[25 years allogenic bone marrow transplantation in Basel: 1973-1998].
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Bone Marrow Transplantation↗
Biomedical subjects
J Sartorius
Publications and source records attributed to J Sartorius.
NMR-titrations with complexes between ds-DNA and indole derivatives including tryptophane containing peptides.
It is shown that NMR titrations can be used on a quantitative basis to derive binding constants and binding modes of ds-DNA ligand complexes from several signals. The results are partially at variance with literature conclusions; they can be interpreted by additive and independent contributions of electrostatic interactions between DNA phosphate and ammonium centers in the side chain of the ligands, and of very weak stacking contributions of the indole rings. While gramine and tryptamine are found to intercalate, tryptophane-containing peptides do so only, if the tryptophane is flanked by at least two lysine units.
Alkaloids↗
A model of the lac repressor-operator complex based on physical and genetic data.
Computer graphics were used to build a molecular model of the complex of Lac repressor and lac operator. The model is based (a) on the NMR data of the Kaptein group [Boelens, R., Lamerichs, R. M. J. N., Rullmann, J. A. C., van Boom, J. H. & Kaptein, R. (1988) Protein Sequence Data Anal. 1, 487-498] and (b) on our genetic and biochemical data including specificity changes [Lehming, N., Sartorius, J., Kisters-Woike, B., von Wilcken-Bergmann, B. & Müller-Hill, B. (1990) EMBO J. 9, 615-621]. Effects of amino acid exchanges in the recognition helix could be predicted by the model and were subsequently tested and confirmed by genetic experiments. Comparison of the modelled lac complex with the known crystallographic structures of several helix-turn-helix DNA complexes reveals striking similarities and suggests rules which govern the recognition between particular amino acid side chains and particular base pairs in these systems.
Amino Acid Sequence↗
The roles of residues 5 and 9 of the recognition helix of Lac repressor in lac operator binding.
We constructed expression libraries for Lac repressor mutants with amino acid exchanges in positions 1, 2, 5 and 9 of the recognition helix. We then analysed the interactions of residues 5 and 9 with operator variants bearing single or multiple symmetric base-pair exchanges in positions 3, 4 and 5 of the ideal fully symmetric lac operator. We isolated 37 independent Lac repressor mutants with five different amino acids in position 5 of the recognition helix that exhibit a strong preference for particular residues in position 2 and, to a lesser extent, in position 1 of the recognition helix. Our results suggest that residue 5 of the recognition helix (serine 21) contributes to the specific recognition of base-pair 4 of the lac operator. They further suggest that residue 9 of the recognition helix (asparagine 25) interacts non-specifically with a phosphate of the DNA backbone, possibly between base-pairs 2 and 3.
Amino Acid Sequence↗
Mutant lac repressors with new specificities hint at rules for protein--DNA recognition.
Proteins which recognize specific sequences of DNA play a fundamental role in the regulation of protein synthesis in all organisms. A particular helix of the bacterial protein lac repressor recognizes the bases in the major groove of the lac operator. We show that the first two residues of this recognition helix interact independently with two base pairs. This allows us in many cases to predict repression as an indicator of strength of the repressor-operator complex. Rules of recognition can be derived for 16 symmetric operators. They also apply to the gal repressor and possibly to other bacterial repressors.
Amino Acid Sequence↗
lac repressor mutants with double or triple exchanges in the recognition helix bind specifically to lac operator variants with multiple exchanges.
Several lac repressor mutants have been isolated which repress beta-galactosidase synthesis in Escherichia coli up to 200-fold. They do so by binding specifically to particular symmetrical lac Oc operator variants. The mutations in the lac repressor are localized in two separate parts of the recognition helix comprising (i) residues 1 and 2 which interact with base pairs 4 and 5 of lac operator and (ii) residue 6 which recognizes operator base pair 6. Mutations of residues 1 and 2 may be combined with a mutation of residue 6. The resulting mutant protein binds specifically to an operator variant with three symmetric exchanges in base pairs 4, 5 and 6.
Base Sequence↗
Recognition helices of lac and lambda repressor are oriented in opposite directions and recognize similar DNA sequences.
