Biomedical subjects

M Fanelli

Publications and source records attributed to M Fanelli.

At least 37 records · Page 2Linked to original sources

PubMed2001

Thrombospondin-1 and -2 in node-negative breast cancer: correlation with angiogenic factors, p53, cathepsin D, hormone receptors and prognosis.

OBJECTIVE: Thrombospondins (TSP(s)) are a multigene family of five secreted glycoproteins involved in the regulation of cell proliferation, adhesion and migration. Two members of the TSP family, namely TSP-1 and TSP-2, are also naturally occurring inhibitors of angiogenesis. The aim of the present study was to determine the prognostic significance of the determination of TSP-1 and -2 and their correlation with the angiogenic peptides vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP), as well as with other biological and clinicopathological features investigated. METHODS: We evaluated a series of 168 women with node-negative breast cancer with a median follow-up period of 66 months, not treated with adjuvant therapy. The cytosolic levels of TSP-1 and -2 were determined in the primary tumour by a commercially available immunometric assay. RESULTS: We found that 166 tested tumours had measurable levels of TSP-1 and -2 protein (median value 5.978, range 0.579-31.410 ng/mg of protein). On the basis of Spearman's rank correlation coefficient, a weak inverse association of TSP-1 and -2 with tumour size and cathepsin D was found. Moreover, principal component analysis on ranks evidenced a poor association between TSP-1 and -2, VEGF and TP. The results of the clinical outcome were analysed by both univariate and multivariate [for relapse-free survival (RFS) only]) Cox regression models. TSP-1 and -2 were not significant prognostic factors in univariate analysis for either RFS (p = 0.427) or overall survival (p = 0.069). To investigate the 'angiogenic balance hypothesis', bivariate analyses were performed to investigate the interactions of TSP-1 and -2 with VEGF, TP or p53, but none were included in the selected models. Finally, in multivariate analysis for RFS a baseline model, previously defined in a larger case series and inclusive of VEGF, TP and their interaction was adopted. It was highly significant (p = 0.002, Harrell c statistic value of 0.703); but when TSP-1 and -2 were added, their contribution was negligible (p = 0.731, Harrell c statistic value of 0.705). CONCLUSIONS: The results of this study suggest that TSP-1 and -2 do not provide additional prognostic contribution to the joint effects of VEGF and TP. In the series of node-negative breast cancer patients investigated, determination of the angiogenic peptides VEGF and TP gave significant prognostic information. On the contrary, TSP-1 and -2, potential naturally occurring negative regulators of angiogenesis, lacked prognostic value.

Biomarkers, Tumor↗

PubMed2001

Prevalence of obstructive sleep apnea syndrome in a cohort of 1,207 children of southern Italy.

STUDY OBJECTIVE: To determine the prevalence of sleep-related breathing disturbances in a large cohort of school-aged and preschool-aged children of Southern Italy. DESIGN AND SETTING: This cross-sectional prevalence study was designed in two phases: a screening phase aimed to identify symptomatic children from a cohort of 1,207 by a self-administered questionnaire, and an instrumental phase for the definition of sleep-related disorders. PATIENTS AND METHODS: One thousand two hundred seven children were screened by a self-administered questionnaire. There were 612 female children (51%) and 595 male children (mean age, 7.3 years; range, 3 to 11 years). According to answers, children were classified in three groups: nonsnorers, occasional snorers, and habitual snorers. All habitual snoring children underwent a polysomnographic home evaluation, and those with an oxygen desaturation index > 2 were considered for nocturnal polygraphic monitoring (NPM). Children with an apnea/hypopnea index > 3 received a diagnosis of obstructive sleep apnea syndrome (OSAS). RESULTS: A total of 895 questionnaires (74.2%) were returned and scored; 710 children (79.3%) were identified as nonsnorers, 141 children (15.8%) were identified as occasional snorers, and 44 children (4.9%) were identified as habitual snorers. The percentage of male children who were habitual snorers was higher than the percentage of female children who were habitual snorers (6.1% vs 3.7%, respectively; p < 0.09). OSAS was diagnosed in nine children by NPM. CONCLUSION: The lower limit of prevalence of OSAS in childhood is 1% (95% confidence interval [CI], 0.8 to 1.2). If we add the five children who underwent adenoidectomy and/or tonsillectomy because of worsening clinical condition and the two children who were shown to have evidence of OSAS on domiciliary oximetry, then the prevalence is 1.8% (higher limit of prevalence; 95% CI, 1.6 to 2.0).

