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S Strano

Publications and source records attributed to S Strano.

At least 19 recordsLinked to original sources
PubMed2006

S100A2 gene is a direct transcriptional target of p53 homologues during keratinocyte differentiation.

The p53 paralogues p73, p63 and their respective truncated isoforms have been shown to be critical regulators of developmental and differentiation processes. Indeed, both p73- and p63-deficient mice exhibit severe developmental defects. Here, we show that S100A2 gene, whose transcript and protein are induced during keratinocyte differentiation of HaCaT cells, is a direct transcriptional target of p73beta and DeltaNp63alpha and is required for proper keratinocyte differentiation. Transactivation assays reveal that p73beta and DeltaNp63alpha exert opposite transcriptional effects on S100A2 gene. While DeltaNp63alpha is found in vivo onto S100A2 regulatory regions predominantly in proliferating cells, p73beta is recruited in differentiating cells. Silencing of p73 impairs the induction of S100A2 during the differentiation of HaCaT cells. Moreover, silencing of p73 or S100A2 impairs the proper expression of keratinocyte differentiation markers. Of note, p53 family members do not trigger S100A2 gene expression in response to apoptotic doses of cisplatin and doxorubicin.

Cell Differentiation↗
PubMed2006

Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression.

Mutations in the TP53 tumor suppressor gene are the most frequent genetic alteration in human cancers. These alterations are mostly missense point mutations that cluster in the DNA binding domain. There is growing evidence that many of these mutations generate mutant p53 proteins that have acquired new biochemical and biological properties. Through this gain of function activity, mutant p53 is believed to contribute to tumor malignancy. The purpose of our study was to explore mutant p53 as a target for novel anticancer treatments. To this aim, we inhibited mutant p53 expression by RNA interference in three different cancer cell lines endogenously expressing mutant p53 proteins, and evaluated the effects on the biological activities through which mutant p53 exerts gain of function. We found that depletion of mutant p53 reduces cell proliferation, in vitro and in vivo tumorigenicity, and resistance to anticancer drugs. Our results demonstrate that mutant p53 knocking down weakens the aggressiveness of human cancer cells, and provides further insight into the comprehension of mutant p53 gain of function activity in human tumor.

Animals↗
PubMed2005

Multidisciplinary approach for diagnosing syncope: a retrospective study on 521 outpatients.

OBJECTIVES: To describe causes of syncope in outpatients in whom structural heart disease was ruled out as a cause, and to analyse the role of a multidisciplinary approach in a syncope unit for the diagnosis of patients with syncope of unknown origin. METHODS: Cardiovascular autonomic nervous system (ANS) function was evaluated extensively in 521 outpatients by careful history, physical examination including orthostatic blood pressure measurement and standard ECG, and tilt testing. RESULTS: Causes of syncope remained unknown in 29.2% of cases. ANS dysfunction was found in 58.6% of those presenting with either neurally mediated syncope (53.6%) or chronic autonomic failure (5%); 3.8% of the patients suffered from syncope of cardiogenic origin (2.5%) or non-neurogenic hypotension (1.3%), and 8.4% had loss of consciousness of non-syncopal origin. Loss of consciousness was confirmed as being related to seizures in under 30% of patients initially diagnosed as having epilepsy. CONCLUSIONS: Neurally mediated syncope represents the commonest type of syncope. ANS evaluation including tilt testing should be considered as preliminary screening in patients with syncope in the absence of definite heart abnormalities. Neurologists should consider syncope from ANS failure as a comorbid factor in patients with seizures where the clinical characteristics are not straightforward.

Adult↗
PubMed2004

Chiral investigation of midodrine, a long-acting alpha-adrenergic stimulating agent.

