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M Cintorino

Publications and source records attributed to M Cintorino.

At least 19 recordsLinked to original sources
PubMed2006

Human decidual natural killer cells as a source and target of macrophage migration inhibitory factor.

The human uterine mucosa of early pregnancy is largely populated by CD56(bright) natural killer (NK) cells (uterine (u) NK cells). The specific functions of these cells are still unknown, but their interaction and response to foetal trophoblasts are thought to be important for the establishment of a successful pregnancy. The study reported herein shows that uNK cells respond to, and produce, macrophage migration inhibitory factor (MIF), a cytokine highly expressed in the human placenta and in the cyclic and pregnant endometrium. Recombinant human MIF reduced in a dose-dependent manner the cytolytic activity of purified uNK cells against K562 cells. RT-PCR, Western blot analysis and ELISA demonstrated the synthesis and secretion of the cytokine by uNK cells. Double immunofluorescence staining showed the presence of MIF in uterine CD56 + cells. Finally, neutralization of the endogenous cytokine by a polyclonal antibody resulted in a sharp increase in the cytolytic activity of uNK cells. These findings indicate the existence of a previously unrevealed paracrine and autocrine action of MIF on uNK cells and support its contribution to the immune privilege at the maternal-foetal interface.

Antibodies, Monoclonal↗
PubMed2005

Clearance of high-risk human papillomavirus (HPV) DNA and PAP smear abnormalities in a cohort of women subjected to HPV screening in the New Independent States of the former Soviet Union (the NIS cohort study).

BACKGROUND: We analysed the temporal relationships of the clearance of human papillomavirus (HPV) DNA and cytological abnormalities in women participating in a screening study in three NIS countries. METHODS: The 274 patients included in this analysis were prospectively followed-up for 21.6 months (range: 0.5-42.9). All 274 women had abnormal PAP test (ASC-US or higher) and high-risk HPV-positive test (HCII) at baseline. Two groups were compared: 132 women who cleared both tests (Group 1), and 142 women who cleared either HPV or abnormal PAP test (Group 2). The first clearance during the follow-up, and the last visit clearance were modeled using life-table techniques, and the predictive factors were analysed using univariate (Kaplan-Meier) and multivariate (Cox) survival analysis. RESULTS: There was no difference in the mean clearance time for the abnormal PAP test (14.4 months; 0.7-40.5 and 12.6 months; 0.5-35.0) and high-risk HPV DNA (12.67 months; 0.6-33.5 and 10.8 months; 0.7-33.4) in Group 1 and Group 2 (Mann-Whitney: P = 0.107 and P = 0.082, respectively). Clearance times for HPV DNA and abnormal PAP test did not deviate from each other in either groups (Wilcoxon: P = 0.063 and P = 0.088). The monthly clearance rates for the abnormal PAP test are 1.32 and 1.38%, and those for the HPV DNA 1.62 and 1.61%, in Groups 1 and 2, respectively. Of the factors predicting the last visit clearance, the issues related to smoking are of particular interest. CONCLUSIONS: The clearance of high-risk HPV type and abnormal PAP test shows a close temporal relationship, the former preceding the latter, however, by an interval of 1.0-2.0 months.

Analysis of Variance↗
PubMed2005

Factors predicting persistence of high-risk human papillomavirus (HPV) infections in women prospectively followed-up in three New Independent States (NIS) of the former Soviet Union.