Child↗

PubMed2000

17-alpha-ethinylestradiol and norgestrel in combination induce micronucleus increases and aneuploidy in human lymphocyte and fibroblast cultures.

Oral contraceptives are highly efficient and easily administered drugs; however, it must not be forgotten that they are composed of chemical substances which can be classified as potential carcinogens. Testing of a substance for genotoxicity represents a reliable approach both to evaluate the genetic hazard and to obtain information on its possible tumorigenic (cancerogenic) properties. The present study was undertaken to evaluate through carefully planned and controlled investigations the in vitro cytogenetic effects of oral contraceptives (ethynilestradiol and norgestrel mixed in the proportion 1:5) using three different concentrations, with two different durations of treatment (48 and 72 h), on two types of human cells (lymphocytes and fibroblasts) and a series of short-term test procedures: sister chromatid exchange (SCE), micronucleus test (MN), and chromosome aberrations (CA). In addition, the FISH procedure and in vitro anaphase and metaphase preparation analyses were performed. In contrast to CA and SCE frequencies, the frequency of MN in treated blood lymphocytes showed higher values by comparison with the controls, although the difference was statistically significant only for the lowest concentration (P = 0. 016). When using pancentromeric alphoid probes, the FISH procedure gave positive signals in more than 85% of micronuclei, clearly indicating that MN may contain whole chromosomes rather than acentric fragments. Unlike the lymphocytes, the fibroblasts showed dose-dependent effects, although those treated with the highest hormone concentrations showed an increased number of highly damaged cells (cytoplasmatic vacuolization, nuclear fragmentation, etc.), a decreased number of anaphase cells, a large number of which were abnormal, and a reduction of mitotic index. In conclusion, our data confirm that hormones do not induce structural chromosome aberrations in lymphocytes and indicate that ethynilestradiol and norgestrel have an aneugenic effect on fibroblast and lymphocyte cultures; FISH analysis on micronuclei from lymphocyte cultures and anaphase preparations from fibroblast cultures support this hypothesis. Teratogenesis Carcinog. Mutagen. 20:147-159, 2000.

Aneuploidy↗

PubMed2000

Behaviour of metastasis in relation to vascular index in patients with node-positive breast cancer treated with adjuvant tamoxifen.

Some experimental studies suggested that one possible oestrogen-receptor-unrelated mechanism of action of tamoxifen involves inhibition of angiogenesis. We evaluated the correlation of the degree of vascularisation of the primary tumour and we assessed it by using the panendothelial marker anti-CD31 and immunohistochemistry with microvessels count, performed at the vascular 'hot spot' of each single cancer, with the risk of recurrence in time. A cohort of 176 consecutive patients with node-positive invasive breast cancer treated with adjuvant tamoxifen (30 mg/daily for 3 years) and a median follow-up of 72 months was studied. Sixty-two patients developed metastasis (30 visceral, 18 skeletal and 14 in soft tissues) during the time of observation. The study of the hazard function for metastasis was performed by a generalized linear modelling approach with a binomial error according to Efron. The risk of first recurrence was strictly associated with vascular index, having the patients with the highest microvessel counts the highest risk of metastasis during all the period of observation. We did not find an interaction of vascularity with oestrogen receptor (ER) status. However, in the subgroup of patients with ER-positive tumours the hazard of metastasis was almost constant in time, while in that with ER-negative tumours it increased rapidly up to 20 months and, thereafter, decreased sharply. The results of our study are an indirect evidence that the patients with highly vascularized breast cancers may gain poor benefit of adjuvant tamoxifen and, therefore. that this antioestrogen is unlikely to retain a clinically relevant antiangiogenic activity in human breast cancer. Our data need confirmation by a prospective randomized clinical trial.

