COVID-19 outbreaks in hospital workers during the first COVID-19 wave.

BACKGROUND: Health care workers (HCWs) are on the frontline, playing a crucial role in the prevention of infection and treatment of patients. AIMS: This study was aimed to evaluate the prevalence of hospital-acquired coronavirus disease 2019 (COVID-19) infection at work and related factors at the University Hospital of Trieste workers exposed to COVID-19 patients. METHODS: From March 1 to May 31, of 4216 employees, 963 were in contact with COVID-19 patients or colleagues and were followed up. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal swabs was determined every 3 days, by RT-PCR. RESULTS: During the follow-up period, 193 workers were positive for COVID-19 (5%), and 165 of these (86%) were symptomatic. We identified five major cluster outbreaks of COVID-19 infection in Trieste Hospitals, four of which occurred before the implementation of universal masking for HCWs and patients (1-14 March 2020). COVID-19 infection was significantly higher in high-risk ward workers (Infectious Diseases, and Geriatric and Emergency Medicine, odds ratio [OR] 13.4; 95% confidence interval [CI] 5.8-31), in subjects with symptoms (OR 5.4; 95% CI 2.9-10) and in those with contacts with COVID-19 patients and colleagues (OR 2.23; 95% CI 1.01-4.9). CONCLUSIONS: Hospital workers were commonly infected due to contact with COVID-19 patients and colleagues, mainly in the first 15 days of the pandemic, before the implementation of universal mask wearing of HCWs and patients. Repetitive testing and follow-up permitted the identification of COVID-19 cases before symptom onset, obtaining better infection prevention and control.

Differences and similarities between arrhythmogenic right ventricular cardiomyopathy and athlete's heart adaptations.

BACKGROUND: Regular intensive physical activity is associated with non-pathological changes in cardiac morphology. Differential diagnosis with arrhythmogenic right ventricular cardiomyopathy (ARVC) constitutes a frequent problem, especially in athletes showing ventricular arrhythmias with left bundle branch block morphology. AIM OF THE STUDY: To assess the different clinical and non-invasive instrumental features of the subjects affected by ARVC and by athletes. METHODS: Three groups of subjects (40 ARVC patients, 40 athletes and 40 controls, mean age 27 (9) years) were examined with family and personal history, physical examination, 12-lead ECG, 24-h ECG, signal-averaged ECG and 2-D and Doppler echocardiography. RESULTS: 12-Lead ECG was abnormal in 62% of ARVC patients versus 7.5% of athletes and 2.5% of controls (p<0.0001). Ventricular arrhythmias and late potentials were present in 70% and 55% of ARVC subjects, respectively (vs 5% of athletes and 7.5% of controls, p<0.0001). Left ventricular parietal wall thickness and left ventricular end-diastolic diameters were significantly higher in athletes. Both athletes and ARVC patients presented a right ventricular (RV) enlargement compared with controls. Moreover, RV outflow tract, measured on parasternal long axis and at the level of aortic root, was significantly larger in ARVC patients (33.6 (4.7) mm vs 29.1 (3.4) mm and 35.6 (6.8) mm vs 30.1 (2.9) mm; p<0.0001), and RV fractional shortening and ejection fraction were significantly lower in ARVC patients compared with athletes (40 (7.9)% vs 44 (10)%; p=0.05 and 52.9 (8)% vs 59.9 (4.5)%; p<0.0001). A thickened moderator band was found to be present in similar percentage in ARVC patients and athletes. CONCLUSIONS: An accurate clinical and instrumental non-invasive evaluation including echocardiography as imaging technique allows to distinguish RV alterations typical of ARVC from those detected in athletes as a consequence of intensive physical activity.

[Risks of repetitive movements in health personnel]. / Rischi da movimenti ripetitivi nel personale sanitario.