BACKGROUND: We completed an analysis of the factors predicting the persistence of high risk (HR) HPV infections in women participating in a multicenter screening trial in three NIS countries. METHODS: The 543 baseline HR HPV-positive women included in this analysis are derived from a sub-cohort of 887 women who were prospectively followed-up for a mean of 21.6 months (range: 0.5-42.9) as a part of a multi-center screening study in three NIS countries (the NIS cohort study; n = 3,187 women). Of these 543 women, 273 showed persistent HR-HPV in serial Hybrid Capture II (HCII) testing during the follow-up (Group 1), whereas 270 women cleared their infection (Group 2). These two groups were compared with their epidemiological, clinical, and virological data (HCII, PCR) to disclose the factors predicting persistent HR-HPV infection. RESULTS: Women with persistent HR-HPV infections were significantly younger (27.3 yrs) than those who cleared their infection (29.1 yrs) (p = 0.006), and their follow-up time was shorter; 14.1 and 21 months, respectively (p = 0.0001). Both variables were treated as confounders in the multivariate analyses. Of the 66 recorded epidemiological variables, only being a current smoker proved to be an independent predictor (OR 1.693; 95% CI 1.114-2.573; p=0.014). Baseline colposcopy, biopsy or Pap smear did not predict HPV persistence, whereas an incident or persistent abnormal Pap during the follow-up were independent predictors in a multivariate model (p = 0.005), together with the high viral load (HCII RLU/CO at 100 pg/ml cut-off), and HR HPV positive PCR test (p = 0.0001). When all significant variables were entered in the regression model, only the follow-up time (OR 0.950, 95% CI 0.924-0.976; p = 0.0001) and HR-HPV positive PCR (OR 4.169, 95% CI 1.741-9.987; p = 0.001), remained independent predictors. CONCLUSIONS: While several factors were related to HR-HPV persistence in univariate analysis and when adjusted for age and follow-up time as confounders, the only independent predictors in the multivariate regression model were follow-up time and HR-HPV positive PCR. Clearly more data are needed on type-specific persistence and HPV integration as its predictors.

Adult↗
PubMed2003

Expression of macrophage migration inhibitory factor in diffuse systemic sclerosis.

OBJECTIVE: To evaluate whether, in patients with the diffuse form of systemic sclerosis (dSSc), macrophage migration inhibitory factor (MIF) production is dysregulated. METHODS: 10 patients with dSSc and 10 healthy controls, matched for age and sex, were studied. MIF expression was evaluated by immunohistochemistry on formalin fixed skin biopsies of patients with dSSc and controls. MIF levels were assayed in the sera and in the supernatants of skin cultured fibroblasts by a colorimetric sandwich enzyme linked immunosorbent assay (ELISA). MIF concentrations in culture medium samples and in serum samples were compared by Student's two tailed t test for unpaired data. RESULTS: Anti-MIF antibody immunostained the basal and mainly suprabasal keratinocytes. Small perivascular clusters of infiltrating mononuclear cells were positive; scattered spindle fibroblast-like cells were immunostained in superficial and deep dermal layers. The serum concentrations of MIF in patients with dSSc (mean (SD) 10705.6 (9311) pg/ml) were significantly higher than in controls (2157.5 (1288.6) pg/ml; p=0.011); MIF levels from dSSc fibroblast cultures (mean (SD) 1.74 (0.16) ng/2 x 10(5) cells) were also significantly higher than in controls (0.6 (0.2) ng/2 x 10(5) cells; p=0.008). CONCLUSION: These results suggest that MIF may be involved in the amplifying proinflammatory loop leading to scleroderma tissue remodelling.

Adult↗
PubMed2003

Static and ELF magnetic fields enhance the in vivo anti-tumor efficacy of cis-platin against lewis lung carcinoma, but not of cyclophosphamide against B16 melanotic melanoma.

Previous works showed that exposure to static and extremely low frequency (ELF) magnetic fields (MF) over 3 mT slows down the growth kinetics of human tumors engrafted s.c. in immunodeficient mice, reducing their metastatizing power and prolonging mouse survival. In the experiments reported here, immunocompetent mice bearing murine Lewis Lung carcinomas (LLCs) or B16 melanotic melanomas were exposed to MF and treated respectively with two commonly used anti-cancer drugs: cis-diamminedichloroplatinum (cis-platin) and N,N-bis (2-chloroethyl)tetra-hydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide (cyclophosphamide). The experiment endpoint was survival time. The survival time of mice treated with cis-platin (3mg/kg i.p.) and exposed to MF was significantly (P<0.01) longer than that of mice treated only with cis-platin or only exposed to MF, superimposing that of mice treated with 10mg/kg i.p. of the drug, showing that MF act synergically with the pharmacological treatment. On the contrary, when mice treated with cyclophosphamide (50mg/kg i.p.) were exposed to MF no synergic effects were observed, the survival curve being exactly the same as that of mice treated with the drug alone. No clinical signs or toxicity were seen in any of the mice exposed to MF alone or along with cis-platin or cyclophosphamide treatment, compared to mice given only the two known drugs.A possible explanation for the synergic effect of MF being found in mice treated with cis-platin could be that the platinum ion stimulates radical production and that MF enhance active oxygen production bringing about changes in tumor cell membrane permeability, influencing positively the drug uptake. Alternatively, or in addition to this, it has been demonstrated that the rate of conversion of cis-platin to reactive species able to bind to DNA, is increased by localized production of free radicals by MF.