Midodrine hydrochloride is a peripheral alpha(1)-adrenoreceptor agonist that induces venous and arterial vasoconstriction. Midodrine, after oral or intravenous administration, undergoes enzymatic hydrolysis and releases deglymidodrine, a pharmacologically active metabolite. Midodrine and deglymidodrine have a chiral carbon in the 2-position. To investigate the bioactivity of racemates and enantiomers of the drug and metabolite, three chromatographic chiral stationary phases, Chiralcel OD-H, Chiralcel OD-R, and alpha(1)-AGP, were evaluated for enantiomeric resolution. Good enantioseparation of midodrine racemate was obtained using the Chiralcel OD-H column. This stationary phase was then used to collect separately the midodrine enantiomers. By alkaline hydrolysis of rac-midodrine and each separated enantiomer, rac-deglymidodrine and its enantiomers were prepared. The control of the enantiomeric purity was carried out by alpha(1)-AGP stationary phase, while the hydrolysis of rac-midodrine and its enantiomers was controlled by capillary electrophoresis using trimethyl-beta-cyclodextrin as chiral selector. The pharmacological activity of the two racemates and the two enantiomeric pairs was tested in vitro on a strip of rabbit descending thoracic aorta. The tests continued that the activity of the drug and metabolite is due only to the (-)-enantiomer because neither of the (+)-enantiomers is active.

Adrenergic alpha-Agonists↗
PubMed2003

Nonlinear coupling among heart rate, blood pressure, and respiration in patients susceptible to neuromediated syncope.

The aim of this study is to evaluate the degree of coupling between the cardiovascular variability series and the respiration in subjects susceptible to neurally mediated syncope. Twenty-one informed patients susceptible to syncope and ten sex- and age-matched control subjects were enrolled in the study. ECG, respiration activity, and arterial blood pressure were simultaneously recorded at rest (controlled and free breathing) and during the 70 degrees head-up TILT test (free breathing). The degree of nonlinear coupling among heart rate variability (HRV), blood pressure variability (BPV), and respiration was quantified by means of two indices according to a multivariate embedding-based approach. Eleven patients developed syncope during the TILT test. We found that during the late TILT phase, the TILT-positive group experienced a significant increase in nonlinear coupling respect to the mid TILT phase (p < 0.01, Wilcoxon nonparametric test for pair data) while the TILT-negative group did not (p < 0.01, Mann-Whitney U-test). If the proposed nonlinear coupling indexes can be considered expression of the coupling mechanisms involved in the vagal regulation of the cardiovascular system, an increase in vagal tone accompanied by a decrease in sympathetic activity seem to occur before a vasovagal event.

Adolescent↗
PubMed2001

From p63 to p53 across p73.

Most genes are members of a family. It is generally believed that a gene family derives from an ancestral gene by duplication and divergence. The tumor suppressor p53 was a striking exception to this established rule. However, two new p53 homologs, p63 and p73, have recently been described [1-6]. At the sequence level, p63 and p73 are more similar to each other than each is to p53, suggesting the possibility that the ancestral gene is a gene resembling p63/p73, while p53 is phylogenetically younger [1,2].The complexity of the family has also been enriched by the alternatively spliced forms of p63 and p73, which give rise to a complex network of proteins involved in the control of cell proliferation, apoptosis and development [1,2,4,7-9]. In this review we will mainly focus on similarities and differences as well as relationships among p63, p73 and p53.

Animals↗
PubMed2001

Physical interaction with Yes-associated protein enhances p73 transcriptional activity.

Specific protein-protein interactions are involved in a large number of cellular processes and are mainly mediated by structurally and functionally defined domains. Here we report that the nuclear phosphoprotein p73 can engage in a physical association with the Yes-associated protein (YAP). This association occurs under physiological conditions as shown by reciprocal co-immunoprecipitation of complexes from lysates of P19 cells. The WW domain of YAP and the PPPPY motif of p73 are directly involved in the association. Furthermore, as required for ligands to group I WW domains, the terminal tyrosine (Y) of the PPPPY motif of p73 was shown to be essential for the association with YAP. Unlike p73alpha, p73beta, and p63alpha, which bind to YAP, the endogenous as well as exogenously expressed wild-type p53 (wt-p53) and the p73gamma isoform do not interact with YAP. Indeed, we documented that YAP interacts only with those members of the p53 family that have a well conserved PPXY motif, a target sequence for WW domains. Overexpression of YAP causes an increase of p73alpha transcriptional activity. Differential interaction of YAP with members of the p53 family may provide a molecular explanation for their functional divergence in signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The transcriptional repressor ZEB regulates p73 expression at the crossroad between proliferation and differentiation.

