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Biomedical subjects

G Giannini

Publications and source records attributed to G Giannini.

At least 55 records · Page 3Linked to original sources
PubMed1997

Activation of three distinct RXR/RAR heterodimers induces growth arrest and differentiation of neuroblastoma cells.

Naturally occurring retinoids, like all-trans retinoic acid and 9-cis retinoic acid, are known to affect proliferation and differentiation of sensitive neuroblastoma cell lines. Cellular responsiveness to retinoic acid depends on its interaction with two distinct classes of receptors, the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs). Both receptor classes have three different subtypes (RARalpha, RARbeta, and RARgamma and RXRalpha, RARbeta, and RARgamma) that act as ligand-dependent transcription factors. To examine the involvement of the different receptor classes and subtypes in the biological responses of neuroblastoma cells to retinoids, we analyzed the effects of a panel of receptor-selective retinoids on cell growth, differentiation, and gene expression on in vitro cultured KCNR cells. Any association of per se inactive RXR-selective with RAR-selective ligands efficiently regulates growth inhibition, differentiation (neurite extension), and expression of RARbeta, TrkB, and N-myc. SR11383 alone, a very potent retinoid, entirely reproduces the pattern of biological responses induced by naturally occurring retinoids. In contrast to other tumor cell lines, the growth of neuroblastoma cell lines is not altered using AP1-antagonistic retinoids. These studies raise the possibility that three distinct RXR/RAR heterodimers mediate the effects of retinoids on neuroblastoma cells through an AP-1 antagonism-independent mechanism.

Cell Differentiation↗
PubMed1997

Synthesis and binding properties of conjugates between oligodeoxynucleotides and daunorubicin derivatives.

Conjugation of an anthracycline to a triplex-forming oligonucleotide (TFO) allows delivery of this drug to a specific DNA site, preserving the intercalation geometry of this class of anticancer agents. Conjugate 11, in which the TFO is linked via a hexamethylene bridge to the O-4 on the D ring of the anthraquinone moiety, affords the most stable triple helix, through intercalation of the planar chromophore between DNA bases and binding of both the TFO and the amino sugar to the major and the minor groove respectively.

Antibiotics, Antineoplastic↗
PubMed1997

Correlation between changes in plasma HIV RNA levels and in plasma infectivity in response to antiretroviral therapy.

We evaluated the degree of correlation between the variation of different HIV-1 viral load measures in response to antiretroviral therapy. A quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for plasma HIV-RNA, and HIV plasma infectivity titration, were performed on prospective samples obtained from 86 antiretroviral-naive patients with symptomatic infection and CD4+ < 300/mm3, enrolled in a randomized double-blind trial of the HIV protease inhibitor saquinavir (SQV) in combination with zidovudine (ZDV). Subjects were stratified according to plasma virus infectivity and examined for correlations between distinct response categories with respect to CD4 count and HIV RNA copy number changes. Infectious virus could be titrated in 72% of patients at baseline. A significant reduction (< 1 log10) in HIV plasma infectivity titer was observed during the study in 69% of these patients. The reduction in plasma infectivity was a good predictor of sustained CD4+ cell increases and of sustained decrease in HIV RNA plasma copies. A decrease of at least 0.5 log10 in HIV RNA copy number was observed in 82% of the treated patients. A good correlation was found between HIV plasma infectivity titer and plasma HIV RNA copy number variations (p < 0.001). However, 10 of 17 patients with unchanged plasma infectivity titer showed a significant reduction in HIV RNA copies. While a good correlation was found between plasma infectivity and RNA plasma copies variations, only a minor correlation was found between CD4+ cell count variation and plasma infectivity titer variation. However, reduction in plasma infectivity was a very good predictor of high CD4 changes.

Anti-HIV Agents↗
PubMed1997

2-Aminopurine unravels a role for pRB in the regulation of gene expression by transforming growth factor beta.

Transforming growth factor type beta (TGFbeta) is a pleiotropic factor that regulates different cellular activities including cell growth, differentiation, and extracellular matrix deposition. All the known effects of TGFbeta appear to be mediated by its interaction with cell surface receptors that possess a serine/threonine kinase activity. However, the intracellular signals that follow receptor activation and lead to the different cellular responses to TGFbeta are still largely unknown. On the basis of the different sensitivity to the protein kinase inhibitor 2-aminopurine and the phosphatase inhibitor okadaic acid, we identified two distinct pathways through which TGFbeta activates a genomic response. Consistently, 2-aminopurine prevented and okadaic acid potentiated the induction of JE by TGFbeta. The induction of PAI-1 and junB was instead potentiated by 2-aminopurine, after a transient inhibition and was unaffected by okadaic acid. The superinducing effect of 2-aminopurine required the presence of a functional RB protein since it was abolished in SV40 large T antigen-transfected cells, absent in the BT549 and Saos-2 RB-defective cell lines, and restored in BT549 and Saos-2 cells after reintroduction of pRB. The effects of 2-aminopurine on the TGFbeta inducible junB expression occur in all the cell lines examined suggesting that junB, and possibly other genes, can be regulated by TGFbeta through a distinct pRB-dependent pathway.

