Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 15 de 15
Filter
Add more filters










Publication year range
1.
Am J Transplant ; 16(8): 2473-8, 2016 08.
Article in English | MEDLINE | ID: mdl-27109874

ABSTRACT

Most countries exclude human immunodeficiency virus (HIV)-positive patients from organ donation because of concerns regarding donor-derived HIV transmission. The Swiss Federal Act on Transplantation has allowed organ transplantation between HIV-positive donors and recipients since 2007. We report the successful liver transplantation from an HIV-positive donor to an HIV-positive recipient. Both donor and recipient had been treated for many years with antiretroviral therapy and harbored multidrug-resistant viruses. Five months after transplantation, HIV viremia remains undetectable. This observation supports the inclusion of appropriate HIV-positive donors for transplants specifically allocated to HIV-positive recipients.


Subject(s)
Graft Survival/immunology , HIV Infections/surgery , HIV Seropositivity , HIV-1/immunology , Liver Transplantation , Tissue Donors/supply & distribution , Tissue and Organ Procurement , Aged , HIV Infections/virology , Humans , Male , Middle Aged , Prognosis
2.
Rev Med Suisse ; 10(426): 869-72, 874-5, 2014 Apr 16.
Article in French | MEDLINE | ID: mdl-24834646

ABSTRACT

Zostavax, a live attenuated vaccine against shingles (herpes zoster) has been available in Switzerland since 2008. In a population aged 60 and over, evidence suggests the vaccine effectively reduces the incidence of shingles and some of its corresponding complications. More importantly, in terms of public health, vaccination appears to reduce the burden of illness and be pharmaco-economically viable. Despite being part of the vaccination programmes in the United States and several European countries, the vaccine is not yet part of the Swiss vaccination programme. Should Switzerland follow suit by incorporating Zostavax into their vaccination policy?


Subject(s)
Herpes Zoster Vaccine/administration & dosage , Herpes Zoster/prevention & control , Vaccination/methods , Cost of Illness , Economics, Pharmaceutical , Health Policy , Herpes Zoster/economics , Herpes Zoster/epidemiology , Herpes Zoster Vaccine/economics , Humans , Immunization Programs , Incidence , Middle Aged , Public Health , Switzerland , Vaccination/economics , Vaccines, Attenuated/administration & dosage , Vaccines, Attenuated/economics
3.
Glycobiology ; 11(8): 613-20, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11479272

ABSTRACT

We have chosen E. coli K92, which produces the alternating structure alpha(2-8)neuNAc alpha(2-9)neuNAc as a model system for studying bacterial polysaccharide biosynthesis. We have shown that the polysialyltransferase encoded by the K92 neuS gene can synthesize both alpha(2-8) and alpha(2-9) neuNAc linkages in vivo by 13C-nuclear magnetic resonance analysis of polysaccharide isolated from a heterologous strain containing the K92 neuS gene. The K92 polysialyltransferase is associated with the membrane in lysates of cells harboring the neuS gene in expression vectors. Although the enzyme can transfer sialic acid to the nonreducing end of oligosaccharides with either linkage, it is unable to initiate chain synthesis without exogenously added polysialic acid. Thus, the polysialyltransferase encoded by neuS is not sufficient for de novo synthesis of polysaccharide but requires another membrane component for initiation. The acceptor specificity of this polysialyltransferase was studied using sialic acid oligosaccharides of various structures as exogenous acceptors. The enzyme can transfer to the nonreducing end of all bacteria polysialic acids, but has a definite preference for alpha(2-8) acceptors. Gangliosides containing neuNAc alpha(2-8)neuNAc are elongated, whereas monsialylated gangliosides are not. Disialylgangliosides are better acceptors than short oligosaccharides, suggesting a lipid-linked oligosaccharide may be preferred in the elongation reaction. These studies show that the K92 polysialyltransferase catalyzes an elongation reaction that involves transfer of sialic acid from CMP-sialic acid to the nonreducing end of two different acceptor substrates.


