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Biomedical subjects

A Turner

Publications and source records attributed to A Turner.

At least 109 records · Page 6Linked to original sources
PubMed1994

Improved tumor targeting with chemically cross-linked recombinant antibody fragments.

The construction and use of recombinant chimeric and later fully humanized (CDR-grafted) antibodies to tumor-associated antigens has reduced the immune response generated to these antibodies in clinical studies. However, their long circulating half-life is a disadvantage for tumor imaging and therapy. Fragments such as F(ab')2, Fab', Fv and single chain Fv (scFv) offer faster blood clearance but also lower overall tumor doses. We have examined the tumor targeting of several novel fragments produced by chemical cross-linking of Fab' or scFv to dimeric and trimeric species. To facilitate cross-linking of Fab' fragments, a chimeric B72.3 Fab' fragment has been expressed with a hinge sequence containing a single cysteine residue. B72.3 scFv was also produced with a similar hinge region peptide attached to the COOH terminus to allow cross-linking. These fragments, Fab' delta Cys and scFv' delta Cys were cross-linked with linkers containing two or three maleimide groups to produce dimeric and trimeric molecules with increased avidity for antigen. Cross-linkers were also designed to contain a 12-N-4 macrocycle capable of stable radiolabeling with 90Y. This allowed the production of site-specifically-labeled, fully immunoreactive proteins. Biodistribution studies in the nude mouse LS174T xenograft model with scFv, di-scFv, and tri-scFv demonstrated that these fragments clear extremely rapidly from the circulation and give rise to only low levels of activity accumulated at the tumor. Di-Fab (DFM) and tri-Fab (TFM) however, accumulated relatively high levels of activity at the tumor with high tumor:blood ratios generated, demonstrating improved targeting compared to IgG. cB72.3 90Y-labeled tri-Fab was found not to accumulate in the kidney or the bone, resulting in an attractive antibody fragment for tumor therapy.

Animals↗
PubMed1994

Color Doppler imaging of the uteroplacental circulation in the middle trimester: observations on the development of a low-resistance circulation.

We aimed to study the changes in the flow dynamics of the uteroplacental and umbilical circulations in the middle trimester of normal pregnancy, and establish normal ranges for indices of the Doppler flow velocity waveforms (FVWs) from both circulations at 14, 18 and 24 weeks. A longitudinal study was conducted with the use of color Doppler imaging to localize both uterine arteries and umbilical arteries and obtain FVWs from 106 healthy nulliparous women with a singleton pregnancy. Of these, 70 did not have a complicated pregnancy outcome, defined as hypertension, growth retardation, preterm delivery or perinatal death. We measured the resistance index (RI), pulsatility index (PI), systolic/diastolic (S/D) ratio and presence of early diastolic notching in both uterine arteries, and RI, PI and S/D in one umbilical artery. The results showed a fall in all measured indices of blood flow impedance in the uteroplacental and umbilical circulations and a marked reduction in the incidence of the early diastolic notch in the uterine artery FVWs during the mid-trimester. Our conclusion was that color Doppler imaging allows for the accurate localization of both uterine and umbilical arteries. Doppler FVWs then obtained confirm the development of the low-resistance uteroplacental and umbilical circulations in the mid-trimester. Diastolic notching is common at 14 weeks in normal pregnancy but uncommon at 24 weeks.

Journal Article↗
PubMed1994

Comparative biodistributions of indium-111-labelled macrocycle chimeric B72.3 antibody conjugates in tumour-bearing mice.

