Bacteriophage (phage) have been used for clinical applications since their initial discovery at the beginning of the twentieth century. However, they have never been subjected to the scrutiny--in terms of the determination of efficacy and pharmacokinetics of therapeutic agents--that is required in countries that enforce certification for marketed pharmaceuticals. There are a number of historical reasons for this deficiency, including the overshadowing discovery of the antibiotics. Nevertheless, present efforts to develop phage into reliable antibacterial agents have been substantially enhanced by knowledge gained concerning the genetics and physiology of phage in molecular detail during the past 50 years. Such efforts will be of importance given the emergence of antibiotic-resistant bacteria.

/pdf/the-prospect-for-bacteriophage-therapy-in-western-medicine-236589y12n.pdf

The prospect for bacteriophage therapy in Western medicine

Loss of heterozygosity on chromosome 16 is a common genetic alteration in human hepatocellular carcinoma (HCC). To clarify the pathogenetic significance of allele loss on chromosome 16, we performed restriction fragment length polymorphism analysis of 70 surgically resected tumors by using 15 polymorphic DNA markers for chromosome 16. Loss of heterozygosity on chromosome 16 was detected in 36 (52%) of 69 informative cases, and the common region of allele loss in these 36 tumors was located between the HP locus (16q22.1) and the CTRB locus (16q22.3-q23.2). These losses occurred more frequently in HCCs of poor differentiation, of larger size, and with metastasis, whereas they were not detected in HCC at the earliest stage. In addition, these losses were not associated with presence or absence of hepatitis B virus DNA integration or hepatitis C virus infection. These results show that loss of heterozygosity on chromosome 16 is a late event occurring after hepatocarcinogenesis and strongly suggest that this phenomenon is involved in enhancement of tumor aggressiveness during progression of HCC.

Allele loss on chromosome 16 associated with progression of human hepatocellular carcinoma.

Publisher Summary This chapter discusses the role of DNA methylation in carcinogenesis and tumor diversification The methylation of HpaII and Hha1 sites in DNA isolated from the normal rat livers and from transplantable hepatomas shows that the Hha1 sites in the α-fetoprotein genes are less methylated in hepatoma cell DNA than in the liver DNA A decreased methylation of the CCGG sequences in the rat hepatoma DNA than in the normal rat livers is also observed There are two corollaries to the hypothesis that chemical carcinogens act in part by inhibiting the DNA methylation: first, chemical carcinogens should be able to activate nonexpressed genes in suitable selectable systems in a similar manner to that of 5-Aza-CR, and second, agents that inhibit methylation such as 5-Aza-CR should be carcinogenic The methylation of poly dC–dG with ethyl methane sulfonate (EMS) stimulates the methyl-accepting ability of the DNA by rat DNA methyltransferase Thus, carcinogens can have multiple effects on DNA methylation, acting either to decrease or to increase methylation, depending on the specific lesion induced in DNA

The role of DNA methylation in cancer

Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL

Gonadotropins: Physicochemical and Immunological Properties

Genetic information from the bacterium Escherichia coli was transferred to human cells by means of the specialized transducing phage lambda plac carrying the bacterial z gene for the enzyme beta-galactosidase (geta-D-galactoside galactohydrolase, EC 3.2.1.23). As recipient cells, cultured skin fibroblasts from a patient with generalized gangliosidosis (GMI-gangliosidosis Type I) characterized by a severe deficiency of beta-galactosidase activity were used. The deficient human cells were incubated with the bacteriophage lambda plac or lambda plac DNA and beta-galactosidase activity was measured in order to detect gene transfer and acceptance of the prokaryotic information in the mammalian system for transcription and translation. The expression of the phage genome in the deficient fibroblasts could be demonstrated by detection of higher beta-galactosidase activity after incubation with phage lambda plac in three out of 19 experiments and in four out of 16 experiments after treatment with lambda plac DNA. Lambda plac DNA induced much higher enzyme activities than infective phage particles. Immunochemical and physicochemical assays could not distinguish the induced beta-galactosidase activity from that of the z-gene product of E. coli.

Gene transfer to human cells: transducing phage lambda plac gene expression in GMI-gangliosidosis fibroblasts.

DNA haplotype constellations of the beta-globin gene cluster have been analyzed in German families with hemoglobinopathies (Hb Freiburg, Hb Koln, Hb Presbyterian) and beta-thalassemias. The polymorphic patterns obtained were compared to those found in families from Greece, Italy, and Turkey affected by beta-thalassemia syndromes. With the combined analysis of seven restriction site polymorphisms a DNA-diagnostic prediction for additional offspring could be made with an overall frequency of 75% in the four ethnic groups.

DNA-polymorphic patterns linked to the beta-globin genes in German families affected with hemoglobinopathies and thalassemias: a comparison to other ethnic groups.

A mutant RsaI restriction endonuclease site of high frequency has been identified in individuals of German, Greek, Italian, and Turkish origin. The mutation was found within the α-globin gene complex and is located 0.7 kb 5′ to the α-globin gene. In individuals of central European origin 34 out of 58 chromosomes exhibited the α-gene linkage to the presence of the polymorphic site, and thus a preliminary estimate of the gene frequency for this allele would be 0.59. DNA analysis data of individuals derived from Mediterranean populations indicate a distribution of this polymorphic marker in similar frequencies.

Detection of a restriction site polymorphism within the human alpha-globin gene complex.

Numerous types of interaction between pro-and eucaryotes exist in nature, from the endosymbiosis of some bacteria with unicellular organisms and insects to the complex systems of bacterial flora associated with the skin and intestines of animals and man, and nitrogen-fixation and crown-gall tumor induction in plants. Until recently, such interactions were not thought to include genetic transfer, but an increasing body of evidence points to the probability of similar naturally-occuring exchanges with wide-ranging implications for evolution and genetic manipulation. Experiments to elucidate the possible effects of procaryotic genes in eucaryotic systems have included in vitro and in vivo studies with both plant and animal systems, for instance the translation of bacterial messenger RNAs in the wheat germ and rabbit reticulocyte systems and the introduction of bacterial genes into plant protoplasts, animal cells and whole organisms. In the present paper we have tried to summarize the results of experiments involving the uptake, replication, transcription, translation and integration of procaryotic genes in various eucaryotic systems and to discuss the implications of such findings for basic research as well as for possible biomedical applications. Awareness of the possibility of procaryotic-eucaryotic genetic interactions may help to elucidate unresolved questions in pathology, such as possible involvement of the intestinal flora in carcinogenesis, as well as to provide valuable probes of eucaryotic control mechanisms and new approaches in agricultural genetic engineering.

On procaryotic gene expression in eucaryotic systems.

Restriction endonuclease mapping of cellular DNA has been used to identify chromosomes that carry the mutant Hb Presbyterian β-globin genes in a family with individuals heterozygous for this disease. The presence of the polymorphic Hind III restriction site in the Gγ-globolin gene and its absence in the Aγ-globolin gene were shown to be in phase with the Hb Presbyterian mutation yielding a haplotype constellation that is diagnostic for any further affected offspring.

DNA restriction mapping identifies the chromosome carrying the mutant Hb Presbyterian beta-globin gene.

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