Inactivation of the putative ubiquitin-E3 ligase PDLIM2 in classical Hodgkin and anaplastic large cell lymphoma.

Apart from its unique histopathological appearance with rare tumor cells embedded in an inflammatory background of bystander cells, classical Hodgkin lymphoma (cHL) is characterized by an unusual activation of a broad range of signaling pathways involved in cellular activation. This includes constitutive high-level activity of nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), activator protein-1 (AP-1) and interferon regulatory factor (IRF) transcription factors (TFs) that are physiologically only transiently activated. Here, we demonstrate that inactivation of the putative ubiquitin E3-ligase PDLIM2 contributes to this TF activation. PDLIM2 expression is lost at the mRNA and protein levels in the majority of cHL cell lines and Hodgkin and Reed-Sternberg (HRS) cells of nearly all cHL primary samples. This loss is associated with PDLIM2 genomic alterations, promoter methylation and altered splicing. Reconstitution of PDLIM2 in HRS cell lines inhibits proliferation, blocks NF-κB transcriptional activity and contributes to cHL-specific gene expression. In non-Hodgkin B-cell lines, small interfering RNA-mediated PDLIM2 knockdown results in superactivation of TFs NF-κB and AP-1 following phorbol 12-myristate 13-acetate (PMA) stimulation. Furthermore, expression of PDLIM2 is lost in anaplastic large cell lymphoma (ALCL) that shares key biological aspects with cHL. We conclude that inactivation of PDLIM2 is a recurrent finding in cHL and ALCL, promotes activation of inflammatory signaling pathways and thereby contributes to their pathogenesis.

[Prophylaxis and treatment of venous thromboembolism in cancer patients. Clinical value of low-molecular-weight heparins]. / Prophylaxe und Therapie venöser Thromboembolien bei Tumorerkrankungen. Stellenwert niedermolekularer Heparine.

Venous thromboembolism (VTE) is a common complication in patients with cancer. Because of their improved subcutaneous bioavailability and reliable antithrombotic efficiency low-molecular-weight heparins (LMWH) are preferably used for prevention and treatment of cancer-related VTE. Thromboprophylaxis with LMWH is well established in patients undergoing cancer surgery and hospitalized cancer patients, while outpatient prophylaxis remains contentious. LMWH are recommended over unfractionated heparins and vitamin K antagonists for initial treatment and secondary prophylaxis (3-6 months) after cancer-related VTE. Long-term secondary prophylaxis should be considered for patients with ongoing active malignancy and low bleeding risk. Due to absence of clinical studies in cancer patients, the use of novel oral anticoagulants is currently not recommended.

The tumour suppressor p53 is frequently nonfunctional in Sézary syndrome.

BACKGROUND: Primary cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group with Sézary syndrome (SS) as one of the most aggressive variants. Recently, we identified a loss of E2A as a recurrent event in SS, which enhanced proliferation via upregulation of the proto-oncogene MYC. MYC-induced transformation usually requires deleterious alterations of key apoptotic genes including p53; however, p53 functionality and mutation status in SS are unclear. OBJECTIVES: We investigated functionality of p53 signalling by pharmacological treatment with the MDM2 antagonist nutlin-3, which might result in p53 activation. Furthermore, we analysed the TP53 mutation status in CTCL cell lines and highly purified tumour cells from patients with SS by mRNA and DNA sequencing. METHODS: We analysed the apoptosis induction due to nutlin-3 treatment in various SS cell lines and primary patient samples by annexin V/propidium iodide staining. Induction of p53 target genes was analysed by immunoblotting, and TP53 was sequenced at the mRNA and DNA level. RESULTS: We identified various TP53 mutations and an impaired p53 signalling in the vast majority of the investigated cell lines and primary SS cells. CONCLUSIONS: In accordance with the importance of MYC deregulation in SS, p53 signalling is frequently nonfunctional in SS. However, although most likely ineffective as exclusive treatment in SS, it remains possible that pharmacological p53 activation could be beneficial in combination with other approaches including classical chemotherapeutics.

High-level expression of Mastermind-like 2 contributes to aberrant activation of the NOTCH signaling pathway in human lymphomas.