Animals↗
PubMed2002

Identification of urocortin mRNA and peptide in the human endometrium.

Urocortin is a 40-amino acid peptide belonging to the corticotropin-releasing factor (CRF) family. In human reproductive tissues, urocortin expression has been previously demonstrated in the ovary, in the placenta and fetal membranes and in pregnant uterine tissues, while no data are available on the expression of the peptide in the nonpregnant uterus. In this study, urocortin expression was evaluated by both immunohistochemistry and reverse transcription-polymerase chain reaction, in human uterine tissues and cells at different phases of the menstrual cycle. Urocortin was immunolocalized in endometrial epithelial and stromal cells, as well as in the myometrium, and in vascular smooth muscle cells. No differences between proliferative and secretory phase were observed. These results were confirmed by reverse transcription-polymerase chain reaction analysis of isolated endometrial epithelial and stromal cells, and myometrial specimens. These findings open new questions on the roles played by urocortin in the human uterus.

Corticotropin-Releasing Hormone↗
PubMed2002

Interferons and their receptors in human papillomavirus lesions of the uterine cervix.

PURPOSE OF INVESTIGATION: In this study we analyzed the immunohistochemical expression of specific types of interferon (IFN) in human papillomavirus (HPV) associated cervical lesions. METHODS: Reactivity to anti-IFN-alpha,-beta and -gamma and to anti-IFN-alpha/beta- and gamma-receptors was tested in 33 cervical punch biopsies from 24 HPV-infected women and nine healthy controls. The HPV-infected cases were subdivided into low-risk and high-risk groups, according to the known "oncogenic" potential of the HPV-types detected by PCR. RESULTS: Cervical epithelium and stroma in HPV-negative as well as low-risk HPV-positive samples were diffusely stained by anti IFN-alpha, beta and gamma antibodies. In contrast, a significantly lower percentage of high-risk HPV-infected tissues was immunoreactive to IFN-beta in the stroma and IFN-gamma in the epithelium. There were no relevant differences between control and HPV cases in the expression of IFN-receptors. CONCLUSION: We show that a decreased production of some specific classes of IFN is associated with high-risk-type HPV lesions suggesting an important role of IFN distribution patterns in the pathogenesis of HPV lesions.

Adult↗
PubMed2001

Thymic hyperplasia and lung carcinomas in a line of mice transgenic for keratin 5-driven HPV16 E6/E7 oncogenes.

Human Papillomavirus type 16 (HPV-16) is the cause of both benign lesions and ano-genital cancers. In HPV-associated cancers the transforming properties of the expressed viral E6 and E7 proteins have been revealed by a number of different assays. We have generated transgenic mice expressing HPV-16 E6/E7 genes under the control of the murine keratin 5 gene promoter, which should confer cell-type specific expression in the basal cells of squamous stratified epithelia. Transgenic mice developed thymic hyperplasia and lung neoplasia with 100% frequency, the thymus showing a size increase at 2 months and reaching the maximum dimension at 6 months, when lung carcinomas appeared. After this time the size of hyperplastic thymi decreased, while malignant formations invaded the mediastinal area. Hepatic metastasis could be also observed in some of the animals at the autopsy and death invariably occurred around 10-11 months of age.

Animals↗
PubMed2001

Altered glutathione anti-oxidant metabolism during tumor progression in human renal-cell carcinoma.

