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Biomedical subjects

S Iacobelli

Publications and source records attributed to S Iacobelli.

At least 37 records · Page 2Linked to original sources
PubMed1999

Isolation and functional characterization of the human 90K promoter.

90K is a secreted protein thought to be involved in the body's defense against pathogens and cancer. To elucidate its transcriptional regulation, the promoter of human 90K (HGMW-approved symbol LGAL S3BP) was isolated and characterized. Analysis of the 3. 3-kb 5'-flanking region revealed that it is a TATA-less promoter, but neither GC-rich nor dependent on SP1 sites. RNase protection assays detected one major transcription start site (+1) and several minor transcription start sites upstream and downstream. Deletion studies defined a minimal promoter (-103 --> -49) and indirectly suggested positive synergism between different elements within it. Consistent with the proposed function of 90K, its promoter activity could be stimulated by poly(I). poly(C), mimicking viral infection. Two regions mediating induction by poly(I). poly(C) (-171 --> -112, -32 --> 46) were identified by deletion mutants. A small region around the minimal promoter (-99 --> -12) was highly homologous between human and mouse. While both human and mouse minimal promoters contained an interferon-responsive element (IRF-E), the human minimal promoter was not inducible by poly(I). poly(C) in contrast to that of the mouse. Point mutations 30 bp upstream of the IRF-E, however, conferred inducibility to the human minimal promoter, suggesting interaction between different promoter elements.

3T3 Cells↗
PubMed1999

Endocrinological and clinical evaluation of two depot formulations of leuprolide acetate in pre- and perimenopausal breast cancer patients.

PURPOSE: To evaluate the endocrinological and clinical activity of a new slow-release formulation of leuprolide acetate in breast cancer patients. METHODS: A total of 50 pre- or perimenopausal patients with early- or late-stage breast cancer who were candidates for endocrine treatment were included in the study and randomly allocated to receive either 3.75 mg of leuprolide acetate every month or 11.25 mg of leuprolide acetate every 3 months. Patients were treated until disease recurrence or progression or for a maximum of 24 months. Treatment outcome, side effects, and serum levels of gonadotrophins, estradiol, progesterone, and delta4-androstenedione were analyzed at different time points. RESULTS: In all, 23 patients were allocated to the monthly formulation and 27, to the 3-monthly formulation. The median time on treatment was comparable. There was no evidence of any difference in clinical outcome or drug-induced side effects, hot flushes being recorded in about 50% of patients in both groups. Altogether, 35 patients were actively menstruating at the beginning of treatment; all of them became amenorrhoic after 3 months and remained so until treatment with leuprolide was continued, irrespective of the allocated treatment. All endocrine parameters, particularly estradiol levels, were suppressed to a similar extent. CONCLUSIONS: The present results indicate that the two formulations exert a comparable estrogen-suppressive effect and warrant further study of the 3-monthly formulation of leuprolide acetate in breast cancer patients.

Adult↗
PubMed1999

Elevated levels of circulating immunostimulatory 90K in Henoch-Schoenlein purpura.

In order to clarify the immunologic reaction present in Henoch-Schoenlein purpura (HSP), 20 children (11 boys and 9 girls; median age, 5.8 +/- 2.8 years) with HSP and 20 sex- and age-matched healthy children were studied. The 90K/Mac-2 BP serum concentrations were significantly higher in the patients than in the healthy controls (12.5 +/- 7.5 vs 4.5 +/- 2.7 micrograms/ml, respectively; P < 0.0001). 90K/Mac-2 BP values higher than the cutoff value were observed in 13 of 20 (65%) patient. The soluble intercellular adhesion molecule 1 concentrations were significantly higher in HSP patients than controls (P < 0.0001), with mean values of 1631 +/- 703 and 85 +/- 16 ng/ml, respectively. The 90K/Mac-2 BP serum levels were significantly correlated with soluble intercellular adhesion molecule 1 (r = 0.90, P < 0.0001). Although the underlying causes of these immunological abnormalities are unclear, these observations suggest that the 90K/Mac-2 BP protein may play a role in the immunological reactions involved in the development of HSP.

Age Distribution↗
PubMed1999

Human milk 90K (Mac-2 BP): possible protective effects against acute respiratory infections.

