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Biomedical subjects

M Bologna

Publications and source records attributed to M Bologna.

At least 19 recordsLinked to original sources
PubMed2006

GnRH agonists and antagonists decrease the metastatic progression of human prostate cancer cell lines by inhibiting the plasminogen activator system.

Prostate cancer (PCa) growth initially depends on circulating androgens. Gonadotropin-releasing hormone (GnRH) agonists are currently used for the treatment of PCa. However, after an initial responsiveness to hormonal deprivation, PCa progresses and metastasizes. Recently, also GnRH antagonists have been used for clinical trials in patients with PCa and the results seem promising. The components of the plasminogen activator (PA) system (urokinase-type PA, uPA; PA inhibitors, PAI-1/2; uPA receptor, uPAR) have been implicated in the local degradation of the extracellular matrix (ECM) and PCa progression. The aim of this study was to test the possible effects of the treatment with an agonist (Leuprolide, GnRH-A) and an antagonist (Cetrorelix, GnRH-ANT) of GnRH on the expression and activity of uPA and PAI-1 in the conditioned media of DU145 and PC3, two PCa androgen-independent cell lines. The involvement of the PA system in the control of cellular migration was also investigated. The results obtained in DU145 and PC3 cells show that both GnRH-A and GnRH-ANT: i) inhibit cell proliferation; ii) significantly decrease the enzymatic activity and the secretion of uPA; iii) significantly increase the protein levels of PAI-1; iv) induce a significant decrease of the migratory and invasion PCa capabilities. This study suggests that GnRH analogues exhibit not only an antiproliferative effect, but also an anti-metastatic action exerted through the inhibition of the activity of PA system and might provide a rational basis for the development of clinical strategies for those tumours that progress towards an androgen-independent condition characterized by a higher metastatic potential.

Antineoplastic Agents, Hormonal↗
PubMed2005

Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases.

An important factor implicated in tumor cell predisposition for invasion and metastasis is the malignancy-related upregulation of urokinase plasminogen activator receptor (uPAR). uPAR signals by activating different tyrosine kinases in different cells. We examined the effects of inhibiting uPAR signaling by inhibition of uPAR expression with antisense oligonucleotides (aODNs) in PC3 human prostate cancer cells and evaluated aODN effect in a mouse model of prostate cancer bone metastasis. Following uPAR aODN treatment, PC3 cells exhibited a strong decrease in uPAR expression, evaluated by flow cytometry and by polymerase chain reaction, and of FAK/JNK/Jun phosphorylation. The synthesis of cyclins A, B, D1 and D3 was inhibited, as shown by Western blotting, flow cytometry and polymerase chain reaction, and PC3 cells accumulated in the G2 phase of the cell cycle. PC3 cells' adhesion was unaffected, while proliferation and invasion of Matrigel were impaired. A total of 60 mice were subjected to intracardiac injection of PC3 cells and were randomly assigned to three groups: aODN (treated with 0.5 mg intraperitoneum/mouse/day), dODN (treated with the same amounts of a degenerated ODN) and control (injected with a saline solution). At 28 days after heart injection, mice were subjected to a digital scan of total body radiography, which revealed 80% reduction in mice affected by bone metastasis. The use of uPAR aODNs produced a substantial prophylactic effect against prostate cancer bone metastasis, which has to be ascribed to downregulation of uPAR expression.

Animals↗
PubMed2005

Molecular aspects of gefitinib antiproliferative and pro-apoptotic effects in PTEN-positive and PTEN-negative prostate cancer cell lines.

