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Biomedical subjects

P May

Publications and source records attributed to P May.

At least 55 records · Page 3Linked to original sources
PubMed1997

Further characterisation of the p53 responsive element--identification of new candidate genes for trans-activation by p53.

The p53 protein is known to trans-activate a number of genes by specific binding to a consensus sequence containing two decamers of the type: PuPuPuCA/TT/AGPyPyPy. In order to identify new p53 trans-activated genes, we defined a set of criteria for computer search of p53-responsive elements. Based on experimental data, we proposed an extended consensus sequence composed of the two decamers of the El-Deiry consensus sequence flanked by two additional ones. A maximum of 3 bp substitutions was accepted for the two decamers of the El-Deiry consensus sequence, as well as for each additional decamer, except when the two decamers of the El-Deiry consensus sequence are contiguous. In this case, each additional decamer is allowed to bear one base insertion or deletion between the median C and G. This set of criteria was validated by identifying within the promoter region of the IGF-BP3 gene the existence of a novel p53-responsive element whose functional significance was verified. By limiting our computer search to Vertebrate genes involved in cell cycle regulation, cellular adhesion or metastatic processes and to gene families most often found in HOVERGEN database, 7785 gene sequences were first analysed. Among the oncogenes, kinases, proteases and structural proteins, 55 new genes were selected; six of them were retrieved in more than one species.

ADP-ribosyl Cyclase↗
PubMed1997

The transient 40-Hz response, mismatch negativity, and attentional processes in humans.

1. Recent experimental studies on the neurophysiological basis of auditory selective attention and sensory memory forming the sensory-data basis for tuning the selective-attention system in humans are reviewed. 2. The results demonstrate that the transient 40-Hz response is enhanced by selective attention, attenuated in the course of long-term stimulation, but is not affected by changes in auditory stimuli. 3. Therefore, the 40-Hz response seems to be closely related to selective and sustained attention, whereas it does not seem to be associated with passive attention, as it does not reflect the detection of changes in auditory stimuli. 4. Changes in auditory stimulation are registered by pre-attentive sensory memory, indexed by the mismatch negativity (MMN), a change-specific component of the event-related potentials (ERPs). By this time, the transient 40-Hz response has already terminated. The magnitude of stimulus change is reflected in MMN latency. These latency changes predict changes in attentive reaction time (RT). 5. Thus, the pre-attentive memory mechanism seems to govern attentive detection of changes in the auditory environment. 6. It is concluded that the transient 40-Hz response is related to active attention and MMN is related to passive attention.

Attention↗
PubMed1997

Paediatric surgical oncology. 8--Central nervous system tumours in children.

A review is presented of tumours of the brain and spinal cord, the most common group of solid neoplasms in childhood. General management strategies are discussed, including recent advances in neurosurgery, radiation therapy and chemotherapy. The importance of a multidisciplinary approach to treatment is stressed. An overview is given of the features and treatment of the more important individual tumour types.

Brain Neoplasms↗
PubMed1997

High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.

PURPOSE: To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors. PATIENTS AND METHODS: Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded. RESULTS: There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34). CONCLUSION: The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.

Adolescent↗
PubMed1997

Prolonged p53 protein accumulation in trichothiodystrophy fibroblasts dependent on unrepaired pyrimidine dimers on the transcribed strands of cellular genes.

Trichothiodistrophy (TTD), xeroderma pigmentosum (XP), and Cockayne's syndrome (CS) are three distinct human diseases with sensitivity to ultraviolet (UV) radiation affected by mutations in genes involved in nucleotide excision repair (NER). Among the many responses of human cells to UV irradiation, both nuclear accumulation of p53, a tumor suppressor protein, and alterations in cell-cycle checkpoints play crucial roles. The purpose of this study was to define the signals transmitted after UV-C-induced DNA damage, which activates p53 accumulation in TTD/XP-D fibroblasts, and compare this with XP-D cell lines that carry different mutations in the same gene, XPD. Our results showed that p53 was rapidly induced in the nuclei of TTD/XP-D and XP-D fibroblasts in a dose-dependent manner after UV-C irradiation, as seen in XP-A and CS-A fibroblasts, much lower doses being required for the protein accumulation than in normal human fibroblasts, XP variant cells, and XP-C cells. The kinetics of accumulation of p53 and two effector proteins involved in cell-cycle arrest, WAF1 and GADD45, were also directly related to the repair potential of the cells, as in normal human fibroblasts their levels declined after 24 h, the time required for repair of UV-induced lesions, whereas NER-deficient TTD/XP-D cells showed p53, WAF1, and GADD45 accumulation for over 72 h after irradiation. Our results indicate that p53 accumulation followed by transcriptional activation of genes implicated in growth arrest is triggered in TTD/XP-D cells by the persistence of cyclobutane pyrimidine dimers, which are known to block transcription, on the transcribed strands of active genes.

Adolescent↗
PubMed1996

Comparative study on the phosphotyrosine motifs of different cytokine receptors involved in STAT5 activation.

