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Biomedical subjects

L Lombardi

Publications and source records attributed to L Lombardi.

At least 19 recordsLinked to original sources
PubMed2005

Semantic relevance best predicts normal and abnormal name retrieval.

The relevance of a semantic feature measures its contribution to the "core" meaning of a concept. In a naming-to-description task, we investigated the predictive power of relevance in comparison with frequency, familiarity, typicality, and Age-of-Acquisition. In a group of Alzheimer patients with semantic disorder, relevance turned out to be the best predictor of name retrieval accuracy in a naming-to-description task. The same pattern of results was observed in normal controls. Relations between semantic relevance and the parameters of the concepts are discussed in order to highlight the mechanism of concept activation in a naming-to-description task.

Age Factors↗
PubMed2005

Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I.

The proteasome inhibitor PSI is potently cytotoxic in vitro against human chronic myeloid leukemia (CML) and acute myeloid leukemias (AML). Here, we have tested proteasome inhibitor I (PSI) in a panel of 11 human multiple myeloma (MM) cell lines and found that it has antiproliferative activity, with an IC50 between 4.5 and 557 nM at 48 h. PSI potentiated the toxicity of a number of chemotherapeutic agents in myeloid leukemia but not in MM cell lines, while in combination with therapeutic proteasome inhibitor PS-341 (Bortezomib) it had a synergistic effect. PSI suppressed the growth of AML cell lines more effectively than PS-341. CFU-GM colony assays revealed that CD34+ bone marrow progenitors from CML and AML patients were more sensitive to PSI than those from normal subjects (IC50: 5, 15 and 50 nM for AML, CML and normal, respectively). Moreover, the growth of normal primitive progenitors (LTC-IC) was unaffected by 15 nM PSI (P=0.576). PSI-induced cell death required RNA transcription and protein synthesis, but not DNA replication, was accompanied by the upregulation of Bcl-2 and modest reduction of Bax and Bcl-XL proteins, and involved the activation of caspases 2, 3, 7 and 8. These findings lend additional support to preclinical investigations with PSI.

Antineoplastic Agents↗
PubMed2005

[Preeclampsia and high serum levels of homocysteine].

AIM: Preeclampsia, a syndrome that can arise in the second half of pregnancy and that is characterised essentially by the presence, alone or variously combined, of three symptoms, oedemas, proteinuria and hypertension, has an incidence which varies between 5-7% and 25%. It seems that the element which determines the start and the continuation of the syndrome is located in the placenta and, in particular, in structural and functional changes of the trophoblast syncytium. In addition, the literature contains numerous studies that have evidenced endothelial damage as a key element to the pathogenetic mechanism in EPH-gestosis and recently an important role is attributed to a condition of hyperhomocysteinaemia. METHODS: Blood samples obtained from 30 primigravidas with term pregnancies and physiological course were taken within 1 week of delivery and from the same number of primigravidas hospitalised for preeclampsia. RESULTS: The homocysteine levels observed were significantly higher in women with preeclampsia (8.8+/-2.7 mol/l compared with the control group (4.1+-1.8 mol/l) (P<0.05). Haematocrit values measured on the day the sample was taken did not present any particular differences in the two groups. CONCLUSIONS: Our research, carried out on gravid patients at term of a physiological pregnancy and without intercurrent diseases and on primigravidas with preeclampsia who came to our observation at the moment of delivery and with a negative history for chronic hypertension, diabetes or other, showed a high concentration of homocysteine in the primigravidas with preeclampsia close to childbirth.

Adult↗
PubMed2004

[Outcome of pregnancy in patient with cloacal dysgenesis].

The cloacal dysgenesis or persistent cloaca is an anomaly included in urogenital tract malformations (UGM) and, in particular, in anomalies due to a missed development of the urogenital septum. The UGM occur during 6-11th weeks of gestation owing to a stop and/or alteration of the normal development and subdivision process of the cloaca, the embryonic structure from which gives origin to the ano-rectal segment of midgut, bladder, ureters, vagina and uterus. The case of a patient submitted to many surgical treatments for urogenital tract congenital malformations is described; when pregnant, she carried other pregnancy until the 34th week of gestation, giving birth a newborn by cesarean section. The patient was checked constantly for her general conditions and, in particular, her renal functions by an active collaboration between internist, nephrologist and gynecologist.

