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Biomedical subjects

V Esposito

Publications and source records attributed to V Esposito.

At least 73 records · Page 4Linked to original sources
PubMed1997

Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer.

Despite its potential role as a tumor suppressor, p27 gene, a member of the Cip/Kip family of cyclin-dependent kinase inhibitor genes, has never been found mutated in human tumors. We investigated p27 protein expression in a series of 108 non-small cell lung cancers (57.4% stage 1, 16.7% stage 2, and 25.9% stage 3) to determine whether the lack or altered expression of this protein correlates with neoplastic transformation and/or progression. We performed immunohistochemistry and Western blot analysis of each specimen. We found that tumors expressing low to undetectable levels of p27 contained high p27 degradation activity. When we evaluated the outcome of the patients in relationship to p27 expression, we found p27 to be a prognostic factor correlating with the overall survival times (P = 0.0012). The possibility of a simple assay, such as the immunohistochemical analysis of p27 expression on routinely formalin-fixed, paraffin-embedded specimens, has considerable value for the prognosis of patients who undergo surgical resection. In addition, confirmation of the involvement of the proteasome-mediated proteolysis in p27 degradation should stimulate new strategies of nonsurgical treatments of non-small cell lung cancer.

Adenocarcinoma↗
PubMed1997

CDC2-related kinase PITALRE phosphorylates pRb exclusively on serine and is widely expressed in human tissues.

Mammalian cell cycle progression is regulated by sequential activation and inactivation of cyclin-dependent kinases (cdks). Recently, several new members of the cdk family were cloned, and some of these were shown to complex with different cyclins and to be active at discrete stages of the cell cycle. PITALRE, a new member of this family, was cloned by our laboratory and was shown to be able to phosphorylate pRb protein in vitro. In the current work, we found that PITALRE kinase activity phosphorylated pRb at sites similar to those phosphorylated by the CDC2 kinase, which itself is known to mimic, in vitro, the in vivo phosphorylation of pRb. Phosphorylation of pRb by the PITALRE-associated kinase activity was on Ser residues exclusively. Moreover, we investigated the expression pattern of PITALRE in normal human tissues, using immunohistochemical techniques so as to gain additional data on the characteristics of this new cdk family member. The protein was widely expressed, although a different tissue distribution and/or level of expression was found in various organs. Some specialized tissues such as blood, lymphoid tissue, ovarian cells, and the endocrine portion of the pancreas showed a high expression level of PITALRE. The specific expression pattern found suggests that PITALRE may be involved in specialized functions in certain cell types.

Antibodies↗
PubMed1997

Prognostic value of p53 in non-small cell lung cancer: relationship with proliferating cell nuclear antigen and cigarette smoking.

p53 mutations are among the most frequent genetic alterations reported in human lung cancer. Although the prognostic value of altered p53 expression is still debated, it is accepted widely that estimation of the proliferation rate has an important prognostic role. Moreover, an association between certain types of human lung cancers and tobacco use is well known. Drawing from this background, we investigated the immunohistochemical expression of mutant oncogenic p53 protein, and related it to the smoking history of 61 patients with non-small cell lung carcinoma (NSCLC) and to the expression pattern of proliferating cell nuclear antigen (PCNA), which is considered to be an important negative prognostic factor in several neoplasms. We found p53 overexpression in 22 (36.1%) specimens, including 16 squamous carcinomas (41%) and six (27.2%) adenocarcinomas. PCNA nuclear staining was detected in 98.4% of the specimens, and a significantly higher PCNA expression score was found in all of the p53-positive samples. When the patient survival time was compared, p53 accumulation had a statistically significant negative prognostic value (P < .001). This was supported by a Kaplan-Meier survival percentage plot of immunohistochemically p53-undetectable specimens and p53-detectable specimens. These latter patients had a greatly reduced survival time. A relationship was established between p53 immunohistochemical detection and the smoking history of the patients. None of the specimens from the nonsmoking patients expressed immunohistochemically detectable p53 protein. Altered p53 expression was detected in 40.7% of smoking patients. Our findings support the hypothesis of involvement of p53 mutations in tobacco-induced carcinogensis and indicate that altered p53 expression plays an important prognostic role in NSCLC in smokers.

Biomarkers, Tumor↗
PubMed1997

Effect of blood gas derangement on QTc dispersion in severe chronic obstructive pulmonary disease: evidence of an electropathy?

