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PubMed2001

Muscle cell outside and inside: the nascent approach of a clinician.

Understanding muscle cell in disease and health is an unfinished process. Following the lead of Jaime Alvarez, I have had the opportunity of working on two complementary approaches to this field. One is the study of muscle cell surface molecules. Both synaptic muscle molecules, such as the asymmetric form of acetylcholinesterase, and extrasynaptic molecules, such as the extracellular matrix proteoglycans, are regulated by the motor nerve activity. This illustrates one of Jaime's teachings: cell phenotypes are a dynamic process that reflects the influence of other cells (Alvarez, 2001). Proteoglycans have many functions, including growth factor receptors. Studying them in muscular dystrophy will contribute to the comprehension of the muscle regeneration failure, characteristic of this disease. Muscle cells are highly dependent upon energy production, and the mitochondriae produce most of it. These organelles are unique in having their own genome. Mutations in these genes have recently been recognized as the cause of human disease and originally in muscle pathology. The physiopathology of these diseases is summarized here.

Acetylcholinesterase↗
PubMed1999

Re-expression of SPR1 in breast cancer cells by phorbol 12-myristate 13-acetate (PMA) or UV irradiation is mediated by the AP-1 binding site in the SPR1 promoter.

BACKGROUND: Invasive tumor cells are characterized by multiple phenotypic changes as a result of the large number of cDNAs being differentially expressed in tumor cells compared to normal progenitors. Expression genetics focuses on changes at the RNA level with the aim of identifying functionally important genes whose aberrant expression in cancer cells is regulated at the level of transcription. These genes were named class II genes and are distinguished from class I genes, which are characterized by genomic mutations, deletions, or other alterations. Reversal of the tumor cell phenotype accompanying normalization of the expression of such genes may be exploited therapeutically if gene expression can be specifically modulated by drugs or other treatments. Considering that genes are coordinately regulated in complex networks, it is likely that the expression of multiple genes can be simultaneously modulated in tumor cells by drugs acting on the signal transduction pathway that regulates their expression. The SPR1 gene is associated with differentiation and its expression is down-regulated or inactivated in malignant cells. Analysis of the SPR1 promoter showed that down-regulation of SPR1 expression in breast tumor cells occurs at the level of transcription. SPR1 presents an example of class II genes, since its expression was up-regulated in tumor cells by phorbol 12-myristate 13-acetate (PMA) or by ultraviolet (UV) irradiation. MATERIALS AND METHODS: The SPR1 gene was identified by differential display on the basis of its reduced or absent expression in human breast tumor cell lines compared to normal mammary epithelial cell strains. Differential expression was confirmed by Northern blot analysis employing multiple normal and tumor cell lines. The promoter region -619 to +15 of the SPR1 gene was sequenced and analyzed by CAT assays, deletion analysis, and mutagenesis. Up-regulation of SPR1 expression by PMA and UV irradiation was monitored by Northern analysis and analyzed by CAT assays. RESULTS: The mechanism of down-regulation of SPR1 expression in breast tumor cells was investigated. It was found that the -619 to +15 upstream promoter region is sufficient for SPR1 expression in normal breast cells, but it is transcriptionally silent in most breast tumor cell lines. By deletion analysis and mutagenesis, two upstream cis-acting promoter elements were identified. Our data indicate that the AP-1 element located between -139 and -133 acts as a major enhancer of SPR1 transcription only in normal mammary epithelial cells but not in corresponding tumor cells, whereas the sequences flanking the AP-1 site do not affect its promoter enhancing activity. In addition, a transcriptional repressor was identified that binds unknown factor(s) and is active in both normal and tumor breast cells. Inhibitor function was mapped to a 35-bp element located from -178 to -139 upstream of the human SPR1 mRNA start site. The expression of SPR1 could be induced in the 21MT-2 metastatic breast tumor cell line by PMA treatment or by short UV irradiation via a transcriptional mechanism. AP-1 is the cis element mediating the transcriptional activation of SPR1 by PMA, which induces the expression of AP-1 factors in 21MT-2 cells. Mutation of the AP-1 site abolishes the induction of SPR1 expression by PMA. CONCLUSIONS: Our results demonstrate that loss of SPR1 expression in breast tumor cells results from impaired transactivation through the AP-1 site in the SPR1 promoter, as well as from the presence of a negative regulatory element active in both normal and tumor cells. Furthermore, our results provide a basis for therapeutic manipulation of down-regulated genes, such as SPR1, in human cancers.