Eighty-six children fed human milk were followed prospectively from birth to 12 months of age to assess the effect of milk 90K, a secreted glycoprotein with immune-stimulatory properties, on development of acute respiratory infections (ARI). The level of human milk 90K was inversely related to episodes of ARI (r = - 0.34; P = 0.001). The average 90K level in human milk fed to children who did not develop ARI was significantly higher than in milk fed to children in whom infection occurred on multiple occasions (156.6 +/- 144.8 microg/ml versus 70.9 +/- 92.3 microg/ml; P = 0.001). These data suggest that the protective effects of human milk against ARI may be due in part to immune maturation effects by secreted 90K.

Acute Disease↗
PubMed1998

Increased levels of soluble P-selectin in hypercholesterolemic patients.

BACKGROUND: Hypercholesterolemia is considered a major risk factor for the development of atherosclerosis. Enhanced lipid peroxidation and persistent platelet activation can be observed in vivo in hypercholesterolemic patients and may have pathophysiological implications in the occurrence of cardiovascular events. P-selectin may play an important role in the pathogenesis of multicellular events, including atherosclerosis. We studied the impact of hypercholesterolemia and oxidative stress on plasma levels of P-selectin. METHODS AND RESULTS: Plasma levels of P-selectin were measured by means of an enzyme immunoassay in 20 hypercholesterolemic patients with no clinical evidence of cardiovascular disease and in 20 sex- and age-matched normocholesterolemic subjects. Hypercholesterolemic patients had higher levels of P-selectin compared with that of control subjects (98+/-61 versus 56+/-14 ng/mL; P=.001). They also displayed increased von Willebrand Factor (vWF) levels (176+/-22 versus 119+/-12%; P=.0001). A direct correlation was observed between P-selectin and LDL cholesterol levels (p=.453). Administration of vitamin E (600 mg/d for 2 weeks) to hypercholesterolemic patients significantly reduced plasma P-selectin (40%), and an inverse correlation was observed between vitamin E and P-selectin plasma levels (p=-.446). CONCLUSIONS: Hypercholesterolemia is associated with elevated plasmatic P-selectin. Altered oxidative processes leading to endothelial dysfunction and persistent platelet activation may contribute to increased soluble P-selectin levels. P-selectin may be proposed as a marker of endothelial dysfunction in hypercholesterolemic patients.

Cholesterol, LDL↗
PubMed1998

90K (MAC-2 BP) gene expression in breast cancer and evidence for the production of 90K by peripheral-blood mononuclear cells.

The tumor-derived antigen 90K (Mac-2 BP) is a widely expressed, secreted glycoprotein found in the serum of healthy individuals and at elevated levels in the serum of patients with breast cancer and other types of cancer. The precise function of 90K, particularly in the context of tumor-host relationships, has not yet been established. In this study, the clinical significance of 90K mRNA expression was studied in relation to other established prognostic parameters in 86 patients with primary breast carcinoma. The 2.2-kb 90K message was detected in all tumor samples, but there was marked variation in expression levels from tumor to tumor. Patients were classified into 2 groups on the basis of 90K expression: group 1 (n = 62) included patients with low expression, and group 2 (n = 24) consisted of patients with high expression. An inverse significant correlation was found between the levels of 90K mRNA expression and overexpression of c-erbB2/Neu receptor kinase, a marker of poor prognosis for patients with breast cancer. There was no significant difference between the groups with respect to tumor size, number of involved axillary lymph nodes, hormone-receptor status, p53 expression or proliferation activity as estimated by Ki-67 count. Similarly, no association was found between the level of 90K expression and the risk of death from breast cancer. These data are at variance with published findings showing that high serum 90K levels are associated with poor survival. Significantly, investigation of 90K-gene expression in peripheral-blood mononuclear cells (PBMC) revealed higher levels of 90K message in PBMC of breast-cancer patients than in healthy individuals. This new finding suggests that PBMC activated in response to tumor growth and progression may be an important source of serum 90K in breast cancer.

Adult↗
PubMed1998

Differential effect on TCR:CD3 stimulation of a 90-kD glycoprotein (gp90/Mac-2BP), a member of the scavenger receptor cysteine-rich domain protein family.