To date, scant attention has been devoted to the occupational risk related to repetitive movements in health personnel. Using three database, PubMed, Scopus, and EMBASE, we found 57 papers on this topic, and on possibly related upper limb symptoms and diseases. In these studies, evaluation of the risk, e.g. using the methods currently applied in industry, are lacking. Although in several studies data on the prevalence of upper limb symptoms and disorders are presented, a comparison of results is difficult as different methods were applied. Furthermore, a comparison with adequate controls is frequently lacking, and/or correlation with the risk was not studied. Despite these limitations, an overall evaluation of the results shows that in health personnel the prevalence of upper limb symptoms/disorders is generally high. Highest prevalences were observed for the neck, shoulder, wrist/hand symptoms and for Carpal Tunnel Syndrome (CTS) in dental personnel, for symptoms to the neck, shoulder and wrist/hand in sonographers, and to the neck, shoulder, elbow, and, especially, wrist/hand in laboratory technicians using manual pipettes. In the nursing personnel highly variable prevalences were observed; this is possibly due to the variability of the tasks performed by this occupational group. Repetitive movements of upper limb are a known risk factor for symptoms to the neck, shoulder, elbow, and wrist/hand, and some disorders, as CTS: the high prevalences observed in health workers may be related to this risk. Nevertheless, other factors such as effort, posture and precision work may play an important role too. As a conclusion, available data are insufficient for an adequate evaluation of the occupational risk related to repetitive movements in health workers.

Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland.

The p53 gene was analyzed in tumor specimens obtained from 52 patients with various types of carcinoma of the thyroid gland by a combined molecular and immunocytochemical approach. The histologic types included 37 well-differentiated papillary and follicular carcinomas, 8 poorly differentiated, and 7 undifferentiated carcinomas. The p53 gene was shown to be unaffected in all differentiated tumors by single-strand conformation polymorphism analysis. However, in two out of eight (25%) of poorly differentiated carcinomas and five out of seven (71%) undifferentiated carcinomas, p53 mutations were identified and subsequently characterized by DNA sequencing. One undifferentiated carcinoma displayed two areas with varying degrees of differentiation. The comparative analysis of the p53 gene, in both the more and the less differentiated area of this tumor, clearly showed that the p53 mutation was confined to the latter component of the tumor specimen. These results indicate that mutations of the p53 gene are associated with the most aggressive histologic types of thyroid tumors, such as the undifferentiated carcinoma and, to a certain extent, the poorly differentiated carcinoma, and that the alterations of this gene represent a late genetic event in human thyroid carcinogenesis.

Stimulation of the platelet-derived growth factor beta receptor signaling pathway activates protein kinase C-delta.

The murine myeloid progenitor cell line 32D was recently shown to undergo monocytic differentiation when protein kinase C-delta (PKC-delta) was overexpressed and activated by 12-O-tetradecanoylphorbol-13-acetate (TPA) (H. Mischak, J.H. Pierce, J. Goodnight, M.G. Kazanietz, P.M. Blumberg, and J.F. Mushinski, J. Biol. Chem. 268:20110-20115, 1993). Tyrosine phosphorylation of PKC-delta occurred when PKC-delta-transfected 32D cells were stimulated by TPA (W. Li, H. Mischak, J.-C. Yu, L.-M. Wang, J.F. Mushinski, M.A. Heidaran, and J.H. Pierce, J. Biol. Chem. 269:2349-2352, 1994). In order to elucidate the role played by PKC-delta in response to activation of a receptor tyrosine kinase, we transfected platelet-derived growth factor beta receptor (PDGF-beta R) alone (32D/PDGF-beta R) or together with PKC-delta (32D/PDGF-beta R/PKC-delta) into 32D cells. NIH 3T3 cells which endogenously express both PDGF-alpha R and PDGF-beta R were also transfected with PKC-delta (NIH 3T3/PKC-delta). Like TPA treatment, PDGF-BB stimulation caused striking phosphorylation of PKC-delta in vivo and translocation of some PKC-delta from the cytosol fraction to the membrane fraction in both cell systems. Some of the phosphorylation induced by PDGF-BB treatment was found to be on a tyrosine residue(s). Tyrosine-phosphorylated PKC-delta was observed only for the membrane fraction after stimulation with PDGF-BB or TPA. The enzymatic activity of PKC-delta in the membrane fraction also increased after stimulation with TPA or PDGF, providing a positive correlation between PKC-delta tyrosine phosphorylation and its activation. Overnight treatment of 32D/PDGF-beta R/PKC-delta cells with PDGF-BB induced monocytic differentiation as judged by an increase in expression of cell surface macrophage differentiation markers. PDGF-BB had much weaker effects on 32D/PDGF-beta R cell differentiation, suggesting that increased PKC-delta expression enhanced monocytic differentiation. These results indicate that PKC-delta is a downstream molecule in the PDGFR signaling pathway and may play a pivotal role in PDGF-beta R-mediated cell differentiation.

