Search PubMed⌕ Search

Biomedical subjects

J Jones

Publications and source records attributed to J Jones.

At least 91 records · Page 5Linked to original sources
PubMed2002

Equivalent efficacy and safety of a new HFA-134a formulation of BDP compared with the conventional CFC in adult asthmatics.

The present study demonstrates the equivalent efficacy for BDP 500 microg bid given via MDI with the new HFA-134a propellant (Chiesi Farmaceutici S.p.A., Parma) compared to a conventional CFC propellant (Becotide, Allen & Hanburys, UK). One hundred and sixteen adult patients with stable mild to moderate asthma (FEV1 > or = 60% of predicted normal) entered a 2-week run-in period where they maintained their own inhaled corticosteroids and were then assigned to a 12-week treatment with the test drug in a randomized, multicentre, double-blind, double-dummy, parallel-group design. Ninety-one patients completed the study period. Morning and evening peak expiratory flow rate (PEFR), use of rescue salbutamol, number of daytime and nighttime asthma attacks, number of nighttime awakenings, and clinical symptoms were recorded daily by patients on a diary card. Pulmonary function tests (FEV1, FVC, PEFR, MEF50 and FEF25) were completed at study entry, at the start of treatment and every 2 weeks thereafter. Morning (08.00-10.00 AM) serum cortisol was measured at the start and at the end of treatment. Adverse events were collected for the total study period. Equivalence between groups was demonstrated for the primary end-point morning PEFR, as well as for evening PEFR and FEV1 (the 95% CI of the treatments' difference was within the 5% of the LSM of BDP CFC). The other secondary pulmonary function tests measured at the clinic visit showed a satisfactory asthma control, albeit without statistically significant differences between groups. Decreases in the use of rescue salbutamol and in clinical symptoms were also reported in both groups, with no differences between them. Adverse events were reported in 81.4% of patients in the BDP HFA group and in 82.5% in the CFC group. There were 73 and 59 adverse drug reactions in the two groups, respectively; the difference was mainly due to differences in taste. No drug-related serious adverse events were reported in either group. No difference was seen for morning serum cortisol between baseline and end of treatment, or between groups. In conclusion, the BDP-HFA 134a formulation proved to be statistically equivalent to the standard BDP CFC product over 12 weeks in adult patients with mild to moderate asthma.

Adult↗
PubMed2002

Coroner's Rule 9 is necessary for health protection: implications of possible legislative changes concerning the use of human organs and tissues.

Legislation around the retention and use of human organs and tissues is currently being reviewed to ensure that there is an appropriate emphasis on consent, human dignity and sensitivity towards bereaved relatives. In a public health emergency such as an outbreak of severe unexplained illness, the priorities are to treat the affected and prevent further cases. Human tissue retention can have a vital role to play and there may be a conflict of interest between individual and public health needs. It is essential to ensure that any legislative changes are compatible with effective and efficient responses to public health emergencies.

Disease Outbreaks↗
PubMed2001

Conversion of poorly immunogenic malaria repeat sequences into a highly immunogenic vaccine candidate.

The recent success of a Plasmodium falciparum malaria vaccine consisting of circumsporozoite protein (CSP) T and B cell epitopes has rekindled interest in the development of a pre-erythrocytic vaccine. In order to optimize immunogenicity, well-characterized CSP-specific neutralizing B cell epitopes and a universal T cell epitope were combined with an efficient and flexible particulate carrier platform, the hepatitis B core antigen (HBcAg), to produce a novel pre-erythrocytic vaccine candidate. The vaccine candidate, V12.PF3.1, is a potent immunogen in mice eliciting unprecedented levels (greater than 10(6) titers) of sporozoite-binding antibodies after only two doses. The anti-sporozoite antibodies are long lasting, represent all IgG isotypes, and antibody production is not genetically restricted. CSP-specific CD4+ T cells are also primed by V12.PF3.1 immunization in a majority of murine strains. Furthermore, the hybrid HBcAg-CS particles can be produced inexpensively in bacterial expression systems. These and other characteristics suggest that V12.PF3.1 represents an efficient and economical P. falciparum vaccine candidate for use separately or in combination with other formulations.

Adjuvants, Immunologic↗
PubMed2001

Horizontal transfer of a bacterial gene involved in polyglutamate biosynthesis to the plant-parasitic nematode Meloidogyne artiellia.