We studied the effects of a 90-kD glycoprotein (gp90/Mac-2BP) belonging to the scavenger receptor family, present in normal serum and at increased levels in inflammatory disease and cancer patients, on some T cell function parameters. Whereas the lymphocyte proliferative response to non-specific mitogens such as phytohaemagglutinin (PHA) and concanavalin A (Con A), but not pokeweed mitogen (PWM), was strongly reduced, probably due to the lectin-binding properties of gp90/Mac-2BP, the response to T cell receptor (TCR) agonists such as superantigens and allogeneic cells was potentiated. When lymphocytes were stimulated with different anti-TCR:CD3 MoAbs, both in soluble and solid-phase form, gp90/Mac-2BP was able to down-regulate the proliferative response to anti-CD3 MoAb, whereas the response to anti-TCR alphabeta MoAb was enhanced. A similar differential effect was observed when a MoAb against CD5 (another member of the scavenger receptor superfamily) was added to anti-CD3 or anti-TCR-stimulated cells; anti-CD5 MoAb strongly down-modulated the CD3-mediated response, whereas its presence in culture was associated with potentiation of the response to TCR alphabeta agonists. gp90/Mac-2BP was able per se to up-regulate Ca2+ levels in freshly isolated lymphocytes; moreover, its presence in culture was associated with increased Ca2+ mobilization following stimulation with anti-TCR alphabeta, but not anti-CD3 MoAb. These data indicate that gp90/Mac-2BP could be able to influence some immune responses, possibly through multiple homologous interactions with other members of the scavenger receptor family; moreover, our findings suggest that signalling through the different components of the TCR:CD3 complex may follow distinct activation pathways into the cells.

3T3 Cells↗
PubMed1998

90K (Mac-2 BP) predicts CD4 decline in human immunodeficiency virus-infected patients with CD4 counts above 200 x 10(6) cells/L.

OBJECTIVE: To evaluate the ability of serum levels of 90K, previously reported as a progression marker of human immunodeficiency virus infection, to predict the future rate of CD4 lymphocyte decline. DESIGN: Retrospective analysis of data from outpatients enrolled in a multi-institutional study. PATIENTS: One hundred five human immunodeficiency virus-positive intravenous drug users who had at least six serial CD4 lymphocyte measurements and starting CD4 levels of 200 x 10(6) cells/L or higher. MAIN OUTCOME MEASURE: Rate of CD4 lymphocyte decline. RESULTS: During a median follow-up of 28 months (range, 20-36 months), the estimated loss of CD4 cells in the whole patient population was 3.4 x 106 cells/L per month (P = .0045). Subjects who were on zidovudine treatment at study entry showed an average loss of 3.8 x 10(6) cells/L per month, significantly higher than in untreated subjects (P = .02), but similar to the loss observed for those requiring initiation of treatment during the course of the study. At baseline, 56 subjects had 90K levels of 10 microg/mL or less, and 49 had more than 10 microg/mL. The rate of CD4 decline in the high-90K group was approximately 5 x 10(6) cells/L per month (P < .0015), whereas in the low-90K group it was not different from zero (P = ns). No difference emerged in the rate of CD4 decline when subjects were stratified according to baseline 90K levels and zidovudine treatment, beta2-microglobulin, or neopterin serum levels. CONCLUSION: 90K serum levels are predictive of CD4 decline.

Antigens, Neoplasm↗
PubMed1997

Identification of the tumor antigen 90K domains recognized by monoclonal antibodies SP2 and L3 and preparation and characterization of novel anti-90K monoclonal antibodies.

The tumor antigen 90K (Mac-2BP, L3 antigen), which has been shown to have T cell costimulatory activity, is a approximately 90 kDa secreted protein found in high levels in plasma, saliva, breast milk and other human fluids. The 90K antigen can be divided into three domains: an amino terminal scavenger receptor cysteine-rich (SRCR)-like domain (D1), followed by a heavily glycosylated mucin-like domain (D2) and a approximately 27 kDa carboxy-terminal domain (D3). In this study we report on the construction of six different 90K immunoglobulin (Ig) fusion proteins containing different 90K domain combinations. Initially these fusion proteins were used to identify which 90K domain contains the epitopes recognized by the anti-90K monoclonal antibodies (mAb) SP2 and L3. Both of these mAbs were found to recognize 90K-D2. A new panel of anti-90K mAb was then generated by immunizing mice with ascites derived 90K protein. The 90K domain specific fusion proteins were then used to identify novel anti-90K mAbs which recognize the amino terminal SRCR domain and the carboxy terminal approximately 27 kDa domain of 90K. Two novel anti-90K SRCR (D1) and one anti-90 27 kDa domain (D3) mAbs were obtained. These 90K-Ig fusion proteins, as well as the novel and existing anti-90K mAbs, provide a set of tools which will allow further dissection of the structure and function of this immune modulatory protein.

Antibodies, Monoclonal↗
PubMed1997

Expression of the 90K immunostimulator gene is controlled by a promoter with unique features.

