| 51. |
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| 52. |
- Abel, Andreas, 1974, et al.
(author)
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Normalization by Evaluation for Martin-Löf Type Theory with Equality Judgements
- 2007
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In: Proceedings of 22nd IEEE Annual Symposium on Logic in ComputerScience, Wroclaw, Poland, July 2007.. - : IEEE. - 1043-6871. - 0769529089 ; , s. 3-12
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Journal article (peer-reviewed)abstract
- The decidability of equality is proved for Martin-Löf type theory with a universe a la Russell and typed beta-eta-equality judgements. A corollary of this result is that the constructor for dependent function types is injective, a property which is crucial for establishing the correctness of the type-checking algorithm. The decision procedure uses normalization by evaluation, an algorithm which first interprets terms in a domain with untyped semantic elements and then extracts normal forms. The correctness of this algorithm is established using a PER-model and a logical relation between syntax and semantics.
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| 53. |
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| 54. |
- Abel, Andreas, 1974, et al.
(author)
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Untyped algorithmic equality for Martin-Löf's logical framework with surjective pairs
- 2007
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In: Fundamenta Informaticae. - 0169-2968. ; 77:4, s. 345-395
-
Journal article (peer-reviewed)abstract
- Martin-Löf's Logical Framework is extended by strong Sigma-types and presented via judgmental equality with rules for extensionality and surjective pairing. Soundness of the framework rules is proven via a generic PER model on untyped terms. An algorithmic version of the framework is given through an untyped beta eta-equality test and a bidirectional type checking algorithm. Completeness is proven by instantiating the PER model with eta-equality on beta-normal forms, which is shown equivalent to the algorithmic equality.
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| 55. |
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| 56. |
- Abel, Edvard, 1970, et al.
(author)
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Early disturbance of microvascular function precedes chemotherapy-induced intestinal injury
- 2005
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In: Dig Dis Sci. - : Springer Science and Business Media LLC. - 0163-2116. ; 50:9, s. 1729-33
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Journal article (peer-reviewed)abstract
- Intestinal injury 4-48 hr after cytotoxic therapy (etoposide phosphate, 100 mg/kg body weight [bw], intravenously [i.v.]) was studied in rats using ligated intestinal loops. Chromium-51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) and rubidium-86 chloride ((86)RbCl) were deposited intraluminally to determine the extent of the increase in intestinal permeability and ion channel disruption. Evans Blue (EB) was used for detection of endothelial leakage. Intestinal morphology was documented. Endothelial dysfunction, as observed by an increased extravasation of EB, was evident already 4 hr after cytotoxic therapy. Intestinal epithelial injury, as observed by an increase in (51)Cr-EDTA permeation and a decrease in (86)Rb absorption, occurred after 48 hr. Finally, histology disclosed a reduced crypt cell proliferation, displayed as a decrease in Ki67-positive cells. The findings suggest that, in the development of intestinal injury after cytotoxic therapy, endothelial disruption is an early event, whereafter epithelial dysfunction and crypt stem cell arrest occur. This knowledge could be of importance in the design of future intervention trials.
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| 57. |
- Abel, Frida, 1974, et al.
(author)
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Analyses of apoptotic regulators CASP9 and DFFA at 1P36.2, reveal rare allele variants in human neuroblastoma tumours.
- 2002
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In: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 86:4, s. 596-604
-
Journal article (peer-reviewed)abstract
- The genes encoding Caspase-9 and DFF45 have both recently been mapped to chromosome region 1p36.2, that is a region alleged to involve one or several tumour suppressor genes in neuroblastoma tumours. This study presents an update contig of the 'Smallest Region of Overlap of deletions' in Scandinavian neuroblastoma tumours and suggests that DFF45 is localized in the region. The genomic organization of the human DFF45 gene, deduced by in-silico comparisons of DNA sequences, is described for the first time in this paper. In the present study 44 primary tumours were screened for mutation by analysis of the genomic sequences of the genes. In two out of the 44 tumours this detected in the DFFA gene one rare allele variant that caused a non-polar to a polar amino acid exchange in a preserved hydrophobic patch of DFF45. One case was hemizygous due to deletion of the more common allele of this polymorphism. Out of 194 normal control alleles only one was found to carry this variant allele, so in respect of it, no healthy control individual out of 97 was homozygous. Moreover, our RT-PCR expression studies showed that DFF45 is preferably expressed in low-stage neuroblastoma tumours and to a lesser degree in high-stage neuroblastomas. We conclude that although coding mutations of Caspase-9 and DFF45 are infrequent in neuroblastoma tumours, our discovery of a rare allele in two neuroblastoma cases should be taken to warrant further studies of the role of DFF45 in neuroblastoma genetics.