Analysis of a genomic fragment from the plant parasitic nematode Meloidogyne artiellia revealed the presence of a gene which, in bacteria, is involved in the formation of polyglutamate capsule. Searching of various databases, including the Caenorhabditis elegans genome sequence and the large EST datasets from a variety of parasitic nematodes, showed that no similar genes have been identified in other nematodes or in any other eukaryotic organisms. The M. artiellia gene has a typical eukaryotic structure and its mRNA is present in the intestine. The gene is expressed in all life cycle stages tested. These findings demonstrate horizontal gene transfer may be important in catalyzing the diversification of nematode lineages.

Amino Acid Sequence↗
PubMed2001

Solubilisation and immunoprecipitation of rat striatal adenosine A(2A) receptors.

In the present study, we have sought to solubilise adenosine A(2A) receptors from rat striatal membranes using a variety of different detergents. Of the detergents tested, 1% CHAPS (3-[(3-deoxycholic acid (cholamidopropyl) dimethylammonio]-1-propanesulfonate) yielded optimal conditions for solubilisation (in the presence of 3 mg/ml protein, 44% of receptor was solubilised, 50% of total protein was solubilised). An antipeptide antibody was raised against a 15 amino-acid sequence within the predicted third intracellular loop region of the human and rat adenosine A(2A) receptor. The antibody was coupled to protein A immobilised on sepharose CL-4B and used to immunoprecipitate adenosine A(2A) receptors from solubilised rat striatal preparations. Radioligand-binding studies were performed using the selective adenosine A(2) antagonist [(3)H]ZM 241385 (4-(2-[7-amino-2-(2-fury1)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol). Using [(3)H]ZM 241385, the pharmacology of immunoprecipitated adenosine A(2A) receptors was composed to striatal membrane bound adenosine A(2A) receptors and detergent solubilised adenosine A(2A) receptors. [(3)H]ZM 241385 labelled a single saturable binding site with high affinity in all three preparations (membrane bound K(d) 2.7 nM+/-1.0; solubilised K(d) 1.9 nM+/-0.3; immunoprecipitated K(d) 2.2 nM+/-0.7). Additionally, all three assays confirmed a rank order of potency for displacers consistent with adenosine A(2A) receptor pharmacology: ZM 241385>KW 6002 ((E)-8-[2-(3,4-dimethoxyphenyl)ethynyl]-1-3-diethyl-3,7-dihydro-7-methyl-1-purine 2,6 dione)>CGS 21680, (2-(4-(2 carboxyethyl)phenylethylamino)-5'-N-ethylcarboxamidoadenosine)>DPCPX (8-cyclopentyl-1,3-dipropylxanthine). We conclude that we have solubilised and immunoprecipitated adenosine A(2A) receptors from rat striatum and that their pharmacology is consistent with native striatal adenosine A(2A) receptors.

Adenosine↗
PubMed2001

Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling.

In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival. Normally, NF-kappaB dimers are sequestered in the cytoplasm by binding to inhibitory IkappaB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of IkappaBs. Activation of NF-kappaB antagonizes apoptosis or programmed cell death by numerous triggers, including the ligand engagement of 'death receptors' such as tumour-necrosis factor (TNF) receptor. The anti-apoptotic activity of NF-kappaB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer. Cytoprotection by NF-kappaB involves the activation of pro-survival genes; however, its basis remains poorly understood. Here we report that NF-kappaB complexes downregulate the c-Jun amino-terminal kinase (JNK) cascade, thus establishing a link between the NF-kappaB and the JNK pathways. This link involves the transcriptional upregulation of gadd45beta/myd118 (ref. 4), which downregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-kappaB-dependent inhibition of the JNK pathway is central to the control of cell death. Our findings define a protective mechanism that is mediated by NF-kappaB complexes and establish a role for the persistent activation of JNK in the apoptotic response to TNF-alpha.

3T3 Cells↗
PubMed2001

Dok-R plays a pivotal role in angiopoietin-1-dependent cell migration through recruitment and activation of Pak.

Tek/Tie-2 is an endothelial cell (EC)-specific receptor tyrosine kinase that plays a critical role in angiogenesis via its regulation by the angiopoietin family of growth factor ligands. Angiopoietin-1 (Ang1) can promote EC migration; however, the signaling mechanisms underlying this process remain elusive. Here we demonstrate that Dok-R/Dok-2 can associate with Tek in ECs following Ang1 stimulation, resulting in tyrosine phosphorylation of Dok-R and the subsequent recruitment of Nck and the p21-activating kinase (Pak/Pak1) to the activated receptor. Ang1-mediated migration is increased upon Dok-R overexpression and this requires a functional Nck binding site on Dok-R. Localization of this Dok-R-Nck-Pak complex to the activated Tek receptor at the cellular membrane is coincident with activation of Pak kinase. The ability of Dok-R to bind Nck is required for maximal activation of Pak and overexpression of Pak results in increased Ang1-mediated cell motility. Our study outlines a novel signaling pathway underlying Ang1-driven cell migration that involves Dok-R and its recruitment of Nck and the subsequent activation of Pak.

