Anterior sphenoid in modern humans.
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Animals↗
Biomedical subjects
C Dean
Publications and source records attributed to C Dean.
Presence of glutamate receptor subtypes on barosensitive neurons in the nucleus tractus solitarius of the dog.
Afferent baroreceptor information is transmitted to the nucleus tractus solitarius (NTS) in the dorsal medulla where glutamate is thought to be the primary neurotransmitter. However, the subtypes of glutamate receptors involved in the baroreflex remain to be established. The present study compared the distribution of immunohistochemically labeled ionotropic receptor subtypes to the distribution of physiologically stimulated barosensitive neurons in the NTS of the dog and also identified ionotropic receptor subtypes located on barosensitive neurons. Both NMDA and non-NMDA receptors were located in barosensitive areas and on barosensitive neurons, suggesting that both may be involved in the baroreflex.
Animals↗
Genetic interactions of the Arabidopsis flowering time gene FCA, with genes regulating floral initiation.
The genes controlling the timing of the transition from vegetative to reproductive growth are likely candidates for regulators of genes initiating floral development. We have investigated the interaction of one particular gene controlling flowering time, FCA, with the meristem identity-genes TERMINAL FLOWER 1 (TFL1), APETALA 1 (AP1) and LEAFY (LFY) and the floral repression gene EMBRYONIC FLOWER 1 (EMF1). Double mutant combinations were generated and the phenotypes characterized. The influence of strong and intermediate fca mutant alleles on the phenotype conferred by a 35S-LFY transgene was also analysed. The results support a model where FCA function promotes flowering in multiple pathways, one leading to activation of LFY and AP1, and another acting in parallel with LFY and AP1. Only the latter pathway is predicted to be non-functional in the intermediate fca-4 allele. The results are also consistent with AP1 and TFL1 negatively regulating FCA function. Combination of Columbia fca and emf1 mutant alleles confirmed that FCA is required for the early flowering of emf1. EMF1 and FCA are therefore likely to operate in different floral pathways.
Alleles↗
Dose-Response Study of Vigabatrin as add-on therapy in patients with uncontrolled complex partial seizures.
PURPOSE: This placebo-controlled, randomized, double-blind, multicenter study examined the efficacy and safety of three daily doses of vigabatrin (VGB; 1, 3, or 6 g) as add-on therapy in 174 patients with previously uncontrolled complex partial seizures with or without secondary generalization. METHODS: A 12-week pretreatment assessment period was followed by drug therapy with a 6-week titration period and a 12-week maintenance phase. RESULTS: VGB doses of 3 and 6 g/day reduced median monthly frequency of seizures by 4.3 and 4.5 seizures, respectively, compared with 0.2 seizures for placebo (p = 0.0001). The percentages of patients classified as therapeutic successes (> or =50% reduction in seizure frequency) were 7% for placebo and 24, 51, and 54% for patients taking daily VGB doses of 1, 3, and 6 g, respectively; the comparison with placebo was significant for all treatment groups. The linear trend for dose response was highly significant (p< or =0.0001) for both median monthly seizure frequency and therapeutic success. Vigabatrin was well tolerated, causing no clinically significant changes in laboratory parameters, brain magnetic resonance imaging, evoked potentials, cognitive function, or psychosocial tests. Fatigue, drowsiness, and dizziness were the most common treatment-related adverse events in all treatment groups. Dropouts due to adverse events were higher in the 6-g/day group. CONCLUSIONS: VGB was significantly more effective than placebo as add-on therapy in reducing seizure frequency. VGB at 3 and 6 g/day produced the best efficacy: however, adverse events may limit the use of the 6-g/day dose in some patients.
Adult↗
Prognostic role of cyclin D1 in lung cancer. Relationship to proliferating cell nuclear antigen.
We developed an immunohistochemical assay specific for cyclin D1 and suitable for formalin-fixed and paraffin-embedded sections, to evaluate cyclin D1 expression in a group of 135 surgically resected lung-cancer patients for the purpose of investigating the prognostic role of this protein in lung cancer. In addition, we compared cyclin D1 expression with the expression of proliferating cell nuclear antigen (PCNA), considered to be a reliable index of the proliferation rate. We found cyclin D1 expressed in more than 60% of the neoplastic cells in 26.5% of our specimens. A total of 24.5% of the specimens showed cyclin D1 expression in a percentage of cells ranging from 30 to 60%; 36.7% of the specimens expressed cyclin D1 in less than 30% of the cells; and 12.2% of the specimens expressed cyclin D1 in less than 1% of the evaluated cells. Western blot analyses confirmed the specificity of this assay by correlating statistically in a highly significant fashion with the immunohistochemical results (P = 0.0003). Furthermore, we found a direct relationship between cyclin D1 and PCNA immunodetection (P = 0.0004), which correlated cyclin D1 overexpression with a higher tumor proliferation rate. When we analyzed our data statistically, cyclin D1 expression was found to be a negative prognostic marker (P < 0.00005) whose expression correlates with a shorter patient survival time.
