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Biomedical subjects

D Ruggero

Publications and source records attributed to D Ruggero.

At least 19 recordsLinked to original sources
PubMed2006

Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha.

Recurrent chromosomal translocations involving the RAR alpha locus on chromosome 17 are the hallmark of acute promyelocytic leukemia (APL). The RAR alpha gene fuses to variable partners (PML, PLZF, NPM, NuMA and STAT5B: X genes) leading to the expression of APL-specific fusion proteins with identical RAR alpha moieties. To analyse whether the variable X moiety could affect the activity of the fusion protein in vivo, we generated and characterized, on a comparative basis, NPM/RAR alpha transgenic mice (TM) in which the fusion gene is expressed under the control of a human Cathepsin G (hCG) minigene. We compared the features of the leukemia observed in these TM with those in hCG-PML/RAR alpha and hCG-PLZF/RAR alpha TM. In all three transgenic models, leukemia developed after a variably long latency, with variable penetrance. However, the three leukemias displayed distinct cytomorphological features. hCG-NPM/RAR alpha leukemic cells resembled monoblasts. This phenotype contrasts with what was observed in the hCG-PML/RAR alpha TM model in which the leukemic phase was characterized by the proliferation of promyelocytic blasts. Similarly, hCG-PLZF/RAR alpha TM displayed a different phenotype where terminally differentiated myeloid cells predominated. Importantly, the NPM/RAR alpha oncoprotein was found to localize in the nucleolus, unlike PML/RAR alpha and PLZF/RAR alpha, thus possibly interfering with the normal function of NPM. Similarly to what was observed in human APL patients, we found that NPM/RAR alpha and PML/RAR alpha, but not PLZF/RAR alpha leukemia, was responsive to all-trans retinoic acid (ATRA) or As2O3 treatments. Taken together, our results underscore the critical relevance of the X moiety in dictating the biology of the disease and the activity of the APL fusion oncoprotein.

Animals↗
PubMed2000

Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis.

The promyelocytic leukemia protein (PML) gene of acute promyelocytic leukemia (APL) encodes a cell growth and tumor suppressor essential for multiple apoptotic signals. Daxx was identified as a molecule important for the cytoplasmic transduction of the Fas proapoptotic stimulus. Here, we show that upon mitogenic activation of mature splenic lymphocytes, Daxx is dramatically upregulated and accumulates in the PML nuclear body (NB) where PML and Daxx physically interact. In the absence of PML, Daxx acquires a dispersed nuclear pattern, and activation-induced cell death of splenocytes is profoundly impaired. PML inactivation results in the complete abrogation of the Daxx proapoptotic ability. In APL cells, Daxx is delocalized from the NB. Upon retinoic acid treatment, which induces disease remission in APL, Daxx relocalizes to the PML NBs. These results indicate that PML and Daxx cooperate in a novel NB-dependent pathway for apoptosis and shed new light in the role of PML in tumor suppression.

Animals↗
PubMed2000

The puzzling multiple lives of PML and its role in the genesis of cancer.

PML, the gene associated with acute promyelocytic leukemia (APL); PML, the target of numerous viral agents; PML, the growth suppressor; PML, the mediator of multiple apoptotic pathways; PML, the tumor suppressor; PML, the protein which epitomizes a novel nuclear structure, the nuclear body; PML, the transcription co-factor. Despite the recent flurry of reports attributing multiple biological roles to the PML protein, PML still lacks a definitive biochemical function. This is probably the reason why PML is so attractive to many investigators. Here, we will summarize the facts and speculations on this puzzling protein.

Cell Differentiation↗
PubMed1999

Cis-acting signals controlling translational initiation in the thermophilic archaeon Sulfolobus solfataricus.

