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Biomedical subjects

R Brown

Publications and source records attributed to R Brown.

At least 199 records · Page 11Linked to original sources
PubMed1999

Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth in severe combined immunodeficient mice.

Members of the Bcl-2 gene family have been implicated in the regulation of cell death induced by cytostatic drugs. In some malignancies such as B-cell lymphoma, there is evidence that high expression of Bcl-2 is an independent negative prognostic marker and the overexpression of Bcl-2 has been shown to confer resistance to cytotoxic drugs by preventing drug-induced apoptosis. This function of Bcl-2 can be antagonized by apoptosis-promoting members of the Bcl-2 family. We previously showed that overexpression of Bax restores the chemosensitivity of Bax-deficient breast cancer cell lines. Therefore, we investigated whether the death-promoting Bcl-2 homologue Bik/Nbk can enhance cytostatic drug-induced apoptosis. As a model, we used the T-cell leukemia H9 (CD3(+) and CD4(+)CD8(-)), which is resistant to corticosteroid-induced cell death and does not express endogenous Bik/Nbk. Sensitivity for drug-induced apoptosis was increased 10- to 39-fold in cells transfected with the full-length coding sequence of Bik/Nbk. In addition, apoptosis induced via CD95/Fas or heat shock was increased to a similar extent. These data show that Bik/Nbk, which, unlike Bax, carries only a BH3 but no BH1 or BH2 domain may be a target to enhance chemosensitivity. The complete suppression of tumor growth in a severe combined immunodeficient mouse xenotransplant model suggests that, in analogy to Bax, Bik/Nbk may function as a tumor suppressor gene.

Adrenal Cortex Hormones↗
PubMed1999

Modulation of drug resistance mediated by loss of mismatch repair by the DNA polymerase inhibitor aphidicolin.

Loss of expression of mismatch repair (MMR) proteins leads to resistance of tumor cells to a variety of DNA-damaging agents, including bifunctional alkylating and monofunctional methylating agents such as cis-diaminedichloroplatinum II (CDDP) and N'-methyl-N-nitrosourea (MNU). It has been suggested that coupling to cell death does not occur in the absence of MMR, but instead, DNA lesions are bypassed during replication, giving a drug-tolerant phenotype. In the present study, we have used aphidicolin (Ap), an inhibitor of DNA polymerases, to study the role of replicative bypass in drug resistance mediated by loss of MMR. We have examined the survival of matched ovarian carcinoma cell lines with known MMR status after sequential treatment with CDDP or MNU and Ap. We show that Ap increases the sensitivity of MMR-deficient cell lines to CDDP and MNU to a greater extent than their MMR-proficient counterparts. Furthermore, loss of MMR correlates with loss of CDDP-induced G2 arrest, but this is partially restored after Ap treatment. These data support Ap sensitizing drug-resistant cancer cells that have lost MMR to CDDP and MNU and suggest that the potential use of Ap as a modulator of drug resistance should be targeted to MMR-defective tumors.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Secretory villous adenomas that cause depletion syndrome.

Secretory villous adenomas of the colon have been known to cause a depleting syndrome characterized by dehydration, prerenal azotemia, hyponatremia, hypokalemia, metabolic acidosis, obtundation, and, in severe cases, death. We describe 1 case of classic depleting syndrome and review the literature on possible mechanisms. Both cyclic adenosine monophosphate and prostaglandin E2 have been implicated as possible secretagogue compounds in the pathogenesis of this syndrome unique to the secretory variant form of villous adenomas. Indomethacin as a prostaglandin inhibitor has been used with apparent benefit in controlling the volume of rectal effluent in patients with secretory villous adenomas.

Adenoma, Villous↗
PubMed1999

A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer.