It has been proposed that oxidative stress develops in tumors, with important consequences for growth and progression. To investigate this hypothesis, we measured low m.w. thiols, disulfides, protein-mixed disulfides and a pool of major anti-oxidant enzymes in renal-cortex as well as renal-cell carcinoma (RCC) specimens at stages I-II and III. Our data showed (i) a significant increase in the levels of total intracellular glutathione at both tumor stages (levels were 2.6-2.8 fold higher than those in the normal renal cortex), (ii) a marked lowering of the GSH/GSSG ratio in stage I-II accompanied by a significant decrease of many GSH-dependent enzymes (i.e., GPX, GST, GGT, GR) and (iii) unchanged GSH/GSSG ratio and GSH-dependent enzyme activity in stage III with respect to normal renal cortex. These results indicate that relevant variations exist in the glutathione antioxidant system in the different stages of RCC and support the hypothesis that oxidative stress plays an important role in RCC growth and progression.

Adult↗
PubMed2001

Static and ELF magnetic fields induce tumor growth inhibition and apoptosis.

The ability of static and extremely low frequency (ELF) Magnetic Fields (MF) to interfere with neoplastic cell function has been evaluated. In vitro experiments were carried out to study the role of MF characteristics (intensity, frequency, and modulation) on two transformed cell lines (WiDr human colon adenocarcinoma and MCF-7 human breast adenocarcinoma) and one nontransformed cell line (MRC-5 embryonal lung fibroblast). Increase in cell death morphologically consistent with apoptosis was reported exclusively in the two transformed cell lines. Cell-death induction was observed with MF of more than 1 mT. It was independent of the MF frequency and increased when modulated MF (static with a superimposition of ELF at 50 Hz) were used. Based on the in vitro results, four different MF exposure characteristics were selected and used to treat nude mice xenografted with WiDr cells. The treatment of nude mice bearing WiDr tumors subcutaneously. with daily exposure for 70 min to MF for 4 weeks caused significant tumor growth inhibition (up to 50%) by the end of the treatment when modulated MF were used for at least 60% of the whole treatment period and the time-averaged total MF intensity was higher than 3.59 mT. No toxic morphological changes induced by exposure were observed in renewing, slowly proliferating, or static normal cells. A discussion on the possible biophysical mechanism at the base of the observed biological results is also offered.

Adenocarcinoma↗
PubMed2001

Prediction of lymph node status by analysis of prognostic factors and possible indications for elective axillary dissection in T1 breast cancers.

OBJECTIVE: To identify those patients with T1 breast cancers with lower risk of nodal metastases who can safely be spared axillary dissection. DESIGN: Retrospective study. SETTING: University hospital, Italy. SUBJECTS: Review of clinical records and histopathological slides of 547 patients with T1 breast cancer, operated on between 1984 and 1997. MAIN OUTCOME MEASURES: Incidence of axillary metastases in relation to age, menopausal status, diameter and grade of tumour, vascular invasion, DNA ploidy, S-phase fraction and hormone receptor state, by univariate and multivariate analysis. RESULTS: Axillary metastases were present in 159 patients (29%). On univariate analysis, diameter of tumour 10 mm or less (pT1a/pT1b cancers), no vascular invasion, and grade 1 tumour were significantly correlated with a lower risk of nodal metastases, but only vascular invasion (p = 0.0001, odds ratio = 3.1) and diameter of tumour (p = 0.04, odds ratio = 1.6) were independent predictors on multivariate analysis. Among 34 pT1a/pT1b cancers, with low grade of tumour and no vascular invasion, only 2 (6%) had axillary metastases. When only one favourable predictive factor was associated with diameter of tumour of 10 mm or less, the incidence of axillary metastases ranged from 12% for 43 patients with grade 1 cancers to 13% for 76 patients with no vascular invasion. CONCLUSIONS: Axillary dissection may be avoided in pT1a and pT1b breast cancers (< or = 10 mm), with low grade of tumour or no vascular invasion. T1 breast cancers 10 mm or less in diameter should be treated by a two-step approach, first wide excision of the tumour and then axillary dissection or not depending on pathological examination of the primary tumour.

Adult↗
PubMed2001

Macrophage migration inhibitory factor in the human endometrium: expression and localization during the menstrual cycle and early pregnancy.

