Multi-case review of the application of the precautionary principle in European Union Law and Case Law

The precautionary principle was formulated to provide a basis for political action to protect the environment from potentially severe or irreversible harm in circumstances of scientific uncertainty that prevent a full risk or cost-benefit analysis. It underpins environmental law in the European Union and has been extended to include public health and consumer safety. The aim of this study was to examine how the precautionary principle has been interpreted and subsequently applied in practice, whether these applications were consistent, and whether they followed the guidance from the Commission. A review of the literature was used to develop a framework for analysis, based on three attributes: severity of potential harm, standard of evidence (or degree of uncertainty), and nature of the regulatory action. This was used to examine 15 pieces of legislation or judicial decisions. The decision whether or not to apply the precautionary principle appears to be poorly defined, with ambiguities inherent in determining what level of uncertainty and significance of hazard justifies invoking it. The cases reviewed suggest that the Commission's guidance was not followed consistently in forming legislation, although judicial decisions tended to be more consistent and to follow the guidance by requiring plausible evidence of potential hazard in order to invoke precaution

The digital readout system for the CMS electromagnetic calorimeter

The CMS Electromagnetic Calorimeter is a high-precision detector demanding innovative solutions in order to cope with the high dynamic range and the extreme high resolution of the detector as well as with the harsh environment created by the high level of radiation and the 4 T magnetic field. The readout system is partly placed within the detector and partly in the adjacent counting room. As the on-detector electronics must cope with the harsh environment the use of standard components is excluded for this part of the system. This paper describes the solutions adopted for the high-precision analogue stages, the A-D conversion, the optical transfer of the raw data from the on-detector part to the so-called Upper Level Readout, placed in the counting room, and the functionality of the latter. The ECAL is instrumental in providing information to the first-level trigger process and the generation of this information will be described. Also, the problem of reducing the raw data volume (6*10/sup 12/ bytes /s) to a level that can be handled by the central DAQ system (10/sup 5/ bytes/s) without degrading the physics performance will be discussed. (3 refs)

"To Conquer and Subdue" - Okonkwo's Masculinity in Chinua Achebe's Things Fall Apart

This essay examines the masculinity of Okonkwo, the protagonist of Chinua Achebe's Things Fall Apart, and how it brings about his undoing, despite the fact that he lives in a conservative society where masculinity is revered

Transcriptional Regulation by Hypoxia-Inducible Factors in Tumor Cells

Cancer is a major cause of human morbidity and mortality, and the risk of developing cancer is about one in three life times. Neuroblastoma is the most common extra-cranial solid tumor among children and arises from early sympathetic nervous system (SNS) cells arrested in their development. Generally, a low tumor cell differentiation correlates to poor prognosis. Solid tumors, like neuroblastoma, frequently contain regions of oxygen deficiency ? hypoxia ? caused by a high rate of cellular proliferation and abnormal intratumoral blood supply. In this hypoxic microenvironment cancer cells undergo genetic and molecular changes, allowing continued survival and proliferation. Tumor hypoxia is also associated with increased aggressiveness, resistance to therapy and poor outcome. Cancer cells become less differentiated in response to hypoxia, which we previously demonstrated in neuroblastoma as well as breast cancer cells, indicating an evolvement of a more aggressive phenotype. In the present studies we find evidence of potential mechanisms behind the hypoxia-mediated de-differentiation of neuroblastoma cells. Hypoxia (1% O2) induced the expression of the negative transcription factor ID2 (Paper I), involved in blocking the function of tissue-specific basic helix-loop-helix (bHLH) proteins, such as the SNS-specifying transcription factors HASH-1 and dHAND. Hypoxic up-regulation of ID2 was dependent on direct in vivo DNA-binding and activity of hypoxia-inducible factors (HIF), the master transcriptional regulators of oxygen homeostasis. Induction of ID2 expression occurs as an early HIF-mediated hypoxic event, potentially leading to a more immature state. HIF-1alpha and HIF-2alpha, however differently, are both essential for normal development and are highly implicated in tumor progression. In Paper II we show that HIF-1alpha and HIF-2alpha share several target genes, but mediate regulation of these under different temporal and oxygen-dependent conditions. Interestingly, HIF-2alpha, but not HIF-1alpha, was present in neuroblastoma tumor cells near blood vessels, and thus in apparently better oxygenized tumor regions. In vitro, HIF-1alpha protein was transiently stabilized at hypoxia and primarily governed acute hypoxic responses, whereas HIF-2alpha became more important at prolonged hypoxia. In addition, high HIF-2alpha activity, including induction of classic hypoxic targets such as VEGF, was detected in cultured neuroblastoma cells already at 5% O2, a physiologically relevant oxygen level, similar to the findings in vivo. In a large clinical neuroblastoma material, significant correlations between high HIF-2alpha levels and high VEGF content, advanced tumor stage and poor outcome were found. These observations clearly suggest an oncogenic role of HIF-2alpha, and implicate HIF-2alpha as an independent prognostic marker in neuroblastoma. The MXI1 (MAX-interactor 1) gene, a reported MYC antagonist, has been detected by us and others as a commonly hypoxia-induced gene. In Paper III we further demonstrate that HIF proteins, via direct binding to hypoxia-response elements (HRE), up-regulate MXI1 mRNA and protein in both hypoxic neuroblastoma and breast cancer cells. Interestingly, reducing MXI1 levels had no overall effects on MYC/MYCN activity in hypoxic neuroblastoma cells. Instead, MXI1 appeared to be important in augmenting the hypoxic response, potentially by enhancing specific HIF-1 target gene induction. HIF proteins are primarily stabilized and activated in response to lowered oxygen concentrations. However, growth factor-induced signaling can promote HIF-1alpha protein synthesis as well as transactivation, even under normoxic conditions. In Paper IV we characterize a novel such a pathway, where stem cell factor (SCF)-evoked c-Kit-signaling leads to increased HIF-1alpha protein, HRE-activation and induction of several HIF-1alpha targets, such as VEGF and GLUT1, already at normoxia. In addition we find a reciprocal positive feedback loop between c-Kit and HIF-1alpha, where induced HIF-1alpha mediates reinforcement of c-Kit expression. Overall, this thesis shows the impact of HIF proteins on tumor cell behavior, principally as central hypoxic transcriptional regulators governing the expression of genes with potential importance in several biological processes, such as growth and differentiation, determining cancer cell aggressiveness as well as adaptation to low oxygen conditions