[Freedom from smoking for health care workers. A project from Trieste]. / Operatori della sanità liberi dal fumo. Attivazione di un progetto in Provincia di Trieste.

A tree years interventional study to modify smoking habits in health workers in Trieste province was planed in the collaboration of occupational health unit and Tobacco's Dependence Study Center. The aim of this paper is refer about preliminary data of the project started in 2007 regarding smoking habits in health workers of the Azienda per i Servizi Sanitari n.1 "Triestina" (ASS1) and the Azienda Ospedaliera Universitaria Ospedali Riuniti di Trieste (AOUTS). The project consist of several actions. i) information about risks and opportunities of project; ii) pursuance of the law 51 L 3/2003; iii) Occupational Health Unit and Tobacco's Dependence Study Center collaboration; iv) follow-up of the subjects that choose the disaccustom program. During occupational medical surveillance we collected the data related to 492 workers, 37% of the cases were smokers (180). The results of test of dependence to smoke (test di Fagestrom) showed an high dependence in 19% and an high motivation to stop smoke (test di Richmond) in 39% of the smokers. More than fifty percent of this subjects gave their adhesion to the disaccustom program.

Induction of WAF1/CIP1 by a p53-independent pathway.

The p53-inducible gene WAF1/CIP1 encodes a M(r) 21,000 protein (p21) that has been shown to arrest cell growth by inhibition of cyclin-dependent kinases. Induction of WAF1/CIP1 in cells undergoing p53-dependent G1 arrest or apoptosis supports the idea that WAF1/CIP1 is a critical downstream effector of p53. In the present study, we used embryonic fibroblasts from p53 "knock-out" mice to demonstrate p53-independent induction of WAF1/CIP1. We show that serum or individual growth factors such as platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor but not insulin are able to induce WAF1/CIP1 in quiescent p53-deficient cells as well as in normal cells. The kinetics of this transient induction, which is enhanced by cycloheximide, demonstrates that WAF1/CIP1 is an immediate-early gene the transcript of which reaches a peak at approximately 2 h following serum or growth factor stimulation. On the other hand, DNA damage elicited by gamma-irradiation induces WAF1/CIP1 in normal human and mouse fibroblasts but does not affect WAF1/CIP1 expression in p53-deficient cells. These results suggest the existence of two separate pathways for the induction of WAF1/CIP1, a p53-dependent one activated by DNA damage and a p53-independent one activated by mitogens at the entry into the cell cycle. The possible function of p21 at this early stage is discussed.

A single nucleotide substitution at codon 31 (Ser/Arg) defines a polymorphism in a highly conserved region of the p53-inducible gene WAF1/CIP1.

The recently discovered WAF1/CIP1 gene is a mediator of p53 tumor suppressor activity. To analyse WAF1/CIP1 for possible mutations, polymerase chain reaction (PCR) amplified cDNAs from several tumor cell lines were cloned and sequenced. A single point mutation which changes codon 31 from AGC to AGA (Ser to Arg) was found. This change resulted in the loss of a Bpu1102I and gain of an Esp3I restriction site, allowing for rapid screening of this mutation in human DNAs. Analysis of genomic DNAs from 50 randomly selected individuals revealed that this base pair substitution represents a polymorphism with an allelic frequency of 0.14. Transfection studies demonstrated that the expression of the Arg allele of WAF1/CIP1 was not associated with loss of tumor suppressor activity. Moreover, screening of 22 tumor DNA samples revealed no association between the tumor phenotype and the Arg allele of WAF1/CIP1 (two out of 22 tumor DNAs contained the Arg31 allele). This polymorphism will be a useful molecular marker in the analysis of loss of heterozygosity in human cancers, and further studies using a larger panel of tumors may reveal an association between this polymorphism and specific types of cancer.

Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists.

