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Biomedical subjects

E May

Publications and source records attributed to E May.

At least 55 records · Page 3Linked to original sources
PubMed1995

Mutations clustered in exon 5 of the p53 gene in primary nasopharyngeal carcinomas from southeastern Asia.

Mutations in the p53 tumor suppressor gene play an important role in the development of many common human malignancies. In nasopharyngeal carcinomas (NPC), p53 gene mutations were not detected in primary tumors, with one exception for a primary tumor displaying a p53 mutation at codon 280, whereas p53 mutations were identified in some metastatic and nude mouse-passaged NPC specimens. In the present report, 41 NPC primary tumors of the undifferentiated carcinoma nasopharyngeal type (UCNT; 21 from Hong Kong and 20 from Guangxi, southeastern China) were studied. Four point mutations that result in amino acid substitutions were identified by PCR amplification of exons 2-9 and direct DNA sequencing, combined with PCR-single-strand conformation polymorphism analysis. The 4 mutations detected were clustered within the DNA stretch from codon 175 to 177. Our data, taken together with those of others, suggest that mutation in p53 may occur in NPC at various points during tumorigenesis. Alternative mechanisms of p53 inactivation in NPC are also possible.

Animals↗
PubMed1995

p53 protein accumulation in European hepatocellular carcinoma is not always dependent on p53 gene mutation.

BACKGROUND/AIMS: Immunohistochemical reactivity for p53 protein is common in various human malignancies and often related to p53 gene mutation. However, in some tumor types, accumulation of wild-type p53 has been shown. Previously, we analyzed 96 European hepatocellular carcinomas using immunohistochemistry and found that 31% of these tumors overexpressed p53 in the cell nucleus. The aim of the present study was to establish whether p53 positivity correlates with the presence of structural p53 gene abnormalities in European hepatocellular carcinoma. METHODS: DNA from 20 tumors, 10 with strong immunostaining and 10 with undetectable staining for p53, was extracted from frozen sections, and the entire coding portion of the p53 gene was sequenced. RESULTS: Five of the 10 tumors containing high levels of p53 protein showed missense point mutations. The remaining 5 tumors with high p53 levels showed the wild-type coding sequence. One of the 10 tumors containing undetectable levels of p53 protein had a 1-base pair deletion in the splice acceptor site of intron 4. CONCLUSIONS: The results strongly suggest that, in European hepatocellular carcinomas, stabilization of the p53 protein depends on factors other than p53 gene mutation, such as binding to other molecules of cellular or viral origin.

Adult↗
PubMed1995

Regression of transplant coronary artery disease during chronic HELP therapy: a case study.

This report concerns a heart transplant patient with hypercholesterolemia who showed rapid development of a severe transplant coronary artery disease. The patient received 10 mg pravastatine per day. Quantitative coronary angiography analyses of 4 serial angiograms clearly demonstrated that in the first 2.5 years following surgery, there was a rapid simultaneous progression in both the transplant coronary disease, involving the entire coronary system, and the development of segmental stenotic lesions. During one year of weekly heparin-mediated extracorporeal LDL-cholesterol precipitation (HELP) therapy in addition to diet and pravastatine therapy, the serum low density lipoprotein (LDL), lipoprotein (a) (Lp(a)), and fibrinogen levels could be reduced from 185 +/- 45 mg/dl, 138 mg/dl and 248 mg/dl, respectively, to interval values of 136 +/- 17 mg/dl, 48 +/- 15 mg/dl, and 185 +/- 44 mg/dl, respectively [interval value = (the concentration after HELP + the concentration before the next HELP treatment):2]. This therapy halted further progression of coronary diameter throughout the whole coronary system and brought about marked regression of segmental obstructive lesions.

Arteriosclerosis↗
PubMed1995

Human estrogen receptor messenger RNA variants in both normal and tumor breast tissues.

By using the PCR-SSCP technique we characterized various ER-specific RNA species present in a series of primary breast cancers, as well as in cell lines established from breast carcinomas and in mammary gland tissues from healthy specimens. A series of six truncated messenger RNAs generated by alternative splicing was characterized. These RNAs correspond to specific deletions of one (exons 2-7, except exon 6) or two (exons 3 + 4) exons. All these RNA variants are observed in each one of the analyzed RNAs, regardless of origin. In addition, the relative amount of these different variants in ER + tumors is comparable to that measured in ER - tumors and healthy mammary gland tissues. This data suggests that tumor progression is not related to the emergence of any of the ER mRNA variants.

Alternative Splicing↗
PubMed1995

Is the negative prognostic value of high oestrogen receptor (ER) levels in postmenopausal breast cancer patients due to a modified ER gene product?

