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Biomedical subjects

R Palumbo

Publications and source records attributed to R Palumbo.

At least 19 recordsLinked to original sources
PubMed2001

Retinoids induce fibroblast growth factor-2 production in endothelial cells via retinoic acid receptor alpha activation and stimulate angiogenesis in vitro and in vivo.

The effect of retinoic acid (RA) on endothelial cells is still controversial and was examined in the present study. In bovine aortic endothelial cells (BAECs), all-trans RA (ATRA) and 9-cis RA (9CRA), but not 13-cis RA (13CRA), induced fibroblast growth factor-2 (FGF-2) production and exhibited a biphasic dose-dependent effect to enhance BAEC proliferation and differentiation into tubular structures on reconstituted basement membrane proteins (Matrigel); both processes were inhibited by FGF-2-neutralizing antibody. The pan RA receptor (RAR)-selective ligand (E)-4-[2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphtalenyl)-1-propenyl] benzoic acid and the RARalpha-selective ligand 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphtyl)-ethenyl] benzoic acid stimulated the production of FGF-2, whereas the addition of the RARalpha-antagonist RO 41-5253 inhibited this effect. In BAECs, the forced expression of RARalpha, but not RARbeta or RARgamma, enhanced FGF-2 production, whereas the RARalpha-dominant negative, Delta403, blocked this effect. Furthermore, RARalpha overexpression directly stimulated BAEC differentiation on Matrigel and potentiated the effects of ATRA in this assay. Finally, ATRA-treated BAECs coinjected with Matrigel subcutaneously in mice induced neovascularization within the Matrigel plug, and ATRA also enhanced angiogenesis in the chicken chorioallantoic membrane assay. In conclusion, RA can stimulate endothelial cell proliferation and differentiation in vitro via enhanced RARalpha-dependent FGF-2 production, and it can also induce angiogenesis in vivo. The full text of this article is available at http://www.circresaha.org.

Animals↗
PubMed2001

Biodegradable microspheres of novel segmented poly(ether-ester-amide)s based on poly(epsilon-caprolactone) for the delivery of bioactive compounds.

A novel class of multiblock poly(epsilon-caprolactone)-based polymers containing hydrophilic trioxyethylene segments and potentially relevant to the delivery of drugs is described in this work. L-phenylalanine residues may also be inserted into the hydrophilic blocks to generate peptide bonds susceptible to enzymatic attack. The investigated polymers were poly(ether-ester-amide)s (PEEAs) obtained by a two-step polymerization procedure from OH-end capped low molecular weight poly(epsilon-caprolactone), sebacoyl chloride and either 4,7,10-trioxa-1,13-tridecanediamine (PEEA1) or 1,13-di(L-phenylalaninamido)-4,7,10-trioxatridecane (PEEA2). PEEAs were characterized by 1H-NMR spectroscopy, differential scanning calorimetry, gel permeation chromatography and were tested for their suitability in producing microspheres. Particles obtained by the single emulsion-solvent evaporation technique were regular and smooth (SEM analysis) showing a monomodal distribution of dimensions. To assess the potentiality of PEEAs in the oral delivery of drugs, three model compounds with different pKa and solubilities--diclofenac, nicardipine and dicumarol--were encapsulated within PEEA microspheres. For the sake of comparison, microspheres prepared from poly(epsilon-caprolactone) (PCL) with a molecular weight similar to PEEAs were also prepared and tested. The release of diclofenac from all the microspheres was very rapid (100% released within 2 h) whereas nicardipine release was slower and biphasic. The initial phase approximated a near zero-order release, being the fraction of nicardipine released after 8 h from PEEA microspheres higher with respect to PCL particles (about 70 vs. 30%). This result was ascribed to the lower crystallinity of PEEAs with respect to PCL which results in a facilitated access of water molecules through the polymer matrix. The lipophilic-unionizable dicumarol was released from PEEA microspheres at a very slow rate. Therefore, dicumarol-loaded PEEA2 microspheres allowed the study of the influence on the release rate of the insertion into the polymer chain of enzymatically degradable bonds. PEEA2 microspheres released dicumarol at the same rate in a medium with or without the proteolitic enzyme alpha-chymotrypsin. Although the insertion of an isolated amino acid was not sufficient to confer enzyme susceptibility to the polymer, the distinctive properties of PEEAs make their use very attractive in the field of controlled release.

