Biomedical subjects

C Pastore

Publications and source records attributed to C Pastore.

53 records · Page 3Linked to original sources

PubMed1996

AIDS-related Burkitt's-type lymphomas are a target for lymphokine-activated killers induced by interleukin-2 and prolactin.

The development of non-Hodgkin's lymphomas (NHL) is one of the major complications of AIDS. Although several biologic aspects of AIDS-related NHL have been clarified, their sensitivity to immune system cytotoxic effectors has not been tested. In this study, we have investigated the susceptibility of one major AIDS-related NHL type, Burkitt's-type lymphoma (BL), to the cytotoxic activity of lymphokine-activated killers (LAK) and prolactin-activated killers (PAK), which were generated from peripheral blood mononuclear cells upon stimulation with interleukin-2 (in the case of LAK cells) and prolactin (in the case of PAK cells). The sensitivity of AIDS-related BL to in vitro raised cytotoxic effectors was compared with that of BL variants of the general population, including sporadic BL and endemic BL. The data show that AIDS-related BL is susceptible to cytolysis by LAK cells, whereas both LAK and PAK cells can efficiently kill endemic BL. In contrast, sporadic BL showed resistance to all cytotoxic effectors tested. Intriguingly, in the case of AIDS-related and endemic BL suboptimal doses of interleukin-2 in combination with prolactin displayed a cytotoxic effect similar to that of LAK cells, suggesting a synergistic activity of the two agents. Overall, these data corroborate the notion that the distinct BL variants differ in their biologic features despite their morphologic and genetic similarity.

Burkitt Lymphoma↗

PubMed1996

Association of 6q deletions with AIDS-related diffuse large cell lymphoma.

Deletions of chromosome 6 at band q27 represent the site of a putative novel tumor suppressor gene in non-Hodgkin's lymphomas (NHL) of the immunocompetent host. Although several genetic lesions have been identified in AIDS-related NHL (AIDS-NHL), the involvement of 6q27 loss has not been investigated in this NHL category. In this report, we tested the presence of a 6q deletion at the molecular level in a panel of AIDS-NHL representative of the major histologic types, including AIDS-related small non-cleaved cell lymphoma (AIDS-SNCCL; n = 10), AIDS-related diffuse large cell lymphoma (AIDS-DLCL; n = 13) and AIDS-related anaplastic large cell lymphoma (AIDS-ALCL; n = 3). We report that 6q deletions occur in 5/26 AIDS-NHL tested (19.2%). Notably, 6q deletions do not randomly distribute throughout the spectrum of AIDS-NHL histologic types, but rather selectively cluster with AIDS-DLCL (5/13; 38.4%). Overall, these data add to the notion that the molecular pathogenesis of AIDS-NHL is heterogeneous and that distinct genetic pathways associate with specific histologic categories of AIDS-NHL.

Blotting, Southern↗

PubMed1995

Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery.

BACKGROUND: Most strategies designed to reduce restenosis by the use of pharmacological or biological reagents involve direct inhibition of vascular smooth muscle cell (SMC) proliferation. Alternatively, SMC proliferation might be indirectly inhibited if reendothelialization could be specifically facilitated at sites of balloon-induced arterial injury. Accordingly, we investigated the hypothesis that application of an endothelial cell (EC)-specific mitogen to a freshly denuded intimal surface could accelerate reendothelialization and thereby attenuate intimal hyperplasia. METHODS AND RESULTS: The left carotid artery of 31 Sprague-Dawley rats was subjected to balloon injury, after which 16 rats were treated with a 30-minute incubation with 100 micrograms of vascular endothelial growth factor (VEGF), an EC-specific mitogen. Control animals (n = 15) received a 30-minute incubation with 0.9% saline. At 2 weeks after balloon injury, carotid artery reendothelialization was markedly superior in the VEGF-treated group compared with the control group (14.59 +/- 1.12 versus 7.96 +/- 0.51 mm2, P < 0.005). The extent of reendothelialization measured at 4 weeks after balloon injury remained superior for arteries treated with VEGF (18.04 +/- 0.90 mm2) versus saline (13.42 +/- 0.84 mm2, P < .005). Neointimal thickening was correspondingly attenuated to a statistically significant degree in arteries treated with VEGF versus the control group at both the 2-week and 4-week time points. Immunostaining for proliferating cell nuclear antigen (PCNA) disclosed a threefold increase in PCNA-positive cells in the neointima of control arteries versus VEGF-treated arteries at 2 weeks after injury. CONCLUSIONS: Application of VEGF, an EC-specific growth regulatory molecule, may be effectively used in vivo to promote reendothelialization and thereby indirectly attenuate neointimal thickening due to SMC proliferation.

