Search PubMed⌕ Search

Biomedical subjects

B Dickson

Publications and source records attributed to B Dickson.

At least 19 recordsLinked to original sources
PubMed2001

A multi-center controlled study of rapid hepatitis B vaccination using a novel triple antigen recombinant vaccine.

Hepatitis B vaccines have been available for 20 years, however, the disease still remains a global problem. Clearly, the protection of at-risk groups could be improved if a more potent vaccine with a shorter vaccination regimen were available. Hepacare is new recombinant vaccine, which contains three of the surface antigens of the HB virus and has higher immunogenicity than present single antigen (HBsAg only) vaccines. This study evaluates the potential for developing seroprotection rapidly and the viability of a 1 month/two dose regimen. A total of 400 adult subjects were vaccinated using either the present accelerated 2 month/three dose regimen of Engerix-B or a 1 month/two dose regimen of a novel triple antigen vaccine (Hepacare). Both vaccines were well tolerated. Four weeks after a single dose, the seroprotective rates for Engerix-B and the triple antigen vaccine were 5 and 17%, respectively. By month 2, 4 weeks after two doses of vaccine, it was 38 and 61%. Finally by month 3, 4 weeks after a third dose of Engerix-B or placebo, respectively, the seroprotection rates were 71 and 82%. The geometric mean titres (GMTs), of these responders was then 119 and 120 IU/l, respectively. Both vaccines were well tolerated. At all points up to and including 3 months after beginning vaccination, the novel 1 month/two dose regimen of Hepacare was significantly more effective in producing seroporotective titres than the 2 month/three dose regimen of Engerix-B (P = 0.001).

Adolescent↗
PubMed2001

Comparison of a triple antigen and a single antigen recombinant vaccine for adult hepatitis B vaccination.

Hepatitis B and its sequelae are a major public health problem. Vaccines have been available for almost 20 years; however the disease still remains a global problem. Many factors contribute to the failure to control hepatitis B, including the limited nature of the vaccination programs implemented initially. Only relatively recently has mass childhood vaccination begun to be implemented and vaccination of high-risk groups, other than healthcare workers, is still not general policy. Additional factors contributing to continued persistence of hepatitis B in the developed world are that the present vaccines are not fully used by those recommended to be vaccinated and even when vaccination is carried out appropriately, there remain some who fail to achieve adequate protection. Clearly, the protection of at-risk groups who have inadequate response to current vaccines, and those who are unwilling or unable to comply with protracted multi-dose vaccine regimens, could be improved if there were a more potent vaccine and/or a shorter vaccination regimen available. Adults who had never been vaccinated against hepatitis B were randomised to receive a vaccination course of either a present single antigen (S) vaccine (Recombivax-HB) or a novel triple antigen (S, pre-S1, and pre-S2) recombinant vaccine (Hepacare Medeva Pharma plc). Doses were given at baseline and 1 month and 6 months later. Hepatitis B surface antibody (anti-HBs) levels were measured at 2, 4, 6, and 7 months after beginning vaccination. The primary efficacy parameter was the degree of protection, measured as the percentage of subjects with anti-HBs titres > or = 10 IU/L, 6 or 7 months (26 +/- 2 weeks) after beginning vaccination. A total of 303 adult subjects entered the study and were vaccinated. Of these, 11 failed to complete the study (4 on Hepacare and 7 on Recombivax-HB); however all but 2 (1 to receive the triple antigen vaccine and 1 to receive Recombivax-HB) were included in the intent-to-treat population for efficacy evaluation. Treatment randomisation was stratified at entry based on age (above and below 40 years old) and gender. The standard three-dose/6-month vaccination regimen of the single antigen vaccine protected 83% of subjects by 7 months after starting vaccination whereas the triple antigen vaccine as a two-dose/1-month regimen protected 88% within 6 months and as a three-dose/6-month regimen protected 97% by 7 months after starting vaccination. Thus the protection rate provided by the shortened (0, 1) regimen of the novel vaccine was "essentially equivalent" (i.e., not statistically inferior) to that provided by the full (0, 1, and 6) regimen of today's vaccine (88% vs. 81%, P < 0.001), and the protection rate provided by a three-dose/6-month (0, 1, and 6) regimen of the new vaccine was significantly superior to that provided by present vaccines (97% vs. 83% P < 0.001). The percentage of subjects protected increases with time after beginning vaccination and at all time points up to and including 6 months was significantly greater with the two-dose regimen of the triple antigen vaccine than with the single antigen vaccine regimen. In adults at risk for a reduced response to hepatitis B vaccination [i.e., older adults (>/=40), the obese, males, and smokers], the triple antigen vaccine produced a significantly greater percentage of protected subjects (P < 0.001) and higher geometric mean titre (P < 0.001). Indeed as a three-dose/6 month regimen, the triple antigen vaccine raised the level of protection in these vulnerable subgroups to that seen when a single antigen vaccine is used in the optimal younger adult group. Both vaccines were well tolerated and had similar safety profiles. The most frequently (> or = 10%) reported adverse events with the use of either vaccine were pain at the site of injection (38% vs. 41% vs. 20% for the two-dose Hepacare regimen, the three-dose Hepacare regimen, and the three-dose Recombivax-HB regimen, respectively), infections at the site of injection (1% vs. 14% vs. 9%), headache (9% vs. 13% vs. 11%), and nausea (7% vs. 11% vs. 3%). It is concluded that in healthy normal adults, a triple antigen hepatitis B vaccine that contained S and pre-S antigens produced an enhanced immunological response. This was exemplified by the novel vaccine's ability to overcome factors such as advancing age (> or = 40 years), obesity, and smoking, each of which is known to reduce the potential for protection with present recombinant S only vaccines. A two-dose/1-month (0 and 1) regimen of this triple antigen vaccine was as effective as the standard three-dose/6 month (0, 1, and 6) regimen of present single antigen vaccines. (c) 2001 Wiley-Liss, Inc.