Adenocarcinoma↗
Modulation of arterial baroreflexes by antisense oligodeoxynucleotides to NMDAR1 receptors in the nucleus tractus solitarius.
An antisense oligodeoxynucleotide which specifically blocked the production of the glutamate receptor subtype NMDAR1 was administered to the nucleus tractus solitarius (NTS) in order to examine the role of this receptor in baroreflex control of heart rate. Baseline blood pressure and heart rate were unchanged by NTS treatment with the antisense oligodeoxynucleotide to the NMDAR1 receptor subunit. However, the reflex bradycardia evoked in response to the hypertension induced by bolus administration of phenylephrine was significantly attenuated following bilateral NTS antisense oligodeoxynucleotide treatment. Administration of the corresponding mismatched antisense oligodeoxynucleotide did not significantly alter the reflex bradycardia. These data indicate that NMDAR1 receptors are involved in neurotransmission in the baroreflex arc at the level of the NTS. The specificity of antisense oligodeoxynucleotides may prove to be a useful technique to analyze the role of receptor subtypes mediating neurotransmission in central pathways.
Animals↗
Arabidopsis thaliana: a model plant for genome analysis.
Arabidopsis thaliana is a small plant in the mustard family that has become the model system of choice for research in plant biology. Significant advances in understanding plant growth and development have been made by focusing on the molecular genetics of this simple angiosperm. The 120-megabase genome of Arabidopsis is organized into five chromosomes and contains an estimated 20,000 genes. More than 30 megabases of annotated genomic sequence has already been deposited in GenBank by a consortium of laboratories in Europe, Japan, and the United States. The entire genome is scheduled to be sequenced by the end of the year 2000. Reaching this milestone should enhance the value of Arabidopsis as a model for plant biology and the analysis of complex organisms in general.
Arabidopsis↗
Genome maps 9. Arabidopsis thaliana. Wall chart.
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Arabidopsis↗
Two erbB-4 transcripts are expressed in normal breast and in most breast cancers.
ErbB-4 is a recently described member of the epidermal growth factor receptor (EGFR) family which together with erbB-3 acts as a receptor for a group of ligands known as the neuregulins (NRGs) or heregulins (HRGs). Unlike the EGFR and erbB-2 relatively little is known about the expression of erbB-4 in human tumours. Using RT-PCR and Southern blotting analysis we have investigated the expression of erbB-4 mRNA in a range of human tumour cell lines and in normal and malignant breast tissue. Using primers which amplified a 658 base pair (bp) region corresponding to part of the cytoplasmic domain of c-erbB-4 we found the receptor was expressed in some but not all breast and ovarian tumour cell lines and also in a glioma cell line. The highest level of erbB-4 expression was found in the ovarian carcinoma OVCAR-3 and the breast carcinoma T-47D. In all cell lines where the 'full-length' erbB-4 was detected, a second previously undescribed c-erbB-4 sequence was also found as a 610 bp PCR product. The alternative PCR product was identical in sequence to c-erbB-4 except for a deletion of 48 bp which encodes a consensus phosphatidylinositol 3-kinase (PI3K) binding site. This suggested that the two forms of erbB-4 might interact with different intracellular signalling pathways and therefore influence a wider variety of cellular responses to heregulin than previously thought. Expression of both erbB-4 variants was found in 7/7 normal breast tissues but only in 9/12 breast tumours analysed. In line with the terminology of Elenius et al. (1997b) we have designated the two isoforms of the C-terminal transcripts as CT-a (full-length) and CT-b which lacks the P13K binding motif. These results identify suitable cell lines for the further investigation of erbB-4 expression and function and suggest that the role of erbB-4 in breast cancer warrants further investigation with larger numbers of normal and malignant breast tissues.
Alternative Splicing↗
Analysis of 1.9 Mb of contiguous sequence from chromosome 4 of Arabidopsis thaliana.
The plant Arabidopsis thaliana (Arabidopsis) has become an important model species for the study of many aspects of plant biology. The relatively small size of the nuclear genome and the availability of extensive physical maps of the five chromosomes provide a feasible basis for initiating sequencing of the five chromosomes. The YAC (yeast artificial chromosome)-based physical map of chromosome 4 was used to construct a sequence-ready map of cosmid and BAC (bacterial artificial chromosome) clones covering a 1.9-megabase (Mb) contiguous region, and the sequence of this region is reported here. Analysis of the sequence revealed an average gene density of one gene every 4.8 kilobases (kb), and 54% of the predicted genes had significant similarity to known genes. Other interesting features were found, such as the sequence of a disease-resistance gene locus, the distribution of retroelements, the frequent occurrence of clustered gene families, and the sequence of several classes of genes not previously encountered in plants.
