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Biomedical subjects

M Harding

Publications and source records attributed to M Harding.

At least 91 records · Page 5Linked to original sources
PubMed1986

Phase I and pharmacokinetic study of LM985 (flavone acetic acid ester).

We have conducted a Phase I and initial clinical pharmacological evaluation of LM985, the first of a series of compounds based on the flavone ring structure to be considered for clinical trial in malignant disease. The drug was administered i.v. to 26 patients with advanced cancer on an every-21-day schedule. Patients were treated at 14 dosage levels ranging from 10 to 1500 mg/m2. Dose limiting toxicity was identified as acute reversible hypotension occurring during drug infusion; no leukopenia, alopecia, hepatic toxicity, or renal toxicity was observed, but at the higher dose range, mild sedation was apparent. Twenty patients had measurable disease and were evaluable for response. One patient with colorectal carcinoma had stable disease after three courses of LM985; however, no other responses were seen. Pharmacokinetic and in vitro drug degradation studies imply that the ester LM985 is hydrolyzed to LM975 (flavone acetic acid) rapidly in vivo. LM975 is active in a variety of animal tumor models, but it does not have the cardiovascular side effects seen with LM985 (hypotension and bradycardia) in pithed or anesthetized rats. We would recommend that LM975 be considered for clinical trial, because it seems likely that substantially higher doses of LM975 than of LM985 can be given without dose limiting cardiovascular toxicity.

Adult↗
PubMed1985

Putative amino acid sequence of chick calcium-binding protein deduced from a complementary DNA sequence.

Two DNA fragments coding for chick CaBP have been isolated and sequenced. cDNA was prepared from enriched intestinal mRNA and cloned in pUC12. The recombinant clones were screened by differential hybridisation with 32P-cDNA probes synthesized from vitamin D replete and deficient chick intestinal mRNA. Two clones had outstanding affinity with the +D probe. Hybrid-arrested and hybrid-selected translation systems showed that both clones hybridised to mRNA coding for immunoprecipitable CaBP. The mRNA for CaBP has a 100 bp G,C rich sequence before a 786 bp coding region followed by 1250 nucleotides 3' untranslated region. Nucleotides coding for the Ca-binding sites show a high degree of homology for Ca-binding sites in chick calmodulin and rat intestinal CaBP. The amino acid sequence specified by the longest open reading frame contains five Ca-binding sites but is too large for the native CaBP; post-translational modification must therefore occur.

Amino Acid Sequence↗
PubMed1983

Effect of pregnancy on graft function and graft survival in renal cadaver transplant patients.

Variable experience is documented for pregnancy in renal transplant patients. Furthermore, little information is available that compares graft function and graft survival of cadaver transplant patients who undergo pregnancy with those of a similar group of patients who do not undergo pregnancy. From 1970 to 1979, 30 patients of childbearing age were identified who were first-time recipients of cadaver-donor kidneys. Long-term follow-up was from 32 to 136 months. Five patients have undergone seven pregnancies that resulted in six viable infants and one therapeutic termination. Pregnancy complications included severe preeclampsia, spontaneous premature rupture of membranes, and proteinuria. One infant was small for gestational age. There were no neonatal problems, and no congenital anomalies. Rejection episodes were more common in the postpartum than in the antepartum period (four of six versus one of six). Chronic rejection that led to graft loss occurred in two patients. Ten patients who did not undergo pregnancy were identified for comparison of graft function and graft survival. Late graft rejections occurred in four patients, two of whom eventually suffered graft loss. Survival rates of the grafts by actuarial analysis for the two groups were not significantly different.

Abortion, Therapeutic↗
PubMed1983

Effect of simple sugars on natural killing: evidence against the involvement of a lectin like mechanism in target recognition.

The spontaneous lysis of target cells sensitive to natural killer (NK) activity is accomplished in two distinct phases: (i) binding between target and effector cells and (ii) post-binding events leading to target cell destruction. To test the hypothesis that cell surface carbohydrate(s) might be involved in recognitive and/or lytic events, the binding and cytotoxicity of peripheral blood lymphocytes (PBL) towards NK sensitive K-562 targets was studied in the presence of simple sugars and after treatment of the targets with the antibiotic, tunicamycin. Lysis by peripheral blood lymphocytes was found to be inhibited by N-acetyl glucosamine, N-acetyl galactosamine and alpha-methyl mannoside in a dose-dependent manner under conditions where neither these sugars nor those (fucose, galactose) which had little effect on lysis inhibited the binding of effector cells to targets. Further, growth of K-562 in tunicamycin (which inhibits N-linked glycosylations occurring through the lipid intermediate pathway) with or without subsequent treatment with the enzyme neuraminidase, markedly reduced cell surface expression of sugars monitored by lectin binding. Treated cells showed no loss of NK susceptibility and were frequently more sensitive to lysis. Sugar inhibition profiles were the same as for untreated cells. These data suggest that carbohydrates are not the target sites of NK recognition but that simple sugars may have an inhibitory action at a later stage of the lytic process.

Acetylgalactosamine↗
PubMed1982

Successful renal transplantation in patients with T-cell reactivity to donor.

A positive crossmatch due to T-cell reactivity against donor cells is considered a strong contraindication to renal transplantation because of the risk of graft loss from rejection. However, the significance of T-cell reactivity before but not at the time of transplantation is unknown. To determine whether transplantation can be successful under these circumstances, graft survival was observed in 15 highly sensitised patients whose T cells were reactive to donor sera before but not at the time of transplantation. All patients have been followed up for at least 1 year post transplant. Immunosuppression was by azathioprine, prednisone, and rabbit antithymocyte sera. 9 (60%) have functioning grafts and a mean serum creatinine of 1.6 mg/dl. Early non-function occurred in 12 patients. One graft was lost to early acute humoral rejection and two other to chronic rejection. 14 of the 15 had a fall in reactivity to a panel of normal lymphocytes before transplant. 4 of the 15 had donor-specific B-cell antibodies at the time of transplantation and 3 of these lost their grafts because of rejection.