Experimental evidence from several sources has identified a link between mismatch repair deficiency and cytotoxic drug resistance. Selection for cisplatin resistance in the human ovarian cancer cell line A2780, results in loss of expression of the mismatch repair protein hMLH1 in most (90%) of the resultant cisplatin-resistant cell lines. Here we demonstrate that the cisplatin sensitive parental cell line displays methylation of the promoter of only one hMLH1 allele, but that the resistant cell lines all exhibit hyper-methylation of the promoters of both hMLH1 alleles. Full methylation of all sites tested was found to be invariably associated with loss of hMLH1 expression, whereas a partial increase in methylation appears compatible with either loss or maintenance of expression. In addition treatment of two of the resistant cell lines with 5-azacytidine, a known inhibitor of methylation, results in re-expression of hMLH1. Clonogenic assays demonstrate that the 5-azacytidine treated cells show increased sensitivity to cisplatin. Furthermore, 12.5% (3/ 24) of ovarian tumours show hypermethylation of the hMLH1 promoter. Expression of hMLH1 is absent in the tumours that are hypermethylated, while all the unmethylated tumours still express the protein. This analysis suggests that methylation of the hMLH1 promoter may be a common mechanism for loss of hMLH1 expression, and possibly for cisplatin-resistance, in ovarian cancer.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Multicenter phase III trial to evaluate CD34(+) selected versus unselected autologous peripheral blood progenitor cell transplantation in multiple myeloma.

High-dose chemotherapy followed by autologous transplantation has been shown to improve response rates and survival in multiple myeloma and other malignancies. However, autografts frequently contain detectable tumor cells. Enrichment for stem cells using anti-CD34 antibodies has been shown to reduce autograft tumor contamination in phase I/II studies. To more definitively assess the safety and efficacy of CD34 selection, a phase III study was completed in 131 multiple myeloma patients randomized to receive an autologous transplant with either CD34-selected or unselected peripheral blood progenitor cells after myeloablative therapy. Tumor contamination in the autografts was assessed by a quantitative polymerase chain reaction detection assay using patient-specific, complementarity-determining region (CDR) Ig gene primers before and after CD34 selection. A median 3.1 log reduction in contaminating tumor cells was achieved in the CD34 selected product using the CEPRATE SC System (CellPro, Inc, Bothell, WA). Successful neutrophil engraftment was achieved in all patients by day 15 and no significant between-arm difference for time to platelet engraftment occurred in patients who received an infused dose of at least 2.0 x 10(6) CD34(+) cells/kg. In conclusion, this phase III trial demonstrates that CD34-selection of peripheral blood progenitor cells significantly reduces tumor cell contamination yet provides safe and rapid hematologic recovery for patients receiving myeloablative therapy.

Adolescent↗
PubMed1999

Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes.

Mismatch repair (MMR) proteins repair mispaired DNA bases and have an important role in maintaining the integrity of the genome [1]. Loss of MMR has been correlated with resistance to a variety of DNA-damaging agents, including many anticancer drugs [2]. How loss of MMR leads to resistance is not understood, but is proposed to be due to loss of futile MMR activity and/or replication stalling [3] [4]. We report that inactivation of MMR genes (MLH1, MLH2, MSH2, MSH3, MSH6, but not PMS1) in isogenic strains of Saccharomyces cerevisiae led to increased resistance to the anticancer drugs cisplatin, carboplatin and doxorubicin, but had no effect on sensitivity to ultraviolet C (UVC) radiation. Sensitivity to cisplatin and doxorubicin was increased in mlh1 mutant strains when the MLH1 gene was reintroduced, demonstrating a direct involvement of MMR proteins in sensitivity to these DNA-damaging agents. Inactivation of MLH1, MLH2 or MSH2 had no significant effect, however, on drug sensitivities in the rad52 or rad1 mutant strains that are defective in mitotic recombination and removing unpaired DNA single strands. We propose a model whereby MMR proteins - in addition to their role in DNA-damage recognition - decrease adduct tolerance during DNA replication by modulating the levels of recombination-dependent bypass. This hypothesis is supported by the finding that, in human ovarian tumour cells, loss of hMLH1 correlated with acquisition of cisplatin resistance and increased cisplatin-induced sister chromatid exchange, both of which were reversed by restoration of hMLH1 expression.

Antineoplastic Agents↗
PubMed1999

A two-factor model of the Depression Coping Questionnaire.

