Biomedical subjects

A Perry

Publications and source records attributed to A Perry.

At least 37 records · Page 2Linked to original sources

PubMed2001

PS6K amplification characterizes a small subset of anaplastic meningiomas.

PS6K, a putative oncogene mapped to chromosome 17q23, encodes a serine/threonine kinase, which phosphorylates ribosomal subunit 6 and is part of the insulin receptor signal transduction pathway involved in the regulation of messenger RNA translation, protein synthesis, cell cycle progression, and cell size. Comparative genomic hybridization studies have detected 17q23 amplifications in a subset of meningiomas, particularly those with aggressive histologic features. PS6K amplifications have been reported in breast cancer, another hormonally driven neoplasm. We assessed PS6K dosage in 94 archival paraffin-embedded meningiomas using dual-color fluorescence in situ hybridization. We found high-level PS6K amplifications in 3 of 22 anaplastic grade III meningiomas. Amplification was confirmed by differential polymerase chain reaction in 1 of these cases. In contrast, no amplifications were identified in 37 benign (grade I) and 35 atypical (grade II) meningiomas. To our knowledge, this represents the first report of gene amplification in primary human meningiomas. Given its exclusive association with anaplastic meningiomas, PS6K amplification likely occurs during the malignant progression of a small subset of anaplastic tumors. Further studies are needed to map the 17q23 amplicon to determine whether additional genes in this region are amplified in high-grade meningiomas.

DNA Primers↗

PubMed2001

Attitudes toward suicide prevention in front-line health staff.

A questionnaire assessing attitudes toward suicide prevention was constructed and shown to have satisfactory reliability and internal consistency. The determinants and distribution of these attitudes were investigated in four groups of health professionals who are in contact with suicidal patients: general practitioners, accident and emergency nurses, psychiatrists in training, and community psychiatric nurses. Attitudes toward suicide prevention were shown to differ significantly between professional groups. More positive attitudes were associated with mental health professionals, working in the community, and previous training in suicide risk assessment. Negative attitudes should be assessed and targeted in training designed to improve the management of suicide risk.

Analysis of Variance↗

PubMed2001

Evaluating pediatric brain tumor cellularity with diffusion-tensor imaging.

OBJECTIVE: MR imaging of central nervous system (CNS) malignancies falls short of a definitive evaluation. Tissue diagnosis remains the gold standard. Diffusion-tensor MR imaging measures the apparent diffusion coefficient and diffusion anisotropy of water in tissue. The purpose of this study was to test the hypothesis that the apparent diffusion coefficient may improve the MR imaging evaluation of newly diagnosed CNS neoplasms. We examined the relationship between the apparent diffusion coefficient, anisotropy, and tumor cellularity in 12 pediatric patients. MATERIALS AND METHODS: On the basis of histopathologic evaluation, tumors in this case series were segregated into three types: low-grade gliomas, embryonal tumors, and nonembryonal high-grade tumors. Mean apparent diffusion coefficient and anisotropy values obtained from the solid components of each tumor were compared with cellularity, total cellular area, and total nuclear area derived from biopsy material. RESULTS: The apparent diffusion coefficient ratio (tumor to normal brain) correlated well with tumor classification (p = 0.001). Anisotropy was decreased similarly in all tumor classifications. The absolute apparent diffusion coefficient correlated well with cellularity (p = 0.014) and total nuclear area (p = 0.005) per high-power field. The correlation between apparent diffusion coefficient and total cellular area per high-power field was not statistically significant. CONCLUSION: The apparent diffusion coefficient may be predictive of tumor classification and may be a useful tool in characterizing tumor cellularity and total nuclear area. These parameters are not available in standard MR imaging. Therefore, diffusion-tensor imaging may enhance the diagnostic process in pediatric CNS malignancies.

Adolescent↗

PubMed2001

Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic features.

