Biomedical subjects

L Sachs

Publications and source records attributed to L Sachs.

At least 109 records · Page 6Linked to original sources

PubMed1989

Cell differentiation and tumour suppression.

Identification of growth and differentiation-inducing proteins and how they interact in normal development has made it possible to identify the molecular basis of normal development and the mechanisms that uncouple growth and differentiation so as to produce malignant cells. When normal cells have been changed into cancer cells, the malignant phenotype can again be suppressed. Results on the molecular control of growth and differentiation in normal myeloid haemopoietic cells, changes in the normal developmental programme in myeloid leukaemia, and the suppression of malignancy in myeloid leukaemia and sarcomas have shown that (1) malignancy can be suppressed either with or without genetic changes in the malignant cells, (2) suppression of malignancy by inducing differentiation does not have to restore all the normal controls, and (3) genetic abnormalities which give rise to malignancy can be bypassed and their effects nullified by inducing differentiation which stops cells from multiplying.

Animals↗

PubMed1989

Effect of smokeless tobacco on the development of the CD-1 mouse fetus.

The objective of this study was to examine the effect of an aqueous extract of smokeless tobacco (ST) on the development of the CD-1 mouse fetus. Three ST dosages were administered three times daily by gastric intubation during gestational days 1-17: 1 X ST equivalent to a dose of 4 mg nicotine/kg body weight, 3 X ST equivalent to 12 mg nicotine, and 5 X ST equivalent to 20 mg nicotine/kg body weight. Maternal plasma nicotine levels were determined 30 minutes after the second daily intubation at five different times during the gestational period. At these ST dosages, the weight gain of ST-treated dams was not significantly affected in comparison to treated controls, though the difference was significant (P less than .05) in comparison to untreated controls. The mean maternal plasma nicotine level for the low dosage (1 X) group was 99.0 ng/ml, which reasonably approximates human consumption levels. The 3 X ST and 5 X ST dosages produced higher nicotine plasma values, 398 ng/ml and 623 ng/ml, respectively, were considerably more toxic to the dams, and resulted in 18% and 31% maternal deaths. Fetal weights were reduced by 7.4% (P less than .001) in the highest ST dosage group (5 X), whereas at the 1 X and 3 X dosages fetal weight differences were not significantly different from treated controls. Resorptions increased in a dose-related manner (P less than .05), ranging from 4.7% in the 1 X, to 6.4% in the 3 X and 8.9% in the 5 X dosage compared to 3.2% in treated controls. External malformations were few and minor in extent. Internal malformations increased in a linear, dose-related manner (P less than .05). Placental weights were unaffected by ST. The results of skeletal examinations were inconclusive. Precocious ossification was seen in 60% and 70% of the parameters measured in the 1 X and 3 X dosage groups, respectively, in comparison to controls. In the 5 X ST group ossification levels were less than in controls for 30% of the parameters measured. Under these experimental conditions the lowest ST dosage (1 X) produced a negligible effect on the CD-1 mouse fetus and the dam. The highest ST dose (5 X) demonstrated embryotoxicity, growth retardation, few malformations, and maternal toxicity. The intermediate dose (3 X) showed a range of effects between the highest and lowest doses to both the fetus and the dam.

Abnormalities, Drug-Induced↗

PubMed1989

Misunderstanding as therapy: doctors, patients and medicines in a rural clinic in Sri Lanka.

In this paper I want to draw attention to the integration of Western medicine into therapeutic choices among patients in rural Sri Lanka. These patients' interpretation and use of Western pharmaceuticals is discussed in relation to the Ayurvedic theory of balance. The influence of this theory on people's ideas of health and illness is highlighted in encounters where laymen and professionals alike use Western medicines according to context and their respective perspectives. Such therapeutic encounters are used to describe how the meaning of therapy is negotiated and communicated. The modes of perception used by doctors and patients seem to be mutually exclusive but each has its own logic. Western medicines are used as a symbolic means which help the patients and the practitioners of Western clinical medicine in a rural health unit to communicate through - rather than despite - "misunderstandings" based on their differing cultural assumptions about the body, about disease and about therapy. This argument is raised in relation to recent theoretical discussions among medical anthropologists concerning doctor-patient relationships, asymmetric medical relations and the analysis of meaning systems.

