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Biomedical subjects

A Riva

Publications and source records attributed to A Riva.

At least 19 recordsLinked to original sources
PubMed1999

A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts.

Clinically available taxanes represent one of the most promising class of antitumor agents, despite several problems with their solubility and toxicity. In an attempt to improve the pharmacological profile of taxanes, a new series of analogues was synthesized from 14beta-hydroxy-10-deacetylbaccatin III and tested in a panel of human tumor cell lines. On the basis of the pattern of cytotoxicity and lack of cross-resistance in tumor cell lines expressing the typical multidrug-resistant phenotype, a compound (IDN5109) was selected for preclinical development. A comparative efficacy study of IDN5109 and paclitaxel was performed using a large panel of human tumor xenografts, characterized by intrinsic (seven tumors) or acquired (four tumors) resistance to cisplatin or doxorubicin, including four ovarian, one breast, one cervical, three lung, one colon, and one prostatic carcinoma. Drugs were delivered i.v. according to the same schedule (four times every 4th day). IDN5109 achieved a very high level of activity (percentage tumor weight inhibition >70%; log10 cell kill >1) in all but one of the tested tumors. Compared to paclitaxel, IDN5109 exhibited a significantly superior activity in six tumors (including the four tumors that were resistant to paclitaxel) and a comparable activity against the other five paclitaxel-responsive tumors. Additional advantages of IDN5109 over paclitaxel were also suggested by its toxicity profile. IDN5109 was not only less toxic (maximal tolerated doses were 90 and 54 mg/kg for IDN5109 and paclitaxel, respectively), but it also appeared to be endowed with a reduced neurotoxic potential and an improved profile of tolerability compared to the parent drug. Furthermore, the best antitumor efficacy was often already reached with doses lower than the maximal tolerated dose, suggesting an improved therapeutic index for the new drug. In conclusion, the results support the preclinical interest of IDN5109 in terms of the toxicity profile and of the efficacy with particular reference to the ability to overcome multiple mechanisms of drug resistance.

Animals↗
PubMed1999

Simultaneous apocrine and merocrine secretion in the rat coagulating gland.

The coagulating gland of the rat synthesizes two prevalent secretory proteins (transglutaminase and 115 K) that are discharched in a different manner, one being secreted in an apocrine fashion (transglutaminase) and the other one in a merocrine way (115 K). Differences in the intra- cellular pathway and the release of either protein were studied using immunofluorescence on semithin sections, immunoelectron microscopy of preembedding-processed chopper sections and postembedding-processed ultrathin sections of rat coagulating gland. Immunohistochemical staining using an anti-transglutaminase antibody resulted in dense labeling of the cytoplasm of secretory cells and their apical blebs, whereas the cisternae of the rough endoplasmic reticulum and the Golgi apparatus were completely unlabeled. When, on the contrary, the anti-115 K antiserum was used, dense labeling of the cisternae of the rough endoplasmic reticulum, the Golgi apparatus, and the secretory granules was seen. Intraluminal secretion was also labeled, but the secretory blebs remained unlabeled. Our findings show that, in the coagulating gland of the male rat, the two secretory proteins studied are processed in parallel, but at completely different intracellular pathways. They are released via different extrusion mechanisms. Transglutaminase is synthesized outside the endoplasmic reticulum, reaches the apical cell pole by free flow in the cytoplasm, and is released via apocrine blebs, the membranes of which appear to be derived from the apical plasma membrane. The protein 115 K, on the other hand, follows the classic route, being synthesized within the cisternae of rough endoplasmic reticulum, subsequently glycosylated in the Golgi apparatus, and released in a merocrine fashion. The mutual exclusion of the two secretory pathways and the regulation of the alternative release mechanism are still unresolved issues.

Animals↗
PubMed1999

Protocol-based reasoning in diabetic patient management.

We propose a system for teleconsultation in Insulin Dependent Diabetes Mellitus (IDDM) management, accessible through the use of the net. The system is able to collect monitoring data, to analyze them through a set of tools, and to suggest a therapy adjustment in order to tackle the identified metabolic problems and to fit the patient's needs. The therapy revision has been implemented through the Episodic Skeletal Planning Methodi, it generates an advice and employs it to modify the current therapeutic protocol, presenting to the physician a set of feasible solutions, among which she can choose the new one.

Adult↗
PubMed1998

Transcription factor B-cell-specific activator protein (BSAP) is differentially expressed in B cells and in subsets of B-cell lymphomas.

