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Biomedical subjects

P Porcu

Publications and source records attributed to P Porcu.

At least 37 records · Page 2Linked to original sources
PubMed2000

Acquired immunodeficiency syndrome-related lymphomas: future directions.

Despite some exciting new leads, human immunodeficiency virus-I (HIV-I)-related non-Hodgkin's lymphoma (HIV-NHL) remains a fatal malignancy for the vast majority of patients. The use of highly active antiretroviral therapy (HAART) has not produced a fall in the incidence of HIV-NHL and conventional cytotoxic chemotherapy is associated with a negligible cure rate. New treatment options are needed. Future therapeutic directions in HIV-NHL should be based on a better understanding of three fundamental aspects of lymphomagenesis in the setting of acquired immunodeficiency. (I) New information on the molecular and pathological heterogeneity of HIV-NHL should be applied to the development of risk-adapted therapy. The identification of patient subsets with different susceptibility to cytotoxic chemotherapy, immunomodulation, or antiviral strategies is essential for the design of clinical trials of investigational new agents in HIV-NHL. (2) Known viral pathogens need to be better understood. The presence and role of new viruses should be investigated. Key biological interactions between virus and host, mediated by oncogenic, immunomodulatory, and antiapoptotic viral proteins, should become the main target for new drug development. (3) Immune reconstitution with HAART and immunostimulatory cytokines such as interleukin-2 (IL-2) and IL-12, combined with drugs that downregulate the replication or gene expression of tumor-associated viruses such as Epstein-Barr virus (EBV) and human herpes virus-8 (HHV-8), possibly in combination, should remain a primary goal in the treatment of HIV-NHL. Preventive immunization, using autologous tumor cell vaccines or antigen-specific cellular adoptive immunotherapy should be explored.

Anti-HIV Agents↗
PubMed2000

[Popliteal vein aneurysms].

We report our experience with four cases of popliteal vein aneurysms treated over the last five years. The pathogenesis of these rare lesions is unknown. The inner wall of true venous aneurysms exhibit a reduced number of muscle fibers and fragmented elastic fibers replaced by fibrous tissue. The most dangerous risk related to popliteal vein aneurysm is pulmonary embolism. Diagnosis is based on phlebography and duplex Doppler findings. Surgery can provide cure and prevent complications. We treated our four patients with an asymptomatic aneurysm of the popliteal vein with aneurysmectomy using an atraumatic clamp and direct suture. Oral anticoagulants were given and elastic compression was maintained for six months, with satisfactory results.

Adult↗
PubMed1999

Sacrococcygeal teratoma in adults: case reports and a review of the literature.

BACKGROUND: The sacrococcygeal area is the most frequent site of teratoma in infants, but it is a rare location for teratoma in adults. METHODS: The authors report two patients in their sixth decade of life with the pathologic diagnosis of sacrococcygeal teratoma. The clinical presentations, the histologic findings, and the patients' clinical outcomes are described. A review of the literature on sacrococcygeal teratoma in adults is also presented. RESULTS: In the first patient, who had no evidence of recurrence after adequate resection, examination of the specimens showed mature teratoma. The second patient had mature teratoma with adenocarcinomatous component and possible leptomeningeal involvement. She died 2 months after the operation. CONCLUSIONS: Although rare in adults, sacrococcygeal teratoma should be considered in the differential diagnosis of patients with a pelvic mass presenting with obstructive symptoms. These two cases suggest that sacrococcygeal mature teratoma is surgically curable if teratoma is completely resected. The presence of leptomeningeal involvement and malignant transformation are associated with a less favorable outcome.

Adenocarcinoma↗
PubMed1998

Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery.

The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of gamma-aminobutyric acid type A (GABAA) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36Cl- uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for gamma2L GABAA receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also alpha1, alpha2, alpha3, alpha4, beta1, beta2, beta3, and gamma2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5alpha-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36Cl- uptake and the decrease of gamma2L mRNA observed during pregnancy. These results indicate that the plasticity of GABAA receptors during pregnancy and after delivery is functionally related to fluctuations in endogenous brain concentrations of AP whose rate of synthesis/metabolism appears to differ in the brain, compared with plasma, in pregnant rats.