To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer (PCa) to more invasive forms. One of the major targets for the therapy in PCa can be epidermal growth factor receptor (EGFR), which signals via the phosphoinositide 3'-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways, among others. Despite multiple reports of overexpression in PCa, the reliance on activated EGFR and its downstream signalling to the PI3K and/or MAPK/extracellular signal-regulated kinase (ERK) pathways has not been fully elucidated. We reported that the EGFR-selective tyrosine kinase inhibitor gefitinib (ZD1839; Iressa) is able to induce growth inhibition, G(1) arrest and apoptosis in PCa cells and that its effectiveness is associated primarily with phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression (and thus Akt activity). In fact PTEN-negative PCa cells are slowly sensitive to gefitinib treatment, because this molecule is unable to downregulate PI3K/Akt activity. PI3K inhibition, by LY294002 or after PTEN transfection, restores EGFR-stimulated Akt signalling and sensitizes the cells to pro-apoptotic action of gefitinib. The MAPK pathway seems to be involved primarily on cell-growth modulation because dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition (both not cell apoptosis) in PTEN-positive PCa cells and reduced EGF-mediated growth in PTEN-negative cells. Thus the effectiveness of gefitinib requires growth factor receptor-stimulated PI3K/Akt and MAPK signalling to be intact and functional. The loss of the PTEN activity leads to uncoupling of this signalling pathway, determining a partial gefitinib resistance. Moreover, gefitinib sensitivity may be maintained in these cells through its inhibitory potential in MAPK/ERK pathway activity, modulating proliferative EGFR-triggered events. Therefore, our data suggest that the inhibition of EGFR signalling can result in a significant growth reduction and in increased apoptosis in EGFR-overexpressing PCa cells with different modalities, which are regulated by PTEN status, and this may have relevance in the clinical setting of PCa.

Antineoplastic Agents↗
PubMed2005

A two-year course of specific immunotherapy or of continuous antihistamine treatment reverse eosinophilic inflammation in severe persistent allergic rhinitis.

Aim of the study was to evaluate the effect of a 2-year course of subcutaneous specific immunotherapy or continuous oral antihistamine treatment on the eosinophilic inflammation in nasal secretions of patients with severe persistent allergic rhinitis caused by house dust-mites. After informed consent, 31 rhinitis patients, sensitive to dust-mite antigens, were enrolled: 12 were randomly assigned to specific immunotherapy (group A), 11 to continuous oral antihistamine (cetirizine) treatment (group B), and 8 to an oral antihistamine (cetirizine) on demand (group C). Nasal scrapings were performed with a cotton-tipped swab and cells counted before and after 24 months of therapy. Intercellular adhesion molecule-1 and eosinophil cationic protein expression in cytological smears were assessed by immuno-histochemistry. All patients completed the study. The percentage of inflammatory cell types was comparable in the 3 groups at the beginning of the study. Eosinophils, identified as cells expressing eosinophil cationic protein, significantly decreased dropping to zero after 2 years of treatment in groups A and B, while no change was observed in group C. Expression of intercellular adhesion molecule-1 also decreased significantly in groups A and B, but not in group C. This decrease was associated with a significant reduction in epithelial shedding. In the 2-year period studied, specific subcutaneous immunotherapy and continuous oral antihistamine treatment were found to be effective in reducing eosinophilic infiltration and adhesion molecule expression in the nasal mucosa of patients with persistent allergic rhinitis. Furthermore, immunotherapy was more effective in controlling epithelial disruption while antihistamines appeared to be more active in controlling nasal inflammation. Both treatments induced a significant decrease in intercellular adhesion molecule-1 expression in epithelial cells and also a dramatic reduction of eosinophil cationic protein positive staining. These parameters can be considered useful means for controlling the state of persistent inflammation which is typical of persistent respiratory allergy. Nasal scraping was demonstrated to be a simple and safe procedure for monitoring some nasal inflammation parameters.

Administration, Oral↗
PubMed2003

Pyrrolopyrimidine c-Src inhibitors reduce growth, adhesion, motility and invasion of prostate cancer cells in vitro.

