Biomedical subjects

S Francisci

Publications and source records attributed to S Francisci.

At least 19 recordsLinked to original sources

PubMed2006

Estimating regional cancer burden in countries with partial registration coverage: an application to all malignant neoplasms in Italy over the period 1970-2010.

Regional epidemiological indicators of cancer burden are essential information for cancer surveillance and health resources planning, especially in countries with partial registration coverage and geographically variable risk patterns, such as Italy. This paper presents a methodology to derive cancer incidence and prevalence at the regional and national scale and illustrates its application to all malignant neoplasms in Italy for the period 1970-2010. The method, denoted as MIAMOD, is based on a back-calculation approach and derives cancer-specific morbidity measures by using official mortality data and model-based relative survival from local Cancer Registries data. The output includes time-trends and projections of a complete set of epidemiological indicators, i.e. mortality, incidence and prevalence. Results for all cancers in Italy show different incidence patterns by gender and a pronounced regional variability among men: male incidence is estimated to decrease in almost all northern-central regions, while more stable or even rising trends are estimated in the southern regions. No incidence reduction is expected for women. Prevalence increases country-wide in both sexes. The proposed approach can be applied to derive regional up-to-date time trends of cancer burden indicators in countries with local and sparse cancer registration systems. These estimates are useful for planning health services on a national and regional basis and for highlighting regional differences.

Adolescent↗

PubMed2006

Mutations in yeast mt tRNAs: specific and general suppression by nuclear encoded tRNA interactors.

Mutations in mitochondrial tRNA genes can produce alterations in tRNA structure resulting in defective mitochondrial protein synthesis and hence respiratory defects. Such defects are often at the origin of neurodegenerative diseases in humans and can be easily studied in yeast since respiratory deficient mutants are viable. Several nuclear encoded tRNA interactors have been shown to rescue the mitochondrial defects due to mutations in mitochondrial tRNAs. Among these, we have identified the gene for the mitochondrial protein synthesis elongation factor EF-Tu and the specific mt aminoacyl-tRNA synthetases. We also observed that the respiratory defects and the effect of the TUF1 over-expression were strongly strain dependent. The importance of the nuclear background in which the mitochondrial mutation is expressed was investigated by changing the nuclear context. Finally, we demonstrated, using the RT-PCR method, the existence of significantly variable levels of the TUF1 transcript among strains with functional and dysfunctional mitochondria.

Amino Acyl-tRNA Synthetases↗

PubMed2003

Nucleo-mitochondrial interactions in Saccharomyces cerevisiae: characterization of a nuclear gene suppressing a defect in mitochondrial tRNA(Asp) processing.

We utilized the heat-sensitive mutant strain (Ts932), bearing a mutation at position 61 in the mitochondrial tRNA(Asp) gene, to identify nuclear genes involved in tRNA biogenesis; this mutant is defective in 3'-end processing and consequently in the production of mature mitochondrial tRNA(Asp). We transformed this strain with a yeast nuclear library and we isolated among other suppressors, an unknown, non-essential gene (called SMM1, corresponding to open reading frame YNR015w), which restored the growth on glycerol and a normal amount of processed tRNA(Asp) in the mutant. The gene contains a domain highly conserved in evolution from bacteria to human and its product has been recently shown to have dihydrouridine synthase activity.

Amino Acid Sequence↗

PubMed2003

The yeast counterparts of human 'MELAS' mutations cause mitochondrial dysfunction that can be rescued by overexpression of the mitochondrial translation factor EF-Tu.

We have taken advantage of the similarity between human and yeast (Saccharomyces cerevisiae) mitochondrial tRNA(Leu)(UUR), and of the possibility of transforming yeast mitochondria, to construct yeast mitochondrial mutations in the gene encoding tRNA(Leu)(UUR) equivalent to the human A3243G, C3256T and T3291C mutations that have been found in patients with the neurodegenerative disease MELAS (for mitochondrial 'myopathy, encephalopathy, lactic acidosis and stroke-like episodes'). The resulting yeast cells (bearing the equivalent mutations A14G, C26T and T69C) were defective for growth on respiratory substrates, exhibited an abnormal mitochondrial morphology, and accumulated mitochondrial DNA deletions at a very high rate, a trait characteristic of severe mitochondrial defects in protein synthesis. This effect was specific at least in the pathogenic mutation T69C, because when we introduced A or G instead of C, the respiratory defect was absent or very mild. All defective phenotypes returned to normal when the mutant cells were transformed by multicopy plasmids carrying the gene encoding the mitochondrial elongation factor EF-Tu. The ability to create and analyse such mutated strains and to select correcting genes should make yeast a good model for the study of tRNAs and their interacting partners and a practical tool for the study of pathological mutations and of tRNA sequence polymorphisms.

