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Biomedical subjects

L Frederick

Publications and source records attributed to L Frederick.

At least 19 recordsLinked to original sources
PubMed2000

Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas.

Several types of epidermal growth factor receptor (EGFR) gene mutations have been reported in glioblastomas, and in nearly all cases the alterations have been reported in tumors with EGFR amplification. The objectives of this study were to determine the frequency and diversity of EGFR mutations in glioblastomas and to determine whether gene mutation is inevitably associated with increased EGFR gene dosage. To accomplish these aims, we sequenced cDNA products representing the entire EGFR coding region in 44 glioblastomas, half of which had EGFR amplification. Coding sequence alterations were identified in 17 of the tumors, and each of these cases had amplified EGFR. No mutations were identified in the 22 tumors without EGFR amplification. An additional 26 glioblastomas with EGFR amplification were then examined to establish more reliable frequencies for each type of mutation identified in the tumors for which the entire gene was sequenced. Transcripts associated with the most common mutation lacked coding sequence for amino acids 6-273 (67%). This mutation has been described extensively in the literature. Transcripts encoding receptors that would truncate at amino acid 958 and transcripts encoding receptors that would lack amino acids 521-603 were the next most common types of alteration. Each of these were observed in 15% of the tumors with EGFR amplification. Other mutations were observed at lower frequencies, but among these were three cases with missense mutations. Sixteen of the 48 tumors with EGFR amplification showed multiple types of EGFR mutations (33%), and in one case it was determined that multiple alterations had occurred in the same transcript. In total, these data are consistent with EGFR mutation being exclusively and frequently associated with EGFR amplification. Furthermore, the determination of multiple EGFR mutations within individual tumors suggests that glioblastomas with EGFR amplification have the capacity to produce a variety of functionally distinct EGFRs.

Brain Neoplasms↗
PubMed2000

Analysis of genomic rearrangements associated with EGRFvIII expression suggests involvement of Alu repeat elements.

We have developed a polymerase chain reaction (PCR)-based strategy for the synthesis and analysis of rearranged epidermal growth factor receptor (EGFR) fragments associated with the vIII mutant receptor expressed in glioblastomas with EGFR amplification. The sequencing of aberrant tumor fragments showed that intragenic deletion rearrangements consistently involve an approximately 600-bp region in intron 7 of EGFR and several rearrangement sites interspersed throughout the large (>100 kb) first intron of this gene. Examination of the intron 7 breakpoint region revealed an Alu repeat element, and all intron 7 rearrangement sites were located within or downstream of this repeat sequence. Analysis of intron 1 for similar sequences resulted in the identification of 11 sites containing >80% homology with parts of the Alu element in intron 7. Reverse transcriptase-PCR and/or Western analysis of the tumors showed the presence of EGFRvIII cDNAs and/or proteins, respectively, in all cases for which a rearranged genomic fragment was generated by long-range PCR. Collectively, these data suggest that EGFR rearrangements, associated with the synthesis of the most common EGFR mutant, are mediated by a specific sequence element.

Brain Neoplasms↗
PubMed1999

Quality through metrics.

The Quality Assurance Unit analyzed 18 months of departmental data regarding the report-audit cycle. Process mapping was utilized to identify milestones in the cycle for measurement. Five milestones were identified in the audit cycle, as follows: (1) time from report receipt in quality assurance to start of audit, (2) total calendar days to audit a report, (3) actual person-hours to perform a report audit, (4) time from completion of audit to issuance of report, and (5) total time a report is in quality assurance. An interrelationship diagraph is a quality tool that is used to identify what activities impact the overall report-auditing process. Once the data collection procedure is defined, a spreadsheet is constructed that captures the data. The resulting information is presented in time charts and bar graphs to visually aid in interpretation and analysis. Using these quality tools and statistical analyses, the Quality Assurance Unit identified areas needing improvement and confirmed or dispelled previous assumptions regarding the report-auditing process. By mapping, measuring, analyzing, and displaying the data, the overall process was examined critically. This resulted in the identification of areas needing improvement and a greater understanding of the report-audit cycle. A further benefit from our increased knowledge was the ability to explain our findings objectively to our client groups. This sharing of information gave impetus to our clients to examine their report-generation process and to make improvements.

Data Collection↗
PubMed1999

Induced expression of CYP2A5 in inflamed trematode-infested mouse liver.

Trematode infections have long been associated with specific types of cancer. We investigated the ability of the liver fluke Fasciola hepatica to alter host enzymes in a manner that might provide insight into the phenomenon of biologically associated cancers. Our data demonstrate an increased activity of the CYP2A5 isozyme in male mouse liver infected with F.hepatica. Induction of this enzyme was further assessed immunohistochemically. The infection affected CYP2A5 distribution in hepatic tissue. Inflammation and proliferation in liver tissue were observed at the same time that CYP2A5 activity increased. This enzyme is known to participate in the metabolism of several carcinogens which are common contaminants in environments of developing countries where parasitic infections may be prevalent.