Base Sequence↗
PubMed2000

[Increased variability of (TCC)n microsatelline loci in populations of the parthenogenetic lizard Lacerta unisexualis Darevsky].

In four isolated populations of parthenogenetic Caucasian rock lizard Lacerta unisexualis, variability of (TCC)n loci was examined using multilocus DNA fingerprinting. Unexpectedly high variability of (TCC)n microsatellites was found in all four populations. The mean similarity index was 0.825, which is higher than similarity estimates obtained for other mini- and microsatellite loci in L. unisexualis and parthenogenetic species L. dahli and L. armeniaca studied earlier. The high variation level of (TCC)n loci was shown to be at least partially associated with the presence of a diverged (TCC)n sequence fraction in the L. unisexualis genome. Mutations at some other genetically unstable (TCC)n loci may cause their structural diversity in populations of L. unisexualis.

Animals↗
PubMed2001

[Establishment of suc2 signal sequence trap system].

The secretion of proteins depends on the signal peptide located to the N-terminal of the protein precursor. We established a genetic system in yeast to screen cDNA library for the signal peptide encoding sequences. To do it, we mutated genomic suc2 gene (encoding yeast invertase) of EGY48 by one-step gene disruption method, and got yeast cell lines without invertase expression (EGY48-delta suc). To get vector for library screening, we inserted suc2 gene encoding mature peptide of invertase downstream to yeast promoter P-ADH1, and multiple cloning sites for insertion of library is between suc2 and P-ADH1. EGY48-delta suc transformed with the vector can grow on the medium with glucose as carbon source, but not on the medium with raffinose. Signal peptide of suc2 and alpha chain of human interleukin-2 was fused in frame to suc2 gene, then the two resulting vectors were transformed into EGY48-delta suc, all the transformants can grow in the medium with either raffinose or glucose as carbon source. Hence, the system established here can discern cDNA encoding signal peptide from the one not encoding signal peptide.

Amino Acid Sequence↗
PubMed2001

Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma.

Retinoids induce apoptosis and differentiation of hepatocellular carcinoma (HCC) cells and are used clinically in the chemoprevention of HCC. We have shown previously that hepatocarcinogenesis is accompanied by accumulation of full-length retinoid X receptor alpha (RXRalpha), although the underlying mechanisms and biological implications have remained unclear. The present studies were based on the finding that the accumulated full-length RXRalpha was phosphorylated at serine/threonine residues both in all human HCC tissues examined and in human HCC-derived HuH7 cells. Phosphorylation at serine 260 of RXRalpha, a consensus site of mitogen-activated protein kinase, was closely linked to its retarded degradation, low transactivating activity, and the promotion of cancer cell growth. There was no genomic mutation in the RXRalpha gene, and abrogation of phosphorylation by mitogen-activated protein kinase-specific inhibitors restored the degradation of RXRalpha in an RXR ligand-dependent manner. These results suggest that phosphorylation of RXRalpha may interfere with its metabolism and signaling in human HCC, which could lead to growth promotion of these tumors.

Carcinoma, Hepatocellular↗
PubMed2002

Differential expression of FEZ1/LZTS1 gene in lung cancers and their cell cultures.

PURPOSE: The FEZ1/LZTS1 (FEZ1) gene, located on chromosome 8p22 (8p22), was identified recently as a candidate tumor suppressor gene. Because loss of heterozygosity at 8p21-22 is a frequent event in lung cancers, we studied FEZ1 alteration in short-term cultures of resected lung cancer tumors and cell lines. EXPERIMENTAL DESIGN: We examined FEZ1 expression in 17 non-small cell lung cancer (NSCLC), 19 small cell lung cancer (SCLC) cell lines, and 6 pairs of short-term cultures of resected NSCLCs and accompanying nonmalignant bronchial cells (NBECs) by reverse transcription-PCR and Western blotting. To investigate the mechanism for silencing, cells were cultured with 5-aza-2'-deoxycytidine or trichostatin A. We screened for genomic mutations by PCR-single-strand conformational polymorphism. RESULTS: Thirteen of 17 NSCLC (76%) and 3 of 19 SCLC (16%) of cell lines showed absent expression (P = 0.001). Of the paired NSCLC-NBEC cultures, 3 of 6 showed loss of expression in tumor cell cultures. In the cell lines retaining expression, the amplicon products in SCLCs were more intense than those of NSCLCs and NBECs. Expression of FEZ1 was not restored by 5-aza-2'-deoxycytidine and trichostatin A. Although FEZ1 expression was moderately correlated with loss of heterozygosity of specific microsatellite makers at 8p21-22 in NSCLC cell lines, it was strongly correlated to D8S261 and LPL loci in SCLC cell lines. No mutation was found within cording region of FEZ1 by PCR-single-strand conformational polymorphism. CONCLUSIONS: We found differential FEZ1 expression in NSCLC and SCLC cell lines, and the absent expression in 3 of 6 short-term cultures of NSCLC tumors. FEZ1 may be related to tumorigenesis of lung cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2001

