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Biomedical subjects

C West

Publications and source records attributed to C West.

At least 37 records · Page 2Linked to original sources
PubMed2003

Association of transforming growth factor beta-1 single nucleotide polymorphisms with radiation-induced damage to normal tissues in breast cancer patients.

PURPOSE: To investigate whether transforming growth factor beta-1 (TGFbeta1) single nucleotide polymorphisms were associated with the susceptibility of breast cancer patients to severe radiation-induced normal tissue damage. MATERIALS AND METHODS: PCR-RFLP assays were performed for TGFbeta1 gene polymorphisms on DNA obtained from 103 breast cancer patients who received radiotherapy. The G-800A, C-509T, T+869C and G+915C polymorphic sites were examined, and genotype and allele frequencies of two subgroups of patients were calculated and compared. RESULTS: The less prevalent -509T and +869C alleles were significantly associated with a subgroup of patients who developed severe radiation-induced normal tissue fibrosis (n=15) when compared with those who did not (n=88) (odds ratio=3.4, p=0.0036, and 2.37, p=0.035, respectively). Furthermore, patients with the -509TT or +869CC genotypes were between seven and 15 times more likely to develop severe fibrosis. CONCLUSIONS: These findings imply a role for the -509T and +869C alleles in the pathobiological mechanisms underlying susceptibility to radiation-induced fibrosis. Their predictive value would be limited to patients who are -509TT or +869CC, but if "fibrosis-associated" polymorphic sites in other genes could be identified, it may be possible to detect fibrosis prone individuals before radiotherapy with greater certainty.

Alleles↗
PubMed2002

A previously undescribed nonsense mutation of the HFE gene.

A patient with clinically manifest hereditary hemochromatosis was found to be heterozygous for the c.845 A-->G (C282Y) mutation. As simple heterozygotes for this mutation do not develop the hemochromatosis phenotype, the coding region of the patient's HFE gene was sequenced and a previously undescribed nonsense mutation was identified at c.211 C-->T (R74X). The patient's brother who also had the hemochromatosis phenotype shared his HFE genotype. To determine how common such mutations might be, the coding and 5' region of the HFE genes of 11 subjects who had been found in a large population survey to be heterozygous for the C282Y mutation and had elevated ferritin levels were sequenced. No mutations were found. Sequencing of the HFE gene also revealed two polymorphisms that had not previously been noted, -467 C-->G and -970 T-->G. Neither of these mutations appear to cause an abnormality in iron metabolism.

Codon, Nonsense↗
PubMed2002

A chimeric mouse model of Gaucher disease.

BACKGROUND: There is a major need for a mouse model of Gaucher disease, but the glucocerebrosidase knockout mouse is not viable; it dies shortly before or immediately after birth, apparently because of involvement of the central nervous system and/or skin. The most common form of Gaucher disease, type I, has a phenotype that is limited to the monocyte-macrophage system. MATERIALS AND METHODS: We have created a chimeric mouse by infusing hematopoietic stem cells from fetuses that are homozygous for the glucocerebrosidase knockout into irradiated mice. RESULTS: The chimeric mice manifested a severe deficiency of glucocerebrosidase activity in peripheral blood cells and spleen indicating a lack of cell-cell correction. Levels of glucocerebroside in spleen and liver are increased, and infusing the mice with exogenous glucocerebroside/albumin particles produced a marked increase in the amount of glucocerebroside stored in liver and spleen. Morphologically identifiable Gaucher cells were not present. CONCLUSIONS: The chimeric model reflects the increased glycolipid storage in the reticuloendothelial system that is characteristic of Gaucher disease, and could be useful as a model for studying treatment of Gaucher disease.

Animals↗
PubMed2001

Intra-follicular activin availability is altered in prenatally-androgenized lambs.

