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Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression is deregulated in many cancers. Genetic and biochemical approaches coupled with functional assays in cultured cells were used to explore the consequences of Nrf2 repression. Nrf2 suppression by Keap1-directed ubiquitylation or the expression of independent short hairpin RNA (shRNA)/siRNA sequences enhanced cellular levels of reactive oxygen species, Smad-dependent tumor cell motility and growth in soft agar. Loss of Nrf2 was accompanied by concomitant Smad linker region/C-terminus phosphorylation, induction of the E-cadherin transcriptional repressor Slug and suppression of the cell-cell adhesion protein E-cadherin. Ectopic expression of the wildtype but not dominant-negative Nrf2 suppressed the activity of a synthetic transforming growth factor-beta1-responsive CAGA-directed luciferase reporter. shRNA knock-down of Nrf2 enhanced the activity of the synthetic CAGA reporter, as well as the expression of the endogenous Smad target gene plasminogen activator inhibitor-1. Finally, we found that Nrf2/Smad3/Smad4 formed an immunoprecipitable nuclear complex. Thus, loss of Nrf2 increased R-Smad phosphorylation and R-Smad signaling, supporting the hypothesis that loss of Nrf2 in an oncogenic context-dependent manner can enhance cellular plasticity and motility, in part by using transforming growth factor-beta/Smad signaling.

The rate and direction of neurite growth have been shown in a number of studies to be determined by the distribution of adhesive sites on the growth cone. Recent evidence showing that the application of extrinsic electric fields can redistribute membrane molecules and alter both the rate and direction of neurite growth have raised the question whether endogenous electric fields might be produced by steady currents in growth cones. To investigate this question, we have devised a novel circularly vibrating microprobe capable of measuring current densities in the range of 5 nA/cm2 (near the theorectical limit of sensitivity), with a spatial resolution of 2 micron. The design of this device and the development of a novel algorithm for computing current vectors on-line is described. Using this probe we have found that cultured goldfish retinal ganglion cell growth cones generate steady inward currents at their tips. The measured currents, in the range of 10-100 nA/cm2, appear to flow into the filopodia at their tips and back outward near the junctures of the filopodia and the growth cone. The currents appear to be produced only during active growth. Ion substitution experiments support the conclusion that the majority of this current is carried by Ca2+ ions, which we postulate flow through a population of activated voltage-sensitive Ca2+ channels located on the filopodial tips. Calculation of the transmembrane current density (4 X 10(-6) nA/cm2) leads to an estimate of channel density (10 channels/micron2) in close agreement with the measured density of Ca2+ channels in other systems. The assumption that calcium channel proteins are conveyed to nerve terminals by active transport, whereas sodium channel proteins are conveyed passively by a slower somatofugal diffusion process [Strichartz et al, 1984], would explain why developing neurons tend to display Ca2+-sensitive electrogenesis at their growing tips, and Na+-sensitive action potentials later in development. In order to gain some insight into the possible role of these steady growth currents, we estimated the membrane depolarization and axial voltage gradient they produce. It is likely that the currents produce sufficient membrane depolarization (approximately equal to 4 mV) to cause autogenous activation of ion channel permeabilities. Similarly, the axial voltage gradient (approximately equal to 4 mV/cm) would be expected to move intracytoplasmic vesicles by electrophoresis at a rate (20-40 microns/hr) very close to that at which the filopodia are observed to grow.(ABSTRACT TRUNCATED AT 400 WORDS)

Attention if directed to explanation of the endothoracic fascia in several operations described by pioneer thoracic surgeons. The extrapleural plane was extensively and successfully employed in a number of these operations. Re-emphasis of its use seems advisable even today when open thoracotomy is the rule rather than the exception. In selected cases the extrapleural plane can and should be dissected in the aggressive management of relatively localized empyema, with complete enucleation of the infected sac (empyemectomy). This operation can reduce morbidity and prevent prolonged external drainage. The surgical advantage of the extrapleural plane is also apparent in complete parietal pleurectomy for effective palliation of repeated fluid formation. Other instances of intrathoracic disease are mentioned for which dissection in the extrapleural plane can be a safe and time-saving method of treatment. The anatomic considerations relating to the rapid, safe, and effective dissection of the major hilar vessels are also emphasized.