[Persistent microbial infection and therapeutic vaccine].

Microbial persistent infection usually occurs due to invasion of the immune system, microbial genomic mutation or integration of microbial DNA with host chromosomal DNA. Defective host immune responses or immune tolerance are also related to persistent infection. Therapeutic vaccine is aimed at inducing specific humoral and cellular immune responses to terminate microbial persistent infection or to prevent progression of diseases. Different categories of therapeutic vaccines have been presented and the prospect of research as well as the development of novel effective therapeutic vaccines are discussed.

Bacterial Vaccines↗
PubMed1976

[Comparative study of the effect of haloperidol and maptil on the karyotype and immunoproliferative response of lymphocytes].

The author examined the action of haloperidol and magetyl on the mitotic activity, blast transformation and karyotype of the lymphocytic cultures, obtained from the peripheral blood in vitro. The experiments were carried out on flymphycytes, obtained from ten healthy individuals. Nontreated cultures, obtained from the same cultures, were used as controls. The following concentrations were used: haloperidol--0.1 mkg/ml, 10 mkg/ml and 10.0 mkg/ml; mageptyl--2.0 mkg/ml, 10,0 mkg/ml and 50 mkg/ml. There was a significant inhibition of the mitotic and blast transformation index after using concentrations of 10.0 mkg/ml both of haloperidol and magentyl. Concentration of 50.0 mkg/ml was toxic for the lymphocytes, obtaine from all donors. Furthermore the two preparations did not induce genomic mutations. Polyploidia, established in the treated cultures, varied slightly from that of the nontreated cultures. There was a weak mutagenic activity of the two preparations at chromosomal level in a concentration of 10.0 mkg/ml.

Cells, Cultured↗
PubMed2004

The peptide nucleic acids, efficient tools for molecular diagnosis (Review).

Peptide nucleic acids (PNAs) are synthetic analogs of DNA that hybridize with complementary DNAs or RNAs with high affinity and specificity, essentially because of an uncharged and flexible polyamide backbone. Originally conceived as ligand for the recognition of double stranded DNA, the unique physico-chemical properties of PNAs have led to the development of a variety of research and diagnostic assays. Initially used as antisense and antigene reagents, the more recent applications of PNA have involved their use as molecular hybridization probes. Thus, sensitive and robust PNA-dependent methods have been designed for developing anti-cancer drugs, modulating PCR reactions, detecting genomic mutation or labelling chromosomes in situ.

Animals↗
PubMed1992

Nosography and immunopathogenesis of viral hepatitis.

Five viruses are responsible for the vast majority of cases of viral related hepatitis. They have been named hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV). The more recent literature concerning the viral structure, the epidemiology, the serological identification, the clinical course and the prevention of each type of hepatitis is reviewed. HBV is not directly cytopathic. Hepatitis is a consequence of the destruction of the virus-infected cells. The efficient elimination of the virus relies on the viral antigenic determinants (HBs, pre-S1, pre-S2, HBc, HBe) and on the immune system of the host. The viral persistence may be caused by defect of the host immunity (interferon production, T and B lymphocyte function) or by factors related to the virus such as a genome mutation (lack of HBe formation). Some evidence suggesting an immunopathogenetic mechanism also for HCV, HDV and HAV is reported.

Hepatitis Viruses↗
PubMed2004

[Resistance to antiretroviral therapy].

