Biomedical subjects

G C Avanzi

Publications and source records attributed to G C Avanzi.

At least 19 recordsLinked to original sources

PubMed2003

Remission of refractory lupus nephritis with a protocol including rituximab.

Immunosuppression with corticosteroids and cyclophosphamide is the standard of care for lupus nephritis. We report a 19-year old woman with lupus nephritis and nephrotic syndrome who had not achieved complete remission after treatment with 15.7 g cyclophosphamide and 13.7 g prednisone. We planned a consolidation phase with: 1) cyclophosphamide 20 mg/kg i.v. every 28 days for three cycles; 2) anti-CD20 chimeric monoclonal antibody (rituximab) 375 mg/m2 i.v. weekly for four weeks; and 3) slow tapering of prednisone p.o., q.o.d., after a reinduction dose during rituximab administration. At the end of this phase the patient achieved complete remission. An indefinite maintenance treatment with methotrexate, cyclosporin and low-dose prednisone was then started. Twenty-four months later the patient remains in remission. In the immunosuppressive treatment of lupus nephritis the insertion of a consolidation phase with rituximab combined with cyclophosphamide achieves a therapeutically important and lasting deletion of the lymphocyte clone responsible for autoimmunity.

Adult↗

PubMed2002

Making, disseminating and using clinical guidelines.

Clinical guidelines are statements designed to help physicians make decisions about appropriate health care for specific circumstances. The constant rise in the number of published guidelines has been accelerated by the need of healthcare organizations to integrate evidence from clinical research with rational health policy, with the prospect of improving the quality and reducing the costs of health care at a local level. The best guidelines are developed from a systematic examination and appraisal of good evidence from well conducted trials, supported by appropriate clinical expertise, and leading to unambiguous recommendations. Great care needs to be taken both to maximize the validity of guidelines and to ensure their use within clinical practice. Moreover, the evidence on which clinical guidelines are based can change with time and therefore they should be reviewed regularly. The critical approaches to making high-quality guidelines, the value of implementation strategies, and how healthcare organizations and individual physicians can use medical guidelines to enhance clinical effectiveness will be discussed.

Delivery of Health Care↗

PubMed2000

Mutation of BAX occurs infrequently in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas.

Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHLs) consistently derive from B cells, are histologically heterogeneous, and are associated with distinct molecular pathways depending upon histology. Recently, it has been proposed that inactivating mutations of the bax death agonist may contribute to the pathogenesis of human tumors. In particular, among B-cell malignancies, BAX mutations have been detected at a certain frequency in Burkitt lymphomas. This study is aimed at defining the status of the BAX gene throughout the clinicopathologic spectrum of AIDS-NHL (n = 54), including AIDS-related Burkitt lymphoma (n = 14), AIDS-related Burkitt-like lymphoma (n = 8), AIDS-related diffuse large cell lymphoma (n = 15), AIDS-related primary central nervous system lymphoma (n = 6), and AIDS-related primary effusion lymphoma (n = 11). All 6 BAX exons and flanking sequences were subjected to mutational analysis by polymerase chain reaction-single strand conformation polymorphism followed by DNA direct sequencing of positive cases. Mutations of BAX among AIDS-NHL were restricted to a cell line of AIDS-related primary effusion lymphoma, which harbored a frameshift mutation causing the introduction of a proximal stop codon. All other AIDS-NHL displayed wild-type BAX alleles. In order to investigate whether BAX inactivation in AIDS-NHL may occur through mechanisms other than gene mutation, bax protein expression was investigated by Western blot analysis or immunohistochemistry in selected cases. All AIDS-NHL analyzed expressed normal bax proteins. Overall, this study indicates that deregulation of apoptotic control in AIDS-NHL is not caused by BAX alterations. Genes Chromosomes Cancer 27:177-182, 2000.

Blotting, Western↗

PubMed2000

Molecular characterization of HHV-8 positive primary effusion lymphoma reveals pathogenetic and histogenetic features of the disease.

