Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett’s associated esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is still associated with poor prognosis, despite modern multi-modal therapies. New molecular markers, which control cell cycle and promote lymph node metastases or tumor growth, may introduce novel target therapies. Dickkopf-1 (DKK1) is a secreted glycoprotein that blocks the oncogenic Wnt/β-catenin signaling and its aberrant expression has been observed in many malignancies, including EAC. In this study, we investigated the biological role of DKK1 in EAC. Analysis of DKK1 and active β-catenin expression in human esophageal tissues confirmed a simultaneous DKK1-overexpression together with aberrant activation of β-catenin signaling in EAC in comparison with Barrett’s and healthy mucosa. To elucidate the molecular role of DKK1, the OE33 adenocarcinoma cells, which were found to overexpress DKK1, were subjected to functional and molecular assays following siRNA-mediated DKK1-knockdown. At the functional level, OE33 cell viability, proliferation, migration and invasion were significantly attenuated by the absence of DKK1. At the molecular level, neither DKK1-knockdown nor application of exogenous recombinant DKK1 were found to alter the baseline β-catenin signaling in OE33 cells. However, DKK1-knockdown significantly abrogated downstream Akt-phosphorylation. On the other hand, the Wnt-agonist, Wnt3a, restored the Akt-phorphorylation in the absence of DKK1, without, however, being able to further stimulate β-catenin transcription. These findings suggest that the β-catenin transcriptional activity in EAC is independent of Wnt3a/DKK1 site-of-action and define an oncogenic function for DKK1 in this type of malignancy via distinct activation of Akt-mediated intracellular pathways and independently of Wnt-axis inhibition. Taken together, DKK1 may present a novel therapeutic target in EAC

Diverse histologic appearances in pulmonary mucinous cystic neoplasia: A case report

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Atrial fibrillation after transhiatal esophagectomy with transcervical endoscopic esophageal mobilization: one institution’s experience

Abstract Background There have been numerous studies regarding atrial fibrillation (AF) associated with cardiac and pulmonary surgery; however, studies looking at esophagectomy and atrial fibrillation are sparse. The goal of this study was to review our institution’s atrial fibrillation rate following esophagectomy in order to better define the incidence and predisposing factors in this patient population. Methods A retrospective chart review of all patients undergoing esophagectomy with transcervical endoscopic mobilization of the esophagus (TEEM) at the Medical College of Wisconsin and Affiliated Hospitals from July 2009 through December 2012. Results Seventy-one patients underwent TEEM esophagectomy during the study period. Of those, 23 (32.4%) patients developed new atrial fibrillation postoperatively. ICU (Intensive Care Unit) length of stay was 7.1 days for those that did not receive amiodarone, compared to 5.3 days for those that did receive amiodarone (p < 0.025). Those that went into AF spent on average 9.3 days in the ICU compared to 4.7 days for their counterparts that did not go into AF (p < 0.006). Total length of stay was not statistically different between populations [15.1 +/− 11.3 days compared to 13.5 +/− 9.4 days for those who did not go into AF (p < 0.281)]. Receiving preoperative amiodarone was found to reduce the overall incidence of AF. There was a trend towards decreased risk of going into AF in those who received preoperative amiodarone with an adjusted hazard ratio of 0.555 (p = 0.057). Conclusion Similar to data reported in previous literature, postoperative atrial fibrillation was found to increase ICU length of stay as well as overall length of hospital stay. Preoperative amiodarone administration displayed a trend toward decreasing the rates of atrial fibrillation in patients undergoing TEEM

Atrial fibrillation after transhiatal esophagectomy with transcervical endoscopic esophageal mobilization: one institution\u27s experience