Cardiac arrhythmias are common in patients with respiratory failure from chronic obstructive pulmonary disease (COPD). Several factors may be potentially arrhythmogenic in these patients, including hypoxemia and hypercapnia, acid-base disturbances, cor pulmonale and the use of digitalis, methylxanthines, and sympathomimetic drugs. The aim of this study was to examine the effect of hypoxemia and hypercapnia on QTc dispersion (QTcD) in COPD patients, and to evaluate the effect of a partial correction of one of these pro-arrhythmic factors, the hypoxemia, on Qtc dispersion, as QTcD has been proposed as a marker of heterogeneous repolarization and, hence of ventricular electrical instability. We showed that in 15 hypoxemic/hypercapnic COPD patients, compared to 20 controls, the QTcD was significantly higher (49.7 +/- 10.6 vs. 22.9 +/- 9.8 ms; P = 0.0001); furthermore, after only 24 h of oxygen therapy, and hence after a partial correction of hypoxemia, there was a significant reduction in QTcD in COPD patients (49.7 +/- 10.6 vs. 36.3 +/- 10.1 ms; P = 0.018). The data of the present study suggest that the increase in QTcD may be an early marker of a blood gas mediated electropathy in COPD patients.

Adult↗
PubMed1997

Simian virus-40 large-T antigen binds p53 in human mesotheliomas.

We found that simian virus 40 (SV40) induces mesotheliomas in hamsters and that 60% of human mesotheliomas contain and express SV40 sequences, results now confirmed by others [ref. 3-5, and presentations by D. Griffiths & R. Weiss, F. Galateau-SallE, and H.I.P. at "Simian virus 40: A possible human polyoma virus," NIH workshop, 27-28 January 1997, Bethesda, MD (transcript available through SAG Corp., Washington, DC 20008)]. Mesothelioma, an aggressive malignancy resistant to therapy, originates from the serosal lining of the pleural, pericardial and peritoneal cavities. The incidence of mesothelioma continues to increase worldwide because of exposure to crocidolite asbestos. However, at least 20% of mesotheliomas in the United States are not associated with asbestos exposure, and only a minority of people exposed to high concentrations of asbestos develop mesothelioma. Thus, other carcinogens may induce mesothelioma in individuals not exposed to asbestos, and/or may render particular individuals more susceptible to the carcinogenic effect of asbestos. We investigated whether the expression of the SV40 large T-antigen (Tag) interferes with the normal expression of the tumor suppressor gene p53 in human mesotheliomas. We found that SV40 Tag retains its ability to bind and to inactivate p53, a cellular protein that when normally expressed plays an important role in suppressing tumor growth and in inducing sensitivity to therapy. Our findings do not establish a cause-and-effect relation, but indicate that the possibility that SV40 contributes to the development of human mesotheliomas should be carefully investigated.

Antigens, Polyomavirus Transforming↗
PubMed1997

The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas.

The oncoprotein of simian virus-40, SV40 large T-antigen (Tag), is reported to target and to inactivate growth suppressive proteins such as the retinoblastoma family and p53 (ref. 4, 5), leading to transformation of human cell lines in vitro, tumor production in rodents, and detection of Tag in several human cancers including mesotheliomas. The retinoblastoma family contains three members, pRb, p107 and pRb2/p130 (ref. 9), that are phosphorylated in a cell cycle-dependent manner, have cell growth suppressive properties and bind to specific members of the E2F family and various cyclins. Even though mesotheliomas are among the most aggressive human cancers, alterations of important cell-cycle "controllers," such as the Rb family genes, have never been reported in these tumors. We found the presence of SV40-like sequences in 86% of 35 archival specimens of mesothelioma. We also demonstrated that SV40 Tag, isolated from frozen biopsies of human mesothelioma, binds each of the retinoblastoma family proteins, pRb, p107 and pRb2/p130, in four of four specimens. We propose that the tumorigenic potential of SV40 Tag in some human mesotheliomas may arise from its ability to interact with and thereby inactivate several tumor and/or growth suppressive proteins.

Adult↗
PubMed1997

Neurotensin-like immunoreactivity in the brain of the chicken, Gallus domesticus.

The distribution of neurons containing neurotensin in the central nervous system of the chicken was studied immunohistochemically. The majority of the neurotensin-immunoreactive (-ir) cell bodies were located in the hypothalamus. Extensive groups of labelled perikarya were found in the hypothalamic periventricular nucleus and in the magnocellular periventricular nucleus. In addition, ir-perikarya were scattered throughout the lateral hypothalamic area and in the ventromedial hypothalamic nucleus. The only extrahypothalamic site of ir-perikarya was in the region immediately under the lateral forebrain bundle. Immunoreactive fibres were detected in the hippocampus, the parahippocampal area, the hypothalamus, the region of the tractus corticohabenular and corticoseptal tracts, the median eminence, the region above the posterior commissure and in the intercollicular nucleus. The distribution pattern of the neurotensin-ir neurons suggests that neurotensin-like peptides are involved in the hypophysiotropic functions.

