PubMed Health⌕ Search

Biomedical subjects

A Asplund

Publications and source records attributed to A Asplund.

9 recordsLinked to original sources
PubMed2005

PTCH codon 1315 polymorphism and risk for nonmelanoma skin cancer.

BACKGROUND: The PTCH tumour suppressor gene is involved in the development of nearly all basal cell carcinomas (BCCs) of the skin and a fraction of squamous cell carcinomas (SCCs). A nonconservative Pro/Leu nucleotide polymorphism within PTCH exon 23 at codon 1315 was recently reported to be potentially important for the development of breast epithelial cell cancers. Objectives Accordingly, the status of PTCH codon 1315 was analysed for a possible association with the development of nonmelanoma skin cancers (NMSCs) in a pilot study. Because skin cancer risk is affected by specific population-dependent phenotypes such as skin and hair colour, codon 1315 was also analysed for normal allele frequency variation in human populations having differing extents of eumelanin vs. phaeomelanin. METHODS: The single nucleotide polymorphism in codon 1315 of the human PTCH gene was analysed in genomic DNA from six different populations comprising 472 blood samples and from 170 patients in four different categories with NMSC. Polymerase chain reaction and pyrosequencing were used to determine the allele frequencies. Allelic loss was furthermore determined in tumours following microdissection. RESULTS: The Pro/Pro genotype frequency ranged from 30% to 65% between populations, with a significant trend for a reduced frequency of the Pro/Pro genotype in populations having lighter pigmentation (P = 0.020). Pro/Pro frequency showed an increasing trend with increasing tumour case severity (P = 0.027). In 260 samples from 180 Swedish patients with NMSC and a control group of 96 healthy ethnically matched volunteers, no statistically significant pairwise differences between groups were detected in the PTCH codon 1315 allelic distribution, neither was a difference seen for multiple or early onset cases of BCC in the Swedish population. In Swedish patients with single tumours, allelic loss (loss of heterozygosity) was observed in 20 of 30 (67%) patients with BCC and four of 22 (18%) patients with SCC, with no preference in the allele lost. In contrast, the Pro/Pro genotype was frequent in seven U.S. patients having multiple independent BCCs. One of these patients was heterozygous, enabling allelic loss studies. Of 20 independent tumours, 11 had lost an allele; 10 of the 11 had lost Leu, suggesting nonrandom loss that favoured retention of Pro (P = 0.0059). CONCLUSIONS: Our results indicate an association between the eumelanin-to-phaeomelanin shift and a shift from the Pro/Pro genotype to Leu-containing genotypes. Failure to lose Pro during the shift to phaeomelanin may be associated with an increased population risk for BCC and increased individual risk for multiple BCC. During development of a tumour, the effect of Pro may be magnified by loss of the Leu allele.

Basal Cell Carcinoma↗
PubMed2001

Analysis of intratumoral heterogeneity of chromosome 3p deletions and genetic evidence of polyclonal origin of cervical squamous carcinoma.

