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991.
Overexpression of adenosine deaminase (ADA) in red blood cells is characterized by a marked, tissue-specific increase in levels of structurally normal ADA mRNA and enzymatic activity in the erythrocytes of affected individuals, leading to adenosine triphosphate (ATP) depletion and hemolytic anemia. This autosomal dominant trait is linked to the ADA gene. To investigate the molecular mechanism responsible for this disorder, we examined relative reporter gene activity using constructs containing 10.6 kb of 5' flanking sequence and 12.3 kb of the first intron of the ADA gene from the normal and mutant alleles. No differences in chloramphenicol acetyltransferase (CAT) activity were found in transient transfection experiments using erythroleukemia cell lines. Transgenic mice containing the ADA constructs expressed CAT in the appropriate tissue-specific fashion, with 10(2)- to 10(4)-fold higher activity in the thymus. However, CAT activities in erythrocytes and bone marrow of mice containing high transgene copy numbers did not differ between the normal and mutant alleles. These results indicate that the mutation responsible for ADA overexpression is unlikely to reside in the 5' and promoter regions or in the regulatory regions of the first intron. It is possible that the erythroid-specific overexpression of ADA results from a mutation at some distance from the gene or requires an interaction of a proximal mutation with more distal DNA elements. 相似文献
992.
Urbini B Arpinati M Bonifazi F Chirumbolo G Falcioni S Stanzani M Bandini G Motta MR Perrone G Giannini B Tura S Baccarani M Rondelli D 《Experimental hematology》2003,31(10):959-965
OBJECTIVE: This study examined whether the CD34(+) cell dose in allografts correlates with the dose of myeloid dendritic cells (mDC) and plasmacytoid DC (pDC), and with DC reconstitution and clinical outcome after a myeloablative HLA-matched transplant. PATIENTS AND METHODS: Fifty-three patients were included in this study: 37 who had undergone a granulocyte colony-stimulating factor mobilized peripheral blood stem cells (PBSC) transplant from related donors and 16 who had undergone a marrow transplant from unrelated donors. The number of CD34(+) cells, lin(-)HLA-DR(+)CD11c(+) mDC, lin(-)HLA-DR(+)CD123(+) pDC, CD14(+) monocytes, and CD3(+)CD4(+), CD3(+)CD8(+), CD56(+), and CD19(+) lymphocytes was compared in the graft, as well as in the peripheral blood after transplant, in patients receiving more than versus less than or equal to the median number of CD34(+) cells in PBSC (5.78 x 10(6)/kg) or in marrow (2.8 x 10(6)/kg). RESULTS: A higher CD34(+) cell dose was associated with larger numbers of mDC in PBSC (p=0.01) and pDC in marrow grafts (p=0.004). However, neither mDC nor pDC recovery after transplant correlated with the number of CD34(+) cells infused. Finally, higher doses of CD34(+) cells appeared to negatively affect (p=0.02) the overall survival in PBSC transplantation and were associated with a trend for higher acute graft-vs-host disease in PBSC and lower acute graft-vs-host disease in marrow transplant. CONCLUSIONS: CD34(+) cell dose correlates with the dose of different DC subsets in PBSC and marrow grafts, but it does not affect DC reconstitution after transplant. Higher doses of CD34(+) cells in PBSC, but not in marrow, seem to adversely affect survival after transplant. 相似文献
993.
Giannini D Di Franco A Bacci E Dente FL Vagaggini B Taccola M Tonelli M Zingoni M Paggiaro P 《Pulmonary pharmacology & therapeutics》2003,16(6):355-360
The aim of this study was to assess the distribution of the occurrence of tolerance to the protective effect of salmeterol on allergen challenge in a large sample of asthmatic subjects. We investigated 53 subjects (45 male and eight female), mean age 24+/-8.2 years, with mild intermittent asthma, in stable phase of the disease, never previously treated with regular beta2-agonists. All subjects with a previous positive early airway response (EAR) to a screening allergen challenge underwent, in double blind randomized, cross-over manner, three further allergen challenges: after placebo (T0), after a single dose (50 microg) of inhaled salmeterol (T1), and after regular treatment with inhaled salmeterol (50 microg bid) for 1 week (T2). All subjects showed an EAR after placebo treatment (T0), and were completely protected against EAR by the single dose of salmeterol (T1). After 1-week regular treatment with salmeterol (T2). 24 out of 53 subjects (45%) were still protected, whereas 29 subjects (55%) showed a significant EAR. The distribution of the response to allergen challenge, which was quite homogeneous at T0 and T1, showed considerable heterogeneity at T2. Tolerance to the protective effect of salmeterol on allergen challenge can be observed in a large group of previously untreated mild asthmatic subjects. This phenomenon is heterogeneously distributed, with some subjects still showing a complete protection similar to that obtained after a single dose of salmeterol and others showing a response similar to that obtained after placebo. The reason of this heterogeneity needs to be elucidated. 相似文献
994.