Two bona fide c-Src inhibitors, denominated CGP77675 and CGP76030, reduced in a time- and concentration-dependent manner (i) the proliferation of the PC3 prostate carcinoma cell line, as assessed by the [3H]-thymidine incorporation test, (ii) the capacity of PC3 cells to adhere and spread on Matrigel substrate, as determined by crystal violet staining, (iii) the ability of PC3 cells to migrate through a gelatine boundary and invade a Matrigel substrate. The latter effect was not due to a decrease of urokinase-type plasminogen activator (uPA), nor of metalloproteinase-2 (MMP-2) activities. The MMP-9 activity, along with the expression of the Tissue Inhibitor of Metalloproteinases (TIMP)-1 and TIMP-2, were reduced by the two inhibitors, consistent with the ability of c-Src to enhance MMP-9 and TIMP expression levels. Collectively, these data demonstrate that the pyrrolopyrimidine-derived c-Src inhibitors significantly reduced PC3 cell activities associated with their malignant phenotype.

Antineoplastic Agents↗
PubMed2002

Simplified local nasal immunotherapy in mite dust allergic rhinitis.

The present work aimed at evaluating the efficacy and tolerance of an alternative schedule of local nasal immunotherapy for the treatment of mite dust allergic rhinitis. The authors suggest the nasal administration of the maximum tolerated dosage chosen on the basis of nasal provocation test threshold, comparing allergen extracts in micronized powder and watery solution. Forty-five patients (25 men and 20 women), aged 18 to 66 years, affected by allergic rhinitis to Dermatophagoides (Dpt) were selected and treated either by local immunotherapy in watery solution (15) or in powder form (15) or by parenteral specific hyposensitizing treatment (15). Before and one year after the beginning of the study, the clinical diaries and the total and specific IgE variation were evaluated. The monthly symptoms and drugs use are comparable among the three treatment groups. No significant difference was found, with the exception of local symptomatology, which improved more in patients undergoing local immunotherapy (p > 0.05); and oral antihistamines use, which was lower in patients treated with the watery solution (p < 0.05). Thus, local simplified hyposensitizing treatment is able to combine the absence of symptomatological worsening with the decrease of both local and systemic drugs use. The advantages of the LNIT protocol proposed herein are as follows: simplified schedule for self-administration; improved patient compliance; reduction of local side effects; clinical efficacy comparable with subcutaneous specific immunotherapy.

Administration, Intranasal↗
PubMed2001

Trajectory versus probability density entropy.

We show that the widely accepted conviction that a connection can be established between the probability density entropy and the Kolmogorov-Sinai (KS) entropy is questionable. We adopt the definition of density entropy as a functional of a distribution density whose time evolution is determined by a transport equation, conceived as the only prescription to use for the calculation. Although the transport equation is built up for the purpose of affording a picture equivalent to that stemming from trajectory dynamics, no direct use of trajectory time evolution is allowed, once the transport equation is defined. With this definition in mind we prove that the detection of a time regime of increase of the density entropy with a rate identical to the KS entropy is possible only in a limited number of cases. The proposals made by some authors to establish a connection between the two entropies in general, violate our definition of density entropy and imply the concept of trajectory, which is foreign to that of density entropy.

Journal Article↗
PubMed2001

Melanoma cells stimulate osteoclastogenesis, c-Src expression and osteoblast cytokines.

Malignant melanomas metastasise to the bone and enhance osteoclast bone resorption. We demonstrated that a 48-h-B16 melanoma cell conditioned media (B16CM) induced osteoclastogenesis in mouse bone marrow cultures, without the requirement of B16 cell-bone marrow cell co-culture. B16 cells transcriptionally expressed detectable levels of TGFbeta1, IL-6, M-CSF, GM-CSF and TNFalpha mRNAs, albeit to a lower extent compared with levels in osteoblasts, and failed to express PTHrP, OPGL, OPG and IL-1beta. Interestingly, B16CM greatly upregulated IL-1beta, IL-6 and GM-CSF, and modestly enhanced TNFalpha and OPGL mRNA expression in osteoblasts, suggesting a potential indirect stimulation of osteoclastogenesis via the osteogenic lineage. B16CM barely upregulated c-Fos, but strongly and time-dependently enhanced c-Src expression in the total bone marrow cultures during osteoclast differentiation. Moreover, c-Src expression was enhanced in differentiated and purified osteoclast preparations to higher levels than in stromal cells. In conclusion, melanoma induces osteoclast generation with a paracrine mechanism independent of cell-cell contact, specifically upregulating c-Src in osteoclasts and cytokine expression in osteoblasts.