Attitude of Health Personnel↗

PubMed1989

Indirect induction of differentiation of normal and leukemic myeloid cells by recombinant interleukin 1.

Different clones of myeloid leukemic cells can be induced to differentiate to mature macrophages or granulocytes by different normal hematopoietic regulatory proteins. The present experiments with recombinant IL-1 alpha and recombinant IL-1 beta show that, (a) that there are clones of myeloid leukemic cells which can be induced to differentiate to mature cells by the myeloid cell differentiation-inducing protein MGI-2 and can also be induced to differentiate to mature macrophages and granulocytes by both types of IL-1; (b) this IL-1-induced differentiation is mediated by endogenous production of differentiation-inducing protein MGI-2; (c) IL-1 and MGI-2 induce production of GM-CSF in these leukemic cells; and (d) IL-1 also induces cell differentiation and production of MGI-2 and GM-CSF in normal myeloid precursor cells. The results indicate that IL-1 induces differentiation indirectly.

Animals↗

PubMed1989

The molecular control of normal and leukemic hematopoiesis: myeloid cells as a model system.

The establishment of a cell culture system for the clonal development of hematopoietic cells has made it possible to identify the proteins that control growth and differentiation of different hematopoietic cell lineages and to discover the molecular basis of normal and abnormal cell development in blood-forming tissues. A model system with myeloid cells has shown that normal hematopoietic cells require different proteins to induce cell multiplication and cell differentiation and that a cascade of interactions between proteins determines the correct balance between immature and mature cells in normal development. Gene cloning has shown that there is a family of different genes for these proteins. Normal protein regulators of hematopoiesis can control the abnormal growth of certain types of leukemic cells and suppress malignancy by inducing differentiation to mature non-dividing cells, and there are different pathways of inducing differentiation. Results from studies on the molecular control of growth and differentiation in normal myeloid hematopoietic cells, on changes in the normal developmental program, and on the suppression of malignancy in myeloid leukemia have shown that (a) malignancy can be suppressed by inducing differentiation either with or without genetic changes in the malignant cells, (b) this suppression of malignancy does not have to restore all the normal controls, and (c) genetic abnormalities that give rise to malignancy, which include changes in homeobox genes, can be bypassed and their effects nullified by inducing differentiation that stops cells from multiplying.

Bone Marrow↗

PubMed1989

The molecular regulators of macrophage and granulocyte development. Role of MGI-2/IL-6.

The development of a cell culture system for the in vitro cloning and clonal differentiation of normal hematopoietic cells made it possible to identify the proteins that regulate growth and differentiation of different hematopoietic cell lineages and the change in normal controls that produce leukemia. A model system with myeloid cells has identified different myeloid cell colony-inducing proteins, which we called MGI-1 (= CSF, including IL-3). There is another protein that we first described in 1976 and called MGI-2 in 1980 that induces differentiation of myeloid cells to macrophages or granulocytes without inducing the clonal growth of myeloid cells. The four CSF proteins and IL-1 induce the production of MGI-2 in myeloid cells and MGI-2 induces the production of GM-CSF. This shows the participation of MGI-2 in the network of interactions with different myeloid regulatory proteins. Using a monoclonal antibody to MGI-2, amino acid sequencing, and recombinant protein, we have shown in collaboration with the Genetics Institute that the major form of MGI-2 (MGI-2A) is IL-6. This shows that IL-6 is a myeloid cell differentiation inducing protein. The results also suggest new clinical potentials for MGI-2/IL-6.

