ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas.

Endometrial carcinoma (EC) is the most frequent among infiltrating tumors of the female genital tract, with myometrial invasion representing an increase in the rate of recurrences and a decrease in survival. We have previously described ETV5 transcription factor associated with myometrial infiltration in human ECs. In this work, we further investigated ETV5 orchestrating downstream effects to confer the tumor the invasive capabilities needed to disseminate in the early stages of EC dissemination. Molecular profiling evidenced ETV5 having a direct role on epithelial-to-mesenchymal transition (EMT). In particular, ETV5 modulated Zeb1 expression and E-Cadherin repression leading to a complete reorganization of cell-cell and cell-substrate contacts. ETV5-promoted EMT resulted in the acquisition of migratory and invasive capabilities in endometrial cell lines. Furthermore, we identified the lipoma-preferred partner protein as a regulatory partner of ETV5, acting as a sensor for extracellular signals promoting tumor invasion. All together, we propose ETV5-transcriptional regulation of the EMT process through a crosstalk with the tumor surrounding microenvironment, as a principal event initiating EC invasion.

Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells.

Scaffold proteins form multiprotein complexes that are central to the regulation of intracellular signaling. The scaffold protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is highly expressed at the plasma membrane of normal biliary epithelial cells and binds epidermal growth factor receptor (EGFR), a tyrosine kinase receptor with oncogenic properties. This study investigated EBP50-EGFR interplay in biliary cancer. We report that in a collection of 106 cholangiocarcinomas, EBP50 was delocalized to the cytoplasm of tumor cells in 66% of the cases. Ectopic expression of EBP50 was correlated with the presence of satellite nodules and with the expression of EGFR, which was at the plasma membrane, implying a loss of interaction with EBP50 in these cases. In vitro, loss of interaction between EBP50 and EGFR was mimicked by EBP50 depletion using a small interfering RNA approach in human biliary carcinoma cells co-expressing the two proteins at their plasma membrane, and in which interaction between EBP50 and EGFR was validated. EBP50 depletion caused an increase in EGFR expression at their surface, and a sustained activation of the receptor and of its downstream effectors (extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3) in both basal and EGF-stimulated conditions. Cells lacking EBP50 showed epithelial-to-mesenchymal transition-associated features, including reduction in E-cadherin and cytokeratin-19 expression, induction of S100A4 and of the E-cadherin transcriptional repressor, Slug, and loss of cell polarity. Accordingly, depletion of EBP50 induced the disruption of adherens junctional complexes, the development of lamellipodia structures and the subsequent acquisition of motility properties. All these phenotypic changes were prevented upon inhibition of EGFR tyrosine kinase by gefitinib. These findings indicate that loss of EBP50 at the plasma membrane in tumor cells may contribute to biliary carcinogenesis through EGFR activation.

Conditional mouse models of cancer.

The development of inducible and conditional technologies allowed us to generate transgenic mouse models that faithfully recapitulate human tumorigenesis. It is possible to control, in time and space, the development of tumors in almost every mouse tissue. The result is that now we have available mouse models for all major human cancers. Novel noninvasive approaches to tumor imaging will enable us to follow tumor development and metastasis in vivo, as well as the effects of candidate therapeutic drugs. Such new generation tumor models, which accurately emulate the disease state in situ, should provide a useful platform with which to experimentally test drugs targeted to specific gene products, or combinations of genes that control rate-limiting steps of tumor development. In this review, we focus on the different mouse models for colon cancer.

Dendritic organization of actin comet tails.

