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Biomedical subjects

J Flach

Publications and source records attributed to J Flach.

16 recordsLinked to original sources
PubMed2001

The nuclear receptors FXR and LXRalpha: potential targets for the development of drugs affecting lipid metabolism and neoplastic diseases.

The orphan nuclear receptors FXR and LXRalpha have become challenging targets for the discovery of new therapeutic agents. Bile acids and hydroxysterol intermediates are the respective natural ligands of these two structurally and functionally closely related receptors. Both FXR and LXRalpha; are thought to play a major role in the control of cholesterol catabolism by regulating the expression of cholesterol 7alpha-hydroxylase, the rate limiting enzyme of bile acid synthesis. Reverse cholesterol transport might also be affected by FXR and LXR since they control the expression of PLTP and CETP, two proteins involved in the transfer of phospholipid, cholesterol and cholesteryl esters among plasma lipoproteins. A new class of potent synthetic activators of FXR, the 1,1-bisphosphonate esters, has been discovered which up regulate the Intestinal Bile Acid Binding Protein gene (I-BABP) as demonstrated for chenodeoxycholic acid, however there are no known synthetic activators yet identified for LXRalpha. The evaluation of FXR as a potential target for the development of drugs affecting plasma cholesterol can take advantage of the fact that the activators of FXR (farnesol, bile acids and the 1,1-bisphosphonate esters) have been studied in various in vitro and in vivo models. Administration of chenodeoxycholic acid to animals and man did not result in the increase in plasma cholesterol expected from a decrease in cholesterol 7alpha-hydroxylase expression. Like farnesol, the 1,1-bisphosphonate esters increase the rate of degradation of HMGCoA reductase and have the unexpected property of inducing hypocholesterolemia in normal animals. The natural and synthetic FXR agonists trigger differentiation, inhibit cell proliferation and are potent inducers of apoptosis. The 1,1-bisphosphonate ester SR-45023A (Apomine) is presently being developed as an antineoplastic drug.

Amino Acid Sequence↗
PubMed2000

The mevalonate/isoprenoid pathway inhibitor apomine (SR-45023A) is antiproliferative and induces apoptosis similar to farnesol.

Apomine (SR-45023A) is a new antineoplastic compound which is currently in clinical trials and representative of the family of cholesterol synthesis inhibitors 1,1-bisphosphonate esters. Apomine inhibits growth of a wide variety of tumor cell lines with IC(50) values ranging from 5 to 14 microM. The antiproliferative activity of apomine was studied in comparison with that of other inhibitors of the mevalonate/isoprenoid pathway of cholesterol synthesis, simvastatin, farnesol, and 25-hydroxycholesterol. All these compounds inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity. Apomine (IC(50) = 14 microM), simvastatin (IC(50) = 3 microM), farnesol (IC(50) = 60 microM), and 25-hydroxycholesterol (IC(50) = 2 microM) inhibited HL60 cell growth. Growth inhibition due to simvastatin was reverted by mevalonate, whereas the antiproliferative activity of apomine, farnesol, and 25-hydroxycholesterol was not. Apomine triggered apoptosis in HL60 cells in less than 2 h. Apomine and farnesol induced caspase-3 activity at concentrations similar to their IC(50) values for cell proliferation, whereas a 10-fold excess of simvastatin was necessary to trigger apoptosis compared to its potency on proliferation. Caspase-3 activity was not induced by 25-hydroxycholesterol. The overall similar profile on mevalonate synthesis inhibition, cell growth inhibition, and apoptosis suggests that apomine acts as a synthetic mimetic of farnesol.

Anticholesteremic Agents↗
PubMed2000

Bioethical considerations in cancer prevention and early detection practice and research.

PURPOSE/OBJECTIVES: To review current ethical issues in cancer prevention and early detection, discuss some of the key methods and theories in contemporary bioethics, present clinical scenarios that illustrate moral problems that nurses may encounter, and show how the theories and methods can assist ethical decision making. DATA SOURCES: Published articles, abstracts, and books; case studies developed from clinical experience and literary sources. DATA SYNTHESIS: Oncology nurses face a host of ethical considerations when providing cancer prevention and early detection education and services and when conducting research in this arena. A variety of ethical methods and theories--including principlism, casuistry, utilitarianism, rights-based theories, virtue ethics, ethics of care, and communitarian ethics--may assist nurses in tackling ethical challenges. CONCLUSIONS: The growing field of cancer prevention and early detection raises a number of moral issues that have implications for oncology nursing. Because no single method or theory provides a complete account of bioethics, ethical problem solving should be approached using a variety of methods and theories whereby they can be coherently and appropriately applied together. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses need to increase their awareness of ethical issues related to cancer prevention and control and consider them when planning patient care and research programs.

Bioethics↗
PubMed1999

National efforts to improve the informed consent process.

OBJECTIVES: To inform oncology nurses about several national efforts to improve the informed consent document and process. DATA SOURCES: A federally funded grant program to stimulate research of informed consent, an initiative from the National Cancer Institute to improve informed consent documents in cancer clinical trials, and a model consent document developed by the National Action Plan on Breast Cancer. CONCLUSIONS: These initiatives assist investigators and institutional review boards in presenting relevant and understandable information to potential clinical trial participants. IMPLICATIONS FOR NURSING PRACTICE: These national efforts will raise awareness of providing potential research participants with clear information to assist them in making an educated, informed decision.

