Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis.

Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.

Cardiac catheterization in patients with end-stage liver disease: safety and outcomes.

INTRODUCTION: Patients with end-stage liver disease (ESLD) awaiting transplant are at increased risk of bleeding. Nevertheless, these patients routinely undergo cardiac catheterization for various indications. Safety and outcomes of cardiac catheterization in these patients are not well reported. METHODS: In a case-control study 43 patients with ESLD who underwent angiography for liver transplant work-up were compared to 43 age and gender-matched controls with no liver dysfunction. In-hospital outcomes and procedural variables were compared. RESULTS: Patients with ESLD had a lower baseline hemoglobin (12.1 ± 2.1 vs. 13.7 ± 1.8, P < 0.0005), lower platelet counts (86.8 ± 66 vs. 247 ± 80, P < 0.0001) and higher international normalized ratio (INR) (1.4 ± 0.2 vs. 1.1 ± 0.2, P < 0.0001) than controls. Among ESLD group, five (11.6%) patients received platelet transfusions, one received blood transfusion, and three patients (7%) with INR > 1.6 received fresh frozen plasma (FFP) compared with none in the control group. Smaller size (four French) vascular sheaths were used more frequently in the group with ESLD (16% vs. 4%, P = 0.04). There were no significant vascular or bleeding complications in either group. CONCLUSIONS: Elective cardiac catheterization can be safely performed in patients with ESLD with outcomes (vascular and bleeding complications, length of hospital stay and in-hospital mortality) similar to patients without liver disease despite significant thrombocytopenia and elevated INR in patients with ESLD. Practices such as platelet transfusion for platelets <60,000 µL, prophylactic FFP transfusion for INR ≥ 1.6, less frequent use of antiplatelet therapy and more frequent use of smaller vascular sheaths may have contributed to the safety of cardiac catheterization in ESLD patients.

Impact of bisphosphonates on the risk of atrial fibrillation.

Osteoporosis is a major public health problem resulting in significant morbidity, mortality, and utilization of healthcare resources. Bisphosphonates are the most widely prescribed drugs for increasing bone mass and preventing osteoporosis-related fractures. Although these drugs have proven efficacy and are generally considered safe, a clinical trial of once-yearly zoledronic acid reported an unexpected increase in the risk of cardiac arrhythmias, primarily due to serious atrial fibrillation (AF). Subsequently, a post hoc analysis of another clinical trial reported a nonsignificant trend toward an increased risk of serious AF. Based on these concerns, the US FDA issued a cautionary advisory and is conducting an ongoing safety review. A major limitation of the clinical trials was the fact that none were designed or powered to evaluate arrhythmia endpoints. In search of more definitive answers, several observational studies using both population-based cohort and case-control designs have attempted to verify this association. However, only two studies, one cohort and one case-control study, have found a positive association, while six additional studies have reported negative findings. While most of the observational studies attempted to control for confounders, the chosen variables have varied considerably, and other key potential confounders such as smoking were not controlled for in any of the studies. Because the occurrence of AF events in the studies was relatively low, four meta-analyses have been conducted to increase sample size by using pooled data from multiple studies. Again, results have been inconsistent, with two of the analyses reporting a significant increase in serious AF and two finding no association. Additionally, no direct evidence has identified any underlying mechanism to explain an increased arrhythmia risk with bisphosphonate therapy. However, several possible mechanisms have been proposed, including an activated inflammatory state, altered electrolytes impacting cardiac conduction, and long-term atrial structural changes. Due to the widespread use of bisphosphonates in a population for whom the baseline risk of AF also increases with advancing age, further prospective assessment of this possible association is clearly warranted. If an association does exist between bisphosphonates and an increased risk for AF, several additional questions will need to be answered including impact of baseline risk, the time course for increased risk, relationship to drug dose, and whether or not this represents a drug-class adverse effect. Until definitive evidence is available, clinicians will continue to have to make clinical judgments based on the available and often inconsistent evidence to date. To provide further perspective on this possible association, we performed a systematic search of the PubMed database from 1966 to 30 June 2010, drug regulatory websites, and drug manufacturer websites. In this review we summarize the findings from clinical trials, observational studies, and meta-analyses evaluating the risk of AF following bisphosphonate exposure, and discuss possible mechanisms that could explain an increased risk.

Evolution of Paroxysmal Atrial Fibrillation to Persistent or Permanent Atrial Fibrillation: Predictors of Progression.

Introduction: Paroxysmal atrial fibrillation (PAF) eventually progresses to persistent and permanent AF. The predictors of progression from PAF to persistent and permanent AF are poorly understood. Methods: Electronic medical records of 437 patients with PAF were reviewed in a retrospective cohort study. Patients were followed in time and progression to persistent/permanent AF was recorded. Demographic, clinical and echocardiographic information was collected. A logistic regression analysis was performed to identify predictors of progression to persistent/permanent AF. Results: Over a mean duration of 57.3±55.9 months, 32.4% of patients progressed to persistent/permanent AF. Mean age of the population was 67.9±13.4 years with 57% males and 92% Caucasian. Univariate analysis identified higher body higher mass index (BMI), cardiomyopathy, diabetes, valvular heart disease (VHD), larger left atrial size (LA) and higher pulmonary artery pressure as predictors of progression. Multivariate logistic regression analysis larger left atrial size (OR 1.46, CI 1.05-2.04, P 0.002), cardiomyopathy (OR 2, CI 1.1- 3.3, P 0.003), and moderate to severe valvular heart disease (OR 3.3, CI 1.4-5, P 0.008) as significant predictors of progression to persistent/permanent AF. Conclusions: Our study shows that PAF patients with larger LA, valvular heart disease and cardiomyopathy predict progression of PAF to persistent/permanent AF. Higher BMI and cardiomyopathy predicted progression to persistent AF while larger LA size and VHD predicted progression to permanent AF.