Adaptor Proteins, Signal Transducing↗
PubMed2001

A phase II study of the bispecific antibody MDX-H210 (anti-HER2 x CD64) with GM-CSF in HER2+ advanced prostate cancer.

The proto-oncogene HER2 presents a novel therapeutic target. We report results in 25 patients with HER2+ advanced prostate cancer treated with the bispecific antibody MDX-H210 15 microg m(-2)by intravenous infusion plus GM-CSF 5 microg kg(-1)day(-1)by subcutaneous injection for 4 days repeated weekly for 6 weeks. Patients with stable disease or better received further cycles of treatment until disease progression or study withdrawal. 1 patient received no treatment and 4 received less than 1 cycle and are included in the toxicity analysis only. Median duration of follow up was 105+ (range 21-188) days. Toxicity was generally NCI-CTG 0-2. There were 2 grade 4 adverse events (heart failure and dyspnoea) and 1 grade 3 event (allergic reaction) resulting in discontinuation of the study medication. There were 9 further grade 3 events not resulting in trial withdrawal. There were no treatment-related deaths. 7/20 (35%) evaluable patients had a >50% PSA response of median duration 128 (range 71-184+) days. 7/12 (58%) patients with evaluable pain had improvements in pain scores. The PSA relative velocity on therapy decreased in 15/18 (83%) assessable patients compared to pre-study. GM-CSF and MDX-H210 is active in hormone refractory prostate carcinoma with acceptable toxicity; further studies are warranted.

Adenocarcinoma↗
PubMed2001

Characterisation of agonist binding on human 5-HT2C receptor isoforms.

The 5-HT2C receptor is expressed in different isoforms as a result of mRNA editing. Both INI (unedited) and VSV (a fully edited version) isoforms are abundant in rat brain. The VSV isoform lacks the high affinity recognition site for 5-HT, which may be caused by low efficiency coupling to G-proteins. In this study we have investigated the pharmacology of the agonist binding site of these two isoforms of the 5-HT2C receptor. The VSV isoform was expressed in Chinese hamster ovary cells (CHO) and the INI isoform in both Chinese hamster ovary cells and human embryonic kidney cells (HEK-293). Saturation analysis using [3H]5-HT revealed high and low affinity recognition sites on the INI isoform in both cell types whilst the VSV isoform did not have the high affinity binding site for [3H]5-HT. Displacement studies were undertaken using [3H]5-HT to label the receptors. In these studies the affinity of agonists (5-HT, Ro600175 ((S)-2-(6-Chloro-5-fluoroindol-1-yl)-1-methylethylamine), MK212 (6-Chloro-2-(piperazinyl) pyrazine), mCPP (1-(m-chlorophenyl)-piperazine), TfMPP (N-(m-trifluoromethylphenyl)piperazine), DOI (1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane), DOB (1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane) and 8OH-DPAT (8-hydroxy-2-(di-N-propylamino)tetralin) was higher at the INI isoform, whilst antagonist affinity (ketanserin and mesulergine) did not change between the two receptor isoforms. There were no differences between the INI isoform expressed in the CHO and HEK-293. This suggests that the INI isoform of the 5-HT2C receptor is pharmacologically similar to the VSV form of the 5-HT2C receptor but that it couples more efficiently to G-proteins.

Animals↗
PubMed2001

Invasion-specific genes in malignancy: serial analysis of gene expression comparisons of primary and passaged cancers.

The invasive growth of malignant cells induces an admixture of host reactions including desmoplasia, angiogenesis, and immune reactions Pancreatic cancer has a prominent and characteristic host reaction at the site of primary invasion. To obtain new insights into the process of tumor invasion, we studied global patterns of gene expression using serial analysis of gene expression in pancreatic cancer, with extension to other tumor types. Here we report a cluster of invasion-specific genes in pancreatic and other cancers. This cluster contains genes that derive from distinct components of the host reaction, including some that may be useful as diagnostic markers and therapeutic targets.

Cluster Analysis↗