Animals↗

PubMed1995

Expression of gax, a growth arrest homeobox gene, is rapidly down-regulated in the rat carotid artery during the proliferative response to balloon injury.

gax is a recently described homeobox gene whose expression in the adult is largely confined to cardiovascular tissues, gax has been shown to be rapidly down-regulated in cultured vascular smooth muscle cells (VSMC) upon stimulation by serum or platelet-derived growth factor. The temporal profile of gax expression in vitro matches that of two families of growth arrest genes: the gas genes and the gadd genes. All of these genes are expressed at their highest levels in quiescent cells and are down-regulated following mitogen activation. Here we report that gax is also down-regulated in vivo in the vascular wall in response to endothelial denudation by balloon angioplasty. The reduction in steady state levels of gax mRNA is transient and occurs with a similar time course to that seen in vitro. The down-regulation of gax in response to balloon injury mirrors the up-regulation seen in a number of early response genes such as c-myc and c-fos. This report is the first to document the in vivo expression of a growth arrest gene which regulates proliferation of vascular smooth muscle cells. In addition, in contrast with previous reports which have demonstrated up-regulation of several genes following balloon injury and/or angioplasty, the present report demonstrates the down-regulation of a regulatory gene within hours of balloon injury. The characteristics of gax suggest it may be required to maintain the gene expression of proteins in VSMC that are associated with the nonproliferative or contractile phenotype in smooth muscle cells.

Angioplasty, Balloon↗

PubMed1995

The effects of dopamine on the subthreshold electrophysiological responses of rat prefrontal cortex neurons in vitro.

The rat prefrontal cortex is densely innervated by dopaminergic fibres originating in the mesencephalic ventral tegmental area, and dopamine application in vivo has an inhibitory effect. We have studied the effects of dopamine on the persistent sodium current that is present in prefrontal cortex neurons and on the subthreshold electrophysiological responses generated by that current: a slow depolarization and a fast oscillatory activity. Experiments were made in coronal slices of rat frontal cortex (300-400 microns thickness) and intracellular recordings from regularly spiking cells were obtained with 3 M potassium acetate-filled glass microelectrodes (80-150 M omega). Dopamine was applied dissolved in the extracellular medium and, in current-clamp recordings, reversibly inhibited the slow subthreshold depolarization. Dopamine was ineffective when applied after tetrodotoxin (1 microM) had blocked the action potentials. This inhibition was dose-dependent in the range of 0.1-10 microM). Dopamine, applied at 10 microM, decreased the steady-state firing frequency and also inhibited the subthreshold fast oscillatory activity. The currents activated in the subthreshold range were recorded with the single-electrode voltage-clamp technique and a clear persistent, tetrodotoxin-sensitive component was isolated. This component was inhibited by 50% in a reversible way by 20 microM dopamine. These results show that dopamine increases the threshold for spike firing and suggest a mechanism for the inhibitory action of this neurotransmitter in the prefrontal cortex.

Animals↗

PubMed1995

Genetic analysis of chromosome 13 deletions in BCR/ABL negative chronic myeloproliferative disorders.

Chromosomal deletions of band 13q14 occur recurrently in BCR/ABL negative chronic myeloproliferative disorders (CMPD), including myelosclerosis with myeloid metaplasia (MMM), polycythemia vera (PV), essential thrombocythemia (ET), juvenile chronic myeloid leukemia (JCML), and the so-called BCR/ABL- chronic myeloid leukemia (CML). The RBI tumor suppressor locus, mapping to 13q14, has long since been hypothesized as the important gene. In this report, we have determined the frequency of 13q14 deletions at the molecular level in a large panel of BCR/ABL- CMPD at different disease stages and performed a detailed genetic analysis of gross rearrangements/deletions and point mutations of the RBI gene in these disorders. Our data show that molecular deletions of 13q14 are detected in a relatively large fraction of BCR/ABL- CMPD (38%), that they appear to be more frequent in MMM than in other BCR/ABL- CMPD, and that they may be present at diagnosis or occur during blastic evolution of the neoplasia. The RBI gene displayed a germline configuration in all BCR/ABL- CMPD tested, suggesting that 13q14 deletions in these disorders affect a tumor suppressor locus distinct from RBI.

