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Biomedical subjects

M Rubini

Publications and source records attributed to M Rubini.

At least 19 recordsLinked to original sources
PubMed2006

Colorectal cancer screening: results of a 5-year program in asymptomatic subjects at increased risk.

BACKGROUND AND AIMS: The province of Ferrara has one of the highest incidences of colorectal cancer (CRC) in Italy. In January 2000, we set up a colonoscopy screening program focussing on first-degree relatives of CRC patients. We now report the results 5 years after the beginning of the project. SCREENEES AND METHODS: In October 1999, we started a campaign stressing the usefulness of colonoscopy for the first-degree relatives of CRC patients. Subjects included in the screening program were aged between 45 and 75 years with at least one first-degree relative affected by CRC. They were invited to an interview where a physician suggested colonoscopy as a screening option. RESULTS: In 5 years, 776 subjects were interviewed and 733 (94.4%) agreed to an endoscopic examination (M/F:375/401; mean age 55 years): 562 colonoscopies were performed. Adenomas and cancers were found in 122 (21.7%) and 12 (2.1%) subjects, respectively. Histological examination in 181 persons with lesions (32.8%) showed (most serious lesion quoted) 47 hyperplastic polyps (26% of all lesions), 2 serrated adenomas (1.1%), 68 tubular adenomas (48%), 24 tubulovillous adenomas (13.3%), 9 adenomas with high grade dysplasia (5%) and 12 adenocarcinomas (6.6%). The majority of the cancers were at an early stage (8 Dukes A and 3 Dukes B). Sedation was used in only 42 colonoscopies (7.5%). CONCLUSIONS: A colonoscopy-based screening in this selected high-risk population is feasible. Even without sedation subjects readily agreed to the endoscopic procedure. We identified a significant number of advanced neoplasms and cancers at an early stage suggesting that this could be a useful tool in early identification of CRC.

Adenoma↗
PubMed2005

Development of strategies for the use of anti-growth factor treatments.

Aberrant signalling through the epidermal growth factor receptor (EGFR) is associated with increased cancer cell proliferation, reduced apoptosis, invasion and angiogenesis. Over-expression of the EGFR is seen in a variety of tumours and is a rational target for antitumour strategies. Among the classes of agent targeting the EGFR are small-molecule inhibitors, which include gefitinib (IRESSA), which acts by preventing EGFR phosphorylation and downstream signal transduction. De novo and acquired resistance, however, have been reported to gefitinib and here we describe evidence which indicates that the type II receptor tyrosine kinases (RTKs) insulin-like growth factor-I receptor (IGF-IR) and/or insulin receptor (InsR) play important roles in the mediation of responses to gefitinib in the de novo- and acquired-resistance phenotypes in several cancer types. Moreover, combination strategies that additionally target the IGF-IR/InsR can enhance the antitumour effects of gefitinib.

Antineoplastic Agents↗
PubMed2005

Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer.

Breast cancer models of acquired tamoxifen resistance, oestrogen receptor (ER)+ /ER- de novo resistance and gene transfer studies cumulatively demonstrate the increased importance of growth factor receptor signalling, notably the epidermal growth factor receptor (EGFR)/HER2, in tamoxifen resistance. Our recent in vitro studies also suggest that EGFR signalling productively cross-talks with insulin-like growth factor receptor (IGF-1R) and, where present, activates ER on key AF-1 serine residues to facilitate acquired tamoxifen-resistant growth. This paper presents our immunohistochemical evidence that EGFR/HER2 signalling (i.e. transforming growth factor (TGF)alpha, EGFR and HER2 expression; phosphorylation of EGFR, HER2 and ERK1/2 MAP kinase) is also prominent in clinical de novo resistant and modestly increased in acquired tamoxifen-resistant states, suggesting that anti-EGFR/HER2 strategies may prove valuable treatments. Primary breast cancer samples employed were obtained for (1) patients subsequently treated with tamoxifen for advanced disease where endocrine response and survival data were available and (2) ER+ elderly patients during tamoxifen response and relapse. We also present our clinical immunohistochemical findings that IGF-1R expression, its phosphorylation on tyrosine 1316, and also phosphorylation on serine 118 of ER are not only prominent in ER+ tamoxifen-responsive disease, but are also detectable in ER+ de novo and acquired tamoxifen-resistant breast cancer, where there is evidence of EGFR/ER cross-talk. Our data suggest that agents to deplete effectively ER or IGF-1R signalling may be of value in treating ER+ de novo/acquired tamoxifen resistance in addition to tamoxifen-responsive disease in vivo. IGF-1R inhibitors may also prove valuable in ER- patients, since considerable IGF-1R signalling activity was apparent within approximately 50% of such tumours.

