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Biomedical subjects

L Sachs

Publications and source records attributed to L Sachs.

At least 19 recordsLinked to original sources
PubMed2006

Epigenetics and the plasticity of differentiation in normal and cancer stem cells.

Embryonic stem cells are characterized by their differentiation to all cell types during embryogenesis. In adult life, different tissues also have somatic stem cells, called adult stem cells, which in specific niches can undergo multipotent differentiation. The use of these adult stem cells has considerable therapeutic potential for the regeneration of damaged tissues. In both embryonic and adult stem cells, differentiation is controlled by epigenetic mechanisms, and the plasticity of differentiation in these cells is associated with transcription accessibility for genes expressed in different normal tissues. Abnormalities in genetic and/or epigenetic controls can lead to development of cancer, which is maintained by self-renewing cancer stem cells. Although the genetic abnormalities produce defects in growth and differentiation in cancer stem cells, these cells have not always lost the ability to undergo differentiation through epigenetic changes that by-pass the genomic abnormalities, thus creating the basis for differentiation therapy. Like normal stem cells, cancer stem cells can show plasticity for differentiation. This plasticity of cancer stem cells is also associated with transcription accessibility for genes that are normally expressed in different tissues, including tissues other than those from which the cancers originated. This broad transcription accessibility can also contribute to the behavior of cancer cells by overexpressing genes that promote cell viability, growth and metastasis.

Adult Stem Cells↗
PubMed2001

Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1.

The tumor suppressor gene wild-type p53 encodes a labile protein that accumulates in cells after different stress signals and can cause either growth arrest or apoptosis. One of the p53 target genes, p53-inducible gene 3 (PIG3), encodes a protein with significant homology to oxidoreductases, enzymes involved in cellular responses to oxidative stress and irradiation. This fact raised the possibility that cellular oxidation-reduction events controlled by such enzymes also may regulate the level of p53. Here we show that NADH quinone oxidoreductase 1 (NQO1) regulates p53 stability. The NQO1 inhibitor dicoumarol caused a reduction in the level of both endogenous and gamma-irradiation-induced p53 in HCT116 human colon carcinoma cells. This reduction was prevented by the proteasome inhibitors MG132 and lactacystin, suggesting enhanced p53 degradation in the presence of dicoumarol. Dicoumarol-induced degradation of p53 also was prevented in the presence of simian virus 40 large T antigen, which is known to bind and to stabilize p53. Cells overexpressing NQO1 were resistant to dicoumarol, and this finding indicates the direct involvement of NQO1 in p53 stabilization. NQO1 inhibition induced p53 degradation and blocked wild-type p53-mediated apoptosis in gamma-irradiated normal thymocytes and in M1 myeloid leukemic cells that overexpress wild-type p53. Dicoumarol also reduced the level of p53 in its mutant form in M1 cells. The results indicate that NQO1 plays an important role in regulating p53 functions by inhibiting its degradation.

Animals↗
PubMed2001

From a lived body to a medicalized body: diagnostic transformation and chronic fatigue syndrome.

This paper addresses the diagnostic dilemma posed by chronic illness that offers no demonstrable evidence of serious physical disorders or pathology. Is a diagnosis such as chronic fatigue syndrome (CFS) disabling because it encourages people to identify with it? Does it become a self-fulfilling prophecy? In providing people with a name, and thus allowing them to confirm the legitimacy of their suffering, a diagnosis of CFS may help them to relate to their world and, hence, facilitate their recovery. One of the most relevant questions pertaining to a diagnosis of CFS concerns how people deal with suffering when it does not come with a biomedically established pathology. I draw upon material provided by 21 men and women diagnosed with CFS. My analysis concerns the ambivalence involved in the diagnostic process and its implications for the relationship between self-identity and chronicity.

Adult↗
PubMed2001

Risk in numbers--difficulties in the transformation of genetic knowledge from research to people--the case of hereditary cancer.

Difficulties in communicating diagnostic information are exacerbated when the 'diagnosis' is a 'genetic risk' for cancer. The risk estimation demanded in this situation differs from other types of probability estimations. Observations of participants in 45 consultation sessions between physicians and potential patients were conducted at a clinic for hereditary cancer to explore the communication of genetic information. Thirty-three sessions were audiotaped, transcribed verbatim and analyzed, along with notes from the other sessions. A dominant theme was found to be numerical discussion of risk. Further analysis resulted in the description of problems for practitioners in the process of translating scientific knowledge into clinical management. Problems in providing information include unclear aims of the consultation sessions, mixing various types of background information and probabilities, recognizing how low the predictive values are, and difficulties in communicating the relationship between probability and conclusions. Problems in communicating information about the genetic risk for cancer are of at least two types: dilemmas arising from uncertainties implicit in the nature of the information itself and difficulties in communicating information in a manner that those concerned can interpret. These issues need clarification, so that information with far-reaching consequences can be made as clear and comprehensible as possible for those involved.