Macrophage migration inhibitory factor (MIF) was discovered as an activated T-lymphocyte-derived protein that inhibits the random migration of macrophages in vitro. Subsequently, knowledge of the physiological actions of MIF was extended to include its role as a proinflammatory cytokine that affects several functions of macrophages and lymphocytes. Previous reports have suggested an involvement of MIF in reproduction. However, no data are currently available on the presence of this cytokine in the human endometrium. In this study, the expression and tissue localization of MIF was evaluated in specimens of cycling endometrium, first trimester placenta bed biopsy, and isolated endometrial glands by Western blot analysis, immunohistochemistry, ELISA, and reverse transcription-polymerase chain reaction. The results demonstrated that MIF is expressed in human endometrium across the menstrual cycle and in early pregnancy. Immunohistochemical localization identified the protein in glandular epithelium, in stromal and predecidualized stromal cells of cycling endometrium, as well as in the decidua of first-trimester placenta. The proinflammatory features and specific actions of MIF on lymphoid cells suggest its potential involvement in several aspects of endometrial physiology.

Blotting, Western↗
PubMed2000

Macrophage migration inhibitory factor in prostatic adenocarcinoma: correlation with tumor grading and combination endocrine treatment-related changes.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a ubiquitary cytokine whose expression has been investigated in tumors, showing a correlation between tumor aggressiveness and production of this protein by neoplastic cells. The aim of our study was to correlate MIF expression with tumor grade (Gleason scoring system) and histopathological changes after combined endocrine treatment (CET) of prostate adenocarcinoma. METHODS: We analyzed MIF immunoreactivity in 124 paired needle biopsies and radical prostatectomy specimens from 62 prostate cancer patients, of which 20 had been treated with CET. RESULTS: In untreated prostates, MIF expression significantly correlated with tumor grading, being stronger in low-grade than in high-grade adenocarcinoma. In treated prostates, histopathological changes also correlated with MIF immunoreactivity, but not in a significant manner. CONCLUSIONS: The results of the current study demonstrated that with histological dedifferentiation, prostate adenocarcinoma cells show a reduced MIF expression. This finding may be the consequence of a reduced MIF synthesis or the result of an enhanced and altered secretion by tumor cells into the surrounding stroma. The consequent abnormal interaction between MIF and environmental factors might influence tumor growth and diffusion. On the other hand, the minor but not significantly reduced MIF expression by tumor cells after CET seems to exclude a hormonal regulation of MIF secretion.

Adenocarcinoma↗
PubMed2000

Progestin regulation of 11beta-hydroxysteroid dehydrogenase expression in T-47D human breast cancer cells.

This study examined the enzymatic characteristics and steroid regulation of the glucocorticoid-metabolizing enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in the human breast cancer cell line T-47D. In cell homogenates, exogenous NAD significantly increased the conversion of corticosterone to 11-dehydrocorticosterone, while NADP was ineffective. There was no conversion of 11-dehydrocorticosterone to corticosterone either with NADH or NADPH demonstrating the lack of reductase activity. In keeping with these results, RT-PCR analysis indicated a mRNA for 11beta-HSD2 in T-47D cells, while 11beta-HSD1 mRNA levels were undetectable. In T-47D cells treated for 24 h with medroxyprogesterone acetate (MPA), 11beta-HSD catalytic activity was elevated 11-fold, while estrone (E(1)), estradiol (E(2)) and the synthetic glucocorticoid dexamethasone (DEX) were ineffective. The antiprogestin mifepristone (RU486) acted as a pure antagonist of the progestin-enhanced 11beta-HSD activity, but did not exert any agonistic effects of its own. In addition, RT-PCR analysis demonstrated that MPA was a potent inducer of 11beta-HSD2 gene expression, increasing the steady-state levels of 11beta-HSD2 mRNA. Taken together, these results demonstrate that 11beta-HSD2 is the 11beta-HSD isoform expressed by T-47D cells under steady-state conditions and suggest the existence of a previously undocumented mechanism of action of progestins in breast cancer cells.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2000

Microcystic adenoma of the pancreas (glycogen-rich cystadenoma) with stromal amyloid deposits.