Amides↗
PubMed2000

Adenovirus-mediated VEGF(121) gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia.

BACKGROUND: Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF(121)) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia. METHODS AND RESULTS: Rabbits and rats received IM injections of AdCMV.VEGF(121), AdCMV.Null, or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF(121), we found 96% and 29% increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF(121) group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF(121)=5.69+/-0.40, AdCMV.Null=2.97+/-0.50, and saline=2.78+/-0.43 mL x min(-1) x 100 g(-1), P<0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV. VEGF(121)=50.58+/-1.48, AdCMV.Null=29.08+/-4.22, saline=11.83+/-1.90, P<0.0001), and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by (31)P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF(121) group persisted until it was equalized by spontaneous collateral vessel development in untreated animals. CONCLUSIONS: IM administration of AdCMV.VEGF(121) stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.

Adenoviridae↗
PubMed2000

Shear stress downregulation of platelet-derived growth factor receptor-beta and matrix metalloprotease-2 is associated with inhibition of smooth muscle cell invasion and migration.

BACKGROUND: After endovascular injury, smooth muscle cells (SMCs) may be exposed to hemodynamic shear stress (SS), and these forces modulate neointima accumulation. The effect of SS on SMC migration and invasion is unknown, and it was examined in the present study. METHODS AND RESULTS: Bovine aortic SMCs were exposed to laminar SS of 12 dyne/cm(2) for 3 (SS3) or 15 (SS15) hours; control (C3 and C15) SMCs were kept under static conditions. Platelet-derived growth factor (PDGF)-BB-directed SMC migration and invasion were evaluated by a modified Boyden chamber assay with filters coated with either gelatin or reconstituted basement membrane proteins (Matrigel), respectively. SS15 inhibited both SMC migration and invasion (P<0.0001). There was no significant difference between SS3 and C3 cells. Media conditioned with SS15 cells exhibited a reduction in matrix metalloprotease-2 (MMP-2) by zymography and Western analysis. Northern blot analysis revealed no effect of SS15 on MMP-2 mRNA. In contrast, SS15 decreased MMP-2 activator and membrane-type MMP (MT-MMP or MMP-14) mRNA and protein. Furthermore, SS15 decreased PDGF receptor-beta (PDGF-Rbeta) mRNA and protein (P<0.05), and the SS-dependent decrease in PDGF-BB-directed cell migration was rescued by overexpressing PDGF-Rbeta. CONCLUSIONS: SS inhibits SMC migration and invasion via diminished PDGF-Rbeta expression. This effect of SS is associated with decreased MMP-2 secretion and MT-MMP downregulation.

Animals↗
PubMed2000

Controlled clinical trial of a novel hemostatic agent in cardiac surgery. The Fusion Matrix Study Group.

BACKGROUND: We performed a prospective randomized trial to compare FloSeal Matrix (Fusion Medical Technologies, Inc, Mountain View, CA), a gelatin-based hemostatic sealant, with Gelfoam-Thrombin (Gelfoam, Pharmacia and Upjohn, Kalamazoo, MI; Thrombin, Gentrac Inc, Middeton, WI) (control group) to control perioperative bleeding. METHODS: A total of 93 patients undergoing cardiac operations were randomized into the FloSeal or control group after standard surgical means to control bleeding had failed. The bleeding site was evaluated at 1, 2, 3, 6, and 10 minutes after applying the hemostatic agent. If bleeding stopped within 10 minutes, the application was considered to be successful. In the case of a failure, the surgeon could use any means preferred (except FloSeal) to achieve hemostasis. All bleeding sites in a patient were treated with the hemostatic agent to which the patient was randomized. Follow-up evaluation was performed at 12 to 36 hours and 6 to 8 weeks after operation. RESULTS: FloSeal stopped bleeding in 94% of the patients (first bleeding site only) within 10 minutes, compared to 60% in the control group (p = 0.001). At 3 minutes, successful hemostasis was achieved in 72% of the FloSeal group compared with 23% in the control group (p = 0.0001). There was no difference in the adverse event profile between the two groups. CONCLUSIONS: FloSeal Matrix demonstrated efficacy superior to that of Gelfoam-Thrombin and had a safety profile similar to that of Gelfoam-Thrombin when used as a topical hemostatic agent during cardiac surgery procedures.