Antineoplastic Agents, Hormonal↗

PubMed2000

Effect of aging on serum gonadotropin levels in healthy subjects and patients with nonfunctioning pituitary adenomas.

OBJECTIVE: Nonfunctioning pituitary adenomas (NFPA), which represent about one-quarter of human pituitary tumors, occur in middle or old age. Determination of gonadotropin levels, which are not expected to be high during the early postmenopause in normal women and which are low in women with NFPA, is important to distinguishing hypogonadal status due to the normal decline of gonadal function from that due to hypothlalamic-pituitary dysfunction. The aim of the study was to verify whether this difference still persists in old subjects, despite the physiological decline of gonadotropins in the last decades of life. DESIGN AND METHODS: The study included 154 healthy subjects (aged 50-104 years) and 47 patients with NFPA (aged 50-80 years). Blood samples were collected after an overnight fast and hormone levels were measured by two immunofluorimetric assays. RESULTS: In healthy women the highest serum levels of gonadotropins were present in the 50-60 year age group, with a slight but progressive age-associated decrease in serum FSH and LH being observed thereafter. In healthy men serum gonadotropin levels were stable up to 70 years, increased up to 75-85 years and thereafter gradually decreasing. Female patients with NFPA showed levels of gonadotropins which were far lower than controls. Only three patients had levels of both FSH and LH above the 2.5 centile for normal subjects. A high sensitivity and specificity of gonadotropin measurements (about 90%) for the diagnosis of NFPA was observed in female patients aged 50-80 years. In male subjects, a large overlap of gonadotropin values in NFPA and controls, namely over the 50-70 years age range, was observed. CONCLUSIONS: Our study demonstrates that despite the gradual decline of gonadotropin levels in healthy postmenopsausal women, the reduction of both FSH and LH persists in old patients with NFPA, suggesting that measurement of gonadotropin levels could prove useful in the evaluation of pituitary lesions even in old women. More subtle differences seem to occur in male subjects.

Adenoma↗

PubMed2000

Increased activity of matrix metalloproteinases in the cerebrospinal fluid of patients with HIV-associated neurological diseases.

Matrix metalloproteinases (MMPs) have been identified as mediators of brain injury in HIV-associated neurological diseases. The activity of the 72 kDa gelatinase A (MMP-2) and 92 kDa gelatinase B (MMP-9) was detected by zymography in the cerebrospinal fluid (CSF) of 138 HIV-infected patients (40 with AIDS dementia, 83 with brain opportunistic infections and 15 neurologically asymptomatic), 26 HIV-seronegative individuals with inflammatory neurological diseases (IND) and 12 HIV-seronegative subjects with noninflammatory neurological diseases (NIND). MMP-2 was present in all CSF samples from HIV-seropositive and HIV-seronegative individuals, including those of subjects with NIND. On the contrary, MMP-9 was absent in the CSF of NIND controls, whereas the activity of this MMP was found in the 77 - 100% of CSF samples from HIV-infected patients, including those with HIV dementia, central nervous system (CNS) opportunistic infections or neurologically asymptomatic subjects. The highest levels of MMP-9 were found in the CSF of patients with cryptococcosis, cytomegalovirus encephalitis and tuberculous meningitis and were comparable with those found in the CSF of HIV-negative patients with multiple sclerosis or meningitis. A significant correlation between CSF MMP-9 activity and CSF cell count was found only in patients with HIV dementia. The increased CSF activity of MMPs capable to degrade components of the extracellular matrix of blood-brain barrier may contribute to the transendothelial migration of virus-infected cells into the CNS and development of HIV-associated neurologic damage.

AIDS Dementia Complex↗

PubMed2000

Increment of sister chromatid exchange frequencies (SCE) due to epichlorohydrin (ECH) in vitro treatment in human lymphocytes.