Polymerization of actin filaments is necessary for both protrusion of the leading edge of crawling cells and propulsion of certain intracellular pathogens, and it is sufficient for generating force for bacterial motility in vitro. Motile intracellular pathogens are associated with actin-rich comet tails containing many of the same molecular components present in lamellipodia, and this suggests that these two systems use a similar mechanism for motility. However, available structural evidence suggests that the organization of comet tails differs from that of lamellipodia. Actin filaments in lamellipodia form branched arrays, which are thought to arise by dendritic nucleation mediated by the Arp2/3 complex. In contrast, comet tails have been variously described as consisting of short, randomly oriented filaments, with a higher degree of alignment at the periphery, or as containing long, straight axial filaments with a small number of oblique filaments. Because the assembly of pathogen-associated comet tails has been used as a model system for lamellipodial protrusion, it is important to resolve this apparent discrepancy. Here, using a platinum replica approach, we show that actin filament arrays in comet tails in fact have a dendritic organization with the Arp2/3 complex localizing to Y-junctions as in lamellipodia. Thus, comet tails and lamellipodia appear to share a common dendritic nucleation mechanism for protrusive motility. However, comet tails differ from lamellipodia in that their actin filaments are usually twisted and appear to be under significant torsional stress.

Primary prevention of perinatal impairments in the newborn.

The effects of intrauterine hypoxia on the motorial development of forty infants was studied by synthesizing the findings obtained by a team of obstetricians, neonatologists and physiatrists. The pH of the blood of the examinees was measured during delivery to detect hypoxia. Analyses of the results obtained have shown that the degree of deviation from a normal neurophysiological development is directly proportional to the degree of hypoxia. The findings indicate the importance of the early detection of intrauterine hypoxia.

[Genital infections in adolescence]. / Genitalne infekcije u adolescenciji.

In 126 patients with relapsing cervicitis or abnormal cytologic findings, aged 13-19 years (12.5% were virgins), the most frequently bacteria were Ureaplasma urealyticum (30.2%), Mycoplasma hominis, and Gardnerella vaginalis (14.3%), and Chlamydia trachomatis (9.5%). In patients with abnormal cytologic findings, Ureaplasma urealyticum was isolated most frequently--5 times in group IIIa after Papanicolaou and 4 times in group IIIb, followed by Mycoplasma hominis 3 times in group IIIa and IIIb each. Koilocytes were found twice in groups IIIa and IIIb each.

[Hemorrhage from the digestive tract in neonates]. / Krvarenje iz probavnog trakta novorodencadi.

From 1975 to 1984 there were 28,177 newborns 26,367 of them being born at term. In 96 term delivered newborns, bleeding from the gastrointestinal tract occurred at the rate 0.36% of term delivered newborns and at rate of 0.34% of all newborns in the period observed. A higher frequency of bleeding was observed in male (58.3%) than in female (41.7%) newborns. Hematemesis was found in 67.7% and melena in 12.5% of newborns, while 19.8% showed associated symptoms K-vitamin was not given to newborns. The most frequent hematological causes of bleeding were singled out on the basis of normal coagulation findings. There were neither hemorrhagic amniotic fluid nor fissures on the nipples. Fetal hemoglobin was found in the bloody stool. In these children there were no lesions of the mucosa in the oral cavity. The subconjunctival and petechial bleeding in the face already at birth was observed in 18.75% of children. Most of the bleeding observed (44.79%) occurred 48 hours after birth. In 46.9% of cases, the delivery was protracted and in 75% of cases it was terminated surgically: in 43.8% by vacuum extraction and in 31.2% by cesarean section. The percentage of pregnant women who did not take any drugs during pregnancy was 66.7%. Bleeding stopped after the administration of K vitamin and Dicynon in 70.8% of newborns, while in 17.7% transfusion had to be applied. Not a single child was operated on. In the authors' opinion, bleeding in the newborns observed caused by stress: 75% of them were delivered surgically because of asphyxia.

[Use of vaginoscopy in pediatric and adolescent gynecology]. / Primjena vaginoskopije u djecjoj i adolescentnoj ginekologiji.

The authors present 180 patients examined by the vaginoscope. Their age ranged from 4 to 18 years. The most frequent indications were genital inflammations (51.1%), disorders in the menstrual cycle (40,6%), lesions of the vulva and hymen (1.1%), foreign bodies in the vagina (1.1%), anomalies of the genital organs (1.7%), and abdominal colics (4.4%).