Prenatal exposure of sheep to testosterone (T) disrupts ovarian cyclicity and leads to anovulation in adulthood. We propose that the disruption of ovarian function in prenatally-androgenized sheep is mediated via follicular defects stemming from reduced intrafollicular activin availability/action. The intra-follicular activin availability/action that facilitates follicular development is dictated by the relative proportions of activins, inhibins (antagonists of activin action) and follistatins (FS; binding proteins of activin and negator of activin action). Inhibin alpha, beta A, beta B, and FS mRNA expression were determined by in situ hybridization in 5 week-old ovaries from control (C) lambs or those exposed to testosterone (T) or DHT from 30-90 days of gestation. In utero exposure to T, but not DHT, increased total ovarian weight (0.4+/-0.1,1.5+/-0.5 and 0.3+/-0.1 g, C, T and DHT, respectively) and total number of follicles (16.5+/-2.8,37.8+/-7.9, and 18.8+/-3.0). With the exception of two follicles in T animals, all follicles were < or = 2 mm in diameter. All follicles < or = 2 mm in all groups expressed FSH receptor mRNA in the granulosa cells and LH receptor only in the thecal cells. The percentage of follicles expressing FS mRNA was increased (P<0.05) in sheep prenatally-androgenized with either T (80.4+/-8) or DHT (80.3+/-5.5) as compared to C (50.8+/-8.2). In contrast, the percentage of follicles expressing activin beta B mRNA tended to be lower (P=0.06) in the T (30.9+/-7.1) and DHT (40.5+/-3.3) groups as compared to C (66.1+/-15.6). Increased expression of FS along with the reduced expression of activin beta B mRNA provides evidence for compromised intra-follicular activin availability in the majority of follicles in the androgenized groups. The increase in ovarian weight and follicular number in the T, but not in the DHT group, suggests that the effects of T are mediated through the action of estrogen. We speculate that the decrease in relative abundance of activin may contribute to the selection defects in prenatally-androgenized sheep. If true, this may be a useful model to understand the etiology of polycystic ovarian syndrome.

Activins↗
PubMed2001

Lack of adherence with the analgesic regimen: a significant barrier to effective cancer pain management.

PURPOSE: To evaluate oncology outpatients' level of adherence to their analgesic regimen during a 5-week period. PATIENTS AND METHODS: A random sample of 65 adult oncology outpatients with a Karnofsky performance status score of >or= 50, an average pain intensity score of >or= 2.5, and radiographic evidence of bone metastasis were recruited for this longitudinal study from seven outpatient settings. On a daily basis, patients rated their level of pain intensity and recorded pain medication intake. Adherence rates for opioid analgesics prescribed on an around-the-clock (ATC) and on an as-needed (PRN) basis were calculated on a weekly basis. RESULTS: Overall adherence rates for ATC opioid analgesics ranged from 84.5% to 90.8% and, for PRN analgesics, from 22.2% to 26.6%. No significant differences over time were found in either of these adherence rates. CONCLUSION: One factor that seems to contribute to ineffective cancer pain management is poor adherence to the analgesic regimen.

Analgesics↗
PubMed2001

Small molecule/nucleic acid affinity chromatography: application for the identification of telomerase inhibitors which target its key RNA/DNA heteroduplex.

The purpose of this work is to develop methods for identifying high-affinity nucleic acid binding species from soluble mixtures of compounds. We have developed and applied an affinity chromatography method for identifying small molecules with high affinity for the telomerase RNA/DNA duplex. An affinity resin was derivatized with an RNA/DNA duplex which represents the key structure that forms during telomerase's catalytic cycle. A soluble mixture of compounds was applied to this resin and the compounds which bound to the highest extent were also confirmed to be the best inhibitors of the enzyme. This correlation of affinity for the RNA/DNA duplex with telomerase inhibition both supports the duplex as the target of these compounds, and suggests that the affinity method may be applied for the identification of higher affinity inhibitors from soluble mixtures of compounds.

Catalysis↗
PubMed2001

Radiation response and cure rate of human colon adenocarcinoma spheroids of different size: the significance of hypoxia on tumor control modelling.

PURPOSE: To evaluate the adequacy of a Poisson tumor control probability (tcp) model and the impact of hypoxia on tumor cure. METHODS AND MATERIALS: A human colon adenocarcinoma cell line, WiDr, was grown as multicellular spheroids of different diameters. Measurements were made of cell survival and spheroid cure following 300-kV X-ray external beam irradiation in air and nitrogen. Cell survival data were fitted using a two-compartment and an oxygen diffusion model. Spheroid cure data were fitted using the tcp model. RESULTS: Hypoxia was seen only for spheroids greater than 500 microm in diameter. For small spheroids tcp estimates of radiosensitivity and clonogenic number showed excellent agreement with experimentally derived values. For large spheroids, although tcp estimates of radiosensitivity were comparable with measurements, estimates of the clonogenic number were considerably lower than the experimental count. Reoxygenation of large spheroids before irradiation resulted in the tcp estimates of the number of clonogenic cells agreeing with measured values. CONCLUSIONS: When hypoxia was absent, the tcp model accurately predicted cure from measured radiosensitivity and clonogen number. When hypoxia was present, the number of cells capable of regrowth in situ was considerably lower than the number of clonogenic cells that initially survived irradiation. As this counteracted the decreased radiosensitivity, hypoxia was less important for cure than predicted from cell survival assays. This finding suggests that chronic hypoxia may not limit directly the success of radiation therapy.