Amino Acid Substitution↗

PubMed2003

Cancer prevalence in Central Europe: the EUROPREVAL Study.

BACKGROUND: Information on cancer prevalence is either absent or largely unavailable for central European countries. MATERIALS AND METHODS: Austria, Germany, The Netherlands, Poland, Slovakia, Slovenia and Switzerland cover a population of 13 million inhabitants. Cancer registries in these countries supplied incidence and survival data for 465 000 cases of cancer. The prevalence of stomach, colon, rectum, lung, breast, cervix uteri, corpus uteri and prostate cancer, as well as skin melanoma, Hodgkin's disease, leukaemia and all malignant neoplasms combined was estimated for the end of 1992. RESULTS: A large heterogeneity was observed within central European countries. For all cancers combined, estimates ranged from 730 per 100 000 in Poland (men) to 3350 per 100 000 in Germany (women). Overall cancer prevalence was the highest in Germany and Switzerland, and the lowest in Poland and Slovenia. In Slovakia, prevalence was higher than average for men and lower than average for women. This was observed for almost all ages. As shown by incidence data, breast cancer was the most frequent malignancy among women in all countries. Among men, prostate cancer was the leading malignancy in Germany, Austria and Switzerland, and lung cancer was the major cancer in Slovenia, Slovakia and Poland. The Netherlands had a high prevalence of both prostate and lung cancer. Time-related magnitude of prevalence within each country and the variability of such proportions across the countries has been estimated and cancer prevalence is given by time since diagnosis (1 year, 1-5 years, 5-10 years, >10 years) for each site. The weight of 1-year prevalence (248 per 100 000 among men and 253 per 100 000 among women) was <15% of total prevalence. Prevalent cases between 1 and 5 years since diagnosis represented between 22% and 34% of the total prevalence. Prevalent cases diagnosed from 5 to 10 years before (335 per 100 000 for men and 505 per 100 000 for women) represented between 17% and 23% of prevalent cancers. Finally, long-term cancer prevalence (diagnosed >10 years before), reflecting long-term survival, and number of people considered as cured from cancer were 490 per 100 000 for men and 1028 per 100 000 for women, with a range between 26% (The Netherlands, men) and 50% (Slovakia, women). CONCLUSION: It is clear from observing countries in Central Europe, that high cancer prevalence is associated with well-developed economies. This burden of cancer could be interpreted as a paradoxical effect of better treatments and thereby survival. It could also be taken as a sign for not being satisfied with the advances in treating patients diagnosed with cancer, and for supporting more primary prevention.

Adolescent↗

PubMed2002

Measuring cancer prevalence in Europe: the EUROPREVAL project.

Cancer prevalence is the proportion of individuals in a population who at some stage during their lifetime have been diagnosed with cancer, irrespective of the date of diagnosis. Cancer prevalence statistics have generally been provided by a limited number of well established cancer registries that have been in existence for several decades. The advent of systematic follow-up of life status of incident cases and the availability of new statistical methodologies, now makes it possible for registries established during the 1970s or 1980s to provide prevalence data. The main problems encountered in the estimation of prevalence are the inclusion of: (i) cases lost to follow-up; (ii) cases known only from their death certificate; (iii) cases diagnosed before the start of registration; and (iv) the treatment of multiple tumours and migrations. The main aim of this paper was to review these problems and discuss, through the experience gained with EUROPREVAL, how they can be overcome. A method is presented for the calculation of prevalence of all cancers combined in the populations covered by the 45 cancer registries participating in EUROPREVAL. Prevalence of cancer is estimated to be 2% on average, with the highest values (3%) in Sweden and the lowest in Eastern Europe, with a minimum of approximately 1% in Poland.

