Lipoprotein lipase SNPs rs13702 and rs301 correlate with clinical outcome in chronic lymphocytic leukemia patients

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and is characterized by a heterogeneous clinical course. This variability in clinical course has spiked the search for prognostic markers able to predict patient evolution at the moment of diagnosis. Markers demonstrated to be of value are the mutation status of the immunoglobulin heavy chain variable region genes (IGHV) and lipoprotein lipase (LPL) expression. High LPL mRNA expression has been associated with short treatment free (TFS) and decreased overall survival (OS) in CLL. The LPL SNPs rs301 (T<C), rs328 (C<G) and rs13702 (T<C) have been associated with various metabolic disorders, but the association with CLL evolution is unknown. Here, in a cohort of 248 patients, we show that patients with the LPL SNP rs13702 wild-type T/T genotype had significantly shorter OS than patients with C/C and T/C genotypes (median time until CLL related death: 90 and 156 months respectively, p=0.008). The same was observed for LPL SNP rs301 (median time until CLL related death T/T: 102 and C/C, T/C: 144 months, p=0.03). Both SNPs rs301 and rs13702 were significantly associated with each other and notably, no association was found between IGHV status and presence of the SNP genotypes, indicating that these LPL SNPs are reliable prognostic markers that could add extra prognostic and predictive information to classical markers and help to improve the management of CLL

Technical assessment of the Portuguese national programme for dams with high hydropower potential (PNBEPH)

The Portuguese National Programme for Dams with High Hydropower Potential (PNBEPH) foresees the construction of 10 new hydropower installations in several river basins. Among other relevant impacts that fall out of the scope of this study, hydropower projects can have an important impact on water quality - mainly on hydro-morphological conditions for aquatic life to sustain. According to the Water Framework Directive (WFD), the deadline for achieving a good status of surface waters is 2015. In the meantime, Member States should avoid taking action that could jeopardize the achievement of the objectives of the directive, notably the general objective of good status of water bodies. Derogations for building new infrastructure projects (notably dams) are possible under Article 4.7, if certain strict conditions are met and an assessment is done according to these conditions. These conditions include amongst others that there are no significantly better environmental options, the benefits of the new infrastructure outweigh the benefits of achieving the WFD environmental objectives and all practicable mitigation measures are taken to address the adverse impact of the status of the water body. In addition, the justification for those modifications should be included in the river basin management plans due to be adopted in December 2009 after public consultation

Characterization of the unfolded protein response by pharmacological agents in lymphoid malignancies

Normal B cell development is tightly regulated by transcription factors and is characterized by the formation of the B-cell receptor. When the regulation and activation of B cell differentiation is disrupted, lymphomas and leukemias can occur. These lymphoid malignancies often resemble normal stages of the B cell differentiation. During normal B cell development a precursor B cell will ultimately form a terminal differentiated lymphocyte or plasma cell. These terminal differentiated B cells require massive increase in their biosynthetic capacity to synthesize thousands of antibodies per second for secretion. For this purpose, these cells rely on a highly developed endoplasmic reticulum (ER), the compartment where proteins are assembled and modified into functional antibodies. However, upon perturbations in ER function a stress response pathway can be activated, named the "unfolded protein response" (UPR). In the first place, the UPR is a cytoprotective signaling response and several studies have demonstrated already that activation of the UPR might have a crucial role in cancer. Until now, little is known about the role of the UPR in the germinal center (GC)-derived lymphomas since most investigations were performed on healthy B cells and multiple myeloma. Therefore, the initial aim of this doctoral work was to evaluate the expression levels of baseline and inducible UPR-related markers in DLBCL cell lines and in a plasma cell line. Besides its protective role, the UPR may balance in the direction of cell death upon severe and prolonged stress. Manipulation of the UPR may be used as an alternative cell death mechanism since conventional treatments frequently activate the classical cell death pathways, like the intrinsic and extrinsic cell death program. Therefore, this cell death strategy is used on CLL patient samples. To accomplish this goal, the anticancer activities of two plant-derived compounds, xanthohumol (isolated from hop, Humulus lupulus L.) and withaferin A (isolated from Withania somnifera), were investigated. In conclusion, our results provide a scientific basis for further investigations of the involvement of the UPR in DLBCL. Moreover, targeting the ER may be an interesting therapeutic strategy for CLL and other lymphoid malignancies, and for further development of new therapeutic agents

Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia remains the most common adult leukaemia in Western countries. In this review we tried to give an overview of the important prognostic markers and the developments in this field. We also reflected about the accumulative character of the disease and the influence of the micro-environment on the CLL cell