Gastaldi R Martino P Gentile G Cafolla A Cordone I Giannini G Torromeo C Palmisano L Picardi V Andreotti M Avvisati G Mandelli F 《Haematologica》2001,86(10):1051-1059
BACKGROUND AND OBJECTIVES: Intensive chemotherapy (CHT) in AIDS-related non-Hodgkin's lymphoma (AIDS-NHL patients) is a vexing problem. Our purpose was to evaluate the feasibility of a high dose idarubicin (HD-IDA)-based regimen in diffuse large cell (DLC) AIDS-NHL patients. DESIGN AND METHODS: Fourteen stage I-IV untreated DLC AIDS-NHL patients with a performance status <3 and no prior AIDS-related diseases received CIOD: cyclophosphamide, HD-IDA (25 mg/m2 in 8 patients, 20 mg/m2 in 6 patients) vincristine and dexamethasone plus granulocyte colony-stimulating factor (G-CSF) and prophylaxis against infections. The outcomes measured were: rate of response, disease-free survival (DFS), overall survival (OS) and the impact of chemotherapy on immunologic and virological parameters. RESULTS: Complete response was achieved in 13/14 cases (response rate: 93%). The median time of response and survival was 33 (range 5-79) and 35.5 (range 6-84) months, respectively. At 60 months the DFS and OS were 71% and 44%, respectively. CIOD with idarubicin 20 mg/m2 was better tolerated than that with 25 mg/m2 and was administered with a higher mean average-relative-dose-intensity (95.38+/-7% vs 83.35+/-15.59%, p=0.0001). Opportunistic infections were more frequent in patients with a baseline CD4 <100 than those with >100 cells/microL (4/5 vs 1/9: p=0.0229). After 3 CIOD courses the mean CD4 cells/microL was significantly lower (p=0.001) and the mean HIV.1 RNA load was significantly higher (p=0.045) than at baseline. INTERPRETATION AND CONCLUSIONS: The proposed chemotherapeutic regimen for AIDS-related non-Hodgkin's lymphoma is feasible in an outpatient setting in selected patients with relatively well-preserved immune function. 相似文献
995.
Monoclonal antibody therapy in rheumatoid arthritis 总被引:1,自引:0,他引:1
Monoclonal antibodies bind to their targets with high specificity and
therefore have excellent potential as therapeutic agents. Biotechnological
advances have allowed the production of large quantities of engineered
monoclonal antibodies for therapeutic use. Recent research in rheumatoid
arthritis has identified important mediators of synovitis. Monoclonal
antibodies targeting these have been tested in clinical trials over the
last decade. Anti-cytokine therapies, in particular anti-tumour necrosis
factor alpha monoclonal antibodies, suppressed inflammation and produced
rapid symptomatic improvement. Anti-lymphocyte monoclonal antibodies
produced long- lasting disease suppression in animal models of rheumatoid
arthritis. The use of depleting anti-lymphocyte monoclonal antibodies in
rheumatoid arthritis had been disappointing as they did not penetrate the
synovial joint in sufficient quantity to suppress disease without producing
severe and protracted peripheral blood lymphopenia. Consequently, their use
in rheumatoid arthritis had been abandoned. In contrast, clinical trials of
non-depleting anti-CD4 monoclonal antibodies in rheumatoid arthritis showed
that they could suppress synovitis. However, it remains unclear whether
they could lead to prolonged disease improvement.
相似文献
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1000.
HJ Ng M Yule M Twoon NR Binnie EH Aly 《Annals of the Royal College of Surgeons of England》2015,97(2):151-156