Animals↗
PubMed2001

Agar specimen orientation technique revisited: a simple and effective method in histopathology.

The agar technique represents an important method to obtain optimal orientation of small specimens during paraffin embedding and to avoid tissue loss during processing. This method is advisable for ocular, temporal artery, gastrointestinal, cervical, and skin biopsies and may be applied with formalin-fixed specimens as well as with fresh tissue. Microwave oven can be successfully used to make the small specimen orientation technique with agar quicker and easier. Ann Diagn Pathol 5:107-109, 2001.

Agar↗
PubMed2000

Specific neurons of brain cortex and cerebellum are PIPPin positive.

We recently cloned a cDNA encoding an RNA-binding protein, that we called PIPPin, which is highly enriched in the rat brain and contains two putative double stranded RNA-binding domains (PIP1 and PIP2) and a central cold shock domain (CSD). Here we report that PIPPin is specifically enriched in some pyramidal neurons of the cerebral cortex and in the Purkinje cells of the cerebellum. We also show that PIPPin inhibits translation of H1(o) and H3.3 mRNA in a cell-free system. The results reported suggest that PIPPin down-regulates histone variant expression in the developing rat brain.

Animals↗
PubMed2000

Osteoblast-derived TGF-beta1 modulates matrix degrading protease expression and activity in prostate cancer cells.

Tumor progression and metastasis may result in part from the selection of cell clones competent for survival, invasion and growth at secondary sites and characterized by loss of growth inhibitory responses, acquisition of increased adhesiveness and enhanced motility and protease expression. Transforming growth factor-beta1 (TGF-beta1) is produced by osteoblasts (OB) in a latent form and is activated by proteases in a cell-dependent manner. We show here that OB conditioned medium (OB CM) modulates Matrigel invasion of a bone metastatic prostate cancer cell line (PC3) and that this effect is blocked by antibody against TGF-beta1 and by uPA/plasmin inhibitors, suggesting that TGF-beta1 can modulate OB-mediated cell recruitment and that PC3 cells can activate TGF-beta1. TGF-beta1 induces uPA and PAI-1 secretion and promotes binding of uPA at the external plasma membrane with increased membrane-associated plasmin activity. Matrix metalloprotease-9 (MMP-9) is induced both in the medium and in the membrane associated form. Moreover, the balance between proteolytic activity and inhibition is crucial in the metastatic event. Indeed, the increment of PAI-1 could have an important regulatory role on the extracellular proteolysis and might explain the decrease of net PA and gelatinolytic activities measured in the medium. In addition, PAI-1 plays a regulative role localizing matrix degradation in some specific sites, such as areas of cell-to-cell or cell-to-ECM contacts. In conclusion, TGF-beta1 enhances PC3 Matrigel invasion by a uPA/plasmin-dependent mechanism, also involving the MMP-9, and thus may play a central role in malignant prostate tumor progression as a result of stimulating bone matrix invasion.

Animals↗
PubMed2000

Vesicle-associated urokinase plasminogen activator promotes invasion in prostate cancer cell lines.

The ability of a cell to modify the extracellular matrix is important in several pathophysiological alterations including tumorigenesis. Cell transformation is accompanied by changes in the surrounding stroma as a result of the action of specific proteases such as the urokinase plasminogen activator (uPA), which has been associated with invasive potential in many tumor types. In this study, we analyzed the release of vesicle-associated uPA by the aggressive prostatic carcinoma cell line PC3 and the implications of this release for the invasive behaviour of prostatic tumor cells. Zymography and Western blot analysis revealed the presence of vesicle-associated uPA in the high-molecular weight form. Vesicles adhered to and degraded both collagen IV and reconstituted basal membrane (Matrigel), and plasminogen enhanced the degradation in a dose-dependent manner. Addition of membrane vesicles shed by PC3 cells to cultures of the poorly invasive prostate cancer cell line LnCaP enhanced the adhesive and invasive capabilities of the latter, suggesting a mechanism involving substrate recognition and degradation. Together, these findings indicate that membrane vesicles can promote tumor invasion and point to the important role of vesicle-associated uPA in the extracellular compartment.