Blood Loss, Surgical↗
PubMed2000

Antioxidant effect of red wine polyphenols on red blood cells.

The protective effect of red wine polyphenols against hydrogen peroxide (H(2)O(2))-induced oxidation was investigated in normal human erythrocytes (RBCs). RBCs, preincubated with micromolar amounts of wine extract and challenged with H(2)O(2), were analyzed for reactive oxygen species (ROS), hemolysis, methemoglobin production, and lipid peroxidation. All these oxidative modifications were prevented by incubating the RBCs with oak barrel aged red wine extract (SD95) containing 3.5 mM gallic acid equivalent (GAE) of phenolic compounds. The protective effect was less apparent when RBCs were incubated with wines containing lower levels of polyphenols. Furthermore, resveratrol and quercetin, well known red wine antioxidants, showed lower antioxidant properties compared with SD95, indicating that interaction between constituents may bring about effects that are not necessarily properties of the singular components. Our findings demonstrate that the nonalcoholic components of red wine, mainly polyphenols, have potent antioxidant properties, supporting the hypothesis of a beneficial effect of red wine in oxidative stress in human system.

Journal Article↗
PubMed2000

Is salvage chemotherapy for metastatic breast cancer always effective and well tolerated? A phase II randomized trial of vinorelbine versus 5-fluorouracil plus leucovorin versus combination of mitoxantrone, 5-fluorouracil plus leucovorin.

Metastatic breast cancer remains an incurable disease and the median overall survival has not significantly improved over the past two decades. Aims of the present randomized phase II trial were to analyse activity and toxicity of chemotherapies with single agent or with combination regimens in previously treated patients with advanced breast cancer. Ninety-nine eligible patients were randomized to receive the following chemotherapies: Arm A - vinorelbine 30 mg/m2 i.v. weekly; Arm B - leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --> 5, q 28 days; Arm C - mitoxantrone 12 mg/m2 i.v. only day 1 + leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --> 3, q 28 days. Patients characteristics are comparable in the three groups. The median number of chemotherapy courses administered was 7, 6 and 5 in arm A, B and C, respectively. Objective responses were 24%, 30% and 21% and the median duration of responses were 2, 2.5 and 5.5 months in the arm A, B and C, respectively. Median overall survivals were 9.5, 9 and 9 months in the three arms. No difference was noted comparing the survivals of responding or non responding patients. General toxicity was not mild, with 27.5% of patients experiencing WHO grade 3-4 toxicities. Our results are similar in the three groups of patients and comparable to those reported by other authors. Chemotherapy applied to patients with second or subsequent recurrence allow objective responses in a small percentage of patients. Moreover responders have a negligible prolongation of survival.

Adult↗
PubMed2000

Transcriptionally active drugs improve adenovirus vector performance in vitro and in vivo.

