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Biomedical subjects

S Ferrari

Publications and source records attributed to S Ferrari.

At least 91 records · Page 5Linked to original sources
PubMed2001

Correlation between cystatin C and serum creatinine as markers of renal function in patients with neoplasms of the locomotor system.

Creatinine levels and clearance are used to monitor renal function in clinical practice. Cystatin C is produced by most nucleated cells in a consistent manner, uninfluenced by inflammatory processes, sex, age, eating habits or nutritional status. Serum cystatin C concentrations are mainly dependent on glomerular activity and are an endogenous biochemical marker of glomerular filtration. The aim of this study was to test the efficiency of cystatin C assay as an alternative marker of renal function. Statistical analysis of our results showed that cystatin C levels were significantly correlated to creatinine and creatinine clearance levels. However, it is still premature to suppose that cystatin C can replace creatinine in routine tests. Establishing cystatin C levels can be useful in cases in which it is not possible to determine creatinine clearance.

Adolescent↗
PubMed2001

Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases.

Between January 1995 and December 1999, 11 patients with synchronous multifocal osteosarcoma (SMO) received neoadjuvant treatment with high-dose methotrexate, cisplatinum, Adriamycin, and ifosfamide. After primary chemotherapy in 4 patients who had only two bone localizations, it was possible to treat all tumor foci locally. The remaining patients, with more than three bones involved, were treated surgically only in 3 cases at the primary site, while secondary lesions did not receive any treatment. The final results of our study were disappointing. All patients died of the tumor 6 to 24 months after the beginning of treatment (mean 11.9 months). Nevertheless, the survival time of the 4 patients with locally treated lesions was significantly longer than the one of 7 patients in whom the secondary lesions were not locally treated (18.2 vs 9.1 months; P<0.008). It should be noted that those patients simultaneously operated on two sites, the response to chemotherapy of "primary" and "secondary" lesions was always similar. This homogeneity supports the thesis that in synchronous multifocal osteosarcoma the tumors are not multicentric in origin but represent bone-to-bone metastases from a monocentric tumor.

Adolescent↗
PubMed2001

The nuclear localization domain of the MEF2 family of transcription factors shows member-specific features and mediates the nuclear import of histone deacetylase 4.

Targeting of myocyte enhancer binding factor 2 (MEF2) proteins to the nucleus depends on a C-terminal bipartite nuclear localization signal (NLS). By expression of green fluorescent protein (GFP)/MEF2 fusion proteins in transfected myoblasts, we show that MEF2C contains an additional 13 amino acids domain, located immediately upstream of the NLS, which contributes to its nuclear retention. We also show that the NLS present in MEF2 proteins is required for efficient nuclear localization of histone deacetylase 4 (HDAC4). In muscle cells, transfected HDAC4 is largely cytoplasmic or, to a lesser extent, pancellular. Co-transfection of either MEF2A or MEF2C causes HDAC4 to accumulate in the nucleus in association with MEF2. This effect strongly depends on MEF2 NLS; it also requires the specific interaction of HDAC4 with MEF2, since the isolated NLS is not sufficient for targeting HDAC4 to the nucleus and other nuclear proteins, such as NF-Y, cannot substitute MEF2. Therefore, we demonstrate that HDAC4, different from HDAC5, is mainly a cytoplasmic resident protein, requiring a trans-acting NLS for nuclear localization. The physiological implications of MEF2 carrying its own inhibitor to the nucleus are discussed.

Active Transport, Cell Nucleus↗
PubMed2001

Update on antifolate drugs targets.