Animals↗
PubMed1998

Alloantigen-induced unresponsiveness in cord blood T lymphocytes is associated with defective activation of Ras.

Human umbilical cord blood T lymphocytes (CBTL) respond to primary allostimulation but they do not proliferate upon rechallenge with alloantigen. Using PKH-26-labeled cells created a proliferative block that was observed only in CBTL that have divided during primary stimulation (PKH-26(dim)) but not in unstimulated (PKH-26(bright)) CBTL. CBTL's secondary unresponsiveness resembles anergy and can be overcome by treatment with phorbol myristate acetate (PMA) and ionomycin or by high doses (50-100 units/ml) of interleukin 2. Addition of interleukin 2 to the primary cultures does not prevent the induction of secondary unresponsiveness. Defective Ras activation is detected in PKH-26(dim) CBTL during secondary response to alloantigen or after antibody-mediated T cell receptor stimulation whereas Ras is activated and proliferation is induced in CBTL during primary alloantigenic stimulation. Upon stimulation with PMA plus ionomycin, PMA plus alloantigen, but not alloantigen plus ionomycin, Ras is activated in PKH-26(dim) CBTL, and the block in proliferation is overcome. Correction of PKH-26(dim) CBTL's proliferative defect correlates with PMA-induced Ras activation, suggesting a defect in the signaling pathway leading to Ras. Ras-independent signals, necessary but not sufficient to induce PKH-26(dim) CBTL proliferation, are provided by alloantigen exposure, as evident by the ability of PMA plus alloantigen but not PMA alone to overcome the proliferative block. Functional signal transduction through CD28 in PKH-26(dim) CBTL is supported by detectable CD28-mediated PI-3 kinase activation after PKH-26(dim) CBTL's exposure to alloantigen or CD28 cross-linking. These results suggest that defective activation of Ras plays a key role in PKH-26(dim) CBTL's secondary unresponsiveness and point to a defect along the T cell receptor rather than the CD28 signaling pathway.

Adult↗
PubMed1998

Modulation of gamma-aminobutyric acid (GABA) receptors and the feeding response by neurosteroids in Hydra vulgaris.

Gamma-Aminobutyric acid (GABA) receptors are present in membrane preparations from Hydra vulgaris, one of the most primitive organisms with a nervous system. These receptors are sensitive to muscimol and benzodiazepines and appear to be important in the regulation of the feeding response. The effects of neurosteroids, general anaesthetics, and GABA antagonists on GABA(A) receptors in membranes prepared from Hydra and on the feeding response have now been investigated. The neurosteroids tetrahydroprogesterone and tetrahydrodeoxycorticosterone increased [3H]GABA binding to hydra membranes with nanomolar potency (EC50, 141+/-11 and 623+/-36 nM, respectively) and high efficacy (maximal increase 79+/-6.5 and 62+/-4%, respectively), whereas the 3beta-hydroxy epimer of tetrahydroprogesterone was ineffective. The benzodiazepine receptor ligands diazepam (100 microM), clonazepam (100 microM) and abecarnil (30 microM) enhanced [3H]GABA binding to Hydra membranes by 22, 20 and 24%, respectively; effects abolished by the specific benzodiazepine antagonist flumazenil (100 microM). On the contrary, the peripheral benzodiazepine receptor ligand 4'chlorodiazepam failed to affect [3H]GABA binding to Hydra membranes. The general anaesthetics propofol and alphaxalone similarly increased (+38% and +30% respectively) [3H]GABA binding. Moreover, [3H]GABA binding to Hydra membranes was completely inhibited by the GABA(A) receptor antagonist SR 95531, whereas bicuculline was without effect. The modulation of GABA(A) receptors in vitro by these various drugs correlated with their effects on the glutathione-induced feeding response in the living animals. Tetrahydroprogesterone and tetrahydrodeoxy-corticosterone (1 to 10 microM) prolonged, in a dose-dependent manner, the duration of mouth opening induced by 10 microM glutathione, with maximal effects of +33 and +29%, respectively, apparent at 10 microM neurosteroid. Alphaxalone (10 microM) similarly increased (+33%) the effect of glutathione. The effects of steroids on the feeding response were inhibited by SR 95531 in a dose-dependent manner; t-butylbyclophosphorothyonate (1 microM), a specific Cl- channel blocker, which per se, like picrotoxin but not bicuculline, shortened the duration of the response, also counteracted the steroids effects at 1 microM. These results suggest that the modulation of GABA(A) receptors by steroids is an ancient characteristic of the animal kingdom and that the pharmacological properties of these receptors have been highly conserved through evolution.

