Precision therapeutic targeting of human cancer cell motility.

Increased cancer cell motility constitutes a root cause of end organ destruction and mortality, but its complex regulation represents a barrier to precision targeting. We use the unique characteristics of small molecules to probe and selectively modulate cell motility. By coupling efficient chemical synthesis routes to multiple upfront in parallel phenotypic screens, we identify that KBU2046 inhibits cell motility and cell invasion in vitro. Across three different murine models of human prostate and breast cancer, KBU2046 inhibits metastasis, decreases bone destruction, and prolongs survival at nanomolar blood concentrations after oral administration. Comprehensive molecular, cellular and systemic-level assays all support a high level of selectivity. KBU2046 binds chaperone heterocomplexes, selectively alters binding of client proteins that regulate motility, and lacks all the hallmarks of classical chaperone inhibitors, including toxicity. We identify a unique cell motility regulatory mechanism and synthesize a targeted therapeutic, providing a platform to pursue studies in humans.

Delays in seeking medical care in hospitalized patients with decompensated heart failure.

PURPOSE: The magnitude of, and factors associated with, prolonged delay in seeking medical care in patients with acute myocardial infarction has been well described. It is unknown, however, what the extent of, and factors associated with, prehospital delay are in patients hospitalized with acute heart failure. The purpose of this study was to examine patterns of prehospital delay, and factors associated with delay in seeking medical care, in patients hospitalized with acute heart failure at all 11 medical centers in the Worcester, Massachusetts metropolitan area. METHODS: The medical records of 2587 greater Worcester residents with decompensated heart failure who were hospitalized in 2000 were reviewed for the collection of information about prehospital delay and demographic and clinical factors associated with extent of delay. RESULTS: Information about acute symptom onset and duration of delay in seeking medical care was available in only 44% of the hospital charts of patients with heart failure. The average delay time was 13.3 hours, while the median was 2.0 hours. Male sex, multiple presenting symptoms, absence of a history of heart failure, and seeking medical care between midnight and 6:00 am were associated with prolonged prehospital delay. CONCLUSIONS: The results of this study in residents of a large New England metropolitan area suggest that patients hospitalized with acute heart failure exhibit considerable delays in seeking medical care. Several demographic and clinical characteristics were associated with prolonged delay. More research is needed to better understand the reasons why patients with this serious and increasingly prevalent clinical syndrome delay seeking medical care in a timely fashion.

A community-wide perspective into changing trends in the utilization of diagnostic and interventional procedures in patients hospitalized with acute myocardial infarction.

BACKGROUND: Limited data are available describing contemporary trends in the utilization of diagnostic and interventional procedures in patients hospitalized with acute myocardial infarction (AMI). The objectives of our population-based investigation were to examine long-term trends (1986-2003) in the utilization of cardiac catheterization, percutaneous coronary interventions (PCI), and coronary artery bypass graft surgery (CABG) in a community sample of patients hospitalized with AMI. We examined the demographic and clinical characteristics of patients who received these diagnostic and interventional procedures and determined whether the profile of patients undergoing these procedures had changed over time. METHODS: The study sample consisted of 9422 greater Worcester (MA) residents hospitalized with confirmed AMI at all metropolitan Worcester medical centers in 10 annual periods between 1986 and 2003. Information on patient demographics, clinical course, and treatment practices was obtained through the review of hospital medical records. RESULTS: Marked increases were observed in the utilization of cardiac catheterization (18.4% to 55.8%) and PCI (2.0% to 42.1%) between 1986 and 2003, respectively. Utilization of CABG showed modest increases in the early 1990s, whereas its use was relatively stable thereafter. Several demographic and clinical characteristics were associated with the receipt of these diagnostic and interventional procedures. CONCLUSIONS: The results of this study of patients hospitalized with AMI in a large New England community suggest evolving trends in the use of cardiac catheterization, PCI, and CABG. Despite these changing patterns, our findings suggest that there remains room for improvement in the therapeutic management of patients hospitalized with AMI, including certain high-risk groups.