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Biomedical subjects

Giuseppe Monaco

Publications and source records attributed to Giuseppe Monaco.

6 recordsLinked to original sources
PubMed2005

Bcr-Abl-mediated suppression of normal hematopoiesis in leukemia.

A variety of experimental evidence including findings in various mouse models indicates that the BCR-ABL oncogene is the cause of chronic myeloid leukemia (CML). Since normal hematopoietic cells in marrow and spleen are replaced with proliferating leukemic blasts, we determined whether this is an active process mediated by the leukemia cells. The lipocalin 24p3 was reported to be secreted by mouse hematopoietic cells deprived of IL-3, resulting in apoptosis induction in a variety of hematopoietic cells including bone marrow cells. Here, we show that BCR-ABL+ mouse hematopoietic cells induced persistent expression and secretion of 24p3. Importantly, BCR-ABL+ hematopoietic cells were resistant to the apoptotic effects of 24p3. The expression of the Bcr-Abl oncoprotein and its tyrosine kinase were required for induction of 24p3 expression. Co-culture studies showed that BCR-ABL+ cells induced apoptosis in BCR-ABL negative cells. Antisense 24p3/siRNA expression reduced the level of 24p3 protein in both BCR-ABL+ cells and in conditioned medium (CM) obtained from these cells. CM from BCR-ABL+ cells expressing antisense 24p3/siRNA had reduced apoptotic activity for target cells; 24p3 antibody also reduced the apoptotic activity of the CM. Leukemic mice induced by BCR-ABL+ cells expressing either antisense 24p3 or 24p3 siRNA had increased levels of normal hematopoiesis and reduced invasion of leukemia cells in marrow and spleen tissues. These findings indicate that suppression of normal hematopoiesis in BCR-ABL-induced leukemia is an active process involving secretion of the cell death-inducing factor 24p3 by mouse leukemia cells, raising the possibility that similar factors are involved in BCR-ABL+ CML.

Acute-Phase Proteins↗
PubMed2004

The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia.

In acute myeloid leukemia (AML), resistance to chemotherapy is associated with defects in both the extrinsic and intrinsic pathways of apoptosis. Novel agents that activate endogenous apoptosis-inducing mechanisms directly may be potentially useful to overcome chemoresistance in AML. We examined the mechanisms of apoptosis induction by the novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) in AML cells. CDDO-induced apoptosis was associated with the loss of mitochondrial inner transmembrane potential, caspases activation, the translocation of apoptosis-inducing factor to the nucleus, and DNA fragmentation in AML cells. Apoptosis was equally evident in cells deficient in caspase-9 or caspase-8 after exposure to CDDO, suggesting caspase-independent cell death. The use of small interfering RNA to reduce the expression of apoptosis-inducing factor partially inhibited CDDO-induced apoptosis in AML cells. Cells overexpressing Bcl-2 were markedly resistant to CDDO-induced apoptosis. Moreover, CDDO promoted the release of cytochrome c from isolated mitochondria, suggesting that CDDO targets the mitochondria directly to trigger the intrinsic pathway of cell death in intact cells. Together, these results suggest that CDDO functions by activating the intrinsic pathway of apoptosis and initiates caspase-dependent and independent cell death. The direct modulation of mitochondrial-mediated, caspase-independent apoptosis by CDDO may be advantageous for overcoming chemoresistance in AML.

Antineoplastic Agents↗
PubMed2004

Reliability of panoramic radiography in evaluating the topographic relationship between the mandibular canal and impacted third molars.

BACKGROUND: The authors conducted a study to evaluate the predictive value of five radiographic markers on the panoramic radiograph, or PR, to point out the relationship between the mandibular canal and the impacted third molar. METHODS: The authors evaluated the accuracy of the radiographic markers by comparing the PR with an axial computed tomographic, or CT, scan. They identified a sample of 73 third molars that showed a close relationship between the tooth roots and the mandibular canal on the PR, and then classified them on the basis of five radiographic markers. They also detected contact between the third molar and the mandibular canal on the CT scan. RESULTS: The distribution of the five radiographic markers was as follows: 37 teeth exhibited increased radiolucency, 13 exhibited superimposition, 14 exhibited interruption of the radiopaque border, 14 exhibited narrowing of the canal and seven exhibited diversion of the canal. In 11 cases, two or more markers were recognizable. The predictive values of a positive test result were as follows: increased radiolucency, 73 percent; superimposition, 38.5 percent; interruption of the radiopaque border, 71.4 percent; narrowing, 78.6 percent; and diversion, 100 percent. The authors detected contact in all of the cases that exhibited two or more markers. CONCLUSION: Increased radiolucency, narrowing and interruption of the radiopaque border, as well as the concomitant presence of two or more radiographic markers, on the PR were highly predictive of contact between the third molar and the mandibular canal. An axial CT scan probably is indicated in such cases. CLINICAL IMPLICATIONS: The results of this study may lead to some guidelines for oral surgeons evaluating whether to obtain an axial CT scan for further investigation after examining an impacted mandibular third molar via PR.

Adolescent↗
PubMed2004

Engraftment of acute myeloid leukemia in NOD/SCID mice is independent of CXCR4 and predicts poor patient survival.

The aim of this study was to investigate factors influencing the engraftment potential of acute myeloid leukemia (AML) CD34+ cells in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. We examined the relationship between engraftment, CXCR4 expression on CD34+ and CD34+CD38- cells, and patient (Pt) clinical/laboratory characteristics in 44 samples from 11 Pts. Engraftment, evaluated by Southern blot and CD45 flow cytometric analyses, was observed in murine bone marrow of 6 of 11 Pt samples, ranging from 0.1% to 73.9% by Southern blot and from 0.1%-36.8% by flow cytometry. Poor Pt prognosis was inversely correlated with engraftment; the median overall survival was 95.9 weeks for Pts whose cells did not engraft and 26.1 weeks for those whose cells did engraft (p = 0.012, log-rank test). No other clinical/laboratory variable predicted engraftment. No correlation between the level of CXCR4 expression on AML cells and engraftment was observed. Cells with virtually absent CXCR4 expression were able to engraft, and cells from two Pts with high expression levels of CXCR4 did not engraft. Furthermore, anti-CXCR4 antibody failed to block the engraftment of AML cells into NOD/SCID mice. In conclusion, we demonstrated that CXCR4 is not critical for the engraftment of AML CD34+ cells in NOD/SCID mice. The model may, however, reflect the clinical course of the disease.

Animals↗