Anesthetics↗
PubMed1997

Therapeutic leukapheresis in hyperleucocytic leukaemias: lack of correlation between degree of cytoreduction and early mortality rate.

The clinical and laboratory data of 48 leukapheresis-treated patients with hyperleucocytic leukaemia (HL) was reviewed to assess the correlation between the degree of leucoreduction and early mortality. Leukapheresis resulted in > 50% leucoreductions and postapheresis WBC counts < 100 x 10(9)/l in most patients (64.5%). Patients presenting with neurological, respiratory or renal complications had higher early mortality rates than patients without such complications, despite similar initial WBC counts and comparable leucoreductions. Thus, in these patients, more efficient leucoreduction was not associated with improved early survival.

Adolescent↗
PubMed1994

The role of the IGF-I receptor in the growth and transformation of mammalian cells.

Recent developments in the molecular biology of the insulin-like growth factor I (IGF-I) receptor have clarified its role in cellular growth and transformation. Although cells homozygous for a targeted disruption of the IGF-I receptor genes can grow in serum-supplemented medium, the IGF-I receptor is required for optimal growth, and is required equally in all phases of the cell cycle. The receptor plays an even more stringent role in cellular transformation and tumorigenicity, which seem to be dependent on its normal expression in several cell types. The expression of both the IGF-I receptor and its ligands is regulated by other growth factors (especially PDGF and EGF), by oncogenes (like SV40 T antigen and c-myb) and by tumour suppressor genes (like WT1 and RB). The picture emerging from these studies is that several transforming agents may exert their growth promoting effects through the direct or indirect activation of the IGF autocrine loop.

Animals↗
PubMed1994

An E2F binding sequence negatively regulates the response of the insulin-like growth factor 1 (IGF-I) promoter to simian virus 40T antigen and to serum.

The promoter of the Insulin-like growth factor I (IGF-I) gene is activated by the Simian Virus 40 large T antigen (SVLT), and one of the elements responding to SVLT activation has been localized to a short 124 bp immediately upstream of the first initiation of transcription site. This short promoter contains an E2F binding site, that, in gel shifts, binds a protein complex, but only when the promoter activity is reduced or absent. A mutation in the E2F binding site deregulates the activity of the promoter, which becomes active even in those conditions in which the wild type promoter is inactive. By using antibodies in gel retardation analyses, we can show that the different protein complexes include, at least, the following proteins: E2F, cyclin A and p107. We conclude that the short IGF-I promoter is negatively regulated by an E2F binding site that complexes with several proteins. Our data suggest that disaggregation of these complexes by the action of SVLT (or other activators) increases expression from the promoter, thus establishing a link between the regulation of cell proliferation by growth factors and the E2F-associated proteins.

3T3 Cells↗
PubMed1993

Oncogenes, growth factors and control of the cell cycle.

Recent advances in the field of cell cycle progression have extended our knowledge of the mechanism(s) of cellular proliferation and have placed it on a solid molecular basis. This survey highlights some of these findings, selecting the most intriguing in the hope of providing new insights on cell cycle controls. We have considered two large groups of factors involved in cell cycle control: extracellular (environmental signals, ie growth factors, and their cellular receptors) and intracellular (oncogenes and anti-oncogenes), indicating which, to us, may be the most promising areas of investigation. These include the events occurring after the IGF1 receptor is activated by its ligand, the role of anti-oncogenes in preventing the activation of growth factor receptors, the mechanism(s) by which some proto-oncogenes may short circuit the cell cycle and the use of peptide analogues and the antisense strategy to study and to regulate cellular proliferation.