Adolescent↗

PubMed2001

Reintroduction of a characterized Mit tRNA glycine mutation into yeast mitochondria provides a new tool for the study of human neurodegenerative diseases.

We report the identification and characterization of a new mutation (ts9) in the Saccharomyces cerevisiae mitochondrial genome, which was first genetically mapped in the tRNAgly region and further identified by means of sequencing as consisting of a G to A transition at position 30 in the tRNA. The mutation causes an almost complete disappearance of mature tRNAgly, while a second mitochondrial mutation with a compensatory C to T change restores it in normal quantities; this points to the importance of the strong bond between bases 30 and 40 of the anticodon stem in the stabilization of the tRNA. In addition to resulting in a clear-cut heat-sensitive phenotype, the ts9 mutation creates a new EcoRV restriction site. Both properties were used as markers to monitor the successful (re) introduction of the mutated allele into a wild-type mitochondrial genome through biolistic transformation. The mutant frequency in the progeny as well as the correct integration of the mutated allele at its proper site demonstrate the feasibility of this method for creating and investigating specific mitochondrial tRNA mutations. The method will provide important applications for the use of yeast as a model system of human mitochondrial pathologies.

Bacterial Proteins↗

PubMed2000

Disruption of six novel genes from chromosome VII of Saccharomyces cerevisiae reveals one essential gene and one gene which affects the growth rate.

Six ORFs of unknown function located on chromosome VII of Saccharomyces cerevisiae were disrupted in two different genetic backgrounds, and the phenotype of the generated mutants was analysed. Disruptions of ORFs YGR256w, YGR272c, YGR273c, YGR275w and YGR276c were carried out using the disruption marker kanMX4 flanked by short homology regions, whereas ORF YGR255c was inactivated with a long flanking homology (LFH) disruption cassette (Wach et al., 1994). Tetrad analysis of the heterozygous disruptants revealed that ORF YGR255c, previously identified as COQ6 and encoding a protein involved in the biosynthesis of coenzime Q (Tzagoloff and Dieckmann, 1990), is an essential gene. The same analysis also revealed that sporulation of the ygr272cDelta heterozygous diploid produced two small colonies per ascus that were also G418-resistant, indicating that the inactivation of ORF YGR272c could result in a slower growth rate. This result was confirmed by growth tests of the haploid disruptants and by complementation of the phenotype after transformation with a plasmid carrying the cognate gene. No phenotypes could be associated to the inactivation of ORFs YGR256w, YGR273c, YGR275w and YGR276c. Two of these genes have recently been further characterized: ORF YGR255w, renamed RTT102, encodes a regulator of the Ty1-element transposition, whereas ORF YGR276c was found to encode the 70 kDa RNase H activity and was renamed RNH70 (Frank et al., 1999).

Chromosomes, Fungal↗

PubMed1998

Ts mutations in mitochondrial tRNA genes: characterization and effects of two point mutations in the mitochondrial gene for tRNAphe in Saccharomyces cerevisiae.

Two new mitochondrial mutations conferring heat sensitivity on glycerol medium to the cells that carry them and affecting mitochondrial protein synthesis were investigated. Both map in the mitochondrial tRNAphe gene and have C-to-U transitions, one at position 2 (ts22b16) and the other at 62 (ts1345). The latter mutation clearly affects the 3' end-maturation of tRNAphe, while the former presents normal patterns of both tRNA processing and amino-acylation. The defective phenotype resulting from the ts22b16 mutation can be corrected by over-expressing either the mitochondrial elongation factor EF-Tu or the mutated form of the tRNA. These results suggest that this mutation's primary effect might involve modified interactions during the ternary complex formation.

Base Sequence↗

PubMed1994

Suppression of a mitochondrial point mutation in a tRNA gene can cast light on the mechanisms of 3' end-processing.