Antifolate drugs are molecules directed to interfere with the folate metabolic pathway at some level. They can be recognized among the first rationally designed compounds applying the principle of structural analogy with the substrate developing the antimetabolite strategy. This strategy has taken advantage of the basic different features of the microbial and human folate metabolism and therefore allows targeting the pathway at different steps generating a specificity tools for Medicinal Chemists. Two main problems are giving renewed importance to such targets and therefore improving the efforts to discover new targets in the folate metabolism area. The first one is the increasing resistance to the present drugs due to different mechanisms such as the enzyme modification and the increased production of enzymes with not well recognized importance. The second one is the development of techniques directed to highlight the interference at genetic level of molecular probes as antifolate drug to develop new enzymes previously unknown. This approach is defined as genetic approach to drug discovery, from gene to drugs. The present article describes the importance in drug design and discovery of some antifolate targets among the best known at the present status of research such as thymidylate synthase (TS), dhydrofolate reductases, (DHFR) serine hydroxymethyltransferase (SHMT), folyilpolyglutamyl synthetase (FPGS), gamma-glutamyl hydrolase (gamma-GH), glycinamide-ribonucleotide transformylase (GARTfase), amino-imidazole-carboxamide-ribonucleotide transformylase (AICARTfase) and Folate transporters. Discovery, known functions, structure/function studies and inhibition will be described.

Carrier Proteins↗
PubMed2001

Strategies of medical treatment for metastatic breast cancer (Review).

Presently, metastatic breast cancer cannot be cured and therefore good palliation of symptoms and longer overall survival make the most important targets, always considering quality of life. In addition to the established hormonal therapies or chemotherapy regimens, several recent advances have accelerated progress in metastatic breast cancer treatment. As demonstrated in recent studies, the third-generation aromatase inhibitors are playing a significant role in the improvement of the therapeutic approach. The development of new drugs with novel mechanisms of action, such as taxanes, used alone in innovative schedules or in association with other drugs (mainly the anthracyclines), vinorelbine and gemcitabine, or capecitabine, which is administered orally, has broadened the scope of metastatic breast cancer chemotherapy. A new investigation field is represented by high-dose chemotherapy with stem cell support, which has provided controversial preliminary results but is also acknowledged to deserve larger and randomized trials. Finally, the emergence of biological therapies such as the anti-HER2 monoclonal antibody Trastuzumab opens new and exciting prospects for the treatment of this disease. Moreover, the present trend is to try to rationalize the therapeutic approach on the basis of biological parameters which are prognostic and predictive of treatment response.

Antibodies, Monoclonal↗
PubMed2001

Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and in vitro.

Exponential tumor growth is angiogenesis-dependent. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are potent angiogenic inducers that act synergistically in vivo and in vitro. We assessed the effect of specific inhibitors of VEGF receptor (VEGFR)-2 tyrosine kinase activity in in vivo and in vitro models of VEGF- and bFGF-induced angiogenesis. In an implant mouse model of angiogenesis, VEGFR-2 inhibitors completely blocked angiogenesis induced by VEGF, and, surprisingly, also inhibited the effect of bFGF to various extents. In vitro, VEGF- and bFGF-induced bovine microvascular and aortic endothelial (BME and BAE) cell collagen gel invasion could be blocked by the VEGFR-2 inhibitors by 100 and approximately 90%, respectively. Similar results were obtained with VEGFR-1-IgG and VEGFR-3-IgG fusion proteins and with VEGFR-2 blocking antibodies. Both BME and BAE cells produce VEGF and VEGF-C, which is not modulated by bFGF. Thus, the unexpected inhibition of bFGF-induced angiogenesis by VEGFR-2 antagonists reveals a requirement for endogenous VEGF and VEGF-C in this process. These findings broaden the spectrum of mediators of angiogenesis that can be inhibited by VEGFR-2 antagonists and highlight the importance of these compounds as agents for inhibiting tumor growth sustained by both VEGF and bFGF.

Angiogenesis Inhibitors↗
PubMed2001

[Primary reconstruction of lateral oro-mandibular defects using titanium plates (Thorp) and revascularized non-osseous flaps: a personal experience].