Adenocarcinoma↗
PubMed2001

Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma.

PURPOSE: This study was designed to compare tumor hypoxia assessed by invasive O2 sensitive electrodes and pimonidazole labeling in primary human cervix carcinomas. METHODS AND MATERIALS: Twenty-eight patients with primary cervix carcinomas (FIGO Stage Ib-IVa) were investigated. Both invasive pO2 measurements and pimonidazole labeling were obtained in all patients. Before treatment, patients were given pimonidazole as a single injection (0.5 g/m2 i.v.). Ten to 24 h later, oxygenation measurements were done by Eppendorf histography, and after this procedure biopsies were taken for pimonidazole-binding analysis. Tumor oxygen partial pressure (pO2) was evaluated as the median tumor pO2 and the fraction of pO2 values < or = 10 mmHg (HF10). Biopsies were formalin fixed and paraffin embedded, and hypoxia was detected by immunohistochemistry using monoclonal antibodies directed against reductively activated pimonidazole. Pimonidazole binding was evaluated by a semiquantitative scoring system. RESULTS: Both Eppendorf measurements and pimonidazole binding showed large intra-and intertumor variability. A comparison between pimonidazole binding expressed as the fraction of fields at the highest score and HF10 showed a trend for the most well-oxygenated tumors having a low fraction of fields; however, the correlation did not reach statistical significance (p = 0.43, r = 0.165; Spearman's rank correlation test). CONCLUSION: Hypoxia measured in human uterine cervix carcinomas is heterogeneously expressed both within and between tumors when assessed by either invasive pO2 measurements or pimonidazole binding. Despite a trend that tumors with high pO2 values expressed less pimonidazole binding, no correlation was seen between the two assays in this preliminary report.

Adult↗
PubMed2001

Targeting telomerase via its key RNA/DNA heteroduplex.

Telomerase is a promising "universal" anticancer target. It has been demonstrated that inhibition of telomerase leads to mortalization and death of previously immortal cell lines. We are interested in targeting telomerase by binding to the RNA/DNA duplex that forms during its catalytic cycle. The RNA strand of this duplex is a component of telomerase and acts as a template to direct the synthesis of the single-stranded DNA telomere. We have hypothesized that molecules that bind to this duplex will inhibit the enzyme by either preventing strand dissociation or by sufficiently distorting the substrate, thereby causing a misalignment of key catalytic residues. To test this hypothesis we have examined the activity of telomerase in the presence of a range of intercalating molecules, known for their broad duplex binding properties. Of the nine compounds we examined, four show promising lead activity in the low micromolar range. A kinetic analysis of the telomeric products suggests that these compounds do not act by stabilizing G-quartets, thereby supporting the telomeric RNA/DNA heteroduplex as the site of action. We anticipate using these lead compounds as the basis for combinatorial variation to increase the affinity and specificity for the target telomerase.

DNA↗
PubMed2001

Large-scale molecular screening for galactosemia alleles in a pan-ethnic population.

DNA samples from 4,796 subjects from diverse ethnic groups were screened for five frequently encountered galactose-1-phosphate uridyl transferase (GALT) mutations: S135L (cDNA nt 404C-->T, as numbered from the initiator ATG codon, with A=1); Q188R (cDNA nt 563A-->G); K285 N (cDNA nt 855G-->T); the Duarte variant, N314D (cDNA nt 940A-->G); and the Los Angeles variant, which contains L218L (cDNA nt 652C-->T) and N314D. Among Whites, the gene frequency of the Q188R mutation was 0.29%, and that of the K285 N mutation was 0.062%. Only one S135L mutation was encountered among 505 African-Americans (gene frequency 0.10%). The pan-ethnic gene frequencies of the Duarte and the Los Angeles variants were 5.1% and 2.7%, respectively. Both of these frequencies were significantly less among African-Americans and Asians than among Whites and Hispanics. Native Americans revealed a higher incidence of the both variants. Based upon the gene frequency of the Q188R mutation in the White population, the birth incidence of classic galactosemia is estimated at one patient per 47,000 in the White population. This prevalence would be increased by inbreeding. It agrees well with the results from newborn screening programs and is only minimally higher than that reported in most studies, suggesting that most, if not all, infants with the galactosemia genotype are born and survive sufficiently long to be screened.