Subject(s)
Escherichia coli Proteins , Escherichia coli/enzymology , Sialic Acids/biosynthesis , Sialyltransferases/metabolism , Amino Acid Motifs/genetics , Amino Acid Motifs/physiology , Carbohydrate Sequence , Escherichia coli/genetics , Escherichia coli/metabolism , Gangliosides/chemistry , Gangliosides/metabolism , Molecular Sequence Data , N-Acetylneuraminic Acid/metabolism , Polysaccharides, Bacterial/biosynthesis , Sialyltransferases/genetics , Sialyltransferases/physiology
4.
Biochem Pharmacol ; 60(11): 1611-9, 2000 Dec 01.
Article in English | MEDLINE | ID: mdl-11077043

ABSTRACT

Tumor tissue specimens from human ovarian cancer patients were assessed for relative mRNA abundance levels of several genes thought to be involved in the development of in vitro drug resistance in this disease. Higher mRNA levels of Xeroderma pigmentosum group B (XPB), which links DNA repair with DNA transcription, and of Cockayne's syndrome group B (CSB), which is essential for gene-specific repair, were observed in tumor tissues that were clinically resistant to platinum-based chemotherapy, as compared with tissues from patients responding to therapy. In a cohort of 27 patients, mRNA levels of XPB averaged 5-fold higher in platinum-resistant tumors (P = 0.001); and for CSB, mRNA levels averaged 6-fold higher but with greater variability (P = 0.033). Concurrently, these platinum-resistant tumor tissues did not exhibit significantly higher mRNA levels for the MDR1 (multidrug-resistance) gene (P = 0.134) or of the metallothionein-II (MT-II) gene (P = 0.598). Since these platinum-resistant tumors also show higher mRNA levels of ERCC1 and XPA, platinum resistance appears to be associated with concurrent up-regulation of four genes (XPA, ERCC1, XPB, and CSB). These four genes participate in DNA damage excision activity, gene-specific repair, and linkage of DNA repair with DNA transcription. These data suggest that concurrent up-regulation of genes involved in nucleotide excision repair may be important in clinical resistance to platinum-based chemotherapy in this disease.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , DNA Helicases/genetics , DNA-Binding Proteins/genetics , Drug Resistance, Neoplasm/physiology , Metallothionein/genetics , Ovarian Neoplasms/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , DNA Helicases/metabolism , DNA Repair , DNA Repair Enzymes , DNA-Binding Proteins/metabolism , Female , Gene Expression , Humans , Metallothionein/metabolism , Ovarian Neoplasms/metabolism , Platinum/pharmacology , Poly-ADP-Ribose Binding Proteins , RNA, Messenger/metabolism , Transcription, Genetic
5.
Glycobiology ; 9(5): 481-7, 1999 May.
Article in English | MEDLINE | ID: mdl-10207180

ABSTRACT

CMP-beta-N-acetylneuraminic acid (CMP-neuNAc) is the substrate for the sialylation of glycoconjugates by sialyltransferases in microbes and higher eukaryotes. CMP-neuNAc synthetase catalyzes the formation of this substrate, CMP-neuNAc, from CTP and neuNAc. In this report we describe the purification of CMP-neuNAc synthetase from bovine anterior pituitary glands. The enzyme was purified by ion exchange, gel filtration, and affinity chromatography. The protein was homogeneous on SDS-PAGE with a molecular weight of 52 kDa, a subunit size similar to that of the E.coli K1 (48.6 kDa). The identity of the 52 kDa protein band was confirmed by native gel electrophoresis in that the position of the enzyme activity in gel slices coincided with the position of major bands in the stained gel. Photoaffinity labeling with 125I-ASA-CDP ethanolamine resulted in the modification of a 52 kDa polypeptide that was partially protected against modification by the substrate CTP. Enzyme activity in crude fractions could be adsorbed onto an immunoadsorbent prepared from antibody against the purified 52 kDa protein. Taken together these data suggest that the 52 kDa polypeptide purified by this procedure described in this report is indeed CMP-neuNAc synthetase. The active enzyme chromatographed on a gel filtration column at 158 kDa suggesting it exists in its native form as an oligomer.


Subject(s)
N-Acylneuraminate Cytidylyltransferase/isolation & purification , Pituitary Gland, Anterior/enzymology , Animals , Cattle , Cell Nucleus/enzymology , Chromatography, Affinity , DNA/metabolism , Electrophoresis, Polyacrylamide Gel , Glycosylation , Isoelectric Point , Molecular Weight , N-Acylneuraminate Cytidylyltransferase/chemistry , N-Acylneuraminate Cytidylyltransferase/metabolism
7.
Mol Carcinog ; 17(1): 1-7, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8876669