AIMS: We report a case of a pancreatic glycogen-rich microcystic serous adenoma with stromal amyloid deposits, focusing on the significance of isolated amyloid deposits in tumours. METHODS AND RESULTS: The architectural pattern was characterized by thin-walled cysts lined by a single layer of flat or cuboidal epithelial cells intensely stained by the PAS-reaction only before diastase digestion, suggesting the presence of glycogen. Tumour stroma was composed of broad fibrocollagenous tissue with lamellar hyalinized areas which were positively stained by Congo red and showed green birefringence and dichroism with polarized light. For amyloid protein characterization, immunohistochemical studies were performed with anti-beta amyloid protein and anti-amyloid precursor pre-A4695. The former antibody diffusely stained tumour stroma, while the latter stained only scattered stroma cells. CONCLUSIONS: This is the first documented case of amyloid deposition in pancreatic serous adenoma. We indicate that the source of amyloid is an APP-like precursor secreted by stromal myofibroblasts.

Adenoma↗
PubMed2000

Human papillomavirus involvement in esophageal carcinogenesis in the high-incidence area of China. A study of 700 cases by screening and type-specific in situ hybridization.

BACKGROUND: Human papillomavirus (HPV) DNA has been identified in esophageal precancerous lesions and carcinomas. However, there are marked variations in the prevalence of HPV infection reported in different studies. Most previous studies on HPV and esophageal carcinomas have been based on a limited number of biopsy samples studied by different HPV detection methods with highly variable sensitivity and specificity, making systematic studies of larger series clearly warranted. METHODS: A series of 1876 surgical specimens (primary tumor, adjacent epithelium, regional lymph nodes, resection margins) from 700 patients surgically resected for an invasive squamous cell carcinoma of the esophagus in the high-incidence area of China was analyzed for the presence of HPV DNA with screening in situ hybridization (ISH) using biotinylated HPV DNA probes and followed by type-specific ISH for HPV 6, 11, 16, 18, 30, and 53. RESULTS: Of the 700 esophageal carcinomas, 118 (16.9%) were shown to contain HPV DNA sequences by screening ISH. Positive signals were most frequent in the cancer cells (16.6%), more rare in the surrounding hyperplastic and dysplastic epithelia (5.6%), and infrequently present in the resection margins (0.2%). HPV signals were also detected in cancer cells in 6.9% of the lymph node metastases. HPV types 6, 11, 16, 18, and 30 account for 39.8% of the HPV-positive lesions, of which the high-risk types HPV 16 and 18 were present in 27.1% (32 of 118). Notably, 60.2% of the HPV-positive lesions contained DNA sequences other than HPV types 6, 11, 16, 18, 30, and 53. CONCLUSIONS: This study reports the largest series of esophageal cancers ever analyzed for the presence of HPV DNA. Our results confirm the presence of common mucosal HPV types in esophageal carcinomas but also suggest the involvement of other (novel?) HPV types that are unusually detected in genital cancers in a significant proportion of these lesions. The results further indicate that HVP has an etiologic role in esophageal carcinogenesis, at least in the high-incidence area of northern China.

Biopsy↗
PubMed1999

Macrophage migration inhibitory factor in the human prostate: identification and immunocytochemical localization.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a lymphokine originally identified for its capacity to inhibit the random migration of macrophages. Recent data have further extended knowledge of the physiological role of this protein, showing that MIF is produced by several human organs and tissues. The present study was intended to evaluate the expression and tissutal localization of MIF in the human prostate. METHODS: Prostate tissues were obtained from patients undergoing surgical adenomectomy for benign prostatic hyperplasia and were analyzed by Western blot, reverse transcriptase-polymerase chain reaction, immunohistochemistry, and immunoelectron microscopy. RESULTS. The presence of both MIF protein and mRNA was demonstrated in the prostate. Immunocytochemical studies localized MIF protein in the secretory luminal epithelial and basal layer cells. CONCLUSIONS: The present study demonstrated that the human prostate is a site of MIF synthesis. Macrophages populate the human prostate and represent an important mechanism of defense of integrity and functionality of the gland. It is speculated that MIF might play a role in preserving prostate physiological activity by maintaining its macrophage population.

Blotting, Western↗