BACKGROUND: Primary effusion lymphoma (PEL) associates with HHV-8 infection, preferentially develops in immunodeficient patients and grows in the serous body cavities. PEL derives from post-germinal center, pre-terminally differentiated B-cells. The pathogenesis of PEL is unclear and the sole identified genetic lesions are human herpesvirus type-8 (HHV-8) infection in all cases and EBV infection in 70% of cases. Epstein-Barr virus (EBV) infection in PEL displays a latency I phenotype. OBJECTIVES: To clarify the pathogenesis and histogenesis of PEL by investigating (1) the lymphoma karyotype; (2) the expression status of the Met tyrosine kinase receptor and of its ligand hepatocyte growth factor (HGF); (3) the molecular profile of EBV, with particular focus on mutations of EBNA-1 genes, which are thought to affect viral tumorigenicity in EBV-infected neoplasms displaying the latency I phenotype. STUDY DESIGN: Twenty-four PEL (nine cell lines and 15 primary specimens) formed the basis of the study. Karyotypes were investigated by conventional cytogenetics and fluorescent in situ hybridization (FISH) in selected cases. The expression status of Met and HGF was defined by multiple techniques, including RT-PCR, FACS analysis, immunocytochemistry, Western blot studies and ELISA. The molecular profile of EBNA-1 genes of EBV were investigated by DNA direct sequencing. RESULTS: Trisomy 7, trisomy 12 and breaks at 1q21-q25 are recurrently associated with PEL. PEL consistently co-express Met and HGF both at the mRNA and protein level. Among aggressive B-cell lymphomas, Met/HGF co-expression appears to be relatively specific for PEL. The EBNA-1 gene of EBV displays a high degree of genetic heterogeneity in PEL, with no preferential association with one specific variant. CONCLUSIONS: PEL associates with recurrent chromosomal alterations, suggesting that viral infection is not sufficient for tumor development and that lesions of cellular genes may be required. The expression of Met/HGF by PEL cells may bear implications for the lymphoma proliferation and growth pattern, since Met/HGF interactions influence cell mitogenesis and motogenesis. EBV infection in PEL displays a latency I phenotype and fails to associate with specific EBNA-1 variants, suggesting that the role of EBV in PEL is not mediated by the major transforming pathways currently known in EBV positive lymphomas.

Epstein-Barr Virus Nuclear Antigens↗

PubMed2000

The tyrosine kinase receptor met and its ligand HGF are co-expressed and functionally active in HHV-8 positive primary effusion lymphoma.

Primary effusion lymphoma (PEL) harbors consistent infection by human herpesvirus-8, preferentially develops in immunodeficient patients and selectively localizes to the serous body cavities. Histogenetic analysis has suggested that PEL originates from post-germinal center, pre-terminally differentiated B cells sharing phenotypic features with plasma cells. Here we have investigated the expression status and functional integrity of the Met tyrosine kinase receptor and of its ligand hepatocyte growth factor (HGF). Thirteen PEL (nine cell lines and four primary specimens) were analyzed for Met and HGF expression and function by multiple assays. For comparison, a panel of 34 high grade B cell non-Hodgkin lymphomas (NHL) other than PEL was also investigated. Co-expression of Met and HGF was found in all PEL analyzed, whereas it was restricted to 1/34 B cell NHL other than PEL (P < 0.001; chi2 test). The Met protein expressed by PEL displays biochemical characteristics typical of Met expressed by other cell types and is capable of tyrosine autophosphorylation. By using a combination of immunological and biological assays, production and secretion of a functional HGF species was identified in all PEL cell lines analyzed. HGF stimulation of PEL cells rapidly induces Met tyrosine phosphorylation, demonstrating the functional integrity of the Met/HGF loop. Because of the well known mitogenic and motogenic properties of Met/HGF interactions, these data may bear implications for PEL growth and dissemination. Among B cell neoplasms, Met/HGF co-expression selectively clusters with PEL and, as demonstrated by previous studies, with multiple myeloma plasma cells, thus reinforcing the notion that PEL displays biologic similarities with tumors derived from late stages of B cell differentiation.

Gene Expression Regulation, Neoplastic↗

PubMed1998

GAS6 inhibits granulocyte adhesion to endothelial cells.