Exchanges in positions 1 and 2 of the putative recognition helix allow lac repressor to bind to ideal lac operator variants in which base pair 4 has been replaced. We show here that an Arg-22----Asn exchange in position 6 of the putative recognition helix of lac repressor abolishes lac repressor binding to ideal lac operator. This lac repressor variant, however, binds to a variant of the ideal lac operator 5' TTTGAGCGCTCAAA 3' in which the original G.C of position 6 has been replaced by T.A. This result and our previous data confirm our suggestion that the N terminus of the recognition helix of lac repressor enters the major groove close to the center of symmetry of lac operator and that its C terminus leaves the major groove further away from the center of symmetry. The consequences of this model are discussed in regard to various phage and bacterial repressor operator systems.
Base Sequence↗
The interaction of the recognition helix of lac repressor with lac operator.
We have constructed a system which allows systematic testing of repressor--operator interactions. The system consists of two plasmids. One of them carries a lac operon in which lac operator has been replaced by a unique restriction site into which synthetic operators can be cloned. The other plasmid carries the gene coding for the repressor, in our case a semisynthetic lacI gene of which parts can be exchanged in a cassette-like manner. A galE host allows us to select for mutants which express repressors with altered specificities. Here we report the change of specificity in the lac system by changing residues 1 and 2 of the recognition helix of lac repressor. The specificity changes are brought about cooperatively by the change of both residues. Exchanges of just one residue broaden the specificity. Our results hint that the recognition helix of lac repressor may possibly have the opposite orientation to those in Lambda cro protein or 434 CI repressor.
Amino Acid Sequence↗
A synthetic operon containing 14 bovine pancreatic trypsin inhibitor genes is expressed in E. coli.
A synthetic gene encoding the protein sequence of mature bovine pancreatic trypsin inhibitor (BPTI) has been cloned into a novel E. coli expression vector. After in vitro gene amplification by successive DNA duplications, more than 600 000 mostly inactive inhibitor molecules may be recovered from a single cell. After purification the inhibitory activity can be reconstituted almost completely. The specificity of BPTI for trypsin is abolished by a single amino acid exchange from lysine to isoleucine at position 15. The altered protein is shown to be an efficient inhibitor of human leukocyte elastase.
Amino Acid Sequence↗
[Chance of a second remission in acute juvenile lymphoblastic leukemia with favorable prognosis].
24 children with low risk acute lymphoblastic leukemia (ALL) in first relapse were re-treated with an aggressive protocol. Therapy of the first episode had adopted two different but equivalent approaches (SAKK-ALL "low risk" 76 and CALGB protocol 7611). With one exception, relapse occurred in all children before discontinuation of therapy. complete remission was achieved in 20 of the 24 children (83%). Five of 11 children in whom the length of the second remission could be evaluated had, at the time of the cutoff, been in continuous remission for 18 to 40 months. The therapy displayed considerable toxicity. From this study it is concluded that remission is achieved in the majority of children with first relapse of ALL, but that the remission can be maintained beyond 18 months only in a few children.
Adolescent↗
[Therapy of juvenile disseminated histiocytosis X. First results of a prospective study at the pediatric section of the Swiss Work Group for Clinical Cancer Research (SAKK)].
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Child↗
[Progress in bone marrow transplantation in acute leukemia and aplastic anemia].
Experience with 17 allogeneic bone marrow transplantation (BMT) patients with refractory acute leukemia is reported. The authors show that it is extremely difficult to cure patients with end stage disease by this procedure. Based on experience that, if performed early, BMT can bring about over 50% potential cures, it is postulated that marrow grafts should be performed much earlier than is done at present. From the results in 45 patients with severe aplastic anemia it is concluded that the majority do not have a defect at the pluripotent stem cell itself. There is disturbed maturation to functional end cells which can be corrected in most instances by ALG, infusion of allogeneic marrow and low dose androgens. BMT between HLA-identical siblings need not cause major problems, but it involves a considerable risk of fatal complications such as irreversible marrow rejection and GvH.
Acute Disease↗
[Immunosuppression, bone marrow infusion and low dose androgens, successful therapy of severe aplastic anemia].