ABSTRACT

Nucleotide excision repair (NER) is an ordered process in nonmalignant cells, in both human and nonhuman systems. We previously reported that in human brain there is discordant mRNA expression of excision repair cross-complementing (ERCC) 1 and ERCC2 in malignant tissues, concurrent with excellent concordance of these genes in nonmalignant tissues from the same patients. Here we have extended these studies to compare low-grade tumors to high-grade tumors and to include ERCC3 (which links DNA repair with DNA transcription) and ERCC6 (which is essential for gene-specific repair). Glial tumor and adjacent normal brain specimens from 19 individuals were studied. Paired malignant and nonmalignant tissues were obtained from 12 of these patients. For ERCC3, there was excellent concordance of mRNA expression between malignant and nonmalignant tissues from the same individuals (P = 0.003). For ERCC6, no concordance was observed (P = 0.314). Tumor tissue from patients with high-grade gliomas exhibited marked discordance of mRNA expression patterns in situations in which good concordance was observed in tumor tissue from low-grade gliomas. We previously established that malignant brain tumors show increased disorder of genes in the NER process, as compared with nonmalignant tissues. These data suggest that increasing disorder in the NER process may occur as cells move from low-grade to high-grade malignancy.


Subject(s)
Brain Neoplasms/genetics , Brain/physiology , DNA Helicases/genetics , DNA Repair , DNA-Binding Proteins/genetics , Drosophila Proteins , Gene Expression Regulation, Neoplastic , Glioma/genetics , Astrocytoma/genetics , Astrocytoma/therapy , Brain Neoplasms/therapy , DNA Repair Enzymes , Glioblastoma/genetics , Glioblastoma/therapy , Glioma/therapy , Humans , Oligodendroglioma/genetics , Oligodendroglioma/therapy , Poly-ADP-Ribose Binding Proteins , RNA, Messenger/genetics , RNA, Neoplasm/genetics , Regression Analysis
8.
Cancer Res ; 55(6): 1261-6, 1995 Mar 15.
Article in English | MEDLINE | ID: mdl-7882319

ABSTRACT

Perturbation of the DNA repair process appears to be responsible for the occurrence of a number of human diseases, which are usually associated with a propensity to develop internal malignancies and/or disorders of the central nervous system. We have been interested in the possibility that a subtle abnormality in DNA repair competency might be associated with the transformation of nonmalignant cells to the malignant state. To study this question, we assayed malignant and nonmalignant brain tissues from 19 individuals for mRNA expression levels of the human DNA repair genes ERCC1, ERCC2, and XPAC and for differential splicing of the ERCC1 transcript. We separately compared expression levels of these genes in the following situations: concordance of expression within malignant tissues; concordance of expression within nonmalignant tissues; concordance between malignant and nonmalignant tissues within individuals of the cohort; and concordance of gene expression between two nonmalignant tissue sites within a single individual. Linear regression analyses of mRNA values obtained suggested orderly concordance of these three DNA repair genes in nonmalignant tissues within the patient cohort and an excellent concordance of these genes between two separate biopsy sites from the same individual. In contrast, malignant tissues showed disruption of concordance between the full-length ERCC1 transcript and ERCC2, which have excision and helicase functions, respectively. Furthermore, within the same individuals, malignant tissues were discordant with nonmalignant tissues for ERCC1 and ERCC2, although concordance for XPAC was preserved. These data suggest that one molecular characteristic of human malignancy may be the disruption of the normal relationship between the excision and the helicase functions of the nucleotide excision repair pathway.


Subject(s)
Brain Neoplasms/metabolism , Brain/metabolism , DNA Helicases , DNA Repair , Endonucleases , Proteins/genetics , RNA, Messenger/analysis , Transcription Factors , DNA Damage , DNA-Binding Proteins/genetics , Humans , Polymerase Chain Reaction , Xeroderma Pigmentosum Group A Protein , Xeroderma Pigmentosum Group D Protein
9.
Oncol Rep ; 2(2): 209-14, 1995 Mar.
Article in English | MEDLINE | ID: mdl-21597714

ABSTRACT

We have previously shown that in non-drug-selected human T lymphocytes, DNA repair is the primary determinant of cellular resistance to cisplatin (1). In this system, we have assessed mRNA levels of expression of the nucleotide excision repair (NER) genes ERCC1 and XPA, as well as the alternatively spliced species of ERCC1 which lacks exon VIII. The focus of these studies, was to try to identify the possible relative roles of normal XPA, full-length ERCC1, and alternatively spliced ERCC1, in a system where DNA repair is a clear determinant of cisplatin resistance. ERCC1 expression was directly related to cisplatin-DNA adduct repair capability, as well as directly related to cisplatin resistance, suggesting a primary role for ERCC1 in effecting DNA repair. XPA expression was approximately equivalent in each cell line, regardless of the level of DNA repair activity, suggesting a helper role for the product of this gene. The mRNA levels of the alternatively spliced species of ERCC1 were strongly inversely related to DNA repair activity, suggesting a possible inhibitory influence on the DNA repair process. This interpretation is consistent with alternative splicing of several known oncogenes, where the alternatively spliced species has an inhibitory effect on the full-length gene product. The NER pathway appears to be vitally important in effecting cisplatin resistance in non-drug-selected T lymphocytes. Further, it appears that NER may have at least one inhibitory regulatory component.