GAS6 is a ligand for the tyrosine kinase receptors Rse, Axl, and Mer, but its function is poorly understood. Previous studies reported that both GAS6 and Axl are expressed by vascular endothelial cells (EC), which play a key role in leukocyte extravasation into tissues during inflammation through adhesive interactions with these cells. The aim of this work was to evaluate the GAS6 effect on the adhesive function of EC. Treatment of EC with GAS6 significantly inhibited adhesion of polymorphonuclear cells (PMN) induced by phorbol 12-myristate 13-acetate (PMA), platelet-activating factor (PAF), thrombin, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), but not that induced by FMLP and IL-8. GAS6 did not affect adhesion to resting EC. Titration experiments showed that high concentrations of GAS6 were needed to inhibit PMN adhesion and that inhibition was dose-dependent at the concentration range of 0.1 to 1 microg/mL. One possibility was that high concentrations were needed to overwhelm the effect of endogenous GAS6 produced by EC. In line with this possibility, treatment of resting EC with soluble Axl significantly potentiated PMN adhesion. Analysis of localization of GAS6 by confocal microscopy and cytofluorimetric analysis showed that it is concentrated along the plasma membrane in resting EC and treatment with PAF induces depletion and/or redistribution of the molecule. These data suggest that GAS6 functions as a physiologic antiinflammatory agent produced by resting EC and depleted when proinflammatory stimuli turn on the proadhesive machinery of EC.

Cell Adhesion↗

PubMed1998

Hematopoietic growth factors in autologous transplantation.

Hematopoietic growth factors (HGFs) sustain the survival, proliferation and differentiation of hematopoietic stem cells and some functions of mature blood cells. In man several HGFs have been characterised and cloned so far, and this has allowed investigators to confer the rationale for the clinical application of these molecules in hematology and oncology. In particular G-CSF and GM-CSF are currently utilised to abrogate the hematological toxicity of chemotherapy for standard and dose-intensified therapy, neutropenia following bone marrow and peripheral blood stem cell transplantation. Moreover there has recently been great interest in the ex vivo expansion of hematopoietic stem and progenitor cells for a variety of applications, such as in vitro tumor cell purging or for reducing the volume of blood processed by the leukapheresis. Several combinations of HGFs have been described to sustain the ex vivo survival and proliferation of these cells disclosing new opportunities in the field of stem cells transplants.

Animals↗

PubMed1997

An erythroid and megakaryocytic common precursor cell line (B1647) expressing both c-mpl and erythropoietin receptor (Epo-R) proliferates and modifies globin chain synthesis in response to megakaryocyte growth and development factor (MGDF) but not to erythropoietin (Epo).

A human megakaryocyte cell line (B1647) has been established from bone marrow cells obtained from a patient with acute myelogenous leukaemia (FAB M2). The cells were CD34-, CD33+, HLA-DR+, CD38+, and expressed the immunophenotypic markers of the megakaryocyte lineage (CD41 and von Willebrand factor). Moreover the cells expressed the c-mpl (thrombopoietin receptor) mRNA and protein. On the other hand, the B1647 cells also possessed erythroid lineage characteristics: the vast majority of cells were glycophorin positive, and about 10% of unstimulated cells stained with an anti-globin gamma chain MoAb. In addition, S1 protection analysis demonstrated expression of beta-globin mRNA, and Epo receptor (Epo-R) protein was detected by cytofluorimetric assay. Several growth factors, when tested alone or in combination, failed to influence the B1647 cell growth. A significant increase of cell proliferation was observed only after the addition, in serum-free culture, of recombinant human megakaryocyte growth development factor (MGDF), a recombinant c-mpl ligand encompassing the receptor-binding domain and identical to thrombopoietin (TPO), at concentrations ranging from 0.01 to 1 ng/ml. Interestingly, MGDF failed to induce megakaryocytic differentiation of the B1647 cells, but significantly increased the synthesis of the globin gamma-chain. B1647 cells could be a useful model for studying the biological effect of TPO on common megakaryocyte and erythroid progenitors.

Cell Division↗

PubMed1997

GAS6, the ligand of Axl and Rse receptors, is expressed in hematopoietic tissue but lacks mitogenic activity.

GAS6, a gene previously identified as growth arrest specific, has been demonstrated to be the ligand of Axl, a novel tyrosine kinase receptor widely expressed in both normal and neoplastic hematopoietic tissue. We have observed previously that GAS6 mRNA was present in whole bone marrow. This preliminary finding prompted us to investigate the presence of GAS6 in hematopoietic tissue and the possible role of this molecule in controlling the proliferation of hematopoietic precursors. We report here that the protein GAS6 is diffusely present in hematopoietic tissue, both in stromal and in hematopoietic cells, and that, among these cells, positivity is observed in megakaryocytes and myelomonocytic precursors. Furthermore, our data suggest that GAS6 is not a growth factor for hematopoietic progenitors or stromal fibroblasts. Despite the fact that both the Axl receptor and its ligand, GAS6, are expressed in hematopoietic tissue, the biological role of their interactions remains to be determined.

