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Biomedical subjects

D Parry

Publications and source records attributed to D Parry.

At least 37 records · Page 2Linked to original sources
PubMed1995

Complex structure and regulation of the P16 (MTS1) locus.

The p16 gene (P16, MTS1, CDKN2) encodes a negative regulator of the cell cycle. Molecular genetic techniques have been used to explore the role of p16 in normal development and cancer. Two transcripts derived from the p16 gene with distinct protein coding potentials are described. The previously undescribed transcript form has the same exons 2 and 3 as the p16-encoding mRNA but contains a different exon 1. The human p16 transcripts are detected in various tissues, and the ratio of the transcripts is regulated in both a tissue-specific and cell cycle-specific manner. The P16-derived mRNAs are probably generated from separate promoters, and transcription from one of the promoters appears to be regulated, at least in part, by the retinoblastoma gene product.

Base Sequence↗
PubMed1995

Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16.

D-type cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, promote progression through the G1 phase of the cell cycle by phosphorylating the retinoblastoma protein (RB). The activities of Cdk4 and Cdk6 are constrained by inhibitors such as p16, the product of the CDKN2 gene on human chromosome 9p21 (refs 12-14). The frequent deletion or mutation of CDKN2 in tumour cells suggests that p16 acts as a tumour suppressor. We show that wild-type p16 arrests normal diploid cells in late G1, whereas a tumour-associated mutant of p16 does not. Significantly, the ability of p16 to induce cell-cycle arrest is lost in cells lacking functional RB, including primary fibroblasts from Rb-/- mouse embryos. Thus, loss of p16, overexpression of D-cyclins and loss of RB have similar effects on G1 progression, and may represent a common pathway to tumorigenesis.

Animals↗
PubMed1995

Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.

D-type cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, regulate events in the G1 phase of the cell cycle and may contribute to the phosphorylation of the retinoblastoma gene product (Rb). However, in cells in which the function of Rb has been compromised, either by naturally arising mutations or through binding to proteins encoded by DNA tumour viruses, Cdk4 and Cdk6 are not associated with D cyclins. Instead, both kinases form binary complexes with a stable 16 kDa protein (p16) encoded by the putative tumour suppressor gene INK4/MTS1 on human chromosome 9p21. Here we show an inverse correlation between Rb status and the expression of p16. Since Rb-negative cells express high levels of p16, we suggest that in these cells p16 competes with D cyclins for binding to Cdk4 and Cdk6 and prevents formation of active complexes. In line with these predictions, DNA tumour virus oncoproteins do not disrupt cyclin D1-Cdk4 complexes in cells lacking p16.

Carrier Proteins↗
PubMed1995

Synthesis, radiolabeling, and preliminary evaluation in mice of some (N-diethylaminoethyl)-4-iodobenzamide derivatives as melanoma imaging agents.

N-(2-Diethylaminoethyl)-4-iodobenzamide (BZA) is a radiopharmaceutical recently developed in our laboratory for the scintigraphic detection of melanoma and metastases. Optimal time for imaging was between 18-24 h p.i. of [123I] BZA. With a view to selecting compounds able to provide quality images shortly after the injection, synthesis of an initial series of BZA derivatives and their evaluation in B16 melanoma bearing mice have been carried out. The [125I] radiolabeled products were obtained by a simple isotopic exchange procedure with high radiochemical yields (85-95%). After i.v. administration of the compounds we observed a good tumoral targeting ability. Tumoral activity peaked at 2.6 to 7.70% injected dose per g within 1 h post-injection. One of the benzamides with a blood clearance faster than that of BZA--0.06 vs. 0.2% I D/g--6 h p.i. gave the same tumor to blood and to organ ratios as BZA at 12-18 h p.i. Based on these preclinical data we hope to obtain good tumoral images 6 h p.i. in scintigraphic studies in man.

Animals↗
PubMed1995

Predictors of severity of illness on presentation in children with cerebral malaria.

The presenting features of 195 children with cerebral malaria were analysed to determine which correlated with severity of coma and anaemia. The children, who came from a single community in southern Zambia, were enrolled in an ongoing blinded drug trial in 1992 and 1993. Children with deep coma (scoring 0-2) had significantly longer duration of coma before presentation (P = 0.019) and were more likely to have been treated with chloroquine (P = 0.022) than children with light coma (scoring 3 or 4 on the Blantyre coma scale). Children with severe anaemia (haematocrit < 18%) were younger (P = 0.005), had been febrile longer (P = 0.005), had splenomegaly (P < 0.005) and hypoglycaemia (P < 0.008) more often and were more likely to have been treated with chloroquine (P < 0.005) than those without severe anaemia. The counts of asexual parasites in the peripheral blood were not significantly correlated with depth of coma or severity of anaemia. The observed widespread and uncontrolled use of chloroquine has probably led to the development of resistant malaria and of many severe complications despite early consultation. While early treatment of febrile illnesses in young children and immediate medical attention for altered consciousness must be emphasized in the community approach to severe malaria, our data indicate that effective public health measures will be difficult to develop in the face of a high prevalence of chloroquine resistance.

