Citations

AbstractIntroductionTakotsubo syndrome (TTS), also known as Takotsubo cardiomyopathy or stress‐induced cardiomyopathy, has been described following a variety of surgeries and disease states. The relationship between intra‐operative anesthesia management and the development of this syndrome has never been fully elucidated.ObjectivesThe primary objective of this study was to determine the relationship of multiple intra‐operative factors on the pathogenesis of TTS.MethodsA single‐center retrospective review of all liver transplants performed at Mayo Clinic Florida from January 2005 to December 2014. Patients developing left ventricular dilation and a concomitant decrease in ejection fraction, a negative cardiac catheterization, or stress test within 30 days of transplantation were identified. Cases were matched 2:1 to controls with respect to MELD, age, sex, and indication for transplantation. Our evaluation included liver graft characteristics, intra‐operative medications, and intra‐operative hemodynamic measurements.ResultsWe identified 24 cases of TTS from a pool of 1752 transplants, for an incidence of 1.4%. No statistically significant differences in intra‐operative measures between the two groups were identified (all P ≥ .08).ConclusionOur exploratory, single‐center retrospective review evaluating 46 intra‐operative characteristics found no association with the development of TTS.

SummaryBackgroundMatrix metalloproteinase‐9 is a proteolytic enzyme whose expression is increased in ulcerative colitis.AimTo evaluate the safety and efficacy of GS‐5745, a fully humanised anti‐matrix metalloproteinase‐9 monoclonal antibody, in moderately‐to‐severely active ulcerative colitis.MethodsWe randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS‐5745 or placebo. Multiple‐dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS‐5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS‐5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS‐5745. Exploratory analyses in the multiple‐dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS‐5745 were explored using histological and molecular approaches.ResultsTwenty‐three of the 42 patients (55%) receiving multiple doses of GS‐5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS‐5745 showed target‐mediated drug disposition, approximately dose‐proportional increases in maximum plasma concentration and more than dose‐proportional increases in the area under the plasma drug concentration‐time curve. Clinical response occurred in 18/42 patients (43%) receiving GS‐5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS‐5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS‐5745 had reductions in matrix metalloproteinase‐9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation.ConclusionThis phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS‐5745 in the treatment of ulcerative colitis.

Hyperplastic polyps of the stomach are routinely encountered during upper endoscopy and often arise in the setting of abnormal surrounding mucosa, particularly Helicobacter pylori, autoimmune gastritis, and reactive gastropathy. Not infrequently gastroenterologists fail to biopsy the surrounding mucosa, thus determining the underlying etiology of the gastric hyperplastic polyp can be difficult. Recently, the Rodger C. Haggitt Gastrointestinal Pathology Society published guidelines on the use of special stains. The society guidelines indicate that H pylori are not usually present in hyperplastic polyps and special stains in this setting may have limited utility. We analyzed the histologic features of 32 gastric hyperplastic polyps in which the nonpolypoid mucosa demonstrated H pylori gastritis. A consecutive series of 50 hyperplastic polyps in which no surrounding mucosa was sampled was also analyzed. When H pylori are identified in biopsies of the nonpolypoid mucosa, it is also commonly present within the polyp tissue (22/32, 69%). The majority of H pylori organisms were identified on routine hematoxylin and eosin stain (16/22, 72%). In contrast, H pylori were only seen in 2/50 consecutive hyperplastic polyps in which the surrounding mucosa was not sampled. Compared with the hyperplastic polyps that lack the organisms, H pylori associated hyperplastic polyps more commonly had dense lymphoplasmacytic inflammation ( P = .0001) and neutrophils within gastric epithelium ( P = .036). Polyp location, number, size, and presence of intestinal metaplasia was not associated with H pylori. These results provide empirical data to guide evaluation of hyperplastic polyps for H pylori.

Intracardiac thrombosis (ICT) during orthotopic liver transplantation (OLT) is an uncommon event. However, it is a devastating complication with high mortality when it occurs. This study aimed to identify possible predisposing factors for ICT during OLT. We retrospectively identified the cases of all patients with ICT during OLT at our institution from 1998 to 2014. Of 2750 OLTs performed, 10 patients had ICT intraoperatively. The patients' immediate prethrombosis intraoperative hemodynamic and coagulation values and thromboelastography (TEG) data were reviewed. Preexisting venous thrombosis, atrial fibrillation, and the prior placement of a transjugular intrahepatic portosystemic shunt for portal hypertension were noted in several patients and may be related to ICT during OLT. A high Model of End‐Stage Liver Disease score, low cardiac output, and sepsis did not appear to be associated with ICT. ICT occurred in some patients without the administration of antifibrinolytic agents. TEG and coagulation parameters did not appear to be helpful in predicting the onset of ICT. Four patients had ICT in both right‐ and left‐sided heart chambers; none of these 4 patients survived. All 6 patients with only right‐sided thrombus survived. In those who survived, improved hemodynamics and clot disappearance on transesophageal echocardiography (TEE) occurred over time, even without the use of thrombolytics. Whether this is because of endogenous thrombolysis or distal clot propagation into the pulmonary vasculature, or both, is unclear. Tissue plasminogen activator may have a role in the resuscitation procedure. In conclusion, without the routine use of TEE during OLT, the incidence of ICT will remain an under‐recognized event. Liver Transpl 21:1280‐1285, 2015. © 2015 AASLD.