Biopsy↗

PubMed1995

Transcriptional and post-transcriptional regulation of granulocyte-macrophage colony-stimulating factor production in human growth factor dependent M-07e cells.

To elucidate the regulatory mechanisms of granulocyte-macrophage colony-stimulating factor (GM-CSF) production in human myeloid leukaemic cells we studied GM-CSF gene transcription, mRNA expression and GM-CSF secretion in human growth factor dependent M-07e cells. GM-CSF transcript was detected in cells cultured in the presence of interleukin-3 (IL-3). GM-CSF or mast cell growth factor (MGF), whereas it was undetectable in growth factor deprived cells. Growth factor re-addition induced, within 2 h, the appearance of GM-CSF mRNA. Nuclear run-on experiments demonstrated that the increase of GM-CSF mRNA levels depends on GM-CSF gene transcription. The simultaneous addition, to deprived cells, of the growth factor, and of cycloheximide (CHX) for 2 h inhibited GM-CSF mRNA expression, suggesting the requirement for newly made proteins for GM-CSF gene transcription. By means of the M-07e bioassay, which allows the detection of GM-CSF, IL-3 and MGF activities, and neutralizing antibodies to each of these factors, GM-CSF activity was detected in the cell-free extract of both IL-3- and MGF-sustained cells and of cells deprived for 24 h. This finding demonstrates that M-07e cells produce and store biologically active GM-CSF in response to both IL-3 and MGF. In contrast, analysis of the growth stimulatory activity present in the culture supernatants revealed that MGF, unlike IL-3, is able to induce the secretion of consistent amounts of GM-CSF. Taken together, our results suggest that, in M-07e cells, GM-CSF gene transcription and GM-CSF production are mediated, unlike its secretion, by mechanisms shared by IL-3 and MGF.

Blotting, Northern↗

PubMed1993

Regulation of c-kit expression in human myeloid cells.

In both murine and human systems the c-kit ligand, also known as mast cell growth factor (MGF), acts synergistically with several colony stimulating factors, including the granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 3 (IL-3), in stimulating the proliferation and differentiation of different types of hematopoietic progenitors. In addition, MGF is also known to enhance the effects of GM-CSF and IL-3 on the in vitro proliferative activity of myeloid leukemic cells. MGF synergizes with a number of other cytokines such as GM-CSF, IL-3, IL-2, IL-4, IL-6 and IL-9 in sustaining the proliferation of growth factor dependent M-07e cells. In order to explore the molecular basis of this synergistic activity and to elucidate the regulatory mechanisms of c-kit expression, we investigated the effects of GM-CSF, IL-3 and MGF on c-kit mRNA and protein levels in M-07e cells. GM-CSF, unlike MGF and IL-3, induced a transient but significant increase of c-kit mRNA levels. Moreover, following MGF and GM-CSF treatment, c-kit protein expression in M-07e cells decreased, whereas all the other cytokines tested are unable to modulate c-kit protein. These data together with the results of protein turnover analysis suggest that MGF and GM-CSF regulate c-kit expression at the post-transcriptional level. In addition, the finding that IL-3 has no detectable effect on c-kit expression raises the possibility that GM-CSF-induced c-kit regulation is not mediated by the common signal transducing element: the beta subunit of the IL-3/GM-CSF receptor complex.

Gene Expression Regulation, Leukemic↗

PubMed1993

Interleukin 3 stimulates proliferation and triggers endothelial-leukocyte adhesion molecule 1 gene activation of human endothelial cells.

Proliferation and functional activation of endothelial cells within a tissue site of inflammation are regulated by humoral factors released by cells, such as T lymphocytes and monocytes, infiltrating the perivascular space. In the present study we investigated the effects of interleukin 3 (IL-3), an activated T lymphocyte-derived cytokine, on cultured human umbilical vein endothelial cells (HUVEC). Proliferative activity, evaluated both by estimation of the fraction of cells in the S phase and by direct cell count demonstrated that IL-3, at the dose of 25 ng/ml, enhances more than threefold both DNA synthesis and cell proliferation above baseline control conditions. Binding studies with radioiodinated ligand demonstrated that HUVEC constitutively express a smaller number of IL-3 binding sites (approximately 99 binding sites per cell, with an apparent Kd of 149 pM). Accordingly, molecular analysis showed the presence of transcripts for both alpha and beta subunits of the IL-3 receptor. Functional activation of endothelial cells was evaluated by the expression of the endothelial-leukocyte adhesion molecule 1 (ELAM-1) transcript and by leukocyte adhesion. The ELAM-1 gene transcript was clearly detectable 4 h after IL-3 addition and started to decrease after 12 h. Moreover, IL-3-induced ELAM-1 transcription was followed by enhanced adhesion of neutrophils and CD4+ T cells to HUVEC. The findings that IL-3 can stimulate both proliferation and functional activation of endothelial cells suggest that this cytokine can be involved in sustaining the process of chronic inflammation.