Adult↗
PubMed2004

[Recurrent spontaneous miscarriages and hyperhomocysteinemia].

AIM: Recurrent fetal loss is defined as the number of consecutive miscarriages which is not less than 2 occurred within the 16th week of gestation and it is a very interesting pathology of pregnancy. Further to thrombophilia, very important causes have been identified, since the damage of the vascular system supporting the placenta may cause a deficiency of placenta functions and development, leading to a loss of the conception product, also in a condition of hyperhomocystinemia, causing a damage to the vascular endothelium. Hyperhomocystinemia seems to be a risk factor for artero-venous thrombotic diseases, even not in pregnancy. METHODS: We have examined 40 patients referred to our Institute for unexplained fetal loss (at least 2 consecutive miscarriages within the 16th week of gestation) and the same number of patients who had at least 1 spontaneous delivery with a healthy and alive newborn and none abortion nor fetal death nor abruptio placentae. RESULTS: The mean levels of homocystinemia observed were significantly different in the 2 groups (p = or < 0.05). In the control group the values of plasmatic homocysteine were 10+/-4 micromol/L, corresponding to normal range, while in the other group the values of plasmatic homocysteine were 21+/-6 micromol/L, values certainly elevated, also because during the 1st trimester of pregnancy the levels of homocysteine decrease, reaching the lowest value during the 2nd trimester of pregnancy. In particular, high levels of homocysteine have been found in 25% (10) of women with unexplained early fetal loss. CONCLUSION: Hypercystinemia, as a consequence of an interaction between a primary genetic defect and a nutrition condition (folate deficiency), may be a cause of recurrent miscarriages. Therefore, in these cases, a possible hypercystinemia should be searched and an association of folic acid and vitamin B6, a non teratogenic treatment, should be useful to restore the metabolic picture and to favour the pregnancy outcome.

Abortion, Habitual↗
PubMed2001

Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations.

The t(4;14)(p16.3;q32) chromosomal translocation occurs in approximately 20% of multiple myelomas (MM) and leads to the apparent deregulation of two genes located on 4p16.3: the fibroblast growth factor receptor 3 (FGFR3) and the putative transcription factor WHSC1/MMSET. Interestingly, FGFR3 mutations known to be associated with autosomal dominant human skeletal disorders have also been found in some MM cell lines with t(4;14) but their pathogenetic role in MM is still controversial. Since cell lines may represent useful models for investigating the effects of deregulated FGFR3 mutants in MM, we analysed the expression, activation, signaling pathways and oncogenic potential of three mutants identified so far: the Y373C and K650E in the KMS-11 and OPM-2 cell lines respectively, and the novel G384D mutation here identified in the KMS-18 cell line. All of the cell lines present a heterozygous FGFR3 gene mutation and transcribe the mutated allele; unlike KMS-11 and OPM-2 (which express the IIIc isoform), the KMS-18 cell line expresses prevalently the isoform IIIb. We demonstrated that, under serum-starved conditions, KMS-11 and OPM-2 cells express appreciable levels of phosphorylated FGFR3 mutants indicating a constitutive activation of the Y373C and K650E receptors; the addition of the aFGF ligand further increased the level of receptor phosphorylation. Conversely, the FGFR3 mutant in KMS-18 does not seem to be constitutively activated since it was phosphorylated only in the presence of the ligand. In all three MM cell lines, ligand-stimulated FGFR3 mutants activated the MAP kinase signaling pathway but did not apparently involve either the STAT1 or STAT3 cascades. However, when transfected in 293T cells, G384D, like Y373C and K650E, was capable of activating MAPK, STAT1 and STAT3 under serum-starved condition. Finally, a focus formation assay of NIH3T3 cells transfected with FGFR3-expressing plasmid vectors showed that Y373C and K650E (albeit at different levels) but not G384D or the wild-type receptor, can induce transformed foci. Overall, our results support the idea that FGFR3 mutations are graded in terms of their activation capability, thus suggesting that they may play a critical role in the tumor progression of MM patients with t(4;14).

3T3 Cells↗
PubMed2001

Anticardiolipin antibodies in patients with primary antiphospholipid syndrome: a correlation between IgG titre and antibody-induced cell dysfunctions in neuronal cell cultures.

