Ventricular tachycardia, premature ventricular contractions, and mortality in unselected patients with lung, colon, or pancreatic cancer: a prospective study

Aims: Many cancer patients die due to cardiovascular disease and sudden death, but data on ventricular arrhythmia prevalence and prognostic importance are not known. Methods and results: Between 2005 and 2010, we prospectively enrolled 120 unselected patients with lung, colon, or pancreatic cancer due to one of three diagnoses: colorectal (n = 33), pancreatic (n = 54), or non-small cell lung cancer (n = 33). All were free of manifest cardiovascular disease. They were compared to 43 healthy controls similar in age and sex distribution. Each participant underwent 24 h electrocardiogram recording and cancer patients were followed for up to 12.5 years for survival (median 21 months). Ninety-six cancer patients (80%) died during follow-up [5-year survival: 27% (95% confidence interval 19–35%)]. Non-sustained ventricular tachycardia (NSVT) was more frequent in cancer patients vs. controls (8% vs. 0%, P = 0.021). The number of premature ventricular contractions (PVCs) over 24 h was not increased in cancer patients vs. controls (median 4 vs. 9, P = 0.2). In multivariable analysis, NSVT [hazard ratio (HR) 2.44, P = 0.047] and PVCs (per 100, HR 1.021, P = 0.047) were both significant predictors of mortality, independent of other univariable mortality predictors including tumour stage, cancer type, potassium concentration, prior surgery, prior cardiotoxic chemotherapy, and haemoglobin. In patients with colorectal and pancreatic cancer, ≥50 PVCs/24 h predicted mortality (HR 2.30, P = 0.0024), and was identified in 18% and 26% of patients, respectively. Conclusions: Non-sustained ventricular tachycardia is more frequent in unselected patients with colorectal, pancreatic, and non-small cell lung cancer and together with PVCs predict long-term mortality. This raises the prospect of cardiovascular mortality being a target for future treatment interventions in selected cancers

Optimizing the treatment of metastatic breast cancer with special consideration of the Pi3K/Akt/mTOR pathway

Die Arbeit beschäftigt sich mit der Optimierung der Therapie des metastasierten Mammakarzinoms sowohl in vitro als auch in vivo. Im besonderen Focus steht die Wirkung des mTOR-Inhibitors Everolimus in Kombination mit Chemotherapie, Metformin oder Honokiol auf das Mammakarzinom. Darüber hinaus werden Daten einer klinischen Phase-I-Studie mit Carboplatin und Everolimus und eine retrospektive Chemotherapie-Studie mit 5-FU beim Mammakarzinom analysiert.The work is focused on optimizing the treatment of metastatic breast cancer in vitro as well as in vivo. Especially the treatment of breast cancer with the mTOR-Inhibitor everolimus in combination with chemotherapy, metformin or honokiol is analyzed. Furhtermore, this work comprises a phase-I-trial with carboplatin and everolimus and a retrospective clinical trial with 5-FU in breast cancer

Reverse Differentiation as a Gene Filtering Tool in Genome Expression Profiling of Adipogenesis for Fat Marker Gene Selection and Their Analysis