Animals↗
PubMed1997

Changes in gut neurotensin and modified colonic motility following whole-body irradiation in rat.

Exposure to ionizing radiation induces gastrointestinal dysfunction often associated with disorders of intestinal motility. Neurotensin is one of the mediators involved in the control of intestinal muscle activity. The aim of this study was to relate neurotensin tissue content and specific receptor binding with contractile effect of neurotensin in rat colon after irradiation. Rats were exposed to whole-body gamma-irradiation (60Co; 6 Gy). Intestinal (caecum, colon) neurotensin-like immunoreactivity, colonic muscle neurotensin receptor binding and neurotensin-induced contractions in isolated colon were investigated 3 and 7 days after irradiation. Irradiation produced a marked increase in the intestinal muscle content of neurotensin-like immunoreactivity (2.5-fold in caecum, 5-fold in colon) 3 days post-irradiation. At 7 days, the intestinal neurotensin content was close to that of the control values. Three days after irradiation, neurotensin receptors in colonic muscle were characterized by the appearance of a transient second class of sites of low affinity-high capacity. A three-fold increase in the total number of sites was observed. In addition, effects of neurotensin on isolated colon preparations showed an increase (37%) of potency but a decrease (7-fold) of efficacy. Seven days after irradiation, the efficacy was close to the control. Modifications of intestinal neurotensin content and specific receptor characteristics induced by irradiation can influence the colonic contractile activity.

Animals↗
PubMed1997

Gut lavage IgG and interleukin 1 receptor antagonist:interleukin 1 beta ratio as markers of intestinal inflammation in children with inflammatory bowel disease.

BACKGROUND: Whole gut lavage is currently used as preparation before radiological or endoscopic examination of the large bowel. AIM: To validate the gut lavage technique for the assessment of mucosal inflammation, by measuring intestinal IgG and interleukin 1 beta (IL-1 beta) in the fluid obtained. PATIENTS: Sixteen children with Crohn's disease (CD), 14 with ulcerative colitis (UC), and 22 age matched controls. METHODS: Isotonic, non-absorbable polyethylene glycol based lavage solution was given orally or by nasogastric tube. Clear fluid was collected, filtered, and treated with protease inhibitors. IgG, IL-1 beta and IL-1-receptor antagonist (IL-1-ra) were measured by sandwich enzyme linked immunosorbent assay (ELISA). RESULTS: In patients with UC and CD, IgG and IL-1 beta levels were significantly (p < 0.001) higher than in controls. A positive correlation (p < 0.05) was found with disease activity scores. IL-1-ra levels were not significantly different in UC and CD, when compared with controls, but the IL-1-ra:IL-1 beta ratio was significantly (p < 0.01) lower in patients with UC and CD, and negatively (p < 0.001) correlated with IgG levels in lavage fluid. CONCLUSIONS: Gut lavage fluid IgG and IL-1 beta levels and IL-1-ra:IL-1 beta ratio may provide objective discrimination between active and inactive disease in children with inflammatory bowel disease.

Adolescent↗
PubMed1997

Diagnosis and radioguided surgery with 111In-pentetreotide in a patient with paraneoplastic Cushing's syndrome due to a bronchial carcinoid.

In a 28-year-old man with Cushing's syndrome, studies investigating a hypophyseal and/or adrenal origin of the disease, including computed tomography and magnetic resonance imaging, were negative. In agreement with reports showing somatostatin receptors on the cell membrane of ectopically secreting ACTH tumours, scintigraphy was performed after intravenous injection of 111 MBq 111In-pentetreotide (OCT). The radiolabelled OCT scan showed a small focal area of intense uptake at the inferior lobe of the right lung. Subsequent radioguided surgery located and defined a small mass (1.8 x 1.4 x 1.6 cm). The probe pinpointed the mass to the right inferior chest lobe, with a tumour/normal tissue count ratio of 6:1 and tumour/hilar normal lymph node ratio of 12:1, thus permitting the complete excision of the tumour to exclude lymph node and/or parietal involvement. A lung carcinoid was diagnosed at histology. The patient is still alive and disease-free 24 months after surgery. 111In-OCT was found to be useful for localizing the ACTH-secreting tumour and also permitted rapid non-invasive differential diagnosis between an ACTH-secreting pituitary adenoma and malignancy causing ectopic ACTH syndrome. This study also showed the clinical usefulness of radioguided surgery in the treatment of bronchial carcinoid.