Arabidopsis↗
Anti-EGFR monoclonal antibodies which act as EGF, TGF alpha, HB-EGF and BTC antagonists block the binding of epiregulin to EGFR-expressing tumours.
Epiregulin is the newest member of the epidermal growth factor (EGF) family of ligands that was isolated from conditioned medium of the murine fibroblast-derived tumour cell line NIH3T3/T7. Here, using a panel of anti-EGFR receptor (EGFR) monoclonal antibodies (MAbs) directed against 4 distinct epitopes on the external domain of the receptor, we have investigated the importance of the EGFR in transmitting the biological action of epiregulin. We found that MAb ICR9, which enhances the binding of EGF, TGF alpha, HB-EGF and betacellulin to the EGFR, also increases the binding of 125I-epiregulin to a number of EGFR-expressing tumour cell lines, including EJ, SKBR3, SKOV3, MDA-MB468 and HN5. In addition, anti-EGFR MAbs ICR15, ICR16, ICR61, ICR62 and ICR80, which block the binding of 125I-EGF to the EGFR, inhibit the binding of 125I-epiregulin to these tumour cell lines. Like EGF, we found that both the epiregulin-induced growth inhibition of HN5 and MDA-MB468 cells and tyrosine phosphorylation of the 170 kDa EGFR on HN5 cells are reversed in the presence of anti-EGFR MAbs ICR62 and ICR80. Surprisingly and unlike 125I-EGF, radiolabelled epiregulin bound very poorly to human bladder carcinoma EJ cells and its binding to SKOV3 cells was not inhibited efficiently in the presence of blocking antibodies. We conclude that the EGFR plays an important role in transmitting the biological action of epiregulin and that these effects could be blocked in the presence of anti-EGFR MAbs. The low level of binding of epiregulin compared with EGF to EJ cells suggests that the EGFR may not be the primary receptor for epiregulin.
3T3 Cells↗
Control of flowering time.
The multiple promotive and repressive pathways controlling flowering have been further defined by analysis of genetic interactions and the activation of floral meristem identity genes. Cloning of additional genes in these pathways has uncovered some of the molecular processes that control the timing of the transition to reproductive development.
Arabidopsis↗
Effects of real and imagined training on voluntary muscle activation during maximal isometric contractions.
In this study we directly tested the hypothesis that isometric strength training increases voluntary drive to muscles. In addition, it was attempted to replicate the findings of an earlier study that showed imagined training increases voluntary strength as much as actual training, as this finding provides key support for the hypothesis that training increases voluntary drive (Yue & Cole 1992). Fifty-four subjects were randomly allocated to groups that performed 8 weeks of isometric training of the elbow flexor muscles, imagined isometric training, or a control task involving the lower limbs. Voluntary isometric strength and activation of the elbow flexor muscles were measured before and after training. Voluntary activation was measured with a sensitive form of twitch interpolation. Training, imagined training and control groups increased voluntary isometric elbow flexor strength by means of 17.8% (+/- 3.1 SEM), 6.8% (+/- 2.6) and 6.5% (+/- 3.0), respectively. The training group increased in strength significantly more than imagined training and control groups (P = 0.01 for both comparisons), but the small difference between imagined training and control groups was not significant (P = 0.31). Prior to training, voluntary activation of all subjects was high (96.2 +/- 0.5%). This did not change significantly with training and there were no significant differences between groups. These data challenge the hypothesis that training of the elbow flexor muscles increases isometric strength by inducing adaptations of the central nervous system, because they show that training does not increase voluntary activation and imagined training does not increase strength.
Adult↗
Development of an AFLP based linkage map of Ler, Col and Cvi Arabidopsis thaliana ecotypes and construction of a Ler/Cvi recombinant inbred line population.
An amplified fragment polymorphism (AFLP) based linkage map has been generated for a new Landsberg erecta/ Cape Verde Islands (Ler/Cvi) recombinant inbred line (RIL) population. A total of 321 molecular PCR based markers and the erecta mutation were mapped. AFLP markers were also analysed in the Landsberg erecta/Columbia (Ler/Col) RIL population (Lister and Dean, 1993) and 395 AFLP markers have been integrated into the previous Arabidopsis molecular map of 122 RFLPs, CAPSs and SSLPs. This enabled the evaluation of the efficiency and robustness of AFLP technology for linkage analyses in Arabidopsis. AFLP markers were found throughout the linkage map. The two RIL maps could be integrated through 49 common markers which all mapped at similar positions. Comparison of both maps led to the conclusion that segregating bands from a common parent can be compared between different populations, and that AFLP bands of similar molecular size, amplified with the same primer combination in two different ecotypes, are likely to correspond to the same locus. AFLPs were found clustering around the centromeric regions, and the authors have established the map position of the centromere of chromosome 3 by a quantitative analysis of AFLP bands using trisomic plants. AFLP markers were also used to estimate the polymorphism rate among the three ecotypes. The larger polymorphism rate found between Ler and Cvi compared to Ler and Col will mean that the new RIL population will provide a useful material to map DNA polymorphisms and quantitative trait loci.