90K is a secreted glycoprotein with tumor suppressive functions, which is up-regulated in various types of cancer and in AIDS. In order to understand the regulation of its expression, the mouse 90K gene was isolated and analyzed. The gene spans about 8.8-kilobase pairs and consists of 6 exons and was localized on chromosome 11, region E. RNase protection identified one major transcription start site (+1) and three minor ones (-3, +32, +34). The mouse 90K gene was found to have a TATA-less promoter of unusual structure. The 2. 3-kilobase pair 5'-flanking region exhibited strong promoter activity in NIH 3T3 cells; however, it contained neither a TATA-box nor a SP1 site and was not GC-rich. No known initiator motif was found around the transcription start site. 5'- and 3'-deletions defined a minimal promoter of 51 base pairs (-66 --> -16), not including the start site, essential and sufficient for promoter activity. This minimal promoter showed increased activity after stimulation with interferon-gamma or poly(I.C), a substance mimicking viral infection. Essential for both inductions was the integrity of an interferon regulatory factor element within this sequence, a potential binding site for the anti-oncogenic transcription factor interferon regulatory factor-1.

3T3 Cells↗
PubMed1997

Clinical efficacy and endocrine activity of vorozole in postmenopausal breast cancer patients. Results of a multicentric phase II study.

BACKGROUND: Aminoglutethimide was the first aromatase inhibitor to be used successfully in breast cancer patients. However, this drug also inhibits mineralcorticoid and glucocorticoid synthesis, making co-medication with corticosteroids necessary, and it is often poorly tolerated. The primary objective of this trial was to evaluate the clinical efficacy and tolerability of vorozole, a new non-steroidal oral aromatase inhibitor, in postmenopausal breast cancer patients. The secondary objective was to evaluate the pharmacodynamic activity of the drug. SUBJECTS AND METHODS: Thirty-four postmenopausal patients previously treated with tamoxifen in the adjuvant setting and/ or for advanced disease were treated with vorozole, 2.5 mg once daily. Patients were monitored with respect to treatment efficacy and safety. Hormonal evaluations were performed at baseline and during the course of treatment in order to evaluate the pharmacodynamic efficacy and safety of vorozole. RESULTS: According to UICC criteria, there were seven responders, one complete and six partial, for an overall response rate of 21% (95% confidence interval (CI) 9%-38%). The median duration of response was 9.6 months (95% CI 4.6-0), the median time to progression for the entire group was 4.7 months (95% CI 2.9-6.6) and the median survival time was 29.7 months (95% CI 19.1-0). Tolerability was excellent to good in 97% of the patients. Oestradiol and oestrone levels were suppressed to the limit of detection of the assays used. No effect was observed on the other endocrine parameters. CONCLUSIONS: Our results suggest that vorozole is an effective and safe drug for the treatment of advanced postmenopausal breast cancer following tamoxifen failure.

Aged↗
PubMed1996

Tumor-associated antigen 90K activates myelomonocytic cell line THP-1.

90K is a tumor-associated antigen. Using myelomonocytic cell line THP-1 we determined neopterin production and tryptophan degradation after exposure of cells to 90K in the presence and the absence of interferon-gamma. Interferon-gamma is a well known stimulus for THP-1 cells inducing e.g. neopterin production and tryptophan degradation. Treatment of cells with 50 micrograms/ml 90K induced significant neopterin formation, and the exposure of cells to 90K in addition to 100 U/ml interferon-gamma amplified neopterin production compared to the sole effect of interferon-gamma. In parallel, a significant degradation of tryptophan was observed in culture supernatants leading to the formation of kynurenine. When the cells were treated with the combination of 90K and interferon-gamma the degradation of tryptophan was further enhanced. The data demonstrate that tumor-associated antigen 90K interferes with immunocompetent target cells and is able to induce a biochemical response in monocytic cells.

Adjuvants, Immunologic↗
PubMed1996

Circulating immunostimulatory protein 90K and soluble interleukin-2-receptor in human ovarian cancer.

The tumor-associated antigen 90K is thought to play an important role in cellular immune defense against malignant cells. It is therefore of interest to investigate whether circulating 90K could be used as a prognostic variable in ovarian cancer, and whether this immunostimulatory antigen is related to other parameters known to be involved in the cellular immune response. In the present retrospective study, circulating levels of antigen 90K were measured before primary surgery in 152 ovarian-cancer patients. A very close association between antigen 90K and s-IL-2R concentrations was pointed out in a stepwise logistic regression model. Univariate analysis of overall survival revealed that antigen 90K and s-IL-2R were associated with poor prognosis. In the multivariate Cox regression, however, neither antigen 90K nor s-IL-2R retained independent prognostic significance. Urinary neopterin was shown to be the only independent prognostic variable among the "immunological parameters" investigated. Additionally, residual disease after primary tumor debulking and histopathologic tumor grade were the most prominent clinico-pathologic parameters for the independent prediction of poor clinical outcome in ovarian-cancer patients.