A novel 111In ligand (a C-functionalised derivative of 1,4,7-triazacyclononanetriacetic acid), termed 9N3, was covalently attached to chimeric B72.3, labelled with 111In and compared with 111In-labelled chimeric B72.3 diethylenetriaminepentaacetic acid (DTPA) cyclic anhydride conjugate (cDTPA) and a C-linked derivative of DTPA (CT-DTPA) in athymic mice bearing human colon carcinoma xenografts. Significant differences in biodistribution were observed between 9N3 and cDTPA conjugates especially in the tumour uptake and blood, liver, femur and colon levels at 24, 48 and 144 h. Significantly higher tumour uptake was observed for 111In-cB72.3-9N3 compared with 111In-cB72.3-cDTPA at all time points. Radiolocalisation (RI) indices increased with time for the 9N3 conjugate but remained constant for the cDTPA conjugate. The biodistribution of 111In-labelled cB72.3-CT-DTPA was similar to that of 111In-labelled cB72.3-9N3 except for elevated kidney levels. A 12N4 macrocycle (a C-functionalised derivative of 1,4,7,10-tetraazacyclododecanetetraacetic acid) was also tested for its ability to chelate 111In and its biodistribution examined. Labelled conjugates with this macrocycle were more difficult to prepare in a stable form but gave a very similar biodistribution to the 9N3 macrocycle conjugate. Macrocycle-antibody conjugates of this type offer considerable promise for tumour imaging in patients.

Amines↗
PubMed1994

The potential for enhanced tumour localisation by poly(ethylene glycol) modification of anti-CEA antibody.

Attachment of poly(ethylene glycol) (PEG) to proteins can greatly alter their pharmacological properties, including extending the plasma half-life and reducing immunogenicity, both of which are potentially beneficial to tumour targeting. IgG, F(ab')2 and Fab' fragments of the anti-CEA antibody A5B7 were chemically modified with PEG (M(r) 5,000), labelled with 125I and their pharmacokinetics compared with the unmodified forms in the LS174T colonic xenograft in nude mice. PEG modification of the intact antibody had little effect on biodistribution, although tumour localisation was slightly reduced. In contrast, similar modification of F(ab')2 and Fab'A5B7 significantly prolonged plasma half-life and increased radioantibody accumulation in the tumour and to a lesser extent in normal tissues, but reduced tissue to blood ratios. Prior to modification, Fab' A5B7 (M(r) 50,000) cleared more rapidly from the circulation than F(ab')2 (M(r) 100,000), but after PEG attachment their biodistributions converged, while the tumour to blood ratios were reduced and resembled that of the intact antibody. The enhanced tumour accumulation, reduced normal tissue to blood ratios and potentially reduced immunogenicity of fragments after PEG attachment may therefore prove superior to either unmodified fragments or intact antibody for antibody-targeted therapy, although the increased plasma half-life may necessitate the use of a clearance mechanism.

Adenocarcinoma↗
PubMed1994

The ultimate price.

Explore the source record for details and available documents.

Accidents, Aviation↗
PubMed1994

Plasmodesmata of maize root tips: structure and composition.

A procedure is described for obtaining clean maize cell wall preparations that contain embedded plasmodesmata. Negative staining and rotary shadowing have been used with transmission electron microscopy to visualise the plasmodesmata in these isolated walls, and to assess the effects of simple biochemical treatments on plasmodesmal components. Light protease treatment removes material from the exposed ends of plasmodesmata but does not extract the plasmodesmal core, which lies within the cell wall. However, heavy proteolysis occasionally removes the complete plasmodesma, including its enclosing collar structure, from the wall. Extraction with urea has a similar effect. The collar itself appears not to be proteinaceous in composition, although protein may bind it into the wall. Callose is localised in the wall around plasmodesmata, but does not appear to be a constituent of the collar. The membrane components of the plasmodesma (plasma membrane and desmotubule) can be extracted with membrane-solubilising detergents. This treatment releases from the wall a small number of proteins that are regarded as being potentially of plasmodesmal origin. These results show that plasmodesmata from maize can be dissected biochemically and suggest a strategy for the characterisation of individual molecular components.

Cell Fractionation↗
PubMed1993

Primary cardiac sarcomas. A report of three cases and a review of the current literature.

Primary cardiac sarcomas are uncommon but they may mimic a wide range of common cardiac pathologies by their modes of presentation. Surgery is the mainstay of treatment for non-metastatic disease however, the incidence of tumour recurrence and late metastases is high. For metastatic disease, the response to chemotherapy and radiotherapy is poor and surgery should be reserved for palliation where appropriate. The emphasis should be on early diagnosis of primary cardiac sarcoma, enabling prompt and relevant management.

Adult↗
PubMed1993

Family pesticide use and childhood brain cancer.

