Search PubMed⌕ Search

Biomedical subjects

A Perry

Publications and source records attributed to A Perry.

At least 19 recordsLinked to original sources
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

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↗
PubMed1999

Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype.

Allelic alterations of chromosomes 1 and 19 are frequent events in human diffuse gliomas and have recently proven to be strong predictors of chemotherapeutic response and prolonged survival in oligodendrogliomas (Cairncross et al., 1998; Smith et al., submitted). Using 115 human diffuse gliomas, we localized regions of common allelic loss on chromosomes 1 and 19 and assessed the association of these deletion intervals with glioma histological subtypes. Further, we evaluated the capacity of multiple modalities to detect these alterations, including loss of heterozygosity (LOH), fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH). The correlation coefficients for detection of 1p and 19q alterations, respectively, between modalities were: 0.98 and 0.87 for LOH and FISH, 0.79 and 0.60 for LOH and CGH, and 0.79 and 0.53 for FISH and CGH. Minimal deletion regions were defined on 19q13.3 (D19S412-D19S596) and 1p (D1S468-D1S1612). Loss of the 1p36 region was found in 18% of astrocytomas (10/55) and in 73% (24/33) of oligodendrogliomas (P < 0.0001), and loss of the 19q13.3 region was found in 38% (21/55) of astrocytomas and 73% (24/33) of oligodendrogliomas (P = 0.0017). Loss of both regions was found in 11% (6/55) of astrocytomas and in 64% (21/33) of oligodendrogliomas (P < 0.0001). All gliomas with LOH on either 1p or 19q demonstrated loss of the corresponding FISH probe, 1p36 or 19q13.3, suggesting not only locations of putative tumor suppressor genes, but also a simple assay for assessment of 1p and 19q alterations as diagnostic and prognostic markers.

Astrocytoma↗
PubMed1999

"Malignancy" in meningiomas: a clinicopathologic study of 116 patients, with grading implications.

BACKGROUND: Due to the rarity of malignancy in meningiomas, prior studies have been limited to small series. Controversies regarding the definition of malignant meningioma have complicated matters further. Although histologic anaplasia and extracranial metastasis are established criteria, the former is difficult to define and the latter represents a clinical finding. Traditionally, brain invasion has also been accepted, although this has recently been debated. In a prior series, the authors were unable to prove that 23 meningiomas that had invaded the brain were more aggressive than atypical meningiomas. METHODS: The authors expanded their analysis to include 116 patients diagnosed with "malignant meningioma" due to brain invasion, frank anaplasia (20 mitoses per 10 high-power fields or histology resembling carcinoma, sarcoma, or melanoma), and/or extracranial metastasis. Patients were followed until death or for a median of 3.7 years. RESULTS: Survival time was highly variable, ranging from 10 days to 24 years. In multivariate analysis, histologic anaplasia (P=0.0035), subtotal resection (P=0.0038), 20 mitoses per 10 high-power fields (P=0.0071), and nuclear atypia (P=0.0068) were associated with poor survival. Of the 89 cases of meningioma that had invaded the brain, 23% were otherwise benign, 61% were otherwise atypical, and 17% were frankly anaplastic. Those without anaplasia behaved similarly to atypical meningiomas from the authors' prior study. In contrast, anaplastic meningiomas were usually fatal, associated with a median survival of 1.5 years. CONCLUSIONS: Based on these findings, the authors suggest that brain invasion constitutes an additional criterion for the diagnosis of atypical meningioma (World Health Organization [WHO] Grade II), whereas frank anaplasia indicates high grade (WHO Grade III-IV) malignancy.

Adolescent↗
PubMed1999

Randomised controlled trial of efficacy of teaching patients with bipolar disorder to identify early symptoms of relapse and obtain treatment.