Recently, it was found that, among post menopausal breast cancer patients receiving no adjuvant therapy, the highest oestrogen receptor (ER) levels (ER++) as opposed to the intermediate ER levels (ER+) indicated a poorer prognosis in terms of recurrence-free survival (Thorpe et al. Eur J Cancer 1993, 29A, 971-977). In the present study, we confirm, in a series of 218 node negative, postmenopausal patients in whom ER was determined using a one-dose saturating method, that ER+ tumours have a more negative effect on disease-free survival (DFS) than ER+ tumours (P = 0.02). In another series of 87 ER positive, postmenopausal patients, we found a significant correlation (P = 0.04) between the ER level and ER+R ratio (ER protein/ER-specific mRNA): the higher the ER level, the more numerous the high ER+R ratio cases (ER+R > 1.5), reflecting an imbalance between the ER protein level and ER-specific mRNA. From these results, we hypothesise that high ER levels related to a high ER+R ratio suggest the presence of a modified ER gene product.

Adult↗
PubMed1995

Nonisotopic competitive RT-PCR assay to measure MDR1 gene expression.

We report an original application of competitive reverse transcription-polymerase chain reaction (RT-PCR) for the quantification of MDR1 mRNA in clinical specimens by simultaneous reverse transcription and PCR amplification of cellular RNA with decreasing amounts of an internal standard. The competitor RNA shares the same MDR1 primer sequences as the cellular mRNA, but yields a different-sized PCR product. This allows resolution of the amplified cDNA fragments after agarose gel electrophoresis and ethidium bromide staining. The concentration of MDR1 mRNA is derived from the ratio between the intensities of the bands corresponding to the amplified products. We have used this assay to measure MDR1 expression in breast carcinomas and assessed the precision, sensitivity, and accuracy of the method. Competitive RT-PCR is a simple, highly specific, nonradioactive procedure for the quantification of MDR1 mRNA and is particularly suitable for use in the clinical laboratory.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

[P53 and cancers].

The p53 gene, located on chromosome 17p 13.1 and coding for a nuclear 393 amino-acids phosphoprotein acts to constrain or antagonize cell growth, and as such, is a tumor suppressor gene. In fact, inactivation of p53 tumor suppressor gene is a common event in the development of all or most types of human cancers. About half of cell cancer cases analysed thus far involve missense mutation of one p53 allele combined with the deletion of the second allele, and many of the remaining cases involve a functional inactivation of p53 protein through non mutational mechanisms. The importance of p53 as an inherited cancer susceptibility gene has been demonstrated in Li-Fraumeni syndrome. In some circumstances, it has been shown that in response to DNA damage, the p53 level in the cell increases considerably and induces a cell growth arrest late in G1 phase. This cycle arrest allows the altered DNA to be repaired before entry of the cell into S phase. This function of p53 helps to insure the genomic stability of the cell. Mutations in p53 eliminate this response and result in enhanced frequency of genomic rearrangements. In other circumstances wild type p53 may act by triggering cell death by apoptosis. The p53 protein exerts its physiological functions through various biochemical activities. These include its ability to be a site-specific transcriptional transactivator as well as a repressor of transcription. The oncoproteins derived from several oncogenic DNA viruses including SV40 large T antigen, the adenovirus E1B protein, and papillomavirus E6 protein, as well as specific cellular gene products e.g. mdm2 form complexes with the p53 protein, causing its inactivation.(ABSTRACT TRUNCATED AT 250 WORDS)

Genes, Tumor Suppressor↗
PubMed1994

Estrogen receptors (ER) in human breast cancer. The significance of a new prognostic factor based on both ER protein and ER mRNA contents.

BACKGROUND: The response to endocrine therapy is not entirely predictable from the estrogen receptor (ER) and progesterone receptor (PgR) status of primary breast tumors. The authors previously proposed a new prognostic factor, ER.R, which was based on both ER protein and mRNA levels. A previous analysis of 88 primary breast carcinomas showed that ER.R permits the identification of a subset of ER-positive women with a higher risk of early relapse. The purpose of the present study was to confirm the prognostic significance of ER.R. METHODS: Estrogen receptor protein levels were determined for 171 patients with primary breast cancer either by radio-ligand binding assay (ER-LBA) or enzyme immunoassay (ER-EIA). Estrogen receptor, pS2, and c-erbB-2 mRNA were measured by Northern blot analysis. RESULTS: ER.R factor is determined by calculating the ratio of the values (ER protein in fentomoles per milligram of total proteins) to (ER mRNA in picograms per 4 micrograms of total RNA). A cutoff value of 1.5 (protein levels measured by ER-LBA) or 3 (protein levels measured by ER-EIA) discriminate the two ER.R1 (lower ratio) and ER.R2 (higher ratio) subgroups, which present a significantly lower and higher risk of early relapse, respectively. No association was found between ER.R status and either PgR status or c-erbB-2 and pS2 expression. According to a Cox multivariate analysis for disease free survival, the two stronger factors in predicting a poor prognosis were c-erbB-2 overexpression and ER.R2. In the present analysis, ER.R2 was a stronger predictor of recurrence than was ER negativity. CONCLUSIONS: In accordance with the authors' first published data, the analysis of a larger population with a longer follow-up showed that ER.R2 keeps its significance to predict a poorer outcome for a patient, regardless of which assay was used to quantify ER.