Breast Neoplasms↗
PubMed1997

Participants strengthen clinical trial research: the vital role of participant advisors in the Breast Cancer Prevention Trial.

Views regarding the rights and roles of participants in clinical trial research have changed extensively over the past several decades. Such changes have included moving from paternalistic views, in which human subjects often were totally uninformed of research participation, to a perspective that recognized certain rights of human subjects. In recent years, the consumer rights movement, a growing customer service perspective in health care, and the growth of a variety of advocacy groups have brought further change in attitudes and efforts to include consumer representatives and research participants in a variety of advisory roles. The BCPT PAB is a model for a way to involve research study participants in an expanded role. Members of the board initiate efforts to promote participation and inform potential participants about the trial. They help establish outreach efforts to recruit individuals from underrepresented populations. They serve as effective spokespersons for the trial to the media at both local and national levels, and they give highly useful guidance to the NSABP and the NCI regarding a variety of aspects of clinical trials. Beyond the formal responsibilities that were outlined when the board was established, the trial participants serving on the advisory board also have provided inspiration and motivation for other participants as well as for the clinicians, researchers, and administrators conducting the BCPT. The extensive contributions of the advisory board members confirm and add to the understanding of the variety of ways that clinical research participants can play a role in strengthening such research efforts. Further, the BCPT PAB may serve as a model strategy for drawing on the unique resource represented by the participants in clinical trial studies.

Breast Neoplasms↗
PubMed1995

Glyoxysomal malate dehydrogenase and malate synthase from soybean cotyledons (Glycine max L.): enzyme association, antibody production and cDNA cloning.

In order to investigate a possible association between soybean malate synthase (MS; L-malate glyoxylate-lyase, CoA-acetylating, EC 4.1.3.2) and glyoxysomal malate dehydrogenase (gMDH; (S)-malate: NAD+ oxidoreductase, EC 1.1.1.37), two consecutive enzymes in the glyoxylate cycle, their elution profiles were analyzed on Superdex 200 HR fast protein liquid chromatography columns equilibrated in low- and high-ionic-strength buffers. Starting with soluble proteins extracted from the cotyledons of 5-d-old soybean seedlings and a 45% ammonium sulfate precipitation, MS and gMDH coeluted on Superdex 200 HR (low-ionic-strength buffer) as a complex with an approximate relative molecular mass (Mr) of 670,000. Dissociation was achieved in the presence of 50 mM KCl and 5 mM MgCl2, with the elution of MS as an octamer of M(r) 510,000 and of gMDH as a dimer of M(r) 73,000. Polyclonal antibodies raised to the native copurified enzymes recognized both denatured MS and gMDH on immunoblots, and their native forms after gel filtration. When these antibodies were used to screen a lambda ZAP II expression library containing cDNA from 3-d-old soybean cotyledons, they identified seven clones encoding gMDH, whereas ten clones encoding MS were identified using an antibody to SDS-PAGE-purified MS. Of these cDNA clones a 1.8 kb clone for MS and a 1.3-kb clone for gMDH were fully sequenced. While 88% identity was found between mature soybean gMDH and watermelon gMDH, the N-terminal transit peptides showed only 37% identity. Despite this low identity, the soybean gMDH transit peptide conserves the consensus R(X6)HL motif also found in plant and mammalian thiolases.

Amino Acid Sequence↗
PubMed1994

A yeast RNA-binding protein shuttles between the nucleus and the cytoplasm.

RNA-binding proteins have been suggested to move in association with RNA as it leaves the nucleus. The NPL3 gene of the yeast Saccharomyces cerevisiae encodes in nuclear protein with consensus RNA-binding motifs and similarity to heterogeneous nuclear ribonucleoproteins and members of the S/R protein family. We show that although Npl3 is located in the nucleus, it can shuttle between nuclei in yeast heterokaryons. In contrast, other nucleus-targeted proteins do not leave the nucleus under similar conditions. Mutants missing the RNA-binding motifs or the N terminus are still capable of shuttling in and out of the nucleus. Npl3 mutants missing the C terminus fail to localize to the nucleus. Overproduction of Npl3 in wild-type cells shows cell growth. This toxicity depends on the presence of series of unique repeats in the N terminus and localization to the nucleus. We suggest that the properties of Npl3 are consistent with it being involved in export of RNAs from the nucleus.

Biological Transport↗
PubMed1986

Analysis of tropomyosin cDNAs isolated from skeletal and smooth muscle mRNA.

Several clones containing alpha tropomyosin sequences were isolated from cDNA libraries prepared from quail skeletal or smooth muscle RNA. All of these clones contain identical sequences coding for amino acids 81-257 of alpha skeletal muscle tropomyosin where they overlap, strongly indicating they are derived from the same gene. However, there are differences among these clones in sequences coding for the final 27 amino acids, as well as 3' untranslated sequences. In addition, S1 nuclease and Northern analyses indicate that coding sequences at the 5' end of the tropomyosin mRNA are also differentially expressed in smooth and skeletal muscle. These data point to the likelihood that differential splicing at both the 5' and 3' ends of a single tropomyosin gene results in the appearance of multiple tissue-specific transcripts.

Amino Acid Sequence↗