The paired box containing gene PAX-5 encodes the transcription factor BSAP (B-cell-specific activator protein), which plays a key role in B-lymphocyte development. Despite its known involvement in a rare subtype of non-Hodgkin's lymphoma (NHL), a detailed examination of BSAP expression in NHL has not been previously reported. In this study, we analyzed normal and malignant lymphoid tissues and cell lines, including 102 cases of B-cell NHL, 23 cases of T- and null-cell NHL, and 18 cases of Hodgkin's disease. Normal lymphoid tissues showed strong nuclear BSAP expression in mantle zone B cells, less intense reactivity in follicular center B cells, and no expression in cells of the T-cell-rich zones. Monocytoid B cells showed weak expression, whereas plasma cells and extrafollicular large transformed B cells were negative. Of the 102 B-cell NHLs, 83 (81%) demonstrated BSAP expression. All of the 13 (100%) B-cell chronic lymphocytic leukemias (B-CLLs), 21 of (100%) mantle cells (MCLs), and 20 of 21 (95%) follicular lymphomas (FLs) were positive. Moderate staining intensities were found in most B-CLL and FL cases, whereas most MCLs showed strong reactions, paralleling the strong reactivity of nonmalignant mantle cells. Eight of 12 (67%) marginal zone lymphoma cases showed negative or low BSAP levels, and 17 of 24 (71%) large B-cell lymphomas displayed moderate to strong expression. None of the 23 T- and null-cell lymphomas reacted with the BSAP antisera, whereas in Hodgkin's disease, 2 of 4 (50%) nodular lymphocytic predominance and 5 of 14 (36%) classical cases showed weak nuclear or nucleolar BSAP reactions in a fraction of the tumor cells. Western blot analysis showed a 52-kD BSAP band in B-cell lines, but not in non-B-cell or plasma cell lines. We conclude that BSAP expression is largely restricted to lymphomas of B-cell lineage and that BSAP expression varies in B-cell subsets and subtypes of B-cell NHL. The high levels of BSAP, especially those found in large-cell lymphomas and in some follicular lymphomas, may be a consequence of deregulated gene expression and suggest a possible involvement of PAX-5 in certain B-cell malignancies. This is a US government work. There are no restrictions on its use.

Antigens, CD20↗
PubMed1998

Exocytosis in human salivary glands visualized by high-resolution scanning electron microscopy.

The luminal membrane of salivary acinar cells creates a specialized cell surface area that accepts exocytosis and undergoes dynamic changes during secretion. These changes were visualized three-dimensionally from both the inside and outside of the cell in human parotid and submandibular glands, by application of in vitro secretory stimulation and then of OsO4 maceration to remove cytoplasmic organelles by varying degrees. In control glands treated without secretagogues, the luminal surface of serous acinar cells bore well-developed microvilli with only an occasional incidence of exocytotic profiles. Following treatment with the beta-adrenergic agonist, isoproterenol, considerable shortening and loss of microvilli occurred along the luminal membrane where, on its cytoplasmic side, many protuberances of sizes similar to or smaller than those of single secretory granules (approximately 1 micron in diameter) appeared. The cytoplasmic surface of these protuberances exhibited small vesicles (approximately 100-150 nm in diameter) that, by transmission electron microscopy, were shown to be coated pits or vesicles present on or around the exocytosed granule membranes. Treatment of tissues with the muscarinic agonist carbachol also caused a decrease of microvilli and the appearance of protrusions at the luminal membrane. However, unlike isoproterenol treatment, many of these protrusions were devoid of small pits or vesicles and were much larger than a single secretory granule. These results indicate that (1) secretory stimulation causes the dynamic transformation of microvilli at the luminal membrane, where granule docking and membrane fusion take place, and (2) after fusion, the exocytosed membranes are processed differently, by coated pit/vesicle mediated or non-mediated mechanisms, according to the autonomic receptor control.

Adrenergic beta-Agonists↗
PubMed1998

A novel sensitive assay to define immune status using short-term peripheral blood derived cell culture and dual-color flow cytometry.