Mutations in the genes encoding for Met, Ret and Kit receptor tyrosine kinases invariably result in increased kinase activity and in the acquisition of transforming potential. However, the requirement of receptor ligands for the transformation process is still unclear. We have investigated the role of hepatocyte growth factor (HGF), the high-affinity ligand for Met, in mutant Met-mediated cell transformation. We provide evidence that the transforming potential displayed by mutant forms of Met found in human cancer is not only sensitive but entirely dependent on the presence of HGF, by showing that mutant Met transforms NIH3T3 fibroblasts, which produce endogenous HGF, but is not able to transform epithelial cells, unless exogenous HGF is supplied. Accordingly, mutant Met-induced transformation of NIH3T3 cells can be inhibited by HGF antagonists and increased by HGF stimulation. We also show that an engineered Met receptor which contains an oncogenic mutation but is impaired in its ability to bind HGF completely loses its transforming activity, which can be rescued by causing receptor dimerization using a monoclonal antibody. These results indicate that point mutations resulting in Met kinase activation are necessary but not sufficient to cause cell transformation, the latter being dependent on ligand-induced receptor dimerization. They also suggest that mutant Met-driven tumour growth depends on the availability and tissue distribution of active HGF, and provide proof-of-concept for the treatment of mutant-Met related pathologies by HGF-antagonizing drugs.

Inhibition of oncogene-mediated transformation by ectopic expression of p21Waf1 in NIH3T3 cells.

The p53-regulated p21Waf1 protein is a universal inhibitor of cyclin-dependent kinases (CDKs). To study the potential tumor-suppressive properties of CDK inhibitors, the ability of p21Waf1 to interfere with oncogene-mediated cellular transformation was analysed in the NIH3T3 cell system. Cotransfection of waf1 together with activated ras or several other oncogenes into NIH3T3 cells potently inhibited the formation of transformed foci in a dose-dependent manner. Expression of the CDK-binding N-terminal half of p21Waf1 (N-p21Waf1) was necessary and sufficient to inhibit Ras-induced focus formation. In contrast, expression of the C-terminal domain (C-p21Waf1) had no effect on Ras-induced focus formation. Immunofluorescence analysis revealed that ectopically expressed p21Waf1 and C-p21Waf1 were localized in the nucleus, while N-p21Waf1 was found in the cytoplasm, with the tendency to accumulate around the nuclear membrane. Surprisingly, stable NIH3T3 transfectants expressing ectopic p21Waf1 grew at the same rate and displayed similar cell cycle distribution as NIH3T3 cells transfected with the same vector containing no insert. However, ectopic p21Waf1 expression did inhibit Ras-mediated anchorage-independent colony formation, indicating that p21Waf1 can selectively interfere with oncogene-mediated transformation without affecting NIH3T3 cell growth, at least at the levels of p21Waf1 expression achieved in these experiments. Transient transfection of waf1 into NIH3T3 cells inhibited Ras-induced transcription from a E2F-responsive element but not from a serum-responsive element, indicating that p21Waf1 acts downstream of early transcriptional events induced by Ras but upstream of E2F-controlled gene transcription. These results provide evidence that p21Waf1 potently suppresses oncogene-mediated cellular transformation of NIH3T3 cells and that it may do so by inhibiting E2F-driven transcription of S phase genes.

Molecular cloning, sequencing, chromosomal localization and expression of mouse p21 (Waf1).

The recent discovery that expression of Waf1 (p21), an inhibitor of cyclin-dependent kinases, is induced by the tumor suppressor p53 provides an important linkage between growth suppression and the cell cycle. We report here the cloning and sequencing of a mouse p21 cDNA that contains the entire coding region. Hybridization of the mouse p21 probe in Southern blot analyses confirms that p21 is a single-copy gene and that the corresponding locus, Waf1, lies proximal to H-2 on mouse chromosome 17. In northern analyses, the expression of p21 is found in most normal mouse tissues, but a surprising lack of correlation is found between mRNA levels of p21 and p53. In order to determine which regions of p21 are most evolutionarily conserved, we have compared the cDNA sequences for the entire p21 coding region in 13 different mouse strains or species and the human p21 sequence. We conclude that two regions (corresponding to human codons 21-60 and 130-164) are strongly conserved in p21 and that these regions may represent domains that are especially critical to a functional p21 protein.

Expression of an ATP binding mutant of PKC-delta inhibits Sis-induced transformation of NIH3T3 cells.