CD4-Positive T-Lymphocytes↗

PubMed1992

Effect of stem cell factor on colony growth from acquired and constitutional (Fanconi) aplastic anemia.

The aim of this study was to evaluate the effect of stem cell factor (SCF) on the in vitro growth of bone marrow hematopoietic progenitors from patients with acquired severe aplastic anemia (AA) or Fanconi's anemia (FA). For this purpose, we studied 11 patients with acquired AA (5 at diagnosis, 6 after ALG treatment), 12 patients with FA, and nine normal controls. Bone marrow cells were plated in vitro for colony-forming unit granulocyte-macrophage (CFU-GM) (in the presence of granulocyte-macrophage colony-stimulating factor [GM-CSF]), and for burst-forming unit-erythroid (BFU-E) and CFU-granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM) colonies (in the presence of erythropoietin and interleukin-3 [IL-3]), with or without 20 ng/mL of SCF. In normal controls, SCF enhanced the growth of CFU-GM colonies from 103 to 263 (median), of BFU-E from 168 to 352, and of GEMM colonies from 6 to 38/10(5) cells plated. In patients with acquired AA, SCF induced a significant enhancement of BFU-E growth (8 to 29; P = .01) and allowed the formation of GEMM colonies that were not scored in baseline culture conditions (0 to 8; P = .01). CFU-GM growth was enhanced (4 to 20), but not significantly (P = .3). This was true both for patients at diagnosis and after antilymphocyte globulin treatment. By contrast, 10 of 12 FA patients grew no CFU-GM, BFU-E, or CFU-GEMM colonies, with or without SCF. In two FA patients (one transfusion-dependent and one transfusion-independent), an enhancement of CFU-GM and/or BFU-E was observed. The lack of response of hematopoietic progenitor cells from FA patients to GM-CSF+SCF or IL-3+SCF was not dependent on a defective expression of cytokine receptor messenger RNAs. Northern blot analysis showed in marrow cells from acquired AA and FA patients the presence of normal transcripts for alpha- and beta-chains of GM-CSF/IL-3 receptor and for c-kit protein. In conclusion, SCF promotes the in vitro growth of hematopoietic progenitors in patients with acquired AA, but not in patients with FA, pointing out the intrinsic nature of the defect in the latter disorder.

Adolescent↗

PubMed1991

In vitro growth and regulation of bone marrow enriched CD34+ hematopoietic progenitors in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital red blood cell aplasia. No clear explanation has been given of its defective erythropoiesis, although different humoral or cellular inhibitory factors have been proposed. To clarify the nature of this defect we studied the effect of several human recombinant growth factors on an enriched CD34+ population obtained from the bone marrow of 10 DBA patients. We observed a defect underlying the early erythroid progenitors, which were unresponsive to several growth factors (erythropoietin, interleukin-3 [IL-3], IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF], erythroid potentiating activity), either alone or in association. The production of cytokines was not impaired, and high levels of IL-3 and GM-CSF were found in phytohemagglutinin-leukocyte-conditioned medium (PHA-LCM) when tested with a sensitive biologic assay on the M-07E cell line. Hematopoietic stem cells in DBA patients may be induced to differentiate to the granulocyte megakaryocyte, but not the erythroid compartment, as shown after CD34+ cell preincubation with IL-3. Addition of the stem cell factor to IL-3 and erythropoietin induces a dramatic in vitro increase in both the number and the size of BFU-E, which also display a normal morphologic terminal differentiation.

Antigens, CD↗

PubMed1991

Interleukin 3-dependent proliferation of the human Mo-7e cell line is supported by discrete activation of late G1 genes.