Reconstruction of a particular defect is an highly complex problem, that is reflected in the number and variety of techniques proposed. This is particularly true for reconstruction of mandibular segment defects usually together with the need to repair oro-pharnygeal soft tissues defects of various size. The high rate of successes that can be obtained today using microvascular reconstruction techniques explains the reason why bone free flaps have progressively become the "gold standard" used as benchmark for all other forms of primary mandibular reconstruction. However, for selected patients (elderly patients or individuals in poor general health; the presence of lateral oro-mandibular defects or soft tissue defects significantly exceeding the bone defect) the association of non-osseous microvascular free flaps (such as forearm skin flaps or miocutaneous free flaps of the abdominal rectus muscle) with a titanium mandibular reconstruction plate (THORP) can prove a valid alternative. Indeed, in these cases reconstruction of choice would be the association of two free flaps, one osseous and the other non osseous. The use of THORP-type mandibular reconstruction plates in repairing lateral defects increases the overall risk of complications related to the reconstruction technique which is already hindered by the risks associated with the use of microvascular free flaps. The present work starts with a retrospective evaluation of 5 years series of primary mandibular reconstruction for lateral oro-mandibular defects following oncological surgery. The role of THORP-type titanium mandibular plates, used in combination with non-osseous free flaps in the treatment of selected patients, is then described and discussed.

Aged↗
PubMed2000

Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report.

PURPOSE: To provide an estimate of long-term prognosis for patients with osteosarcoma of the extremity treated in a single institution with neoadjuvant chemotherapy and observed for at least 10 years. PATIENTS AND METHODS: Patients with nonmetastatic osteosarcoma of the extremity were preoperatively treated with high-dose methotrexate, cisplatin, and doxorubicin (ADM). Postoperatively, good responders (90% or more tumor necrosis) received the same three drugs used before surgery, whereas poor responders (less than 90% tumor necrosis) received ifosfamide and etoposide in addition to those three drugs. RESULTS: For the 164 patients who entered the study between September 1986 and December 1989, surgery was a limb salvage in 136 cases (82%) and a good histologic response was observed in 117 patients (71%). At a follow-up ranging from 10 to 13 years (median, 11.5 years), 101 patients (61%) remained continuously free of disease, 61 relapsed, and two died of ADM-induced cardiotoxicity. There were no differences in prognosis between good and poor responding patients. ADM-induced cardiotoxicity (six patients), male infertility (10 of the 12 assessable patients), and second malignancies (seven patients) were the major complications of chemotherapy. Despite the large number of limb salvages performed, only four local recurrences (2.4%) were registered. CONCLUSION: With an aggressive neoadjuvant chemotherapy, it is possible to cure more than 60% of patients with nonmetastatic osteosarcoma of the extremity and amputation may be avoided in more than 80% of them. Because local or systemic relapses, myocardiopathies, and second malignancies are possible even 5 years or more after the beginning of treatment, a long-term follow-up is recommended for these patients.

Adolescent↗
PubMed2000

An alternatively spliced isoform of B-Myb is a transcriptional inhibitor.

B-Myb is a highly conserved member of the Myb transcription factor family. The primary transcript of the B-myb gene is spliced alternatively in two mRNAs which either contain or lack a sequence corresponding to the so-called exon 9A of c-myb. Recent studies showed that full-length B-Myb containing the exon 9A encoded amino acids is a cell cycle regulated transcription factor whose activity is stimulated by cyclin A/Cdk 2-dependent phosphorylation at the carboxyl-terminus of B-Myb. We have now investigated in more detail the transactivation potential of the shorter isoform of B-Myb lacking exon 9A. Here, we show that B-Myb lacking exon 9A has no transactivation activity even in the presence of cyclin A. This inactivity of the shorter isoform of B-Myb is not due an improper subcelluar localization. Our work suggests that B-Myb lacking exon 9A may act as an inhibitor for full-length B-Myb mediated transactivation. Furthermore, by analysing the transactivation potential of Gal4/B-Myb fusion proteins we have identified the amino-terminal part of the exon 9A as the principal transactivation domain of full-length B-Myb. The results presented here demonstrate that B-myb encodes both an activator and an inhibitor of transcription and, thus, reveal an additional level of regulation of B-Myb activity beside the known cyclin dependent mechanisms.

Alternative Splicing↗
PubMed2000

A new Arabidopsis thaliana root gravitropism and chirality mutant.