OBJECT: Medulloblastoma is the most common malignant central nervous system neoplasm found in children. A distinct variant designated large cell/anaplastic (LC/A) medulloblastoma is characterized by frequent dissemination of cerebrospinal fluid (CSF) at presentation and a more aggressive clinical course. The authors report on their examination of the clinicopathological and genetic features of seven such cases encountered at their institution. METHODS: Eighty cases of medulloblastomas were reviewed and seven (8.8%) of these were believed to fit the histological and immunohistochemical criteria for LC/A medulloblastoma. In three cases (43%) either desmoplastic or classic medulloblastoma was the underlying subtype, and in two cases (28%) the LC/A tumor was found within the setting of medullomyoblastoma. Fluorescence in situ hybridization was used in six of the seven cases to characterize the presence of isochromosome 17q, deletion of chromosome 22q (a deletion characteristically found in atypical teratoid/rhabdoid tumors), and c-myc amplification. The patients' clinical histories revealed CSF dissemination in all cases and lymph node metastasis in one case. Isochromosome 17q was found in five (83%) of six cases. Evidence of chromosomal gains indicated aneuploidy in three tumors (50%), and amplification of c-myc was found in three tumors (50%). No 22q deletions were encountered. CONCLUSIONS: A high percentage of LC/A medulloblastomas arise within a background of typical medulloblastomas or medullomyoblastomas. As is the case in conventional medulloblastomas, the presence of 17q is a common early tumorigenic event; however, in a significant percentage of specimens there is also evidence of aneuploidy and/or amplification of c-myc. These findings indicate that LC/A morphological characteristics reflect a more advanced tumor stage than that found in pure medulloblastomas or in typical medullomyoblastomas.

Adolescent↗

PubMed2000

Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas.

Meningiomas are common nervous system tumors, whose molecular pathogenesis is poorly understood. To date, the most frequent genetic alteration detected in these tumors is loss of heterozygosity (LOH) on chromosome 22q. This finding led to the identification of the neurofibromatosis 2 (NF2) tumor suppressor gene on 22q12, which is inactivated in 40% of sporadic meningiomas. The NF2 gene product, merlin (or schwannomin), is a member of the protein 4.1 family of membrane-associated proteins, which also includes ezrin, radixin and moesin. Recently, we identified another protein 4.1 gene, DAL-1 (differentially expressed in adenocarcinoma of the lung) located on chromosome 18p11.3, which is lost in approximately 60% of non-small cell lung carcinomas, and exhibits growth-suppressing properties in lung cancer cell lines. Given the homology between DAL-1 and NF2 and the identification of significant LOH in the region of DAL-1 in lung, breast and brain tumors, we investigated the possibility that loss of expression of DAL-1 was important for meningioma development. In this report, we demonstrate DAL-1 loss in 60% of sporadic meningiomas using LOH, RT-PCR, western blot and immunohistochemistry analyses. Analogous to merlin, we show that DAL-1 loss is an early event in meningioma tumorigenesis, suggesting that these two protein 4.1 family members are critical growth regulators in the pathogenesis of meningiomas. Furthermore, our work supports the emerging notion that membrane-associated alterations are important in the early stages of neoplastic transformation and the study of such alterations may elucidate the mechanism of tumorigenesis shared by other tumor types.

Animals↗

PubMed2000

Synthesis and antiviral activity of acyclovir-5'-(phenyl methoxy alaninyl) phosphate as a possible membrane-soluble nucleotide prodrug.

We describe a synthesis of acyclovir-5'-(phenyl methoxy alaninyl) phosphate (2) from acyclovir (1). This compound was designed to act as a lipophilic, membrane-soluble prodrug of the free nucleotide. However, the biological activities of this derivative against a range of viruses indicated poor intracellular phosphate delivery, in marked contrast to the earlier successful delivery of several dideoxy anti-HIV nucleotides.

Acyclovir↗

PubMed2000

Mapping of the chromosome 19 q-arm glioma tumor suppressor gene using fluorescence in situ hybridization and novel microsatellite markers.

Allelic loss of chromosome arm 19q is a frequent event in human diffuse glioma, suggesting the presence of a tumor suppressor gene. Previous loss of heterozygosity (LOH) analyses have mapped this gene to a 1.4-megabase interval, between the genetic markers D19S412 and STD. Further narrowing of this interval has been limited by the resolution of mapped polymorphic markers. In the present study, we have used genomic clones mapped to 19q as fluorescence in situ hybridization (FISH) probes to map the breakpoints of 13 gliomas with 19q13.3 deletion boundaries. In addition, we have developed three new polymorphic microsatellite markers (D19S1180, D19S1181, and D19S1182) that map between D19S412 and STD and have used these new markers to identify two gliomas with small deletions between the D19S412 and STD markers. Collectively, these data suggest that the region of common deletion may be as narrow as 150 kb and should facilitate future efforts to identify the glioma 19q tumor suppressor gene.