Cytomegalovirus (CMV) promoter is often present in recombinant adenovirus vectors (AdVs) suitable for gene therapy, ensuring high levels of transgene production in a wide range of hosts. Despite this characteristic, the presence of the AdV genome in target cells and tissues typically lasts longer than transgene production that may be rapidly extincted by ill-defined silencing mechanisms. In the present article, it is reported that transcriptionally active drugs, retinoic acid (RA) and histone deacetylase inhibitor trichostatin A (TSA), enhance AdV transgene expression in infected cells and tissues. The association of RA and TSA increased more than seven-fold above control the activity of AdVs encoding for LacZ or VEGF165. This effect was, at least in part, mediated by the direct activation of retinoic acid receptors. Finally, administration of RA and TSA alone at days 0 and 5 after infection prolonged transgene production up to 21 days after infection versus 6-8 days in untreated controls. These results indicate that transcriptionally active drugs improve AdV function and may represent a novel strategy to more efficiently design AdVs for gene therapy interventions.

Adenoviridae↗
PubMed2000

The chemotactic and mitogenic effects of platelet-derived growth factor-BB on rat aorta smooth muscle cells are inhibited by basic fibroblast growth factor.

In response to endovascular injury, platelet-derived growth factor-BB (PDGF-BB) and basic fibroblast growth factor (bFGF) are released locally and modulate vascular smooth muscle cells (SMC) proliferation and migration within the vascular wall. The aim of the present in vitro study was to determine how rat aorta SMC respond to the simultaneous exposure to PDGF-BB and bFGF. In a modified Boyden chamber assay bFGF exhibited a dose-dependent effect to inhibit the chemotactic action of PDGF-BB. A comparable result was observed in proliferation assays. In contrast, MIP-1 beta, epidermal growth factor (EGF), fibronectin and acidic FGF (aFGF) did not inhibit the chemotactic effect of PDGF-BB. Denatured bFGF did not exert an inhibitory effect and neutralizing antibodies either to bFGF or to bFGF-receptor abolished the inhibition observed in the presence of bFGF. The role played by PDGF receptor alpha (PDGF-Ralpha) was investigated in PDGF-Ralpha-dominant negative-transfected SMC, by selectively blocking PDGF-BB-binding to PDGF-Ralpha with neomycin, by neutralizing PDGF-Ralpha with a monoclonal antibody and by selectively stimulating PDGF-Ralpha with PDGF-AA; in all cases the effect of bFGF to inhibit PDGF-BB-directed SMC migration was abolished. These in vitro studies show that bFGF significantly inhibits PDGF-BB-induced SMC migration and proliferation and that this effect is mediated by both PDGF-Ralpha and bFGF receptor.

Animals↗
PubMed1999

Quercetin and anti-CD95(Fas/Apo1) enhance apoptosis in HPB-ALL cell line.

Several malignant cell lines are resistant to CD95-(Apo1/Fas)-mediated apoptosis, even when the CD95 receptor is highly expressed. Sensitivity to CD95-induced apoptosis can be restored using different molecules. In this study, we showed that quercetin, a naturally occurring flavonoid, in association with the agonistic anti-CD95 monoclonal antibody, increases DNA fragmentation and caspase-3 activity in HPB-ALL cells. These cells have been selected for their known resistance to CD95-induced apoptosis. At molecular level, quercetin lowers the level of intracellular reactive oxygen species, reduces mitochondrial transmembrane potential, thereby leaving the expression of CD95 receptor unchanged.

Apoptosis↗
PubMed1999

Interferon beta treatment in relapsing-remitting multiple sclerosis: a post-marketing study in Lombardia, Italy. Multiple Sclerosis Centers of Lombardia, Italy.

The aim of the study was to evaluate the efficacy of interferon beta-1a (IFN-beta-1a) and beta-1b (IFN-beta-1b) in clinical practice for the treatment of relapsing-remitting multiple sclerosis (RR MS). Patients were selected and prospectively monitored according to a predefined protocol. An appropriate form was prepared to collect clinical data of multiple sclerosis patients attending the MS Centers of Lombardia, Italy. On 30 June 1998, 317 patients were treated with IFN-beta-1b and 156 with IFN-beta-1a. Basal expanded disability status scale (EDSS) and relapse frequency were similar in both groups of patients. The annual relapse rate consistently decreased from 1.76 to 0.63 at 1 year and to 0.51 at 2 years for the IFN-beta-1b group and from 1.6 to 1.0 at 1 year for the IFN-beta-1a group. Disability remained stable in most patients. Dropouts (20.5%) were affected by more active disease compared to patients who continued to be treated. This study confirms the efficacy of both treatments, showing a more marked effect than expected from the clinical trials' results, probably due to differences in selection criteria and exclusion of dropouts.