10.
J Clin Invest ; 94(2): 703-8, 1994 Aug.
Article in English | MEDLINE | ID: mdl-8040325

ABSTRACT

Nucleotide excision repair is a DNA repair pathway that is highly conserved in nature, with analogous repair systems described in Escherichia coli, yeast, and mammalian cells. The rate-limiting step, DNA damage recognition and excision, is effected by the protein products of the genes ERCC1 and XPAC. We therefore assessed mRNA levels of ERCC1 and XPAC in malignant ovarian cancer tissues from 28 patients that were harvested before the administration of platinum-based chemotherapy. Cancer tissues from patients whose tumors were clinically resistant to therapy (n = 13) showed greater levels of total ERCC1 mRNA (P = 0.059), full length transcript of ERCC1 mRNA (P = 0.026), and XPAC mRNA (P = 0.011), as compared with tumor tissues from those individuals clinically sensitive to therapy (n = 15). In 19 of these tissues, the percentage of alternative splicing of ERCC1 mRNA was assessed. ERCC1 splicing was highly variable, with no difference observed between responders and nonresponders. The alternatively spliced species constituted 2-58% of the total ERCC1 mRNA in responders (median = 18%) and 4-71% in nonresponders (median = 13%). These data suggest greater activity of the DNA excision repair genes ERCC1 and XPAC in ovarian cancer tissues of patients clinically resistant to platinum compounds. These data also indicate highly variable splicing of ERCC1 mRNA in ovarian cancer tissues in vivo, whether or not such tissues are sensitive to platinum-based therapy.


Subject(s)
Carboplatin/therapeutic use , Cisplatin/therapeutic use , DNA Repair , DNA-Binding Proteins/genetics , Endonucleases , Ovarian Neoplasms/drug therapy , Proteins/genetics , RNA, Messenger/analysis , Female , Humans , Ovarian Neoplasms/genetics , Xeroderma Pigmentosum Group A Protein
11.
Cancer Res ; 53(16): 3694-9, 1993 Aug 15.
Article in English | MEDLINE | ID: mdl-8339278

ABSTRACT

Using atomic absorbance spectrometry with Zeeman background correction, we measured platinum-DNA adduct levels in leukocyte DNA of 49 patients receiving therapy consisting of only carboplatin and cisplatin. Twenty-four histological types of malignancy were included in the cohort. Peripheral blood leukocytes were collected at defined times during the first two cycles of treatment. The relationship between adduct level and disease response was highly statistically significant during cycle 1 of therapy (two-sided P = 0.007 at day 2), but statistical significance was lost during cycle 2. On all days studied, median and mean adduct levels were consistently higher in responders as compared to nonresponders (summary two-sided P = 0.0004). These data suggest that the processes which protect cellular DNA may be common to malignant and nonmalignant rapidly dividing tissues of the same individual, regardless of the type of tumor that individual may harbor.


Subject(s)
Carboplatin/metabolism , Cisplatin/blood , DNA Adducts , DNA/blood , Leukocytes/metabolism , Neoplasms/blood , Carboplatin/therapeutic use , Cisplatin/analysis , DNA/analysis , Humans , Leukocytes/chemistry , Neoplasms/drug therapy , Prospective Studies , Spectrophotometry, Atomic
12.
Cancer Res ; 53(2): 242-7, 1993 Jan 15.
Article in English | MEDLINE | ID: mdl-8417816

ABSTRACT

The human ovarian cancer cell lines A2780 and A2780/CP70 were studied to investigate the cellular basis for their relative sensitivities to tetrachloro(DL-trans)-1,2-diamminecyclohexaneplatinum(IV) (ormaplatin). Cells were exposed to ormaplatin for 1 h in all experiments. As assessed by colony formation assays, the A2780/CP70 cell line [50% inhibitory dose (IC50) = 3.6 microM] was 9.5-fold more resistant to ormaplatin than the A2780 cell line [IC50 = 0.38 microM]. For cisplatin, the IC50 doses were 40 and 3 microM, respectively. Both cell lines were treated with ormaplatin at doses ranging from 0.10 to 40 microM, for the purpose of studying drug accumulation and efflux, and DNA adduct formation and repair. When these cell lines were treated at their respective IC50 doses, drug accumulation was greater in the resistant cells. When treated at equal microM doses, the sensitive cells formed 8-fold more DNA adduct than the resistant cells. When cells were treated with ormaplatin so as to achieve equivalent levels of platinum-DNA modification, sensitive cells removed 53% of the platinum-DNA damage in the first 6 h after drug exposure, compared to 68% in the resistant cells. We conclude that in human ovarian cancer cells made resistant to cisplatin, there is moderate cross-resistance to ormaplatin. This cross-resistance is not explained by differences in drug accumulation but is associated with reduced platinum-DNA adduct formation, which may be attributable in part to cytosolic inactivation of drug.