The original 11 factors reported for the 29-item Depression Coping Questionnaire (DCQ) unnecessarily limits its potential usefulness as a clinically interpretable self-report measure. Therefore, the goal of this study was to reduce the number of DCQ factors to equal the number of core dimensions of depression coping addressed by the measure. Study participants (N = 668) completed the original 29-item DCQ and the Center for Epidemiological Studies-Depression (CES-D) scale. The total sample was then split into two equal randomized subsamples. Using a factor loading value cutoff of .40, an initial LISREL exploratory factor analysis produced a 22-item, three-dimension model of positive (10 items), negative (8 items), and substance/sexual (4 items) depression coping behaviors. Because both the negative and substance/sexual dimensions addressed detrimental dimensions of depression coping, these factors were intercorrelated, however, the negative dimension accounted for greater variance. Consequently, given the stated goal of this study the model was then restricted to two core dimensions of positive and negative depression coping. Using the second split-half subsample, a LISREL confirmatory factor analysis produced a 17-item, two-factor model. One negative item (daydreaming) failed to maintain a loading value of .40 or higher and was deleted. The Goodness-of-Fit index for the 17-item, two-factor DCQ was .87 and the Root Mean Square Residual was .08. DCQ alpha coefficients were acceptable at .82 (positive) and .74 (negative). Significant CES-D subgroup differences and correlations were observed.

Adaptation, Psychological↗
PubMed1999

Suppression of glioblastoma cell growth following antisense oligonucleotide-mediated inhibition of fibroblast growth factor receptor expression.

Astrocytes exhibit significant changes in fibroblast growth factor receptor (FGFR) gene expression during malignant progression. These changes include induction of FGFR1 and concomitant loss of FGFR2 expression. The induction of FGFR1 is believed to endow malignant astrocytes with a selective growth advantage. Glioblastoma (the most malignant form of astrocytoma) cell lines, which exhibit the same pattern of FGFR gene expression as glioblastoma biopsies, were used to evaluate the contribution of FGFR1 expression to glioblastoma cell growth. Addition of phosphorothioate-modified antisense oligonucleotides complementary to the initiation site or the alpha exon of the FGFR1 gene suppressed growth of human glioblastoma-derived cell lines. Reverse antisense controls or antisense oligonucleotide complementary to FGFR2 had no effect on proliferation. Consistent with its growth-suppressive effect, FGFR1 antisense oligonucleotides markedly reduced expression of both FGFR1 mRNA and high-affinity bFGF binding sites, whereas FGFR1 reverse antisense control oligonucleotide had no effect. Antisense oligonucleotide targeted to the alpha exon of the FGFR1 gene suppressed alpha and beta alternatively spliced FGFR1 mRNA isoforms but did not alter the expression of related FGFR family members. Fluorescein-labeled antisense and reverse control oligonucleotides demonstrated cellular uptake and nuclear accumulation. These results indicate that alterations in FGFR expression may contribute to malignant proliferation in human astrocytomas. These findings also illustrate the high degree of selectivity that can be obtained with antisense oligonucleotides, a property that is essential for employing these reagents therapeutically.

Blotting, Southern↗
PubMed1999

The adaptiveness of mothers' working models of caregiving through the first year: infant and mother contributions.

How a mother's working model of caregiving develops through an infant's first post-term year has implications for the infant's health. Change in the adaptiveness of the working model of caregiving through the first year and influencing conditions (mother and infant) were examined for 33 premature infants and 44 full-term infants. Adaptiveness was coded from the transcription of a video-assisted interview at 1, 4, 8 and 12 months postterm age. Mother conditions included years of education, symptoms of depression, and evaluation of caregiving. Infant conditions included status at birth, birth weight, weight-for-age, and amenability of temperament. Hierarchical fixed occasions repeated measures analysis showed significant change in working-model adaptiveness with time. The highest adaptiveness scores were at 4 months and the lowest scores were at 8 months. At 8 months, mother's education had a significant positive effect on adaptiveness, mother's symptoms of depression had a negative effect, and infant weight-for-age had a positive effect. Further research is needed to learn what features of a mother's education enhance working model adaptiveness and to identify mechanisms that explain the effects of the infant's weight-for-age on adaptiveness.