Adolescent↗
PubMed2001

Adult hepatitis B vaccination using a novel triple antigen recombinant vaccine.

Present hepatitis B vaccines use multidose prolonged regimens, which even healthcare workers at risk do not always complete. Moreover, when vaccination is completed there remain some who fail to achieve adequate protection. The protection of adults at risk could be improved if there were a more potent vaccine and/or a shorter vaccination regimen available. Vaccine-naive adults were randomized to vaccination with either Engerix-B (SmithKline Biologicals, Rixensart, Belgium) or a novel triple antigen (S, pre-S1, and pre-S2) recombinant vaccine (Hepacare; Medeva Pharma Plc, Speke, UK). The primary efficacy parameter was the degree of seroprotection 6 or 7 months (26 +/- 2 weeks) after beginning vaccination. A total of 304 adults entered the study. Of these, 16 failed to complete the study (9 on Hepacare and 7 on Engerix-B). With the Engerix-B standard (0, 1, 6) regimen, 88% of subjects were protected by month 7, whereas with the triple antigen vaccine a 2-dose regimen (0, 1) provided equivalent protection (91%) within 6 months and a 3-dose (0, 1, 6) regimen was significantly superior (98% seroprotected by 7 months after starting vaccination P <.001). With adults at risk for a suboptimal response (i.e., older adults, the obese, men, and smokers) the triple antigen vaccine produced a greater degree of protection. The vaccines had similar safety profiles. Both vaccines were well tolerated. In healthy normal adults, a triple antigen hepatitis B vaccine containing S and pre-S antigens produced an enhanced immunologic response and was as effective as a 2- and 3-dose regimen.

Adult↗
PubMed2001

Evaluation of a new hepatitis B triple-antigen vaccine in inadequate responders to current vaccines.