State of the art transparency: lessons from Europe and North America

This Special Issue of the Journal of Risk Research was initiated to increase the evidence base supporting critical understanding of the use and impacts of transparency as a policy tool in risk management and regulation in Europe and North America. The lead research articles and perspectives were initially presented at a two-day workshop supported by the Journal of Risk Research and its publisher Taylor and Francis, which took place in Lavandou, Provence, 19th - 20th June 2014. In this editorial we introduce the motivations for the special issue and offer a brief summary of the contribution of each article highlighting key intersections and points of concurrenc

Hemophagocytic lymphohistiocytosis and associations with malignancies

In immune homeostasis, natural killer cells and cytotoxic T cells are responsible for clearance of virus-infected and tumor transformed cells, but also for turning off the immune response. Patients with familial hemophagocytic lymphohistiocytosis (HLH) have impaired cytotoxic function due to genetic aberrations in genes in the perforindependent cytotoxic pathway. This results in an inability to turn off the immune response and, typically, a fatal hyperinflammation, often with onset already during the first months of life. The only curative treatment is hematopoietic stem cell transplantation. Patients with hypomorphic, ‘milder’, mutations in HLH-causing genes often have later onset of disease. Notably, an increased risk of hematological malignancies has been reported in these patients. The hyperinflammation of HLH can also occur in individuals without known Mendelian genetic predisposition. In these cases, often occurring later in life, it is termed ‘secondary HLH’ and it is most often triggered by an infection or a malignancy. In paper I we established the incidence of malignancies in relatives to patients with familial HLH by combining two incidence studies of familial HLH in Sweden with the Swedish multigeneration register and the Swedish national cancer register. We report an almost three-fold increased incidence rate of all cancers in mothers of patients with HLH compared to matched controls (4.4 vs 1.6, p=0.0014). In paper II we investigated individuals diagnosed with lymphoma in a defined population in northern Sweden. We found a higher prevalence of the most common HLH-causing aberration in Sweden, an inversion of UNC13D, in patients with lymphoma (3.1% vs 1%, p=0.002). In paper III, we investigated the incidence of secondary HLH in patients with malignancies. All patients with an ICD-10 diagnosis of HLH and cancer between 1997 and 2018 were identified from the Swedish inpatient register and the Swedish cancer register. During the 22 years studied, the incidence increased 10-fold, and at least 0.6% of all patients with hematological malignancies were affected. The last seven years the incidence corresponded to 0.45 per 100 000 individuals annually in Sweden. Importantly, the shortterm survival in malignancy-associated HLH was improved. By reporting a higher risk of malignant disease in relatives of patients with familial HLH as well as a higher frequency of the HLH-causing UNC13D inversion in patients with lymphoma, the studies included in this thesis further support the notion that malignant disease and HLH are tightly linked together. A striking increase in incidence of malignancy-associated HLH is reported over the 22 years studied. This and the improved short-term survival is likely a result of increased awareness of HLH, high-lighting the value of increasing awareness even further