Age of Onset↗
PubMed1994

Murine PGK-1 promoter drives widespread but not uniform expression in transgenic mice.

Pgk-1 is an X-linked gene encoding 3-phosphoglycerate kinase, an enzyme necessary in every cell for glycolysis. The regulatory sequences of the Pgk-1 gene were used to drive the E. coli lacZ reporter gene and 2 strains of transgenic animals created with this Pgk-lacZ transgene carried on autosomes. The levels of expression of Pgk-1 varied from one adult tissue to another and the transgene was similarly regulated. However, in situ staining of the beta-galactosidase encoded by the transgene indicated extensive cell-to-cell variability in its level of expression. A reproducible subset of cells stained darkly for the transgene product. Some of these beta-galactosidase positive cells were rapidly proliferating while others appeared to be metabolically very active, suggesting that the Pgk-1 promoter is regulated so as to be more active in cells requiring high levels of glycolysis. Although Pgk-1 is X-linked and subject to X chromosome inactivation, the transgenes were not inactivated in either female somatic or male germ cells. Thus, the Pgk-1 promoter drives transgene expression in all tissues but the levels of expression are not uniform in each cell.

Aging↗
PubMed1994

Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein.

Cyclins D1, D2 and D3 are thought to function in the G1 phase of the cell division cycle by regulating the activity of cyclin-dependent protein kinases. All three D-type cyclins can be shown to associate with two specific kinases, cdk4 and cdk6, providing at least six possible combinations. To establish whether different cell types require different subsets of these complexes and whether they are altered in tumours where D-cyclin expression is perturbed, we surveyed a series of tumour cell lines and compared them where possible to non-tumorigenic counterparts. Although complexes involving cdk4 or cdk6 were readily observed in many of the cell lines, no complexes were detectable in human cells harbouring DNA tumour virus oncoproteins or in which the retinblastoma gene product (pRb) is mutated or missing. These data suggest that as well as being a potential substrate for D-cyclin-kinases, functional pRb contributes to the formation or stability of the complexes, at least in human cells.

Breast Neoplasms↗
PubMed1994

CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1.

Deregulated expression of cyclin D1 is a feature of several neoplastic and proliferative disorders, but its normal role in the cell cycle remains unclear. Here we show that in a squamous carcinoma cell line with 11-fold amplification of the CCND1 gene, cyclin D1 associates specifically with p33cdk4 (PSK-J3) and p38cdk6 (PLSTIRE), two closely related members of the cyclin-dependent kinase (CDK) family. In these tumour cells, there is little evidence for an association between cyclin D1 and other CDKs, but in diploid human fibroblasts both CDK2 and CDK5 can be co-precipitated with cyclin D1, as well as CDK4. The data suggest that D-type cyclins participate in multiple interactions with CDKs but that the nature or stoichiometry of these associations may differ in different types of cell.

Amino Acid Sequence↗
PubMed1993

Iron chelation as a chemotherapeutic strategy for falciparum malaria.

To examine the effect of iron chelation against human malaria, 37 Zambians with asymptomatic Plasmodium falciparum infections were randomly assigned to 72-hr infusions of desferrioxamine B or placebo. Mean concentrations of ring forms decreased significantly with desferrioxamine B (P < 0.001) but not with a placebo. Over seven days of observation, mean parasite concentrations remained at the initial levels in six individuals originally given placebo, but decreased promptly with administration of desferrioxamine B (P = 0.001). Mean parasitemia was significantly lower for up to four weeks in 16 subjects treated with desferrioxamine B when compared with the eight who had received placebo only (P = 0.027). We conclude that iron chelation has antiplasmodial activity and may offer a new therapeutic strategy for falciparum malaria.

Adult↗
PubMed1992

Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria.

BACKGROUND: Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15 to 50 percent despite antimalarial therapy. METHODS: To determine whether combining iron chelation with quinine therapy speeds the recovery of consciousness, we conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be less than six years old, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they could not be aroused. Deferoxamine (100 mg per kilogram of body weight per day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pyrimethamine. The time to the recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. RESULTS: The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 times that among the 41 given placebo (95 percent confidence interval, 0.7 to 2.3); the median time to recovery was 20.2 hours in the deferoxamine group and 43.1 hours in the placebo group (P = 0.38). Among 50 patients with deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95 percent confidence interval, 1.1 to 4.7), decreasing the median recovery time from 68.2 to 24.1 hours (P = 0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95 percent confidence interval, 1.2 to 3.6). Among all 83 patients, mortality was 17 percent in the deferoxamine group and 22 percent in the placebo group (P = 0.52). CONCLUSIONS: Iron chelation therapy may hasten the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.

Child, Preschool↗
PubMed1992

Iron chelation with desferrioxamine B in adults with asymptomatic Plasmodium falciparum parasitemia.