Chromosome Deletion↗

PubMed2000

Dynamics and ordering in a spin-labeled oligonucleotide observed by 220 GHz electron paramagnetic resonance.

The dynamics of a newly synthesized cytosine spin-label and the spin-labeled pentamer TTC*TT have been observed by high-frequency (220 GHz) electron paramagnetic resonance (EPR) in aqueous solution at ambient temperature using only nanomolar amounts of spin-label. Temperature studies were carried out for both labeled species in buffer containing glycerol. The motion of the spin-labeled monomer could be fitted using a model of fully anisotropic rotation (FAR) over the entire temperature range studied. In the single-stranded pentamer, the high-field spectra are best interpreted using a model of microscopic ordering with macroscopic disorder (MOMD) with the probe in a highly nonpolar environment. The observed local order parameters of 0.60-0.70 suggest a micelle-like structure in which the label is tightly packed with the hydrophobic bases. These preliminary studies illustrate how the excellent orientation selectivity of high-field EPR provides new dynamic information about local base motions in DNA, and also how high-field EPR of spin-labels allows one to discriminate accurately between the effects of local versus global motions in spin-labeled macromolecules.

Base Sequence↗

PubMed2000

Differential destabilization of the DNA oligonucleotide double helix by a T.G mismatch, 3,N(4)-ethenocytosine, 3,N(4)-ethanocytosine, or an 8-(hydroxymethyl)-3,N(4)-ethenocytosine adduct incorporated into the same sequence contexts.

The T.G mismatch and the exocyclic adduct 3,N(4)-ethenocytosine (epsilonC) are repaired by the same enzyme, the human G/T(U) mismatch-DNA glycosylase (TDG). This enzyme removes the T, U, or epsilonC base from duplex DNA. The rate of cleavage was found to differ with the lesion and was also affected by neighbor sequences [Hang, B., Medina, M., Fraenkel-Conrat, H., and Singer, B. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 13561-13566]. Since sequence influences duplex stability, we determined the thermodynamic stability of T.G and epsilonC-containing 15-mer duplexes in which the bases flanking the lesion were systematically varied. The duplexes contained central 5'-TTXTT, 5'-AAXAA, 5'-CCXCC, or 5'-GGXGG sequences, where X is T, epsilonC, or two closely related structural derivatives of epsilonC: 3,N(4)-ethanocytosine (EC) and 8-(hydroxymethyl)-epsilonC (8-HM-epsilonC). Each of the four lesions, incorporated opposite G, decreased both the thermal (T(m)) and thermodynamic stability (DeltaG degrees (37)) of the 15-mer control duplexes. On the basis of the T(m) and DeltaG degrees (37) values, the order of destabilization of the TTXTT sequence in 15-mer duplexes was as follows: 8-HM-epsilonC > EC > epsilonC > T.G. The DeltaT(m) values range from -15.8 to -9.5 degrees C when C(t) = 8 microM. Duplexes with flanking AA or TT neighbors were more destabilized, by an average of 2 degrees C, than those with flanking GG or CC neighbors. The base opposite the modified base also influenced duplex stability. Within the TT context, of the four changed bases opposite the adducts, C had the greatest destabilizing effect, up to -18.4 degrees C. In contrast, a G opposite an adduct was generally the least destabilizing, and the smallest value was -3. 0 degrees C. Destabilizations were enthalpic in origin. Thus, this work shows that independently changing the modified base, the sequence, or the base opposite the lesion each affects the stability of the duplex, to significantly varying extents. The potential contribution of the thermodynamic stability to repair efficiency is discussed.

Base Pair Mismatch↗

PubMed2000

Synthesis of 8-(hydroxymethyl)-3,N(4)-etheno-2'-deoxycytidine, a potential carcinogenic glycidaldehyde adduct, and its site-specific incorporation into DNA oligonucleotides.