Amino Acid Sequence↗

PubMed1989

Autoregulation of interleukin 6 and granulocyte-macrophage colony-stimulating factor in the differentiation of myeloid leukemic cells.

Induction of differentiation in one type of clone of mouse myeloid leukemic cells by mouse or human interleukin 6 (IL-6) and in another type of clone by mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to be associated with induction of IL-6 and GM-CSF mRNA and protein. The results indicated that IL-6 and GM-CSF could positively autoregulate their own gene expression during myeloid cell differentiation. It is suggested that this autoregulation may serve to enhance and prolong the signal induced by these proteins in cells transiently exposed to IL-6 or GM-CSF.

Animals↗

PubMed1989

Clonal variation in susceptibility to differentiation by different protein inducers in the myeloid leukemia cell line M1.

Differentiation-competent clones of myeloid leukemic cells, independently isolated from the M1 cell line in Rehovot, Israel, and in Saitama, Japan, can be induced to differentiate to mature cells by the protein which we called macrophage and granulocyte differentiation-inducing protein-2 (MGI-2) that we have shown is interleukin 6 (IL-6). We now show that our MGI-2/IL-6-susceptible clones of M1 cells were not induced to differentiate with the differentiation-inducing protein called D-factor/leukemia inhibitory factor (LIF) which has also been called human interleukin for DA cells (HILDA), whereas this protein induced differentiation to macrophages in the M1 clone isolated in Saitama which was also used in Melbourne, Australia, The D-factor/LIF susceptible clone also showed a 4-fold lower sensitivity to MGI-2/IL-6 than the D-factor/LIF resistant clone. Both types of clones differentiated with interleukin-1 alpha (IL-1 alpha) and dexamethasone, whereas the D-factor/LIF resistant clone, but not the D-factor/LIF susceptible clone, was induced by bacterial lipopolysaccharide (LPS) to differentiate to mature macrophages. The present results show that clonal differences in susceptibility to differentiation-inducing proteins in the M1 cell line can explain the isolation of different differentiation-inducing proteins in M1 leukemic cells in different laboratories.

Cell Differentiation↗

PubMed1989

Regulation of the genes for interleukin-6 and granulocyte-macrophage colony stimulating factor by different inducers of differentiation in myeloid leukemic cells.

Different clones of myeloid leukemic cells can be induced to differentiate to mature macrophages and/or granulocytes by hematopoietic regulatory proteins and by other compounds. We now show that induction of differentiation in different clones of myeloid leukemic cells with the normal hematopoietic proteins granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), or interleukin 3 and by compounds such as dexamethasone or cytosine arabinoside (ara C) induces the expression of genes for the myeloid differentiation inducing protein MGI-2 that we have shown is interleukin 6 (IL-6) and for GM-CSF. We have previously shown that induction of differentiation with interleukin-1, IL-6, or bacterial lipopolysaccharide (LPS) also induces IL-6 and GM-CSF gene expression. Treatment of these leukemic clones with hematopoietic proteins that do not induce differentiation did not induce IL-6 or GM-CSF gene expression. The results indicate that induction of IL-6 and GM-CSF gene expression is part of the normal differentiation program in myeloid cells and support our previous evidence that there is transregulation of gene expression between different hematopoietic regulatory proteins.

Cell Differentiation↗

PubMed1989

Regulation of megakaryocyte development by interleukin-6.

Megakaryocytes develop in densely seeded normal mouse bone marrow (BM) cells cultured in agar or in liquid medium. This formation of megakaryocytes is enhanced by the myeloid differentiation-inducing protein MGI-2, which we have shown to be interleukin-6 (IL-6). Monoclonal antibody (MoAb) that specifically neutralizes mouse IL-6 but not human IL-6 inhibited megakaryocyte development in cells cultured either with or without the addition of mouse IL-6 but did not inhibit megakaryocyte development induced by human IL-6. This MoAb to mouse IL-6 that does not neutralize mouse IL-3 also inhibited mouse IL-3-induced megakaryocyte development. Antibody to mouse GM-CSF did not inhibit the formation of megakaryocytes. The results show that the induction of megakaryocyte development by IL-3 is due to the production of IL-6 in the BM cultures. The present experiments demonstrate a new property of IL-6 and indicate that IL-6 is a regulatory protein of normal megakaryocyte development.