The relationship between family pesticide use and childhood brain cancer was examined in a case-control study. Telephone interviews were conducted from June 1989 through March 1990 with the natural mothers of 45 childhood brain cancer cases, 85 friend controls, and 108 cancer controls. In comparisons to friend controls, significant positive associations were observed for use of pesticides to control nuisance pests in the home, no-pest-strips in the home, pesticides to control termites, Kwell shampoo, flea collars on pets, diazinon in the garden or orchard, and herbicides to control weeds in the yard. In comparisons to cancer controls, significant positive associations were observed for use of pesticide bombs in the home, pesticides to control termites, flea collars on pets, insecticides in the garden or orchard, carbaryl in the garden or orchard, and herbicides to control weeds in the yard. In general, positive associations in comparisons to one control group were supported by elevated odds ratios in comparisons to the other control group. Several potentially important associations were identified in this study. However, small sample sizes, potential recall bias, multiple comparisons, and lack of detailed exposure verification require further research to confirm these findings.

Brain Neoplasms↗
PubMed1993

A single amino acid substitution abolishes the heterogeneity of chimeric mouse/human (IgG4) antibody.

Human immunoglobulin G4 (IgG4) exists in two molecular forms due to the heterogeneity of the inter-heavy chain disulphide bridges in the hinge region in a proportion of secreted human IgG4. This heterogeneity is only revealed under denaturing, non-reducing conditions in which an HL "half antibody" is detected, a phenomenon not seen in other human IgG isotypes. In native conditions noncovalent interactions hold the antibody together as the H2L2 tetramer. Analysis of the hinge sequences of human IgG heavy chains suggested that the presence of serine at residue 241 might be the cause of this heterogeneity. We therefore changed the serine at 241 to proline (found at that position in IgG1 and IgG2) in a mouse/human chimeric heavy chain. This single residue substitution leads to the production of a homogeneous antibody. Further, the variant IgG4 has significantly extended serum half-life and shows an improved tissue distribution compared to the original chimeric IgG4.

Amino Acid Sequence↗
PubMed1993

Nalmefene enhances LH secretion in a proportion of oligo-amenorrheic athletes.

The influence upon LH secretion of doses of nalmefene, an orally effective congener of naloxone, and a placebo was compared in nine oligo-amenorrheic athletes with that in five regularly menstruating non-athletic women as a test for periodic elevations in hypothalamic opioid tone. After a 360-min control period, LH levels were followed for an additional 360 min following ingestion of the medications in random order approximately six weeks apart, 10-min blood sampling being employed throughout. The mean amplitude post-nalmefene in the athletes was significantly greater than pre (p < 0.05), although there were no differences in the frequency of LH pulses after placebo or nalmefene ingestion. Subjects were labelled as "responders" if their peak AUC after treatment exceeded their pretreatment AUC for LH by more than 1.96 SD (p < 0.05). There were no placebo responders, but 5/9 of the athletes and 1/5 of the menstruating controls were classified as nalmefene responders (p < 0.05). In addition, a variable proportion of the athletes (but none of the controls) experienced symptoms suggestive of narcotic withdrawal 1-4 h after ingesting nalmefene and again 12-18 h later. It appears that demonstrable increases in opioid tone occur at least transiently in a proportion of oligo-amenorrheic athletes.

Adult↗
PubMed1993

Further localization of the gene for nevoid basal cell carcinoma syndrome (NBCCS) in 15 Australasian families: linkage and loss of heterozygosity.

Nevoid basal cell carcinoma syndrome (NBCCS; basal cell nevus syndrome or Gorlin syndrome) is a cancer-predisposition syndrome characterized by multiple basal cell carcinomas (BCCs) and diverse developmental defects. The gene for NBCCS has been mapped to 9q23.1-q31 in North American and European families. In addition, loss of heterozygosity (LOH) for genetic markers in this region has been detected in sporadic BCCs, indicating that the NBCCS gene is probably a tumor-suppressor gene. In this study we have determined that the NBCCS gene is also linked to this region in Australasian pedigrees and that there is no significant evidence of heterogeneity. We have defined the localization of the gene by multipoint and haplotype analysis of 15 families, using four microsatellite markers. LOH at these loci was detected in 50% of sporadic BCCs, a rate that is significantly higher than that in other skin lesions used as controls.