We used a genetic approach to study the nuclear factors involved in the biogenesis of mitochondrial tRNAs. A point mutation in the mitochondrial tRNA(Asp) gene of Saccharomyces cerevisiae had previously been shown to result in a temperature-sensitive respiratory-deficient phenotype as a result of the absence of 3' end-processing of the tRNA(Asp). Analysis of mitochondrial revertants has shown that all revertants sequenced have a G-A compensatory change at position 53, which restores the hydrogen-bond with the mutated nucleotide. We then searched for nuclear suppressors to identify the nuclear gene(s) involved in mitochondrial tRNA 3' end-processing. One such suppressor mutation was further characterized: it restores tRNA(Asp) maturation and growth at 36 degrees C on glycerol medium in heterozygous diploids, but leads to a defective growth phenotype in haploids.

Base Sequence↗

PubMed1989

A point mutation in a mitochondrial tRNA gene abolishes its 3' end processing.

A temperature sensitive mutation mapping in the tRNA region of the mitochondrial genome of S. cerevisiae has been found to abolish 3' processing of tRNA(asp). Mutant cells grown for a few generations at the non-permissive temperature were found to specifically lack mature tRNA(asp) and to accumulate 3' unprocessed precursors of this tRNA. The accumulation of precursors of other mitochondrial tRNAs was also observed under the same conditions. After longer incubation times, a generalized decrease of mitochondrial transcripts could be observed. The mutation was genetically mapped in a limited region surrounding the tRNA(asp) gene and found, by sequencing, to consist of a C- greater than T transition at position 61 of the tRNA(asp) gene.

Base Sequence↗

PubMed1987

Analysis of transcripts of the major cluster of tRNA genes in the mitochondrial genome of S. cerevisiae.

The transcripts of a 6Kbp region of the mitochondrial genome of S. cerevisiae, localized in the 21S rRNA-OXI1 span and including 12 tRNA genes (from tRNA(thr) to tRNA(ala)) and several G+C clusters, have been studied by analysis of in vitro capped primary transcripts and by fine mapping of the 5' ends of transcripts. The study was performed in the w.t. strain D273-10B and in several rho- mutants retaining different, partially overlapping portions of the studied region; the mutants accumulate incompletely-processed precursors of tRNAs due to the absence of the tRNA synthesis locus. Results show the presence in the region of four sites at which initiation occurs at a consensus nonanucleotide ATTATAAGTA (or a minor variant of the same); however different initiation sites are used in different strains, and several differences as compared to initiation in vitro can also be observed. Termini arising by processing are often localized at AATATAA or AATATATTTT sequences localized immediately adjacent to a G+C cluster or a tRNA sequence.

Base Sequence↗

PubMed1984

Initiation of transcription of a mitochondrial tRNA gene cluster in S. cerevisiae.

In Saccharomyces cerevisiae most mitochondrial tRNA genes are clustered in a 9 kbp region between the cap and oxil genes. Polygenic transcripts of this region have been previously identified. A transcriptional initiation site at a TTATAAGTA box, located upstream from the tRNAcys gene, has now been detected by S1 mapping experiments and by the capping of primary transcripts. Results are consistent with the hypothesis that this box represents the initiation site for transcription of a cluster of tRNA genes, while the adjacent tRNA2thr is cotranscribed with the 21S rRNA. Results obtained with various strains are compared, and the efficiency of this sequence as a transcriptional initiation site in different mitochondrial contexts is discussed.

Base Sequence↗

PubMed1984

Expression of the clustered mitochondrial tRNA genes in Saccharomyces cerevisiae: transcription and processing of transcripts.

The transcripts of a cluster of eight tRNA genes localized in the Cap-oxiI region of the mitochondrial genome of Saccharomyces cerevisiae were investigated by hybridization of gene-specific probes on Northern blots of mitochondrial RNA and by S1 mapping of the 5' termini of the transcripts. Two rho- mutants that lack mature tRNA species and accumulate precursors have been used to detect transcripts that are not detectable in wild-type (w.t.) mitochondria. The results have shown the existence of polygenic transcripts carrying at least 5-7 tRNA sequences, both in w.t. and in rho- strains. The existence of several alternative processing pathways, which involve cleavage at the 3' and 5' ends of the tRNA sequences and in the long intergenic regions (possibly at GC clusters), is suggested. Cleavage at the 5' ends of tRNA sequences is defective in the mutant strains. The transcripts of the genes for tRNAThrACN and tRNACys (the tRNA genes immediately downstream from the 21S rRNA gene) have been analyzed; the possibility that these species represent primary transcripts is considered, and potential sites for initiation of transcription of the clustered tRNA genes are discussed.

