Citations

Abstract Purpose: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the stem cell properties of GBM contribute to the development of therapy resistance. Experimental Design: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo. Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro. Results: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin–Ran protein complex in cancer cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo. This inhibition was dependent on caspase activity and associated with p53 status of cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment. Conclusions: Disruption of the Survivin–Ran complex by LLP-3 abolishes survival and growth of GSCs both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM. Clin Cancer Res; 19(3); 631–42. ©2012 AACR.

BackgroundOctogenarians (>80 years) have been underrepresented in clinical trials of cardiac resynchronization therapy (CRT).ObjectiveTo determine the benefit of CRT with or without a defibrillator in older elderly patients.MethodsWe retrospectively studied consecutive patients who received CRT at our institution from 2002 through 2008. New York Heart Association (NYHA) class and echocardiographic parameters were assessed before and after CRT. Thirty‐day complications after device implant were collected. Survival data were obtained from the national death and location database. Data were compared between those 80 years and younger and those older than 80 years.ResultsOf 728 patients identified, 90 (12.4%) were older than 80 years. After CRT, older and younger patients had similar improvements in NHYA class (P = 0.41), ejection fraction (P = 0.48), and mitral valve regurgitation (MR) severity (P = 0.42). In the older patients, defibrillator implantation was associated with comparable improvement in NYHA class, ejection fraction, and MR grade severity (P > 0.05), as in those without a defibrillator. Overall survival was worse in octogenarians than in the younger patients by Kaplan‐Meier estimates (P = 0.001). Multivariate analysis showed similar survival between the younger and older subjects (hazard ratio, 1.23; 95% confidence interval, 0.83–1.84; P = 0.31). The observed complication rate in all study subjects was 12.2%, with no difference between the two age groups.ConclusionOctogenarian patients who received CRT with or without a defibrillator for advanced heart failure had similar clinical benefits as younger patients. CRT should not be withheld from octogenarians meeting current selection guidelines.

AbstractA plenary panel session at the 2012 Academic Emergency Medicine consensus conference “Education Research in Emergency Medicine: Opportunities, Challenges, and Strategies for Success” discussed barriers educators face in imagining, designing, and implementing studies to address educational challenges. This proceedings article presents a general approach to getting started in education research. Four examples of studies from the medical education literature that illustrate a distinct way to approach specific research questions are discussed. The study designs used are applicable to a variety of education research problems in emergency medicine (EM). Potential applications of studies are discussed, as well as effects and lessons learned.

Pulmonary embolic disease is most commonly a manifestation of venous thromboembolism (VTE). However, fat, tumor, and air may all embolize to the pulmonary vasculature and lymphatics resulting in various clinical manifestations. Tumor emboli to small pulmonary vessels and lymphatics can lead to hypoxemic respiratory failure and shock. We present a 62-year-old male with history of mild COPD and end-stage liver disease secondary to hepatitis C admitted due to progressive shortness of breath and hypoxemia who developed shock and right ventricular failure. After a negative evaluation for venous thromboembolic disease, he had progressive respiratory and hemodynamic deterioration despite mechanical ventilation, renal replacement therapy, and vasopressive/inotropic support. Postmortem examination revealed diffuse micronodular moderately differentiated hepatocellular carcinoma (HCC) without a discrete mass, as well as numerous HCC tumor emboli to the lung and focally to the heart, consistent with disseminated hepatocellular tumor microembolism.

A new mechanism involving cleavage of a transcription factor called CREB3L1 has been proposed to explain the anti-tumour effects of doxorubicin.

Abstract PRSS3/mesotrypsin is an atypical isoform of trypsin that has been associated with breast, lung, and pancreatic cancer cell malignancy. In analyses of open source transcriptional microarray data, we find that PRSS3 expression is upregulated in metastatic prostate cancer tissue, and that expression of PRSS3 in primary prostate tumors is prognostic of systemic progression following prostatectomy. Using a mouse orthotopic model with bioluminescent imaging, we show that PRSS3/mesotrypsin is critical for prostate cancer metastasis. Silencing of PRSS3 inhibits anchorage-independent growth of prostate cancer cells in soft agar assays, and suppresses invasiveness in Matrigel transwell assays and three-dimensional (3D) cell culture models. We further show that treatment with recombinant mesotrypsin directly promotes an invasive cellular phenotype in prostate cancer cells and find that these effects are specific and require the proteolytic activity of mesotrypsin, because neither cationic trypsin nor a mesotrypsin mutant lacking activity can drive the invasive phenotype. Finally, we show that a newly developed, potent inhibitor of mesotrypsin activity can suppress prostate cancer cell invasion to a similar extent as PRSS3 gene silencing. This study defines mesotrypsin as an important mediator of prostate cancer progression and metastasis, and suggests that inhibition of mesotrypsin activity may provide a novel modality for prostate cancer treatment. Mol Cancer Res; 10(12); 1555–66. ©2012 AACR.