Adult↗
PubMed1997

Is growth hormone bad for your heart? Cardiovascular impact of GH deficiency and of acromegaly.

At present, there is growing evidence implicating GH and/or IGF-I in the intricate cascade of events connected with the regulation of heart development and hypertrophy. Moreover, GH excess and/or deficiency have been shown to include in their advanced clinical manifestations almost always an impaired cardiac function, which may reduce life expectancy. This finding is related both to a primitive impairment of heart structure and function and to metabolic changes such as hyperlipidemia, increase of body fat and premature atherosclerosis. Patients with childhood or adulthood-onset GH deficiency have a reduced left ventricular mass and ejection fraction and the indexes of left ventricular systolic function remain markedly depressed during exercise. Conversely, in acromegaly the cardiac enlargement, which is disproportionate to the increase in size of other internal body organs, has been a rather uniform finding. The severity of the acromegalic cardiomyopathy was reported to be correlated better with the disease duration than with circulating GH and/or IGF-I levels. Myocardial hypertrophy with interstitial fibrosis, lymphomononuclear infiltration and areas of monocyte necrosis often results in concentric hypertrophy of both ventricles. The treatment of GH deficiency and excess improved cardiac function. Interestingly, based on the evidence that GH increases cardiac mass, recombinant GH was administered to patients with idiopathic dilated cardiomyopathy. It increased the myocardial mass and reduced the size of the left ventricular chamber, resulting in improvement of hemodynamics, myocardial energy metabolism and clinical status. These promising results open new perspectives for the use of GH in heart failure.

Acromegaly↗
PubMed1997

Differential expression of Rb2/p130 and p107 in normal human tissues and in primary lung cancer.

Two proteins, p107 and pRb2/p130, which are structurally and functionally similar to the product of the retinoblastoma gene (pRb), were cloned by taking advantage of their ability to bind transforming proteins of DNA tumor viruses through a particular region called the "pocket domain." Like pRb, both proteins play a fundamental role in growth control. Using immunocytochemical techniques, we examined a variety of normal human tissues for the expression of pRb2/p130 and p107. Both proteins were expressed ubiquitously, although a different tissue distribution and/or level of expression were found in various organs. Terminally differentiated cells, such as neurons and skeletal muscle, showed high expression levels for Rb2/p130, whereas p107 was expressed at higher levels in other cell types such as epithelia of the breast and prostate. We then examined the expression pattern of Rb2/p130 in 158 specimens of human lung cancer and found an inverse correlation between the histological grading of the tumors, the development of metastasis, and the level of expression of Rb2/p130.

Blood Cells↗
PubMed1996

VIP-like immunoreactive cells in the kidney of goldfish (Carassius auratus).

By immunohistochemistry VIP-like immunoreactive cells were observed in the second segment of some renal proximal tubules of Carassius auratus. Immunoreactivity displayed a granular appearance all over the cells. VIP-like immunoreactive cells showed a shape of an over-turned flask whose globe-like part looks like the tubular lumen. No immunoreactive material was observed in other tracts of the nephron and in the interstitial cells. The presence of VIP-like immunoreactive cells is discussed in relation to their possible function.

Animals↗
PubMed1996

Modulation of gut substance P after whole-body irradiation. A new pathological feature.

Exposure to ionizing radiation induces gastrointestinal dysfunction and inflammatory reactions. The present study carried out in the rat, focuses on substance P, an inflammatory mediator implicated in the control of intestinal motility. We have investigated the effects of gamma irradiation on plasma and tissue substance P levels, ileal smooth muscle activity, and properties of specific receptors. Plasma and ileal (mucosa and muscle) substance P concentrations were measured by radioimmunoassay. At doses ranging from 1 to 8 Gy, plasma substance P levels increased in a dose-dependent manner up to four days after irradiation. Ileal mucosal concentration decreased rapidly 1 hr after a 6-Gy irradiation as compared to controls. A second class of binding sites appeared three days after 6 Gy irradiation. In addition, substance P contractile effects measured on isolated ileum showed a fourfold decrease of EC50, three days after 6 Gy irradiation. These results indicated that gamma irradiation induced an increase of plasma levels concomitant with a modification of gastro-intestinal substance P specific binding sites and contractile activity.

Animals↗
PubMed1996

Lung volumes and respiratory muscle strength in adult patients with childhood- or adult-onset growth hormone deficiency: effect of 12 months' growth hormone replacement therapy.

