Loss of TAK1 increases cell traction force in a ROS-dependent manner to drive epithelial-mesenchymal transition of cancer cells.

Epithelial-mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGFß-SMAD signaling pathway as an inductor of EMT in many tumor types is well recognized. However, the role of non-canonical TGFß-TAK1 signaling in EMT remains unclear. Herein, we show that TAK1 deficiency drives metastatic skin squamous cell carcinoma earlier into EMT that is conditional on the elevated cellular ROS level. The expression of TAK1 is consistently reduced in invasive squamous cell carcinoma biopsies. Tumors derived from TAK1-deficient cells also exhibited pronounced invasive morphology. TAK1-deficient cancer cells adopt a more mesenchymal morphology characterized by higher number of focal adhesions, increase surface expression of integrin α5ß1 and active Rac1. Notably, these mutant cells exert an increased cell traction force, an early cellular response during TGFß1-induced EMT. The mRNA level of ZEB1 and SNAIL, transcription factors associated with mesenchymal phenotype is also upregulated in TAK1-deficient cancer cells compared with control cancer cells. We further show that TAK1 modulates Rac1 and RhoA GTPases activities via a redox-dependent downregulation of RhoA by Rac1, which involves the oxidative modification of low-molecular weight protein tyrosine phosphatase. Importantly, the treatment of TAK1-deficient cancer cells with Y27632, a selective inhibitor of Rho-associated protein kinase and antioxidant N-acetylcysteine augment and hinders EMT, respectively. Our findings suggest that a dysregulated balance in the activation of TGFß-TAK1 and TGFß-SMAD pathways is pivotal for TGFß1-induced EMT. Thus, TAK1 deficiency in metastatic cancer cells increases integrin:Rac-induced ROS, which negatively regulated Rho by LMW-PTP to accelerate EMT.

TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis.

Dysregulated reactive oxygen species (ROS) generation contributes to many human pathologies, including cancer and diabetes. During normal wound repair, inflammation-induced ROS production must be tightly controlled, but the mechanisms reining their generation remain unclear. Herein, we show that transforming growth factor ß-activated kinase 1 (TAK1) directly regulates stem cell factor (SCF) expression, which activates the protein kinase B (PKB)α pro-survival pathway in a cell-autonomous manner to protect keratinocytes from ROS-mediated cell death. TAK1 is a pivotal inflammatory mediator whose expression was transiently elevated during wound healing, paralleling the ROS production profile. TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-α treatment and was associated with elevated ROS level as analyzed by FACS. Using organotypic skin co-culture and comparative growth factor array analysis, we revealed a cell-autonomous mechanism that involved the SCF/c-Kit/PKBα signaling cascade. Ectopic expression of TAK1 or treatment with exogenous recombinant SCF restored the increased ROS production and apoptotic cell death in TAK1-deficient keratinocytes. Conversely, normal keratinocytes treated with various inhibitors targeting the SCF/c-Kit/PKBα pathway exhibited increased ROS production and TNF-α- or anoikis-induced apoptosis. Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology.

Diagnosis and surgical treatment of "H-type" tracheoesophageal fistulas.

Four cases of H-type tracheoesophageal fistula are reported. The patients all had chronic aspiration from the esophagus. Although serious symptoms were present in all, definitive diagnoses were not made until the patients had reached 1, 6, 12, and 50 years of age, because ordinary radiologic methods failed to establish the diagnosis. The angulation of the fistula usually prevents contrast medium in the esophagus from entering the trachea, especially with the subject upright. On the other hand, air easily passes from the trachea to the esophagus, eventually producing megaesophagus which may be confused with the picture of achalasia. An ill-advised Heller esophagomyotomy was done on 1 patient. All 4 patients eventually had successful closure of the fistulas. Three operations were by the transthoracic route, and 1 high fistula in an infant was closed through a cervical approach.

Late results of atrial septal defect repair in adults.

Repair of secundum atrial septal defects in 75 patients older than age 40 years was associated with a good long-term result, from five to 21 years postoperatively, in 89% of patients who were class I and II preoperatively and in 86% of those in normal sinus rhythm preoperatively. Functional class III or IV, atrial fibrillation, a higher pulmonary artery mean pressure and higher pulmonary vascular resistance affected the prognosis adversely. Repair of atrial septal defect in adults did not reverse existing atrial fibrillation and did not protect against the onset of new atrial fibrillation.

