Cyclic variations in coronary blood flow (CFVs) in dogs with experimental coronary artery stenosis and endothelial injury appear to result primarily from the aggregation of platelets at the site of stenosis followed by dislodgement and distal embolization. Using this canine model, we tested the hypotheses: (a) that thrombin is an important mediator of CFVs in dogs with coronary stenoses and endothelial injury; (b) that inhibition of thrombin with heparin, or MCI-9038, a selective thrombin inhibitor, abolishes CFVs in this model; and (c) that abolition of CFVs by thrombin inhibition is time dependent. CFVs, produced in open-chest dogs by placing a flow-reducing plastic constrictor around the left anterior coronary artery, were monitored for either 30 min (group I) or 3 h (group II) before treatment with either heparin or 4-methyl-14N'-+(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl
The design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-KB (NF-KB) and cyclooxygenase (COX), known to be activated or overexpressed, respectively, in pancreatic cancer. We have previously shown that parthenolide, a proapoptotic drug associated with NF-KB inhibition, enhanced the growth suppression of pancreatic cancer cells by the COX inhibitor sulindac in vitro. In the present study, a bioavailable analogue of parthenolide, LC-1, and sulindac were evaluated in vivo using a xenograft model of human pancreatic cancer. Treatment groups included placebo, low-dose/high-dose LC-1 (20 and 40 mg/kg), low-dose/ high-dose sulindac (20 and 60 mg/kg), and low-dose combination LC-1/sulindac (20 mg/kg each). In MiaPaCa-2 xenografts, tumor growth was inhibited by either highdose sulindac or LC-1. In BxPC-3 xenografts, tumor size was significantly reduced by treatment with the low-dose LC-1/sulindac combination or high-dose sulindac alone (P < 0.05). Immunohistochemistry of BxPC-3 tumors revealed a significant decrease in Ki-67 and CD31 staining by high-dose sulindac, with no significant changes in COX-1/ COX-2 levels or activity in any of the treatment groups. NF-KB DNA-binding activity was significantly decreased by high-dose LC-1. Cyclin D1 protein levels were reduced by the low-dose LC-1/sulindac combination or high-dose sulindac alone, correlating with BxPC-3 tumor suppression. These results suggest that LC-1 and sulindac may mediate their antitumor effects, in part, by altering cyclin D1 levels. Furthermore, this study provides preclinical evidence for the therapeutic efficacy of these agents. [Mol Cancer Ther 2007;6(6):1736 -44]
Background Chronic ethanol intake is a significant risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). The effects of ethanol on extracellular signal-regulated kinase (ERK) activation, transforming growth factor alpha (TGF-α) and HCC growth were examined in this study. Methods HepG2, SKHep, Hep3B human HCC cells or normal human hepatocytes were treated with ethanol (0-100mM), exogenous TGF-α, TGF-α neutralization antibody or the MEK inhibitor U0126. TGF-α levels were quantified by ELISA. Growth was determined by trypan blue-excluded cell counts. Cell cycle phase distribution was determined by flow cytometry. Protein expression was determined by Western blot. Results Ethanol treatment (10-40mM) increased ERK activation in HepG2 and SKHep HCC cells but not in Hep3B or human hepatocyte cells. Growth increased in HepG2 (174 ± 29 %, P<0.05) and SKHep (149 ± 12 %, P<0.05) cells in response to ethanol treatment. Correspondingly, ethanol increased S phase distribution in these cells. U0126 suppressed ethanol-induced growth increases. Ethanol treatment for 24 hours also raised TGF-α levels in HepG2 cells (118-198 %) and SKHep cells (112-177 %). Exogenous administration of recombinant TGF-α mimicked the ethanol-induced growth in HepG2 and SKHep cells; TGF-α neutralization antibody effectively abrogated this effect. The TGF-a neutralization antibody also prevented ERK activation by ethanol in HepG2 cells. Conclusion These data demonstrate that clinically relevant doses of ethanol stimulate ERK-dependent proliferation of HCC cells. Ethanol up-regulates TGF-α levels in HCC cells and enhances growth through cell cycles changes, which appear to be mediated through TGF-α-MEK-ERK signaling. Ethanol-MEK signaling in normal hepatocytes is absent, suggesting that ethanol promotion of HCC growth may in part depend upon the acquisition of cancer-specific signaling by hepatocytes.
Myocardial bridging of the left anterior descending (LAD) coronary artery occurs in 1% to 4.5% of coronary angiographies. 1 Although the majority of the patients are asymptomatic, a small percentage will require surgery. 2 Surgery for symptomatic myocardial bridge of the LAD may include myotomy, coronary artery bypass surgery, or both. 2,3 Procedure selection is based on the size of the underlying artery during diastole, the presence of concomitant proximal coronary artery disease, and the presence of anatomic factors that would increase the risk of myotomy. We present 2 patients with myocardial bridges of the LAD, 1 treated with myotomy and 1 treated with both myotomy and bypass surgery.
Intrapleural foreign bodies are rare and there are few reports on the occurrence and management of this uncommon clinical presentation. We report a case of a patient with a history of ingesting multiple foreign bodies, which resulted in multiple laparotomy procedures for extraction. The patient recently required surgical removal of innumerable ingested foreign bodies from the stomach and developed a left empyema post-operatively. Subsequent imaging studies revealed evidence of a foreign object in the left pleural space without evidence of an esophageal perforation or diaphragm injury.
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