Adult↗
PubMed2000

[Interpreting messages from across knowledge boundaries in health care encounters].

Anthropological research into health issues may contribute to the discussion regarding doctor/patient communication and to understanding across knowledge boundaries. Anthropological studies in "other cultures" provide a mirror, and the question "Why are we doing what we are doing?" becomes relevant. Examples from research among immigrants in Swedish health care bring this question into focus. The relationship between scientific knowledge and lay knowledge is seen as problematical with regard not only to immigrants but also to any patient involved in today's preventive care, steeped as it is in rapid medical technological development. Scientific knowledge is recontextualized, interpreted and understood in all clinical situations. Research into this process is an urgent matter.

Anthropology, Cultural↗
PubMed2000

Targeting of N-CoR and histone deacetylase 3 by the oncoprotein v-erbA yields a chromatin infrastructure-dependent transcriptional repression pathway.

Transcriptional repression by nuclear hormone receptors is thought to result from a unison of targeting chromatin modification and disabling the basal transcriptional machinery. We used Xenopus oocytes to compare silencing effected by the thyroid hormone receptor (TR) and its mutated version, the oncoprotein v-ErbA, on partly and fully chromatinized TR-responsive templates in vivo. Repression by v-ErbA was not as efficient as that mediated by TR, was significantly more sensitive to histone deacetylase (HDAC) inhibitor treatment and, unlike TR, v-ErbA required mature chromatin to effect repression. We find that both v-ErbA and TR can recruit the corepressor N-CoR, but, in contrast to existing models, show a concomitant enrichment for HDAC3 that occurs without an association with Sin3, HDAC1/RPD3, Mi-2 or HDAC5. We propose a requirement for chromatin infrastructure in N-CoR/HDAC3-effected repression and suggest that the inability of v-ErbA to silence on partly chromatinized templates may stem from its impaired capacity to interfere with basal transcriptional machinery function. In support of this notion, we find v-ErbA to be less competent than TR for binding to TFIIB in vitro and in vivo.

Adenosine Triphosphatases↗
PubMed2000

Midwives' descriptions of their familiarity with cancer: a qualitative study of midwives working with population-based cervical cancer screening in urban Sweden.

Nurse-midwives are responsible for taking Papanicolaou (Pap) smears in Swedish population-based cervical cancer screening programs. A research project examining the screening program from the perspective of different stakeholders includes an interview study of 21 midwives working in Stockholm. This article explores the way the midwives describe cancer-related knowledge and aspects of screening, contrasting this with relevant findings from a substudy of 66 healthy women participating in screening. A semistructured interview guide with open-ended questions was used to investigate ideas about benefits and risks in the screening program, risk factors for cervical cancer, the reliability of the test itself, sources of information/knowledge relevant for cervical cancer screening, and the manner in which the midwife described her role in the screening program. The transcripts of the audiotaped interviews were analyzed thematically using a team approach. The interviewed midwives showed a great deal of consensus in their descriptions of lacking familiarity with cervical cancer and its prevention and treatment. The midwives said they lack recent education and knowledge, often avoiding use of the word "cancer" with women attending screening. It seems that the midwives experienced little professional guidance in discussing cancer-related issues with women attending the screening program. In this study, they appeared to rely on personal knowledge, values, and experience instead.

Adult↗
PubMed1999

Suppression or induction of apoptosis by opposing pathways downstream from calcium-activated calcineurin.

Ca(2+)-mobilizing compounds such as the Ca(2+) ionophore A23187 or the endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin can suppress or induce apoptosis in the same cells. The use of different calcineurin inhibitors has shown that both suppression and induction of apoptosis by the Ca(2+)-mobilizing compounds were mediated by calcineurin activation. Ca(2+)-mobilizing compounds activated p38 and p44/42 mitogen-activated protein kinases (MAPKs). Induction of apoptosis by the Ca(2+)-mobilizing compounds was suppressed by an inhibitor of p38 MAPK but not by an inhibitor of p44/42 MAPK. These MAPK inhibitors did not suppress apoptosis induction by wild-type p53 or by withdrawal of IL-6 from IL-6-dependent cells that are mediated by calcineurin-independent pathways. These MAPK inhibitors also did not affect the ability of Ca(2+)-mobilizing compounds to suppress apoptosis. The results indicate that (i) Ca(2+)- mobilizing compounds activate different and opposing pathways that diverge downstream from calcineurin activation that can either suppress or induce apoptosis in the same cells; (ii) p38 MAPK but not p44/42 MAPK is involved in induction of apoptosis but not in its suppression by the Ca(2+)-mobilizing compounds; and (iii) neither p38 nor p44/42 MAPKs mediate induction of apoptosis by some calcineurin-independent pathways.