Adaptation, Psychological↗
PubMed1999

Medical treatment patterns of ASCRS members for primary open-angle glaucoma--1998 survey.

A survey of medical treatment patterns for primary open-angle glaucoma (POAG) was mailed to all United States members of the American Society of Cataract and Refractive Surgery (ASCRS) in March 1998; 21.2% responded. Demographic information pertinent to glaucoma care was also obtained. The use of diagnostic ancillary tests, as well as the sequential order of preferred therapy, in 3 hypothetical patient populations was analyzed: patients with mild, moderate, and advanced POAG. Preferred medical therapy was cross-tabulated with number of years in practice, fellowship training in glaucoma, and geographic location.

Adult↗
PubMed1999

p53-oriented cancer therapies: current progress.

Nearly twenty years after the initial discovery of p53, we are now in an ideal position to exploit our vast knowledge of p53 biology in the creation of novel cancer therapies. Disruption of p53 function through mutation, or other means, occurs very frequently in human cancer. Loss of p53 function has been linked with unfavourable prognosis in a large number of tumour types, as indicated by more aggressive tumours, early metastasis and decreased survival rates. Many different avenues of research have converged upon p53 to highlight this protein as being one of the foremost cellular responders to stress, in particular to DNA damage. Huge advances have been made in understanding the complex role p53 plays in the regulation of apoptosis and cell cycle arrest. This review is not meant to be a comprehensive description of p53 biology, but rather serves to highlight current progress in the development of p53-oriented cancer therapies. These may be categorised into three basic strategies: gene replacement therapy using wild-type p53, restoration of p53 function by other means and, finally, targeting of the p53 dysfunction itself. Rapid progress is expected to be made regarding the identification of conventional pharmaceutical agents which either work in a p53-independent manner or act preferentially in p53 defective cells. Gene replacement therapy with wild-type p53 also holds considerable potential for obtaining clinically relevant results quickly. The other forms of cancer therapies based around p53 are much further behind in the developmental process, but may prove to more efficacious in the long run, especially in terms of specificity. As with many other fields, the innovation of successful p53-oriented cancer therapies is only limited by our understanding of p53 biology and the creative use of such knowledge.

Animals↗
PubMed1999

Autism and congenital blindness.

The nature of autism in congenitally blind children has long been a source of interest and perplexity. A group of nine congenitally blind children with an autism-like syndrome were closely matched on chronological age and verbal mental age with nine sighted autistic children, and were compared on the Childhood Autism Rating Scale (Schopler, Reichler, & Renner, 1986) and the Behavior Checklist for Disordered Preschoolers, together with the Play Items for Disordered Preschoolers (Sherman, Shapiro, & Glassman, 1983). A checklist of clinical features characteristic of autism (derived from DSM-III-R) was also completed through an interview with teachers. There was substantial similarity between the groups, but also suggestive evidence of possible group differences, specifically in the domain of social-emotional responsiveness. Research on the psychological development of congenitally blind children promises to yield insights into the nature of autism itself.

Affect↗
PubMed1999

Promoting patient participation in the cancer consultation: evaluation of a prompt sheet and coaching in question-asking.

Active participation in the medical consultation has been demonstrated to benefit aspects of patients' subsequent psychological well-being. We investigated two interventions promoting patient question-asking behaviour. The first was a question prompt sheet provided before the consultation, which was endorsed and worked through by the clinician. The second was a face to face coaching session exploring the benefits of, and barriers to, question-asking, followed by coaching in question-asking behaviour employing rehearsal techniques. Sixty patients with heterogeneous cancers, seeing two medical oncologists for the first time, were randomly assigned to one of three groups: two intervention groups and one control group. Sociodemographic variables and anxiety were assessed prior to the intervention which preceded the consultation. The consultations were audiotaped and subsequently analysed for question-asking behaviour. Anxiety was assessed again immediately following the consultation. Questionnaires to assess patient satisfaction, anxiety and psychological adjustment were sent by mail 2 weeks following the consultation. Presentation and discussion of the prompt sheet significantly increased the total number of questions asked and the number of questions asked regarding tests and treatment. Coaching did not add significantly to the effects of the prompt sheet. Psychological outcomes were not different among the groups. We conclude that a question prompt sheet addressed by the doctor is a simple, inexpensive and effective means of promoting patient question asking in the cancer consultation.