Anticardiolipin antibodies (aCL) of the immunoglobulin (Ig) G isotype have been significantly associated with neurological manifestations of antiphospholipid syndrome (APS). In a previous study we described the direct pathogenic effects of IgG aCL on living neurons in culture. Therefore, we studied the IgG aCL titre as a factor influencing the extent of this effect. Seventeen patients with a history of primary antiphospholipid syndrome were grouped according to their IgG aCL titre into low positive (GPL < or = 40), high positive (40< GPL <100) and very high positive (GPL >100). IgG from these patients were incubated with cerebellar neurons in primary culture for 24h and the effect was evaluated by using the tetrazolium salt (MTT) assay. We found that almost all patients' IgGs reduced cell viability in vitro, but the differences in the extent of the effect were statistically significant only for patients with >40 GPL. Our results reinforce the causal association between increasing level of IgG aCL and clinical features of aPS.

Adult↗
PubMed2001

Analysis of FGFR3 gene mutations in multiple myeloma patients with t(4;14).

The t(4;14)(p16.3;q32) in multiple myeloma (MM) leads to an apparent deregulation of the FGFR3 and WHSC1/MMSET genes. FGFR3 mutations, known to be associated with genetic skeletal disorders, have also been identified in a few cases of MM (mainly cell lines) with t(4;14). We investigated FGFR3 mutations in a series of 53 MM cases; 11 cases with t(4;14) and FGFR3 overexpression were analysed using reverse transcription polymerase chain reaction, while the remaining cases were studied at DNA level. The Arg248Cys mutation, which is associated with some lethal forms of skeletal disorders, was found in one case with t(4;14). Our results indicate that FGFR3 mutations occur in only a small fraction of MM cases with t(4;14).

Chromosomes, Human, Pair 14↗
PubMed2001

Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos.

Mitochondria play a vital role in the metabolism of energy-containing compounds in the oocyte cytoplasm to provide adenosine trisphosphate for fertilization and preimplantation embryo development. In this study, ratiometric confocal microscopy with the mitochondrion-specific membrane potential-sensitive fluorescence dye JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide) was used to measure the activity of mitochondria in human oocytes and developing preimplantation embryos. Mitochondria in oocytes and embryos were characterized by distinct localized aggregation patterns. These patterns however did not determine localized regions of heterogeneity in mitochondrial activity. Mitochondrial activity was analysed during oocyte maturation and after fertilization. The activity of mitochondria in fresh metaphase II oocytes was negatively correlated with maternal age. This trend continued when the activity of developing embryos was analysed. Mitochondrial activity was strongly correlated with the rate of embryo development on day 3 after fertilization, but not on day 2. Partial regression analysis showed that the rate of cleavage of preimplantation embryos was more highly correlated with embryo mitochondrial activity than maternal age. These data suggest that the efficiency of mitochondrial respiration in oocytes and preimplantation embryos is closely correlated with the programmed rate of embryo development, and suggest that maternal age further influences this factor. The loss of mitochondrial activity in oocytes obtained from ageing couples may therefore contribute to lower embryo development and pregnancy rates observed during cycles of IVF.

Benzimidazoles↗
PubMed2001

Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia.

Monocarboxylate transporters (MCTs) are a family of highly homologous membrane proteins that mediate the 1:1 transport of a proton and a lactate ion. In chicken, MCT3 is preferentially expressed in the retinal pigment epithelium (RPE). We have isolated the mouse MCT3 cDNA and gene and characterized the pattern of tissue expression. MCT3 is a single copy gene with a 1.8-kb transcript that encodes a protein with a predicted molecular mass of 51.5 kDa. Based on Northern hybridization analysis, MCT3 transcript was expressed in only two tissues: RPE and choroid plexus epithelium (CPE). The choroid plexus forms a barrier between the cerebrospinal fluid and fenestrated capillaries, similar to the organization of the RPE and choroidal vessels. Immunohistochemical staining demonstrated that MCT3 was restricted to the basolateral membranes of both epithelia but was more abundant in RPE than CPE. Differences in the level of protein expression were confirmed by Western blot analysis. The cloning of MCT3 identifies a specific transporter that could regulate lactate levels in fluid-bathing neuronal tissues.

5' Untranslated Regions↗
PubMed2001

Ultrastructural characteristics, biological activity and pharmacological relevance of synthetic malaria pigment (beta-haematin).