Animals↗
PubMed1999

Modification of Chromatin Structure by the Thyroid Hormone Receptor.

Pioneering experiments and recent observations have established the thyroid hormone receptor as a master manipulator of the chromosomal environment in targeting the activation and repression of transcription. Here we review how the thyroid hormone receptor is assembled into chromatin, where in the absence of thyroid hormone the receptor recruits histone deacetylase to silence transcription. On addition of hormone, the receptor undergoes a conformational change that leads to the release of deacetylase, while facilitating the recruitment of transcriptional coactivators that act as histone acetyltransferases. We discuss the biological importance of these observations for gene control by the thyroid hormone receptor and for oncogenic transformation by the mutated thyroid hormone receptor, v-ErbA.

Journal Article↗
PubMed1999

Cytokines as suppressors of apoptosis.

Many cytokines have been isolated by their ability to induce growth and have been called growth factors. But these cytokines are also essential to induce cell viability, and cell viability and growth can be separately regulated. Using as examples myeloid hematopoietic cells, lymphocytes and neuronal cells, in vitro and in vivo studies have shown the role of cytokines in inducing viability of different cell types during development to mature cells. Some cytokines can act on more than one cell type. Cytokines induce viability of normal and cancer cells by suppressing the apoptotic machinery activated by wild-type p53, or by cytotoxic agents including irradiation and compounds used in cancer chemotherapy. Cytokines can be used to decrease apoptosis in normal cells and inhibition of cytokine activity may improve cancer therapy by enhancing apoptosis in cancer cells. The apoptosis suppressing function of cytokines is mediated by changing the balance in the activity of apoptosis inducing and suppressing genes. Apoptosis suppression is upstream of caspase activation in the apoptotic process. Cytokines can suppress multiple pathways leading to apoptosis, only some of which were suppressed by other agents such as some antioxidants, Ca(2+)-mobilizing compounds and protease inhibitors.

Journal Article↗
PubMed1999

Knowledge of no return--getting and giving information about genetic risk.

New genetic information can provide constructive preventive possibilities for individuals and for society but can also create new dilemmas for them. In consultations dealing with the risk of inheriting cancer, many problems connected with the notion of information exchange come to the surface. Individuals have to deal not only with the information given by the doctor, or how to give information to the doctor, but also with the problem of informing others, close kin with a similar risk potential, or getting information from them. In all these information exchanges concerning risk of cancer, different notions of 'information' are being invoked and used as resources in the talks, implying communicative problems at different levels. Some of these problems are discussed in this article.

Genetic Counseling↗
PubMed1999

Research on risk and risk in research: theoretical and practical experiences from a multidisciplinary study on cervical cancer screening in urban Sweden.

This article describes a qualitative research project on secondary cancer prevention that was conducted using a multidisciplinary team and that was inspired by perspectives from feminist research and fourth-generation evaluation. A screening program for cervical cancer was investigated from the perspective of different stakeholders through a series of substudies using a variety of qualitative approaches, in order to have a broad basis for consideration and negotiation of improvements. The first sections of this article describe the theoretical and methodological basis for the project, which triangulates a variety of qualitative and quantitative research strategies, whereas the latter sections describe some of our experiences, positive and negative, as a research team (and thus also as stakeholders) in actually conducting the studies.

Female↗
PubMed1998

Antitumor activity of bax and p53 naked gene transfer in lung cancer: in vitro and in vivo analysis.