The newly discovered p73 gene encodes a nuclear protein that has high homology with p53. Furthermore, ectopic expression of p73 in p53(+/+) and p53(-/-) cancer cells recapitulates some of the biological activities of p53 such as growth arrest, apoptosis, and differentiation. p73(-/-)-deficient mice exhibit severe defects in proper development of the central nervous system and pheromone sensory pathway. They also suffer from inflammation and infections. Here we studied the transcriptional regulation of p73 at the crossroad between proliferation and differentiation. p73 mRNA is undetectable in proliferating C2C12 cells and is expressed at very low levels in undifferentiated P19 and HL60 cells. Conversely, it is upregulated during muscle and neuronal differentiation as well as in response to tetradecanoyl phorbol acetate-induced monocytic differentiation of HL60 cells. We identified a 1-kb regulatory fragment located within the first intron of p73, which is positioned immediately upstream to the ATG codon of the second exon. This fragment exerts silencer activity on p73 as well as on heterologous promoters. The p73 intronic fragment contains six consensus binding sites for transcriptional repressor ZEB, which binds these sites in vitro and in vivo. Ectopic expression of dominant-negative ZEB (ZEB-DB) restores p73 expression in proliferating C2C12 and P19 cells. Thus, transcriptional repression of p73 expression by ZEB binding may contribute to the modulation of p73 expression during differentiation.

Animals↗
PubMed2000

Physical and functional interaction between p53 mutants and different isoforms of p73.

p53 is the most frequently inactivated tumor suppressor gene in human cancer, whereas its homologue, p73, is rarely mutated. Similarly to p53, p73 can promote growth arrest or apoptosis when overexpressed in certain p53-null tumor cells. It has previously been shown that some human tumor-derived p53 mutants can exert gain of function activity. The molecular mechanism underlying this activity remains to be elucidated. We show here that human tumor-derived p53 mutants (p53His175 and p53Gly281) associate in vitro and in vivo with p73 alpha, beta, gamma, and delta. This association occurs under physiological conditions, as verified in T47D and SKBR3 breast cancer cell lines. The core domain of mutant p53 is sufficient for the association with p73, whereas both the specific DNA binding and the oligomerization domains of p73 are required for the association with mutant p53. Furthermore, p53His175 and p53Gly281 mutants markedly reduce the transcriptional activity of the various isoforms of p73. Thus, human tumor-derived p53 mutants can associate with p73 not only physically but also functionally. These findings define a network involving mutant p53 and the various spliced isoforms of p73 that may confer upon tumor cells a selective survival advantage.

Breast Neoplasms↗
PubMed2000

Microvascular blood flow fluctuations during tilt table induced syncope.

Aim of this study is to investigate the changes, in the frequency domain, of microvasculature blood flow (BF) occurring in neurally mediated syncope. We studied 20 patients with history of recurrent syncope and 10 control subjects. Peripheral BF was measured (laser Doppler technique) in the palmar region (PBF) and the manubrium sterni (SBF), together with ECG, respiration activity (RA) and blood pressure (BP), at rest (5 minute) and during 70 degrees head-up tilt test. SBF and PBF appear to be characterized by oscillations around 0.16 Hz (0.15-0.19 Hz), that do not have correspondence in the other cardiovascular variability signals. Mean BF was not significantly altered in tilt negative, control and tilt positive groups (11 patients) during tilt. In the tilt positive group a decrease of mean PBF and SBF and an increase of the oscillation frequency of PBF and SBF was observed in close proximity of the development of symptoms.

Blood Flow Velocity↗
PubMed1999

The C-terminus of the kinase-defective neuregulin receptor ErbB-3 confers mitogenic superiority and dictates endocytic routing.