A new Arabidopsis thaliana (L.) Heynh. root mutant, named clg1, was isolated from the Feldmann-Du Pont T-DNA insertional mutagenesis collection. It is characterized by primary roots that make early right-handed coils, show increased right-handed slanting, and reduced positive gravitropism. The mutant roots however did not exhibit increased resistance to IAA, but only a modest increment of resistance to the auxins 2,4 D, and NAA, and to the auxin transport inhibitors TIBA and NPA. By contrast, the mutant roots showed a notable resistance to plant hormone ethylene (given as ACC). clg1 appears to be new, since it complements the most known auxin and gravitropism mutants, maps to chromosome 5, and shows a phenotype largely different from that of the known ethylene mutants. The increased right-handed slanting (chirality) can possibly be a consequence of the reduced gravitropic response, since gravitropism and slanting are competitive growth-direction leading forces. The increased resistance to ethylene, seems to indicate that this phythormone plays a role in the gravitropic response of roots (as already proposed for shoots), and possibly in the regulation of the connected signal transduction pathway. The gene involved in the clg1 mutation, which is recessive, was mapped, as above reported, to chromosome 5, close to the visible marker tt3.

Journal Article↗
PubMed2000

New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.

The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.

Administration, Oral↗
PubMed2000

Degradation of B-Myb by ubiquitin-mediated proteolysis: involvement of the Cdc34-SCF(p45Skp2) pathway.

B-Myb, a highly conserved member of the Myb oncoprotein family, is a 110 kDa sequence-specific DNA binding protein expressed in virtually all proliferating cells. B-myb expression reaches its maximum at the G1/S phase boundary and during the S phase of the cell cycle. We have previously shown that B-Myb activity is cell cycle regulated and it is controlled by the antagonistic effects of cyclin D1 and A. Here we show that ectopic expression of cyclin A causes a pronounced reduction of B-Myb protein level. We provide evidence that in addition to triggering B-Myb activity an important effect of cyclin A is to facilitate multiple ubiquitination of B-Myb. The C-terminal domain of B-Myb is of key importance in mediating this effect of cyclin A. Contrary to full-length B-Myb, a C-terminal deletion mutant displays activity irrespective of cyclin A expression, does not undergo ubiquitination, and its half-life is not affected by cyclin A. Ectopic expression of either Cdc34 or the F-box protein p45Skp2, respectively the E2 and E3 components of a ubiquitination pathway that regulates the G1/S transition, accelerates degradation of B-Myb. We show that B-Myb physically and functionally interacts with components of the Cdc34-SCFp45Skp2 ubiquitin pathway and propose that B-Myb degradation may be required for controlling the correct alternation of events during progression through the cell division cycle. Oncogene (2000).

Anaphase-Promoting Complex-Cyclosome↗
PubMed2000

Two histone fold proteins, CHRAC-14 and CHRAC-16, are developmentally regulated subunits of chromatin accessibility complex (CHRAC).

The ISWI ATPase of Drosophila is a molecular engine that can drive a range of nucleosome remodelling reactions in vitro. ISWI is important for cell viability, developmental gene expression and chromosome structure. It interacts with other proteins to form several distinct nucleosome remodelling machines. The chromatin accessibility complex (CHRAC) is a biochemical entity containing ISWI in association with several other proteins. Here we report on the identification of the two smallest CHRAC subunits, CHRAC-14 and CHRAC-16. They contain histone fold domains most closely related to those found in sequence-specific transcription factors NF-YB and NF-YC, respectively. CHRAC-14 and CHRAC-16 interact directly with each other as well as with ISWI, and are associated with functionally active CHRAC. The developmental expression profiles of both subunits suggest specialized roles in chromatin remodelling reactions in the early embryo for both histone fold subunits.

Adenosine Triphosphatases↗
PubMed2000

PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration.

PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

Angiogenesis Inhibitors↗
PubMed2000

Regulation of B-Myb activity by cyclin D1.