Inappropriate activation of the NOTCH signaling pathway, for example, by activating mutations, contributes to the pathogenesis of various human malignancies. Here, we demonstrate that aberrant expression of an essential NOTCH coactivator of the Mastermind-like (MAML) family provides an alternative mechanism to activate NOTCH signaling in human lymphoma cells. We detected high-level MAML2 expression in several B cell-derived lymphoma types, including classical Hodgkin lymphoma (cHL) cells, relative to normal B cells. Inhibition of MAML-protein activity by a dominant negative form of MAML or by small hairpin RNAs targeting MAML2 in cHL cells resulted in downregulation of the NOTCH target genes HES7 and HEY1, which we identified as overexpressed in cHL cells, and in reduced proliferation. Furthermore, a NOTCH gene-expression signature in cHL cells confirmed their cell-autonomous NOTCH activity. Finally, in line with the essential role of MAML proteins for assembly and activity of the NOTCH transcriptional complex (NTC), we show that MAML-derived small-peptide constructs block NOTCH activity and disrupt NTC formation in vitro. These data strongly suggest direct targeting of the NTC as treatment strategy for NOTCH-dependent malignancies.

Fatal immune haemolysis due to antibodies to individual metabolites of 5-fluorouracil.

Confusion still exists in the diagnosis of drug-induced immune haemolysis (DIH). The aim of this study was to demonstrate antibodies specific to 5-fluorouracil (5-FU) in a patient with fatal immune haemolysis (IH). The case of a patient who died due to protracted IH is described. A 57-year-old female underwent treatment with oxaliplatin, 5-FU and folinic acid due to cholangiocarcinoma. Following drug administration, she was transfused because of a mild non-haemolytic anaemia and died following haemolysis. Serological testing including antibody screening, direct antiglobulin test and detection of drug-dependent antibodies was performed using standard techniques. The patient's serum was observed to be red in colour due to the presence of free haemoglobin prior to and following blood transfusion, and contained antibodies reactive with RBCs only in the presence of urine from several patients treated with 5-FU (ex vivo antigens). Drug-induced immune haemolysis (DIH) and metabolite-dependent antibodies should always be taken into consideration when a patient being administered any type of drug develops haemolysis.

[Reduction of technology fears in psychosomatic rehabilitation--concepts and results based on a computer training for older employees]. / Verminderung von Technologieängsten in der psychosomatischen Rehabilitation-Konzepte und Ergebnisse zu einem Computertraining für ältere Arbeitnehmer*

A computer training program was developed specifically oriented toward middle-aged employees, their learning needs and their computer-related fears. This program was based on a pilot study showing a high degree of stresses associated with the introduction of computer technology at the workplace in this age group (50-59 years). A survey of 623 patients confirmed that these persons experienced technological change predominantly as disadvantageous or threatening. Based on 114 patients, concepts and results of the computer training are presented. Participation reduced avoidance behaviors, fears and increased interest and initiative based both on the patients' and their trainers' perspectives.

Genetic variation within and among patches of the clonal species, Vaccinium stamineum L.

Once thought to be dominated by a few genets, clonal plant populations can contain high levels of genetic diversity. Sexual reproduction and vegetative growth strategy affect the amount and distribution of genetic diversity within clonal plant populations. We determined the scale of genetic diversity in a population of Vaccinium stamineum, a clonal shrub that forms discrete patches. Using the random amplified polymorphic DNA (RAPD) technique, we surveyed the genetic diversity of V. stamineum within and among patches from a 1-ha site. We found 67 unique RAPD profiles among the 99 sampled individuals from 22 patches. In two patches, all the sampled individuals had the same RAPD profile. In seven patches, every individual sampled had a different RAPD profile. The remaining patches showed mixed RAPD profiles which suggested both clonal and sexual reproduction. Each unique RAPD profile was restricted to one patch (with one exception), which suggests that clonal growth occurs at the patch scale. High levels of genetic variation within some patches may be explained by somatic mutation; however, seedling recruitment is a more likely explanation.

Frequent occurrence of occult pulmonary embolism from venous sheaths during endomyocardial biopsy.

To determine the frequency of occult right heart thromboembolism during endomyocardial biopsy, 51 cardiac transplant recipients undergoing routine endomyocardial biopsy were studied echocardiographically. Patients were randomized to two groups. In Group 1, the venous sheath was flushed between each biopsy attempt; in Group 2, it was flushed only at the time of initial placement. Right heart thromboemboli were identified in 18 (35%) of 51 patients. Seventeen (94%) of these 18 patients were in Group 2. Patients requiring more than six biopsy attempts had a significantly higher incidence of embolism. Other variables such as antiplatelet therapy, operator experience and total time of the procedure did not correlate with occurrence of thrombus. All right heart emboli were asymptomatic. These data demonstrate a high incidence of occult pulmonary embolism during uncomplicated routine endomyocardial biopsy. Meticulous flushing of the introducer sheath significantly reduces the incidence of thrombus formation in intravenous sheaths.