Loss of chromosome 11q21–23.1 and 17p and gain of chromosome 6p are independent prognostic indicators in B-cell non-Hodgkin's lymphoma

Comparative genomic hybridization (CGH) was employed to study chromosomal aberrations in relation to cell proliferation, apoptosis, and patient survival in 94 cases of B-cell non-Hodgkin's lymphoma diagnosed between 1983 and 1993. Eighty cases had aberrations by CGH. Chromosomal regions 1p21–31.1 (10%), 6cen-q24 (12%), 8p (11%), 9p21-ter (14%), 11q21–23.1 (11%), 13q13–21.1 (12%), and 17p (15%) were frequently lost. Gains were found at 3q21-ter (22%), 6p (11%), 7p (12%), 8q23-ter (13%), 12cen-q15 (17%), 17q24-ter (13%), and 18q13.3–21 (20%). A high number of aberrations (≥ 4, 33 cases) was associated (P ≤ 0.001) with the mantle cell and diffuse large B-cell lymphoma subtypes, a high fraction of tumour cells in S phase, and short survival (RR (relative risk) = 3.7). Loss of 1p21–31.1, 8p, 9p21-ter, 11q21–23.1, and 13q13–21.1 were associated with mantle cell lymphoma (P ≤ 0.03), while gain of 6p and 12cen-q15 were more frequent in diffuse large B-cell and small lymphocytic lymphoma, respectively (P = 0.04). Loss of 8p and 17p, and gain of 3q21-ter, 6p, 7p, and 8q23-ter were associated with a high S phase fraction (P ≤ 0.03), but none of the aberrations were associated with tumour apoptotic fraction (P ≥ 0.13). The most important prognostic CGH parameters (P < 0.001) were losses of 11q21–23.1 (RR = 3.8) and 17p (RR = 4.4), and gain of 6p (RR = 4.2). The latter parameters and IPI were the only ones with independent prognostic value (RR = 10, 5.0, 6.7, and 3.7, respectively; P < 0.001) when assessed together with lymphoma sub-type, primary versus relapse cases, treatment, B symptoms, S phase fraction, and presence of BCL1 and BCL2 translocations. A combined CGH/IPI binary parameter had high prognostic value for patients receiving different treatments, with various lymphoma sub-types, and for primary as well as relapse cases.© 2001 Cancer Research Campaign http://www.bjcancer.co

Rapid and sustained environmental responses to global warming: the Paleocene–Eocene Thermal Maximum in the eastern North Sea

The Paleocene–Eocene Thermal Maximum (PETM; ∼ 55.9 Ma) was a period of rapid and sustained global warming associated with significant carbon emissions. It coincided with the North Atlantic opening and emplacement of the North Atlantic Igneous Province (NAIP), suggesting a possible causal relationship. Only a very limited number of PETM studies exist from the North Sea, despite its ideal position for tracking the impact of both changing climate and NAIP activity. Here we present sedimentological, mineralogical, and geochemical proxy data from Denmark in the eastern North Sea, exploring the environmental response to the PETM. An increase in the chemical index of alteration and a kaolinite content up to 50 % of the clay fraction indicate an influx of terrestrial input shortly after the PETM onset and during the recovery, likely due to an intensified hydrological cycle. The volcanically derived zeolite and smectite minerals comprise up to 36 % and 90 % of the bulk and clay mineralogy respectively, highlighting the NAIP's importance as a sediment source for the North Sea and in increasing the rate of silicate weathering during the PETM. X-Ray fluorescence element core scans also reveal possible hitherto unknown NAIP ash deposition both prior to and during the PETM. Geochemical proxies show that an anoxic to sulfidic environment persisted during the PETM, particularly in the upper half of the PETM body with high concentrations of molybdenum (MoEF > 30), uranium (UEF up to 5), sulfur (∼ 4 wt %), and pyrite (∼ 7 % of bulk). At the same time, export productivity and organic-matter burial reached its maximum intensity. These new records reveal that negative feedback mechanisms including silicate weathering and organic carbon sequestration rapidly began to counteract the carbon cycle perturbations and temperature increase and remained active throughout the PETM. This study highlights the importance of shelf sections in tracking the environmental response to the PETM climatic changes and as carbon sinks driving the PETM recovery.publishedVersio

GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data

Absolute tumor DNA copy numbers can currently be achieved only on a single gene basis by using fluorescence in situ hybridization (FISH). We present GeneCount, a method for genome-wide calculation of absolute copy numbers from clinical array comparative genomic hybridization data. The tumor cell fraction is reliably estimated in the model. Data consistent with FISH results are achieved. We demonstrate significant improvements over existing methods for exploring gene dosages and intratumor copy number heterogeneity in cancers

Europeanisation should meet international constructivism: the Nordic Plus group and the internalisation of political conditionality by France and the United Kingdom

This article is a plausibility probe for the significance of international constructivist ‘mediating factors’ to explain variation in Europeanisation outcomes. It applies a most similar systems design (or Mill's method of difference) to show that the UK has internalised political conditionality to a larger extent than France at least partially because it has been the object of stronger socialisation pressures within the ‘Nordic Plus’ group. The article contributes to the literature on Europeanisation and development cooperation in two important ways. First, it enlarges its scope of analysis, both geographically (beyond new European Union member states) and thematically (beyond simple measures of aid quality and/or quantity). Second, it emphasises the importance of international (versus domestic) mediating factors. The empirical analysis focusses on three cases of aid sanctions in response to human rights abuses and democratic setbacks: Zimbabwe 2002, Madagascar 2009 and Mozambique 2009

Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma

Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma

A randomized study on migration of the Spectron EF and the Charnley flanged 40 cemented femoral components using radiostereometric analysis at 2 years

Background and purpose: We performed a randomized study to determine the migration patterns of the Spectron EF femoral stem and to compare them with those of the Charnley stem, which is regarded by many as the gold standard for comparison of implants due to its extensive documentation. Patients and methods: 150 patients with a mean age of 70 years were randomized, single-blinded, to receive either a cemented Charnley flanged 40 monoblock, stainless steel, vaquasheen surface femoral stem with a 22.2-mm head (n = 30) or a cemented Spectron EF modular, matte, straight, collared, cobalt-chrome femoral stem with a 28-mm femoral head and a roughened proximal third of the stem (n = 120). The patients were followed with repeated radiostereometric analysis for 2 years to assess migration. Results: At 2 years, stem retroversion was 2.3° and 0.7° (p < 0.001) and posterior translation was 0.44 mm and 0.17 mm (p = 0.002) for the Charnley group (n = 26) and the Spectron EF group (n = 74), respectively. Subsidence was 0.26 mm for the Charnley and 0.20 mm for the Spectron EF (p = 0.5). Interpretation: The Spectron EF femoral stem was more stable than the Charnley flanged 40 stem in our study when evaluated at 2 years. In a report from the Norwegian arthroplasty register, the Spectron EF stem had a higher revision rate due to aseptic loosening beyond 5 years than the Charnley. Initial stability is not invariably related to good long-term results. Our results emphasize the importance of prospective long-term follow-up of prosthetic implants in clinical trials and national registries and a stepwise introduction of implants