The previously unreported glycidaldehyde adduct, 8-(hydroxymethyl)-3, N(4)-etheno-2'-deoxycytidine (8-HM-epsilondC), has been synthesized for the first time by reaction of 2'-deoxycytidine with bromoacetaldehyde at pH 4.5, followed by reduction with sodium borohydride. The adduct was characterized by UV, MS, and NMR. The compound was stable to neutral and acidic conditions but not in alkaline solution. The corresponding phosphoramidite was synthesized in good yield from the intermediate, 3, N(4)-ethenocarbaldehyde-2'-deoxycytidine, using the standard methodology and site-specifically incorporated in both 15- and 25-mer oligonucleotides, for studies on biochemical and biophysical properties. The resulting oligonucleotides were purified using HPLC, and the base composition was verified by HPLC after enzymatic digestion.

Chromatography, High Pressure Liquid↗

PubMed2000

Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas.

The critical role of the neurofibromatosis 1 (NF1) gene as a tumour suppressor has been clearly demonstrated for malignancies arising in NF1 patients. However, little is known about the more common benign tumours, such as the pilocytic astrocytoma. Most NF1-associated astrocytomas are benign and clinically non-progressive, though aggressive tumours are occasionally encountered. In this study, eight pilocytic astrocytomas from six individuals affected with NF1 were analysed for NF1 expression. All eight tumours demonstrated loss of neurofibromin expression by immunohistochemistry, which was confirmed in one case using Western blot analysis. Microsatellite analysis showed loss of a single NF1 allele (LOH) in two of four NF1-associated tumours. These results demonstrate that, in contrast to sporadic astrocytomas, loss of NF1 expression is an important primary genetic event in the pathogenesis of NF1-associated pilocytic astrocytomas.

Adolescent↗

PubMed2000

Treatment of choroidal melanoma by stereotactic radiosurgery.

The case of a 49-year-old woman with an intermediate-sized choroidal melanoma who was treated with stereotactic radiosurgery with good tumour resolution is presented. Sight and globe preservation were achieved. The treatment technique is discussed.

Choroid Neoplasms↗

PubMed2000

Iodine-I25 episcleral plaque therapy in uveal melanoma.

PURPOSE: To assess the efficacy of iodine-125 (I-125) episcleral plaque therapy in the management of uveal melanoma with regard to local control, survival, globe preservation and visual outcome. METHODS: Between January 1985 and January 1997, 50 patients with the diagnosis of uveal melanoma were treated with I-125 episcleral plaques. The mean initial tumour height was 5.5 mm (range, 2.0-9.5 mm) and basal diameter 9.5 mm (range, 4.0-14.5 mm). I-125 seeds with a mean activity of 1259.1 MBq were used. The mean apical dose was 80.5 Gy (range, 68.0-95.0 Gy). Scleral dose ranged from 225.0 to 940.0 Gy. Pretreatment visual acuity was 6/60 or better in 43 patients. RESULTS: One patient was lost to follow up and excluded from analysis. The remaining 49 patients had a mean follow up of 39.5 months. There were seven local failures, with a mean duration to tumour progression of 16.7 months. All seven patients were successfully managed with enucleation. Five other enucleations were performed for treatment-related complications. At the time of analysis, 10 patients have died, five of metastatic melanoma. Of the patients with preserved globes, corrected visual acuity was 6/60 or better in 31 patients. CONCLUSIONS: Good local tumour control and survival can be achieved with episcleral plaque therapy. Globe preservation with useful vision was possible in the majority of cases. Our findings are in keeping with other reported series.

Adult↗

PubMed2000

Merlin, DAL-1, and progesterone receptor expression in clinicopathologic subsets of meningioma: a correlative immunohistochemical study of 175 cases.