In an effort to determine the role of protein kinase C-delta (PKC-delta) in cellular transformation mediated by the sis proto-oncogene, we cotransfected expression vectors containing cDNAs that encode for c-sis with an ATP binding mutant of PKC-delta (PKC-delta K376R) or wild type PKC-delta (PKC-delta WT) into NIH3T3 cells. Our results showed that expression of PKC-delta K376R severely impaired Sis-induced focus formation, whereas cotransfection of PKC-delta WT cDNA had no effect on Sis-mediated transformation. Consistent with this result, PKC-delta K376R expression also inhibited PDGF-BB-mediated anchorage-independent colony formation. While cotransfection of a vector containing a dominant negative mutant of ras (N17 ras) cDNA potently inhibited Sis-induced transformation, the expression of PKC-delta K376R did not block transformation mediated by v-H-Ras or v-Raf. In addition, PDGF-BB-induced Raf and mitogen-activated protein kinase activation, which are known to be downstream molecules in the Ras cascade, were not affected by the expression of PKC-delta K376R, indicating that PKC-delta and Ras are segregated in mediating Sis-induced transformation. Interestingly, expression of PKC-delta K376R strongly reduced TPA responsive element (TRE) transactivation induced by PDGF stimulation, suggesting that activation of TRE-containing genes, which may be involved in Sis-mediated transformation, are negatively regulated by expression of PKC-delta K376R.

Delayed effect of nitric oxide synthase inhibition on the survival of rats after acute decompression.

AIM: The formation of bubbles in the blood stream together with the ensuing sickness after rapid decompression is assumed to depend on the physiological condition of the vascular system. In order to gain insight into the vascular function of nitric oxide in acute decompression sickness, the effects of the nitric oxide synthase inhibition by N(omega)-nitro-L-arginine methyl ester was studied in rats. METHODS: Wistar rats under anaesthesia were exposed to hyperbaric conditions for two hours and decompressed approximately 2.5 hours after a single subcutaneous injection of N(omega)-nitro-L-arginine methyl ester. Scalar doses and different pressures were tested. RESULTS: The fraction of the rats that died after decompression was greater in rats treated with N(omega)-nitro-L-arginine methyl ester at doses greater than 8 mg Kg-1 body weight compared to untreated rats. CONCLUSION: Although we have not excluded effects of nitric oxide synthase inhibition on distribution of perfusion and therefore inert gas elimination from tissue during decompression as a factor, this result highlights a delayed benefit of nitric oxide synthase activity in preventing death in acute decompression sickness.

ABA-deficiency results in reduced plant and fruit size in tomato.

Abscisic acid (ABA) deficient mutants, such as notabilis and flacca, have helped elucidating the role of ABA during plant development and stress responses in tomato (Solanum lycopersicum L.). However, these mutants have only moderately decreased ABA levels. Here we report on plant and fruit development in the more strongly ABA-deficient notabilis/flacca (not/flc) double mutant. We observed that plant growth, leaf-surface area, drought-induced wilting and ABA-related gene expression in the different genotypes were strongly correlated with the ABA levels and thus most strongly affected in the not/flc double mutants. These mutants also had reduced fruit size that was caused by an overall smaller cell size. Lower ABA levels in fruits did not correlate with changes in auxin levels, but were accompanied by higher ethylene evolution rates. This suggests that in a wild-type background ABA stimulates cell enlargement during tomato fruit growth via a negative effect on ethylene synthesis.

A novel dual specificity phosphatase induced by serum stimulation and heat shock.

To identify new members of a family of protein-tyrosine phosphatases (PTPs), of which VH1 is prototype, we screened a B5/589 human mammary epithelial cell cDNA library by low stringency hybridization with probes for the catalytic domains of the human VHR and mouse 3CH134 phosphatases. Two overlapping clones of 1.8 and 2.5 kilobase pairs were detected by 3CH134 but not VHR probes. Sequence analysis of the largest clone, B23, revealed a 2470-nucleotide open reading frame encoding a novel protein. Within the 397 amino acid sequence, the HCXAGXXR signature sequence for PTPs was located at positions 261-268. The closest similarities were to 3CH134, its human homolog CL100, and PAC-1, PTPs induced as early response genes to mitogen stimulation. Less relatedness was observed with VHR and VH1 dual specificity phosphatases of human and vaccinia virus, respectively. A bacterially expressed recombinant protein containing the catalytic domain of B23 showed significant but consistently lower activity than VHR in vitro. Among the substrates tested, B23 displayed the highest relative activity toward phosphorylated extracellular signal regulated kinase-1, suggesting that it may be a target for B23 activity in vivo. The B23 transcript was detected in a wide variety of normal human tissues, with relatively high expression in pancreas and brain. B23 was induced by serum stimulation of human fibroblasts as well as by heat shock with similar kinetics to those observed with CL100. Thus, B23 is a new human protein phosphatase which appears to be regulated in response to mitogenic signaling and at least some forms of stress.