Malaria pigment (haemozoin, HZ) is the detoxification product of haemoglobin-derived haem of intraerythrocytic malaria parasites. At schizont rupture, haemozoin accumulates inside host phagocytic cells. The chemical structure and the spectroscopic characteristics of haemozoin are identical to those of beta-haematin (BH), a synthetic pigment obtained from Ferriprotoporphyrin IX (Fe (III) PPIX) in acidic conditions. The process of BH formation is the target of quinoline antimalarials. Here, we summarise the results of our studies on the ultrastructural characteristics, biological and pharmacological relevance of synthetic vs. native haemozoin. 1) By electron microscopy, native HZ and synthetic BH appear as dark brown crystals, morphologically indistinguishable and are internalised by phagocytes at the same extent. 2) Both HZ and BH modulate the production of cytokines (TNF and NO) and increase the susceptibility to lipid peroxidation of mouse or human phagocytes. The antioxidant status of the phagocytes regulates the susceptibility to BH/HZ-mediated effects. 3) The process of BH formation from Fe(III)PPIX, hence haem detoxification, can be inhibited by electrochemically-reduced, Fe(II)PPIX molecules. Maintaining iron in the reduced state can thus be considered a new pharmacological target. This was confirmed by the observation that thiol-reducing agents (NAC, cystein) were able to inhibit BH formation and were toxic to parasites in vitro.

Animals↗
PubMed2000

Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by reverse transcription-polymerase chain reaction analysis of IGH-MMSET fusion transcripts.

We and others have recently identified a novel recurring t(4;14)(p16.3; q32) translocation in multiple myeloma (MM) that leads to an apparent deregulation of the FGFR3 and WHSC1/MMSET genes. Because the presence of IGH-MMSET hybrid transcripts has been found in MM cell lines with t(4;14), they may represent a specific tumor-associated marker in MM. In this study, we developed a reverse transcription-PCR (RTPCR) assay for detecting chimeric transcripts from all of the 4p16.3 breakpoints identified thus far, and we used it to investigate a representative panel of 53 MM patients and 16 patients with monoclonal gammopathy of uncertain significance; in addition, t(4;14) was investigated in all of the MM patients by means of two-color fluorescence in situ hybridization. IGH-MMSET transcripts were found in 11 of the 53 (20%) MM cases and 1 of 16 (6%) cases of monoclonal gammopathy of uncertain significance. There was complete concordance between the RT-PCR and fluorescence in situ hybridization analyses of the MM cases. The results of this study indicate that RT-PCR is a sensitive and reliable method of detecting t(4;14) and suggest that it may be useful for monitoring the disease in a significant proportion of patients.

Adult↗
PubMed2000

Immunohistochemical analysis of cyclin D1 shows deregulated expression in multiple myeloma with the t(11;14).

The t(11;14)(q13;q32) chromosomal translocation, the hallmark of mantle cell lymphoma (MCL), is recurrently found in multiple myelomas (MM) by means of conventional cytogenetics. Unlike MCL, recent molecular studies of MM-derived cell lines with t(11;14) have indicated that the breakpoints are highly dispersed over the 11q13 region; however, the fact that cyclin D1 is generally overexpressed in these cell lines suggests that this gene is the target of the translocation. To evaluate further the involvement of cyclin D1 in MM, we used immunohistochemistry and fluorescence in situ hybridization to investigate cyclin D1 expression and the presence of chromosome 11 abnormalities in a representative panel of 48 MM patients (40 at diagnosis and 8 at relapse). Cyclin D1 overexpression occurred in 12/48 (25%) of cases; combined immunohistochemistry and fluorescence in situ hybridization analyses in 39 patients showed cyclin D1 positivity in all of the cases (7/7) bearing the t(11;14), in two of the 13 cases with trisomy 11, and in one of the 19 cases with no apparent abnormalities of chromosome 11. Our data indicate that the t(11;14) translocation in MM leads to cyclin D1 overexpression and that immunohistochemical analysis may represent a reliable means of identifying this lesion in MM.

Adult↗
PubMed2000

Characterization of carrot nuclear proteins that exhibit specific binding affinity towards conventional and non-conventional DNA methylation.

