Semaphorin 4D promotes bone invasion in head and neck squamous cell carcinoma

Head and neck squamous cell carcinomas (HNSCCs) frequently invade the bones of the facial skeleton. Semaphorin 4D (Sema4D) is an axon guidance molecule produced by oligodendrocytes. Sema4D was also identified in the bone microenvironment and many cancer tissues including HNSCC. To date, however, the role of Sema4D in cancer-associated bone disease is still unknown. This is the first study to demonstrate the role of Sema4D in bone invasion of cancer. In the clinical tissue samples of bone lesion of HNSCC, Sema4D was detected at high levels, and its expression was correlated with insulin-like growth factor-I (IGF-I) expression. In vitro experiments showed that IGF-I regulates Sema4D expression and Sema4D increased proliferation, migration and invasion in HNSCC cells. Sema4D also regulated the expression of receptor activator of nuclear factor κβ ligand (RANKL) in osteoblasts, and this stimulated osteoclastgenesis. Furthermore, knockdown of Sema4D in HNSCC cells inhibited tumor growth and decreased the number of osteoclasts in a mouse xenograft model. Taken together, IGF-I-driven production of Sema4D in HNSCCs promotes osteoclastogenesis and bone invasion

Genomewide association analysis of coronary artery disease

Background - Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods - We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Results - Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10–14 and P=3.40x10–6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions - We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease

Influence of disease related factors and medication on the QTc interval in 100 HCM patients.

<p>Values are given as total number of patients (n) or as mean ± SD.</p><p>Influence of disease related factors and medication on the QTc interval in 100 HCM patients.</p

Relationship between orthostatic test result and QTc prolongation.

<p>The percentages of patients with a positive and negative orthostatic test result are given for the group with and without QTc prolongation.</p

Impact of QTc prolongation on the occurrence of adverse events in HCM patients.

<p>Sensitivity, specificity, PPV (positive predictive value), NPV (negative predictive value) and OR (odds ratio; adjusted for age and sex) with 95%-CI (confidence intervals) are given in the table below. AE = adverse events (syncope, presyncope, VT).</p

Influence of disease related factors and medication on the orthostatic test result in 69 HCM patients older than or equal to 40 years.

<p>Values are given as total number of patients (n) or as mean ± SD.</p><p>Influence of disease related factors and medication on the orthostatic test result in 69 HCM patients older than or equal to 40 years.</p

Impact of orthostatic test on the occurrence of adverse events in HCM patients for all patients (A) and for the subgroup of patients > 40 yrs (B).

<p>Sensitivity, specificity, PPV (positive predictive value), NPV (negative predictive value) and OR (odds ratio; adjusted for age and sex) with 95%-CI (confidence intervals) are given in the table below. AE = adverse events (syncope, presyncope, VT).</p

Gene expression levels of the IFN regulatory factors <i>Irf3</i> and <i>Irf7</i> in different HF models of diverse etiology.

<p>Cardiac tissue of healthy and diseased C57BL/6J mice was used for TaqMan based gene expression analysis of the IFN regulatory factors <i>Irf3</i> and <i>Irf7</i>. Expression levels of cardiac tissue from control mice are shown as white boxes, from diseased animals as red, blue, green or yellow boxes corresponding to the analyzed heart failure model. In viral-induced myocarditis (shown in red), gene expression of <i>Irf7</i> showed by far the highest increase 7 days after infection compared to healthy controls. However, <i>Irf3</i> displayed no changes in gene expression during viral myocarditis. Moreover, in the model of myocardial infarction (shown in blue), gene expression of <i>Irf3</i> and <i>Irf7</i> was highly increased 5 days post infarction in the scar tissue when compared to the non-infarcted LV or sham, whereas <i>Irf7</i> showed a clearly higher gene expression when compared to the expression of <i>Irf3</i>. In STZ-induced diabetic cardiomyopathy (shown in green), an opposite effect on gene expression of <i>Irf3</i> and <i>Irf7</i> was observed. Whereas, <i>Irf3</i> showed a decreased gene expression, <i>Irf7</i> displayed an increased gene expression under diabetic conditions. However, in the heart failure model caused by chronic AngII-infusion for 21 days (shown in yellow), no differences in gene expression of <i>Irf3</i> and <i>Irf7</i> were detected. Data are presented in box plots as relative mRNA expression in fold change to the corresponding untreated control using the formula 2^−ΔΔCt. * = significantly different compared to corresponding control; ^# = significantly different compared to VM (acute—7 days) or RZ (remote zone).</p

Gene and protein expression of plasma membrane and intracellular localized TLRs and of the IFN regulatory factors IRF3 and IRF7 in murine and human cardiac tissue under basal conditions.

<p>Cardiac tissue of healthy C57BL/6J wildtype mice was used for TaqMan based gene expression analysis of various TLRs and their IFN regulatory factors <i>Irf3</i> and <i>Irf7</i> under basal conditions. Gene expressions of <i>Tlr4</i>, <i>Tlr9</i>, <i>Irf3</i> and <i>Irf7</i> were highly expressed when compared to the remaining TLRs under basal conditions in murine cardiac tissue. The highest gene expression under basal condition was detected for <i>Irf7</i>. In addition, we detected similar human protein expression patterns when compared with murine gene expression in cardiac tissue under basal conditions. Data are presented in box plots as absolute mRNA expression normalized to the house keeping gene <i>Cdkn1b</i> and human protein abundance are presented as rhombus sign on the right-hand of each mRNA expression.</p

Gene expression levels of the plasma membrane localized TLRs <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr4</i>, <i>Tlr5</i>, and <i>Tlr6</i> in different heart failure models of diverse etiology.

<p>Cardiac tissue of healthy and diseased C57BL/6J mice was used for TaqMan based gene expression analysis of the plasma membrane localized TLRs <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr4</i>, <i>Tlr5</i>, and <i>Tlr6</i>. Expression levels of cardiac tissue from control mice are shown as white boxes, from diseased animals as red, blue, green or yellow boxes corresponding to the analyzed heart failure model. In viral-induced myocarditis (shown in red), gene expression of <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr4</i>, <i>Tlr5</i>, and <i>Tlr6</i> was highly increased 7 days after infection compared to healthy controls. However, <i>Tlr2</i> and <i>Tlr6</i> displayed the highest increase during acute myocarditis. The initially increased gene expression levels returned almost with exception to basal levels 28 days after infection. In the model of myocardial infarction (shown in blue), gene expression of <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr4</i>, <i>Tlr5</i>, and <i>Tlr6</i> was highly increased 5 days post infarction in the infarction zone when compared to the remote zone. In the remote zone, no increased TLR gene expression was observed. In STZ-induced diabetic cardiomyopathy (shown green), a decreased gene expression of <i>Tlr5</i> in comparison to their healthy controls was detected; the remaining plasma membrane localized TLRs displayed no changes in gene expression levels. In the heart failure model caused by chronic AngII-infusion for 21 days (shown in yellow), all plasma membrane localized TLRs displayed a significant decrease when compared to their controls. Data are presented in box plots as relative mRNA expression in fold change to the corresponding untreated control using the formula 2^−ΔΔCt. * = significantly different compared to corresponding control; ^# = significantly different compared to VM (acute—7 days) or RZ (remote zone).</p