Base Sequence↗

PubMed1995

Distribution of Kaposi's sarcoma herpesvirus sequences among lymphoid malignancies in Italy and Spain.

In this study we have tested the distribution of Kaposi's sarcoma herpesvirus (KSHV) DNA sequences throughout the spectrum of lymphoid neoplasia in Italy and Spain. 180 cases of lymphoid malignancies representative of the major histologic and immunophenotypic categories of B- and T-cell tumours were analysed by means of a polymerase chain reaction-based assay. KSHV sequences were consistently absent in all categories of lymphoid malignancies studied, with the exception of a subset of B-cell non-Hodgkin's lymphomas localizing in the pleural, pericardial or peritoneal cavities, and fulfilling the diagnostic criteria of body-cavity-based lymphoma. The selective and consistent association of KSHV sequences with cases of body-cavity-based lymphoma throughout the spectrum of lymphoid neoplasms suggests that KSHV may be involved in the pathogenesis of this peculiar type of lymphoid malignancy.

Base Sequence↗

PubMed1995

p53 gene inactivation in acute lymphoblastic leukemia of B cell lineage associates with chromosomal breakpoints at 11q23 and 8q24.

The clinical heterogeneity of acute lymphoblastic leukemia (ALL) of B cell lineage reflects the presence of distinct molecular pathways leading to well-defined ALL molecular subtypes. These molecular pathways include the formation of the fusion transcripts BCR/ABL and E2A/PBX1, due to t(9;22) and t(1;19), respectively, as well as rearrangements of the MLL gene at 11q23 and of c-MYC at 8q24. Hyperdiploid ALL in the absence of chromosomal structural abnormalities is an additional ALL molecular subtype. Mutations of the RAS family genes and of the p53 tumor suppressor gene represent additional genetic lesions detected in a fraction (10-20%) of ALL cases. RAS activation in ALL may be detected in all molecular subtypes of ALL and denotes poor prognosis. Conversely, little is known regarding the clinical and biological features of ALL cases carrying p53 mutations. In order to help clarify the role of p53 inactivation in ALL development, we have determined the frequency of p53 mutations throughout the molecular spectrum of B cell lineage ALL. We report that p53 inactivation in ALL of B cell lineage is restricted to cases carrying a rearrangement of MLL or c-MYC, whereas it is consistently negative in other molecular subgroups. These data underline the molecular heterogeneity of ALL of B cell lineage and indicate that at least some of the molecular pathways involved in ALL pathogenesis require more than one genetic lesion.

Base Sequence↗

PubMed1995

[Recent insights on the pathogenesis of non-Hodgkin's lymphoma].

Molecular pathology findings that are related to lymphomagenesis may be used as diagnostic tools, in conjunction with conventional methods. In particular, the use of genetic lesions as diagnostic markers of non-Hodgkin's lymphomas is supported by the selective association of certain genetic alterations with specific histological entities.

Biomarkers, Tumor↗

PubMed1994

Early diagnosis of n-hexane-caused neuropathy.

n-Hexane neuropathy was studied in 20 workers exposed for prolonged periods to this solvent, and with urinary 2,5-hexanedione concentrations exceeding the biological exposure index recommended by the American Conference of Governmental Industrial Hygienists (5 mg/L) with a mean of 11.02 mg/L (range 5.3-24.2 mg/L). Although neurological examination did not detect significant anomalies in any of the patients, and the conduction velocity and F waves of all the nerves tested were normal, neurographic studies revealed significant differences in the amplitude of sensory nerve action potentials (SNAP) recorded from the sural (mean 14.0 microV), median (mean 17.3 microV), and ulnar (mean 7.9 microV) nerves when compared with normal values from healthy adults of the same age range, examined under identical conditions. The amplitude of the SNAP in sural and median nerves correlated significantly with the number of years worked. The notable decrease in mean amplitude of the SNAP appeared to reflect the primary neurotoxic effects of 2,5-hexanedione.