In this study we describe a novel and highly sensitive in vitro system to determine the functionality of immune cells based on short term culture of peripheral blood derived mononuclear cells (PBMCs) and subsequent analysis of cellular proliferation and surface marker expression by automated dual-color flow cytometry. The standardized mild stimuli introduced into the culture system by supplemented medium (containing exogenous interleukin-2 (IL-2), and fetal bovine serum (FBS)) allow a more physiological interaction of the different cell subsets contained in PBMCs (including CD14+ accessory cells) than other methods that are based on potent and harsh cell activators, such as phytohemagglutinin (PHA) or anti-CD3 antibodies. Measurement of T-cell proliferation and cell surface marker (CD3, C25, CD26, CD71, HLA-DR) analysis revealed that activation response capacity in our assay depends on both the status of the obtained cells and their ability to interact in culture with CD14+ cells. This in vitro assay proved to be very sensitive in detecting changes in the status of T-cell activation and proliferation capacity, and avoid the use of radioactive reagents.

Animals↗
PubMed1998

A distributed system for diabetic patient management.

This paper describes a telemedicine system for diabetic patients management, presenting its architecture, the technical solutions adopted and the methodologies on which it is based. The system, designed to provide decision support in a distributed environment, is composed of two modules, a Patient Unit and a Medical Unit, connected by telecommunication services. We outline how the two modules can interact to perform an effective monitoring and a cooperative control of glucose metabolism. In particular, we detail the data analysis tasks performed by the two units and how the results are exploited to assist patients and physicians in revising and adjusting the therapeutic protocol. We will finally describe the current prototypical implementation of the system that uses HTTP as the communication protocol and HTML pages as the graphical user interface.

Diabetes Mellitus, Type 1↗
PubMed1998

A development environment for knowledge-based medical applications on the World-Wide Web.

The World-Wide Web (WWW) is increasingly being used as a platform to develop distributed applications, particularly in contexts, such as medical ones, where high usability and availability are required. In this paper we propose a methodology for the development of knowledge-based medical applications on the web, based on the use of an explicit domain ontology to automatically generate parts of the system. We describe a development environment, centred on the LISPWEB Common Lisp HTTP server, that supports this methodology, and we show how it facilitates the creation of complex web-based applications, by overcoming the limitations that normally affect the adequacy of the web for this purpose. Finally, we present an outline of a system for the management of diabetic patients built using the LISPWEB environment.

Artificial Intelligence↗
PubMed1998

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.

PURPOSE: The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.

Adult↗
PubMed1998

Antiproliferative activity of colchicine analogues on MDR-positive and MDR-negative human cancer cell lines.

In this study the in vitro antitumor activity of a series of 20 colchicine analogues was tested and compared with colchicine and thiocolchicine on three different human cancer cell lines, two of which express the multidrug-resistance (MDR) phenotype. At concentrations from 1 nM to 100 microM, all compounds tested inhibited cancer cell proliferation. The IC50 values indicate that the three fluorinated analogues were the most active compounds, with a similar decreasing order of potency (IDN 5005 > IDN 5079 > IDN 5080) on the two MDR-expressing cell lines, whereas thiocolchicine was the most effective compound on the MDR-negative MDA-MB 231 cells. A strong correlation (r = 0.94; P = 0.004) was found between IC50 values obtained using the two MDR-positive cell lines. Conversely, IC50 values obtained in MDA-MB 231 cells did not show a significant correlation with MDR-positive cell lines, thereby suggesting some difference in the antiproliferative mechanism(s) of colchicine analogues. Cell cycle analysis of the most active analogues in breast cancer cells showed a relationship between cell cycle blocking activity and growth inhibition. The most active agents on the MDR-positive MCF7 ADRr cell line, after 24 h of culture, in terms of cell cycle blocking activity were the three fluorinated analogues. Interestingly, after 72 h, when the cell cycle block subsided, a consistent amount of DNA fragmentation was evident. The extent of cell cycle block, measured as the G2/G1 ratio, was significantly correlated with the apoptosis rate expressed as a percentage of DNA fragmentation on both cell lines, thereby suggesting that a large number of blocked cells underwent the apoptotic pathway.

Antineoplastic Agents↗
PubMed1998

Role of basic fibroblast growth factor in the formation of the capillary plexus in the chick embryo chorioallantoic membrane. An in situ hybridization, immunohistochemical and ultrastructural study.

The chick embryo chorioallantoic membrane (CAM) is supplied by an extensive capillary network. We have previously demonstrated that a Mr 16,000 basic fibroblast growth factor (FGF2)-like molecule is present in the CAM. At present, no data are available on the cellular source(s) of FGF2 in the CAM. In this work, CAM has been investigated by in situ hybridization with the aim to identify the source(s) of endogenous FGF2 during development. The immunohistochemical expression of fibronectin, laminin and type IV collagen in the CAM extracellular matrix (ECM) and the ultrastructural relationships between chorionic epithelium and the underlying capillary plexus were also studied. Our findings strongly suggest that FGF2 regulates the development of the capillary plexus by two sequential steps. In an early paracrine phase, chorionic epithelial cells secrete FGF2, thus eliciting an angiogenic response in the undifferentiated mesodermal blood vessels. In response to this paracrine signalling, the newly formed endothelial cells move through a permissive ECM and migrate beneath the chorion. Here, they synthesize an autocrine supply of FGF2 necessary to further proliferate and differentiate, thus originating the capillary plexus.

