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N Bailey

Publications and source records attributed to N Bailey.

At least 19 recordsLinked to original sources
PubMed1996

A phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid.

Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.

Acyltransferases↗
PubMed1995

Laminin mediates tissue-specific gene expression in mammary epithelia.

Tissue-specific gene expression in mammary epithelium is dependent on the extracellular matrix as well as hormones. There is good evidence that the basement membrane provides signals for regulating beta-casein expression, and that integrins are involved in this process. Here, we demonstrate that in the presence of lactogenic hormones, laminin can direct expression of the beta-casein gene. Mouse mammary epithelial cells plated on gels of native laminin or laminin-entactin undergo functional differentiation. On tissue culture plastic, mammary cells respond to soluble basement membrane or purified laminin, but not other extracellular matrix components, by synthesizing beta-casein. In mammary cells transfected with chloramphenicol acetyl transferase reporter constructs, laminin activates transcription from the beta-casein promoter through a specific enhancer element. The inductive effect of laminin on casein expression was specifically blocked by the E3 fragment of the carboxy terminal region of the alpha 1 chain of laminin, by antisera raised against the E3 fragment, and by a peptide corresponding to a sequence within this region. Our results demonstrate that laminin can direct tissue-specific gene expression in epithelial cells through its globular domain.

Amino Acid Sequence↗
PubMed1995

Cellular growth and survival are mediated by beta 1 integrins in normal human breast epithelium but not in breast carcinoma.

We previously established a rapid three-dimensional assay for discrimination of normal and malignant human breast epithelial cells using a laminin-rich reconstituted basement membrane. In this assay, normal epithelial cells differentiate into well-organized acinar structures whereas tumor cells fail to recapitulate this process and produce large, disordered colonies. The data suggest that breast acinar morphogenesis and differentiation is regulated by cell-extra-cellular matrix (ECM) interactions and that these interactions are altered in malignancy. Here, we investigated the role of ECM receptors (integrins) in these processes and report on the expression and function of potential laminin receptors in normal and tumorigenic breast epithelial cells. Immunocytochemical analysis showed that normal and carcinoma cells in a three-dimensional substratum express profiles of integrins similar to normal and malignant breast tissues in situ. Normal cells express alpha 1, alpha 2, alpha 3, alpha 6, beta 1 and beta 4 integrin subunits, whereas breast carcinoma cells show variable losses, disordered expression, or downregulation of these subunits. Function-blocking experiments using inhibitory anti-integrin subunit antibodies showed a > 5-fold inhibition of the formation of acinar structures by normal cells in the presence of either anti-beta 1 or anti-alpha 3 antibodies, whereas anti-alpha 2 or -alpha 6 had little or no effect. In experiments where collagen type I gels were used instead of basement membrane, acinar morphogenesis was blocked by anti-beta 1 and -alpha 2 antibodies but not by anti-alpha 3. These data suggest a specificity of integrin utilization dependent on the ECM ligands encountered by the cell. The interruption of normal acinar morphogenesis by anti-integrin antibodies was associated with an inhibition of cell growth and induction of apoptosis. Function-blocking antibodies had no inhibitory effect on the rate of tumor cell growth, survival or capacity to form colonies. Thus under our culture conditions breast acinar formation is at least a two-step process involving beta 1-integrin-dependent cellular growth followed by polarization of the cells into organized structures. The regulation of this pathway appears to be impaired or lost in the tumor cells, suggesting that tumor colony formation occurs by independent mechanisms and that loss of proper integrin-mediated cell-ECM interaction may be critical to breast tumor formation.

Adenocarcinoma↗
PubMed1993

Testing the FOCOMETER--A new refractometer.

The FOCOMETER, an optometer which measures spherical refractive errors, is intended to provide rural or economically disadvantaged populations spherical prescriptions without the need for complicated protocols, expensive equipment, or electricity. FOCOMETER readings were compared with the spherical equivalent determined from autorefraction and subjective trial lens refractions in children, and with retinoscopy in adults. Over the range of refractive errors tested (-4 to +5 D) reasonably close readings, within one-half a diopter, were found for comparisons with autorefraction and retinoscopy and about one-tenth of a diopter difference was found between subjective refractions and the FOCOMETER.

Adolescent↗
PubMed1991

Interferon-alpha 2b in the treatment of follicular lymphoma: preliminary results of a trial in progress.

Since 1985 the combination of chlorambucil (10 mg daily, initially for six weeks, then alternating fortnights for 12 weeks) and interferon-alpha 2b (Schering-Plough; 2 x 10(6) U/m2 three times weekly by subcutaneous injection for 18 weeks) has been compared in a randomised trial with chlorambucil alone in previously untreated patients with stage III or IV follicular lymphoma. Responding patients have subsequently been randomised to receive maintenance interferon-alpha 2b or no further treatment. Of the 124 treated patients, 108 are evaluable for response with a median follow-up of 30 months. The major toxicity was myelosuppression which was more frequent with chlorambucil and IFN alpha 2b in combination than with chlorambucil alone (P less than 0.01). There was no treatment-related mortality. Actuarial survival at three years is 75% for all patients, regardless of therapy. There was no significant difference in response rate according to initial therapy. For the 60 patients achieving a good response to initial therapy who have entered the second part of the trial, there has been a significant prolongation of remission duration in favour of maintenance IFN-alpha 2b (median not yet reached versus two years for the 'no treatment' arm, P less than 0.015). Fewest relapses have been seen in patients who received IFN-alpha 2b throughout. Accrual to this trial continues; this preliminary analysis indicates that maintenance IFN-alpha 2b may extend remission duration in follicular lymphoma.