<div><p>Background</p><p>During mesenchymal stem cell (MSC) conversion into adipocytes, the adipogenic cocktail consisting of insulin, dexamethasone, indomethacin and 3-isobutyl-1-methylxanthine not only induces adipogenic-specific but also genes for non-adipogenic processes. Therefore, not all significantly expressed genes represent adipogenic-specific marker genes. So, our aim was to filter only adipogenic-specific out of all expressed genes. We hypothesize that exclusively adipogenic-specific genes change their expression during adipogenesis, and reverse during dedifferentiation. Thus, MSC were adipogenic differentiated and dedifferentiated.</p><p>Results</p><p>Adipogenesis and reverse adipogenesis was verified by Oil Red O staining and expression of <i>PPARG</i> and <i>FABP4</i>. Based on GeneChips, 991 genes were differentially expressed during adipogenesis and grouped in 4 clusters. According to bioinformatic analysis the relevance of genes with adipogenic-linked biological annotations, expression sites, molecular functions, signaling pathways and transcription factor binding sites was high in cluster 1, including all prominent adipogenic genes like <i>ADIPOQ</i>, <i>C/EBPA</i>, <i>LPL</i>, <i>PPARG</i> and <i>FABP4</i>, moderate in clusters 2–3, and negligible in cluster 4. During reversed adipogenesis, only 782 expressed genes (clusters 1–3) were reverted, including 597 genes not reported for adipogenesis before. We identified <i>APCDD1</i>, <i>CHI3L1</i>, <i>RARRES1</i> and <i>SEMA3G</i> as potential adipogenic-specific genes.</p><p>Conclusion</p><p>The model system of adipogenesis linked to reverse adipogenesis allowed the filtration of 782 adipogenic-specific genes out of total 991 significantly expressed genes. Database analysis of adipogenic-specific biological annotations, transcription factors and signaling pathways further validated and valued our concept, because most of the filtered 782 genes showed affiliation to adipogenesis. Based on this approach, the selected and filtered genes would be potentially important for characterization of adipogenesis and monitoring of clinical translation for soft-tissue regeneration. Moreover, we report 4 new marker genes.</p></div

Gene expression profile of fat specific marker genes to assess adipogenesis and reverse adipogenesis.

<p>Gene expression analysis was performed using qRT-PCR and the resulted expression data were normalized to <i>GAPDH</i> for stepwise assessment of adipogenesis and reverse adipogenesis. Gene expression of adipogenic-specific marker genes (<b>A</b>) <i>PPARG</i> and (<b>B</b>) <i>FABP4</i> is given for different stages of adipogenic differentiation i.e. at day 5, day 10 and day 15. Similarly, the gene expression of (<b>C</b>) <i>PPARG</i> and (<b>D</b>) <i>FABP4</i> is given for different stages of reverse adipogenesis (dedifferentiation). Error bars, Means ± S.E.M (n = 3); <i>*P</i><0.05; <i>**P</i><0.01; <i>***P</i><0.001, NS, not significant (student t test performed for statistical analysis).</p

MSC isolation, adipogenic differentiation and dedifferentiation.

<p>MSC were induced to adipogenic differentiation for 15 days. (<b>A</b>) Oil Red O staining showed the formation of lipid droplets on day 5, (<b>B</b>) which increased in size and number, as shown on day 10, and (<b>C</b>) reached a peak value on day 15 of adipogenic differentiation. (<b>D</b>) Control samples showed no lipid formation even after day 15 of adipogenesis. Oil Red O staining during the conversion of adipogenic differentiated cells into dedifferentiated cells showed (<b>G</b>) an intermediate conversion after day 7 and (<b>H</b>) complete conversion after day 35 of reverse adipogenesis. Morphology of (<b>F</b>) dedifferentiated cells and (<b>E</b>) undifferentiated MSC are shown by phase contrast microscopy. Bar: 100 µm.</p

New potential fat marker genes, selected based on the coupling model of adipogenesis and reverse adipogenesis.

<p>Gene expression analysis was performed using qRT-PCR and the expression values were normalized to <i>GAPDH</i> for stepwise assessment of adipogenesis and reverse adipogenesis (dedifferentiation). Gene expression of new potential fat marker genes (<b>A</b>) <i>APCDD1</i>, (<b>B</b>) <i>SEMA3G</i>, (<b>C</b>) <i>CHI3L1</i> and (<b>D</b>) <i>RARRES1</i> is given for different stages of adipogenesis, i.e. at day 5, day 10 and day 15. Similarly, the expression of (<b>E</b>) <i>APCDD1</i>, (<b>F</b>) <i>SEMA3G</i>, (<b>G</b>) <i>CHI3L1</i> and (<b>H</b>) <i>RARRES1</i> is given for different stages of dedifferentiation (reverse adipogenesis). Here the gene expression of adipogenic differentiated cells is represented by day 0 as a reference for dedifferentiation. Error bars, Means ± S.E.M (n = 3); <i>*P</i><0.05; <i>**P</i><0.01; <i>***P</i><0.001, NS, not significant (student t test, performed for statistical analysis).</p