|
11. |
Bilirubin‐UDP‐glucuronosyltransferase: Genetic defect of the hyperbilirubinemic gunn rat, a model of crigler‐najjar syndrome type I |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 117-123
Hiroshi Sato,
Sachiko Aono,
Olivier Darios,
Jean Michel Heard,
Osamu Koiwai,
Preview
|
PDF (631KB)
|
|
摘要:
AbstractThe hyperbilirubinemic Gunn rat lacks hepatic uridine diphosphate‐glucuronosyltransferase (UDPGT) activity toward bilirubin, and has been used as an animal model for human Crigler‐Najjar syndrome type I. Although the rat was discovered 50 years ago as a useful model of the disease, the gene encoding the enzyme had not yet been isolated. We isolated the bilirubin UDPGT cDNA from the cDNA library of a normal rat and revealed that the cDNA shared an identical 913 bp sequence (corresponding to the 247 carboxyl‐terminal amino acid residues) with that for phenol UDPGT, whose activity was also deficient in the Gunn rat. The genetic defect of bilirubin UDPGT in the mutant rat was proved to be a ‐1 frameshift mutation. The mutation was found not only to be located in the region where the cDNA for bilirubin UDPGT shared the identical sequence with that for phenol UDPGT, but it also occurred in the same position in the two cDNA from the mutant. At the 5′ end of the identical region there was a consensus sequence for splicing. In addition, both the bilirubin and phenol UDPGT genes were mapped at position 37 on mouse chromosome 1 by an analysis of restriction endonuclease fragment length variations using the rat bilirubin and phenol UDPGT cDNA as probes. These results indicate that both UDPGTs are transcribed by alternative use of promotors and that a point frameshift mutation on a common exon produced the multiple defects of UDPGT isozymes observed in the homozygous Gunn rat. Accordingly, Gunn rats are an interesting model for the study of gene therapy of genetic liver diseases. Introduction of bilirubin UDPGT cDNA into the liver of Gunn rat by retrovirus‐mediated gene transfer showed a significant and stable correction of the hyperbilirubinemia. Recent studies of the genomic structure of bilirubin UDPGT are also briefl
ISSN:1066-5099
DOI:10.1002/stem.5530120714
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
12. |
Porphyrias in Japan |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 125-132
Masao Kond,
Yuzo Yand,
Preview
|
PDF (692KB)
|
|
摘要:
AbstractPorphyrias are a clinically diverse group of diseases due to inherited deficiencies of enzymes in the heme biosynthetic pathway. Much progress has been made in the analysis of porphyrin metabolism, and the molecular biology of the enzymes in heme biosynthesis and their mutations in the porphyrias are now actively investigated. These diseases are classified into two types: erythropoietic and hepatic, depending on the major site of the clinical expression of the enzyme defect. They are further classified into eight subtypes according to the porphyrin metabolites that are over‐produced and according to the causative enzyme defects. These diseases are all inherited as autosomal dominant traits, except for congenital erythropoietic porphyria (CEP) and δ‐aminolevulinic acid dehydratase (ALAD) deficiency porphyria (ADP), which are recessive. In addition, a few homozygous forms of the dominantly inherited porphyrias have also been recognized, which are presumably due to mutations with a milder enzymatic defect. The main clinical manifestations of the porphyrias are neurologic syndromes and skin photosensiti
ISSN:1066-5099
DOI:10.1002/stem.5530120715
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
13. |
Glossary |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 133-134
Preview
|
PDF (132KB)
|
|
ISSN:1066-5099
DOI:10.1002/stem.5530120716
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
14. |
Peripheral blood stem cells: In vivo biology and therapeutic potential |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 203-211
Stefan Scheding,
Wolfram Brugger,
Roland Mertelsmann,
Lothar Kanz,
Preview
|
PDF (816KB)
|
|
摘要:
AbstractPeripheral blood stem cells (PBSC) have been studied for their use after high‐dose chemotherapy. The combination of a standard‐dose chemotherapy [VIP: VP16 (etoposide), ifosfamide, cisplatin] in combination with hematopoietic growth factors was shown to provide effective anti‐cancer activity as well as to enable sufficient stem cell mobilization for clinical use. Different growth factor regimens [granulocyte‐colony‐stimulating factor (G‐CSF), granulocyte‐macrophage (GM)‐CSF, interleukin (IL)‐3/GM‐CSF]resulted in a differential induction of high levels of circulating PBSC after VIP chemotherapy, with the sequential combination of IL‐3 and GM‐CSF inducing maximal numbers of CD34° cells as well as clonogenic progenitors. Our studies revealed a correlation between prior treatment and PBSC recruitment: the highest numbers of PBSC were mobilized in untreated