2-Aminopurine↗
PubMed1997

Sonochemical production of a non-crystalline phase of palladium.

A non-crystalline phase of palladium was produced by cavitation technique starting from a solution of palladium acetylacetonate and toluene. The microscopic structure of the sample, a very fine powder, was investigated by X-ray diffraction and it showed the characteristic features of a disordered system. Further details about the phase of the sample were gained by studying the crystallization process induced by thermal treatments.

Journal Article↗
PubMed1997

HIV phenotype switching during antiretroviral therapy: emergence of saquinavir-resistant strains with less cytopathogenicity.

OBJECTIVES: The aim of the study was to investigate changes in virological characteristics of HIV strains isolated from 38 HIV-seropositive subjects during antiretroviral therapy. DESIGN AND METHODS: Patients with a CD4+ cell count < or = 300 x 10(6)/l were treated with zidovudine (12 individuals) and saquinavir (10 individuals) alone or in combination (16 individuals). CD4+ cell count, viral load, HIV biological phenotype and drug resistance were evaluated during the study period. RESULTS: After 52 weeks, 28 subjects (74%) harboured drug-resistant strains. In patients with a syncytium-inducing (SI) strain, a decline of CD4+ cell count and an increase of viral load were observed aside from the emergence of drug resistance. Conversely, at the emergence of antiretroviral resistance, an immunological and virological deterioration was observed only in patients who had a non-syncytium-inducing (NSI) strain. During the study, a phenotype switching of HIV isolates was detected in eight (21%) patients and a temporal correspondence between the appearance of phenotype switching and the emergence of drug resistance was found in seven cases. Three patients harbouring saquinavir-resistant strains showed a switch from SI to NSI variants associated with a moderate increase in CD4+ cell count. CONCLUSIONS: The emergence of resistant strains during antiretroviral therapy may be associated with the selection of viral strains with less cytopathogenicity, while it could become a poor prognostic sign in patients with NSI isolates.

Anti-HIV Agents↗
PubMed1996

Expression of trKB neurotrophin receptor during T cell development. Role of brain derived neurotrophic factor in immature thymocyte survival.

The relationships between the nervous and the immune systems raise the question of whether neurotrophic factors, in addition to the regulation of neural cell ontogeny, may influence lymphocyte development. We report in this work that the pattern of neurotrophin receptor expression depends on the developmental stage of T cells. The presence of nerve growth factor receptor trkA could not be detected in any of the thymocyte subsets, whereas brain-derived neurotrophic factor (BDNF) receptor trkB was expressed in all thymocyte subpopulations. Interestingly, both trkB mRNA and protein expression inversely correlated with the maturation stage and the differentiation potential of thymocytes, being more expressed in CD4-8- immature thymocytes and progressively declining in CD8+ and CD4+ single-positive and CD4+8+ more mature thymocytes. The developmentally regulated expression of trkB is further shown by the inhibition or enhancement of trkB expression induced by signals that either trigger or impair the transition from immature to more differentiated stages of the thymocyte developmental pathway. Signals generated following the interaction of BDNF with trkB receptor resulted in the stimulation of trkB autophosphorylation and in the up-regulation of the expression of the c-fos gene in CD4-8- cells and enhanced thymocyte survival. Finally, BDNF is expressed in thymic stroma and is further up-regulated by signals generated by the thymocyte/stromal cell interaction. These data suggest that BDNF may be a novel survival factor for thymocyte precursors and support the presence of developmentally regulated feedback mechanisms based on autocrine/paracrine neurotrophin/receptor interactions that may be involved in the thymocyte differentiation process.

Animals↗
PubMed1996

cDNA cloning reveals a tissue specific expression of alternatively spliced transcripts of the ryanodine receptor type 3 (RyR3) calcium release channel.

Ryanodine receptors (RyRs) are a family of intracellular calcium release channels. Three cDNAs encoding different isoforms of RyR have been identified and cloned. We report the complete sequence of the mink RyR3 cDNA and the characterization of three alternative spliced regions. The first two splicing sites are represented by insertions of five and six amino acids, respectively. The third site is represented by a mutually exclusive splicing. The tissue distribution of the alternatively spliced transcripts revealed a ubiquitous expression of splicing site I and a differential distribution of sites II and III, indicating that a further level of complexity in RyR3 expression may result from alternative splicings in this gene.

Alternative Splicing↗
PubMed1995

The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues.

