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Biomedical subjects

A Smith

Publications and source records attributed to A Smith.

At least 433 records · Page 24Linked to original sources
PubMed1999

A nonsteroidal anti-inflammatory drug, flufenamic acid, inhibits the expression of the androgen receptor in LNCaP cells.

Nonsteroidal anti-inflammatory drugs (NSAIDs) play potential roles in chemoprevention of colon cancer and others by inhibiting prostaglandin synthesis. In this report, we used LNCaP cells, an androgen-responsive human prostate carcinoma cell line, to study the effects of two NSAIDs, flufenamic acid (FA) and piroxicam (PXM), on the cancer cell growth stimulated by androgens. We found that FA had much higher potency to inhibit LNCaP cell growth than PXM. FA dramatically reduced the expression of androgen inducible genes, such as prostate-specific antigen (PSA) and the homeo-domain transcription factor Nkx3.1, but PXM did not. In vitro transfection experiments showed that FA down regulated the PSA expression at the transcription level. Western and northern blot analyses demonstrated that FA inhibited the androgen receptor (AR) expression at mRNA and protein levels. Suppressed AR expression may be the cause of FA-mediated inhibition of the androgen inducible gene expression. Our data also showed that FA significantly reduced the AR promoter-mediated transcription activities. This study indicated that AR might be a target for FA to inhibit LNCaP cell growth. FA and other similar NSAIDs may be potential candidates for chemoprevention of human prostate cancer by modulating the expression of AR.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Stereotactic proton radiosurgery.

The technique of stereotactic proton radiosurgery is discussed in depth in this article. The physics of the proton beam in radiosurgery is explained, and the different factors of beam delivery are examined. These key factors (correspondence to shape, accuracy of delineation of volume, correspondence to volume, and accuracy of delivery vary) with each of the radiosurgical techniques, from Gamma Knife surgery to linear accelerator therapy. Clinical series in the use of proton radiosurgery are also presented, with an emphasis on efficacy and uses.

Biophysical Phenomena↗
PubMed1999

Type 2 diabetes mellitus in Navajo adolescents.

Diabetes mellitus afflicts over one-fifth of the Navajo population aged over 20 years, but the prevalence of diabetes in Navajo adolescents is unclear. We conducted voluntary testing for diabetes mellitus at two high schools on the Navajo reservation to clarify the prevalence as well as to assess the utility of a high-school based screening program. Body mass index measurements (BMI), oral glucose tolerance tests, and hemoglobin A1C measurements were obtained in consenting high school students. Of the 276 students that participated, 234 were Navajo. Only one Navajo student (0.4%) had diabetes mellitus, although eight (3%) had impaired glucose tolerance or impaired fasting glucose. Participant BMI did not differ significantly from nonparticipant BMI. No correlation existed between BMI or impaired glucose handling, and significant overlap existed between the hemoglobin A1C values of students with impaired glucose handling and students without impaired glucose handling. Increased participation in screening programs may reveal higher disease prevalence, but high school-based screening is not justified by this study, despite the high rates of diabetes mellitus in the Navajo population.

Adolescent↗
PubMed1999

Comparison of metaphase and interphase FISH monitoring of minimal residual disease with MLL gene probe: case study of AML with t(9;11).

The place of FISH in the monitoring of minimal residual disease (MRD) is yet to be fully characterised. Routine bone marrow cytogenetics at diagnosis in a 22 year old patient with acute myeloid leukemia FAB type M5 detected a translocation t(9;11)(p22;q23). We report our investigations to assess residual levels of translocation using a FISH probe designed to detect a gene split by the translocation. We used MLL (Oncor), a probe which spans the MLL gene at 11q23, in both metaphase and interphase preparations. At diagnosis, metaphase FISH showed 3 distinct cell lines-normal with 2 signals, abnormal with 3 signals and abnormal with 2 signals, while interphase FISH showed only 2 cell lines, one with 2 signals (which could be normal or abnormal) and one with 3 signals (split MLL). Following treatment, with the patient in clinical remission, 7 further cytogenetic analyses and 2 further FISH analyses were compared. Our results suggest that monitoring of the t(9;11) by metaphase FISH is feasible and straightforward compared to cytogenetics but interphase FISH may be problematic.

Adult↗
PubMed1999

Association between outcome and telomere DNA content in prostate cancer.

PURPOSE: To perform an initial retrospective investigation of the relationship between outcome in patients with organ confined prostate adenocarcinoma and the tumor cells' content of telomere DNA. MATERIALS AND METHODS: The case-controlled study group was composed of eighteen men diagnosed with prostatic adenocarcinoma prior to 1993. The group was selected so that approximately one half died within ten years of diagnosis and one half survived ten years or longer. Archival, paraffin-embedded tumor tissue was recovered for each patient. DNA was extracted from newly cut sections, fixed to nylon membranes and hybridized with P32-labeled centromere- and telomere-specific probes. Telomere DNA contents were quantitated from the hybridized radioactivities. The relationships between telomere DNA content and survival, and telomere DNA content and disease recurrence in men receiving prostatectomies were determined. RESULTS: Death and disease recurrence were associated with reduced telomere DNA content (p <0.0001, p <0.0001, respectively). CONCLUSIONS: Telomere DNA content may differentiate high-risk patients with metastatic prostate cancer from men with indolent disease who can be spared the unnecessary side effects and expense of treatment by management with "watchful waiting."