Adjuvants, Immunologic↗
PubMed1999

Dose-intensive first-line chemotherapy with epirubicin and continuous infusion ifosfamide in adult patients with advanced soft tissue sarcomas: a phase II study.

This phase II study was designed to verify the activity and safety of an intensive epirubicin/ifosfamide schedule in untreated soft tissue sarcoma (STS) patients by using both the agents at the identified maximal tolerated doses. 39 adult patients were treated with epirubicin at 55 mg/m2, on days 1 and 2 (total dose per cycle 110 mg/m2) combined with ifosfamide at 2.5 g/m2 days 1-4 (total dose per cycle 10 g/m2), with equidose mesna uroprotection and G-CSF support. Treatment was given on an ambulatory basis, at 3-week intervals. The overall objective response (OR) rate was 59% (95% confidence interval, CI, 43-72%), with 5 complete responses (13%) at 18 partial responses (46%); 12 partial responders were rendered disease-free following surgery. The median survival time was 19 months, being 23 and 13 months, respectively, for responding and non-responding patients. The median time to response was 40 days (range 21-60). Treatment-related toxicity was overall acceptable. The OR of 59% was the highest ever reported in our consecutive studies in advanced STS, confirming that improved therapeutic efficacy can be obtained with intensified regimens in such a disease; both the response duration and survival were also longer. The observed activity proved to be interesting with regard to the high response rate in the lung (86%), as well as the proportion of patients rendered disease-free by early surgery after the achievement of a partial response (55%). Both these findings may be important in the multimodality approach to patients with lesions potentially resectable for cure.

Adult↗
PubMed1999

Vascular 131I-low-density lipoprotein imaging in patients with hypertension and early atherosclerotic lesions in the carotid artery.

BACKGROUND: The reinjection of autologous 131I-labelled low-density lipoprotein (LDL) followed by vascular scintigraphy has been used to investigate lipid-containing plaques, but no information is available on the early stages of plaques in hypertensives. Vascular scintigraphy after re-injection of autologous 131I-labelled LDL was used to investigate early atherosclerotic lesions visualized by sonography in the carotid arteries of patients with hypertension. PATIENTS AND METHODS: 10 male patients (4 smokers; mean age 56 +/- 8 years;) with early carotid atherosclerosis (mono- or bilateral; intima-media-thickness ranging from 1.5 to 3.5 mm) as shown by sonography were studied. All these normolipemic patients suffered from primary hypertension and were treated with diuretics. As controls 6 healthy male subjects (3 smokers; mean age 54 +/- 9 years;), with normal blood pressure and lipid pattern were recruited. RESULTS: Hot spots appeared in the areas with early atherosclerosis in 7 patients, while none were seen in controls. Positive kinetic curves were observed in 4 patients. No significant differences emerged in the target/non-target ratios. CONCLUSIONS: Vascular lipoprotein uptake in hypertensive patients is apparently late and rather limited; the uptake pattern may depend on plaque composition.

Adult↗
PubMed1999

Retinoids in lung cancer chemoprevention and treatment.