In this work, we have studied the in vitro translational features of a bicistronic mRNA of the extremely thermophilic Archaeon Sulfolobus solfataricus, with the aim of determining the nature of the cis-acting signals controlling the recognition of the translation initiation sites in the Archaea. We found that the most important feature for efficient initiation was the presence of a Shine-Dalgarno (SD)-like ribosome-binding motif, whose disruption entirely abolished the translation of the corresponding cistron. The influence of other features, such as the type of initiation codon, was variable and depended upon the gene and its position in the mRNA. However, the translational block caused by the disruption of the SD sequences could be removed by deleting the 5' untranslated region altogether, thereby creating a 'leaderless' mRNA. This suggests that 'leaderless' initiation operates by a default mechanism that does not require a specific mRNA-rRNA interaction and may be common to all three primary domains of life.

5' Untranslated Regions↗
PubMed1998

The chaperonin of the archaeon Sulfolobus solfataricus is an RNA-binding protein that participates in ribosomal RNA processing.

The 60 kDa molecular chaperones (chaperonins) are high molecular weight protein complexes having a characteristic double-ring toroidal shape; they are thought to aid the folding of denatured or newly synthesized polypeptides. These proteins exist as two functionally similar, but distantly related families, one comprising the bacterial and organellar chaperonins and another (the so-called CCT-TRiC family) including the chaperonins of the archaea and the eukaryotes. Although some evidence exists that the archaeal chaperonins are implicated in protein folding, much remains to be learned about their precise cellular function. In this work, we report that the chaperonin of the thermophilic archaeon Sulfolobus solfataricus is an RNA-binding protein that interacts specifically in vivo with the 16S rRNA and participates in the maturation of its 5' extremity in vitro. We further show that the chaperonin binds RNA as the native heterooligomeric complex and that RNA binding and processing are inhibited by ATP. These results agree with previous reports indicating a role for the bacterial/organellar chaperonins in RNA protection or processing and suggest that all known chaperonin families share specific and evolutionarily ancient functions in RNA metabolism.

Archaeal Proteins↗
PubMed1998

PML is essential for multiple apoptotic pathways.

The PML gene of acute promyelocytic leukaemia (APL) encodes a cell growth and tumour suppressor, however, the mechanisms by which PML suppresses tumorigenesis are poorly understood. We show here that Pml is required for Fas- and caspase-dependent DNA-damage-induced apoptosis. We also found that Pml is essential for induction of programmed cell death by Fas, tumour necrosis factor alpha (TNF), ceramide and type I and II interferons (IFNs). As a result, Pml-/- mice and cells are protected from the lethal effects of ionizing radiation and anti-Fas antibody. Pml is required for caspase 1 and caspase 3 activation upon exposure to these stimuli. The PML-RAR alpha fusion protein of APL renders haemopoietic progenitor cells resistant to Fas-, TNF- and IFN-induced apoptosis with a lack of caspase 3 activation, thus acting as a Pml dominant-negative product. These results demonstrate that Pml is a mediator of multiple apoptotic signals, and implicate inhibition of apoptosis in the pathogenesis of APL.

Animals↗
PubMed1998

A novel aminopeptidase associated with the 60 kDa chaperonin in the thermophilic archaeon Sulfolobus solfataricus.

The chaperonins are high-molecular-weight protein complexes having a characteristic double-ring toroidal shape; they are thought to aid the folding of denatured or newly synthesized polypeptides. These proteins exist as two functionally similar but distantly related families, one including the bacterial and organellar chaperonins and the other (termed the CCT-TRiC family) including the chaperonins of the Archaea and the eukaryotes. The CCT-TRiC chaperonins, particularly their archeal members, are less well known than their bacterial counterparts, and their main cellular function is still doubtful. In this work, we report that the chaperonin of the thermophilic archaeon Sulfolobus solfataricus interacts with several polypeptides other than the two subunits that constitute the 18-mer double-ring structure. We have cloned and sequenced the gene encoding one 90 kDa chaperonin-associated protein and have shown, using biochemical assays, that the product is an enzyme belonging to the family of zinc-dependent aminopeptidases. The Sulfolobus protein shows maximal homology to eukaryotic (yeast and mouse) aminopeptidases. It contains a leucine zipper motif and can be phosphorylated by an unidentified kinase present in the cell extracts. The possible significance of an association between an aminopeptidase and a chaperonin is discussed.

