[Prognostic value of cardiovascular MRI in diabetics]. / Prognostischer Wert der kardiovaskulären MRT bei Diabetikern.

CLINICAL/METHODICAL ISSUE: Despite an increased cardiovascular risk in patients with diabetes mellitus they are a heterogeneous population with very different individual manifestation of diseases; therefore, a profound stratification is recommended. STANDARD METHODS: Clinical examinations and blood biomarkers are typically used in diabetic patients to determine the risk for developing cardio-cerebrovascular events. METHODICAL INNOVATIONS: Cardiac as well as whole-body magnetic resonance imaging (MRI) including cardiovascular sequences are established methods for clinical diagnostics. Their significance in predicting the outcome and the corresponding risk stratification for patients with diabetes is becoming increasingly more important based on recent study results. PERFORMANCE: Late gadolinium enhancement (LGE) in cardiac MRI detects silent myocardial ischemia in up to 30% of diabetic patients, which is associated with a hazard ratio of 3-6 for cardiovascular events. Regional left ventricular wall motion abnormalities and decreased ejection fraction also have a prognostic value in diabetics. Based on whole-body MRI, the vessel score as well as carotid artery stenosis have been evaluated as additional predictors for cardio-cerebrovascular events. ACHIEVEMENTS: The MRI-based predictors have independent and incremental prognostic value beyond traditional risk stratification for cardio-cerebrovascular events; however, only the comprehensive assessment of whole-body MRI including angiography allows the identification of patients who remain free of cardio-cerebrovascular events over a period of 6 years. PRACTICAL RECOMMENDATIONS: Cardiac MRI, particularly the detection of LGE, can be recommended for risk stratification of patients with diabetes mellitus. The clinical relevance of the added prognostic value of whole-body MRI needs to be clarified in further studies.

[Incidental radiological findings]. / Der radiologische Zufallsbefund.

All findings which arise in the context of radiological diagnostics, potentially affect the health of a subject but with no intention to detect the corresponding finding are considered to be incidental radiological findings (IF). The prevalence of IFs is increasing due to the wider use of modern imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT) in routine clinical practice and the inclusion of imaging, such as whole body MRI in large population-based cohorts. The reporting of radiological IFs can lead to further diagnostics and treatment. The management of IFs in the clinical routine is regulated by the guidelines of the various academic societies. The management of IFs in the setting of research studies differs depending on various factors, such as study design and health status of enrolled subjects. In general, IFs must be disclosed to the subject if the radiological IFs are potentially clinically relevant; however, subjects must also be protected from the consequences of false positive findings. This review article discusses radiological IFs in the setting of the clinical routine and research studies and provides a basic summary of the management recommendations for commonly occurring IFs.

Genomic evolution in Barrett's adenocarcinoma cells: critical roles of elevated hsRAD51, homologous recombination and Alu sequences in the genome.

A prominent feature of most cancers including Barrett's adenocarcinoma (BAC) is genetic instability, which is associated with development and progression of disease. In this study, we investigated the role of recombinase (hsRAD51), a key component of homologous recombination (HR)/repair, in evolving genomic changes and growth of BAC cells. We show that the expression of RAD51 is elevated in BAC cell lines and tissue specimens, relative to normal cells. HR activity is also elevated and significantly correlates with RAD51 expression in BAC cells. The suppression of RAD51 expression, by short hairpin RNA (shRNA) specifically targeting this gene, significantly prevented BAC cells from acquiring genomic changes to either copy number or heterozygosity (P<0.02) in several independent experiments employing single-nucleotide polymorphism arrays. The reduction in copy-number changes, following shRNA treatment, was confirmed by Comparative Genome Hybridization analyses of the same DNA samples. Moreover, the chromosomal distributions of mutations correlated strongly with frequencies and locations of Alu interspersed repetitive elements on individual chromosomes. We conclude that the hsRAD51 protein level is systematically elevated in BAC, contributes significantly to genomic evolution during serial propagation of these cells and correlates with disease progression. Alu sequences may serve as substrates for elevated HR during cell proliferation in vitro, as they have been reported to do during the evolution of species, and thus may provide additional targets for prevention or treatment of this disease.

Telomerase inhibitor GRN163L inhibits myeloma cell growth in vitro and in vivo.

Human telomerase, the reverse transcriptase which extends the life span of a cell by adding telomeric repeats to chromosome ends, is expressed in most cancer cells but not in the majority of normal somatic cells. Inhibition of telomerase therefore holds great promise as anticancer therapy. We have synthesized a novel telomerase inhibitor GRN163L, a lipid-attached phosphoramidate oligonucleotide complementary to template region of the RNA subunit of telomerase. Here, we report that GRN163L is efficiently taken up by human myeloma cells without any need of transfection and is resistant to nucleolytic degradation. The exposure of myeloma cells to GRN163L led to an effective inhibition of telomerase activity, reduction of telomere length and apoptotic cell death after a lag period of 2-3 weeks. Mismatch control oligonucleotides had no effect on growth of myeloma cells. The in vivo efficacy of GRN163L was confirmed in two murine models of human multiple myeloma. In three independent experiments, significant reduction in tumor cell growth and better survival than control mice was observed. Furthermore, GRN163L-induced myeloma cell death could be significantly enhanced by Hsp90 inhibitor 17AAG. These data provide the preclinical rationale for clinical evaluation of GRN163L in myeloma and in combination with 17AAG.