Alleles↗
PubMed2001

The prediction of mental health service use in residential care.

The purpose of this study was to characterize the clinical and psychosocial factors of residents living in psychiatric nursing homes, assess residents' levels of mental health service utilization, and examine the factors that predict the utilization of mental health services. Data were collected from 200 randomly selected residents with schizophrenia living in four intermediate care facilities. Fewer than 60% of residents received mental health services beyond medication and nearly one-half of the residents were readmitted to the hospital in the course of a year. Family contact and involvement in activities were associated with mental health service utilization. Hospital readmission was predicted, not by substance use, but rather by not using substances. There is a growing need among service providers to better identify relevant factors that are important in treatment planning and service delivery. Attention to these issues may impact treatment provision and outcomes for persons with schizophrenia and their families.

Activities of Daily Living↗
PubMed2001

A study of the application of a frequency transposition hearing system in children.

The aim of this retrospective study was to investigate the use of the frequency transposition Transonic FT 40 system in a group of 36 children with profound sensorineural hearing loss. The group comprised 36 children (11 boys, 25 girls) aged between 2.8 and 15.6 years (mean 7.6 years) at fitting of the FT 40 device. At 48 months post-FT 40 fitting, only 11 children (30%) were still wearing the device. The children discontinued wearing the FT 40 for the following reasons: ergonomic (11%); no perceived benefit from the system (11%); cosmetic (17%); and subsequent cochlear implantation (30%). The performance of the long-term FT 40 users was investigated using the following outcome measures: aided soundfield hearing thresholds: closed set speech tests (the E2L toy test and the Manchester Picture Test discrimination test) and a speech intelligibility rating score. The 11 long-term FT 40 users (three boys, eight girls) were aged from 5.3 to 12.9 years (mean 7.2 years) at the time of initial fitting of the FT 40 device. At time of fitting, the aided soundfield thresholds with the FT 40 were significantly better at 500 Hz (p<0.04), 1 kHz (p<0.019), 2 kHz (p<0.001) and 4 kHz (p <0.001) compared to thresholds with conventional hearing aids. Six of 11 children did not show any change in performance on the closed set speech tests and two children had intelligible speech at 48 months' follow-up. A small subgroup of good performers was identified. These children were younger at age of fitting (mean 6.2 years compared to a mean of 7.7 years for the remainder of the group), were predominantly oral communicators and had identified aetiologies for their deafness. The present study suggests that there is a small subgroup of hearing-impaired children who benefit from frequency transposition hearing systems, and future suggested fitting criteria and outcome measures are listed.

Acoustic Stimulation↗
PubMed2001

Ovarian estrogen receptor-beta (ERbeta) regulation: I. Changes in ERbeta messenger RNA expression prior to ovulation in the ewe.

Ovarian growth and development are critically dependent upon the influence of endogenous estrogens, and both are highly regulated during the reproductive cycle. The observation that estrogen-receptor-alpha-deficient mice still exhibit follicular growth and development, together with other evidence, suggests that responsiveness of the ovary to estradiol occurs predominantly through the second estrogen receptor, ERbeta. We characterized the physiological regulation of ERbeta expression in ovarian follicles during the follicular phase of sheep that were synchronized for estrus during the breeding season with intravaginal progesterone implants (controlled internal drug release [CIDR] device; InterAg, Hamilton, New Zealand). Ovaries were removed at times corresponding to the early (EF) and late follicular phases (LF) of the ovine estrous cycle (12 h [n = 5] and 32 h [n = 5] after CIDR device removal, respectively). Sections of ovary were then hybridized with a cRNA probe corresponding to the 5' region of ovine ERbeta. ERbeta mRNA expression within the granulosa layer of different size follicles (size classes: < or =3 mm, 3.1-4.0 mm, 4.1-5.0 mm, >5 mm) was quantified. ERbeta mRNA expression varied both with follicle size (P < 0.01) and with cycle stage (P < 0.01). In EF ewes, the highest levels of ERbeta mRNA expression were found in follicles < or = 3 mm in size. ERbeta mRNA expression declined progressively thereafter among the different size classes with lowest levels expressed in >5-mm follicles. By contrast, expression of ERbeta mRNA in the 3.1- to 4.0-mm follicles of LF group was significantly higher than in the < or =3-mm size follicles and declined thereafter progressively to the >5-mm size levels as in the EF group. Furthermore, expression of ERbeta mRNA in < or =3-mm size follicles of LF group was significantly lower than the corresponding size class in the EF group. Lower expression of ERbeta mRNA in >5-mm follicle is suggestive of a down-regulation by the local estrogen milieu.

