The expression of a number of human paired box-containing (PAX) genes has been correlated with various types of tumors. Novel fusion genes encoding chimeric fusion proteins have been found in the pediatric malignant tumor alveolar rhabdomyosarcoma (RMS). They are generated by two chromosomal translocations t(2;13) and t(1;13) juxtaposing PAX3 or PAX7, respectively, with a forkhead domain gene FKHR. Here we describe that specific down-regulation of the t(2;13) translocation product in alveolar RMS cells by antisense oligonucleotides results in reduced cellular viability. Cells of embryonal RMS, the other major histiotype of this tumor, were found to express either wild type PAX3 or PAX7 at elevated levels when compared with primary human myoblasts. Treatment of corresponding embryonal RMS cells with antisense olignucleotides directed against the mRNA translational start site of either one of these two transcription factors similarly triggers cell death, which is most likely due to induction of apoptosis. Retroviral mediated ectopic expression of mouse Pax3 in a PAX7 expressing embryonal RMS cell line could partially rescue antisense induced apoptosis. These data suggest that the PAX3͞FKHR fusion gene and wild-type PAX genes play a causative role in the formation of RMS and presumably other tumor types, possibly by suppressing the apoptotic program that would normally eliminate these cells.

A subtractive cloning procedure was used to characterize the molecular changes involved in transformation of normal myoblasts to rhabdomyosarcoma (RMS) cells. Here we describe the cloning of DRAL, a novel LIM-domain protein expressed in primary myoblasts but down-regulated in the RMS cell line RD. DRAL is a LIM-only protein with five LIM domains whereby one LIM domain consists only of the second half of the consensus motif. Interestingly, down-regulation of DRAL was not confined to the RD RMS cells, but was a phenomenon extended to other RMS cell lines of both embryonal and alveolar subtype, and to some breast cancer cell lines. Analysis of the expression pattern in normal human tissues revealed that DRAL is expressed at high levels in the heart, suggesting an important function in the specification of the terminally differentiated phenotype of heart muscle cells. Immunofluorescence studies using an antibody directed against recombinant DRAL localized the protein predominantly in the nucleus of cultured cells. On the basis of these results, we conclude that down-regulation of DRAL correlates with the tumor phenotype of RMS cells.

Background-Osteopontin, a glycoprotein that can be detected in plasma, was found to be upregulated in several animal models of cardiac failure and may thus represent a new biomarker that facilitates risk stratification in patients with heart failure. We therefore tested whether osteopontin plasma levels are elevated in patients with chronic heart failure and whether they provide independent prognostic information. Methods and Results-We analyzed osteopontin plasma levels in 420 patients with chronic heart failure due to significantly impaired left ventricular systolic function and correlated the results with disease stage and prognostic information (median follow-up of 43 months). We found that osteopontin plasma levels were significantly elevated in patients with heart failure as compared with healthy control subjects (532 versus 382 ng/mL, Pϭ0.008), irrespective of heart failure origin (ischemic versus dilated cardiomyopathy). Furthermore, osteopontin levels were higher in patients with moderate to severe heart failure than in patients with no or mild symptoms (672 ng/mL for New York Heart Association class III/IV versus 479 ng/mL for class I/II, PϽ0.0001). Estimated 4-year death rates in patients with osteopontin levels above or below a cutoff value derived from receiver operating characteristic analyses were 56.5% and 28.4%, respectively (hazard ratio 3.4, 95% confidence interval 2.2 to 5.3, PϽ0.0001). In a multivariable model that included demographic, clinical, and biochemical parameters such as N-terminal prohormone brain natriuretic peptide, osteopontin emerged as an independent predictor of death (hazard ratio 2.3, 95% confidence interval 1.4 to 3.5, PϽ0.001). Conclusion-Our findings suggest that osteopontin might be useful as a novel prognostic biomarker in patients with chronic heart failure. (Circ Heart Fail. 2008;1:43-49.)Key Words: heart failure Ⅲ prognosis Ⅲ biomarker H eart failure is a highly prevalent syndrome throughout the industrialized world and is associated with significant morbidity and mortality. In the United States, heart failure affects more than 5 million people and is responsible for nearly 50 000 deaths each year. 1 Furthermore, annual hospitalizations for heart failure have increased over the past 20 years, from 377 000 to almost 1 million. 2 Clinical Perspective p 49Thus, in patients with heart failure, an accurate diagnosis and prognostic evaluation are critical to identify those at greatest risk for cardiac decompensation and death. Traditional risk stratification by clinical parameters and assessment of left ventricular ejection fraction has proved helpful in the clinical management of heart failure patients. 3 More recently, the natriuretic peptides, in particular brain natriuretic peptide (BNP) or its fragment N-terminal prohormone BNP (NT-pro-BNP), have emerged as biomarkers that convey additional information for diagnosis and prognostication of death. 4 However, even when clinical information is combined with BNP levels, there is considerable variation in the outcome. 5 A...

In end-stage renal disease (ESRD) both an inappropriately high sympathetic drive and the activation of tissue-based renin-angiotensin systems lead to a complex pattern of comorbidity appearing early on in renal disease. In this context, uremic cardiomyopathy, diabetes, and renal failure display an intimate interaction that critically defines the prognosis in dialysis patients. Importantly, patients with moderate to severe loss of renal function not only carry a high burden of traditional cardiovascular risk factors, but also are exposed to uremia-specific risk factors that in concert induce an excessively increased cardiovascular mortality. Although cardiovascular guidelines may not simply be applicable to ESRD patients--these have invariably been excluded from larger cardiovascular trials--an early cardiological workup appears rational as the prevailing mode of death is characterized by sudden cardiac death and heart failure. This short review will therefore go beyond coronary heart disease, focus on the specific cardiac pathology in renal failure, and summarize the contemporary therapeutic strategies in ESRD.