Tumor heterogeneity dictates sensitivity to gefitinib (Iressa(TM)/ZD1839) in solid tumor models

The epidermal growth factor receptor (EGFR) and its ligands are overexpressed in many human tumors, including bladder and pancreas, correlating with a more aggressive tumor phenotype and poor patient prognosis. We initiated the present study to characterize the heterogeneity of gefitinib responsiveness in a panel of human bladder and pancreatic cancer cell lines in order to identify the biological characteristics of EGFR-dependent proliferation that could be used to prospectively identify drug-sensitive tumors. A second objective was to elucidate how to best exploit these results by utilizing gefitinib in combination therapy. To these ends, we examined the effects of the EGFR antagonist gefitinib on proliferation and apoptosis in a panel of 18 human bladder cancer cell lines and 9 human pancreatic cancer cell lines. Our data confirmed the existence of marked heterogeneity in Iressa responsiveness with less than half of the cell lines displaying significant growth inhibition by clinically relevant concentrations of the drug. Gefitinib responsiveness was found to be p27 kip1 dependent as DNA synthesis was restored following exposure to p27siRNA. Unfortunately, Iressa responsiveness was not closely linked to surface EGFR or TGF-α expression in the bladder cancer cells, however, cellular TGF-α expression correlated directly with Iressa sensitivity in the pancreatic cancer cell lines. These findings provide the potential for prospectively identifying patients with drug-sensitive tumors. ^ Further studies aimed at exploiting gefitinib-mediated cell cycle effects led us to investigate if gefitinib-mediated TRAIL sensitization correlated with increased p27kip1 accumulation. We observed that increased TRAIL sensitivity following gefitinib exposure was not dependent on p27 kip1 expression. Additional studies initiated to examine the role(s) of Akt and Erk signaling demonstrated that exposure to PI3K or MEK inhibitors significantly enhanced TRAIL-induced apoptosis at concentrations that block target phosphorylation. Furthermore, combinations of TRAIL and the PI3K or MEK inhibitors increased procaspase-8 processing above levels observed with TRAIL alone, indicating that the effects were exerted at the level of caspase-8 activation, considered the earliest step in the TRAIL pathway. ^

Systematic review of current trends of cardiovascular disease (CVD) and association between health insurance coverage and CVD mortality among women aged 60--65 in Texas in 2000--2011

Cardiovascular disease (CVD) is highly preventable, yet it is a leading cause of death among women in Texas. The primary goals of this research were to examine past and current trends of CVD, as well as identify whether there is an association between the insurance coverage and mortality from CVD among women aged 60–65 in Texas between 2000 and 2011. ^ The systematic review of the research is based on the guidelines and recommendations set by the Centre for Reviews and Dissemination for conducting reviews in health care. Over 47 citations of peer-reviewed articles from Ovid MEDLINE and PubMed databases and five websites were identified, of which 7 studies met inclusion criteria for the first systematic review to examine the trends of CVD in Texas. Ten citations of peer-reviewed articles from Ovid MEDLINE and PubMed databases and five web sites were reviewed for the second systematic review (to study the association between insurance coverage and cardiovascular health among Texas women 60–64 years of age), of which 3 studies met inclusion criteria and were included in the research. The results of the study highlighted key gaps in the existing literature and important areas for the further research, as well as determined directions for future public health CVD prevention programs in Texas. ^ Based on the conducted research, the major determinants of premature mortality among women attributed to cardiovascular disease are based on individual level characteristics, more specifically sex, age, race/ethnicity, and education. The results indicate that African American and non-Hispanic white women are more likely to have higher CVD mortality rates than Hispanic women due to higher prevalence of cardiac risk factors. The data also shows higher levels of mortality from CVD in the southeastern United States, with Texas ranking as the third state with the highest prevalence of CVD among women. According to the Texas Department of State Health Services, there are approximately 56,000 deaths caused by CVD annually in Texas, which represents about one death every ten minutes. Coronary artery disease and stroke were the causes of 31.2 percent of all female deaths in Texas in 2009, meaning that approximately 68 women die from any form of cardiac disease in Texas each day. ^ The data of the reviewed studies indicate that women' lack of health insurance was significantly associated with a higher prevalence of cardiovascular disease. The uninsured women were more likely to be unaware of their risk factors and more likely to have undiagnosed diabetes—a co-morbidity factor of CVD. One of the studies also reports strong correlation between state rates of uninsured and lower rates of preventive care. Given these strong correlations, those who were chronically uninsured were at a higher risk of mortality than the insured, due to prolonged periods of time without basic access to preventive and medical care. ^ Suggested recommendations to decrease CVD mortality rates in Texas are consistent with the existing literature and include state policy development that addresses elimination of health disparities, consideration of potential benefits of universal health coverage by the legislative policymakers, and maintenance of solid partnerships between public health agencies and hospitals to educate on, diagnose, and treat CVD among the female population in Texas. ^