BACKGROUND: There have been numerous studies regarding atrial fibrillation (AF) associated with cardiac and pulmonary surgery; however, studies looking at esophagectomy and atrial fibrillation are sparse. The goal of this study was to review our institution\u27s atrial fibrillation rate following esophagectomy in order to better define the incidence and predisposing factors in this patient population. METHODS: A retrospective chart review of all patients undergoing esophagectomy with transcervical endoscopic mobilization of the esophagus (TEEM) at the Medical College of Wisconsin and Affiliated Hospitals from July 2009 through December 2012. RESULTS: Seventy-one patients underwent TEEM esophagectomy during the study period. Of those, 23 (32.4%) patients developed new atrial fibrillation postoperatively. ICU (Intensive Care Unit) length of stay was 7.1 days for those that did not receive amiodarone, compared to 5.3 days for those that did receive amiodarone (p \u3c 0.025). Those that went into AF spent on average 9.3 days in the ICU compared to 4.7 days for their counterparts that did not go into AF (p \u3c 0.006). Total length of stay was not statistically different between populations [15.1 +/- 11.3 days compared to 13.5 +/- 9.4 days for those who did not go into AF (p \u3c 0.281)]. Receiving preoperative amiodarone was found to reduce the overall incidence of AF. There was a trend towards decreased risk of going into AF in those who received preoperative amiodarone with an adjusted hazard ratio of 0.555 (p = 0.057). CONCLUSION: Similar to data reported in previous literature, postoperative atrial fibrillation was found to increase ICU length of stay as well as overall length of hospital stay. Preoperative amiodarone administration displayed a trend toward decreasing the rates of atrial fibrillation in patients undergoing TEEM

Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett’s associated esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is still associated with poor prognosis, despite modern multi-modal therapies. New molecular markers, which control cell cycle and promote lymph node metastases or tumor growth, may introduce novel target therapies. Dickkopf-1 (DKK1) is a secreted glycoprotein that blocks the oncogenic Wnt/β-catenin signaling and its aberrant expression has been observed in many malignancies, including EAC. In this study, we investigated the biological role of DKK1 in EAC. Analysis of DKK1 and active β-catenin expression in human esophageal tissues confirmed a simultaneous DKK1-overexpression together with aberrant activation of β-catenin signaling in EAC in comparison with Barrett’s and healthy mucosa. To elucidate the molecular role of DKK1, the OE33 adenocarcinoma cells, which were found to overexpress DKK1, were subjected to functional and molecular assays following siRNA-mediated DKK1-knockdown. At the functional level, OE33 cell viability, proliferation, migration and invasion were significantly attenuated by the absence of DKK1. At the molecular level, neither DKK1-knockdown nor application of exogenous recombinant DKK1 were found to alter the baseline β-catenin signaling in OE33 cells. However, DKK1-knockdown significantly abrogated downstream Akt-phosphorylation. On the other hand, the Wnt-agonist, Wnt3a, restored the Akt-phorphorylation in the absence of DKK1, without, however, being able to further stimulate β-catenin transcription. These findings suggest that the β-catenin transcriptional activity in EAC is independent of Wnt3a/DKK1 site-of-action and define an oncogenic function for DKK1 in this type of malignancy via distinct activation of Akt-mediated intracellular pathways and independently of Wnt-axis inhibition. Taken together, DKK1 may present a novel therapeutic target in EAC

Functional and oximetric assessment of patients after lung reduction surgery

AbstractObjective: The goal of this study was to clarify the issue of functional oxygen requirement by regimented exercise oximetry in patients undergoing lung reduction surgery.Methods: Thirty-seven patients underwent lung reduction surgery and were followed up for at least 3 months. Patients routinely completed a 6-week program of cardiopulmonary rehabilitation. Preoperative and postoperative spirometry, dyspnea scores, 6-minute walk distances, respiratory mechanics, and exercise oximetry were recorded.Results: After the operation, patients had a 37% increase in forced vital capacity and a 59% increase in forced expiratory volume in 1 second. Six-minute walk distance increased from 913 ± 310 feet before the lung reduction operation to 1202 ± 274 feet 6 months after the operation (p < 0.001). Maximal inspiratory and expiratory pressures were significantly increased in 16 patients after lung reduction surgery. Perceived dyspnea was significantly improved. Exercise pulse oximetry demonstrated that 83% of patients met American Thoracic Society criteria for supplemental oxygen use before lung reduction surgery. After the operation, 70% of patients continued to meet American Thoracic Society criteria for supplemental oxygen use. Notably, 10 patients with exertional desaturation while breathing room air discontinued supplemental oxygen use because of a reduction in dyspnea.Conclusions: These findings demonstrate significant subjective and functional improvements related to lung reduction surgery. Exercise-induced hypoxia was not reversed by lung reduction surgery. Discontinuance of supplemental oxygen use owing to reduction in dyspnea and improved physical performance may not be warranted in lieu of continued exertional desaturation. (J Thorac Cardiovasc Surg 1997;113:675-82