Adult↗
PubMed1991

Interferon alfa-2b in addition to chlorambucil in the treatment of follicular lymphoma: preliminary results of a randomized trial in progress.

One hundred and twenty four patients with follicular lymphoma (32 with Stage III and 92 with Stage IV disease) have been randomized to receive chlorambucil alone or chlorambucil plus interferon alfa-2b. Responding patients are then randomized to receive either interferon alfa-2b maintenance therapy for up to 12 months or no further treatment. One hundred and eight patients are evaluable for response, the remainder are still receiving initial therapy. Clinical remission (complete or good partial remission) was achieved in 42/59 (71%) patients receiving chlorambucil alone and in 27/49 (55%) patients receiving the combination (P = NS). Preliminary analysis of remission duration shows a trend in favour of those patients receiving interferon throughout (P = 0.02). There is no significant difference between the groups in terms of survival, at a median follow up of 2.5 years. Interferon-associated toxicity was minor in most patients but led to discontinuation of therapy in six cases. Larger trials with longer follow-up periods are needed to confirm the beneficial role of interferon in the treatment of follicular lymphoma.

Adult↗
PubMed1991

Control of mammary epithelial differentiation: basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity.

Functional differentiation in mammary epithelia requires specific hormones and local environmental signals. The latter are provided both by extracellular matrix and by communication with adjacent cells, their action being intricately connected in what appears to be a cascade of events leading to milk production. To distinguish between the influence of basement membrane and that of cell-cell contact in this process, we developed a novel suspension culture assay in which mammary epithelial cells were embedded inside physiological substrata. Single cells, separated from each other, were able to assimilate information from a laminin-rich basement membrane substratum and were induced to express beta-casein. In contrast, a stromal environment of collagen I was not sufficient to induce milk synthesis unless accompanied by cell-cell contact. The expression of milk proteins did not depend on morphological polarity since E-cadherin and alpha 6 integrin were distributed evenly around the surface of single cells. In medium containing 5 microM Ca2+, cell-cell interactions were impaired in small clusters and E-cadherin was not detected at the cell surface, yet many cells were still able to produce beta-casein. Within the basement membrane substratum, signal transfer appeared to be mediated through integrins since a function-blocking anti-integrin antibody severely diminished the ability of suspension-cultured cells to synthesize beta-casein. These results provide evidence for a central role of basement membrane in the induction of tissue-specific gene expression.

Animals↗
PubMed1991

Adjuvant effect of human growth hormone with an inactivated flavivirus vaccine.

Vaccines made by inactivating pathogenic microorganisms have been dramatically successful in controlling diseases in humans and animals. Despite their successes, they have a major disadvantage in that several inoculations are required for them to be effective. To overcome this problem, a commercial inactivated vaccine preparation against tickborne encephalitis was combined with human growth hormone (HGH). This formulation produced complete protection in a murine model with only one dose of vaccine, apparently by binding hormone and antigen to an insoluble matrix containing aluminium hydroxide. Thus it is postulated that when virus-specific lymphocytes are attracted to the site of injection, the hormone is at a high local concentration and stimulates the clonal expansion of antigen-specific T cells. The development of genetically engineered HGH now gives unlimited supplies of hormone, potentially resulting in an increase in efficacy of a wide variety of vaccines, especially those needing prolonged immunization schedules such as those being developed to combat human immunodeficiency virus infection.

Adjuvants, Immunologic↗
PubMed1990

Mutation of the human FMS gene (M-CSF receptor) in myelodysplastic syndromes and acute myeloid leukemia.

We studied 41 patients with myelodysplastic syndromes or acute myeloid leukemia to assess the presence of point mutations in the human FMS gene (M-CSF receptor). Using the polymerase chain reaction and hybridization of oligonucleotide probes to the amplified sequences, we have detected mutations in eight of 41 patients, at codons 301 and 969. In vitro work has highlighted mutations at these codons as being oncogenic. We now report the detection of potentially activating mutations of the human FMS gene in vivo. The consequence of these mutations in the multistep pathogenesis of myeloid malignancy and their relevance to prognosis remains to be determined.

Alleles↗
PubMed1989

Back to school.

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Adolescent↗
PubMed1989

Tissue distortion in three-dimensional reconstruction of wax or plastic embedded microscopic structures.

Three-dimensional reconstruction at the light microscopic level depends on obtaining reliable serial sections without "distortion" i.e., expansion and compression during section preparation. We have studied the extent of such distortion in serial sections from paraffin and resin embedded blocks of brain, kidney, liver and lung, using an IBAS 2000 Image Analyser. We found that, taking the uncut block as 100%, the section area, perimeter and minimum diameter varied by no more than 8%, except for the lung sections which varied up to 14%. There was no progressive compression due to knife bluntening. Resin sections also varied up to 8% (16% for lungs) but in addition creasing was a problem. We conclude that, provided the serial sectioning is carefully standardised for block shape and orientation, floating out temperature and time, serial paraffin sections are more suitable for three dimensional reconstruction than resin sections.

Acrylic Resins↗