Adult↗
PubMed1992

Preimplantation diagnosis of a human beta-globin transgene in biopsied trophectoderm cells and blastomeres of the mouse embryo.

The preimplantation diagnosis of a HbSA-globin transgene in biopsied trophectoderm cells and blastomeres in embryos using a transgenic mouse model for the trait of human sickle-cell anaemia has been undertaken. A sensitive procedure was developed for the amplification of the human beta-globin gene sequence flanking the sickle mutation. Polymerase chain reaction (PCR) assays were undertaken on one to five biopsied trophectoderm cells and isolated blastomeres of the preimplantation mouse embryo. After biopsy the blastocysts were cultured whilst the cells were analysed for the presence of the transgene, and a high proportion (82-91%) were viable as assessed by the presence of a blastocoele cavity within a 5-h period. The majority of the biopsied cultured blastocysts were frozen and used to confirm the diagnosis; 90 biopsied cultured blastocysts were transferred to pseudopregnant recipients and 34% established pregnancy. Material from day 13.5 post-coitum fetuses was also used to confirm the original diagnosis. The time (4-5 h) required to carry out the analysis obviates a need for extended culture or cryopreservation of the biopsied embryo. In individual experiments under optimal conditions, the presence of the transgene in biopsied cells was detected with 100% accuracy, and the PCR analysis was sensitive at the 1-cell level. The overall success rate of diagnosis and confirmation of the presence or absence of the human beta-globin sequence in the biopsied embryo was 70%. Over the entire experimental period (14 months) DNA contamination from a variety of sources did occasionally occur; the methods used to overcome this problem are discussed.

Anemia, Sickle Cell↗
PubMed1992

Corticotropin-independent effect of ovine corticotropin-releasing hormone on cortisol release in man.

The effect of corticotropin-releasing hormone (CRH), independent of adrenocorticotropin hormone (ACTH), was evaluated in nine healthy individuals. Cortisol release and corresponding ACTH production were determined after separate intravenous administration of ovine-CRH (1 micrograms/kg BW) and insulin inducing hypoglycemia (0.1 u/kg BW). Adrenocorticotropin hormone (1-24; 250 micrograms intravenous bolus) revealed an adequate adrenal reserve capacity in all subjects. At the time of peak cortisol response following CRH and insulin administration, IR-cortisol increments were 14 +/- 1 micrograms/dl and 9 +/- 1 micrograms/dl (mean +/- SE), respectively (p less than .05); whereas ACTH (IR-ACTH) increments were 40 +/- 10 ng/l and 53 +/- 14 ng/l, respectively. The cortisol increment/ACTH increment ratios were 0.53 +/- 0.09 and 0/36 +/- 0.09, respectively (p less than 0.05), suggesting an ACTH-independent effect of CRH on cortisol production. The authors speculate that CRH may have a direct effect on the human adrenal gland or it may release ACTH-like factors that stimulate the human adrenal cortex.

Adrenocorticotropic Hormone↗
PubMed1992

Differential bacteriology in adenoid disease.

In order to define the differential bacteriology in adenoid disease, adenoids were obtained from 10 children with adenoid hypertrophy and 29 children with chronic adenoiditis. The patients' ages ranged from 18 months to 13 years. After removal of the adenoids, the surface organisms were destroyed by alcohol and flame disinfection. One gram of tissue was sampled for aerobic and anaerobic culture. There was an average of 4.8 isolates per specimen, with 4.2 aerobes and 0.6 anaerobes. The most common isolates were: Haemophilus influenzae (84%), diphtheroids (66%), non-pathogenic Neisseria species (66%), alpha-hemolytic streptococci (64%) and non-hemolytic streptococci (59%). Anaerobes were present in 56% of all cases. The distribution of organisms was similar, regardless of clinical diagnosis. Only eight (21%) of the 39 cases had 'significant' (> or = 10(5) organisms/gm) colony counts. Our study detected no difference in either organism distribution or in total colony counts in chronic adenoiditis vs. adenoid hypertrophy.

Adenoids↗