Adaptation, Psychological↗
PubMed1999

Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents.

Mismatch DNA repair deficiency is associated with resistance to certain major groove alkylating agents including methylating agents and cisplatin. We have now studied the relevance of mismatch repair alterations to the cytotoxicity induced by drugs which alkylate N3 adenines in the minor groove of DNA. We have used the mismatch repair defective human colocarcinoma cell line HCT-116 which has a mutation in the hMLH1 gene, and a subline where hMLH1 expression is restored by chromosome 3 transfer (HCT-116+ch3). We have tested three alkylating minor groove binders (tallimustine, carzelesin and CC1065) and one non-covalent minor groove binder (PNU 151807). The HCT-116+ch3 subline was more sensitive than the parental line to the treatment with the three alkylating minor groove binders, while the non-alkylating compound had a similar activity in both cell lines. Further support for mismatch repair being involved in sensitivity of the minor groove alkylators is that two cisplatin-resistant sublines of the human ovarian adenocarcinoma cell line A2780 (A2780/CP70 and A2780/MCP-1) are defective in hMLH1 expression and are more resistant to these agents than the parental mismatch repair proficient cells. Furthermore, the restoration of hMLH1 activity in the A2780/CP70 cell line, by introduction of chromosome 3, was associated with an increased sensitivity to the three alkylating minor groove binders. Again, the non-covalent minor groove binder was equally effective in mismatch repair deficient and proficient clones. The data indicate that mismatch repair deficiency mediated by loss of hMLH1 expression is associated not only with drug-resistance to major groove binders, but also to minor groove binders. However, loss of mismatch repair does not mediate resistance to the non-covalent minor groove binder PNU 151807.

Adenocarcinoma↗
PubMed1999

Successful treatment of cerebral toxoplasmosis in a marrow transplant recipient: contribution of a PCR test in diagnosis and early detection.

We report successful treatment of cerebral toxoplasmosis in an unrelated donor marrow transplant recipient. The clinical diagnosis was confirmed by polymerase chain reaction (PCR) amplification for T. gondii-DNA performed both on cerebrospinal fluid and blood leukocytes. Retrospective testing of stored blood samples demonstrated positive leukocyte PCR signal detected up to 52 days prior to onset of clinical symptoms. This case highlights the value of PCR in the diagnosis and early detection of cerebral toxoplasmosis.

Adult↗
PubMed1999

Tularemia--an unusual cause of a solitary pulmonary nodule in the post-transplant setting.

We report a case of tularemia presenting as a solitary pulmonary nodule following syngeneic PBSC transplant. Seven months after undergoing a syngeneic PBSC transplant for AML, our patient presented with fever without localizing signs. Chest X-ray revealed a solitary pulmonary nodule. Culture of a CT guided needle aspiration revealed Francisella tularensis. The patient was successfully treated with ciprofloxacin. His fever resolved and clearance of the nodule was documented on a CT scan 2 months after diagnosis and initiation of treatment. To our knowledge, this is the only reported case of tularemia occurring in the post-transplant setting. The possible relationship between transplant-induced immune dysfunction and the occurrence of this rare infection is discussed.

Anti-Infective Agents↗
PubMed1999

Stress and adaptation: preparation for successful retirement.

Retirement from work can present a significant adjustment challenge for the older population financially, socially and emotionally. Retirement has been identified as a significantly stressful event. Work provides both a structured activity within a regular time frame and a sense of purpose and daily meaning. Energy is channelled into intellectual, creative, and/or physical tasks that offer a sense of satisfaction when they are completed. The planning for retirement is associated with successful adaptation. A realization of the potential and rewards of retirement will also facilitate this adaptation.

Adaptation, Psychological↗