[Show abstract][Hide abstract] ABSTRACT: Endothelial-mesenchymal transition (EndoMT) has been recognized as a key determinant of tumor microenvironment in cancer progression and metastasis. Endothelial cells undergoing EndoMT lose their endothelial markers, acquire the mesenchymal phenotype and become more invasive with increased migratory abilities. Early stages of esophageal adenocarcinoma (EAC) are characterized by strong microvasculature whose impact in tumor progression remains undefined. Our aim was to determine the role of EndoMT in esophageal adenocarcinoma by investigating the impact of tumor cells on normal primary human esophageal microvascular endothelial cells (HEMEC).
Preview · Article · Aug 2014 · AJP Cell Physiology
[Show abstract][Hide abstract] ABSTRACT: Increased intraluminal pressure can reduce endothelial function in resistance arteries; however the mechanism of this impairment is unknown. The purpose of this study was to determine the effect of local renin-angiotensin system inhibition on the pressure-induced blunting of endothelium-dependent vasodilation in human adipose arterioles. Arterioles (100-200 µm) were dissected from fresh adipose surgical specimens, cannulated onto glass micropipettes, pressurized to an intraluminal pressure of 60 mmHg, and constricted with endothelin-1. Vasodilation to acetylcholine (ACh) was assessed at 60 mmHg, and again after a 30 minute exposure to an intraluminal pressure of 150 mmHg. The vasodilator response to ACh was significantly reduced in vessels exposed to 150 mmHg. Exposing the vessels to the superoxide scavenger PEG-SOD (100 U/mL), the AT1 receptor antagonist losartan (10(-6) mol/L), or the ACE inhibitor captopril (10(-5) mol/L) prevented the pressure-induced reduction in acetylcholine-dependent vasodilation observed in untreated vessels. High intraluminal pressure had no effect on papaverine-induced vasodilation or angiotensin II sensitivity. Increased intraluminal pressure increased dihydroethidium fluorescence in cannulated vessels, which could be prevented by PEG-SOD or losartan treatment, and endothelial denudation. These data indicate that high intraluminal pressure can increase vascular superoxide and reduce NO-mediated vasodilation via activation of the vascular renin-angiotensin system. This study provides evidence that the local renin-angiotensin system in the human microvasculature may be pressure sensitive, and contribute to endothelial dysfunction after acute bouts of hypertension.
No preview · Article · Apr 2014 · AJP Heart and Circulatory Physiology
[Show abstract][Hide abstract] ABSTRACT: Inflammatory bowel disease (IBD) has a bimodal distribution with approximately 15 % of patients manifesting after age 65. Previous reports suggest an increased risk of surgical complications in the elderly.
To compare surgical outcomes in elderly IBD patients (≥65 years at the time of surgery) to matched younger IBD cohorts.
This was a retrospective cohort study at a single academic center of patients who underwent surgery for IBD. Forty-two elderly patients (≥65 years) were matched at least 1:1 (median 1:5) to patients in each of three control groups [18-35 years (n = 71); 36-49 years (n = 62); 50-64 years (n = 58)] according to gender, disease type/location, and type of surgery. Postoperative complications were compared. Patient characteristics were used in multivariate risk models. Analysis was performed using ordinary logistic regression.
Twenty ileal or ileocolonic resections, 12 partial or total colectomies, four stricturoplasties, and six laparoscopic partial or total colectomies were performed in the elderly group. The post-operative complication rate was not statistically different between the elderly and younger cohorts (38 % vs. 39 % vs. 40 % vs. 48 % in the 18-35, 36-49, 50-64, and ≥65 years groups, respectively, p = 0.26). The only significant risk factors for complication were Charlson comorbidity index (p = 0.0002), preoperative hemoglobin (p = 0.0065), total parenteral nutrition use (p = 0.024), and failed medical therapy (as the indication for surgery) (p = <0.0001).
The surgical complication rate among elderly and younger IBD patients was similar. Advanced age by itself should not be considered a risk factor for adverse operative outcome.
No preview · Article · Jul 2013 · Digestive Diseases and Sciences
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal (GI) surgery associated with resection or bypass can affect the absorption and kinetics of certain drugs. The goal of this article is 3-fold: (1) highlight the physiologic changes associated with selected GI surgeries (specifically gastric, small intestine, and colon), (2) review the implications for drug and nutrient absorption, and (3) suggest modifications of the pharmacologic agents, dosing regimens, and routes of delivery. Few large trials are available to use as references, but there is a wealth of individual reports and small series. Understanding the predictable challenges of drug administration in these patients will improve care.
No preview · Article · Jul 2013 · Nutrition in Clinical Practice
[Show abstract][Hide abstract] ABSTRACT: To elucidate the signaling mechanisms involved in the protective effect of EUK-207 against irradiation-induced cellular damage and apoptosis in human intestinal microvasculature endothelial cells (HIMEC).