In this double-blind, randomized, controlled study, healthcare professionals with a history of inadequate response to currently available single-antigen hepatitis B vaccines confirmed by measuring hepatitis B surface antibody titer before entry to the study were revaccinated with a 20-microg dose either of a novel triple-antigen (S, pre-S1, and pre-S2) recombinant vaccine or of a present single-antigen (S only) vaccine. Hepatitis B surface antibody titers were measured 8 weeks' post revaccination. A total of 925 individuals were randomized and vaccinated, of whom 915 (98.9%) completed the study and were included in the efficacy analysis. A single dose of the new triple-antigen hepatitis B vaccine (Hepacare) produced a successful response in over three quarters of these subjects who had not mounted an adequate response to current vaccines. The antibody response was statistically significantly superior (P =.002) to that after a single dose of current vaccines. An evaluation of the overall response showed that only the triple-antigen vaccine was able to raise the average antibody response (geometric mean titer [GMT]) to over 100 IU/L. The superior effect of the new vaccine was most pronounced in subjects who were previously complete nonresponders to currently available hepatitis B vaccines. Both vaccines were well tolerated and had similar safety profiles. This study demonstrated that in healthcare workers who had responded inadequately to at least a full course of immunization (median, 5 doses), a single 20-microg dose of a new triple-antigen vaccine induced protective antibody level in more vaccinees (P =.002) and increased the average antibody titer (GMT) in those protected successfully to a greater degree (P <.001) than a further attempt with a current vaccine (Engerix-B).

Adult↗
PubMed1997

The heat shock protein 83 (Hsp83) is required for Raf-mediated signalling in Drosophila.

The heat shock protein Hsp90 has been shown to associate with various cellular signalling proteins such as steroid hormone receptors, src-like kinases and the serine/threonine kinase Raf. While the interaction between steroid hormone receptors and Hsp90 appears to be essential for ligand binding and activation of the receptors, the role of Hsp90 in Raf activation is less clear. We have identified mutations in the hsp83 gene, the Drosophila homologue of hsp90, in a search for dominant mutations that attenuate signalling from Raf in the developing eye. The mutations result in single amino acid substitutions in the Hsp83 protein and cause a dominant-negative effect on the function of the wild-type protein. We show that both wild-type and mutant forms of Hsp83 bind to the activated Drosophila Raf but the mutant Hsp83 protein causes a reduction in the kinase activity of Raf. Our results indicate that Hsp83 is essential for Raf function in vivo.

Amino Acid Sequence↗
PubMed1995

Biochemical and genetic analysis of the Drk SH2/SH3 adaptor protein of Drosophila.

The Drk SH3-SH2-SH3 adaptor protein has been genetically identified in a screen for rate-limiting components acting downstream of the Sevenless (Sev) receptor tyrosine kinase in the developing eye of Drosophila. It provides a link between the activated Sev receptor and Sos, a guanine nucleotide release factor that activates Ras1. We have used a combined biochemical and genetic approach to study the interactions between Sev, Drk and Sos. We show that Tyr2546 in the cytoplasmic tail of Sev is required for Drk binding, probably because it provides a recognition site for the Drk SH2 domain. Interestingly, a mutation at this site does not completely block Sev function in vivo. This may suggest that Sev can signal in a Drk-independent, parallel pathway or that Drk can also bind to an intermediate docking protein. Analysis of the Drk-Sos interaction has identified a high affinity binding site for Drk SH3 domains in the Sos tail. We show that the N-terminal Drk SH3 domain is primarily responsible for binding to the tail of Sos in vitro, and for signalling to Ras in vivo.

Amino Acid Sequence↗
PubMed1995

Nuclear factors in sevenless signalling.

Recent studies in both vertebrates and invertebrates support an 'hourglass' model for signal transduction from receptor tyrosine kinases: Ras channels signals from diverse receptor tyrosine kinases into a common cytoplasmic kinase cascade, the targets of which are an even more diverse collection of nuclear proteins. What are these nuclear factors, and how do they interact to direct specific cellular responses to a generic signal? The past year has brought considerable progress in our quest to answer these questions in one model genetic system, the Drosophila eye.

Animals↗
PubMed1994

The Drosophila rolled locus encodes a MAP kinase required in the sevenless signal transduction pathway.

Mitogen-activated protein (MAP) kinases have been proposed to play a critical role in receptor tyrosine kinase (RTK)-mediated signal transduction pathways. Although genetic and biochemical studies of RTK pathways in Caenorhabditis elegans, Drosophila melanogaster and mammals have revealed remarkable similarities, a genetic requirement for MAP kinases in RTK signaling has not been established. During retinal development in Drosophila, the sevenless (Sev) RTK is required for development of the R7 photoreceptor cell. Components of the signal transduction pathway activated by Sev in the R7 precursor include proteins encoded by the gap1, drk, Sos, ras1 and raf loci. In this report we present evidence that a Drosophila MAP kinase, ERK-A, is encoded by the rolled locus and is required downstream of raf in the Sev signal transduction pathway.