Amino Acid Sequence↗
PubMed1996

Differential antibiotic sensitivity determined by the large ribosomal subunit in thermophilic archaea.

Hybrid ribosomes obtained by mixing the ribosomal subunits of the extremely thermophilic archaea Sulfolobus solfataricus and Desulfurococcus mobilis were tested for their sensitivity to selected antibiotics. It is shown that structural differences in the large ribosomal subunits determine qualitatively and quantitatively the patterns of response to alpha-sarcin and paromomycin in these species.

Anti-Bacterial Agents↗
PubMed1982

Lithium and granulocytopenia during induction treatment of adult acute lymphoblastic leukemia.

Twelve adult patients with acute lymphoblastic leukemia (ALL) received lithium carbonate, 300 mg, three times a day during induction treatment. They were compared to 12 similar patients consecutively treated with the same induction regimen; patients and controls were comparable for age, degree and presence of splenomegaly, hemoglobin level, blast cell count, polymorphonuclear (PMN) cell count and platelet count at diagnosis. All patients developed a severe neutropenia. PMN count at nadir was slightly higher in the lithium group, but not at a level of statistical significance (p = 0.100). The median number of days with PMN less than 1 x 10(9)/liter was 4 in the lithium group and 14.5 in the non-lithium group (p = 0.014), while the median number of days with PMN less than 0.5 x 10(9)/liter was 0 and 2 days, respectively (p = 0.004). Duration of thrombocytopenia was similar in the 2 groups and so was the remission rate; 2 infective episodes occurred, one in the lithium group and one in the controls.

Adult↗
PubMed1981

Treatment of severe aplastic anaemia with antilymphocyte globulin or bone-marrow transplantation.

Fifty-three patients with severe aplastic anaemia were admitted to this hospital between January 1976 and June 1980, of whom three arrived in terminal condition and died before treatment for their basic disease could be given. Thus 50 patients were treated and evaluated in a prospective study according to one protocol. Eighteen patients with an HLA-identical sibling underwent bone-marrow transplantation with the aim of achieving haematopoietic chimerism. Thirty-two patients without an HLA-identical sibling were given antilymphocyte globulin with or without an infusion of HLA-haplotype-identical marrow. All these 32 patients received low-dose androgens after the procedure. In the first group eight patients (44%) survived. In the two other groups, 22 patients survived (69%), of whom 20 were completely self-sustaining (63%). Engraftment and graft-versus-host disease did not occur in the group who received antilymphocyte globulin and haploidentical marrow, and the haematopoietic reconstitutions in these patients were all autologous. These results confirm the efficacy of antilymphocyte globulin in the treatment of severe aplastic anaemia and show that such treatment is at least as good as bone-marrow transplantation. Its mechanism of action remains unknown, but most patients with aplastic anaemia have a pool of haematopoietic stem cells able to repopulate the marrow after this type of treatment.

Adolescent↗
PubMed1980

[Experience with intensive plasma exchange].

Experience with a total of 49 plasma exchanges in 14 patients is reported. All exchanges were performed with the Aminco cellseparator in an attempt to remove documented or suspected antibodies completely. Indications were ABO-barrier before bone marrow-transplantation (6), acute rejection following renal transplantation (3), autoimmune diseases (3), Moschowitz disease, antithrombocytic antibodies and hepatic coma (1 each). The technique was modified to make it possible routinely to exchange 121 of plasma in 4 hours with no major untoward side effects even in anuric or thrombopenic patients. Complete removal of circulating antibodies was possible and often followed by impressive clinical benefit.

ABO Blood-Group System↗
PubMed1979

Adult acute lymphoblastic leukaemia: study of 32 patients and analysis of prognostic factors.