To determine if iron chelation therapy has activity against human malaria, we administered desferrioxamine B in amounts of 100 mg/kg per day by continuous 72-hour subcutaneous infusions to 28 volunteers with asymptomatic Plasmodium falciparum infection in a randomized, double-blind, placebo-controlled crossover trial. Peripheral blood concentrations of P falciparum ring forms were determined at 12-hour intervals in all subjects and serum concentrations of desferrioxamine B + ferrioxamine (the iron complex of desferrioxamine B) were measured in 26 subjects. Geometric mean concentrations of asexual intraerythrocytic parasites decreased with both chelator and placebo treatment, but the decrement with desferrioxamine B was significantly greater than that with placebo (P less than .006) during both the initial and crossover periods. Compared with placebo, desferrioxamine B treatment was associated with an almost 10-fold enhancement of the rate of parasite clearance during both phases of the trial (P less than .007). Mean +/- SEM steady state concentrations of desferrioxamine B + ferrioxamine were 6.90 +/- 0.60 mumol/L at 36 hours and 7.72 +/- 0.68 mumol/L at 72 hours; in vitro, the ID50 has been reported to be approximately 4 to 20 mumol/L. No drug toxicity was detected. Parasitemia recurred in 19 of 24 participants followed-up over 1 to 6 months. We conclude that desferrioxamine B enhances the clearance of P falciparum parasitemia and that iron chelation may provide a new strategy to be developed for the treatment of malaria.

Adolescent↗
PubMed1992

Actinomycosis associated with pilonidal sinus of the penis.

We report a case of actinomycosis associated with a penile pilonidal sinus. This association does not appear to have been described previously. We recommend the submission of biopsies of unusual lumps in the genital region (fresh biopsies for bacteriological examination and fixed biopsies for histomorphological assessment).

Actinomycosis↗
PubMed1989

The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2.

This study of 47 patients from 11 families with neurofibromatosis type 2 (NF 2) confirms our previously reported association between posterior capsular cataract and NF 2. A highly significant statistical association was found between the presence of posterior capsular lens opacities and the presence of NF 2 as determined by magnetic resonance imaging or pathologic diagnosis. This association was not present for other types of lens opacities that could be the result of age-related or nonspecific changes. When considering the diagnosis of NF 2, this finding now makes it essential to use a careful dilated biomicroscopic examination of the lens to evaluate known, suspected, or at-risk individuals for this potentially early associated manifestation.

Cataract↗
PubMed1986

Main excretion metabolites of 7-methoxy-2-nitronaphtho[2,1-b]furan (R 7000) in rats.

Major metabolites, isolated from rat bile and urine after administration of a single dose of 7-methoxy-2-nitronaphtho[2,1-b]furan (R 7000; MNNF) labelled with 14C on the furan ring and on the methoxy group, were identified by comparison of their chromatographic behaviour and mass spectra with synthetic authentic reference compounds. Analysis of metabolites indicated three metabolic pathways for this compound in vivo, namely, demethylation of the methoxy group, hydroxylation of the aromatic ring and cleavage of the furan ring, followed by the reduction of the nitro group to amine.

Administration, Oral↗
PubMed1985

New cysteamine (2-chloroethyl)nitrosoureas. Synthesis and preliminary antitumor results.

Three chemical pathways were used for the synthesis of four new N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]- and N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N- or N'-nitrosoureas. These compounds are plasma metabolites of CNCC, a promising antineoplastic (2-chloroethyl)nitrosourea. Preliminary antitumor evaluation was performed against L1210 leukemia implanted intraperitoneally in mice. Among these compounds, two of them exhibited a greater antitumor activity compared to that of the parent mixture.

Animals↗
PubMed1985

Identification of oenanthotoxin and related compounds in hemlock water dropwort poisoning.

The case histories are presented of three separate incidents of poisoning by ingestion of Hemlock Water Dropwort tubers (Oenanthe crocata). Two of these cases involved a fatality. An analytical profile is provided for oenanthotoxin, the major toxic principal of the tubers. Chromatographic, spectroscopic and mass spectral data for related compounds are also given.

Adult↗
PubMed1985

Disposition in rats and mice of 7-methoxy-2-nitronaphtho[2,1-b]furan.

The disposition of 7-methoxy-2-nitronaphtho[2,1-b]furan (MNNF), labelled with 14C in the furan ring (label 1) and in the methoxy group (label 2) has been studied in rats and mice. After i.p. administration to rat (5 mg/kg), both labelled species were absorbed by the lymphatics; and after oral administration, through the intestinal lumen. Excretion of the furan ring (label 1) is mainly urinary (44% dose in 24 h); label 2 was mostly expired as 14CO2 (48% dose in 24 h), indicating considerable demethylation. No target organ was found for MNNF, except liver and kidney. For both labelled species given orally, radioactivity was bound to the intestinal wall. Preliminary metabolic studies, using t.l.c. and h.p.l.c., have shown the presence of an urinary metabolite, namely, the glucuronide of 7-hydroxy-2-nitronaphtho[2,1-b]furan (15-20% of the urinary radioactivity). The remaining radioactivity comprises basic compounds, that bind to a cationic resin, which might be formed by enzymic reduction of the nitro group.

Administration, Oral↗