Animals↗
PubMed1994

Elucidation of the role of breathless, a Drosophila FGF receptor homolog, in tracheal cell migration.

DFGF-R1 (breathless), a Drosophila FGF receptor homolog, is required for the migration of tracheal cells and the posterior midline glial cells during embryonic development. To define the role of this receptor in cell migration, we have monitored the biological effects of a deregulated receptor containing the extracellular and transmembrane regions of the torso dominant allele and the cytoplasmic domain of DFGF-R1. Ubiquitous expression of the chimeric receptor at the time of tracheal cell migration did not disrupt migration in wild-type embryos. However, induction of the chimeric receptor corrected the tracheal defects of breathless (btl) mutant embryos, allowing the tracheal cells to migrate along their normal tracts. This result indicates that the normal activity of DFGF-R1 in promoting cell migration does not require spatially restricted cues. Late inductions of the chimeric construct, after the normal initiation of tracheal migration, allowed the definition of a broad time window during which the external signals guiding migration persist and the tracheal cells retain the capacity to respond to these cues. Rescue of tracheal migration in btl mutant embryos by the chimeric construct provides a sensitive biological assay for the activity of other Drosophila receptor tyrosine kinases (RTKs). Deregulated receptors containing the cytoplasmic domains of DFGF-R2, DER, torso, and sevenless were all able to partially rescue the migration defects. Consistent with the notion that these RTKs share a common signaling pathway, constructs containing the activated downstream elements Dras1 and Draf were also able to rescue tracheal migration, demonstrating that these two proteins are key players in the DFGF-R1 signaling pathway.

Animals↗
PubMed1994

Genetic dissection of signal transduction mediated by the sevenless receptor tyrosine kinase in Drosophila.

The specification of the R7 photoreceptor cell fate in the developing eye of Drosophila depends on the local activation of the sevenless (sev) receptor tyrosine kinase by boss, a protein expressed on the membrane of the neighboring R8 cell. Constitutive activation of the sev receptor results in a dosage dependent increase in the number of R7 cells per ommatidium. Genetic screens have been used to identify mutations that alter the efficiency of signal transduction. Subsequent molecular characterization of the corresponding genes has led to the identification of a number of proteins involved in transducing the signal from the receptor to the nucleus. In contrast to the receptor and its ligand, these components are shared between different signal transduction pathways not only in Drosophila but are also homologous to components involved in signal transduction in other organisms.

Animals↗
PubMed1994

Genetics of signal transduction in invertebrates.

Receptor tyrosine kinases regulate a number of different cell fate decisions during invertebrate development. Genetic analysis of the signal transduction pathways activated by these kinases suggests that they converge upon a common pathway involving Ras and a cascade of cytoplasmic kinases, diverging again in the nucleus with the regulation of specific transcription factors.

Amino Acid Sequence↗
PubMed1993

Genetic dissection of signal transduction mediated by the sevenless receptor tyrosine kinase in Drosophila.

The specification of the R7 photoreceptor cell fate in the developing eye of Drosophila depends on the local activation of the sevenless (Sev) receptor tyrosine kinase by Boss, a protein expressed on the membrane of the neighbouring R8 cell. Constitutive activation of the Sev receptor results in a dosage-dependent increase in the number of R7 cells per ommatidium. Genetic screens have been used to identify mutations that alter the efficiency of signal transduction. Subsequent molecular characterization of the corresponding genes has led to the identification of a number of proteins involved in transducing the signal from the receptor to the nucleus. In contrast to the receptor and its ligand, these components are shared between different signal transduction pathways not only in Drosophila but are also homologous to components involved in signal transduction in other organisms.

Animals↗
PubMed1993

A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos.