The clinical and haematological characters and the response to therapy of 32 consecutive patients with acute lymphoblastic leukaemia, aged more than 12 years, were reviewed. All patients were given vincristine (V) and (6-methyl) prednisolone (P) for 6 weeks; daunomycin (D) was added in 9 cases, and cyclophosphamide (C) + D in another 10 cases. 3 patients died during induction. 4 patients failed to achieve remission. 25 patients (78%) achieved complete remission (CR). All of them but one received 'prophylactic' central nervous system (CNS) therapy with cranial irradiation and i.t. methotrexate (MTX) and arabinosyl cytosine. CR was maintained with daily 6-mercaptopurine and weekly MTX. Median duration of CR was of 22 months. 2 patients are currently disease-free and off-therapy, 78 and 53 months after diagnosis, respectively. Blast cell membrane markers were studied in 21 consecutive cases: 3 patients had T-cell leukaemia and 2 patients B-cell leukaemia. Prognostic factors were evaluated basing on the present series of 32 patients, and on further 106 cases reported by others. Age (under and above 40) influenced significantly both the CR rate and the length of survival. In patients aged under 40, a circulating blast cell count higher than 25,000/microliter, or a platelet count lower than 50,000/microliter, negatively affected the survival.

Adolescent↗
PubMed1978

Therapy of chronic myeloid leukemia (CML): interim report on protocols CML/73 and CML/74.

Current therapies of chronic myeloid leukemia (CML) do not prevent the progression of the disease towards blastic metamorphosis, and have not resulted in a remarkable prolongation of survival. Splenectomy was proposed with the aim of removing a part of the tumor without cytotoxics and of removing a potentially privileged pool of malignant blast cells. Acute leukemia-like chemotherapy was proposed with the aim of eradicating or better controlling the highly malignant subclones that emerge during the chronic phase. A preliminary analysis of 2 clinical trials these therapeutic measures, suggests that splenectomy does not modify the rate of blastic transformation, during the first 2 to 3 years from diagnosis. Also the rate of blastic transformation is similar for patients receiving hydroxyurea at first, and arabinosyl cytosine (ARA-C), vincristine (VCR) and prednisone (P) thereafter, as for patients receiving from the clinical onset of CML a more intensive chemotherapy with ARA-C, thioguanine (TG) and daunomycin (DAUNO), but not VCR + P.

Antineoplastic Agents↗
PubMed1977

Immunological study of patients with Hodgkin's disease in long-lasting not-maintained complete remission.

Immunological parameters have been evaluated both in vitro and in vivo in 20 Hodgkin's disease patients in continuous not maintained complete remission for at least 3 years. IgG, IgA and IgM levels were within the normal range. Delayed sensitivity, assayed by a battery of recall antigens, was normal too, in the majority of patients. The number of circulating lymphocytes was slightly inferior to normal controls. T cells, evaluated by the rosette E formation, seems to be diminished; on the contrary, B cells, evaluated by the membrane immunofluorescence, were increased in respect to normal controls. The differences are statistically significant. Timidine uptake of PHA stimulated lymphocytes was diminished too. It is concluded that even if these patients' clinical behaviour is like that of normal population, it is possible to find a disorder in vitro parameters, which could be attributable to long lasting effect of the therapy and/or to the persistence of serum factors acting as anti-T cells antibodies.

Adolescent↗
PubMed1977

Acute promyelocytic leukemia: results of therapy and analysis of 13 cases.

Acute promyelocytic leukemia (APL) was diagnosed in 13 of 84 adult patients (15.4%) with acute myeloid leukemia (AML) first admitted between 1972 and 1976. All patients had clinical and/or laboratory evidence of defibrination syndrome. Four patients died of cerebral hemorrhage within 2 days of admission. Two patients died of generalized infection on days 7, and 16, respectively, after admission. The remaining 7 patients (54%) underwent complete remission (CR) with daunomycin, arabinosyl cytosine, and adriamycin. All patients received massive platelet transfusion, no heparin, and no granulocyte transfusion. CR was more frequent in patients with a very low blast cell count and a fibrinogen level higher than 100 mg/100 ml. Median survival of these seven CR patients with APL is similar (15 months) to that of CR patients with other types of AML treated at the same institution during the same period.

Adolescent↗