Animals↗
PubMed2001

Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix.

Hypoxic tumors are known to be more malignant, to be more likely to metastasize, and to have a poor prognosis. They are also radio- and chemoresistant. For this reason, it is desirable that a clinically useful marker of hypoxia is found, so that treatment with radiotherapy and bioreductive chemotherapy can be rationally applied to individual patients. Glut-1 is a facilitative glucose transporter that is ubiquitously expressed in normal tissue and expressed at higher levels in a number of tumors. Its potential as an intrinsic hypoxia marker arises from its dual control in hypoxic conditions by reduced oxidative phosphorylation and the hypoxia-inducible factor (HIF-1) oxygen-sensing pathway. Eppendorf histography, by virtue of its proven predictive qualities, is a suitable gold standard used in our laboratory to validate new hypoxia markers. Using this technique, pretreatment pO(2) measurements were performed on 54 patients with locally advanced cervical carcinoma. Then, immunohistochemical staining was used to detect Glut-1 protein in individual tumor biopsy sections. Both measurements were made before initiation of treatment. By using a low-tech scoring system, pO(2) was found to correlate weakly with Glut-1 score (r = 0.28; P = 0.04). To extrapolate this correlation to the known adverse effects of tumor hypoxia on outcome, we examined the prognostic significance of Glut-1 staining in a retrospective series of 121 patients. An absence of Glut-1 significantly increased the likelihood of metastasis-free survival (P = 0.022) but did not significantly effect disease-free or recurrence-free survival. These findings suggest that Glut-1 be an intrinsic marker of hypoxia that can easily be applied in a clinical setting.

Biomarkers, Tumor↗
PubMed2000

Tumor radiosensitivity (SF2) is a prognostic factor for local control in head and neck cancers.

PURPOSE: To evaluate prospectively the prognostic value of SF2 for local control and survival in patients undergoing radiation therapy for head and neck cancers. METHODS AND MATERIALS: Following informed consent tumor specimens were obtained from 156 patients with primary carcinomas of the head and neck region. The specimens were assessed for the ability to grow in vitro (colony forming efficiency, CFE) and inherent radiosensitivity measured as the surviving fraction at 2 Gy (SF2) using a soft-agar clonogenic assay. Patients were treated mainly with neoadjuvant chemotherapy plus radiation therapy usually as a combination of accelerated external beam and interstitial radiotherapy. The probabilities of local control and survival were analyzed by univariate, bivariate and Cox multivariate analyses. RESULTS: Successful growth was achieved in 110/156 specimens and SF2 values were obtained from 99/156. Eighty four out of these patients underwent radical treatment. The median SF2 value for the 84 tumors was 0.40. At a mean follow-up time of 25 months (range 7-65) the median SF2 value of tumors from 14 patients who developed local recurrence was 0.53, which was significantly higher than the median of 0.38 for tumors from 70 patients without local recurrence (p = 0.015). Tumor SF2 was a significant prognostic factor for local control (p = 0.036), but not for overall survival (p = 0.20). Tumor SF2 was an independent prognostic factor for local control within bivariate and Cox multivariate analyses. CONCLUSIONS: This study has shown that tumor radiosensitivity measured as SF2 is a significant prognostic factor for local control in head and neck cancers.

Adult↗
PubMed2000

In vitro cytotoxicity of aromatic aerobic biotransformation products in bluegill sunfish BF-2 cells.

Toluene (methylbenzene) is a common environmental pollutant that is found in many hazardous waste sites and it is an aquifer contaminant. A concern is the potential risk to human and ecosystem health due to exposure to toluene and its major biotransformation products. The cytotoxicity of eight aromatic products of toluene aerobic biotransformation was investigated in bluegill sunfish BF-2 cells. The cytotoxicity was determined using several in vitro assay endpoints. BF-2 cells were propagated at 32 degrees C in an atmosphere of 5% CO2-95% air. The concentrations of these products causing 50% inhibition in cell replication, protein content, uptake of natural red, and colony formation were evaluated and compared. The results of the study indicate a direct relationship between the exposure concentration of these products and observed cytotoxic effects. In descending order of cytotoxicity, the compounds were 3-methylcatechol, 4-methylcatechol, catechol, o-cresol, p-cresol, m-cresol, benzaldehyde, and methyl benzoate.

Aerobiosis↗