Adult↗
PubMed1980

1,25-Dihydroxycholecalciferol stimulation of a mitochondrial protein in chick intestinal cells.

The steroid hormone 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) stimulates the absorption of dietary calcium by the small intestine of animals although the exact mechanism by which this is achieved remains unclear. However, it has long been known that a soluble, calcium-binding protein (CaBP), is produced in large amounts in the cytoplasm of the intestinal cells of animals after in vivo administration of vitamin D3 or 1,25-(OH)2D3 (refs 1,2). We report here that 1,25-(OH)2D3 administered in vivo to rachitic chickens also stimulates production of another protein with molecular weight (MW) 39,000-42,000 which is insoluble in the absence of detergent, is found in the outer mitochondrial membrane and is produced in advance of maximum calcium transport.

Animals↗
PubMed1980

A controlled trial evaluating intensive plasma exchange in renal transplant recipients.

Sixty patients have been entered into a controlled trial evaluating the use of intensive plasma exchange (IPE) in renal transplant recipients. During the first three months post-transplant, patients receive either conventional anti-rejection therapy alone (control group) or conventional anti-rejection therapy and IPE (IPE group) for all rejection episodes. Twenty percent of the grafts in the control group versus 10% in the IPE group have been lost to rejection (p = NS). The actual three month patient and graft survival in the control group (97% and 70%), respectively, is similar to the IPE group (94% and 80%), as is the one year actuarial graft and patient survival in the two groups. No statistically significant benefit of IPE has yet been demonstrated but the trend is encouraging and the complication rate sufficiently low so as to justify continuing the study.

Clinical Trials as Topic↗
PubMed1978

Preparation and efficacy of an inactivated subunit vaccine (NFUIBHK) against type 2 Herpes simplex virus infection.

A vaccine against Herpes simplex virus infection was prepared by Nonidet NP 40 and formalin treatment of a type 1, infected-cell extract; virus particles were removed by ultracentrifugation over sucrose. These procedures were not detrimental to the antigenic quality of the vaccine preparation. The vaccine afforded significant protection to experimental type 2 genital herpes virus infection in mice, as adjudged by clinical observations, cytopathological change, and virus yields.

Animals↗
PubMed1977

A lack of correlation between 'T' antigen and any particular human chromosome in hybrids made between SV40 transformed human fibroblasts and mouse LMTK cells.

Lines of hybrid cells were established by fusion of mouse LMTK- cells with SV40 transformed human fibroblasts. The lines were examined for the presence of SV40 'T' antigen and the human chromosomes they carried identified by Giemsa banding. No significant correlation could be found between any particular human chromosome and the presence of SV40 virus.

Antigens, Viral↗
PubMed1977

Chromosome complement and SV40 transformation of cells from patients susceptible to malignant disease.

A comparative study has been made of fibroblasts obtained from patients with differing susceptibilities to malignant disease, both with respect to their chromosome complements and their transformation with SV40 virus. Fibroblasts from 2 Bloom's syndrome patients were found not to have raised SV40 transformation rates and no correlation was found between chromosome abnormality per se and transformation. Of 2 cell types with greatly increased rates, one was derived from a neurofibromatosis patient and the other from an A-T heterozygote. When SV40 DNA was employed as the transforming agent for the latter, the transformation rate was no longer raised.

Antigens, Viral↗
PubMed1977

The chromosome analysis and susceptibility to transformation by Simian Virus 40 of fibroblasts from ataxia-telangiectasia.

Chromosome analyses are reported for 14 lines of fibro-blasts derived from 8 ataxia-telangiectasia (ATT) patients and for 14 lines of control cells. An elevated incidence of chromosome damage including gaps and breaks, rings, dicentrics and fragments, and chromosome figures has been found to occur in ATT cells. Similar abnormalities present in different cell lines suggest that common break points occur in ATT fibroblast chromosomes. The SV40 virus transformation rates found for ATT cells lie within the range found for normal cells, and there is no direct correlation between the degree of chromosome damage exhibited by any ATT cell line and its transformation rate with SV40.

Ataxia Telangiectasia↗
PubMedDate not supplied

An alternating chemotherapy combination (MACOBLE) for intermediate and high-grade non-Hodgkin's lymphoma.

From June 1983 to February 1986, 48 patients with intermediate or high-grade non-Hodgkin's lymphomas (NHL) received a CHOP based combination with the addition of etoposide on days 1 and 2, bleomycin days 1 and 10 and methotrexate 1.5 g/m2 on day 10 (MACOBLE). Their median age was 59 years, 20 (42 per cent) had an ECOG performance status (PS) of 2 or 3, 24 (50 per cent) had stage IV disease, 25 (52 per cent) B symptoms and 21 (44 per cent) bulk (greater than 10 cm) disease. With a median follow-up of 62 months, 12 patients are alive, 10 of whom are disease-free. Median overall survival was 13 months (95 per cent confidence interval 6-23 months) with actuarial 5-year survival of 25 per cent (95 per cent confidence interval 13-37 per cent). Factors associated with inferior survival were ECOG PS 2 or 3 (P = 0.004), B symptoms (P = 0.013) and bulk disease (P = 0.017). These data suggest that, when treating an unselected patient population, attempts to increase the intensity of first-line chemotherapy may not improve the outcome.

Adult↗