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| 58. |
- Abel, Frida, 1974
(author)
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Genetic studies of neuroblastoma with emphasis on the apoptotic pathway
- 2004
-
Doctoral thesis (other academic/artistic)abstract
- Aim: The objective of this thesis was to find genes and chromosomal regions involved in neuroblastoma (NB) tumor progression. NB is a childhood tumor of the sympathetic nervous system that generally occurs spontaneously. Biologically, NB has a complex heterogeneity from tumor progression to tumor regression, dependent on clinical stage and age at diagnosis. The main genetic markers, which are also of prognostic value in NB, are amplification of the oncogene MYCN, deletion of chromosome arm 1p and gain of chromosome arm 17q. Results: We have been shown using fluorescence in situ hybridization (FISH) on a Scandinavian tumor material, that 17q gain is present in approximately 65% of all NB stages, is significantly associated with poor prognosis and predicts survival. The gene encoding somatostatin receptor 2 (SSTR2), localized in chromosome region 17q24, was not found to be mutated in any NB, when analyzed with PCR-based single stranded conformation polymorphism/heteroduplex (SSCP/HD) and DNA sequencing. In a tentative effort of defining of the location of a general embryonal tumor suppressor gene (TSG) on 1p, we combined the smallest region of overlap (SRO) of 1p deletions in NB tumors and germ cell tumors (GCTs). We thus delimited the NB/GCT SRO to approximately 5 cM between markers D1S508 and D1S244, and fine-mapped this region by radiation hybrid mapping and construction of a bacterial artificial chromosome (BAC) contig. A homozygously deleted region in an NB cell line was found to partially overlap the proximal part of the 5 cM-SRO defined by us, which further focused our search for a TSG to a 500 kb candidate region in 1p36.22. Two attractive candidate NB TSGs, DFFA and CASP9, are both located in 1p36.2 and encode key apoptotic mediators. In fact, DFFA resides in the 500 kb TSG candidate region. Via sequence analysis of the entire tumor material, we found three different coding alterations in DFFA which all affect the highly conserved N-terminal regulatory domain of DFF45. Using RT-PCR and real-time RT-PCR (TaqMan) studies, we were able to show that both DFFA and CASP9 are preferably expressed in NB tumors with favorable outcome. It has been proposed that lack of apoptosis plays an important role in tumor progression. We therefore screened an array with cDNAs involved in the apoptotic process, to find genes differentially expressed in NB tumors with unfavorable versus favorable biology. Using real-time RT-PCR analysis, we verified the differential expression of several transcripts encoding mitochondrial apoptotic mediators. Conclusions: We have shown that 17q gain is the most frequently detected alteration in NB and that it is associated with established prognostic factors. We narrowed down the TSG candidate region on 1p and found mutations in a gene localized in the region possessing fundamental functions in apoptosis. Our results also suggest that the mitochondrial apoptotic pathway is suppressed at multiple steps in advanced stages of NB tumors, due to imbalance between anti-apoptotic and pro-apoptotic mediators.
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| 59. |
- Abel, Frida, 1974, et al.
(author)
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Imbalance of the mitochondrial pro- and anti-apoptotic mediators in neuroblastoma tumours with unfavourable biology.
- 2005
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In: European journal of cancer (Oxford, England : 1990). - : Elsevier BV. - 0959-8049. ; 41:4, s. 635-46
-
Journal article (peer-reviewed)abstract
- It has been proposed that a lack of apoptosis plays an important role in neuroblastoma (NB) progression. We therefore screened cDNA array filters, including 198 apoptotic genes, in order to identify mRNA transcripts that are differentially expressed in tumours with unfavourable versus favourable biology. Twenty-one genes were analysed further using real-time reverse-transcriptase-polymerase chain reaction (RT-PCR). Significantly lower levels of DNCL1 (PIN; P(c)(corrected) = 0.0054) and NTRK1 (TrkA; P(c) = 0.039) were found in NB tumours with unfavourable biology. In addition, BID, BCL2, APAF1, CASP2, CASP3 and CASP9 were found to be preferentially expressed in tumours with favourable biology, whereas CDKN1A (p21), IL2RA, and MCL1, were found to be preferentially expressed in NB tumours with unfavourable biology. In conclusion, mRNA levels of transcripts encoding pro-apoptotic mediators of the mitochondrial apoptotic pathway were found to be expressed to a lower extent in tumours with unfavourable biology. Our data also suggest that the mitochondrial pathway is suppressed in advanced stages of NB tumours, due to an imbalance between anti-apoptotic and pro-apoptotic mediators which is a finding that may have therapeutic significance.
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| 60. |
- Abel, Frida, 1974, et al.
(author)
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Mutations in the N-terminal domain of DFF45 in a primary germ cell tumor and in neuroblastoma tumors.
- 2004
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In: International journal of oncology. - 1019-6439 .- 1791-2423. ; 25:5, s. 1297-302
-
Journal article (peer-reviewed)abstract
- DFF45 has essential functions in the final stage of apoptosis by acting both as a folding chaperone and a DNase inhibitor of DFF40. The gene encoding DFF45 (DFFA) maps to the consensus deleted region in primary neuroblastoma (NB; 1p36.2-3) and within the homozygously deleted region in an NB cell line (1p36.2). DFF45 is therefore an attractive candidate NB tumor suppressor. In a previous study we found a rare allele variant, causing a non-polar to a polar amino acid exchange (Ile69Thr) in a preserved hydrophobic patch of DFF45, and we also found DFFA to be preferentially expressed in favorable NB tumors. We have extended the previous study and performed mutation analyses in another 56 NB tumors (100 in total) as well as a set of other tumors for coding mutations in DFFA. We have also performed studies of the DFFA expression in tumors using real-time PCR. We found a missense mutation (Ile15Met) in the remaining allele of a teratoma with heterozygous deletion of 1p, and a three base-pair deletion in an NB of unknown stage causing a deletion of amino acid 37 in DFF45. The one-base substitution detected in the teratoma was not present in the patients constitutional DNA, i.e. it is a true mutation present in the tumor DNA only. In conclusion, three different coding alterations have been found in the region encoding the N-terminal regulatory domain of DFF45, responsible for binding and achieving its chaperone and inhibitor functions on other proteins. Moreover, by real-time RT-PCR expression study, we found the mRNA level of DFFA to be significantly (p=0.038) reduced by a factor of 1.7 times in NB tumors of unfavorable outcome.
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