Animals↗
PubMed1999

Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation.

We have examined a series of 135 gliomas for alterations of the p53, CDKN2A (p16) and PTEN tumor suppressor genes (TSGs) in order to evaluate the incidence of their inactivation as a function of tumor malignancy and cellular differentiation, and to examine potential associations with patient outcome. The composition of this series, classified using WHO criteria, is as follows: 27 grade 2 tumors (11 astrocytomas, 12 oligoastrocytomas, 4 oligodendrogliomas), 42 grade 3 tumors (22 astrocytomas, 16 oligoastrocytomas, 4 oligodendrogliomas), and 66 grade 4 tumors (63 astrocytomas and 3 oligoastrocytomas). Similar frequencies of p53 mutation were observed among grade 2 (37.0%), and grade 3 tumors (38.1%), as well as between astrocytomas and mixed tumors. CDKN2A and PTEN mutations were clearly associated with increasing tumor malignancy (occurring in 0% of grade 2 tumors, 14.3% and 4.8% respectively of grade 3 tumors, and 27.3% and 30.3% respectively of grade 4 tumors) and were observed at substantially higher rates among astrocytomas. For the tumor suppressor genes examined, there was no relationship between the occurrence of any two TSG inactivation events. With regard to outcome, the p53 genetic status showed no significant relationship with patient survival. The CDKN2 and PTEN alterations were negative prognostic indicators of survival when evaluated in all 135 gliomas, but failed to predict outcome when evaluated in either of the high grade (3 or 4) tumor groups.

Adolescent↗
PubMed1999

Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations.

Although common among adult intracranial neoplasms, pediatric malignant astrocytomas (PMAs) comprise a relatively small proportion of the brain tumors that occur in children. The scarcity of such cases generally requires that molecular analyses of PMAs are based on the utilization of paraffin-embedded material, and here we have used 39 such specimens to examine the incidence and prognostic significance of oncogene and tumor suppressor gene alterations (including amplifications of EGFR, CDK4, and MDM2 as well as inactivating mutations of CDKN2A, TP53, and PTEN) in these tumors. In general, the frequency of alteration for the genes we have studied fell within ranges that have been reported for adult astrocytomas. However, EGFR amplification, which is usually observed in approximately 40% and 15% of adult grade 4 and grade 3 astrocytomas, respectively, was not detected in any member of this series. With regard to prognosis, PTEN mutations were significantly associated with decreased survival among grade 3 and grade 4 PMA patients, a potentially important observation because neither patient age nor tumor malignancy grade was correlated with outcome for these individuals. In total, our data suggest at least one significant distinction between the genetic etiology of pediatric and adult astrocytomas and additionally reveal that analysis of PTEN mutations in PMA patients may be useful in the differential diagnosis of these tumors.

Adolescent↗
PubMed1998

Analysis of EGF receptor amplicons reveals amplification of multiple expressed sequences.

In this study we have examined the epidermal growth factor receptor gene (EGFR) region for the amplification of novel expressed sequences in 28 glioblastoma tumors and two cell lines with EGFR gene amplification. Southern analysis with expressed sequence tag (EST) probes revealed instances of amplification for 11 of 13 loci investigated. Northern blot analysis with the same probes indicated that three ESTs identified transcripts that are over-expressed in cell lines having corresponding sequence amplification. The determination of increased dosage and transcript levels for multiple expressed sequences raises the possibility that there are genes in addition to EGFR whose elevated expression contribute to the biologic behavior of tumors with amplification of this region.

ErbB Receptors↗
PubMed1998

3' end structure and rearrangements of EGFR in glioblastomas.

Rearrangements of EGFR are known to occur in a significant fraction of glioblastomas, the most common and malignant form of central nervous system tumor. Although the consequences of these alterations have been described at the mRNA and protein level, little is known about human EGFR genomic sequence or organization at the rearrangement sites. To investigate one group of alterations in glioblastoma, we used long-range PCR to synthesize a segment of the gene near its 3' end, which is frequently rearranged in tumors with EGFR amplification. The sequence of this PCR product provided a precise map for the five 3'-terminal exons of EGFR, designated as exons 22-26. Ten tumors were identified with rearrangements in this part of the gene, most of which resulted in the loss of 325 coding bases that constitute exons 23-25. No two tumors shared identical donor or acceptor rearrangement sites, and the examination of sequences at these sites failed to support homologous recombination as a mechanism responsible for any of the rearrangements. However, examination of the entire exon 22-26 region for sequence motifs associated with genomic instability identified two large, CA-rich tracts in intron 25.

3' Untranslated Regions↗
PubMed1997

PTEN/MMAC1 mutations and EGFR amplification in glioblastomas.