Ryanodine receptors (RyRs) are intracellular calcium release channels that participate in controlling cytosolic calcium levels. At variance with the probably ubiquitous inositol 1,4,5-trisphosphate-operated calcium channels (1,4,5-trisphosphate receptors), RyRs have been mainly regarded as the calcium release channels controlling skeletal and cardiac muscle contraction. Increasing evidence has recently suggested that RyRs may be more widely expressed, but this has never been extensively examined. Therefore, we cloned three cDNAs corresponding to murine RyR homologues to carry a comprehensive analysis of their expression in murine tissues. Here, we report that the three genes are expressed in almost all tissues analyzed, where tissue-specific patterns of expression were observed. In the uterus and vas deferens, expression of RyR3 was localized to the smooth muscle component of these organs. In the testis, expression of RyR1 and RyR3 was detected in germ cells. RyR mRNAs were also detected in in vitro-cultured cell lines. RyR1, RyR2, and RyR3 mRNA were detected in the cerebrum and in the cerebellum. In situ analysis revealed a cell type-specific pattern of expression in the different regions of the central nervous system. The differential expression of the three ryanodine receptor genes in the central nervous system was also confirmed using specific antibodies against the respective proteins. This widespread pattern of expression suggests that RyRs may participate in the regulation of intracellular calcium homeostasis in a range of cells wider than previously recognized.

Animals↗
PubMed1995

Plasma viremia titration and RNA quantitation in ICD-p24 negative HIV type-1-infected patients.

Quantitative culture of human immunodeficiency virus (HIV) was performed on 202 plasma samples obtained from asymptomatic and early symptomatic HIV-1 infected patients (mean CD4+ count: 186/mm3) before antiretroviral therapy was started. HIV could be isolated from 84% of the plasma samples (titers ranging from 10(0) to 10(2.75) TCID50/ml). Immune complex dissociated p24 antigen (ICD-p24) was detected in 66% of the samples. Only 23 samples (11%) were negative for both ICD-p24 as well as HIV culture. Discordant results were obtained in 55 samples, and 45 samples negative for ICD-p24 were positive for HIV culture. A significant proportion (42%) of patients that were negative for ICD-p24 belonged to a very advanced group with very low CD4+ cell count. However, almost 90% of these ICD-p24 negative samples were positive for HIV plasma viremia, stressing the value of this virological marker in patients with low CD4+ cell count and without any detectable ICD-p24 antigenemia. HIV-1 RNA was detected in all ICD-p24 negative plasma samples tested by the branched DNA (bDNA) assay. A very good correlation was found between high RNA copy number and HIV plasma isolation in samples obtained from patients with low CD4+ cell count, suggesting that HIV-1 RNA quantitation may also reflect viral infectivity of plasma.

Antigen-Antibody Complex↗
PubMed1995

Synthesis and conformational preference of novel 8-fluoroanthracyclines.

Analogues of daunorubicin possessing a fluorine atom at position C(8) of ring A have been synthesized with the aim of comparing their DNA-drug interaction and antitumour properties with those of the clinically useful anthracyclines doxorubicin and idarubicin. The synthesis of (8S)-8-fluoro-4-demethoxydaunorubicin, 1, is reported and molecular mechanics and NMR studies which guided towards the synthesis of the epimeric (8R)-8-fluoro-4-demethoxydaunorubicin, 2, are discussed. Both compounds were prepared by divergent routes starting from the common intermediate, 6, obtained via the Diels-Alder cyclisation between quinizarin diquinone, 3, and 2-(1-hydroxyethyl)-1,3-butadiene, 4. The synthesis of the (8S)-fluoroepimer proceeded via epoxidation of the C(8)-C(9) olefinic bond of 6, oxidation, oxirane cleavage by BF3.Et2O to give the fluorohydroxyketone, 9, followed by the introduction of the hydroxyl moiety at C(7) and glycosylation. Conversely, the synthesis of the (8R)-fluoroepimer involved the fluorobromination of the C(8)-C(9) olefinic bond of 6, formation of the C(9)-C(13) epoxide, 20 which, after regioselective hydrolysis and oxidation of the resulting fluorodiol to the epimeric fluorohydroxyketone, 21, similarly gave the desired fluoroaglycone, 25 and, hence, the corresponding glycoside, 2. The cytotoxic properties of the two 8-fluoroanthracycline analogues, 1 and 2, were markedly affected by the stereochemistry of the fluorine substituent.

Antineoplastic Agents↗
PubMed1994

Chromosomal localization of murine ryanodine receptor genes RYR1, RYR2, and RYR3 by in situ hybridization.

In situ hybridization experiments were performed using complementary DNA probes to determine the location on murine chromosomes of the three genes of the ryanodine receptor/Ca2+ channel family: RYR1, RYR2, and RYR3. The skeletal ryanodine receptor, or type 1 (Ryr1), maps to bands 7A2-7A3; the cardiac ryanodine receptor, or type 2 (Ryr2), to 13A1-13A2; and type 3 (Ryr3) to 2E5-2F3.

Animals↗