A Drosophila gene (drk) encodes a widely expressed protein with a single SH2 domain and two flanking SH3 domains, which is homologous to the Sem-5 protein of C. elegans and mammalian GRB2. Genetic analysis suggests that drk function is essential for signaling by the sevenless receptor tyrosine kinase. Drk biological activity correlates with binding of its SH2 domain to activated receptor tyrosine kinases and concomitant localization of drk to the plasma membrane. In vitro, drk also binds directly to the C-terminal tail of Sos, a Ras guanine nucleotide-releasing protein (GNRP), which, like Ras1 and drk, is required for sevenless signaling. These results suggest that drk binds autophosphorylated receptor tyrosine kinases with its SH2 domain and the Sos GNRP through its SH3 domains, thereby coupling receptor tyrosine kinases to Ras activation. The conservation of these signaling proteins during evolution indicates that this is a general mechanism for linking tyrosine kinases to Ras.

Amino Acid Sequence↗
PubMed1993

Genetic analysis of the sevenless signal transduction pathway of Drosophila.

The specification of the R7 photoreceptor cell fate in the developing eye of Drosophila depends on the local activation of the sevenless (sev) receptor tyrosine kinase (RTK) by boss, a protein expressed on the membrane of the neighboring R8 cell. Constitutive activation of the sev receptor results in a dosage dependent increase in the number of R7 cells per ommatidium. Genetic screens have been used to identify mutations that alter the efficiency of signal transduction. Subsequent molecular characterization of the corresponding genes has led to the identification of a number of proteins involved in transducing the signal from the receptor to the nucleus. In contrast to the receptor and its ligand, these components are shared between different signal transduction pathways not only in Drosophila but homologous components are also involved in signal transduction in other organisms.

Animals↗
PubMed1992

Raf functions downstream of Ras1 in the Sevenless signal transduction pathway.

Specification of the R7 cell fate in the developing Drosophila eye requires activation of the Sevenless (Sev) receptor tyrosine kinase, located on the surface of the R7 precursor cell, by its interaction with the Boss protein, expressed on the surface of the neighbouring R8 cell. Four genes that participate in the intracellular transmission of this signal have so far been identified and molecularly characterized: Ras1, Sos, Gap1 and sina (refs 4-8). The Drosophila homologue of the mammalian Raf-1 serine/threonine kinase, which has been implicated in signal transduction pathways activated by many receptor tyrosine kinases (reviewed in refs 9 and 10), is encoded by the raf locus (also known as l(1)polehole, Draf-1 or Draf). Here we show that the Drosophila Raf serine/threonine kinase also plays a crucial role in the R7 pathway: the response to Sev activity is dependent on raf function, and a constitutively activated Raf protein can induce R7 cell development in the absence of sev function. We also present genetic evidence suggesting that Raf acts downstream of Ras1 and upstream of Sina in this signal transduction cascade.

Animals↗
PubMed1992

Embryonal sarcoma of the liver in an adult treated with preoperative chemotherapy, radiation therapy, and hepatic lobectomy.

A rare case of embryonal sarcoma of the liver in a 28-year-old man is reported. The patient was treated preoperatively with a combination of chemotherapy and radiation therapy. Complete surgical resection, 4.5 months after diagnosis, consisted of a left hepatic lobectomy. No viable tumor was found in the operative specimen. The patient was disease-free 20 months postoperatively.

Adult↗
PubMed1992

Prepattern in the developing Drosophila eye revealed by an activated torso--sevenless chimeric receptor.

Induction of the R7 photoreceptor cell fate in the developing eye of Drosophila depends on the activation of the sevenless receptor tyrosine kinase in the R7 precursor cell. The sevenless protein is expressed transiently in 8 of the 20 precursors of an ommatidium. Activation of the sevenless kinase in these eight cells indicates that six of them are competent to become R7 cells. To test the competence of all 20 ommatidial precursors in a temporally unrestricted manner we have used a constitutively activated sevenless kinase created by fusing the extracellular domain of a mutant torso protein, another Drosophila receptor tyrosine kinase, to the sevenless kinase. Our results show that competence to develop as neuronal cells in response to sevenless activity is spatially and temporally limited to the cells expressing sevenless. Therefore, the expression of sevenless marks a preexisting pattern of developmental potential in the disc epithelium.

Animals↗