Signaling by the epidermal growth factor (EGF) family and the neuregulin group of ligands is mediated by four ErbB receptor tyrosine kinases, that form homo- and heterodimeric complexes. Paradoxically, the neuregulin receptor ErbB-3 is devoid of catalytic activity, but its heterodimerization with other ErbBs, particularly the ligand-less ErbB-2 oncoprotein of carcinomas, reconstitutes superior mitogenic and transforming activities. To understand the underlying mechanism we constructed a chimeric EGF-receptor (ErbB-1) whose autophosphorylation C-terminal domain was replaced by the corresponding portion of ErbB-3. Consistent with the possibility that this domain recruits a relatively potent signaling pathway(s), the mitogenic signals generated by the recombinant fusion protein were superior to those generated by ErbB-1 homodimers and comparable to the proliferative activity of ErbB-2/ErbB-3 heterodimers. Upon ligand binding, the chimeric receptor recruited an ErbB-3-specific repertoire of signaling proteins, including Shc and the phosphatidylinositol 3-kinase, but excluding the ErbB-1-specific substrate, phospholipase Cgamma1. Unlike ErbB-1, which is destined to lysosomal degradation through a mechanism that includes recruitment of c-Cbl and receptor poly-ubiquitination, the C-terminal tail of ErbB-3 shunted the chimeric protein to the ErbB-3-characteristic recycling pathway. These observations attribute the mitogenic superiority of ErbB-3 to its C-terminal tail and imply that the flanking kinase domain has lost catalytic activity in order to restrain the relatively potent signaling capability of the C-terminus.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Role of wire-guided breast biopsy for diagnosis of malignant nonpalpable mammographic lesions.

Biopsies of mammographically detected nonpalpable lesions have resulted in increased numbers of diagnosed early breast malignancies. From June 1992 to September 1996 a total of 433 consecutive patients underwent 438 biopsies. The mean age was 55.7 years (range 30-82 years); 150 patients were younger than 50 years. Mammographic findings were classified as microcalcifications (C), masses (M), masses with microcalcifications (MC), architectural distortions (A), and stellate lesions (S). In 30 women two needles were placed to localize a lesion in the ipsilateral side and in 5 on the contralateral side. There were 182 (41.6%) biopsies performed for M, 144 (32.9%) for C, 78 (17.8%) for A, 25 (5.7%) for MC, and 9 (2.1%) for S. The overall malignancy rate was 34% (149/438). Thirty-four women (23%) who presented malignancy were younger than 50 years of age. From year to year, it increased from 27% during the first year to 51% during the fourth year. Altogether 100 (67%) patients had invasive carcinoma, 40 (27%) ductal carcinoma in situ (DCIS), 6 (4%) lobular carcinoma in situ, and 3 (2%) tubular carcinoma. Four patients had simultaneous bilateral palpable and nonpalpable carcinoma. Among the patients, 9 of 20 with previously operated breast carcinoma and 9 of 19 with other previous malignancies were found to have early breast carcinoma. The mammographic finding with high rates of malignancy were S 67%, MC 40%, M 34%, C 33%, and A 28%. A group of 11 of 110 (10%) patients had histologically proven axillary lymph node metastasis. Results from this large retrospective study of wire-guided localization biopsies showed a relatively high rate of malignancy (34%) and DCIS (27%).

Adult↗
PubMed1999

Breast fibroadenoma: mapping of pathophysiologic features with three-time-point, contrast-enhanced MR imaging--pilot study.

The capability of three-time-point, gadolinium-enhanced magnetic resonance imaging to depict vascular permeability and extracellular volume fraction of breast fibroadenoma was evaluated with histopathologic correlation. This method demonstrated an even distribution of high extracellular volume fraction and low to moderate microvascular permeability in these common breast lesions, providing a nonsurgical means of improving the accuracy of diagnosis of fibroadenoma.

Adult↗
PubMed1998

Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network.