Antineoplastic Agents, Hormonal↗
PubMed2004

Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells.

De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 microM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinib-resistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)delta, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 microM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinib-resistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.

Antineoplastic Agents↗
PubMed2001

Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas.

Insulin-like growth factor I receptor (IGF-IR) has been implicated in the normal and malignant growth of many cell types including cells from the central nervous system. In the cerebellar cortex IGF-IR mRNA is found in granular cells and IGF-I stimulation is mitogenic and protects cells from low-potassium-induced apoptosis. Since primitive neuroectodermal tumors/medulloblastomas (PNETs/medulloblastomas) are suspected to originate from the external cerebellar granular layer, it is reasonable to postulate that IGF-IR and/or its signaling molecules may contribute to the transformation of these poorly differentiated cells. To study activation of the IGF-IR system in medulloblastomas, we have utilized an antibody (anti-pY1316) that specifically recognizes the phosphorylated (active) form of the IGF-IR. Medulloblastoma biopsy specimens were positive when examined immunohistochemically with anti-Y1316 antibody. Further analysis of the IGF-IR system was performed in three human (Daoy, TE-671, D283 Med) and four mouse (BsB8, BsB13, Bs-1b, Bs-1c) medulloblastoma cell lines. All the murine cell lines examined express IGF-IR and PI3-kinase at relatively normal levels, and grossly overexpress IRS-1, when compared with normal mouse cerebellum. Within 15 min following IGF-I stimulation both mouse and human cell lines phosphorylate the beta subunit of the IGF-IR, IRS-1, Akt, and MAP kinases. They respond with cell proliferation when stimulated solely with IGF-I and are strongly inhibited when challenged with a dominant negative mutant of the IGF-IR (486/STOP), or with antisense oligonucleotides against the IGF-IR mRNA.

Animals↗
PubMed2001

[Upper gastrointestinal bleeding - Review of our ten years results].

Acute upper gastrointestinal bleeding (UGIB) is a common reason for emergency hospitalisation. Early upper gastrointestinal endoscopy is the corner stone of management; the alternative option for achieving primary hemostasis is emergency surgery. The aim of this study was to analyse the frequency of UGIB in the last 10 years and to present our surgical results. We observed 5 955 bleeding patients (68.4 % male and 31.6 % female) with a mean age of 57.7 inverted question mark 15.8 years. The most frequent causes of bleeding were gastric and duodenal ulcers (61 %) followed by gastroduodenal erosions (15.4 %) and varicous veins (5.7 %). Indications for emergency surgery were massive UGIB or rebleeding after active endoscopic treatment. On operation, gastric and duodenal ulcers were responsible for massive UGIB in 86.4 % cases. Overall hospital mortality rate during 10 years was 13.2 % and depended on age and concomitant diseases. In total 5.9 % of operated patients were rebleeding. Those with rebleeding underwent a second operation and showed a statistically higher mortality rate (35.7 % vs 11.8 %) compared to those surgical patients without rebleeding; p < 0.001. The mortality rate after vagotomy and pyloroplasty was 13.2 % (14/106) and did not differ significantly from that after gastric resection (15.2 %; 9/59).

Adult↗
PubMed1999

Characterization of an antibody that can detect an activated IGF-I receptor in human cancers.

