Biomedical subjects

Alex Harris

Publications and source records attributed to Alex Harris.

3 recordsLinked to original sources

PubMed2006

Microvascular versus macrovascular dysfunction in type 2 diabetes: differences in contractile responses to endothelin-1.

Vascular dysfunction characterized by a hyperreactivity to vasoconstrictors and/or impaired vascular relaxation contributes to increased incidence of cardiovascular disease in diabetes. Endothelin (ET)-1, a potent vasoconstrictor, is chronically elevated in diabetes. However, the role of ET-1 in resistance versus larger vessel function in mild diabetes remains unknown. Accordingly, this study investigated vascular function of third-order mesenteric arteries and basilar arteries in control Wistar and Goto-Kakizaki (GK) rats, a model of mild Type 2 diabetes. Six weeks after the onset of diabetes, contractile responses to 0.1-100 nM ET-1 and relaxation responses to 1 nM-10 microM acetylcholine (ACh) in vessels preconstricted (baseline + 60%) with serotonin (5-HT) were assessed by myograph studies in the presence or absence of a nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine (L-NNA). Maximum contractile response to ET-1 was augmented in mesenteric vessels (155 +/- 18% in GK vs. 81 +/- 6% in control; n = 5-7) but not in the basilar artery (134 +/- 29% in GK vs. 107 +/- 17% in control; n = 4 per group). However, vascular relaxation was impaired in the basilar arteries (22 +/- 4% in GK vs. 53 +/- 7% in control; n = 4 per group) but not in mesenteric arteries of GK rats. Inhibition of NOS decreased the relaxation response of basilar arteries to 15 +/- 8% and 42 +/- 5% in GK and control rats, respectively; whereas, in resistance vessels, corresponding values were 56 +/- 7% and 89 +/- 3% (vs. 109 +/- 2% and 112 +/- 3% without NOS blockade), indicating the involvement of different vasorelaxation-promoting pathways in these vascular beds. These findings provide evidence that the ET system is activated even under mild hyperglycemia and that it contributes to the hyperreactivity of resistance vessels, therefore, the ET system may play an important role in elevated blood pressure in Type 2 diabetes.

Acetylcholine↗

PubMed2005

Pretreatment and during treatment risk factors for dropout among patients with substance use disorders.

OBJECTIVE: The aim of this study was to use pretreatment and treatment factors to predict dropout from residential substance use disorder program and to examine how the treatment environment modifies the risk for dropout. METHOD: This study assessed 3649 male patients at entry to residential substance use disorder treatment and obtained information about their perceptions of the treatment environment. RESULTS: Baseline factors that predicted dropout included younger age, greater cognitive dysfunction, more drug use, and lower severity of alcohol dependence. Patients in treatment environments appraised as low in support or high in control also were more likely to drop out. Further, patients at high risk of dropout were especially likely to dropout when treated in a highly controlling treatment environment. CONCLUSION: Better screening of risk factors for dropout and efforts to create a less controlling treatment environment may result in increased retention in substance use disorder treatment.

Adult↗

PubMed2005

In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models.

PURPOSE: To evaluate the therapeutic and biological effects of CHIR-258, an orally bioavailable, potent inhibitor of class III-V receptor tyrosine kinases, in colon cancer models. EXPERIMENTAL DESIGN: The pharmacologic activity of CHIR-258 was characterized by monitoring target modulation as well as by evaluating the antitumor and antiangiogenic effects in human colon xenograft models. RESULTS: CHIR-258 inhibits vascular endothelial growth factor receptor 1/2, fibroblast growth factor receptor 1/3, and platelet-derived growth factor receptor beta (PDGFRbeta) and shows both antitumor and antiangiogenic activities in vivo. Treatment of KM12L4a human colon cancer cells with CHIR-258 resulted in a dose-dependent inhibition of vascular endothelial growth factor receptor 1 and PDGFRbeta phosphorylation and reduction of phosphorylated extracellular signal-regulated kinase (ERK) levels, indicating modulation of target receptors and downstream signaling. In vivo administration of CHIR-258 resulted in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm(3)). Immunohistochemical analysis showed a reduction of phosphorylated PDGFRbeta and phosphorylated ERK in tumor cells after oral dosing with CHIR-258 compared with control tumors. These changes were accompanied by decreased tumor cell proliferation rate and reduced intratumoral microvessel density. CHIR-258 inhibited the phosphorylation of PDGFRbeta and ERK phosphorylation in tumors within 2 hours following dosing and the inhibitory activity was sustained for >24 hours. Significant antitumor activity was observed with intermittent dosing schedules, indicating a sustained biological activity. CONCLUSION: These studies provide evidence that biological activity of CHIR-258 in tumors correlates with efficacy and aids in the identification of potential biomarkers of this multitargeted receptor tyrosine kinase inhibitor. CHIR-258 exhibits properties that make it a promising candidate for clinical development in a variety of solid and hematologic malignancies.

Animals↗