In vitro and in vivo data have demonstrated that virus-mediated p53 gene transfer can induce active cell death and lung tumor regression. In contrast, the therapeutic potential of bax, another apoptosis-inducing gene, has not been described. We compared p53 and bax cytotoxic effects by transient transfection of an average of 25 +/- 5% of the H-322 and H-358 bronchioloalveolar carcinoma cell lines in vitro. Under these conditions, bax expression killed 70 to 90% of the transfected cells whereas p53 killed only 40% of them. The killing activity of both genes involved apoptosis, as shown by TUNEL staining. Surprisingly, BrdU incorporation indicated that the cells that did resist Bax toxicity were blocked in the pre-S phase of the cell cycle, a result expected for p53 only. In vivo, repeated injections of naked DNA encoding Bax or p53 inhibited the growth of 4-mm preestablished H-322 tumors in nude mice. Growth retardation only, and not inhibition, was observed in H-358, a poorly transfectable and rapidly growing tumor. These results indicate that Bax and p53 share a similar, strong antitumor activity in vivo, even if the former is a more potent inducer of apoptosis in vitro.

Animals↗
PubMed1998

Different mechanisms for suppression of apoptosis by cytokines and calcium mobilizing compounds.

Overexpression of wild-type p53 in M1 myeloid leukemia cells induces apoptotic cell death that was suppressed by the calcium ionophore A23187 and the calcium ATPase inhibitor thapsigargin (TG). This suppression of apoptosis by A23187 or TG was associated with suppression of caspase activation but not with suppression of wild-type-p53-induced expression of WAF-1, mdm-2, or FAS. In contrast to suppression of apoptosis by the cytokines interleukin 6 (IL-6) and interferon gamma, a protease inhibitor, or an antioxidant, suppression of apoptosis by A23187 or TG required extracellular Ca2+ and was specifically abolished by the calcineurin inhibitor cyclosporin A. IL-6 induced immediate early activation of junB and zif/268 (Egr-1) but A23187 and TG did not. A23187 and TG also suppressed induction of apoptosis by doxorubicin or vincristine in M1 cells that did not express p53 by a cyclosporin A-sensitive mechanism. Suppression of apoptosis by A23187 or TG was not associated with autocrine production of IL-6. Apoptosis induced in IL-6-primed M1 cells after IL-6 withdrawal was not suppressed by A23187 or TG but was suppressed by the cytokines IL-6, IL-3, or interferon gamma. The results indicate that these Ca2+-mobilizing compounds can suppress some pathways of apoptosis suppressed by cytokines but do so by a different mechanism.

Animals↗
PubMed1998

The diagnostic process and the boundaries of normality.

This article illustrates a group of cancer patients' descriptions and explanations of their experiences of health care encounters involving professional and lay processes of diagnosis related to definitions of normality. An interdisciplinary approach, representing nursing and medical anthropology, has been used in attempting to better understand data derived from semistructured interviews with 46 persons diagnosed with cancer in the greater Stockholm area and with 29 of their significant others. We argue that people in this study tend to deal with disruptive situations by attempting to construct order. In the stories presented by these cancer patients, a diagnostic process becomes evident in which patients first become "nonnormal" within a popular framework and later meet positive criteria to become "normally diseased" with the legitimization this provides. We thus see a way for the involved actors to deal with potentially difficult situations by redefining the concept of normality.

Attitude to Health↗
PubMed1997

Cytokine suppression of protease activation in wild-type p53-dependent and p53-independent apoptosis.

M1 myeloid leukemic cells overexpressing wild-type p53 undergo apoptosis. This apoptosis can be suppressed by some cytokines, protease inhibitors, and antioxidants. We now show that induction of apoptosis by overexpressing wild-type p53 is associated with activation of interleukin-1beta-converting enzyme (ICE)-like proteases, resulting in cleavage of poly(ADP- ribose) polymerase and the proenzyme of the ICE-like protease Nedd-2. Activation of these proteases and apoptosis were suppressed by the cytokine interleukin 6 or by a combination of the cytokine interferon gamma and the antioxidant butylated hydroxyanisole, and activation of poly(ADP-ribose) polymerase and apoptosis were suppressed by some protease inhibitors. In a clone of M1 cells that did not express p53, vincristine or doxorubicin induced protease activation and apoptosis that were not suppressed by protease inhibitors, but were suppressed by interleukin 6. In another myeloid leukemia (7-M12) doxorubicin also induced protease activation and apoptosis that were not suppressed by protease inhibitors, but were suppressed by granulocyte-macrophage colony-stimulating factor. The results indicate that (i) overexpression of wild-type p53 by itself or treatment with cytotoxic compounds in wild-type p53-expressing or p53-nonexpressing myeloid leukemic cells is associated with activation of ICE-like proteases; (ii) cytokines exert apoptosis-suppressing functions upstream of protease activation; (iii) the cytotoxic compounds induce additional pathways in apoptosis; and (iv) cytokines can also suppress these other components of the apoptotic machinery.

Animals↗