Breast Neoplasms↗
PubMed1994

Concomitant p53 gene mutation and increased radiosensitivity in rat lung embryo epithelial cells during neoplastic development.

A rat lung cell population had been treated with benzo(a)pyrene, and a set of different epithelial cell lines was derived from it. These cell lines carried either a wild-type or mutant p53 gene and represented grading states of neoplastic development. We demonstrate here that the cells lacking both wild-type p53 alleles display a significant decrease in survival after gamma-irradiation with doses of 2 to 12 Gy, compared with their counterparts carrying wild-type p53 alleles. This is the first reported model in which cells bearing a mutation of the p53 gene display enhanced sensitivity to ionizing radiation.

Animals↗
PubMed1994

Induction of apoptosis by transiently transfected metabolically stable wt p53 in transformed cell lines.

Biochemical and functional properties of wild-type (wt) and mutant p53 were studied under the same cellular environment by transient transfection. Exogenous wt p53 expressed in transformed cell lines was found to be as metabolically stable as mutant p53. Yet only mutant p53 bound to hsp70 whereas wt p53 did not, suggesting that the metabolic stability of p53 does not depend on its ability to form complexes with hsp70. The wt protein was expressed essentially in the nucleus, while mutant p53 showed both nuclear and cytoplasmic expression, as determined by immunofluorescence staining with PAb122. In addition, staining with PAb1801 revealed a number of strongly fluorescent cell fragments in cultures transfected by wt p53. Morphological features of apoptosis were observed in these cultures. Quantitative analysis by flow cytometry confirmed that only the cell population expressing wt p53 had a significant amount of cell debris. Thus, transient expression of a metabolically stable wt, but not mutant, p53 induces cell death by apoptosis. The present study demonstrates a model system to investigate the functional domains of p53 in the induction of apoptosis.

Journal Article↗
PubMed1994

[Comparative biometric studies of school children from Kenya and Braunschweig].

Constitution and growth biology of 6 to 7 years old children from a European city ("Braunschweiger Längsschnitt") and a country with rather original habits (extreme rural area of Kenya, "Abaluya"--administrative name of Bantuid tribes from W-Kenya--out of the region of Idakho and Tiriki, elevated in spring 1990) were comparatively studied. To achieve comparability in physique and body height, the elevated data were "allometrically standardized". The statistical parameters and the results of correlation statistics were shown by comparing the two groups of children. This paper is thought to be the first attempt of a more extensive study in which further more comparative data from other age groups of children and different ecological factors as climate or nutrition should be involved in the analysis. At least the knowledge of standardized data is a cogent assumption to judge about constitution, typology and health of populations.

Anthropometry↗
PubMed1994

Low-dose enoximone therapy in pre-transplant patients: hemodynamic, echocardiographic, and neurohumoral findings.

Keeping pre-transplant patients alive while waiting for a suitable donor to be found is still a major challenge. New pharmacological agents which can provide improved hemodynamics are urgently needed in patients with severe heart failure who are on the waiting list for cardiac transplantation. Intravenous enoximone therapy (an initial 0.5 mg/kg bolus, then 1.25-5.0 mcg/kg/min infusion) was administered to 18 transplant candidates with heart failure progression despite optimal drug regimen including digoxin, diuretics, and ACE-inhibitors. Complete hemodynamic, echocardiographic, and neurohumoral studies were performed before and 24 h after intravenous enoximone infusion. Enoximone infusion increased cardiac index (1.78 +/- 0.45 l/min/qm vs. 3.04 +/- 0.83 l/min/qm; p < 0.001) and stroke volume index (22.33 +/- 9.45 ml/qm vs. 32.28 +/- 7.29 ml/qm; p < 0.05) and decreased wedge pressure (24.1 +/- 11.98 mmHg vs. 17.78 +/- 8.76 mmHg; p < 0.05) and systemic vascular resistance (1700.8 +/- 555.8 dyn x s x cm-5 vs. 952.8 +/- 384.0 dyn x s x cm-5; p < 0.001). Heart rate and mean arterial pressure were unchanged. Left ventricular ejection time (225.1 +/- 26.9 ms vs. 242.2 +/- 25.8 ms; p < 0.05) was increased, whereas other echocardiographic parameters were unchanged (left ventricular end-diastolic dimension, left ventricular end-systolic dimension, fractional shortening, early diastolic relaxation parameter Te). Plasma neurohumoral parameters did not change (aldosterone, epinephrine, renin, atrial natriuretic factor) except for a significant drop of norepinephrine (936.7 +/- 443.2 pg/ml vs. 522.4 +/- 287.6 pg/ml; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Directional selection associated with clonal expansion of p53 mutant cells during neoplastic development of carcinogen-treated rat embryo lung epithelial cells.