Animals↗

PubMed1988

DNA rearrangement of a homeobox gene in myeloid leukaemic cells.

A homeobox gene rearrangement has been detected in WEHI-3B mouse myeloid leukaemic cells. The rearranged gene was identified as Hox-2.4 which is a member of the Hox-2 gene cluster on mouse chromosome 11. Both the normal and the rearranged genes were cloned and analysed, and the rearranged genomic Hox-2.4 gene was sequenced. The results indicate that the rearrangement is due to insertion of an intracisternal A particle 5' upstream to Hox-2.4 and that this resulted in constitutive expression of the homeobox gene. It is suggested that constitutive expression of the homeobox gene may interrupt the normal development program in these leukaemic cells.

Amino Acid Sequence↗

PubMed1988

Deletion of a homeobox gene in myeloid leukemias with a deletion in chromosome 2.

Mouse myeloid leukemias are characterized by a frequent deletion in one chromosome number 2. We now show that there is a deletion of one copy of the Hox-4.1 homeobox gene in the myeloid leukemias with this deletion in chromosome 2. It is suggested that deletion of this homeobox gene plays a role in determining the abnormal developmental program in myeloid leukemia.

Animals↗

PubMed1988

Target-cell specificity of hematopoietic regulatory proteins for different clones of myeloid leukemic cells: two regulators secreted by Krebs carcinoma cells.

The normal myeloid hematopoietic regulatory proteins include one class of proteins that induces viability and multiplication of normal myeloid precursor cells to form colonies (called MGI-1 = CSF or IL-3) and another class (called MGI-2 = DF) that induces differentiation of normal myeloid precursors without inducing cell multiplication. Different clones of myeloid leukemia cells can differ in their response to these regulatory proteins. The present experiments characterize proteins secreted by Krebs ascites carcinoma cells that induce differentiation of 2 different types of myeloid leukemic cell clones (clones II and 7-M12). The results indicate the following: (1) Krebs cells produce 2 distinct and separable proteins, each inducing differentiation in one of the leukemic clones. (2) One protein induced differentiation of clone-II myeloid leukemic cells and of normal myeloid precursor cells was free of any colony-inducing (MGI-1 = CSF or IL-3) activity, bound to double-stranded mammalian DNA, and was thus a differentiation-inducing protein MGI-2. This MGI-2 protein (MGI-2A) was purified to a single silver-stained band on an SDS polyacrylamide gel. (3) The other protein induced differentiation of clone 7-M12 myeloid leukemic cells, did not bind to double-stranded DNA and could not be separated from the myeloid growth-inducing protein MGI-1GM (GM-CSF) after 6 steps of purification including high-pressure liquid chromatography. The use of specific antisera confirmed that the protein which induced differentiation of clone 7-M12 leukemic cells was MGI-1 GM. The results show that Krebs ascites tumor cells produce 2 different myeloid hematopoietic regulatory proteins that differ in their target specificity for different clones of myeloid leukemic cells.

Animals↗

PubMed1988

Role of different normal hematopoietic regulatory proteins in the differentiation of myeloid leukemic cells.