MET(PRC) mutations in the Ron receptor result in upregulation of tyrosine kinase activity and acquisition of oncogenic potential.

Ron and Met are structurally related receptor tyrosine kinases that elicit a complex biological response leading to invasive growth. Naturally occurring point mutations activate the Met kinase in papillary renal carcinomas (MET(PRC) mutations). By site-directed mutagenesis, we generated homologous amino acid substitutions in the Ron kinase domain and analyzed the biochemical and biological properties of the mutant receptors. Among the mutations studied, D(1232)H and M(1254)T displayed transforming activity in NIH3T3 cells, inducing focus formation and anchorage-independent growth. The D(1232)H and M(1254)T substitutions resulted in increased Ron autophosphorylation both in vivo and in vitro and constitutive binding to intracellular signal transducers. Both mutations yielded a dramatic increase in catalytic efficiency, indicating a direct correlation between kinase activity and oncogenic potential. Molecular modeling of the Ron D(1232)H mutation suggests that this single amino acid substitution favors the transition of the kinase from the inactive to the active state. These data demonstrate that point mutations can confer transforming activity to the Ron receptor and show that RON is a potential oncogene.

p53 functional impairment and high p21waf1/cip1 expression in human T-cell lymphotropic/leukemia virus type I-transformed T cells.

Human T-cell lymphotropic/leukemia virus type I (HTLV-I) is associated with T-cell transformation both in vivo and in vitro. Although some of the mechanisms responsible for transformation remain unknown, increasing evidence supports a direct role of viral as well as dysregulated cellular proteins in transformation. We investigated the potential role of the tumor suppressor gene p53 and of the p53-regulated gene, p21waf1/cip1 (wild-type p53 activated fragment 1/cycling dependent kinases [cdks] interacting protein 1), in HTLV-I-infected T cells. We have found that the majority of HTLV-I-infected T cells have the wild-type p53 gene. However, its function in HTLV-I-transformed cells appears to be impaired, as shown by the lack of appropriate p53-mediated responses to ionizing radiation (IR). Interestingly, the expression of the p53 inducible gene, p21waf1/cip1, is elevated at the messenger ribonucleic acid and protein levels in all HTLV-I-infected T-cell lines examined as well as in Taxl-1, a human T-cell line stably expressing Tax. Additionally, Tax induces upregulation of a p21waf1/cip1 promoter-driven luciferase gene in p53 null cells, and increases p21waf1/cip1 expression in Jurkat T cells. These findings suggest that the Tax protein is at least partially responsible for the p53-independent expression of p21waf1/cip1 in HTLV-I-infected cells. Dysregulation of p53 and p21waf1/cip1 proteins regulating cell-cycle progression, may represent an important step in HTLV-I-induced T-cell transformation.

Induction of epithelial tubules by growth factor HGF depends on the STAT pathway.

Hepatocyte growth factor (HGF) induces a three-phase response leading to the formation of branched tubular structures in epithelial cells. The HGF receptor tyrosine kinase works through a Src homology (SH2) docking site that can activate several signalling pathways. The first phase of the response (scattering), which results from cytoskeletal reorganization, loss of intercellular junctions and cell migration, is dependent on phosphatidylinositol-3-OH kinase and Rac activation. The second phase (growth) requires stimulation of the Ras-MAP kinase cascade. Here we show that the third phase (tubulogenesis) is dependent on the STAT pathway. HGF stimulates recruitment of Stat-3 to the receptor, tyrosine phosphorylation, nuclear translocation and binding to the specific promoter element SIE. Electroporation of a tyrosine-phosphorylated peptide, which interferes with both the association of STAT to the receptor and STAT dimerization, inhibits tubule formation in vitro without affecting either HGF-induced 'scattering' or growth. The same result is obtained using a specific 'decoy' oligonucleotide that prevents STAT from binding to DNA and affecting the expression of genes involved in cell-cycle regulation (c-fos and waf-1). Activation of signal transducers that directly control transcription is therefore required for morphogenesis.