Action Potentials↗

PubMed1994

Molecular pathology of AIDS-related lymphomas. Biologic aspects and clinicopathologic heterogeneity.

A high frequency of lymphoma in human immunodeficiency virus-infected individuals has been reported since the outbreak of the acquired immunodeficiency syndrome (AIDS) epidemic in 1982. AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL) is almost invariably derived from B cells and is classified as high- or intermediate-grade NHL, according to the working formulation. Two main histologic types are recognized, including small noncleaved cell lymphoma (SNCCL) and diffuse large cell lymphoma (DLCL). Pre-existing host factors putatively involved in lymphoma development include disrupted immunosurveillance, deregulated cytokine production, chronic antigen stimulation, and infection by Epstein-Barr virus (EBV). These alterations are associated with the development of multiple oligoclonal expansions which correspond to the clinical phase known as persistent generalized lymphadenopathy (PGL). The appearance of a true AIDS-NHL is characterized by the presence of a monoclonal B-cell population displaying several genetic lesions, including monoclonal EBV infection, c-MYC and BCL-6 rearrangements, RAS mutations, p53 inactivation, and 6q deletions. These genetic lesions cluster into two distinct molecular pathways, which specifically associate with the different histologic subtypes of AIDS-NHL, i.e., AIDS-SNCCL and AIDS-DLCL. The presence of distinct genetic pathways for AIDS-SNCCL and AIDS-DLCL correlate with a number of clinical features which distinguish these two groups of tumors, including differences in the age of onset, CD4 counts at the time of presentation, time elapsed since HIV infection, and clinical outcome.

Chromosomes, Human, Pair 8↗

PubMed1994

[Retroperitoneal ganglioneuroma. A case report and review of the literature].

Ganglioneuromas are typically of slow growth and benign evolution and may remain clinically silent for a considerable time if favourably situated. Many large examples are discovered incidentally on X-ray examination, routine abdominal palpation or at necropsy. Ganglioneuromas are often encountered in childhood and are found more frequently in the posterior mediastinum than in any other single situation; other sites are the lumbar and pelvic retroperitoneal tissues, the gastrointestinal tract and the mesentery. Diffuse alimentary tract ganglioneuromatosis has been described as port of the multiple endocrine neoplasia syndrome (MEN) type II-B. Sometimes ganglioneuromas are found in the von Recklinghausen Syndrome. The authors report in this paper a rare case of a retropancreatic ganglioneuromas.

Female↗

PubMed1993

Human beta 1-integrin gene expression is regulated by two promoter regions.

We report the cloning of two full-length cDNAs coding for the human beta 1-integrin which diverge from each other for their 5'-untranslated sequences. Characterization of a genomic clone containing these two sequences showed that they are contiguous, spaced by 261 nucleotides, and both followed by donor splice sites. Analysis by primer extension and transient transfection in a human osteogenic sarcoma cell line (MG-63) demonstrated the existence of two independent promoters for transcription initiation. The two promoter regions are very G+C-rich, and lack both a TATA box and a CAAT box. Northern blot analysis showed that transcripts starting from the distal promoter (with respect to the first coding exon) are at least 20-fold more abundant than transcripts originating from the proximal one. The levels of both transcripts increase after transforming growth factor-beta 1 induction, however, mRNAs originating from the proximal promoter increase at an higher extent. Reverse transcriptase/polymerase chain reaction analysis performed on different human tissues and cell lines revealed that, while the distal promoter is ubiquitously active, the proximal promoter is not. These findings suggest a possible complex pattern for regulation of the human beta 1-integrin gene expression.

Base Sequence↗

PubMed1993

The beta 1 integrin distal promoter is developmentally regulated in transgenic mice.

Transgenic mice harbouring 5' flanking sequences of the human beta 1 integrin gene linked to the Escherichia coli lacZ gene have been generated to examine spatial and temporal distribution of the promoter activity during development. Our previous data showed that this regulatory region is composed by two promoters, called distal and proximal, located closely on the human genome. To determine the role of each promoter region during development we generated transgenic mice using these two sequences linked to the lacZ reporter gene. Their analysis shows that these two sequences, as determined by in vitro studies, have different efficiencies in promoting transcription. Actually mice carrying the proximal promoter region exhibit a weak lacZ expression resulting in an undetectable beta-galactosidase activity in both embryonic and adult tissues. On the other hand, transgenic mice carrying the distal promoter express beta-galactosidase at high efficiency during embryonic development. The pattern of transgene expression is consistent with the localization of beta 1 protein on mouse embryos evidenced by immunohistochemistry. Moreover the distal promoter is subjected to a temporal modulation since in adult transgenic mice lacZ expression decreases to a level detected only by RT-PCR analysis. We have determined a similar down-regulation analysing by Northern blot beta 1 mRNA in adult and embryonic organs such as heart and gut.

