Highlights d Integrated proteogenomic characterization in 103 ccRCC cases d Delineation of chromosomal translocation events leading to chromosome 3p loss d Tumor-specific proteomic/phosphoproteomic alterations unrevealed by mRNA analysis d Immune-based subtypes of ccRCC defined by mRNA, proteome, and phosphoproteome

In the originally published version of this article, Daniel Geiszler's last name was misspelled. This error has now been corrected in the article online.

PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-β expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to loadinduced stress resulted in cardiac dysfunction and heart failure. Mechanistically, we showed that cardiomyocyte PDGFR-β signaling plays a vital role in stress-induced cardiac angiogenesis. Specifically, we demonstrated that cardiomyocyte PDGFR-β was an essential upstream regulator of the stress-induced paracrine angiogenic capacity (the angiogenic potential) of cardiomyocytes. These results demonstrate that cardiomyocyte PDGFR-β is a regulator of the compensatory cardiac response to pressure overload-induced stress. Furthermore, our findings may provide insights into the mechanism of cardiotoxicity due to anticancer PDGFR inhibitors.

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.

Background We sought to determine the incidence and severity of cardiovascular toxicity due to imatinib mesylate(IM) in GIST and other sarcoma patients, and to explore cardiotoxicity due to IM using cell culture and in vitro models. Methods To determine the incidence and significance of serious cardiac adverse events in GIST and other sarcoma patients receiving IM, we performed a retrospective analysis of 219 consecutive patients treated with IM. In vitro studies of IM on cultured cardiomyocytes and biochemical studies of cardiac lysates from mice treated with IM were performed to define the potential cardiotoxic effects of IM. Results Grade III or IV potentially cardiotoxic adverse events (mostly edema or effusions) occurred in 8.2% of patients, were manageable with medical therapy, and infrequently required dose reduction or discontinuation of IM. Arrhythmias, acute coronary syndromes, or heart failure were uncommon, occurring in less than 1% of treated patients. However, administration of imatinib in a mouse model system resulted in inhibition of activation of protein kinases that are known to be important in the cardiac stress response. Conclusion We conclude that imatinib is an uncommon cause of cardiotoxicity and that the cardiovascular adverse events that occur are manageable when recognized and treated. Nevertheless, our pre-clinical findings suggest that imatinib remains a potential cardiotoxin. Furthermore the cardiac consequences of long-term imatinib therapy remain unknown. We therefore recommend treatment of risk factors for cardiovascular disease in imatinib treated patients in accord with the American Heart Association guidelines for the prevention and treatment of heart failure.

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