patients whereas stem cell harvest was considerably impeded in heavily pretreated patients. Phase I/II trials demonstrated that transplantation of PBSC collected after VIP plus growth factor mobilization was safe, and engraftment was rapid and sustained. However, PBSC mobilization carried the risk of concomitant tumor cell recruitment in patients with detectable levels of tumor cells prior to therapy and in 21 % of patients without circulating tumor cells. Positive selection of CD34° cells by immunoadsorption that leads to an approximately three‐log depletion of contaminating tumor cells therefore was investigated with regard to feasibility and capability as a source for PBSC transplantation. Twenty‐one patients with advanced malignancies received autologous CD34° cell transplantation after highdose chemotherapy. Hematological recovery was as rapid as recorded for unseparated PBSC preparations, indicating that CD34° cells can be safely used for autologous PBSC transplantation. Finally, combinations of hematopoietic growth factors were tested for their ability to expand hematopoietic progenitors in liquid culture. A five‐factor combination consisting of stem cell factor, erythropoietin, IL‐1β, IL‐3 and IL‐6 was found to amplify progenitor cells optimally thereby providing the possibility of gaining large numbers of committed progenitor ce
ISSN:1066-5099
DOI:10.1002/stem.5530120717
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
15. |
The clinical utility of granulocyte colony‐stimulating factor: Early achievements and future promise |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 213-228
Maryann Foote,
David Perkins,
Martha Vincent,
George Morstyn,
Preview
|
PDF (1155KB)
|
|
摘要:
AbstractRecombinant granulocyte colony‐stimulating factor (rHuG‐CSF) is a hematopoietic growth factor that acts selectively on the neutrophil lineage, and has had a major impact on clinical practice. Two forms are in clinical use: filgrastim has been approved for use in more than 45 countries for the amelioration of chemotherapy‐induced neutropenia and restoration of granulopoiesis following bone‐marrow transplantation and lenograstim has been approved in Europe and Japan. In some countries, rHuG‐CSF is also approved for various other indications, such as severe chronic neutropenia.Infection and neutropenia are a major cause of morbidity and mortality following cytotoxic chemotherapy, and there is a known correlation between neutropenia and the risk of infection. Hematopoletic growth factors have been used successfully in the prevention and treatment of neutropenia. There is evidence to suggest that use of rHuG‐CSF before the onset of neutropenia allows patients to receive the maximum benefit; however, patients who do not receive rHuG‐CSF prophylactically still benefit from the use of rHuG‐CSF for the treatment of febrile neutropenia. These patients have an accelerated neutrophil recovery and a shorter duration of febrile neutropenia. These effects seem to translate into a significant reduction in the number of patients requiring prolonged hospitalization. This paper reviews the use of rHuG‐CSF in the treatment of febrile neutropenia and describes how it is routinely used by hematologists and oncologists in non‐clin
ISSN:1066-5099
DOI:10.1002/stem.5530120718
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
16. |
Future uses of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 229-240
Thomas C. Jones,
Preview
|
PDF (994KB)
|
|
摘要:
AbstractGranulocyte‐macrophage colony‐stimulating factor (GM‐CSF) has been used extensively to restore hematopoietic system function after damage by diseases such as myelodysplastic syndrome or by cytotoxic anti‐cancer agents used during cancer chemotherapy or prior to bone marrow transplantation. The clinical benefits of this approach have included fewer infections, fewer hospital days and less antibiotic use. In the future, the use of GM‐CSF will be focused on special situations within these general areas, plus new directions that were not previously given sufficient attention. Examples of focused approaches include the use of GM‐CSF in the control of fungal or protozoal disease and to take advantage of anti‐tumor effects of myeloid cell activation. The anti‐microbial effects will also be explored in patients who are not neutropenic but have serious infections which may be benefited by increased stimulation to myeloid cell function. The use will also be focused on mobilization of peripheral blood progenitor cells and in cycling of normal hematopoietic and malignant cells. The new directions will include use of GM‐CSF by local application in healing of cutaneous ulcers, rapid wound closure and skin grafting. Because of its potent effects on immunologic mechanisms of antigen presentation, it will be used in several ways as a vaccine adjuvant. This adjuvant action will be directed at enhancing immunologic responses to antimicrobial antigens and anti‐tumor antigens. The future of GM‐CSF as a tool for hematopoietic and immunologic stimulation with resulting important clini