Loss of heterozygosity (LOH) from chromosome 10 is a hallmark of glioblastoma, the most malignant (grade IV) form of glioma. A candidate tumor suppressor gene, PTEN/MMAC1, that may be targeted for deletion in association with chromosome 10 LOH has recently been identified. Here we have investigated 63 glioblastomas for PTEN/MMAC1 alterations and identified DNA sequence changes that would affect the encoded protein in 17 (27%) tumors. Microsatellite analyses of normal-tumor DNA pairs were performed on 14 of these cases and revealed LOH at locations flanking and/or near PTEN/MMAC1 in all but 1 instance, suggesting that deletion of the remaining wild-type allele had occurred in the large majority of tumors with PTEN/MMAC1 mutations. Competitive PCR assays were developed to address the possible occurrence of PTEN/MMAC1 homozygous deletions in glioblastomas, and this analysis identified three samples having loss of both PTEN/MMAC1 alleles. EGFR amplification was determined to occur at similar frequencies among cases with or without PTEN/MMAC1 homozygous deletions or mutations, suggesting that a growth-promoting effect resulting from amplification-associated increases in epidermal growth factor receptor signaling is not necessarily dependent on the inactivation of PTEN/MMAC1.

Alternative Splicing↗
PubMed1997

Sporadic medulloblastomas contain PTCH mutations.

Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin's syndrome, is an autosomal dominant disorder that predisposes to developmental defects and various forms of cancer. PTCH was recently proposed as a candidate gene for NBCCS due to its frequent mutation in basal cell carcinomas, the cancer most often associated with this syndrome. Another NBCCS-associated cancer is medulloblastoma, a common central nervous system tumor in children. Most medulloblastomas, however, occur without indication of an inherited predisposition. We have examined 24 sporadic medulloblastomas for loss of heterozygosity (LOH) at loci flanking as well as within PTCH. In cases with LOH, single-strand conformational polymorphism and sequencing analysis were performed to determine the status of the remaining PTCH allele. Microsatellite analysis indicated LOH of PTCH in 5 of 24 tumors, and in three of these cases a mutation of the remaining allele was identified. Two of the mutations were duplication insertions, and the third consisted of a single base deletion. It is interesting that all three mutations occur in exon 17 of the PTCH gene. These data suggest that inactivation of PTCH function is involved in the development of at least a subset of sporadic medulloblastomas.

Chromosomes, Human, Pair 9↗
PubMed1995

Quality improvement with a culturally diverse staff: implications for nurse managers.

Cultural diversity is a noticeable reality in today's work force. The problems resulting from cultural diversity pose special challenges to nurse managers. If nurse managers are to be successful at managing diversity, they need to not only be aware of the specific issues created by diversity, but they must plan effective management and leadership strategies to enable staff to collectively meet the desired goals of the work setting. The authors of this article are employed in one of the most culturally diverse work settings in the world. Their experiences in successfully implementing a quality improvement program, and in using strategies to gain shared vision and commitment by management and staff, will be explored and the implications for nurse managers outlined.

Cultural Characteristics↗
PubMed1992

A comparison of nutrition knowledge and attitudes, dietary practices, and bone densities of postmenopausal women, female college athletes, and nonathletic college women.

This study evaluated the nutrition knowledge and attitudes, dietary practices, and bone densities of four groups of women: 18 postmenopausal women, 14 college-aged dancers, 13 members of a college track team, and 14 nonathletic college women. Subjects completed a personal information questionnaire, a 24-hour food recall, a food frequency questionnaire, a nutrition knowledge test, and an attitude survey; measurements of the subjects' spinal bone density were also taken. The mean (+/- 0.5 standard error [SEM]) nutrition knowledge score of the dancers (22.5) was significantly lower than the mean scores of the postmenopausal women (28.5), the nonathletes (29.7), and the track team members (26.5). Dancers also reported eating fewer mean (+/- 4.0 SEM) servings of high-calcium foods per month (43) than did postmenopausal women (77), nonathletes (66), or track team members (73). Track team members had a significantly higher mean (+/- 0.2 SEM) anorexia/bulimia score (3.7) than did postmenopausal women (2.5), nonathletes (2.1), or dancers (2.2). There were no significant differences in bone mineral density among the four groups. The number of servings of high-calcium foods eaten was significantly correlated with nutrition knowledge scores (r = .38) and attitude scores (R = .32), but nutrition knowledge and attitude scores were not significantly correlated with each other. The track team members exercised significantly more than women in all other groups--mean (+/- 40 SEM) minutes exercise time was 700 minutes/week for track team members, 79 minutes/week for postmenopausal women, 92 minutes/week for nonathletes, and 500 minutes/week for dancers--and also experienced the most amenorrhea.

Adolescent↗