3T3 Cells↗
PubMed2000

Anomalous diffusion associated with nonlinear fractional derivative fokker-planck-like equation: exact time-dependent solutions

We consider the d=1 nonlinear Fokker-Planck-like equation with fractional derivatives ( partial differential/ partial differentialt)P(x,t)=D( partial differential(gamma)/ partial differentialx(gamma))[P(x,t)](nu). Exact time-dependent solutions are found for nu=(2-gamma)/(1+gamma)(-infinity<gamma</=2). By considering the long-distance asymptotic behavior of these solutions, a connection is established, namely, q=(gamma+3)/(gamma+1)(0<gamma</=2), with the solutions optimizing the nonextensive entropy characterized by index q. Interestingly enough, this relation coincides with the one already known for Levy-like superdiffusion (i.e., nu=1 and 0<gamma</=2). Finally, for (gamma,nu)=(2,0) we obtain q=5/3, which differs from the value q=2 corresponding to the gamma=2 solutions available in the literature (nu<1 porous medium equation), thus exhibiting nonuniform convergence.

Journal Article↗
PubMed1999

Osteoblast conditioned media contain TGF-beta1 and modulate the migration of prostate tumor cells and their interactions with extracellular matrix components.

Prostate cancers (PRCAs) frequently metastasize to bone. We show here that this process is facilitated by osteoblast-mediated tumor cell recruitment. Transforming growth factor-beta1 (TGF-beta1) is produced by osteoblasts in a latent form and is activated by proteases in a cell-dependent manner. This cytokine exhibits pleiotropic effects on cell-extracellular matrix (ECM) interactions and may influence tumor cell invasion and metastasis. Our purpose was to identify the potential molecular mechanisms involved in osteoblast-mediated cell recruitment and to characterize the effect of TGF-beta1 on adhesion, motility and invasiveness of a human prostate cancer cell line with high bone metastatic potential (PC3 cell line) in vitro. Conditioned media from osteoblast cultures (OB CM) enhanced PC3 cell chemotaxis and invasion of reconstituted basement membrane. These effects were blocked by a neutralizing TGF-beta1 polyclonal antibody but not by elution of the OB CM in agarose-heparin columns, suggesting that TGF-beta1, but not EGF-like proteins, contribute to PC3 cell recruitment. In addition, TGF-beta1 directly induced chemotaxis and invasion of PC3 cells in a dose-dependent manner. The TGF-beta1-mediated invasion and motility were accompanied by increased PC3 cell adhesion, spreading and alpha2beta1 and alpha3beta1 integrin expression. These events are involved in the cell adhesion to several components of basement membrane and ECM and in the selective invasion of metastatic tumor cells. Our results suggest that TGF-beta1 can influence cellular recognition of ECM components by prostatic cancer cells and can modulate cell adhesion and invasion leading to increased invasive potential. Given the widespread tissue distribution of TGF-beta1, and the high levels present in the bone, this cytokine may be an important autocrine-paracrine modulator of the bone invasive phenotype in vivo.

Animals↗
PubMed1999

Lévy diffusion as an effect of sporadic randomness.

The Lévy diffusion processes are a form of non-ordinary statistical mechanics resting, however, on the conventional Markov property. As a consequence of this, their dynamic derivation is possible provided that (i) a source of randomness is present in the corresponding microscopic dynamics and (ii) the consequent process of memory erasure is properly taken into account by the theoretical treatment.

Journal Article↗