Investigation on intratumoral genetic heterogeneity provides an important insight into the roles of genetic alterations in human carcinogenesis and clues to clonal origin of tumors. Intratumoral heterogeneity of genetic changes of cervical cancer has not been described so far. In this study, we analyzed the intratumoral heterogeneity of chromosome 3p deletions and X-chromosome inactivation patterns in multiple microdissected samples from each individual cervical cancer, attempting to understand the roles of 3p deletions in development of cervical cancer and its clonal origin. Totally, 120 normal and lesional samples from 14 cases of fresh cervicalcancers were analyzed. Frequency and patterns of allelic losses of 3p were assessed by polymerase chain reaction (PCR) amplification of 12 microsatellite markers flanking the frequently deleted regions of 3p, followed by Genescan analysis in an ABI 377 DNA sequencer. Loss of heterozygosity was recorded as heterogeneous pattern (LOH present in parts of samples or LOH involving different alleles among different samples) and homogeneous pattern (LOH involving identical alleles in all samples from the tumor). Allelic loss affecting at least one marker was detected in 8 of 14 cases (57%). Allelic losses, both homogeneous and heterogeneous, were frequently detected at FHIT gene region (D3S1300, 40% and 60%; D3S4103, 27.3% and 54.6%), 3p21.3-21.2 (D3S1478, 27.3% and 45.5%), and 3p24.2-22 (D3S1283, 30% and 50%). Seven of eight LOH-positive tumors exhibited homogeneous allelic loss involving at least one of these three 3p loci. Allelic losses were present in the CIN lesions synchronous with invasive lesions positive for LOH. Our findings suggest essential roles of genes on these 3p loci, particularly the FHIT gene in participating in clonal selection and early development of cervical cancer. Most interestingly, with the combination of LOH analysis and X-chromosome inactivation analysis, we provided the first clear genetic evidence of polyclonal origin of cervical invasive cancer in two of eight cases. This finding strongly suggests the importance of field defect (possible human papilloma virus) in cervical carcinogenesis.

Adult↗
PubMed2001

Mosaic pattern of maternal and paternal keratinocyte clones in normal human epidermis revealed by analysis of X-chromosome inactivation.

During early development of the female embryo, one X-chromosome is randomly inactivated in each cell. As a result of growth, migration, and differentiation, the adult female becomes a mosaic of cells with either the paternal or the maternal X-chromosome inactivated. It is not known what structure the X-chromosome inactivation pattern has in skin of normal individuals. We investigated normal skin from four healthy females, heterozygous for the HUMARA microsatellite on the X-chromosome. Following careful microdissection, DNA from adjacent epidermal samples consisting of approximately 35 basal keratinocytes was digested with the methylation-sensitive enzyme HpaII. The inactivated X-chromosome remained intact due to extensive methylation. The enzyme-digested DNA was amplified using polymerase chain reaction and fragments were analyzed for size. Through examination of adjacent samples and consecutive sections, we found normal human skin to be composed of a fine mosaic of tiles with either maternal or paternal X-chromosome inactivated. The sizes of these tiles were between 20 and 350 basal cells. The method described has the potential to resolve the clonal status in normal as well as pathologic conditions.

Adult↗
PubMed1997

Cardiovascular safety of MnDPDP and MnCl2.

PURPOSE: To investigate the apparent discrepancy between expected basic physiological responses at the cellular level and the in vivo behaviour of both MnDPDP and MnCl2 administered i.v. prompted parallel investigations of these substances. MATERIAL AND METHODS: Studies were performed in isolated perfused rat hearts, isolated bovine mesenteric arteries, conscious dogs, and dogs with acute ischaemic heart failure. RESULTS: These studies confirmed that Mn+2 at high concentrations acted as a calcium antagonist inducing negative inotropy. Mn+2 at low concentrations was an effective superoxide scavenger, conserving nitric oxide and facilitating vasodilation. Mn+2 maintained or elevated heart rate (HR) and blood pressure (BP), and did not worsen existing cardiac failure. MnDPDP was about 10 times less potent than MnCl2 in eliciting these cardiovascular responses. CONCLUSION: The ex vivo properties of Mn+2, inducing vasodilation and negative inotropy, are counter-balanced in vivo through the action of 2 mechanisms: extensive plasma protein binding reducing active M+2, and the release of catecholamines which maintain or even raise HR and BP. Taken together with pharmacokinetic factors, including maximal plasma concentrations in humans given the recommended 5 mumol/kg dose, it is concluded that MnDPDP in normal clinical use represents no safety risk to the cardiovascular system.

Animals↗
PubMed1994

Mangafodipir (MnDPDP)-and MnCl2-induced endothelium-dependent relaxation in bovine mesenteric arteries.