In this review, we aim to synthesize the emerging picture of retinoids in lung cancer through a summary of ongoing investigations in biology, chemoprevention and therapy settings, in an attempt to clarify the possible role of these agents in such a disease. Early work in head and neck cancer has evidenced the capability of retinoids to interrupt field carcinogenesis by reversing premalignant lesions and decreasing the incidence of second primary tumors (SPTs). At this time, the completed randomized trials in lung cancer have failed to demonstrate an evident chemopreventive effect of the tested agents on different study end points, although both a marginally significant benefit of retinol palmitate in time-to-development rates for smoke-related SPTs and a potential preventive effect of retinol supplementation against mesothelioma in selected populations of asbestos-exposed workers have been recently reported. Concerning the role of retinoids in lung cancer treatment, a moderate activity of 13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents has been reported in small series of advanced, mostly pretreated lung cancer patients. More encouraging findings derive from combination studies, in which retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy and radiotherapy. Major recent advances have been made towards the understanding of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or treatment-induced levels seems to be of particular interest as intermediate end point and/or independent prognostic factor, besides their known importance in lung carcinogenesis. Future research for chemopreventive and therapeutic programs with retinoids in lung cancer should be focused on the investigation of new generation compounds with a specificity for individual retinoid nuclear receptors. Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as recently suggested by our preliminary data on Ro 41-5253.

Cell Transformation, Neoplastic↗
PubMed1999

Tamoxifen in the treatment of metastatic malignant melanoma: still a controversy? (Review).

This review attempts to summarize the available preclinical and clinical evidence supporting the inclusion of tamoxifen (TAM) in the treatment of malignant melanoma, in the attempt to identify what role, if any, the antiestrogen could have in the present and future therapeutic approach to this disease. Emphasis has been given to the biological basis of the potential TAM mechanisms of action, as well as to the rational basis underlying the study design of the reported clinical experiences. Results to date show that TAM has no useful activity as a single agent in melanoma patients, most published response rates reaching less than 10%. A still controversial question is the inclusion of the antiestrogen in different active chemotherapy regimens, since clinical investigations on the role of TAM in combination therapy of advanced melanoma have produced inconclusive results. While several early trials suggested that TAM may improve the response rates when combined with different cytotoxic agents, the majority of subsequent reports, including recent randomized studies, did not show a significant benefit stemming from TAM addition to various single-agent or multi-agent combinations. Only one controlled trial showed a significant improvement in both response rate and survival for patients receiving dacarbazine plus TAM, an effect primarily noted in women, and confirmatory studies have not been reported. From a biological standpoint, why the activity of this poorly effective single-agent is potentiated when given in combination with some cytotoxic agents is not clearly understood, although preclinical and clinical experiences support a possible synergistic effect of TAM combined with cisplatin, particularly when the former is added at high doses. Of major interest is a body of experimental studies producing confirmatory data that induction of apoptosis, probably through the inhibition of protein kinase C, as well angiogenesis inhibition, at least in part mediated by TGF-beta stimulation, are alternative ways through which TAM suppresses tumor cell growth, independently of the expression of estrogen receptors. These findings also provide a model and rationale for combining TAM with agents which are able to modify cell biology in melanoma. The investigation on TAM-containing biological combinations appears to be a promising avenue to be explored in the near future. To this end, clinical research should incorporate biological studies to allow the selection of subgroups of patients who are most likely to benefit from TAM-based treatment.

Antineoplastic Agents, Hormonal↗
PubMed1998

Affective disorders and multiple sclerosis: a controlled study on 65 Italian patients.

A high prevalence of major mood disorders in multiple sclerosis (MS) patients has been reported. In this study, we investigated the frequency of previous or present major mood disorders in 65 patients with clinically definite multiple sclerosis (Poser criteria) and in 31 polyneuropathy (PNP) patients. All patients underwent a questionnaire designed after DSM-IV definitions for major mood disorders. A higher lifetime risk for development of a major mood disorder was evident in MS patients (log rank test, p<0.001). Of all MS patients with a major mood disorder, at least 34% had one first-degree relative affected by a mood disorder, while the corresponding figure was 14% among PNP cases. Our data confirm the high lifetime risk for depression in MS patients and suggest that, at least in a subset of MS patients with depression, the genetic basis for depression operates with similar mechanisms as those at work in families with primary depression. However, this is not necessarily true for other subsets of depressed MS patients' families.

Adolescent↗