The type 1 insulin-like growth factor receptor (IGF-IR) plays an important role in malignant transformation and in apoptosis. Its role in human cancer has now been firmly established. IGF-IR signaling occurs only when the receptor is activated by its ligands, which induce autophosphorylation of the receptor at several tyrosine residues. Although the IGF-IR (phosphorylated or not) can be detected in human cancers with conventional antibodies, it would be desirable to obtain antibodies that can detect the IGF-IR only when activated by its ligands. We describe and characterize in this paper such an antibody and show that it can be used in sections of human cancers to detect an autophosphorylated IGF-IR. This antibody will be useful in detecting autocrine or paracrine influences on normal and tumor cells and could eventually be also useful in diagnostic and prognostic studies of human primary and metastatic cancer.

Amino Acid Sequence↗
PubMed1998

Size correlation in Wormian bones.

This study examines the correlation in size between some Wormian bones (lambda bone and lambdoid ossicles) and between them and some cranial measurements concerning the cephalic index and cranial capacity. The sizes of the lambda bone and lambda ossicles are not correlated among themselves. The female ossicle sizes are correlated with cranial length and width.

Adult↗
PubMed1997

Protective effect of the insulin-like growth factor I receptor on apoptosis induced by okadaic acid.

Okadaic acid (OKA), a potent inhibitor of serine phosphatases at concentrations as low as 20-25 nM, induces apoptosis of R- mouse embryo fibroblasts, which are 3T3-like cells devoid of type 1 insulin-like growth factor receptors (IGF-IRs). From R- cells, we have generated (by stable transfection) cell lines with IGF-IR numbers ranging from 0 (R- cells) to >10(6) receptors per cell. The wild-type IGF-IR protects R- cells from OKA-induced apoptosis, its protective effect being exquisitely dependent on the number of receptors. A small increment in wild-type receptor number (from 15 x 10(3) to 22 x 10(3) receptors/cell) is sufficient to change R(-)-derived cells from sensitive to resistant to apoptosis. We have also studied the effect of various mutations of the IGF-IR on its ability to protect R(-)-derived cells from OKA-induced apoptosis. Our data indicate a correlation between protection from apoptosis and the ability of the receptor to respond to insulin-like growth factor I with mitogenesis.

Animals↗
PubMed1997

Identification of signalling components in tyrosine kinase cascades using phosphopeptide affinity chromatography.

Various methods are now available to identify the molecular partners of the component of a signal transduction pathway. Some interactions, however, can be technically difficult to detect because they depend upon transient tyrosine phosphorylation. Here, we present a simple affinity chromatography approach based on synthetic phosphopeptides to purify potential partners of phosphotyrosine-containing proteins. With this approach, we confirm the previously characterized interaction between Grb2 and the EGF receptor, and we identify novel partners of the IGF-1 receptor and of the JAK proteins. Methenyltetrahydrofolate synthetase (MTHFS) was identified as a potential mediator of IGF-1R dependent transformation. P85alpha, the regulatory subunit of PI3 kinase, was identified as one of four proteins recruited by a phosphopeptide mimicking a motif conserved in all JAK family members.

Adaptor Proteins, Signal Transducing↗
PubMed1997

The IGF-I receptor in mitogenesis and transformation of mouse embryo cells: role of receptor number.

The type 1 receptor for insulin-like growth factors (IGF-IR) plays an important role in the growth and transformation of several types of cells. We have investigated the role of IGF-IR number in IGF-I-mediated mitogenesis and transformation of mouse embryo fibroblasts. We have used R- cells (3T3-like cells originating from mouse embryos with a targeted disruption of the IGF-IR genes) transfected with a plasmid expressing the human IGF-IR cDNA to generate clones with receptor numbers ranging from zero to 10(6) receptors per cell. In this model, between 15,000 and 22,000 receptors per cell are sufficient to render mouse embryo cells competent to grow in serum-free medium supplemented solely with IGF-I. For growth in soft agar, 30,000 receptors per cell seem to be the minimum requirement. These experiments indicate that a small increment in the number of receptors per cell, well within the physiological range, can modulate the mitogenic and transforming activities of the IGF-IR in 3T3-like cells.