Mn++ complexed to DPDP (N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) generic name: mangafodipir), abbreviated MnDPDP, acts as an effective contrast enhancing agent for liver MRI. In clinical trials, a commonly reported side effect after i.v. administration of MnDPDP was facial flushing, most probably due to peripheral vasodilation. The present study was conducted to address possible mechanisms to explain the flushing effect. Nitric oxide is known to be stabilized in the presence of both uncomplexed and complexed Mn++ and this stabilization is probably due to the superoxide-scavenging properties of Mn++. The present study has demonstrated that both MnDPDP and MnCl2 relax phenylephrine precontracted bovine mesenteric artery strips in concentration-dependent manner. It was also found that a concentration of 10 microM MnDPDP, MnEDTA or MnCl2 gave approximately the same relaxation response as 0.1 microM acetylcholine. DPDP and EDTA had no appreciable intrinsic relaxation potential Mn(++)-induced relaxation was abolished when the endothelial layer was removed from the arteries. In addition, the Mn(++)-induced relaxation was attenuated by the nitric oxide synthase inhibitor N-nitro-arginine and the putative superoxide anion generator 6-anilino-5,8-quinolinedione, but not by the cyclooxygenase inhibitor indomethacin. Both N-nitro-arginine and 6-anilino-5,8-quinolinedione were found to induce an endothelium-dependent constriction of the bovine mesenteric artery strips. An approximately 2-fold increase in the intracellular concentration of cyclic GMP was detected after the addition of 10 microM MnDPDP or 0.1 microM acetylcholine. The increase in cyclic GMP coincided with the onset of relaxation and was effectively abolished by pretreatment with N-nitro-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid.

Thirty-one consecutive unselected hyperlipidaemic patients were treated daily with 4 g of nicotinic acid for 6 weeks. The concentrations in serum of lipoprotein Lp(a), and the major lipoprotein classes, were determined before and after the treatment. Nicotinic acid significantly reduced the serum levels of Lp(a) in the whole patient group. Linear regression analysis showed a strong negative relationship between the percentage reduction of Lp(a) and the serum triglyceride level before treatment (r = -0.78), which implied that for patients with a serum triglyceride concentration above 7.5 mmol l-1 there was a rise of Lp(a). The average individual percentage decrease of the concentration of Lp(a) was calculated after the exclusion of four patients who had serum triglyceride levels above 10 mmol l-1. The decrease was 38% with a 95% confidence interval of 28-47%. The absolute decrease of Lp(a) was correlated with the pretreatment levels of Lp(a) (r = 0.91). Within the whole group of patients there was a linear relationship between the percentage decrease of Lp(a) and that of LDL cholesterol (r = 0.88). This latter strong relationship might be due to an inhibition of the synthesis of the protein common to the two lipoproteins, apolipoprotein B.

Adult↗
PubMed1989

Pituitary-testicular axis in obese men during short-term fasting.

To investigate whether short-term fasting affects the pituitary-testicular axis in obese subjects, 9 massively obese men (Body Mass Index 39.0 +/- 1.3, mean +/- SEM) were given two identical iv GnRH tests, the first (control) after an overnight fast, the second after 56 h of food deprivation. Short-term fasting augmented the GnRH-induced LH incremental area by 26% (1317 +/- 251 vs 1661 +/- 297 U.l-1.min-1, p less than 0.05), but failed to affect the corresponding testosterone incremental area. Eight non-obese normal men (Body Mass Index 22.2 +/- 0.5) were investigated for comparison. All of them were studied according to the same protocol as the obese group. Short-term fasting increased the GnRH-elicited LH response by 67% in the non-obese group (LH incremental areas 2147 +/- 304 vs 3581 +/- 256, p less than 0.01), and the corresponding testosterone response by 180% (testosterone incremental areas 111 +/- 61 vs 311 +/- 49 micrograms.l-1.min-1, p less than 0.01). These results imply that food deprivation affects the pituitary-testicular axis differently in obese and non-obese men.

Adult↗