TOWARD A POLITICAL CONCEPTION OF MINORITY RIGHTS: RECONCILING SOVEREIGNTY, HUMAN RIGHTS AND MINORITY CLAIMS

The question that I will explore in this research dissertation is whether one can defend the rights of homeland minorities as a progressive extension of the existing norms of human rights. This question calls for several deeper inquiries about the nature, the function and the underlying justifications for both human rights and minority rights. In particular, this research project will examine the following issues: on what normative grounds the available norms of human rights and minority rights are justified; if there is any methodic way to use the normative logic of human rights to support substantial forms of minority claims, such as the right to self-determination; whether human rights can take the form of group rights; and finally, whether there is any non-sectarian basis for justifying the minority norms, which can be acceptable from both liberal and non-liberal perspectives. This research project has some implications for both theories of minority rights and human rights. On the one hand, the research employs the topic of minority rights to shed light on deficiencies of the existing political theories of human rights. On the other hand, it uses the political theory to shed light on how existing theories of minority rights could be improved and amended. The inquiry will ultimately clarify how to judge the merit of the claim that minority rights are or should be a part of human rights norms.

Databases for quantitative history

This paper will propose that, rather than sitting on silos of data, historians that utilise quantitative methods should endeavour to make their data accessible through databases, and treat this as a new form of bibliographic entry. Of course in many instances historical data does not lend itself easily to the creation of such data sets. With this in mind some of the issues regarding normalising raw historical data will be looked at with reference to current work on nineteenth century Irish trade. These issues encompass (but are not limited to) measurement systems, geographic locations, and potential problems that may arise in attempting to unify disaggregated sources. It will discuss the need for a concerted effort by historians to define what is required from digital resources for them to be considered accurate, and to what extent the normalisation requirements for database systems may conflict with the desire for accuracy. Many of the issues that the historian may encounter engaging with databases will be common to all historians, and there would be merit in having defined standards for referencing items, such as people, places, locations, and measurements.

Epistemic, Ontic, Axiologic, and Praxic Constructs in Knowledge Organization Research

The work of knowledge organization requires a particular set of tools. For instance we need standards of content description like Anglo-American Cataloging Rules Edition 2, Resource Description and Access (RDA), Cataloging Cultural Objects, and Describing Archives: A Content Standard. When we intellectualize the process of knowledge organization – that is when we do basic theoretical research in knowledge organization we need another set of tools. For this latter exercise we need constructs. Constructs are ideas with many conceptual elements, largely considered subjective. They allow us to be inventive as well as allow us to see a particular point of view in knowledge organization. For example, Patrick Wilson’s ideas of exploitative control and descriptive control, or S. R. Ranganathan’s fundamental categories are constructs. They allow us to identify functional requirements or operationalizations of functional requirements, or at least come close to them for our systems and schemes. They also allow us to carry out meaningful evaluation.What is even more interesting, from a research point of view, is that constructs once offered to the community can be contested and reinterpreted and this has an affect on how we view knowledge organization systems and processes. Fundamental categories are again a good example in that some members of the Classification Research Group (CRG) argued against Ranganathan’s point of view. The CRG posited more fundamental categories than Ranganathan’s five, Personality, Matter, Energy, Space, and Time (Ranganathan, 1967). The CRG needed significantly more fundamental categories for their work.1 And these are just two voices in this space we can also consider the fundamental categories of Johannes Kaiser (1911), Shera and Egan, Barbara Kyle (Vickery, 1960), and Eric de Grolier (1962). We can also reference contemporary work that continues comparison and analysis of fundamental categories (e.g., Dousa, 2011).In all these cases we are discussing a construct. The fundamental category is not discovered; it is constructed by a classificationist. This is done because it is useful in engaging in the act of classification. And while we are accustomed to using constructs or debating their merit in one knowledge organization activity or another, we have not analyzed their structure, nor have we created a typology. In an effort to probe the epistemological dimension of knowledge organization, we think it would be a fruitful exercise to do this. This is because we might benefit from clarity around not only our terminology, but the manner in which we talk about our terminology. We are all creative workers examining what is available to us, but doing so through particular lenses (constructs) identifying particular constructs. And by knowing these and being able to refer to these we would consider a core competency for knowledge organization researchers.