Animals↗
PubMed1992

Inhibition of cellular proliferation by peptide analogues of insulin-like growth factor 1.

The activation of the insulin-like growth factor 1 (IGF-1) receptor by its ligand plays a central role in the growth of most cell types. We have used the techniques of computational chemistry in order to design and synthesize several novel analogues of IGF-1. These analogues were able to inhibit the autophosphorylation of the IGF-1 receptor as well as the growth of several different cell types, including prostate carcinoma cells and SV40-transformed cells. Additionally, we have found that D-amino acid analogues of these peptides are apparently resistant to the proteolytic degradation that occurs in the presence of whole sera. Consequently, these analogues seem to show great potential both as probes of the structure/function activities of the IGF-1 signalling pathway and as novel clinical strategies in controlling abnormal cellular growth.

3T3 Cells↗
PubMed1992

The growth-stimulatory effect of simian virus 40 T antigen requires the interaction of insulinlike growth factor 1 with its receptor.

We have used a plasmid expressing a temperature-sensitive (ts) mutant of simian virus 40 (SV40) T antigen, stably transfected into 3T3 cells, to study the role of insulinlike growth factor 1 (IGF-1) and its receptor in T-antigen-mediated growth. While 3T3 cells do not grow in serum-free medium, in 1% serum, or with the sole addition of either platelet-derived growth factor (PDGF) or IGF-1, cells expressing the tsA T antigen (BALB 58 cells) grow at 34 degrees C in either PDGF or 1% serum but not in IGF-1. At the restrictive temperature (39.6 degrees C), these cells can only grow in 10% serum. We show that BALB 58 cells, at 34 degrees C, have a markedly increased expression of IGF-1 and IGF-1 mRNA and that their growth in 1% serum (at 34 degrees C) is inhibited by an antisense oligodeoxynucleotide to the IGF-1 receptor RNA. When this tsA plasmid is stably transfected into cells constitutively overexpressing the human IGF-1 receptor cDNA, the resulting cell lines show a constitutively phosphorylated IGF-1 receptor and grow in serum-free medium at 34 degrees C (but not at 39.6 degrees C). A functional SV40 T antigen also increases the expression of a plasmid in which the reporter luciferase gene is under the control of a rat IGF-1 promoter. We conclude (i) that the SV40 T antigen induces the expression of IGF-1 and IGF-1 mRNA, at least in part by a transcriptional mechanism, thus altering the growth factors requirements, and (ii) that, in BALB/c3t3 cells, the SV40 T antigen necessitates a functional IGF-1 receptor for its growth-stimulating effect in low serum (or PDGF).

3T3 Cells↗
PubMed1992

The insulin-like growth factor 1 receptor is required for the proliferation of hemopoietic cells.

We have investigated the role of the insulin-like growth factor one (IGF1) receptor and its relationship to the proto-oncogene c-myb in the growth of two types of hemopoietic cells: mitogen-stimulated human peripheral blood mononuclear cells and a human promyelocytic cell line (HL-60). Using the antisense strategy and the reverse transcriptase polymerase chain reaction (RT-PCR), we show that expression of the IGF1 receptor is required for the entry into S phase of both stimulated lymphocytes and HL-60 cells. The inhibition of DNA synthesis by antisense oligomers to the IGF1 receptor RNA is accompanied by an inhibition of the expression of the mRNA for a DNA synthesis gene, proliferating cell nuclear antigen (PCNA), the co-factor of DNA polymerase delta. Inhibition of c-myb expression results in a decrease in IGF1 receptor mRNA levels; on the other hand, inhibition of IGF1 receptor expression has no effect on c-myb mRNA levels. A tentative temporal relationship between these three genes (c-myb, IGF1 receptor, PCNA) is proposed.

Base Sequence↗