There are 4 different normal myeloid hematopoietic cell growth-inducing proteins MGI-1 (CSF or IL-3) that induce normal precursor cells to multiply and form clones containing only macrophages (MGI-1M = M-CSF = CSF-1), only granulocytes (MGI-1G = G-CSF), both granulocytes and macrophages (MGI-1GM = GM-CSF), or granulocytes, macrophages, eosinophils, mast cells, megakaryocytes and erythroid cells (interleukin-3) (IL-3). There is another type of normal myeloid regulatory protein (MGI-2) with no MGI-1 (CSF or IL-3) activity which can induce differentiation of normal myeloid precursors and certain clones of myeloid leukemic cells. The present results with MGI-2 and pure recombinant MGI-1G, MGI-1GM and IL-3 have shown that different clones of myeloid leukemic cells can be induced to differentiate by different hematopoietic regulatory proteins. One type of leukemic clone is induced to differentiate to mature cells only by MGI-2 and is partially differentiated by MGI-1G, a second type is differentiated only by MGI-1GM or IL-3, and other workers have found a third type that is differentiated only by MGI-1G. The presence of surface receptors does not necessarily make leukemic cells differentiation-competent for these hematopoietic regulatory proteins. All 4 types of MGI-1 (CSF or IL-3) induce endogenous synthesis of MGI-2 in normal myeloid precursor cells. It is suggested that, in addition to their potential therapeutic effect on the development of normal hematopoietic cells, MGI-2, MGI-1G, MGI-1GM and IL-3 all have the potential for differentiation-directed therapy of leukemia in leukemic cells that can be differentiated by one of these normal hematopoietic regulatory proteins.

Animals↗

PubMed1988

Effect of smokeless tobacco on the development of the CD-1 mouse fetus.

The objective of this study was to examine the effect of smokeless tobacco (ST) on the development of the CD-1 mouse fetus. ST was administered continuously via Alzet osmotic minipumps during the critical gestational days 7-14 and 6-13. Two ST dosages were administered, 3.2 mg/ml (Dosage I) and 6.4 mg/ml (Dosage II), which yielded plasma nicotine levels within the range comparable to those of an average ST user or smoker (36.0 ng/ml). Plasma nicotine levels were maintained in the range of 29.4 +/- 4.8 ng/ml to 44.3 +/- 16.0 ng/ml for the Dosage I group of dams, and in the range of 34.6 +/- 10.9 ng/ml of 75.5 +/- 19.9 ng/ml for the Dosage II group of dams. The main effect on the fetus was weight reduction, with Dosage I producing a tendency toward weight reduction (p = .08). Dosage II produced a significant 8.6% weight reduction from normal (p less than .0001) and an increase in fetal deaths (p less than .03). Dosage I produced an increase in the incidence of hemorrhages and supernumerary ribs, and a significant delay (p less than .05) in ossification of the supraoccipital bone, the sacrococcygeal vertebrae, and the bones of the forefoot and hindfoot. There were no significant differences between placental weights. Weights of dams were significantly reduced only at the higher ST exposure levels. We conclude that at plasma nicotine levels comparable to those of an average ST user, ST produces weight reduction, delayed ossification, and increase in hemorrhages and fetolethality in the CD-1 mouse fetus.

Animals↗

PubMed1988

The impact of subspecialties on obstetrics and gynecology.

The role of subspecialties in obstetrics and gynecology was evaluated by a mail questionnaire to department chairpersons, members of the American Gynecological and Obstetrical Society, nonuniversity directors of obstetrics and gynecology residency programs, and others. Results from the questionnaire were evaluated by conventional statistical methods. The issues identified included subspecialties and the further development of our specialty in role modeling, enhanced education for both residents and students, and the recruitment of a higher-quality resident for our specialty. Additional issues included: Were subspecialties a mistake, and have they fragmented our specialty? Some of the results include the following: (1) More than 90% of respondents agree that subspecialties have helped in the development of obstetrics and gynecology. (2) The subspecialties have enhanced our image in medical schools (88%) and in the community hospitals (77%). (3) The education of medical students (73%) and of residents (86%) has been enhanced by the development of subspecialties. (4) As predicted, the subspecialties have fragmented our specialty (69%), but patient care has not suffered. (5) Disagreement is noted between chairpersons and other respondents that a higher-quality resident is going into subspecialties, but all agreed that the improved quality of residents was due to the development of subspecialties. (6) Only 10% of respondents wished subspecialties had never been developed as contrasted to 82% of all respondents who felt they were commendable. (7) If another subspecialty area is to be identified, more respondents prefer reproductive urology than the next two areas combined.