The molecular pathogenesis of meningiomas is poorly characterized. Loss of NF2 (merlin) expression has been reported in 30%-80% of all sporadic meningiomas. Recently, we found that loss of expression for a second Protein 4.1-family tumor suppressor. DAL-1, is also common. A biologically important role for progesterone receptor (PR) has also been proposed based on its reported inverse relationship with tumor grade. In order to better define the pathogenetic roles of these proteins, we studied the merlin, DAL-1, and PR immunoprofiles in 175 fully characterized meningiomas, including nonrecurring versus recurring benign, proliferative versus brain invasive atypical and anaplastic subtypes. Loss of expression for either Protein 4.1-family tumor suppressor (merlin or DAL-1) was almost universal (92%), with combined losses being common (58%). Individually, absence of merlin or DAL-1 protein was detected in 74% and 76% respectively, with no significant differences among the 5 subsets. PR immunoreactivity was commonly associated with retained DAL-1 expression (p < 0.001) and with tumor grade, with 51% of benign, 21% of atypical, and 11% of anaplastic tumors staining positive (p < 0.001). We conclude that PR immunohistochemistry may have diagnostic utility in meningothelial neoplasms. Protein 4.1-family tumor suppressor losses are likely important early events in meningioma pathogenesis, whereas PR expression is associated with benignity.

Humans↗

PubMed2000

Measuring the costs and benefits of heart disease monitoring.

OBJECTIVE: To evaluate the costs and benefits of alternative systems of coronary heart disease monitoring in Scotland. DESIGN: An option appraisal was conducted to evaluate the costs and benefits of implementing a coronary heart disease monitoring system. This involved a review of existing Scottish datasets and relevant reports, specification of options, definition and weighting of benefit criteria by key stakeholders, assessment of options by experts, and costing of options. The options were assessed by 33 stakeholders (grouped as cardiologists, patient representatives, general practitioners, public health physicians, and policy makers), plus 13 topic experts. SETTING: Scotland (population 5.1 million). RESULTS: Between group mean benefit weights were: mortality rates and case fatality (10.6), quality of life (9.8), patient function (8.8), hospital activity (7.8), primary care activity (9.25), prescribing (5.72), socioeconomic impact (4.0), risk factors (7.4), prevalence (5.0), incidence (6.0), case registration (6.82), international comparability (4.2), breadth of coverage (8.8), and frequency (5.8). Differences between group weights were significant for prevalence (p = 0.048) and international comparability (p = 0.032). Four monitoring options were identified: a community epidemiology model, based on MONICA (monitoring trends and determinants in cardiovascular disease) study methodology applied to a series of eight representative communities, had the highest benefits, at an average annual discounted cost of approximately pound 360,000; models based on the Australian cardiovascular disease monitoring scheme and on enhanced routine data offered fewer benefits at discounted average annual costs ranging from pound 165,000 to pound 195,000; finally, a coronary heart disease registry modelled on the Scottish Cancer Registry scheme would have had fewer benefits and substantially higher costs than the other options. CONCLUSIONS: The most beneficial coronary heart disease monitoring system is the community epidemiology model, based on MONICA methodology. Option appraisal potentially offers an explicit and transparent methodology for evidence based policy development.

Coronary Disease↗

PubMed2000

Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas.

PURPOSE: A recent report suggests that alterations of chromosome arms 1p and 19q are associated with chemotherapeutic response and overall survival in anaplastic oligodendroglioma patients treated with procarbazine, lomustine, and vincristine chemotherapy. We set out to further clarify the diagnostic and prognostic implications of these alterations in a broader set of diffuse gliomas, including astrocytic neoplasms and low-grade oligodendrogliomas. PATIENTS AND METHODS: Fluorescence in situ hybridization (FISH) signals from DNA probes mapping to 1p and 19q common deletion regions were enumerated in 162 diffuse gliomas (79 astrocytomas, 52 oligodendrogliomas, and 31 mixed oligoastrocytomas), collected as part of an ongoing prospective investigation of CNS tumors. RESULTS: The oligodendroglial phenotype was highly associated with loss of 1p (P =.0002), loss of 19q (P <.0001), and combined loss of 1p and 19q (P <.0001). Combined loss of 1p and 19q was identified as a univariate predictor of prolonged overall survival among patients with pure oligodendroglioma (log-rank, P =.03) and remained a significant predictor after adjusting for the effects of patient age and tumor grade (P <.01). This favorable association was not evident in patients with astrocytoma or mixed oligoastrocytoma. CONCLUSION: Combined loss of 1p and 19q is a statistically significant predictor of prolonged survival in patients with pure oligodendroglioma, independent of tumor grade. Given the lack of this association in patients with astrocytic neoplasms and the previously demonstrated chemosensitivity of oligodendrogliomas, a combined approach of histologic and genotypic assessment could potentially improve existing strategies for patient stratification and management.