Allantois↗
PubMed1998

[The incidence of stress ulcers and the effectiveness of preventive alkalization treatment in patients scheduled for major vascular surgery. Prospective study].

BACKGROUND: A prospective double blind study has been carried out in order to evaluate the current incidence of stress ulceration and the efficacy of acid-reducing prophylaxis, in patients scheduled for major vascular surgery, without a documented history of ulcer disease or previous upper GI-tract surgery. METHODS: Seventy patients have been randomly assigned to treatment group with ranitidine 50 mg e.v. every six hours or to control group with placebo at the same intervals. Gastric juice has been evaluated for pH and for occult blood by a slide test four times a day and cultured once a day on a suitable ground in the postoperative period. Data have been analyzed on a "treatment efficacy" and not "intention to treat" basis: patients have been considered alkalinized if more than 80% of pH measurement were > 4.5. Patients have been therefore divided into two groups, the "alkaline" one (43 patients) and the "acid" one (27 patients). RESULTS: Twenty-five patients (58.1%) in the alkaline group vs four patients (14.8%) in the acid group, showed positive gastric-juice cultures (p > 0.01). Twenty-three patients in the alkaline group (53.4%) and nine patients in the acid group (33.3%) showed occult gastric bleeding (p = NS). Overall, nine patients (12.8%) had overt gastrointestinal bleeding, four in the alkaline group (9.3%) and five in the acid group (18.5%) (p = NS). Endoscopic evaluation revealed erosive gastropathy in six patients, gastric ulcer in two patients and duodenal ulcer in one. Neither occult nor overt gastrointestinal bleeding did correlate with gastric pH values. On the contrary, the development of overt gastrointestinal bleeding has been positive associated with length of aortic cross-clamping and with postoperative score index. CONCLUSIONS: This observation suggests that factors other than gastric acidity contribute to mucosal damage and bleeding, as intraoperative mesenteric ischemia/hypoperfusion, or oxygen free radicals damage produced during reperfusion of districts below the level of aortic cross-clamping. The results obtained suggest that routinary alkalisation of gastric juice is not warranted in the prevention of gastrointestinal bleeding in major vascular surgical patients.

Aged↗
PubMed1998

Antitumor activity of paclitaxel (taxol) analogues on MDR-positive human cancer cells.

A series of newly developed paclitaxel analogues have been tested for their growth inhibitory activity on two human breast cancer cell lines, one of which expresses the MDR (multidrug resistance) phenotype. Paclitaxel (taxol) was used as a reference compound. Three new classes of taxanes were analyzed: the cephalomannine compounds, the pyrazoline derivatives and the seco-derivatives. Our results demonstrated an increased antiproliferative activity of pyrazoline derivatives on drug-resistant cancer cells with respect to paclitaxel. These compounds were able to block MDR-bearing MCF-7 ADRr cells in the G2/M phase of cell cycle and, consequently, induce programmed cell death. In keeping with the antiproliferative effects, cells treated with paclitaxel derivatives showed a more pronounced cell cycle arrest than the parent compound paclitaxel. Also, apoptotic cell death, calculated as a percent of DNA fragmentation, occurred to a greater extent in cells exposed to pyrazoline derivatives. The development of new paclitaxel analogues with greater antitumour activity on MDR-positive cells may be useful in selecting new taxanes effective on resistant tumors.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Human salivary gland parenchymal cells seen by SEM from the cytoplasmic side using a new osmium maceration method.