OVERVIEW: After some time under treatment, HIV+ patients have a virologic failure rate of 50%, being development of resistance to therapy responsible for up to 80% of the virologic failure. In addition, resistance rates in naive patients is around 10% in developed countries. Inherent characteristics of HIV (replication cycle, viral subtype), of patients (therapy compliance, intra-/interindividual variability, genetic polymorphisms), and of therapy (genetic barrier to drug resistance, inhibitory ratio, drug interactions) are the factors involved in the development of resistance, and their interpretation requires to be studied. Resistance identification will be carried out using genotypical and/or phenotypical methods, and their adequacy has been validated by various expert panels on resistance. The role of the pharmacokinetic and pharmacodynamic monitoring of antiretroviral therapy is also crucial within the field of resistance, and concerns us directly as pharmacists. Finally, understanding the resistance patterns of currently available or experimental antiretroviral drug families will provide the necessary tools to prevent and/or manage their development. OBJECTIVES: To know and understand the mechanisms and patterns of resistance for each antiretroviral family. To identify factors involved in the development of resistance to ART, and to interpret various resistance tests. SEARCH STRATEGY: Studies were identified using Medline, the Cochrane database of systemic reviews, abstracts from international meetings on AIDS, Conference on Retroviruses and Opportunistic Infections, international meetings on resistance to antiretrovirals, and product monographs from January 1999 to February 2004. SELECTION CRITERIA: To be eligible, studies had to describe viral genome mutations responsible for resistance or hypersusceptibility to ART in relation to precipitating factors. Papers describing resistance identification techniques were also selected. DATA COLLECTION AND ANALYSIS: In all, 1,083 full articles and 64 abstracts and communications at international meetings were retrieved, of which 74 articles and 20 abstracts met the inclusion criteria for our review. PRIMARY RESULTS: Of the 94 reports selected, 86 discussed factors involved in the development of resistance and resistance test interpretation. The remaining 8 reports focused on resistance patterns to the various antiretroviral drug families. Every article described the enzymatic mechanisms induced by mutations responsible for resistance or hypersusceptibility to each antiretroviral family, the classification and nomenclature for each mutation, and the influence of each mutation on the success or failure of patient treatment. REVIEWER S CONCLUSIONS: Knowledge of the mechanisms and patterns of resistance to each antiretroviral family will allow us to overall understand the evolution and outcome of treatment for any given patient. Only thus shall we be able to play an integral role in the therapy of patients.

Anti-Retroviral Agents↗
PubMed2005

[Molecular genetic study of causes of the Prader-Willi and Angelman syndrome].

BACKGROUND: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinctive diseases with severe impairment of psychomotoric development and behaviour. Both syndromes are caused by the loss of paternal (PWS) or maternal (AS) gene expression of chromosomal region 15q11-13. The work reveals the various causes of this loss. The choice of the most suitable method for screening of the genome mutations in the patients suspected of PWS and AS is another purpose of the work. METHODS AND RESULTS: The methyl specific analysis (MS PCR) in locus SNRPN, short tandem repeat (STR) analysis and fluorescent in situ hybridization (FISH) were used. In the group of 55 patients tested for PWS and AS only maternal allele was present in 11 patients and only paternal allele was present in 1 patient in the locus SNRPN: 10 microdeletions 15q11-13, 1 UPD(15)mat and 1 UPD(15)pat. CONCLUSIONS: MS PCR seems to be the most profitable method for the first step of selection of PWS patients. In positive cases is inevitable to use also additional tests of molecular diagnosis to distinguish the particular mechanism leading to the disorders. In AS patients is also MSPCR recommended as the first step although it is necessary to exclude mutation in UBE3A gene in case of MS PCR negativity.

Adolescent↗
PubMedDate not supplied

Pathogenic pathways in acute myeloid leukemias.

Despite the common clinical, hematological and prognostic features that define acute myeloid leukemia (AML) there is considerable heterogeneity among individual cases, suggesting different pathogenic pathways. Based on a simple theoretical model, according to the vital characteristics of the leukemic clone (proliferative rate and resistance to apoptosis) we propose a classification of AML into two broad categories: a) high leukemic clone vitality (HLV) AML, corresponding roughly to the World Health Organization (WHO) classification group of entities "AML with recurrent cytogenetic abnormalities" and b) low leukemic clone vitality (LLV) or "opportunistic" AML corresponding to the WHO groups "AML with multilineage dysplasia" and "therapy-related AML". HLV-AML leukemic clones are characterized by rate-limiting genomic mutations capable of conferring proliferation/survival advantage over a normal hematopoietic environment while in LLV-AML, the leukemic clones are not particularly proliferative or apoptosis-resistant, but are nevertheless selected against an impaired, previously damaged hematopoietic environment. Such a pathogenesis-oriented classification might have therapeutic and prognostic implications, providing a theoretical basis for a further adaptation of the current standard treatment strategies to the individual characteristics of the AML patients.