Attitude of Health Personnel↗

PubMed1988

In vivo control of differentiation of myeloid leukemic cells by recombinant granulocyte-macrophage colony-stimulating factor and interleukin 3.

The normal myeloid hematopoietic regulatory proteins include one class of proteins that induces viability and multiplication of normal myeloid precursor cells to form colonies (colony-stimulating factors [CSF] and interleukin 3 [IL-3], macrophage and granulocyte inducing proteins, type 7 [MGI-1]) and another class (called MGI-2) that induces differentiation of normal myeloid precursors without inducing cell multiplication. Different clones of myeloid leukemic cells can differ in their response to these regulatory proteins. One type of leukemic clone can be differentiated in vitro to mature cells by incubating with the growth-inducing proteins granulocyte-macrophage (GM) CSF or IL-3, and another type of clone can be differentiated in vitro to mature cells by the differentiation-inducing protein MGI-2. We have now studied the ability of different myeloid regulatory proteins to induce the in vivo differentiation of these different types of mouse myeloid leukemic clones in normal and cyclophosphamide-treated mice. The results show that in both types of mice (a) the in vitro GM-CSF- and IL-3-sensitive leukemic cells were induced to differentiate to mature cells in vivo in mice injected with pure recombinant GM-CSF and IL-3 but not with G-CSF, M-CSF, or MGI-2; (b) the in vitro MGI-2-sensitive leukemic cells differentiated in vivo by injection of MGI-2 and also, presumably indirectly, by GM-CSF and IL-3 but not by M-CSF or G-CSF; (c) in vivo induced differentiation of the leukemic cells was associated with a 20- to 60-fold decrease in the number of blast cells; and (d) all the injected myeloid regulatory proteins stimulated the normal myelopoietic system. Different normal myeloid regulatory proteins can thus induce in vivo terminal differentiation of leukemic cells, and it is suggested that these proteins can have a therapeutic potential for myeloid leukemia in addition to their therapeutic potential in stimulating normal hematopoiesis.

Animals↗

PubMed1988

Inhibition of differentiation and affinity purification with a monoclonal antibody to a myeloid cell differentiation-inducing protein.

The normal myeloid hematopoietic regulatory proteins include four growth-inducing proteins called colony-stimulating factors (CSF), including interleukin-3 (IL-3), or macrophage and granulocyte inducers, type 1 (MGI-1), and another type of protein (MGI-2) with no myeloid cell growth-inducing activity that induces differentiation of normal myeloid precursor cells and certain clones of myeloid leukemic cells. An IgG2a monoclonal antibody was prepared and it neutralized two forms of MGI-2 (MGI-2A and MGI-2B) produced by mouse Krebs ascites tumor cells. The monoclonal antibody was used for affinity purification of MGI-2. This antibody also neutralized MGI-2 produced by normal mouse macrophages, normal myeloblasts incubated with IL-3, and MGI-2 produced by the lungs and found in the serum of mice injected with lipopolysaccharide (LPS). The anti-MGI-2 antibody did not inhibit the activity of any one of the four myeloid growth-inducing proteins (CSF or IL-3 = MGI-1), IL-1, tumor necrosis factor, or lymphotoxin. This antibody also inhibited induction of differentiation of myeloid leukemic cells by LPS, which is mediated by the endogenous production of MGI-2, but did not inhibit induction of differentiation in these leukemic cells by dexamethasone or cytosine arabinoside, which is not mediated by MGI-2. Anti-MGI-2 antibody thus inhibited differentiation when MGI-2 was added externally to cells or when it was mediated by endogenously produced MGI-2.

Animals↗