An investigation of the relationship between the components of tumour microenvironment, signal transduction pathways and outcome in breast cancer

Breast cancer, the most commonly diagnosed type of cancer in women, is a major cause of morbidity and mortality in the western world. Well-established risk factors of breast cancer are mostly related to women’s reproductive history, such as early menarche, late first pregnancy and late menopause. Survival rates have improved due to a combination of factors, including better health education, early detection with large-scale use of screening mammogram, improved surgical techniques, as well as widespread use of adjuvant therapy. At initial presentation, clinicopathological features of breast cancer such as age, nodal status, tumour size, tumour grade, and hormonal receptor status are considered to be the standard prognostic and predictive markers of patient survival, and are used to guide appropriate treatment strategies. Lymphovascular invasion (LBVI), including lymphatic (LVI) and blood (BVI) vessel invasion, has been reported to be prognostic and merit accurate evaluation, particularly in patients with node negative tumours who might benefit from adjuvant chemotherapy. There is a lack of standard assessment and agreement on distinguishing LVI from BVI despite the major challenges in the field. A systematic review of the literatures, examining methods of detection and the prognostic significance of LBVI, LVI and BVI, was carried out. The majority of studies used haematoxylin and eosin (H&E) and classical histochemistry to identify LVI and BVI. Only few recent studies used immunohistochemistry (IHC) staining of the endothelium lining lymphatic and blood vessels, and were able to show clear differences between LVI and BVI. The prognostic significance of LBVI and LVI was well-documented and strongly associated with aggressive features of breast tumours, while the prognostic value and the optimal detection method of BVI were unclear. Assessment and prognostic value of LBVI on H&E sections (LBVIH&E) was examined and compared to that of LVI and BVI detected using IHC with D2-40 for LVI (LVID2–40) and Factor VIII for BVI (BVIFVIII) in patients with breast cancer including node negative and triple negative patients (n=360). LBVIH&E, LVID2–40 and BVIFVIII were present in 102 (28%), 127 (35%) and 59 (16%) patients respectively. In node negative patients (206), LBVIH&E, LVID2–40 and BVIFVIII were present in 41 (20%), 53 (26%) and 21 (10%) respectively. In triple negative patients (102), LBVIH&E, LVID2–40 and BVIFVIII were present in 35 (29%), 36 (35%) and 14 (14%) respectively. LBVIH&E, LVID2–40 and BVIFVIII were all significantly associated with tumour recurrence in all cohorts. On multivariate survival analysis, only LVID2–40 and BVIFVIII were independent predictors of cancer specific survival (CSS) in the whole cohort (P=0.022 and P<0.001 respectively), node negative (P=0.008 and P=0.001 respectively) and triple negative patients (P=0.014 and P<0.001 respectively). Assessment of LVI and BVI by IHC, using D2-40 and Factor VIII, improves prediction of outcome in patients with node negative and triple negative breast cancer and was superior to the conventional detection method. Breast cancer is recognised as a complex molecular disease and histologically identical tumours may have highly variable outcomes, including different responses to therapy. Therefore, there is a compelling need for new prognostic and predictive markers helpful of selecting patients at risk and patients with aggressive diseases who might benefit from adjuvant and targeted therapy. It is increasingly recognised that the development and progression of human breast cancer is not only determined by genetically abnormal cells, but also dependent on complex interactions between malignant cells and the surrounding microenvironment. This has led to reconsider the features of tumour microenvironment as potential predictive and prognostic markers. Among these markers, tumour stroma percentage (TSP) and tumour budding, as well as local tumour inflammatory infiltrate have received recent attention. In particular, the local environment of cytokines, proteases, angiogenic and growth factors secreted by inflammatory cells and stromal fibroblasts has identified crucial roles in facilitating tumour growth, and metastasis of cancer cells through lymphatic and/or blood vessel invasion. This might help understand the underlying process promoting tumour invasion into these vessels. An increase in the proportion of tumour stroma and an increase in the dissociation of tumour cells have been associated with poorer survival in a number of solid tumours, including breast cancer. However, the interrelationship between these variables and other features of the tumour microenvironment in different subgroups of breast cancer are not clear. Also, whether their prognostic values are independent of other components of the tumour microenvironment have yet to be identified. Therefore, the relationship between TSP, clinicopathological characteristics and outcome in patients with invasive ductal breast cancer, in particular node negative and triple negative disease was examined in patients with invasive ductal breast cancer (n=361). The TSP was assessed on the haematoxylin and eosin-stained tissue sections. With a cut-off value of 50% TSP, patients with ≤50% stroma were classified as the low-TSP group and those with >50% stroma were classified as the high-TSP group. A total of 109 (30%) patients had high TSP. Patients with high TSP were old age (P=0.035), had involved lymph node (P=0.049), Her-2 positive tumours (P=0.029), low-grade peri-tumoural inflammatory infiltrate (P=0.034), low CD68+ macrophage infiltrate (P<0.001), low CD4+ (P=0.023) and low CD8+ T-lymphocytes infiltrate (P=0.017), tumour recurrence (P=0.015) and shorter CSS (P<0.001). In node negative patients (n=207), high TSP was associated with low CD68+ macrophage