ISSN:1066-5099
DOI:10.1002/stem.5530120719
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
17. |
Present and future clinical relevance of interleukin 3 |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 241-248
A. Gianella‐Borradori,
Preview
|
PDF (559KB)
|
|
摘要:
AbstractInterleukin 3 (IL‐3) is a hematopoietic growth factor with a pronounced thrombopoietic activity as well as a broad spectrum of activities on multipotent, committed and mature cells of different lineages. Available for clinical trials since 1989, IL‐3 has been used in well over two thousand patients. In numerous phase I‐II clinical trials, the tolerability profile and the various biologic activities have been defined, and ongoing phase III trials will finally establish its clinical relevance. Doses between 2.5 and 10 μg/kg/d given subcutaneously are well tolerated, cause low grade fever, occasional flu‐like symptoms and headache. At these doses IL‐3 enhances platelet and neutrophil recovery after cycles of myelotoxic chemotherapy, resulting in better adherence to the planned chemotherapy doses and schedules and a decrease in the need for platelet transfusions. Accelerated engraftment of platelets and neutrophils is seen with IL‐3 also after bone marrow transplantation. The effect on neutrophil recovery can be enhanced by the use of a myeloid growth factor such as granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) or granulocyte (G)‐CSF after five to 10 days of IL‐3. Treatment enhancement is related to the effect of IL‐3 on the proliferation of hematopoietic progenitors, which leads to an increase in target cells for GM‐ or G‐CSF. Because of the increase in bone marrow proliferation, IL‐3 is being used to increase the mobilization of progenitor cells to the blood and in bone marrow failure.All data derived from phase 1‐11 studies so far indicate that IL‐3 alone or in combination with other cytokines is likely to become the first thrombopoietic factor available for clinical use and that it will allow cancer patients to receive standard chemotherapy at the scheduled intervals and planned doses and to intensify treatment where a higher dose is
expect
ISSN:1066-5099
DOI:10.1002/stem.5530120720
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
18. |
The present and future of hematopoietic cytokines in clinical practice |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 249-255
Martine J. George,
Preview
|
PDF (441KB)
|
|
摘要:
AbstractHematologic toxicities can be a major problem in the delivery of some chemotherapy regimens. The way clinicians manage myelosuppression has evolved from a symptomatic approach to the use of cytokines to ameliorate or prevent anemia and neutropenia. Soon, new cytokines will be commercially available to manage thrombocytopenia. Cytokines are transforming oncology by permitting dose intensification through delivery of chemotherapy at the full dose and on time, as well as permitting highdose chemotherapy. Clinical trials are also exploring the benefits of cytokines for myeloablative chemotherapy with cellular support (bone marrow transplantation or peripheral blood progenitor cell transplantation). Future applications of cytokines include ex vivo expansion and gene transfer therapy. For cancer patients, the ability to receive intensive doses of chemotherapy might mean improved survival rates.
ISSN:1066-5099
DOI:10.1002/stem.5530120721
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
19. |
Implications of the polyfunctionality of hemopoietic regulators |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 259-275
Donald Metcalf,
Preview
|
PDF (1239KB)
|
|
摘要:
AbstractStudies on the expanding group of hemopoietic regulators have identified several types of situations indicating the polyfunctionality of these regulators. In actions on hemopoietic populations, this polyfunctionality is seen in cross‐lineage actions, in proliferative actions on cells at multiple stages within a lineage and, above all, in actions that do not simply control cell proliferation but also aspects of differentiation commitment, maturation and the functional activity of mature cells.More perplexing are the growing lists of actions on non‐hemopoietic tissues, seen in extreme form with the leukemia inhibitory factor group of regulators. The bizarre range of actions exhibited by regulators of this group is difficult to explain but may be indicating the unsuspected existence of some novel integrated bioorgan syst
ISSN:1066-5099
DOI:10.1002/stem.5530120722
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
20. |
“The forum” |
|
STEM CELLS,
Volume 12,
Issue S1,
1994,
Page 277-287
Donald Metcalf,
Preview
|
PDF (937KB)
|
|
ISSN:1066-5099
DOI:10.1002/stem.5530120723
出版商:John Wiley&Sons, Ltd.
年代:1994
数据来源: WILEY
|
|