We have described impairment of the respiratory function in adult patients with childhood-onset growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient before and after 6 and 12 months of recombinant GH treatment. Ten adults diagnosed as GH deficient in childhood, ten adults diagnosed as GH deficient in adulthood and ten healthy subjects entered the study. For each subject, evaluation of respiratory function followed the same standard approach, consisting of respiratory muscle strength assessment, record of flow-volume curves, measurement of static lung volumes and lung diffusing capacity. Childhood-onset GH-deficient patients had a significant reduction of maximal inspiratory (p < 0.01) and maximal expiratory (p < 0.05) mouth pressures. Total lung capacity, vital capacity and functional residual capacity were significantly reduced compared to healthy subjects (p < 0.05). Conversely, residual volume and diffusing lung capacity did not show any significant change. No significant change of the ratio between the percentage forced expiratory volume in 1 s and the forced vital capacity was observed. The decrease of respiratory mouth pressures was not correlated to the decrease of lung volumes. Adult-onset GH-deficient patients had only a significant reduction of maximal expiratory pressure compared to healthy subjects (p < 0.05). After 6 months of treatment no significant differences in any of the evaluated parameters were found. After 12 months of treatment patients with childhood-onset GH deficiency show a significant improvement of lung volumes (p < 0.01) and maximal respiratory mouth pressures (p < 0.005), whereas adult-onset GH-deficient patients show a significant improvement of maximal expiratory pressure (p < 0.05). In conclusion, the results of this study showed that adult patients affected with childhood-onset GH deficiency suffer from an impairment of the ventilatory function due to a reduction of lung volumes and a decrease of respiratory pressures probably due to a reduction of respiratory muscle strength. This impairment was reversed after 12 months of treatment with recombinant GH. Conversely, adult-onset GH-deficient patients had only an impairment of the maximal expiratory pressure, probably due to respiratory muscle weakness re-established after 12 months of GH therapy.

Adult↗
PubMed1996

Cellular receptors for sex steroids in human pituitary adenomas.

Cellular receptors for sex steroids (SSRs) were studied in an unselected series of 55 human pituitary tumors. Cytosolic receptors for estrogen (ERcs) and progesterone (PgRcs) were determined in all cases and cytosolic androgen receptors (ARcs) in 47 cases. Nuclear receptors (ERns, PgRns, ARns) were also studied in 33 cases. ERs and PgRs were determined by an ELISA and ARs by [3H]methyltrienolone binding. Where both cytosolic and nuclear receptors were studied (n = 33), ERs, PgRs and ARs were found in at least one subcellular fraction in 66.7, 60.6 and 81.8% of cases respectively, ERs and ARs being mainly recovered from the cytosol and PgRs from the nucleus. No linear correlation was found between pre-operative plasma steroid hormones and their specific cellular receptors. Nonetheless, the differential expression of SSRs according to sex and gonadal status at the time of surgery strongly supports their regulation by the steroid environment in vivo: PgRcs were more frequent in tumors found in women (41.4 vs 15.4%, P < 0.05), whereas a high expression of ERcs and ARcs (> 15 fmol/mg protein) was more common in tumors found in men (34.5 vs 10.3%, P < 0.05 and 54.5 vs 24.0% respectively). PgRs were positively correlated with ERns, indicating the possibility of estrogen priming of their expression, and negatively correlated with ARs in nuclear fractions. SSRs appeared to be widely distributed among pituitary tumors, although, compared with other hormone-secreting groups, prolactinomas displayed a higher ERc expression (34.8 +/- 11.3 vs 4.8 +/- 5.1 fmol/mg protein, P = 0.007) and gonadotroph cell adenomas lower ARc values (1.3 +/- 0.8 vs 38.2 +/- 10.6 fmol/mg protein, P = 0.048). Microadenomas were characterized by a higher PgR expression than macroadenomas, whereas hemorrhagic (macro)adenomas were characterized by a high ER expression (> 90%). The present results indicate that most pituitary tumors are targets for sex steroids, SSR expression being partially triggered by the steroid environment itself. Possible physiopathological and therapeutic implications of these findings are discussed.

Adenoma↗
PubMed1996

The retinoblastoma gene family and its role in proliferation, differentiation and development.

The retinoblastoma gene family is composed of three members: the retinoblastoma gene, one of the most well studied tumor suppressor genes and two related proteins, p107 and pRb2/p130. These three proteins share many structural and functional features and play a fundamental role in growth control. Intense investigation of these proteins has identified a series of similar cell-cycle regulators and transcription factors with which they interact. Although the precise function of the retinoblastoma gene product and its relatives remains unknown, recent data suggests that they play parallel roles in controlling cell cycle progression and promoting cellular differentiation. In this review, we will attempt to clarify some of the molecular mechanisms by which these three related proteins cooperate to control cellular proliferation and differentiation.

Animals↗