In this study, rat embryo lung organ cultures were exposed to benzo[a]pyrene (B[a]P). After carcinogen-treatment the cells were dissociated and an epithelial cell line (BP) was developed from the primary cell culture derived from the carcinogen-treated explants. Investigations were performed on the sequential changes occurring in the course of neoplastic progression of BP cells and in the tumor cells that arose in vivo from implanted BP cells. During the neoplastic progression a mutation was shown to occur in p53 gene at codon 130 (AAG > AGG; Lys > Arg) in a single cell which expanded and gave rise to a predominant subpopulation. This mutational event was already detected at passage 14 but was probably not a direct consequence of a specific alteration caused by the carcinogen in the target cell. This mutation was retained through the subsequent progressional steps first as a heterozygous mutation, then converted to a homozygous state. From passage 18 on, it was possible in BP cell cultures to detect foci of larger morphologically distinct cells emerging on a background of cells maintaining the original morphology. These foci were shown to derive from a single cell carrying the p53 mutation in a homozygous state. During the neoplastic progression the mutant p53 allele frequency steadily increased and this mutant allele eventually came to predominate completely in the late stages of the neoplastic progression, including in the transplantation-induced tumors. The pattern of a directional selection for mutant p53 gene towards fixation is probably applicable to a wide range of human malignancies and may reflect the particular importance of this gene for tumorigenesis.

Animals↗
PubMed1993

Human transforming growth factor alpha: sequence analysis of the 4.5-kb and 1.6-kb mRNA species.

Two transforming growth factor alpha (TGF alpha) mRNA species with the apparent sizes of 4.5 and 1.6 kb were identified in all human cell lines analysed. The cDNA corresponding to the 4.5-kb species was entirely sequenced, revealing the presence of a 3'-untranslated region (3'-UTR) of 3571 nucleotides, which contained several potential polyadenylation signals. Our results indicate that the 1.6-kb species is derived from the same precursor by alternative polyadenylation. In addition, we present evidence suggesting that TGF alpha-specific mRNAs could be initiated from transcription start points (tsp) located upstream from the tsp previously identified by Jakobovitz et al. [Mol. Cell. Biol. 8 (1988) 5549-5554].

Amino Acid Sequence↗
PubMed1993

Genetic variation in transforming growth factor alpha: possible association of BamHI polymorphism with bilateral sporadic cleft lip and palate.

Non-syndromic cleft lip with or without cleft palate (CL/P) is one of the most common birth defects affecting 1/1000 Caucasians. Genetic factors are thought to contribute to the development of this disorder. A significant association between two restriction fragment length polymorphisms, the TGF alpha TaqI 2.7-kb allele and the TGF alpha BamHI 40-kb allele, at the transforming growth factor alpha (TGF alpha) locus and the occurrence of clefting has previously been reported. A total of 98 Caucasian patients of Alsacian ancestry was recruited from our registry of congenital malformations. These patients had isolated CL/P but no other anomalies. In addition 57 patients with cleft palate, but without cleft lip, were studied. A control group comprised 99 unrelated healthy Caucasians of the same Alsacian ancestry. TaqI and BamHI identify two-allele polymorphisms. The TGFA Taq and BamHI alleles showed no significant association with the presence of clefting, the only exception being that the BamHI 10.0-kb allele was significantly more frequent in patients with bilateral CL/P.

Child↗
PubMed1993

p53-mediated cell death: relationship to cell cycle control.

M1 clone S6 myeloid leukemic cells do not express detectable p53 protein. When stably transfected with a temperature-sensitive mutant of p53, these cells undergo rapid cell death upon induction of wild-type (wt) p53 activity at the permissive temperature. This process has features of apoptosis. In a number of other cell systems, wt p53 activation has been shown to induce a growth arrest. Yet, wt 53 fails to induce a measurable growth arrest in M1 cells, and cell cycle progression proceeds while viability is being lost. There exists, however, a relationship between the cell cycle and p53-mediated death, and cells in G1 appear to be preferentially susceptible to the death-inducing activity of wt p53. In addition, p53-mediated M1 cell death can be inhibited by interleukin-6. The effect of the cytokine is specific to p53-mediated death, since apoptosis elicited by serum deprivation is refractory to interleukin-6. Our data imply that p53-mediated cell death is not dependent on the induction of a growth arrest but rather may result from mutually incompatible growth-regulatory signals.

Animals↗