Although several studies have examined the effects on health of exposure to epichlorohydrin (ECH) through normal industrial operations and production, there is still considerable interest in its potential harmful effects on humans. The aim of the present study was to evaluate ECH effects in vitro through controlled investigations by using sister chromatid exchange (SCE), micronucleus (MN), and chromosome aberrations (CA) as the test battery. Cultures for cytogenetic tests were set up from blood samples of four healthy non-smoking and three smoking males. The experiments were performed using four different concentrations: 10(-10) M, 10(-8) M, 10(-6) M, and 10(-4) M, of ECH in DMSO. Analysis of variance showed that concentrations of ECH had significant effects on SCE/cell frequencies in the lymphocyte cultures of all donors (F=100.25, P<0.001). We were unable to find any evidence of significant increases in CA and MN frequencies in ECH-treated lymphocyte cultures with respect to the controls.

Adult↗

PubMed2000

Socio-demographic factors and indications in second trimester voluntary abortion.

BACKGROUND: According to Italian Law, second trimester termination of pregnancy is allowed for life threatening conditions or for severe psychological distress, linked or not to prenatal diagnosis of foetal abnormalities. Socio-demographic factors related to this condition have been analysed. METHODS: Clinical records of 330 patients admitted during the years 1988-1997 to the Obstetrics and Gynaecology Department, University of Bari, Italy, for voluntary second trimester abortion, were examined. Maternal psychiatric indications have been given in nearly all of the cases. In 123 cases the indications were secondary to the women suffering a psychiatric disorder due to foetal pathologies. In 205 cases--where poor social conditions were more frequent--the indication was given on the ground of a psychiatric disorder linked to the pregnancy itself. RESULTS: Significantly higher incidence of teenagers (23.3%) and singles (50%) in women who underwent a late abortion. Students were 16.4% in this group. In primary psychiatric indication singles prevail (74.4%) and students represent 23.6% while in secondary psychiatric indication the married were 84.7%, students only 4.8%. In primary psychiatric indication 32.5% of women aged nineteen or less, while in secondary psychiatric indication this percentage was 8%. CONCLUSIONS: Among patients who have a late abortion, teenagers students and singles are prevalent, these patients have significantly more primary psychiatric indications, not linked to foetal abnormalities. The high percentage of teenagers with primary psychiatric indication could depend on inadequate information and social service. Reduction of mid-trimester terminations of pregnancy can be significantly achieved intervening in this group of young women. On the other hand, in secondary indications earlier diagnosis of foetal abnormalities must be encouraged (villocentesis instead of amniocentesis) and abortion discouraged when the foetal pathology is minor, treatable or unlikely to significantly impair the future quality of life.

Abortion, Induced↗

PubMed1999

Formation of PML/RAR alpha high molecular weight nuclear complexes through the PML coiled-coil region is essential for the PML/RAR alpha-mediated retinoic acid response.

Retinoic Acid (RA) treatment induces disease remission of Acute Promyelocytic Leukaemia (APL) patients by triggering terminal differentiation of neoplastic cells. RA-sensitivity in APL is mediated by its oncogenic protein, which results from the recombination of the PML and the RA receptor alpha (RAR alpha) genes (PML/RAR alpha fusion protein). Ectopic expression of PML/RAR alpha into haemopoietic cell lines results in increased response to RA-induced differentiation. By structure-function analysis of PML/RAR alpha-mediated RA-differentiation, we demonstrated that fusion of PML and RAR alpha sequences and integrity of the PML dimerization domain and of the RAR alpha DNA binding region are required for the effect of PML/RAR alpha on RA-differentiation. Indeed, direct fusion of the PML dimerization domain to the N- or C-terminal extremities of RAR alpha retained full biological activity. All the biologically active PML/RAR alpha mutants formed high molecular weight complexes in vivo. Functional analysis of mutations within the PML dimerization domain revealed that the capacity to form PML/RAR alpha homodimers, but not PML/RAR alpha-PML heterodimers, correlated with the RA-response. These results suggest that targeting of RAR alpha sequences by the PML dimerization domain and formation of nuclear PML/RAR alpha homodimeric complexes are crucial for the ability of PML/RAR alpha to mediate RA-response.