HIMECs were irradiated and treated with EUK-207. Using hydroethidine and DCF-DA fluorescent probe the intracellular superoxide and reactive oxygen species (ROS) were determined. By real-time PCR and western blotting caspase-3, Bcl2 and Bax genes and proteins were analyzed. Proliferation was determined by [(3)H]-thymidine uptake. Immunofluorescence staining was used for translocation of p65 NFκB subunit. KEY FINDING: Irradiation increased ROS production, apoptosis, Bax, Caspase3 and NFkB activity in HIMEC and inhibited cell survival/growth/proliferation. EUK-207 restored the endothelial functions, markedly inhibited the ROS, up-regulated the Bcl2 and down-regulated Bax and prevented NFκB caspase 3 activity in HIMEC.
HIMEC provide a novel model to define the effect of irradiation induced endothelial dysfunction. Our findings suggest that EUK-207 effectively inhibits the damaging effect of irradiation.
[Show abstract][Hide abstract] ABSTRACT: GSK962040, a small molecule motilin receptor agonist, was identified to address the need for a safe, efficacious gastric prokinetic agent. However, as laboratory rodents lack a functional motilin system, studies in vivo have been limited to a single dose, which increased defecation in rabbits. Motilin agonists do not usually increase human colonic motility, so gastric prokinetic activity needs to be demonstrated.
The effect of intravenous GSK962040 on gastro-duodenal motility was assessed in fasted dogs implanted with strain gauges. Activity was correlated with blood plasma concentrations of GSK962040 (measured by HPLC-MS/MS) and potency of GSK962040 at the dog recombinant receptor [using a Fluorometric Imaging Plate Reader (Molecular Devices, Wokingham, UK) after expression in HEK293 cells].
GSK962040 activated the dog motilin receptor (pEC(50) 5.79; intrinsic activity 0.72, compared with [Nle(13) ]-motilin). In vivo, GSK962040 induced phasic contractions, the duration of which was dose-related (48 and 173 min for 3 and 6 mg kg(-1) ), driven by mean plasma concentrations >1.14 μmol L(-1) . After the effects of GSK962040 faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg(-1) GSK962040 but at 6 mg kg(-1) , MMCs returned 253 min after dosing, compared with 101 min after saline (n=5 each).
The results are consistent with lower potency for agonists at the dog motilin receptor, compared with humans. They also define the doses of GSK962040 which stimulate gastric motility. Correlation of in vivo and in vitro data in the same species, together with plasma concentrations, guides further studies and translation to other species.
Full-text · Article · Oct 2011 · Neurogastroenterology and Motility
[Show abstract][Hide abstract] ABSTRACT: Radiation increases the frequency of small intestinal and colonic giant migrating contractions (GMCs). These contractions contribute to the diarrhea and cramping after radiation therapy and are coordinated with one another across the ileocolonic (IC) junction.
We investigated the coordination of contractile activity between the small intestine, cecum and colon in five canines following circumferential myotomy on the ileum at the IC junction and compared it to intact animals. Studies were performed before and during a radiation schedule.
Myotomy increased the frequency of small intestinal GMCs prior to irradiation. In intact animals, the duration and amplitude of cecal GMCs decreased when multiple contractions occurred in rapid succession. This is in contrast to small intestinal and colonic GMCs and suggests a different mechanism of propagation for GMCs within the cecum. Ileal myotomy dramatically decreased the frequency of propagating radiation-induced colonic GMCs. The total number of colonic GMCs was not altered. Colonic contractile activity was disrupted in intact animals during irradiation. However, after ileal myotomy, irradiation did not affect the pattern of colonic contractile states. Diarrhea in irradiated animals with myotomy started earlier than intact animals. This may be related to the frequency of small intestinal GMCs.
Our findings suggest importance of the enteric neural connections at the IC region to contractile disorders of both the small and large intestine. The anatomic relationship between the canine IC junction is similar to the human ileo-appendiceal-colonic region and surgical manipulations of this area may likewise affect human contractile activity.
Full-text · Article · Aug 2010 · Neurogastroenterology and Motility
[Show abstract][Hide abstract] ABSTRACT: Since September 11, 2001, there has been the recognition of a plausible threat from acts of terrorism, including radiological or nuclear attacks. A network of Centers for Medical Countermeasures against Radiation (CMCRs) has been established across the U.S.; one of the missions of this network is to identify and develop mitigating agents that can be used to treat the civilian population after a radiological event. The development of such agents requires comparison of data from many sources and accumulation of information consistent with the "Animal Rule" from the Food and Drug Administration (FDA). Given the necessity for a consensus on appropriate animal model use across the network to allow for comparative studies to be performed across institutions, and to identify pivotal studies and facilitate FDA approval, in early 2008, investigators from each of the CMCRs organized and met for an Animal Models Workshop. Working groups deliberated and discussed the wide range of animal models available for assessing agent efficacy in a number of relevant tissues and organs, including the immune and hematopoietic systems, gastrointestinal tract, lung, kidney and skin. Discussions covered the most appropriate species and strains available as well as other factors that may affect differential findings between groups and institutions. This report provides the workshop findings.
Full-text · Article · Apr 2010 · Radiation Research