Exploring Anti-FVIII Antibodies in Haemophilia A - Role in In Vitro Haemostasis and Clinical Disease

Haemophilia A (HA) is caused by defective synthesis of coagulation factor VIII(FVIII), which has serious effects on haemostasis; joints being the most common site of bleeding. The development of FVIII replacements has improved the situation for patients with haemophilia such that chronic arthropathy can be prevented, and life expectancy and the quality of life have increased. However, approximately 20-30% of patients suffering from severe HA develop neutralizing antibodies (inhibitors) against FVIII. Alternative treatment, using by-passing agents, is available for patients exhibiting inhibitors, although these can only be used for the short-term treatment of acute haemorrhage and as prophylaxis during surgery. Furthermore, the clinical response to by-passing products is unpredictable. Two of the studies included in this thesis evaluated the response to by-passing therapy in plasma from patients with HA. The variation in thrombin production within families was found to be significantly lower than the variation between families, indicating that a familial predisposition may influence thrombin formation in response to by-passing agents (Paper I). Moreover, FVIII clotting factors were found to potentiate the in vitro effect of by-passing agents on thrombin formation in plasma from patients with HA exhibiting inhibitors, indicating that further assessment of this treatment strategy in a clinical context is warranted (Paper II). Not all anti-FVIII antibodies have neutralizing capacity. In the studies presented in Papers III & V, non-neutralizing anti-FVIII antibodies(NNAs) were investigated in two different cohorts, using an enzyme-linked immunosorbent assay (ELISA). NNAs were detected in 18.9% of siblings with HA, and in 12.8% of unrelated HA subjects followed for four years. The antibody response was assayed using three different rFVIII products. The antibody response was found to be heterogeneous, to vary considerably between individuals (Papers III and V), and also over time (Paper V). None of the patients in the cohort with NNAs observed longitudinally developed inhibitors (Paper V). However, in one patient with moderate HA, the detection of Bethesda-negative anti-FVIII antibodies coincided with a change in bleeding phenotype four years prior to FVIII inhibitor development. This finding suggests that immunoassays may be a useful complement in evaluating the immune response to FVIII (Paper IV). The potential clinical impact of NNAs was evaluated in the long term study (Paper V), showing no association between age, F8 mutation, or the influence of immune system challenges on NNA development. Interestingly, patients with NNAs had significantly fewer bleeding episodes than NNA-negative patients (p=0.048), raising questions about the possibility of yet undefined types of anti-FVIII antibodies with protective or potentiating effects on FVIII

Toy Consumption as Political : Challenges for Making Dreams Come True

This chapter looks at political consumerism in the toy sector, offering a brief history of consumer concerns and distinguishing among four strands of political consumerist research in this sector. A primary factor facilitating political consumerism of toys is that toy companies are extremely concerned about their reputation. Manufacturers cannot assume that parents and other carers do their usual risk-benefit analysis with the same level of risk acceptance concerning toys. Factors constraining political consumerism in this sector include long product chains and difficulties in discovering unethical practices and dangerous substances. Actors involved in the political consumerism of toys come from all societal spheres, including retailers. Regulators take action when risks have been discovered by civil society actors or scientists, but international divergence in regulation constitutes an obstacle to concerted action. Future research needs to examine synergies and trade-offs among various risks in toy products

Attityder och delaktighet vid etablering av vindkraft till havs

The political objectives on national and international levels towards a larger proportion of renewable energy require considerable planning activities on a local level. These activities inevitably must relate to the local community and its various groups; their culture, economy, social activities as well as their views on environmental problems and nature values. This applies to all energy plants. Wind power has previously been regarded as small-scale in character, as it has often been built as small groups of windmills. In recent years, wind power projects on a larger scale have been developed and established, making wind power more significant for the local community and its inhabitants. The present report is based on a study of views expressed by locals as regards a special kind of wind-power plant, namely large-scale, offshore wind power. The report aims at examining the coordination between different stakeholders; decision-makers, communities and entrepreneurs concerning two wind power projects: Lillgrund in The Sound (Öresund), and Utgrunden II in the Kalmar Strait (Kalmarsund). The report is intended to provide an understanding of attitudes and perceptions of risks and possibilities of various local stakeholders in these two cases. Conceptual tools are borrowed from our own studies as well as other researchers’ previous studies of attitudes, values, and forms of public participation. Since the study objective has been to seek the stakeholders’ own formulations of problems and opportunities concerning the projects, we have used a qualitative research design. Three types of techniques have been used to gather information: document analysis, field observations and in-depth interviews. Important to note is that the report is not based on statistical data of public attitudes. Positive as well as negative attitudes towards the two wind power projects have been analyzed in both regions. The positive attitude is mainly based on ethical values (wind is seen as an environmentally sound energy source that we should invest in), and for some also on material values (projects can create jobs and economic growth in the local community). The negative attitude is partly based on aesthetic values (scenery and local nature values are thought to be threatened) and a combination of substantive and ethical values (wind power is seen as unprofitable and inefficient). The analysis shows that there is need for increased knowledge, both through the provision of facts about economic and technical conditions of wind power and, as a reversed mediation of knowledge, by better understanding of local stakeholders’ conceptions of wind power projects. Criticism of wind power is largely based on a view that it could not be an effective way to produce energy, and that it could not possibly bear its own costs. Thus, wind power entrepreneurs should clearly show environmental benefits, profitability and efficiency in a specific project draft. Moreover, negative emotions towards wind power projects are closely associated with aesthetic values. We were able to note that the scale of the projects had given rise to greater hesitation and more concern about visual intrusion. It is therefore essential to take human experience seriously, for example by maintaining a dialogue around each specific project from an aesthetic point of view in order to establish what local values and experiences are thought to be threatened, and how the project might be altered