Subject(s)
Organoplatinum Compounds/pharmacology , Ovarian Neoplasms/drug therapy , Cisplatin/metabolism , Cisplatin/pharmacology , DNA/metabolism , Drug Resistance , Female , Humans , In Vitro Techniques , Organoplatinum Compounds/metabolism , Ovarian Neoplasms/metabolism , Tumor Cells, Cultured/metabolism
13.
Int J Oncol ; 3(2): 331-5, 1993 Aug.
Article in English | MEDLINE | ID: mdl-21573369

ABSTRACT

Sixteen patients with squamous cell carcinoma of the head and neck region were studied for the formation of platinum-DNA adduct in leukocyte DNA. Every patient received carboplatin and cisplatin, each given intravenously on day 1 of 21-day treatment cycles. Blood was obtained for DNA isolation 24 hours after treatment on cycles 1 and 2; and on the morning before cycle 2 of therapy (21 days after cycle 1 drug delivery). Adduct was measured by atomic absorbance spectrometry with Zeeman background correction. As has been shown in previous studies, adduct persistence and accumulation could be demonstrated in a portion of the cohort. Adduct removal from blood cell DNA during the 21 days of cycle number 1, was determined for 12 patients. In these patients, adduct removal was directly i-elated to clinical resistance to the cisplatin/carboplatin treatment regimen; and adduct removal was inversely related to leukocyte toxicity. These data demonstrate that changes in adduct levels with time may provide valuable information, in the study of the human in vivo biology of platinum-DNA damage and repair.

14.
Carcinogenesis ; 12(7): 1253-8, 1991 Jul.
Article in English | MEDLINE | ID: mdl-2070490

ABSTRACT

Previous studies have shown that platinum-DNA adduct level in leukocyte DNA (measured by antibody methodology) is directly related to disease response in ovarian cancer and testicular cancer. To determine if this principle could be more broadly applied, platinum-DNA damage was studied in a blinded fashion in leukocyte DNA of 21 cancer patients who received carboplatin (day 1) and cisplatin (day 3) in a phase 1 clinical trial. Fifteen different tumor types were included in this cohort. Using atomic absorption spectrometry with Zeeman background correction, DNA-bound platinum was measured during cycles 1 (C1) and 2 (C2) of therapy for most patients. For each of two cycles of therapy, most patients developed measurable levels of adduct after carboplatin, and in most patients adduct levels increased further after cisplatin, often in a supra-additive fashion. Total mg dose levels varied by less than 2-fold, whereas individual patients differed by as much as 10(3) in their adduct measurements after C1 and after C2, and by 29-fold after the very first carboplatin dose. All patients had refractory disease at the initiation of therapy, and 19 patients were evaluable for disease response. Adduct determinations were made 24 h after the first dose of platinum therapy in 17 of these individuals. Mean adduct levels after the first dose of carboplatin were higher in six responders (50 fmol/micrograms DNA +/- 26) than in 11 non-responders (14 fmol/micrograms DNA +/- 10); Wilcoxon two sample test two-sided P = 0.0071. The six responders were patients with pleural mesothelioma (2), breast cancer, buccal mucosa cancer, esophageal cancer and ovarian cancer. Adduct levels were consistently higher in the group of responders on each day that adduct was measured, with a summary two-sided P value of 0.00011. We conclude that analysis of platinum-DNA adduct formation may help determine whether pharmacogenetics are important in cancer drug resistance; and may help to determine the relationship between DNA damage in the peripheral blood compartment and internal organ response to in vivo exposures to DNA-damaging agents.


Subject(s)
Carboplatin/therapeutic use , Cisplatin/therapeutic use , DNA Damage , DNA/metabolism , Leukocytes/metabolism , Neoplasms/drug therapy , Platinum/metabolism , Carboplatin/administration & dosage , Carboplatin/metabolism , Cisplatin/administration & dosage , Cisplatin/metabolism , Double-Blind Method , Drug Administration Schedule , Female , Humans , Male , Neoplasms/metabolism , Prospective Studies , Spectrophotometry, Atomic
SELECTION OF CITATIONS
SEARCH DETAIL
...