Several cytokines and growth factors activate transcription of their target genes via the JAK/STAT signalling pathway. It has been shown that the interaction between SH2 domains of STAT factors and receptor phosphotyrosine residues plays an essential role in the specific recruitment of STATs. For STAT5, however, the importance of receptor tyrosines is still controversial. Using a chimeric receptor system in COS-7 cells, we studied the activation of STAT5 through the interleukin-6 signal transducer gp130. In contrast to previous reports, we did not detect gp130-mediated STAT5 activation. However, STAT5 activation was achieved when tyrosine motifs of other cytokine receptors were fused to the membrane-proximal part of gp130. The comparison of the relative potency of different tyrosine motifs revealed that hydrophobic amino acids, preferentially leucine, in positions +1 and +3, and an aspartate residue in position -1 or -2 with respect to the tyrosine are likely to be required for efficient STAT5 recruitment. In summary, we show here for the first time that phosphotyrosine motifs can confer the ability to activate STAT5 to a heterologous receptor.

Animals↗
PubMed1996

Structural aspects of the p53 protein in relation to gene evolution: a second look.

Several years ago, a comparison of the amino acid sequences of p53 proteins from a variety of species enabled us to reveal structural features of this protein, giving clues to its function. Since then, numerous studies on the biochemical, immunological and biological functions of p53 as well as on its structure (including crystallography data) have provided considerable insight into the multifunctional aspects of p53. The purpose of this review is to present the most recent data concerning the various structural features of the p53 protein with special emphasis on its flexibility, which plays a key role in regulation of its biological activity.

Amino Acid Sequence↗
PubMed1996

Joint training for mental health key workers: Part 2.

The first part of this series last week outlined a joint training initiative for key workers in mental health. This week, the author describes the impressions of some of those who took part in the programme and reviews the implications for clinical practice and staff development.

Allied Health Personnel↗
PubMed1996

Joint training for mental health key workers: part 1.

This is the first of two articles on training for key workers in mental health. In this article, current mental health policy is examined and the conflicts this may cause for mental health key workers are discussed. The author also describes a two-day training programme that has been set up to help key workers manage the conflicts of their role. Next week, participants' impressions of the programme to date and the implications of their responses will be explored, highlighting issues for further debate.

Conflict, Psychological↗
PubMed1996

Chronic hepatitis B infection and autoimmune thyroiditis in Down syndrome.

Although it is well known that viral hepatitis can be complicated by autoimmune phenomena, the evidence for a pathogenetic role of viral hepatitis in the etiology of autoimmune thyroiditis is unclear. Because both hepatitis B and autoimmune thyroiditis occur frequently in Down syndrome, we decided to determine whether a cause-and-effect relationship might exist. Such a relationship might provide insight into basic mechanisms that could generalize to other populations. Accordingly, the frequency of hepatitis B surface antigen (HBsAg) positivity and thyroiditis was determined in 57 adults with Down syndrome and compared with frequencies in 450 age-, sex-, and environmentally matched mentally retarded patients without Down syndrome. We found no relationship of HBsAg positivity and thyroiditis in those mentally retarded patients without Down syndrome. On the other hand, the frequency of thyroiditis in those Down syndrome patients who were also carriers of HBsAg was threefold higher than the frequency of thyroid disease in those patients with Down syndrome who were not carriers of HBsAg (65% vs. 23%, p < 0.01). This relationship of hepatitis B and thyroid disease in Down syndrome might be explained by cytokine and/or cellular immune abnormalities linked to extra genetic material in trisomy 21. Clinically, patients with Down syndrome who are also hepatitis B carriers should be closely monitored for development of thyroid disease.

Adolescent↗
PubMed1995

[Apoptosis and cancer].

Apoptosis is a mode of active cell death having distinct biochemical and morphological features including chromatin condensation, polynucleosomal DNA fragmentation, and disruption of cells into apoptotic bodies. The apoptotic process plays a major role both during development and in the functioning of the immune system. Apoptosis may in part be genetically regulated, and may also be linked to physiological and non physiological signals from the environment. Apoptosis may be a defense at the cellular level against cancer. Moreover, there is evidence that a number of pro-oncogenes and tumor suppressor genes are involved in regulating apoptosis. Further understanding of the molecular events underlying the apoptotic process should provide new insights into the mechanism of tumorigenesis and facilitate the development of new strategies for the treatment of cancer.

Apoptosis↗
PubMed1995

Mutations clustered in exon 5 of the p53 gene in primary nasopharyngeal carcinomas from southeastern Asia.

Mutations in the p53 tumor suppressor gene play an important role in the development of many common human malignancies. In nasopharyngeal carcinomas (NPC), p53 gene mutations were not detected in primary tumors, with one exception for a primary tumor displaying a p53 mutation at codon 280, whereas p53 mutations were identified in some metastatic and nude mouse-passaged NPC specimens. In the present report, 41 NPC primary tumors of the undifferentiated carcinoma nasopharyngeal type (UCNT; 21 from Hong Kong and 20 from Guangxi, southeastern China) were studied. Four point mutations that result in amino acid substitutions were identified by PCR amplification of exons 2-9 and direct DNA sequencing, combined with PCR-single-strand conformation polymorphism analysis. The 4 mutations detected were clustered within the DNA stretch from codon 175 to 177. Our data, taken together with those of others, suggest that mutation in p53 may occur in NPC at various points during tumorigenesis. Alternative mechanisms of p53 inactivation in NPC are also possible.

Animals↗