Base Sequence↗

PubMed1982

Transcripts of mitochondrial tRNA genes in Saccharomyces cerevisiae.

The transcription of a group of tRNA genes from the large tRNA gene cluster of mitochondrial DNA from Saccharomyces cerevisiae has been investigated by hybridization with DNA probes carrying tRNA coding sequences and small portions of the A + T rich intergenic regions. Results have shown that in some rho- mutants (DS502, F11) mature tRNA was absent, but a few transcripts could be detected. Some high molecular weight species actually hybridized with DNA probes carrying different tRNA coding sequences. Low molecular weight transcripts (100-150 nucleotides, carrying one tRNA sequence) were also present in these mutants. A high molecular weight transcript was also observed in the wild type, though in much more limited amount. The low molecular weight transcripts were analysed by the S1 mapping technique and found to include both a tRNA sequence and the upstream 5' flanking region extending as far as the 3' end of the preceding tRNA gene. The results suggest the existence of a common transcript bearing several tRNA sequences and indicate a possible mechanism of processing, which might be defective in mutants.

Base Sequence↗

PubMed1982

Mutations releasing mitochondrial biogenesis from glucose repression in Saccharomyces cerevisiae.

Mutants which exhibit a constitutive glucose-insensitive expression of respiratory activity were selected by use of a triphenyltetrazolium staining technique. These mutants lack carbon catabolite repression, as was demonstrated by measuring cytochromes, the activity of succinate cytochrome c reduction, total cellular respiration, mitochondrial protein, and DNA synthesis. High growth rates of mutant cells in glucose medium and normal fermentative CO2 production exclude the possibility that this carbon catabolite insensitivity of mitochondrial functions is merely due to a decreased utilization of glucose. Accordingly, the activities of the two cytoplasmic enzymes measured, maltase and malate synthase, were glucose repressible to the same extent in the mutants as in the wild type. The mutations are dominant and showed nuclear inheritance. The results are discussed in terms of carbon catabolite-regulated expression of genes involved in the biogenesis of mitochondria.

DNA, Mitochondrial↗

PubMed1979

Mitochondrial protein-synthesizing machinery in Saccharomyces cerevisiae grown in different metabolic conditions. Variability of seryl-tRNA and alanyl-tRNA isoacceptor patterns.

1. The isoacceptor patterns of mitochondrial seryl and alanyl-tRNAs from Saccharomyces cerevisiae grown under different conditions and committed to fermentative or respiratory metabolism have been studied by reversed-phase chromatography. 2. An extensive variability of the chromatographic patterns of the four isoacceptors for serine and of the three isoacceptors for alanine has been observed as a function of carbon source and stage of growth, but the main differences were observed in the different stages of growth on glucose. 3. In order to distinguish the effects due to stage of growth from those due to relief from glucose repression, the isoacceptor patterns of mitochondrial tRNA were compared in repressed and derepressed resting cells; results show that some of the mitochondrial species are almost undetectable in resting repressed cells, but are the major ones after recovery of respiration. 4. Two of the serine isoacceptors (species 1 and 2), one of which is absent or not acylable in repressed resting cells, are different gene products.

Alanine↗

PubMedDate not supplied

Symmetrical transcription in the tRNA region of the mitochondrial genome of Saccharomyces cerevisiae.

The occurrence of discrete transcripts originating from the non-coding strand of the yeast mitochondrial genome is described. The region under investigation is localized in the large tRNA gene cluster between the LSU ribosomal RNA and OXI 1 genes. The transcripts originating from the non-coding strand were detected in a wild-type strain and in a rho- mutant. Their size range includes transcripts of about 2000 nucleotides able to accommodate more than one "anti-tRNA". In some cases their extremities can be mapped near highly-conserved nonanucleotides that could function as origins of transcription. The involvement of the tRNA-processing machinery in the cleavage of these transcripts is also hypothesized.

Base Sequence↗