psicologizados e estruturas muito ténues e, por isso, necessitam ser estudadas, documentadas e teorizadas, particularmente numa dimensão praxiológica do conhecimento. O estudo inseriu-se no quadro das metodologias qualitativas, seguiu o paradigma interpretativo e o raciocínio indutivo. O referencial metodológico reuniu os princípios e procedimentos da Grounded Theory. A colheita de dados efetuou-se em jardins-de-infância da rede pública; a amostra teórica envolveu seis educadoras de infância e as crianças com idades compreendidas entre os três e os seis anos. Adotámos o uso de multitécnicas, entre as quais, a observação, a entrevista e a narrativa escrita. Fizemos vinte observações, repartidas pelos dois períodos do dia (manhã e tarde); vinte e seis entrevistas e seis narrativas escritas. Da análise dos dados emergiu a Atitude Diagnóstica como uma predisposição que caracteriza o ato de agir e as suas características foram-se tornando evidentes com o desenvolvimento da caracterização do processo de diagnóstico. Desta emergiu o modelo teórico definido em três eixos fundamentais. O “Processo de avaliação diagnóstica e planeamento” representativo das etapas, segundo as quais o educador desenvolve um conjunto de ações propiciadoras de um conhecimento previamente organizado, visando o bem-estar, o conforto, a segurança e o desenvolvimento. Em concomitância emerge o segundo, “Processo de intervenção educativa e pedagógica”, expressivo do conjunto de ações coerentes e evolutivas, empreendidas com vista à execução dos objetivos do ensino aprendizagem. Trata-se de dois processos sistematizados e perspetivados sob as dimensões diacrónica e sincrónica, compostos por uma sequência de pensamentos, permanentemente averbados pela “Atitude Diagnóstica” que dá um caráter coerente e evolutivo às tomadas de decisão nas ações educativas. Estes dois eixos integrados e entrelaçados são auxiliados por um terceiro, o “Processo de relação” que os harmoniza e dá especificidade a cada situação experienciada. A relação consolida-se e assume-se uma ajuda na confiabilidade necessária para a promoção da confiança entre os pares e o conhecimento vai evoluindo gradualmente em função do tempo e dos compromissos. O educador age com intencionalidade e para cada ator traça objetivos a cada momento do agir. A gestão do tempo, dos sentimentos e emoções funciona como variável importante na relação orientada sob a tríade: educador, criança e família e é concomitante com o Desenvolvimento pessoal e profissional do educador; ### ABSTRACT: The Diagnostic Attitude as an Analysis Instrument in Educational Action The conducted investigation is inserted in the area of Education Sciences. Its main aim was to understand the diagnostic attitude in the frame of the educative and pedagogical activities developed by the educators of some kindergartens in the district of Évora, and its purpose was to build a medium range theory elaborated in a structure explaining the whole of the phenomena in context. In child education, the act of caring is established in a relationship of help towards the child and is oriented towards goals as specific as promoting the well-being, the comfort and the development in all dimensions. This implies knowing and understanding each child or group of children and the educational and pedagogical situations in context. It includes a practical exercise that determines a complex scenario and for which we project a conciliating diagnostic practice towards the understanding of the social phenomena, structured in specific behaviors, actions and attitudes. We recognize some gaps regarding the way how this exercise is fulfilled and evolves in the different phases. Weaknesses regarding the mobilization of knowledge, attitudes and competences in each acting moment are repeated. We notice psichologized concepts and very superficial structures that need thus to be studied, documented and theorized, particularly in a praxeological dimension of knowledge. The study is inserted in the frame of qualitative methodologies, following an interpretative paradigm and an inductive reasoning. The methodological referential has gathered the principles and procedures of the Grounded Theory. The gathering of data was done in public kindergartens; the theoretical sample involved six child educators and children aged between three and six years. Several techniques were used, such as observation, interview and written narrative. We did twenty observations, divided between the two periods of the day (morning and afternoon); twenty-six interviews and six written narratives. The analysis of the data resulted in the Diagnostic attitude, like a predisposition that characterizes the act of acting and its characteristics became evident with the development of the characterization of the diagnostic process. From this rose the theoretical model defined in three fundamental axes. The Process of diagnostic evaluation and planning that represents the stages according to which the educator develops a group of actions that allow the transmission of a previously organized knowledge that aims well-being, comfort, safety and development. Concomitantly arises the second, Process of educative and pedagogic intervention, that expresses a group of coherent and evolving actions, undertaken to reach the goals of the teaching-learning process. These are two systematized processes, perspectivated under the diachronical and synchronical dimensions, composed by a sequence of thought, permanently confirmed by the Diagnostic attitude that gives a coherent and evolving character to the decision making in educative actions. These two integrated and intertwined axis are aided by a third one, Process of relation that harmonizes them and gives specificity to each experienced situation. The relation is consolidated and one assumes a kind of help in the trustworthiness necessary for the promotion of the trust between pairs and the knowledge keeps evolving gradually according to time and commitments. The educator acts with intent and sets goals for each actor at each acting moment. Time, feeling and emotion management works as an important variable in the relation oriented according to the triad educator, child and family, being also concomitant with the Personal and professional development of the educator.