Acute Disease↗
PubMed2005

Exon skipping partially restores factor VIII coagulant activity in patients with mild hemophilia A with exon 13 duplication.

Ectopic mRNA was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) in patients with duplication of F8 gene exon 13, a mutation which has been demonstrated to be a cause of mild hemophilia A in 32% of Northern Italian subjects. Two different transcripts originate from mutated genomic DNA, due to alternative splice processes. The larger-sized transcript contains both duplicated exons 13, the smaller one contains only one exon 13. The residual FVIII:C activity which accounts for the mild hemophilia A phenotype derives from the latter transcript.

Alternative Splicing↗
PubMed2006

[Acquired tumor "robustness" in the case of prostate cancer].

Tumors are highly robust and maintain their proliferative potential against both a wide range of host-defense mechanisms and anticancer therapies. In this study, we investigated the levels of human leukocyte antigen (HLA) class I, multi-drug resistance 1 (MDR1), and androgen receptor (AR) expressions in untreated prostate cancers harvested by radical prostectomy. The mean percentages of cancer cells expressing HLA class I, MDR1, and AR among the 10 cancer samples were 41, 35, and 74%, respectively. In addition, double-staining of HLA class I and MDR1 revealed the four definite populations (HLA class I(+)/MDR(+), HLA class I(+)/MDR(-), HLA class I (-)/MDR(+), and HLA class I(-)/MDR(-)) in cancer tissues from the majority of cancer patients tested, and the mean percentages of cells expressing these combinations were 13, 29, 22, and 38%, respectively. Similar results were obtained by double staining of HLA class I and AR, except for 2 cases in which HLA class I(-)/AR (+) cancer cells predominated. These results indicated that untreated prostate cancer cells acquired a wide range of genomic mutation, which may have been caused by internal host pressure to eliminate malignant cells, and would provide evidence of the robustness of untreated prostate cancer.

Aged↗
PubMed1991

[Simple methods of enzymatic amplification of DNA for clinical practice].

The methods for enzymatic DNA amplification in vitro that allow to avoid the step of preliminary DNA extraction and purification are proposed. Lysates of blood cells in the solution or immobilized on the nylon membrane filters and dried blood spots on the filter paper blotters were used directly in amplification permitting one to solve the problems of adapting the method of polymerase chain reaction in clinical practice, for instance, in massive screening of genome mutations, viral infections etc.

Alleles↗
PubMed1991

[The contribution of genetic factors to perinatal pathology and infant mortality].

The authors consider the contribution made by genetic factors to perinatal and infant mortality on the basis of many-year studies performed in the Minsk Teratology Center and analysis of the data available in the literature. In 1972-1984 there was an increase in the incidence of congenital malformations among deceased children. Genetic factors predispose to at least 7-8% postimplantation embryonal and fetal elimination. Perinatal and neonatal mortality is caused by congenital malformations in 19.1 and 37% of cases, respectively. A genetic analysis has indicated that 23.2% of them are induced by genic, chromosomal, and genomic mutations and 51.0% are caused multifactorially. The prevention of genetically determined perinatal mortality is most effective in implementing the screening programs for detection of heterozygous carriage along with subsequent prospective examination and prenatal diagnosis.

Anemia, Hemolytic, Congenital↗
PubMedDate not supplied

[Aneuploidy in man (facts and hypotheses)].

Mechanisms of the human aneuploidy formation are discussed proceeding from the review of the published data obtained by Soviet and foreign authors. It is supposed that hereditary determination of this process plays a main role as compared with new genomic mutations resulting from the induction by ecological factors. Microstructural rearrangements and nonhomologous recombination in nondisjunction of chromosomes during cell division are considered parallel with mosaicism as one of possible reasons of genetic predisposition.

Aneuploidy↗