Adenocarcinoma↗
PubMed1999

Changes in the levels of soluble adhesion molecules and coagulation factors in patients with deep vein thrombosis.

Current biochemical markers of thrombosis, such as d-dimer, are of little value in demonstrating the presence of thrombus postoperatively, as their levels are elevated by surgery. Thrombosis involves adhesive interactions between the endothelium, platelets and leukocytes. The aim of the study was to determine which of a panel of haemostatic and adhesion factors are altered by the presence of thrombus, but not by surgery. These factors were measured in 20 patients with established spontaneous DVTs, 13 patients having hip replacement surgery and 28 control patients. Circulating levels of P-selectin, VCAM-1 and tissue factor were found to be increased when thrombus was present (p <0.018, p <0.0001, p <0.0028 respectively), but were not altered by surgery. The significance of these circulating factors in venous thrombosis remains to be established, but it is conceivable that they are the product of increased leukocyte trafficking and activity. Assay of VCAM-1, in particular, may be of use in the early detection of venous thrombi in postoperative patients.

Adult↗
PubMed1999

Novel translocation t(3;11)(p21;q24) in multiple myeloma characterised by FISH.

We present a 72 year old man with multiple myeloma (MM). Cytogenetic and FISH analysis of bone marrow aspirate showed a novel translocation -der(11)t(3;11)(p21;q24). The unbalanced karyotype led to substantial partial trisomy for chromosome 3p and small partial monosomy 11q. Structural rearrangements of chromosome 3 are uncommon in MM and these are reviewed. The patient died 2 years after the diagnosis of MM was made.

Aged↗
PubMed1998

Molecular basis for p38 protein kinase inhibitor specificity.

p38 is a member of the mitogen-activated protein (MAP) kinase family and is a critical enzyme in the proinflammatory cytokine pathway. Other MAP kinase group members that share both structural and functional homology to p38 include the c-Jun NH2-terminal kinases (JNKs or SAPKs) and the extracellular-regulated protein kinases (ERKs). In this study, we determined the molecular basis for p38alpha inhibitor specificity exhibited by five compounds in the diarylimidazole, triarylimidazole, and triarylpyrrole classes of protein kinase inhibitors. These compounds are significantly more potent inhibitors of p38 compared to the JNKs and ERKs. Three active site ATP-binding domain residues in p38, T106, M109, and A157, selected based on primary sequence alignment, molecular modeling, and X-ray crystal structure data, were mutated to assess their role in inhibitor binding and enzymatic catalysis. All mutants, with the exception of T106M, had kinase activity within 3-fold of wild-type p38. Mutation of T106 to glutamine, the residue present at the corresponding position in ERK-2, or methionine, the corresponding residue in p38gamma, p38delta, and the JNKs, rendered all five inhibitors ineffective. The diarylimidazoles had approximately a 6-fold decrease in potency toward M109A p38. For the mutant A157V, all diarylimidazoles and triarylimidazoles tested were 5-10-fold more potent compared with wild-type p38. In contrast, two triarylpyrroles were 15-40-fold less potent versus A157V p38. These results showed that the molecular basis for the specificity of the p38 inhibitors was attributed largely to threonine 106 in p38 and that methionine 109 contributes to increased binding affinity for imidazole based inhibitors.

Adenosine Triphosphate↗
PubMed1998

Cell therapy: in search of pluripotency.

Cell replacement as a route to treat cellular disease and injury is currently limited by the availability of suitable donor cell populations, but recent results with mouse embryonic stem cells suggest that isolated human pluripotent cells could provide a source of cells for transplantation and gene therapy.

Animals↗
PubMed1998

Paracrine induction of stem cell renewal by LIF-deficient cells: a new ES cell regulatory pathway.

The propagation of pluripotential mouse embryonic stem (ES) cells is sustained by leukemia inhibitory factor (LIF) or related cytokines that act through a common receptor complex comprising the LIF receptor subunit (LIF-R) and the signal transducer gp130. However, the findings that embryos lacking LIF-R or gp130 can develop beyond gastrulation argue for the existence of an alternative pathway(s) governing the maintenance of pluripotency in vivo. In order to define those factors that contribute to self-renewal in ES cell cultures, we have generated ES cells in which both copies of the lif gene are deleted. These cells showed a significantly reduced capacity for regeneration of stem cell colonies when induced to differentiate, confirming that LIF is the major endogenous regulatory cytokine in ES cell cultures. However, self-renewal was not abolished and undifferentiated ES cell colonies were still obtained in the complete absence of LIF. A differentiated, LIF-deficient, parietal endoderm-like cell line was derived and shown to support ES cell propagation via production of a soluble, macromolecular, trypsin-sensitive activity. This activity, which we name ES cell renewal factor (ESRF), is distinct from members of the IL-6/LIF family because (i) it is effective on ES cells lacking LIF-R; (ii) it is not blocked by anti-gp130 neutralizing antibodies; and (iii) it acts without activation of STAT3. ES cells propagated clonally using ESRF alone can contribute fully to chimaeras and engender germline transmission. These findings establish that ES cell pluripotency can be sustained via a LIF-R/gp130-independent, STAT-3 independent, signaling pathway. Operation of this pathway in vivo could play an important role in the regulation of pluripotency in the epiblast and account for the viability of lifr -/- and gp130 -/- embryos.