Animals↗

PubMed1993

[Malignant tumors or the small intestine. Review of the literature and report of a clinical case].

The authors present one case of patients with adenocarcinoma of the small bowel. Primary malignant tumors of the small intestine are uncommon neoplasms accounting for 1-2 per cent of all gastrointestinal malignancies. Patients are usually seen late in the course of their illness when curative therapy is unlikely. The rarity of these neoplasms explains in part why the early signs and symptoms frequently go unrecognized and is undoubtedly a major factor contributing to their poor prognosis. Despite a fourfold greater length and a nearly tenfold greater mucosal surface area, the incidence of adenocarcinoma of the small intestine is about a fortieth that of the colon. This relative immunity of the small bowel to the development of the malignant tumors is unexplainable. Several theories have been suggested and include the following: a) the rapid transit time of the small intestine may reduce its exposure to dietary carcinogens; b) the relative sterility of the small intestine compared with the colon may lessen the formation of carcinogenic substances by the action of bacteria on components of bile or other substances within the intestinal lumen; c) certain mucosal enzymes such as benzopyrene hydroxylase that detoxify potential carcinogens are present in higher concentrations in the small intestine than in the colon; d) immunoglobulin A which is found in high concentrations in the small bowel, may protect it against carcinogenic viruses. Interestingly, patients deficient in IgA and those receiving immunosuppressive therapy have been found to have a higher incidence of small intestinal cancer. Adenocarcinoma is the most common primary malignant small bowel neoplasm.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

PubMedDate not supplied

Molecular pathogenesis of non-Hodgkin lymphoma: a clinical perspective.

Despite a common origin from mature lymphoid cells, non-Hodgkin lymphomas (NHL) represent a surprisingly heterogeneous group of lymphoid malignancies whose classification is continuously being remodeled. The most recent proposal, the Revised European-American classification, introduces pathogenetic features among the classification criteria. In this respect, knowledge of the molecular pathogenesis of NHL, which is based upon genetic lesions leading to activation of proto-oncogenes (e.g. BCL-1, BCL-2, BCL-6, c-MYC) or disruption of tumor suppressor genes (e.g. p53), is becoming increasingly relevant for the clinician. These lesions combine into multiple molecular pathways which are selectively associated with distinct NHL types. Thus, for example, rearrangements of BCL-1, BCL-2, BCL-6, and c-MYC ar the genetic hallmarks of mantle cell, follicular, diffuse large cell, and Burkitt's lymphoma, respectively. Overall, from clinical perspective, NHL genetic lesions serve three purposes: a) they assist and complement histologic diagnosis; b) they provide a molecular marker with prognostic relevance; c) they allow evaluation of minimal residual disease through highly specific and highly sensitive technologies.

Cell Transformation, Viral↗

PubMedDate not supplied

Use of an enzymatic mixture against met-Hb excess during oximetry of dilute Hb-A solutions.

A mixture of NADH, cytochrome-C-reductase and methylene blue was employed to antagonize ferri(met)-Hb formation during oximetries of dilute samples of human Hb-A. Its efficacy is clear at any pH between 6.8, 7.3 and 7.8, in the presence of 100 mM NaCl. In these cases, ferri(met)-Hb decreases of about 2/3, compared with the enzyme-free controls, and p50 increases. On the contrary, when samples are examined at pH 7.3 with 600 mM NaCl and/or 100 mM NaCl plus 1 mM DPG, ferri(met)-Hb of the samples containing the enzymes also decreases, but not more than 1/2 of its initial value, whereas also p50 decreases. Finally, Bohr effect is lower in the samples containing the enzymes. In conclusion, the enzymatic mixture is very useful, but not easy to be handled; so, some observations for its correct use are required.

Adult↗