The hemopoietic growth factor interleukin 3 (IL-3) supports the survival and proliferation of multipotent and committed progenitor cells in vitro. To elucidate the molecular mechanisms triggered by IL-3 we studied the expression of cell cycle-related genes in a recently established human IL-3-dependent clone (M-07e). No changes in the level of expression of early (c-myc), mid (ornithine decarboxylase), or mid-late G1 (p53, c-myb) cell cycle genes were detected after restoration of IL-3 in deprived cells. The fact that only late G1-S-phase genes [proliferating cell nuclear antigen (PCNA) thymidine kinase (TK), histone H3] are modulated by IL-3 suggests that this factor may control human cell proliferation by acting at the G1-S boundary.

Cell Division↗

PubMed1991

GM-CSF and phorbol esters modulate GM-CSF receptor expression by independent mechanisms.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.1 nM) down-modulates its receptor in IL-3/GM-CSF dependent M-07e cells, in KG-1 cells and normal granulocytes, whereas phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) (2 nM) down-modulates the GM-CSF receptor in M-07e cells and granulocytes but not in KG-1 cells. As data analysis shows by nonlinear regression, the decreased binding ability depends on a reduction of the binding sites with no significant change of their dissociation constant. To gain insight into the mechanisms involved in the GM-CSF receptor regulation, we investigated the role of protein kinase C (PKC). GM-CSF, unlike TPA, was unable to activate PKC in all the cells studied. Moreover, unlike TPA, GM-CSF was still able to down-modulate its receptor in cells where PKC was inhibited by 1-(5-isoquinolonesulphonyl)-2-methylpiperazine (H7) and staurosporine or in cells where PKC was exhausted by prolonged incubation with 1 microM TPA. Finally, the receptor re-expression rate was accelerated by protein kinases inhibitors. These results, taken together, indicate the presence of a PKC-dependent and -independent down-modulation mechanism and a negative role of the endogeneous protein kinases in GM-CSF receptor re-expression.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1991

Hematopoietic growth factor receptors.

The molecular cloning for most of the hematopoietic growth factor receptors has been achieved over the past few years and revealed that they can by assigned to two discrete receptor families, namely the hematopoietic growth factor superfamily (HRS) and the receptor tyrosine kinase family (RTK). The members of the HRS, including granulocyte-macrophage colony-stimulating factor receptor (GM-CSF-R), interleukin 3 receptor (IL-3-R), granulocyte CSF receptor (G-CSF-R) and erythropoietin receptor (Epo-R), share a common binding domain and the absence of a tyrosine kinase domain in their cytoplasmic portion. In some cases (e.g., GM-CSF-R), the high-affinity receptor structure is obtained through the association of the low-affinity binding chain (alpha chain) with an accessory protein (beta chain). It is conceivable that this protein might also represent the common subunit shared by GM-CSF-R and by IL-3-R when they are co-expressed to form the putative GM-CSF-R/IL-3-R complex. Although tyrosine phosphorylation following ligand receptor activation seems to be a common event in the HRS, its role in the signal transduction mechanisms is unknown. Due to the structural analogies among the members of this family any new insight into one particular receptor member, such as its subunit structure and its signal transduction pathways, will be generalizable to the other family members. The subclass III of the RTK family, including the CSF-1-R and c-kit, is characterized by an additional insert into the kinase domain that recognizes and binds protein substrates. Ligand induced activation of the kinase domain and its signaling potential are mediated by receptor oligomerization which stabilizes interactions between adjacent cytoplasmic domains and leads to activation of kinase function by molecular interaction. Interestingly, the receptors included in this subclass are the products of well known cellular proto-oncogenes. A large variety of structural alteration found in receptor-derived oncogene products may lead to constitutive activation of receptor signals that, consequently, result in the subversion of the mechanisms controlling the cell growth.

Hematopoietic System↗

PubMed1990

Cytogenetics and occupational exposure to solvents: a pilot study on leukemias and myelodysplastic disorders.

In a pilot study, 57 patients affected by leukemias or myelodysplastic syndromes were interviewed to identify potential exposure to organic solvents. Cytogenetic analyses were performed in 40 of the 57 patients. Unlike previous investigations, no association was found between the occurrence of chromosomal abnormalities and exposure to organic solvents. An original finding was a strong association between solvent exposure and myelodysplastic disorders (4 certainly exposed and 1 possibly exposed out of 11 patients). Such an observation warrants confirmation from case-control studies.

Anemia, Refractory↗