OBJECTIVE: To determine the efficacy of teaching patients with bipolar disorder (manic-depressive psychosis) to identify early symptoms of relapse and seek prompt treatment from health services. DESIGN: Single blind randomised controlled trial with matching on four baseline variables using a minimisation algorithm. SETTING: Mental health services in four NHS trusts (one teaching, three non-teaching). SUBJECTS: 69 patients with bipolar disorder who had had a relapse in the previous 12 months. INTERVENTIONS: Seven to 12 individual treatment sessions from a research psychologist plus routine care or routine care alone. MAIN OUTCOME MEASURES: Time to first manic or depressive relapse, number of manic or depressive relapses, and social functioning examined by standardised interviews every six months for 18 months. RESULTS: 25th centile time to first manic relapse in experimental group was 65 weeks compared with 17 weeks in the control group. Event curves of time to first manic relapse significantly differed between experimental and control groups (log rank 7.04, df=1, P=0.008), with significant reductions in the number of manic relapses over 18 months (median difference 30% (95% confidence interval 8% to 52%), P=0.013). The experimental treatment had no effect on time to first relapse or number of relapses with depression, but it significantly improved overall social functioning (mean difference 2.0 (0.7 to 3.2), P=0.003) and employment (mean difference 0.7 (0.1 to 1.3), P=0.030) by 18 months. CONCLUSION: Teaching patients to recognise early symptoms of manic relapse and seek early treatment is associated with important clinical improvements in time to first manic relapse, social functioning, and employment.

Adolescent↗
PubMed1999

Expression of TGFalpha in meningiomas.

The objective of this study was to examine the expression of transforming growth factor alpha (TGFalpha), a mitogen for many cell types, and its receptor in basic subtypes of meningiomas as well as in meningiomas of varying grade. Formalin-fixed tissues from 26 meningiomas including 15 benign (5 meningothelial, 5 transitional, and 5 fibrous variants), 6 atypical, and 5 malignant examples were immunohistochemically examined for both TGFalpha protein and EGF/TGFalpha receptor protein. In addition, in situ hybridization (ISH) was used to detect TGFalpha mRNA expression. Immunostaining for TGFalpha was strongest in fibrous and atypical meningiomas, followed closely by transitional and malignant tumors. Only weak reactivity was observed in the meningothelial variant. In all but 4 tumors (2 fibrous, 2 atypical), ISH showed TGFalpha mRNA to be present, the signal being stronger in malignant than in conventional or atypical tumors. Lastly, immunostaining for EGF/TGFalpha receptor was positive in all tumors studied. Strong TGFalpha protein expression in meningiomas is commonly associated with fibrous morphology. Although the frequent detection of both TGFalpha protein and its mRNA, as well as of EGF/TGFalpha receptor within tumors of all type and grades, suggests that TGFalpha serves to promote tumor growth, its possible role in tumorigenesis or malignant progression is uncertain. In summary, demonstration of these substances is of no utility in the classification or grading of this common tumor because the differences in their expression among the various meningioma subtypes were not statistically significant.

Adult↗
PubMed1999

Early PCR-negativity after allogeneic BMT in adults with t(4;11) ALL in the absence of acute or chronic GVHD.

Acute lymphoblastic leukaemia (ALL) with the t(4;11) translocation has a very poor prognosis following conventional chemotherapy. Many patients are offered an allogeneic BMT in first remission. We report on the impact of allogeneic BMT on three patients with t(4;11) ALL in first remission. Median age was 20 years. One patient received marrow from an HLA-identical sibling and the other two from unrelated donors. All three engrafted and none of the patients developed acute or chronic GVHD. Remission status was monitored using a sensitive nested RT-PCR to detect the ALL-1/AF-4 hybrid transcript. All three were PCR-negative at 3 months post-BMT. One of the unrelated recipients died of a fungal infection 4 months post-BMT. The other two are alive and in molecular remission at 21 and 24 months post-BMT. This is the first report of longitudinal follow-up of t(4;11) ALL post-allogeneic BMT by PCR. The early attainment of molecular remission in the absence of GVHD suggests that the conditioning regimen may have been more important than a graft-versus-leukaemia effect in these patients. Follow-up of larger numbers of patients will be required to confirm these preliminary observations.

Acute Disease↗