Symptomatic anomalies of the aortic arch.

Twenty-eight patients with anomalies of the aortic arch producing compression of the trachea and the esophagus have undergone surgical correction at this hospital since 1949. Of the vascular rings encountered, 15 had a double aortic arch and eight, a right aortic arch with a constricting ligamentum arteriosum. Five had an aberrant right subclavian artery passing posterior to the esophagus producing dysphagia. The patients with the double aortic arch were all infants. Two of the patients with a right arch and constricting ligamentum arteriosum and one patient with a retroesophageal subclavian artery were adults. Stridor from pressure on the trachea was the common symptom in the infants. The diagnosis was confirmed by esophagograms; aortography was less helpful. The surgical approach was the same for all of the anomalies, through a posterolateral incision in the left fourth interspace. For the double arches, the smaller limb, usually the anterior, was divided. Division of the ligament relieved the constriction of the right aortic arches, and the anomalous right subclavian artery was divided near the aorta. There were no hospital deaths, but one infant with a double aortic arch operated upon at the age of two weeks and with a tracheostomy died at home seven months later.

Mitral valve--the third time around.

Twenty-eight patients have undergone three operations on the mitral valve during 1958-1977. The first operation was closed mitral commissurotomy in 27 and open commissurotomy in one. After an average interval of 5.7 years, the 28 patients underwent a second operation. Operative procedures were: closed mitral commissurotomy in four, open commissurotomy in 14, and valve replacement in 10. After an average interval of 7.4 years, the third mitral valve operation was undertaken for congestive heart failure due to primary disease in 17 patients, prosthetic valve dysfunction in 10, and angina pectoris in one. At this time two patients were class II (New York Heart Association), 14 were class III, and 12 were class IV. Four died at 24 to 48 hours postoperatively, for a mortality rate of 14%. Analysis of risk factors revealed a significantly lower cardiac index (1.12 L/min/m2 +/- 0.35 SD) in those patients dying in the hospital compared to the cardiac index (2.73 L/min/m2 +/- 1.29 SD) of survivors. Deaths of patients undergoing a third operation on the mitral valve were related to poor ventricular function and not to previous surgery.

A safe technique for closure of the recurrent patent ductus arteriosus.

In an early series of 73 operations for patent ductus arteriosus, closure was by the triple ligation method. Over a short period, recurrence of patency was observed in 2 cases and after that the technique of division and suture rather than ligation became standard. For closure of the recurrent ductus, a modification of the usual technique is necessary to minimize danger of injury to the recurrent nerve and the great vessels. A safe method was devised which involves an intrapericardial approach to the superior aspect of the ductus and dissection inferiorly which avoids denudation of the aorta. This technique was used with satisfaction in 6 cases of recurrent patent ductus arteriosus.

Fatal air embolism during thoracotomy for gunshot injury to the lung. Report of a case.

Fatal coronary air embolism occurred during thoracotomy in a patient with a gunshot wound involving the hilum of the right lung. Embolism was observed during a second period of failure of heart action. Evidently, air entered the pulmonary veins from the bronchus, which was receiving positive-pressure ventilation. The literature contains reports of only 3 similar cases, but we suspect that air embolism may be responsible for death and morbidity in additional cases in which accidental or iatrogenic lung trauma has produced a pathway between the bronchial tree and the pulmonary veins.

Recurrent ulcer of the thoracic stomach penetrating the heart. Report of a case and review of the literature.

Recurrent and severe gastrointestinal bleeding caused the death of a 67-year-old man who had had resection of carcinoma of the cardiac end of the stomach. The hemorrhage was eventually found to be due to perforation of the wall of the left ventricle by a benign ulcer in the region of the esophagogastric anastomosis. At first, resection of the ulcer appeared to be successful, but recurrence of the penetrating ulcer caused fatal hemorrhage 4 1/2 months later. In our review of the literature, we found only one other instance in which an ulcer on an anastomosis perforated the heart. There were reports of 24 other cases of benign ulcers of the stomach or esophogus which penetrated the heart.