18 patients with severe aplastic anemia (SAA) but without an HLA-identical sibling were treated by antilymphocyte globulin (ALG) followed by infusion of marrow cells from a semi-compatible family donor. 13 of these received low dose androgens after ALG: 11 (85%) achieved stable remission without transfusion requirement. One patient relapsed after 4 months, one patient with only partial remission died from infection. None of the 4 patients who did not receive androgens after ALG achieved remission. ALG, marrow and low-dose androgens represent a promising therapy for SAA and can be favorably compared with allogeneic bone marrow transplantation.
Adolescent↗
[Malignat non-Hodgkin Lymphoma in childhood. Therapeutic results in 47 patients].
A preliminary report is presented on survival in 16 children with non-Hodgkin's lymphoma treated since 1975, as compared with that in 31 similar children treated between 1962 and 1974. In the former group, 10 of 14 children (71%) survived one or more years and 5 of 9 children (56%) two or more years with no evidence of disease. In the latter group, the corresponding survival rates were 26% and 19% respectively. This improvement is due to the introduction of an aggressive multidrug chemotherapy combined with radiotherapy, similar to the LSA2-L2 protocol. Considerable toxicity was observed with the new treatment. 23 of the 46 patients with diffuse non-Hodgkin's lymphoma had a Burkitt-type tumor. Treatment failures occurred mainly in children with a Burkitt-type tumor with primary intraabdominal localization.
Adolescent↗
[Bone marrow transplantation in severe aplastic anemia and acute leukemia].
Much progress has been made in allogeneic bone marrow transplantation for severe aplastic anemia (SAA) and acute leukemia (AL). In SAA it was shown that hemopoietic chimerism and apparently permanent cures can be achieved in the majority of patients by conditioning with cyclophosphamide followed by bone marrow transplantation (BMT) from an HLA-identical sibling. The previous transfusion history is crucial for failure or success: untransfused patients do very well while graft rejection is an enormous problem in most polytransfused ones. We have shown that most patients without HLA-identical sibling donors can be adequately helped as well. After conditioning with ALG followed by transfusion of haploidentical marrow and low dose androgens there is partial to complete autologous hemopoietic reconstitution in virtually all patients. This points to the fact that most of these patients have pluripotent hemopoietic stem cells that are intact, but apparently unable to differentiate to mature cells, because they are inhibited by autoimmune mechanisms. The results of BMT in patients with endstage leukemia are modest. New pilotstudies with early marrow grafts, i.e. for ANLL in first remission and for ALL in second remission indicate that with this type of approach potentially over 50% of all patients with HLA-identical siblings can be cured. We recommend that HLA-typing should be performed early in families with SAA and AL and that the possibility of a marrow graft should be seriously considered before the patients have endstage disease. Marrow grafts are technically simple but they may pose enormous problems such as graft versus host reaction (GvH), interstitial pneumonia, graft rejection and leukemic recurrence. Therefore, the procedure should only be performed in highly specialized centers with much knowledge and experience in the immunobiology of bone marrow transplantation.
Acute Disease↗
The Basel experience with total body irradiation for conditioning patients with acute leukemia for allogeneic bone marrow transplantation.
We are reporting our experience with 13 patients suffering from end stage acute leukemia that were prepared for allogeneic bone marrow transplantation by combined chemotherapy followed by high dose cyclophosphamide (Cy) and total body irradiation (TBI). Only one patient became a long term survivor. Of the evaluable 12 patients, 6 died of interstitial pneumonia, 4 of GvH and 1 of recurrent leukemia. We conclude that adding combined chemotherapy to the standard conditioning program with Cy and TBI probably increases the risk of developing fatal interstitial pneumonia without eliminating the risk of recurrent leukemia. We suggest that allogenic marrow grafts should be performed earlier in the course of refractory acute leukemias, because in patients with end stage disease its chances of being curative are small.
Adolescent↗
[Synovectomy and synoviorthesis in hemophiliae (author's transl)].
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Adolescent↗
[Optimal care of the oncologic patient: a question of organization].
The rapid development of oncology as a subspecialty in internal medicine presents a dilemma for the specialist and the private practitioner. How can one offer the best technical and scientific care which often requires an institutional setting for its delivery and at the same time maintain a continuous meaningful relationship with a primary care physician? The outpatient clinic of the oncology center of the Basle University clinics as a paragon for the patient care in these changing times may represent one of several possible solutions to this contemporary dilemma.
Ambulatory Care↗