␣-Catenin is essential in cadherin-mediated epithelium development and maintenance of tissues and in cancer progression and metastasis. However, recent studies question the conventional wisdom that ␣-catenin directly bridges the cadherin adhesion complex to the actin cytoskeleton. Therefore, whether ␣-catenin plays a direct role in cadherin-dependent cell adhesion is unknown. Here, single-molecule force spectroscopy measurements in cells depleted of ␣-catenin or expressing the hereditary diffuse gastric cancer associated V832M E-cadherin germ-line missense mutation show that ␣-catenin plays a critical role in cadherin-mediated intercellular recognition and subsequent multibond formation within the first 300 ms of cell contact. At short contact times, ␣-catenin mediates a 30% stronger interaction between apposing E-cadherin molecules than when it cannot bind the E-cadherin-␤-catenin complex. As contact time between cells increases, ␣-catenin is essential for the strengthening of the first intercellular cadherin bond and for the ensuing formation of additional bonds between the cells, all without the intervention of actin. These results suggest that a critical decision to form an adhesion complex between 2 cells occurs within an extremely short time span and at a single-molecule level and identify a previously unappreciated role for ␣-catenin in these processes.cancer ͉ cell adhesion ͉ single-molecule force spectroscopy ͉ actin I ntercellular adhesion depends critically on the cadherin family of transmembrane proteins, which play a central role in the normal development and maintenance of solid tissues and during cancer progression and metastasis (1, 2). The study of early invasive diffuse gastric cancers in carriers of E-cadherin germline mutations demonstrates that its deregulation may also be an initiating event in tumorigenesis (3, 4). When a cell-cell contact is formed, cadherins expressed on neighboring cells interact through their extracellular domain whereas their cytoplasmic domain interacts with the cytoskeleton through the catenin family of cadherin-binding proteins. The basic molecular entity responsible for cell adhesion in epithelial cells is a 1:1:1 complex comprising E-cadherin, ␤-catenin, and ␣-catenin (5). In the intracellular space, the cytoplasmic domain of E-cadherin binds ␤-catenin, which in turn binds ␣-catenin through its N terminus (Fig. 1A). On the extracellular side, adhesive interaction between E-cadherins expressed on apposing cells occurs through a little understood molecular mechanism. Surface force apparatus measurements suggest that this mechanism involves full-length Ecadherin cis-dimers, which bind to other cis-dimers on apposing cells, through a trans-configuration (6, 7). However, experiments using recombinant proteins suggest that E-cadherins dimerize through the EC1 domain of E-cadherin through a site that promotes both lateral and adhesive interactions (8, 9). It has also been reported that formation of cis-or trans-dimers is governed by the presence of Ca 2ϩ (10). Given the...

This study was designed to investigate whether reduced adenosine formation linked to deficits in extracellular ATP hydrolysis by NTPDases contributes to detrusor neuromodulatory changes associated with bladder outlet obstruction in men with benign prostatic hyperplasia (BPH). The kinetics of ATP catabolism and adenosine formation as well as the role of P1 receptor agonists on muscle tension and nerve-evoked [ ) or (2) extracellular adenosine accumulation with dipyridamole or EHNA, as these drugs inhibit adenosine uptake and deamination, respectively. In conclusion, reduced ATP hydrolysis leads to deficient adenosine formation and A 1 receptor-mediated inhibition of cholinergic nerve activity in the obstructed human bladder. Thus, we propose that pharmacological manipulation of endogenous adenosine levels and/or A 1 receptor activation might be useful to control bladder overactivity in BPH patients.

No abstract

Hereditary diffuse gastric cancer (HDGC) is a rare cancer susceptibility syndrome. One third of HDGC syndrome families carry germline mutations of the E-cadherin gene. Owing to the limitation of the current endoscopic screening techniques and since no chemoprevention is yet available, total prophylactic gastrectomy is the only option offered to carriers of inactivating mutations in genetic counseling. In this regard, 30% of the E-cadherin germline mutations reported to date are of the missense type, and since their pathogenic significance is not straightforward, the management of carriers of such mutations is suboptimal. In the absence of definitive clinical evidence, functional in vitro studies together with in silico analysis have been used to infer the pathogenic significance of germline missense mutations. Since most of the HDGC families reported to date are negative for E-cadherin germline mutations, the identification of alternative genes underlying the tumorigenesis of diffuse gastric has become an important target for research.

Bouveret’s syndrome is a rare cause of gastric outlet obstruction. We report a case of a 68-year-old woman admitted with upper digestive obstruction. A few months later, and after several diagnostic tests and clinical surveillance, a cholecystoduodenal fistula was suspected. During exploratory laparotomy, the diagnosis of Bouveret’s syndrome was confirmed and a pyelolithotomy, pyloroplasty and a cholecystectomy were performed. The patient was asymptomatic 7 months after the operation. This syndrome represents only 1% - 3% of all cases of gallstone ileus, being more frequent in women and in the elderly. The presentation is quite nonspecific, but in most cases the symptomatology suggests an upper digestive occlusion. Treatment can be achieved by lithotripsy, but most patients require a surgical approach.