Antineoplastic Agents↗

PubMed1999

Constitutive degradation of PML/RARalpha through the proteasome pathway mediates retinoic acid resistance.

PML/RARalpha is the leukemogenetic protein of acute promyelocytic leukemia (APL). Treatment with retinoic acid (RA) induces degradation of PML/RARalpha, differentiation of leukaemic blasts, and disease remission. However, RA resistance arises during RA treatment of APL patients. To investigate the phenomenon of RA resistance in APL, we generated RA-resistant sublines from APL-derived NB4 cells. The NB4.007/6 RA-resistant subline does not express the PML/RARalpha protein, although its mRNA is detectable at levels comparable to those of the parental cell line. In vitro degradation assays showed that the half-life of PML/RARalpha is less than 30 minutes in NB4.007/6 and longer than 3 hours in NB4. Treatment of NB4.007/6 cells with the proteasome inhibitors LLnL and lactacystin partially restored PML/RARalpha protein expression and resulted in a partial release of the RA-resistant phenotype. Similarly, forced expression of PML/RARalpha, but not RARalpha, into the NB4/007.6 cells restored sensitivity to RA treatment to levels comparable to those of the NB4 cells. These results indicate that constitutive degradation of PML/RARalpha protein may lead to RA resistance and that PML/RARalpha expression is crucial to convey RA sensitivity to APL cells.

Antineoplastic Agents↗

PubMed1999

Histological and cytological studies on the developing thymus of sharpsnout seabream, Diplodus puntazzo.

The structure of the developing thymus of the marine teleost, Diplodus puntazzo, was studied by light and transmission electron microscopy. The first anlage of the thymus developed by d 20 postfertilisation (p.f.) as a group of undifferentiated cells dorsal to the epithelium of the branchial chamber. The organ increased significantly in size around d 51-66 p.f. and differentiation of cortex and medulla occurred concomitantly. On the basis of their localisation, 4 main types of epithelial cell were distinguished: (1) limiting, adjacent to the connective capsule; (2) medullary and cortical reticular cells; (3) nurse cells, located in the corticomedullary boundary; (4) Hassall-like corpuscles. The majority of medium to large blast-like lymphoid cells were localised in the medulla, while small lymphocytes were housed in the cortical region. These morphological features were maintained at later stages. However, in juveniles in the medulla we observed reticular epithelial cells with cysts and rare Hassall-like corpuscles. The study was designed to obtain more information concerning the histology of the developing thymus of sharpsnout seabream and give a concise description of the differentiation of epithelial cells and lymphoid cells in the thymic parenchyma.

Animals↗

PubMed1998

Hepatitis C virus infection involves CD34(+) hematopoietic progenitor cells in hepatitis C virus chronic carriers.

Although hepatitis C virus (HCV) mainly affects hepatocytes, infection is widespread and involves immunologically privileged sites. Whether lymphoid cells represent further targets of early HCV infection, or whether other cells in the hematopoietic microenvironment may serve as a potential virus reservoir, is still unclear. We studied whether pluripotent hematopoietic CD34(+) cells support productive HCV infection and can be used to establish an in vitro infection system for HCV. Six patients were selected as part of a cohort of HCV chronic carriers who developed a neoplastic disease. Reverse transcriptase-polymerase chain reaction (RT-PCR) and branched DNA signal amplification assays were used to detect and quantitate HCV RNA in extracted nucleic acids from purified bone marrow and peripheral blood CD34(+) cells. Direct in situ RT-PCR, flow cytometry analysis, and immunocytochemistry were applied to demonstrate specific viral genomic sequences and structural and nonstructural virus-related proteins in intact cells. Results indicated that both positive and negative HCV RNA strands and viral proteins were present in CD34(+) cells from all HCV-positive patients and in none of the controls. Additional experiments showed that a complete viral cycle took place in CD34(+) cells in vitro. Spontaneous increases in viral titers indicated that virions were produced by infected hematopoietic progenitor cells. To further define the cellular tropism, we attempted to infect CD34(+) cells in vitro. We were unable to demonstrate viral uptake by cells. These findings suggest that HCV replication can occur in the early differentiation stages of hematopoietic progenitor cells, and that they may be an important source of virus production.