3T3 Cells↗
PubMed1997

PROTOANEMONIN-INDUCED CYTOTOXIC EFFECTS IN EUGLENA GRACILIS

The changes that protoanemonin, an antimicrobial agent of natural origin, brought about in the alga Euglena gracilis were studied with light and electron microscopy and with flow cytometry. The compound proved lethal for the alga at a dose of 5x10(-5)m. At the sublethal dose of 3.5x10(-5)m it caused: marked inhibition of growth; increase in the average cell volume; inhibition of cytokinesis and induction of coenocytic organisms; loss of the flagellum and stigma. Most nuclei were arrested in the G2/M phase of the cellular cycle. The chloroplasts were still well organized, but there was a conspicuous decrease in carotenoids and chlorophylls a and bwith a corresponding increase in pheophytins. The multifarious alterations seen in Euglena are discussed on the basis of a possible interaction between this lactone and several enzymatic systems.Copyright 1997 Academic Press Limited Copyright 1997Academic Press Limited

Journal Article↗
PubMed1997

Brief encounters ending in estrangement: motivated language use and interpersonal rapport in the question-answer paradigm.

Three experiments explored need-for-for-closure effects in the question-answer paradigm. In experiment 1, participants under high (vs. low) need for closure selected more abstract interview questions. In Experiments 2 and 3, such questions elicited more abstract answers--answers that casually implicated the object (vs. the subject) of the sentence and that prompted a less positive perceived rapport between the interviewer and the interviewee. These findings are discussed in reference to the role of motivation in language and the possible interpersonal consequences of motivated language use.

Adult↗
PubMed1996

An ATP-activated channel is involved in mitogenic stimulation of human T lymphocytes.

We investigated the effect of pharmacologic modulation of the ATP receptor on intracellular ion changes and proliferative response of human peripheral blood lymphocytes (PBLs) and purified T lymphocytes. Extracellular ATP (ATPe) triggered in these cells an increase in the cytoplasmic Ca2+ concentration ([Ca2+]i) and plasma membrane depolarization. Whereas both Ca2+ release from intracellular stores and influx across the plasma membrane were detected in the whole PBL population, only Ca2+ influx was observed in T cells. In the presence of near physiologic extracellular Na+ concentrations (125 mmol/L), Ca2+ permeability through the ATPe-gated channel was very low, suggesting a higher selectivity for monovalent over divalent cations. The selective P2Z agonist benzoylbenzoic ATP (BzATP) increased [Ca2+]i in the presence but not the absence of extracellular Ca2+ and also caused plasma membrane depolarization. The covalent blocker oxidized ATP (oATP), an inhibitor of P2X and P2Z receptors, prevented Ca2+ influx and plasma membrane depolarization, but had no effect on Ca2+ release from stores. Stimulation with ATPe alone had no significant effects on PBL 3H-thymidine incorporation. On the contrary, ATPe or BzATP had a synergistic effect on DNA synthesis stimulated by selective T-cell mitogens such as phytohemagglutinin, anti-CD3 monoclonal antibody, or allogenic PBLs (mixed lymphocyte cultures). Treatment with oATP inhibited mitogenic stimulation by these receptor-directed agents but not by the combined application of the Ca2+ ionophore ionomycin and phorbol myristate acetate. Interleukin-2 partially relieved inhibition by oATP. These results suggest that human T lymphocytes express a plasma membrane channel gated by ATPe that is involved in mitogenic stimulation.

Adenosine Triphosphate↗
PubMed1996

RAPD analysis of systematic relationships among the Cervidae.

We investigated the possible application of RAPD (Random Amplified Polymorphic DNA) analysis to the study of the systematic relationships of five cervid taxa. Amplifications with eight different primers gave reproducible electrophoretic patterns which could be regarded as a data-set consisting of monomorphic and polymorphic characters. Some of these characters are species- and subspecies-specific. Band-sharing analysis and numerical taxonomy methods allowed us to generate a phenetic tree. Our results point out new possible systematic considerations within the examined taxa.

Animals↗