DNA methylation is associated with transcriptional silencing in vertebrates and plants. In mammals, the effects of methylation are mediated by a family of methyl-CpG-binding proteins. In plants the mechanisms by which methylation represses transcription are still not clear. In this paper we describe protein factors in carrot nuclear extracts exhibiting specific affinities for conventional or non-conventional methylation acceptor sites. We characterized two classes of proteins: the first, dcMBPI (Daucus carota methylated DNA-binding protein 1), shows high affinity for sequences containing 5-methylcytosine; the second, dcMBP2 (Daucus carota methylated DNA-binding protein 2), efficiently complexes sequences containing 5-methylcytosine in both CpXpX and CpXpG trinucleotides and shows much lower affinity for 5-methyl CpG dinucleotides. Both dcMBP1 and dcMBP2 are abundant proteins differing in molecular weight and binding features. Their activities are modulated during carrot vegetative cell growth and somatic embryo development. This is the first time that, in either plants or mammals, proteins exhibiting specific binding affinities for conventional or non-conventional DNA methylation have been shown. Based on these results, the possibility that both the extent and the context of the methylation might contribute to modulate gene expression is discussed.

5-Methylcytosine↗
PubMed1999

Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by double-color fluorescent in situ hybridization.

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus at chromosome 14q32 represent a common mechanism of oncogene activation in lymphoid malignancies. In multiple myeloma (MM), variable chromosome partners have been identified by conventional cytogenetics, including the 11q13, 8q24, 18q21, and 6p21 loci. We and others have recently reported a novel, karyotypically undetectable chromosomal translocation t(4;14)(p16. 3;q32) in MM-derived cell lines, as well as in primary tumors. The 4p16.3 breakpoints are relatively scattered and located less than 100 kb centromeric of the fibroblast growth factor receptor 3 (FGFR3) gene or within the recently identified WHSC1 gene, both of which are apparently deregulated by the translocation. To assess the frequency of the t(4;14)(p16.3;q32) translocation in MM, we performed a double-color fluorescent in situ hybridization (FISH) analysis of interphase nuclei with differently labeled probes specific for the IGH locus (a pool of plasmid clones specific for the IGH constant regions) or 4p16.3 (yeast artificial chromosome (YAC) 764-H1 spanning the region involved in breakpoints). Thirty MM patients, the MM-derived cell lines KMS-11 and OPM2, and six normal controls were examined. The identification of a t(4;14) translocation, evaluated as the presence of a der(14) chromosome, was based on the colocalization of signals specific for the two probes; a cutoff value of 15% (mean + 3 standard deviation [SD]) derived from the interphase FISH of the normal controls (range, 5% to 11%; mean +/- SD, 8.16 +/- 2.2) was used for the quantification analysis. In interphase FISH, five patients (one in clinical stage I, two in stage II, one in stage III, and a plasma cell leukemia) were found to be positive (approximately 15%). FISH metaphases with split or colocalized signals were detected in only two of the translocated cases and confirmed the pattern found in the interphase nuclei. Furthermore, in three of the five cases with the translocation, FISH analysis with the IGH joining probe (JH) showed the presence of the reciprocal product of the translocation [der(4) chromosome]. Overall, our study indicates that the t(4;14)(p16. 3;q32) chromosomal translocation is a recurrent event in MM tumors and may contribute towards the detection of this lesion and our understanding of its pathogenetic and clinical implications in MM.

Aged↗
PubMed1999

Molecular analysis of 11q13 breakpoints in multiple myeloma.

The t(11;14)(q13;q32) chromosomal translocation, which is the hallmark of mantle cell lymphoma (MCL), is found in approximately 30% of multiple myeloma (MM) tumors with a 14q32 translocation. Although the overexpression of cyclin D1 has been found to be correlated with MM cell lines carrying the t(11;14), rearrangements of the BCL-1/cyclin D1 regions frequently involved in MCL rarely occur in MM cell lines or primary tumors. To test whether specific 11q13 breakpoint clusters may occur in MM, we investigated a representative panel of primary tumors by means of Southern blot analysis using probes derived from MM-associated 11q13 breakpoints. To this end, we first cloned the breakpoints and respective germ-line regions from a primary tumor and the U266 cell line, as well as the germ-line region from the KMS-12 cell line. DNA from 50 primary tumors was tested using a large panel of probes, but a rearrangement was detected in only one case using the KMS-12 breakpoint probe. Our results confirm previous findings that the 11q13 breakpoints in MM are scattered throughout the 11q13 region encompassing the cyclin D1 gene, thus suggesting the absence of 11q13 breakpoint clusters in MM.

Base Sequence↗