Aged↗

PubMed1998

Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARalpha fusion protein.

All-trans-retinoic acid (RA) treatment induces morphological remission in acute promyelocytic leukemia (APL) patients carrying the t(15;17) and expressing the PML/RARalpha product by inducing terminal differentiation of the leukemic clone. RA treatment induces downregulation of PML/RARalpha and reorganization of the PML-nuclear bodies. These events have been proposed to be essential for the induction of APL cell differentiation by RA. Here, we show that in the APL-derived NB4 cell line as well as in myeloid precursor U937 cells expressing the PML/RARalpha (U937/PR9) and in blasts from APL patients, the PML/RARalpha fusion protein is cleaved by a caspase 3-like activity induced by RA treatment. In fact, a caspase 3-like activity is detectable in PML/RARalpha expressing cells after RA treatment, and selective caspase inhibitor peptides are able to prevent the RA-induced degradation of the fusion protein in vivo and in vitro. Using recombinant caspases and PML/RARalpha deletion mutants we mapped a caspase 3 cleavage site (Asp 522) within the alpha-helix region of the PML component of the fusion protein. The extent of PML/RARalpha cleavage directly correlates with the ability of RA to restore the normal PML nuclear bodies (NBs) pattern. However, RA-induced differentiation is not prevented by the persistence of the fusion product and occurs in the absence of normally structured PML NBs. These results indicate that PML/RARalpha is directly involved in conferring RA sensitivity of APL cells and that the RA-induced reassembly of PML NBs is the consequence of the disappearance of PML/RARalpha.

Antineoplastic Agents↗

PubMed1998

Sister chromatid exchange (SCE) and micronucleus (MN) frequencies in lymphocytes of gasoline station attendants.

Peripheral blood lymphocytes from 22 men with low average exposure (229 micrograms/m3 = 0.72 ppm) to benzene and 19 control men were investigated for Sister Chromatid Exchange (SCE) frequency. The majority of the men (21 exposed, 19 controls) were also investigated using the micronucleus assay (MN). The exposed subjects were employed at 10 different gas stations in or near the city (Bari/South Italy). SCE frequencies were significantly related with age and smoking habits, on the contrary no relation was observed between SCE and length of employment (SCE = 7.41 + 0.03.age (*) + 0.0001.length of employment (n.s.) + 0.03.cigarette consumption (*); F = 4.87; p < 0.01; (*) significant; (n.s.) non-significant). MN frequencies were significantly increased in relation with length of employment; but no relation was observed when age and smoking habits were taken into consideration (regression model: MN = 18.03 + 0.006.age (n.s.) + 0.32.length of employment (*) - 0.1.cigarette consumption (n.s.); F = 4.138; p < 0.05).

Benzene↗

PubMed1998

Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia.

The transforming proteins of acute promyelocytic leukaemias (APL) are fusions of the promyelocytic leukaemia (PML) and the promyelocytic leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-alpha (RARalpha). These proteins retain the RARalpha DNA- and retinoic acid (RA)-binding domains, and their ability to block haematopoietic differentiation depends on the RARalpha DNA-binding domain. Thus RA-target genes are downstream effectors. However, treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML-RARalpha APLs, whereas PLZF-RARa APLs are resistant to RA. Transcriptional regulation by RARs involves modifications of chromatin by histone deacetylases, which are recruited to RA-target genes by nuclear co-repressors. Here we show that both PML-RARalpha and PLZF-RARalpha fusion proteins recruit the nuclear co-repressor (N-CoR)-histone deacetylase complex through the RARalpha CoR box. PLZF-RARalpha contains a second, RA-resistant binding site in the PLZF amino-terminal region. High doses of RA release histone deacetylase activity from PML-RARalpha, but not from PLZF-RARalpha. Mutation of the N-CoR binding site abolishes the ability of PML-RARalpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biological effects of PLZF-RARalpha from being an inhibitor to an activator of the RA signalling pathway. Therefore, recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of RA on the stability of the PML-RARalpha and PLZF-RARalpha co-repressor complexes determines the differential response of APLs to RA.