Virulence of poxviruses, the causative agents of smallpox, depends on virus-encoded growth factors related to the mammalian epidermal growth factor (EGF). Here we report that the growth factors of Shope fibroma virus, Myxoma virus and vaccinia virus (SFGF, MGF and VGF) display unique patterns of specificity to ErbB receptor tyrosine kinases; whereas SFGF is a broad-specificity ligand, VGF binds primarily to ErbB-1 homodimers, and the exclusive receptor for MGF is a heterodimer comprised of ErbB-2 and ErbB-3. In spite of 10- to 1000-fold lower binding affinity to their respective receptors, the viral ligands are mitogenically equivalent or even more potent than their mammalian counterparts. This remarkable enhancement of cell growth is due to attenuation of receptor degradation and ubiquitination, which leads to sustained signal transduction. Our results imply that signal potentiation and precise targeting to specific receptor combinations contribute to cell transformation at sites of poxvirus infection, and they underscore the importance of the often ignored low-affinity ligand-receptor interactions.

Animals↗
PubMed1998

Cardiac autonomic dysfunction in patients with Alzheimer disease: possible pathogenetic mechanisms.

We studied a possible correlation between autonomic cardiac activity and the level of the red blood cell acetylcholinesterase (AChE) in patients with probable Alzheimer disease (AD). The influence of cholinesterase inhibitor treatment on this autonomic activity was evaluated. Twelve patients satisfying the NINCDS-ADRDA criteria of probable AD and 10 healthy controls were studied. Autonomic cardiac activity was evaluated by means of power spectral analysis (PSA) of heart rate variability (HRV) using an autoregressive algorithm on 250 consecutive electrocardiographic R-R intervals. All patients received oral eptastigmine, a new cholinesterase inhibitor, for 1 month. Before treatment, a simultaneous recording of the electrocardiographic and respiratory activities was performed at rest and subsequently during head-up tilt test at 700. Recording was repeated on the last day of treatment. The level of AChE activity during each recording was also evaluated. Spectrum power was calculated in three main frequency bands: high frequency (HF), 0.15-0.4 Hz; low frequency (LF), 0.04-0.15 Hz; very low frequency (VLF), <0.04 Hz. In addition, we calculated the total spectrum power (TSP) and the LF/HF ratio. The TSP and the absolute value of each spectral component were significantly lower in AD patients than in controls. In contrast with controls, AD patients did not show any significant change before treatment in either the LF and HF components or in the LF/HF ratio during the tilt test. However, the modification in the LF component, induced by tilting, showed a significant correlation with the level of AChE activity (p < 0.03). During the tilt test, the treatment caused changes in LF and HF components and in the LF/HF ratio similar to those observed in controls. These results suggest that the presence of autonomic cardiac dysfunction in AD patients might be due to a cholinergic deficit in the peripheral autonomic nervous system. Some aspects of this autonomic dysfunction can be normalized by cholinesterase inhibitor treatment.

Acetylcholinesterase↗
PubMed1998

Respiratory sinus arrhythmia and cardiovascular neural regulation in athletes.

Studies using spectral analysis of cardiovascular variability as a noninvasive means for assessing autonomic nervous system activity have provided controversial results in athletes. One reason is that a slow breathing rate--a common feature in athletes--affects spectral estimation because it causes the low-frequency (LF) and high-frequency (HF) components to overlap. Low-frequency power increases during sympathetic activation; high-frequency corresponds to respiratory sinus arrhythmia. In this study, to assess how controlled respiration influences autonomic nervous system activity, we determined the effect of controlled and uncontrolled breathing conditions on cardiovascular variability. Our aim was to identify a standard respiratory rate for spectral estimation of cardiovascular neural control in athletes. During electrocardiographic recordings, subjects lay supine and breathed at their spontaneous frequency and at rates of 15, 12, and 10 to 14 (random) breaths x min(-1). Uncontrolled and random breathing rates significantly altered spectral sympathetic indices; conversely, 15 and 12 breaths x min(-1) redistributed respiratory related power through the HF, thus yielding correct LF power estimation. None of the breathing conditions significantly changed mean heart rate, arterial blood pressure, or spectral total power of cardiovascular variability. In conclusion, when power spectral analysis is used for assessing autonomic activity in athletes, respiration should be standardized at 15 breaths x min(-1). Controlled respiration at this rate leaves autonomic nervous system activity unchanged.

Adolescent↗