Maten märks: förutsättningar för konsumentmakt

Många människor anser sig numera ha större makt i rollen som konsumenter än som medborgare som röstar i partival. Som konsumenter kan vi idag ta ställning till en rad olika anspråk som görs på produkter och tjänster. Hur ser vi konsumenter på livsmedel som genom olika märken påstås ha unika egenskaper i produktionsledet: för miljön, för konsumentens hälsa, för arbetsförhållanden för fabriks- och jordbruksarbetarna, för djurens väl och ve, eller för det egna produktionslandets välstånd? Förekommer motsättningar och konkurrens mellan olika miljö- och varumärken? Vilka aktörer har makt att vara med och bestämma om vad som ska räknas som miljövänligt, socialt rättvis eller djurvänlig produktion? Går det – om det är önskvärt – att göra den gröna och etiska konsumtionens informationsredskap mer “demokratiska”? Finns det viktiga egenskaper hos varor och produktion som måste falla utanför konsumentmakten? Dessa frågor, som alla behandlas i boken, knyter an till frågan om vilka förutsättningar konsumenter egentligen har att fatta fria och politiska beslut som även går bortom var och ens egennytta. I den allmänna samhällsdebatten ses konsumenters makt av allt fler aktörer som en central förutsättning för att miljöproblem och andra samhällsproblem ska kunna lösas. Därmed blir en ökad kunskap om konsumentmaktens förutsättningar extra betydelsefull. Boken riktar sig till studenter, forskare, myndigheter och till alla andra med intresse för samhällsvetenskap och humaniora med inrikning på konsument- och livsmedelsfrågor, samt andra livsmedelsrelaterade vetenskaper. Mikael Klintman är docent och universitetslektor vid Forskningspolitiska institutet, Lunds universitet. Magnus Boström är docent, lektor och forskare vid institutionen för livsvetenskaper, Södertörns Högskola. Lena Ekelund är fil dr i nationalekonomi och docent i trägårdsvetenskap med ekonomisk inriktning vid Sveriges lantbruksuniversitet i Alnarp. Anna-Lisa Lindén är professor vid sociologiska institutionen, Lunds universitet

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease.

Purpose The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression.Experimental design Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs.Results After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER(-), PgR(-), and HER2(-) status. In ER(+)/HER2(-) patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER(-)/HER2(-) patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2.Conclusions Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras-ERK activation predicted outcome in residual disease. The multivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis. Clin Cancer Res; 22(10); 2405-16. ©2016 AACR

FGF/FGFR1 system in paired breast tumor-adjacent and tumor tissues, associations with mammographic breast density and tumor characteristics

IntroductionMammographic breast density (MBD) is an established breast cancer risk factor, yet the underlying molecular mechanisms remain to be deciphered. Fibroblast growth factor receptor 1 (FGFR1) amplification is associated with breast cancer development and aberrant FGF signaling found in the biological processes related to both high mammographic density and breast cancer microenvironment. The aim of this study was to investigate the FGF/FGFR1 expression in-between paired tumor-adjacent and tumor tissues from the same patient, and its associations with MBD and tumor characteristics.MethodsFGFR1 expression in paired tissues from 426 breast cancer patients participating in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort study was analyzed by immunohistochemistry. FGF ligand expression was obtained from RNA-sequencing data for 327 of the included patients.ResultsFGFR1 levels were differently expressed in tumor-adjacent and tumor tissues, with increased FGFR1 levels detected in 58% of the tumors. High FGFR1 expression in tumor tissues was associated with less favorable tumor characteristics; high histological grade (OR=1.86, 95% CI 1.00–3.44), high Ki67 proliferative index (OR=2.18, 95% CI 1.18–4.02) as well as tumors of Luminal B-like subtype (OR=2.56, 95%CI 1.29–5.06). While no clear association between FGFR1 expression and MBD was found, FGF ligand (FGF1, FGF11, FGF18) expression was positively correlated with MBD.DiscussionTaken together, these findings support a role of the FGF/FGFR1 system in early breast cancer which warrants further investigation in the MBD–breast cancer context

Beyond Accountability: Political Legitimacy and Delegated Water Governance in Australia

Studies of delegated agencies commonly emphasize the importance of accountability for these unelected bodies to secure authority to govern. This article argues that beyond formal accountability measures, developing legitimacy through interaction with external stakeholders is critical to agency authority. In doing so, the article makes a distinctive contribution by applying a new conceptual model based on organizational sociology and identifying multiple dimensions along which legitimacy is lost and won, and hence authority secured. The article presents original findings from a case study of how the Murray–Darling Basin Authority, an Australian water agency established in 2007, attempted to achieve ‘political legitimacy’. Findings show that the Agency achieved legitimacy via appeals to common normative/ethical values and developing commonly used information and news outlets, despite facing opposition from stakeholders on the socioeconomic impact of its policies. The conclusion argues that the framework can usefully be applied to other agencies in ‘wicked problem’ policy areas