Binding Sites↗

PubMed1998

Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells.

BACKGROUND: Retinoids, which are derivatives of vitamin A, induce differentiation of acute promyelocytic leukemia (APL) cells in vitro and in patients. However, APL cells develop resistance to retinoic acid treatment. Arsenic trioxide (As2O3) can induce clinical remission in patients with APL, including those who have relapsed after retinoic acid treatment, by inducing apoptosis (programmed cell death) of the leukemia cells. In this study, we investigated the molecular mechanisms by which As2O3 induces apoptosis in retinoic acid-sensitive NB4 APL cells, in retinoic acid-resistant derivatives of these cells, and in fresh leukemia cells from patients. METHODS: Apoptosis was assessed by means of DNA fragmentation analyses, TUNEL assays (i.e., deoxyuridine triphosphate labeling of DNA nicks with terminal deoxynucleotidyl transferase), and flow cytometry. Expression of the PML/RAR alpha fusion protein in leukemia cells was assessed by means of western blotting, ligand binding, and immunohistochemistry. Northern blotting and ribonuclease protection assays were used to evaluate changes in gene expression in response to retinoic acid and As2O3 treatment. RESULTS AND CONCLUSIONS: As2O3 induces apoptosis without differentiation in retinoic acid-sensitive and retinoic acid-resistant APL cells at concentrations that are achievable in patients. As2O3 induces loss of the PML/RAR alpha fusion protein in NB4 cells, in retinoic-acid resistant cells derived from them, in fresh APL cells from patients, and in non-APL cells transfected to express this protein. As2O3 and retinoic acid induce different patterns of gene regulation, and they inhibit the phenotypes induced by each other. Understanding the molecular basis of these differences in the effects of As2O3 and retinoic acid may guide the clinical use of arsenic compounds and provide insights into the management of leukemias that do not respond to retinoic acid.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Clinical significance of angiogenic factors in breast cancer.

Growth, progression, and metastasis of breast cancer, as well as of most of the other tumors, are angiogenesis-dependent processes. Several pro-angiogenic growth factors and endogenous inhibitors of angiogenesis have been identified and sequenced, and experimental studies suggest that angiogenic activity of a tumor may result from downregulation of inhibitors of angiogenesis or up-regulation of endothelial growth factors. The mechanisms leading to the alteration of the balance between positive and negative modulators of angiogenesis are only partially known. We are at the beginning of research to identify the more active angiogenic factors in human breast cancer, and little information is presently available on their clinical significance. Preliminary results suggest that among the known angiogenic peptides, both vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor / thymidine phosphorylase (PD-ECGF/TP) have promising prognostic and, perhaps, predictive value. No data are available on the clinical value of co-determination of positive and negative regulators of angiogenesis to look at the angiogenic balance of each single tumor. Only a few studies have assessed the role of endogenous inhibitors of angiogenesis in human breast cancer, with results available only on thrombospondin-1 and -2 (TSP-1, -2). Finally, the determination of some integrins such as alpha6 and alphavbeta3 and of some other endothelial-adhesion molecules seems to be of potential prognostic value. Recognizing which are the more biologically active positive and negative angiogenic factors is the key for the identification not only of new prognostic markers but also of targets for antiangiogenic therapy in human breast cancer.

Angiogenesis Inducing Agents↗

PubMed1998

A randomised placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy.

A randomised placebo controlled study was performed in 32 women with intrahepatic cholestasis of pregnancy. The population was divided into four groups: for 20 days each group was treated only with ursodeoxycholic acid, or S-adenosylmethionine, or a combination of both drugs, or a placebo (vitamin). Itching, standard liver function tests and serum total bile acids were measured before, during, and after treatment. Itching improved in all the women as well as the biochemical abnormalities. No side-effects in the mother or in the infant were recorded during and after therapy. A combination of ursodeoxycholic acid and S-adenosylmethionine is more effective than placebo and than either drug alone.

Adenosylmethionine Decarboxylase↗