Evidence obtained during recent years suggests that B-Myb, a highly conserved member of the Myb transcription factor family, plays a key role in cell proliferation. We have shown previously that the activity of B-Myb is stimulated by cyclin A/Cdk2-dependent phosphorylation of the carboxyl-terminus of B-Myb. We have now investigated in more detail the effect of other cyclins on B-Myb. Here, we show that cyclin D1, in contrast to cyclin A, strongly inhibits the activity of B-Myb. This inhibitory effect does not involve increased phosphorylation of B-Myb but seems to rely on the formation of a specific complex of B-Myb and cyclin D1. Our work identifies B-Myb as an interacting partner for cyclin D1 and suggest that the activity of B-Myb during the cell cycle is controlled by the antagonistic effects of cyclin D1 and A. The results presented here suggest a more general role of cyclin D1 as regulator of transcription in addition to the known effect on RB phosphorylation.

3T3 Cells↗
PubMed2000

Interleukin-2 induces cell cycle perturbations leading to cell growth inhibition and death in malignant mesothelioma cells in vitro.

Previous report indicated that Interleukin-2 (IL-2) is able to inhibit the growth of IL-2-receptor-positive cancer cell lines without any involvement of the immune system, through IL-2-induced alterations of the cell cycle kinetics. In this study we provide evidence that IL-2 exerts anti-proliferative effect on three human malignant mesothelioma (MMe) cells in vitro, while no effects were observed on normal human mesothelial cell (HMC) primary cultures. The growth inhibitory effect of IL-2 on neoplastic cells appeared to depend on the baseline proliferative status of these cells. Indeed, in highly proliferating MMe cells, we observed a reduction of malignant cells in the S-phase of the cell cycle, with an accumulation in G0/G1, followed by apotosis for longer incubations or exposure to higher doses. On the contrary, in MMe cells proliferating at lower rate, IL-2 induces only a late cytotoxic effect, leading to apoptosis, without significantly affecting the cell cycle. IL-2Rbeta mRNA was detectable by RT-PCR in all MMe cells, IL-2Ralpha mRNA in one only out the three assayed and IL-2Rgamma mRNA in none. In addition, mRNA specific for the IL-2Rbeta-associated Jak-1 tyrosine kinase was expressed in all MMe cell lines, further suggesting that IL-2Rbeta may play a role in the observed effects. Very low, albeit detectable, levels of IL-2Rbeta chain appeared to be expressed at the cell surface of MMe cells by indirect immunofluorescence and FACS analyses. Finally, Ca(++) fluxes were rapidly induced when MMe cells were exposed to exogenous IL-2.

Apoptosis↗
PubMed2000

Granisetron, tropisetron, and ondansetron in the prevention of acute emesis induced by a combination of cisplatin-Adriamycin and by high-dose ifosfamide delivered in multiple-day continuous infusions.

The antiemetic efficacy of granisetron, ondansetron and tropisetron was evaluated in patients treated with cisplatin-Adriamycin (CDP/ADM) and ifosfamide (IFO) by continuous infusion (CI). In all, 90 patients with osteosarcoma were randomly assigned to receive granisetron (2 mg/m2), or ondansetron (5.3 mg/m2), or tropisetron (3.3 mg/m2) plus dexamethasone 8 mg/m2. Chemotherapy consisted of CDP (120 mg/m2, 48-h CI) followed by ADM (75 mg/m2, 24-h CI) and then, in the second cycle, delivered 3 weeks later, IFO 15 g/m2 (120-h CI). Complete protection (CP) from emesis was obtained on 59% of the 717 days of treatment, without significant differences among the three study drugs. A significantly higher rate of CP was obtained during chemotherapy with IFO than with CDP/ ADM (69% vs 44%; P<0.0001). The rate of CP declined from the first to the last day of treatment for both CDP/ADM (61% to 27%, P<0.0001) and IFO (95% to 43%) cycles (P<0.0001). When CDP/ ADM and IFO are delivered on multiple days by CI, granisetron, ondansetron and tropisetron have the same antiemetic efficacy, which declines from the first day onward through successive days.

Acute Disease↗