Arabidopsis↗
The transition to flowering
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Journal Article↗
The transposition frequency of Tag1 elements is increased in transgenic Arabidopsis lines.
Tag1 was identified as a highly active endogenous transposable element in transgenic Arabidopsis thaliana Landsberg erecta plants carrying the maize transposable element Activator (Ac). Here, we describe experiments designed to determine the basis for the high activity of Tag1. The frequency of transposition of Tag1 elements was compared in lines containing or lacking Ac transposase to assess the effect of Ac transposase on Tag1 activity. Three populations of nontransgenic plants, including nontransformed regenerants, were also analyzed. The high level of activity of Tag1 did not correlate with the presence or absence of Ac transposase but was significantly higher in transgenic lines. This result was maintained through at least six generations after transformation. These data suggest that Tag1 transposition is stimulated by processes that occur during the Agrobacterium transformation and that thereafter remain active. Two Tag1 elements are tightly linked in the Landsberg erecta genome and map to the lower arm of chromosome 1. Tag1 elements were found in only a few A. thaliana ecotypes but were present in four other Arabidopsis species.
Arabidopsis↗
p21waf1/cip1mda-6 expression in non-small-cell lung cancer: relationship to survival.
In order to clarify critical events during bronchial carcinogenesis, and to evaluate a possible prognostic role for p21 immunohistochemical detection, we assessed the immunohistochemical expression of p21 protein in 60 surgically resected non-small-cell lung cancers (NSCLCs) that had been investigated previously for their p53 protein status. We found that p21 protein was expressed in both normal and neoplastic tissue. In normal tissue, p21 immunoreactivity was detectable in a low percentage of well-differentiated cells. We found immunostaining for p21 in 80% of the investigated neoplasms. In 73.3% of the neoplasms, p21 was considered to be overexpressed. No relationship was found between p21 overexpression and tumor stage or tumor-nodal-metastatic (TNM) status. The histologic grading was slightly correlated with the p21 status (P = -0.51), with no significant differences noted between squamous carcinomas and adenocarcinomas. Survival percentage curves for our lung-cancer patients, based on a comparison of different p21 expression levels and constructed through a Kaplan-Meier analysis, showed significant differences in mean (P < 0.001) and overall (P < 0.001) survival time between patients of different p21 status, suggesting a favorable prognostic value of p21 immunostaining for NSCLC patients.
Adenocarcinoma↗
EGFR blockade by tyrosine kinase inhibitor or monoclonal antibody inhibits growth, directs terminal differentiation and induces apoptosis in the human squamous cell carcinoma HN5.
Human squamous cell carcinomas frequently overexpress the epidermal growth factor receptor (EGFR) and this is often associated with poor prognosis in patients with these cancers. The high level of expression of the EGFR provides an important target for therapy and we and others have shown that monoclonal antibodies (mAbs) which block the activation of the receptor by the EGF family of ligands inhibit the growth of EGFR overexpressing tumours in vitro and induce the regression of established tumours grown as xenografts in athymic mice. Inhibitors of the tyrosine kinase associated with the EGFR have also been shown to block receptor activation and prevent tumour cell proliferation. Using the EGFR-overexpressing head and neck carcinoma cell line HN5, we have compared the biological consequences of treatment with an inhibitor of EGFR tyrosine kinase (PD153035) with anti-EGFR monoclonal antibodies (mAbs) ICR63 or ICR80. We found that both the anti-EGFR mAbs and the TK inhibitor produce similar biological changes namely, they inhibit the EGF and TGFá-induced tyrosine phosphorylation of the receptor and the growth in culture of HN5 cells. At concentrations above 100 nM, the TK inhibitor prevented the growth in culture of HN5 cells completely with an IC50 of 40 nM. With the anti-EGFR mAbs, growth of HN5 cells was inhibited completely at concentrations above 4 nM with an IC50 of 1 nM. More importantly we found that, like the anti-EGFR mAbs, treatment with the TK inhibitor directs HN5 cells to undergo terminal differentiation as monitored by the expression of cytokeratin 10. In addition, our results indicate that the growth inhibitory effects of the anti-EGFR agents also lead to induction of apoptosis as determined by 7-amino actinomycin D staining (7-AAD). We conclude that EGFR blockade by anti-EGFR mAbs or TK inhibitor influences the growth in culture of EGFR overexpressing tumours by directing terminal differentiation and inducing apoptosis.
Antibodies, Monoclonal↗