By removing all or most organelles, we have exposed the cytoplasmic side of the plasmalemma and its specializations in serous cells and in cells of striated and excretory ducts of human major salivary glands. The areas of plasmalemma located beneath the lumen and those bordering the intercellular canaliculi are covered by evenly distributed particles arranged in a continuous band and, below it, in regularly spaced clusters. A similar pattern of particles is seen on the internal aspects of the juxtaluminal plasmalemma of cells of both striated and excretory ducts. Small isolated clusters of particles are seen in other regions of serous and ductal cells as well, being particularly numerous along the basal processes of cells of striated ducts. A distribution of particles resembling that present along intercellular canaliculi of serous cells also is seen on the plasmalemma bordering the biliary canaliculi where, however, the clusters look smaller and farther apart. Large clusters of particles, matching those seen on salivary glands and on liver, are present at the base of the short processes of cells of the stratum spinosum of squamous stratified epithelia. Since the sites of location of the clusters closely correspond to the areas where transmission electron microscopy (TEM) reveals the presence of desmosomes, we believe that the clusters may be related to these cellular junctions. Of more difficult interpretation are the particles present on the juxtaluminal band corresponding both to the zonula occludens and to the zonula adhaerens.

Adult↗
PubMed1998

Cytoskeletal regulation of human salivary secretion studied by high resolution electron microscopy and confocal laser microscopy.

To study the cell regulation mechanisms of human salivary secretion, surgical specimens of human parotid and submandibular glands were treated in vitro with isoproterenol (beta-agonist), carbachol (muscarinic agonist), and cytochalasin D (microfilament disruptive agent), and morphological changes occurring in serous acinar cells were observed. Control acinar cells treated without secretagogues exhibited only occasional examples of exocytosis. Microfilaments, revealed by transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM) of F-actin fluorescence stained by rhodamine-phalloidin, were localized underneath the luminal membrane to separate the secretory granules from the luminal membrane. Following isoproterenol treatment, secretory granules made direct contact with the luminal membrane and many omega-shaped exocytotic profiles appeared. TEM and scanning electron microscopy (SEM) showed these profiles to be of granule size or somewhat smaller and to be provided on their cytoplasmic surface with coated pits. Furthermore, CLSM detected the appearance of F-actin fluorescence around the exocytosed granule membranes. Carbachol treatment also evoked the formation in acinar cells of omega-shaped exocytotic profiles some of which were larger than the granules and which exhibited neither coated pits nor associated F-actin fluorescence. To determine if microfilaments regulate the post-exocytotic process of membrane retrieval, we combined isoproterenol treatments with cytochalasin D or carbachol. Following these treatments, F-actin fluorescence surrounding the exocytosed membrane was dispersed or diffused and the exocytotic profiles enlarged remarkably. These results led to the hypothesis that exo/endocytotic processes in human salivary serous acinar cells are regulated differently under autonomic receptor control mediated by microfilaments.

Adult↗
PubMed1998

Taxoids in combination with anthracyclines and other agents: pharmacokinetic considerations.

The combination in clinical trials of taxoids with doxorubicin has focused attention on possible drug interactions. One specific finding requiring explanation is the relative lack of cardiotoxicity of the docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France)/doxorubicin combination compared with that of the paclitaxel/doxorubicin combination. Data in mice demonstrate that epirubicin concentrations in cardiac tissue 24 hours after treatment are approximately doubled by the coadministration of paclitaxel. This effect appears to be less marked with docetaxel administered in its normal polysorbate vehicle or when the drug is given in Cremophor EL (Sigma, St Louis, MO). Both Cremophor EL or polysorbate appear to cause an increase in epirubicin tissue levels, although the levels were less than those seen with paclitaxel. Pharmacokinetic data from women being treated with combination therapy for advanced breast cancer demonstrate that the administration of docetaxel following doxorubicin does not alter doxorubicin's area under the plasma concentration-time, curve, maximum plasma concentration, or time until maximum plasma concentration is reached. However, the area under the curve of docetaxel is significantly increased by the prior administration of doxorubicin. These findings may explain both the low cardiotoxicity and the high clinical efficacy of the docetaxel/doxorubicin combination. Phase I clinical trials of combinations in which docetaxel was used together with vinorelbine, ifosfamide, or 5-fluorouracil have shown no evidence of relevant pharmacokinetic interactions.

Animals↗
PubMed1998

Mining biomedical time series by combining structural analysis and temporal abstractions.

This paper describes the combination of Structural Time Series analysis and Temporal Abstractions for the interpretation of data coming from home monitoring of diabetic patients. Blood Glucose data are analyzed by a novel Bayesian technique for time series analysis. The results obtained are post-processed using Temporal Abstractions in order to extract knowledge that can be exploited "at the point of use" from physicians. The proposed data analysis procedure can be viewed as a Knowledge Discovery in Data Base process that is applied to time-varying data. The work here described is part of a Web-based telemedicine system for the management of Insulin Dependent Diabetes Mellitus patients, called T-IDDM.

Algorithms↗