Animals↗
PubMed1998

Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.

Oct4 is a mammalian POU transcription factor expressed by early embryo cells and germ cells. We report that the activity of Oct4 is essential for the identity of the pluripotential founder cell population in the mammalian embryo. Oct4-deficient embryos develop to the blastocyst stage, but the inner cell mass cells are not pluripotent. Instead, they are restricted to differentiation along the extraembryonic trophoblast lineage. Furthermore, in the absence of a true inner cell mass, trophoblast proliferation is not maintained in Oct4-/- embryos. Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4. Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm.

Animals↗
PubMed1998

Floating dosage forms: an in vivo study demonstrating prolonged gastric retention.

Gastroretentive dosage forms have potential for use as controlled-release drug delivery systems. The use of floating dosage forms (FDFs) is one method to achieve prolonged gastric residence times (GRTs), providing opportunity for both local and systemic drug action. Multiple-unit systems avoid the 'all-or-nothing' gastric emptying nature of single-unit systems. A freeze-dried calcium alginate multiple-unit FDF has been developed which demonstrated favourable in vitro floating characteristics. The aim of this study was to investigate the in vivo behaviour of this system compared to a multiple-unit non-floating dosage form manufactured from identical material. The study was performed in seven healthy volunteers, who swallowed the radiolabelled formulations after a standard breakfast. Transit was monitored by gamma-scintigraphy and subjects were maintained in the fed state. Prolonged GRTs of over 5.5 h were achieved in all subjects for the floating formulations, which remained high up in the stomach for the whole of the test period. In contrast, the non-floating beads displayed short GRTs, with a mean onset emptying time of 1 h. The results of this study suggest that, in the fed state, this FDF has potential for sustained drug delivery for either local or systemic purposes.

Adult↗
PubMed1998

[Public health work in connection with a new international airport].

During the six years between the parliament decision in 1992 to build a new international airport and the opening of this airport at Gardermoen, public health authorities experienced strong challenges when exercising their authority, when planning and implementing the airport health services, and when trying to describe possible health hazards to the population living in the area. Environmental and population health considerations led in some instances to opposite conclusions. The opinions of local health authorities were overruled by national authorities as regards noise limits. The food control authorities were not included in the first stage of planning. Efforts to cooperate emergency health services, ambulance services, and services for the prevention of contagious diseases did not succeed initially. Population studies before and during the airport construction period showed that persons being forced to move because of the new airport reported increased illness, developed a lower self-assessed health quality, more often generalized pain, and more often moderate mental problems.

Aircraft↗
PubMed1998

Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase.

Alzheimer disease is characterized by a specific type of neuronal degeneration in which the microtubule associated protein tau is abnormally hyperphosphorylated causing the disruption of the microtubule network. We have found that the phosphorylation of human tau (tau3L) by A-kinase, GSK-3 or CK-1 inhibits its microtubule assembly-promoting and microtubule-binding activities. However, the inhibition of these activities of tau by GSK-3 is significantly increased if tau is prephosphorylated by A-kinase or CK-1. The most potent inhibition is observed by combination phosphorylation of tau with A-kinase and GSK-3. Under these conditions, only very few microtubules are seen by electron microscopy. Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. Thus a combined role of A-kinase and GSK-3 should be considered in Alzheimer neurofibrillary degeneration.

Alzheimer Disease↗
PubMed1998

Generation of purified neural precursors from embryonic stem cells by lineage selection.

Mouse embryonic stem (ES) cells are non-transformed cell lines derived directly from the pluripotent founder tissue in the mouse embryo, the epiblast [1-3]. Aggregation of ES cells triggers the generation of a diverse array of cell types, including neuronal cells [4-7]. This capacity for multilineage differentiation is retained during genetic manipulation and clonal expansion [8]. In principle, therefore, ES cells provide an attractive system for the molecular and genetic dissection of developmental pathways in vitro. They are also a potential source of cells for transplantation studies. These prospects have been frustrated, however, by the disorganised and heterogeneous nature of development in culture. We have therefore developed a strategy for genetic selection of lineage-restricted precursors from differentiating populations. Here, we report that application of such lineage selection enables efficient purification of neuroepithelial progenitor cells that subsequently differentiate efficiently into neuronal networks in the absence of other cell types.

Animals↗