Adolescent↗

PubMed2000

Medulloblastomas with extensive posttherapy neuronal maturation. Report of two cases.

The authors report on two patients with classic medulloblastoma, each of whom underwent extensive therapy-associated neuronal maturation. The first patient presented at 3 months of age with hydrocephalus caused by a 5-cm tumor in the cerebellar vermis. He underwent a gross-total resection of a desmoplastic medulloblastoma. No mature elements were identified. Despite adjuvant chemotherapy, a 1.5-cm recurrent tumor developed 6 months later. Sections from the subtotally resected tumor demonstrated exclusively mature neuronal elements, ranging from neurocytes to ganglion cells. Four months later, a second recurrent tumor was resected. The specimen collected this time demonstrated classic medulloblastoma morphological characteristics. The patient was subsequently treated with radiation therapy, which seemed to have an effect; however, the tumor eventually progressed and the patient died. The second patient presented at 3 years of age with a midline medulloblastoma and was treated with subtotal resection, radiation therapy, and chemotherapy. Although the tumor remained stable on radiographic imaging, a second resection was performed 8 years later to alleviate hydrocephalus. Histological examination revealed predominantly small mature neurons with scattered ganglion cells and extensive calcification. No adjuvant therapy was given and the patient is alive and well as of his last follow-up examination. The mature neuronal neoplasms resected in both patients demonstrated negligible proliferative indices and stained appropriately with neuronal immunohistochemical markers. The smaller neuronal population resembled those of a central neurocytoma and medullocytoma/cerebellar neurocytoma. Analogous to neuroblastoma, our cases suggest that adjuvant therapy can induce extensive or complete neuronal maturation in medulloblastoma. Additional cases must be studied to determine the prognostic significance of this rare phenomenon.

Adolescent↗

PubMed1999

Clinicopathologic study of 85 similarly treated patients with anaplastic astrocytic tumors. An analysis of DNA content (ploidy), cellular proliferation, and p53 expression.

BACKGROUND: The biologic behavior of anaplastic (World Health Organization Grade III) astrocytomas and oligoastrocytomas is highly variable, ranging from rapid progression to prolonged survival. It is difficult to predict the outcome of an individual patient based on morphology alone. METHODS: To determine the prognostic value of commonly used clinicopathologic markers, we reviewed our experience with 85 similarly treated patients enrolled in 3 North Central Cancer Treatment Group high grade glioma protocols. The pathology was comprised exclusively of primary anaplastic astrocytic tumors (66 astrocytomas and 19 oligoastrocytomas). Variables examined included patient age, morphologic type, preoperative performance score, extent of surgery, solitary versus multiple mitoses, DNA flow cytometric and image morphometric parameters, and expression of proliferating cell nuclear antigen, MIB-1, and p53 expression. RESULTS: The study was comprised of 48 men and 37 women ranging in age from 14-79 years (median age, 47 years). Overall survival ranged from <1 month to >12 years (median, 21.6 months). Statistical analyses revealed that age accounted for the majority of this extensive variability in survival. The median survival times were 65. 5 months, 22.1 months, and 4.4 months, respectively, for the groups <40 years, 40-59 years, and >/=60 years, respectively (P < 0.0001). On univariate analyses, aneuploidy by flow cytometry and a low performance score also predicted a better survival (P values of 0.04 and 0.009, respectively). Statistical trends predicting a better survival were observed for patients with a solitary mitosis and p53 immunopositivity. However, only patient age remained significant in multivariate models. CONCLUSIONS: In a small but relatively uniformly treated cohort of patients with anaplastic astrocytomas and oligoastrocytomas, patient age was associated strongly and inversely with overall survival. Once patient age was taken into account, the clinical and pathologic markers tested appeared to be of limited prognostic value.

Adolescent↗