Adult↗
PubMed1996

The immune stimulatory protein 90K increases major histocompatibility complex class I expression in a human breast cancer cell line.

90K is a widely expressed, secreted 90 kDa human serum protein found both in normal individuals and at elevated levels in the serum of cancer patients. Functional characterization revealed stimulatory effects of 90K on immune defense systems, such as natural killer and lymphokine-activated killer cell activity. Recently, experiments have shown that 90K expression in several tumor cell lines inversely correlates with tumor formation in athymic mice. The mechanism of this tumor suppressive effect is unknown. In the present study, we evaluated the ability of 90K to affect the expression of MHC class I molecules in the human breast cancer cell line EVSA-T. Treatment with 90K (1-50 micrograms/ml) caused the levels of MHC class I expression to increase approximately sixfold above control levels, as measured by flow cytometry. IFN-gamma was used as a positive control and yielded increased expression of MHC class I molecules approximately 8 times over control levels. These data demonstrate that 90K can directly affect the expression of molecules that are engaged in protective antitumor response.

Antigens, Neoplasm↗
PubMed1996

Elevated serum levels of 90K/MAC-2 BP predict unresponsiveness to alpha-interferon therapy in chronic HCV hepatitis patients.

BACKGROUND: The clinical outcome of hepatitis virus infections is though to depend on the complex interplay between the host immune response profile and virus factors. 90K/MAC-2 BP is a novel member of the Scavenger Receptor Cysteine Rich protein superfamily that functions as a molecular alarm signal for the cellular immune system against both cancer cells and virus infections. METHODS: To assess the significance and the potential clinical usefulness of testing for serum levels of 90K/MAC-2 BP in chronic viral hepatitis patients we studied 115 consecutive patients with chronic HCV hepatitis, 28 HBsAg chronic hepatitis patients, 12 asymptomatic HCV carriers and 11 asymptomatic HBV carriers. 103 out of the 115 HCV patients have been treated with recombinant alpha 2a-interferon at the dose of 3 Mega Units (MU) t.i.w. for 6 months followed by 1.5 MU t.i.w. for 6 months, and have been followed up for a further 12 months. Serum levels of 90K/MAC-2 BP were measured by an immunoradiometric assay based on the specific SP-2 monoclonal antibody. RESULTS AND CONCLUSIONS: Serum 90K/MAC-2 BP levels are increased in chronic viral hepatitis patients, being significantly higher in HCV than in HBV patients. In chronic HCV hepatitis, serum 90K/MAC-2 BP levels are related to both the degree of disease severity and duration of infection. Moreover, elevated 90K/MAC-2 BP serum levels are an independent predictor of failure to respond to alpha-interferon treatment in a cohort of community-acquired chronic hepatitis C patients.

Adult↗
PubMed1996

90K (Mac-2 BP) in human milk.

Human 90K, also known as Mac-2 binding protein (Mac-2 BP), is a secreted glycoprotein which is widely expressed, binds to the human macrophage-associated lectin Mac-2, and may have a role in host defence. We have measured the concentrations of 90K in human breast milk from eight healthy mothers delivering mature healthy infants after full-term pregnancy using a specific immunoenzymatic assay. Maximal 90K concentrations were observed on days 2-3 post-partum, and ranged from 13.4 to 79.2 microg/ml. The concentrations of 90K in the milk had no correlation with those in the maternal blood.

Adult↗
PubMed1996

[Immunostimulating protein 90K in ovarian carcinoma].

Protein 90K is a tumor-associated antigen, which is able to enhance the cytotoxic activity in lymphokine-activated and natural killer cells as well as the IL-2 release in peripheral blood lymphocytes. In our in vitro experiences we observed a stimulatory effect by IFN-alpha and IFN-gamma on 90K-specific mRNA expression and protein release in ovarian cancer cells, and 90K was furthermore found to be a potent stimulator of macrophage activity. Protein 90K seems to be involved in tumor immunology; it may represent a critical link between tumor and immune system.

Adjuvants, Immunologic↗