Because of frequent failures in nonoperative therapy, we have adopted early surgical drainage of the pericardium in the management of uremic pericardial effusion. This series presents the longest follow-up period of any group of patients with uremic pericardial effusion treated by surgical drainage. There have been no intraoperative deaths and no recurrences. The total hospital mortality rate was 8.3 per cent and the late mortality rate over a 72 month period was 25 per cent. Internal pericardiostomy drainage is a simple yet effective surgical solution to the life-threatening problem of uremic pericardial effusion.

Traumatic interruption of the phrenic nerve causing diaphragmatic paralysis occurs much more commonly than realized. Patients present with symptoms referable to the respiratory, gastrointestinal, or cardiovascular systems as a result of anatomic displacement of the respective organ (eventration). Symptoms often occur shortly after the injury but may be delayed for many years; consequently, prolonged follow-up of these patients is essential. If patients are symptomatic after trauma, judicious observation is dictated, since many will experience gradual return of normal diaphragmatic function over the succeeding six to twelve months. In those who remain significantly symptomatic, thoracotomy and imbrication of the eventration is a simple and effective surgical procedure.

The following case report describes a previously unreported cause of extrapleural empyema thoracis, namely, direct extension of a submandibular abscess, which occurred following dental extraction and presented initially as Ludwig's angina.

This review considers all possible modes of esophageal injury, based on a schema originally published in 1954 and more recently modified in 1970. For each category of injury there are detailed discussions of diagnosis and treatment. The best available knowledge of present-day modalities has been based on a survey of the literature for the past decade. When diverse methods of treatment were encountered, we have made comments consistent with our personal experience, when appropriate. The medicolegal literature contains a number of references to esophaegeal injury. Certain excerpts dealing with several types of potential actions are extracted: (1) suits to recover damages for esophageal perforation in which negligent endoscopy was claimed; (2) suits following endoscopic accidents in which lack of informed consent was claimed; and (3) suits for professional liability based on misdiagnosis, delayed diagnosis, or wrong treatment of esophaegeal perforation.

The following case report demonstrates the occasional necessity for staged thoracic surgical intervention in the management of a clinical condition commonly associated with high mortality: overwhelming pseudomonas pulmonary infection and septic shock. Intervention included the use of emergency wide-open drainage of gangrene of the lung and empyema, followed by sequential, interval lobectomy.

Management of septic pulmonary embolism now suggests a predictability of the clinical course which often allows an early decision regarding the need for definitive thoracotomy. Sixty patients have been treated within the past 5 years. Antibiotics were employed in all patients, administered whenever possible according to cultures. In 12 patients thoracotomy was required. This involved decortication and varying amounts of pulmonary resection from wedge excision to pneumonectomy. Early appreciation of septic pulmonary embolism and prompt thoracotomy can frequently obviate the need for tardy open drainage procedures with consequent prolonged recovery. Sources of emboli must be controlled. Interruption of the inferior vena cava, vein excision, aggressive control of peripheral abscesses, and excision of the tricuspid valve may be required. Reliance on antiocagulants alone to control emboli is dangerous, and proper surgical intervention and antibiotic therapy reduce the need for long-term anticoagulation.

Extrapleural pneumothorax is a valuable method of treatment of pulmonary tuberculosis. However, it is applicable in a relatively few cases which meet stringent criteria. Moreover, it entails the absolute necessity for continuity of care following operation. Within these limitations, the procedure will control tuberculosis in a small but significant number of patients.

In this, a preliminary report, the advantages and disadvantages of upper lobe lobectomy and concomitant thoracoplasty in tuberculosis have been summarized. There has been no undue increase in the operative hazard, there have been no complications, and the immediate results have been entirely satisfactory.Twenty-six patients were subjected to a combined operation (17 upper lobectomy-thoracoplasty and nine pneumonectomy-thoracoplasty) with one postoperative death. Indications for primary lobectomy have been discussed. The technique of resection and concomitant thoracoplasty has been briefly described.

A new working classification of esophageal injuries and their complications is presented. The immediate recognition of perforations and ruptures is of prime importance. In some cases the rents heal with conservative therapy. It is emphasized, however, that early surgical exposure and direct repair will result nearly always in uncomplicated cure without the development of prolonged, costly, debilitating and sometimes fatal complications.