Abstract The canonical function of plasminogen activator inhibitor-1 (PAI-1/SERPINE1) is as an inhibitor of urokinase-type plasminogen activator for blood clot maintenance, but it is now also considered a pleiotropic factor that can exert diverse cellular and tumorigenic effects. However, the mechanism controlling its pleiotropic effects is far from being understood. To elucidate the tumorigenic role of PAI-1, we tested the effects of PAI-1 after manipulation of its expression or through the use of a small-molecule inhibitor, tiplaxtinin. Downregulation of PAI-1 significantly reduced cellular proliferation through an inability to progress from the G0–G1 phase of the cell cycle. Accordingly, overexpression of PAI-1 augmented proliferation by encouraging S-phase entry. Biochemically, cell-cycle arrest was associated with the depletion of the G1-phase transition complexes, cyclin D3/cdk4/6 and cyclin E/cdk2, in parallel with the upregulation of the cell-cycle inhibitors p53, p21Cip1/Waf1, and p27Kip1. PAI-1 depletion significantly decreased the tumor size of urothelial T24 and UM-UC-14 xenografts, and overexpression of PAI-1 substantially increased the tumor size of HeLa xenografts. Finally, immunohistochemical analysis of human bladder and cervical tumor tissue microarrays revealed increased expression of PAI-1 in cancerous tissue, specifically in aggressive tumors, supporting the relevance of this molecule in human tumor biology. Implications: Targeting PAI-1 has beneficial antitumoral effects and should be further investigated clinically. Mol Cancer Res; 12(3); 322–34. ©2014 AACR.

Abstract We have previously reported that the protease activity of uPA delays tumor progression in a syngeneic model of breast cancer, and that the inhibitory effects are due to the protease activity of uPA (Merchan et. al, JNCI, 2006: 7; 98(11)). We also reported that changes in the uPA/PAI-1 balance favoring the proteolytic activity of uPA are associated with delayed tumor growth and reduction in lung metastases in vivo (Jing, et al, AACR 2009 meeting, #1124). The aim of this study was to extend the above findings in other in vivo syngeneic cancer models and to characterize the changes in gene expression mediated by uPA overexpression. We generated stably uPA overexpressing murine renal cancer (RENCA) and murine colon cancer (MC-38) cell lines using lentiviral vectors carrying m-uPA and selecting high uPA expressing clones for in vivo studies. uPA protein expression and in vitro growth was similar between the uPA overexpressing and control cancer cells. Similar with our findings in the 4T1 model, mice harboring RENCA tumors overexpressing uPA had reduced tumor growth than controls. Conversely, mice carrying uPA-overexpressing MC-38 tumors had significantly enhanced tumor growth compared to controls. To understand the causes for the opposite in vivo effects of uPA overexpressing RENCA and MC-38 tumors, we first compared uPA's proteolytic activity vs. protein concentration between both cell lines. To our surprise, the uPA proteolytic activity of (uPA overexpressing) MC-38 conditioned medium (CM) was significantly lower (> 15-fold) than that of stable RENCA cell lines even though uPA protein levels were comparable. To assess if the differences in uPA proteolytic activity between MC38 and RENCA transfectants was due to differential endogenous PAI-1 expression, we measured PAI-1 levels in MC38 and RENCA transfectants CM (ELISA). We found that PAI-1 expression in MC 38 was significantly higher (30-fold) than RENCA cells. The above data strongly suggest that in MC-38 tumors, uPA overexpression promoted tumor growth in part due to high endogenous PAI-1 levels. On the other hand, in the RENCA model, uPA overexpression (and low PAI-1 expression) was associated with significantly enhanced proteolytic activity and delayed tumor growth. Gene expression arrays of early murine mammary tumors overexpressing active uPA, showed significant tumor down regulation of several members of the MMP family, which may explain the in vivo antitumor effects. The above data suggest that the pro-or anti tumorigenic/metastatic effects of uPA overexpression depend on its proteolytic activity, and indicate that the status of endogenous tumor PAI-1 may regulate uPA's effects on tumor progression and metastases. The above data may help reconcile contradictory experimental and clinical findings on the role of proteases and protease inhibitors on tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 516.