infiltrate (P=0.001), low CD4+ (P=0.040) and low CD8+ T-lymphocytes infiltrate (P=0.016) and shorter CSS (P=0.005). In triple negative patients (n=103), high TSP was associated with increased tumour size (P=0.017) high tumour grade (P=0.014), low CD8+ T-lymphocytes infiltrate (P=0.048) and shorter CSS (P=0.041). The 15-year cancer specific survival rate was 79% vs 21% in the low-TSP group vs high-TSP group. On multivariate survival analysis, a high TSP was associated with reduced CSS in the whole cohort (P=0.007), node negative patients (P=0.005) and those who received systemic adjuvant therapy (P=0.016), independent of other pathological characteristics including local host inflammatory responses. Therefore, a high TSP in invasive ductal breast cancer was associated with recurrence and poorer long-term survival. The inverse relation with the tumour inflammatory infiltrate highlights the importance of the amount of tumour stroma on immunological response in patients with invasive ductal breast cancer. Implementing this simple and reproducible parameter in routine pathological examination may help optimise risk stratification in patients with breast cancer. Similarly, the relationship between tumour budding, clinicopathological characteristics and outcome was examined in patients with invasive ductal breast cancer (n=474), using routine pathological sections. Tumour budding was associated with several adverse pathological characteristics, including positive lymph node (P=0.009), presence of LVI (P<0.001), and high TSP (P=0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.002). In node negative patients, a high tumour budding was associated with presence of LVI (P<0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.038). On multivariate survival analysis, tumour budding was associated with reduced CSS (P=0.001), independent of nodal status, tumour necrosis, CD8+ and CD138+ inflammatory cells infiltrate, LVI, BVI and TSP. Furthermore, tumour budding was independently associated with reduced CSS in node negative patients (P=0.004) and in those who have low TSP (P=0.003) and high-grade peri-tumoural inflammatory infiltrative (P=0.012). A high tumour budding was significantly associated with shorter CSS in luminal B and triple negative breast cancer subtypes (all P<0.001). Therefore, tumour budding was a significant predictor of poor survival in patients with invasive ductal breast cancer, independent of adverse pathological characteristics and components of tumour microenvironment. These results suggest that tumour budding may promote disease progression through a direct effect on local and distant invasion into lymph nodes and lymphatic vessels. Therefore, detection of tumour buds at the stroma invasive front might therefore represent a morphologic link between tumour progression, lymphatic invasion, spread of tumour cells to regional lymph nodes, and the establishment of metastatic dissemination. Given the potential importance of the tumour microenvironment, the characterisation of intracellular signalling pathways is important in the tumour microenvironment and is of considerable interest. One plausible signalling molecule that links tumour stroma, inflammatory cell infiltrate and tumour budding is the signal transducer and activator of transcription (STAT). The relationship between total and phosphorylated STAT1 (ph-STAT1), and total and ph-STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer was examined. IHC of total and ph-STAT1/STAT3 was performed on tissue microarray of 384 breast cancer specimens. Cellular STAT1 and cellular STAT3 expression at both cytoplasmic and nuclear locations were combined and identified as STAT1/STAT3 tumour cell expression. These results were then related to CSS and phenotypic features of the tumour and host. A high ph-STAT1 and a high ph-STAT3 tumour cell expression was associated with increased ER (P=0.001 and P<0.001 respectively) and PR (all P<0.05), reduced tumour grade (P=0.015 and P<0.001 respectively) and necrosis (all P=0.001). Ph-STAT1 was associated with increased general peri-tumoural inflammatory infiltrate (P=0.007) and ph-STAT3 was associated with lower CD4+ T-lymphocyte infiltrate (P=0.024). On multivariate survival analysis, including both ph-STAT1 and ph-STAT3 tumour cell expression, only high ph-STAT3 tumour cell expression was significantly associated with improved CSS (P=0.010) independent of other tumour and host-based factors. In patients with high necrosis grade, high ph-STAT3 tumour cell expression was independent predictor of improved CSS (P=0.021). Ph-STAT1 and ph-STAT3 were also significantly associated with improved cancer specific survival in luminal A and B subtypes. STAT1 and STAT3 tumour cell expression appeared to be an important determinant of favourable outcome in patients with invasive ductal breast cancer. The present results suggest that STATs may affect disease outcome through direct impact on tumour cells, and the surrounding microenvironment. The above observations of the present thesis point to the importance of the tumour microenvironment in promoting tumour budding, LVI and BVI. The observations from STATs work may suggest that an important driving mechanism for the above associations is the presence of tumour necrosis, probably secondary to hypoxia. Further work is needed to examine the interaction of other molecular pathways involved in the tumour microenvironment, such as HIF and NFkB in patients with invasive ductal breast cancer.

José Rodrigues Santos de Sousa Ramos (1948-2007): The diversity of dynamical systems

José Rodrigues Santos de Sousa Ramos, mathematician of great merit, passed away on January 1st, 2007, in Lisbon. He was buried in Sobral da Adiça. His death was a huge loss for the development of mathematics in Portugal. The course of time will increase the dimension of this loss. Therefore, we dedicated this theme issue on Dynamical Systems to recall his memory and underline his work. We never forget you.